2016 Section 5 Green Book

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

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