Anatomy of a Randomized Clinical

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					  Aminoglycoside Ototoxicity:
The Need to Consider More Than
       Auditory Status

     Jaynee A. Handelsman, Ph.D.
            ASHA Convention
           November 20, 2008
                Ototoxicity
Damage to the inner ear from toxic agents
Negative consequence of the availability and use
 of medications that prolong life through treatment
 of serious infections and cancer
  • Chemotherapy agents
  • Antibiotics
Result is damage to cochlear and/or the
 vestibular end organs
Evidence suggests that there are no “safe” levels
           Session Objectives

Discuss clinical features of auditory and vestibular
 system damage
Discuss the challenges involved in monitoring for
 auditory and vestibular system changes
Discuss our experience in monitoring patients with
 CF during aminoglycoside exposure
Propose guidelines for monitoring auditory and
 vestibular function during and following exposure
  Factors Determining Individual
           Ototoxicity
Individual tolerance including genetic
 predisposition
Impaired renal function
Hyperthermia
Prior or concomitant exposure to other ototoxic
 agents
Dosing strategy perhaps, although recent
 evidence suggests this might not be the case
Age
           Aminoglycosides
Selective cochlear and/or vestibular toxic agents
Readily absorbed from intramuscular and
 subcutaneous sites; poorly absorbed from
 intestinal tract
From blood, about 50% is excreted unchanged
 in 24 hours
With renal insufficiency, blood levels may remain
 high for many days
Distributed to all extra-cellular fluids (e.g.
 endolymph and perilymph)
    Mechanisms of Ototoxicity

It appears that ototoxicity is not caused by
 accumulation of the substance in the ear
Rather, it appears to be caused by the
 drug’s penetration into compartments from
 which the half-life of distribution is
 extremely long
Likely results from rapid uptake, early
 saturation, and long exposure of the inner-
 ear tissues to the drug
 Clinical Features of Ototoxicity on
              Audition
Tinnitus
Hearing loss
  • Difficulty understanding speech in noise
  • Sensorineural, usually bilateral, symmetric
  • Progresses from high to low frequencies
Symptoms can be delayed days, months
Usually permanent but some recovery
 may occur
 Clinical Features of Ototoxicity on
         Vestibular Function
Acute bilateral vestibular loss
  •   Ataxia of stance
  •   Ataxia of gait
  •   Saccadic eye movements with rapid head turns
  •   Changes in visual acuity with head shaking or
      nodding
Acute unilateral vestibular loss
  • Vertigo, nausea, unsteadiness
  • May have changes in visual acuity with head
    movement
      Onset May be Acute or
            Insidious
dramatic onset of        slowly increasing
 severe imbalance and      unsteadiness of gait
 loss of orientation in    and imbalance
 space                    oscillopsia
vertigo                  frequent use of
illusion of tilting       contact cues in
                           darkness or when
                           walking on uneven
                           ground
      Definition of Symptoms
Oscillopsia – an illusory movement of
 viewed stationary objects or surrounds
 occurring with head movement

Gait ataxia – uncoordinated wide-based
 gait that is commonly associated with a
 variety of disorders including cerebellar
 disease and bilateral peripheral vestibular
 loss
  Vestibular System is Responsible
 for Sensing and Controlling Motion
Receptors located within the labyrinth of each
 inner ear transduce information about angular and
 linear acceleration as well as gravity
Information combined with visual and
 somatosensory signals on neurons in vestibular
 nuclei
Integration of sensory signals produces
 information required to control vestibulo-ocular
 reflex (VOR) and the vestibulo-spinal reflex (VSR)
    Responsibilities of VOR and
               VSR
VOR facilitates maintenance of binocular fixation,
 thereby stabilizing gaze during rapid, short-
 duration head movements
Reflexes move the eyes in the correct direction
 and by the precise angle required to offset the
 effects of head movements
VSR enables person to maintain desired head
 and body positions with respect to gravity, even
 following imposed movement of the head or
 trunk
     Explanation of Symptoms
Oscillopsia is a direct result of the loss of the
 VOR, which is responsible for maintaining foveal
 vision when the head is moving, especially at
 relatively high speeds
Quick movements of the head are associated
 with saccadic gaze readjustments rather than
 smooth compensatory eye movements
Ataxic gait is due to loss of vestibular input and
 the need to rely on visual and proprioceptive
 information for maintenance of postural control
        Challenges - Audition
Complaints of ototoxic damage on hearing
 are uncommon until communication
 problem becomes significant
  • How much change at how many frequencies is
    “significant”

Difficult to predict ototoxic damage
  • Relationship to drug dosage, peak serum
    levels, and other toxicities is variable
      Challenges - Vestibular
The symptoms of vestibular loss are not
 appreciated by physicians
Belief among many that monitoring blood
 levels and using “safe” levels will prevent
 loss
When ototoxicity follows a long illness,
 symptoms may be attributed to
 deconditioning
There are no accepted protocols for
 monitoring function
Factors Determining Oscillopsia
  in Bilateral Vestibular Loss
Age at onset

Severity of semicircular canal dysfunction

Extent of otolithic dysfunction

Individual compensatory faculties
Evaluation Protocol for Ototoxicity:
        Things to Consider
 Define the purpose of the monitoring protocol
 Define the target population
 Create a referral base by communicating with
  physicians
 Select the monitoring tools
   • Test schedule
   • Definition of “significant” change
 Communicate results
 Education, Counseling, and Rehabilitation
     Purpose of Monitoring

 Early Identification and
 Prevention

   Should we care about early
   changes enough to take the time
   to measure them?
Rationale for Monitoring Hearing
 Hearing loss within 2 to 9 kHz range is
  clinically significant for children
 Some impact of high frequency loss on
  speech understanding, even in adults
 The use of amplification to remediate
  hearing loss above 5 kHz is problematic
 Continued damage may affect more of
  the critical speech frequencies
   Reasons to Monitor Cochlear
     and Vestibular Function
Cochlear function is affected by almost all
 aminoglycosides
Even slight ototoxic cochlear dysfunction is
 noticeable, particularly via high frequency
 audiometry and otoacoustic emissions
Slowly progressive vestibular dysfunction
 may go undetected for some time
Vestibular ototoxicity is variable in terms of
 onset and progression
      Benefits of Monitoring
Early detection may prevent hearing damage
 that requires amplification/rehabilitation
If change observed, treatment modification can
 prevent further hearing loss
If no change observed, continued treatment is
 warranted
Provides an opportunity for counseling and
 rehabilitation during and post treatment
It is the basis for informed medical decision
 making
  Target Patient Population
Receiving highly ototoxic drugs
Very old and very young people
Poor medical condition
Poor renal function
Poor hydration status
Familial tendency for susceptibility
 (aminoglycoside antibiotics)
Receiving more than one ototoxic drug
Receiving large or multiple doses
        At- Risk Populations
Diabetic patients may be more profoundly
 affected by bilateral vestibular loss due to
 concurrent loss of vision and proprioception
Renal patients are more susceptible to
 aminoglycoside ototoxicity because drugs are
 metabolized by the kidneys
Dialysis patients are frequently at increased risk
 of infection, and may be more likely to have
 repeated exposure to aminoglycosides
Patients with cystic fibrosis are frequently
 treated with aminoglycosides
Incidence is Difficult to Define
Patient population differences
    –Different risk factors
Methodological differences
    –Established baseline
 No standard monitoring techniques
    –Criteria
    –Frequency range tested for hearing
     change
           Ototoxic Medications
Antineoplastic Agents          Loop diuretics
  •   Cisplatin                   •   Furosemide
  •   Carboplatin                 •   Ethacrynic acid
  •   Vinblastine *               •   Bumetanide
  •   Vincristine                 •   Torsemide *
  •   Vinorelbine *
  •   Difluoromethylornithine
      (DFMO)
  •   Nitrogen mustard            * Limited evidence of
  •   Methotrexate                   ototoxicity
  •   Dactinomycin
  •   Bleomycin
          Ototoxic Medications

Aminoglycosides     Other Antibiotics
  •   Gentamicin       • vancomycin
  •   Sisomicin
  •   Kanamycin
  •   Neomycin
  •   Paromomycin
  •   Tobramycin
  •   Streptomycin
  •   Amikacin
  •   Dibekacin
  •   Netilimicin
   Most Vestibulotoxic
Aminoglycosides in Humans
   Gentamicin

   Streptomycin

   Tobramycin
        Evaluation Tools
Pure-tone thresholds
  • near upper frequency hearing limit (for
   example ultra-high frequency audiometry)
Otoacoustic emissions
High frequency ABR
Tests of high frequency responses are
 likely to be the most sensitive
 indicators of early change
   Criteria for Hearing Change
Always referenced to baseline measures
Criteria from ASHA 1994 guidelines:
  • > 20 dB change at any one test frequency
  • > 10 dB change at any two consecutive test
    frequencies
  • Loss of response at three consecutive test
    frequencies where responses were previously
    obtained.
  • Hearing change by any of these criteria was
    confirmed by retest
      ASHA Change Criteria
Normal variability in pure-tone thresholds
 occurs at random frequencies
Threshold shifts at adjacent test
 frequencies indicate more systematic
 change
Threshold shifts on repeated tests are
 also a stronger indication of a true
 threshold change
      Extended High Frequency
       Audiometry - Sensitivity
High- to low- frequency progression
High-frequency testing is reliable
Studies have shown the efficacy of high-
  frequency monitoring
Studies have shown testing in 1/6-octave
  intervals provides earlier detection
Individualized protocols targeting the highest
  frequencies a person can hear
       Extended High Frequency
        Audiometry - Problems
There are no normative high-frequency
 sensitivity (threshold) standards due to lack of
 standardization in
  • Calibration
  • Instrumentation
  • Methodological procedures
There is a high degree of inter-subject variability
 in sensitivity
  • Threshold variability increases with age and with
    higher frequencies
   Does it Matter for Monitoring?
The key to serial monitoring is intra-subject
 (test-retest) reliability

High-frequency test-retest threshold
 variability is within a clinically acceptable
 range (+ 10 dB)

As a result, monitoring near individual’s
 high-frequency hearing limit is effective
            ABR Sensitivity

Elongation of latency and/or disappearance
 of click-evoked wave V following
 administration of ototoxic drugs

Ultra-high frequency tone bursts (8-14 kHz)
 have been shown to be more sensitive than
 clicks
Problem: Frequency Specificity

Two problems at high stimulus levels
  • Increased spectral splatter (stimulus energy spreads)
  • Response could be due to tails of off-frequency
    neurons
Pertains to all measures of auditory function with
 all kinds of stimuli
  • Evoked potentials, behavioral measures
  • Clicks, tone bursts, pure tones
  Problem: Change Criteria

There is no broadly accepted ABR
 latency change criteria
  • Adults
  • Children
  • Neonates
        ABR Advantages

Good test-retest reliability
Can be performed at bedside
Can estimate thresholds (magnitude of
 ototoxicity-induced hearing loss)
Can obtain in patients with substantial
 pre-existing hearing loss (up to severe
 to profound)
      ABR Disadvantages
Time consuming
Limited frequency specificity
 (depending on how performed)
Limited high-frequency output
Response interpretation at high
 frequencies
Subject noise, hearing loss may
 preclude measurement
Infants & children may require sedation
         DPOAE Advantages
Highly selective to outer hair cell function
  • Most ototoxic drugs attack outer hair cells
  • Might provide earliest detection of ototoxicity
It is frequency specific and can include a
 wide frequency range
Objective and can be performed at bedside
Good test-retest reliability
Rapid
       Aminoglycoside Ototoxicity:
Outer hair cells and otoacoustic emissions

Distortion product otoacoustic emissions test
 protocol
 • Intensity: L1 = 65 dB SPL; L2 = 55 dB SPL
 • f2/f1 ratio = 1.20
 • Frequency range: 500 or 1000 Hz to > 8000 Hz
   Newer equipment now available clinically for higher
    frequencies
 • Frequencies/octave: 5 to 8


                                          James W. Hall III, Ph.D.
      Problems: Change Criteria

 Greater than or equal to 6 dB change
  •   Based on test-retest variability in normal subjects
  •   6 dB change was more than variability in about 95% of
      subjects tested--so likely to be real change
  •   Confirm by re-test to decrease false positive rates
  •   Change at two adjacent frequencies would decrease
      false positive rates
  •   Each clinic should establish its own change criteria
   DPOAE Disadvantages

Limited high-frequency (> 6 kHz)
 measurements typical for clinical systems
DPOAE amplitudes are linked to hearing
 sensitivity only for losses < 50-60 dB
Hearing loss may preclude measurable
 responses at baseline
Depends on normal middle ear function
    DPOAEs: Essentials of Analysis and
             Interpretation
Verify that noise floor is low
  • below upper limit for a normal population
Verify the presence of reliable OAEs for each
 frequency
  • amplitude > 6 dB above noise floor
Interpret amplitudes for each frequency relative to
 the normal region
  • OAEs within normal limits = “normal”
  • OAEs present but below normal limits = “abnormal”
  • OAEs < 6 dB above noise floor (OAE – NF = < 6 dB) = “absent”

                                                 James W. Hall III, Ph.D.
      Relation Between OAE Amplitude and Hearing
                         Loss
       DPOAE 65/55 dB SPL     TEOAE 80 dB SPL


                                                        WNL
  OAE                                                   (Amplitude > 95%ile)
Amplitude
            Normal


            Present
            but not
            normal
                                                No
                                                OAE
                                                           No OAE
                                                           (OAE – NF < 6 dB)

            -10      0     10   20    30   40     50
            60
                         Hearing Level in dB HL        James W. Hall III, Ph.D.
Laboratory Tests for Monitoring
    Vestibular Ototoxicity
 Dynamic visual acuity testing

 Caloric testing

 Rotational testing

 Dynamic posturography
  Rotational Testing Has Value

Caloric testing evaluates only very low
 frequency function (<.003 Hz)
Rotational testing tests mid- to high
 frequency function (.01-.64 Hz)
Testing the VOR at lowest rotational
 frequencies may provide early signs of
 vestibular dysfunction
      Dynamic Posturography

Useful for quantifying ataxia
Useful for evaluating patient’s ability to use
 visual and proprioceptive information to
 maintain postural stability following
 bilateral loss of vestibular function
In patients with CF, some have abnormal
 function even when they deny problems
 Bedside Tests of Vestibular
         Function
Head thrust

Testing of dynamic visual acuity

Romberg, tandem walking, stepping
 test
       Cystic Fibrosis Project
First aim of the project is to establish the
 prevalence of vestibular system involvement
 in patients treated with aminoglycosides for
 pulmonary exacerbations secondary to CF
Secondary aim is to determine whether
 incremental changes in function can be
 detected reliably over time
Hope is to develop guidelines for optimal
 monitoring protocol
   Original Plan with CF Patients
Patients admitted into the hospital for initiation of
 aminoglycoside antibiotics
Test vestibular function while inpatient when
 possible, ideally within a couple of days of
 initiation of treatment
Completion of Dizziness Handicap Inventory (DHI)
Also complete audiological testing when possible
Test patients again at their three month follow-up
 appointment with pulmonologist
 Categories of Vestibular Loss
Non-lateralized vestibular system
 involvement
Unilateral vestibular loss
Bilateral peripheral vestibular paresis
     Non-lateralized Vestibular
           Involvement
Significant spontaneous, positional, or
 post head shaking nystagmus
Increased phase leads in sinusoidal
 rotational testing
Short time constants in rotational step
 testing
Patient may not be symptomatic
    Unilateral Involvement
Significant unilateral weakness in caloric
 testing
During the acute phase, might have
 spontaneous nystagmus and asymmetries
 in rotational testing
Patient more likely to describe vertigo and
 unsteadiness, although oscillopsia is
 possible
     Bilateral Vestibular Loss

Significant bilateral caloric reduction
Significant gain reductions in sinusoidal
 rotational tests
Significant gain reductions in rotational
 step testing
Gait instability and oscillopsia are common
 symptoms
          Data Trends to Date
We have completed vestibular testing on 49
 patients to date
  • We do not have audiological test data on 11 of those
    individuals
  • Testing was attempted with minimal results obtained on
    additional patients
18 have evidence of non-lateralized vestibular
 involvement
5 have significant unilateral loss
14 have bilateral peripheral vestibular paresis
4 have documented normal hearing and vestibular
 function, with 5 others without hearing tests
           Data Trends to Date
We have completed serial monitoring on a
 subset of patients
When comparing individual patient data for
 absolute caloric and rotational chair values, it
 appears that sub-clinical but consistent changes
 are occurring over time
 • From normal calorics to an eventual significant unilateral
   weakness
 • From evidence of non-lateralizing findings to bilateral
   involvement
 • From mild bilateral involvement to severe bilateral loss
    Pragmatic Issues to Consider
Not all patients will tolerate vestibular testing
It is unrealistic to conduct serial testing as often as
 we had anticipated
When patients are admitted for initiation of
 aminoglycosides, there are time and scheduling
 constraints
Patients and parents are generally not well
 informed about the importance of monitoring
 function over time
Physicians, parents, and patients may not want to
 know when damage occurs
        Acknowledgement
N008681-385013 Vestibular and Auditory
 Sensory Loss in CF Patients
W. Michael King, Ph.D., Jaynee
 Handelsman, Ph.D. and Samya Nasr, M.D.
Cystic Fibrosis Foundation Therapeutics,
 Inc.
Test Battery for Monitoring and Diagnosis:
           University of Florida
Diagnosis of auditory dysfunction
 • Distortion product otoacoustic emissions
 • Aural immittance measurement
    Tympanometry
    Acoustic reflexes
 • Pure tone audiometry
    Conventional audiometric frequencies
    High frequencies (10 K to 20 K Hz)
 • Speech audiometry
    Word recognition (10 most difficult words first)
    Speech-in-noise (as indicated by history)

                                               James W. Hall III, Ph.D.
 Hearing Findings in Patients with
Cystic Fibrosis: University of Florida

                                                                                       OAEs
                         100
Abnormal Findings in %




                                                                                       Audio
                         80                                                            < 8K Hz

                                                                 57 (N = 33)           Audio
                         60               50 (N = 2)                                   > 8K Hz
                                                       43
                         40     30
                                                            25
                                     20
                         20


                               Children                Adults
                               (N = 15)                (N = 81)                James W. Hall III, Ph.D.
Vestibular Rehabilitation is Effective in
 Aiding Patients with Unilateral and
       Bilateral Vestibular Loss
Therapy aimed at fostering the
 substitution of visual and somatosensory
 cues for lost vestibular function

Gaze stabilization exercises

Balance retraining exercises
   Adaptive and Compensatory
Mechanisms Involved in Stabilization
        of Eye Movements
Adaptation of saccadic eye and head
 movement
Use of neck and other somatosensory
 afferents
Enhanced eye tracking
Centrally preprogrammed eye movements
Central suppression of undesired image
 movement across the retina
  Functional Adaptations Build
        within One Year
Gaze stabilization most improved through
 centrally preprogrammed slow eye movements
 during active (predictable) head movement
During unpredictable head movements, cervico-
 ocular reflexes and increased fixation may yield
 best stabilization
Strongest suppression of oscillopsia achieved
 by central adaptive rearrangements
    Compensatory Mechanisms
     Effective in Suppressing
            Oscillopsia
Only one third of adult patients with
 acquired bilateral vestibular loss of
 function suffer from permanent oscillopsia
This underlines the paramount biological
 importance of maintaining clear vision
 during locomotion
        Roles of Vision and
          Propriception
Patients are able to use vision and
 somatosensory input to maintain postural
 control in the absence of vestibular
 function
When circumstance prevent their use (e.g.
 in darkness or when walking on uneven or
 compressible surfaces), gait ataxia
 persists for almost every patient
    Bilateral Vestibular Loss -
      Practical Implications
Oscillopsia, which results in visual blurring
 or “bobbling” - may prevent patients from
 driving, or even walking unassisted
Because patients rely on vision and
 proprioception to maintain postural control
 while ambulating, darkness combined with
 compressible or uneven support surfaces
 result in increase risk of falling
      Vestibular Rehabilitation
          The Good News
Research supports the fact that responses
 of a partially functioning vestibular system
 can be modified
For patients with some residual function, VR
 is focused on optimizing the use of the
 remaining VOR, as well as increasing the
 effectiveness of the COR
For all patients with bilateral vestibular loss,
 increasing the use of vision and
 proprioception is a goal
 Variables Affecting Therapy
          Outcome

Extent of the vestibular loss
The presence of coexisting disease that
 may impact sensory system function
Overall patient heath and fitness
Patient motivation and compliance with
 program
Our Hope for the Future…




 Pharmacologic
 Protection from Aminoglycoside
 Induced Ototoxicity
  Proposed Otoprotective Agents
  for Aminoglycoside Ototoxicity
Lipoic Acid
N-acetylcysteine (NAC)
Aspirin
Iron chelators
Caspase inhibitors
Gene therapies
D-methionine (D-met)

                          Kathleen C.M. Campbell, Ph.D
         D-methionine (D-met)
Provides excellent but not complete protection
 against aminoglycoside-induced hearing loss in
 animal studies to date.
Excellent protection from noise-induced hearing
 loss for pre/peri- and even post exposure
 administration.
Also effective in preventing NIHL, cisplatin-
 induced ototoxicity, and radiation induced oral
 mucositis in studies to date.
Some patients are exposed to a combination of
 these factors.
                              Kathleen C.M. Campbell, Ph.D
      Current Status of D-met
            Research
FDA approved ISU’s Investigational New Drug
 Application January 2005 for D-met protection
 from radiation induced oral mucositis.
FDA approved Clinical Trials in progress
Phase II clinical trials for cisplatin in progress
 in India.
Looking for US patient populations.
In discussions with military for NIHL protection.
More bench work also needed. Currently
 performing additional basic research to go to
 clinical trials for aminoglycoside otoprotection.
                               Kathleen C.M. Campbell, Ph.D
    Protection from Amikacin Induced
       Ototoxicity by D-methionine
         Klemens and Campbell

Three Groups: 5 albino guinea pigs each
Amikacin: 200 mg/kg/day subcutaneously for
 28 days
D-methionine: 300mg/kg/day ip 30 minutes
 prior to the amikacin
Control animals given equal volume saline

                          Kathleen C.M. Campbell, Ph.D
D-met Protection from Aminoglycoside
       Induced Hearing Loss

D-met provides partial but significant
 protection against amikacin-induced
 hearing loss.
Planning further studies on dosing
 protocols and additional aminoglycosides



                         Kathleen C.M. Campbell, Ph.D
   Sha and Schacht: Two Studies
        Published in 2000
Both Studies used pigmented male guinea pigs
 and 19 day administration of amikacin
Study 1
  •   100 mg/kg histidine combined w/gent
  •   3) 200 mg/kg D-met combined w/gent
  •   4) saline only
  •   5) D-met only
  •   6) histidine only
Study 2200 mg/kg d-met twice daily
  • First dose combined with 120mg gentamicin
  • Second dose of D-met injected 7 hours later

                                  Kathleen C.M. Campbell, Ph.D
            Conclusions
D-methionine can protect against
 aminoglycoside induced ototoxicity.
More work needs to be done on dosing
 protocols.
More work needs to be done on
 nephroprotection
More work needs to be done to be done to
 ensure lack of interference with the
 aminoglycosides’ antimicrobial activity
                         Kathleen C.M. Campbell, Ph.D
        Current Work: D-met and
            Aminoglycosides
 Thanks to NIH/NIDCD:
 The group at ISU is performing the translational research
  laboratory studies to prepare for FDA approved clinical
  trials.
 Studies include developing D-met protection for
  gentamicin, amikacin, and tobramycin.
 Performing dosing studies (i.e. fractionated versus daily
  dosing, dose response curves)
 Performing antimicrobial interference studies.
 Collecting control data on patients currently on
  aminoglycosides to establish data base for clinical trials.


                                     Kathleen C.M. Campbell, Ph.D
                  Summary
Ototoxicity not only relates to hearing, but to
 vestibular system function
Bilateral vestibular loss can be devastating,
 causing ataxia and oscillopsia
Unilateral loss is possible as well
There is a need to monitor closely patients at risk
 for vestibular loss
Vestibular rehabilitation should be considered in all
 cases of uncompensated vestibular system
 involvement
Future Outlook: Protective Drugs May Limit
 Aminoglycoside Ototoxicity