Comparison of Mitomycin-C with Normal Saline in preventing Synechiae formation in patients undergoing Endoscopic Sinus Surgery

INTRODUCTION

Chronic rhinosinusitis (CRS) is a frequently encountered condition affecting the sinonasal region, with an estimated prevalence of 5% to 12% [1]. It often necessitates referral to an ear, nose, and throat (ENT) specialist for further evaluation and treatment. Endoscopic sinus surgery (ESS) is a widely accepted and commonly performed procedure for treating chronic rhinosinusitis (CRS) and other sinonasal pathologies[2,3]. Although ESS has significantly advanced the treatment of sinus diseases, one of the frequent post-operative complications is the formation of synechiae, or adhesions, within the nasal cavity[4]. Synechiae can obstruct the normal drainage pathways of the sinuses, leading to recurrent infections, impaired healing, and reduced surgical outcomes[5]. Consequently, the prevention of synechiae formation is a critical aspect of post-operative care following ESS.

The development of adhesions is among the most frequent complications following nasal surgeries. Previous research has highlighted that it is the most prevalent complication after functional endoscopic sinus surgery, with an incidence rate ranging from 10% to 40%[2]. Several approaches have been employed to minimize synechiae formation, including mechanical spacers, topical corticosteroids, and saline irrigation[7]. However, one agent that has gained attention for its anti-fibrotic properties is Mitomycin-C (MMC), an antineoplastic antibiotic known for its ability to inhibit fibroblast proliferation and scar formation[8]. MMC has been used in various surgical fields to reduce scar formation, such as in ophthalmic surgery and airway procedures, and its potential application in sinus surgery presents a promising avenue for investigation.

The comparison of Mitomycin-C and normal saline in preventing synechiae formation in patients undergoing endoscopic sinus surgery (ESS) is crucial. While normal saline irrigation is routinely employed post-operatively to maintain nasal hygiene and prevent crusting, it does not possess any direct anti-fibrotic properties. In contrast, Mitomycin-C has shown promising results in both experimental and clinical studies for its ability to reduce fibrosis and prevent adhesions. This prospective randomized trial aims to compare the efficacy of topical Mitomycin-C versus normal saline in preventing postoperative synechiae formation after endoscopic sinus surgery.

METHODS

This comparative prospective randomized controlled trial was conducted in the ENT Department Ahmed Medical Center Rawalpindi. The study lasted over a period of six months starting from (March 9, 2024 to September 9, 2024. A total of 60 patients were included and the sample size calculated using the WHO calculator, maintaining a significance level of 5% and power of the study of 80%. Patients were randomly allocated (1:1) to Mitomycin-C or saline groups using a computer-generated sequence and sealed envelopes, ensuring allocation concealment.“Group assignments were determined by a computer-generated random sequence, and group allocation was concealed in opaque envelopes. Group A consisted of 30 patients in whom mitomycin-C (MMC) solution was applied topically to the middle meatus after endoscopic sinus surgery (ESS), while Group B included 30 patients who received normal saline in the same manner, serving as the control group. Consecutive sampling was adopted for patient selection.

The study included patients of both genders, aged 15 to 45 years, diagnosed with bilateral allergic nasal polyps, recurrent nasal polyps, or chronic rhinosinusitis that had persisted for more than three months despite conservative treatment. The exclusion criteria consist of patients with pregnancy, or bleeding disorders. Ethical approval was granted by the Health Education Research foundation committee under letter no: (HERF/Research/REC/No-2024-03 dated 04-03-26) and written informed consent were obtained from patients. Postoperatively, antibiotics, nasal decongestants, saline douches, and medications were administered. Synechiae formation was assessed at 4 weeks postoperatively via anterior rhinoscopy (binary outcome: yes/no) by otorhinolaryngologist.

Data were analyzed with SPSS version 26, with quantitative variables presented as mean ± SD and qualitative data as frequencies and percentages. As the data was qualitative in nature a chi-square tests were used to compare synechiae formation between groups. A p-value <0.05 was considered significant. Data were analyzed with SPSS v.26. Quantitative variables are presented as mean ± SD. Categorical variables are summarized as counts (%) and compared between groups using the chi-square test or Fisher’s exact test (when expected counts <5). Odds ratios (OR) and 95% confidence intervals (CI) were calculated to quantify treatment effects. A two-sided P-value <0.05 was considered statistically significant.

*Student’s t-test.

RESULTS

The patients' ages ranged from 15 to 45 year. “Mean patient age was 30.2 ± 8.1 years in Group A and 29.7 ± 7.5 years in Group B (p=0.78, Student’s t-test), indicating no significant age difference.”  Out of this study participants 58% were male and 42% were females. They were further divided in two groups A and B. In Group A (Mitomycin-C), there were 19 male patients (63.3%) and 11 female patients (36.7%), while Group B (Normal Saline) consisted of 16 male patients (53.3%) and 14 female patients (Table 1).

Patients were followed clinically and endoscopically at 1 week, 4 week and 3 months postoperatively to monitor for synechiae formaltion and each side for the nasal cavity. Postoperative synechiae formation was observed in 5 patients (8.3%) at the 4-week follow-up. A comparison was made between the two treatment groups: Group A, which received mitomycin-C, and Group B, which received normal saline. In Group A, 2 patients (6.7%) developed synechiae, while in Group B, 3 patients (10%) experienced the same complication. Despite the variation in treatment modalities, the difference in synechiae formation between the two groups was not statistically significant. Postoperative synechiae occurred in 2/30 (6.7%) of the Mitomycin-C group and 3/30 (10%) of the saline group; the relative risk (RR) of synechiae with MMC was 0.67 (95% CI 0.12–3.71), with no statistically significant difference (P=0.640).” Synechiae in 2/30 vs. 3/30 patients (RR=0.67, 95% CI 0.12–3.71; p=0.64), indicating that the use of mitomycin-C did not result in a substantial reduction in postoperative synechiae compared to normal saline (Table 2).

DISCUSSION

The present study aimed to evaluate the efficacy of Mitomycin-C (MMC) in reducing postoperative nasal synechiae formation in patients undergoing nasal surgery, comparing it to a control group treated with normal saline. Synechiae formation is a frequent complication in nasal surgeries, potentially leading to discomfort, airway obstruction, and the need for additional interventions. Several methods, including topical agents like MMC, have been investigated to reduce this risk.

In this study, 60 patients were divided into two groups: Group A received MMC, and Group B was treated with normal saline. Although the incidence of synechiae formation was lower in Group A (6.7%) than in Group B (10%), the difference was not statistically significant (p = 0.64). This lack of statistical significance suggests that MMC did not offer a substantial advantage in preventing postoperative synechiae formation compared to normal saline. Consequently, the routine use of MMC in nasal surgeries solely for synechia prevention may not be justified.

When compared to previous studies, our findings align with some similar trends. Several studies have shown a reduction in synechiae formation with MMC, indicating its potential to reduce postoperative adhesions[9,10,11]. However, synechiae incidence varied across studies, including our own. For instance, Konstantinidis et al.[10] reported that MMC effectively prevented adhesions and restenosis, but our study recorded a higher synechiae rate of 38.7% in the MMC group. This discrepancy may be due to the lower MMC dose (0.5 mg/ml) and shorter follow-up period in our study. Such conflicting results are consistent with earlier research that questioned MMC's clinical efficacy in reducing synechiae. While MMC's fibroblast-inhibiting properties suggest theoretical benefits, real-world evidence remains inconsistent.

Mitomycin-C is an alkylating agent that inhibits fibroblast proliferation and has been applied in various surgical procedures to minimize scar tissue formation and adhesion development. In ophthalmic surgeries, particularly pterygium excision, MMC has demonstrated clear benefits in reducing postoperative fibrosis[12]. However, its success in nasal surgeries has been more inconsistent. Some studies have reported reductions in synechiae formation with MMC use, but others have found no significant differences compared to control groups[13,14,16]. This inconsistency could be related to variations in surgical techniques, MMC concentrations, and patient characteristics. For example, while Konstantinidis et al.[10] emphasized MMC's efficacy in preventing adhesions and restenosis, our study noted a higher synechiae incidence, likely due to the lower MMC dose and shorter follow-up duration. This discrepancy highlights the influence of study design, dosage, and follow-up periods on the inconsistent outcomes of MMC in synechiae prevention. Although MMC theoretically inhibits fibroblasts and reduces scarring, its effectiveness in real-world settings varies.

In addition to MMC, postoperative irrigation solutions also play a crucial role in recovery. Kurtaran et al.[17] found that hypertonic 2.3% sea water was the most effective irrigation solution for reducing dryness, swelling, adhesions, and nasal obstruction after nasal septum surgery with conchoplasty. In contrast, a smaller study on 0.9% sodium chloride with sodium hyaluronate nebulizations post-FESS showed no significant reduction in adhesions but demonstrated improvements in cilia motility, mucosal healing, and nasal patency[18,19]. Comparing these approaches, MMC targets fibroblast inhibition to prevent synechiae, while hypertonic saline solutions and sodium hyaluronate focus on enhancing mucosal healing and function. These differences underscore the importance of individualized treatment plans that consider the patient's condition, type of surgery, and postoperative care protocol to optimize outcomes. Larger studies are necessary to establish the definitive roles of these interventions.

Moreover, the safety profile of MMC should not be overlooked. While it has been shown to be safe in low concentrations, concerns about potential side effects such as delayed wound healing and mucosal atrophy persist[15]. The findings of this study reinforce the notion that the routine use of MMC in nasal surgeries may not be warranted unless there are clear indications based on individual patient risk factors for synechiae formation. Our study was limited by its small size and single-center design, which may affect generalizability. Additionally, while follow-up was short-term, longer follow-up would better assess synechiae recurrence. “Our study’s modest sample size (n=60) and the low incidence of synechiae (only 5 total events) limit the power to detect anything but a large effect. As highlighted by Sullivan et al., P-values are confounded by sample size, so the lack of statistical significance here may reflect limited power rather than true equivalence. We therefore interpret our negative finding cautiously and recommend larger trials to more precisely estimate MMC’s effect. Overall, the analysis is simple and generally appropriate, but including discussion of sample size limitations would improve the manuscript.

Future studies with larger sample sizes, longer follow-up periods, and varying concentrations of MMC are needed to draw more conclusive results regarding its role in synechiae prevention. Additionally, the exploration of alternative agents and techniques to minimize postoperative synechiae remains a critical area of research.

CONCLUSION

This study found that while Mitomycin-C (MMC) may reduce the incidence of postoperative synechiae formation in nasal surgery patients compared to normal saline, the difference was not statistically significant. This suggests that MMC does not provide a substantial advantage in preventing synechiae in routine nasal surgeries. The findings align with other studies that have shown conflicting results regarding MMC’s efficacy, likely due to variations in dosage, surgical techniques, and follow-up durations.

ACKNOWLEDGMENT

The authors acknowledge the use of AI-based tools for language editing and clarity enhancement. The final content, interpretation, and conclusions remain the sole responsibility of the authors.

Author Contributions:

MJ, WDS, SRM, SNH, KMK, MZ:

Each author made substantial contributions to the conception and design of the study, or acquisition, analysis, and interpretation of data.

All authors were involved in drafting the manuscript or critically revising it for important intellect content.

All authors approved the final version of the manuscript to be published and agree to be accountable for all aspects of the work.

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