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Safety of budesonide irrigations
suppression can be relatively sinister. As the dose and the
duration of corticosteroid therapy increases, the risk of sup-
pression increases. Therefore, as long as the patients con-
tinue to receive the corticosteroids, they may not experience
any symptoms. When they do, symptoms tend to be non-
specific such as malaise, weakness, and decreased appetite.
HPA axis suppression tends to manifest either when pa-
tients are placed in an acutely physiologically stressful sit-
uation, such as surgery or a significant illness, or when the
corticosteroid is abruptly stopped. In these instances, the
downregulated HPA axis is unable to mount an appropri-
ate response, which clinically results in an adrenal crisis, a
life-threatening condition. As such, identifying patient who
have HPA axis suppression is essential in order to appro-
priate prevent and manage potential complications.
24–26
Budesonide is a potent topical corticosteroid that is ap-
proximately 1000 times more potent than cortisol, which
has a reported systemic bioavailability of approximately
35%. It binds to the glucocorticoid receptor and stimulates
its anti-inflammatory properties though a variety of mech-
anisms including: altering the release of arachidonic acid
metabolites, inhibiting the accumulation of leukocytes in
affected tissue, decreasing vascular permeability, inhibiting
neuropeptide-mediated responses, and altering the secre-
tion of glycoproteins from submucosal glands.
5
Budesonide
respules added to high-volume saline irrigations provide a
total daily dose between 0.25 mg and 2 mg.
5
These rela-
tively higher dosages have raised concerns regarding the po-
tential for increased systemic exposure and complications
from high-volume sinonasal budesonide irrigations.
4,5,27
To date, there have been 3 studies that evalu-
ated the safety of high-volume sinonasal budesonide
irrigations.
28–30
Bhalla et al.
28
retrospectively evaluated 18
patients with CRS with nasal polyposis who received a
total budesonide dose of 2 mg/day in high-volume irriga-
tions. Serum
AM
cortisol levels were measured after 8 weeks
of use and showed no evidence of HPA axis suppression.
28
Welch et al.
29
prospectively examined 10 patients who re-
ceived a total daily dose of 1 mg/day in high-volume irriga-
tions. At 6 weeks, serum
AM
cortisol levels and 24-hour uri-
nary cortisol showed no signs of HPA axis suppression.
29
Seiberling et al.
30
examined the effects of high-volume
sinonasal budesonide irrigations (0.5 mg/day) on intraoc-
ular pressure and found no effect of intraocular pressure
after at least 4 weeks of use. The results from these studies
suggest high-volume sinonasal budesonide irrigations are
safe for short-term use (4 to 8 weeks).
This is one of the first studies to examine the long-term
effects of high-volume sinonasal budesonide irrigations on
the HPA axis. After an average of 38.2 months (2.9 years)
of daily use, patients receiving a total daily budesonide dose
of 2 mg/day showed no evidence of HPA axis suppression.
One potential explanation for the lack of systemic effects
associated with high-volume sinonasal budesonide irriga-
tions is that the actual retained dose of budesonide is rela-
tively low. Harvey et al.
8
demonstrated that less than 5%
of irrigation solution remains in the sinuses after rinsing,
suggesting patients’ actual budesonide exposure is much
lower than the prescribed dose. Regardless, the results
from this study suggest that long-term use of high-volume
sinonasal budesonide irrigations may not be associated with
HPA axis suppression and may be considered safe up to
2.9 years of daily use.
When interpreting the results from this study, the fol-
lowing limitations should be considered. First, the sample
size of our cohort is relatively small which predisposes to
a type II error by incorrectly accepting the null hypothesis.
Therefore, future studies with larger sample sizes should be
performed to confirm the findings from this study. Second,
the retrospective nature of CRS characteristic data collec-
tion does not allow us to examine compliance to medica-
tions, which may result in patients receiving less than the
intended 2 mg total dose of topical budesonide. Although
there is a risk of including patients who were noncompli-
ant with their budesonide irrigations, the cohort of CRS
patients evaluated in this study had severe inflammatory
phenotypes requiring twice daily budesonide irrigations for
longer than 12 months and are followed routinely to ensure
disease control is optimized. At each follow-up, compli-
ance to topical therapy was questioned and none reported
stopping their budesonide irrigations. Third, there was no
control group for this study, which makes it challenging
to understand how prolonged high-volume budesonide ir-
rigation therapy compares to patients receiving prolonged
low-volume metered dose corticosteroid sprays. However,
inhaled budesonide has been FDA approved for the main-
tenance treatment of asthma and as a prophylactic therapy
in children 12 months to 8 years of age with safety reports
comparable to FDA approved low-volume intranasal cor-
ticosteroid sprays.
31
Fourth, the retrospective nature of the
study prevented the ability to obtain “baseline”
AM
serum
cortisol levels which could have been used as a comparison.
However, unless the patient had a rare baseline adrenal in-
sufficiency condition, it may be assumed that all patients
had normal
AM
serum cortisol levels prior to beginning
treatment. Finally, this study looks specifically at the ef-
fects of high-volume sinonasal budesonide irrigations on
the HPA axis, and did not evaluate patient-reported out-
comes or other systemic effects, such as increased intraoc-
ular pressure or osteoporosis. Despite these limitations, we
feel the results from this study provide useful outcomes to
justify further investigation into the prolonged use of topi-
cal high-volume sinonasal budesonide irrigations.
Conclusion
Due to improved sinus access and proven short-term safety,
high-volume sinonasal budesonide irrigations have become
a popular method of topical corticosteroid therapy during
management of CRS. However, the poorly defined safety
profile of budesonide irrigations beyond 8 weeks of con-
tinuous use represents a gap in our knowledge to counsel
patients. Outcomes from this study suggest that after a
mean of 38.2 months (2.9 years) of twice daily budesonide
International Forum of Allergy & Rhinology, Vol. 6, No. 3, March 2016
155