Safety and Hemostatic Effectiveness of SURGICEL® Powder (Oxidized Regenerated Cellulose) in Controlling Mild or Moderate Parenchymal or Soft-Tissue Intraoperative Bleeding

Background. Topical hemostats reduce blood loss and optimize patient outcome and health care costs. The choice of agent depends on mode of action and surgical situation. This post-market clinical study evaluated the safety and effectiveness of Surgicel®-P, a powdered form of oxidized regenerated cellulose, designed to help control mild-to-moderate bleeding on broad or raw tissue surfaces. Methods. In a prospective, single-arm, multicenter trial, adult subjects with a target bleeding site (TBS) (mild-to-moderate bleeding for which conventional hemostatic methods were impractical or ineffective) were treated with Surgicel®-P. The primary endpoint was the proportion of subjects showing hemostasis at 5 minutes after application, without re-bleeding needing other hemostatic treatment. Secondary endpoints were these proportions at 3 and 10 minutes. The investigators’ ease-of-use evaluation of Surgicel®-P was recorded via questionnaire. Safety endpoints were the incidences of re-bleeding and thromboembolic events through day 30, and serious adverse events requiring surgical intervention through month 6 with a causal (including unlikely or at least possible) relationship to Surgicel®-P. Results. In 8 centers, 103 subjects were enrolled [median(range) age 64.0(33-88) years], of which 100 completed the study. Two deaths occurred, due to causes unrelated to Surgicel®-P. Surgeries were open (53.4%) or laparoscopic/thoracoscopic (46.6%), and mostly urological (37.9%) and abdominal (32.0%); TBSs included various tissue types, with mild (69.9%) or moderate (30.1%) bleeding over a median(range) surface area of 4(0.02–72.0) cm 2 . The 5-minute hemostatic success rate (primary endpoint) was 87.4%; the 3-and 10-minute rates (secondary endpoints) were 77.7% and 92.2%, respectively. Subgroup analyses showed 3-, 5-and 10-minute rates of 84.7%, 93.1%, 95.8% for mild, versus 61.3%, 74.2%, 83.9% for moderate bleeding, and 80.0%, 90.9%, 96.4% for open versus 75.0%, 83.3%, 87.5% for laparoscopic/thoracoscopic procedures. Within 10 minutes, initial manual compression (27.5%) was progressively abandoned, and additional Surgicel®-P was applied to 17.4% of TBSs. Investigators reverted to suture, cautery or other topical hemostats in 6.8% of procedures. No safety signals were identi�ed. Investigators favorably evaluated the ease of use of Surgicel®-P device. Conclusions. This post-market clinical study supports the safety and e�cacy of Surgicel®-P in controlling mild-to-moderate surgical bleeding in a broad range of surgical procedures


Background
Topical hemostatic agents have acquired an important role in the modern surgical management of perioperative bleeding.[1,2] Uncontrolled surgical bleeding is responsible for a substantial clinical and health care resource utilization burden, speci cally given population ageing and the associated increased prevalence of comorbidities and use of anticoagulants.[3][4][5][6][7] By facilitating hemostasis in situations of mild-to-moderate bleeding where conventional hemostatic measures are insu cient or impractical, the adjunctive use of topical hemostatic agents reduces blood loss and the need for systemic hemostatic drugs and blood transfusions.By reducing surgical time and surgical complications, they ultimately optimize patient health and health care costs.[2,8,9] A variety of absorbable topical hemostatic agents are available which differ in physicochemical properties and mode of action, as well as ease of use, safety, and cost.The optimal choice of agent depends on the surgical scenario and bleeding situation (visibility, anatomy and access) and on the patient's coagulation and comorbidity status.[1,10] The current armamentarium distinguishes mechanical topical agents which provide a structural matrix for hemostasis and are considered the easiest, safest and most economical to use, active agents which rely on human, bovine or recombinant thrombin, gelatin-thrombin matrix generically termed owables, and sealants which are based on human brinogen or (semi)synthetic compounds.[1] Oxidized regenerated cellulose (ORC) is a plant-based polymer, consisting of continuous bers with mechanical hemostatic properties, that was rst introduced as a hemostat in 1943 but is now available in various topical hemostatic formulations.[11,12] ORC provides a matrix for clot formation and enhances platelet activation and adhesion.In addition, because it creates a local acidic milieu, ORC produces coagulative necrosis with a tamponade effect, and exerts local antimicrobial action.[13] As absorbable mechanical hemostats, ORC-based agents are suitable for use in patients with an intact coagulation system.They have been shown effective in facilitating hemostasis in randomized controlled trials in various open, laparoscopic and endoscopic surgery settings, and are one of the most frequently used mechanical hemostats.[1,10] SURGICEL® Original and its family of products were developed to aid in controlling continuous surgical oozing in distinct surgical bleeding situations, and their performance and safety pro le are supported by clinical studies in a wide spectrum of surgical procedures.[14] The recently marketed powdered delivery form of these products, Surgicel® Powder (Surgicel®-P), was designed to aid in mild-to-moderate intensity bleeding in a range of tissue surfaces including broad or raw surfaces and in locations where access or placement of fabric ORC products may be challenging or impractical.[15] Composed of aggregates of ORC ne bers, Surgicel®-P has superior hemostatic e cacy compared to the constituent ORC ne bers because of more favorable surface energetics and surface area.
[16] Studies with liver punch biopsy and liver abrasion in swine, which are acute experimental models of mild-to-moderate bleeding and mild diffuse oozing, respectively, Surgicel®-P has shown superior hemostatic e cacy and faster time-to-hemostasis compared to other commercially available polysaccharide absorbable hemostats.[17] In addition, in the porcine liver abrasion model, Surgicel®-P provided more effective and sustained hemostasis and faster time-to-hemostasis than a combination powder hemostat consisting of thrombin, collagen and chondroitin sulphate.[14] Surgicel®-P combines the ORC powder formulation with a delivery system suitable for either open or laparoscopic/thoracoscopic approaches, that is particularly useful for large surfaces and di cult-toaccess anatomical locations where application of other forms of topical hemostats may be impractical.[15] Here we present a post-market clinical study designed to further evaluate the safety and hemostatic effectiveness of Surgicel®-P in controlling mild or moderate parenchymal or soft-tissue intraoperative bleeding in a clinical practice setting of general, gynecological, urological, and cardiothoracic surgery.

Study Design
This was a prospective, single arm, multicenter trial on the adjunctive use of Surgicel®-P to control surgical hemorrhage (capillary, venous or small-arterial) for which conventional hemostatic methods are impractical or ineffective.The trial was designed as a post-marketing study across multiple surgical subspecialties and across open, laparoscopic or thoracoscopic procedures in adult subjects with a mild to moderate 'target bleeding site' (TBS).The TBS was de ned as the rst active bleeding site that was identi ed during surgical dissection, that was related to the primary operative procedure, and that required an adjunctive hemostat.The study intended to include at least 100 evaluable subjects from approximately 8 investigational sites (up to 20 subjects per site) in the United Kingdom and Belgium.The study was performed in accordance with the ICH tripartite guideline for Good Clinical Practice (1996)

Study Subjects and Procedure
Patients aged 18 years or older who required a non-emergent, open or endoscopic, and general, gynecological, hepatopancreatobiliary, cardiothoracic, or urological surgical procedure were considered for enrollment if informed consent was obtained and an INR <1.5 was documented within 24 hours of starting surgery.Subjects were included in the study if an appropriate TBS was identi ed intra-operatively and if none of the exclusion criteria were met (Supplementary information 1).These included: residual anticoagulant medication (except aspirin) or antiplatelet/P2Y12 inhibitor medication beyond the appropriate pre-operative wash-out period; any pre-or intra-operative nding that precluded the use of the study product; major arterial or venous bleeding or defect and/or risk of introducing study product into an open blood vessel; a TBS where silver nitrate or any other escharotic chemicals had been applied; a TBS in, around, or in proximity to foramina in bone, or areas of bony con ne, the spinal cord, or optic nerve and chiasm; a TBS in urological procedures where study product could risk blocking the urethra, ureter or a catheter.
For each subject, two Surgicel®-P kits were available in the operating room, made ready-to-use prior to TBS identi cation.The Surgicel®-P single-use applicator and angling tip were used in open procedures, and the Surgicel®-P Endoscopic Applicator in laparoscopic and thoracoscopic procedures.After Surgicel®-P application, the TBS was assessed for hemostasis at 3, 5, and 10 minutes, and just prior to initiating fascial closure in open procedures or to port-site closure in laparoscopic and thoracoscopic procedures.If hemostasis could not be achieved, re-application of Surgicel®-P was allowed during the 10-minute assessment, and, if necessary, also other hemostatic measures.Post-operatively, subjects were followed until hospital discharge, and evaluated for adverse events (AEs) at 30 (+14) days clinically, and for serious adverse events (SAE) related to SURGICEL®-P and requiring surgical intervention at 6 months (±30 days) clinically or by voice call.
Each investigator was asked to complete an Ease-of-Use survey for their rst 2 open and rst 2 endoscopic procedures performed within the study.Questionnaires were to be completed as soon as possible, but within approximately 72 hours.

Study Endpoints
The primary endpoint was the proportion of subjects achieving hemostatic success at 5 minutes, which was de ned as hemostatic control at the TBS at the 5-minute evaluation point after the application of Surgicel®-P, without re-occurrence of bleeding needing other hemostatic treatment, until the initiation of fascia closure.Re-application of Surgicel®-P was allowed and did not affect subsequent effectiveness endpoints.The secondary effectiveness endpoints were the proportions of subjects achieving this criterium at 3 and 10 minutes following the initial Surgicel®-P application.The 5-minute primary endpoint has conventionally been employed in similar studies, [14,18] and the secondary 3-and 10-minute endpoints were included for comparison with broader preclinical and clinical experience with topical hemostats.[14,17,[19][20][21] The investigators' evaluation of the ease-of-use of the Surgicel®-P delivery system was investigated using a questionnaire survey.

Safety Monitoring
Investigators monitored AEs from the time of Surgicel®-P application through the 30-day and 6-month follow-up points and adjudicated all AEs for their relationship with study product and procedure.Speci c safety endpoints were the incidence of thromboembolic events and TBS re-bleeding events requiring medical/surgical intervention through day 30, and SAEs requiring surgical intervention through month 6, which were considered to have an unlikely, possible, probable, or causal relationship to the study treatment.An internal independent Product Safety Committee reviewed cumulative safety data and adjudicated all events for the speci c safety endpoints.

Statistical Analysis
Primary and secondary endpoints were analyzed using the intention-to-treat (ITT) set, which consisted of all subjects for whom a TBS was identi ed, and summarized descriptively [frequency count and percentage with 2-sided Clopper-Pearson 95% con dence interval (CI)]; missing data were considered as failures.Analyses on the per-protocol (PP) set (evaluable set), which consisted of all ITT subjects who had no major protocol deviation affecting the primary endpoint and who had data available for this endpoint, were considered supportive.Effectiveness endpoints were also strati ed by bleeding severity (mild or moderate) and surgical approach (open versus endoscopy).The primary endpoint was compared between surgical approaches using the Chi-Square test.Ease-of-Use questionnaire data were summarized descriptively.Safety endpoints were analyzed using the safety set, which consisted of all subjects who received study product, and summarized descriptively (frequency count and percentage); missing safety data were not imputed.Software SAS ® version 9.4 or higher was used.

Subjects and Surgical Procedures
Of the 132 subjects who provided informed consent, 29 subjects were screen failures for either intraoperative ndings precluding study treatment (16 subjects), failing in-or exclusion criteria (12 subjects), and patient withdrawal prior to surgery (1 subject) (Figure 1).As a result, 103 subjects were included in the ITT set.A total of 100 subjects completed the study as planned, while 2 subjects died during followup prior to the 6-month visit and one subject was lost to follow-up.One subject, although treated, had a major protocol deviation due to failing to meet an inclusion criterion and was excluded from the PP set, which resulted in 102 evaluable subjects included in the PP set.There were 8 investigative sites, each having enrolled 2-20 evaluable subjects.
The median total surgical procedure duration was 197 min (range 32-895 min), median total time in the operating room was 244 min (range 81-995 min) and median total postoperative hospital stay was 5 nights (range 0-76 nights, data unavailable for n=1).The median estimated total intra-operative blood loss amounted to 150 mL (range 5-4,000 mL), and blood and blood product transfusions were given in 13/103 subjects (12.6%).

Effectiveness Endpoints
The primary endpoint analysis (Figure 3) in the ITT set showed the percentage of subjects achieving hemostatic success at Of note, for two subjects, the 10-minute hemostasis assessment was not performed as the fascia was closed at 5 minutes and 8 minutes; these subjects were considered as successes given the speci c clinical bleeding scenarios with hemostatic success at 3 and 5 minutes without rebleeding or the subsequent need for additional treatment.

Safety
Over 6-month follow-up, a total of 257 AEs occurred in 70/103 subjects (68.0%) (safety set), which included 33 SAE in 24 subjects (23.3%) and 19 severe AEs in 15 subjects (14.6%) (Table 2).There were no AEs or SAEs, speci cally, no post-operative TBS-rebleeding or thrombo-embolic events, considered by the investigator to be unlikely, possibly, probably or causally related to Surgicel®-P.A total of 64 subjects (62.1%) experienced at least one AE that was categorized as unlikely, possibly, probably or causally related to the study procedure.Seven subjects experienced AEs of ileus, which were considered anticipated for their procedure.All cases of ileus were dynamic/functional and resolved with non-surgical treatment and without sequalae.The AE and SAE occurred most frequently within the system classes of gastro-intestinal disorders (43/103 subjects [41.7%]) and infections and infestations (27/103 subjects [26.2%]).Two subjects (1.9%), both known with pancreatic cancer, died between the day-30 and the month-6 visit: one subject died at 3 months from an undetermined cause, and one subject died at 6 months due to pulmonary embolism after chemotherapy.Surgeon Ease-of-Use Questionnaire were collected for a total of 43 procedures, including 19 open and 22 laparoscopic and 2 thoracoscopic procedures (Supplementary Information 2).For the majority of procedures, investigators either 'agreed' or 'strongly agreed' that Surgicel®-P was easy and quick to prepare for application [41/43 (95.3%)] and could be easily applied to the TBS [39/43 (90.7%)], that the investigator could exactly control the amount of Surgicel®-P applied to the TBS [30/43 (69.8%)] and could adequately cover a broad area of bleeding [40/43 (93.0%)], and that excess Surgicel®-P was easy to irrigate/aspirate out of surgical site without disturbing the clot at the TBS [29/36 (80.5%)].Similarly, for the majority of procedures, the investigators 'agreed' or 'strongly agreed' feeling con dent about the ability of the product to achieve and maintain hemostasis [37/43 (86.1%) and 37/43 86.1%), respectively].A subgroup analysis according to surgical approach (Figure 4) showed a similar response pattern for open and laparoscopic/thoracoscopic procedures; across the different survey items, the proportion of surgeons who 'strongly agreed' varied between 42.1% and 84.2% for the open approach (median 63.2%), and between 28.6% and 54.2% for the laparoscopic/thoracoscopic approach (median 45.8%) (Figure 4).

Discussion
This post-market clinical follow-up study shows that Surgicel®-P is effective and safe in controlling mildto-moderate surgical bleeding in adults undergoing major general, gynecological, urological and cardiothoracic procedures.Hemostatic success and safety were demonstrated for both open and laparoscopic or thoracoscopic approaches, and surgeons favorably the use of Surgicel®-P and the delivery system.This real-world data supports the Surgicel®-P e cacy data from in vivo animal models and con rms its indication within the Surgicel® group of products for continuous bleeding on raw or broad surfaces, or anatomically complex surgical sites.[14,17] The observed 5-minute hemostatic success rate of 87.4% indicates that the adjuvant use of Surgicel®-P can control most appropriately selected mild-to-moderate bleeding sites and thus helps to avoid bystander damage from additional hemostatic measures such as ligature or cautery.Longitudinal evaluation showed that most of these bleeding sites were controlled earlier, at 3 minutes.Manual compression, which was initially applied in approximately one third of bleeding sites, was almost completely abandoned within 10 minutes, when hemostatic success exceeded 90%.These data con rm that Surgicel®-P exhibits equal or superior hemostatic performance to other Surgicel® formulations used for similar indications.[19,20,22] Expectedly, the 5-minute hemostatic success rate was lower for moderate (74.2%) than mild (93.1%) bleeding sites.Although the optimal choice of a topical hemostat is primarily dependent on the surgical scenario and the agent's mechanism of action, bleeding intensity critically determines time to hemostasis.However, secondary endpoint analyses at earlier and later time points showed that over time, the difference between mild and moderate bleeding sites declined, with both reaching more than 80% hemostatic control within 10 minutes.This is consistent with ndings in the animal models where Surgicel®-P was shown to be effective for both mild and moderate bleeding from liver punch biopsies or liver abrasions.[17] Within the 10-minute time frame of the study, approximately one fth of procedures required additional treatment, but this consisted mostly of repeat application of Surgicel®-P.Subsequent reversion to standard of care was deemed necessary in only 6.8% of procedures, further con rming the e cacy of Surgicel®-P for the selected indications.Success rates for laparosopic/thoracoscopic procedures and open procedures showed no statistically signi cant difference, and the ease-of-use survey demonstrated similar agreement pro les for both surgical approaches.
Procedure time and procedural blood loss were captured for the entire surgical procedure.Although median values were consistent with the nature of the procedures, these parameters, along with hospital length-of-stay, showed a high upper end-of-range value due to 1 subject who experienced surgical complications unrelated to the TBS.In this patient, who underwent a laparotomy for a retroperitoneal tumor resection, the target bleeding site exhibited moderate bleeding on the mesentery and showed 5minute hemostatic success with no re-bleeding requiring additional treatment.Also, the maximal procedure time of 895 minutes and hospital length-of-stay of 76 days were observed in a single patient who underwent a Whipple pancreaticoduodenectomy and whose target bleeding site was a mildly bleeding area of the liver parenchyma that showed effective hemostasis for all primary and secondary endpoints.
For the large majority of the procedures, surgeons indicated in the ease-of-use survey that they either agreed or strongly agreed that Surgicel®-P was easy and quick to prepare and could adequately cover a broad area of bleeding, and that they felt con dent in the ability of the product to achieve and maintain hemostasis at the TBS.Similar to its fabric forms, the powdered Surgicel®-P is resorbable, but it is recommended to apply the least amount necessary to obtain hemostasis, and to remove any excess powder when bleeding is controlled.In 97.1% of the procedures, a single applicator was used while most surgeons agreed that this allowed adequate coverage of the bleeding site and that excess product could be easily removed.Considering that two thirds of bleeding sites were mild and one third was moderate, this real-world data con rm that the Surgicel®-P applicator is adequately dosed for its clinical indication.
Whereas appropriately dosed Surgicel®-P product is essentially resorbed within 2-5 weeks, follow-up in this post-market study was extended to 6 months to monitor longer-term complications.Although infrequent, complications of ORC use have been reported.Most concern in ammatory foreign body reactions with granuloma or pseudotumor formation, which are thought to be related to the characteristic acidic environment created by ORC, particularly if excess product is present.[10,23] In addition, mass effect complications have been described due to ORC swelling, resulting, for example, in neural compression syndromes.[10,24] As per manufacturer's instructions, in this study, investigators were advised to irrigate or aspirate excess powder once hemostasis was achieved, while not disturbing the clot.During the extended 6-month follow-up, no safety signals were identi ed, supporting the safety of the adjunctive use of Surgicel®-P.The AEs and SAEs reported were those anticipated following the distinct major surgical procedures in the study, in an adult population with high rates of pre-existing medical and surgical histories.While several AEs were considered to have a possible causal relationship with the procedure, such was not the case for a relationship with the Surgicel®-P device.Speci cally, there were no SAEs, post-operative re-bleeding or thromboembolic events assessed as having a causal relationship (including unlikely or at least possible) to Surgicel®-P.
Because of its single-arm design, the study lacks comparative evaluation of e cacy and safety with other hemostatic agents.However, the longitudinal assessment of hemostasis and the prospective 6month clinical follow-up in an adequately sized patient sample and broad range of major surgical procedures with open and laparoscopic/thoracoscopic approaches provide a robust set of real-world data that validate the e cacy and safety of the product.
Oxidized regenerated cellulose hemostats are particularly useful for surgical sites that show continuous bleeding from broad or raw surfaces, and that is unlikely to stop with conventional methods.Retrospective studies have shown that appropriate use of ORC is associated with reduced hemostatic agent use and hemostat spending relative to the use of other hemostats, while leaving clinical outcome unaffected.[25] Within the Surgicel® family of products, the use of the advanced brillar and SNoW forms were associated with a shorter length of stay and lower all-cause cost than the original sheerwoven Surgicel® product.[26]While these advanced Surgicel®-P products share a superior hemostasis performance, the powder structure of Surgicel®-P also offers improved conformability and adherence to broad surfaces and anatomically complex wound geometry.A recent comparative study in porcine liver and spleen bleeding models showed both powder and sponge gelatin-based mechanical hemostats to be effective for parenchymal surgical bleeding, but powder to be more suitable for mild diffuse bleeding.[27]

Conclusion
The ndings of this post-market clinical follow-up study support the safety and e cacy of the new powder form of oxidized regenerated cellulose, Surgicel®-P in controlling mild to moderate parenchymal surgical bleeding in a broad range of surgical procedures.The design of Surgicel®-P applicators is intuitive and easy to use offering a controlled and consistent expression of powder regardless of device orientation.

Supplementary Files
This is a list of supplementary les associated with this preprint.Click to download.AlAttaretal.SurgicelPManuscriptBMCSurgerySupplementaryinformation.docx

Figure 2 Evaluation
Figure 2

Figure 3 Primary
Figure 3

Table 1 .
Subject Demographics, Surgical Procedure and Target Bleeding Site Characteristics.
*possibly related, probably related, or related