Double Blinded Randomized Controlled Trial Comparing Budesonide and Saline Nasal Rinses in the Post-operative Management of Chronic Rhinosinusitis

Abstract

Post-operative management of chronic rhinosinusitis is very crucial for outcomes following surgery, Normal saline nasal irrigation and steroid spray form the standard treatment of care in this period. However nasal irrigation may not be adequate and spray is usually started after 2 weeks of surgery which in any case does not deliver optimum dosage of drug to the paranasal sinus mucosa. Budesonide nasal irrigation in a high-volume low-pressure system could be the solution for a better outcome. A double blinded randomized control trial with 88 patients in 2 groups of 44 each received normal saline or Budesonide nasal irrigation (0.5 mg in 200 ml) twice daily. Patients were followed up at 2 weeks post-operatively and 3 months, a SNOT 22 and Lund Kennedy Endoscopic scores were assessed for subjective and objective assessment. Subset analysis of only CRS patients (55) were done, and results presented. Patient reported subjective score at 3 months post operatively, SNOT22 was significantly (p < 0.0001) improved with the use of Budesonide irrigation (26.69 ± 2.92) as compared to Normal saline (30.54 ± 2.81) and objective assessment score, LKES was significantly (p = 0.0031) better in Budesonide group (4.06 + 0.74) in comparison to Normal saline in the saline (4.50 + 0.67) respectively. The mean scores 3 months post op visit was significantly lower for both subjective SNOT (p < 0.001) and objective score LKES (p < 0.0001) in Budesonide groups. Budesonide nasal irrigation with positive pressure high volume device has better patient benefits and wound healing when compared to normal saline irrigation in the post-operative management of chronic rhinosinusitis.

Introduction

Rhinosinusitis has conventionally been classified as acute and chronic rhinosinusitis (CRS). Chronic rhinosinusitis has been defined by the EPOS group as “presence of two or more symptoms, one of which should be either nasal blockage/obstruction/congestion or nasal discharge, the others being facial pain/pressure and reduction or loss of smell for a period more than 12 weeks” [1].

The main stays in the treatment of CRS are topical corticosteroids and establishment of adequate access to the sinuses. This needs to be combined with optimum techniques of medication delivery for best results [2]. The role of endoscopic sinus surgery in the management of CRS has changed along with the paradigm shift in the understanding of CRS pathophysiology. As CRS was traditionally thought to be caused by blocked sinus ostia and poor ventilation, the role of FESS was to enlarge the natural ostia of the paranasal sinuses to improve ventilation and aid in mucociliary clearance. This theory still holds good for certain types of localized sinusitis. However, with the current understanding of CRS pathophysiology, medical therapy forms the cornerstone of long-term disease control [3]. Endoscopic sinus surgery performed as an adjunct treatment has shown to significantly improve clinical outcomes in CRS [4]. The role of endoscopic sinus surgery in diffuse CRS is to overcome the complex anatomy of the ostiomeatal unit and the ostial obstructions caused by inflammation. This would help provide access to the inflamed sinus mucosa and facilitate the delivery of intranasal corticosteroids [5, 6].

The value of topical treatment in CRS has now been well established and topical corticosteroids have been shown to improve symptom score, reduce polyp size and prevent polyp recurrence with no major safety concerns [7]. In addition to its anti-inflammatory effects, topical steroids have exhibited anti biofilm properties in an in-vitro environment [8]. However, in the past there have been limitations in the delivery mechanism. Nasal irrigation has been a well-established adjunct in the management of chronic rhinosinusitis and remains one of the most important treatment strategies post ESS [9]. Nasal irrigation post ESS has been shown to reduce nasal discharge and mucosal edema and promote wound healing within the sinus cavities [10].

Several drug delivery techniques have been compared to determine which was most effective in reaching these regions. With the conventional metered dose nasal sprays, majority of the spray has been found to be deposited in the nasal vestibule and over the inferior turbinate [11]. Nasal sprays and nasal drops into the nasal cavity were compared in a study and found that neither of them was effective in penetrating to spaces superior to the middle turbinate including the anterior and posterior middle meatus [12]. Thomas et al. studied the various methods of distribution of topical agents and recommended that high volume low pressure nasal lavages resulted in better distribution to the sinuses especially in post ESS patients [13]. Tait et al. evaluated the effect of adding budesonide to large volume low pressure saline irrigation on patients with CRS and found good improvement in quality-of-life measures as well as objective measures [14].

The evidence comparing the two modalities has been limited and of low level. A systematic review of literature done by Rudmik et al. in 2013 has concluded that topical sinonasal steroid irrigation can be an option in management of CRS but could not be provided as a recommendation due to the paucity of evidence [15]. There has been ongoing research since then. Currently the highest evidence is a recent RCT done by Harvey et al. comparing mometasone delivered by saline irrigation and simple nasal sprays and has proven irrigations to be more effective [16]. A similar RCT done by Huang et comparing budesonide and saline showed improvement in endoscopic outcomes but not in patent reported outcomes [17].The only RCT comparing steroid nasal irrigation and steroid sprays in an Indian population has been done on an allergic rhinitis patient cohort and found irrigations to be useful [18]. The objective of our study was to evaluate the efficiency of budesonide added to large volume low pressure saline nasal irrigation as an effective drug delivery system in post ESS CRS patients by conducting a parallel, double blinded randomized placebo-controlled trial measuring both subjective and objective outcomes.

Materials and Methods

A parallel, double blinded randomized controlled trial approved by the Institutional Review Board (IRB) for research ethics (IRB Min. No:9800) and registered with the Clinical Trials Registry—India (CTRI) was carried out at a tertiary hospital. 88 patients who underwent Endoscopic sinus surgery (ESS) between July 2016 and May 2017, patients above the age of 18 were consented and recruited for the study. The trial design was double blinded randomized controlled study with two arms with allocation ratio of 1:1. The initial allocation included a wider gamut of pathologies as the study also aimed to look at sinus mucosal changes in non-CRS post-operative patients as well. Amongst all patient’s subgroup of CRS patients have been looked at to study the effects of topical budesonide in CRS. Participants who were on concomitant use of oral steroids and had known hypersensitivity to corticosteroids or had undergone CSF leak closure were excluded from the study. The exclusion criteria were further expanded to comprise tumors and secondary sinusitis and only the patients with CRS undergoing endoscopic surgery above the age of 18 years were included in the final analysis.

The criteria used for diagnosis of CRS were based on the EPOS guidelines which are, presence of 2 or more symptoms for > 12 weeks, 1 of which should be: either nasal, blockage/obstruction/congestion nasal discharge (anterior/posterior nasal drip) ± facial pain/pressure ± reduction or loss of smell AND endoscopic or radiographic evidence of mucosal inflammation.

The recruited patients were randomly assigned groups from post-operative day 1 to either the corticosteroid irrigation group or the placebo irrigation group. Both groups were given steroid nasal spray as the standard of practice, all patients received post op care which included post-operative course of oral antibiotics, amoxicillin/clavulanic acid (875/125 mg) for 7 days with endoscopic cleaning and sinus care done at first week, second week and 3 months follow up. All patients performed a 200 ml nasal irrigation with either corticosteroid or placebo (normal saline free of corticosteroid) twice a day. The irrigations were delivered using Naso wash squeeze bottles (Cipla Med) which were 200 ml sterile squeeze bottles used for nasal washing. In the intervention arm, the steroid used was budesonide, as respules (1 mg/2 ml) compounded into a colorless, odorless 100 ml suspension by pharmacist. In the control arm, a similar 100 ml container containing normal saline was provided to the participants to be added to the irrigation. The CONSORT guidelines were adhered to in reporting of the study.

Flowchart of Process

Follow up Protocol and Outcome Measurements

The outcomes were assessed at 2 weeks and 3 months post-surgery. The outcome assessment was done by the principal investigator and both patient and assessor were blinded to the treatment group. The outcomes were measured subjectively by patient reported outcome measures using the SNOT 22 (Sino Nasal Outcome Test) score, which is a 22-item standard questionnaire which measures the disease specific quality of life. Each item in the SNOT 22 questionnaire is scored from 0 to 5 based on severity with a total score of 120. The scores of the two groups at each visit were measured and compared.

Objective outcome measure was done by endoscopic assessment using the Lund Kennedy Endoscopic scoring system. The post-surgery sinus cavities of all the patients were assessed and quantified for the following: mucosal edema (0 = absent, 1 = mild/moderate, 2 = polypoidal changes), polyps (0 = absent, 1 = within the middle meatus, 2 = extending to the nasal cavity), discharge (0 = absent, 1 = clear thin discharge, 2 = purulent), scarring (0 = absent, 1 = mild, 2 = severe), crusting (0 = absent, 1 = mild, 2 = severe).

Randomization and Statistical Analysis

Study used to calculate sample size was Hartwig S et al. Budesonide nasal spray as prophylactic treatment after polypectomy (a double-blind clinical trial). 1988 (66)”. The Power of study was taken as 80%. Significance level was 95%. Sample size was calculated to be an estimated 44 patients in each arm.

Simple randomization was done based on computer generated code. Statistical Analysis was done using SPSS v 21.0 software, the baseline data comparing the two groups were presented with descriptive statistical methods such as mean and standard deviation. The continuous variables were compared with Student T-test and the categorical variables were compared with chi square test.

Results

A total of 55 patients with chronic rhinosinusitis (CRS) among the patient who participated in the study were analysed, the mean age of this subgroup was 42.2 ± 12.7 years with 35 men and 20 women of a comparable demographic background. Of these 55 patients who were included in the final analysis, 30 patients had CRS with nasal polyposis (CRSwNP) and 25 patients did not have polyps (CRSsNP) (Fig. 1). Table 1 shows a comparison of baseline characteristics of both groups which were comparable. Compliance was defined as treatment for at least 5 days a week for 3 months. Medications for the first 2 weeks were administered following the surgery and for the next 10 weeks at the first post-operative visit. Compliance was confirmed by telephonic interview by the principal investigator on a weekly basis.

Fig. 1.

Clinical diagnosis

Table 1.

Baseline patient characteristics

Characteristics	Saline rinse + spray	Budesonide rinse
Age	41.9 ± 11.5	42.3 ± 13.6
Gender (M:F)	14:8	21:12
CRSwNP	12	18
CRSsNP	10	15
SNOT score at 1st visit	30.54 ± 2.81	26.69 ± 2.92

Subjective Scores

The SNOT 22 scores of all the patients who participated in the trial had improved. However, the steroid irrigation group had a significantly greater improvement compared to the saline irrigation group at 2 weeks (30.54 ± 2.81 vs 26.69 ± 2.92; p =  < 0.01) (Table 2) and 3-month conclusion (17.27 ± 5.41 vs 11.34 ± 3.94; p =  < 0.01) (Table 3).

Table 2.

Group-wise SNOT scores at 1st post op visit

SNOT1
Group	N	Mean	SD	p-value
1 (saline)	22	30.54	2.81	< 0.0001
2 (budesonide)	33	26.69	2.92

Table 3.

Group-wise SNOT scores at 2nd post op visit

SNOT2
Group	N	Mean	SD	p-value
1 (saline)	22	17.27	5.41	< 0.001
2 (budesonide)	33	11.34	3.94

Objective Scores

The objective outcome was the endoscopic assessment at 2 weeks and 3 months using the Lund Kennedy endoscopic scoring system. The steroid irrigation group showed a better control of polyps as indicated by the lower Lund Kennedy scores at 2 weeks (4.06 ± 0.74 vs 4.50 ± 0.67) (Table 4) and 3 months (1.45 ± 0.9 vs 2.68 ± 1.07 p =  < 0.01) (Table 5).

Table 4.

Group-wise Lund Kennedy scores at 1st post op visit

LK1
Group	N	Mean	SD	p-value
1 (saline)	22	4.50	0.67	0.031
2 (budesonide)	33	4.06	0.74

Table 5.

Group-wise Lund Kennedy scores at 2nd post op visit

LK2
Group	N	Mean	SD	p-value
1(saline)	22	2.68	1.07	< 0.0001
2(budesonide)	33	1.45	0.99

There was no treatment related adverse effects in the experiment group and all the patients tolerated the steroid washes well.

Discussion

Our study has shown that the use of steroid nasal washes has better post-operative outcomes as compared to steroid nasal sprays and saline washes administered separately. Both the SNOT 22 scores and Lund Kennedy Endoscopic Scores showed improved outcomes which were statistically significant. The improvement in the outcomes was noticed from the first post-operative visit at 2 weeks through to the second post-operative visit at 3 months. There was improvement in the SNOT 22 of the entire study population between the first and second post-operative visit (mean difference of 14.58), however the improvement observed in the budesonide group was greater than the saline group and was statistically significant (15.35 vs 13.27).

The Lund Kennedy Endoscopic Scores were observed to be better in the experimental group both at 2 weeks and 3 months. The 3-month LKES were 1.45 (± 0.99) in the experimental group and 2.68 (± 1.47) in the control group. A similar study done by Huang et al. showed comparable results (1.96 in the budesonide group vs 2.83 in the saline group). It was also reported in their study that there was significant improvement in the scores of polyposis, mucosal edema, secretions and scarring (except crusting) along with the total score [17]. Interestingly the same study reported no significant change in the SNOT 22 scores which was contrary to our findings.

Neubauer et al., in a systematic review, supported the use of budesonide respules over fluticasone sprays after ESS. However, there was no conclusive evidence on the mechanism of drug delivery in their study [19]. Cadaver studies have been done to ascertain the ideal delivery method and have found the high-volume squeeze bottles to be more effective than pressurized sprays [6, 20].

The results of the current study were comparable to Harvey et al. [16] in having a significant change in outcomes with the topical steroid nasal washes in both SNOT 22 scores and Lund Kennedy scores, although their study had a 12 month follow up period which means recurrence of symptoms and polyps would be better accounted for. The other difference being the study done by Harvey et al. had used the Modified Lund Kennedy scoring system which consists of only polyposis, edema and discharge in its sub scores.

The safety of steroid nasal sprays has been well established. Although we haven’t specifically looked at the side effects of budesonide irrigations in our study, the effect of high-volume budesonide nasal irrigations on the hypothalamo-pituitary-adrenal axis (HPAA) has been looked at and found to have no significant adrenal suppression both with short term and long-term use [21, 22].

There are certain limitations in our study which could have affected the overall outcome, the most significant one being segregation of patients post randomization which could have compromised the power of the study. Our short follow up period, as mentioned earlier, would be another limitation as corticosteroids have a long-lasting effect and a longer post-operative surveillance may have yielded more accurate results.

Conclusion

This is the first RCT comparing saline and steroid nasal washes in management of CRS post ESS done in the Indian subcontinent. The use of topical steroid irrigation is more benefitable than topical sprays in the management of CRS post ESS. Considering, the use of budesonide in saline nasal washes is still an off-label use in Asia, this evidence would help in standardizing it’s use.

Author Contribution

SA—study design and data collection, DS—manuscript writing and editing, RS—manuscript writing and editing, BB—statistical analysis, RT—study design, manuscript writing and editing, supervision of the project.

Declarations

Conflict of interest

The authors declare that they have no conflict of interest.