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A prospective comparison of systemic-bladder versus portal-enteric drainage in vascularized pancreas transplantation
A prospective comparison of systemicbladder versus portal-enteric drainage in vascularized pancreas transplantation Robert J. Stratta, MD, A. Osama Gaber, MD, M. Hosein Shokouh-Amiri, MD, K. Sudhakar Reddy, MD, M. Francesca Egidi, MD, Hani P. Grewal, MD, and Lillian W. Gaber, MD, Memphis, Tenn
Background. Most pancreas transplants are performed with systemic venous delivery of insulin and bladder drainage of the exocrine secretions (systemic-bladder [S-B]). To develop a more physiologic procedure, we performed pancreas transplantations with portal venous delivery of insulin and enteric drainage of the exocrine secretions (portal-enteric [P-E]). Methods. During an 11-month period, we prospectively alternated 32 consecutive pancreas transplant recipients to either S-B (n = 16) or P-E (n = 16) drainage with standardized immunosuppression. Results. Patient, kidney, and pancreas graft survival rates after simultaneous kidney-pancreas transplantation were 91% S-B versus 92% P-E, 91% S-B versus 92% P-E, and 82% S-B versus 92% P-E, respectively. Pancreas graft survival rates after solitary pancreas transplantation were 80% S-B versus 75% P-E. There were no graft losses either to immunologic or infectious complications in either group, but the incidence of acute rejection was slightly higher in the S-B group (44% S-B vs 31% P-E, P = NS). The cost and length of the initial hospital stay were similar between groups. The incidence of operative complications, major infections, and cytomegalovirus infections were likewise comparable. However, the S-B group was characterized by a slight increase in the number of readmissions, urinary tract infections, and urologic complications. Furthermore, metabolic acidosis and dehydration were more common in the S-B group. Conclusions. Pancreas transplantation with P-E drainage can be performed with short-term results comparable to those of transplantation with S-B drainage. (Surgery 2000;127:217-26.) From the Transplant Division, Departments of Surgery and Pathology, University of Tennessee, Memphis
THE RESULTS OF PANCREAS TRANSPLANTATION continue to improve as a result of refinements in surgical techniques and advances in immunosuppression. According to the International Pancreas Transplant Registry Data, more than 11,000 pancreas transplantations have been performed worldwide through 1998.1 In the United States, approximately 1200 pancreas transplantations are performed annually, with 87% being simultaneous kidney-pancreas transplantations (SKPTs).1 In the United States, the current 1-year actuarial patient, kidney, and pancreas (with complete insulin independence) graft survival rates after SKPT are 94%, 90%, and 83%, respectively.1 Solitary pancreas transplantations comprise the remaining activity, Presented at the 24th Annual Scientific Meeting of the American Society of Transplant Surgeons, Chicago, Ill, May 15, 1998. Accepted for publication September 18, 1999. Reprints not available from the authors. Copyright © 2000 by Mosby, Inc. 0039-6060/2000/$12.00 + 0
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including either sequential pancreas after kidney transplantations (PAKT, 9%) or pancreas transplantations alone (PTA, 4%). The current 1-year actuarial pancreas graft survival rates are 73% for PAKT and 67% for PTA.1 Most pancreas transplantations are performed with systemic venous delivery of insulin and bladder drainage of the exocrine secretions (systemicbladder [S-B]) with use of the duodenal segment technique.1,2 Although S-B drainage is safe and effective, it results in peripheral hyperinsulinemia and is associated with unique metabolic and urologic complications caused by an altered physiology.3-6 When these complications become persistent or refractory, conversion from bladder to enteric drainage (enteric conversion) has been shown to be a safe and effective method of managing these problems.6-8 Because of favorable experiences with enteric conversion—coupled with advances in preservation and immunosuppression that place the duodenal segment at a lower risk for ischemic or immunologic injury resulting in a fistula— there is renewed interest in primary enteric SURGERY 217
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Table 1. Group characteristics Systemic-bladder (S-B) N=16 Age (y) Sex Female Male Years of diabetes Race: white Pretransplant dialysis Prior transplant Current PRA ≥ 10% Pancreas ischemia (h) HLA-match HLA-mismatch Waiting time (m) Type of transplant: SKPT PAKT PTA
Portal-enteric (P-E) N=16
38 ± 6
37 ± 7
7 (44%) 9 (56%) 25.5 ± 6 16 (100%) 11/11 (100%) 1 (6%) 1 (6%) 15.1 ± 3.4 1.8 ± 1.3 4.2 ± 1.3 4.6 ± 4.3
7 (44%) 9 (56%) 26 ± 4 16 (100%) 6/12 (50%)* 3 (19%) 1 (6%) 13.4 ± 3.0 1.8 ± 1.3 4.1 ± 1.3 4.4 ± 3.1
11 (69%) 1 (6%) 4 (25%)
12 (75%) 2 (12.5%) 2 (12.5%)
PRA, Panel-reactive antibody. Data are expressed as mean ± SD. *P = .01.
drainage.9-12 From 1988 through 1995, more than 90% of pancreas transplant procedures were performed by the standard technique of S-B drainage.1 However, in the last 3 years, the number of pancreas transplant procedures performed with primary enteric drainage has steadily increased, with more than 50% being performed with enteric drainage in 1998.1 The majority of pancreas transplantations with enteric drainage are performed with systemic venous delivery of insulin (systemic-enteric). To further improve the physiology of pancreas transplantation and to avoid the potential complications of systemic hyperinsulinemia, a new surgical technique was developed at our center, using portal venous delivery of insulin and enteric drainage of the exocrine secretions (portal-enteric [P-E]).13,14 We have previously reported our experience with P-E drainage, including a retrospective comparison to a historical control group of patients who underwent pancreas transplantation with S-B drainage.15,16 The purpose of this study was to compare pancreas transplantation using S-B drainage with transplantation using P-E drainage in a prospective fashion with standardized immunosuppression. MATERIALS AND METHODS Study design. The Memphis Pancreas Transplant Program at the University of Tennessee began in 1989. The first pancreas transplantation using P-E drainage was performed in 1990. Since
this time, we have performed 102 pancreas transplantations with P-E drainage and 76 with S-B drainage. During an 11-month period from February 1997 to January 1998, there were 32 consecutive pancreas transplantations performed at our center and entered into a prospective study. The technique to be performed was determined before the transplant with selection determined by an alternating methodology. In 5 cases, the preselected technique could not be performed because of intraoperative findings that favored one technique over the other. These 5 patients were included in the study and subsequent pre-transplant selection of technique continued on an alternating basis. A total of 16 patients were allocated to each technique. Organ procurement, preservation, and preparation. The pancreas or kidney, or both, were procured from heart-beating cadaveric donors in conjunction with multiple-organ retrieval by standard techniques.17 University of Wisconsin solution was used for both in situ flush and storage of all organs under cold-storage conditions. Whole organ pancreaticoduodenosplenectomy was performed by an en bloc technique.17 Cold ischemia was kept to a minimum, and preservation times were less than 20 hours in 31 (97%) of the cases and less than 12 hours in 8 (25%) of the cases.18 Before transplantation, the pancreas was reconstructed on the back table with a donor iliac artery bifurcation Y graft to the splenic and superior mesenteric arteries.19 In
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cases of S-B drainage, an 8- to 10-cm length of duodenal segment, incorporating the ampulla of Vater, was fashioned and left attached to the head of the pancreas. In cases with P-E drainage, the proximal duodenal closure remained the same (just distal to the pylorus), but the distal duodenal closure incorporated the third part, and a variable portion of the fourth part, of the duodenum as previously described.13 The P-E procedure, unlike the S-B technique, requires that the arterial bifurcation graft be constructed intentionally long for subsequent arterialization. Other than the duodenal and arterial preparation, the remainder of the back table dissection was similar regardless of technique, leaving the spleen attached as a handle but ligating the splenic hilar structures in continuity. Recipient selection and operative procedure. Patients were selected for transplantation based on ABO blood type compatibility, period of time on the waiting list, and a negative T lymphocytotoxic cross-match, in accordance with United Network for Organ Sharing guidelines. After preparation of the organ, the recipient operation was performed through a midline intraperitoneal approach. For SB cases, the whole organ pancreas was transplanted to the right iliac vessels with end to side vascular anastomoses, followed by bladder drainage by the duodenal segment technique.2 The surgical technique of P-E drainage has been previously described in detail by our group.13,15 The portal vein of the pancreas graft is anastomosed end-toside to a major tributary of the superior mesenteric vein. The donor iliac artery bifurcation graft is brought through a window made in the distal ileal mesentery and anastomosed end-to-side to the right common iliac artery. The transplanted duodenum is anastomosed distally end to end to a diverting Roux-en-Y limb of the recipient jejunum. With both techniques, splenectomy is performed after revascularization, and an attempt is made to anchor the tail of the pancreas to the anterior abdominal wall with interrupted sutures. These anchoring sutures permit subsequent percutaneous, ultrasound-guided pancreas allograft core biopsies to be performed as needed.20 In SKPT with either technique, the renal allograft is anastomosed end to side to the left external iliac vessels, followed by an extra-vesical ureteroneocystostomy by standard techniques. The kidney is then “retroperitonealized” by anchoring the sigmoid colon mesentery to the lateral peritoneal reflection with interrupted sutures. Perioperative management and immunosuppression. Perioperative antibiotic prophylaxis consisted of a preoperative, intraoperative, and 3 post-
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operative doses of cefazolin (1 g intravenously). All patients received 1 tab/day of sulfamethoxazole /trimethoprim, single strength, for 6 to 12 months as a prophylaxis for pneumocystis pneumonia. Antifungal prophylaxis consisted of 200 mg/day of oral fluconazole taken for 2 to 3 months.21 Antiviral prophylaxis included intravenous ganciclovir (2.5-5 mg/kg, twice daily) during the initial hospitalization, followed by oral ganciclovir (1 g, 3 times daily) for 3 months to all patients (for 6 months if the donor was cytomegalovirus (CMV) seropositive and the recipient was CMV seronegative).21,22 All SKPT and PAKT recipients received primary immunosuppression with tacrolimus, mycophenolate mofetil, and steroids without anti-lymphocyte induction therapy.23,24 Tacrolimus was started immediately post-transplant at a dose of 0.1 to 0.2 mg/kg orally in 2 divided doses titrated to a 12hour trough level of 15 to 20 ng/mL by IMX assay (Abbott Diagnostics, Chicago, Ill) for the first 3 months. After 3 months, tacrolimus levels were maintained at 10 to 15 ng/mL. Oral mycophenolate mofetil (MMF) was started immediately posttransplant at 2 to 3 g/day in 2-4 divided doses. The MMF dose was reduced in patients with gastrointestinal intolerance (nausea, vomiting, diarrhea) or with a total white blood cell count below 3000/mm3. MMF was discontinued temporarily in patients with septicemia, active CMV infection, or when the total white blood cell count was below 2000/mm3. Corticosteroids were administered as intravenous methylprednisolone at a rate of 500 to 1000 mg intraoperatively followed by 250 mg on postoperative day 1. By days 7 to 10, the dosage was tapered to 30 mg/day of oral prednisone. A gradual steroid taper was used, with the goal of reaching an oral prednisone dose of 5 to 10 mg/day at 1 year. In PTA recipients, the described triple therapy was used in combination with OKT3 induction at a dose of 2.5 to 5 mg/day for 5 to 7 days. The first dose of OKT3 was administered intraoperatively, with subsequent doses titrated to maintain CD3 counts below 10/mm3. Anti-platelet therapy, consisting of oral aspirin (81 mg/day), was administered to all patients. In addition, all P-E cases and solitary pancreas transplant recipients received 3000 to 5000 units of intravenous heparin intraoperatively before the vessels were clamped. In solitary pancreas transplant and selected P-E cases, heparin prophylaxis was continued postoperatively (5000 units subcutaneous twice daily) for 3 to 5 days. Finally, warfarin sodium crystalline (Coumadin) was administered in a single, oral daily dose of 1 mg/day to patients who required prolonged vascular access with the
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Table 2. Results Systemic-bladder (S-B) N=16 Patient survival Graft survival: Kidney Pancreas Follow-up (m) ATN (dialysis) Early technical problems/pancreatitis Initial LOS (d) Readmissions Acute rejection Major infection Re-operations Initial hospital charges ($) Urologic complication UTI Dehydration/acidosis CMV infection Multiple re-operations
14 (88%) 11/12 (92%) 13 (81%) 7.5 ± 3.4 0 3 (19%) 13.7 ± 9 2.6 ± 1.8 7 (44%) 8 (50%) 4 (25%) 100,215 ± 54,012 4 (25%) 8 (50%) 16 (100%) 2 (12.5%) 0
Portal-enteric (P-E) N=16 15 (94%) 13/14 (93%) 14 (88%) 8.9 ± 3.8 0 3 (19%) 12.8 ± 7 1.75 ± 1.2 5 (31%) 10 (62.5%) 4 (25%) 94,083 ± 25,873 2 (12.5%) 3 (19%) 7 (44%)* 3 (19%) 2 (12.5%)
ATN, Acute tubular necrosis; LOS, length of stay; UTI, urinary tract infection. Data are expressed as mean ± SD. *P < .01.
subsequent placement of a permanent central venous catheter. Postoperative monitoring. After transplantation, duplex ultrasonography of the pancreas or the kidney, or both, was performed on the first postoperative day and whenever clinically indicated. Recipients were monitored for daily fasting serum glucose, amylase, and lipase levels and for renal profiles, tacrolimus levels, and complete blood cell counts. In addition, urine amylase levels were monitored in patients with S-B drainage. Metabolic control and hormonal profiles were assessed by intravenous glucose tolerance testing, fasting and stimulated C-peptide levels, lipid profiles and glycosylated hemoglobin levels.25 The diagnosis of rejection was based on clinical criteria, renal allograft dysfunction, serum and urine amylase levels, serum glucose and lipase levels, and renal or pancreas allograft histopathology.16,26 Renal allograft rejection was suggested by an unexplained rise in serum creatinine of 0.3 mg/dL or greater and confirmed by an ultrasound-guided percutaneous biopsy. Pancreas allograft rejection was suggested by an unexplained elevation in serum amylase, lipase, glucose, or a serial decrease in urine amylase levels in patients with S-B drainage. Pancreas allograft rejection was confirmed by ultrasound-guided percutaneous biopsy.20 Most rejection episodes were confirmed by biopsy before specific anti-rejection therapy was initiated. The severity of the rejection was defined according to Banff and Maryland criteria.27,28 Mild renal allograft rejection was treated with intravenous methylprednisolone at 500 to 1000 mg/day for 3 doses.
Anti-lymphocyte therapy with OKT3 or anti-thymocyte gamma globulin (Atgam) for 7 to 10 days was used as the initial treatment for moderate or severe renal allograft rejection or for any pancreas allograft rejection. Steroid-resistant mild renal allograft rejection was also treated with anti-lymphocyte therapy. CMV infection was defined as a positive blood culture, antigenemia, or positive IgM titer. Invasive CMV infection (CMV disease) was defined as symptomatic CMV infection or histologic evidence of tissue invasion. Treatment of CMV infection consisted of the administration of intravenous ganciclovir for 2 to 4 weeks and a reduction in immunosuppression therapy. Oral ganciclovir was given for a variable period after treatment of documented CMV infection. Other infections were recorded, with major infection defined as a need for hospitalization for diagnosis and treatment. STATISTICAL ANALYSIS Data are reported as mean ± SD. Univariate analysis was performed by the Student t test for continuous variables, the chi-square test for categorical variables, and Fisher exact test when data were sparse. Actuarial patient and graft survival rates were computed by Wilcoxon life-table analysis. Renal allograft loss was defined as a return to dialysis or to the pre-transplant serum creatinine level, and pancreas graft loss was defined as the need for continued insulin therapy. RESULTS A total of 32 consecutive pancreas transplant
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recipients were enrolled in the prospective study during an 11-month period. The S-B group included 11 SKPT, 1 PAKT, and 4 PTA recipients, while the P-E group included 12 SKPT, 2 PAKT, and 2 PTA recipients. Demographic, immunologic, and transplant characteristics of the 2 groups are listed in Table 1. The 2 groups were well matched for age, sex, weight, race, and pre-transplant duration of diabetes. In the S-B group, all 11 SKPT recipients were receiving dialysis at the time of transplant. In the P-E group, only 6 of 12 (50%, P = .01) were dialysis-dependent at the time of SKPT. However, time spent on the waiting list was similar for both groups. Retransplantation was slightly more prevalent in the P-E group, and pancreas cold ischemia was slightly longer in the S-B group. None of these differences achieved significance. Panel reactive antibody titers and HLA-matching and mismatching were similar between groups. Five patients (16%) were selected for one technique of transplantation but subsequently received the alternative technique because of technical considerations identified intraoperatively. One SKPT recipient was selected for the S-B group but urethral catheter placement after induction of anesthesia revealed pyocystis. To reduce the risk of infection, this patient received a P-E pancreas transplant and bladder drainage was aborted. In another SKPT recipient selected for S-B drainage, a previous kidney transplant in the pelvis and severe iliac atherosclerosis prevented safe placement of the pancreas in a pelvic location. Therefore, the patient was a crossover to the P-E technique, as the infrarenal aorta was used for the arterial reconstruction. Three other SKPT recipients initially selected for P-E drainage were switched to S-B drainage because of the following: (1) a small mesenteric vein, which was deemed inadequate for the donor portal venous outflow, (2) obesity with a severely thickened mesentery and deep mesenteric vein, which was likewise deemed a high risk for anastomosis, and (3) a patient with severe gastroparesis with an indwelling gastrostomy and extensive upper abdominal adhesions. In each of these 3 cases, pelvic placement of the pancreas had a technical advantage. Results are provided in Table 2. There were no significant differences in patient, renal, or pancreas allograft survival rates after a mean follow-up of 8 months. In the S-B group, there were 2 deaths: 1 from cardiac failure 2 months after PTA, and 1 from a myocardial infarction 7 months after SKPT. These deaths resulted in 2 pancreas graft losses and 1 kidney graft loss. The only other graft failure in the S-B group was a pancreas loss at 6 months
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caused by insulin resistance. In the P-E group, there was 1 death from a cardiac arrhythmia 1 month after SKPT. This death resulted in 1 kidney and 1 pancreas graft loss. The only other graft failure in the P-E group was a pancreas graft loss caused by thrombosis 1 day after the PTA procedure. All 23 transplanted renal allografts started functioning immediately, and 31 pancreas allografts had initial function. The initial length of hospital stay, readmissions, and the incidence of acute rejection were slightly higher in the S-B group, but none of these differences were significant. For all patients, the mean length of the initial hospital stay was 13 days, the mean number of readmissions was 2, and the incidence of acute rejection was 37.5%. The incidence of major infections and operative complications was comparable between the 2 groups. Initial hospital charges were likewise similar—approximately $100,000. The incidence of urologic complications was doubled in the S-B group. Two patients had persistent hematuria, and 1 of them underwent cystoscopy, suture removal, and fulguration of a bleeding site. Another patient had recurrent reflux pancreatitis, which was treated with repeated catheter drainage and then intermittent selfcatheterization. A final patient had both reflux pancreatitis and hematuria, which eventually was managed by enteric conversion. In the P-E group, 2 patients had urosepsis. The S-B group was also characterized by a higher incidence of urinary tract infections (50% S-B vs 19% P-E). Metabolic acidosis with oral bicarbonate supplementation was universal in the S-B group but rarely occurred with P-E drainage. The incidence of CMV infection was similar between the 2 groups, and 1 patient in the S-B group had post-transplant lymphoproliferative disease associated with Epstein-Barr viral infection. Four patients in each group underwent relaparotomy. In the S-B group, 2 patients underwent enteric conversion, 1 underwent laparotomy for a deep wound infection, and 1 underwent laparotomy for a perforated gastric ulcer. In the P-E group, 1 patient underwent pancreatectomy for thrombosis after PTA, and another patient underwent splenic artery thrombectomy with a graft salvage. Two patients in the P-E group required a second reoperation; 1 patient (6%) had an enteric leak with intra-abdominal infection. Another patient underwent repair of a wound dehiscence and then a laparotomy for pancreatitis caused by rejection, which was determined by means of an open pancreas allograft biopsy. There was no graft loss in this series either to immunologic or infectious complications.
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DISCUSSION The history of clinical pancreas transplantation largely revolves around the development and application of various surgical techniques.29 According to United Network for Organ Sharing Registry data, bladder drainage with a duodenal segment conduit is the preferred technique for managing exocrine secretions after vascularized pancreas transplantation.1 From October 1, 1987, through November 30, 1995, this method was used in 94% of the pancreas transplantations performed in the United States. Bladder drainage by the duodenal segment technique became popular because it is safe, sterile, and convenient, because it enables urinary monitoring of pancreatic secretions, affords access for cystoscopic biopsy, and because it permits easy control of anastomotic problems with urethral catheter drainage.12,29,30 However, this technique also creates a nonphysiologic connection between the allografted pancreas with a duodenal conduit and the urinary bladder. This results in obligatory fluid and bicarbonate losses in the urine and alterations in the normally acidic enzyme-free milieu of the lower genitourinary tract.6,29 Although well tolerated in many pancreas transplant recipients, bladder drainage has been associated with unique metabolic and urologic complications resulting from an altered physiology.3-6 When these complications become intractable, conversion from bladder to enteric drainage (enteric conversion) may be therapeutic. Enteric conversion rates range from 10% to 20% in most large series.6-8 According to registry data, the rate of enteric conversion is 7% at 1 year and 11% at 2 years after pancreas transplantation with bladder drainage.1 In an effort to avoid these complications, some centers have returned to primary enteric drainage and are reporting improved results.9-12,29 In the past, the disadvantages of primary enteric drainage included the inability to directly monitor exocrine secretions, septic complications (such as peritonitis, abscess, and mycotic aneurysm), and healing problems. The healing problems were related to the anastomosis of an ischemic organ and an inadequately prepared bowel in the setting of high-dose immunosuppression with incomplete distal decompression.29 Registry data through 1993 continued to show a 10% to 15% improvement in the 1-year pancreas graft survival rate for bladder versus enteric drainage.1 In the 1990s, Tyden et al31 simplified the technique for pancreaticoduodenal transplantation with enteric drainage by first eliminating the Roux limb and then the ductal catheter. Based on the favorable experience with enteric conversion6-8 and recent improvements in organ
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retrieval and preservation, surgical techniques, immunosuppression, diagnostic technology, and anti-microbial prophylaxis, the results of primary enteric drainage are now approaching those of bladder drainage.9-12,31-36 Centers at which primary enteric drainage is done generally employ the duodenal segment technique with either a direct sideto-side anastomosis to the small bowel or an anastomosis to a diverting Roux limb. In the United States, the number of pancreas transplantations performed with enteric drainage has increased, from 15% in 1995 to 33% in 1996 to 46% in 1997.1 In addition to exocrine drainage, other nonphysiologic aspects of the procedure include transplantation of a completely denervated organ into an ectopic location with systemic venous drainage of insulin. At present, most pancreas transplantations are performed with either S-B or systemic-enteric drainage. According to the latest registry report analyzing pancreas transplantations performed between January 1, 1994 and June 6, 1998, the 1-year pancreas graft survival rates with bladder and enteric drainage were 83% and 81%, respectively (P ≤ .05).1 The slight improvement in graft survival associated with bladder drainage is almost entirely accounted for by a slightly lower technical failure rate associated with this technique. In those patients with primary enteric drainage, however, Roux limb diversion was also associated with a slight improvement in graft survival as a result of a lower technical failure rate.1 A few centers have reported success transplanting the pancreas to a mesenteric vein to establish portal venous drainage of insulin.13-16,37 This technique can be performed with enteric drainage (P-E) to develop a more physiologic procedure. A recent survey of pancreas transplant centers revealed that 39 perform bladder drainage, 21 both bladder and enteric drainage, and 18 enteric drainage exclusively.37 Seven centers reported experience with the P-E technique—5 of these also used a diverting Roux limb. The P-E technique was first described clinically by our group in 199238 and was based on experimental work by Shokouh-Amiri et al in a porcine model.39 This new technique employed a tributary of the superior mesenteric vein to reestablish portal venous drainage and differed substantially from the original reports of portal pancreatic transplantations as reported by Calne in 198440 and Muhlbacher et al in 1990.41 Calne’s technique of paratopic segmental pancreas grafting used the recipient’s splenic vein as the site of anastomosis, while Muhlbacher’s group used the recipient portal vein directly. In 1992, Rosenlof et al42 applied Calne’s technique to whole organ pancreas trans-
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plantation with a duodenal segment conduit. In each of these series, however, the procedure was not widely applied because of technical problems associated with the vascular reconstruction. In 1993, our group reported that P-E pancreas transplantation with Roux limb diversion not only achieves acceptable metabolic control and eliminates hyperinsulinemia but is also associated with reduced postoperative complications.14 In 1995, we compared 19 patients undergoing SKPT with the P-E technique versus a retrospective control group of 28 patients receiving SKPT with the conventional S-B technique.15 Actuarial patient and graft survival rates at 1 and 3 years were no different in the 2 groups. Metabolic and urologic complications and urinary tract infections were more common in the S-B group. Metabolic control was comparable between groups, and peripheral hyperinsulinemia did not occur in patients with P-E drainage. In 1995, Newell et al43 from the University of Chicago reported their initial experience with a similar P-E technique in 12 SKPT recipients compared with a retrospective matched control group of 12 SKPT patients with S-B drainage. Six-month patient and graft survival rates were comparable, and the P-E group had less acidosis, dehydration, hematuria, rejection, and need for enteric conversion. There were no differences in technical complications, and renal and pancreas allograft functions were similar. In 1996, Newell et al44 presented a 12-month follow-up on the same 2 groups with similar findings. In addition, the initial length of stay and total hospital days in the first year after transplantation were slightly lower in the P-E group. There were no significant differences in costs, no delay in the diagnosis of rejection, and the authors concluded that their results confirmed the safety and effectiveness of this new technique. In 1997, Nymann et al45 from our group reported improving outcomes with increased experience with the P-E technique. Two groups were compared: 23 SKPTs with P-E drainage performed from 1991 to 1994 versus 23 P-E pancreas transplantations (17 SKPT, 3 PTA, 3 PAKT) performed during 1995-96. The latter group received tacrolimusbased immunosuppression, while the former group was managed with cyclosporine. Cold ischemia time and perioperative blood transfusions were significantly lower in the latter group. In addition, the incidence of technical graft loss was reduced from 26% to 9%. Consequently, 1-year patient and pancreas graft survival rates were improved in the most recent era. In 1998, Nymann et al16 analyzed 47 SKPTs with graft function at 1 month, including 30 with S-B and 17 with P-E drainage. All patients had
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been managed with cyclosporine-based therapy. Although the authors noted comparable patient and graft survival and surgical complication rates, the incidence of rejection, graft loss due to rejection, and the density of rejection were all lower in patients with P-E drainage. Also in 1998, Eubanks et al46 from our group compared 12 solitary pancreas transplantations with S-B drainage performed during 1991-95 with 16 solitary pancreas transplantations with P-E drainage performed between July 1995 and March 1997. The former group was managed with cyclosporine and the latter group with tacrolimus-based immunosuppression. One patient in each group experienced graft loss as a result of thrombosis. In the remaining patients, the incidence and density of rejection was lower in the more recent era, leading to an improvement in the 1-year pancreas graft survival rate to 80%. In each of these studies, the authors concluded that the results of pancreas transplantation with the P-E technique are now comparable to the other reported techniques. In 1998, Bruce et al47 from the University of Chicago reported their experience with 70 consecutive SKPTs with P-E drainage performed between January 1992 and August 1997. They compared this group with a “historical” control group of 70 SKPTs with S-B drainage performed between January 1987 and December 1994. One-year patient, kidney, and pancreas graft survival rates were comparable between groups. There were no significant differences in technical or immunologic graft failure rates, as no enteric anastomotic leaks were reported in this series. Renal and pancreas allograft function at 1 year were similar. However, the total number of hospital days and the operative complications in the first year were significantly higher in the S-B group, with the difference in these results almost entirely accounted for by a 21% rate of enteric conversion. In addition, the authors noted a possible “learning curve” effect, with improved results in the latter 35 versus the former 35 SKPTs with P-E drainage. In 1998, Busing et al33 reported on 70 consecutive SKPTs without anastomotic complications, including 2 with P-E drainage. We believe that our study represents the first prospective analysis comparing pancreas transplantation performed with a standardized technique of P-E drainage versus the conventional technique of S-B drainage. During an 11-month period, we alternately performed each technique in 32 consecutive pancreas transplant recipients. Five patients (3 S-B, 2 P-E) were included in the study but not “alternated” because of intraoperative technical considera-
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tions that favored 1 technique over the other. The 2 groups were well matched for donor and recipient demographic, immunologic, and transplant characteristics. Therefore, we do not believe that either the selection process or the inclusion of the 5 patients who were not truly alternated introduced a bias in the interpretation of the study results. It is important to emphasize that 23 patients (72%) underwent SKPT while the remaining 9 (28%) received solitary pancreas transplantations. The categories of pancreas transplantation were equally distributed between the 2 groups. Although our overall numbers are small and follow-up is limited (minimum, 3 months; mean, 8 months), most of the technical outcomes relevant to comparing these 2 procedures occur in the first 3 to 6 months after pancreas transplantation. It is also important to note that 26 patients (81%; all SKPT and PAKT recipients) received primary immunosuppression with tacrolimus, mycophenolate mofetil, and steroids without anti-lymphocyte induction.23,24 The remaining 6 PTA recipients (19%) received OKT3 induction in addition to the above triple regimen. Conceding the above limitations in study design, the patient, kidney, and pancreas graft survival rates were comparable between groups, and no immunologic graft losses occurred. All SKPT recipients experienced immediate renal allograft function, and all but 1 of the pancreas allografts had initial function (1 thrombosis). The 3 deaths that occurred in this series were cardiac in origin and probably related to preexisting cardiac disease with autonomic neuropathy. These deaths accounted for 5 (3 pancreas, 2 renal) of the 7 graft losses that occurred in this study. We have previously identified cardiac autonomic neuropathy as a risk factor for sudden death in patients with sustained autonomic dysfunction after pancreas transplantation.48 Immunologic and infectious morbidity were not significantly different between the 2 groups, although the incidences of acute rejection and urinary tract infections were higher in the S-B group. The rate of urologic complications was doubled in the S-B group, and 2 patients underwent enteric conversion during the period of follow-up. Conversely, multiple re-operations occurred in 2 patients with P-E, but there were none with S-B drainage. However, for each of these co-morbidities, the overall numbers were small and did not achieve significance. Surrogate markers of morbidity such as length of hospital stay and re-admissions were slightly higher in patients with S-B drainage. In addition, metabolic acidosis and dehydration were universal among patients with S-B drainage but occurred in less than half of cases with P-E drainage. In our experience, we have
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identified dehydration as the single most common cause for readmission after pancreas transplantation. Furthermore, many of these patients have severe gastroparesis, enteropathy, and autonomic neuropathy with symptomatic orthostatic hypotension. For these reasons, we have a low threshold for placing central venous catheters for intermediate-term (1-3 months) vascular access for either intravenous fluid or medication administration. These preliminary results suggest that whole organ pancreas transplantation with a standardized technique of P-E drainage can be performed with short-term results comparable to the conventional technique of S-B drainage. Depending on individual anatomy, the ability to perform either technique is comparable, and P-E drainage is not associated with an increased risk of either thrombosis or intra-abdominal infections. Although studies with more patients and longer follow-up are needed, both techniques should be included in the repertoire of pancreas transplantation. We thank Linda Bryant, Ginger Hoskins, and Jo Lariviere for their assistance and expertise in the preparation of this article. REFERENCES 1. Gruessner AC, Sutherland DER. Analysis of United States (US) and non-US pancreas transplants as reported to the International Pancreas Transplant Registry (IPTR) and to the United Network for Organ Sharing (UNOS). Cecka JM, Terasaki PI, editors. Clinical Transplants 1998. Los Angeles: UCLA Tissue Typing Laboratory; 1999. p. 53-71. 2. Nghiem DD, Corry RJ. Technique of simultaneous renal pancreatoduodenal transplantation with urinary drainage of pancreatic secretion. Am J Surg 1987;153:405-6. 3. Diem P, Abid M, Redmon JB, Sutherland DER, Robertson RP. Systemic venous drainage of pancreas allografts as independent cause of hyperinsulinemia in Type I diabetic recipients. Diabetes 1990;39:534-40. 4. Sollinger HW, Messing EM, Eckhoff DE, Pirsch JD, D’Alessandro AM, Kalayogou M, et al. Urological complications in 210 consecutive simultaneous pancreas-kidney transplants with bladder drainage. Ann Surg 1993;218:561-70. 5. Stratta RJ, Sindhi R, Sudan D, Jerius JT, Radio SJ. Duodenal segment complications in vascularized pancreas transplantation. J Gastrointest Surg 1997;1:534-44. 6. Sindhi R, Stratta RJ, Lowell JA, Sudan D, Cushing KA, Castaldo P, et al. Experience with enteric conversion after pancreatic transplantation with bladder drainage. J Am Coll Surg 1997;184:281-9. 7. Sollinger HW, Sasaki TM, D’Alessandro AM, Knechtle SJ, Pirsch JD, Kalayogou M, et al. Indications for enteric conversion after pancreas transplantation with bladder drainage. Surgery 1992;112:842-6. 8. West M, Gruessner AC, Metrakos P, Sutherland DER, Gruessner RWG. Conversion from bladder to enteric drainage after pancreaticoduodenal transplantation. Surgery 1998;124:883-93. 9. Kuo PC, Johnson LB, Schweitzer EJ, Bartlett ST. Simultaneous pancreas/kidney transplantation: a compari-
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son of enteric and bladder drainage of exocrine pancreatic secretions. Transplantation 1997;63:238-43. Douzdjian B, Rajagopalan PR. Primary enteric drainage of the pancreas allograft revisited. J Am Coll Surg 1997;185:471-5. Corry RJ, Egidi MF, Shapiro R, Jordan M, Vivas C, Scantlebury V, et al. Enteric drainage of pancreas transplants revisited. Transplant Proc 1995;27:3048-9. Sollinger HW, Odorico JS, Knechtle SJ, D’Alessandro AM, Kalayogou M, Pirsch JD. Experience with 500 simultaneous pancreas-kidney transplants. Ann Surg 1998;228:284-96. Gaber AO, Shokouh-Amiri MH, Grewal HP, Britt LG. A technique for portal pancreatic transplantation with enteric drainage. Surg Gynecol Obstet 1993;177:417-9. Gaber AO, Shokouh-Amiri MH, Hathaway DK, Gaber LW, Elmer D, Kitabchi A, et al. Pancreas transplantation with portal venous and enteric drainage eliminates hyperinsulinemia and reduces post-operative complications. Transplant Proc 1993;25:1176-8. Gaber AO, Shokouh-Amiri MH, Hathaway DK, Hammontree L, Kitabchi AE, Gaber LW, et al. Results of pancreas transplantation with portal venous and enteric drainage. Ann Surg 1995;221:613-624. Nymann T, Hathaway DK, Shokouh-Amiri MH, Gaber LW, Abu-El-Ella K, Abdulkarim AB, et al. Patterns of acute rejection in portal-enteric versus systemic-bladder pancreas-kidney transplantation. Clin Transplant 1998;12:175-83. Stratta RJ, Taylor RJ, Spees EC, Langnas AN, Marujo WC, Li S, et al. Refinements in cadaveric pancreas-kidney procurement and preservation. Transplant Proc 1991;23:2320-2. Grewal HP, Garland L, Novak K, Gaber L, Tolley EA, Gaber AO. Risk factors for post implantation pancreatitis and pancreatic thrombosis in pancreas transplant recipients. Transplantation 1993;56:609-12. Gill IS, Sindhi R, Jerius JT, Sudan D, Stratta RJ. Bench reconstruction of pancreas for transplantation: experience with 192 cases. Clin Transplant 1997;11:104-9. Gaber AO, Gaber LW, Shokouh-Amiri MH, Hathaway D. Percutaneous biopsy of pancreas transplants. Transplantation 1992;54:548-50. Stratta RJ. Ganciclovir/acyclovir and fluconazole prophylaxis after simultaneous kidney-pancreas transplantation. Transplant Proc 1998;30:262. Somerville T, Hurst G, Alloway RR, Shokouh-Amiri MH, Gaber AO, Stratta RJ. Superior efficacy of oral ganciclovir over oral acyclovir for cytomegalovirus prophylaxis in kidney/pancreas and pancreas alone recipients. Transplant Proc 1998;30:1546-8. Reddy KS, Stratta RJ, Shokouh-Amiri MH, Alloway RR, Somerville T, Egidi MF, et al. Simultaneous kidney-pancreas transplantation without anti-lymphocyte induction. Transplantation 1999 (in press) Stratta RJ, Gaber AO, Shokouh-Amiri MH, Reddy KS, Alloway RR, Egidi MF, et al. Evolution in pancreas transplantation techniques: simultaneous kidney-pancreas transplantation using portal-enteric drainage without anti-lymphocyte induction. Ann Surg 1999;229:701-12. Elmer DS, Hathaway DK, Bashar Abdulkarim A, Hughes TA, Shokouh-Amiri MH, Gaber LW, et al. Use of glucose disappearance rates (kG) to monitor endocrine function of pancreas allografts. Clin Transplant 1998;12:56-64. Sugitani A, Egidi MF, Gritsch HA, Corry RJ. Serum lipase as a marker for pancreatic allograft rejection. Transplant Proc 1998;30:645. Solez K, Axelsen RA, Benediksson H, Burdick JF, Cohen AH, Colvin RB, et al. International standardization of crite-
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ria for the histologic diagnosis of renal allograft rejection: the BANFF working classification of kidney transplant pathology. Kidney Int 1993;44:411-24. Kuo PC, Johnson LB, Schweitzer EJ, Klassen DK, HoehnSaric EW, Weir MR, et al. Solitary pancreas allografts: the role of percutaneous biopsy and standardized histologic grading of rejection. Arch Surg 1997;132:52-7. Stratta RJ, Taylor RJ, Gill IS. Pancreas transplantation: a managed cure approach to diabetes. Curr Probl Surg 1996;33:709-816. Sollinger HW, Pirsch JD, D’Alessandro AM, Kalayogou M, Belzer FO. Advantages of bladder drainage in pancreas transplantation: a personal view. Clin Transplant 1990;4:32-6. Tyden G, Tibell A, Sandberg J, Brattstrom C, Groth CG. Improved results with a simplified technique for pancreaticoduodenal transplantation with enteric exocrine drainage. Clin Transplant 1996;10:306-9. Pearson TC, Santa Maria PJ, Routenberg KL, O’Brien DP, Whelchel JD, Neylan JF, et al. Drainage of the exocrine pancreas in clinical transplantation: comparison of bladder versus enteric drainage in a consecutive series. Clin Transplant 1997;11:201-5. Busing M, Martin D, Schulz T, Heimes M, Schindler A, Klempnauer J, et al. Pancreas-kidney transplantation with urinary bladder and enteric exocrine diversion: seventy cases without anastomotic complications. Transplant Proc 1998;30:434-7. Fernandez-Cruz L, Astudillo E, MacMillan N, Ricart MG, Sabater L. Should enteric drainage be used as a primary procedure instead of bladder drainage in clinical pancreas transplantation? Transplant Proc 1998;30:430-1. Tagral CF, Dawhara M, Benchaib M, Lefrancois N, Martin X, Dubernard JM. Effect of the surgical technique on longterm outcome of pancreas transplantation. Transpl Int 1998;11:295-300. Bloom RD, Olivares M, Rehman L, Raja RM, Yang S, Badosa F. Long-term pancreas allograft outcome in simultaneous pancreas-kidney transplantation: a comparison of enteric and bladder drainage. Transplantation 1997;64:1689-95. Di Carlo V, Castoldi R, Cristallo M, Ferrari G, Socci C, Baldi A, et al. Techniques of pancreas transplantation through the world: an IPITA center survey. Transplant Proc 1998;30:231-41. Shokouh-Amiri MH, Gaber AO, Gaber LW, Jensen SL, Hughes TA, Elmer D, Britt LG. Pancreas transplantation with portal venous drainage and enteric exocrine diversion: a new technique. Transplant Proc 1992;24:776-7. Shokouh-Amiri MH, Rahimi-Saber S, Andersen HO. Segmental pancreatic autotransplantation in the pig. Transplantation 1989;47:42-4. Calne RY. Paratopic segmental pancreas grafting: a technique with portal venous drainage. Lancet 1984;1:595-7. Muhlbacher F, Gnant MFX, Auinger M, Steininger R, Klauser R, Prager R, et al. Pancreatic venous drainage to the portal vein: a new method in pancreatic transplantation. Transplant Proc 1990;22:636-7. Rosenlof LK, Earnhardt RC, Pruett TL, Stevenson WC, Douglas MT, Cornett GC, et al. Pancreas transplantation: an initial experience with systemic and portal drainage of pancreatic allografts. Ann Surg 1992;215:586-97. Newell KA, Woodle ES, Millis JM, Piper JB, Huss E, Seaman DS, et al. Pancreas transplantation with portal venous drainage and enteric exocrine drainage offers early advantages without compromising safety or allograft function. Transplant Proc 1995;27:3002-3. Newell KA, Bruce DS, Cronin DC, Woodle ES, Millis JM, Piper JB, et al. Comparison of pancreas transplantation with portal venous and enteric exocrine drainage to the stan-
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dard technique utilizing bladder drainage of exocrine secretions. Transplantation 1996;62:1353-6. 45. Nymann T, Elmer DS, Shokouh-Amiri MH, Gaber AO. Improved outcome of patients with portal-enteric pancreas transplantation. Transplant Proc 1997;29:637-8. 46. Eubanks JW, Shokouh-Amiri MH, Elmer D, Hathaway D, Gaber AO. Solitary pancreas transplantation using the portal-enteric technique. Transplant Proc 1998;30:446-7.
Surgery February 2000 47. Bruce DS, Newell KA, Woodle ES, Cronin DC, Grewal HP, Millis JM, et al. Synchronous pancreas-kidney transplantation with portal venous and enteric exocrine drainage: outcome in 70 consecutive cases. Transplant Proc 1998;30:270-1. 48. Hathaway DK, El-Gebely S, Cardoso S, Elmer DS, Gaber AO. Autonomic cardiac dysfunction in diabetic transplant recipients succumbing to sudden cardiac death. Transplantation 1995;59:634-7.
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Background. Most pancreas transplants are performed with systemic venous delivery of insulin and bladder drainage of the exocrine secretions (systemic-bladder [S-B]). To develop a more physiologic procedure, we performed pancreas transplantations with portal venous delivery of insulin and enteric drainage of the exocrine secretions (portal-enteric [P-E]). Methods. During an 11-month period, we prospectively alternated 32 consecutive pancreas transplant recipients to either S-B (n = 16) or P-E (n = 16) drainage with standardized immunosuppression. Results. Patient, kidney, and pancreas graft survival rates after simultaneous kidney-pancreas transplantation were 91% S-B versus 92% P-E, 91% S-B versus 92% P-E, and 82% S-B versus 92% P-E, respectively. Pancreas graft survival rates after solitary pancreas transplantation were 80% S-B versus 75% P-E. There were no graft losses either to immunologic or infectious complications in either group, but the incidence of acute rejection was slightly higher in the S-B group (44% S-B vs 31% P-E, P = NS). The cost and length of the initial hospital stay were similar between groups. The incidence of operative complications, major infections, and cytomegalovirus infections were likewise comparable. However, the S-B group was characterized by a slight increase in the number of readmissions, urinary tract infections, and urologic complications. Furthermore, metabolic acidosis and dehydration were more common in the S-B group. Conclusions. Pancreas transplantation with P-E drainage can be performed with short-term results comparable to those of transplantation with S-B drainage. (Surgery 2000;127:217-26.) From the Transplant Division, Departments of Surgery and Pathology, University of Tennessee, Memphis
THE RESULTS OF PANCREAS TRANSPLANTATION continue to improve as a result of refinements in surgical techniques and advances in immunosuppression. According to the International Pancreas Transplant Registry Data, more than 11,000 pancreas transplantations have been performed worldwide through 1998.1 In the United States, approximately 1200 pancreas transplantations are performed annually, with 87% being simultaneous kidney-pancreas transplantations (SKPTs).1 In the United States, the current 1-year actuarial patient, kidney, and pancreas (with complete insulin independence) graft survival rates after SKPT are 94%, 90%, and 83%, respectively.1 Solitary pancreas transplantations comprise the remaining activity, Presented at the 24th Annual Scientific Meeting of the American Society of Transplant Surgeons, Chicago, Ill, May 15, 1998. Accepted for publication September 18, 1999. Reprints not available from the authors. Copyright © 2000 by Mosby, Inc. 0039-6060/2000/$12.00 + 0
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including either sequential pancreas after kidney transplantations (PAKT, 9%) or pancreas transplantations alone (PTA, 4%). The current 1-year actuarial pancreas graft survival rates are 73% for PAKT and 67% for PTA.1 Most pancreas transplantations are performed with systemic venous delivery of insulin and bladder drainage of the exocrine secretions (systemicbladder [S-B]) with use of the duodenal segment technique.1,2 Although S-B drainage is safe and effective, it results in peripheral hyperinsulinemia and is associated with unique metabolic and urologic complications caused by an altered physiology.3-6 When these complications become persistent or refractory, conversion from bladder to enteric drainage (enteric conversion) has been shown to be a safe and effective method of managing these problems.6-8 Because of favorable experiences with enteric conversion—coupled with advances in preservation and immunosuppression that place the duodenal segment at a lower risk for ischemic or immunologic injury resulting in a fistula— there is renewed interest in primary enteric SURGERY 217
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Table 1. Group characteristics Systemic-bladder (S-B) N=16 Age (y) Sex Female Male Years of diabetes Race: white Pretransplant dialysis Prior transplant Current PRA ≥ 10% Pancreas ischemia (h) HLA-match HLA-mismatch Waiting time (m) Type of transplant: SKPT PAKT PTA
Portal-enteric (P-E) N=16
38 ± 6
37 ± 7
7 (44%) 9 (56%) 25.5 ± 6 16 (100%) 11/11 (100%) 1 (6%) 1 (6%) 15.1 ± 3.4 1.8 ± 1.3 4.2 ± 1.3 4.6 ± 4.3
7 (44%) 9 (56%) 26 ± 4 16 (100%) 6/12 (50%)* 3 (19%) 1 (6%) 13.4 ± 3.0 1.8 ± 1.3 4.1 ± 1.3 4.4 ± 3.1
11 (69%) 1 (6%) 4 (25%)
12 (75%) 2 (12.5%) 2 (12.5%)
PRA, Panel-reactive antibody. Data are expressed as mean ± SD. *P = .01.
drainage.9-12 From 1988 through 1995, more than 90% of pancreas transplant procedures were performed by the standard technique of S-B drainage.1 However, in the last 3 years, the number of pancreas transplant procedures performed with primary enteric drainage has steadily increased, with more than 50% being performed with enteric drainage in 1998.1 The majority of pancreas transplantations with enteric drainage are performed with systemic venous delivery of insulin (systemic-enteric). To further improve the physiology of pancreas transplantation and to avoid the potential complications of systemic hyperinsulinemia, a new surgical technique was developed at our center, using portal venous delivery of insulin and enteric drainage of the exocrine secretions (portal-enteric [P-E]).13,14 We have previously reported our experience with P-E drainage, including a retrospective comparison to a historical control group of patients who underwent pancreas transplantation with S-B drainage.15,16 The purpose of this study was to compare pancreas transplantation using S-B drainage with transplantation using P-E drainage in a prospective fashion with standardized immunosuppression. MATERIALS AND METHODS Study design. The Memphis Pancreas Transplant Program at the University of Tennessee began in 1989. The first pancreas transplantation using P-E drainage was performed in 1990. Since
this time, we have performed 102 pancreas transplantations with P-E drainage and 76 with S-B drainage. During an 11-month period from February 1997 to January 1998, there were 32 consecutive pancreas transplantations performed at our center and entered into a prospective study. The technique to be performed was determined before the transplant with selection determined by an alternating methodology. In 5 cases, the preselected technique could not be performed because of intraoperative findings that favored one technique over the other. These 5 patients were included in the study and subsequent pre-transplant selection of technique continued on an alternating basis. A total of 16 patients were allocated to each technique. Organ procurement, preservation, and preparation. The pancreas or kidney, or both, were procured from heart-beating cadaveric donors in conjunction with multiple-organ retrieval by standard techniques.17 University of Wisconsin solution was used for both in situ flush and storage of all organs under cold-storage conditions. Whole organ pancreaticoduodenosplenectomy was performed by an en bloc technique.17 Cold ischemia was kept to a minimum, and preservation times were less than 20 hours in 31 (97%) of the cases and less than 12 hours in 8 (25%) of the cases.18 Before transplantation, the pancreas was reconstructed on the back table with a donor iliac artery bifurcation Y graft to the splenic and superior mesenteric arteries.19 In
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cases of S-B drainage, an 8- to 10-cm length of duodenal segment, incorporating the ampulla of Vater, was fashioned and left attached to the head of the pancreas. In cases with P-E drainage, the proximal duodenal closure remained the same (just distal to the pylorus), but the distal duodenal closure incorporated the third part, and a variable portion of the fourth part, of the duodenum as previously described.13 The P-E procedure, unlike the S-B technique, requires that the arterial bifurcation graft be constructed intentionally long for subsequent arterialization. Other than the duodenal and arterial preparation, the remainder of the back table dissection was similar regardless of technique, leaving the spleen attached as a handle but ligating the splenic hilar structures in continuity. Recipient selection and operative procedure. Patients were selected for transplantation based on ABO blood type compatibility, period of time on the waiting list, and a negative T lymphocytotoxic cross-match, in accordance with United Network for Organ Sharing guidelines. After preparation of the organ, the recipient operation was performed through a midline intraperitoneal approach. For SB cases, the whole organ pancreas was transplanted to the right iliac vessels with end to side vascular anastomoses, followed by bladder drainage by the duodenal segment technique.2 The surgical technique of P-E drainage has been previously described in detail by our group.13,15 The portal vein of the pancreas graft is anastomosed end-toside to a major tributary of the superior mesenteric vein. The donor iliac artery bifurcation graft is brought through a window made in the distal ileal mesentery and anastomosed end-to-side to the right common iliac artery. The transplanted duodenum is anastomosed distally end to end to a diverting Roux-en-Y limb of the recipient jejunum. With both techniques, splenectomy is performed after revascularization, and an attempt is made to anchor the tail of the pancreas to the anterior abdominal wall with interrupted sutures. These anchoring sutures permit subsequent percutaneous, ultrasound-guided pancreas allograft core biopsies to be performed as needed.20 In SKPT with either technique, the renal allograft is anastomosed end to side to the left external iliac vessels, followed by an extra-vesical ureteroneocystostomy by standard techniques. The kidney is then “retroperitonealized” by anchoring the sigmoid colon mesentery to the lateral peritoneal reflection with interrupted sutures. Perioperative management and immunosuppression. Perioperative antibiotic prophylaxis consisted of a preoperative, intraoperative, and 3 post-
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operative doses of cefazolin (1 g intravenously). All patients received 1 tab/day of sulfamethoxazole /trimethoprim, single strength, for 6 to 12 months as a prophylaxis for pneumocystis pneumonia. Antifungal prophylaxis consisted of 200 mg/day of oral fluconazole taken for 2 to 3 months.21 Antiviral prophylaxis included intravenous ganciclovir (2.5-5 mg/kg, twice daily) during the initial hospitalization, followed by oral ganciclovir (1 g, 3 times daily) for 3 months to all patients (for 6 months if the donor was cytomegalovirus (CMV) seropositive and the recipient was CMV seronegative).21,22 All SKPT and PAKT recipients received primary immunosuppression with tacrolimus, mycophenolate mofetil, and steroids without anti-lymphocyte induction therapy.23,24 Tacrolimus was started immediately post-transplant at a dose of 0.1 to 0.2 mg/kg orally in 2 divided doses titrated to a 12hour trough level of 15 to 20 ng/mL by IMX assay (Abbott Diagnostics, Chicago, Ill) for the first 3 months. After 3 months, tacrolimus levels were maintained at 10 to 15 ng/mL. Oral mycophenolate mofetil (MMF) was started immediately posttransplant at 2 to 3 g/day in 2-4 divided doses. The MMF dose was reduced in patients with gastrointestinal intolerance (nausea, vomiting, diarrhea) or with a total white blood cell count below 3000/mm3. MMF was discontinued temporarily in patients with septicemia, active CMV infection, or when the total white blood cell count was below 2000/mm3. Corticosteroids were administered as intravenous methylprednisolone at a rate of 500 to 1000 mg intraoperatively followed by 250 mg on postoperative day 1. By days 7 to 10, the dosage was tapered to 30 mg/day of oral prednisone. A gradual steroid taper was used, with the goal of reaching an oral prednisone dose of 5 to 10 mg/day at 1 year. In PTA recipients, the described triple therapy was used in combination with OKT3 induction at a dose of 2.5 to 5 mg/day for 5 to 7 days. The first dose of OKT3 was administered intraoperatively, with subsequent doses titrated to maintain CD3 counts below 10/mm3. Anti-platelet therapy, consisting of oral aspirin (81 mg/day), was administered to all patients. In addition, all P-E cases and solitary pancreas transplant recipients received 3000 to 5000 units of intravenous heparin intraoperatively before the vessels were clamped. In solitary pancreas transplant and selected P-E cases, heparin prophylaxis was continued postoperatively (5000 units subcutaneous twice daily) for 3 to 5 days. Finally, warfarin sodium crystalline (Coumadin) was administered in a single, oral daily dose of 1 mg/day to patients who required prolonged vascular access with the
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Table 2. Results Systemic-bladder (S-B) N=16 Patient survival Graft survival: Kidney Pancreas Follow-up (m) ATN (dialysis) Early technical problems/pancreatitis Initial LOS (d) Readmissions Acute rejection Major infection Re-operations Initial hospital charges ($) Urologic complication UTI Dehydration/acidosis CMV infection Multiple re-operations
14 (88%) 11/12 (92%) 13 (81%) 7.5 ± 3.4 0 3 (19%) 13.7 ± 9 2.6 ± 1.8 7 (44%) 8 (50%) 4 (25%) 100,215 ± 54,012 4 (25%) 8 (50%) 16 (100%) 2 (12.5%) 0
Portal-enteric (P-E) N=16 15 (94%) 13/14 (93%) 14 (88%) 8.9 ± 3.8 0 3 (19%) 12.8 ± 7 1.75 ± 1.2 5 (31%) 10 (62.5%) 4 (25%) 94,083 ± 25,873 2 (12.5%) 3 (19%) 7 (44%)* 3 (19%) 2 (12.5%)
ATN, Acute tubular necrosis; LOS, length of stay; UTI, urinary tract infection. Data are expressed as mean ± SD. *P < .01.
subsequent placement of a permanent central venous catheter. Postoperative monitoring. After transplantation, duplex ultrasonography of the pancreas or the kidney, or both, was performed on the first postoperative day and whenever clinically indicated. Recipients were monitored for daily fasting serum glucose, amylase, and lipase levels and for renal profiles, tacrolimus levels, and complete blood cell counts. In addition, urine amylase levels were monitored in patients with S-B drainage. Metabolic control and hormonal profiles were assessed by intravenous glucose tolerance testing, fasting and stimulated C-peptide levels, lipid profiles and glycosylated hemoglobin levels.25 The diagnosis of rejection was based on clinical criteria, renal allograft dysfunction, serum and urine amylase levels, serum glucose and lipase levels, and renal or pancreas allograft histopathology.16,26 Renal allograft rejection was suggested by an unexplained rise in serum creatinine of 0.3 mg/dL or greater and confirmed by an ultrasound-guided percutaneous biopsy. Pancreas allograft rejection was suggested by an unexplained elevation in serum amylase, lipase, glucose, or a serial decrease in urine amylase levels in patients with S-B drainage. Pancreas allograft rejection was confirmed by ultrasound-guided percutaneous biopsy.20 Most rejection episodes were confirmed by biopsy before specific anti-rejection therapy was initiated. The severity of the rejection was defined according to Banff and Maryland criteria.27,28 Mild renal allograft rejection was treated with intravenous methylprednisolone at 500 to 1000 mg/day for 3 doses.
Anti-lymphocyte therapy with OKT3 or anti-thymocyte gamma globulin (Atgam) for 7 to 10 days was used as the initial treatment for moderate or severe renal allograft rejection or for any pancreas allograft rejection. Steroid-resistant mild renal allograft rejection was also treated with anti-lymphocyte therapy. CMV infection was defined as a positive blood culture, antigenemia, or positive IgM titer. Invasive CMV infection (CMV disease) was defined as symptomatic CMV infection or histologic evidence of tissue invasion. Treatment of CMV infection consisted of the administration of intravenous ganciclovir for 2 to 4 weeks and a reduction in immunosuppression therapy. Oral ganciclovir was given for a variable period after treatment of documented CMV infection. Other infections were recorded, with major infection defined as a need for hospitalization for diagnosis and treatment. STATISTICAL ANALYSIS Data are reported as mean ± SD. Univariate analysis was performed by the Student t test for continuous variables, the chi-square test for categorical variables, and Fisher exact test when data were sparse. Actuarial patient and graft survival rates were computed by Wilcoxon life-table analysis. Renal allograft loss was defined as a return to dialysis or to the pre-transplant serum creatinine level, and pancreas graft loss was defined as the need for continued insulin therapy. RESULTS A total of 32 consecutive pancreas transplant
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recipients were enrolled in the prospective study during an 11-month period. The S-B group included 11 SKPT, 1 PAKT, and 4 PTA recipients, while the P-E group included 12 SKPT, 2 PAKT, and 2 PTA recipients. Demographic, immunologic, and transplant characteristics of the 2 groups are listed in Table 1. The 2 groups were well matched for age, sex, weight, race, and pre-transplant duration of diabetes. In the S-B group, all 11 SKPT recipients were receiving dialysis at the time of transplant. In the P-E group, only 6 of 12 (50%, P = .01) were dialysis-dependent at the time of SKPT. However, time spent on the waiting list was similar for both groups. Retransplantation was slightly more prevalent in the P-E group, and pancreas cold ischemia was slightly longer in the S-B group. None of these differences achieved significance. Panel reactive antibody titers and HLA-matching and mismatching were similar between groups. Five patients (16%) were selected for one technique of transplantation but subsequently received the alternative technique because of technical considerations identified intraoperatively. One SKPT recipient was selected for the S-B group but urethral catheter placement after induction of anesthesia revealed pyocystis. To reduce the risk of infection, this patient received a P-E pancreas transplant and bladder drainage was aborted. In another SKPT recipient selected for S-B drainage, a previous kidney transplant in the pelvis and severe iliac atherosclerosis prevented safe placement of the pancreas in a pelvic location. Therefore, the patient was a crossover to the P-E technique, as the infrarenal aorta was used for the arterial reconstruction. Three other SKPT recipients initially selected for P-E drainage were switched to S-B drainage because of the following: (1) a small mesenteric vein, which was deemed inadequate for the donor portal venous outflow, (2) obesity with a severely thickened mesentery and deep mesenteric vein, which was likewise deemed a high risk for anastomosis, and (3) a patient with severe gastroparesis with an indwelling gastrostomy and extensive upper abdominal adhesions. In each of these 3 cases, pelvic placement of the pancreas had a technical advantage. Results are provided in Table 2. There were no significant differences in patient, renal, or pancreas allograft survival rates after a mean follow-up of 8 months. In the S-B group, there were 2 deaths: 1 from cardiac failure 2 months after PTA, and 1 from a myocardial infarction 7 months after SKPT. These deaths resulted in 2 pancreas graft losses and 1 kidney graft loss. The only other graft failure in the S-B group was a pancreas loss at 6 months
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caused by insulin resistance. In the P-E group, there was 1 death from a cardiac arrhythmia 1 month after SKPT. This death resulted in 1 kidney and 1 pancreas graft loss. The only other graft failure in the P-E group was a pancreas graft loss caused by thrombosis 1 day after the PTA procedure. All 23 transplanted renal allografts started functioning immediately, and 31 pancreas allografts had initial function. The initial length of hospital stay, readmissions, and the incidence of acute rejection were slightly higher in the S-B group, but none of these differences were significant. For all patients, the mean length of the initial hospital stay was 13 days, the mean number of readmissions was 2, and the incidence of acute rejection was 37.5%. The incidence of major infections and operative complications was comparable between the 2 groups. Initial hospital charges were likewise similar—approximately $100,000. The incidence of urologic complications was doubled in the S-B group. Two patients had persistent hematuria, and 1 of them underwent cystoscopy, suture removal, and fulguration of a bleeding site. Another patient had recurrent reflux pancreatitis, which was treated with repeated catheter drainage and then intermittent selfcatheterization. A final patient had both reflux pancreatitis and hematuria, which eventually was managed by enteric conversion. In the P-E group, 2 patients had urosepsis. The S-B group was also characterized by a higher incidence of urinary tract infections (50% S-B vs 19% P-E). Metabolic acidosis with oral bicarbonate supplementation was universal in the S-B group but rarely occurred with P-E drainage. The incidence of CMV infection was similar between the 2 groups, and 1 patient in the S-B group had post-transplant lymphoproliferative disease associated with Epstein-Barr viral infection. Four patients in each group underwent relaparotomy. In the S-B group, 2 patients underwent enteric conversion, 1 underwent laparotomy for a deep wound infection, and 1 underwent laparotomy for a perforated gastric ulcer. In the P-E group, 1 patient underwent pancreatectomy for thrombosis after PTA, and another patient underwent splenic artery thrombectomy with a graft salvage. Two patients in the P-E group required a second reoperation; 1 patient (6%) had an enteric leak with intra-abdominal infection. Another patient underwent repair of a wound dehiscence and then a laparotomy for pancreatitis caused by rejection, which was determined by means of an open pancreas allograft biopsy. There was no graft loss in this series either to immunologic or infectious complications.
222 Stratta et al
DISCUSSION The history of clinical pancreas transplantation largely revolves around the development and application of various surgical techniques.29 According to United Network for Organ Sharing Registry data, bladder drainage with a duodenal segment conduit is the preferred technique for managing exocrine secretions after vascularized pancreas transplantation.1 From October 1, 1987, through November 30, 1995, this method was used in 94% of the pancreas transplantations performed in the United States. Bladder drainage by the duodenal segment technique became popular because it is safe, sterile, and convenient, because it enables urinary monitoring of pancreatic secretions, affords access for cystoscopic biopsy, and because it permits easy control of anastomotic problems with urethral catheter drainage.12,29,30 However, this technique also creates a nonphysiologic connection between the allografted pancreas with a duodenal conduit and the urinary bladder. This results in obligatory fluid and bicarbonate losses in the urine and alterations in the normally acidic enzyme-free milieu of the lower genitourinary tract.6,29 Although well tolerated in many pancreas transplant recipients, bladder drainage has been associated with unique metabolic and urologic complications resulting from an altered physiology.3-6 When these complications become intractable, conversion from bladder to enteric drainage (enteric conversion) may be therapeutic. Enteric conversion rates range from 10% to 20% in most large series.6-8 According to registry data, the rate of enteric conversion is 7% at 1 year and 11% at 2 years after pancreas transplantation with bladder drainage.1 In an effort to avoid these complications, some centers have returned to primary enteric drainage and are reporting improved results.9-12,29 In the past, the disadvantages of primary enteric drainage included the inability to directly monitor exocrine secretions, septic complications (such as peritonitis, abscess, and mycotic aneurysm), and healing problems. The healing problems were related to the anastomosis of an ischemic organ and an inadequately prepared bowel in the setting of high-dose immunosuppression with incomplete distal decompression.29 Registry data through 1993 continued to show a 10% to 15% improvement in the 1-year pancreas graft survival rate for bladder versus enteric drainage.1 In the 1990s, Tyden et al31 simplified the technique for pancreaticoduodenal transplantation with enteric drainage by first eliminating the Roux limb and then the ductal catheter. Based on the favorable experience with enteric conversion6-8 and recent improvements in organ
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retrieval and preservation, surgical techniques, immunosuppression, diagnostic technology, and anti-microbial prophylaxis, the results of primary enteric drainage are now approaching those of bladder drainage.9-12,31-36 Centers at which primary enteric drainage is done generally employ the duodenal segment technique with either a direct sideto-side anastomosis to the small bowel or an anastomosis to a diverting Roux limb. In the United States, the number of pancreas transplantations performed with enteric drainage has increased, from 15% in 1995 to 33% in 1996 to 46% in 1997.1 In addition to exocrine drainage, other nonphysiologic aspects of the procedure include transplantation of a completely denervated organ into an ectopic location with systemic venous drainage of insulin. At present, most pancreas transplantations are performed with either S-B or systemic-enteric drainage. According to the latest registry report analyzing pancreas transplantations performed between January 1, 1994 and June 6, 1998, the 1-year pancreas graft survival rates with bladder and enteric drainage were 83% and 81%, respectively (P ≤ .05).1 The slight improvement in graft survival associated with bladder drainage is almost entirely accounted for by a slightly lower technical failure rate associated with this technique. In those patients with primary enteric drainage, however, Roux limb diversion was also associated with a slight improvement in graft survival as a result of a lower technical failure rate.1 A few centers have reported success transplanting the pancreas to a mesenteric vein to establish portal venous drainage of insulin.13-16,37 This technique can be performed with enteric drainage (P-E) to develop a more physiologic procedure. A recent survey of pancreas transplant centers revealed that 39 perform bladder drainage, 21 both bladder and enteric drainage, and 18 enteric drainage exclusively.37 Seven centers reported experience with the P-E technique—5 of these also used a diverting Roux limb. The P-E technique was first described clinically by our group in 199238 and was based on experimental work by Shokouh-Amiri et al in a porcine model.39 This new technique employed a tributary of the superior mesenteric vein to reestablish portal venous drainage and differed substantially from the original reports of portal pancreatic transplantations as reported by Calne in 198440 and Muhlbacher et al in 1990.41 Calne’s technique of paratopic segmental pancreas grafting used the recipient’s splenic vein as the site of anastomosis, while Muhlbacher’s group used the recipient portal vein directly. In 1992, Rosenlof et al42 applied Calne’s technique to whole organ pancreas trans-
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plantation with a duodenal segment conduit. In each of these series, however, the procedure was not widely applied because of technical problems associated with the vascular reconstruction. In 1993, our group reported that P-E pancreas transplantation with Roux limb diversion not only achieves acceptable metabolic control and eliminates hyperinsulinemia but is also associated with reduced postoperative complications.14 In 1995, we compared 19 patients undergoing SKPT with the P-E technique versus a retrospective control group of 28 patients receiving SKPT with the conventional S-B technique.15 Actuarial patient and graft survival rates at 1 and 3 years were no different in the 2 groups. Metabolic and urologic complications and urinary tract infections were more common in the S-B group. Metabolic control was comparable between groups, and peripheral hyperinsulinemia did not occur in patients with P-E drainage. In 1995, Newell et al43 from the University of Chicago reported their initial experience with a similar P-E technique in 12 SKPT recipients compared with a retrospective matched control group of 12 SKPT patients with S-B drainage. Six-month patient and graft survival rates were comparable, and the P-E group had less acidosis, dehydration, hematuria, rejection, and need for enteric conversion. There were no differences in technical complications, and renal and pancreas allograft functions were similar. In 1996, Newell et al44 presented a 12-month follow-up on the same 2 groups with similar findings. In addition, the initial length of stay and total hospital days in the first year after transplantation were slightly lower in the P-E group. There were no significant differences in costs, no delay in the diagnosis of rejection, and the authors concluded that their results confirmed the safety and effectiveness of this new technique. In 1997, Nymann et al45 from our group reported improving outcomes with increased experience with the P-E technique. Two groups were compared: 23 SKPTs with P-E drainage performed from 1991 to 1994 versus 23 P-E pancreas transplantations (17 SKPT, 3 PTA, 3 PAKT) performed during 1995-96. The latter group received tacrolimusbased immunosuppression, while the former group was managed with cyclosporine. Cold ischemia time and perioperative blood transfusions were significantly lower in the latter group. In addition, the incidence of technical graft loss was reduced from 26% to 9%. Consequently, 1-year patient and pancreas graft survival rates were improved in the most recent era. In 1998, Nymann et al16 analyzed 47 SKPTs with graft function at 1 month, including 30 with S-B and 17 with P-E drainage. All patients had
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been managed with cyclosporine-based therapy. Although the authors noted comparable patient and graft survival and surgical complication rates, the incidence of rejection, graft loss due to rejection, and the density of rejection were all lower in patients with P-E drainage. Also in 1998, Eubanks et al46 from our group compared 12 solitary pancreas transplantations with S-B drainage performed during 1991-95 with 16 solitary pancreas transplantations with P-E drainage performed between July 1995 and March 1997. The former group was managed with cyclosporine and the latter group with tacrolimus-based immunosuppression. One patient in each group experienced graft loss as a result of thrombosis. In the remaining patients, the incidence and density of rejection was lower in the more recent era, leading to an improvement in the 1-year pancreas graft survival rate to 80%. In each of these studies, the authors concluded that the results of pancreas transplantation with the P-E technique are now comparable to the other reported techniques. In 1998, Bruce et al47 from the University of Chicago reported their experience with 70 consecutive SKPTs with P-E drainage performed between January 1992 and August 1997. They compared this group with a “historical” control group of 70 SKPTs with S-B drainage performed between January 1987 and December 1994. One-year patient, kidney, and pancreas graft survival rates were comparable between groups. There were no significant differences in technical or immunologic graft failure rates, as no enteric anastomotic leaks were reported in this series. Renal and pancreas allograft function at 1 year were similar. However, the total number of hospital days and the operative complications in the first year were significantly higher in the S-B group, with the difference in these results almost entirely accounted for by a 21% rate of enteric conversion. In addition, the authors noted a possible “learning curve” effect, with improved results in the latter 35 versus the former 35 SKPTs with P-E drainage. In 1998, Busing et al33 reported on 70 consecutive SKPTs without anastomotic complications, including 2 with P-E drainage. We believe that our study represents the first prospective analysis comparing pancreas transplantation performed with a standardized technique of P-E drainage versus the conventional technique of S-B drainage. During an 11-month period, we alternately performed each technique in 32 consecutive pancreas transplant recipients. Five patients (3 S-B, 2 P-E) were included in the study but not “alternated” because of intraoperative technical considera-
224 Stratta et al
tions that favored 1 technique over the other. The 2 groups were well matched for donor and recipient demographic, immunologic, and transplant characteristics. Therefore, we do not believe that either the selection process or the inclusion of the 5 patients who were not truly alternated introduced a bias in the interpretation of the study results. It is important to emphasize that 23 patients (72%) underwent SKPT while the remaining 9 (28%) received solitary pancreas transplantations. The categories of pancreas transplantation were equally distributed between the 2 groups. Although our overall numbers are small and follow-up is limited (minimum, 3 months; mean, 8 months), most of the technical outcomes relevant to comparing these 2 procedures occur in the first 3 to 6 months after pancreas transplantation. It is also important to note that 26 patients (81%; all SKPT and PAKT recipients) received primary immunosuppression with tacrolimus, mycophenolate mofetil, and steroids without anti-lymphocyte induction.23,24 The remaining 6 PTA recipients (19%) received OKT3 induction in addition to the above triple regimen. Conceding the above limitations in study design, the patient, kidney, and pancreas graft survival rates were comparable between groups, and no immunologic graft losses occurred. All SKPT recipients experienced immediate renal allograft function, and all but 1 of the pancreas allografts had initial function (1 thrombosis). The 3 deaths that occurred in this series were cardiac in origin and probably related to preexisting cardiac disease with autonomic neuropathy. These deaths accounted for 5 (3 pancreas, 2 renal) of the 7 graft losses that occurred in this study. We have previously identified cardiac autonomic neuropathy as a risk factor for sudden death in patients with sustained autonomic dysfunction after pancreas transplantation.48 Immunologic and infectious morbidity were not significantly different between the 2 groups, although the incidences of acute rejection and urinary tract infections were higher in the S-B group. The rate of urologic complications was doubled in the S-B group, and 2 patients underwent enteric conversion during the period of follow-up. Conversely, multiple re-operations occurred in 2 patients with P-E, but there were none with S-B drainage. However, for each of these co-morbidities, the overall numbers were small and did not achieve significance. Surrogate markers of morbidity such as length of hospital stay and re-admissions were slightly higher in patients with S-B drainage. In addition, metabolic acidosis and dehydration were universal among patients with S-B drainage but occurred in less than half of cases with P-E drainage. In our experience, we have
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identified dehydration as the single most common cause for readmission after pancreas transplantation. Furthermore, many of these patients have severe gastroparesis, enteropathy, and autonomic neuropathy with symptomatic orthostatic hypotension. For these reasons, we have a low threshold for placing central venous catheters for intermediate-term (1-3 months) vascular access for either intravenous fluid or medication administration. These preliminary results suggest that whole organ pancreas transplantation with a standardized technique of P-E drainage can be performed with short-term results comparable to the conventional technique of S-B drainage. Depending on individual anatomy, the ability to perform either technique is comparable, and P-E drainage is not associated with an increased risk of either thrombosis or intra-abdominal infections. Although studies with more patients and longer follow-up are needed, both techniques should be included in the repertoire of pancreas transplantation. We thank Linda Bryant, Ginger Hoskins, and Jo Lariviere for their assistance and expertise in the preparation of this article. REFERENCES 1. Gruessner AC, Sutherland DER. Analysis of United States (US) and non-US pancreas transplants as reported to the International Pancreas Transplant Registry (IPTR) and to the United Network for Organ Sharing (UNOS). Cecka JM, Terasaki PI, editors. Clinical Transplants 1998. Los Angeles: UCLA Tissue Typing Laboratory; 1999. p. 53-71. 2. Nghiem DD, Corry RJ. Technique of simultaneous renal pancreatoduodenal transplantation with urinary drainage of pancreatic secretion. Am J Surg 1987;153:405-6. 3. Diem P, Abid M, Redmon JB, Sutherland DER, Robertson RP. Systemic venous drainage of pancreas allografts as independent cause of hyperinsulinemia in Type I diabetic recipients. Diabetes 1990;39:534-40. 4. Sollinger HW, Messing EM, Eckhoff DE, Pirsch JD, D’Alessandro AM, Kalayogou M, et al. Urological complications in 210 consecutive simultaneous pancreas-kidney transplants with bladder drainage. Ann Surg 1993;218:561-70. 5. Stratta RJ, Sindhi R, Sudan D, Jerius JT, Radio SJ. Duodenal segment complications in vascularized pancreas transplantation. J Gastrointest Surg 1997;1:534-44. 6. Sindhi R, Stratta RJ, Lowell JA, Sudan D, Cushing KA, Castaldo P, et al. Experience with enteric conversion after pancreatic transplantation with bladder drainage. J Am Coll Surg 1997;184:281-9. 7. Sollinger HW, Sasaki TM, D’Alessandro AM, Knechtle SJ, Pirsch JD, Kalayogou M, et al. Indications for enteric conversion after pancreas transplantation with bladder drainage. Surgery 1992;112:842-6. 8. West M, Gruessner AC, Metrakos P, Sutherland DER, Gruessner RWG. Conversion from bladder to enteric drainage after pancreaticoduodenal transplantation. Surgery 1998;124:883-93. 9. Kuo PC, Johnson LB, Schweitzer EJ, Bartlett ST. Simultaneous pancreas/kidney transplantation: a compari-
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dard technique utilizing bladder drainage of exocrine secretions. Transplantation 1996;62:1353-6. 45. Nymann T, Elmer DS, Shokouh-Amiri MH, Gaber AO. Improved outcome of patients with portal-enteric pancreas transplantation. Transplant Proc 1997;29:637-8. 46. Eubanks JW, Shokouh-Amiri MH, Elmer D, Hathaway D, Gaber AO. Solitary pancreas transplantation using the portal-enteric technique. Transplant Proc 1998;30:446-7.
Surgery February 2000 47. Bruce DS, Newell KA, Woodle ES, Cronin DC, Grewal HP, Millis JM, et al. Synchronous pancreas-kidney transplantation with portal venous and enteric exocrine drainage: outcome in 70 consecutive cases. Transplant Proc 1998;30:270-1. 48. Hathaway DK, El-Gebely S, Cardoso S, Elmer DS, Gaber AO. Autonomic cardiac dysfunction in diabetic transplant recipients succumbing to sudden cardiac death. Transplantation 1995;59:634-7.
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