Evidence for Adverse Phonatory

Change Following an Inhaled

Combination Treatment

Elizabeth Erickson
Mahalakshmi Sivasankar
Purpose: Voice problems are reported as a frequent side effect of inhaled combination
Purdue University, West Lafayette, IN
( IC) treatments. The purpose of this experimental study was to investigate whether
IC treatments are detrimental to phonation. We hypothesized that IC treatment
would significantly increase phonation threshold pressure ( PTP) and perceived
phonatory effort ( PPE), whereas sham treatment would not.
Method: Fourteen healthy adults participated in a repeated-measures design in which
they received IC and sham treatments in counterbalanced order. PTP and PPE were
measured prior to treatments, immediately following treatments, and at 1 and 2 hr
following treatments.
Results: IC treatment increased PTP, but sham treatment did not. The increase in PTP
was maintained for a 2 hr period following administration. PPE ratings were not
significantly correlated with PTP.
Conclusions: IC treatments can have acute, adverse effects on phonation. Detrimental
phonatory effects were elicited in participants with no self-reported voice problems.
IC treatments are being increasingly prescribed across the lifespan. The current data
increase our understanding of the nature of phonatory deterioration associated with
IC treatment and lay the groundwork for increased research effort to develop IC
treatments that effectively control respiratory disease while minimizing an adverse
effect on phonation.
KEY WORDS: inhaled combination treatments, corticosteroids, beta-agonists,
voice problems

O
ver 35 million Americans have airway diseases such as asthma,
emphysema, and chronic obstructive pulmonary disease (Amer-
ican Lung Association, 2008). These conditions are frequently
controlled with inhaled combination (IC) treatments. IC treatments com-
bine a corticosteroid and long-acting beta agonist ( LABA) to manage
multiple respiratory symptoms with a single treatment (Kavuru et al.,
2000). Since 2000, physicians have dispensed more than 106 million pre-
scriptions for IC treatments in the United States alone (GlaxoSmithKline,
2008a, 2008b).
Inhaled treatments are prescribed to treat diseases of the distal
airway (Barnes & Adcock, 2003; Busse, 1993). However, analysis of drug
distribution patterns using radioactive isotopes in human participants
has revealed that a large portion of the treatment gets deposited in the
throat (Dolovich, Ruffin, Corr, & Newhouse, 1983). Factors contributing
to this high rate of drug deposition in the upper airway include delivery
device (e.g., nebulizer vs. metered dose inhaler), drug particle size, spacer
use, and administration technique (Rau, 2005; Williams et al., 1983). The

Journal of Speech, Language, and Hearing Research • Vol. 53 • 75–83 • February 2010 • D American Speech-Language-Hearing Association 75
phonatory effects associated with inhaled treatments
are posited to result from a direct drug effect on the vocal
folds (DelGaudio, 2002; Gallivan, Gallivan, & Gallivan,
2007; Lavy, Wood, Rubin, & Harries, 2000; Mirza,
Schwartz, & Antin-Ozerkis, 2004). In a retrospective
study, negative phonatory effects were reported in ap-
proximately 58% of patients prescribed inhaled treat-
ments (Williamson, Matusiewicz, Brown, Greening, &
Crompton, 1995).
Voice problems are the most frequently reported
adverse consequence of inhaled medications (Roland,
Bhalla, & Earis, 2004). However, limited investigations
have examined the physiologic mechanisms underly-
ing the adverse phonatory changes. In porcine vocal fold
mucosa, LABA treatment induced a transient increase
in ion transport followed by a sustained decrease in
ion transport, whereas corticosteroid treatment did not
(Sivasankar & Blazer-Yost, 2009). The reduction in ion
transport was posited to result from decreased chloride
(Cl–) secretion. In the vocal folds, Cl– secretion is one
mechanism to increase superficial hydration (Leydon,
Sivasankar, Lodewyck, Atkins, & Fisher, 2009). As de-
creased hydration state is related to increased vocal
fold viscous properties, the decrease in Cl– secretion as-
sociated with LABA treatment could increase the vis-
cosity of the vocal fold mucosa. Increased viscosity can be
detrimental to phonation. On the basis of this prelim-
inary in vitro ion transport investigation, we predicted
that treatments containing corticosteroids and LABAs
could adversely impact phonation by increasing vocal
fold viscosity. However, the effects of corticosteroid–
LABA treatments on other biomechanical properties of
the vocal folds (e.g., cover stiffness) or on surrounding
tissue cannot be disregarded as underlying mechanisms
for adverse phonatory change associated with IC treat-
ment. Understanding the nature of the undesirable
phonatory effects associated with IC treatment may
provide the impetus for developing treatments that con-
trol respiratory symptoms with minimal effect on phona-
tory function.
The clinical evidence for the adverse phonatory ef-
fects of inhaled treatments is based on retrospective
data analyses of patients who already reported dyspho-
nia (Gallivan et al., 2007; Krecicki et al., 2006; Lavy
et al., 2000; Mirza et al., 2004; Williamson et al., 1995).
As such, it is difficult to establish whether the phonatory
side effects are a direct result of the medication, an out-
come of the progression of the respiratory disease, or
whether they are due to some other confounding vari-
able such as laryngopharyngeal reflux disease (DelGaudio,
2002), which may have a similar laryngeal presentation
as chronic steroid use. To the best of our knowledge, no
experimental investigations have examined whether IC
treatments cause adverse phonatory effects. If IC treat-
ments perturb mucosal physiology, then the phonatory
76 Journal of Speech, Language, and Hearing Research • Vol. 53 • 75–83 • February 2010
deterioration should be manifested only after IC treat-
ment and not after sham treatment. In addition, the
phonatory deterioration should be observed in voice mea-
sures that are sensitive to changes in vocal fold mucosal
physiology. In this investigation, phonation threshold
pressure ( PTP) and perceived phonatory effort ( PPE)
were used to assess adverse phonatory effects of IC
treatment. PTP, the minimum lung pressure required
to initiate and sustain vocal fold vibration, is an index
of vocal fold mucosal physiology (Titze, 1988). PTP de-
pends on biomechanical properties of the vocal folds, in-
cluding viscoelasticity (Titze, 1988; Verdolini-Marston,
Titze, & Druker, 1990). Specifically, an increase in vocal
fold viscosity is associated with an increase in PTP. PPE,
is a measure of a speaker’s self-perceived vocal effort
(Chang & Karnell, 2004), and PTP and PPE have been
posited to correlate in participants completing a vocal
loading challenge (Chang & Karnell, 2004). However,
investigations examining the correlation between these
variables after hydration challenge have not confirmed
this relationship (Roy, Tanner, Gray, Blomgren, & Fisher,
2003; Sivasankar, Erickson, Schneider, & Hawes, 2008;
Tanner, Roy, Merrill, & Elstad, 2007).
The purpose of the present study was to investigate
the detrimental effects of IC treatment on PTP and PPE.
We tested the overarching hypothesis that the IC treat-
ment would elevate PTP and PPE but the sham treat-
ment would not. The secondary focus was to examine the
relationship between PTP and PPE in individuals receiv-
ing IC treatment. Each participant received both an IC
treatment and a sham treatment. As the pharmacological
profile of the IC treatment used in this particular inves-
tigation is characterized by a 2 hr postadministration peak
effect, PTP and PPE were measured prior to treatments,
immediately following treatments, and at 1 and 2 hr fol-
lowing treatments.
Method
Participants
Fourteen adults (9 women and 5 men) participated
in this investigation (see Table 1). All participants had
perceptually normal speech and voice as confirmed by a
speech-language pathologist, normal laryngeal appearance
on rigid videostroboscopy as confirmed by an otolaryn-
gologist, and normal spirometry (forced vital capac-
ity [ FVC] ≥ 80% based on age-, gender-, weight-, and
ethnicity-matched norms). All participants completed
the Voice Handicap Index ( VHI) and scored below the
mean (33.69 ± 5.60) for a mild self-perceived voice hand-
icap (Jacobson et al., 1997). VHI total scores are reported
in Table 1. VHI subscales scores are not reported, as only
the VHI total score has been validated as an indicator of
self-perceived voice handicap (Rosen, Lee, Osborne, Zullo,
 Table 1. Participant characteristics.

Participant Gender Age (years) Dosage (CS/LABA in mg) Duration of IC treatment FVC VHI total score

1 F 20 250/50 1 year Normal 7

2 F 22 250/50 2 years Normal 5
3 F 18 250/50 5 years Normal 26
4 M 22 250/50 5 months Normal 17
5 F 19 250/50 2 years Normal 17
6 F 18 250/50 1 year Normal 19
7 F 21 250/50 4 months Normal 21
8 M 36 250/50 2 years Normal 5
9 F 19 250/50 4 years Normal 14
10 M 23 250/50 4 years Normal 9
11 F 20 250/50 5 years Normal 24
12 F 44 250/50 3 years Normal 20
13 M 19 100/50 2 years Normal 19
14 M 22 100/50 7 years Normal 19

Note. Normal forced vital capacity (FVC) indicates values ≥ 80% based on age-, weight-, gender-, and ethnicity-matched normative
values. CS = corticosteroid (fluticasone proprionate); LABA = long-acting beta agonist (salmeterol xinafoate); IC = inhaled combination;
VHI = Voice Handicap Index.

& Murry, 2004). In addition, the participants met the
following criteria on self-report: general good health,
normal hearing, nonsmoking, no respiratory tract in-
fections at the time of the study, and a negative history
for laryngeal pathology. All individuals were taking
Advair diskus® IC treatment for the control of asthma.
Advair diskus® contains the corticosteroid fluticasone
proprionate and the LABA salmeterol xinafoate. The dos-
age of the corticosteroid–LABA treatment is shown in
Table 1. Participants were taking this IC treatment once
daily (N = 6) or twice daily (N = 8) for at least 4 months. To
ensure methodological consistency, data collection for
individuals prescribed the IC treatment once daily was
always completed at the time that they habitually took
their medication (morning, N = 2; evening, N = 4), and
data collection for individuals prescribed the IC treat-
ment twice daily was always completed at the time of the
second dose, scheduled 12 hr following the first dose. In-
dividuals enrolled in this investigation were taking no
additional prescription medications besides oral con-
traceptives at the time of study.
Protocol
Each participant completed two experimental ses-
sions, scheduled at the same time on consecutive days, in
which they took either an IC or sham treatment. The
order of treatments ( IC or sham) was counterbalanced
across participants. The IC treatment was Advair diskus®,
and the sham treatment was an empty Advair diskus® de-
vice. Participants were informed that the sham treatment
was an alternative treatment for asthma. Participants
were not denied treatment on the sham day and took
their IC treatment in the presence of the examiner im-
mediately following completion of the session.
Data-collection procedures were identical during
both experimental sessions (see Figure 1). At the start of
each session, the participant’s vocal pitch range was

Figure 1. Schematic of experimental protocol. Participants completed a combination of a 30 min reading task at comfortable
loudness and a 30 min rest breathing task during the 1 hr and 2 hr periods preceding Post1 and Post2 measurements.
The order of reading and rest breathing tasks were counterbalanced across participants. PTP = phonation threshold pressure;
PPE = perceived phonatory effort; IC = inhaled combination.

Erickson & Sivasankar: Phonatory Effects of IC Treatment 77

calculated. To obtain pitch range, participants were
asked to glide up and down their range in a soft voice.
The highest and lowest pitches produced were rounded
to the nearest semitone (ST) on a keyboard. The 10th,
20th, and 80th percent pitches were calculated from the
ST range. The keyboard notes corresponding to these
pitches were identified. Participants were trained to pro-
duce multiple /pi / productions in soft voice, just above a
whisper, at these three pitches. All participants could
produce the /pi / syllables at 10th and 20th percent
pitches. Three of the 14 participants could not produce
the soft /pi / task at the 80th pitch. For these partici-
pants, the 80th percent pitch was lowered by one ST.
Next, baseline measures ( PTP, PPE, and FVC) were
collected. Participants were provided the IC or sham
treatment, and PTP, PPE, and FVC were reassessed
immediately following the treatment ( hereafter called
Post0) and at 1 and 2 hr following treatment ( Post1 and
Post2, respectively). Participants completed comfortable
reading and rest breathing tasks during the 1 hr and
2 hr periods preceding Post1 and Post2 measurements
(see Figure 1). The procedures are elaborated below.
PTP. Participants were trained on this task per
validated procedures ( Fisher & Swank, 1997; Verdolini-
Marston et al., 1990). In brief, the investigator held a
circumferentially vented pneumotachograph face mask
around each participant’s mouth and nose. Participants
were instructed to produce a five-syllable /pi / string at a
rate of 1.5 syllables/second “as smoothly as possible on a
single breath” at suprathreshold loudness. Participants
gradually reduced their loudness until /pi/ syllable strings
were produced as quietly as possible without whispering.
The investigator modeled this task multiple times, and
each participant practiced while the investigator provided
verbal feedback regarding rate and loudness. In addi-
tion, all individuals received visual feedback from a data-
collection monitor. Participants were trained on the task
until within-trial pressure peaks were at the same height
and oral flows reached 0 ml/s during the /p/ production
(Fisher & Swank, 1997). Following training, participants
produced the five-syllable /pi/ string at each target pitch:
10th (PTP10), 20th (PTP20), and 80th (PTP80). A five-
syllable /pi/ string at one pitch constituted one trial and
participants repeated the task until five trials met the task
criteria. Trials characterized by intermittent phonation or
produced at clear suprathreshold levels were discarded.
Target pitches were maintained for the duration of the
experimental session (according to investigator’s percep-
tual evaluation) because of the direct dependence of PTP
on vocal fundamental frequency (Fisher & Swank, 1997;
Verdolini, Titze, & Fennel, 1994; Verdolini-Marston et al.,
1990). All baseline PTP values were normal (Colton &
Casper, 2005). This experimental procedure was re-
peated to obtain posttreatment PTP10, PTP20, and PTP80.
The likelihood of potential order effects of pitch on PTP
78 Journal of Speech, Language, and Hearing Research • Vol. 53 • 75–83 • February 2010
was minimized because this study exploited a within-
subject design.
PTP instrumentation. A circumferentially vented
pneumotachograph mask was fitted with low- and wide-
bandwidth differential pressure transducers (Glottal En-
terprises). Transducers were coupled to a measurement
system (MSIF-2 system; Glottal Enterprises) for the collec-
tion of pressures and airflows. The pressure and airflow
signals were amplified and digitized at 1 kHz and 100 Hz,
respectively, using a Chart® 5 A /D converter. Flow and
pressure signal calibration was completed prior to each
experimental session (MCU-4 calibration system; Glottal
Enterprises).
PPE. Participants rated vocal effort on a visual
analog scale immediately following PTP80 productions
(Solomon & DiMattia, 2000; Tanner et al., 2007). Par-
ticipants were provided a 10 in. line with two anchors (no
effort and maximum effort) and were asked to draw a
vertical line on the scale corresponding to their perceived
vocal effort during the preceding PTP80 task. The same
procedure was used to obtain baseline and posttreatment
PPE. Participants were shown their previous PPE rating
to minimize scale drift. PTP80 was selected because this
study sought to investigate the relationship between PTP
and PPE, and correlations between PTP and PPE have
been shown previously to be strongest at high pitch
(Solomon et al., 2003).
FVC. This respiratory measure was collected from
each participant at baseline, Post0, Post1, and Post2 ac-
cording to the recommendations of the joint American
Thoracic Society and European Respiratory Society (Miller
et al., 2005). Normal FVC (≥80%) was maintained by all
participants throughout the duration of the study.
Data Analysis
PTP. The investigator excluded the first and last /p/
pressure peaks from each trial and chose three middle
/p/ peaks for analysis ( Fisher & Swank, 1997; Holmberg,
Hillman & Perkel, 1988). Adjacent peaks were mea-
sured to estimate the lung pressures during the inter-
vening /i / vowels (Smitheran & Hixon, 1981). Estimated
lung pressures were averaged across the five trials to
determine PTP values at each target pitch. The inves-
tigator reanalyzed 10% of the data to estimate intrarater
reliability. To estimate interrater reliability, an exam-
iner trained in PTP analysis and naive to the experi-
mental hypothesis and treatment type also reanalyzed
10% of the data. The first and second measurements of
PTP were strongly correlated (rintra = .98, rinter = .98).
PPE. A standard ruler was used to measure the dis-
tance from the far left anchor (no effort) to the vertical
line on the scale corresponding to each participant’s PPE
rating. To minimize measurement errors, the investigator
and an examiner blinded to the experimental hypothesis Figure 2. The interaction effect of Treatment × Time for phonation
remeasured all ratings. First and second PPE measure- threshold pressure (PTP) at the 10th (2A; PTP10), 20th (2B; PTP20), and
ments were strongly correlated (rintra = .99, rinter = .99). 80th (2C; PTP80) percent pitch. The interaction effect of Treatment ×
Time is significant for PTP80, demonstrating that inhaled combination
(IC) treatment increased PTP over time but that sham treatment did
Statistical Analysis not. Error bars represent standard errors.
All data were analyzed using SPSS software ( Ver-
sion 16.0). The dependent variables included PTP10, PTP20,
PTP80, and PPE for IC and sham treatment. Kolmogorov–
Smirnoff and Shapiro–Wilk tests of normality confirmed
that PTP10, PTP20, and PPE data were normally dis-
tributed. Data for PTP80 was transformed (square root
transformation) to fulfill assumptions of normality. Paired
t tests confirmed that baseline measures did not differ
across the two experimental sessions. Separate mixed
general linear model analyses of variance were used to
investigate the temporal effects of IC and sham treat-
ments on PTP10, PTP20, PTP80, and PPE. In these anal-
yses, treatment ( IC/sham) and time ( baseline, Post0,
Post1, Post2) were repeated measures. The p level was
adjusted to .01 for each analysis ( Bonferroni correction)
to control for potential alpha inflation due to the mul-
tiple analyses.

Results
PTP
IC and sham treatments had differential effects on
PTP over time. Figure 2 depicts the temporal effects of
IC and sham treatments on PTP10, PTP20, and PTP80
(Figures 2A, 2B, and 2C, respectively). Numerically, IC
treatment increased PTP over time but sham treatment
did not. This Treatment × Time interaction effect was sig-
nificant at PTP80, F(3, 39) = 5.63, p = .003 (see Figure 2C).
The effect magnitude (h2) for PTP80 was .30, which sug-
gests that the Treatment × Time interaction effect ac-
counted for 30% of total variance. No significant interaction
effects were observed at PTP10, F(3, 39) = 4.79, p = .03,
h2 = .26 (see Figure 2A), or PTP20, F(3, 39) = 1.02, p = .39,
h2 = .07 (see Figure 2B).
Post hoc analyses allowed for further characteriza- treatments on PPE at baseline, Post0, Post1, and Post2.
tion of the differential effects of IC and sham treatments IC and sham treatments had similar temporal effects on
on PTP80 at baseline, Post0, Post1, and Post2 (see Fig- PPE as revealed by a nonsignificant Treatment × Time
ure 2C). Following IC treatment, the mean increase in interaction effect, F(3, 39) = 0.50, p = .68, h2 = .03 (see
PTP80 from baseline was +0.26 cm H2O, +0.61 cm H2O, and Figure 3). Overall, participants reported higher PPE
+0.82 cm H2O for Post0, Post1, and Post2, respectively. ratings following IC treatment as compared to sham
Conversely, following sham treatment, the mean change treatment; however, these treatment differences did
in PTP80 from baseline averaged –0.29 cm H2O, –0.23 cm not reach statistical significance.
H2O, and –0.02 cm H2O for Post0, Post1, and Post2,
respectively. PTP and PPE Correlations
Correlation analysis was applied to investigate the
PPE relationship between PTP and PPE at the 80th per-
Neither IC nor sham treatment significantly affected cent pitch following IC and sham treatments. Weak
PPE over time. Figure 3 depicts the effects of IC and sham correlations between PTP and PPE were observed at

Erickson & Sivasankar: Phonatory Effects of IC Treatment 79

Figure 3. The nonsignificant interaction effect of Treatment × Time for
perceived phonatory effort (PPE). Error bars represent standard
errors. IC = inhaled combination.
Post0 (rIC = –.03, rsham = .29), Post1 (rIC = .33, rsham = .25),
and Post2 (rIC = .33, rsham = .34).
Discussion
This study demonstrates that IC treatments can
have acute, adverse effects on PTP. The chronic ill effects
of inhaled medications on phonation have been documen-
ted retrospectively (DelGaudio, 2002; Gallivan et al., 2007;
Ihre, Zetterstrom, Ihre, & Hammarberg, 2004; Ishizuka
et al., 2007; Mirza et al., 2004). To our knowledge, this is
the first prospective investigation on the acute voice effects
of inhaled medication to incorporate a sham treatment.
PTP80 increased immediately after IC but not after
sham treatment. The increase in PTP80 is notable, as
all participants had normal laryngeal appearance, per-
ceptually normal speech and voice, and normal respira-
tory function as indicated by FVC. Furthermore, this
increase was maintained for up to 2 hr following IC
treatment, which is consistent with the pharmacological
profile of peak effect of the IC treatment used in this
study. It could be argued that the increase in PTP80 was
secondary to asthma; however, elevated PTP was only
observed following IC but not following sham treatment.
In addition, all participants demonstrated normal re-
spiratory function as measured by FVC prior to study
participation and throughout both experimental ses-
sions. Abnormal FVC values are a critical objective in-
dicator of asthma (National Heart, Lung and Blood
Institute, 2007). Although PTP80 increased following IC
treatment, a decrease in PTP80 was observed following
sham treatment ( Post0 and Post1). This decrease in
PTP80 could be attributed to the placebo effect or par-
ticipant awareness that the sham treatment was ac-
tually an empty delivery device. The decrease in PTP80
with sham treatment over time could also be associated
with a training effect, which makes the increase in
PTP80 with IC treatment even more notable.
80 Journal of Speech, Language, and Hearing Research • Vol. 53 • 75–83 • February 2010
The phonatory effects of the IC treatment were
significant at the 80th percent pitch (i.e., PTP80) but not
at the 10th and 20th percent pitch ( PTP10, PTP20). The
80th pitch may be particularly sensitive to changes in
vocal function that are present but are not numerically
identified at other pitches (Verdolini et al., 2002). Our
detection of statistical significance at an extreme pitch is
consistent with previous research suggesting that chal-
lenges to vocal fold mucosal physiology are best detected
by PTP produced at high pitch (Solomon, Glaze, Arnold,
& Van Mersbergen, 2003; Verdolini et al., 2002). Our re-
sults suggest that a PTP task at 80th pitch may be most
useful when investigating phonatory changes induced
by IC treatment.
The underlying mechanism for the elevated PTP
following IC treatment was not directly investigated in
this study. However, it is possible to speculate on one
potential mechanism based on the current results. The
IC treatment examined here contained two medica-
tions (the corticosteroid fluticasone proprionate and the
LABA salmeterol xinafoate) that are rapidly absorbed
into tissue following deposition. The specific amount of
the drug that is deposited on the vocal fold surface is
unknown; however, up to 75% of the IC treatment gets
deposited in the oropharynx and larynx (Hess, Myers,
& Rau, 2007; Rau, 2005). It is therefore likely that
the acute phonatory changes measured here resulted
from the effects of the corticosteroid and /or LABA on
vocal fold mucosal physiology. The increase of PTP, an
objective indicator of vocal fold mucosal biomechanics
(Chan & Titze, 2006; Titze, 1988), immediately after
treatment is also consistent with IC treatment-induced
perturbations to the vocal fold mucosa rather than mus-
cle, as proposed previously (Babu & Samual, 1988). In a
laryngeal imaging investigation, Mirza and colleagues
(2004) also suggested that mucosal changes may under-
lie the phonatory problems in individuals receiving IC
treatment. However, the nature of changes to vocal fold
mucosal physiology following corticosteroid and /or
LABA absorption requires further elucidation. There is
emerging evidence that the LABA treatment salmeterol
reduces Cl– ion transport in porcine vocal fold mucosa
(Sivasankar & Blazer-Yost, 2009). Cl– ion transport is
critical in regulating vocal fold hydration (Leydon et al.,
2009), which governs the viscous properties of the vocal
folds (Chan & Tayama, 2002) and thereby PTP (Titze,
1988, 1992). In porcine vocal fold mucosa, the corticoste-
roid fluticasone proprionate did not alter ion transport,
even after 3 hr of treatment. The differential effects
of corticosteroid and LABA treatment on porcine ion
transport in vitro cannot be directly applied to the cur-
rent investigation. It is notable, however, that the
medications used here, which differed in the amount
of fluticasone proprionate (100 mg or 250 mg) but not in
the amount of salmeterol across participants (see Table 1),
elicited similar magnitude of change in PTP. Whether
the adverse phonatory effects (specifically, increased PTP)
observed with IC treatment are largely related to LABA-
associated effects on viscous properties of the tissue
awaits rheologic study. But, on the basis of the current
results, it is not possible to rule out direct effects of cor-
ticosteroid and LABAs on other biomechanical proper-
ties of vocal fold mucosa or surrounding structures.
Although the underlying mechanism for the acute
phonatory effects of IC treatment is currently unclear,
the clinical impact of detrimental voice changes induced
by this commonly prescribed treatment must not be over-
looked. The adverse phonatory effects of IC treatment
in dysphonic patients have been documented via video-
stroboscopy (Gallivan et al., 2007), but vocally healthy
participants were intentionally selected in this study to
help elucidate the nature of adverse phonatory changes
accompanying IC treatment without confounding variables.
It is essential that we identify the underlying mecha-
nisms for the adverse phonatory effects induced by IC
treatments, given that these medications are being in-
creasingly prescribed for a wide range of respiratory
conditions including asthma, emphysema, and chronic
obstructive pulmonary disease. Voice problems in indi-
viduals taking IC treatments can reduce quality of life
and decrease adherence to the pharmacologic regimen
(Bhalla, Jones, & Roland, 2008). Results from this in-
vestigation lay the foundation for further research on
treatments that can control respiratory symptoms while
minimizing an adverse effect on phonation.
Participant-reported vocal effort ( PPE) ratings were
not affected by treatment type. However, this finding
does not diminish our observation that IC treatments
adversely affect phonation. As reported previously, IC
treatment significantly increased PTP, which is a mea-
sure of effort in phonation (Colton & Brown, 1973). Weak
correlations between PTP and PPE were observed in the
current study. When PPE ratings were collected by
magnitude estimation following vocal loading, moder-
ately strong correlations to PTP were obtained (Chang &
Karnell, 2004). However, other investigations that also
obtained PPE ratings using direct magnitude estima-
tion revealed weak relationships between PTP and PPE
following hydration challenges (Sivasankar et al., 2008;
Verdolini et al., 2002). Possible reasons for this weak cor-
relation could relate to an independent relationship be-
tween PTP and PPE and/or the limited sensitivity of
PPE measures to small laryngeal perturbations to which
PTP measures appear to be more sensitive.
Limitations and Conclusions
The current investigation provides novel insight
into the detrimental effects of IC treatment on PTP. The
increase in PTP at high pitch was observed immediately
following IC but not following sham treatment, and the
increase was maintained for 2 hr following treatment. It
is unlikely that the increase in PTP over time was as-
sociated with vocal fatigue, as the reading and breath-
ing tasks were selected to reflect daily voice use and
therefore exposed participants to minimal vocal loading
(Solomon et al., 2003). It is notable that IC treatment
increased PTP in participants with normal laryngeal
appearance, normal FVC, and perceptually normal speech
and voice. Some limitations of this study, however, re-
quire further elucidation. In this study, sample size was
limited to 14 participants. The sample was also char-
acterized by an unequal gender distribution (9 women,
5 men). Although visual examination of the data did not
reveal gender effects for phonatory change, the small
number of participants precludes including gender as
an independent variable. Although this unequal gen-
der distribution was unintentional, it is notable that
asthma is more prevalent in women than in men (Cen-
ters for Disease Control and Prevention, 2007). Future
studies should therefore examine the differential pho-
natory effects of IC treatment across gender. An ad-
ditional limitation of the study pertains to the nature of
blinding. The 7 participants who received the sham
treatment during the first experimental session knew
they would be receiving their IC treatment during the
next session. In addition, the investigator was aware of
whether participants were receiving IC or sham treat-
ments. The investigator provided standardized training
and instruction during both sessions, and interrater reli-
ability analysis was conducted by an investigator blinded
to treatment type and hypothesis. But we acknowledge
that PTP collection and analysis can be vulnerable to
investigator bias. Elucidating the specific nature of
phonatory effects of IC treatment will mandate double-
blinded, placebo-controlled experimental trials. Today,
IC treatments are among the most commonly prescribed
medications to treat respiratory conditions. The current
data provide emerging evidence into the nature of ad-
verse phonatory effects associated with IC treatments
and lay the foundation for further research aimed at
improving vocal health in individuals prescribed these
common treatments.
Acknowledgments
This work was supported, in part, by the Indiana Lions
Club McKinney Outreach Research Award. This work is
based on a thesis by the first author, submitted in partial
fulfillment of the requirements for the master of science degree
from the Department of Speech, Language, and Hearing
Sciences at Purdue University. We acknowledge the valuable
insights provided by Jessica Huber, Christine Weber-Fox,
and Barbara Solomon throughout this project. We also thank
Daniel Berner and Robert Stephens for their assistance with
Erickson & Sivasankar: Phonatory Effects of IC Treatment 81
videostroboscopic interpretation. We appreciate the con-
tributions of Breanna Stevens, Johanna Hassink, and Mira
Stankovich to reliability analysis. GlaxoSmithKline provided
the empty Advair diskus® shells used in this study.
References
American Lung Association. (2008). Data and statistics.
Retrieved January 24, 2009, from http://www.lungusa.org/
site/c.dvLUK9O0E/b.33347/k.AC09/Data__Statistics.htm.
Babu, S., & Samual, P. (1988). The effect of inhaled steroids
on the upper respiratory tract. Journal of Laryngology
and Otology, 102, 592–594.
Barnes, P. J., & Adcock, I. M. (2003). How do corticosteroids
work in asthma? Annals of Internal Medicine, 139, 359–370.
Bhalla, R., Jones, A., & Roland, N. (2008). Prevalence of
pharyngeal and laryngeal complications in adult asthmatics
using inhaled corticosteroids. Journal of Laryngology and
Otology, 18, 1–6.
Busse, W. W. (1993). What role for inhaled steroids in chronic
asthma? Chest, 104, 1565–1571.
Centers for Disease Control and Prevention. (2007,
October). National surveillance for asthma: United States,
1980–2004 ( Publication No. 56). Retrieved April 7, 2009,
from http://www.cdc.gov/mmwr/preview/mmwrhtml /
ss5608a1.htm#tab2.
Chan, R., & Tayama, N. (2002). Biomechanical effects of
hydration in vocal fold tissues. Otolaryngology: Head and
Neck Surgery, 126, 528–537.
Chan, R., & Titze, I. (2006). Dependence of phonation thresh-
old pressure on vocal tract acoustics and vocal fold tissue
mechanics. The Journal of the Acoustical Society of America,
119, 2351–2362.
Chang, A., & Karnell, M. (2004). Perceived phonatory effort
and phonation threshold pressure across a prolonged voice
loading task: A study of vocal fatigue. Journal of Voice, 18,
454–466.
Colton, R. H., & Brown, J. (1973). Some relationships be-
tween vocal effort and intraoral air pressure. The Journal of
the Acoustical Society of America, 51, 296.
Colton, R. H., & Casper, J. K. (2005). Understanding voice
problems: A physiological perspective for diagnosis and
treatment (3rd ed.). Baltimore, MD: Williams & Wilkins.
DelGaudio, J. M. (2002). Steroid inhaler laryngitis: Dyspho-
nia caused by inhaled fluticasone therapy. Archives of Oto-
laryngology Head and Neck Surgery, 128, 677–681.
Dolovich, M., Ruffin, R., Corr, D., & Newhouse, M. T.
(1983). Clinical evaluation of a simple demand inhalation
MDI aerosol delivery device. Chest, 84, 36–41.
Fisher, K., & Swank, P. (1997). Estimating phonation thresh-
old pressure. Journal of Speech, Language, and Hearing
Research, 40, 1122–1129.
Gallivan, G. J., Gallivan, K. H., & Gallivan, H. K. (2007).
Inhaled corticosteroids: Hazardous effects on voice- an
update. Journal of Voice, 21, 101–111.
GlaxoSmithKline. (2008a). Advair for asthma. Retrieved
January 24, 2009, from http://www.advair.com/asthma /
asthma.html.
82 Journal of Speech, Language, and Hearing Research • Vol. 53 • 75–83 • February 2010
GlaxoSmithKline. (2008b). Advair medication guide. Re-
trieved January 24, 2009, from http://us.gsk.com /products/
assets/us_advair_hfa.pdf.
Hess, D. R., Myers, T. R., & Rau, J. L. (2007). A guide to
aerosol delivery devices for respiratory therapists. Retrieved
March 8, 2008, from http://www.aarc.org/education /
aerosol_devices/aerosol_delivery_guide.pdf.
Holmberg, E., Hillman, R., & Perkel, J. (1988). Glottal
airflow and transglottal air pressure measurements for
male and female speakers in soft, normal, and loud voice.
The Journal of the Acoustical Society of America, 84,
511–529.
Ihre, E., Zetterstrom, O., Ihre, E., & Hammarberg, B.
(2004). Voice problems as side effects of inhaled corticoste-
roids in asthma patients: A prevalence study. Journal of
Voice, 18, 403–414.
Ishizuka, T., Hisada, T., Aoki, H., Yanagitani, N., Kaira,
K., Utsugi, M., et al. (2007). Gender and age risks for
hoarseness and dysphonia with use of dry powder flutica-
sone proprionate inhaler in asthma. Allergy and Asthma
Proceedings, 28, 550–556.
Jacobson, B., Johnson, A., Grywalski, C., Silbergleit, A.,
Jacobson, G., Benninger, M., et al. (1997). The Voice
Handicap Index ( VHI): Development and validation. Amer-
ican Journal of Speech-Language Pathology, 6(3), 66–70.
Kavuru, M., Melamed, J., Gross, G., LaForce, C., House,
K., Prillman, B., et al. (2000). Salmeterol and fluticasone
proprionate combined in a new powder inhalation device
for the treatment of asthma: A randomized, double-blind,
placebo-controlled trial. Journal of Allergy and Clinical
Immunology, 105, 1108–1116.
Krecicki, T., Liebhart, J., Morawska-Kochman, M.,
Liebhart, E., Zatonski, M., & Zalesska-Krecicka, M.
(2006). Corticosteroid-induced laryngeal disorders in asthma.
Medical Science Monitor, 12, 351–354.
Lavy, J. A., Wood, G., Rubin, J. S., & Harries, M. (2000).
Dysphonia associated with inhaled steroids. Journal of
Voice, 14, 581–588.
Leydon, C., Sivasankar, M., Lodewyck, D., Atkins, C., &
Fisher, K. (2009). Vocal fold surface hydration: A review.
Journal of Voice, 23, 658–665.
Miller, M., Hankinson, J., Brusasco, F., Burgos, R.,
Casaburi, A., Coates, R., et al. (2005). Standardization of
spirometry. European Respiratory Journal, 26, 319–338.
Mirza, N., Schwartz, S., & Antin-Ozerkis, D. (2004).
Laryngeal findings in users of combination corticosteroid
and bronchodilator therapy. Laryngoscope, 114, 1566–1569.
National Heart, Lung and Blood Institute. (2007).
National Asthma Education and Prevention Program Expert
Panel Report 3: Guidelines for the diagnosis and management
of asthma ( NIH Publication No. 08-5846). Retrieved from
http://www.nhlbi.nih.gov/guidelines/asthma/asthsumm.pdf.
Rau, J. L. (2005). The inhalation of drugs: Advantages and
problems. Respiratory Care, 50, 367–382.
Roland, N. J., Bhalla, R. K., & Earis, J. (2004). The local
side effects of inhaled corticosteroids: Current understand-
ing and review of the literature. Chest, 126, 213–219.
Rosen, C., Lee, A., Osborne, J., Zullo, T., & Murry, T.
(2004). Development and validation of the Voice Handicap
Index-10. Laryngoscope, 114, 1549–1556.
Roy, N., Tanner, K., Gray, S., Blomgren, M., & Fisher, K.
(2003). An evaluation of the effects of three laryngeal lubri-
cants on phonation threshold pressure ( PTP). Journal of
Voice, 17, 331–342.
Sivasankar, M., & Blazer-Yost, B. (2009). Effects of long-
acting beta adrenergic agonists on vocal fold ion transport.
Laryngoscope, 119, 602–607.
Sivasankar, M., Erickson, E., Schneider, S., & Hawes, A.
(2008). Phonatory effects of airway dehydration: Prelimi-
nary evidence for impaired compensation to oral breathing
in individuals with vocal fatigue. Journal of Speech, Lan-
guage, and Hearing Research, 51, 1494–1506.
Smitheran, J., & Hixon, T. (1981). A clinical method for
estimating laryngeal airway resistance during vowel pro-
duction. Journal of Speech and Hearing Disorders, 46,
138–146.
Solomon, N., & DiMattia, M. (2000). Effects of a vocally
fatiguing task and systemic hydration on phonation thresh-
old pressure. Journal of Voice, 14, 341–362.
Solomon, N., Glaze, L., Arnold, R., & Van Mersbergen,
M. (2003). Effects of a vocally fatiguing task and systemic
hydration on men’s voices. Journal of Voice, 17, 31–46.
Tanner, K., Roy, N., Merrill, R., & Elstad, M. (2007). The
effects of three nebulized osmotic agents in the dry larynx.
Journal of Speech, Language, and Hearing Research, 50,
635–646.
Titze, I. (1988). The physics of small amplitude oscillations
of the vocal folds. The Journal of the Acoustical Society of
America, 83, 1536–1552.
Titze, I. (1992). Phonation threshold pressure: a missing link
in glottal aerodynamics. The Journal of the Acoustical
Society of America, 91, 2926–2935.
Verdolini, K., Min, Y., Titze, I., Lemke, J., Brown, K.,
VanMersbergen, M., et al. (2002). Biological mechanisms
underlying voice changes due to dehydration. Journal of
Speech, Language, and Hearing Research, 45, 268–282.
Verdolini, K., Titze, I., & Fennel, A. (1994). Dependence of
phonatory effort on hydration level. Journal of Speech and
Hearing Research, 37, 1001–1007.
Verdolini-Marston, K., Titze, I., & Druker, D. (1990).
Changes in phonation threshold pressure with induced
conditions of hydration. Journal of Voice, 4, 142–151.
Williams, A. J., Baghat, M. S., Stableforth, D. E., Cayton,
R. M., Shenoi, P. M., & Skinner, C. (1983). Dysphonia
caused by inhaled steroids: Recognition of a characteristic
laryngeal abnormality. Thorax, 38, 813–821.
Williamson, I. J., Matusiewicz, S. P., Brown, P. H.,
Greening, A. P., & Crompton, G. K. (1995). Frequency
of voice problems and cough in patients using pressurized
aerosol inhaled steroid preparation. European Respiratory
Journal, 8, 590–592.
Received February 7, 2009
Accepted June 30, 2009
DOI: 10.1044/1092-4388(2009/09-0024)
Contact author: Mahalakshmi Sivasankar, Department
of Speech, Language, and Hearing Sciences, Purdue
University, West Lafayette, IN 47907.
E-mail: msivasankar@purdue.edu.
Erickson & Sivasankar: Phonatory Effects of IC Treatment 83
Copyright of Journal of Speech, Language & Hearing Research is the property of American Speech-Language-
Hearing Association and its content may not be copied or emailed to multiple sites or posted to a listserv
without the copyright holder's express written permission. However, users may print, download, or email
articles for individual use.