Ann Thorac Surg 1999;68:1308-1312
© 1999 The Society of Thoracic Surgeons
Original Articles: Cardiovascular
Application of AdvaSeal for acute aortic dissection: experimental study
Keita Tanaka, MDa,
Shinichi Takamoto, MDa,
Toshiya Ohtsuka, MDa,
Yutaka Kotsuka, MDa,
Motohiro Kawauchi, MDa
a Department of Cardiothoracic Surgery, Faculty of Medicine, University of Tokyo, Tokyo, Japan
Address reprint requests to Dr. Tanaka, Department of Cardiothoracic Surgery, Faculty of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan
e-mail: tanakak-tho{at}h.u-tokyo.ac.jp
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Abstract
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Background. In the surgical treatment of acute aortic dissection, intractable hemorrhage often occurs. We performed an animal study to test the hypothesis that a new sealant, AdvaSeal (Ethicon Inc, Johnson & Johnson Medical KK, Somerville, NJ), can close the false channel of aortic dissection.
Methods. Acute descending aortic dissection was created surgically in 12 mongrel dogs. In 7 of these (treated group), AdvaSeal was applied to the false cavity for reinforcing and fusing the dissected layers and also to the suture line. The other 5 dogs (control) were left untreated. Specimens were harvested 2 weeks after surgery.
Results. The sealant could be used in wet conditions. In the treated group, hemostasis was easily achieved during surgery. All false cavities were perfectly thrombosed, causing no deleterious effects related to the sealant. In the control group, all false lumina remained patent.
Conclusions. The advantage of AdvaSeal was its effectiveness on wet tissue and its adhesiveness, allowing good hemostasis and closure of the false lumen. The sealant can be an easy and efficacious sealant in treatment for acute aortic dissection.
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Introduction
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In the surgical treatment of acute aortic dissection, intractable hemorrhage often occurs, or a new intimal tear is created due to the fragility of the dissected layers. To reduce such surgical difficulties, many attempts have been made to reinforce the anastomosis between the dissected aorta and the artificial graft, including the use of Teflon (Impra Inc, Tempe, AZ) felt [1], insertion of a sutureless intraluminal graft [2], toughening by direct application of 25% glutaraldehyde [3], and the use of fibrin glue [4] or gelatine-resorcine-formalin (GRF) biological glue [5]. These approaches, particularly the use of GRF glue [5], certainly simplify the surgical procedure and improve the results of treatment. However, the glue may destroy the underlying tissues [6], and it is not effective under wet conditions.
AdvaSeal (Ethicon Inc, Johnson & Johnson Medical KK, Somerville, NJ) [7], a polyethylene, glycol-based synthetic hydrogel, has already been used clinically in Europe for sealing of pulmonary air leakage [8, 9] (Fig 1). It is a bioabsorbable hydrogel delivered in two aqueous solutions (primer and sealant) and photopolymerized with visible light from a xenon arc lamp, forming a clear, flexible, and firmly adherent hydrogel [8]. It is effective on wet tissue and biocompatible. In this animal study, we investigated the efficacy of AdvaSeal for sealing the false channel in acute aortic dissection.
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Fig 1. AdvaSeal sealant system; disposable sealant (S) and primer (P) applicators, light source (L) and light wand (W). The sealant is provided in frozen form, and is thawed until completely liquid before application. Following application of primer solution, sealant solution is applied and exposed to xenon light.
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Material and methods
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Twelve healthy mongrel dogs, each weighing approximately 17 kg, were used for the study. All animals 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 (NIH Publication No. 85-23, revised 1985).
After induction with ketamine (intramuscularly), all dogs were intubated and ventilated with a MARK7 ventilator (Bird Corporation, CA). Lactated Ringer’s solution was administered intravenously through the right forelimb vein throughout the surgical procedure. The animals were anesthetized with intravenous sodium pentobarbital. A blunt-tipped needle was introduced into the left femoral artery, and arterial pressure was monitored with a 78342A Monitor, and 78172A Recorder (Hewlett Packard Co, Andover, MA) during surgery. Then a left thoracotomy was made in the fifth intercostal space, and the fifth rib was divided posteriorly. After exposure of the descending aorta, four or five pairs of intercostal arteries were ligated and transected. Heparin (1 mg/kg) was administered systemically, and the activated clotting time was maintained longer than 200 seconds. Then a temporary bypass was instituted from the aortic arch to the right femoral artery using 14F venous and arterial cannulas (Terumo, Tokyo, Japan).
Acute dissection was artificially created in the midlayer of the descending aorta by a modification of Blanton’s method [10, 11]. Under a temporary bypass, the descending aorta was cross-clamped proximally and distally, and a transverse aortotomy was made along 50% of its circumference. The middle layer of the aortic wall was bluntly split along the distal margin of the aortotomy, and creation of the artificial false lumen was advanced as distally as possible. The inner flap of the split aortic wall was fixed with a stitch to the intact side of the aorta. The split outer layer and the proximal margin of the aortotomy were approximated using an over-and-over suture with 6-0 Prolene (Ethicon Inc). Then the aorta was unclamped. The distal progression of aortic dissection was observed under direct vision (Fig 2A). The created "entry" and the false channel (Fig 2B, C) were observed intraoperatively using ultrasonographic scanning with color Doppler imaging (Sonolayer
SSA-270A, Toshiba Medical System Co, Ltd, Tokyo, Japan). Meanwhile, the arterial pressure was temporarily increased by administering norepinephrine intravenously, until a "reentry" was formed spontaneously. The formation of reentry was confirmed by monitoring the left femoral arterial pressure. The amplitude of the pulse wave increased abruptly when the reentry emerged.
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Fig 2. (A) Intraoperative photograph demonstrating surgically created acute dissection of canine descending aorta (white arrows). (B) Ultrasonography of long-axis view of dissected aorta demonstrating intimal flap. (C) Doppler ultrasonography of short-axis view of dissected aorta showing normograde blood flow. T = true lumen; F = false lumen.
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Experimental protocol
The dogs were divided into two groups. Five dogs were left untreated as a control group, and the remaining 7 received treatment with AdvaSeal (AdvaSeal group). Under a temporary bypass, the descending aorta was cross-clamped again, and then the aortotomy was reopened. The false channel was rinsed using heparinized physiological saline solution. Without any particular maneuver for drying, AdvaSeal was applied into the false channel as far as possible from the entry, and exposed to xenon light directly at the entry site via the aortotomy and indirectly through the aortic wall away from the entry (Fig 3). After fusion and reinforcement with AdvaSeal, the two split layers were directly oversewn together, and the aortotomy was ultimately closed with an over-and-over suture using 6-0 Prolene. AdvaSeal was also applied on the suture line for complete hemostasis, and the aorta was unclamped. The flow pattern in the dissected aorta was probed by ultrasonographic scanning. Two weeks after the operation, all dogs in the two groups were sacrificed and the dissected descending aorta was harvested for microscopic examination.
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Fig 3. Intraoperative photograph showing the device applied to a dissected aorta. (S = sealant; W = light wand.)
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Simultaneously, the kidneys were removed from 3 dogs in the AdvaSeal group at the time of aorta harvest, and studied microscopically to investigate the pathological features caused by embolization.
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Results
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Under a temporary bypass, the mean femoral arterial pressure ranged from 50 to 105 mm Hg. There was no postoperative paraplegia in any of the dogs. In the control group, 1 dog died due to general weakness on postoperative day 2. In the AdvaSeal group, 1 dog died of late hemorrhage from the cannulated site on the aortic arch 7 days after surgery, and 1 died on postoperative day 7 due to general weakness.
A couple of additional stitches for hemostasis were placed in each model animal in the control group. On the other hand, oozing hemorrhage was observed in only 1 dog after the treatment with AdvaSeal, and was easily controlled by additional application of the sealant.
Observations of the false cavity
The mean longitudinal progression of the aortic dissection was 98% (range, 76% to 113%) of the distance between the entry and the celiac axis. There was no proximal extension of dissection or external rupture. In all animals of the two groups, reentry was situated almost at the depth of dissection.
The true and false lumen could be visualized in all animals of the two groups by ultrasonographic scanning during surgery (Fig 2B and C). In the control group, an antegrade blood flow was observed in both the true and false lumina. After the treatment with AdvaSeal, antegrade blood flow was observed only in the true lumen. Stagnant flow was found in the false lumen, which was significantly compressed and reduced.
In harvested specimens, remainders of the sealant were found both in the false lumen and outside the anastomosis. All the false channels remained patent, and thrombi were scarcely observed in the control group. In contrast, in the AdvaSeal group, all the false channels were entirely thrombosed from the entry to the reentry.
Microscopic examination showed that the dissection was created in the media in each animal. In the control group, a nonspecific inflammatory response was observed in the adventitia. The inside of the dissected channels was covered with hyperplastic neointima, unaccompanied by thrombus formation. The aortic dissection was in the process of healing, resulting in a double-barreled chronic dissection (Fig 4A). In the AdvaSeal group, the inflammatory response in the adventitia, including infiltrating neutrophils and macrophages, was similar to that in the control group. The media was scarcely affected by the inflammatory process. The wavy configuration of the medial elastic lamina and the smooth muscle cells were well preserved. There was no necrosis, infection, or giant cell formation, and the intima was intact. The false channel was entirely closed by AdvaSeal and thrombi (Fig 4B).
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Fig 4. Photomicrographs of cross sections of canine descending aortas taken from the control group on day 15 (A) and AdvaSeal group on day 17 (B). In the control group, false lumen (*) was patent and covered with hyperplastic neointima (arrow head). In AdvaSeal group, false lumen was entirely closed with AdvaSeal (arrow) and thrombus. Nonspecific inflammatory response was observed in the adventitia. Media and intima was intact. (Elastica-van Gieson stain; original magnification of x40).
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In 3 dogs of the AdvaSeal group, a microscopic study of the removed kidneys demonstrated no evidence of infarction caused by embolization.
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Comment
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It is difficult to create medionecrosis of the canine aorta [12]. Therefore, spontaneous aortic dissection hardly occurs in the dog. In this study, canine aortic dissection was created surgically using the modified Blanton method [10]. This model is different from the dissection observed clinically in the human aorta with regard to the lack of medionecrosis and aneurysmal change. Hemodynamically, however, it closely resembles human aortic dissection. The aortic dissection in this model was created in the media, and therefore we used it to evaluate the efficacy of a new sealant. Intraoperative ultrasonographic scanning [13] and monitoring of the femoral arterial pressure was very important for evaluating the formation of the aortic dissection.
It is desirable for a surgical sealant to act rapidly even under wet conditions. It should also not cause any toxic reactions, and should be slowly soluble in body fluids but completely biodegradable. Moreover, the sealant should remain elastic and flexible particularly when it is applied to vessels. GRF and fibrin glues are frequently used for aortic and heart surgery. It has been reported that the use of GRF glue is effective for reducing blood loss during surgery, and also hospital and late mortality rates [5, 14]. However, precise instillation of the glue into the dissected false lumen is often troublesome because perfectly dry conditions are needed [15] and adequate pressure [15–17] and a temperature of around 45°C must be maintained. Furthermore, formalin that is used as an activator for the glue, may have toxic [6] and carcinogenic [18] effects. Olivier and associates [19] reported that GRF glue showed high toxicity against the muscular layers of the artery, and Portoghese and associates [20] also described that GRF glue induced destruction of the vascular wall. Although fibrin glue can be used under wet conditions, causing no toxicity or little tissue reaction, its adhesiveness is unsatisfactory for aortic dissection [21], and furthermore it may transfer viral diseases, though viruses are inactivated by heat during processing of the glue. Therefore, we investigated the applicability of a new sealant, AdvaSeal for aortic surgery.
AdvaSeal consists of a copolymer of polyethylene glycol and oligotrimethylene carbonate with acrylate ester end caps, containing triethanolamine and eosin Y as a photoinitiator. All the components are biocompatible. Xenon light is absorbed by the eosin Y. Triethanolamine can donate an electron to eosin Y in the excited state and generate a free radical, which then initiates polymerization of the polyethylene glycol prepolymers via the acrylate ends. The results of the polymerization are a cross-linked polymer network. Ranger and associates [8] demonstrated that AdvaSeal could effectively seal significant pulmonary air leaks in an animal experiment, and histologically it was found to be biocompatible, causing no toxic effects. Alleyne and associates [22] effectively used the sealant to seal dural repair sites in a canine craniotomy model. They described that healing of the underlying dura was not compromised, and that the exposed cortical tissue was not altered histologically. Also in our model, no deleterious effects related to the sealant were observed in the aortic walls. The medial elastic lamina and the smooth muscle cells were well preserved.
Dumanian and associates [23] reported that this sealant was able to effectively seal vessel puncture sites and anastomotic junctions in human placental arteries, without acutely augmenting local vascular thrombogenicity. In the AdvaSeal group in the present study, surgical hemostasis was easily achieved along the suture line under heparinized conditions without any additional stitches. Considering the fact that additional stitches were required for complete hemostasis in each animal of the control group, AdvaSeal seems to be efficacious for secure vascular anastomosis.
In this study, the entry of the aortic dissection was easily reconstructed using AdvaSeal. The AdvaSeal gel instilled between the dissected layers was polymerized directly at the entry space via the aortotomy and indirectly through the aortic wall away from the entry. The effectiveness of indirect photopolymerization through the wall may be reduced in comparison with direct exposure. Lyman and associates [9] reported that light transmission reached a depth of 1.0 mm in lung tissue. Therefore we believe that AdvaSeal gel instilled just beneath the thin adventitia, which is observed in such an acute aortic dissection, can be polymerized effectively. And compression of the dissected space was unnecessary after repair using AdvaSeal.
AdvaSeal can be used satisfactorily under wet conditions. A dry surgical field cannot always be obtained, particularly in vascular surgery, and in this situation, GRF or fibrin glues are ineffective. Therefore, the best advantage of AdvaSeal over other synthetic adhesives is that the sealant can be used under wet conditions.
In conclusion, the AdvaSeal method can be an easy, efficacious, and safe alternative treatment for acute aortic dissection. The short-term results obtained with this procedure are encouraging.
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Acknowledgments
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The authors would like to thank Dr Ikuo Wada for help with histological study, and also thank Mr Nobutaka Furuya, Mr Jun Itoh, and Mr Takashi Kubota, of the Animal Center for Biomedical Research, Faculty of Medicine, University of Tokyo, for their contribution to this experiment. AdvaSeal sets, which were used in this experimental study, were supplied by Ethicon Inc, Johnson & Johnson Medical KK, Somerville, NJ.
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Accepted for publication April 19, 1999.
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Abstract
Introduction
