- Email: [email protected]
Metabolic effects of systemic venous drainage in small bowel transplantation
Metabolic Effects of Systemic Venous Drainage in Small Bowel Transplantation N. Hashimoto and H. Ohyanagi ABSTRACT Small bowel transplantation has proved feasible in rats and in larger animals, but several important questions remain to be addressed before it becomes routine therapy in humans. One consideration is the site of venous outflow of the allograft. While portal drainage reestablishes the physiologic route of venous outflow, systemic drainage creates a partial mesocaval shunt, the metabolic consequences of which have not been studied in detail. Using a canine model of orthotopic small bowel autotransplantation, we compared the metabolic changes following transplantation with portal versus systemic venous drainage. Changes in blood ammonia levels, plasma amino acid composition, and hepatic blood flow were studied, since the Eck procedure produces metabolic changes of hyperammonemia and amino acid imbalances, while portocaval venous drainage of small bowel transplant produces a profile similar to that in controls. These data suggest that there is no metabolic disadvantage of systemic venous drainage as compared with controls. Because of its technical simplicity, systemic venous drainage may be preferable for small bowel transplantation.
A
LTHOUGH small bowel transplantation has proved feasible in rats and in, large animals, several important questions remain to be answered before it can accept as a routine therapy for man. One consideration is the site of venous outflow from the allograft. Vascularized small bowel transplants may be drained by venous outflow from either the portal or the systemic circulation. Studies on a variety of organ allografts, including small bowel allografts, suggest that portal venous drainage confers immunologic benefits that favor prolonged allograft survival. However, these benefits appear to be minor and not sufficient to justify a preferential use of portal drainage to systemic venous drainage for intestinal transplants.1 Portal drainage, however, reestablishes the physiologic route of venous outflow, whereas systemic drainage creates a partial mesocaval shunt, the metabolic consequences of which have not been studied in detail. Therefore, using a canine model of orthotopic small bowel autotransplantation, we compared the metabolic changes— blood ammonia levels, plasma amino acid composition, and hepatic blood flow—following transplantation with portal and with systemic venous drainage. MATERIAL AND METHODS Adult mongrel dogs weighing 10 –15 kg were used in this study following the International Guidelines of Biomedical Research Involving Animals for the care and use of laboratory animals. The © 2003 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710 Transplantation Proceedings, 35, 1567-1568 (2003)
animals were divided into four groups depending upon the type of operation: Group 1 was a sham-operated control group (Control, n ⫽ 6); Group 2, a central end-to-side portacaval shunt (Eck, n ⫽ 6); Group 3, autotransplantation of the entire small bowel with end-to-end, portoportal venous anastomosis (MPA, n ⫽ 7); and Group 4, autotransplantation of the entire small bowel with end-to-side, portacaval venous anastomosis (MCA, n ⫽ 7). The entire small bowel from the distal part of the duodenum to 1 inch proximal to the ileocecal valve was isolated on a mesenteric vascular pedicle. After systemic heparinization, the resected isolated gut was flushed with 500 –700 mL of cold heparinized lactated Ringer solution and further cooled by intraluminal irrigation of the same solution with added kanamycin (0.5 g/L), as previously described. Poorly perfused ends of the transplant were resected (usually about 15 cm at either end) before reimplantation. The graft was revascularized by an anastomosis to the mesenteric vessels for portal drainage (MPA, n ⫽ 7) or to the abdominal aorta and inferior vena cava in an end-to-side fashion for vena caval drainage (MCA, n ⫽ 7). Bowel continuity was restored by an end-to-end anastomosis of the recipient duodenum and ileum to From the Kinki University, Department of Surgery, Osaka, Japan. Address reprint requests to Naoki Hashimoto, Department of Second Surgery, Kinki University, School of Medicine, 377-2, Ohno-Higashi, Osaka Sayama, 589-8511 Japan. E-mail: [email protected] 0041-1345/03/$–see front matter doi:10.1016/S0041-1345(03)00455-X 1567
1568 the upper and lower ends of the transplant, respectively, using a single-layer anastomosis. Cold ischemic time averaged approximately 80 minutes.
Plasma Assay Blood was collected from a peripheral vein. Determination of plasma amino acids was performed by column chromatography using a Beckman M-121 amino acid analyzer on the plasma supernate, which had been rendered protein free by treatment with 4% sulfosalicyclic acid. Ammonia assays were performed using the glutamate dehydrogenase technique.
Hepatic Blood Flow A needle-type electrode was inserted into the left internal hepatic lobe for the measurement of local hepatic blood flow. About 10% hydrogen gas was inhaled for 2–3 minutes from the intratracheal tube, and a hydrogen gas washout curve meter (PHG 300 manufactured by MT Giken-sha). The values of this curve were plotted on semilogarithmic graph paper, with time on the abscissa. A half-life value (t1/2 min) was obtained from the graph; blood flow was calculated on the basis of Kety’s theoretical formula, an application of the Fick principle.
Statistical Analysis Differences between mean values were tested for significance by Student’s t test for unpaired data. Linear correlation coefficients and their significance was calculated using standard methods.
RESULTS
The local hepatic blood flow was 93 ⫾ 5 mL min 100 g in Control; 80 ⫾ 5 in MCA; 95 ⫾ 5 in MPA; and 60 ⫾ 5 in the Eck group. The Eck showed a significant decrease in local hepatic blood flow (P ⬍ .05). The ammonia level was 60 ⫾ 5 g/dL in Control; 70 ⫾ 5 in MCA, 65 ⫾ 5 in MPA and 190 ⫾ 30 in Eck. The Eck group showed a significant elevation of the ammonia level as compared with the controls. The Fisher ratio of VAL⫹LEU⫹ILE/PHE⫹TYR was 3.5 ⫾ 0.2 in Controls, 3.3 ⫾ 0.2 in MPA, 3.1 ⫾ 0.2 in MCA, and 1.2 ⫾ 0.1 in the Eck group. The last group showed a significant lower value (P ⬍ .01) than the controls.
HASHIMOTO AND OHYANAGI
allograft into the host portal circulation restores normal anatomy, although it may be technically more difficult, especially in a patient who has undergone previous abdominal surgery and bowel resections. Conversely, systemic venous drainage of a small bowel allograft—for example, to the inferior vena cava or iliac vessels—would be technically simpler. Most cases of clinical small bowel transplantation have employed systemic venous drainage. Systemic venous drainage of the small bowel graft is anatomically equivalent to a partial mesocaval shunt, diverting small bowel venous outflow into the systemic circulation, but leaving gastric, duodenal, pancreatic, and proximal colonic venous outflow undisturbed. Portal venous drainage is physiologically equivalent to the normal state. Systemic venous drainage causes metabolic disturbances consistent with a partial mesocaval shunt. These changes are less marked than those following complete portosystemic shunt. Eck fistula is derived of portal venous blood or that portion of portal blood that comes from the pancreas, leaving the liver with only an artery supply. The metabolic changes in Eck were hyperammonia and amino acid imbalance,2 while those in portacaval venous drainage were similar to those in controls. These data suggest that the venous effluent from the small intestine may be relatively less important in maintaining normal liver function. Diversion of portal blood flow from the liver despite maintenance of total hepatic blood flow results in liver atrophy. Starzl et al3 attributed this finding to the absence of hepatotrophic factors derived from the pancreas, predominantly insulin. Other investigators4 maintain that intestinal venous blood serves as the main source of hepatotrophic factors. This study demonstrates that portal venous drainage is physiologically equivalent to the normal state, whereas systemic venous drainage causes metabolic disturbances consistent with a partial portosystemic shunt. These changes are less marked than those following complete portosystemic shunting. Our data suggest that there is no metabolic disadvantage of systemic venous drainage as compared with controls and because of its technical simplicity, systemic venous drainage may be preferable in small bowel transplantation.
DISCUSSION
REFERENCES
One major technical question concerning transplantation of the isolated small bowel regards venous drainage of the graft, namely, either the portal or the systemic circulation. In theory, portal drainage would be a better physiologic solution, because of the hepatotrophic effects of the portal flow and of the first passage effect related to the nutrientrich intestinal venous outflow. Drainage of the small bowel
1. Schraut WH, Abraham VS, Lee KKW, et al: Surgery 98:579, 1985 2. Hashimoto N, Ishikawa Y, Utunomiya J: J Surg Res 46:35, 1989 3. Starzl TE, Francavilla A, Halgrimson CG, et al: Surg Gynecol Obstet 137:179, 1973 4. Fischer B, Szuch P, Levine M, et al: Surg Gynecol Obstet 137:210, 1973
A
LTHOUGH small bowel transplantation has proved feasible in rats and in, large animals, several important questions remain to be answered before it can accept as a routine therapy for man. One consideration is the site of venous outflow from the allograft. Vascularized small bowel transplants may be drained by venous outflow from either the portal or the systemic circulation. Studies on a variety of organ allografts, including small bowel allografts, suggest that portal venous drainage confers immunologic benefits that favor prolonged allograft survival. However, these benefits appear to be minor and not sufficient to justify a preferential use of portal drainage to systemic venous drainage for intestinal transplants.1 Portal drainage, however, reestablishes the physiologic route of venous outflow, whereas systemic drainage creates a partial mesocaval shunt, the metabolic consequences of which have not been studied in detail. Therefore, using a canine model of orthotopic small bowel autotransplantation, we compared the metabolic changes— blood ammonia levels, plasma amino acid composition, and hepatic blood flow—following transplantation with portal and with systemic venous drainage. MATERIAL AND METHODS Adult mongrel dogs weighing 10 –15 kg were used in this study following the International Guidelines of Biomedical Research Involving Animals for the care and use of laboratory animals. The © 2003 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710 Transplantation Proceedings, 35, 1567-1568 (2003)
animals were divided into four groups depending upon the type of operation: Group 1 was a sham-operated control group (Control, n ⫽ 6); Group 2, a central end-to-side portacaval shunt (Eck, n ⫽ 6); Group 3, autotransplantation of the entire small bowel with end-to-end, portoportal venous anastomosis (MPA, n ⫽ 7); and Group 4, autotransplantation of the entire small bowel with end-to-side, portacaval venous anastomosis (MCA, n ⫽ 7). The entire small bowel from the distal part of the duodenum to 1 inch proximal to the ileocecal valve was isolated on a mesenteric vascular pedicle. After systemic heparinization, the resected isolated gut was flushed with 500 –700 mL of cold heparinized lactated Ringer solution and further cooled by intraluminal irrigation of the same solution with added kanamycin (0.5 g/L), as previously described. Poorly perfused ends of the transplant were resected (usually about 15 cm at either end) before reimplantation. The graft was revascularized by an anastomosis to the mesenteric vessels for portal drainage (MPA, n ⫽ 7) or to the abdominal aorta and inferior vena cava in an end-to-side fashion for vena caval drainage (MCA, n ⫽ 7). Bowel continuity was restored by an end-to-end anastomosis of the recipient duodenum and ileum to From the Kinki University, Department of Surgery, Osaka, Japan. Address reprint requests to Naoki Hashimoto, Department of Second Surgery, Kinki University, School of Medicine, 377-2, Ohno-Higashi, Osaka Sayama, 589-8511 Japan. E-mail: [email protected] 0041-1345/03/$–see front matter doi:10.1016/S0041-1345(03)00455-X 1567
1568 the upper and lower ends of the transplant, respectively, using a single-layer anastomosis. Cold ischemic time averaged approximately 80 minutes.
Plasma Assay Blood was collected from a peripheral vein. Determination of plasma amino acids was performed by column chromatography using a Beckman M-121 amino acid analyzer on the plasma supernate, which had been rendered protein free by treatment with 4% sulfosalicyclic acid. Ammonia assays were performed using the glutamate dehydrogenase technique.
Hepatic Blood Flow A needle-type electrode was inserted into the left internal hepatic lobe for the measurement of local hepatic blood flow. About 10% hydrogen gas was inhaled for 2–3 minutes from the intratracheal tube, and a hydrogen gas washout curve meter (PHG 300 manufactured by MT Giken-sha). The values of this curve were plotted on semilogarithmic graph paper, with time on the abscissa. A half-life value (t1/2 min) was obtained from the graph; blood flow was calculated on the basis of Kety’s theoretical formula, an application of the Fick principle.
Statistical Analysis Differences between mean values were tested for significance by Student’s t test for unpaired data. Linear correlation coefficients and their significance was calculated using standard methods.
RESULTS
The local hepatic blood flow was 93 ⫾ 5 mL min 100 g in Control; 80 ⫾ 5 in MCA; 95 ⫾ 5 in MPA; and 60 ⫾ 5 in the Eck group. The Eck showed a significant decrease in local hepatic blood flow (P ⬍ .05). The ammonia level was 60 ⫾ 5 g/dL in Control; 70 ⫾ 5 in MCA, 65 ⫾ 5 in MPA and 190 ⫾ 30 in Eck. The Eck group showed a significant elevation of the ammonia level as compared with the controls. The Fisher ratio of VAL⫹LEU⫹ILE/PHE⫹TYR was 3.5 ⫾ 0.2 in Controls, 3.3 ⫾ 0.2 in MPA, 3.1 ⫾ 0.2 in MCA, and 1.2 ⫾ 0.1 in the Eck group. The last group showed a significant lower value (P ⬍ .01) than the controls.
HASHIMOTO AND OHYANAGI
allograft into the host portal circulation restores normal anatomy, although it may be technically more difficult, especially in a patient who has undergone previous abdominal surgery and bowel resections. Conversely, systemic venous drainage of a small bowel allograft—for example, to the inferior vena cava or iliac vessels—would be technically simpler. Most cases of clinical small bowel transplantation have employed systemic venous drainage. Systemic venous drainage of the small bowel graft is anatomically equivalent to a partial mesocaval shunt, diverting small bowel venous outflow into the systemic circulation, but leaving gastric, duodenal, pancreatic, and proximal colonic venous outflow undisturbed. Portal venous drainage is physiologically equivalent to the normal state. Systemic venous drainage causes metabolic disturbances consistent with a partial mesocaval shunt. These changes are less marked than those following complete portosystemic shunt. Eck fistula is derived of portal venous blood or that portion of portal blood that comes from the pancreas, leaving the liver with only an artery supply. The metabolic changes in Eck were hyperammonia and amino acid imbalance,2 while those in portacaval venous drainage were similar to those in controls. These data suggest that the venous effluent from the small intestine may be relatively less important in maintaining normal liver function. Diversion of portal blood flow from the liver despite maintenance of total hepatic blood flow results in liver atrophy. Starzl et al3 attributed this finding to the absence of hepatotrophic factors derived from the pancreas, predominantly insulin. Other investigators4 maintain that intestinal venous blood serves as the main source of hepatotrophic factors. This study demonstrates that portal venous drainage is physiologically equivalent to the normal state, whereas systemic venous drainage causes metabolic disturbances consistent with a partial portosystemic shunt. These changes are less marked than those following complete portosystemic shunting. Our data suggest that there is no metabolic disadvantage of systemic venous drainage as compared with controls and because of its technical simplicity, systemic venous drainage may be preferable in small bowel transplantation.
DISCUSSION
REFERENCES
One major technical question concerning transplantation of the isolated small bowel regards venous drainage of the graft, namely, either the portal or the systemic circulation. In theory, portal drainage would be a better physiologic solution, because of the hepatotrophic effects of the portal flow and of the first passage effect related to the nutrientrich intestinal venous outflow. Drainage of the small bowel
1. Schraut WH, Abraham VS, Lee KKW, et al: Surgery 98:579, 1985 2. Hashimoto N, Ishikawa Y, Utunomiya J: J Surg Res 46:35, 1989 3. Starzl TE, Francavilla A, Halgrimson CG, et al: Surg Gynecol Obstet 137:179, 1973 4. Fischer B, Szuch P, Levine M, et al: Surg Gynecol Obstet 137:210, 1973