Annals of the Royal College of Surgeons of England (1978) vol 6o
Current J Collin
MD
state
of transplantation of the
pancreas
FRCS
Senior Registrar, Royal Victoria Infirmary, Newcastle
Summary Studies of pancreatic transplantation have been made using the pancreatic tail as an autotransplant model. The endocrine function of the pancreas has been shown to be relatively resistant to warm ischaemic injurv. Autotransplantation of the pancreatic tail with a double arterial anastomosis technique can be achieved with ioo% immediate success, the graft maintaining satisfactory glucose tolerance and insulin secretion. No important changes in glucose homoeostasis have been shown to result from diversion of pancreatic insulin secretion from portal to systemic veins.
Introduction A successful pancreatic transplant offers a nuimber of theoretical advantages over insulin injections for the treatment of diabetes mellitus The secretion of insulin would be controlled, continuous, and appropriate to the changing demands of the moment. The insulin would he of the correct species and there would be no risk of overdosage or underdosage. In addition there are possibly other pancreatic hormones at present unkown, as the work of Gates and his colleagues' would suggest. The major stimulus to research into pancreatic transplantation remains the hope that, with all these theoretical advantages, a functioning pancreatic transplant would be able to prevent or reverse the complications of diabetes. One of the disappointing features of pancreatic transplantation has been the very high failure rate in all reported series2'-, results that compare very unfavourably with those of renal transplantation. Leakage of the duodenal anastomoses has occurred frequently after pancreaticoduodenal transplantation3, while other common problems have been pancreatitis in the graft and thrombosis at
upon
Tyne
either arterial or venous anastomoses. A satisfactory pancreatic autotransplant model would permit the study of the special factors affecting surx'val of pancreatic transplants free from the complicating problem of graft rejection. In the experiments reported here the pancreatic tail in the dog has been studied as a model for segmental pancreatic autotransplantation.
Blood supply of the ca ne pancreas In the course of the experiments an anatomical study was made of the pancreatic blood supply in 53 dogs (Fig. i). The head of the pancreas and proximal duodenum were supplied by the cranial pancreaticoduodenal artery from the right gastric artery and drained directly into the portal vein by the cranial pancreaticoduodenal vein. The uncinate process of the pancreas was supplied independently from the caudal pancreaticoduodenal artery by one or two small uncinate branches and drained by corresponding uncinate veins. The blood supply of the pancreatic tail wvas much more variable. In 85 % of dogs the arterial supply arose solely from the splenic artery and consisted usually of a single pancreatic branch arising close to the origin of the splenic artery from the coeliac trunk. In the remaining I5ato the pancreatic branch arose from the cranial mesenteric, hepatic, or coeliac arteries. The venous drainage of the pancreatic tail in 88% of dogs was solely to the splenic vein. As with the arterial supply, anomalies were common, the venous drainage being to either the portal or the cranial mesenteric vein. In 23% of all dogs examined variations in either arterial or venous blood supply were such as to exclude autotransplantation of the pancreatic tail.
Based on an Arris and Gale Lecture delivered on 12th May 1976
22
J Collini Coel iac
FIG. i Normal arterial supply of canine pancreas.
Urncinate branch
In-situ experiments TOTAL PANCREATECTOMY
Seven dogs were subjected to total pancreatectomy. All were diabetic 24 h after operation, the fasting plasma glucose level being above i6 mmol/l (288 mg/ioo ml), while plasma insulin was undetectable. Serum amylase levels were reduced to the range 6oo-iooo U/1, these basal levels being accounted for by salivary gland secretion. Glucose clearance was markedly impaired from the first postoperative day and there was no insulin response to glucose at any time in the postoperative period. All the dogs died in diabetic coma within one week of
In all the experiments intravenous glucose tolerance tests were performed before and on the ist, 4th, and 22nd days after operation. The rate of disappearance of injected glucose from the blood was expressed as the glucose clearance (K value) as described by Lundbaek . As a measure of insulin response to glucose the mean increment in plasma insulin level at 5, I5, and 30 min after glucose injection was calculated for each glucose tolerance test.
operation. RIGHT PANCREATIC LOBECTOMY
To determine whether the pancreatic tail alone of Padl c, el C Tail ipanCj was adequate to maintain carbohydrate tissue( than the other tissue all tolerance pancreatic excised tail was excised in 8 dogs (Fig. 2). The duct of the pancreatic tail was ligated. All the dogs developed steatorrhoea and lost weight as a result of the absence of pancreatic exocrine secretions from the bowel. Serum amylase levels were greatly elevated in the early postoperative period (mean 4720 U/1), but fasting glucose and insulin levels FIG. 9 Tissue excised in right pancreatic lobectomy. were unchanged. I
Current state of transplantation of the pancreas
23
Glucose clearance was unchanged on the I St postoperative day but had decreased significantly by the 4th and 22nd days (P < 0.005). Insulin response was increased on the Ist postoperative day (P < 0.05) but had decreased significantly by the 4th and 22nd days. The dogs were maintained in good health for periods of up to 6 months after operation. Histological examination of the pancreatic tail removed at autopsy revealed a marked degree of fibrosis, with islands of pancreatic exocrine and endocrine tissue of normal appearance.
ligation alone. Normal pancreatic islets were readily identifiable. In order to discover whether there are any detectable adverse effects of warm ischaemia for I h on pancreatic function these results were compared with those obtained in animals exposed to right pancreatic lobectomy alone. There were no significant differences in glucose clearance or insulin response between the groups at any time in the postoperative period. All dogs in which the pancreatic tail was exposed to 2 h of warm ischaemia showed severe impairment of glucose clearance and insulin response. Histological examination of the pancreas revealed appearances ranging from complete necrosis in dogs which died WARM ISCHAEMIC INJURY OF PANCREATIC TAIL The tolerance of the endocrine pancreas from the injury to a nearly normal histological to warm ischaemic injury has hitherto not appearance in 2 dogs with only slight elevation been clearly defined. In order to investigate of fasting plasma glucose. this problem right pancreatic lobectomy was The results of the in-situ experiments showed performed as above and in addition the blood supply of the pancreatic tail was occluded that the duct-ligated tail of the pancreas is by vascular clamps for either I or 2 h (Fig. 3). able to maintain an acceptable level of After I h of warm ischaemia serum amylase carbohydrate tolerance and to prevent the activity was significantly raised for the first early death from diabetes mellitus that invari6 days, while the fasting plasma glucose and ably follows total pancreatectomy. Further, insulin levels were relatively unchanged. they demonstrated that the endocrine function Intravenous glucose tolerance tests showed of the pancreas is relatively resistant to warm the insulin response to glucose to be increased ischaemic injury, I h of warm ischaemia on the Ist postoperative day and decreased being well tolerated, while even 2 h does not later. Glucose clearance, unchanged on the always totally destroy endocrine function. Ist postoperative day, was significantly Pancreatic duct ligation was shown to cause decreased (P < o.os) on the 4th and 22nd progressive destruction of both exocrine and days. Histological examination of the pancreatic endocrine tissue, with increasing fibrosis; tail showed a degree of pancreatic fibrosis however, endocrine function was well preserved similar to that seen after pancreatic duct for iup to 6 months. superior
pancreaticoduoden artery
3rtery rtery
/ FIG. 3 Dog pancreatic blood supply.
inferior pancreat\coduoclenal artery
cranial mesenteric artery
24
J Collin
Autotransplantation experiments
Femoral artery and vein
In all autotransplantation experiments the pancreatic tail was heterotopically transplanted to the left groin or left iliac fossa. In all cases the total time from removal of the pancreatic tail from the donor site to reestablishment of circulation in the recipient site was 3 h. RINGER S LACTATE WASHOUT
In this group of dogs the pancreatic tail was flushed with Ringer's lactate solution and stored in ice before reimplantation. Two types of vascular anastomosis were used: an end-to-side arterial anastomosis with end-to-side venous anastomosis (Fig. 4) or an end-to-end arterial anastomosis with end-to-side venous anastomosis (Fig. 5). Of the 7 autotransplants in this group, 3 showed no evidence of function 24 h after operation. Two of the 4 initially successful grafts failed on the 3rd and 4th postoperative days respectively. Only one of the grafts continued to function for longer than the 3week follow-up period. These results were rather disappointing. The most striking finding was that both of the transplants performed with end-to-side anastomosis failed within 24 h. It has been shown8 that the normal blood flow to the pancreatic tail is less than 5 ml/min and it seems likely
FIG. 5 Pancreatic tail autotransplant: end-toend arterial anastomosis. that the reason for failure of the end-to-side grafts was that this run-off was inadequate to maintain the patency of such a side channel. It has been shown9 that Ringer's lactate is an unsatisfactory washout solution for the kidney, resulting in substantial changes in intracellular electrolyte concentration, and it seems likely that similar changes could be expected in the pancreas.
External iliac artery and vein
A vein
FIG. 4 Pancreatic tail autotransplant: end-toside arterial anastomosis.
Current state of transplantation of the pancreas COLLINS C3 SOLUTION WASHOUT AND STORAGE
'
In order to eliminate the above problems a group of dogs received autotransplants of the pancreatic tail using only end-to-end arterial anastomosis. The grafts were flushed with and stored in Collins C3 solution at 40C. Of the 6 transplants carried out in this way, v 5 were shown to be functioning on glucose tolerance testing 24 h later. Three of these initially successful transplants failed within the following 3 days, however, while 2 transplants continued to function for more than 3 weeks. There are several possible explanations for the failure of more than half of the initially successful autotransplants within a few days of operation. Collins solution has been criticized on the grounds that its high magnesium content may exert a direct cytotoxic effect"0. In addition, precipitation of magnesium salts may results in occlusion of the vessels of the graft. The initial in-situ experiments revealed no deterioration in endocrine function of the pancreatic tail for up to 6 months after pancreatic duct ligation. It is possible, however, that the additional insult of pancreatic duct ligation at the time of transplantation might be sufficient to tip the scales against transplant survival. The time scale of delayed graft failure lends support to this suggestion. With the arterial anastomosis technique used in this group of experiments the total blood flow across the anastomosis and in the proximal splenic artery was the 5 ml/min supplied to the pancreatic tail. As the splenic artery normally carries many times this blood flow it is likely that the small flow was inadequate to maintain the patency of the channel. DOUBLE
ARTERIAL
ANASTOMOSIS
05
TECHNIQUE
To overcome the problem of low blood flow across the arterial anastomosis I have developed a technique of double arterial anastomosis so that the entire blood flow to the hind limb paxses through the splenic artery of the graft (Fig. 6). In this group of dogs the pancreatic duct of the graft was allowed to drain freely to the skin surface. This continuous leakage of exocrine secretions caused none of the problems of skin excoriation
Femoral artery and vein
Ivein
Femoral artery
FIG. 6 Pancreatic tail autotransplant: double
arterial anastomosis. expected with pancreatic fistulae as the dogs continually licked the wound, removing secretions as they appeared. Of 6 transplants performed by this technique, all were immediately successful as shown by normal glucose clearance and insulin response 24 h after operation. Only 2 transplants subsequently failed, both within 4 days of operation. The adequacy of blood flow to the hind limb through the graft splenic artery was confirmed by arteriography. Three weeks after transplantation the pancreatic tail was reduced to half its original size and was somewhat thickened and fibrotic. Histological examination showed increased interlobular fibrosis with a normal distribution of islets of Langerhans.
Portal or systemic venous drainage of the pancreas A possible explanation for the continuing occurrence of the complications of diabetes mellitus despite apparently adequate regulation of insulin requirements is that injected insulin is absorbed into systemic veins rather than the portal venous system. It might be expected that bypass of hepatic insulinase would result in systemic hyperinsulinaemia
26
J Collin
with hypoglycaernia, but while some workers"1 have shown such an effect, the reports in the literature are conflicting. In order to resolve this problem I have compared glucose homocostasis between partially pancreatectomized dogs with the pancreatic tail in situ draining into the portal vein and dogs with a successful pancreatic-tail autotransplant draining into systemic veins. Comparison of glucose clearance and insulin response to glucose between the two groups revealed no significant differences at any time in the postoperative period. However, fasting plasma glucose levels were lower throughout in dogs with venous drainage of the pancreas to systemic veins, while fasting insulin levels were higher; these differein-ces were statistically significant on the i st postoperative day for plasma glucose (P= 0.04) and on the 22nd postoperative day for plasma insulin (P= 0.02). An interesting sidelight has been thrown on these results by the recent work of Starzl et al2, which suggests that the major importance of liberation of insulin irnto the portal circulation may lie in the hepatotrophic effects of the hormone rather than in its glucose homoeostatic functions.
Discussion
in the dog is normally only 5 ml/min and it is likely that this would be progressively reduced after transplantation because of the inevitable pancreatic oedema. Stasis at the anastomosis can be reduced by the double arterial anastomosis technique I have described. A degree of pancreatitis is probably inevitable following transplantation, although several factors may increase its severity. In situ warm ischaemia of I h duration has not resulted in any impairment of endocrine function, though serum amylase levels are persistently higher than in control animals and may be an indication of exocrine damage. The effects of cold storage for 3 h have not been separable from those of transplantation, but it is known that pancreatitis is frequently present in hypothermnia of the elderly"4, and cold storage of the pancreatic graft may well increase the severity of post-transplantation pancreatitis. Ligation of the pancreatic duct might be expected to increase the incidence of pancreatitis, but experimentally this does not seem to be the case, the result of such ligation being merely pancreatic oedema. It has been shown by McCutcheon and Race'5 that the pancreatitis occurring in dogs with a closed duodenal loop can actually be prevented by ligation of the pancreatic duct. Despite recent developments in pancreatic islet implantation16 17, so far the problems of harvesting sufficient numbers of islets have precluded application of the technique to man and vascularized transplantation of the pancreas remains the only practical technique currently available. These studies have shown that improved success rates for pancreatic transplantation are dependent on better control of pancreatitis, reduction in the incidence of thrombosis, and perfection of graft preservation techniques.
A high proportion of early transplant failures have occurred in several reported series of pancreatic allografts, the failures being attributed to early rejection phenomena. The fact that a similar proportion of pancreatic tail autotransplants have failed within 4 days indicates that other cxplanations must be sought. Two main factors are incriminated in graft failure: thrombosis at the vascular anastomoses and graft pancreatitis. Some degree of trauma to the vessel wall is inevitable in any vascular anastomosis, but such trauma can be kept to a minimum by References observing the recognized techniques of I Gates, R J, Hunt, M I, Smith, R, and Lazarus, N R (1972) Lancet, 2, 567. microvascular surgery'3, avoiding picking up the intima of the vessel wall with forceps and 2 Largiader, F, Lyons, G W, Hidalgo, F, Dietzman, R H, and Lillehei, R C (I967) American Journal the use of a Carrel patch carrying the main of Surgery, II3, 70. vessels of supply. Alteratioiis in blood flow R C, Simmons, R L, Najarian, J S, 3 Lillehei, are of two types, turbulence due to change Weil, R, Uchida, H, Ruiz, J 0, Kjellstrand, in vessel diameter at the site of anastomosis C M, and Goetz, F C (0970) Annals of Surgery, and stasis. Blood flow to the pancreatic tail I 72, 405.
Current state of transplantation of the pancreas 4 Bergan, J J, Iloehi, J G, Porter, N, and Dry, L (I965) Archives of Surgery, 90, 521. 5 Choudhury, A (I973) Annals of the Royal College of Surgeons of England, 53, 2I8. 6 De Gruyl, J, Westbroek, D L, Dijkhuis, C M, Vriesendorp, H M, McDicken, I, Elion-Gerritsen, W, Verschoor, L, Hulsmans, H A M, and Horchner, P (1973) Transplantation Proceedings, 5, 7557 ILunkbaek, K (I962) British Medical journal, i, 1507. 8 Kim, J P, and Byrne, J J (I97I) Journal of Surgical Researchl, II, 559. 9 Acquatella, H, Perez-Gonzalez, M, Morales, J M, and Whittembury, G (1972) Transplantation, 14, 480. io Welch, L TF, and Flanigan, W J (I973) Lancet, 2', 1444-
II Sells, R A, Calne, R Y, Hadjiyanakis, V, and Marshall, V C (1972) British Medical journal, 3, 678. 12 Starzl, T E, Porter, K A, and Putnam, C W (1975) Lancet, 2, 1241. I3 Cobbett, J R (I975) British Journal of Hospital Medicine, I3, 3II. I4 Scott, R B ('973) in Price's Textbook of the Practice of Medicine, ed. Scott, R B, iIth edn, pp 374-375. ILondon, Oxford University Press. I5 McCutcheon, A D, and Race, D (I962) Annals of Surgery, I55, 523. 16 Mauer, S M, Steffes, M W, Sutherland, D E F, Najariain, J S, Michael, A F, and Brown, D M (I975) Diabetes, 24, 280. 17 Georgakakis, A (I977) Annals of tile Royal College of Surgeons of England, 59, 23I.
Current J Collin
MD
state
of transplantation of the
pancreas
FRCS
Senior Registrar, Royal Victoria Infirmary, Newcastle
Summary Studies of pancreatic transplantation have been made using the pancreatic tail as an autotransplant model. The endocrine function of the pancreas has been shown to be relatively resistant to warm ischaemic injurv. Autotransplantation of the pancreatic tail with a double arterial anastomosis technique can be achieved with ioo% immediate success, the graft maintaining satisfactory glucose tolerance and insulin secretion. No important changes in glucose homoeostasis have been shown to result from diversion of pancreatic insulin secretion from portal to systemic veins.
Introduction A successful pancreatic transplant offers a nuimber of theoretical advantages over insulin injections for the treatment of diabetes mellitus The secretion of insulin would be controlled, continuous, and appropriate to the changing demands of the moment. The insulin would he of the correct species and there would be no risk of overdosage or underdosage. In addition there are possibly other pancreatic hormones at present unkown, as the work of Gates and his colleagues' would suggest. The major stimulus to research into pancreatic transplantation remains the hope that, with all these theoretical advantages, a functioning pancreatic transplant would be able to prevent or reverse the complications of diabetes. One of the disappointing features of pancreatic transplantation has been the very high failure rate in all reported series2'-, results that compare very unfavourably with those of renal transplantation. Leakage of the duodenal anastomoses has occurred frequently after pancreaticoduodenal transplantation3, while other common problems have been pancreatitis in the graft and thrombosis at
upon
Tyne
either arterial or venous anastomoses. A satisfactory pancreatic autotransplant model would permit the study of the special factors affecting surx'val of pancreatic transplants free from the complicating problem of graft rejection. In the experiments reported here the pancreatic tail in the dog has been studied as a model for segmental pancreatic autotransplantation.
Blood supply of the ca ne pancreas In the course of the experiments an anatomical study was made of the pancreatic blood supply in 53 dogs (Fig. i). The head of the pancreas and proximal duodenum were supplied by the cranial pancreaticoduodenal artery from the right gastric artery and drained directly into the portal vein by the cranial pancreaticoduodenal vein. The uncinate process of the pancreas was supplied independently from the caudal pancreaticoduodenal artery by one or two small uncinate branches and drained by corresponding uncinate veins. The blood supply of the pancreatic tail wvas much more variable. In 85 % of dogs the arterial supply arose solely from the splenic artery and consisted usually of a single pancreatic branch arising close to the origin of the splenic artery from the coeliac trunk. In the remaining I5ato the pancreatic branch arose from the cranial mesenteric, hepatic, or coeliac arteries. The venous drainage of the pancreatic tail in 88% of dogs was solely to the splenic vein. As with the arterial supply, anomalies were common, the venous drainage being to either the portal or the cranial mesenteric vein. In 23% of all dogs examined variations in either arterial or venous blood supply were such as to exclude autotransplantation of the pancreatic tail.
Based on an Arris and Gale Lecture delivered on 12th May 1976
22
J Collini Coel iac
FIG. i Normal arterial supply of canine pancreas.
Urncinate branch
In-situ experiments TOTAL PANCREATECTOMY
Seven dogs were subjected to total pancreatectomy. All were diabetic 24 h after operation, the fasting plasma glucose level being above i6 mmol/l (288 mg/ioo ml), while plasma insulin was undetectable. Serum amylase levels were reduced to the range 6oo-iooo U/1, these basal levels being accounted for by salivary gland secretion. Glucose clearance was markedly impaired from the first postoperative day and there was no insulin response to glucose at any time in the postoperative period. All the dogs died in diabetic coma within one week of
In all the experiments intravenous glucose tolerance tests were performed before and on the ist, 4th, and 22nd days after operation. The rate of disappearance of injected glucose from the blood was expressed as the glucose clearance (K value) as described by Lundbaek . As a measure of insulin response to glucose the mean increment in plasma insulin level at 5, I5, and 30 min after glucose injection was calculated for each glucose tolerance test.
operation. RIGHT PANCREATIC LOBECTOMY
To determine whether the pancreatic tail alone of Padl c, el C Tail ipanCj was adequate to maintain carbohydrate tissue( than the other tissue all tolerance pancreatic excised tail was excised in 8 dogs (Fig. 2). The duct of the pancreatic tail was ligated. All the dogs developed steatorrhoea and lost weight as a result of the absence of pancreatic exocrine secretions from the bowel. Serum amylase levels were greatly elevated in the early postoperative period (mean 4720 U/1), but fasting glucose and insulin levels FIG. 9 Tissue excised in right pancreatic lobectomy. were unchanged. I
Current state of transplantation of the pancreas
23
Glucose clearance was unchanged on the I St postoperative day but had decreased significantly by the 4th and 22nd days (P < 0.005). Insulin response was increased on the Ist postoperative day (P < 0.05) but had decreased significantly by the 4th and 22nd days. The dogs were maintained in good health for periods of up to 6 months after operation. Histological examination of the pancreatic tail removed at autopsy revealed a marked degree of fibrosis, with islands of pancreatic exocrine and endocrine tissue of normal appearance.
ligation alone. Normal pancreatic islets were readily identifiable. In order to discover whether there are any detectable adverse effects of warm ischaemia for I h on pancreatic function these results were compared with those obtained in animals exposed to right pancreatic lobectomy alone. There were no significant differences in glucose clearance or insulin response between the groups at any time in the postoperative period. All dogs in which the pancreatic tail was exposed to 2 h of warm ischaemia showed severe impairment of glucose clearance and insulin response. Histological examination of the pancreas revealed appearances ranging from complete necrosis in dogs which died WARM ISCHAEMIC INJURY OF PANCREATIC TAIL The tolerance of the endocrine pancreas from the injury to a nearly normal histological to warm ischaemic injury has hitherto not appearance in 2 dogs with only slight elevation been clearly defined. In order to investigate of fasting plasma glucose. this problem right pancreatic lobectomy was The results of the in-situ experiments showed performed as above and in addition the blood supply of the pancreatic tail was occluded that the duct-ligated tail of the pancreas is by vascular clamps for either I or 2 h (Fig. 3). able to maintain an acceptable level of After I h of warm ischaemia serum amylase carbohydrate tolerance and to prevent the activity was significantly raised for the first early death from diabetes mellitus that invari6 days, while the fasting plasma glucose and ably follows total pancreatectomy. Further, insulin levels were relatively unchanged. they demonstrated that the endocrine function Intravenous glucose tolerance tests showed of the pancreas is relatively resistant to warm the insulin response to glucose to be increased ischaemic injury, I h of warm ischaemia on the Ist postoperative day and decreased being well tolerated, while even 2 h does not later. Glucose clearance, unchanged on the always totally destroy endocrine function. Ist postoperative day, was significantly Pancreatic duct ligation was shown to cause decreased (P < o.os) on the 4th and 22nd progressive destruction of both exocrine and days. Histological examination of the pancreatic endocrine tissue, with increasing fibrosis; tail showed a degree of pancreatic fibrosis however, endocrine function was well preserved similar to that seen after pancreatic duct for iup to 6 months. superior
pancreaticoduoden artery
3rtery rtery
/ FIG. 3 Dog pancreatic blood supply.
inferior pancreat\coduoclenal artery
cranial mesenteric artery
24
J Collin
Autotransplantation experiments
Femoral artery and vein
In all autotransplantation experiments the pancreatic tail was heterotopically transplanted to the left groin or left iliac fossa. In all cases the total time from removal of the pancreatic tail from the donor site to reestablishment of circulation in the recipient site was 3 h. RINGER S LACTATE WASHOUT
In this group of dogs the pancreatic tail was flushed with Ringer's lactate solution and stored in ice before reimplantation. Two types of vascular anastomosis were used: an end-to-side arterial anastomosis with end-to-side venous anastomosis (Fig. 4) or an end-to-end arterial anastomosis with end-to-side venous anastomosis (Fig. 5). Of the 7 autotransplants in this group, 3 showed no evidence of function 24 h after operation. Two of the 4 initially successful grafts failed on the 3rd and 4th postoperative days respectively. Only one of the grafts continued to function for longer than the 3week follow-up period. These results were rather disappointing. The most striking finding was that both of the transplants performed with end-to-side anastomosis failed within 24 h. It has been shown8 that the normal blood flow to the pancreatic tail is less than 5 ml/min and it seems likely
FIG. 5 Pancreatic tail autotransplant: end-toend arterial anastomosis. that the reason for failure of the end-to-side grafts was that this run-off was inadequate to maintain the patency of such a side channel. It has been shown9 that Ringer's lactate is an unsatisfactory washout solution for the kidney, resulting in substantial changes in intracellular electrolyte concentration, and it seems likely that similar changes could be expected in the pancreas.
External iliac artery and vein
A vein
FIG. 4 Pancreatic tail autotransplant: end-toside arterial anastomosis.
Current state of transplantation of the pancreas COLLINS C3 SOLUTION WASHOUT AND STORAGE
'
In order to eliminate the above problems a group of dogs received autotransplants of the pancreatic tail using only end-to-end arterial anastomosis. The grafts were flushed with and stored in Collins C3 solution at 40C. Of the 6 transplants carried out in this way, v 5 were shown to be functioning on glucose tolerance testing 24 h later. Three of these initially successful transplants failed within the following 3 days, however, while 2 transplants continued to function for more than 3 weeks. There are several possible explanations for the failure of more than half of the initially successful autotransplants within a few days of operation. Collins solution has been criticized on the grounds that its high magnesium content may exert a direct cytotoxic effect"0. In addition, precipitation of magnesium salts may results in occlusion of the vessels of the graft. The initial in-situ experiments revealed no deterioration in endocrine function of the pancreatic tail for up to 6 months after pancreatic duct ligation. It is possible, however, that the additional insult of pancreatic duct ligation at the time of transplantation might be sufficient to tip the scales against transplant survival. The time scale of delayed graft failure lends support to this suggestion. With the arterial anastomosis technique used in this group of experiments the total blood flow across the anastomosis and in the proximal splenic artery was the 5 ml/min supplied to the pancreatic tail. As the splenic artery normally carries many times this blood flow it is likely that the small flow was inadequate to maintain the patency of the channel. DOUBLE
ARTERIAL
ANASTOMOSIS
05
TECHNIQUE
To overcome the problem of low blood flow across the arterial anastomosis I have developed a technique of double arterial anastomosis so that the entire blood flow to the hind limb paxses through the splenic artery of the graft (Fig. 6). In this group of dogs the pancreatic duct of the graft was allowed to drain freely to the skin surface. This continuous leakage of exocrine secretions caused none of the problems of skin excoriation
Femoral artery and vein
Ivein
Femoral artery
FIG. 6 Pancreatic tail autotransplant: double
arterial anastomosis. expected with pancreatic fistulae as the dogs continually licked the wound, removing secretions as they appeared. Of 6 transplants performed by this technique, all were immediately successful as shown by normal glucose clearance and insulin response 24 h after operation. Only 2 transplants subsequently failed, both within 4 days of operation. The adequacy of blood flow to the hind limb through the graft splenic artery was confirmed by arteriography. Three weeks after transplantation the pancreatic tail was reduced to half its original size and was somewhat thickened and fibrotic. Histological examination showed increased interlobular fibrosis with a normal distribution of islets of Langerhans.
Portal or systemic venous drainage of the pancreas A possible explanation for the continuing occurrence of the complications of diabetes mellitus despite apparently adequate regulation of insulin requirements is that injected insulin is absorbed into systemic veins rather than the portal venous system. It might be expected that bypass of hepatic insulinase would result in systemic hyperinsulinaemia
26
J Collin
with hypoglycaernia, but while some workers"1 have shown such an effect, the reports in the literature are conflicting. In order to resolve this problem I have compared glucose homocostasis between partially pancreatectomized dogs with the pancreatic tail in situ draining into the portal vein and dogs with a successful pancreatic-tail autotransplant draining into systemic veins. Comparison of glucose clearance and insulin response to glucose between the two groups revealed no significant differences at any time in the postoperative period. However, fasting plasma glucose levels were lower throughout in dogs with venous drainage of the pancreas to systemic veins, while fasting insulin levels were higher; these differein-ces were statistically significant on the i st postoperative day for plasma glucose (P= 0.04) and on the 22nd postoperative day for plasma insulin (P= 0.02). An interesting sidelight has been thrown on these results by the recent work of Starzl et al2, which suggests that the major importance of liberation of insulin irnto the portal circulation may lie in the hepatotrophic effects of the hormone rather than in its glucose homoeostatic functions.
Discussion
in the dog is normally only 5 ml/min and it is likely that this would be progressively reduced after transplantation because of the inevitable pancreatic oedema. Stasis at the anastomosis can be reduced by the double arterial anastomosis technique I have described. A degree of pancreatitis is probably inevitable following transplantation, although several factors may increase its severity. In situ warm ischaemia of I h duration has not resulted in any impairment of endocrine function, though serum amylase levels are persistently higher than in control animals and may be an indication of exocrine damage. The effects of cold storage for 3 h have not been separable from those of transplantation, but it is known that pancreatitis is frequently present in hypothermnia of the elderly"4, and cold storage of the pancreatic graft may well increase the severity of post-transplantation pancreatitis. Ligation of the pancreatic duct might be expected to increase the incidence of pancreatitis, but experimentally this does not seem to be the case, the result of such ligation being merely pancreatic oedema. It has been shown by McCutcheon and Race'5 that the pancreatitis occurring in dogs with a closed duodenal loop can actually be prevented by ligation of the pancreatic duct. Despite recent developments in pancreatic islet implantation16 17, so far the problems of harvesting sufficient numbers of islets have precluded application of the technique to man and vascularized transplantation of the pancreas remains the only practical technique currently available. These studies have shown that improved success rates for pancreatic transplantation are dependent on better control of pancreatitis, reduction in the incidence of thrombosis, and perfection of graft preservation techniques.
A high proportion of early transplant failures have occurred in several reported series of pancreatic allografts, the failures being attributed to early rejection phenomena. The fact that a similar proportion of pancreatic tail autotransplants have failed within 4 days indicates that other cxplanations must be sought. Two main factors are incriminated in graft failure: thrombosis at the vascular anastomoses and graft pancreatitis. Some degree of trauma to the vessel wall is inevitable in any vascular anastomosis, but such trauma can be kept to a minimum by References observing the recognized techniques of I Gates, R J, Hunt, M I, Smith, R, and Lazarus, N R (1972) Lancet, 2, 567. microvascular surgery'3, avoiding picking up the intima of the vessel wall with forceps and 2 Largiader, F, Lyons, G W, Hidalgo, F, Dietzman, R H, and Lillehei, R C (I967) American Journal the use of a Carrel patch carrying the main of Surgery, II3, 70. vessels of supply. Alteratioiis in blood flow R C, Simmons, R L, Najarian, J S, 3 Lillehei, are of two types, turbulence due to change Weil, R, Uchida, H, Ruiz, J 0, Kjellstrand, in vessel diameter at the site of anastomosis C M, and Goetz, F C (0970) Annals of Surgery, and stasis. Blood flow to the pancreatic tail I 72, 405.
Current state of transplantation of the pancreas 4 Bergan, J J, Iloehi, J G, Porter, N, and Dry, L (I965) Archives of Surgery, 90, 521. 5 Choudhury, A (I973) Annals of the Royal College of Surgeons of England, 53, 2I8. 6 De Gruyl, J, Westbroek, D L, Dijkhuis, C M, Vriesendorp, H M, McDicken, I, Elion-Gerritsen, W, Verschoor, L, Hulsmans, H A M, and Horchner, P (1973) Transplantation Proceedings, 5, 7557 ILunkbaek, K (I962) British Medical journal, i, 1507. 8 Kim, J P, and Byrne, J J (I97I) Journal of Surgical Researchl, II, 559. 9 Acquatella, H, Perez-Gonzalez, M, Morales, J M, and Whittembury, G (1972) Transplantation, 14, 480. io Welch, L TF, and Flanigan, W J (I973) Lancet, 2', 1444-
II Sells, R A, Calne, R Y, Hadjiyanakis, V, and Marshall, V C (1972) British Medical journal, 3, 678. 12 Starzl, T E, Porter, K A, and Putnam, C W (1975) Lancet, 2, 1241. I3 Cobbett, J R (I975) British Journal of Hospital Medicine, I3, 3II. I4 Scott, R B ('973) in Price's Textbook of the Practice of Medicine, ed. Scott, R B, iIth edn, pp 374-375. ILondon, Oxford University Press. I5 McCutcheon, A D, and Race, D (I962) Annals of Surgery, I55, 523. 16 Mauer, S M, Steffes, M W, Sutherland, D E F, Najariain, J S, Michael, A F, and Brown, D M (I975) Diabetes, 24, 280. 17 Georgakakis, A (I977) Annals of tile Royal College of Surgeons of England, 59, 23I.
