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Otoacoustic Emissions for Monitoring Aminoglycoside-Induced Ototoxicity in Children With Cystic Fibrosis
Pelagia Stavroulaki, MD;
Ioannis C. Vossinakis, MD;
Dimitra Dinopoulou, MD;
Spiros Doudounakis, PhD;
George Adamopoulos, PhD;
Nikolaos Apostolopoulos, PhD
Arch Otolaryngol Head Neck Surg. 2002;128:150-155.
ABSTRACT
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Objective To investigate whether transient-evoked and distortion-product (DP)
otoacoustic emissions (OAEs) are more sensitive than pure-tone audiometry
(PTA) in revealing gentamicin-induced ototoxicity in children with cystic
fibrosis (CF).
Design Prospective case-control study.
Setting Tertiary referral audiologic center in conjunction with an academic
pediatric CF unit.
Participants The study group consisted of a consecutive sample of 12 audiologically
normal children with CF and a history of gentamicin exposure (CF-gentamicin
group). The control groups consisted of 8 age-matched children with CF and
11 age-matched healthy volunteers. No member of the control groups had a history
of aminoglycoside exposure.
Intervention Members of the CF-gentamicin study group received 4 mg/kg of gentamicin
per day for a mean of 14.2 days (range, 11-29 days).
Outcome Measures The PTA thresholds (250-8000 Hz) were the criterion standard. Transient-evoked
OAEs' reproducibility at 5 frequency bands (800, 1600, 2400, 3200, and 4000
Hz) and total emission level were measured, as were DP-audiogram (DP-gram)
amplitude (1001-6299 Hz), input-output function dynamic range, and detection
thresholds at 4004, 6006, and 7996 Hz. Baseline measurements were compared
between groups examining the effect of CF and previous gentamicin exposure
(2-way analysis of variance). For the CF-gentamicin group, baseline measurements
were compared with those at the end of the last gentamicin treatment (paired t test).
Results The PTA findings were normal for all groups at baseline and remained
normal in the CF-gentamicin group after treatment. The CF-gentamicin group
had significantly lower transient-evoked OAEs total emission level, DP-gram
amplitude at 5042 Hz, and input-output dynamic ranges with higher detection
thresholds in all frequencies compared with both control groups, which was
attributed completely to previous gentamicin exposure (P<.05). After treatment, further decreases in total emission levels,
DP-gram amplitudes (>3000 Hz), and dynamic ranges were noted, with increased
detection thresholds (P<.05).
Conclusions Otoacoustic emissions measurement (especially of DP OAEs) proved more
sensitive than PTA in revealing minor cochlear dysfunction after gentamicin
exposure. They should be used for monitoring patients receiving ototoxic factors
such as aminoglycosides.
INTRODUCTION
CYSTIC FIBROSIS (CF) is a life-limiting, genetically transmitted disease
characterized by abnormal transepithelial sodium and chloride transport secondary
to mutations of the gene coding for the CF transmembrane conductance regulator.1 The protean manifestations of the disease result from
exocrine gland dysfunction leading to pulmonary and pancreatic insufficiency.
The survival of patients with CF has improved dramatically, and now up to
80% survive to age 20 years.2 This is partly
owing to intensive treatment of the chronic infections that regularly threaten
patients' lives. Treatment usually includes intravenous and nebulized aminoglycoside
antibiotics, and the cumulative dose of these ototoxic antibiotics is quite
large over the lifetime of patients with CF. Additionally, the abnormal metabolism
of these drugs in patients with CF (faster excretion with a greater volume
distribution) enhances their accumulation in serum.3
Until recent years, aminoglycoside-induced ototoxicity in children could
only be monitored in clinical conditions by conventional pure-tone audiometry
(PTA). However, several investigators have questioned the feasibility of PTA
in early detection of hearing loss and suggested the need for more sensitive
and objective measures of assessing cochlear function.4
Evaluation of evoked otoacoustic emissions (OAEs) is becoming one of
the routine audiologic testing methods, especially in neonates and children.
Evoked OAEs provide a rapid, objective, reliable, and noninvasive test for
screening peripheral auditory dysfunction.5
Their high test-retest reliability,5 coupled
with their accuracy and objectivity in assessing cochlear function (outer
hair cell function in particular), permits their use in monitoring dynamic
changes in cochlear responsiveness before these changes become functionally
significant as hearing loss.6-7
Thus, evoked OAEs are ideal for monitoring the effects of aminoglycosides
on cochlear function. The aim of our study was to investigate whether evoked
OAEs (both transient-evoked [TE] and distortion-product [DP] OAEs) are more
sensitive than PTA in revealing functional changes in the cochlea following
ototoxic exposure in children with CF.
SUBJECTS AND METHODS
Children attending the CF clinic at Agia Sophia Children's Hospital,
Athens, Greece, were considered for participation in the study. Entry criteria
included (1) diagnosis of CF confirmed by sweat electrolyte testing; (2) age
5 years or older (responses in children younger than 5 years were considered
unreliable because children this young are potentially unable to cooperate
with PTA protocol); (3) normal renal function; (4) no active or recent history
of otologic disease, ear surgery, head injury, or exposure to excessive noise;
(5) no family history of hereditary hearing loss; and (6) normal baseline
hearing ( 20-dB hearing level).
Twelve of the patients with CF who fulfilled the above entry criteria
had a history of intravenous gentamicin exposure for treatment of chronic
infections due to Pseudomonas aeruginosa. These patients
formed the main study group (CF-gentamicin group). During the period of chronic
infection (mean duration, 6.4 years; range, 4.5-12.3 years) some patients
also occasionally received other aminoglycosides (tobramycin, netilmicin).
Accurate information regarding the dose of aminoglycosides for each patient
is not available since treatment over the years has been administered in many
different pediatric centers. The average age of the 6 girls and 6 boys in
the CF-gentamicin group was 8.3 years (range, 5.2-14.1 years).
During the study period these patients received a new gentamicin regimen
(4 mg/kg, 3 times daily), some in combination with antipseudomonal penicillins
or third-generation cephalosporins. No patients received loop diuretics or
known nephrotoxic or ototoxic drugs other than gentamicin throughout the admission.
The duration of therapy ranged between 11 and 29 days (mean, 14.2 days), depending
on the severity of the infection. Serum concentrations of gentamicin were
measured on all patients twice weekly. Serum trough samples were drawn immediately
before the next dose, and peak samples were drawn 30 minutes after completion
of the infusion/bolus dose. Trough values were routinely adjusted to concentrations
between 1 and 2 mg per liter of serum, while renal function was also closely
monitored and remained normal over that period (serum creatinine, <1.1
mg/dL [97.2 µmol/L]).
Two control groups were used. Because age but not sex is associated
with differences in hearing in young adults,8
age-matched children with CF and healthy volunteers were used as controls.
Eight audiologically normal, age-matched children with CF (mean age, 7.9 years;
age range, 5.4-10.2 years) with no history of ototoxic drug exposure formed
the CF-control group. In addition, 11 audiologically normal, age-matched children
(mean age, 8.8 years; age range, 5.9-13.6 years) with no medical or family
history of CF or hearing loss served as the healthy-control group.
AUDIOLOGIC PROCEDURES
Normal middle ear status was confirmed by otoscopy and standard aural
immittance procedures (tympanometry with measurements of stapedial reflex
thresholds) using the GSI-33 middle ear analyzer (Grason-Stadler Inc, Milford,
NH). In addition, baseline PTA and evoked OAEs measurements (both TE and DP
OAEs) were conducted in the children of all 3 groups. In the CF-gentamicin
group, PTA and evoked OAEs measurements were repeated at the end of the last
gentamicin treatment. Comparisons were performed between baseline measurements
among the 3 tested groups and in the CF-gentamicin group between baseline
measurements and measurements taken within 24 hours after the last gentamicin
dose.
The PTA thresholds were measured using the Maico MA41 audiometer with
TDH 39 headphones (Maico, Eden Prairie, Minn) and calibrated to AS2586 (1983
standards) from 250 to 8000 Hz (250, 500, 1000, 2000, 3000, 4000, 6000, and
8000 Hz). In accord with the American Speech-Language-Hearing Association
standards, threshold shifts in PTA were considered significant if they showed
at least a 10-dB change in more than 2 consecutive frequencies, or if 1 frequency
demonstrated a change that was greater than 15 dB.9
Evoked OAEs were performed in a quiet, although not sound-treated, room
with the children seated comfortably in lounge chairs. Transient-evoked OAEs
were obtained using the computer-based ILO 88V4.2 Analyzer (Otodynamics Ltd,
Hatfield, England) in the standard default mode.10
Transient-evoked OAEs were considered present when stimulus stability was
better than 80% with response reproducibility more than 50% for at least 2
frequency bands. The 2 TE OAEs parameters used to compare the results were
the total emission level (mean response) and the reproducibility of the waveforms
in 800-Hz bands with center frequencies of 800, 1600, 2400, 3200, and 4000
Hz.
Distortion-product OAEs were obtained using the computer-based ILO92
(software version 1.2; Otodynamics Ltd) that has been described in detail
elsewhere.11 Two simultaneous pure-tone signals
were presented to the ear at 2 different frequencies (f1 and f2, where f2>f1), and the 2f1 -
f2 cubic DP component was recorded. Distortion-product OAEs were
collected in 2 formats. In the first, amplitude was considered a function
of f2 frequency at fixed stimuli levels (DP-grams). This plot is
comparable to the traditional audiogram, but provides a measure of outer hair
cell receptor function rather than hearing level. In the second format, amplitude
of a fixed-frequency DP OAE was considered a function of primary level (input-output
[I/O] functions). This plot provides an estimate of threshold (ie, the lowest
stimulus level at which the DP OAEs can be detected above the noise) and DP
OAEs' growth at suprathreshold levels. In the DP-grams, recordings were obtained
with a frequency ratio f2/f1 fixed at 1.22. Nine pairs
of equal level primary frequencies (L1 = L2 = 70-dB
sound pressure level [SPL]) were used at 3 points per octave, spanning an
f2 frequency range from 1001 to 6348 Hz. The 70-dB levels of the
primary tones were used because these stimulus levels most reliably elicit
DP OAEs from ears with hearing difficulties.12
The DP-grams were not extended below 1001 kHz (f2) because subject
noise makes low-frequency DP OAEs difficult to measure. The DP-gram amplitude
across the entire frequency range was determined for each patient. In the
I/O format, data were obtained for f2 frequencies at 4004, 6006,
and 7996 Hz. Stimuli were incremented in 5-dB steps from 30- to 70-dB SPL.
Dynamic range (amplitude of the I/O function at 70-dB SPL) and detection thresholds
were determined for each patient.
STATISTICAL ANALYSIS
The researcher who performed the analysis of results (P.S.) was blinded
to the participants' grouping. Measurements of the baseline TE and DP OAEs
of the 3 groups were compared using 2-way analysis of variance (ANOVA), examining
the effect of CF, the history of gentamicin exposure, and their interaction
(between-subject factors). A separate test was performed for each dependent
variable, including TE OAEs' total emission level, TE OAEs' reproducibility
of the 800-Hz spectral bands, DP-gram amplitude across the entire f2 frequency range, I/O dynamic range at 4004, 6006, and 7996 Hz, and
I/O detection thresholds at the same frequencies. The magnitude of all statistically
significant differences was further evaluated using the eta-squared ( 2) index and Cohen criteria.13 In addition,
for the CF-gentamicin group, comparisons between baseline and final evoked
OAEs measurements (TE and DP OAEs) were performed using the paired 2-tailed t test. Significance was determined at the .05 level for
all statistical testing.
RESULTS
All PTA hearing thresholds were within normal limits for the subjects
of all 3 groups (Figure 1). Furthermore,
for the CF-gentamicin group, no significant threshold shifts (measured by
the American Speech-Language-Hearing Association standards9)
were noted following the last gentamicin treatment.
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Figure 1. Pure-tone audiogram results for
the children of all 3 groups. CF indicates cystic fibrosis.
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In TE OAE testing, robust, well-defined responses were recorded in all
children. Table 1 lists the mean
(SD) values for the baseline total emissions levels and reproducibility for
each frequency band in the 3 tested groups. The baseline DP-gram amplitudes
for the 3 tested groups as well as the posttreatment values for the CF-gentamicin
group are shown in Figure 2. Figure 3 illustrates the baseline I/O functions
at 4004, 6006, and 7996 Hz for the 3 tested groups and the posttreatment recordings
for the CF-gentamicin group.
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Table 1. Results of Transient-Evoked Otoacoustic Emissions Measurements*
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Figure 2. Mean values of distortion-product
otoacoustic emissions amplitude for the children of all 3 groups. The lower
shaded area represents the mean noise floor plus 1 SD, while the upper shaded
area represents 2 SDs above the mean noise floor. SPL indicates sound pressure
level; CF, cystic fibrosis.
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Figure 3. The baseline input-output (I/O)
functions at 4004, 6006, and 7996 Hz for the 3 tested groups and the posttreatment
recordings for the CF-gentamicin group. The mean values of I/O functions are
A, f2 = 4004 Hz; B, f2 = 6006 Hz; and C, f2
= 7996 Hz. The lower shaded areas in all figures represent the mean noise
floor plus 1 SD, while the upper shaded areas represent 2 SDs above the mean
noise floor. SPL indicates sound pressure level; CF, cystic fibrosis.
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Recordings of the effects of CF, history of gentamicin exposure, and
their interaction on baseline TE and DP OAEs in the 3 different groups were
analyzed with a 2-way ANOVA for each type of measurement. Two-way ANOVA with
1 and 59 df revealed that the CF factor had no effect
on the total emission level. However, history of gentamicin exposure had a
significant effect (F1,59 = 5.551, P<.05).
No significant interaction between the 2 factors was observed. Therefore,
patients in the CF-gentamicin group had significantly lower total emissions
levels than both control groups. The 2 index (0.086) revealed
a moderately powerful relationship. Regarding reproducibility at each frequency,
neither grouping factor (CF or history of gentamicin exposure) had any significant
main effect. Additionally, no significant interaction between the 2 factors
was observed.
Regarding DP-gram amplitudes at each f2 frequency, 2-way
ANOVA revealed that the CF factor had no effect. However, history of gentamicin
exposure had a significant effect (F1,59 = 8.255, P<.05) on DP-gram amplitude only at the highest frequency tested
(f2 = 5042 Hz). At this frequency, patients with CF and a history
of gentamicin exposure had DP-grams with significantly lower amplitude than
that of both control groups. The 2 index (0.123) showed a
very powerful relationship. There was no significant interaction between the
2 grouping factors.
Regarding the results for the I/O functions at each frequency, 2-way
ANOVA revealed that the CF factor had no effect on either the dynamic range
or the detection threshold. However, a history of gentamicin exposure had
a significant effect (P<.05) on both at the 2
highest frequencies tested (dynamic range, F[6006 Hz]1,59 = 8.436
and F[7996 Hz]1,59 = 5.023; detection thresholds, F[6006 Hz]1,59 = 7.145 and F[7996 Hz]1,59 = 6.643). The 2 indexes revealed that these relationships were powerful (0.125, 0.78,
0.108, and 0.101, respectively). Therefore, patients with CF and a history
of gentamicin exposure had significantly lower dynamic ranges and significantly
higher detection thresholds than both control groups. There was no significant
interaction between the 2 factors.
In the CF-gentamicin group, paired 2-tailed t
tests were used to compare the baseline evoked OAEs recordings with those
following the last gentamicin treatment. A significant decrease of the posttreatment
total emission level (5.85) compared with the baseline (9.50) was noted (t23 = 4.701, P<.005).
The strength of the relationship between gentamicin exposure and total emission
level, as indicated by a point biserial correlation coefficient (rpb),13 was very high (0.70).
The differences in reproducibility were not statistically significant, although
there was a modest decrease at each frequency at the end of treatment.
Regarding the DP-gram amplitude, a significant decrease was observed
posttreatment for f2 frequencies greater than 3000 Hz (Table 2). The strength of the relationship
between gentamicin exposure and DP-gram amplitude (rpb) was moderately high.
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Table 2. Effect of Aminoglycoside Therapy on Distortion-Product Otoacoustic
Emissions Amplitude*
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Finally, the dynamic range was significantly decreased and the detection
threshold was significantly elevated (Table
3) at the end of the last gentamicin treatment for all 3 frequencies
tested. The strength of the relationship (rpb) between gentamicin treatment and both dynamic range and detection
threshold was also moderate.
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Table 3. Effect of Aminoglycoside Therapy on Input/Output Function
Dynamic Range and Detection Threshold*
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COMMENT
Ototoxic drugs such as aminoglycosides are essential for the prevention
of life-threatening infections in patients with CF.9
The prevalence of aminoglycoside-induced hearing loss in these patients is
not well defined, and the reported incidence varies from 0% to 39%.14-22
This wide discrepancy is most likely the result of diverse testing methods
(eg, conventional PTA, high-frequency audiometry, and auditory brainstem responses),
differences of the populations studied, and varying dosage and duration of
drug regimens. In our study, conventional PTA thresholds were within normal
limits for patients with CF and a history of aminoglycoside intake and remained
virtually unchanged following the last gentamicin exposure.
In some of the previously mentioned studies,15, 19, 21
results are not presented separately for children and adults, although it
is obvious that the cumulative aminoglycoside dose and the potential ototoxicity
in children can be expected to be lower. Furthermore, the number of properly
designed, well-controlled studies is small. To our knowledge, only 2 studies17, 22 used properly selected control groups
(healthy subjects and patients with CF not treated with aminoglycoside), while
in 3 other studies only healthy subjects served as a control group.18, 20-21 Unfortunately, the
criteria for defining hearing loss were not presented clearly in any of these
studies.
Several investigators have used high-frequency audiometry for early
detection of hearing loss.15, 17, 19, 22-23
In these studies the incidence of cochleotoxic damage is the highest reported.
While high-frequency audiometry is a sensitive method for early detection
of ototoxicity, it is not easily applicable to children. It requires cooperation
from the young patient, which cannot always be counted on. Lack of patient
concentration due to poor general condition also affects audiometric results.24 In addition, the procedure must be optimally carried
out in a sound-treated environment and requires a sound of moderate to high
intensity to elicit an observable response, even from children with normal
auditory function. The test is relatively time-consuming, and learning effects
may partially obscure the detection of hearing loss.
With improved survival in CF, quality of life issues are becoming of
paramount importance. Detection of hearing loss at a young age is essential
when education, social integration, and personality development are at a critical
stage. Typically, once damage has occurred, recovery of the cochlea cannot
be expected. Along with primary prevention, early detection of hearing loss
is important for providing management options. The pediatrician might have
the option of adjusting the therapy to a potentially less ototoxic regimen
such as antipseudomonal penicillins or third-generation cephalosporins. Likewise,
early indications of a threshold shift would be useful for planning audiologic
management and counseling.
Evoked OAEs measurement is a recent noninvasive method of objective
cochlear investigation that is especially helpful in children. Evoked OAEs
can be reliably measured from nearly all human ears with normal cochlear and
middle ear function.10 It is now well established
that OAEs measures are more sensitive to inner ear dysfunction than conventional
PTA or auditory brainstem responses.7, 12, 25
In our study, both TE and DP OAEs were significantly affected at the higher
frequencies following recent gentamicin exposure. Decreased emissions in the
presence of normal behavioral hearing may indicate an underlying pathologic
condition, which, if allowed to continue, might result in a clinically significant
hearing loss.
The high sensitivity of DP OAEs in early identification of subtle inner
ear dysfunction has also been emphasized in 2 reports on aminoglycoside used
to treat patients with CF.21-22
However, the outcome measures used were quite different. In a study by Katbamna
et al,22 a significant suppression of DP OAEs
was found in 13 tobramycin-treated children compared with children with CF
not treated with drugs and healthy children of similar age, suggesting that
enhanced contralateral suppression may be the first sign of developing ototoxicity.
In the Mulheran and Degg study,21 a significant
elevation of the stimulus level required to generate a 2f1-f2 DP OAE of 10 dB SPL or lower at 4000 Hz was found in 15 gentamicin-treated
children with CF compared with normal children, suggesting that this elevation
may represent one of the earliest changes in outer hair cell function caused
by gentamicin.
To our knowledge, this is the first study investigating the sensitivity
of both TE and DP OAEs in the early detection of gentamicin-induced cochleotoxicity
in children with CF. Tests for DP OAEs seemed to be more frequency sensitive
than those for TE OAEs for determining minor cochlear dysfunction. This difference
may arise from different generating mechanisms within the cochlea and/or different
propagation mechanisms from the inner to external ear. For monitoring purposes,
DP OAEs would also seem preferable to TE OAEs because they are known to have
a more extensive range regarding hearing loss and can be measured over a broader
frequency range with more sensitive frequency-specific responses.5
Our findings suggest that evoked OAEs are a sensitive and a reliable
indicator of subtle inner ear dysfunction. Their recording is easy for both
technician and patient, does not require a sound-treated environment, and
can be easily performed at the bedside with portable equipment. We believe
that OAEs measurement should be routinely used in monitoring to prevent permanent
damage, not only in the clinical evaluation of auditory function, but also
for regular monitoring of cochlear function in the presence of potentially
toxic factors such as aminoglycosides.
AUTHOR INFORMATION
Accepted for publication September 5, 2001.
Corresponding author and reprints: Pelagia Stavroulaki, MD, 116 Redestou
St, 384 45 N Ionia, Volos, Greece (e-mail: pstavroulaki{at}yahoo.co.uk).
From the University Department of Otolaryngology–Head and Neck
Surgery, Southmead Hospital, Bristol, England (Dr Stavroulaki); Department
of Orthopedic Surgery, Weston General Hospital, Weston-Super-Mare, England
(Dr Vossinakis); and the Ear, Nose and Throat Department, Faculty of Medicine,
University of Athens (Drs Dinopoulou and Adamopoulos), Department of Cystic
Fibrosis, Children's Hospital Agia Sofia (Dr Doudounakis), and Department
of Otorhinolaryngology –Head and Neck Surgery, Children's Hospital Panagiotis
& Aglaia Kyriakou (Dr Apostolopoulos), Athens, Greece.
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