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Background
Chronic rhino-sinusitis (CRS) is defined as an inflammatory condition involving the para-nasal sinuses and linings of the nasal passages that lasts 12 weeks or longer, despite attempts at medical management. It is one of the most frequently diagnosed chronic medical conditions, affect patients of all ages and gender. Treatments of CRS include saline washes and sprays, topical and systemic glucocorticoids, antibiotics, anti-leukotriene agents, as well as anti-fungals. Surgery should be the last resort in most cases of CRS. Endoscopic sinus surgery (ESS) is the most commonly used surgical intervention to treat medically unresponsive CRS. It is intended to restore physiologic sinus ventilation and drainage (Hamilos, 2012). While ESS has become a well-established strategy for the treatment of CRS that is refractory to medical treatment, it is associated with various complications. The incidence of major complications of ESS was estimated to be 1 to 3 %, with cerebrospinal fluid leak being the most common; and the incidence of minor complications was approximately 7.0 %, with middle meatal (MM) synechiae being the most common (May et al, 1994; Ramakrishnan et al, 2012).
Implantable sinus stents/spacers have been used following ESS to maintain patency of the sinuses and deliver local steroids. The Stratus MicroFlow Spacer is designed to provide slow release of steroids into the sinuses over a 2-week period with the intention of maintaining sinus ostial patency. This device may be used in either the frontal or ethmoid sinuses. Propel™ is a steroid-releasing sinus implant that is inserted into the ethmoid sinus. It is indicated for maintaining sinus patency after ESS in patients 18 years of age and older. This steroid releasing implant is comprised of a synthetic bioabsorbable co-polymer and is self-expanding, which allows it to conform to the highly variable contours and size of the sinus anatomy. Propel™ is inserted into the ethmoid sinus cavity by a physician under endoscopic visualization. Upon insertion, the implant expands radially to conform to the sinus cavity. The delivery system is then removed and discarded. Once Propel™ is in place, mometasome furoate is released over a 30-day period. Dosages for Propel™ are measured in terms of the number of implants inserted in a patient's sinus cavities. Each steroid-releasing implant contains 370 micrograms of mometasome furoate.
Catalano et al (2011) evaluated the safety and short-term outcomes of a newly introduced drug-eluting ethmoid stent (the MicroFlow Spacer) in 23 patients with a total of 40 implanted ethmoid sinuses. Patients with medically refractory CRS were treated with patient-appropriate ESS, with the modification of treating the ethmoid sinuses with an ethmoid stent infused with triamcinolone, instead of conventional endoscopic ethmoidectomy. Patients were then followed-up over 6 months. Safety was determined by adverse events. Outcomes were assessed by interval changes in 20-item Sino-Nasal Outcome Test (SNOT-20) and Lund-MacKay CT scores. Overall, the pre-operative SNOT-20 mean score was 2.18, versus post-operative score of 1.02, an improvement of 1.16 that was both statistically (p < 0.001) and clinically significant. Ethmoid-specific and side-specific Lund-MacKay mean scores both also showed statistically significant improvements. Pre-operative ethmoid-specific Lund-MacKay mean score was 1.93, versus post-operative score of 1.10, an improvement of 0.83 (p < 0.001). Pre-operative side-specific Lund-MacKay mean score was 5.75, compared with post-operative score of 2.95, an improvement of 2.80 (p < 0.001). There were no significant intra-operative or post-operative complications encountered. The authors concluded that the MicroFlow spacer appears safe and effective in treating chronic ethmoid sinus disease within the defined follow-up period. They noted that the ability to deliver medication directly to diseased mucosa holds wide-ranging potential. The findings of this small study need to be validated by well-designed studies with long-term follow-up.
In a prospective, multi-center, single-cohort trial (Advance Trial), Forwith et al (2011) evaluated the safety and effectiveness of a bioabsorbable, steroid-eluting implant (the Propel™ device) used following ESS in patients with CRS (n = 50). The study allowed bilateral or unilateral steroid-eluting implant placement. Oral and topical steroids were withheld for 60 days post-operatively. Endoscopic follow-up was performed to 60 days. Patient-reported outcomes (SNOT-22 Questionnaire, Rhinosinusitis Disability Index) were collected to 6 months. Efficacy was assessed by grading inflammation, polyp formation, adhesions, and middle turbinate position. Safety assessment included ocular examinations at baseline and 30 days. Implants were successfully placed in all 90 sinuses. Mean inflammation scores were minimal at all time-points. At 1 month, the prevalence of polypoid edema was 10.0 %, significant adhesions 1.1 %, and middle turbinate lateralization 4.4 %. Changes from baseline in patient-reported outcomes were statistically significant (p < 0.0001). No clinically significant changes from baseline in intra-ocular pressure (IOP) occurred. The authors concluded that this consecutive case-series study provided clinical evidence of the safety, effectiveness, and clinical utility of a bioabsorbable steroid-eluting implant for use in CRS patients. The implant was associated with favorable rates of sinus patency. At 1 month, minimal degrees of inflammation and adhesions were observed, suggesting a positive clinical impact of local steroid delivery without evidence of ocular risks.
In a prospective, multi-center, randomized, controlled, double-blind trial (Advance II Trial), Marple et al (2012) examined the safety and effectiveness of controlled delivery of mometasone furoate to the sinus mucosa via the Propel™ sinus implant deployed at the time of ESS. This study enrolled 105 patients with CRS undergoing bilateral ethmoidectomy to compare the effect of drug-releasing to non-drug-releasing implants using an intra-patient control design. Post-operative interventions, polyposis, and adhesions were assessed post-operatively. Efficacy was determined through independent analysis of randomized video-endoscopies by 3 blinded sinus surgeons. Safety assessments included ocular examinations. Implants were successfully deployed in all 210 ethmoid sinuses. Compared with control sinuses with non-drug-releasing implants, the drug-releasing implant provided a 29.0 % relative reduction in post-operative interventions (p = 0.028) and a 52 % (p = 0.005) decrease in lysis of adhesions. The relative reduction in frank polyposis was 44.9 % (p = 0.002). Similar reductions were observed in real-time grading performed by the clinical investigators. No clinically significant changes from baseline in IOP or cataracts were observed. The authors concluded that this study provided evidence that use of the Propel™ sinus implant that applies a sustained release of corticosteroid improves surgical outcomes by reducing synechiae formation, polyposis, and the need for post-operative interventions, with no observable ocular safety risk.
While the results of the two Advance Trials are promising, they were limited to small, heterogeneous populations with short-term follow-up. Furthermore, the trials were performed in a setting where both sinuses had implants, one with steroid and the other without. The two trials discussed above did not compare the post-operative outcomes using this device with outcomes following standard ESS without an ostial implant but with topical steroid sprays, saline irrigation, debridement, and conventional post-operative packing. The available evidence is insufficient to determine whether sinus spacers and stents improve outcomes when used post-operatively following ESS. Further randomized controlled trials (RCTs) are needed to compare the Propel™ device to optimal post-operative care without the device to determine whether it can improve post-operative outcomes for patients undergoing ESS.
In a randomized, double-blind, placebo-controlled trial, Rudmik et al (2012) evaluated a dexamethasone Sinu-Foam™ spacer following ESS for CRS without nasal polyposis (CRSsNP). Patients with CRSsNP (n = 36) were enrolled into a double-blind, placebo-controlled trial and randomized into either a treatment arm (dexamethasone Sinu-Foam™ mixture; n = 18) or placebo arm (Sinu-Foam™ alone; n = 18). Therapeutic outcomes were evaluated at 1 week, 4 weeks, and 3 months using sino-nasal endoscopy and graded using the Lund-Kennedy scoring system. Post-operative care included nasal saline irrigations and a short course of systemic steroids. All patients completed the study follow-up period. Both study arms experienced significant improvement in endoscopic grading over the study duration (p < 0.001). There was no difference in average endoscopic scores between the treatment and placebo groups at 1 week, 4 weeks, and 3 months (all p > 0.489). The authors concluded that the findings of this study demonstrated that an off-label drug-eluting MM spacer of dexamethasone and Sinu-Foam™ does not improve endoscopic outcomes in the early post-operative period following ESS when combined with post-operative saline irrigations and a short course of systemic steroids.
Weitzel and Wormald (2008) performed a literature review to identify all forms of scientifically evaluated absorbable packing for ESS. Only English studies identifiable within the PubMed database were included. Studies were categorized by level of evidence and evaluated for methodological errors. A total of 38 studies met the inclusion criteria. There was a diverse range of article evidence and quality. The most effective hemostatic agent currently available is FloSeal; however, this product causes an increase in adhesion formation. For the purpose of preventing adhesions, resorbable packs appear to have no benefit over either non-resorbables or no packing. If the middle turbinate is unstable at the conclusion of surgery, suturing it to the septum may reduce adhesions. Although mitomycin C, hyaluronic acid, and retinoic acid all have shown potential in these roles, to date, none has shown to be useful in post-ESS CRS patients.
In a systematic review and meta-analysis, Lee and Grewal (2012) examined if MM spacers actually reduce the risk of synechiae following ESS. The Preferred Reporting of Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines was used for reporting this review of RCT evaluating the effectiveness of MM spacers compared to no spacers in patients undergoing ESS. Where appropriate, a meta-analysis on outcome data using a random effects model was performed. A total of 8 RCTs were included in this systematic review. A pooled analysis on relevant trials found a non-significant trend favoring MM spacers compared to no spacers for the prevention of synechiae following ESS (relative risk [RR], 0.40; 95 % confidence interval [CI]: 0.14 to 1.12). Sub-group analysis suggested that non-absorbable spacers (NAS) may be more effective than absorbable spacers (AS) for reducing the risk of synechiae compared to no spacers. The authors concluded that MM spacers may be more effective than no spacers for the prevention of synechiae following ESS, especially when employing the use of an NAS. However, the authors noted that significant heterogeneity was observed among included trials and future studies are needed to further validate these findings.
Zhao et al (2013) stated that middle meatal (MM) spacers may reduce adhesions following ESS. However, there is no consensus as to which materials and adjuncts are the most effective for this purpose. These investigators examined the effectiveness of absorbable spacers (AS) versus non-absorbable spacers (NAS) in reducing adhesions following ESS for chronic sinusitis. They also assessed steroidal versus non-steroidal MM spacers in reducing adhesions. Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, a systematic review of RCTs was conducted and a meta-analysis on relevant outcome data was performed. Electronic search was done using OVID MEDLINE, EMBASE, Cochrane Central register of Controlled Trials, and Web of Science. Independent data extraction and evaluation was conducted. For the primary objective, a total of 6 RCTs were included in the systematic review. A pooled estimate of relevant trials revealed a non-significant trend favoring AS in reducing adhesion formation compared to NAS (Relative Risk (RR), 0.40; 95 % CI: 0.15 to 1.03). This trend was not apparent if NAS were left for greater than 48 hours after ESS. For the secondary objective, these researchers identified 5 RCTs that compared steroidal versus non-steroidal spacers. Although a pooled analysis could not be achieved due to inconsistent reporting of MM adhesions, 2 studies demonstrated significantly less adhesions in the steroidal spacer group. The authors concluded that comparison between NAS and AS showed that there was no significant difference in adhesion rates if NAS are used for at least 48 hours after surgery. Moreover, they stated that steroidal spacers may reduce adhesions, but more consistent data reporting is needed for meta-analysis.
Hathorn et al (2014) noted that balloon dilation is now commonly used to open sinus ostia while preserving mucosa and minimizing trauma. A new maxillary sinus ostium (MSO) self-dilation device that functions on the principle of osmosis, absorbing a small amount of fluid from the surrounding tissues, can be placed into the MSO under endoscopic visualization and slowly enlarge its outer diameter. The slower dilation may further minimize tissue damage and scarring compared to the currently available balloon dilation systems. The MSO self-dilating expansion device has never been studied before in clinical trials. In a pilot study, these researchers determined the safety and performance of the device in human subjects. A total of 12 CRS patients presenting with maxillary sinus inflammation requiring FESS were enrolled. The device was inserted into the MSO at the start of surgery and removed after 60 minutes. Endoscopic evaluation for patency was performed immediately after removal, and at 1 week, 1 month, and 3 months. Adverse events were recorded intra-operatively and at each subsequent visit. The device was successfully inserted in 100 % of cases attempted (19/19 MSOs, 12 patients); 17 (89 %) devices remained in the MSO for 60 minutes and dilated to a mean diameter of 4.8 ± 0.5 mm. One patient withdrew from the study. No adverse events occurred during insertion or removal of the device. At 3 months post-insertion 14 of 15 MSO dilated (93 %) were confirmed patent. The authors concluded that placement of an osmotic self-dilating expansion device in human MSO is safe, achievable and effective at dilating the ostia. These preliminary findings from a small pilot study need to be validated by well-designed studies.
In a prospective, multi-center, randomized, double-blind, clinical trial, Murr et al (2011) evaluated the safety and effectiveness of a steroid-eluting sinus stent when used following functional endoscopic sinus surgery (FESS) in patients with CRS. This study enrolled 43 patients in 2 groups. One group (n = 38) used an intra-patient control design comparing drug-eluting to non-drug-eluting stents. The other group (n = 5) received bilateral drug-eluting stents to assess systemic safety. Endoscopic follow-up was performed for 60 days. Effectiveness end-points included assessment of inflammation, polyp formation, adhesions, and middle turbinate position. Stents were successfully deployed in all 86 sinuses. Compared to the control stent, the drug-eluting stent provided statistically significant reduction in inflammation at days 21 to 45 (p < 0.003), frequency of polyp formation (p = 0.0391), and frequency of significant adhesion (p = 0.0313). Reduced frequency of middle turbinate lateralization was also apparent though not statistically significant. No device-related adverse events occurred. Eluted steroid was unquantifiable systemically and there was no evidence of adrenal cortical suppression. The authors concluded that the findings of this study demonstrated the safety and effectiveness of a novel bioabsorbable, steroid-eluting stent for use in CRS patients. The steroid-eluting stent is effective in improving wound healing by preserving sinus patency, reducing inflammation, and minimizing adhesions via controlled local steroid delivery without measurable systemic exposure. Moreover, these researchers stated that further assessment and validation of this instrument is needed.
In a prospective, multi-center study, Lavigne et al (2014) assessed the initial feasibility, safety, and effectiveness of steroid-eluting implants placed in the office setting in patients who were candidates for revision ESS. This trial enrolled 12 patients who had prior ESS but experienced recurrent polyposis refractory to medical therapy. Implants were placed bilaterally under topical anesthesia in-office. Follow-up through 6 months included endoscopic grading, patient-reported outcomes (SNOT-22) and need for revision ESS. Implants were successfully inserted in 21 of 24 (88 %) ethmoid sinuses, resulting in 11 evaluable patients. No serious adverse events occurred. Within 1 month, mean bilateral polyp grade was reduced from 4.5 at baseline to 2.3 (p = 0.008) and sustained through 6 months (2.33; p = 0.008). Mean SNOT-22 score was significantly improved from 2.19 at baseline to 0.90 within 1 month (p = 0.001) and sustained to 6 months (1.03; p = 0.012); 64 % of patients were no longer revision ESS candidates at 6 months. The authors concluded that the findings of this study provided initial clinical evidence of the feasibility, safety, and effectiveness of in-office steroid-eluting implant placement in CRS patients with recurrent polyposis after ESS. Moreover, they stated that although further studies are needed, the results suggested this therapy may provide a safe and effective, office-based option for the treatment of obstructive polyposis. The main drawbacks of this study were its small sample size (n = 12), lack of randomization, and lack of a concurrent control group. Thus, the potential contribution of placebo effect cannot be ruled out. Well-designed studies are needed to address these limitations and provide further clinical evidence of the safety and efficacy of the in-office sinus implant strategy for patients with CRS with recurrent polyposis.
In a prospective case-series study, Matheny and colleagues (2014) evaluated the safety, feasibility, and outcomes of bioabsorbable steroid-eluting sinus implants placed in the office after achieving hemostasis. A total of 20 patients with CRS underwent ESS including bilateral ethmoidectomy. A steroid-eluting bioabsorbable implant was deployed into each ethmoid cavity in the office within 7 days after ESS. Endoscopic appearance of the ethmoid cavities was evaluated at 1 week, 2 weeks, and 4 weeks post-operatively by the operating surgeon and an independent blinded evaluator. Procedural tolerance was assessed at week 2 using a patient preference questionnaire. The SNOT-20 questionnaire was completed at baseline, week 2, and week 4. In-office placement of steroid-eluting bioabsorbable implants was well-tolerated, with 90 % of patients very satisfied with the overall experience, and 80 % very satisfied with the recovery process. At 1 month, there were no significant adhesions or frank polyposis, and middle turbinate lateralization was only 5 %. Compared to baseline, ethmoid sinus inflammation was significantly reduced (p = 0.03), and the mean SNOT-20 score was significantly improved (p < 0.001). The authors concluded that in-office placement of steroid-eluting bioabsorbable implants after achieving hemostasis was well-tolerated and might improve local drug diffusion and surgical outcomes. This small study (n = 20) demonstrated the feasibility of in-office placement of the implants, provided there is adequate topical anesthesia. These investigators noted that “the observed statistically significant reduction in inflammation was encouraging ….”.
In a prospective, single-center study, Ow and associates (2014) evaluated the systemic safety and performance of a bioabsorbable sinus implant that gradually releases 1,350 μg of mometasone furoate directly to the sinus mucosa. This trial treated 5 adult patients with recurrent polyposis after bilateral total ethmoidectomy. Each patient received 2 steroid-releasing implants in-office under local/topical anesthesia. Plasma concentrations of mometasone furoate and cortisol were determined before placement and through 30-day follow-up, which also included endoscopic grading and patient-reported outcomes. Five patients (mean age of 46.2 ± 9.2 standard deviation [SD] years; 60 % male) underwent successful placement in all 10 ethmoid sinuses. There were no serious adverse events. The plasma concentrations of mometasone furoate were generally below the lower limit of quantification (LLOQ) of the assay (30 pg/ml). Cortisol concentrations at follow-up ranged from 3.9 to 5.7 mg/dL compared to 4.7 mg/dL at baseline. At 1 month, there was a significant improvement in bilateral polyp grade (p = 0.037), nasal obstruction score (p = 0.002), and SNOT-22 (p = 0.010) compared to baseline. The authors concluded that the reported 100 % placement success, negligible systemic exposure to mometasone furoate released over time, lack of adrenal suppression, and the absence of serious adverse events suggested that the implant provides a valid and safe option for the in-office treatment of recurrent polyposis. Moreover, they stated that randomized, controlled, blinded clinical studies are underway to provide further evidence of safety and effectiveness.
In a randomized, controlled, blinded study, Han and co-workers (2014) evaluated the safety and efficacy of a bioabsorbable steroid-eluting implant with 1,350 μg of mometasone furoate for its ability to dilate obstructed ethmoid sinuses, reduce polyposis, and re-establish sinus patency. This study included 100 CRS patients with nasal polyposis who were refractory to medical therapy and considered candidates for revision ESS. Follow-up included endoscopic grading by investigators and patient-reported outcomes. Treated patients (n = 53; age as mean ± standard deviation [SD] 47.8 ± 12.6 years; 55 % male) underwent in-office bilateral placement. Control patients (n = 47; age 51.6 ± 13.1 years; 66 % male) underwent a sham procedure. At 3 months, treated patients experienced a significant reduction in bilateral polyp grade (p = 0.0269) and ethmoid sinus obstruction (p = 0.0001) compared to controls. Treated patients also experienced a 2-fold improvement in the mean nasal obstruction/congestion score (-1.33 ± 1.47 versus -0.67 ± 1.45; p = 0.1365). This improvement reached statistical significance (p = 0.025) in patients with greater polyp burden (grade greater than or equal to 2 bilaterally; n = 74). At 3 months, 53 % of treated patients compared to only 23 % of controls were no longer indicated for repeat ESS. There was no serious adverse event or clinically significant increases in intraocular pressure or cataract formation. The authors concluded that the symptomatic improvement and statistically significant reduction in polyp grade and ethmoid sinus obstruction supported the efficacy of the steroid-eluting implant for in-office treatment of CRS patient with recurrent polyposis after ESS. They stated that the study results demonstrated that the steroid-eluting implant represents a safe and effective alternative to current management for this patient population. One drawback of this study was that there was not a defined medical treatment prior to enrollment (e.g., a 3-week course of a broad spectrum of antibiotics and 3-week trial of topical steroids as was used in prior studies). Thus, these researchers were not able to control for the possible impact that these various sources of prior treatment variability may have had on objectively determining surgical candidacy or study outcomes. Although nasal sprays were allowed, the use of steroid instillations, which provide superior topical application, was restricted during the first 90 days following surgery. Another drawback was that the clinical investigators performing endoscopic grading were not blinded to the treatment assignment. Another limitation is the short duration of followup. These findings need to be validated by well-designed studies.
Ow, et al. (2014) reported on a prospective, single-center study treating 5 adult patients with recurrent polyposis after bilateral total ethmoidectomy. Each patient received 2 Propel steroid-releasing implants in-office under local/topical anesthesia. Plasma concentrations of mometasone furoate and cortisol were determined before placement and through 30-day follow-up, which also included endoscopic grading and patient-reported outcomes. The authors reported that five patients (mean age 46.2 ± 9.2 standard deviation [SD] years; 60% male) underwent successful placement in all 10 ethmoid sinuses. There were no serious adverse events. The plasma concentrations of mometasone furoate were generally below the lower limit of quantification (LLOQ) of the assay (30 pg/mL). Cortisol concentrations at follow-up ranged from 3.9 to 5.7 mg/dL compared to 4.7 mg/dL at baseline. At 1 month, there was a significant improvement in bilateral polyp grade (p = 0.037), nasal obstruction score (p = 0.002), and 22-item Sino-Nasal Outcome Test (SNOT-22) (p = 0.010) compared to baseline. The authors stated that these results suggest that the implant provides a valid and safe option for the in-office treatment of recurrent polyposis. The authors stated that randomized, controlled, blinded clinical studies are underway to provide further evidence of safety and efficacy.
In summary, a variety of implants/spacers (e.g., the Propel™ sinus implant, the Relieva Stratus™ MicroFlow spacer, and the Sinu-Foam™ spacer) have been employed to maintain patency of the sinuses and deliver local steroids with varying success in the reported literature. However, the available studies have significant heterogeneity in this outcome. There remains a continued debate on whether these devices actually improve the health outcomes following ESS.
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