Steroid-Eluting Ethmoidal Stent Versus Antero- -Posterior Ethmoidectomy: Comparison Of Efficacy And Safety In Allergic Patients

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1 Steroid-Eluting Ethmoidal Stent Versus Antero- -Posterior Ethmoidectomy: Comparison Of Efficacy And Safety In Allergic Patients Authors Contribution: A Study Design B Data Collection C Statistical Analysis D Data Interpretation E Manuscript Preparation F Literature Search G Funds Collection Di Rienzo Businco L 1, Mattei A 2, Laurino S 1, Angelone AM 2, Lauriello M 3, Crescenzi D 4, Di Mario A 5, Radici M 4, Di Rienzo Businco A 6 1 ENT Unit, S. Spirito Hospital, Rome, Italy 2 Department of Life, Health and Environmental Sciences, University of Aquila, Italy 3 Department of Applied Clinical and Biotechnological Sciences, University of Aquila, L Aquila, Italy. 4 ENT Department, S.Giovanni Calibita Hospital Fatebenefratelli Rome, Italy 5 ENT Department, Santo Volto Clinic, Rome, Italy 6 Paediatric Allergology Unit, S. Pertini Hospital, Rome Italy Article history: Received: Accepted: Published: ABSTRACT: KEYWORDS: Background: Allergic and chronic rhinosinusitis is a disabling pathological condition with an 8% prevalence in the European population and 5% in the Italian one. The ethmoidal sinus is the first one involved in the inflammation. The typical surgical procedure to manage ethmoidal sinusitis is an endoscopic antero-posterior ethmoidectomy. Recently introduced on the European market balloon called Relieva Stratus MicroFlow Spacer can be inserted within the ethmoid, with a local slow release of a steroid drug. This study had the aim to evaluate the efficacy and safety of the steroid-eluting ethmoidal stent in the management of allergic chronic rhinosinusitis in comparison with the traditional endoscopic ethmoidectomy. Methodos: 70 allergic patients who presented chronic rhinosinusitis were randomly divided into 2 groups and receive respectively the steroid-eluting ethmoidal stent or endoscopic ethmoidectomy. Results: The most significant observation coming from the comparative analysis of the results is the substantial equivalence of the treatment with the steroid-eluting ethmoidal stent (SEES) compared with endoscopic ethmoidectomy in the management of ethmoid chronic rhinosinusitis with the exception of a reduction of overall discomfort and nasal secretion and better functional results at rhinomanometry in the steroid-eluting ethmoidal stent group. Conclusion: in our experience, the SEES was efficacious in the treatment of allergic patients with ethmoidal CRS when conventional medical treatment had failed, or when wishing to avoid the classic endoscopic ethmoidectomy (EE). However, further long-term studies will be performed in order to confirm the safety and stability, over time, of the results obtained. chronic rhinosinusitis, ethmoiditis, steroid-eluting stent, balloon sinuplasty, allergy INTRODUCTION Allergic chronic rhinosinusitis (CRS) is a frequent and disabling pathological condition with an 8% prevalence in the European population and 5% in the Italian one. It is the cause of frequent absence from work and of impairment in the quality of life (QoL) (1,2). When medical therapy (drugs and immunotherapy with allergenes) fails to treat the patient s symptoms, a surgical treatment becomes necessary, which is typically performed by means of an endoscopic approach. Mostly, the ethmoidal sinus is the first one involved in the inflammation and may contribute to the pathological process in the adjacent para-nasal sinuses. The typical surgical procedure to manage ethmoidal sinusitis is an endoscopic antero-posterior ethmoidectomy. Over the last few years, the surgical techniques have aimed at reducing recurrences and scarring, following surgery in the ethmoidal sinus, by means of topical re-absorbable or not re-absorbable devices positioned within the sinus after the conclusion of the operation (3,4,5,6). Recently introduced on the European market balloon called Relieva Stratus MicroFlow Spacer (Acclarent, Menlo Park, California, USA) consisting of a steroid-eluting stent can be inserted within the ethmoid, with 6 DOI: /

2 a local slow release of a steroid drug for the treatment of antero-posterior ethmoiditis. This device has the characteristics of a minimally-invasive treatment of ethmoidal CRS since it has a low traumatic impact and is easy to implant compared to the traditional endoscopic ethmoidectomy (7,8,9,10,11). This study had a potential aim of evaluating the efficacy and safety of the steroid-eluting ethmoidal stent (SEES) in the management of CRS, involving the antero-posterior ethmoid sinus, in comparison with endoscopic ethmoidectomy (EE) performed by traditional cutting surgical instruments. MATERIAL AND METHODS The study was carried out between January 2010 and December 2013, and 70 consecutive allergic patients were enrolled in the ENT Unit of the S. Spirito Hospital in Rome. According to the ARIA Guidelines, patients showed at least mild-persistent allergic rhinitis. All subjects were polisensitized at Skin Prick test and/or RAST (Immunocap Thermofisher) to house dust mite and different pollens. Subjects were aged over 18 years, presented chronic rhinosinusitis (CRS) according to the European Position Paper on Rhinosinusitis and Nasal Polyps (EPOS 2007) guidelines involving the anterior and posterior ethmoid without moderate to massive polyposis (stage I, intra-meatal), resistant to medical treatment and not previously submitted to sino-nasal surgery (12). All the patients underwent computed tomography (CT), which revealed complete opacity of the anterior and posterior ethmoid on the affected side (Lund-Mackay stage for ethmoid 4) (13) variously associated with maxillary and frontal sinus disease (table III). The 70 patients (38 male, 32 female; age range years; mean age 51) presenting with ethmoid CRS were divided into 2 groups of 35 patients each and randomized to receive respectively the steroid-eluting ethmoidal stent (SEES) or endoscopic ethmoidectomy (EE). In each group twenty patients suffered from bilateral nasal polyposis of low-moderate meatal grade (stage I, intra-meatal) and 15 patients were affected by unilateral purulent ethmoiditis without polyps. Randomization of the patients, who were scheduled to undergo EE or positioning of SEES, was achieved with a sequence of random numbers by a sequence obtained from the computer. The otorhinolaryngologist, who performed the post-operative evaluation and the comparison of the clinical data, was different from the surgeon. An informed consent was obtained from all patients prior to study enrolment. When dictated by the inflammatory disease, patients received treatment to relieve the maxillary sinus obstruction by means of a mini-invasive enlargement of the natural ostium of the sinus with ultra-selective uncinectomy (21 patients, 10 in the Tab I. Lund Mackay Endoscopic scores per side at baseline (mean±sd) GROUPS ES EE P-VALUE* BASELINE BASELINE SE VS. EE N=35 N=35 Polyps 1.14± ± Discharge 1.57± ± Oedema 1.51± ± Scarring Crusting 0.31± ± * no significant difference between groups at baseline, using Mann-Whitney test: p>0.05 Tab II. Lund Mackay Endoscopic scores (mean±sd) per side at 12 months GROUPS ES EE P-VALUE 12 MONTHS 12 MONTHS GRUPPO SE VS EE TO 12 MONTHS Polyps 0.28± ± Discharge 0.94± ± Oedema 1.17± ± Scarring 0.37± ± Crusting 0.28± ± p<0.05: Significant difference between groups, using Mann-Whitney test p>0.05: No significant difference: using Mann-Whitney test. SEES Group and 11 in the EE Group), and dilatation of the frontal recess with balloon sinuplasty (16 patients, 9 in the SEES Group and 7 in the EE Group). Positioning of the SEES was performed (according to the Acclarent Stratus IFU) by means of a specific catheter and a balloon filled with 0.3 ml of triamcinolone acetonide 40 mg/ml (5,6). The SEES system is a cather-based implantable device including a microporous membrane reservoir called Microflow Spacer that permits to release slowly a steroid drug into the ethmoid sinus. The placement of the spacer is achieved using an appropriate deployment guide through the anterior wall of the ethmoid bulla, parallel to the floor of the nasal cavity, under direct endoscopy. Proper insertion of the SEES is set by the endoscopic advancement of coloured markers on the deployment guide. Through the deployment guide a spacer can be inserted into the sinus and the guide now removed in order to ensure the retention wings of the spacer behind the anterior wall of the ethmoidal bulla. The steroid agent can be injected into the spacer while a suture loop is used to remove the device after 28 days (in-office procedure). Endoscopic ethmoidectomy was carried out using cutting forceps and curette along the OTOLARYNGOL POL 2016; 70 (2):

3 entire lamina papyracea to the spheno-ethmoidal recess. The removal of potential meatal polyps was performed by means of the microdebrider. In none of the patients in both groups a postoperative nasal dressing was used. The evaluation of the patients was performed at the beginning and at the end (after one year) of our investigation by means of: nasal endoscopy according to the Lund-Mackay Endoscopic Appearance Score parameters (polyps, oedema, discharge, scarring, crusting) with a semi-quantitative score (0 = absent, 1 = mild/moderate, 2 = severe); VAS for the subjective evaluation of the patient s symptoms (facial pain or pressure, headache, nasal blockage or congestion, nasal discharge, olfactory disturbances, overall discomfort) on an 11-point numeric scale (0 = symptom not present, 10 = most severe symptom) according to Lund-MacKay Symptom Score; SNOT-22 (5 most important items); use of topical steroids (intra-nasal budesnoide); rhinomanometry; paranasal sinus CT. All the patients were allowed to use intra-nasal steroids (budesonide 100 mcg per nostril) in the post-operative period, and were requested to make note of the number of administrations; systemic use of steroids was forbidden but nasal irrigations with a saline solution were widely permitted. A written informed consent form was signed by all participants. The study was approved by the Advisory Board of the Hospital and carried out according to the Helsinki Declaration. STUDY DESIGN AND STATISTICAL ANALYSIS The study was designed as a two-group, mono-centre, prospective randomized trial to compare two different clinical interventions. Patients were assigned to one of two groups of 35 patients each (SEES vs. EE Group). The data were analyzed for normality of distribution by the Shapiro-Wilk test. As the data were not normally distributed, a non-parametric analysis with Mann-Whitney test was performed between groups to baseline values. The same test was used to compare the mean values of clinical parameters (polyps, discharge, oedema, scarring and crusting) 12 months after treatment in the two groups. A 5% significance level was adopted. A comparison of changes between baseline and 12 months for facial pain or pressure, headache, nasal blockage or congestion, nasal discharge, olfactory disturbances, overall discomfort was done using repeated measures analysis of non-parametric variance with Friedman test, with time as the within-participant factors (i.e. baseline vs. 12 months) and treatment (SEES vs. EE) to evaluate the improvement of objective and subjective nasal symptoms between the two groups. In the presence of significant differences, post-hoc analysis was performed with Wilcoxon signed rank test to compare the value at 12 months with the baseline within each group and with Mann-Whitney test between groups with Bonferroni adjustment for multiple comparisons. The data were analyzed using the software Stata 12. RESULTS None of the participants dropped out of the study or was lost to follow-up. The sample, which included more men than women (54.29% vs %) and had a mean age of 51 years, was affected by ethmoid CRS and was divided into two groups of 35 patients each. At baseline the groups were similar (p>0.05) matched for polyps, discharge, oedema, scarring and crusting as shown in Table I. The placement of the SEES was performed under endoscopic control without any intraor post-operative complications. The SEES was removed 28 days after insertion in clinic, without the need of topical anaesthesia and without any adverse effects. Ethmoidectomy was performed without any complications, either intra- or post-operative, and without bleeding requiring nasal dressing. The endoscopic evaluation, made 12 months after surgery, revealed a complete preservation of the ethmoidal labyrinth anatomy in the group of patients submitted to SEES compared to those patients who had undergone the antero-posterior ethmoidectomy and showed evident anatomical changes. Particularly, at 12 months, the EE Group had a significantly greater increase of the mean values of nasal secretion (1.14±0.35 vs. 0.94±0.23), synechiae (1.54 ±0.50 vs. 0.37±0.69) and crusts (1.46±0.50 vs. 0.28±0.46) in the surgical area as compared to the SEES Group (Table II). No recurrences of polyps were pointed out in both groups, thus clearly indicating that recurrence does not depend upon a more or less radical approach. The analysis of the symptoms recorded by means of VAS, comparing pre- and post-operative results in the two groups, revealed equivalent findings regarding the two types of treatment with the exception of overall discomfort and nasal secretion which were significantly reduced in those patients submitted to SEES as compared to the EE Group (12 month-baseline). The comparison of the results regarding the 5 most important questions related to the SNOT-22 questionnaire (facial pain or pressure, headache, nasal blockage or congestion, nasal discharge, olfactory disturbances, overall discomfort) pointed out that there was no difference at baseline between groups with mean values of 7.72±2.65 in the SEES Group and 7.92±2.43 in the EE Group, while it revealed a difference in favour of the SEES Group, after 12 months, with values of 2.69±0.24, com- 8

4 Fig. 1. Results of the 5 most important items (mean±sd) baseline/12 months: Groups ES and EE Comparison of change between baseline and 12 months in the two groups using Friedman test p<0.05 p=0.75 comparing Group EE vs ES at baseline using Manny-Whitney test p=0.002 Group EE vs ES 12 months using Manny-Whitney test p=0.04 Group EE: baseline vs 12 months using Wilcoxon sign rank test p=0.04 Group ES: baseline vs 12 months using Wilcoxon sign rank test Tab III. Overall mean results of rhinomanometry, Lund Mackay combined anterior/ posterior ethmoidal sinuses CT scores and Lund Mackay for all paranasal sinuses CT scores baseline/12 months Mean values SEES Etmoidectomy p-value* overall Baseline 12 months Baseline 12 months rhinomano metry (Pa/ cc/sec) 1.02± ± ± ±0.12 <0.05 CT L-M score for ethmoid on the affected side 4± ± ± ±0.53 >0.05 CT L-M score for all paranasal sinuses 6.11± ± ± ±0.33 >0.05 * Significant difference between baseline vs. postoperative values in both groups using Friedman test p<0.05 only rhinomanometry. No significant difference for CT scores p=0.59 comparing Group EE vs. SEES at baseline using Manny-Whitney test p=0.00 Group EE: baseline vs. 12 months using Wilcoxon sign rank test p=0.00 Group SEES: baseline vs. 12 months using Wilcoxon sign rank test p=0.00 Group EE vs. ES 12 months using Manny-Whitney test pared to the Group EE with values of 3.88±1.62; the difference between the two mean values was statistically significant with p=0.002 (Figure 1). The comparison between the mean value at 12 months and the baseline value within each group showed statistical significance with p=0.04 in the EE Group (7.92±2.43 vs. 3.88±1.62) and p=0.04 in the SEES Group (7.72±2.65 vs. 2.69±0.24). The comparison of the mean values concerning the use (puffs/ nostril) of intra-nasal budesonide showed significant differ- ences between baseline values vs. postoperative values in the EE Group (54.51±6.19 vs ±5.17; p=0.002) and in the SEES Group (55.23±6.27 vs ±5.53; p=0.04) (Figure 2). Significant statistical differences (p=0.04) were observed comparing the postoperative mean values of puff/nostril in the EE Group (37.80±5.17) and in the SEES Group (22.28±5.53). The overall mean values of post-operative rhinomanometry were 0.50±0.16 in the SEES Group and 0.83±0.12 (Pa/cc/sec) in the EE Group, with better functional results in the SEES OTOLARYNGOL POL 2016; 70 (2):

5 Fig. 1. Comparison of the mean values (mean±sd) of puffs/nostril of intra-nasal Budesonide per month baseline/12 months Groups SE and EE. Significance difference between baseline vs. postoperative values in both groups using Friedman test p<0.05 p=0.85 comparing Group EE vs ES at baseline using Manny-Whitney test p=0.002 Group EE: baseline vs 12 months using Wilcoxon sign rank test p=0.04 Group ES: baseline vs 12 months using Wilcoxon sign rank test p=0.04 Group EE vs. EE 12 months using Manny-Whitney test Group (Table III). The overall pre- and post-operative mean score of the ethmoid and all paranasal sinuses Lund-MacKay CT staging revealed no statistically significant differences between the two groups (Table III). No significant complications were observed over time in the patients submitted to surgery, with the exception of a minimal bleeding in both groups in the immediate post-operative period, which did not require either treatment or nasal dressing. DISCUSSION The most significant observation coming from the comparative analysis of the results is the substantial equivalence of the treatment with SEES compared with EE in the management of ethmoid CRS. Therefore, the use of the Relieva Stratus should be taken into consideration in all cases of ethmoidal inflammatory disorders in which ethmoidectomy with extensive removal of the ethmoid bone lamellae would appear an over-treatment. The increase of nasal synechiae (p=0.000), secretions (p=0.008), and crusts (p=0.000), following ethmoidectomy, without a significant decrease in recurrence of nasal polyps, suggests a careful consideration before destroying the ethmoid labyrinth for an inflammatory pathological condition. The recurrence of nasal ethmoidal polyposis in allergic patients does not appear to depend upon the type of operation performed, therefore preservation of the anatomy, avoiding over-treatment, would appear a more appropriate choice. The reduction of overall discomfort and nasal secretion reported by the patients submitted to SEES would appear in keeping with the reduced invasiveness of the operation and better preservation of the naso-sinusal mucosa reported with a drainage action resulting from insertion of the SEES. Less traumatized by SEES compared to ethmoidectomy, the sinus required lower doses of intra-nasal steroid; the greater pharmacological responsiveness (p=0.04) may be ascribed to a better mucosal preservation and to the absence of fibrotic and bone scars. Furthermore, the better rhinomanometry values in the SEES Group (p<0.05) may be explained by the preservation and regaining of the physiological nasal air-flow without scarring and con- 10

6 sequences of bone demolition of the superior and median naso-sinusal area, which are typical of ethmoidectomy performed by traditional instruments. The safety of both SEES and EE surgical techniques was confirmed by the absence of intra- and post-operative complications, even after a 12-month period. Removal of the SEES was carried out in the out-patient department without the need of local anaesthetics and without discomfort; nasal dressings were not necessary in any case, which was particularly appreciated by the patients as they could breathe freely through the nose in the immediate post-operative period. CRS, with or without nasal polyposis, is a challenging problem for ENT specialists with a negative influence on QoL, and mainly on account of a significant rate of relapses (14). The steroids suitable for topical use are the most efficacious and used for CRS and have a well-known preventive action in scars and hyperplasia of the mucosa in patients with rhino-sinusitis, with or without polyposis (15, 16, 17, 18). Local administration and slow release of steroid using SEES offers a chance to reduce the dose of steroid in comparison with the intranasal or systemic approach. Moreover, SEES guarantees a better stenting of the ostium performed in the ethmoid bulla, which represents an efficacious way of ventilation and drainage of the secretions. The safety profile of SEES was found to be high and no side effects were observed. In our experience, SEES was efficacious in the treatment of patients with ethmoidal CRS when conventional medical treatment had failed, or when wishing to avoid the classic endoscopic ethmoidectomy (EE). In the near future, it is tempting to hypothesize a further development of devices releasing drugs, like SEES, and their increasing role in the treatment of CRS, with the possibility of distributing several drugs in synergic association. However, further long-term studies on SEES will be performed in order to confirm the safety and stability, over time, of the results obtained in order to evaluate the possible recurrence of polyps. REFERENCES 1. De Benedetto M, Salerni L, De Benedetto L et al. Le rinosinusiti: aggiornamenti in tema di eziopatogenesi e antibioticoterapia. Acta Otorhinolaryngol Ital (Suppl 1), Lauriello M, Muzi P, Di Rienzo Businco L et al. A two-year course of specific immunotherapy or of continuous antihistamine treatment reverse eosinophilic inflammation in severe persistent allergic rhinitis. Acta Otorhinolaryngol Ital Oct;25(5): Levine HL, Sertich AP, Hoisington DR et al. Multicenter registry of balloon catheter sinusotomy outcomes for 1,036 patients. 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7 Word count: 3000 Tables: 3 Figures: 2 References: 18 Access the article online: DOI: / Full-text PDF: Corresponding author: Di Mario Alessia; ENT department Casa di cura Santo Volto, Piazza del tempio di Diana 12, Roma instead of Policlinico Umberto I, Università di Roma Sapienza via Giovanni Battista de Rossi 15A; dimario.alessia@gmail.com Copyright 2016 Polish Society of Otorhinolaryngologists Head and Neck Surgeons. Published by Index Copernicus Sp. z o.o. All rights reserved. Competing interests: The authors declare that they have no competing interests. Cite this article as: Di Rienzo Businco L., Mattei A., Laurino S., Angelone A.M.. Lauriello M., Crescenzi D., Di Mario A., Radici M., Di Rienzo Businco A.: Steroid-Eluting Ethmoidal Stent Versus Antero-Posterior Ethmoidectomy: Comparison Of Efficacy And Safety In Allergic Pantiens; Otolaryngol Pol 2016; 70 (2):