Randomized Controlled Trial of Steroid-Soaked Absorbable Calcium Alginate Nasal Packing Following Endoscopic Sinus Surgery

The Laryngoscope VC 2017 The American Laryngological, Rhinological and Otological Society, Inc. Randomized Controlled Trial of Steroid-Soaked Absorbable Calcium Alginate Nasal Packing Following Endoscopic Sinus Surgery Chi Sang Hwang, MD; Salma Saud Al Sharhan, MD; Bo Ra Kim, BS; Soo In Kim, BS; Jin Woong Kim, MD; Hyung-Ju Cho, MD, PhD; Joo-Heon Yoon, MD, PhD; Chang-Hoon Kim, MD, PhD Objectives/Hypothesis: To evaluate the potential efficacy of steroid-soaked, absorbable calcium alginate nasal packing following endoscopic sinus surgery. Study Design: Prospective, randomized, single-blinded, placebo-controlled trial. Methods: Twenty-two patients (44 nostrils) who had chronic rhinosinusitis with polyps underwent bilateral endoscopic sinus surgery. Only those with an intersinus difference in Lund-Mackay severity score of 1 or less were included. In each patient, one randomly selected nostril was packed with calcium alginate soaked with 2 ml of triamcinolone (40 mg/ml) (triamcinolone group), whereas the contralateral nostril received an identical packing soaked in 2 ml of normal saline (saline group). Two independent investigators blinded to the packing allocation scored the surgical field using the validated Perioperative Sinus Endoscopy (POSE) scores 1, 4, and 8 weeks after surgery. Results: All 44 nostrils were analyzed; the Lund-Mackay scores did not differ significantly between the groups before surgery. Eight weeks after surgery, the total POSE scores were significantly lower in the triamcinolone group (P 5.014). The POSE scoring parameters were then compared between groups, and the following variables were significantly different: middle turbinate synechiae with the lateral wall (P 5.037), polypoid degeneration of the ethmoid cavity (P 5.006), and sphenoid sinus severity (P 5.036). Conclusions: This study demonstrated that steroid-soaked, absorbable nasal packing can be used to enhance wound healing after endoscopic sinus surgery and to prevent polypoid changes in the nasal mucosa. Key Words: Endoscopic sinus surgery, nasal polyps, triamcinolone, nasal packing, surgical outcomes. Level of Evidence: 1b. Laryngoscope, 128:311 316, 2018 INTRODUCTION Chronic rhinosinusitis (CRS) is a common and challenging disease with a wide diversity of inflammatory Additional Supporting Information may be found in the online version of this article From the Department of Otorhinolaryngology (C.S.H., J.W.K., H.-J.C., J.-H.Y., C.-H.K.); the Research Center for Human Natural Defense System (B.R.K., S.I.K., H.-J.C., J.-H.Y.); and the Brain Korea 21 PLUS Project for Medical Science (C.-H.K.), Yonsei University College of Medicine, Seoul, South Korea; Department of Otorhinolaryngology (S.S.A.), Imam Abdulrahman Bin Faisal University and King Fahd Hospital, Dammam, Saudi Arabia; The Airway Mucus Institute (H.-J.C., J.-H.Y., C.-H.K.), Yonsei University College of Medicine, Severance Hospital, Seoul, South Korea. Editor s Note: This Manuscript was accepted for publication July 31, 2017. C.-H.K. received funding from the Basic Science Research Program through the National Research Foundation of Korea (NRF), funded by the Ministry of Education (2015R1D1A1A02062228), and the Bio and Medical Technology Development Program of the NRF, funded by the Ministry of Science, Information and Communications Technology, and Future Planning (MSIP) (2016M3A9D5A01952414). C.-H.K. is also supported by an NRF grant funded by the Korean Government (MSIP) (2016R1A5A2008630), the Yonsei University Future-Leading Research Initiative of 2015 (<2015-22-0114), and a faculty research grant from Yonsei University College of Medicine (6-2011-0122). The funding organizations had no role in study design, data collection or analysis, manuscript preparation, or the decision to publish. The authors have no other funding, financial relationships, or conflicts of interest to disclose. Send correspondence to Chang-Hoon Kim, MD, Department of Otorhinolaryngology, Yonsei University College of Medicine, 50 Yonseiro, Seodaemun-gu, 03722 Seoul, South Korea. E-mail: entman@yuhs.ac DOI: 10.1002/lary.26871 endotypes. 1,2 If the condition cannot be controlled using medical treatment, endoscopic sinus surgery (ESS) is the most common surgical procedure to treat CRS with or without nasal polyps. 3,4 Specifically, ESS aims to open the sinus ostia and thus improve sinus drainage pathways and mucociliary clearance, as well as to facilitate the wide distribution of topical medications. Although ESS is effective in most patients, 15% to 20% of patients undergo revision surgery during long-term follow-up, mainly prompted by postoperative scarring, edema, polypoid degenerations, and crusting that reobstructs the ostiomeatal complex. 5,6 Meanwhile, recent literature has shown a high rate of nasal polyp recurrence of up to 40% at 18 months postoperatively, highlighting the need for continued improvement in postoperative care. 7 Therefore, various biodegradable or nondegradable materials have been used in postoperative nasal packing to prevent the need for revision surgery. Several studies have investigated the effects of such nasal packing on wound healing and surgical outcomes after ESS. However, there remains a lack of consensus regarding the optimal perioperative nasal packing regimen. 8,9 Calcium alginate, a biodegradable, gel-transforming material, is used for nasal packing, which has been shown in our previously published clinical trials to alleviate edema and adhesions, and to act as a spacer after ESS. 10 From a medical point of view, topical (intranasal) corticosteroids have been widely used to treat CRS, both 311

Fig. 1. Consolidated Standards of Reporting Trials diagram of the randomized controlled trial. This study was designed for intrapatient analysis. preoperatively and postoperatively, and they are known to improve both patient symptoms and recurrence rate without significant adverse effects. 11,12 In particular, corticosteroids act by reducing inflammation a major component of CRS and suppressing the production of proinflammatory mediators, cell chemotactic factors, and adhesion molecules. 13,14 However, the exact efficacy of topical corticosteroids is often unclear, and the literature shows heterogeneity and inconsistent reporting of data regarding dose, duration, frequency, local delivery methods, and type of steroid. In addition, it is uncertain whether patient characteristics such as polyposis or underlying medical conditions affect the efficacy of these drugs. Therefore, we evaluated the potential efficacy of steroid-soaked biodegradable calcium alginate nasal packing in management of chronic sinusitis with nasal polyps (CRSwNP). To do so, we analyzed in a detailed fashion objective outcome measures and assessed interventions in the short-term perioperative period, where treatment is focused on modifying the postsurgical results. MATERIALS AND METHODS Ethical Considerations The present study was approved by the institutional review board (IRB) of Yonsei University College of Medicine (IRB No. 1-2016-0052). Informed consent was obtained from all individual participants. All procedures performed in studies involving human participants were conducted in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments, or with comparable ethical standards. 312 Study Design This prospective, randomized, single-blinded, placebocontrolled trial compared the efficacy of triamcinolone-soaked calcium alginate nasal packing with that of normal saline nasal packing in patients with CRSwNP who had undergone bilateral ESS at Yonsei University Severance Hospital between October 2016 and February 2017. The trial protocol is summarized in a Consolidated Standards Of Reporting Trials flow diagram (Fig. 1). Participants The diagnosis of CRSwNP was based on patient history, nasal endoscopy, and computerized tomography (CT). 15 To qualify for inclusion in this study, patients were required to 1) be aged over 18 years, 2) be refractory to medical treatment and thus require bilateral ESS, and 3) present an intersinus Lund- Mackay severity score difference of 1. 16 None of the patients had taken any form of systemic corticosteroids for at least 2 weeks before the operation. Patients with a history of the following underlying medical conditions, which are associated with an increased rate of revision surgery, were excluded from the study: aspirin intolerance, asthma, mucociliary disorder, and immunocompromised status. In addition, patients were excluded if they had a history of previous unilateral ESS, or a septal deviation at the level of the middle meatus on CT, which could be associated with side-to-side difference. Intervention and Randomization All ESS procedures were performed by the same surgeon (C.H.K.). After the operation, each nostril was randomized using a random table to receive either a triamcinolone- or normal saline-soaked calcium alginate nasal packing. One nasal cavity of each patient was packed using a biodegradable calcium

Fig. 2. Representative intraoperative image of the calcium alginate nasal packing soaked with (A) triamcinolone and (B) saline. Nasal packings were placed in the middle meatus and/or superior meatus to allow more steroids to reach opened sinus ostia. alginate packing (Algi-Pack; MD Pharm, Seoul, South Korea) soaked with 2 ml of triamcinolone solution (Tamceton, 40 mg/ ml; Hanall Biopharma, Seoul, South Korea); the contralateral nostril was packed using calcium alginate packing soaked in 2 ml of saline (Fig. 2). The nasal packs were not removed until they had been suctioned from the middle meatus at the first postoperative visit 1 week later. The random allocations were placed in an envelope, which remained sealed until all the postoperative data had been collected. All patients attended routine follow-up 1, 4, and 8 weeks after surgery. At these visits, an endoscopic inspection was performed, and the patients underwent debridement of the ethmoid cavities when necessary. In addition, endoscopic data regarding the health of the sinonasal mucosa were collected. Two independent investigators, who were blinded to the packing allocation, scored the nasal cavities using the validated Perioperative Sinus Endoscopy (POSE) scoring system as previously described. 17 More specifically, this objective endoscopic scoring system was used to assess surgical outcomes in the sinonasal cavities; it evaluates the middle turbinate, middle meatal antrostomy, ethmoid cavity, and secondary sinuses. Ten categories were reported as follows: 1) middle turbinate, 2) middle meatal antrostomy, 3) maxillary sinus contents, 4) ethmoid cavity crusting, 5) ethmoid cavity mucosal edema, 6) ethmoid cavity polypoid change, 7) ethmoid cavity polyposis, 8) ethmoid cavity secretions, 9) frontal recess/sinus, and 10) sphenoid sinus. A three-point scale (0, 1, and 2) was used to score each category, and the total attainable score for each nostril was 20. A summary of the POSE scoring system is presented in Supporting Table S1 in the online version of this article. Polypoid change in the ethmoid cavity was identified when the degree of mucosal edema was given a score of 2. Similarly, polyposis of the ethmoid cavity was indicated when polypoid change was given a score of 2. The frontal and maxillary sinuses were visualized using a 30 8-angled, rigid endoscope (4 mm). Endoscopic digital photographs were obtained 1, 4, and 8 weeks after surgery, and the POSE scores were checked for inter-rater variability as a measure of reliability. All other aspects of postoperative management were the same in both groups; in particular, the patients were given a 3- week course of oral antibiotics (levofloxacin; 300 mg/d), as well as low-dose oral corticosteroids (methylprednisolone; 16 mg/d for 2 weeks, tapered to 8 mg/d for 1 week). Patients resumed topical corticosteroids (fluticasone furoate) and nasal saline irrigation 1 day after both nasal packings had been removed. Statistical Analysis All continuous data are presented as mean 6 standard deviation. The paired t test was used to compare continuous variables between the triamcinolone and saline groups. Pearson v 2 test or Fischer exact test was used to compare categorical variables. Reproducibility and inter-rater consistency was assessed using the intraclass correlation coefficient and Cronbach a coefficient. All statistical analyses were conducted using the Statistical Package for the Social Sciences version 18.0 (IBM, Armonk, NY). A P value <.05 was considered statistically significant. RESULTS The clinical and demographic data of the patients are summarized in Table I. A total of 22 consecutive patients (44 nostrils; 17 men and 5 women; mean age: 42.05 6 16.18 years; age range: 19 65 years), who had been diagnosed as having CRSwNP, were enrolled in the study. None of the patients were lost to follow-up at the outpatient clinic. No perioperative complications occurred, and no adverse events related to the application of the triamcinolone-soaked calcium alginate packs were observed. The preoperative total Lund-Mackay CT scores of the triamcinolone and saline groups were 9.16 6 2.01 and 9.58 6 1.80, respectively, and the difference between them was not statistically significant (Table II). Histopathological analysis revealed that none of the patients had either allergic fungal sinusitis or inverted papilloma. Table III shows a comparison of postoperative POSE scores between the triamcinolone and saline groups. Inter-rater variability in the results scored by the two investigators was within a statistically acceptable range. Specifically, the intraclass correlation coefficient between the two observers was 0.89 (0.81 0.95, P <.001). The overall total POSE scores were lower in the triamcinolone group than in the saline group at 1 and 4 weeks after surgery, although the differences were not statistically significant (4.53 6 2.00 vs. 5.29 6 2.49, respectively, after 1 week; 5.16 6 2.80 vs. 6.37 6 4.48, respectively, after 4 weeks). A statistically significant 313

TABLE I. Baseline Demographics and Clinical Information. No. of patients 22 Mean age at surgery, yr (range) 42.05 6 16.18 (19 65) Male, no. (%) 17 (77.3) No. of prior bilateral ESS, no. (%) 0 12 (54.5) 1 10 (45.5) Current smokers, no. (%) 9 (40.9) BMI, kg/m 2 24.04 6 3.63 Presence of allergic rhinitis, no. (%) 15 (68.2) BMI 5 body mass index; ESS 5 endoscopic sinus surgery. difference in POSE scores was noted between the triamcinolone and saline groups 8 weeks after surgery (4.65 6 3.20 vs. 7.71 6 4.04, respectively; P 5.014). With respect to each individual cavity category of the POSE score, the triamcinolone-treated sinonasal cavities showed lower scores at 1 and 4 weeks, although this was not a statistically significant difference. Unsurprisingly, several variables in the POSE scoring system showed statistically significant differences in the triamcinolone group at 8 weeks (Fig. 3). Specifically, the middle turbinate score in the triamcinolone group at 8 weeks was 0.03 6 0.11, whereas that in the saline group was 0.34 6 0.62 (P 5.037). The ethmoid cavity score for polypoid change at 8 weeks was 0.76 6 0.61 in the triamcinolone group and 1.37 6 0.66 in the saline group (P 5.006). The ethmoid cavity score for polyposis at 8 weeks was 0.45 6 0.49 in the triamcinolone group and 0.92 6 0.82 in the saline group (P 5.038). Furthermore, the sphenoid sinus severity scores in the triamcinolone group at 8 weeks was 0.42 6 0.45, whereas that in the saline group was 0.79 6 0.58, which is a statistically significant difference (P 5.036). None of the other variables in the POSE scoring system were significantly different between the two groups at 8 weeks (middle meatal antrostomy: 0.34 6 0.62 vs. 0.55 6 0.69; maxillary sinus contents: 0.45 6 0.47 vs. 0.76 6 0.79; ethmoid cavity crusting: 0.39 6 0.52 vs. 0.53 6 0.68; mucosal edema or secretions: 1.24 6 0.66 vs. 1.75 6 0.56; frontal recess/ sinus: 0.53 6 0.66 vs. 0.82 6 0.61). TABLE II. Preoperative Lund-Mackay Computed Tomography Scores in the Two Groups. Site Triamcinolone (n 5 22) Saline (n 5 22) P Maxillary 1.21 6 0.79 1.39 6 0.68.45 Anterior ethmoid 1.89 6 0.27 1.95 6 0.23.52 Posterior ethmoid 1.89 6 0.32 1.84 6 0.37.64 Sphenoid 0.95 6 0.85 1.00 6 0.75.84 Frontal 1.24 6 0.75 1.42 6 0.75.46 Ostiomeatal complex 1.92 6 0.19 1.90 6 0.58.89 Total 9.16 6 2.01 9.58 6 1.80.50 314 TABLE III. Comparison of the Triamcinolone and Saline Groups Using the Perioperative Sinus Endoscopy Scale (Total Score) 1, 4, and 8 Weeks After Surgery. Week Triamcinolone (n 5 22) Saline (n 5 22) P 1 4.53 6 2.00 5.29 6 2.49.30 4 5.16 6 2.80 6.37 6 4.48.33 8 4.65 6 3.20 7.71 6 4.04.014 DISCUSSION CRS is a diverse spectrum of inflammatory diseases, for which individualized treatment is available, including oral antibiotics, oral and/or topical corticosteroids, anti interleukin-5, and adjunctive therapy. In particular, in people with CRS who are already on standard treatments, adjunctive therapy could be used to improve inflammatory responses and symptoms. In the 2012 European Position Paper on Rhinosinusitis and Nasal Polyps, only nasal saline irrigation and topical corticosteroids had level Ia evidence as an adjunctive therapy, and the authors strongly recommended these as postoperative treatments in adults with CRS without nasal polyps. In adults with CRSwNP, oral and topical corticosteroids had level Ia supporting evidence as adjunct therapies for postoperative treatment. 15 A recent Cochrane review analyzed the management options for patients with CRS in randomized controlled trials. Only two trials satisfied the inclusion criteria, which were as follows: follow-up period of at least 3 months, saline irrigation comparison with a placebo, no history of treatment or other pharmacological interventions. The study suggested that saline irrigation using a hypertonic solution is beneficial in the short-term treatment of CRS when used in large volumes (150 ml). However, the quality of the evidence was low. 18 Similarly, there is moderate-quality evidence that topical corticosteroids improve nasal blockage and high-quality evidence that they increase the risk of epistaxis. 19 Consequently, a large number of patients with CRSwNP who underwent ESS presented with early recurrent diseases after being treated with topical corticosteroids and saline irrigation. Previous studies have found that only a small fraction of topical corticosteroids actually reaches the middle meatus. 20 During the postoperative period, topical corticosteroids may be less effective when anatomic factors such as synechia and crusting prevent optimal concentrations of the drug from reaching the opened sinus ostia. In the present study, we assumed that the effects of steroids would be increased if they were deposited in the middle meatus and sinus cavities for a longer time and at sufficient concentrations. We attempted to deliver more steroids to the most difficult and unreachable areas, such as the sphenoid and frontal sinuses, using a steroid-soaked absorbable dressing rather than a topical nasal spray. We adapted the POSE scoring system to evaluate each sinus separately, because it is more detailed and sensitive to treatment-related changes. Unlike the Lund- Kennedy instrument that assesses five specific findings

Fig. 3. Comparison of the individual scores on the Perioperative Sinus Endoscopy scale between the triamcinolone and saline groups after 8 weeks of follow-up. MMA 5 middle meatal antrostomy; MT 5 middle turbinate. in the ethmoid cavities, the POSE scoring system rates the sinuses individually, specifically assessing 10 categories; in this way, the POSE score is more advanced and covers all aspects of postoperative surgical field outcomes (see Supporting Table S1 in the online version of this article). 17,21 In the present study, we detected treatment effects on the basis of endoscopic findings rather than symptoms. It is important to note that postoperative endoscopic findings in patients with CRSwNP frequently do not correlate with symptoms, particularly in the early stages of recurrence. 22,23 Despite the limited number of patients with CRSwNP, our study was a prospective, placebo-controlled trial, where one nostril was randomly assigned to the triamcinolone group and the contralateral nostril was placed in the control group. This approach allowed the steroidsoaked packing to be compared with a placebo in conditions that reduced confounding factors related to patient variability, such as inclusion of both primary and revision bilateral ESS patients and different etiologies of CRSwNP. After 1 and 4 weeks, the triamcinolone-treated group had a lower POSE score than the saline group, although the difference was not statistically significant. Interestingly, triamcinolone-soaked nasal packing was found to significantly reduce synechia formation and early recurrence of nasal polyposis, as well as to enhance healing in the sphenoid sinus 8 weeks after ESS. Although the cause of such timing difference remains uncertain, it may have been related to a healing process. Furthermore, it is much less expensive than a steroid-eluting sinus stent, 24,25 so its costbenefit ratio would be reasonable. Hong et al. postulated that triamcinolone-impregnated nasal dressings show low cortisol level systemic effects that recover gradually and normalize 10 days after the operation. 26 Otherwise, it is considered as a relatively safe treatment modality. One limitation of our study was its short follow-up period. We did not expect the steroid-soaked absorbable packing to have a clinically meaningful impact beyond 2 months. Therefore, it followed that at later time points during follow-up, confounding factors would have a proportionately greater impact. Several studies have reported management of wound healing following ESS using a steroid-soaked nasal dressing. 27 29 However, to our knowledge, no detailed studies have compared the endoscopic appearance of individual contralateral sinuses between steroid and placebocontrolled nasal-packing groups. The strengths of the present study were that 1) the population was composed patients from a single ethnic group, 2) there were broad exclusion criteria associated with disease recurrence, and 3) the study participants were perfectly matched with regard to all other aspects of CRSwNP management. In addition, all subjects were operated on by the same surgeon, thus minimizing variations in the surgical procedure. Because there is no consensus regarding the optimal dosage or duration of steroid-soaked nasal dressing, and the potential synergic effect with the use of budesonide nasal irrigation after ESS, 30,31 future investigations should attempt to clarify this point to ensure maximal clinical benefit. CONCLUSION This study suggests that triamcinolone-soaked calcium alginate nasal packing enhances wound healing and reduces polyp recurrence within the early postoperative follow-up period. The packing can be adapted 315

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