Fibrin Glue Sealing of Pancreatic Injuries, Resections, and Anastomoses Harry B. Kram,
MD,
Stevan R. Clark, MD, Hermenegildo P. Ocampo, MD, Miles A. Yamaguchi, William C. Shoemaker, MD, LOSAngeles, California
Fibrin glue made with highly concentrated human fibrinogen and clotting factors was evaluated as a means of preventing pancreatic fistulas in 15 patients operated on for traumatic and nontraumatic conditions. Fibrin glue was applied directly to penetrating pancreatic injuries, pancreatic suture and staple lines in patients treated by partial resection, and pancreaticointestinal anastomoses. Postoperatively, no patient developed pancreatic fistulas, pancreatic abscesses, or pseudocysts. Fibrin glue sealing of pancreatic injuries, resections, and anastomoses may aid in preventing fistulas after pancreatic surgery. Additional potential uses include the sealing of pancreatic biopsy sites and occlusion of the pancreatic duct in pancreatic transplantation.
P
ancreatic ffitula formation is a frequent complication following the surgical treatment of pancreatic injuries or the performance of pancreaticointestinal anastomoses, occurring in up to a third of patients [J-7]. The morbidity associated with postoperative pancreatic fistulas is often significant and may result in death. Furthermore, associated complications are frequent and include abscess, pseudocyst, hemorrhage, electrolyte losses, skin irritation, and malabsorption. A safe and effective method of preventing fistulas after pancreatic surgery would contribute significantly to the successful treatment of these patients. Nonautologous fibrin glue has been used clinically in the United States since 1984 [8]. More than 250 surgical procedures utilizing fibrin glue have been performed, including the control of parenchymal organ hemorrhage and the sealing of anastomoses [8-111. In the present report, we describe the intraoperative use of fibrin glue to prevent pancreatic fistulas after surgery for traumatic and nontraumatic conditions. From the Department of Surgery, Los Angeles County King/Drew Medical Center, and the UCLA School of Medicine, Los Angeles, California. Requests for reprints should be addressed to Harry B. Kram, MD, King/Drew Medical Center, Department of Surgery, 12021 S. Wilmington Avenue, Los Angeles, California 90059. Manuscript submitted May 16, 1989, and accepted in revised form November 22,1989.
THE AMERICAN
MD,
MATERIAL AND METHODS Fibrin glue: Fibrin glue consists
of four components: highly concentrated fibrinogen (total protein approximately 120 mg/mL), aprotinin (3,000 KIU/mL)*, dried thrombin (500 US [NIH] units/ml)?, and calcium chloride (40 pm/mL). The fibrinogen is obtained from donor human plasma. After the fibrinogen is preheated to 37°C it is dissolved in aprotinin and the dried thrombin is reconstituted in calcium chloride. The two solutions are then drawn up into separate syringes, which are loaded on a double-barreled syringe holder designed to mix and apply the components simultaneously. The reconstitution procedure takes 10 to 15 minutes, and the components should be used within 4 hours. The reconstituted adhesive contains 70 to 100 mg/mL of fibrinogen, 2 to 7 mg/mL of fibronectin (cold-insoluble globulin), 10 units/ml of factor X111$,and 35 pg/mL of plasminogen. Upon application, the components mix to form a clear, viscous solution that firmly adheres to wound surfaces and sets into a white, rubberlike mass within seconds. The adhesive continues to gain in tensile strength over the course of time; 70% of the maximum tensile strength is achieved in 10 minutes [IZ]. During the subsequent course of wound healing, the adhesive slowly dissolves by fibrinolysis and is completely removed from the body within 4 to 6 weeks; aprotinin is added to slow the fibrinolytic process. The essential reactions after mixing of the components are proteolysis, fibrin cross-linking, and finally, lysis and absorption of the clot material during the wound healing process [13]. Clinical data: Fibrin glue was used in 10 patients operated on for pancreatic trauma and in 5 patients who underwent pancreaticointestinal anastomoses for nontraumatic disease. The latter group included two patients with chronic pancreatitis, two with pseudocysts, and one with pancreatic cancer. Fibrin glue was used to seal suture or staple lines in five traumatic injuries treated by pancreatic resection; 4 to 6 mL of fibrin glue was used for each injury. Identification and ligation of the main pancreatic duct was not performed. Five other penetrating pancreatic injuries were treated by completely filling in the defect with a l- to 2-mL fibrin glue plug (Figure 1) ; intraoperative pancreatography was used when necessary to rule out major pancreatic ductal injury. All pancreatic injuries were managed postoperatively with external drainage utilizing sump drains or a closed drainage system. * 1 KIU is equivalent to 1.1 I 1 X 10e3 trypsin inhibitor units. t 1 US (NIH) unit is comparable to 1 International Unit of the First National Standard. 1: 1 unit is that amount of factor XIII which is contained in 1 mL of titrated, pooled, human plasma. JOURNAL
OF SURGERY
VOLUME
161
APRIL
1991
479
Flaure 1. Gunshot wound (arrow) throuah the head of the oancreas before (A) and after (B) sealing with fibrin glue. P = pancreas; D = d&Mum; F = fibrin glk. -
In four patients with pancreatitis, side-to-side pancreaticojejunostomies or cystojejunostomies were performed in a conventional fashion using an inner layer of absorbable suture surrounded by an outer layer of silk sutures. The anastomoses were then sealed with 6 to 10 mL of fibrin glue (Figure 2) ; external drainage was not used. One patient with pancreatic cancer underwent a Whipple operation with end-to-end pancreaticojejunostomy performed in a conventional two-layered fashion, followed by sealing of the anastomosis with 6 to 8 mL of fibrin glue (Figure 3).
RESULTS Postoperatively, pancreatic fistulas were absent in all patients. Pancreatic abscesses or pseudocysts did not occur. One patient developed a subhepatic abscess following a missed gastric injury, and another patient developed a paracolic abscess following extensive intraperitoneal contamination from an associated colon injury. One patient developed a lateral duodenal fistula following repair of an associated gunshot wound of the duodenum. Two patients died secondary to overwhelming sepsis and acute renal failure, respectively.
Figure 2. Pancreaticojejunostomy (side-t*side) sealed with fibrin glue in a patient with chronic pancreatitis. P = pancreas; J = jejunum; F = fibrin glue.
Figure 3. Pancreaticojejunostomy (end-Wend) sealed with fibrin glue following Whipple operation for pancreatic cancer. P = pancreas; J = jejunum; F = fibrin glue.
480
THE AMERICAN
JOURNAL
OF SURGERY
VOLUME
161
APRIL 1991
Patients with pancreatitis who underwent pancreaticojejunostomy or cystojejunostomy had an uneventful postoperative course and were discharged from the hospital within 2 weeks of surgical therapy. One patient who underwent a Whipple operation developed a biliary fistula that eventually closed without operative intervention. COMMENTS This preliminary study evaluated the safety and efficacy of fibrin glue in preventing fistula formation following pancreatic surgery for traumatic and nontraumatic conditions. No complication attributable to fibrin glue was seen and pancreatic fistulas did not occur. Previously, fistulas occurred in 29% of patients operated on for pancreatic trauma at our institution [14], which is signilicantly greater than that of the present series. Similarly, the incidence of pancreatic fistulas after significant traumatic injury has been reported to be greater than 30% [1-
51.
Several methods of managing the pancreas at the site of transection following pancreatic resection have been described, including the use of mattress sutures, continuous or interrupted sutures with or without ligation of the main pancreatic duct, electrocautery, omental patches, and staples [ 1%181. Although identification and ligation of the main pancreatic duct is preferred, it is often impossible to perform and does not prevent pancreatic fistulas in all patients. Use of the TA 55 stapling device (U.S. Surgical, Norwalk, CT) has been recommended when pancreatic duct ligation is not possible; however, Fitzgibbons et al [ 181 reported an identical incidence of postoperative pancreatic fistulas in patients treated by this method compared with those treated by direct suturing of the pancreas. Fibrin glue sealing of pancreatic suture and staple lines may add significant reinforcement to both methods. Intrapancreatic injection of fibrin glue should be avoided, as this may result in intravascular embolization, thrombosis, ductal occlusion, and pancreatic necrosis. Rather, fibrin glue should be applied directly to pancreatic suture and staple lines. Pancreatic injuries secondary to penetrating trauma are managed by completely filling in the defect with a fibrin glue plug; this technique has been previously described in the management of splenic and hepatic trauma [8,9,1 I]. However, fibrin glue should not be injected into a pancreatic defect in the presence of injury to the main pancreatic duct, as this risks intraductal injection and occlusion. Injuries of the main pancreatic duct are best managed by partial resection when possi-
ble and sealing of the pancreatic suture or staple line with fibrin glue. In conclusion, fibrin glue sealing of pancreatic injuries, resections, and anastomoses may aid in preventing tistula formation following pancreatic surgery. Further studies are indicated to confirm these preliminary results. Additional potential uses of fibrin glue include the sealing of pancreatic biopsy sites and occlusion of the pancreatic duct in pancreatic transplantation. REFERENCES 1. Howell JF, Burrus GR, Jordan GL. Surgical management of pancreatic injuries. J Trauma 1961; 1: 32-40. 2. Sturim HS. The surgical management of pancreatic injuries. Surg Gynecol Obstet 1966; 122: 133-40. 3. Graham JM, Mattox KL, Jordan GL. Traumatic injuries of the pancreas. Am J Surg 1978; 136: 744-8. 4. Balasegaram M. Surgical management of pancreatic trauma. Curr Probl Surg 1979; 16: l-59. 5. Graham JM, Mattox KL, Vaughan GD, et al. Combined pancreaticoduodenal injuries. J Trauma 1979; 19: 340-6. 6. Monge JJ, Judd ES, Gage RP. Radical pancreaticoduodenectomy: a 22-year experience with the complications, mortality rate, and survival rate. Ann Surg 1964; 160: 7 1l-22. 7. Nakase A, Matsumoto Y, Uchida K, et al. Surgical treatment of cancer of the pancreas and the periampullary region: cumulative results in 57 institutions in Japan. Ann Surg 1977; 185: 52-7. 8. Kram HB, Nathan RC, Mackabee JR, et al. Clinical use of nonautologous fibrin glue. Am Surg 1988; 54: 570-3. 9. Kram HB, Nathan RC, Stafford FJ, et al. Fibrin glue achieves hemostasis in patients with coagulation disorders. Arch Surg 1989; 124: 385-7. 10. Kram HB, Ocampo HP, Yamaguchi MP, et al. Fibrin glue in renal and ureteral trauma. Urology 1989; 33: 215-8. 11. Kram HB, de1 Junco T, Clark SR, et al. Techniques of splenic preservation using fibrin glue. J Trauma 1990; 30: 97-101. 12. Guttman T. Untersuchungen eines Fibrinklebers Fur die anwendung in der chirugie peripherer nerven. Diplomarbeit Inst F Botanik, Technische Mikroscopie Organ. Rohstofflehre, Vienna: Technische Universitat Wein, 1978. Thesis. 13. Red1 H, Schlag G, Dinges H, et al. Background and methods of fibrin sealing. In: Winter GD, Gibbons DF, Plenk H, eds. Biomaterials. New York: Wiley & Sons, 1982: 669-76. 14. Sims EH, Mandal AK, Schlater T, et al. Factors affecting outcome in pancreatic trauma. J Trauma 1984; 24: 125-8. 15. Yellin AE, Vecchione TR, Donovan AJ. Distal pancreatectomy for pancreatic trauma. Am J Surg 1972; 124: 135-42. 16. Feliciano D, Moore EE, Pachter HL, et al. Symposium on pancreatico-duodenal trauma. Contemp Surg 1986; 29: 107-28. 17. Pachter HL, Pennington R, Chassin J, ef al. Simplified distal pancreatectomy with the auto suture stapler: preliminary clinical observations. Surgery 1979; 85: 166-70. 18. Fitzgibbons TJ, Yellin AE, Maruyama MM, et al. Management of the transected pancreas following distal pancreatectomy. Surg Gynecol Obstet 1982; 154: 225-31.
THE AMERICAN JOURNAL OF SURGERY
VOLUME 161 APRIL 1991
4.81
MD,
Stevan R. Clark, MD, Hermenegildo P. Ocampo, MD, Miles A. Yamaguchi, William C. Shoemaker, MD, LOSAngeles, California
Fibrin glue made with highly concentrated human fibrinogen and clotting factors was evaluated as a means of preventing pancreatic fistulas in 15 patients operated on for traumatic and nontraumatic conditions. Fibrin glue was applied directly to penetrating pancreatic injuries, pancreatic suture and staple lines in patients treated by partial resection, and pancreaticointestinal anastomoses. Postoperatively, no patient developed pancreatic fistulas, pancreatic abscesses, or pseudocysts. Fibrin glue sealing of pancreatic injuries, resections, and anastomoses may aid in preventing fistulas after pancreatic surgery. Additional potential uses include the sealing of pancreatic biopsy sites and occlusion of the pancreatic duct in pancreatic transplantation.
P
ancreatic ffitula formation is a frequent complication following the surgical treatment of pancreatic injuries or the performance of pancreaticointestinal anastomoses, occurring in up to a third of patients [J-7]. The morbidity associated with postoperative pancreatic fistulas is often significant and may result in death. Furthermore, associated complications are frequent and include abscess, pseudocyst, hemorrhage, electrolyte losses, skin irritation, and malabsorption. A safe and effective method of preventing fistulas after pancreatic surgery would contribute significantly to the successful treatment of these patients. Nonautologous fibrin glue has been used clinically in the United States since 1984 [8]. More than 250 surgical procedures utilizing fibrin glue have been performed, including the control of parenchymal organ hemorrhage and the sealing of anastomoses [8-111. In the present report, we describe the intraoperative use of fibrin glue to prevent pancreatic fistulas after surgery for traumatic and nontraumatic conditions. From the Department of Surgery, Los Angeles County King/Drew Medical Center, and the UCLA School of Medicine, Los Angeles, California. Requests for reprints should be addressed to Harry B. Kram, MD, King/Drew Medical Center, Department of Surgery, 12021 S. Wilmington Avenue, Los Angeles, California 90059. Manuscript submitted May 16, 1989, and accepted in revised form November 22,1989.
THE AMERICAN
MD,
MATERIAL AND METHODS Fibrin glue: Fibrin glue consists
of four components: highly concentrated fibrinogen (total protein approximately 120 mg/mL), aprotinin (3,000 KIU/mL)*, dried thrombin (500 US [NIH] units/ml)?, and calcium chloride (40 pm/mL). The fibrinogen is obtained from donor human plasma. After the fibrinogen is preheated to 37°C it is dissolved in aprotinin and the dried thrombin is reconstituted in calcium chloride. The two solutions are then drawn up into separate syringes, which are loaded on a double-barreled syringe holder designed to mix and apply the components simultaneously. The reconstitution procedure takes 10 to 15 minutes, and the components should be used within 4 hours. The reconstituted adhesive contains 70 to 100 mg/mL of fibrinogen, 2 to 7 mg/mL of fibronectin (cold-insoluble globulin), 10 units/ml of factor X111$,and 35 pg/mL of plasminogen. Upon application, the components mix to form a clear, viscous solution that firmly adheres to wound surfaces and sets into a white, rubberlike mass within seconds. The adhesive continues to gain in tensile strength over the course of time; 70% of the maximum tensile strength is achieved in 10 minutes [IZ]. During the subsequent course of wound healing, the adhesive slowly dissolves by fibrinolysis and is completely removed from the body within 4 to 6 weeks; aprotinin is added to slow the fibrinolytic process. The essential reactions after mixing of the components are proteolysis, fibrin cross-linking, and finally, lysis and absorption of the clot material during the wound healing process [13]. Clinical data: Fibrin glue was used in 10 patients operated on for pancreatic trauma and in 5 patients who underwent pancreaticointestinal anastomoses for nontraumatic disease. The latter group included two patients with chronic pancreatitis, two with pseudocysts, and one with pancreatic cancer. Fibrin glue was used to seal suture or staple lines in five traumatic injuries treated by pancreatic resection; 4 to 6 mL of fibrin glue was used for each injury. Identification and ligation of the main pancreatic duct was not performed. Five other penetrating pancreatic injuries were treated by completely filling in the defect with a l- to 2-mL fibrin glue plug (Figure 1) ; intraoperative pancreatography was used when necessary to rule out major pancreatic ductal injury. All pancreatic injuries were managed postoperatively with external drainage utilizing sump drains or a closed drainage system. * 1 KIU is equivalent to 1.1 I 1 X 10e3 trypsin inhibitor units. t 1 US (NIH) unit is comparable to 1 International Unit of the First National Standard. 1: 1 unit is that amount of factor XIII which is contained in 1 mL of titrated, pooled, human plasma. JOURNAL
OF SURGERY
VOLUME
161
APRIL
1991
479
Flaure 1. Gunshot wound (arrow) throuah the head of the oancreas before (A) and after (B) sealing with fibrin glue. P = pancreas; D = d&Mum; F = fibrin glk. -
In four patients with pancreatitis, side-to-side pancreaticojejunostomies or cystojejunostomies were performed in a conventional fashion using an inner layer of absorbable suture surrounded by an outer layer of silk sutures. The anastomoses were then sealed with 6 to 10 mL of fibrin glue (Figure 2) ; external drainage was not used. One patient with pancreatic cancer underwent a Whipple operation with end-to-end pancreaticojejunostomy performed in a conventional two-layered fashion, followed by sealing of the anastomosis with 6 to 8 mL of fibrin glue (Figure 3).
RESULTS Postoperatively, pancreatic fistulas were absent in all patients. Pancreatic abscesses or pseudocysts did not occur. One patient developed a subhepatic abscess following a missed gastric injury, and another patient developed a paracolic abscess following extensive intraperitoneal contamination from an associated colon injury. One patient developed a lateral duodenal fistula following repair of an associated gunshot wound of the duodenum. Two patients died secondary to overwhelming sepsis and acute renal failure, respectively.
Figure 2. Pancreaticojejunostomy (side-t*side) sealed with fibrin glue in a patient with chronic pancreatitis. P = pancreas; J = jejunum; F = fibrin glue.
Figure 3. Pancreaticojejunostomy (end-Wend) sealed with fibrin glue following Whipple operation for pancreatic cancer. P = pancreas; J = jejunum; F = fibrin glue.
480
THE AMERICAN
JOURNAL
OF SURGERY
VOLUME
161
APRIL 1991
Patients with pancreatitis who underwent pancreaticojejunostomy or cystojejunostomy had an uneventful postoperative course and were discharged from the hospital within 2 weeks of surgical therapy. One patient who underwent a Whipple operation developed a biliary fistula that eventually closed without operative intervention. COMMENTS This preliminary study evaluated the safety and efficacy of fibrin glue in preventing fistula formation following pancreatic surgery for traumatic and nontraumatic conditions. No complication attributable to fibrin glue was seen and pancreatic fistulas did not occur. Previously, fistulas occurred in 29% of patients operated on for pancreatic trauma at our institution [14], which is signilicantly greater than that of the present series. Similarly, the incidence of pancreatic fistulas after significant traumatic injury has been reported to be greater than 30% [1-
51.
Several methods of managing the pancreas at the site of transection following pancreatic resection have been described, including the use of mattress sutures, continuous or interrupted sutures with or without ligation of the main pancreatic duct, electrocautery, omental patches, and staples [ 1%181. Although identification and ligation of the main pancreatic duct is preferred, it is often impossible to perform and does not prevent pancreatic fistulas in all patients. Use of the TA 55 stapling device (U.S. Surgical, Norwalk, CT) has been recommended when pancreatic duct ligation is not possible; however, Fitzgibbons et al [ 181 reported an identical incidence of postoperative pancreatic fistulas in patients treated by this method compared with those treated by direct suturing of the pancreas. Fibrin glue sealing of pancreatic suture and staple lines may add significant reinforcement to both methods. Intrapancreatic injection of fibrin glue should be avoided, as this may result in intravascular embolization, thrombosis, ductal occlusion, and pancreatic necrosis. Rather, fibrin glue should be applied directly to pancreatic suture and staple lines. Pancreatic injuries secondary to penetrating trauma are managed by completely filling in the defect with a fibrin glue plug; this technique has been previously described in the management of splenic and hepatic trauma [8,9,1 I]. However, fibrin glue should not be injected into a pancreatic defect in the presence of injury to the main pancreatic duct, as this risks intraductal injection and occlusion. Injuries of the main pancreatic duct are best managed by partial resection when possi-
ble and sealing of the pancreatic suture or staple line with fibrin glue. In conclusion, fibrin glue sealing of pancreatic injuries, resections, and anastomoses may aid in preventing tistula formation following pancreatic surgery. Further studies are indicated to confirm these preliminary results. Additional potential uses of fibrin glue include the sealing of pancreatic biopsy sites and occlusion of the pancreatic duct in pancreatic transplantation. REFERENCES 1. Howell JF, Burrus GR, Jordan GL. Surgical management of pancreatic injuries. J Trauma 1961; 1: 32-40. 2. Sturim HS. The surgical management of pancreatic injuries. Surg Gynecol Obstet 1966; 122: 133-40. 3. Graham JM, Mattox KL, Jordan GL. Traumatic injuries of the pancreas. Am J Surg 1978; 136: 744-8. 4. Balasegaram M. Surgical management of pancreatic trauma. Curr Probl Surg 1979; 16: l-59. 5. Graham JM, Mattox KL, Vaughan GD, et al. Combined pancreaticoduodenal injuries. J Trauma 1979; 19: 340-6. 6. Monge JJ, Judd ES, Gage RP. Radical pancreaticoduodenectomy: a 22-year experience with the complications, mortality rate, and survival rate. Ann Surg 1964; 160: 7 1l-22. 7. Nakase A, Matsumoto Y, Uchida K, et al. Surgical treatment of cancer of the pancreas and the periampullary region: cumulative results in 57 institutions in Japan. Ann Surg 1977; 185: 52-7. 8. Kram HB, Nathan RC, Mackabee JR, et al. Clinical use of nonautologous fibrin glue. Am Surg 1988; 54: 570-3. 9. Kram HB, Nathan RC, Stafford FJ, et al. Fibrin glue achieves hemostasis in patients with coagulation disorders. Arch Surg 1989; 124: 385-7. 10. Kram HB, Ocampo HP, Yamaguchi MP, et al. Fibrin glue in renal and ureteral trauma. Urology 1989; 33: 215-8. 11. Kram HB, de1 Junco T, Clark SR, et al. Techniques of splenic preservation using fibrin glue. J Trauma 1990; 30: 97-101. 12. Guttman T. Untersuchungen eines Fibrinklebers Fur die anwendung in der chirugie peripherer nerven. Diplomarbeit Inst F Botanik, Technische Mikroscopie Organ. Rohstofflehre, Vienna: Technische Universitat Wein, 1978. Thesis. 13. Red1 H, Schlag G, Dinges H, et al. Background and methods of fibrin sealing. In: Winter GD, Gibbons DF, Plenk H, eds. Biomaterials. New York: Wiley & Sons, 1982: 669-76. 14. Sims EH, Mandal AK, Schlater T, et al. Factors affecting outcome in pancreatic trauma. J Trauma 1984; 24: 125-8. 15. Yellin AE, Vecchione TR, Donovan AJ. Distal pancreatectomy for pancreatic trauma. Am J Surg 1972; 124: 135-42. 16. Feliciano D, Moore EE, Pachter HL, et al. Symposium on pancreatico-duodenal trauma. Contemp Surg 1986; 29: 107-28. 17. Pachter HL, Pennington R, Chassin J, ef al. Simplified distal pancreatectomy with the auto suture stapler: preliminary clinical observations. Surgery 1979; 85: 166-70. 18. Fitzgibbons TJ, Yellin AE, Maruyama MM, et al. Management of the transected pancreas following distal pancreatectomy. Surg Gynecol Obstet 1982; 154: 225-31.
THE AMERICAN JOURNAL OF SURGERY
VOLUME 161 APRIL 1991
4.81
