Effect of Steroids for Nasal Polyposis Surgery: A Placebo-Controlled, Randomized, Double-Blind Study

Transcription

1 The Laryngoscope VC 2015 The American Laryngological, Rhinological and Otological Society, Inc. Effect of Steroids for Nasal Polyposis Surgery: A Placebo-Controlled, Randomized, Double-Blind Study Mustafa Cenk Ecevit, MD, FEBORL-HNS; Taner Kemal Erdag, MD; Ersoy Dogan, MD; Semih Sutay, MD Objectives/Hypothesis: Although medical intervention is the first option for treatment of nasal polyps, surgery is still a therapeutic option for symptomatic cases that do not respond or partially respond to medical intervention. However, there is a need for high-level evidence for the preoperative use of steroids in nasal polyposis surgery. We aimed to assess the perioperative effect of preoperative use of oral prednisolone for advanced-stage diffuse nasal polyposis. Study Design: Prospective, double-blind, randomized, placebo-controlled study. Methods: A visual analog scale (VAS) was evaluated for smell, nasal discharge, nasal obstruction, facial pressure, headache, butanol smell threshold, and peak nasal inspiratory flow (PNIF) before and after the use of study drug. Perioperative bleeding volume, visibility of operative field, operative time, hospital stay, and complication rate were also evaluated. Results: The improvement in the corticosteroid group (CG) in the VAS scores, butanol thresholds, and PNIF values showed statistically significant differences compared to the placebo group (PG) (P <.05). The perioperative bleeding volume, visibility score, operative time, and hospital stay for CG/PG were 141 ml/384 ml, 2.4/3.4, 61 min/71.6 min, and 1.1 day/1.8 day, respectively (P <.05). The difference between the complication rates for the two groups did not show any statistically significant difference (P 5.214). Conclusions: Preoperative administration of systemic corticosteroids improves the perioperative visibility by reducing blood loss and shortens the operation time. We recommend the use of preoperative corticosteroid for the safety of the patients. The optimum dose and duration have not been established and require further studies. Key Words: Nasal polyps, endoscopic sinus surgery, corticosteroids, N-butanol olfactory threshold, PNIF, operative bleeding, complication, operative field visibility, randomized controlled trial, double blind. Level of Evidence: 1b Laryngoscope, 125: , 2015 INTRODUCTION Nasal polyposis is a chronic inflammatory disease of the sinonasal mucosa. As a consequence of nasal mucosal inflammation, a cascade of events results in prolapsed nasal mucosa, which manifest as nasal polyps. In clinical practice, nasal polyps represent nasal obstruction, smell and taste disorders, headache, and nasal discharge. Changes in the sinonasal mucosa are the major cause for chronic rhinosinusitis triggered by the interaction of host and environment including a variety of exogenous agents. This persistent inflammation is believed to be an interaction among the host, commensal flora, potential pathogens, and exogenous stresses. 1 The chronic sinonasal inflammation can be associated with asthma and other respiratory disorders. 2 From the Department of Otorhinolaryngology Head and Neck Surgery, Faculty of Medicine, Dokuz Eylul University, Izmir, Turkey Editor s Note: This Manuscript was accepted for publication April 2, The authors have no funding, financial relationships, or conflicts of interest to disclose. Send correspondence to Mustafa Cenk Ecevit, MD, Department of Otorhinolaryngology Head and Neck Surgery, Faculty of Medicine, Dokuz Eylul University, Inciralti, Izmir, Turkey. cenk.ecevit@deu.edu.tr DOI: /lary Inflammatory cells, either eosinophils or neutrophils, play a significant role in development of nasal polyps, with an eosinophilic predominance worsening the prognosis. 3 Today, suppression of the degranulation of activated eosinophils provides the most beneficial outcomes achievable with medical therapy. The most effective medical agents are corticosteroids. 4 Medical intervention is the first option for treatment of nasal polyps. 5 Surgery is still a therapeutic option for symptomatic cases that do not respond or partially respond to medical intervention. 6 As the extent of nasal polyposis increases, response to corticosteroid treatment decreases. Patients with endoscopic stage 3 nasal polyposis are predisposed to a poorer treatment outcome. 7 Consequently, in some instances, surgery is still an option and can range from limited polypectomy to total sphenoethmoidectomy. 8 The limited polypectomy usually results in early recurrences. Eventually, forming a common cavity for the effected sinuses is the main purpose of functional endoscopic sinus surgery. 8 It remains controversial as to whether therapy should begin with corticosteroid therapy or surgery alone, or with surgery as an adjunctive therapy. Diffuse polyposis generally has a weak response to corticosteroid therapy, and these cases may respond better to surgery. 9 Although the effect of the corticosteroids on the pathophysiology of nasal polyposis is well understood, less is known about how preoperative medication using 2041

2 corticosteroids influences the operative phase. We report here a randomized, double-blind, prospective study for the perioperative and early postoperative effect of oral prednisolone for nasal polyposis. In this study, we hypothesized that the preoperative use of an oral steroid might have a beneficial effect on nasal polyposis surgery. Consequently, the implementation of this study can provide evidence-based knowledge for daily practice. MATERIALS AND METHODS Patients with nasal polyposis who sought treatment at the Department of Otorhinolaryngology of Dokuz Eylul University Hospital were recruited for this study. The study was approved by the Dokuz Eylul University Faculty of Medicine Clinical and Laboratory Trials Ethical Committee (approval number 176). The number of patients required for the study was calculated via two-proportions power analysis for amount of bleeding. Namely, the amount of bleeding was the outcome measurement point. The curative proportion for corticosteroid and placebo were estimated as 80% and 20%, respectively. Seeking an 80% power and 95% confidence interval, with an odds ratio of 0.063, the number of patients required for this study was found to be 22. Patient Selection The patient selection criteria and flowchart are shown in Figure 1. Preoperative Treatment The patients who met the inclusion criteria gave informed consent and were prescribed fluticasone nasal drops 13/d, 200 mg, for 6 weeks. Patients who did not respond to this medical treatment were evaluated for the study. The study drug was given to patients 2 weeks prior to the scheduled operation. Either the study drug or a placebo was administered as follows: six pills taken each day for the first 7 days, then reduced to one pill taken every other day, and stopping on day 17. The operation was performed between the 15th and 17th days. Study Drug Subsequent to the approval of the study by ethics committee, the study drug and placebo were prepared by the Department of Pharmaceutical Technology at Ege University. The study drug was composed of 10 mg prednisolone and 90 mg lactose, whereas the placebo was 100 mg lactose. There were 80 pills in each box. The boxes that contained the study and placebo drugs were numbered individually. Four copies of stickers were prepared (drug box, case record form, informed consent, and code list). Every eight boxes, including four study drug boxes and four placebo drug boxes, respectively, were assembled as a group by the pharmacy department. The hospital pharmacy department performed the drug/placebo randomization, and the identity of the contents in the boxes was not disclosed to any clinicians interacting with patients throughout the study. Anesthesia and Surgical Techniques The surgeon was blinded to the patient treatment group (corticosteroid vs. and placebo group). All procedures were performed under total intravenous anesthesia with remifentanil. After decongestion of the nasal mucosa with topical 1% xylometazoline, 2% lidocaine containing 1:100,000 adrenaline solution was injected into the lateral nasal wall, into the anterior edge 2042 Fig. 1. Patient selection criteria and study flowchart. VAS 5 visual analog scale. [Color figure can be viewed in the online issue, which is available at of the middle turbinate along the anterior attachment of the uncinate process, and into the sphenopalatine region. Reinjection at the sphenopalatine region was required after polyp removal in diffuse polyposis cases. The surgical technique for this process has been previously described. 10 Evaluation Scales The patients were evaluated for an endoscopic polyp score (Table I), computerized tomography opacification score (Lund- Mackay score), 11 Connecticut Chemosensory Clinical Research Center (CCCRC) butanol olfactory threshold test, 12 peak nasal inspiratory peak flow (PNIF), and the visual analog scale (VAS). The butanol olfactory threshold test, PNIF test, and VAS evaluation were performed before the treatment and the surgery. The surgeries were performed by one surgeon (M.C.E.). The operation time, amount of bleeding, complications, and the hospitalization time were included in the perioperative evaluation. Total sphenoethmoidectomy including frontal sinusotomy was performed on each patient. VAS Every patient was asked to express a score from 0 (no complaint) to 10 (most annoying) for a combination of factors

3 TABLE I. Endoscopic Polyp Score. Polyps were scored 0 3 according to endoscopic appearance: 0: No polyp 1: Mild polyposis (small polyps not reaching the upper edge of the inferior turbinate) 2: Moderate polyposis (medium polyps between the upper and lower edges of the inferior turbinate) 3: Severe polyposis (large polyps reaching the lower edge of the inferior turbinate, polyps from posterior ethmoidal sinuses, or both) relating to sense of smell, nasal discharge, nasal obstruction, and pressure over the sinuses. Bleeding Scoring All surgical procedures were video recorded. The surgical videos were then evaluated by the same surgeon (M.C.E.) for scoring the operative field visibility based on the Boezaart et al. grading system for assessment of bleeding during endoscopic sinus surgery. Scoring was done knowing the identity of the patent. 13 Statistical Analysis The results were evaluated with Wilcoxon signed rank and Pearson v 2 test, and a P <.05 was considered significant. RESULTS Twenty-three patients were found to meet the inclusion criteria. The patient inclusion flowchart is shown in Figure 1. Patients underwent the surgical procedure after they received the study drug (placebo or corticosteroid). One patient was excluded from the study subsequent to failure to obtain the study drug after surgery. The study was terminated when the required count of patients (n 5 22) as determined by power analysis was met. After all 22 patients seen had completed the course of treatment, members of the study group were made aware of the identity of all drug box assignments so as to assign patients to the corticosteroid group (CG) or placebo group (PG). The data on age, sex, sinus opacification scores, distribution of endoscopic polyp score, and the statistical analysis results are presented in Table II. VAS, butanol smell threshold tests, nasal inspiratory peak flow, perioperative bleeding, visibility of surgical field, surgical time, and hospitalization results are presented in Table III. The distribution of complications in the CG and PG were two and five, respectively. The distributions of the complications between groups were not statistically significant (P 5.268). Complications were as follows: one case of orbital fat herniation and one case of anterior nasal packing in the CG group, and four cases of anterior nasal packing and one case of orbital fat herniation in the PG group. The distributions of the types of complications between groups were also not statistically significant (P 5.214, Pearson v 2 ). The orbital examinations of two patients were normal after the operation. Adverse effects were not observed in either group. DISCUSSION The efficacy of corticosteroid treatment for nasal polyposis is well established. As the long-term benefits of systemic corticosteroids are obscured by its systemic side effects, topical application can be an option. Although endoscopic sinus surgery is a safe surgical procedure, both major and minor complications may occur. 1 The surgical technique used, the experience of the surgeon, and the stage of the disease are factors affecting the complication rate. 14 Systemic corticosteroids can be used preoperatively to improve the surgical procedure by reducing the amount of bleeding. Sieskiewicz et al. did not find any significant difference in reducing the total bleeding amount by preoperative administration of 30 mg of oral prednisone for 5 days compared to no treatment. This group did conclude, however, that preoperative prednisone reduces the operation time from 89 minutes for the placebo to 78 minutes for the steroid group. Furthermore, they observed improvement in the operative field visibility in the steroid-treated group. 15 Albu et al. found that preoperative topical steroids reduced total blood loss and operation time, and also improved the visibility of surgical field. Their study only TABLE II. Age, Sex, and Sinus Opacification Scores and Statistical Analysis Results Between the Corticosteroid and Placebo Groups. Corticosteroid Group Placebo Group Score 2, No. Score 3, No. Score 2, No. Score 3, No. P Age, yr, mean 6 SD (min max) (31 60) (26 58).575* Pretreatment endoscopic polyp score * Preoperative endoscopic polyp score * Sinus opacification score mean 6 SD (min max) (14 23) (15 24).172* Sex Male Female 1 4 *Mann-Whitney test *Pearson v 2. Fisher exact test ax 5 maximum; min 5 minimum; SD 5 standard deviation. 2043

4 TABLE III. The VAS, Butanol Smell Threshold Tests, Nasal Inspiratory Peak Flow, Perioperative Bleeding, Visibility of Surgical Field, Surgical Time, and Hospital Stay Results for Each Group at the First Visit (Before the Study Drug) and Second Visit (After the Study Drug). Corticosteroid Group Placebo Group First Visit Second Visit First Visit Second Visit Mean 6 SD Min Max Mean 6 SD Min Max P* Mean6 SD Min Max Mean 6 SD Min Max P* P First Visit P Second Visit VAS Smell Nasal discharge Nasal obstruction Facial pressure Headache Right butanol threshold test Left butanol threshold test Right PNIF, L/min Left PNIF, L/min Perioperative bleeding, ml Visibility of operative field Operative time, min Hospital stay, d *Statistically significant before and after the study drug. Statistically significant between the groups. Statistically significant betweeen the groups. Pearson v 2. Max 5 maximum; Min 5 minimum; PNIF 5 peak nasal inspiratory flow; SD 5 standard deviation; VAS 5 visual analog scale. used the drug treatment in cases of chronic rhinosinusitis without polyp and in endoscopic stage 1 polyp. 16 The distribution of topical drugs within the nose is very limited. The distribution of the topical agents in the sinonasal cavity not having been operated on is approximately 2% of the whole nasal cavity. 17 The preoperative use of a topical steroid can be helpful only for patients with chronic rhinosinusitis without polyps or chronic rhinosinusitis with polyps (CRSwNP) with stage 1 nasal polyps. Advanced stage nasal polyposis patients were included for this study in which a systemic steroid was preferred. The systemic use of prednisolone for medical treatment is a matter of choice. Vaidyanathan et al. used 25 mg prednisolone for 2 weeks followed by topical steroids, and there was improvement in the steroid group. 18 Rupa et al. used 50 mg for 6 weeks for allergic fungal rhinosinusitis after surgery. They also observed complete relief of symptoms in the steroid group. 19 However, the benefit of a systemic steroid is time limited due to side effects. 1 In this study, we enrolled only patients who were refractory to topical treatment. The VAS scores, PNIF, and smell threshold values did not statistically differ before the use of the study drug. In the present study, the duration of steroid administration is 17 days, beginning with 60 mg prednisolone and attenuated after day 7. The dosage and duration of prednisolone were found to have a statistically significant impact on each variable Recommendation of systemic steroid use for CRSwNP is grade A and the level of evidence is 1a. There is a wide range of steroid use between 25 mg daily for 2 weeks to 50 mg daily for 6 weeks. 1 There is no common consensus about the duration and dosage of systemic steroids for CRSwNP. As in this study, daily use of 60 mg prednisolone for 7 days tapering until day 17 is effective in reducing the symptom scores, PNIF, operation time, perioperative blood loss, improving the smell thresholds, increasing operative field visibility, and shortening the hospital stay time without any adverse effect. Sinonasal polyposis impairs olfaction via nasal congestion and nasal inflammation. The combination of topical and oral steroids improves conduction of odorants to the olfactory epithelium. 20 Additionally, the use of radiofrequency for inferior turbinate in combination intranasal steroid treatment improved nasal cross-sectional area in conjunction with discrimination and total score values for olfaction. 21 The CCCRC test is a quantitative olfaction test. Quantitative olfaction tests are used for monitoring hyposmia patients. 22 The CCCRC test is a simple test that requires less time compared to other quantitative tests. 23 In addition, the reliability of the test is reported to be 92%. The sensitivity, specificity, the positive predictive value and negative predictive value are reported to be 86%, 94%, 93%, and 88%, respectively. The mean of the CCCRC butanol olfactory threshold test for nasal polyposis was initially. We observed

5 no change in the placebo group, and there was a statistically significant improvement in the corticosteroid group (P5.041 and P for right and left sides, respectively). This reveals that nasal polyposis patients were hyposmic initially, and even after the improvement seen in the corticosteroid group, they remained hyposmic. Endoscopic surgery requires a long-term learning curve. 24,25 With more case experience, there is less fluctuation in complication rates. With even the most challenging of cases though, considerably experienced surgeons will see a good outcome in many cases. For this study, all surgical procedures were done by an experienced endoscopic sinus surgeon, whose armamentarium includes cranial base interventions for extended tumors, in collaboration with neurosurgeons. This should be considered when there is a high priority put on standardized outcomes. The daily practice may differ from this structured set for clinical study. A resident or a general otorhinolaryngology physician may perform endoscopic sinus surgery for polyposis patients. Endoscopic surgery can be performed under academic supervision for the education of otorhinolaryngology residents Even under academic supervision, the duration of surgery and the amount of blood loss will vary considerably compared to the experienced surgeon. The limitation of study in the academic setting may not be reflected in daily practice. Although perioperative bleeding volume, visibility of operative field, operative time, and hospital stay showed statistically significant (P 5.022,.003,.046, and.044, respectively) improvement in the corticosteroid group, the changes were very slight, and with the exception of bleeding volume, results were acceptable even for the placebo group. Additionally, there was no statistically significant difference for the rate of the complications. There were four cases of anterior nasal pack placements in the placebo group, and only one case in the corticosteroid group. Although no statistically significant difference could be found because of the low sample size, it should be emphasized that there is an effect of preoperative corticosteroid to lower anterior packing rates for perioperative excessive bleeding. Any color change should especially be interpreted as the possibility of protruding orbital fat. We observed one orbital fat herniation in each group, and use of this approach resulted in no serious orbital complication. The postoperative examinations of these patients were unremarkable. CONCLUSION Preoperative administration of systemic corticosteroids improves perioperative visibility by reducing blood loss and results in the shortening of the operation time. We advise utilization of preoperative corticosteroid for the safety of patients being treated for nasal polyposis. The optimal dose and duration of medication to use in these cases require additional study. Acknowledgments The authors thank Elcin Sequoia Halloran for her help in presubmission English-language editing. BIBLIOGRAPHY 1. Fokkens WJ, Lund VJ, Mullol J, et al. European position paper on rhinosinusitis and nasal polyps Rhinol Suppl 2012;(23):3 p preceding table of contents, Pawankar R. Nasal polyposis: an update. Curr Opin Allergy Clin Immunol 2003;3: Mygind N, Dahl R, Bachert C. Nasal polyposis, eosinophil dominated inflammation, and allergy. Thorax 2000;55(suppl 2):S79 S Mygind N, Lund V. Topical corticosteroid therapy of rhinitis. Clin Immunother 1996;5: Bonfils P, Norès JM, Halimi P, Avan P. Corticosteroid treatment in nasal polyposis with a three-year follow-up period. Laryngoscope 2003;113: Blomqvist EH, Lundblad L, Anggård A, Haraldsson PO, Stj arne P. A randomized controlled study evaluating medical treatment versus surgical treatment in addition to medical treatment of nasal polyposis. J Allergy Clin Immunol 2001;107: Kirtsreesakul V, Wongsritrang K, Ruttanaphol S. Clinical efficacy of a short course of systemic steroids in nasal polyposis. Rhinology 2011;49: Hosemann W. Surgical treatment of nasal polyposis in patients with aspirin intolerance. Thorax 2000;55(suppl 2):S87 S Blomqvist EH, Lundblad L, Bergstedt H, Stj arne P. A randomized prospective study comparing medical and medical-surgical treatment of nasal polyposis by CT. Acta Otolaryngol 2009;129: Ecevit MC, Sutay S, Erdag TK. The microdebrider and its complications in endoscopic surgery for nasal polyposis. J Otolaryngol Head Neck Surg 2008;37: Lund VJ, Mackay IS. Staging in rhinosinusitis. Rhinology 1993;31: Cain WS, Gent JF, Goodspeed RB, Leonard G. Evaluation of olfactory dysfunction in the Connecticut chemosensory clinical research center. Laryngoscope 1988;98: Boezaart AP, van der Merwe J, Coetzee A. Comparison of sodium nitroprusside- and esmolol-induced controlled hypotension for functional endoscopic sinus surgery. Can J Anaesth 1995;42: Stankiewicz JA, Lal D, Connor M, Welch K. Complications in endoscopic sinus surgery for chronic rhinosinusitis: a 25-year experience. Laryngoscope 2011;121: Sieskiewicz A, Olszewska E, Rogowski M, Grycz E. Preoperative corticosteroid oral therapy and intraoperative bleeding during functional endoscopic sinus surgery in patients with severe nasal polyposis: a preliminary investigation. Ann Otol Rhinol Laryngol 2006;115: Albu S, Gocea A, Mitre I. Preoperative treatment with topical corticoids and bleeding during primary endoscopic sinus surgery. Otolaryngol Head Neck Surg 2010;143: Snidvongs K, Chaowanapanja P, Aeumjaturapat S, Chusakul S, Praweswararat P. Does nasal irrigation enter paranasal sinuses in chronic rhinosinusitis? Am J Rhinol 2008;22: Vaidyanathan S, Barnes M, Williamson P, Hopkinson P, Donnan PT, Lipworth B. Treatment of chronic rhinosinusitis with nasal polyposis with oral steroids followed by topical steroids: a randomized trial. Ann Intern Med 2011;154: Rupa V, Jacob M, Mathews MS, Seshadri MS. A prospective, randomised, placebo-controlled trial of postoperative oral steroid in allergic fungal sinusitis. Eur Arch Otorhinolaryngol 2010;267: Alobid I, Benıtez P, Cardelus S, et al. Oral plus nasal corticosteroids improve smell, nasal congestion, and inflammation in sino-nasal polyposis. Laryngoscope 2014;124: Berkiten G, Salturk Z, Topaloglu I. Efficacy of systemic steroid treatment in sinonasal polyposis. J Craniofac Surg 2013;24:e305 e Simmen D, Briner HR. Olfaction in rhinology methods of assessing the sense of smell. Rhinology 2006;44: Toledano A, Gonzalez E, Rodrıguez G, Galindo N. The validity of CCCRC test in patients with nasal polyposis. Rhinology 2007;45: Marks SC. Learning curve in endoscopic sinus surgery. Otolaryngol Head Neck Surg 1999;120: Stankiewicz JA. Complications in endoscopic intranasal ethmoidectomy: an update. Laryngoscope 1989;99(7 pt 1): Nguyen QA, Cua DJ, Ng M, Rice DH. Safety of endoscopic sinus surgery in a residency training program. Ear Nose Throat J 1999;78: , Kinsella JB, Calhoun KH, Bradfield JJ, Hokanson JA, Bailey BJ. Complications of endoscopic sinus surgery in a residency training program. Laryngoscope 1995;105: Gross RD, Sheridan MF, Burgess LP. Endoscopic sinus surgery complications in residency. Laryngoscope 1997;107: Ramadan HH, Allen GC. Complications of endoscopic sinus surgery in a residency training program. Laryngoscope 1995;105(4 pt 1):