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Ann Thorac Surg 2000;70:1384-1388
© 2000 The Society of Thoracic Surgeons

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Original articles: cardiovascular

Arteriotomy closure by glued patch in the porcine carotid artery

^a Department of Cardiology, Heart Lung Institute, Utrecht University Medical Center, Utrecht, The Netherlands

Address reprint requests to Dr Borst, Experimental Cardiology, Utrecht University Hospital (Room G02.523), PO Box 85500, 3508 GA Utrecht, The Netherlands
e-mail: exp.cardio{at}hli.azu.nl

	Abstract

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 
Background. A thoracoscopic approach to coronary bypass grafting warrants renewed search for facilitated vascular anastomosis methods. We reassessed tissue adhesion, sealing properties, and histotoxicity of iso-butyl-cyanoacrylate, in a simplified anastomosis model.

Methods. In 12 Dutch landrace pigs, five arteriotomies were made in each carotid artery. The arteriotomies were closed by conventional microvascular suturing or by pericardial patch (Peri-Strips) and iso-butyl-cyanoacrylate. The animals were sacrificed at 2 hours (n = 2), 2 days (n = 5), and 4 weeks (n = 5). The arteries were examined by flow measurement, angiography, and histologic analysis.

Results. The time required to close arteriotomies by conventional suturing was 257 ± 43 seconds (mean ± SD) and by glued patch 51 ± 27 seconds (p < 0.001). In all arteriotomies covered by glued patch, complete hemostasis was obtained. At 2 days and 4 weeks, with both methods the same histologic results were observed. At follow-up, all carotid arteries were patent without stenoses.

Conclusions. Arteriotomy closure by glued patch was simple, fast, reliable, and without signs of histotoxicity. Adhesives deserve to be reconsidered as an alternative to suturing in closed chest beating-heart coronary surgery.

	Introduction

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Progress in coronary surgery on the beating heart and in reduction of surgical access [1, 2] has fostered interest in the development of methods to perform closed chest, thoracoscopic coronary artery bypass grafting (CABG) on the beating heart. With conventional endoscopic instrumentation coronary anastomosis suturing is exceedingly demanding owing to the complex motions in vascular microsurgery, and to the limited working space when the left internal thoracic artery is grafted to the left anterior descending coronary artery [3]. The recent development of master-slave robotic surgery systems [4], however, opens the way to closed chest CABG on the beating heart when an appropriate tissue stabilizer [5] is used.

An alternative approach to facilitate closed chest CABG is the development of a facilitated coronary anastomosis technique. Alternatives to tissue bonding by suturing are tissue adhesives [6–8], mechanical devices [9], and laser welding [10]. The advantages of synthetic adhesives are a reduction in manual complexity and hence in time required for the vascular microsurgery. There is no consensus, however, on the histotoxicity of tissue adhesives [11, 12].

Before the exploration of a glued anastomosis method suitable to the thoracoscopic approach to coronary bypass grafting, we reassessed the tissue adhesion and sealing properties of iso-butyl-cyanoacrylate, Deltacryl, (Havas Medical BV, Weesp, The Netherlands) as well as its histotoxicity, in a simplified anastomosis model, the closure of a carotid arteriotomy. By employing this intermediate stage model, the properties of this particular cyanoacrylate could be evaluated in a more controled and simple way than in an end-to-side coronary anastomosis. Deltacryl was chosen because of its favorable adhesive properties in combination with relatively low toxicity. The objective was to obtain an immediate closure with a minimal amount of glue to avoid compromise of the arterial geometry. Patency and the extent of vessel wall damage were examined histologically at 2 days. Patency, intimal hyperplasia, and arterial geometry were examined at 4 weeks.

	Material and methods

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Animals
Twelve Dutch landrace pigs weighing about 40 kg were used. The animals were fed a normal diet and received humane care in compliance with the "Guide for the Care and Use of Laboratory Animals" prepared by the Institute of Laboratory Animal Resources and published by the National Institutes of Health (National Institutes of Health Publication 86-23, revised 1985). All procedures performed in this study were approved by the Animal Experimentation Committee of the Utrecht University. One day before surgery, all pigs received acetylsalicylic acid (160 mg orally). This was continued (80 mg per day) until they were sacrificed.

Operation and study protocol
The animals were anesthetized and monitored hemodynamically as described before [13]. In each animal, the left and right common carotid artery (internal diameter 3.5 mm) were exposed through a midline pretracheal incision and clamped proximally and distally with two vascular clamps after administration of a single bolus of 150 IU/kg heparin to obtain an activated clotting time (ACT; Hemotec, Inc, Englewood, CO) of twice the control value. The ACT was determined at 0, 5, 60, 90, and 120 minutes after injection.

The carotid artery (outer diameter about 4.5 mm) was completely denuded from all loose periadventitial tissue. Under the operating microscope (Wild M680; Leica AG, Heerbrugg, Switzerland), five longitudinal arteriotomies of 5 mm length were made in each carotid artery (in two animals, four arteriotomies were made). The proximal arteriotomy was repaired with a running polypropylene 8-0 suture (Ethicon, Somerville, NJ) in six bites to achieve hemostasis and served as control. The other arteriotomies were repaired by 0.5 µL of iso-butyl-cyanoacrylate, Deltacryl, in combination with a piece of porcine pericardium (Peri-Strips; Bio-Vascular, Inc, St. Paul, MN) of 1.5 to 2 x 10 mm. In two arteriotomies, the adhesive was applied to the carotid artery wall adjacent to the arteriotomy and the glue was covered by the patch (Fig 1A). In the remaining two arteriotomies, first a small amount of tissue glue was applied to the patch before covering the arteriotomy (Fig 1B). After allowing the adhesive to polymerize for 2 minutes, the vascular clamps were released to reestablish the circulation. All procedures were performed by one investigator (JB) and videotaped to establish duration of arteriotomy closure. The pigs were evaluated at 2 hours (n = 2), 2 days (n = 5), and 4 weeks (n = 5) after surgery by carotid angiography, flow measurement, and quantitative histology as before [13].

View larger version (11K): [in this window] [in a new window]   Fig 1. Schematic drawing of application of tissue adhesive. (A) A small amount of tissue adhesive was applied to the artery adjacent to the arteriotomy and then glue was covered by patch. (B) Tissue adhesive was applied to the patch before covering the arteriotomy

Histologic analysis
The carotid artery was removed en bloc. To preserve its geometry, the artery was pressure-fixated at 80 mm Hg. After 48 hours of fixation in formalin 4%, in each arteriotomy region, two cross sections were taken: one in the middle of the patch that contained the arteriotomy and one near the end of the patch 1 mm distal to the arteriotomy. Sections were stained with hematoxylin and eosin to assess endothelial denudation and smooth muscle cell necrosis at 2 days, and with elastin van Gieson for morphometric analysis of intimal hyperplasia at 4 weeks. Reendothelialization at 4 weeks was assessed by Lectin staining (Lectin from Bandeira Simplicifolia BS-I; Sigma Chemical Co, St. Louis, MO). At 2 days and 4 weeks, an Oil-Red-O staining (Merck, Darmstadt, Germany) was performed to assess cyanoacrylate.

Endothelial injury
At 400x magnification, endothelial denudation (absence of endothelial cell nuclei) along the circumference of the artery was determined and expressed as percentage of the luminal circumference.

Medial necrosis
Hematoxylin and eosin stained sections were digitized and analyzed using the software package AnalySIS (Soft-Imaging Software GmbH, Münster, Germany). At 2 days, medial necrosis was defined as the absence of smooth muscle cell (SMC) nuclei due to karyolysis. The smooth muscle cell nuclei-free areas were expressed as a percentage of the medial area in the cross section.

Intimal hyperplasia
The area bordered by the lumen and the internal elastic lamina was defined as intimal hyperplasia. In the repaired arteriotomy gap, the part that exceeded the estimated inner circumference of the artery was considered luminal intimal hyperplasia (Fig 2).

View larger version (14K): [in this window] [in a new window]   Fig 2. Schematic representation of a cross-section of an arteriotomy, 4 weeks postoperatively. The arteriotomy gap was filled with a layer of repair tissue (dark gray).The area bordered by the lumen and the internal elastic lamina was defined as intimal hyperplasia. In the repaired arteriotomy gap, the part that exceeded the estimated inner circumference of the artery was considered luminal intimal hyperplasia.

	Results

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Surgical procedure
The carotid clamping time to create and close all five arteriotomies was 24 ± 4 minutes. The time required to close the arteriotomy by conventional suturing (n = 24) was 257 ± 43 seconds. The total duration of the procedure of arteriotomy closure by tissue adhesive and patch was 51 ± 27 seconds (n = 92; p < 0.001 versus suturing). This duration consisted of the time required for preparation and drying of the vessel wall before application of tissue adhesive, 29 ± 18 seconds, and the duration of application of tissue glue and patch, 22 ± 20 seconds.

All conventionally sutured arteriotomies showed initial oozing of blood for several minutes (systolic arterial pressure 108 ± 13 mm Hg). In all arteriotomies covered by a patch, complete hemostasis was obtained. In 2 of 92 cases (2%), however, the carotid artery had to be clamped again, owing to leakage of a patch. After application of a small amount of glue, the blood flow was restored and complete hemostasis was achieved. Since both methods of glue application (see Fig 1) showed equally good results, the combined results are reported.

Flow measurements
Mean blood flow rate in the left and right carotid artery after their exposure was 226 ± 61 mL/min and postoperatively it was 217 ± 61 mL/min. At follow-up, 2 days or 4 weeks after operation, the mean flow rate in the carotid artery was 217 ± 57 and 354 ± 78 mL/min, respectively. At 4 weeks, the weight of the animals had increased from approximately 40 kg to 50 to 55 kg.

Angiography
Before sacrifice all anastomoses were angiographically patent, without any evidence of luminal stenosis or aneurysm formation.

Histology
No dissection of the layers of the vessel wall was noticed at 2 days or 4 weeks.

At 2 days, no endothelial injury or denudation was found, except at a small rim adjacent to the arteriotomy. A small rim of medial necrosis was observed bordering the arteriotomy in both the conventionally sutured arteriotomies and the arteriotomy closed by patch and tissue glue. No mural thrombus was observed outside the arteriotomy gap. No medial necrosis was observed in the vicinity of the application site of tissue adhesive (Fig 3). The sections with conventionally sutured arteriotomies showed 8.6% ± 7.1% medial necrosis and the sections with arteriotomies closed by patch and tissue glue showed 6.6% ± 2.9% medial necrosis (p = 0.45). Polymorphonuclear leukocytes were observed in the media adjacent to the arteriotomy in both the conventionally sutured arteriotomy and the arteriotomy repaired by tissue adhesive and patch.

View larger version (143K): [in this window] [in a new window]   Fig 3. At 2 days: transverse cross-section of an arteriotomy closed by tissue adhesive and patch. No medial necrosis was observed in the vicinity of the application site of tissue adhesive (Hematoxylin and eosin stain; original magnification, x 40), (p = patch; bar = 500 µm.)

View larger version (125K): [in this window] [in a new window]   Fig 4. At 4 weeks: transverse cross-section of an arteriotomy closed by tissue adhesive and patch. (A) The arteriotomy gap has been filled with repair tissue. Note the normal lining of the inner circumference of the artery without luminal intimal hyperplasia. The void between patch and vessel wall used to contain cyanoacrylate, which has been dissolved during histologic processing (Elastin van Gieson stain; original magnification, x 40). (p = patch; bar = 500 µm.) (B) Cyanoacrylate (arrow) was still present (Oil-Red-O stain; original magnification, x 40). (p = patch; bar = 500 µm.)

	Comment

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Tissue adhesives
Currently, two main groups of tissue adhesives can be distinguished: cyanoacrylates and fibrin glues. Fibrin glue has insufficient tensile strength to support sutureless anastomoses and is therefore not easily recommended for (micro)vascular surgery [14]. Cyanoacrylate glue derivatives have been used as surgical adhesives for many years. It has a low viscosity. It gains adhesion quickly and has strong adhesive power. A drawback is, however, that it hardens strongly and as a result, lacks elasticity [15]. The limitation of cyanoacrylates are their potential toxicity [11, 14]. With some adhesives, thrombosis, necrosis of the vessel wall, and aneurysm formation have been reported [11]. Other investigators, in contrast, have reported satisfactory results and attribute thrombus formation to technical failure rather than to cytotoxicity [12].

Histotoxicity
The alkyl side chain of alkyl-cyanoacrylates determines the speed of polymerization, flexibility, and toxicity. The higher homologues are in general less toxic and are degraded more slowly [16, 17]. Most studies indicate that the histotoxic effect of cyanoacrylate adhesives on blood vessels is a function of the type and amount of cyanoacrylate applied relative to the vessel wall thickness [15–18].

In the present study in 3.5 mm luminal diameter arteries with a wall thickness of about 400 µm, iso-butyl-cyanoacrylate did not cause any medial necrosis, endothelial denudation, mural thrombus formation, intimal hyperplasia, or aneurysm formation. No leakage of tissue glue into the lumen of the arteries was observed. Arteriotomy closure with pericardium patch and tissue adhesive was quick and satisfactory, without the pathologic changes reported by others [11, 16]. The results did not differ from the conventionally sutured arteriotomy. The present satisfactory result is attributed to the type of cyanoacrylate and the use of a minimal amount, ie, 0.5 µL, of tissue adhesive. When a minimal amount of glue is used, the released quantities of toxic by-products are low and the heat dissipated during polymerization is low. Thus, the present results support earlier promising findings with this class of cyanoacrylates [12, 18]. Proper application of iso-butyl-cyanoacrylate, however, requires relatively dry tissue surfaces.

Limitations of the study
Both the size (inner diameter 3.5 mm and vessel wall thickness of about 400 µm) and the flow (200 to 300 mL/min) of the porcine carotid artery exceeded the resting corresponding values in the human coronary artery at the regular sites of the distal anastomosis. The lack, however, of any smooth muscle cell necrosis in the subadventitial layers of the media suggests that iso-butyl-cyanoacrylate is a promising adhesive for smaller arteries.

Conclusions
Closure of arteriotomies by patch and a minimal amount (0.5 µL) of iso-butyl-cyanoacrylate, was simple, fast, reliable, and satisfactory as to wound healing. In combination with micromechanical tissue bonding or alone, the use of tissue glue should be reconsidered as alternative to suturing when methods are devised to facilitate the creation of a minimally invasive endoscopic vascular anastomosis.

	Acknowledgments

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The authors acknowledge the contributions of Merel Schurink, Cees W. J. Verlaan, Maringa Emons, and colleagues from the Utrecht University Central Animal Facilities. We thank Dr. Erik W. L. Jansen for comments on the manuscript. We thank Dr. Maria Schipper, consultant biostatistician, for assistance in data analysis.

	References

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 

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