alexa A Comparison of Hemostatic Effectiveness and Safety of Two Fibrin Sealant Patch Products after Severe Renal Hemorrhage in Swine Model of Dilutional and Hypothermic Coagulopathy
ISSN: 2167-1222
Journal of Trauma & Treatment
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A Comparison of Hemostatic Effectiveness and Safety of Two Fibrin Sealant Patch Products after Severe Renal Hemorrhage in Swine Model of Dilutional and Hypothermic Coagulopathy

Richard W. Hutchinson1,*, Pullen Shnoda1, Scott T. Wilson2 and Ira W. Daly3
1Ethicon, Inc., a Johnson & Johnson Company, Somerville, NJ, USA
2MPI Research, Inc., Mattawan, MI, USA
3Regulatory and Technical Associates, Inc., Lebanon, NJ, USA
Corresponding Author : Richard W. Hutchinson
Ethicon, Inc., A Johnson & Johnson
Company, PO Box 151
Somerville, NJ 08876-0151, USA
Tel: 908-218-2557
E-mail: [email protected]
Received February 23, 2015; Accepted May 18, 2015; Published June 02, 2015
Citation: Hutchinson RW, Shnoda P, Wilson ST, Daly IW (2015) A Comparison of Hemostatic Effectiveness and Safety of Two Fibrin Sealant Patch Products after Severe Renal Hemorrhage in Swine Model of Dilutional and Hypothermic Coagulopathy. J Trauma Treat 4:251. doi:10.4172/2167-1222.1000251
Copyright: © 2015 Hutchinson RW, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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Abstract

Background: Two fibrin sealant patch products (EVARREST™ and TachoSil™) are approved by the USFDA for use in surgical settings. While these products are among the most likely to be useful for trauma use, they are not approved for this use. There is a clinical need for trauma hemostats.

Methods: A well characterized animal model for severe soft tissue hemorrhage (partial nephrectomy) was combined with another well characterized model for dilutional and hypothermic coagulopathy. The two fibrin sealant patch materials available in the US were each applied to 12 animals. Animal assignment was randomized. If hemostasis could be achieved, the animals were resuscitated and survived for 48 hours.

Results: TachoSil™ was able to achieve hemostasis in 2 of 12 animals which survived to the scheduled necropsy date without significant pathology. For the two successful animals, the mean time to achieve hemostasis was 6.5 (+/-2.12) minutes, and 178.00 (+/-79.22) grams of blood were lost before hemostasis was achieved. EVARREST™ was able to achieve hemostasis in all 12 animals, and all animals survived to the scheduled necropsy date without significant pathology. The mean time to achieve hemostasis was 3.5 (+/-1.45) minutes, and 52.11 (+/-18.92) grams of blood were lost prior to achieving hemostasis.

Conclusions: When fibrin sealant patch products can achieve intraoperative hemostasis, animals can be resuscitated and survive without significant pathology. The two available products vary considerably in intraoperative efficacy.

Keywords
Severe bleeding; Animal model; Partial nephrectomy; TachoSil™; EVARREST™
Introduction
Uncontrolled hemorrhage after injury is a leading cause of preventable death [1]. In trauma cases, coagulopathic conditions and hypothermia are common. A new class of hemostatic products called fibrin sealant patches has the potential to achieve hemostasis more rapidly than other alternatives, and thus may contribute to improved patient stabilization and survival. This class of combination drug/ device product contains an absorbable matrix along with thrombin and fibrinogen. TachoSil™ was approved in the US in 2010, and EVARREST™ (J&J) in 2012 [2]. These two products vary in the matrix material and the concentrations of actives suggesting that they may have different efficacy. TachoSil™ is made from an equine collagen matrix and contains (per cm2): 5.5 mg fibrinogen; 2.0 Units thrombin [3]. EVARREST™ is made from a fully synthetic matrix (Oxidized Regenerated Cellulose and Polyglactin 910) and contains (per cm2): 7.8 mg fibrinogen and 31.5 Units thrombin [4]. The efficacy of the two products was directly compared in a non-survival model of moderate bleeding with a heparin-induced coagulopathy where TachoSil™ was shown to delaminate (i.e. lift off) the treatment surface [5]. We hypothesized that the porous nature of the EVARREST™ backing material would reduce the potential for accumulation of blood behind the patch, and that the increased concentrations of actives would translate to improved hemostatic efficacy.
Fibrin sealant patch products have been assessed and reported in several nonclinical models including vascular injury [6,7], extremity wounds [8], prostatectomy [9], renal [10,11], and liver wounds [12- 15]. The use of Fibrin sealant patches in coagulopathic animals with liver injuries, and in heparinized animals has been demonstrated; however these animals were not taken through a survival period [16- 18]. These products have also been shown to have no excess risk of thrombogenicity [6,19], and to have no impact on wound healing [20]. EVARREST™ has been studied clinically and found safe and effective for partial nephrectomy [21], liver surgery [22] and soft tissue bleeding [23]. TachoSil™ has been studied clinically for hemostasis in the liver, kidney, and cardiovascular system and for sealing air leaks [24,25].
The objective of this study was to conduct a randomized, headto- head comparison of the two commercially available fibrin sealant patch products currently available in the US; and to test the hypothesis that the porous backing materials, along with increased concentrations of thrombin and fibrinogen would translate to improved hemostatic efficacy in a severe bleeding model with trauma-relevant coagulopathy.
Methods
The guidelines propagated by the Care and Use of Laboratory Animals [26] were observed and the protocol was approved by an IACUC. Female Yorkshire swine approximately 3 months of age (22-45 kg) were used. Only one sex was used in this study because it contributed to better uniformity in organ size than would be achieved if a mixture of males and females were used. It was believed that variability in organ size would be a more significant confounding factor than sex differences since the primary mechanism of action for these products (i.e. thrombin/ fibrinogen clotting cascade) is well known. Animals were randomly divided into two groups of twelve each and placed under general anesthesia.
The severe bleeding wound and the dilutional/hypothermic coagulopathy were created using models described previously [11,27] with the minor modifications described here. The caudal pole of the kidney (1 ± 0.5 cm depth) was amputated to create a 2.5 ± 1 cm diameter surface. MAP was maintained during these procedures above 60 mmHg using LRS. Chilled LRS was administered and ice packs were applied to induce hypothermia and a dilutional coagulopathy. The hypothermic condition was achieved when the core body temperature was lowered to 33 ± 0.5°C. Controlled hemorrhage was initiated with approximately 60% of the blood volume being removed from the animal in three stages. Free blood was collected from the abdomen using a Cell Saver; this blood was pooled with the blood removed by catheter then, heparinized, and centrifuged for auto transfusion during the resuscitation period. In parallel, hemodilution was induced by administration of hetastarch and LRS.
Immediately prior to test article application, the site was cleared of blood. The MAP was brought to ≥60 mmHg and a single patch was applied as directed in the Instructions for Use (IFU) for both products. As directed by the IFU for each product, EVARREST ™ (Omrix Biopharmaceuticals Ltd., 14 Einstein Street Weizmann Science Park Nes-Ziona, Israel) was applied dry and TachoSil™ (Nycomed Austria GmbH , St. Peter Strasse 25 A-4020 Linz Austria) was moistened with saline prior to application. The package insert for TachoSil™ allows for wet or dry use, we chose to use the wet application technique because the product is stiff when in the dry state and was better able to conform to the bleeding site when wet. EVARREST ™ used in this study was approximately 5.0 x 7.6 cm whereas the TachoSil™ was approximately 9.5 × 4.8 cm. The application of each EVARREST™ was followed by 3 minutes of manual tamponade. For TachoSil™, 3 minutes of tamponade was initially applied (as per the US package insert); however, this was increased to 5 minutes for TachoSil™ as suggested in the European summary of product characteristics for TachoSil [28]. This was done after the first animal which failed therefore 11 animals had a 5-minute a tamponade time and one animal had a 3-minute time.
After the initial 3 or 5 minute tamponade time, the site was observed for hemostasis. If necessary, patches were removed and replaced with a new patch as per the EVARREST instructions which describe reapplication of a new patch if the placement of the patch is unsatisfactory. If hemostasis was not achieved after application of EVARREST™ or TachoSil™ then the animal was euthanized. Successfully treated sites were observed for a minimum of 15 minutes before closing the animal. The collected blood was auto-transfused and the abdomen was closed. Hemostasis was defined as a lack of free flow blood leakage, minor oozing, or the presence of petechiae.
Arterial CO2 and O2, NaHCO3, base deficit, pH and electrolytes, routine clinical pathology as well as thrombin-antithrombin (TAT), prothrombin fragment 1+2, fibrin/fibrinogen degradation products, D-dimer, and thromboelastography evaluations were conducted on all animals prior to surgery, after hypothermia and dilutional coagulopathy induction, post-resuscitation, and 1 and 2 days post-surgery.
Surviving animals were euthanized 2-days after surgery and evaluated for evidence of post-operative hemorrhage. The major blood vessels of the thoracic and abdominal cavity were evaluated for thrombosis and the abdominal and thoracic viscera were evaluated for evidence of infarction. The area adjacent to the article was evaluated for edema, hematoma, fluid accumulation, and the presence of intrarenal hemorrhage. The necropsies were performed by trained technicians, supervised directly by a board certified pathologist who confirmed the clinical diagnosis. The kidney and lung tissues were fixed and processed for histopathology.
Results
The portion of the right kidney removed from EVARREST™ treated animals was comparable in size and weight to that removed from TachoSil™ treated animals (Table 1).
Twelve of twelve (100%) of the animals treated with EVARREST™ achieved hemostasis and survived the duration of the study. Two of twelve (17%) of the animals treated with TachoSil™ achieved hemostasis, the failures were delamination failures (i.e. bleeding from under the product).
Hemostasis was achieved with EVARREST™ with a mean application rate of 1.08 articles/animal (n=12).
In those animals that achieved hemostasis the mean time to hemostasis for the EVARREST™ treatment group was 3.5 ± 1.44 minutes versus 6.50 ± 2.12 minutes for the TachoSil™ treatment group (n=12 and n=12 respectively). Animals that failed to achieve hemostasis (83% -TachoSil™ treatment group) were not included in this analysis.
Intra-operative blood loss measured after EVARREST™ (n=12) application was 3.4 fold less than that measured after TachoSil™ (n=2) application (52.11 ± 18.92 vs. >178.00 ± 79.92 g) (Table 2).
The mean volume of blood removed during the blood loss phase of the study was similar between EVARREST™ (1220 mL, n=12) and TachoSil™ (1208 mL, n=12) treatment groups. The core body temperature was maintained at 32.9°C for the EVARREST™ and 33.0 °C in the TachoSil™ treatment groups during the hypothermia and hemodilution phase of the study. There were no fatalities during coagulation/hypothermic induction.
The blood analysis conducted after the induction of the coagulopathic condition and prior to article application showed decreased mean hemoglobin, hematocrit and fibrinogen levels as compared to baseline values in EVARREST™ (36%, 41%, and 47%, respectively, n=12) TachoSil™ (36%, 42%, and 49%, respectively, n=12) treatment groups. In addition, prolongations in APTT (32%) and prothrombin times (15%) were observed relative to baseline values in both groups. These changes confirmed the presence of a coagulopathy (Tables 3 and 4). Hemoglobin and hematocrit values returned to or were approaching pretest levels by the post-resuscitation interval in both groups and remained stable. The alterations in APTT and prothrombin times generally resolved by Day 2 post-surgery in both treatment groups (EVARREST™, n=12 and TachoSil™, n=2). Fibrinogen levels were increased relative to pretest values in both treatment groups. All of these changes were attributed to the coagulopathic condition, resuscitation and/or the surgical procedure. No meaningful differences were evident between the EVARREST™ and TachoSil™ treatment groups at any evaluation interval.
At the post-coagulopathy collection time point lactic acid levels were at least 100% higher than baseline in both groups and were progressively increasing between groups, at times as high as 300% at 24-hour post-surgery. At 48-hours post-surgery mean lactic acid levels were substantially elevated (>400%) in the EVARREST™ treatment group and moderately elevated (>150%) in the two surviving animals from the TachoSil™ treatment group. The increases observed in lactic acid levels in both groups were an expected result of the model.
The coagulopathy was monitored intra-operatively using thromboelastography (TEG) and further supported by the coagulation biomarkers after surgery. Mean TEG values (Table 5) did not differ dramatically between the 12 animals treated with EVARREST™ and the 2 surviving TachoSil™ treated animals at any time point and were consistent with the presence of a coagulopathy. The time to initial fibrin formation (mean R value) and fibrin cross-linking (mean K values) was lower for both treatment groups after initiation of the hypothermic and dilutional coagulopathic conditions and for the duration of the study as compared to baseline values. The strength of the clot (MA) was diminished after the hypothermic and dilutional coagulopathic condition was induced and returned to near baseline levels by 24 hours post-surgery.
Coagulation biomarkers evaluated included D-dimer, prothrombin fragment 1 + 2, thrombin-anti-thrombin, and fibrinogen degradation product (Table 4). There were no differences between groups or across time intervals for these parameters except for a significant, increase in D-dimer in the EVARREST™ treatment group following surgery (p<0.001). While the statistical significance was likely due to the small number of TachoSil ™ animals for comparison, this may also be a consequence of the increased concentration of fibrinogen in EVARREST ™ relative to TachoSil ™.
No post-surgical hemorrhage was noted in the animals that completed the study. There was no evidence of thrombosis of the major vasculature of the thoracic or abdominal cavity in the animals that survived. No evidence of infarction of the thoracic or abdominal viscera was identified in the animals that completed the study. Red fluid located within the retroperitoneal space was found in 2 of 12 EVARREST™ animals. The fluid was attributed to an ultrafiltrate that formed from plasma through the EVARREST™/Clot. Edema fluid accumulation adjacent to EVARREST™ was noted in 4 of 12 animals, intraparenchymal hemorrhage was observed in one EVARREST™ treated animal, and a hematoma was observed subjacent to EVARREST™ in one animal. These fluid accumulations, intraparenychmal hemorrhage and the hematoma were all considered secondary to the surgical procedure and were not treatment related. This opinion was corroborated by an assessment from a board certified veterinary pathologist. Similar findings were not noted for the TachoSil™ animals, however, only 2 of 12 TachoSil™ animals survived beyond the surgical procedure therefore meaningful comparisons could not be drawn.
No test patch related macroscopic findings were present in the animals which survived the surgical procedure. Red discoloration and red fluid on the right kidney corresponded microscopically to hemorrhage (subcapsular and/or interstitial). These were considered secondary to the surgical procedure and unrelated to the test patch. All other macroscopic observations were considered incidental.
Microscopic observations for the right kidney were divided into “kidney, right, incision site, interface” (1-2 mm of the kidney at the incision site), “kidney, right, incision site, subjacent” (kidney parenchyma deep to the incision site including the remainder of the cortex, medulla and pelvis, when present) and “kidney, right” (rest of the kidney parenchyma). Microscopic observations at the interface of the test patch with the unincised kidney were recorded under “test patch, interface excluding the incision site”. Findings on the outer surface of the test patch were recorded under “test patch, outer surface”. Any finding related to (or within the) the test patch itself was recorded under “test patch”.
Microscopic findings in both groups were similar in most aspects except the hemorrhage noted within the test patch itself (described under ‘test patch’) which appeared to be slightly more pronounced in the TachoSil™ group (Table 6).
Microscopic findings at the interface of the incision site and the test patch were present in both groups at similar incidence rates and included tubular degeneration/necrosis, tubular vacuolation, tubular casts (casts of protein and red blood cells occasionally admixed with epithelial cells and pyknotic debris), tubular dilatation and hemorrhage. These findings were consistent with the surgical incision and were not considered to be test patch related.
Many of the microscopic findings observed at the incision site interface were also present in the kidney parenchyma subjacent (deep) to the incision site in both groups. These findings were present at similar incidence rates, but were often less severe at the incision site interface with EVARREST™. These findings included tubular casts, tubular degeneration/necrosis, tubular dilatation and tubular vacuolation. These were considered secondary to the surgical procedure and not test patch related.
Hemorrhage was notably decreased subjacent to the patch compared to the incision site interface in both groups. This was noted in 4 of 12 animals in the EVARREST™ group and 0 of 2 animals in the TachoSil™ group. Vascular dilatation was observed in 7 of 12 animals in the EVARREST™ group and 2 of 2 in the TachoSil™ group. Both hemorrhage and vascular dilatation were considered secondary to the surgical procedure.
Microscopic findings in the rest of the kidney parenchyma included tubular degeneration/necrosis, tubular vacuolation, tubular dilatation, tubular cast and hemorrhage. These findings were variably present in both groups but were less frequent and less severe compared to the findings in the kidney parenchyma subjacent (deep) to the incision site. These were considered secondary effects of the surgical incision and were not considered to be test patch related. Lymphocytic infiltrate, healed infarct, and cysts were considered as incidental and/or background findings.
There was minimal proliferation of the plump fibroblasts admixed with small numbers of lymphocytes, plasma cells and macrophages (subacute inflammation) at the interface between the test patch and unincised kidney. These findings were present in all animals in both groups.
EVARREST™ contained numerous enmeshed, refractile variably sized elements embedded within the fibrin which were presumed to be polyglactin 910. TachoSil™ contained fibrin with no enmeshed elements and was limited by a thread like, convoluted, minimally refractile material. Hemorrhage was the only finding noted within the test patch itself in both groups. Hemorrhage was minimal in all animals in the EVARREST™ group (except for a single animal for which it was mild) and moderate in both the surviving animals in the TachoSil™ group.
Microscopic findings in the lungs included minimal to mild chronic-active inflammation (multifocal interalveolar septal thickening and infiltration of eosinophils, macrophages, fewer neutrophils and occasional multinucleate giant cells within the alveolar and bronchial lumen) and occasional hemorrhage. These findings were attributed to Ascaris suum migration, which is common in farm pigs.
Necropsy was performed on ten animals in the TachoSil™ group euthanized immediately following surgery due to patch failure. Hemorrhage was the most common microscopic finding at the interface of the incision site and TachoSil™ presumably due to the abbreviated time between surgery and necropsy. Common microscopic findings in the kidney parenchyma subjacent to the incision site included tubular and vascular dilatation with rare occurrences of tubular casts and hemorrhage. The rest of the kidney parenchyma was normal with the exception of a single animal where minimal interstitial hemorrhage was present.
Unlike recovery animals, proliferation of fibroblasts and subacute inflammation were absent at the interface between the test patch and unincised kidney since these animals were sacrificed immediately after the patch failure. The hemorrhage was moderate to severe within the patch (TachoSil™) itself in most animals.
Evidence of fluid accumulation was observed in two of twelve animals treated with EVARREST™ and 0 of 2 animals treated with TachoSil™. Evidence of edema fluid in the adjacent tissue was observed in 4 of 12 animals treated with EVARREST™ and 0 of 2 animals treated with TachoSil™. Hematoma subjacent to the test patch was observed in 1 of 12 animals treated with EVARREST™ and 0 of 2 animals treated with TachoSil™. Presence of intrarenal hemorrhage was observed in 1 of 12 animals treated with EVARREST™ and zero of two animals treated with TachoSil™. Fluid accumulation, edema in the adjacent tissue, hematoma subjacent to the test patches and presence of intra-renal hemorrhage are consistent with normal physiological responses to recent abdominal surgical procedures and not related to the test patches.
Discussion
Resuscitation protocols have a clear impact on hemostatic abilities of trauma patients, and despite extensive research and clinical advancements, the mortality rate for trauma hemorrhage remains unacceptably high [29]. Hemorrhage is the second leading cause of death in civilian trauma and coagulopathic conditions induced by consumption, dilution, loss, or inactivation of clotting factors, and/ or hypothermia are often associated with significant morbidity [30]. Achieving rapid hemostasis in these situations is essential to successful patient stabilization and survival.
A new class of hemostatic products called fibrin sealant patches have the potential to achieve hemostasis more rapidly than other alternatives, and are among the most likely options to be useful for trauma use. Currently two fibrin sealant patch products are approved by the USFDA for use in surgical settings. These products are not currently indicated for trauma use. This class of combination drug/ device product contains absorbable matrix along with thrombin and fibrinogen. TachoSil™ was the first of these products to be approved in the US in 2010, followed by EVARREST™ in 2012. These two products vary in the matrix material and also the concentrations of thrombin and fibrinogen suggesting that they have different efficacy. We hypothesized that the increased concentrations of thrombin and fibrinogen would translate to improved hemostatic efficacy, and that the porous nature of the EVARREST™ backing material would reduce accumulation of blood behind the patch which can result in increased stress at the treatment site and eventual failure of patch adherence. This mechanism was described previously [5] and verified in the preset study.
In this study, a well characterized animal model for severe soft tissue hemorrhage was combined with a well characterized model for dilutional and hypothermic coagulopathy.
No post-surgical hemorrhage was noted in the animals that completed the study. There was no evidence of thrombosis of the major vasculature of the thoracic or abdominal cavity in the animals that survived for 48 hours post-surgery. No evidence of infarction of the thoracic or abdominal viscera was identified in the animals that completed the study. Red fluid located within the retroperitoneal space was found in association with EVARREST™ in two animals. The fluid was not further characterized but was believed to represent an ultrafiltrate that is “pushed” by pressure out of the blood clot that forms with EVARREST™. Edema fluid accumulation adjacent to EVARREST™ was noted in 4 of 12 animals, intraparenchymal hemorrhage was observed in one EVARREST™ treated animal, and a hematoma was observed subjacent to EVARREST™ in one animal. These fluid accumulations, intraparenychmal hemorrhage and the hematoma were all considered secondary to the surgical procedure and were not treatment related. Similar findings were not noted for the TachoSil™ animals because only 2 of 12 TachoSil™ animals survived beyond the surgical procedure.
Microscopically surgical trauma due to the resection procedure was similar between the twelve animals of the EVARREST™ group and the two animals that completed the study in the TachoSil™ treatment group. The surgical trauma included a relatively thin band of tubular degeneration consisting of vacuolation of the cells lining the tubules, tubular casts, and tubular dilation and tubular necrosis at the periphery of the kidney. These changes were more prominent subjacent to the resection surface and became less severe further away from the surface. All of these changes were consistent with surgical trauma and can be seen in partially nephrectomies or can be associated with renal biopsy procedures not treated with hemostatic agents. The surgical trauma in central areas of the kidney formed triangles with the base of the surgical trauma located at the resection surface and the apex within the medulla of the kidney. Hemorrhage was scattered within these areas and this also represents part of the surgical trauma. This intraparenchymal hemorrhage occurs because the major blood vessels of the kidney are located in the area and as the blood accumulates adjacent to the newly formed clot at the treatment site, pressure forces the blood into the parenchyma. No thrombi were noted beyond that of the immediate resection surface. The traumatic alterations observed in this study, including the intraparenchymal hemorrhages, have been described in similar animal models [12].
Filaments were embedded in exogenous fibrin lakes and pools of the EVARREST™ treated application surfaces. Some of these filaments penetrated a short distance into the renal parenchyma. In other areas the exogenous fibrin coupled with the enmeshed EVARREST™ filaments conformed to the irregular resection surface. The eosinophilic backing of TachoSil™ (xenograft collagen sheet) sat above the exogenous fibrin and did not penetrate into or conform to the irregular shape of the resection surface at the microscopic level of evaluation. Exogenous fibrin (amorphic eosinophilic lakes and pools), endogenous fibrin (fibrils), free erythrocytes and blood clots were located within both EVARREST™ and TachoSil™. The interface between EVARREST™ and TachoSil™ products and the renal parenchyma at the resection surface were similar. This interface consisted of a few fibroblasts admixed with low inconsistent numbers of macrophages and was attributed to the removal of the renal capsule (minimal surgical trauma). The interface between the peritoneum and EVARREST™ or TachoSil™ was unremarkable.
The authors acknowledge limitations of this study include: the use of a surgical injury model rather than a traumatic injury model. This was important because the surgical wound facilitates easier identification of pathologies and because this study included a survival period, but also potentially limits the applicability of this information to renal trauma. Other investigators do not typically include a survival period for these types of evaluations because of the intense clinical attention needed to successfully recover these acidotic, hemo-diluted, hypothermic animals. The use of a surgical model made this practical. We feel that the ability to assess products after the animals have recovered from anesthesia places additional challenges on the product such as higher blood pressure, fibrinolytic activity, and the potential for mechanical disruption due to movement, thus the inclusion of a survival period is a significant advancement over other published data. We acknowledge that auto transfusion of heparinized blood from the cell saver unit during the resuscitation period likely presented an additional coagulopathic challenge for surviving animals. Because all failures occurred during the treatment period prior to administration of heparinized blood, this did not appear to adversely affect animal survival, and further emphasize the durability of these products if they are able to achieve initial hemostasis. We acknowledge that the low number of TachoSil™ animals surviving surgery made meaningful post-surgery comparisons difficult. We acknowledge that tamponade was applied for 3 minutes for the first Tachosil Animal, and potentially this animal might have achieved hemostasis if it had been allowed 5-minutes of tamponade. This would not significantly change the overall conclusions of the study. There were slight, non-significant, differences between the weights and dimensions of the excised tissue for each group. The width was greater in the one group whereas the length was greater in the other group reflecting biological variation in kidney shape. There was no visual indication that bleeding rate was different between the groups since this lesion consistently results in spurting bleeding. We acknowledge that the thromboelastograph data do not reflect anticipated values [31]. We also acknowledge that the 48 hour time period is a limitation of this model. We chose this period because it allowed for identification of sub-lethal pathologies. If longer recovery times were studied, there may be the potential for sub-lethal hemorrhage to occur and resolve without being detectable and thus the 48 hour endpoint was considered the most crucial time. Lastly we acknowledge that the blinding procedure was challenging since the products have dramatically different handling characteristics and appearances and because one of the products required hydration prior to use. Because the article identification was so obvious the surgeons were not truly blinded.
In conclusion, the creation of the coagulopathic condition and subsequent application of the test patches to a severely bleeding partial nephrectomy in the swine was achieved and used to demonstrate the effectiveness of the test patches. When fibrin sealant patch products can achieve intraoperative hemostasis, animals can be resuscitated and survive without significant pathology. The two available products vary considerably in intraoperative efficacy, with improved efficacy noted in the EVARREST™ group.
 
Acknowledgements
The authors would like to thank the staff at MPI Research, Inc., Matawan, MI for the conduct of this study. The authors would also like to thank Dr. Duan Broughton, Dr. Tim Muench and Ms. Taylor Builee helpful discussions during the preparation of this manuscript.
Authorship
R.H. conceived the study. P.S. and S.W. collected and analyzed the data. R.H. and I.D. wrote and edited the manuscript.
Disclosure
R.H and P.S. are employed by Johnson & Johnson Wound Management who funded this research and markets one of the products described in this report. I.D. and S.W. are employed by independent companies contracted to execute this research.

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Table 1 Table 2 Table 3

 

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