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Ann Thorac Surg 2001;71:1609-1612
© 2001 The Society of Thoracic Surgeons

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Original article: cardiovascular

BioGlue surgical adhesive for thoracic aortic repair during coagulopathy: efficacy and histopathology

^a Department of Surgery, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, Cooper Hospital/University Medical Center, Camden, New Jersey, USA
^b Department of Pathobiology, Auburn University College of Veterinary Medicine, Auburn University, Auburn, Alabama, USA

Address reprint requests to Dr Hewitt, 3 Cooper Plaza, Suite 411, Camden, NJ 08103
e-mail: chewitt{at}umdnj.edu

Presented at the Poster Session of the Thirty-sixth Annual Meeting of The Society of Thoracic Surgeons, Fort Lauderdale, FL, Jan 31–Feb 2, 2000.

	Abstract

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 
Background. We hypothesized that induction of coagulopathy in sheep would model clinical needle hole and surgical bleeding from synthetic graft anastomoses, and that a new tissue bioadhesive (BioGlue) would control postoperative blood loss during surgical repair of the thoracic aorta.

Methods. Sheep were anticoagulated with aspirin and heparin. A bypass was made using end-to-side anastomoses of a graft to a partially occluded descending thoracic aorta. Experimental anastomoses (EXP, n = 9) were treated with BioGlue, and control anastomoses (CON, n = 5) were treated with Surgicel to gain intraoperative hemostasis.

Results. EXP animals exhibited significantly reduced postsurgical bleeding (CON median 955 mL versus EXP median 470 mL, p < 0.003), a reduced rate of blood loss over the first 2 postoperative hours (CON median 210 mL/hr versus EXP median 92.5 mL/hr, p < 0.006), and over the entire recovery period (CON median 158 mL/hr versus EXP median 86 mL/hr, p < 0.05), and reduced total blood loss (CON mean 1497 ± 691 mL versus EXP mean 668 ± 285 mL, p < 0.008). On histologic examination of tissues explanted after 3 months, BioGlue was relatively inert and demonstrated a minimal inflammatory response.

Conclusions. The use of BioGlue significantly reduced the volume and rate of postsurgical bleeding in a coagulopathic sheep model for thoracic aortic operations. Histopathologically, BioGlue generated only a minimal inflammatory response. This new surgical tissue bioadhesive should prove extremely beneficial for coagulopathic patients undergoing thoracic aortic or vascular procedures.

	Introduction

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Thoracic aortic operation for the repair of aneurysms, tissue injury, or other disorders is often complicated by coagulopathy. Several factors may account for this dilemma, including dysfunction of the normal coagulation mechanisms due to excessive hemorrhage, hypothermia, multiple blood transfusions, acidosis, or aortic cross-clamping [1–4]. In turn, this coagulopathy can lead to increased morbidity and mortality secondary to uncontrollable, ensuing hemorrhage. Furthermore, older patients undergoing emergent thoracic aortic operations are frequently using aspirin or other anticoagulants preoperatively for other preexisting conditions; this further predisposes patients to excessive bleeding during surgical intervention.

Various surgical tissue adhesives have been investigated to control bleeding from suture lines and needle holes in synthetic grafts sutured to native aortic tissues. We investigated a new tissue adhesive, BioGlue Surgical Adhesive (CryoLife, Inc, Kennesaw, GA), for the control of bleeding from needle holes and anastomotic suture lines between native thoracic aorta and synthetic bypass grafts using a novel sheep model to induce coagulopathy [5]. We hypothesized that the induction of coagulopathy in sheep would model clinical needle hole bleeding and surgical bleeding from synthetic graft anastomoses, and that this new tissue bioadhesive would provide superior hemostasis and reduce intra- and postoperative blood loss during surgical repair of the thoracic aorta.

	Material and methods

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All experiments were performed under a research protocol approved by the University of Medicine and Dentistry of New Jersey/Robert Wood Johnson Medical School (Camden, NJ) Institutional Animal Care and Use Committee. All animals received humane care in compliance with the "Guide for Care and Use of Laboratory Animals" published by the National Institutes of Health (NIH publication 85-23, revised 1985).

Our method of inducing systemic coagulopathy in a sheep model for thoracic aortic operation has been previously described in detail [5]. Preoperative coagulation profiles were obtained for all animals, including activated clotting time, prothrombin time, activated partial thromboplastin time, fibrinogen, and complete blood count.

Animals were randomly assigned to experimental (EXP) and control (CON) groups preoperatively. The operating surgeon was blinded as to which group each animal was randomized to until completion of the graft anastomoses and attempts to control anastomotic bleeding were begun.

Using sterile operative conditions, a left lateral thoracotomy was performed to expose the descending thoracic aorta and to isolate and protect the posterior spinal arteries. After an intravenous bolus of unfractionated heparin sodium (400 IU/kg; Elkins-Sinn Inc, Cherry Hill, NJ) was administered, the descending aorta was partially cross-clamped distal to the subclavian artery and proximal to the diaphragmatic hiatus. A woven, gelatin-impregnated, synthetic tube graft (Gelweave [15-mm diameter]; Sulzer Vascutek USA, Inc, Austin, TX) was then anastomosed end-to-side to the descending aorta using a clamp-and-sew technique [6]. Intravenous heparin boluses (400 IU/kg) were repeated every 30 minutes after the initial dose, and additional coagulation profiles were obtained. After completion of the anastomoses, the aortic cross-clamps were released and the native aorta was ligated.

Anastomoses in EXP animals (n = 9) were treated with BioGlue, and anastomoses in CON animals (n = 5) were treated with Surgicel (Ethicon, Inc, Somerville, NJ) for control of anastomotic bleeding. The amount of hemostatic agent used in each case was judged by the operating surgeon to be the amount necessary to obtain adequate intraoperative hemostasis. Chest tubes were placed before closure to measure postoperative bleeding.

Total intraoperative and postoperative blood loss was recorded, as were hourly measurements of postoperative chest tube output. Statistical analysis was performed using Student’s t test on normal or log-transformed data or using the post-hypothesis Mann-Whitney rank sum test, as appropriate, assuming statistical significance at p 0.05 or less. Data are presented as either mean ± standard error of the mean or median, as appropriate.

Tissues were harvested at various times, ranging from 2 hours to 3 months. Gross postmortem examination was performed on all animals. Various tissues and organs were harvested for hematoxylin and eosin staining and histopathologic evaluation. Assessments were made for inflammatory changes, hemorrhage, bonding of the BioGlue to tissue, and staining characteristics.

	Results

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Surgical outcomes
Surviving animals (both CON and EXP) did not present with major thrombotic, ischemic, or intracerebral hemorrhagic complications. Postmortem examination of one EXP animal 3 months after operation revealed the presence of an aneurysm at the distal anastomosis of graft to native aorta. Upon pathologic examination, this was concluded to be most likely due to a technical error at the time of the initial operation. With the exception of preoperative mean activated partial thromboplastin time levels that narrowly achieved statistical significance (CON 21 ± 1 seconds versus EXP 25 ± 1 seconds, p = 0.04), there were no substantial differences between CON and EXP with respect to mean preoperative, intraoperative, and postoperative activated clotting time, prothrombin time, activated partial thromboplastin time, fibrinogen, or platelet levels. The mean aortic cross-clamp times were not significantly different between CON and EXP groups (26.0 ± 4.9 minutes versus 26.1 ± 3.6 minutes, p > 0.9).

In comparison to CON, EXP exhibited significantly and dramatically reduced postsurgical bleeding (CON median, 955 mL versus EXP median, 470 mL, p < 0.003) (Fig 1). In addition, the rate of postoperative blood loss (measured through chest tube output) was reduced over the course of the first 2 postoperative hours (CON median, 210 mL/hr versus EXP median, 92.5 mL/hr, p < 0.006), as well as over the course of the entire recovery period (CON median, 158 mL/hr versus EXP median, 86 mL/hr, p < 0.05).

View larger version (20K): [in this window] [in a new window]   Fig 1. Intraoperative, postoperative, and total blood loss in control (CON) versus experimental (EXP) groups.

Histopathology
Explanted tissues were examined at various times, ranging from 2 hours to 3 months after operation. BioGlue deposits were identified in all EXP animals. Grossly, these deposits were brown–red, firm, and pliable. There were solitary, variably sized, circumferential deposits readily observed within the tunica adventitia of the sectioned aortas.

Microscopically, the BioGlue deposits were composed of a homogeneous, eosinophilic material surrounded by a thin, discontinuous zone of mature, fibrous connective tissue. In tissues explanted after 3 months, the histologic examination of specimens with BioGlue was strikingly notable for a relative paucity of prominent inflammatory response (Fig 2). Chronic granulomatous inflammation was seen in rare specimens, which might be expected, as a typical foreign body response. There was no fibrotic response, and multinucleated giant cells were not present in any of the samples. The overall inflammatory response was minimal and inconsistent. It was clear that the BioGlue bonded firmly and was adherent to both surgical tissues and the synthetic graft material (Fig 3).

View larger version (145K): [in this window] [in a new window]   Fig 2. Hematoxylin and eosin-stained specimen demonstrating paucity of inflammatory response in response to BioGlue adjacent to the aortic adventitia. This sample was explanted 3 months after operation (Hematoxylin and eosin, x200).

View larger version (158K): [in this window] [in a new window]   Fig 3. Bonding of BioGlue to synthetic graft material, approximately 3.5 hours after operation (Hematoxylin and eosin, x200).

	Comment

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

The major criticism of the GRF glue appears to be toxicity related to the formaldehyde component [11]. Ennker and associates [12] have described the experimental use of a similar glue in which the formaldehyde component is replaced with pentanedial and ethanedial in an effort to reduce formaldehyde-related toxicity. In lieu of the formaldehyde component used in the GRF glue, BioGlue uses glutaraldehyde, which is thought to demonstrate less histotoxicity. The use of other surgical bioadhesives has become widely accepted in the United States for cardiothoracic and abdominal procedures. The most widely used of these is a two-component fibrin sealant [13–15].

The BioGlue Surgical Adhesive consists of two components, a 10% glutaraldehyde solution and a 45% bovine serum albumin solution, which are kept separate until the time of application [16]. The mechanism of action for BioGlue is based on the chemical reaction between aldehydes and amines. The amines for this reaction are provided by the -amino groups of lysine residues in albumin and extracellular matrix proteins from the tissues. Glutaraldehyde, which is a bifunctional aldehyde, serves as a bridge between albumin molecules and binds albumin to tissue proteins. Thus, this reaction forms a permanent covalent bond between the tissues and the adhesive.

In one animal, it was observed that there was tissue necrosis, consisting of shrunken smooth myocytes with pyknotic nuclei and mineralization in the tunica media. In this animal, aneurysm formation was noted at the distal anastomosis, with loss of elastin fibers and degeneration of the tunica media of the aorta. This medial necrosis appeared to be a consequence of dissection or aneurysm formation due to technical surgical complications and not due to histotoxicity related to BioGlue, as it was not seen in any other EXP subjects and there was no BioGlue in the immediate vicinity of the site of medial degeneration.

The histopathologic findings we have described in sheep are similar to those recently obtained from preliminary investigations of BioGlue explanted from 2 patients enrolled in clinical trials in the United States using this new tissue adhesive for the management of ascending aortic dissection (data not shown). In these 2 patients, BioGlue specimens were explanted at 2 months and 9 months, respectively, after having undergone type A ascending aortic dissection repair. The BioGlue explanted from these 2 patients appeared relatively inert, with only a slight polymorphonuclear inflammatory cell response at the margin of the BioGlue specimen in 1 patient and a complete absence of inflammatory response in the other. Similarly, in neither patient was there a foreign body giant cell reaction, granulomatous inflammation, or obvious phagocytosis of the BioGlue. Therefore, within the time frame reported, BioGlue does not appear to undergo significant resorption or degradation. This finding is considered novel, as it is not typical of the foreign body granulomatous inflammatory response that may have been expected.

BioGlue Surgical Adhesive represents a new entry into the armamentarium of surgical adhesives that does not possess the potential toxicity of formaldehyde seen in the GRF glue. This tissue bioadhesive should prove extremely beneficial, clinically, for coagulopathic patients undergoing thoracic aorta or vascular operations.

	Acknowledgments

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 
This work was supported in part by CryoLife Inc, Kennesaw, Georgia.

	References

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 

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