Gelatin resorcin formalin (GRF) glue was first applied

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1 Type A Acute Aortic Dissection: Immediate and Mid-Term Results of Emergency Aortic Replacement With the Aid of Gelatin Resorcin Formalin Glue Mitsumasa Hata, MD, Motomi Shiono, MD, Akira Sezai, MD, Mitsuru Iida, MD, Nanao Negishi, MD, and Yukiyasu Sezai, MD The Second Department of Surgery, Nihon University School of Medicine, Tokyo, Japan Background. The aim of this study was to assess the mid-term results of operation for type A acute aortic dissection with the aid of gelatin resorcin formalin glue. Methods. Emergency operation was carried out in 84 patients during the last 8 years. Fifty-five patients (65.5%) had mild-to-moderate aortic regurgitation. Gelatin resorcin formalin glue was applied to both the proximal and distal aortic stumps. We evaluated the presence of aortic regurgitation and the patency of the distal false lumen at the time of this study. The survival and reoperation-free rates were also assessed. In case of late reoperation, aortic wall samples of the glued area were examined histologically. Results. Ascending to hemiarch replacement were performed in 71 patients (84.5%). Total aortic arch and root replacement were required in 13 and 7 patients, respectively. Overall hospital mortality was 6.0% (5 patients). Late death was observed in 12 patients (14%). Reoperation for redissection in the aortic root, development of aortic regurgitation, and enlargement of the distal false lumen occurred in 1, 3, and 1 patient, respectively. Histologic examination showed no evidence of infiltration of inflammatory cells in the glued area. Computed tomography scan revealed a patent distal false lumen in 8 (14%) of 58 patients. Echocardiography detected moderate aortic regurgitation in 2 patients. The actuarial survival rate at 1, 5, and 8 years was 85.5%, 80%, and 60.0%, respectively. The reoperation-free rate at 8 years was 89%. Conclusions. The results of emergency aortic replacement with gelatin resorcin formalin glue have shown reasonable early and late mortality and reoperation rates. There was no histologic evidence of adverse tissue reactivity by gelatin resorcin formalin glue. (Ann Thorac Surg 2004;78:853 7) 2004 by The Society of Thoracic Surgeons Gelatin resorcin formalin (GRF) glue was first applied during repair of acute aortic dissection in France, because of its efficacy in providing excellent solidity and hemostasis of the suture sites [1]. Furthermore, use of GRF glue has been reported to improve long-term survival rates after operation for aortic dissection [2]. However, several reports have been published on disadvantages of using GRF glue [3, 4], and its cytotoxicity in human beings is still unknown. Recently, therefore, the use of GRF glue in aortic operation has been questioned [5, 6]. In our institution, a pathology-oriented replacement of the aorta with the aid of GRF glue has been consistently used for type A acute aortic dissection (AAD) over the past 8 years. The aim of this study was to review our experience in emergency surgical intervention with GRF glue for AAD, and to assess the mid-term results with a special interest in pathologic study. Accepted for publication March 15, Address reprint requests to Dr Hata, The Second Department of Surgery, Nihon University School of Medicine, 30-1 Ooyaguchi Kamimachi Itabashi-ku, Tokyo , Japan; mihata@med.nihon-u.ne.jp. Patients and Methods Between July 1995 and September 2003, emergency surgical intervention for AAD was carried out in 84 patients. Forty-three patients (51.2%) were male, and the average age was years (range 19 to 90 years). Seven patients had Marfan s syndrome. All patients had a history of hypertension. Patients profiles are summarized in Table 1. All patients had CT and echocardiography soon after the onset of AAD, and all underwent emergency operation within 24 hours after AAD onset. Contrast computed tomography (CT) was performed on all patients as soon as they were referred to the hospital. Transthoracic echocardiography was then used to detect pericardial effusion and assess aortic valve regurgitation (AR) and cardiac function. Contrast CT revealed DeBakey type I in 64 patients (76.2%) and type II in the other 20 (23.8%) (Table 1). Preoperatively, 7 patients (8.3%) had moderate AR and 45 patients (52.4%) had mild AR (Table 1). In the operative theater, cardiopulmonary bypass (CPB) was implemented through femoral arterial cannulation in all patients. A two-stage venous cannula was inserted into the right atrium, except for patients in 2004 by The Society of Thoracic Surgeons /04/$30.00 Published by Elsevier Inc doi: /j.athoracsur

2 854 HATA ET AL Ann Thorac Surg EFFICACY OF GRF GLUE FOR TYPE A AORTIC DISSECTION 2004;78:853 7 Table 1. Patient Profile July 1995 September 2003 Variable Value Total number of emergency 84 interventions for AAD Age, mean SD (range), years (19 90) Male/female, n 43/41 DeBakey type I/II, n 64/20 Marfan s syndrome 7 (8.3) Thrombosed occlusion type 18 (21.4) Myocardial ischemia 4 (4.8) Hemopericardium 46 (54.8) Moderate aortic regurgitation 7 (8.3) Mild aortic regurgitation 45 (52.4) TIA 19 (22.6) Coma 7 (8.3) Cardiac Tamponade 22 (26.2) Cardiopulmonary resuscitation 5 (6.0) Liver chrosis 1 (1.2) Renal failure 1 (1.2) Values are number (percentage) unless otherwise noted. AAD type A acute aortic dissection; TIA transient ischemic attack. preoperative shock (less than 60 mm Hg of systolic blood pressure). If a patient had evidence of shock due to cardiac tamponade, femoro femoral circulatory assistance was initiated before the chest was opened. We used consistent techniques in all patients. Deep hypothermic circulatory arrest (DHA) and antegrade selective cerebral perfusion were used for cerebral protection. Each patient was cooled to 20 C (rectal temperature). The ascending aorta or aortic arch was then opened longitudinally under DHA. The aortic segment containing the intimal tear was resected, and selective cerebral perfusion was established by introducing balloon cannulas into the three arch vessels. The GRF glue was applied between two dissected walls on both the distal and proximal stumps of the aorta. We initially applied the gelatin just on the dissected wall, instead of inserting it fully into the dissected cavity. Only one or two drops of the formalin-glutaraldehyde mixture were added into the glue. We tried to mix approximately one part formalin to 10 parts gelatin. To reinforce the gluing process, forceps were used to fix the aortic wall circumferentially for about 5 minutes. Furthermore, the aortic walls were reinforced by securing Teflon (DuPont, Parkersburg, WV) felt strips inside and outside the aorta. Antegrade systemic circulation was established through a side branch of the Dacron (C.R. Bard, Covington, GA) prosthesis after completion of the open distal anastomosis. Finally, fibrin glue was applied on the suture sites. Pathology-oriented replacement of the aortic segment containing the intimal tear was used as much as possible. The mean duration of follow-up was 33.2 months (range 1 to 90 months). Follow-up information was obtained for all patients. We evaluated the presence of postoperative AR and the patency of the distal false lumen with echocardiography and contrast CT scan at the time of study. The actuarial survival and reoperationfree rates were also calculated with the Kaplan Meier method. Results The intimal tear was located on the ascending aorta in 48 patients (57.1%); in 3 patients, the intimal tear could not be found. Ascending aortic replacement was performed in these 51 patients (60.7%). Twenty patients (23.8%) received proximal hemiarch replacement, because the intimal tear was located on the lesser curvature of the proximal aortic arch. Extended total arch replacement was required in 13 patients (15.5%). Aortic root replacement was performed concomitantly in 7 patients (8.3%), because the dissecting process had severely damaged the aortic root and was complicated by AR. Average DHA and CPB duration were minutes and minutes, respectively. Overall hospital mortality was 6.0% (5 patients). Late death was observed in 12 patients (14%: senility, 1; malignancy, 3; pneumonia, 1; stroke, 3; rupture of abdominal aneurysm, 1; mediastinitis, 1; operative death at reoperation, 2 (1 in another hospital). Five patients underwent late reoperation due to distal false lumen dilation, development of AR and angina, or redissection at the aortic root (aortic valve replacement and coronary bypass in 1, total arch replacement in 3, and aortic root replacement in 1). At reoperation, neointima had developed in the aortic wall and, microscopically, no infiltration of inflammatory cells was evident in the glued area (Fig 1). Contrast CT scan revealed a totally patent distal false lumen in 4 patients (7%) and a localized patent false lumen on the abdominal aorta in 4 (7%) of 58 surviving patients who had DeBakey type I at initial operation. At the time of the study, echocardiography was performed in 60 patients, including 45 patients with preoperative mild AR. Echocardiography detected mild-tomoderate AR in 2 patients (3.3%), who were treated conservatively. In the other 58 patients, trivial or no AR was found. The actuarial survival rate at 1, 5, and 8 years was 85.5%, 80%, and 60.0%, respectively (Fig 2). The reoperation-free rate at 1 and 8 years was 98.3% and 89.0%, respectively (Fig 3). Comment The mortality of emergency surgical intervention for AAD has been variously reported as 15% to 30%. These findings are often derived from series spanning more than 10 to 20 years [7 9]. Recent advances in surgical techniques, anesthesia, and perioperative medical management are likely to have lowered the mortality of emergency operation over the last few years. Since GRF glue has been used for the surgical procedure of aortic dissection, several investigators have reported improved survival rates of patients with AAD [1, 2]. Using GRF glue on rats, Weisgerber and associates [10] found an absence of local or general toxicity, in addition to long-term tolerance and reabsorption. Furthermore,

3 Ann Thorac Surg HATA ET AL 2004;78:853 7 EFFICACY OF GRF GLUE FOR TYPE A AORTIC DISSECTION 855 Fig 1. Pathologic findings evident microscopically: (A) Infiltration of inflammatory cells; (B) neointima developed in the specimen of the aortic wall around the gelatin resorcin formalin glue. Bachet and colleagues [2] reported that GRF glue was safe and harmless to tissues. Conversely, Kiyotani and associates [3] reported in their histopathological examination using rats that GRF-treated wounds showed greater infiltration of inflammatory cells than fibrin gluetreated wounds. A case report indicated that a permanent pacemaker was implanted to treat complete A-V block that resulted from the aldehyde components of GRF glue used during repair of AAD [4]. Recently, several reports from Japan [5] and Europe [6] have questioned the toxicity and the adverse role of GRF glue in the occurrence of late redissection of the aortic root. Indeed, the formalin-glutaraldehyde mixture is highly toxic. Therefore, we usually apply the gelatin just on the dissected wall, instead of inserting it fully into the dissected cavity. Then only one or two drops of the formalin-glutaraldehyde mixture should be mixed into the glue. In the present study, aortic root redissection occurred in 1 patient. At reoperation, a new dissection was found to have occurred on the proximal anastomosis, but the aortic wall itself was smooth and not deteriorated. However, 3 patients had enlargement of the residual false lumen on the aortic arch. One of those patients had Marfan s syndrome whereas in the other 2 patients the intimal tear had not been found at the time of initial ascending replacement but was found in the distal aortic arch during reoperation. Finally, although 5 patients underwent late reoperation, no infiltration of inflammatory cells was found upon histologic examination of the removed aortic specimens. Therefore, chemical injury by GRF glue seems to be avoidable. Nevertheless, we minimize use of GRF glue and try to mix approximately one part formalin to 10 parts gelatin. We previously reported a microscopic study from an autopsy case revealing the excellent growth of collagen and elastic fibrous tissue where the GRF glue had been used during operation for ventricular septal perforation (Fig 4) [11]. Those findings suggested that GRF glue may conform well to human tissues. The aid of biological glue has enabled us to preserve the native aortic valve whenever possible and to avoid prosthesis-related and anticoagulation-related complications [12]. The quality of the aortic wall adhesion by GRF glue may explain the absence of late AR in most patients because the deformation of the aortic annulus could be repaired and the commissure support system could also be restored by adhesion of the dissected layers. Preoper- Fig 2. The actuarial survival rate at 1, 5, and 8 years (12, 60, and 96 months) was 85.5%, 80%, and 60.0%, respectively. Fig 3. The reoperation-free rate at 1 and 8 years (12 and 96 months) was 98% and 89%, respectively.

4 856 HATA ET AL Ann Thorac Surg EFFICACY OF GRF GLUE FOR TYPE A AORTIC DISSECTION 2004;78:853 7 Fig 4. An autopsy case with ventricular septal perforation (Elastica stain) [11]. Collagen and elastic fibers were well developed where the gelatin resorcin formalin glue was used. ative moderate-to-severe AR is a significant risk factor for the development of postoperative AR and may result in early reoperation on the aortic root [13]. We do not hesitate to replace the aortic root for AAD if necessary, although this procedure has been considered as more risky by some authors [14]. In this series, 7 patients with preoperative moderate-to-severe AR had successful concomitant aortic root replacement. In the other 45 patients with preoperative mild AR, although we did not replace the aortic valve, only 1 patient required late aortic valve replacement and coronary bypass because of postoperative AR and angina. Only 2 patients were left with mild-to-moderate AR after AAD repair; they have been well during follow-up. This result represents a successful outcome, even if further attention is required in the future. Postoperative patency and dilatation of the false lumen is also an important issue as emphasized recently in several reports [15 17]. David and colleagues [18] reported that the prevalence of postoperative patent false lumen was reduced from 91% to 59% by the use of the open distal anastomosis technique. In addition, we believe that during the emergency initial operation for AAD, open repair and fixation of the distal aortic stump with GRF glue decreases the false-lumen patency rate and possibly improves rates of late survival and freedom from reoperation. In the present study, the false lumen was patent in 14% of the patients, an acceptable outcome as compared with previous reports. Among the 3 patients who needed reoperation for enlargement of a distal patent false lumen, one had Marfan s patient and in the other 2 patients the intimal tear could not be found during initial operation but was found in the distal arch at the time of reoperation. Thus attention must be kept on eliminating the intimal tear as much as possible at the time of initial operation. In this series, the overall hospital mortality was 6.0% (5/84). This finding is much better than the average 15% to 25% hospital mortality rates found in previous reports [7 9, 18]. Recently, Westaby and colleagues [19] also reported excellent surgical results, showing an overall hospital mortality of just 6%. Because the first priority of our emergency surgical intervention for AAD is primary tear excision and avoidance of serious complications, most patients (84.5%) in this series had only ascending aorta or hemiarch replacement. However, when the intimal tear is located in the aortic arch, total arch replacement should be carried out for tear excision. Westaby and colleagues [19] advocated the same policy of primary tear excision, namely a conservative pathology-oriented approach. Bachet and colleagues [20, 21] also showed that closure of the entry site at initial emergency operation resulted in a reduced reoperation rate. Conversely, several investigators advocate systematic extended or total aortic arch resection for the initial surgical management of AAD, irrespective of the location of the intimal tear [22, 23]. Although those authors reported satisfactory results, we have to always keep in mind that AAD is an inherently lethal condition. Such an extended approach will possibly increase an already high operative risk [7]. In fact, Kazui and colleagues [22] reported that the early mortality rate of emergency total arch replacement was 16%, and the freedom from reoperation was 77% at 5 years. In our experience, freedom from reoperation was 89% at 8 years. We believe, therefore, that the risk of extended operation may outweigh the relatively low incidence of reoperation and the associated operative risk. Our recent 8-year experience of emergency surgical aortic repair with the aid of GRF glue for AAD has demonstrated satisfactory early and late mortality and freedom from reoperation rates as well as pathophysiological findings. In addition, either clinically or at histologic examination, we found no evidence of any harmful consequence from using the GRF glue in terms of redissection, recurring AR, or inflammatory and necrotic lesions. References 1. Guilmet D, Bachet J, Goudot B, et al. Use of biological glue in acute aortic dissection. J Thorac Cardiovasc Surg 1979;77: Bachet J, Gigou F, Laurian C, et al. Four-year clinical experience with the gelatine-resorcine-formol biological glue in acute aortic dissection. J Thorac Cardiovasc Surg 1982;83: Kiyotani T, Teramachi M, Takimoto Y, et al. Experimental evaluation of gelatin adhesive. Jpn J Artif Organs 1994;23: Von Oppell UO, Chimuka D, Brink JG, Zilla P. Aortic dissection repair with GRF glue complicated by heart block. Ann Thorac Surg 1995;59: Kazui T, Washiyama N, Bashar AHM, et al. Role of biological glue repair of proximal aortic dissection in the development of early and mid-term redissection of the aortic root. Ann Thorac Surg 2001;72: Fukunaga S, Karck M, Harringer W, Cremer J, Rhein C, Haverich A. The use of gelatin-resorcin-formalin glue in acute aortic dissection type A. Eur J Cardiothorac Surg 1999;15: Ehrlich MP, Ergin MA, McCullough JN, et al. Results of immediate surgical treatment of all acute type A dissection. Circulation 2000;102(Suppl 3):III Bachet J, Goudot B, Dreyfus GD, et al. Surgery for acute type

5 Ann Thorac Surg HATA ET AL 2004;78:853 7 EFFICACY OF GRF GLUE FOR TYPE A AORTIC DISSECTION A aortic dissection: The hospital Foch experience ( ). Ann Thorac Surg 1999;67: Ehrlich M, Fang WC, Grabenwöger M, Cartes-Zumelzu F, Wolner E, Havel M. Perioperative risk factors for mortality in patients with acute type A aortic dissection. Circulation 1998;98(Suppl 2):II Weisgerber G, Douvin D, Huguet C, Petit D, Rey C, Lacarriere Y. G.R.F. biological glue applied to hepatectomies in rats. Action on hemostasis. Tissue tolerance [in French]. J Chir 1974;108: Hata M, Shiono M, Orime Y, et al. Pathological findings of tissue reactivity of gelatin resorcin formalin glue: an autopsy case report of the repair of ventricular septal perforation. Ann Thoracic Cardiovasc Surg 2000;6: Weinschebaum EE, Schaumun C, Caramutti V, Tacchi H, Cors J, Favaloro RG. Surgical treatment of acute type A dissecting aneurysm with preservation of the native aortic valve and use of biologic glue: a follow-up to 6 years. J Thorac Cardiovasc Surg 1992;103: Pessotto R, Santini F, Pugliese P, et al. Preservation of the aortic valve in acute type A dissection complicated by aortic regurgitation. Ann Thorac Surg 1999;67: Elefteriades JA. What operation for acute type A dissection? J Thorac Cardiovasc Surg 2002;123: Bernard Y, Zimmermann H, Chocron S, et al. False lumen patency as a predictor of late outcome in aortic dissection. Am J Cardiol 2001;87: Moore NR, Parry AJ, Trottman-Dickenson B, Pillai R, Westaby S. Fate of the native aorta after repair of acute type A dissection: a magnetic resonance imaging study. Heart 1996;75: Fattori R, Bacchi-Reggiani L, Bertaccini P, et al. Evolution of aortic dissection after surgical repair. Am J Cardiol 2000;86: David TE, Armstrong S, Ivanov J, Barnard S. Surgery for acute type A aortic dissection. Ann Thorac Surg 1999;67: Westaby S, Saito S, Katsumata T. Acute type A dissection: conservative methods provide consistently low mortality. Ann Thorac Surg 2002;73: Bachet J, Termignon JL, Goudot B, et al. Aortic dissection: prevalence, cause and results of late reoperations. J Thorac Cardiovasc Surg 1994;108: Bachet J. Acute type A aortic dissection: can we dramatically reduce the surgical mortality? Ann Thorac Surg 2002;73: Kazui T, Washiyama N, Muhammad BA, et al. Extended total arch replacement for acute type A aortic dissection: experience with seventy patients. J Thorac Cardiovasc Surg 2000;119: Hirotani T, Kameda T, Kumamoto T, Shirota S. Results of total aortic arch replacement for an acute aortic arch dissection. J Thorac Cardiovasc Surg 2000;120: INVITED COMMENTARY The study by Hata and colleagues is interesting regarding several view points. First of all, the low mortality rate of 6.0% in a series of 84 consecutive patients with type A acute dissection can be compared with the best series in the literature. The incidence of only 14% (8 of 58 patients) of patent distal false lumen after type A surgical correction is much less than the average, especially if you consider that only 20 cases had limited dissection into the intrapericardial aorta (Type II DeBakey). From our experience it is common to observe distal dissection after appropriate surgical correction because at the time of surgery you have already distal dissection that in some cases extends to the iliac arteries. Residual distal dissection is an independent factor of either using or not using gelatin resorcin formalin (GRF) glue, and depends on preoperative anatomical conditions. Finally, the author presents an important contribution demonstrating that in three reoperations the histologic examination did not manifest important inflammatory reaction or wall weakness that have been pointed out by others as disadvantages of GRF glue use. Enio Buffolo, MD, PhD São Paulo Federal University R. Borges Lagoad, 1080-CJ 701 São Paulo SP Cep , Brazil enio.buffolo@terra.com.br 2004 by The Society of Thoracic Surgeons /04/$30.00 Published by Elsevier Inc doi: /j.athoracsur