Abstract
Background
Budesonide high-volume saline irrigations (HVSIs) are routinely used to treat chronic rhinosinusitis (CRS) due to improved sinonasal delivery and efficacy compared to intranasal corticosteroid sprays. The off-label use of budesonide is assumed to be safe, with several studies suggesting the systemically absorbed dose of budesonide HVSI is low. However, the actual budesonide dose retained in the sinonasal cavity following HVSI is unknown. The objective of this study was to quantify the retained dose of budesonide after HVSI.
Methods
Adult patients diagnosed with CRS who had undergone endoscopic sinus surgery (ESS) and were prescribed budesonide HVSI were enrolled into a prospective, observational cohort study. Patients performed budesonide HVSI (0.5 mg dose) under supervision in an outpatient clinic, and irrigation effluent was collected. High-performance liquid chromatography was employed to determine the dose of budesonide retained after HVSI.
Results
Twenty-four patients met inclusion criteria. The average corrected retained dose of budesonide across the cohort was 0.171 ± 0.087 mg (37.9% of administered budesonide). Increased time from ESS significantly impacted the measured retained dose, with those 3 months post-ESS retaining 27.4% of administered budesonide (P = .0004).
Conclusion
The retained dose of budesonide in patients with CRS after HVSI was found to be significantly higher than previously estimated and decreased with time post-ESS. Given that budesonide HVSI is a cornerstone of care in CRS, defining the retained dose and the potential systemic implications is critical to understanding the safety of budesonide HVSI.
Keywords: endoscopic sinus surgery, budesonide, high volume saline irrigation, chronic rhinosinusitis, glucocorticoids, corticosteriod, post-operative, systemic absorption, CRS, high-performance liquid chromatography
Introduction
The use of corticosteroids is essential for long-term medical treatment of chronic rhinosinusitis (CRS), an inflammatory disease of the sinonasal cavity. 1 Oral corticosteroids have a significant side effect profile, necessitating the use of topical administration to prevent systemic complications. 2 While intranasal corticosteroid sprays have been shown to improve symptoms of sinonasal inflammation,2,3 outcomes are variable, often attributed to the limited delivery of medication to the sinonasal cavity. 4 As such, the off-label use of budesonide in high-volume saline irrigations (HVSI) is commonly employed to improve delivery to the sinonasal cavity to treat diffuse CRS-associated inflammation.1,5 Budesonide HVSI is recommended for the post-operative treatment of CRS, as this delivery mechanism has been demonstrated to improve budesonide distribution in the sinonasal cavity with significant clinical efficacy.1,5 While the efficacy of this treatment is widely acknowledged, our understanding of budesonide HVSI safety is incomplete.
Previous studies examining the safety of budesonide HVSI have been largely limited by small sample size, short follow-up duration, and systemic absorption evaluation using a single metric.6–10 Additionally, the estimated delivered doses of corticosteroid in these investigations were extrapolated from fluid residuals following HVSI and did not consider the pharmacokinetics (PK), pharmacodynamics (PD), and physicochemical properties of budesonide HVSI. Budesonide absorption may also be affected by the state of the nasal mucosa, as recent studies have proposed that inflammatory processes lead to increased sinonasal tissue permeability to facilitate increased drug absorption.11–13 Despite these limitations, budesonide HVSI is generally regarded as safe for long-term use, with an assumed minimal risk of significant systemic absorption and has been expanded to treat other inflammatory diseases of the sinonasal cavity.1,14
The present investigation sought to quantify the retained dose of budesonide HVSI in post-operative patients with CRS, determine whether patient demographics and/or comorbidities impacted the retained dose, and investigate whether the retained dose of budesonide HVSI changed over time post-endoscopic sinus surgery (ESS).
Materials and Methods
Sample Collection and Patients
A prospective, observational cohort study was conducted. Patient eligibility included a guideline-based diagnosis of CRS, 15 a history of ESS, and an active prescription for budesonide HVSI. Patient demographics were collected at enrollment, including polyp status, asthma, aspirin sensitivity (ASA), sinonasal tissue eosinophilia (≥10 eosinophils per high-powered field), 16 and time of HVSI since ESS. All included patients had undergone ESS, with or without concurrent septoplasty, resulting in patient maxillary, ethmoid, sphenoid, and frontal sinuses given their underlying diagnosis of CRS, as per the standard surgical practices at our institution. Patients who underwent open septorhinoplasty or limited ESS were excluded. Sinus computed tomography scans (preoperative) and enrollment endoscopy scores were collected and graded using the Lund-Mackay CT 17 and Lund-Kennedy 18 scoring systems, respectively. Exclusion criteria included cystic fibrosis, granulomatosis with polyangiitis, myelodysplastic syndrome, or autoimmune disease.
Budesonide HVSI Collection
Patients irrigated under supervision using a commercially available nasal irrigation bottle (NielMed® Sinus Rinse; Santa Rosa, California) containing budesonide (0.5 mg/2 mL; Nephron Pharmaceutical Corporation; West Columbia, South Carolina) in 240 mL of normal saline (Baxter International Inc.; Deerfield, Illinois). Approximately 120 mL of the fluid was irrigated per nostril, with head tilted forward at approximately 90°, while leaning over a glass funnel and container to collect the total irrigation effluent from each nostril. The samples were stored at −80 °C until further analysis.
Sample Preparation for Budesonide Dose Quantification in HVSI Effluent
Five-milliliter aliquots (n = 1 to n = 3 per patient) were separated from the total collected effluent. The sample aliquots were lyophilized and subjected to budesonide extraction in acetonitrile, followed by being vortexed (30 s), sonicated (10 min), and centrifuged (10 min, 11 420 g). The supernatants containing budesonide were then separated; three extraction cycles were conducted for each aliquot. Acetonitrile in the supernatant was evaporated using a vacuum desiccator. Dried samples were dissolved in a mixture containing acetonitrile and phosphate buffer (32:68 v/v%, pH 3.2) and quantified using high-performance liquid chromatography (HPLC).
High-performance liquid chromatography Analysis
The concentration of budesonide was quantified using an HPLC (Agilent, Santa Clara, California) equipped with an auto-injector, ultraviolet (U.V.) detector, and C18 column (4.6 × 150 mm, 3.5 µm). The following analytical separation conditions were established: mobile phase of acetonitrile and phosphate buffer (32:68 v/v%, pH 3.2), a flow rate of 1.0 mL/min, injection volume of 50 µL, and detection UV wavelength of 254 nm. Using this method, budesonide epimers 19 at concentrations ranging from 1 to 32 μg/mL were analyzed (Figure 1a). 20 The peak area under each standard concentration of budesonide was calculated as the sum of the peak area for both epimers and plotted against known concentrations of budesonide to generate a linear standard calibration curve (Figure 1b), from which the concentrations of budesonide collected in irrigation effluent were determined.
Figure 1.
Budesonide quantification using high-performance liquid chromatography (HPLC). (a) Superimposed HPLC chromatograms for each budesonide epimer standard at different concentrations to generate a (b) standard calibration (n = 3) curve for the determination of budesonide concentration in irrigation effluent after high-volume saline irrigation.
The HPLC analysis method was validated by spiking the mobile phase with known concentrations of budesonide; the percentage of spiked budesonide recovered was 100.35 ± 0.55%. Budesonide extraction from saline was also validated by spiking normal saline with a known concentration of budesonide; the percentage of spiked budesonide recovered after extraction was 97.4 ± 3.61%. The concentration of budesonide in the irrigation bottle prior to HVSI and in the fluid residual remaining in the bottle after HVSI were validated and compared. The concentration of budesonide measured in the fluid residual remaining in the bottle after HVSI was 94.4 ± 0.047% of the initial budesonide concentration, confirming that the developed HPLC method can accurately measure budesonide in HVSI.
Correction Calculation
A correction calculation was performed to account for the potential fluid residual remaining in the irrigation bottle after budesonide HVSI. A recent investigation estimated that 8.3 ± 2.3% of the total 240-mL volume prepared remains in the bottle and is not delivered to the patient during HVSI. 21 Due to this potential fluid residual and to avoid overestimating the delivered dose of budesonide, a 10% dose reduction was applied to all final dose calculations.
Statistical Analysis
Categorical variables, including patient demographics, were analyzed using descriptive statistics. Continuous variables are reported as the mean and standard deviation for each cohort. Spearman correlations were used to determine whether patient characteristics collected at enrollment were associated with retained budesonide dose. Sub-analysis cohort demographics were compared using nonparametric tests (Wilcoxon Rank Sum) to determine the significance between groups. Analyses were performed in Stata (Version 14.1), and a value of P < .05 was used to determine significance.
Results
Patient Demographics
A total of 24 patients were enrolled and met the inclusion criteria in this study. Patient demographics are provided in Table 1. The mean post-operative month at the time of collection was 15.8 ± 18.4 months (range: 0.20-62.3 months; median: 11.2 months) and the mean irrigation effluent volume collected was 211.4 ± 18.6 mL. All patients underwent bilateral full ESS resulting in patent maxillary, frontal, ethmoid, and sphenoid sinuses, as per the standard surgical practice for patients with CRS at this institution. Approximately two-thirds of the patients (66.7%) represented revision surgeries, and 66.7% also underwent a concurrent septoplasty.
Table 1.
Cohort Demographics.
| CRS (n = 24) | |
|---|---|
| Age (years), mean (SD) | 48 (17.1) |
| Sex, n (%) | |
| Male | 15 (62.5) |
| Female | 9 (37.5) |
| Race, n (%) | |
| White | 23 (95.8) |
| Other | 1 (4.2) |
| Ethnicity, n (%) | |
| Not Hispanic | 22 (91.7) |
| Hispanic | 1 (4.15) |
| Not disclosed | 1 (4.15) |
| Asthma, n (%) | 13 (54.2) |
| ASA sensitivity, n (%) | 4 (16.7) |
| Nasal polyps, n (%) | 10 (41.7) |
| N-ERD, n (%) | 4 (16.7) |
| eCRS, n (%) (n = 19) | 15 (78.9) |
| aAllergy, n (%) | 14 (58.3) |
| Lund-Mackay CT score, mean (SD) (n = 20) | 11.5 (5.1) |
| Lund-Kennedy endoscopy score, mean (SD) (n = 20) | 4.7 (3.6) |
| Months post-ESS | |
| Mean (S.D.) | 15.8 (18.4) |
| Range | 0.20-62.3 |
| Median | 11.2 |
| Irrigation effluent volume (mL), mean (SD) | 211.4 (18.6) |
| Corrected retained irrigation volume (%), mean (SD) | 1.9 (7.8) |
Patient-reported allergy.
Abbreviations: CRS, chronic rhinosinusitis; SD, standard deviation; ASA, aspirin; N-ERD, nonsteroidal anti-inflammatory exacerbated respiratory disease; eCRS, eosinophilic chronic rhinosinusitis; CT, computed tomography; ESS, endoscopic sinus surgery; mL, milliliter.
Quantification of Retained Budesonide Dose After HVSI
The average corrected retained dose of budesonide was 0.17 ± 0.086 mg (Table 2). The mean percentage of retained budesonide was 37.9 ± 19.2% of the delivered dose. The retained doses calculated with respect to month post-ESS are presented in Figure 2.
Table 2.
Calculated Dose of Retained Budesonide in Patients with CRS After HVSI.
| CRS (n = 24) | |
|---|---|
| HPLC-measured budesonidea (mg), mean (SD) | 0.279 (0.087) |
| Calculated retained budesonide (mg), mean (SD) | 0.221 (0.087) |
| Corrected retained budesonide (mg), mean (SD)b | 0.171 (0.087) |
| Calculated retained budesonide (% initial 0.5 mg dose) mean (SD) | 41.8 (18.0) |
| Corrected retained budesonide (% initial 0.5 mg dose) mean (SD)b | 37.9 (19.2) |
Budesonide measured in irrigation effluent; bcorrected for 10% residual volume and dose in irrigation bottle.
Abbreviations: HVSI, high-volume saline irrigations; CRS, chronic rhinosinusitis; HPLC, high-performance liquid chromatography; SD, standard deviation; mg, milligram.
Figure 2.
The relationship between retained dose after high-volume saline irrigation with budesonide (corrected initial dose of 0.45 mg) and post-operative time (months) decreases logarithmically (R2 = 0.55). Based on the dose data distribution, patients were further delineated as early (<3 months post-operative; white) and late (>3 months post-operative; gray).
Correlation with Demographic Data
Spearman correlation tests were performed to determine the associations between patient characteristics and retained budesonide dose (Table 3). No significant correlations between patient demographics and budesonide retention were calculated. A significant, negative correlation between months post-ESS and budesonide retention was determined (rs = −0.692, P = .0002).
Table 3.
Spearman Rank Correlations Between Retained Budesonide Dose (mg) and Patient Demographics.
| CRS (n = 24) | rs |
|---|---|
| Age | −0.248 |
| Sex | 0.198 |
| Race | −0.226 |
| Ethnicity | 0.073 |
| Asthma | 0.018 |
| ASA sensitivity | 0.178 |
| Nasal polyps | 0.134 |
| N-ERD | 0.178 |
| eCRS | 0.024 |
| aAllergy | 0.122 |
| Lund-Mackay CT score | 0.273 |
| Lund-Kennedy endoscopy score | 0.383 |
| Months post-ESS | −0.692** |
Patient-reported allergy;
**P = .0002.
Abbreviations: mg, milligram; CRS, chronic rhinosinusitis; ASA, aspirin; N-ERD, nonsteroidal anti-inflammatory exacerbated respiratory disease; eCRS, eosinophilic chronic rhinosinusitis; CT, computed tomography; ESS, endoscopic sinus surgery.
Subgroup Analysis: Effect of Time from ESS on Budesonide Retention
As a significant correlation between time from ESS and retained budesonide dose was identified, a subgroup analysis was performed. Examining the distribution of the data in Figure 2, two cohorts were defined: an early cohort (0-3 months post-ESS) and a late cohort (>3 months post-ESS). Demographic data for the subgroups are presented in Table 4. There were no significant differences in the demographic characteristics between cohorts.
Table 4.
Cohort Demographics Sub-analysis.
| Early | Late | P-value | |
|---|---|---|---|
| CRS (n = 10) | CRS (n = 14) | — | |
| Months post-ESS (N) | <3 | >3 | — |
| Age (years), mean (SD) | 46.3 (6.5) | 49.9 (17.9) | .48 |
| Sex, n (%) | |||
| Male | 6 (60%) | 9 (64%) | .83 |
| Female | 4 (40%) | 5 (36%) | |
| Race, n (%) | |||
| White | 10 (100%) | 13 (93%) | .40 |
| Other | 1 (7%) | ||
| Ethnicity, n (%) | |||
| Not Hispanic | 9 (90%) | 13 (93%) | .85 |
| Hispanic | 1 (10%) | 0 (0%) | |
| Not disclosed | 0 (0%) | 1 (7%) | |
| Asthma, n (%) | 5 (50%) | 8 (57%) | .73 |
| ASA sensitivity, n (%) | 3 (30%) | 1 (7%) | .15 |
| Nasal polyps, n (%) | 5 (50%) | 5 (36%) | .49 |
| N-ERD, n (%) | 3 (30%) | 1 (7%) | .15 |
| eCRS, n (%) | 8 (80%) | 7 (78%) | .91 |
| aAllergy, n (%) | 6 (60%) | 8 (57%) | .89 |
| Lund-Mackay CT score, mean (SD) | 12.1 (4.1) | 11.0 (5.8) | .64 |
| Lund-Kennedy endoscopy score, mean (SD) | 5.5 (3.5) | 4.3 (3.7) | .41 |
Patient-reported allergy.
Abbreviations: CRS, chronic rhinosinusitis; ESS, endoscopic sinus surgery; SD, standard deviation; ASA, aspirin; N-ERD, nonsteroidal anti-inflammatory exacerbated respiratory disease; eCRS, eosinophilic chronic rhinosinusitis; CT, computed tomography.
For the early cohort (n = 10), the mean post-operative HVSI collection time was 1.10 ± 0.91 months (range: 0.20-2.96 months; median: 0.85 months). The late cohort (n = 14) had a mean post-operative HVSI collection time of 26.3 ± 17.7 months (range: 6.87-62.3 months; median: 20.7 months). The retained budesonide dose calculated for early and late cohorts was 0.24 ± 0.07 mg and 0.12 ± 0.06 mg, respectively (Table 5). The mean percentage of budesonide retained in early and late cohorts were 52.7 ± 16.1%, and 27.4 ± 13.7%, respectively (Table 5). There was a significant difference in retained dose between early and late cohorts (P = .0004) (Figure 3), with the retained dose in the early cohort being nearly double the retained dose in the late cohort.
Table 5.
Calculated Retained Dose of Budesonide in Patients with CRS Following HVSI sub-Analysis.
| Early (<3 Months) | Late (>3 Months) | P-value | |
|---|---|---|---|
| HPLC-measured budesonidea (mg), Mean (SD) | 0.21 (0.07) | 0.33 (0.06) | .0004 |
| Calculated retained budesonide (mg), Mean (SD) | 0.29 (0.07) | 0.17 (0.06) | .0004 |
| Corrected retained budesonide (mg), Mean (SD)b | 0.24 (0.07) | 0.12 (0.06) | .0004 |
| Calculated retained budesonide (% initial 0.5 mg dose, mean (SD) | 57.4 (14.5) | 34.67 (12.4) | .0004 |
| Corrected retained budesonide (% Initial 0.45 mg dose) mean (SD)b | 52.7 (16.1) | 27.4 (13.7) | .0004 |
Budesonide measured in irrigation effluent;
bcorrected for 10% residual volume and dose remaining in the irrigation bottle after HVSI.
Abbreviations: HVSI, high-volume saline irrigations; HPLC, high-performance liquid chromatography; SD, standard deviation; mg: milligram; CRS, chronic rhinosinusitis.
Figure 3.
The retained dose of budesonide in post-operative patients with CRS (n = 24) after high-volume saline irrigation ranges from 27.4 to 52.7% of the administered corrected dose of 0.45 mg total dose and decreases with increasing post-operative time. There is a significant difference in the amount of retained budesonide between the early (<3 months post-operative; n = 10) and late cohorts (>3 months post-operative; n = 14) (P = .004). CRS, chronic rhinosinusitis.
Discussion
The objective of this work was to quantify the retained budesonide dose following HVSI and determine the factors that impacted the delivered dose for the 24 participants enrolled in this study. The mean retained dose after budesonide HVSI was 0.17 ± 0.09 mg, corresponding to 37.9 ± 19.2% of the administrated dose. While patient characteristics were not associated with retained dose, the retained dose was significantly associated with time post-ESS. Patients in the early post-operative collection period (<3 months) had significantly higher retained dosages of budesonide compared to patients in the late post-operative collection period (>3 months) (P = .0004). These retained budesonide dosages were significantly higher than the previously estimated dose, raising concerns about the potential systemic effects of long-term cumulative doses.22,23
The off-label use of budesonide HVSI has been shown to improve the quality of life and endoscopy scores in patients with CRS following ESS and is widely accepted as an effective treatment for post-operative CRS,1,4,24,25 due to the increased distribution in the sinonasal cavity compared to intranasal sprays.26–28 However, our understanding of budesonide HVSI safety is incomplete. Multiple studies have examined the safety of short-term budesonide HVSI use, reporting no evidence of hypothalamic-pituitary-adrenal axis (HPAA) suppression nor raised intraocular pressure.6,7,29 While these studies are limited by sample size, follow-up duration, and single systemic endpoint metrics for safety evaluation, the assumption that long-term use of budesonide HVSI is safe has been based on these works.
Reports examining the effects of long-term budesonide HVSI have generally been reassuring but have raised concerns about the potential for systemic effects. A study examining long-term budesonide HVSI use noted that 54% of patients had low serum AM cortisol levels. 9 These patients were subsequently found to have normal cosyntropin stimulation testing results, suggesting normal HPAA function. A similar investigation found that 23% of patients using budesonide HVSI had evidence of subclinical HPAA suppression, identifying that patients with concurrent inhaled corticosteroid use had an increased risk of subclinical HPAA suppression, which was suggestive of physiologically significant effects of cumulative corticosteroid dose. 10 A recent large retrospective study identified an increased risk of hypocortisolemia associated with budesonide HVSI in 11% of patients, which increased to 23% with concurrent inhaled corticosteroid use. 30
The previously extrapolated retained dose of budesonide after HVSI was reported to range from 5 to 8% of the administered dose. This estimates a retained sinonasal dose ranging from 0.025 to 0.040 mg of an initial 0.5 mg administered dose of budesonide. 24 Our findings calculated a mean retained dose ranging from 0.12 to 0.24 mg depending on the time collected post-ESS. 22 Given that the retained dose of budesonide after HVSI is significantly higher than previously estimated by approximately fivefold, the systemically absorbed dose is also likely to be higher than previously estimated, supporting the evidence of subclinical HPAA suppression with long-term use of budesonide HVSI.9,10,30
Previous estimations of budesonide dosing after HVSI have relied on the volume of saline retained in sinuses and have not considered the PK and PD properties of budesonide. Budesonide is significantly bioavailable, with up to 30% of inhaled budesonide absorbed into the systemic circulation.31,32 It is still preferred for HSVI due to the ease in which budesonide can be obtained in different formulations, such as powder or concentrated liquid, as well as its lower lipophilicity of 2.3 LogP (fluticasone propionate: 3.9; mometasone furoate: 4.7), making it easier to dissolve in aqueous solutions. 33 The results of this study raise concerns about higher retained doses compared to previous estimates, supporting the need for formal clinical PK investigations and PKPD modeling studies to determine the actual sinonasal delivered dose and systemic absorption associated with budesonide HVSI.34–36 These data further support the consideration of using corticosteroids with lower bioavailability, such as mometasone furoate, to treat CRS.
The retained dosage of budesonide after HVSI was also found to vary significantly with respect to post-ESS time. Patients in the early post-operative period had significantly higher retained dosages than patients in the late post-operative period, demonstrating a trend of significantly decreased retained dose with respect to increased time from ESS. Vascular permeability, barrier dysfunction, and available sinus surface area for drug absorption play a vital role in drug deposition in the sinonasal cavity.37,38 The decreased retained dose of budesonide observed with increased time following ESS may be due to decreased neovascularization and decreased inflammation with increased mucosal healing over time. 39 Future studies are needed to elucidate the relationships between budesonide absorption, sinonasal and systemic bioavailability, post-operative time of use, and efficacy to accurately determine its safety. Defining the appropriate dosing of budesonide in various states of sinonasal inflammation and healing is critical.
This study is limited by its small sample size, highly variable post-operative time for sample collection, and non-uniform sample collection and analysis. Additionally, as patients underwent full ESS, the impact of extent of surgery on budesonide retention cannot be assessed in this study. Future longitudinal studies with larger cohort sizes are needed to understand the relationship of budesonide absorption after HVSI to verify these findings. Another limitation is the potential for fluid and dose residuals remaining in the irrigation bottle after HVSI that could lead to an overestimation of the delivered and patient-retained dose. To account for this, a 10% reduction in final dose was applied to all samples, resulting in a retained volume of 1.9 ± 7.8%, which is consistent with previous work from Harvey et al, demonstrating that the volume of irrigation retained in the sinonasal cavity is 2.5% ± 1.6%. 22 The HPLC method developed in this study cannot be used to differentiate between the dose of locally absorbed versus systemically absorbed budesonide. Future investigations to measure the PK of budesonide after HVSI are required to quantify the systemically absorbed dose and determine the long-term safety of budesonide HVSI are needed. Future studies should also consider the prospective measurement of systemic markers of corticosteroid safety to fully understand the impact of short- and long-term budesonide HVSI use in CRS management.
Conclusion
This study found that the mean retained budesonide dose after HVSI was 0.171 ± 0.087 mg, reflecting a 37.9% mean percentage of budesonide retained. This decreases with increased time following ESS. These values are significantly higher than previously estimated and warrant consideration with respect to the potential impact of systemic budesonide absorption. Additional research is needed to better understand the dose of corticosteroids delivered in HVSI.
Footnotes
The authors would like to declare the following conflict of interest with respect to the research, authorship, and/or publication of this article: P.S: None; B.Y.: None; A.P.: GlycoMira Therapeutics, Inc.; A.S.G: None; C.P: None; V.Y.: JSK Therapeutics, Consultant; H.G.: Theratarget; J.A.A: GSK, GlycoMira, Medtronic, OptiNose; K.S: SanofiGenzyme; Consultant.
Funding: The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the National Institute of Allergy and Infectious Diseases (R44AI126987) and the National Center for Advancing Translational Sciences of the National Institutes of Health under Award Numbers UM1TR004409 and 1K12TR004413. The content is solely the responsiblity of the authors and does not necessarily represent the official views of the National Institutes of Health.
Ethical Approval: Ethical approval for this study was obtained from the University of Utah Institutional Review Board-approved protocols (IRB #00129604).
Informed Consent: Patients provided written informed consent to participate in the research.
ORCID iDs: Paige A. Shipman https://orcid.org/0009-0009-1385-4519
Jeremiah A. Alt https://orcid.org/0000-0003-0560-5028
Abigail Pulsipher https://orcid.org/0000-0001-7987-3442
References
- 1.Orlandi RR, Kingdom TT, Smith TL, et al. International consensus statement on allergy and rhinology: Rhinosinusitis 2021. Int Forum Allergy Rhinol. 2021;11(3):213–739. DOI: 10.1002/alr.22741 [DOI] [PubMed] [Google Scholar]
- 2.Poetker DM. Oral corticosteroids in the management of chronic rhinosinusitis with and without nasal polyps: Risks and benefits. Am J Rhinol Allergy. 2015;29(5):339–342. DOI: 10.2500/ajra.2015.29.4223 [DOI] [PubMed] [Google Scholar]
- 3.Rudmik L, Hoy M, Schlosser RJ, et al. Topical therapies in the management of chronic rhinosinusitis: An evidence-based review with recommendations. Int Forum Allergy Rhinol. 2013;3(4):281–298. DOI: 10.1002/alr.21096 [DOI] [PubMed] [Google Scholar]
- 4.Snidvongs K, Kalish L, Sacks R, et al. Sinus surgery and delivery method influence the effectiveness of topical corticosteroids for chronic rhinosinusitis: Systematic review and meta-analysis. Am J Rhinol Allergy. 2013;27(3):221–233. DOI: 10.2500/ajra.2013.27.3880 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Harvey RJ, Snidvongs K, Kalish LH, et al. Corticosteroid nasal irrigations are more effective than simple sprays in a randomized double-blinded placebo-controlled trial for chronic rhinosinusitis after sinus surgery. Int Forum Allergy Rhinol. 2018;8(4):461–470. DOI: 10.1002/alr.22093 [DOI] [PubMed] [Google Scholar]
- 6.Welch KC, Thaler ER, Doghramji LL, et al. The effects of serum and urinary cortisol levels of topical intranasal irrigations with budesonide added to saline in patients with recurrent polyposis after endoscopic sinus surgery. Am J Rhinol Allergy. 2010;24(1):26–28. DOI: 10.2500/ajra.2010.24.3418 [DOI] [PubMed] [Google Scholar]
- 7.Bhalla RK, Payton K, Wright ED. Safety of budesonide in saline sinonasal irrigations in the management of chronic rhinosinusitis with polyposis: Lack of significant adrenal suppression. J Otolaryngol Head Neck Surg. 2008;37(6):821–825. [PubMed] [Google Scholar]
- 8.Rotenberg BW, Zhang I, Arra I, et al. Postoperative care for Samter’s triad patients undergoing endoscopic sinus surgery: A double-blinded, randomized controlled trial. Laryngoscope. 2011;121(12):2702–2705. DOI: 10.1002/lary.22396 [DOI] [PubMed] [Google Scholar]
- 9.Smith KA, French G, Mechor B, et al. Safety of long-term high-volume sinonasal budesonide irrigations for chronic rhinosinusitis. Int Forum Allergy Rhinol. 2016;6(3):228–232. DOI: 10.1002/alr.21700 [DOI] [PubMed] [Google Scholar]
- 10.Soudry E, Wang J, Vaezeafshar R, et al. Safety analysis of long-term budesonide nasal irrigations in patients with chronic rhinosinusitis post endoscopic sinus surgery. Int Forum Allergy Rhinol. 2016;6(6):568–572. DOI: 10.1002/alr.21724 [DOI] [PubMed] [Google Scholar]
- 11.Khurana N, Pulsipher A, Jedrzkiewicz J, et al. Inflammation-driven vascular dysregulation in chronic rhinosinusitis. Int Forum Allergy Rhinol. 2021;11(6):976–983. DOI: 10.1002/alr.22723 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Khurana N, Yathavan B, Jedrzkiewicz J, et al. Vascular permeability in chronic rhinosinusitis enhances accumulation and retention of nanoscale pegylated liposomes. Nanomedicine. 2021;38:102453. DOI: 10.1016/j.nano.2021.102453 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Yathavan B, Ellis A, Jedrzkiewicz J, et al. Systemic administration of budesonide in pegylated liposomes for improved efficacy in chronic rhinosinusitis. J Control Release. 2023;360:274–284. DOI: 10.1016/j.jconrel.2023.06.030 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Wise SK, Damask C, Roland LT, et al. International consensus statement on allergy and rhinology: Allergic rhinitis - 2023. Int Forum Allergy Rhinol. 2023;13(4):293–859. DOI: 10.1002/alr.23090 [DOI] [PubMed] [Google Scholar]
- 15.Rosenfeld RM, Piccirillo JF, Chandrasekhar SS, et al. Clinical practice guideline (update): Adult sinusitis. Otolaryngol Head Neck Surg. 2015;152(2_suppl):S1–S39. DOI: 10.1177/0194599815572097 [DOI] [PubMed] [Google Scholar]
- 16.Fokkens WJ, Lund VJ, Hopkins C, et al. European Position paper on rhinosinusitis and nasal polyps 2020. Rhinology. 2020;58:1–464. DOI: 10.4193/Rhin20.600 [DOI] [PubMed] [Google Scholar]
- 17.Lund VJ, Mackay IS. Staging in rhinosinusitus. Rhinology. 1993;31:183–184. [PubMed] [Google Scholar]
- 18.Lund VJ, Kennedy DW. Staging for rhinosinusitis. Otolaryngol Head Neck Surg. 1997;117(3_suppl):S35–S40. DOI: 10.1016/S0194-59989770005-6 [DOI] [PubMed] [Google Scholar]
- 19.Hou S, Hindle M, Byron PR. A stability-indicating HPLC assay method for budesonide. J Pharm Biomed Anal. 2001;24(3):371–380. DOI: 10.1016/s0731-7085(00)00424-6 [DOI] [PubMed] [Google Scholar]
- 20.USP. Budesonide. United state pharmacopedia convention, 2011. DOI: 10.31003/USPNF_M10458_04_01 [DOI]
- 21.Shipman PYB, Pulsipher A, Smith KA, et al. Quantification of budesonide retained in the sinonasal cavity after high-volume saline irrigation in post-operative chronic rhinosinusitis and healthy subjects. In: Poster session presented at: Burrell College of Osteopathic Medicine Medical Student Research Day, Las Cruces, NM, 2023. August 12 2023. [Google Scholar]
- 22.Harvey RJ, Debnath N, Srubiski A, et al. Fluid residuals and drug exposure in nasal irrigation. Otolaryngol Head Neck Surg. 2009;141(6):757–761. DOI: 10.1016/j.otohns.2009.09.006 [DOI] [PubMed] [Google Scholar]
- 23.Harvey RJ, Snidvongs K, Kalish LH, et al. Corticosteroid nasal irrigations are more effective than simple sprays in a randomized double-blinded placebo-controlled trial for chronic rhinosinusitis after sinus surgery. Int Forum Allergy Rhinol. 2018;8(4):461–470. DOI: 10.1002/alr.22093 [DOI] [PubMed] [Google Scholar]
- 24.Snidvongs K, Pratt E, Chin D, et al. Corticosteroid nasal irrigations after endoscopic sinus surgery in the management of chronic rhinosinusitis. Int Forum Allergy Rhinol. 2012;2(5):415–421. DOI: 10.1002/alr.21047 [DOI] [PubMed] [Google Scholar]
- 25.Jang DW, Lachanas VA, Segel J, et al. Budesonide nasal irrigations in the postoperative management of chronic rhinosinusitis. Int Forum Allergy Rhinol. 2013;3(9):708–711. DOI: 10.1002/alr.21189 [DOI] [PubMed] [Google Scholar]
- 26.Abadie WM, McMains KC, Weitzel EK. Irrigation penetration of nasal delivery systems: A cadaver study. Int Forum Allergy Rhinol. 2011;1(1):46–49. DOI: 10.1002/alr.20002 [DOI] [PubMed] [Google Scholar]
- 27.Harvey RJ, Goddard JC, Wise SK, et al. Effects of endoscopic sinus surgery and delivery device on cadaver sinus irrigation. Otolaryngol Head Neck Surg. 2008;139(1):137–142. DOI: 10.1016/j.otohns.2008.04.020 [DOI] [PubMed] [Google Scholar]
- 28.Miller TR, Muntz HR, Gilbert ME, et al. Comparison of topical medication delivery systems after sinus surgery. Laryngoscope. 2004;114(2):201–204. DOI: 10.1097/00005537-200402000-00004 [DOI] [PubMed] [Google Scholar]
- 29.Seiberling KA, Chang DF, Nyirady J, et al. Effect of intranasal budesonide irrigations on intraocular pressure. Int Forum Allergy Rhinol. 2013;3(9):704–707. DOI: 10.1002/alr.21180 [DOI] [PubMed] [Google Scholar]
- 30.Silva B. Incidence of hypocorticolism with long-term use of budesonide irrigations for chronic rhinosinusitis. In American Rhinologic Society @ COSM, Boston, MA, 2023. [Google Scholar]
- 31.Fowler J, Rotenberg BW, Sowerby LJ. The subtle nuances of intranasal corticosteroids. J Otolaryngol Head Neck. 2021;50:18. DOI: 10.1186/s40463-020-00480-z [DOI] [PMC free article] [PubMed] [Google Scholar]
- 32.Macias-Valle L, Psaltis AJ. A scholarly review of the safety and efficacy of intranasal corticosteroids preparations in the treatment of chronic rhinosinusitis. Ear Nose Throat J. 2021;100(5):295–301. DOI: 10.1177/0145561320967727 [DOI] [PubMed] [Google Scholar]
- 33.Daley-Yates PT. Inhaled corticosteroids: Potency, dose equivalence and therapeutic index. Br J Clin Pharmacol. 2015;80(3):372–380. DOI: 10.1111/bcp.12637 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 34.Yellepeddi VK, Battaglia M, Davies SJC, et al. Pharmacokinetics of intranasal amiloride in healthy volunteers. Clin Transl Sci. 2023. DOI: 10.1111/cts.13514 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 35.Azzeh M, Battaglia M, Davies S, et al. Novel intranasal treatment for anxiety disorders using amiloride, an acid-sensing ion channel antagonist: Pharmacokinetic modeling and simulation. Int J Clin Pharmacol Ther. 2022;60(6):253–263. DOI: 10.5414/CP204217 [DOI] [PubMed] [Google Scholar]
- 36.Yellepeddi VK, Parashar K, Dean SM, et al. Predicting resolving D1 pharmacokinetics in humans with physiologically-based pharmacokinetic modeling. Clin Transl Sci. 2021;14(2):683–691. DOI: 10.1111/cts.12930 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 37.Kumar NN, Gautam M, Lochhead JJ, et al. Relative vascular permeability and vascularity across different regions of the rat nasal mucosa: Implications for nasal physiology and drug delivery. Sci Rep. 2016;6(1):31732. DOI: 10.1038/srep31732 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 38.Protopapa C, Siamidi A, Pavlou P, et al. Excipients used for modified nasal drug delivery: a mini-review of the recent advances. Materials (Basel). 2022;15(19):6547. 10.3390/ma15196547 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 39.Yathavan B, Ellis A, Jedrzkiewicz J, et al. Systemic administration of budesonide in pegylated liposomes for improved efficacy in chronic rhinosinusitis. J Control Release 2023;360:274–284. [DOI] [PMC free article] [PubMed] [Google Scholar]