TY - JOUR
AU - Cruciani, Tashiana R.
AB - Abstract Current surgical management of deep partial-thickness and full-thickness burn wounds involves early excision and grafting. Blood loss during these procedures can be profound, thus prompting the use of topical hemostatic agents to control and minimize hemorrhage during grafting. The primary endpoint of this multicenter trial was to evaluate the efficacy of fibrin sealant as a topical hemostatic agent during skin grafting. The secondary endpoint was to obtain data to support the existing safety profile of a human fibrin sealant (FS) in participating patients as indicated by the type, severity, and frequency of any adverse events within the 24-hour postoperative period. A multicenter prospective, open label, Phase III multicenter, randomized, comparative clinical trial evaluated the use of fibrin sealant in burn patients undergoing skin graft procedures. Each patient served as his or her own control in this randomized, unblinded study of the effect on time to hemostasis in donor sites treated with the investigational FS product. At operation, 1 contiguous donor skin harvest site was bisected into 2 equal halves, 1 of which was then randomly selected and treated with fibrin sealant. At the end of the fibrin sealant application, the time to hemostasis in each of the donor site halves was identified by the operating surgeon and recorded by the research coordinator. The use of any other topical hemostatic agents was prohibited. A significant difference (P < .001) was demonstrated in the mean time to hemostasis between the fibrin sealant treated donor sites when compared painwise to the control sites. The significant difference was consistent across the 6 participating study centers. There were no adverse events associated with the use of fibrin sealant. The investigational FS product was shown to be efficacious, because it significantly decreases the time to hemostasis at the donor skin harvest site in patients undergoing skin grafting and was noted not to cause any adverse reactions. Hemostasis has been one of the primary goals of surgery throughout the history of medicine. Since the initial description of fibrin to enhance wound hemostasis during World War I, 1 a multitude of other applications have been developed during the past century. Current uses of fibrin sealant range from control of bleeding on the cut surface of a spleen or liver 2,3 to the management of enterocutaneous and pancreatic fistulas. 4,5 Additionally, fibrin sealants have been used for hemostasis at vascular cannulation sites during hemodialysis 6 and extracorporeal membrane oxygenation. 7 Fibrin sealants have also been utilized as adhesive agents during skin grafting and flap procedures. 8,–10 The adhesive and hemostatic properties of fibrin sealants have been found to be particularly useful in the surgical management of burn wounds for several reasons. The excision of burn wounds as well as the harvest of donor skin sites can result in significant hemorrhage. 11 One of the major sources of graft loss in burn wounds is hematoma or seroma formation beneath the skin graft, which may compromise angiogenesis. Fibrin sealant use in the treatment of burn wounds has been reported by several authors;12,–14 however, prospective data regarding the efficacy as related to the hemostatic properties has not been previously reported. This was due mainly to the Food and Drug Administration having not approved the use of any of the fibrin sealant application kits. A concern with the use of fibrin sealants in patients has been the possible risk of viral contamination from the human blood components used in the manufacturing process. Data from Greenhalgh et al, 15 obtained from the investigational use of a commercially prepared human fibrin sealant product, demonstrated the safety of a preparation containing human thrombin for use in burn patients. The primary endpoint of the current study was to evaluate the efficacy of human fibrin sealant (FS) as a topical hemostatic agent in burn patients undergoing skin graft procedures. The secondary endpoint was to obtain data to support the existing safety profile of the product in participating patients as indicated by the type, severity, and frequency of any adverse events within the 24-hour postoperative period. Finally, this study also served to evaluate the usefulness of the Duoflo® (Hemaedics Inc., Malibu, CA) delivery system for FS application during surgery. MATERIALS AND METHODS In a prospective manner, all potential burn surgical candidates were screened based on the inclusion and exclusion criteria of the protocol requirements. The use of the topical hemostatic agent was dependent on patients undergoing autologous skin graft procedures that involved greater than 1% but less than 4% total body surface area (TBSA) of donor skin harvested area. The patients or their appointed legal guardians were approached by the investigators at each center for study participation with an Institutional Review Board-approved informed consent document. This study was performed at Loyola University Medical Center, Maywood, Illinois; Shriners Hospital for Children, Sacramento, California; University of South Alabama, Mobile, Alabama; Regions Hospital in St. Paul, Minnesota, University of California San Diego Medical Center, San Diego, California; Harborview Medical Center, Seattle, Washington and the University of California Irvine Medical Center, Orange, California. The study was conducted in cooperation with Baxter Healthcare Corporation, Glendale, California and the American Red Cross, Arlington, Virginia. The intraoperative study coordination was provided by the clinical research coordinator at each of participating centers and the efficacy measurement of the time to hemostasis was assessed by the surgeon performing the operation. The surgeons also evaluated the delivery device system and ease of use of the application system with a sponsor-provided questionnaire. The study patients were monitored in the 24-hour postoperative period for any adverse events as per protocol requirements and the identified adverse events were captured in the case report forms for further safety analysis. Human Fibrin Sealant The investigational human FS agent consisted of a human topical fibrinogen complex (TFC) and a separate solution of human α-thrombin. The TFC consists of fibrinogen, fibronectin, and Human Factor XIII and is reconstituted with sterile water for injection, USP. The human α-thrombin is reconstituted in a solution of 35 to 45 mmol/L calcium chloride, yielding a thrombin concentration of 250 to 350 IU/ml. Once reconstituted, the 2 solutions are drawn into 2 separate syringes and then placed into the Duoflo® Y-shaped adapter, which allows mixing of the 2 components at the distal portion during topical application. The reconstituted TFC and α-thrombin solution yields 6 ml of fibrin sealant product, which is adequate to cover approximately 194 cm2 (30 square inches) of wound surface area. The admixture must be applied within 4 hours of reconstitution to further ensure application of an optimally sterile product. Study Design and Patient Population This was an open label, multicenter, randomized, prospective, within-subjects controlled, Phase III protocol of patients with deep partial-thickness or full-thickness burns that required burn excision, wound debridement, and skin grafting. Inclusion criteria were the following: any patient greater than or equal to 2 years of age in which a single, contiguous donor harvest area of 2 to 8% TBSA was required for autografting of the burn wound. Written informed consent was required to be obtained from all subjects or their legally appointed guardian. Any patient with an acute or chronic medical condition that caused skin grafting to be contraindicated was excluded, as was any pregnant or lactating female patient. No other topical hemostatic agents could be used on the donor sites during the study evaluation period. Any patient taking medication that could affect the hemostatic mechanism, such as aminocaproic acid, aspirin, heparin, warfarin, indomethacin, or dipyridamole, within 2 weeks of surgery was excluded. Concurrent participation in another clinical trial involving the use of an investigational drug, biologic, or medical device was also a cause for exclusion. Burn Excision and Recipient Sites Burn excision was performed by the surgeons who were participating investigators of the protocol. The surgical approach was per the standard of care at each institution. The skin graft recipient sites were treated with each institution's preferred topical hemostatic agent, as well as with either Sulfamylon® solution 5% (mafenide acetate) double antibiotic solution or silver nitrate saturated dressings for postoperative antimicrobial prophylaxis. Donor Site Preparation and Management A single, contiguous donor skin harvest area measuring between 2 to 8% total body surface are (TBSA) was selected in each study subject. The selected donor site was excised using a fixed dermatome setting throughout the harvest procedure; saline clysis was permitted; however, other solutions such as Pitkin's solution were not. The use of any topical hemostatic agents such as epinephrine, topical thrombin, or thrombin-soaked epinephrine laparotomy sponges were prohibited to either side of the randomized donor study site. After skin harvesting the entire donor site wound bed was blotted with a dry laparotomy sponge, then divided into equivalently sized halves identified as Donor A and Donor B with a median guard. The selected sites, A and B, were then randomly assigned, with a sponsor-provided sealed selection card, to either treatment with FS or no treatment as control. FS was then sprayed onto the selected donor site from the median guard division outward, and at the end of product application the coordinator initiated stopwatches in order to determine the time to hemostasis (TTH). Time to hemostasis was defined by the following 3 criteria, all of which were required before the timing of either site was ended: 1) no fresh blood welling up on the surface of the donor wound bed, 2) no fresh blood collecting at the margins of the donor wound site, and 3) no blood present on a laparotomy sponge when placed at the periphery of the donor wound site. If, after 10 minutes hemostasis was not achieved at either donor site A or B, then the site could be treated with the institution's standard topical hemostatic agent or with an added application of FS. If a 10-minute time point was measured, then the study coordinator documented the time as 10:01 as the time to hemostasis, although the actual TTH was viewed from a statistical perspective as being right-censored. Postoperative Assessments Each subject was monitored during the immediate 24-hour postoperative period for any unusual changes in their general medical condition, a change in prescribed medications, or for any adverse events. An adverse event was defined as any noxious and unintended or unexpected event, sign(s) or symptom(s) that occurred during the conduct of this study. The adverse events were rated according to the severity, seriousness, whether it was unexpected and/or an associated event, and included all events regardless of the presumed relationship between the event and the study agent. Statistical Analysis TTH as previously defined was assigned as the primary endpoint of the study. The study protocol allowed for a modified Wilcoxon signed-rank test which permitted censoring with paired data. However, the censored values were replaced with an arbitrary value (10 minutes + 1 second), and analyzed with the usual Wilcoxon signed-rank test, because there were very few censored values (9 in total: 7 in the control arm and 2 in the FS arm) and all were at 10 minutes. Vital signs, physical exam findings, and safety-related observations were analyzed using descriptive statistics. RESULTS Patient and Donor Site Demographics There were 10 female and 51 male participants. The ages ranged from 22 months to 81 years of age, the median age was 36 and the mean (± SD) age was 33.1 ± 19.0 years. There were 33 Caucasian, 16 Hispanic, 9 African American, 2 Asian, and 1 “other” race participants (Table 1). Table 1. Demographics View Large Table 1. Demographics View Large The TBSA percent of harvest donor sites excised ranged from 2 to 7%, with the median being 3% and the mean (± SD) being 3.4 ± 1.2%. The anterior donor site TBSA % ranged from 1 to 5%, with the median being 2.5% and the mean (± SD) being 2.8 ± 126%. The posterior donor site TBSA % ranged from 1 to 7%, with the median being 4% and the mean (± SD) being 3.6 ± 1.6% (Table 2). Table 2. % TBSA of donor site test area View Large Table 2. % TBSA of donor site test area View Large Efficacy A statistically significant (P < .001) reduction in the mean time to hemostasis of approximately 200 seconds in the FS treatment group vs the control group was demonstrated (Table 3). The difference was consistent across the 6 participating centers. The mean ± SD time to hemostasis was 193 ± 131 (n = 61) seconds in the donor harvest sites treated with FS compared with 393 ± 153 (n = 61) seconds in the control donor harvest sites. The calculated difference in time to hemostasis in the treated donor harvest sites vs the control sites was 199 ± 165 seconds, which was significant by the usual Wilcoxon signed-rank test (P < .001;Table 3). Table 3. Time to hemostasis View Large Table 3. Time to hemostasis View Large Safety There were no associated adverse events associated with the use of FS. There were 76 unrelated adverse events that were reported within the 24-hour postoperative period. All of these were identified to be usual burn-related postoperative events, such as airway management, blood volume replacement, and prophylactic or empiric antibiotic administration. Ease of Use A questionnaire regarding the surgeon's evaluation of investigational product was provided for each of the subjects enrolled in the protocol and this was completed at the end of each surgery. The operating surgeon's satisfaction with the reconstitution and preparation, the ease of use, and the method of administration by way of the Duoflo® device was recorded, as well as each investigator's overall rating of the FS for each of the 61 participating patients. An overall rating of “very satisfied” was noted in 44 of the 61 patient applications (72.1%), whereas an overall rating of “not satisfied” was reported in 1 of 61 applications (1.6%). DISCUSSION In medical and surgical settings the adjunctive benefits of fibrin sealant, whether commercially available or locally prepared, have been used to enhance wound hemostasis or as an adjunct adhesive. In burn wound management, anecdotally the use of fibrin sealant has been reported; however, to date, no available prospective data has been reported in the surgical literature. This clinical trial supports the use of FS in achieving hemostasis in the intraoperative management of blood loss at the donor harvest site. This study supports the hypothesis that FS is an effective topical hemostatic agent when measuring the 3 parameters that define time to hemostasis and then comparing the allocated times recorded to reach hemostasis of 1 contiguous donor skin harvest site that is equally bisected, when randomized into a treated vs nontreated site. The grafted sites were not the focus of the study; however, FS, applied to the recipient site clinically, was associated with enhanced hemostasis and further supports the use of FS in burn patients. The study also demonstrates the endpoint of safety in the immediate 24-hour postoperative period. No significant adverse events outside the usual burn postoperative standard of care treatments were encountered after surgery. There were no reported adverse events specifically related to the FS. The concern over the safety of FS in the United States is due largely to the risk of viral contamination, as with the use of any human blood product. Advances in the screening of the blood supply 16 as well as the use of a solvent and detergent suspension for inactivation of lipid-enveloped viridae in blood products 17 and additionally the nanofiltration process has largely eliminated this concern. The widespread use of commercially produced fibrin sealants in Europe 18 (Hock H, unpublished data; Eibl J, unpublished data; Tisseel®, Immuno AG, Vienna, Austria; Biocol®, CRTS, Lille, France; and Beriplast P®, Behringwerke AG, Marburg, Germany) during the past several years further supports the safety of these products, as do recent United States clinical data. 15 The human fibrin sealant Sealagen® as developed results in uniform admixture of the components with use of the delivery system device. Another issue of concern in surgical patients is exposure to bovine products. The advent of a bovine-free product further decreases a patient's risk of exposure to and the possible development of Factor V antibody formation (Lawson et al, unpublished data). The other area of concern is related to bovine spongiform encephalitis contamination from bovine protein exposure. Finally, the ease of use of the investigational product was examined. Although some investigators voiced concerns about the design and use of the kit, they also concurred with the overall satisfaction of the delivery device and product performance. Further modification of the applicator system could be of benefit, because the current delivery system provides for 6 ml of product to be delivered with subsequent changes of the spray tip often required when application is interrupted because the clotting of the spray tip. There is need for a FS spray device capable of multiple application cycles without the need for frequent manipulations to expedite the optimal and timely usage of the product with minimal waste. CONCLUSIONS The data from this clinical trial supports the safety and efficacy of a commercially prepared human fibrin sealant product in burn surgical procedures requiring donor site harvest. The time to hemostasis was significantly improved at the treated harvest site in this patient population. The safety data obtained here are in accordance with previous reports and provide additional support for the clinical use of FS in patients to further enhance hemostasis. References 1. Gibble JW, Ness PM Fibrin glue: the perfect operative sealant?. Transfusion.  1990; 30: 741– 7. Google Scholar CrossRef Search ADS PubMed  2. Ochsner Mg, Maniscalo-Theberge ME, Champion HR Fibrin glue as a hemostatic agent in hepatic and splenic trauma. J Trauma.  1990; 30: 884– 7. Google Scholar CrossRef Search ADS PubMed  3. Berguer R, Staerkel RL, Moore EE Warning: fatal reaction to the use of fibrin glue in deep hepatic wounds. J Trauma.  1991; 31: 408– 11. Google Scholar CrossRef Search ADS PubMed  4. Alfano D'Andrea A, Constantino V, Speri C, Pedrazzoli S Human fibrin sealant in pancreatic surgery: is it useful in preventing fistulas? A prospective randomized study. Ital J Gastroenterol.  1994; 26: 283– 6. Google Scholar PubMed  5. Park JJ, Clinton JR, Orsay CP, Pearl RK, Stone J, Sorg R, Abarian H Repair of chronic anorectal fistulae using commercial fibrin sealant. Arch Surg.  2000; 135: 166– 9. Google Scholar CrossRef Search ADS PubMed  6. Spotnitz WD Fibrin sealant in the United States: clinical use at the University of Virginia. Thromb Haemost.  1995; 74: 482– 5. Google Scholar PubMed  7. Atkinson JB, Gomperts ED, Kang R Prospective, randomized evaluation of the efficacy of fibrin sealant as a topical hemostatic agent at the cannulation site in neonates undergoing ECMO. Am J Surg.  1997; 173: 479– 84. Google Scholar CrossRef Search ADS PubMed  8. Saltz R, Sierra D, Fledman D Experimental and clinical application of fibrin glue. Plast Reconstr Surg.  1991; 88: 1005. Google Scholar CrossRef Search ADS PubMed  9. Tidrick RT, Warner ED Fibrin fixation of skin transplants. Surgery.  1944; 15: 90– 5. 10. Marchac D, Snador G Face lifts and sprayed fibrin glue: an outcome analysis of 200 patients. Br J Plast Surg.  1994; 15: 306– 9. Google Scholar CrossRef Search ADS   11. Housinger TA, Lang D, Warden GD A prospective study of blood loss with excisional therapy in pediatric burn patients. J Trauma.  1993; 34: 262– 3. Google Scholar CrossRef Search ADS PubMed  12. Achauer BM, Miller SR, Lee TE The hemostatic effect of fibrin glue on graft donor sites. J Burn Care Rehabil.  1994; 15: 24– 8. Google Scholar CrossRef Search ADS PubMed  13. Cronkite EP, Lozner EL, Deaver J Use of thrombin and fibrinogen in skin grafting. JAMA.  1944; 124: 976. Google Scholar CrossRef Search ADS   14. Stuart JD, Kenney JG, Lettieri J Application of single-donor fibrin glue to burns. J Burn Care Rehabil.  1988; 9: 619– 22. Google Scholar CrossRef Search ADS PubMed  15. Greenhalgh DG, Gamelli RL, Lee M Multicenter trial to evaluate the safety and potential efficacy of pooled human fibrin sealant for the treatment of burn wounds. J Trauma.  1999; 46: 433– 40. Google Scholar CrossRef Search ADS PubMed  16. Lackritz Em, Satten GA, Aberle-Grasse J Estimated risk of transmission of the human immunodeficiency virus by screened blood in the United States. N Engl J Med.  1995; 333: 1721– 5. Google Scholar CrossRef Search ADS PubMed  17. Horowitz MS, Rooks C, Horowitz B, Hilgartner MW Virus safety of solvent/detergent-treated antihemophilic factor concentrate. Lancet.  1988; 2: 186– 9. Google Scholar CrossRef Search ADS PubMed  18. McCarthy PM Fibrin glue in cardiothoracic surgery. Transfus Med Rev.  1993; 7: 173. Google Scholar CrossRef Search ADS PubMed  Copyright © 2001 by the American Burn Association
TI - A Multicenter Clinical Trial to Evaluate the Topical Hemostatic Efficacy of Fibrin Sealant in Burn Patients
JF - Journal of Burn Care & Research
DO - 10.1097/00004630-200103000-00003
DA - 2001-03-01
UR - https://www.deepdyve.com/lp/oxford-university-press/a-multicenter-clinical-trial-to-evaluate-the-topical-hemostatic-3IBWmwBQeS
SP - 99
EP - 103
VL - 22
IS - 2
DP - DeepDyve
ER -