ORIGINAL STUDY
A Randomized Controlled Trial to Determine the Effect of
Inhaled Corticosteroid on Intraocular Pressure in Open-
Angle Glaucoma and Ocular Hypertension: The ICOUGH
Study
Edward B. Moss, FRCSC, MD,* Yvonne M. Buys, FRCSC, MD,*
Stephanie A. Low, MD,* Darana Yuen, FRCSC, MD,* Ya-ping Jin, PhD,*
Kenneth R. Chapman, MD, MSc, FRCPC,w
and Graham E. Trope, FRCSC, PhD, MD*
Purpose: The purpose of this study was to determine the risk of a
steroid pressure response from inhaled corticosteroids.
Patients and Methods: This randomized, double-masked, placebo-
controlled trial included 22 adults with well-controlled open-angle
glaucoma or ocular hypertension. Consenting participants were
randomized to a 6-week course of twice-daily uticasone propio-
nate 250-mg metered-dose inhaler or saline placebo metered-dose
inhaler. Biweekly clinic visits included masked Goldmann appla-
nation tonometry and assessment to identify adverse eects. Pri-
mary outcome was mean intraocular pressure (IOP) at week 6.
Secondary outcomes included IOP elevation of >20% at 2 con-
secutive visits, adherence, side eects, and logMAR visual acuity.
Results: A total of 10 patients in each arm completed the study.
There were no statistically signicant dierences in IOP between
groups at baseline (14.3 3.0 and 15.6 3.6 mm Hg in steroid and
placebo groups, respectively, P = 0.39) or at week 6 (14.7 2.4
and 14.8 3.8 mm Hg in steroid and placebo groups, respectively,
P = 0.92). Adherence was >80% for all participants. There were
no statistically signicant dierences between groups in any sec-
ondary measures. One patient in the steroid group met the secon-
dary end point of >20% elevation in IOP (IOP increased from
baseline of 9 to 11 mm Hg at weeks 2 and 4).
Received for publication October 7, 2015; accepted March 23, 2016.
From the *Department of Ophthalmology and Vision Sciences; and
wDivision of Respiratory Medicine, University of Toronto,
Toronto, ON, Canada.
The Association for Research in Vision and Ophthalmology Annual
Meeting, May 2015. The Canadian Ophthalmological Society
Annual Meeting & Exhibition, June 2015.
Supported by internal departmental funding.
In the past 3 years, K.R.C. has received compensation for consulting
with AstraZeneca, Baxter, Boehringer-Ingelheim, CSL Behring,
GlaxoSmithKline, Grifols, Kamada, Novartis, Nycomed, Roche,
and Telacris; has undertaken research funded by Amgen, Astra-
Zeneca, Baxter, Boehringer-Ingelheim, CSL Behring, Forest Labs,
GlaxoSmithKline, Grifols, Novartis, Roche, and Takeda; and has
participated in continuing medical education activities sponsored in
whole or in part by AstraZeneca, Boehringer-Ingelheim, Glaxo
SmithKline, Grifols, Merck Frosst, Novartis, Pzer, and Takeda.
He is participating in research funded by the Canadian Institutes of
Health Research operating grant entitled Canadian Cohort
Obstructive Lung Disease (CanCOLD). He holds the GSK-CIHR
Research Chair in Respiratory Health Care Delivery at the Uni-
versity Health Network, Toronto, ON, Canada. The other authors
declare no conict of interest.
Reprints: Yvonne M. Buys, FRCSC, MD, Department of Oph-
thalmology and Vision Sciences, University of Toronto, Toronto,
ON, Canada M5T 2S8 (e-mail: y.buys@utoronto.ca).
Copyright r 2016 Wolters Kluwer Health, Inc. All rights reserved.
DOI: 10.1097/IJG.0000000000000429
J Glaucoma  Volume 00, Number 00, 2016
Copyright r 2016 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
Conclusions: We found no clinically signicant increase in mean
IOP in patients with well-controlled open-angle glaucoma and
ocular hypertension after 6 weeks of twice-daily inhaled uticasone
propionate compared with inhaled placebo. No participants
exceeded their individualized target IOP. There were no dierences
in secondary outcomes.
Key Words: glaucoma, ocular hypertension, intraocular pressure,
corticosteroids/glucocorticoids, uticasone propionate
(J Glaucoma 2016;00:000000)
E levated intraocular pressure (IOP) is the major causal
risk factor for glaucoma, the leading cause of irrever-
sible blindness worldwide.1 In approximately one third of
the general population and 95% of patients with primary
open-angle glaucoma (POAG), topical corticosteroid eye
drops administered for at least 2 weeks will cause a 6 to
15 mm Hg elevation in IOP, known as a steroid
response.27
Inhaled corticosteroids (ICS) represent the founda-
tional treatment for patients with persistent asthma and are
a useful adjunct for patients with chronic obstructive
pulmonary disease (COPD). Asthma, the most common
chronic respiratory condition in Canada, aects approx-
imately 10% of the population.8 In all, 3% of Canadians
aged 35 to 79 years report a diagnosis of COPD.9 Systemic
absorption of ICS has been quantied, and at least some
ocular side eects have been established. Cumming et al,10
in an observational study, showed a dose-response rela-
tionship between ICS use and the risk of cataract for-
mation. A pharmacoepidemiologic study has suggested that
even low-dose ICS use increases the risk of cataract for-
mation in the elderly, although no such eect was seen with
nasal corticosteroids.11 Other clinically relevant ocular side
eects remain poorly dened.12,13
There are case reports of glaucoma attributed to
ICS.14,15 However, large population-based cross-sectional
studies have failed to arrive at a consensus regarding any
increased glaucoma risk secondary to ICS use.1620 In 2013,
our group published a randomized controlled trial of 19
patients with stable POAG and ocular hypertension (OHT),
which revealed no clinically signicant IOP elevation after
the use of beclomethasone nasal spray for 6 weeks.21
No prospective study has been conducted to determine
whether patients at highest risk are likely to demonstrate a
steroid response from ICS. We report the results of the rst
1 www.glaucomajournal.com |
 Moss et al
double-masked, placebo-controlled trial in which patients
with well-controlled OHT and POAG randomized to 6-
week use of twice-daily uticasone propionate 250-mg
metered-dose inhaler (MDI) versus inhaled placebo MDI
were monitored for IOP elevation.
MATERIALS AND METHODS
Study Design
This was a randomized, double-masked, placebo-
controlled trial. The study was approved by the University
Health Network Research Ethics Board and registered with
the United States National Institutes of Health (clinical-
trials.gov identier NCT02338362). The research described
herein adhered to the tenets of the Declaration of Helsinki.
Patients scheduled to attend clinics of 2 glaucoma sub-
specialists (Y.M.B. and G.E.T.) in a university-based ter-
tiary care center in Toronto, Canada (Toronto Western
Hospital) were screened for eligibility. Enrollment con-
tinued until 10 participants in each group completed all 4
study visits.
Participants
Charts of patients aged 18 to 85 years were screened
for eligibility the week before scheduled clinic appoint-
ments. Informed consent was obtained for participants who
met the following inclusion criteria: (1) bilateral mild-to-
moderate POAG, pseudoexfoliation glaucoma, pigmentary
glaucoma or OHT, dened by a vertical cup-to-disc ratio
<0.85 and a mean deviation > 12.00 dB on static auto-
mated perimetry and (2) well-controlled disease in both
eyes. Control was dened by 6 months of IOP < 21 mm Hg
and meeting individualized targets, with no documented
progression by functional (visual eld) and structural
(clinical examination of optic disc and optical coherence
tomography of the retinal nerve ber layer) criteria. The eye
with the poorer mean deviation on visual eld testing was
included in the analyses. The exclusion criteria were as
follows: the use of any steroid medication within the prior 6
weeks, incisional surgery in the study eye (including laser
refractive procedures), no light perception vision in either
eye, unwilling or unable to provide written consent for
participation, unwilling to accept randomization, or unable
to attend scheduled follow-up visits.
Randomization and Masking
After a baseline ophthalmic assessment, each partic-
ipant met with the clinical coordinator who randomized
participants according to a schedule created using a ran-
dom number generator. The coordinator was neither an
assessor of clinical data nor involved in data analysis and
interpretation of results. The allocation code was concealed
until completion of the trial.
Placebo MDIs contained built-in counters that dis-
played the number of inhaled doses left in the device and
were not identical to the treatment inhalers, which did not
contain counters. MDIs were taped to conceal identifying
script, and participants were directed to preserve allocation
concealment by preventing investigators from viewing the
MDI and avoiding discussion with study personnel
regarding MDI attributes such as appearance or inhalant
taste.
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J Glaucoma  Volume 00, Number 00, 2016
Procedures
After randomization, a Certied Respiratory Educa-
tor, accredited by the Canadian Network for Respiratory
Care, conducted a standardized MDI training program
with each participant. Participants were then provided an
MDI, based on allocation. The educator instructed partic-
ipants to take 1 pu every 12 hours from the day of
randomization until the end of the study and to track the
time of each dose in a standardized study diary.
Visits were conducted at 2, 4, and 6 weeks following
randomization, and they were scheduled within 1 hour of
the time of day of the baseline visit. The primary end point
was IOP at the 6-week visit, and the safety end point was
IOP elevation >20% from baseline at 2 consecutive visits.
A single investigator (E.B.M.) conducted assessments
using the same examination equipment at all visits for each
participant. Assessment included the following: standard
interview regarding side eects and compliance, measure-
ment of monocular best-corrected distance visual acuity,
slit-lamp assessment, and IOP measurement by masked
Goldmann applanation tonometry. Masking was achieved
using a second observer who recorded the IOP values and
scrambled the initial dial position before each reading. The
mean of 2 measurements falling within 1 mm Hg was
recorded. Adherence was determined using study diaries
and veried using the counter incorporated into the placebo
MDIs. Last observations were carried forward for eyes that
met the safety end point.
Outcomes
The primary outcome measure was IOP. Secondary
outcome measures included IOP elevation of >20% at 2
consecutive visits (safety end point), adherence, side eects,
and logMAR visual acuity. For participants meeting the
safety end point, IOP was reassessed 2 weeks after
discontinuation of the MDI. Ocular hypotensive therapy
was instituted or augmented to maintain IOP below target.
Statistical Analyses
The sample size was calculated based on the assump-
tion that the study was concerned only with an elevation in
IOP caused by steroid administration (ie, 1 sided). It was
determined that for a power of 80%, 8 patients would be
required in each arm, to detect a dierence of 3.2 mm Hg
with a SD of 2.5 mm Hg. This dierence (3.2 mm Hg)
represented a 20% increase from a baseline of 16 mm Hg, to
align with the safety end point. Data between groups were
statistically compared using the Student t test for con-
tinuous data and Fisher exact test for categorical data. The
relationship between self-reported adherence and inhaler
use logged by the built-in counters was measured using the
Pearson correlation coecient. Changes in IOP between
study visits were statistically assessed using prole analysis
with unstructured covariance to account for the correlation
of repeated IOP readings from the same individuals. A P-
value <0.05 was considered to be statistically signicant.
SAS 9.3 (SAS Institute, Cary, NC) software package was
used.
RESULTS
A total of 1960 medical records of glaucoma patients
with scheduled clinic appointments were screened for eli-
gibility between August 1, 2014 and November 7, 2014
(Fig. 1). In all, 98 eligible patients were identied, 22 con-
sented to participate and 20 completed the study with an
 J Glaucoma  Volume 00, Number 00, 2016 Inhaled Corticosteroids: Effect on Intraocular Pressure

TABLE 1. Demographic and Baseline Data of Steroid and

Placebo Groups
Mean (SD)
Baseline Information Steroid Group Placebo Group P
No. patients 10 10
Age (y) 65.7 (9.0) 65.7 (11.0) 1.00
Sex: female [n (%)] 4 (40) 4 (40) 1.00
IOP (mm Hg) 14.3 (3.0) 15.6 (3.6) 0.39
No. medications 1.3 (0.7) 1.3 (1.4) 1.00
[number per class] [8 PG, 4 b, 1 CAi] [4 PG, 5 b, 4 CAi, 1 a]
Prior laser 1 (10) 0
trabeculoplasty [n (%)]
CCT 553.1 (31.7) 549.1 (30.8) 0.78
Cup-disc ratio 0.49 (0.2) 0.38 (0.2) 0.25
Visual eld mean deviation 0.72 (2.6) 1.13 (2.5) 0.72
LogMAR VA 0.19 (0.1) 0.18 (0.1) 0.81
Diagnosis [n (%)] 0.20
OHT 1 (10) 4 (40)
POAG 6 (60) 4 (40)
PDG 3 (30) 1 (10)
PXG 1 (10)

FIGURE 1. Trial profile.
even distribution between the study arms. A total of 11
patients were randomized to each group. One participant in
each group was withdrawn after randomization and before
the rst study visit. One participant was concerned
regarding the eect of participation on an insurance policy,
and the other participant withdrew after presenting with a
spontaneous rhegmatogenous retinal detachment. One
participant was diagnosed with bronchitis 11 days before
the nal visit and was treated with steroid MDI by the
family physician. This participant continued to use the
study MDI along with the prescribed MDI, and data were
analyzed according to the original (placebo) assignment.
There were no statistically signicant dierences
between the groups at baseline (Table 1). Figure 2 details
the IOP results. Mean IOP was not statistically dierent
between the 2 groups at any time. At the 6-week visit, the
mean IOP was 14.7 2.4 mm Hg in the steroid group and
14.8 3.8 mm Hg in the placebo group (P = 0.92). One
participant in the steroid group (P = 1.00) met the secon-
dary end point of >20% elevation in IOP (IOP increased
from 9 to 11 mm Hg at weeks 2 and 4). Neither group had a
statistically signicant change in IOP from baseline to week
6. There were no changes in ocular hypotensive treatment
during follow-up, and no IOP measurements exceeded
patients individualized targets. Figure 3 compares the
frequency of IOP change from baseline and illustrates that
IOP for the majority (>70%) of visits was within the pre-
dicted SD ( 2.5 mm Hg) of baseline for both the steroid
and placebo groups.
The mean number of self-reported inhaled doses was
80.7 6.2, with 84 doses representing the median for
complete compliance. All participants reported >80%
adherence, with no statistically signicant dierence
between groups: steroid 93.6 7.1% versus placebo
96.1 4.4% (P = 0.37). Data from the built-in counters in
the placebo MDIs correlated signicantly with self-reported
data from study diaries (Pearson correlation coecient
0.908, P = 0.002). A total of 2 placebo MDIs were excluded
from this analysis: one because of additional uses for par-
ticipant training, and the second because of the extremely
high number of doses dispensed (B60 more than the
required number). There were no statistically signicant
CAi indicates carbonic anhydrase inhibitor(s); CCT, central corneal
thickness; IOP, intraocular pressure; MAR, minimal angle of resolution; OHT,
ocular hypertension; PDG, pigment dispersion glaucoma; PG, prostaglandin
analogs; POAG, primary open-angle glaucoma; PXG, pseudoexfoliation
glaucoma; VA, visual acuity; a, a-adrenergic agonist; b, b-adrenergic
antagonists.
dierences in logMAR visual acuity at baseline (0.19 0.13
and 0.18 0.09, P = 0.81) or at week 6 (0.15 0.12
and 0.15 0.08, P = 0.90) in the treatment and placebo
groups, respectively. There were no observed changes in
lens opacity compared with baseline in either group. Side-
eect proles were similar between groups: 1 patient in
each group reported throat discomfort, 1 patient in the
steroid group reported headache, and 1 patient in the pla-
cebo group reported diculty sleeping.
The SD for IOP data ranged from 2.4 in the steroid
group to 3.8 in the placebo group at week 6. With an a-
error of 5%, power calculation, using s = 3.8 mm Hg,
resulted in 59% power to detect the dierence of 3.2 mm
Hg. This 3.2 mm Hg dierence was selected a priori to align
with the secondary end point of Z20% IOP increase from
baseline. Post hoc analysis indicates that the study was
powered at 86% to detect a dierence of Z6 mm Hg if Z6
(60%) participants in the treatment arm exhibited a steroid
response.
FIGURE 2. Mean intraocular pressure (IOP). There were no
statistically significant IOP differences between the groups at any
time and no IOP changes at week 6 compared with baseline.

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 Moss et al
FIGURE 3. Frequency of mean IOP change from baseline in (A)
steroid and (B) placebo groups. IOP remained within 1 predicted
SD ( 2.5 mm Hg) of baseline for the majority of study visits in
both groups. IOP indicates intraocular pressure.
DISCUSSION
Given the high prevalence of airway disease (up to 10%
of Canadians)8 and glaucoma (3.54% in adults aged 40 to
80 y),1 these diseases often coexist, making it important to
understand the potential complications of treatment for one
disease on the other. For example, topical b-blockers are
commonly used in the treatment of glaucoma, but they
should be avoided in patients with bronchospastic disease.22
The use of ICS for airway disease has become the standard
of care because of a substantially improved therapeutic
index, compared with oral corticosteroids.8,23 Directly
administered steroids are well known to increase IOP. Fewer
than 4 weeks duration of topical ocular corticosteroid drops
administered to patients with POAG or OHT will cause an
IOP rise Z6 to 10 mm Hg, known as a steroid response, in
up to 95% of treated eyes.2,47 Despite this knowledge, to
date there are no prospective randomized controlled studies
to evaluate the eect of ICS on IOP in patients at high risk of
a steroid response, and the degree to which ICS may aect
IOP remains controversial.
A total of 4 case reports14,15 suggest a link between ICS
use and IOP elevation with incident glaucomatous nerve
damage. A prospective study of 183 pulmonary disease
patients without glaucoma showed no IOP rise >4 mm Hg
after 12 weeks of ICS use.24 Several retrospective and cross-
sectional studies have failed to reach consensus regarding the
glaucoma risk of ICS. In a large case-control study using a
comprehensive provincial health insurance database, Garbe
et al16 reported an increased risk of glaucoma (odds
ratio = 1.44; 95% condence interval, 1.01-2.06) in those
prescribed higher ICS doses for Z3 months. Interviews of
3654 participants in the Blue Mountains Eye Study revealed
an association (odds ratio = 2.6; 95% condence interval,
1.2-5.8) between ICS use and the presence of glaucoma or
OHT among those with a family history of glaucoma.17
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J Glaucoma  Volume 00, Number 00, 2016
In contrast, an analysis of pooled data from 4 pro-
spective randomized, controlled trials evaluating 12 to 20
weeks of inhaled budesonide in 1255 asthmatic patients
found no treatment eect on IOP, including a subset
analysis of those at the highest dose, 800 mg bid.18 Notably,
30% of these patients were aged younger than 18 years.
Gonzalez et al19 extracted data from a health care database
to examine a large cohort of elderly patients, over 65 years
of age, who were treated for airway disease. The group
reported no increased risk from high-dose ICS in 2291 cases
of newly treated glaucoma compared with 13,445 controls.
Corticosteroid use was recorded in the Rotterdam Study,20
a population-based cohort study examining patients aged
55 years or older for 4 to 15 years. Among 108 cases of
incident open-angle glaucoma (OAG), there was no asso-
ciated risk from the use of inhaled steroid or any other class
of steroid. We previously reported no evidence of IOP
elevation after 6 weeks of beclomethasone nasal spray in 19
patients with stable OHT and POAG.19
We present the rst prospective, randomized, placebo-
controlled trial evaluating IOP following ICS in patients
with well-controlled OAG and OHT. We report no clin-
ically signicant IOP eect after 6 weeks of inhaled uti-
casone. An IOP elevation >20% from baseline (9 mm Hg)
to weeks 2 and 4 (11 mm Hg) did occur in 1 participant in
the treatment group. The baseline IOP was atypically low
(>6 mm Hg lower than prior clinic IOP measurements),
consistent with an erroneous pressure measurement in this
case. The IOP change was not clinically signicant, sug-
gesting factors other than a steroid response.
One limitation of this study was the IOP distribution
in this small sample. With a greater-than-expected SD, the
analysis was, in retrospect, underpowered to detect a dif-
ference of r3.2 mm Hg between groups. Notably, the
documented steroid response to topically administered
corticosteroid in patients with POAG and OHT is 6 to
15 mm Hg,2,47 and IOP increases ranged from 7 to 21 mm
Hg in case reports linking incident glaucoma to ICS
use.14,15 A post hoc power calculation showed that this
study was well powered to detect a moderate steroid
response of 6 mm Hg in a low fraction (60%) of the treat-
ment group. It remains possible, however, that rare indi-
viduals may be sensitive enough to respond to ICS; our
sample could have missed such statistical outliers.
The short treatment duration reported here is a limi-
tation to the generalizability of these results, as manage-
ment of airway disease often requires long-term therapy.8
One case-control study examining the risk of glaucoma
diagnosis with ICS use did nd long duration (Z3 mo) of
ICS as a risk factor16; however, this result was not repli-
cated by 2 other groups who examined the same relation-
ship to duration of therapy.18,19 We believe that a 6-week
exposure was adequate to reveal a dierence between study
arms. The response to topical steroid requires <4 weeks in
the majority of POAG patients. Moreover, systemic levels
of uticasone propionate are not expected to increase over
time. On the basis of a half-life of 5 to 7 hours in normal
individuals,23,25 inhaled uticasone propionate should
reach steady-state concentration in plasma 3 to 4 days after
initiation of therapy.
Fluticasone propionate is the most systemically potent
and most commonly prescribed individual ICS treatment in
Canada.19,26 The studied dose (250 mg twice daily) was below
the maximum recommended dose for adults with very severe
asthma (1000 mg twice daily),27 and it was selected as
 J Glaucoma  Volume 00, Number 00, 2016
representative of a typical dose for moderate disease. A
rationale for the lower dosage in our study of glaucoma
patients without lung disease is that volunteers with healthy
airways who received inhaled uticasone achieve sig-
nicantly greater plasma concentration and suppression of
plasma cortisol, compared with patients with asthma23 or
COPD.25 The dierence is attributed to airow obstruction
and ventilation-perfusion mismatch in the diseased state.
A major strength of this study is independence from
industry support or oversight. In addition, despite the small
sample size, groups were balanced for important variables
that may have aected the outcome measures. The study
design provided a unique opportunity to minimize sources
of bias and to maximize the sensitivity to detect a steroid
response to ICS in well-controlled OAG and OHT.
In conclusion, our primary nding was that patients
with glaucoma taking 500 mg of inhaled uticasone propi-
onate daily for 6 weeks showed no clinically signicant
steroid-induced IOP response. This may be reassuring, but
in acknowledgment of study limitations and the potential
for irreversible vision loss from an undetected steroid
response, we hope that this report serves as a reminder to
physicians who prescribe corticosteroids of the relationship
between steroids and glaucoma, which may be under-
appreciated among nonophthalmologists.28 We suggest
that patients with a history of glaucoma be instructed to
seek visual care for measurement of IOP at least 6 weeks
after initiation of ICS therapy. Furthermore, ophthalmol-
ogists managing glaucoma patients with airway disease
should not only remain vigilant for a steroid response but
should also consider the available evidence before recom-
mending against ICS therapy, a mainstay and potentially
life-saving treatment for common respiratory conditions.
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