Suture reinforcement using a modified cyanoacrylate glue prevents anastomotic leak in colorectal surgery: A prospective multicentre randomised trial.

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Giovanni Tomasicchio, Gennaro Martines, Nicola Tartaglia, Massimo Buonfantino, and 11 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4299938/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 05 Aug, 2024 Read the published version in Techniques in Coloproctology → Version 1 posted 8 You are reading this latest preprint version Abstract Introduction Anastomotic leakage (AL) is the most frequent life-threating complication following colorectal surgery. Several attempts have been made to prevent AL. This prospective, randomised, multicentre trial aimed to evaluate the role of nebulised modified cyanoacrylate in preventing AL after rectal surgery Methods Patients submitted to colorectal surgery for carcinoma of the high-medium rectum across five high-volume centres between June 2021 and January 2023 entered the study and were randomized into group A (anastomotic reinforcement with cyanoacrylate) and group B (no reinforcement) and followed-up for 30 days. Anastomotic reinforcement was performed via nebulization of 1 cc of a modified cyanoacrylate glue. Preoperative features and intraoperative and post-operative results were recorded and compared. The study was registered at ClinicalTrials.gov (ID number: NCT03941938). Results 133 out of 152 patients (control group, n = 72; cyanoacrylate group, n = 61) completed the follow-up. Clavien–Dindo complications grade >2 were significantly higher in the control group (12.5% vs. 3.3%, p=0.04). ALs were detected in nine patients (12.5%) in the control group (four grade B and five grade C) and in four patients (6.6%), in the cyanoacrylate group (three grade B and one grade C); however, despite this trend, the differences were not statistically significant (p = 0.36). No adverse effects were reported. Conclusion Use of modified Cyanoacrylate application to seal colorectal anastomoses is safe and could help to reduce severe post-operative complications; however, its role in the AL prevention remains unclear. Colorectal surgery suture reinforcement cyanoacrylate anastomotic leakage Figures Figure 1 Figure 2 Introduction Managing anastomotic leakage (AL) remains challenging for colorectal surgeons. The incidence of AL is estimated to be 2–4% following colon cancer resection [1] and 10–20% after rectal anastomosis [2]. AL considerably affects clinical outcomes with an increased risk of permanent stoma, urinary, defaecatory, and sexual dysfunction, thereby increasing health care expenditure [3, 4]. Moreover, AL increases the risk of local recurrence and decreases overall survival by delaying the initiation of adjuvant cancer treatments [5, 6]. The aetiology of AL is complex and multifactorial. Many preoperative risk factors [7], including patient-related factors (such as sex, malnutrition, obesity, American Society of Anesthesiologists (ASA) score, smoking history, cardiovascular disease, nonsteroidal anti-inflammatory drugs usage, neoadjuvant chemoradiotherapy, age, altered gut microbiota), cancer-related factors (stage, distance from the anal verge), and surgeon-related factors [8, 9], such as the surgeon’s expertise and experience, type of anastomosis, and use of faecal diversion by temporary stoma, are implicated [10, 11]. Therefore, adopting preventive measures is highly recommended. Although patient- and cancer-related risk factors cannot be modified, several intraoperative procedures have been implemented to prevent this serious complication, such as indocyanine green injection to assess adequate perfusion of the distal colon, reinforcement of the anastomosis by additional manual stitches and/or collagen patches or sealants, and suture protection with an omental flap [12-16]. Among the possible options to reinforce and protect anastomosis, cyanoacrylate glue application has significantly reduced AL in colon anastomosis in a porcine model [17-20] and prevents suture leakage after sleeve gastrectomy [21]. Furthermore, cyanoacrylate is widely used in endoscopy for the emergency management of patients with upper gastrointestinal bleeding because of its adhesive and haemostatic seal when nebulised and sprayed on injured tissues [22]. Furthermore, the sealing effect creates an antiseptic barrier against bacteria [23]. The application of cyanoacrylate glue in vascular surgery [24], urology [25], and bariatric surgery [21] has been previously described. Considering its mechanical, physical, and biological properties and safety, cyanoacrylate glue can facilitate the healing of colorectal anastomoses and reduce the AL rate, as demonstrated in experimental and uncontrolled clinical studies [26]. The distance of the anastomosis from the anal verge is a well-recognised risk factor for AL; therefore, low/ultralow anastomosis is generally protected by a covering ileostomy, whereas anastomoses performed on the intraperitoneal tracts of the colon and rectum are considered to have a low AL risk. Therefore, using a covering stoma to protect the surgical anastomosis involving the upper part of the rectum remains ambiguous, and is often left to the discretion of the surgeon. This prospective, randomised, multicentre trial aimed to evaluate the role of a nebulised modified cyanoacrylate in preventing AL in colorectal surgery. Patients and methods A prospective, multicentre, parallel-arm, randomised controlled superiority trial was conducted between June 2021 and January 2023 across five high-volume tertiary referral centres for colorectal surgery. A power analysis was conducted to determine the number of patients enrolled in each study arm. The study protocol was approved by all local ethics committees in accordance with the Declaration of Helsinki and registered at ClinicalTrials.gov (ID number: NCT03941938). This study included consecutive patients diagnosed with histologically confirmed primary adenocarcinoma of the high-medium rectum without internal and/or external sphincter muscle involvement, with a distal margin of the tumour at least 8 cm from the anal verge, stage T2-T4 on magnetic resonance imaging (MRI) before neoadjuvant chemoradiation. Patients with squamous cell carcinoma, stage T1 or T4 adenocarcinoma with pelvic side wall involvement or requiring sacrectomy or prostatectomy (partial or total), unresectable primary rectal cancer or inability to complete R0 resection, rectal cancer < 8 cm from the anal verge requiring coloanal or ultra-low rectal anastomosis, recurrent rectal cancer, previous pelvic malignancy, inability to return for postoperative follow-up, and inability to sign informed consent were excluded. Preoperative colonoscopy of the entire colon, computed tomography (CT) scan staging, and preoperative tumour and nodal staging using MRI and/or endorectal ultrasonography were performed for all participants. Surgery was performed within 8–12 weeks (56–84 days) after the completion of neoadjuvant therapy, when indicated. All patients were fully informed about the study, and informed consent for inclusion in the study was obtained. The participants were informed of their right to withdraw from the study or refuse initial enrollment at any point. Randomisation Computer-generated randomisation was used to create an allocation sequence to assign patients to different study arms. Randomisation was centrally controlled by an operator who was not involved in the study. Patients were randomised only after the completion of neoadjuvant chemotherapy (when indicated) and before surgery. Patients randomised to the cyanoacrylate glue arm received anastomotic reinforcement with nebulised modified cyanoacrylate glue using the related special catheters for open or or laparoscopic surgery, whereas no anastomotic reinforcement was used in the control group. The modified cyanoacrylate used to reinforce the anastomosis is Glubran 2 (GEM S.r.l – Viareggio -Italy), a synthetic surgical biodegradable cyanoacrylate-based glue (NBCA+MS), modified by the addition of a monomer Metacryloxysulfolane (MS) into N-Butyl-CyanoAcrylate (NBCA). As part of the educational intervention, all surgeons underwent training using a video demonstrating the surgical technique for the application of nebulised NBCA+MS.. Operative protocol Patient preparation for rectal surgery followed the general Rules for Good Clinical Practice. Mechanical bowel preparation using an oral polyethylene glycol solution was performed according to the surgeon’s preference, and antibiotic and antithrombotic prophylaxis were started immediately before surgery. The patients were placed in the lithotomy position for the abdominal and perineal procedures. Abdominal procedures (open or laparoscopic) were performed according to the oncological guidelines, including total mesorectal excision with adequate lymph node retrieval and at least 1 cm of distal clearance with an end-to-end or latero-terminal Knight–Griffen anastomosis. A pneumohydraulic test was performed to check for AL, and additional sutures were applied in positive tests. Following the enhanced recovery after surgery protocol [27], the nasogastric tube was removed in the operating room after surgery completion, and the urinary catheter was removed within 72 h for rectal resection. Early mobilisation was strongly encouraged in all patients on the first post-operative day. Patients were allowed to drink clear liquids in the post-operative period once awake and were able to drink safely. Post-operative management Postoperative care was provided in accordance with the current standards directed by the operative surgeon. Narcotics or analgesics for pain were initially administered through the parenteral route (intramuscular, intravenous, or epidural), followed by oral administration when the patient resumed oral intake. Oral intake was allowed according to the patients’ tolerance. The patients returned to the ambulatory clinic for post-operative follow-up after 30 days. During follow-up, the post-operative data were recorded, and proctography was performed by transanal injection of 100 mL of hydro-soluble contrast medium (Gastrografin, sodium amidotrizoate and meglumine amidotrizoate, Bayer S.p.A.) to check the integrity of the anastomosis. AL was graded according to the classification system developed by Rahbari NN, et al. Patients who did not attend the follow-up were contacted by a research nurse by phone or email, where available, to ascertain whether the patient had experienced any complications and/or adverse events treated in other hospitals. Patients unavailable for postoperative evaluation were considered “lost to follow-up”. Outcomes measures Demographic data (age, sex, weight, BMI (kg/m 2 ), ASA classification, smoking status, and comorbidities) and intraoperative data (type of operative approach, operative time, type of anastomosis, and sutures) were recorded. Postoperative complications were classified in accordance with the Clavien–Dindo classification [28] and recorded along with the length of in-hospital post-operative days, 30-day readmission rate, and death. AL was defined as a defect in the intestinal wall integrity at the colorectal anastomotic site, leading to communication between the intra- and extraluminal compartments [29], with the presence of faecal discharge from the pelvic drainage at any time after surgery, rectovaginal fistula (defined as faecal or mucus discharge from the vagina), and pelvic sepsis (defined by the collection of pus/faecal material in the pelvis documented by a CT scan). ALs were classified according to the Rahbari et al. classification: grade A, AL requiring no active therapeutic intervention; grade B, AL requiring active therapeutic intervention but manageable without relaparotomy; and grade C, AL requiring re-laparotomy [29]. Statistical analysis Sample size determination: The expected mean percentage of AL after rectal cancer is 16%, and a reduction to 10% was considered clinically significant. The sample size calculation determined that 67 patients per arm was sufficient to reject the null hypothesis with a power of 0.8 and a type I error probability of 0.05, with a confidence level of 95% (sample size calculated by R Studio Version 1.1.419 – © 2009-2018 RStudio, Inc.). To account for a predicted 5% estimated loss to follow-up, the sample size was calculated as 138 (134+4). Statistical methods All statistical analyses were performed in an intention-to-treat manner. No interim analyses were planned. A P-value of 0.05 indicated statistical significance. The Student’s t-test was used to provide an unadjusted estimate of the difference between treatment arms. Analysis of covariance, a more robust method that allows the control of key differences in baseline characteristics, was used to enable adjusted comparisons. Similar to the primary outcome, continuous secondary outcomes (such as safety and efficacy) were modelled using t-tests and analysis of covariance. The relationship between AL and other possible adverse factors was evaluated using univariate and multivariate regression analyses. When the complete case analysis excluded more than 5% of patients owing to missing data, exploratory analyses were performed to investigate the effect of missing data. To explore the mechanism of missing data and the validity of a complete case analysis for each endpoint, patient characteristics were compared between those with and without missing data, and multilevel logistic regression models were used to identify any associations between prognostic variables and determine if data were missing at random. The prognostic effect of each baseline parameter on AL outcomes (present/absent) was analysed using logistic regression. All parameters were analysed individually using logistic regression, and parameters with a probability level less than 0.1 were selected for analysis using stepwise multivariable regression. A polychotomous stepwise logistic regression model was used to correlate prognostic factors with Clavien–Dindo classification grades. Multilevel logistic regression was used to estimate the odds ratios (ORs) for conversion to laparotomy, intraoperative complications, and postoperative complications between the treatment groups. Results This study included 152 patients with primary adenocarcinoma of the high-medium rectum who were randomised into two arms. Following the completion of 30-day post-operative follow-up by 133 patients (Figure 1) , 72 and 61 were randomised into the control (median age, 68, interquartile range [IQR] 58–76.5; 34.7% women) and the anastomotic reinforcement groups (median age, 72, IQR 61–77; 47.5% women), respectively. No statistically significant differences in baseline characteristics were observed between the two groups ( Table 1) . However, the operative approach significantly differed between the two groups; 53 patients (86.9%) in the anastomotic reinforcement group underwent a laparoscopic approach compared to 51 patients (70.8%) in the control group ( p = 0.0255). Moreover, the operative time was significantly longer in the control group than in the anastomotic reinforcement group (180 min, IQR 150–240 vs. 160, IQR 135–180, respectively; p = 0.0129 ). No conversion to laparotomy was reported in patients who had laparoscopic intervention. The end-to-end anastomosis was the most frequent type of anastomosis performed in both groups (65.3 % vs. 78.7%), without statistical difference (p = 0.088) . Only two patients (1.5 %) in the control group had a hand anastomosis. The air leak test was positive in one patient (1.4%) in the control group and five patients (8.2%) in the anastomotic reinforcement group ( p = 0.059 ), and all patients had hand suture reinforcement. A protocol deviation with a temporary protective ileostomy was done in five (6.9%) and six (9.8%) patients in the control and anastomotic reinforcement groups, respectively, with no statistically significant difference (p = 0.54). No significant difference was observed in the duration of in-hospital stays between the two groups (7.5 days, IQR 6–10 vs. 7 days, IQR 6–9; p = 0.23). Clavien–Dindo complications (grade >2) were significantly higher in the control group (9 [12.5%] vs. 2 [3.3%]; p = 0.04) ( Figure 2) . Four patients in the control group had Clavien–Dindo grade 3 complications; one had grade 3A, and three had grade 3B, while only one patient in the cyanoacrylate group had grade 3B, which required intervention under general anaesthesia. Fatal complications requiring intensive care unit management were reported in two patients in the control group, one with single-organ failure (grade 4A) and one with multi-organ failure (grade 4B). None of the patients in the anastomotic reinforcement group experienced grade 4 complications. Mortality due to post-operative complications was reported in one patient in both groups (grade 5). ALs were observed in nine patients (12.5%): four grade B and five grade C in the control group vs. four patients (6.6%), three grade B and one grade C in the anastomotic reinforcement group; however, this difference was not statistically significant (p = 0.36). No adverse effects were reported due to the application of nebulised NBCA+MS around the colorectal anastomosis. No significant differences in 30-day readmission and post-operative death rates were observed between the groups ( Table 2). None of the parameters analysed using logistic regression and/or stepwise multivariate regression were statistically significant for AL. Among them, heart diseases increased the risk of leakage by 2.89 times (OR 2.89; 95% CI: 0.84–9.89), which was not statistically significant ( p = 0.091). Concerning the Clavien–Dindo grade > 1 complications, patients with higher ASA scores (> 2) are at significantly increased risk (three times higher) of developing complications (OR = 3.35, 95% CI: 1.37–8.18) than those in the control group (p 1 complications was lower in women than in men (OR = 0.41, 95% CI: 0.15–1.08). Moreover, two patients who had undergone hand anastomosis experienced five times higher risk than those who underwent stapler procedures to develop Clavien–Dindo complications grade ˃ 1 (OR = 8.7, 95% CI: 0.64–119); however, the difference for both parameters was not statistically significant. Discussion AL remains the most fatal post-operative complication in colorectal surgery. Several sealants and tissue adhesives have been investigated in animal and human models to limit the incidence of AL [30].NBCA+MS, classified by the manufacturer as a class III medical device, possesses haemostatic and adhesive features [31].Upon solidification, it forms an antiseptic barrier in surgical settings [32]. When NBCA+MS glue comes into contact with vital tissue, it creates an elastic layer with high tensile strength [31], ensuring firm adhesion conforming to the anatomy of tissue [23]. Since its introduction, cyanoacrylate has gained considerable attention as an anastomotic sealant in colorectal surgery, with controversial results [33-35]. Most studies were animal experiments that reported positive outcomes. Few clinical studies have been conducted on patients undergoing bowel anastomosis. D’amore et al. conducted a single-centre retrospective, uncontrolled study to assess the safety of Glubran 2® for colorectal anastomosis in humans [36]. Their findings revealed AL in only one patient (0.9%), which was lower than that observed in our study. However, they included patients with histological diagnoses of cancer in all possible colorectal locations, and different types of surgical procedures, and lacked a control group for comparison. To our knowledge, this study is the first randomised controlled multicentre study investigating the efficacy of nebulised NBCA+MS in preventing colorectal AL. Our findings indicate that only 6.6% of the patients treated with this glue developed AL, compared to 12.5 % in the control group; however, the difference was not statistically significant, suggesting the possibility of a type II error in the sample size calculation. However, the incidence of Clavien–Dindo complications (grade >2) was significantly lower in the cyanoacrylate group (p = 0.04). Consistent with previous studies [26, 36], no adverse reactions to the modified cyanoacrylate were recorded in our patient cohort, highlighting its safety as an anastomotic sealant in clinical settings. The effectiveness of other biological sealants in preventing AL has been evaluated in clinical settings, and most studies reported a decreased AL rate in their intervention group, suggesting a beneficial effect on colorectal anastomosis healing [26]. However, only Oliver et al. [37], in a randomised, single-blind, parallel study, found a statistically significant difference (18.8% vs. 52.5%, p = 0.039) using fibrin-based biological adhesive (Tissucol Duo ® , Baxter AG, Vienna, Austria) in patients who underwent rectal resection. However, the high incidence of AL reported in their small sample size compared to that in the literature may have influenced the outcome of their statistical analysis. Furthermore, Valsamidis et al. [26] in their systematic review emphasised that variations in defining, identifying, and detecting AL between studies introduce heterogeneity that undermines the reliability of the results. To overcome this limitation, our study adopted the Rahbari NN et al. classification for AL and used a widely accepted classification of postoperative complications such as the Clavien–Dindo classification [26]. Shamiyed et al. [38] reported a complication rate of 5.7% classified as Clavien–Dindo III/IV using Obsidian ASG ® autologous platelet-rich fibrin matrix. However, this study did not include controls. Our study had certain limitations. First, the low statistical power (0.80) and the risk of type II error for the relatively low number of patients recruited, although this is counterbalanced by stringent eligibility criteria. Moreover, protocol deviations occurred in 11 patients who underwent a temporary protective ileostomy at the discretion of the surgeon. Furthermore, the short-term follow-up cannot account for any long-term oncological outcomes caused by sealants. Conclusion The application of the modified cyanoacrylate to seal colorectal anastomoses could be considered safe and could contribute to reducing severe post-operative complications; however, its role in preventing AL remains unclear. Declarations Author Contributions Conceptualization: GT, GM, DFA and AP; Methodology: GT, DFA and AP. Data curation: TN, BM, RE,AD, CG, BC, CR, LG, LV, AA, DFM and GM; Writing - Original draft preparation: GT, GM,DFA and AP; Writing - Reviewing and Editing: all authors. All authors contributed to the article and approved the submitted version. Funding Sources This research did not receive any specific funding from any agencies in the public, commercial, or not-for-profit areas. Conflict of Interest/Disclosure The authors have no conflicts of interests or disclosures to report. Data availability statement All data generated or analysed during this study are included in this article. Further enquiries can be directed to the corresponding author. Ethics statement The studies involving human participants were reviewed and approved by the Ethics Committee of “Azienda Ospedaliera Universitaria Policlinico di Bari”. The patients/participants provided their written informed consent to participate in this study. 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Obsidian ASG(R) Autologous Platelet-Rich Fibrin Matrix and Colorectal Anastomotic Healing: A Preliminary Study. Surg Technol Int. 2021;39:147-54. Tables Table 1 : Baseline characteristics of patients in the control and cyanoacrylate groups Control n=72 Cyanoacilate n=61 p-value Age (years) 68 (58 – 76.5) 72 (61 – 77) 0.30 Sex • Female • Male 25 (34.7%) 47 (65.3%) 29 (47.5%) 32 (52.5 %) 0.13 BMI (Kg/m 2 ) 27 (24.4 – 30) 26 (23.5 -28.7) 0.07 Comorbidities • Smoker • Cardiopathy • Hypertension • Diabetes 11 (15.3%) 15 (20.8 %) 42 (58.3 %) 30 (49.2) 17 (27.9 %) 14 (23 %) 13 (18.1 %) 12 (19.7%) 0.07 0.76 0.29 0.81 ASA • I • II • III • IV 2 (2.8 %) 46 (63.9 %) 23 (31.9 %) 1 (1.4%) 3 (4.9%) 41 (67.2 %) 16 (26.2 %) 1 (1.6 %) 0.83 Table 2 : Operative and post-operative data of patients in the control and cyanoacrylate groups Control n=72 Cyanoarcilate n=61 p-value Operative approach: - Open - Laparoscopy 21 (29.2 %) 51 (70.8 %) 8 (13.1 %) 53 (86.9 %) 0.025 Type of anastomosis - LT - TT 25 (34.7 %) 47 (65.3 %) 13 (21.3 %) 48 (78.7 %) 0.088 Temporary Ileostomy - Yes - No 5 (6.9%) 67 (93.1%) 6 (9.8%) 55 (90.2%) 0.54 Type of Suture - Hand - Stapler 2 (2.8 %) 70 (97.2 %) 0 61 (100%) 0.189 Air leak test - Positive - Negative 1 (1.4 %) 71 (98.6 %) 5 (8.2%) 56 (91.8%) 0.06 Post operative stay (days) 7.5 (6 -10) 7 (6-9) 0.23 Anastomotic Leak Grade (sec. Rahbari NN) - B - C 4 (5.5 %) 5 (7 %) 3 (5 %) 1 (1.6 %) 0.22 Clavien Dindo - 0 - 1 - 2 - >2 0 51 (70.9 %) 12 (16.6 %) 9 (12.5 %) 2 (3.3%) 50 (82 %) 7 (11.5 %) 2 (3.3 %) 0.04 Re-admission at 30 days - Yes - No 2 (2.8%) 70 (97.2 %) 1 (1.6 %) 60 (98.4 %) 0.65 Post-operative death - Yes - No 1 (1.4 %) 71 (98.6 %) 1 (1.6 %) 60 (98.4 % 0.9 Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 05 Aug, 2024 Read the published version in Techniques in Coloproctology → Version 1 posted Editorial decision: Revision requested 15 May, 2024 Reviewers agreed at journal 12 May, 2024 Reviews received at journal 08 May, 2024 Reviewers agreed at journal 08 May, 2024 Reviewers invited by journal 06 May, 2024 Editor assigned by journal 06 May, 2024 Submission checks completed at journal 22 Apr, 2024 First submitted to journal 21 Apr, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4299938","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":301480972,"identity":"e451cf25-ddbd-4921-9301-eb80caf4d949","order_by":0,"name":"Giovanni Tomasicchio","email":"data:image/png;base64,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","orcid":"","institution":"General Surgery Unit “M. Rubino”, DiMePRe-J, University of Bari Aldo Moro, Bari","correspondingAuthor":true,"prefix":"","firstName":"Giovanni","middleName":"","lastName":"Tomasicchio","suffix":""},{"id":301480973,"identity":"67161023-5b98-4a8b-a363-3ee0cf852bc5","order_by":1,"name":"Gennaro Martines","email":"","orcid":"","institution":"Azienda Universitaria Ospedaliera Consorziale - Policlinico Bari","correspondingAuthor":false,"prefix":"","firstName":"Gennaro","middleName":"","lastName":"Martines","suffix":""},{"id":301480974,"identity":"de82c4f6-90ad-443e-9e69-ba9ccb3507d1","order_by":2,"name":"Nicola Tartaglia","email":"","orcid":"","institution":"Department of Medical and Surgical Sciences, DSMC, University of Foggia, Foggia","correspondingAuthor":false,"prefix":"","firstName":"Nicola","middleName":"","lastName":"Tartaglia","suffix":""},{"id":301480975,"identity":"6386a110-037e-45bc-b5be-b6312d4f6f72","order_by":3,"name":"Massimo Buonfantino","email":"","orcid":"","institution":"General Surgery Unit, Hospital “San Paolo”, Bari","correspondingAuthor":false,"prefix":"","firstName":"Massimo","middleName":"","lastName":"Buonfantino","suffix":""},{"id":301480976,"identity":"eb50d246-25f2-4369-8232-4c5106ecc46a","order_by":4,"name":"Enrico Restini","email":"","orcid":"","institution":"General Surgery Unit, Hospital “L. Bonomo”, Andria","correspondingAuthor":false,"prefix":"","firstName":"Enrico","middleName":"","lastName":"Restini","suffix":""},{"id":301480977,"identity":"0827c181-8915-4648-8c72-dafcc84c8233","order_by":5,"name":"Barbara Carlucci","email":"","orcid":"","institution":"General Surgery Unit “M. Rubino”, DiMePRe-J, University of Bari Aldo Moro, Bari","correspondingAuthor":false,"prefix":"","firstName":"Barbara","middleName":"","lastName":"Carlucci","suffix":""},{"id":301480978,"identity":"7018e3dd-4c60-4505-af6a-0fd2b01895a4","order_by":6,"name":"Carlo Giove","email":"","orcid":"","institution":"General Surgery Unit “M. Rubino”, DiMePRe-J, University of Bari Aldo Moro, Bari","correspondingAuthor":false,"prefix":"","firstName":"Carlo","middleName":"","lastName":"Giove","suffix":""},{"id":301480979,"identity":"2d39ed8c-89e6-47e3-9cc6-6d08b871bab3","order_by":7,"name":"Agnese Dezi","email":"","orcid":"","institution":"General Surgery Unit “M. Rubino”, DiMePRe-J, University of Bari Aldo Moro, Bari","correspondingAuthor":false,"prefix":"","firstName":"Agnese","middleName":"","lastName":"Dezi","suffix":""},{"id":301480980,"identity":"998c48e7-0992-425b-90b5-1def86a55bb3","order_by":8,"name":"Chiara Ranieri","email":"","orcid":"","institution":"General Surgery Unit “M. Rubino”, DiMePRe-J, University of Bari Aldo Moro, Bari","correspondingAuthor":false,"prefix":"","firstName":"Chiara","middleName":"","lastName":"Ranieri","suffix":""},{"id":301480981,"identity":"8a5ff9bb-9fbc-4fd7-b242-8a65bc9230d9","order_by":9,"name":"Gaetano Logrieco","email":"","orcid":"","institution":"General Regional Hospital \"F. Miulli\", Acquaviva delle Fonti, Bari","correspondingAuthor":false,"prefix":"","firstName":"Gaetano","middleName":"","lastName":"Logrieco","suffix":""},{"id":301480983,"identity":"47bfa1b6-5dd2-45c4-b533-62db20d12d96","order_by":10,"name":"Leonardo Vincenti","email":"","orcid":"","institution":"General Surgery Unit, IRCCS “Saverio De Bellis”, Castellana Grotte","correspondingAuthor":false,"prefix":"","firstName":"Leonardo","middleName":"","lastName":"Vincenti","suffix":""},{"id":301480986,"identity":"a2d05d75-f301-4fbb-af91-0903213afbb8","order_by":11,"name":"Antonio Ambrosi","email":"","orcid":"","institution":"Department of Medical and Surgical Sciences, DSMC, University of Foggia, Foggia","correspondingAuthor":false,"prefix":"","firstName":"Antonio","middleName":"","lastName":"Ambrosi","suffix":""},{"id":301480988,"identity":"561099f6-142a-4bec-b71d-f3751054f11e","order_by":12,"name":"Donato Francesco Altomare","email":"","orcid":"","institution":"General Surgery Unit “M. Rubino”, DiMePRe-J, University of Bari Aldo Moro, Bari","correspondingAuthor":false,"prefix":"","firstName":"Donato","middleName":"Francesco","lastName":"Altomare","suffix":""},{"id":301480989,"identity":"c69bb4b1-36c6-4a2f-9e43-326c4bda7fb8","order_by":13,"name":"Michele De Fazio","email":"","orcid":"","institution":"General Surgery Unit “M. Rubino”, DiMePRe-J, University of Bari Aldo Moro, Bari","correspondingAuthor":false,"prefix":"","firstName":"Michele","middleName":"","lastName":"De Fazio","suffix":""},{"id":301480990,"identity":"9e1d90ce-835d-4a54-aa4f-8b61eb5fec26","order_by":14,"name":"Arcangelo Picciariello","email":"","orcid":"","institution":"Department of Experimental Medicine, University of Salento, Lecce","correspondingAuthor":false,"prefix":"","firstName":"Arcangelo","middleName":"","lastName":"Picciariello","suffix":""}],"badges":[],"createdAt":"2024-04-21 08:29:04","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4299938/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4299938/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s10151-024-02967-7","type":"published","date":"2024-08-05T15:57:21+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":56478680,"identity":"6069642b-df52-471c-9ab4-eca1a9130211","added_by":"auto","created_at":"2024-05-14 17:52:45","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":470927,"visible":true,"origin":"","legend":"\u003cp\u003eCONSORT diagram of patients in the control and cyanoacrylate groups\u003c/p\u003e","description":"","filename":"Figure1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4299938/v1/5f4acbb18d2e6fb046032583.jpg"},{"id":56478679,"identity":"07515338-3b04-415d-9816-c3e1a6ebb247","added_by":"auto","created_at":"2024-05-14 17:52:44","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":154679,"visible":true,"origin":"","legend":"\u003cp\u003eClavien–Dindo grade and comparison of control and cyanoacrylate groups\u003c/p\u003e","description":"","filename":"Figure2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4299938/v1/f447d22705e07cafa9e952fa.jpg"},{"id":62298725,"identity":"0c847079-88cc-4637-a3dc-a2d223065622","added_by":"auto","created_at":"2024-08-12 16:16:18","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1207975,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4299938/v1/2d75cb61-c15e-4088-9e5c-2829b9859035.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Suture reinforcement using a modified cyanoacrylate glue prevents anastomotic leak in colorectal surgery: A prospective multicentre randomised trial.","fulltext":[{"header":"Introduction ","content":"\u003cp\u003eManaging anastomotic leakage (AL) remains challenging for colorectal surgeons. The incidence of AL is estimated to be 2\u0026ndash;4% following colon cancer resection [1] and 10\u0026ndash;20% after rectal anastomosis [2]. AL considerably affects clinical outcomes with an increased risk of permanent stoma, urinary, defaecatory, and sexual dysfunction, thereby increasing health care expenditure [3, 4]. Moreover, AL increases the risk of local recurrence and decreases overall survival by delaying the initiation of adjuvant cancer treatments [5, 6].\u003c/p\u003e\n\u003cp\u003eThe aetiology of AL is complex and multifactorial. Many preoperative risk factors [7], including patient-related factors (such as sex, malnutrition, obesity, American Society of Anesthesiologists (ASA) score, smoking history, cardiovascular disease, nonsteroidal anti-inflammatory drugs usage, neoadjuvant chemoradiotherapy, age, altered gut microbiota), cancer-related factors (stage, distance from the anal verge), and surgeon-related factors [8, 9], such as the surgeon\u0026rsquo;s expertise and experience, type of anastomosis, and use of faecal diversion by temporary stoma, are implicated [10, 11].\u003c/p\u003e\n\u003cp\u003eTherefore, adopting preventive measures is highly recommended. Although patient- and cancer-related risk factors cannot be modified, several intraoperative procedures have been implemented to prevent this serious complication, such as indocyanine green injection to assess adequate perfusion of the distal colon, reinforcement of the anastomosis by additional manual stitches and/or collagen patches or sealants, and suture protection with an omental flap [12-16].\u003c/p\u003e\n\u003cp\u003eAmong the possible options to reinforce and protect anastomosis, cyanoacrylate glue application has significantly reduced AL in colon anastomosis in a porcine model [17-20] and prevents suture leakage after sleeve gastrectomy [21]. Furthermore, cyanoacrylate is widely used in endoscopy for the emergency management of patients with upper gastrointestinal bleeding because of its adhesive and haemostatic seal when nebulised and sprayed on injured tissues [22]. Furthermore, the sealing effect creates an antiseptic barrier against bacteria [23]. The application of cyanoacrylate glue in vascular surgery [24], urology [25], and bariatric surgery [21] has been previously described.\u003c/p\u003e\n\u003cp\u003eConsidering its mechanical, physical, and biological properties and safety, cyanoacrylate glue can facilitate the healing of colorectal anastomoses and reduce the AL rate, as demonstrated in experimental and uncontrolled clinical studies [26].\u003c/p\u003e\n\u003cp\u003eThe distance of the anastomosis from the anal verge is a well-recognised risk factor for AL; therefore, low/ultralow anastomosis is generally protected by a covering ileostomy, whereas anastomoses performed on the intraperitoneal tracts of the colon and rectum are considered to have a low AL risk. Therefore, using a covering stoma to protect the surgical anastomosis involving the upper part of the rectum remains ambiguous, and is often left to the discretion of the surgeon.\u003c/p\u003e\n\u003cp\u003eThis prospective, randomised, multicentre trial aimed to evaluate the role of a nebulised modified cyanoacrylate in preventing AL in colorectal surgery.\u003c/p\u003e"},{"header":"Patients and methods ","content":"\u003cp\u003eA prospective, multicentre, parallel-arm, randomised controlled superiority trial was conducted between June 2021 and January 2023 across five high-volume tertiary referral centres for colorectal surgery. A power analysis was conducted to determine the number of patients enrolled in each study arm. The study protocol was approved by all local ethics committees in accordance with the Declaration of Helsinki and registered at ClinicalTrials.gov (ID number: NCT03941938).\u003c/p\u003e\n\u003cp\u003eThis study included consecutive patients diagnosed with histologically confirmed primary adenocarcinoma of the high-medium rectum without internal and/or external sphincter muscle involvement, with a distal margin of the tumour at least 8 cm from the anal verge, stage T2-T4 on magnetic resonance imaging (MRI) before neoadjuvant chemoradiation. Patients with squamous cell carcinoma, stage T1 or T4 adenocarcinoma with pelvic side wall involvement or requiring sacrectomy or prostatectomy (partial or total), unresectable primary rectal cancer or inability to complete R0 resection, rectal cancer \u0026lt; 8 cm from the anal verge requiring coloanal or ultra-low rectal anastomosis, recurrent rectal cancer, previous pelvic malignancy, inability to return for postoperative follow-up, and inability to sign informed consent were excluded. Preoperative colonoscopy of the entire colon, computed tomography (CT) scan staging, and preoperative tumour and nodal staging using MRI and/or endorectal ultrasonography were performed for all participants. Surgery was performed within 8\u0026ndash;12 weeks (56\u0026ndash;84 days) after the completion of neoadjuvant therapy, when indicated. All patients were fully informed about the study, and informed consent for inclusion in the study was obtained. The participants were informed of their right to withdraw from the study or refuse initial enrollment at any point.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRandomisation\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eComputer-generated randomisation was used to create an allocation sequence to assign patients to different study arms. Randomisation was centrally controlled by an operator who was not involved in the study. Patients were randomised only after the completion of neoadjuvant chemotherapy (when indicated) and before surgery. Patients randomised to the cyanoacrylate glue arm received anastomotic reinforcement with nebulised modified cyanoacrylate glue using the related special catheters for open or or laparoscopic surgery, whereas no anastomotic reinforcement was used in the control group. The modified cyanoacrylate used to reinforce the anastomosis is Glubran 2 (GEM S.r.l \u0026ndash; Viareggio -Italy), a synthetic surgical biodegradable cyanoacrylate-based glue (NBCA+MS), modified by the addition of a monomer Metacryloxysulfolane (MS) into N-Butyl-CyanoAcrylate (NBCA). As part of the educational intervention, all surgeons underwent training using a video demonstrating the surgical technique for the application of nebulised NBCA+MS..\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eOperative protocol\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePatient preparation for rectal surgery followed the general Rules for Good Clinical Practice. Mechanical bowel preparation using an oral polyethylene glycol solution was performed according to the surgeon\u0026rsquo;s preference, and antibiotic and antithrombotic prophylaxis were started immediately before surgery. The patients were placed in the lithotomy position for the abdominal and perineal procedures. Abdominal procedures (open or laparoscopic) were performed according to the oncological guidelines, including total mesorectal excision with adequate lymph node retrieval and at least 1 cm of distal clearance with an end-to-end or latero-terminal Knight\u0026ndash;Griffen anastomosis. A pneumohydraulic test was performed to check for AL, and additional sutures were applied in positive tests. Following the enhanced recovery after surgery protocol [27], the nasogastric tube was removed in the operating room after surgery completion, and the urinary catheter was removed within 72 h for rectal resection. Early mobilisation was strongly encouraged in all patients on the first post-operative day. Patients were allowed to drink clear liquids in the post-operative period once awake and were able to drink safely.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePost-operative management\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePostoperative care was provided in accordance with the current standards directed by the operative surgeon. Narcotics or analgesics for pain were initially administered through the parenteral route (intramuscular, intravenous, or epidural), followed by oral administration when the patient resumed oral intake. Oral intake was allowed according to the patients\u0026rsquo; tolerance. The patients returned to the ambulatory clinic for post-operative follow-up after 30 days. During follow-up, the post-operative data were recorded, and proctography was performed by transanal injection of 100 mL of hydro-soluble contrast medium (Gastrografin, sodium amidotrizoate and meglumine amidotrizoate, Bayer S.p.A.) to check the integrity of the anastomosis. AL was graded according to the classification system developed by Rahbari NN, et al. Patients who did not attend the follow-up were contacted by a research nurse by phone or email, where available, to ascertain whether the patient had experienced any complications and/or adverse events treated in other hospitals. Patients unavailable for postoperative evaluation were considered \u0026ldquo;lost to follow-up\u0026rdquo;.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eOutcomes measures\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDemographic data (age, sex, weight, BMI (kg/m\u003csup\u003e2\u003c/sup\u003e), ASA classification, smoking status, and comorbidities) and intraoperative data (type of operative approach, operative time, type of anastomosis, and sutures) were recorded. Postoperative complications were classified in accordance with the Clavien\u0026ndash;Dindo classification [28] and recorded along with the length of in-hospital post-operative days, 30-day readmission rate, and death. AL was defined as a defect in the intestinal wall integrity at the colorectal anastomotic site, leading to communication between the intra- and extraluminal compartments [29], with the presence of faecal discharge from the pelvic drainage at any time after surgery, rectovaginal fistula (defined as faecal or mucus discharge from the vagina), and pelvic sepsis (defined by the collection of pus/faecal material in the pelvis documented by a CT scan). ALs were classified according to the Rahbari et al. classification: grade A, AL requiring no active therapeutic intervention; grade B, AL requiring active therapeutic intervention but manageable without relaparotomy; and grade C, AL requiring re-laparotomy [29].\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSample size determination:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe expected mean percentage of AL after rectal cancer is 16%, and a reduction to 10% was considered clinically significant. The sample size calculation determined that 67 patients per arm was sufficient to reject the null hypothesis with a power of 0.8 and a type I error probability of 0.05, with a confidence level of 95% (sample size calculated by R Studio Version 1.1.419 \u0026ndash; \u0026copy; 2009-2018 RStudio, Inc.). To account for a predicted 5% estimated loss to follow-up, the sample size was calculated as 138 (134+4).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical methods\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll statistical analyses were performed in an intention-to-treat manner. No interim analyses were planned. A P-value of 0.05 indicated statistical significance. The Student\u0026rsquo;s t-test was used to provide an unadjusted estimate of the difference between treatment arms. Analysis of covariance, a more robust method that allows the control of key differences in baseline characteristics, was used to enable adjusted comparisons.\u003c/p\u003e\n\u003cp\u003eSimilar to the primary outcome, continuous secondary outcomes (such as safety and efficacy) were modelled using t-tests and analysis of covariance. The relationship between AL and other possible adverse factors was evaluated using univariate and multivariate regression analyses. When the complete case analysis excluded more than 5% of patients owing to missing data, exploratory analyses were performed to investigate the effect of missing data. To explore the mechanism of missing data and the validity of a complete case analysis for each endpoint, patient characteristics were compared between those with and without missing data, and multilevel logistic regression models were used to identify any associations between prognostic variables and determine if data were missing at random. The prognostic effect of each baseline parameter on AL outcomes (present/absent) was analysed using logistic regression. All parameters were analysed individually using logistic regression, and parameters with a probability level less than 0.1 were selected for analysis using stepwise multivariable regression. A polychotomous stepwise logistic regression model was used to correlate prognostic factors with Clavien\u0026ndash;Dindo classification grades. Multilevel logistic regression was used to estimate the odds ratios (ORs) for conversion to laparotomy, intraoperative complications, and postoperative complications between the treatment groups.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eThis study included 152 patients with primary adenocarcinoma of the high-medium rectum who were randomised into two arms. Following the completion of 30-day post-operative follow-up by 133 patients \u003cstrong\u003e\u003cem\u003e(Figure 1)\u003c/em\u003e\u003c/strong\u003e, 72 and 61 were randomised into the control (median age, 68, interquartile range [IQR] 58\u0026ndash;76.5; 34.7% women) and the anastomotic reinforcement groups (median age, 72, IQR 61\u0026ndash;77; 47.5% women), respectively. No statistically significant differences in baseline characteristics were observed between the two groups (\u003cstrong\u003e\u003cem\u003eTable 1)\u003c/em\u003e\u003c/strong\u003e\u003cem\u003e.\u003c/em\u003e However, the operative approach significantly differed between the two groups; 53 patients (86.9%) in the anastomotic reinforcement group underwent a laparoscopic approach compared to 51 patients (70.8%) in the control group (\u003cem\u003ep = 0.0255).\u003c/em\u003e Moreover, the operative time was significantly longer in the control group than in the anastomotic reinforcement group (180 min, IQR 150\u0026ndash;240 vs. 160, IQR 135\u0026ndash;180, respectively; \u003cem\u003ep = 0.0129\u003c/em\u003e). No conversion to laparotomy was reported in patients who had laparoscopic intervention. The end-to-end anastomosis was the most frequent type of anastomosis performed in both groups (65.3 % vs. 78.7%), without statistical difference \u003cem\u003e(p = 0.088)\u003c/em\u003e. Only two patients (1.5 %) in the control group had a hand anastomosis. The air leak test was positive in one patient (1.4%) in the control group and five patients (8.2%) in the anastomotic reinforcement group (\u003cem\u003ep = 0.059\u003c/em\u003e), and all patients had hand suture reinforcement.\u003c/p\u003e\n\u003cp\u003eA protocol deviation with a temporary protective ileostomy was done in five (6.9%) and six (9.8%) patients in the control and anastomotic reinforcement groups, respectively, with no statistically significant difference (p = 0.54). No significant difference was observed in the duration of in-hospital stays between the two groups (7.5 days, IQR 6\u0026ndash;10 vs. 7 days, IQR 6\u0026ndash;9; p = 0.23). Clavien\u0026ndash;Dindo complications (grade \u0026gt;2) were significantly higher in the control group (9 [12.5%] vs. 2 [3.3%]; p = 0.04) (\u003cstrong\u003e\u003cem\u003eFigure 2)\u003c/em\u003e\u003c/strong\u003e. Four patients in the control group had Clavien\u0026ndash;Dindo grade 3 complications; one had grade 3A, and three had grade 3B, while only one patient in the cyanoacrylate group had grade 3B, which required intervention under general anaesthesia. Fatal complications requiring intensive care unit management were reported in two patients in the control group, one with single-organ failure (grade 4A) and one with multi-organ failure (grade 4B). None of the patients in the anastomotic reinforcement group experienced grade 4 complications. Mortality due to post-operative complications was reported in one patient in both groups (grade 5).\u003c/p\u003e\n\u003cp\u003eALs were observed in nine patients (12.5%): four grade B and five grade C in the control group vs. four patients (6.6%), three grade B and one grade C in the anastomotic reinforcement group; however, this difference was not statistically significant (p = 0.36). No adverse effects were reported due to the application of nebulised NBCA+MS around the colorectal anastomosis. No significant differences in 30-day readmission and post-operative death rates were observed between the groups (\u003cstrong\u003e\u003cem\u003eTable 2).\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNone of the parameters analysed using logistic regression and/or stepwise multivariate regression were statistically significant for AL. Among them, heart diseases increased the risk of leakage by 2.89 times (OR 2.89; 95% CI: 0.84\u0026ndash;9.89), which was not statistically significant (\u003cem\u003ep = 0.091).\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eConcerning the Clavien\u0026ndash;Dindo grade \u0026gt; 1 complications, patients with higher ASA scores (\u0026gt; 2) are at significantly increased risk (three times higher) of developing complications (OR = 3.35, 95% CI: 1.37\u0026ndash;8.18) than those in the control group (p \u0026lt; 0.01).\u003c/p\u003e\n\u003cp\u003eThe risk of developing Clavien\u0026ndash;Dindo grade \u0026gt; 1 complications was lower in women than in men (OR = 0.41, 95% CI: 0.15\u0026ndash;1.08). Moreover, two patients who had undergone hand anastomosis experienced five times higher risk than those who underwent stapler procedures to develop Clavien\u0026ndash;Dindo complications grade ˃ 1 (OR = 8.7, 95% CI: 0.64\u0026ndash;119); however, the difference for both parameters was not statistically significant.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eAL remains the most fatal post-operative complication in colorectal surgery. Several sealants and tissue adhesives have been investigated in animal and human models to limit the incidence of AL [30].NBCA+MS, classified by the manufacturer as a class III medical device, possesses haemostatic and adhesive features [31].Upon solidification, it forms an antiseptic barrier in surgical settings [32]. When NBCA+MS glue comes into contact with vital tissue, it creates an elastic layer with high tensile strength [31], ensuring firm adhesion conforming to the anatomy of tissue [23].\u003c/p\u003e\n\u003cp\u003eSince its introduction, cyanoacrylate has gained considerable attention as an anastomotic sealant in colorectal surgery, with controversial results [33-35]. Most studies were animal experiments that reported positive outcomes. Few clinical studies have been conducted on patients undergoing bowel anastomosis. D\u0026rsquo;amore et al. conducted a single-centre retrospective, uncontrolled study to assess the safety of Glubran 2\u0026reg; for colorectal anastomosis in humans [36]. Their findings revealed AL in only one patient (0.9%), which was lower than that observed in our study. However, they included patients with histological diagnoses of cancer in all possible colorectal locations, and different types of surgical procedures, and lacked a control group for comparison.\u003c/p\u003e\n\u003cp\u003eTo our knowledge, this study is the first randomised controlled multicentre study investigating the efficacy of nebulised NBCA+MS in preventing colorectal AL. Our findings indicate that only 6.6% of the patients treated with this glue developed AL, compared to 12.5 % in the control group; however, the difference was not statistically significant, suggesting the possibility of a type II error in the sample size calculation. However, the incidence of Clavien\u0026ndash;Dindo complications (grade \u0026gt;2) was significantly lower in the cyanoacrylate group (p = 0.04). Consistent with previous studies [26, 36], no adverse reactions to the modified cyanoacrylate were recorded in our patient cohort, highlighting its safety as an anastomotic sealant in clinical settings.\u003c/p\u003e\n\u003cp\u003eThe effectiveness of other biological sealants in preventing AL has been evaluated in clinical settings, and most studies reported a decreased AL rate in their intervention group, suggesting a beneficial effect on colorectal anastomosis healing [26]. However, only Oliver et al. [37], in a randomised, single-blind, parallel study, found a statistically significant difference (18.8% vs. 52.5%, p = 0.039) using fibrin-based biological adhesive (Tissucol Duo\u003csup\u003e\u0026reg;\u003c/sup\u003e, Baxter AG, Vienna, Austria) in patients who underwent rectal resection. However, the high incidence of AL reported in their small sample size compared to that in the literature may have influenced the outcome of their statistical analysis. Furthermore, Valsamidis et al. [26] in their systematic review emphasised that variations in defining, identifying, and detecting AL between studies introduce heterogeneity that undermines the reliability of the results. To overcome this limitation, our study adopted the Rahbari NN et al. classification for AL and used a widely accepted classification of postoperative complications such as the Clavien\u0026ndash;Dindo classification [26]. Shamiyed et al. [38] reported a complication rate of 5.7% classified as Clavien\u0026ndash;Dindo III/IV using Obsidian ASG\u003csup\u003e\u0026reg;\u003c/sup\u003e autologous platelet-rich fibrin matrix. However, this study did not include controls.\u003c/p\u003e\n\u003cp\u003eOur study had certain limitations. First, the low statistical power (0.80) and the risk of type II error for the relatively low number of patients recruited, although this is counterbalanced by stringent eligibility criteria. Moreover, protocol deviations occurred in 11 patients who underwent a temporary protective ileostomy at the discretion of the surgeon. Furthermore, the short-term follow-up cannot account for any long-term oncological outcomes caused by sealants.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThe application of the modified cyanoacrylate to seal colorectal anastomoses could be considered safe and could contribute to reducing severe post-operative complications; however, its role in preventing AL remains unclear.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAuthor Contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eConceptualization: GT, GM, DFA and AP; Methodology: GT, DFA and AP. Data curation: TN, BM, RE,AD, CG, BC, CR, LG, LV, AA, DFM and GM; Writing - Original draft preparation: GT, GM,DFA and AP; Writing - Reviewing and Editing: all authors. All authors contributed to the article and approved the submitted version.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding Sources\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis research did not receive any specific funding from any agencies in the public, commercial, or not-for-profit areas.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of Interest/Disclosure\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors have no conflicts of interests or disclosures to report.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll data generated or analysed during this study are included in this article. Further enquiries can be directed to the corresponding author.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe studies involving human participants were reviewed and approved by the Ethics Committee of \u0026ldquo;Azienda Ospedaliera Universitaria Policlinico di Bari\u0026rdquo;. The patients/participants provided their written informed consent to participate in this study. This study protocol was reviewed and approved the Ethics Committee of \u0026ldquo;Azienda Ospedaliera Universitaria Policlinico di Bari\u0026rdquo;. The study protocol was approved by all local ethics committees in accordance with the Declaration of Helsinki and registered at ClinicalTrials.gov (ID number: NCT03941938).\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eThomas MS, Margolin DA. Management of Colorectal Anastomotic Leak. 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Obsidian ASG(R) Autologous Platelet-Rich Fibrin Matrix and Colorectal Anastomotic Healing: A Preliminary Study. Surg Technol Int. 2021;39:147-54.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003e\u003cstrong\u003eTable 1\u003c/strong\u003e: Baseline characteristics of patients in the control and cyanoacrylate groups\u003c/p\u003e\n\u003ctable border=\"1\" width=\"660\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd valign=\"top\" width=\"25%\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd valign=\"top\" width=\"25%\"\u003e\n\u003cp\u003e\u003cstrong\u003eControl\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003en=72\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd valign=\"top\" width=\"25%\"\u003e\n\u003cp\u003e\u003cstrong\u003eCyanoacilate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003en=61\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd valign=\"top\" width=\"25%\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003ep-value\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd valign=\"top\" width=\"25%\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eAge (years)\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd valign=\"top\" width=\"25%\"\u003e\n\u003cp\u003e68 (58 \u0026ndash; 76.5)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd valign=\"top\" width=\"25%\"\u003e\n\u003cp\u003e72 (61 \u0026ndash; 77)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd valign=\"top\" width=\"25%\"\u003e\n\u003cp\u003e0.30\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd valign=\"top\" width=\"25%\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eSex\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u0026bull; Female\u003c/p\u003e\n\u003cp\u003e\u0026bull; Male\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd valign=\"top\" width=\"25%\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e25 (34.7%)\u003c/p\u003e\n\u003cp\u003e47 (65.3%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd valign=\"top\" width=\"25%\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e29 (47.5%)\u003c/p\u003e\n\u003cp\u003e32 (52.5 %)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd valign=\"top\" width=\"25%\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e0.13\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd valign=\"top\" width=\"25%\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eBMI\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e(Kg/m\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd valign=\"top\" width=\"25%\"\u003e\n\u003cp\u003e27 (24.4 \u0026ndash; 30)\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd valign=\"top\" width=\"25%\"\u003e\n\u003cp\u003e26 (23.5 -28.7)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd valign=\"top\" width=\"25%\"\u003e\n\u003cp\u003e0.07\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd valign=\"top\" width=\"25%\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eComorbidities\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u0026bull; Smoker\u003c/p\u003e\n\u003cp\u003e\u0026bull; Cardiopathy\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026bull; Hypertension\u003c/p\u003e\n\u003cp\u003e\u0026bull; Diabetes\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd valign=\"top\" width=\"25%\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e11 (15.3%)\u003c/p\u003e\n\u003cp\u003e15 (20.8 %)\u003c/p\u003e\n\u003cp\u003e42 (58.3 %)\u003c/p\u003e\n\u003cp\u003e30 (49.2)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd valign=\"top\" width=\"25%\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e17 (27.9 %)\u003c/p\u003e\n\u003cp\u003e14 (23 %)\u003c/p\u003e\n\u003cp\u003e13 (18.1 %)\u003c/p\u003e\n\u003cp\u003e12 (19.7%)\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd valign=\"top\" width=\"25%\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e0.07\u003c/p\u003e\n\u003cp\u003e0.76\u003c/p\u003e\n\u003cp\u003e0.29\u003c/p\u003e\n\u003cp\u003e0.81\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd valign=\"top\" width=\"25%\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eASA\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u0026bull; I\u003c/p\u003e\n\u003cp\u003e\u0026bull; II\u003c/p\u003e\n\u003cp\u003e\u0026bull; III\u003c/p\u003e\n\u003cp\u003e\u0026bull; IV\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd valign=\"top\" width=\"25%\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e2 (2.8 %)\u003c/p\u003e\n\u003cp\u003e46 (63.9 %)\u003c/p\u003e\n\u003cp\u003e23 (31.9 %)\u003c/p\u003e\n\u003cp\u003e1 (1.4%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd valign=\"top\" width=\"25%\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e3 (4.9%)\u003c/p\u003e\n\u003cp\u003e41 (67.2 %)\u003c/p\u003e\n\u003cp\u003e16 (26.2 %)\u003c/p\u003e\n\u003cp\u003e1 (1.6 %)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd valign=\"top\" width=\"25%\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e0.83\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2\u003c/strong\u003e: Operative and post-operative data of patients in the control and cyanoacrylate groups\u003c/p\u003e\n\u003ctable border=\"1\"\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd width=\"160\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"160\"\u003e\n\u003cp\u003e\u003cstrong\u003eControl\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003en=72\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"160\"\u003e\n\u003cp\u003e\u003cstrong\u003eCyanoarcilate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003en=61\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"160\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003ep-value\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"160\"\u003e\n\u003cp\u003e\u003cstrong\u003eOperative approach: \u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e-\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; Open\u003c/p\u003e\n\u003cp\u003e-\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; Laparoscopy\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"160\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e21 (29.2 %)\u003c/p\u003e\n\u003cp\u003e51 (70.8 %)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"160\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e8 (13.1 %)\u003c/p\u003e\n\u003cp\u003e53 (86.9 %)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"160\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e0.025\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"160\"\u003e\n\u003cp\u003e\u003cstrong\u003eType of anastomosis \u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e-\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; LT\u003c/p\u003e\n\u003cp\u003e-\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; TT\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"160\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e25 (34.7 %)\u003c/p\u003e\n\u003cp\u003e47 (65.3 %)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"160\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e13 (21.3 %)\u003c/p\u003e\n\u003cp\u003e48 (78.7 %)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"160\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e0.088\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"160\"\u003e\n\u003cp\u003e\u003cstrong\u003eTemporary Ileostomy\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e-\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; Yes\u003c/p\u003e\n\u003cp\u003e-\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; No\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"160\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e5 (6.9%)\u003c/p\u003e\n\u003cp\u003e67 (93.1%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"160\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e6 (9.8%)\u003c/p\u003e\n\u003cp\u003e55 (90.2%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"160\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e0.54\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"160\"\u003e\n\u003cp\u003e\u003cstrong\u003eType of Suture \u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e-\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; Hand\u003c/p\u003e\n\u003cp\u003e-\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; Stapler\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"160\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e2 (2.8 %)\u003c/p\u003e\n\u003cp\u003e70 (97.2 %)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"160\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e0\u003c/p\u003e\n\u003cp\u003e61 (100%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"160\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e0.189\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"160\"\u003e\n\u003cp\u003e\u003cstrong\u003eAir leak test \u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e-\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; Positive\u003c/p\u003e\n\u003cp\u003e-\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; Negative\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"160\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e1 (1.4 %)\u003c/p\u003e\n\u003cp\u003e71 (98.6 %)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"160\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e5 (8.2%)\u003c/p\u003e\n\u003cp\u003e56 (91.8%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"160\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e0.06\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"160\"\u003e\n\u003cp\u003e\u003cstrong\u003ePost operative stay\u003c/strong\u003e (days)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"160\"\u003e\n\u003cp\u003e7.5 (6 -10)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"160\"\u003e\n\u003cp\u003e7 (6-9)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"160\"\u003e\n\u003cp\u003e0.23\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"160\"\u003e\n\u003cp\u003e\u003cstrong\u003eAnastomotic Leak Grade \u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e(sec. Rahbari NN)\u003c/p\u003e\n\u003cp\u003e-\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; B\u003c/p\u003e\n\u003cp\u003e-\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; C\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"160\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e4 (5.5 %)\u003c/p\u003e\n\u003cp\u003e5 (7 %)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"160\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e3 (5 %)\u003c/p\u003e\n\u003cp\u003e1 (1.6 %)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"160\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e0.22\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"160\"\u003e\n\u003cp\u003e\u003cstrong\u003eClavien Dindo \u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e-\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; 0\u003c/p\u003e\n\u003cp\u003e-\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; 1\u003c/p\u003e\n\u003cp\u003e-\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; 2\u003c/p\u003e\n\u003cp\u003e-\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; \u0026gt;2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"160\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e0\u003c/p\u003e\n\u003cp\u003e51 (70.9 %)\u003c/p\u003e\n\u003cp\u003e12 (16.6 %)\u003c/p\u003e\n\u003cp\u003e9 (12.5 %)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"160\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e2 (3.3%)\u003c/p\u003e\n\u003cp\u003e50 (82 %)\u003c/p\u003e\n\u003cp\u003e7 (11.5 %)\u003c/p\u003e\n\u003cp\u003e2 (3.3 %)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"160\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e0.04\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"160\"\u003e\n\u003cp\u003e\u003cstrong\u003eRe-admission at 30 days\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e-\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; Yes\u003c/p\u003e\n\u003cp\u003e-\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; No\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"160\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e2 (2.8%)\u003c/p\u003e\n\u003cp\u003e70 (97.2 %)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"160\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e1 (1.6 %)\u003c/p\u003e\n\u003cp\u003e60 (98.4 %)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"160\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e0.65\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"160\"\u003e\n\u003cp\u003e\u003cstrong\u003ePost-operative death \u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e-\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; Yes\u003c/p\u003e\n\u003cp\u003e-\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; No\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"160\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e1 (1.4 %)\u003c/p\u003e\n\u003cp\u003e71 (98.6 %)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"160\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e1 (1.6 %)\u003c/p\u003e\n\u003cp\u003e60 (98.4 %\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"160\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e0.9\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"techniques-in-coloproctology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"tcol","sideBox":"Learn more about [Techniques in Coloproctology](http://link.springer.com/journal/10151)","snPcode":"10151","submissionUrl":"https://submission.nature.com/new-submission/10151/3","title":"Techniques in Coloproctology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Colorectal surgery, suture reinforcement, cyanoacrylate, anastomotic leakage","lastPublishedDoi":"10.21203/rs.3.rs-4299938/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4299938/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eIntroduction\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAnastomotic leakage (AL) is the most frequent life-threating complication following colorectal surgery. Several attempts have been made to prevent AL. This prospective, randomised, multicentre trial aimed to evaluate the role of nebulised modified cyanoacrylate in preventing AL after rectal surgery\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePatients submitted to colorectal surgery for carcinoma of the high-medium rectum across five high-volume centres between June 2021 and January 2023 entered the study and were randomized into group A (anastomotic reinforcement with cyanoacrylate) and group B (no reinforcement) and followed-up for 30 days. Anastomotic reinforcement was performed via nebulization of 1 cc of a modified cyanoacrylate glue. Preoperative features and intraoperative and post-operative results were recorded and compared. The study was registered at ClinicalTrials.gov (ID number: NCT03941938).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e133 out of 152 patients (control group, n = 72; cyanoacrylate group, n = 61) completed the follow-up. Clavien–Dindo complications grade \u0026gt;2 were significantly higher in the control group (12.5% vs. 3.3%, p=0.04). ALs were detected in nine patients (12.5%) in the control group (four grade B and five grade C) and in four patients (6.6%), in the cyanoacrylate group (three grade B and one grade C); however, despite this trend, the differences were not statistically significant (p = 0.36). No adverse effects were reported.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eUse of modified Cyanoacrylate application to seal colorectal anastomoses is safe and could help to reduce severe post-operative complications; however, its role in the AL prevention remains unclear.\u003c/p\u003e","manuscriptTitle":"Suture reinforcement using a modified cyanoacrylate glue prevents anastomotic leak in colorectal surgery: A prospective multicentre randomised trial.","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-05-14 17:52:38","doi":"10.21203/rs.3.rs-4299938/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-05-15T19:39:37+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"200611676132340296190634992006521743387","date":"2024-05-12T07:31:43+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-05-08T09:37:52+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"14097263999895069973012534849623305461","date":"2024-05-08T09:19:34+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-05-06T18:28:50+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-05-06T18:26:39+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-04-22T09:51:09+00:00","index":"","fulltext":""},{"type":"submitted","content":"Techniques in Coloproctology","date":"2024-04-21T08:26:33+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"techniques-in-coloproctology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"tcol","sideBox":"Learn more about [Techniques in Coloproctology](http://link.springer.com/journal/10151)","snPcode":"10151","submissionUrl":"https://submission.nature.com/new-submission/10151/3","title":"Techniques in Coloproctology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"f19634dc-b3c3-44fa-96e3-661c7a082e0e","owner":[],"postedDate":"May 14th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2024-08-12T16:08:25+00:00","versionOfRecord":{"articleIdentity":"rs-4299938","link":"https://doi.org/10.1007/s10151-024-02967-7","journal":{"identity":"techniques-in-coloproctology","isVorOnly":false,"title":"Techniques in Coloproctology"},"publishedOn":"2024-08-05 15:57:21","publishedOnDateReadable":"August 5th, 2024"},"versionCreatedAt":"2024-05-14 17:52:38","video":"","vorDoi":"10.1007/s10151-024-02967-7","vorDoiUrl":"https://doi.org/10.1007/s10151-024-02967-7","workflowStages":[]},"version":"v1","identity":"rs-4299938","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4299938","identity":"rs-4299938","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}