Annals of Vascular Surgery
Volume 21, Issue 1 , Pages 56-60, January 2007

Efficacy of Acrylate Tissue Adhesive as Vascular Repair and Hemostatic Material

  • Bassem Y. Sheikh, MD, FRCS, SBNS

      Affiliations

    • Corresponding Author InformationCorrespondence to: Bassem Y. Sheikh, MD, FRCS, FICS, Department of Neurosurgery, King Faisal University, King Fahd Hospital, Jeddah 21382, Saudi Arabia

Department of Neurosurgery, King Faisal University, Jeddah, Saudi Arabia

Jeddah, Saudi Arabia

Article Outline

The objective of the study was to determine the efficacy of utilizing n-butyl cyanoacrylate (NBCA) tissue adhesive glue as a vascular repair and hemostatic material in the closure of vascular wounds using a prospective, animal-based design. The study was performed on the carotid arteries of 22 goats. The experiment was performed on bilateral carotid arteries (44 procedures). In each animal, both carotid arteries were opened by a procedure simulating carotid endarterectomy. On one side, the repair material was conventional sutures; on the other side, NBCA tissue glue was utilized. The main outcome measures were duration of total flow arrest (clamping time), duration of time from start of arterial repair to complete hemostasis after clip removal (repair time), any additional stitches required after repairing either by stitch or by NBCA, and hematoxylin and eosin histopathology preparations. Forty-four simulated carotid endarterectomy and repair procedures were performed in 22 adult goats. The average repair time on the stitch side was 437 sec and on the NBCA side, 169 sec (P < 0.001). The average clamping time on the stitch side was 716 sec and on the NBCA side, 477 sec (P < 0.001). Macroscopic pathological study did not reveal any significant luminal stenosis. Foreign body microscopic changes were similarly present in both the NBCA and stitch groups, with no significant difference. This is a prospective animal-based controlled study looking into the efficacy of NBCA tissue glue as a material for arterial repair in comparison to classical suture repair. NBCA tissue adhesive glue may be of value especially when fast control of bleeding is required.

 

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Introduction 

Hemostasis remains essential during and after any surgical intervention. Careful hemostasis must be maintained to decrease overall blood loss and allow for a dry operative field. It is a dry operative field that permits fine surgical technique. However, in some situations, bleeding may be difficult to control. The use of “monopolar” and “bipolar” cautery machines is commonplace as vascular coagulation devices.1, 2 However, at certain anatomical locations, the use of coagulation machines may not always be feasible or effective.3 A number of topical hemostatic agents that enhance coagulation or bleeding point sealing have been utilized in surgery, varying from absorbable to permanent. These include oxidized cellulose (Oxycel, Becton Dickinson and Company, Franklin Lakes, NJ), oxidized regenerated cellulose (Sugicel, ETHICON, Inc., Johnson and Johnson, Gatwaya, USA), purified gelatin (Gelfoam, Pharmacia and Upjohn Company, Kalamazoo, USA), microfibrillar collagen (Avitene, C.R. Band, Inc., Murray Hill, NJ), and tissue adhesives.4, 5, 6, 7, 8, 9, 10

Even in experienced hands, arterial closure and repair by suturing is a time-consuming procedure. The introduction of varieties of tissue adhesives has led to their use in surgical procedures, providing an acceptable alternative to classical suture technique.11, 12 Cyanoacrylates are hemostatic, rapidly solidifying liquid tissue adhesives that have been utilized in the medical field since the early 1960s.11

n-Butyl cyanoacrylate (NBCA) has been utilized in several surgical applications, including gum repair, corneal perforation repair, skin closure and grafting, tendon and bone repair, and middle ear reconstruction.11, 12, 13, 14, 15, 16 Moreover, NBCA has been utilized to occlude pathological vascular channels in vascular malformations such as cerebral arteriovenous malformations.17, 18 Having hemostatic capability, strong bonding effect, and fast action, NBCA has high potential as an arterial repair and hemostatic material, especially in emergency situations when fast action combined with efficient results are required. To our knowledge, there are currently no animal data comparing the efficacy and safety of arteriotomy closure utilizing NBCA versus the traditional suture technique.

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Materials and Methods 

A prospective animal-based controlled study was designed and performed at King Faisal University (Dammam, Saudi Arabia). The structured research was approved by the research committee of King Faisal University. Twenty-two male adult goats were used in this study. The experiment was performed on both carotid arteries, making a total of 44 procedures. Of these, 22 arterial repairs made the control group utilizing 6-0 polypropylene sutures and 22 arterial repairs comprised the study group utilizing NBCA. Each procedure was performed in a way that simulated carotid artery sharp trauma insult.

Procedure 

In each animal, the procedure was performed on one side of the carotid artery and the wound was closed. The animal was then turned over, and the procedure was repeated on the other side of the carotid artery. Each procedure was performed in the following steps. Under general anesthesia, the animal was prepared on the operating table in the lateral position. Both sides of the neck were shaved, sterilized, and draped, alternating left and right sides to perform the procedure under sterile conditions. The arterial pulses of the carotid arteries were detected manually and marked. Each operative side (right and left) was finished separately before starting the next side. The skin was incised, and a self-retaining retractor was inserted. An operating microscope was used to perform the whole procedure. Intravenous heparin was given just prior to arterial flow interruption. The artery was exposed and dissected circumferentially from the surrounding soft tissues. The arterial flow was interrupted using nontraumatic temporary angled Sugita (Mizuho, Holland) aneurysmal clips, first proximally and then distally. Timing of the procedure started with applying the aneurysmal clips and ended when both clips were removed and complete hemostasis was assured. An incision was made in the carotid artery sharply using a stabbing blade knife, size 11. The arteriotomy was then completed with straight-tip microscissors. A total length of 10 mm arteriotomy was performed. The material used for the arterial repair on the side with stitching was polypropylene 6-0 sutures in interrupted fashion. Each carotid suture arteriorrhaphy was performed with five stitches. On the other side, the carotid trauma arteriotomy was closed solely by NBCA without any additional sutures. On the side where NBCA was used, the following precautions were taken: (1) the ends of the arteriotomy incision were held with a microforceps so as to appose the artery edges, (2) NBCA material was applied directly over the edges in minidroplets using a 1 cc syringe and 25 gauge needle, and (3) the apposition of the edges was maintained with the microforceps until polymerization of the material was completed as indicated by change in the color and texture of the glue. This process of polymerization took an average of 3 sec. All procedures on both sides were performed by the same operator to insure uniformity of the results and unbiased comparison of outcomes. After each arterial repair was performed, the site was observed for 30 min for any bleeding. The time of each procedure (repair time) was calculated from the start of repair (stitch or NBCA) until clip removal and full hemostasis. The total procedure time (clamping time) was calculated from the start of application of the hemostatic clips until their removal after arterial closure and complete stoppage of blood leaking from the arterial repair site. The wound was closed in anatomical layers. Six months later, the animals were killed and specimens underwent hematoxylin and eosin histopathology preparation and study.

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Results 

Twenty-two goats underwent bilateral carotid artery trauma simulation by surgical opening and repair. Carotid arteriorrhaphy was performed successfully on 44 carotid arteries. No postprocedure clinical neurological complication was noted. No evidence of any NBCA arterial emboli was present. The data collected from the study included duration of total flow arrest (clamping time), duration of time from start of arterial repair to complete hemostasis after clip removal (repair time), any additional stitches required either after repair by polypropylene or by NBCA, and hematoxylin and eosin histopathology preparations.

The repair time on the stitch side averaged 437 sec, with minimal time of 399 sec and maximal time of 475 sec. On the NBCA side, the repair time averaged 169 sec, with minimal time of 119 sec and maximal time of 219 sec. The clamping time on the stitch side averaged 716 sec, with minimal time of 665 sec and maximal time of 767 sec. On the NBCA side, the clamping time averaged 477 sec, with minimal time of 391 sec and maximal time of 568 sec. This demonstrates statistically significant differences between the groups in both the repair and clamping times (P < 0.001) (Table I).

Table I. Repair and clamping time (sec) compared between the NBCA and stitch groups, showing a highly statistically significant difference
NBCAStitchP
Repair time169 ± 50437 ± 38
Clamping time477 ± 86716 ± 51<0.001

Additional stitches were used after repair on the NBCA side in one animal (4.5%) and after repair on the stitch side in eight animals (36.4%), with a statistically significant difference between the groups (P = 0.041).

Pathological evaluation included both macroscopic and microscopic studies. Macroscopically, the specimens from both groups did not reveal any luminal stenotic changes or any occlusive complication (Fig. 1). The effects of NBCA glue and stitches on the arterial wall layers, including intima (endothelium, subendothelial connective tissue), internal elastic lamina, media, and adventitia, were evaluated under hematoxylin and eosin histopathological preparations. All preparations failed to show any significant pathological differences between NBCA and stitches in the reaction to adjacent tissue (Fig. 2).

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  • Fig. 1 

    Arterial specimen in cross section taken 6 months after arteriotomy repair utilizing NBCA glue (top) and stitches (bottom). This figure demonstrates preservation of the vascular lumen with no difference between the two groups.

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  • Fig. 2 

    Hematoxylin and eosin histopathological preparations 6 months after arteriotomy repair utilizing NBCA glue (top) and stitches (bottom). Examined under a light microscope ×40. This figure shows a foreign body reaction to NBCA glue (arrowhead) and to stitch, with remnants of a stitch fragment (arrow).

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Discussion 

In spite of advances in the management of bleeding associated with surgery, hemorrhage remains a troublesome concern, particularly in complex cases and high-risk patients. It is not possible to perform technically demanding, often microsurgical procedures without controlling hemorrhage. Moreover, the limited exposure in minimally invasive surgery may make accurate suturing difficult and increase the risk of surgical bleeding. The use of “monopolar” and “bipolar” cautery machines is commonplace as vascular coagulation devices.1, 2 However, at certain anatomical locations, the use of coagulation machines may not always be feasible or effective or may take time to give effective hemostasis.3 Patients suffering from severe blood loss caused by trauma or major surgery require rapid control of bleeding points. A number of topical hemostatic agents that enhance coagulation or bleeding point sealing have been utilized in surgery, varying from absorbable to permanent. These include oxidized cellulose (Oxycel), oxidized regenerated cellulose (Sugicel), purified gelatin (Gelfoam), microfibrillar collagen (Avitene), and tissue adhesives.4, 5, 6, 7, 8, 9, 10 A surgical sealant that effectively secures vascular injury and enhances hemostasis would be of great value for surgeons and might facilitate minimal access surgery. Different kinds of tissue adhesive were investigated before and include fibrin glue, cyanoacrylates, resorcinol formaldehyde, dicarboxylic acid polyethyleneglycol, and gelatin glue.11, 12, 15, 16 The hemostatic agent may have either immediate action, delayed sustained action, or both to maintain hemostasis. Immediate action is required for spontaneous control of bleeding; the action of the agent will decline gradually depending on its half-life and absorption. Sustained hemostasis is important for maintaining adhesive and sealing effects; thus, the agent is expected to remain in tissues for much longer than the time required for normal healing process.

The classical and most widely utilized method for arteriorrhaphy is still suturing. Although suturing is the standard method against which other techniques are compared, it requires certain training and skills to perform and still carries complications: postoperative bleeding, thrombosis and ischemia, and delayed stenosis. Stenosis after suturing may result either from bad technique of tight suture pulling or from a tissue reaction to the suture material itself, leading to intimal hyperplasia at the suture line. Ischemia time during arterial repair is of extreme importance when dealing with blood supply to a vital organ, such as brain ischemia during carotid endarterectomy. The present study clearly showed significantly less ischemia time when NBCA was utilized compared to suturing. Patients who undergo carotid endarterectomy are fully heparinized during the procedure, and many surgeons will not reverse heparinization following arteriorrhaphy. Moreover, postarteriorrhaphy bleeding can be a potential source of morbidity in clinical practice. In such situations, excellent bleeding point control should be assured at the end of the operation. This was significantly faster when NBCA was used compared to sutures.

Cyanoacrylates are hemostatic, biodegradable, and rapidly solidifying liquid tissue adhesives that were discovered in the 1940s and have been utilized in the medical field since the early 1960s.11 When exposed to an ionic environment, such as blood or saline, cyanoacrylate will instantly polymerize, the essential step being the addition of a negative ion to open the carbon-carbon double bond.11 The resultant polymer makes extremely strong bonds with tissue and has been used as a tissue adhesive in various clinical applications. The use of the initial forms of cyanoacrylate was associated with adverse effects like neural toxicity and excessive inflammatory reaction, which led to its discontinuation.11 Only with the appearance of the isobutyl type, with better biocompatibility and a longer half-life, did interest in its medical use reemerge. The concern of carcinogenicity has been raised with the initial utilization of short chain cyanoacrylates. However, there has been a lack of data on this complication since the start of isobutyl cyanoacrylate use. The relative nontoxicity of cyanoacrylates has been suggested by documenting partial degradation into carbon dioxide.11 Medical applications include obliteration of arteriovenous fistulae as well as malformations, dural repair, middle ear reconstruction, gum repair, corneal perforation repair, skin closure and grafting, and tendon and bone repair.11, 12, 13, 15, 17, 18 Complete disappearance of the glue cast has been documented on follow-up of 12-20 months.8 Therefore, the liquid adhesive will immediately bind to tissue and stay for enough time to allow healing of the arterial wall.

These liquid adhesive polymers tend to provoke a mild foreign body reaction over the first 4 weeks, followed by a lymphocytic infiltration, and eventually enhance the process of healing.15 In a dental study on the use of NBCA in patients who underwent root resections of the upper incisors on both sides, the incision lines were closed with silk sutures on one side and by NBCA on the other side of the frenum.15 Clinical observation and examination under a transmission electron microscope revealed that epithelialization was better on the sides treated with NBCA, with preservation of normal ultrastructural morphology. Moreover, NBCA has been shown to have bacteriostatic activity, which was most pronounced against gram-positive microorganisms, with no activity observed against gram-negative organisms.14

Other tissue adhesive materials exist. A widely used form, fibrin glue, is the combination of thrombin, fibrinogen, and calcium chloride, mimicking the first step in the coagulation cascade. The use of fibrin sealant tissue adhesives has been reported in repair of liver and splenic injury, management of arterial trauma, management of difficult-to-clip aneurysms, and as an adjunct to suturing in vein grafting.3, 9, 10, 16 Fibrin sealants have several drawbacks in comparison to NBCA potential risk of transmission of infection as they are prepared from blood products and increased time to set, resulting in increased ischemia time during repair, formation of weaker bonds in the tissue applied, and a shorter time from application to degradation that may not allow for total arterial wall healing. In addition, these agents have the potential to produce allergic reactions.

The effectiveness of NBCA as a tissue adhesive is dependent on proper application technique. Our application technique was used strictly and uniformly in all specimens. The use of a 1 cc syringe and 25-gauge needle allowed for application of specific small amounts and prevented unwanted excessive glue in the tissue. Holding the arterial edges approximately together while the NBCA is being applied helps to keep a perfect line of fusion of the arterial wall. This has been established regularly in all our specimens using fine-tip microforceps.

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Conclusion 

The new generation of hemostatic agents, tissue sealants, and adhesive products will offer improved safety and efficacy, creating better surgical results with advanced immediate control of hemostasis. Because these products facilitate the wound healing process and reduce the risk of intra- and postoperative complications, they will be in high demand. The present study shows the fast, effective, and safe repair and hemostatic character of NBCA glue compared to the classical stitching method. This efficacy was proved to have no side effects from the pathological microscopic preparations. NBCA glue may be of significant value and potential advantage in a variety of surgical interventions. This report gives a rationale for further study of NBCA as an adjunct for hemostasis.

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I thank Dr. Mohamed AlMahi, veterinary pathologist, for reviewing the microscopic preparations; Dr. Husam Al-Habeeb for technical help in animal preparation; and Ms. Shoaa Al-Hijaili for editorial support.

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PII: S0890-5096(06)00021-5

doi:10.1016/j.avsg.2006.08.001

Annals of Vascular Surgery
Volume 21, Issue 1 , Pages 56-60, January 2007

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