FIGURE 73.1 Number of pancreas transplants worldwide tabulated by the International Pancreas Transplant Registry from 1966 to 2013.
FIGURE 73.1 Number of pancreas transplants worldwide tabulated by the International Pancreas Transplant Registry from 1966 to 2013.
Outcomes after pancreas transplants have consistently improved over the years (5,6). The latest report from the International Pancreas Transplant Registry (6) outlined recent results, focusing on U.S. transplants from 2009 through 2013, including more than 3,900 SPK, more than 500 PAK, and 389 PTA cases. Patient survival rates for all three categories was more than 95% at 1 year posttransplant (Fig. 73.7). Primary pancreas graft survival rates at 1 year posttransplant were higher for SPK (88.9%) than for PAK (84.4%) and PTA (81.5%) recipients (Fig. 73.8). Graft loss from rejection was low at 1 year in all three categories (1.7% SPK, 4.4% PAK, 5.5% PTA). In the majority of all transplants, ED was used for duct management, and of the ED transplants, portal venous drainage was used in about 20% of SPK and 10% of solitary transplants. Although overall graft function did not vary with ED or BD, the PTA group had a higher immunologic graft loss rate in ED versus BD cases. BD may result in earlier diagnosis of rejection because of the ability to monitor for a decline in urine amylase activity as a marker (28). Nevertheless, the late rejection rate is higher in the PTA than in other categories.
INDICATIONS AND CONTRAINDICATIONS
The indications for a pancreas transplant have evolved and expanded over the years as the results have improved. The position statement of the American Diabetes Association (58) on indications for a pancreas transplant (Table 73.1) is conservative. A pancreas transplant is also indicated for patients who have developed secondary complications of diabetes. The progression of complications is halted by a functioning pancreas graft. In fact, even an improvement in neuropathy has been documented (5,22,34,59,60). In addition to improvement in glomerular architecture, a recent study shows that interstitial expansion is reversible, and atrophic tubules can be reabsorbed (61). Advanced retinopathy and vascular disease, however, are unaffected (62). Atherosclerotic risk factors decrease and endothelial function improves posttransplant (63). A pancreas transplant should be offered early, before the onset of complications of diabetes, to interested patients who understand the risk of immunosuppression versus the benefit of insulin independence and freedom from diabetic complications.
|TABLE 73.1 Summary of American Diabetes Association (ADA) Recommendations for Indications for Pancreas Transplants|
Contraindications include those for any other transplant, such as malignancy, active infections, noncompliance, serious psychosocial problems, and prohibitive cardiovascular risk. Candidates with advanced vascular disease have an increased risk of surgical complications, yet those who do well posttransplant greatly benefit from stabilization of their cardiovascular risk.
Although it was clear that insulin-dependent recipients with renal failure benefited from a pancreas transplant in addition to the kidney, the survival benefit for pancreas transplant in patients with preserved renal function was questioned by at least one study (64). However, a more comprehensive reanalysis revealed that there was no increased mortality for solitary pancreas transplant recipients over wait-listed patients (65,66).
The pretransplant workup should include a detailed medical and psychosocial evaluation. Cardiac risk assessment is mandatory because diabetes is a major risk factor for coronary artery disease (CAD). Cardiologists vary on the type of test to screen for CAD in pretransplant diabetic patients. Coronary angiograms are performed in most candidates. Noninvasive tests are not very sensitive for CAD and poorly predictive for subsequent postoperative events in long-standing diabetic patients (67,68). With the use of iso-osmolar radio contrast, there does not seem to be an increased risk of contrast-induced nephropathy in patients with chronic kidney disease (69). In selected patients (i.e., young, healthy patients with short-duration diabetes), dobutamine stress echocardiograms are used for cardiac evaluation with good results (70). Once significant CAD is detected, aggressive treatment by revascularization, angioplasty, or stenting is recommended. In one study, revascularized transplant candidates had significantly fewer postoperative cardiac events, as compared with those who received medical therapy alone (71).
A detailed vascular examination must be done to rule out significant vascular insufficiency. If such insufficiency is found, it may need correction pretransplant because the transplant surgery, involving an anastomosis to the iliac artery, may further diminish lower-extremity blood flow. Pulmonary function tests are indicated in chronic smokers and patients with a history of chronic pulmonary disease. Postoperative intensive care unit monitoring and perioperative bronchodilator therapy may be indicated in some patients. Liver function tests should be done to rule out hepatic insufficiency and viral hepatitis. The diagnosis of viral hepatitis (either B or C) is associated with worse long-term outcome after extrahepatic transplantation (72). Abnormal liver function tests or the diagnosis of viral hepatitis should be followed up with a liver biopsy to rule out cirrhosis. The presence of cirrhosis is a contraindication for pancreas transplant. A gastrointestinal evaluation must be done to rule out autonomic dysfunction. Some immunosuppressive medications may worsen gastrointestinal dysfunction. A prokinetic agent may be indicated to treat gastroparesis. A urologic examination is especially important for BD recipients because bladder dysfunction predisposes to graft pancreatitis.
DECEASED DONOR SELECTION
Pancreas donor selection criteria are not standardized, but instead vary from center to center. Absolute contraindications are the obvious ones applied to most solid organs: active hepatitis B, C, and non A–non B; human immunodeficiency virus; non–central nervous system (CNS) malignancy; surgical or traumatic damage to the pancreas; history of diabetes mellitus; pancreatitis; and extremes of age (younger than 10 or older than 60 years). Prolonged intensive care unit stay and duration of brain death have been associated with an increased risk of graft failure (73). Other studies have shown that donor age is important; even middle-aged donors (older than 40 years) are associated with increased complications and graft failure (73–75). However, the so-called marginal donor organs are associated with good outcome if the pancreas, on inspection, is found to be “healthy” in appearance (76,77).
Donors after cardiac death (DCD) are being used increasingly to expand the donor pool. However, there may be a higher rate of early organ dysfunction with these donors (78). A recent survey showed equivalent patient and graft survival at 1, 3, and 5 years in SPK transplant recipients from DCD compared with donors after brain death (78).
UW solution was first used for pancreas preservation in a preclinical model in 1987 (79). As with most solid organs, in vivo flush followed by simple storage in cold UW solution is the standard for pancreas preservation. In the original model, pancreases were preserved for up to 96 hours (80). In clinical transplantation, pancreas cold preservation exceeding 24 hours has been associated with increased graft dysfunction (81). Even when there is less than 24 hours, it has been shown that the longer the cold ischemia time, the greater the technical complication rate (82). Therefore, every effort should be made to minimize the cold ischemia time in order to optimize graft function and to lower complication rates. Recent data suggest a new method of preservation that may be advantageous: the two-layer method using UW solution and perfluorochemical (83). This method allows for longer preservation time while providing a mechanism for repair of ischemic damage due to cold storage (84–86). More clinical trials are needed before the two-layer method becomes routine.
Recently, histidine-tryptophan ketoglutarate solution has been increasingly used in pancreas transplantation (87). Advantages include lower viscosity, less potassium, and lower cost. Early outcome studies do not show inferiority compared to the more expensive UW solution (88,89).
HUMAN LEUKOCYTE ANTIGEN MATCHING
The impact of human leukocyte antigen (HLA) matching on outcome varies. It is generally accepted that HLA matching has little effect on graft outcome for the SPK category (90,91), although higher rejection rates have been reported with poor matches (92–94). For solitary pancreas transplants (PAK and PTA), the data are mixed, ranging from studies showing no impact (95) to registry data showing that HLA A and B matches have a significant impact (91). At the University of Minnesota, SPKs are done regardless of HLA match; for PAKs, generally at least one antigen in the B locus matches, and for PTAs, at least one antigen in each of the A, B, and DR loci matches.
A patient with brittle diabetes and secondary complications (e.g., CAD, autonomic neuropathy) can pose special problems for the anesthesiologist. Dysautonomic response to drugs or hypoxia can lead to significant morbidity and even death (96). It has also been documented that long-standing diabetes poses a challenge to the anesthesiologist during intubation (97). Awareness of these risks and employment of an experienced anesthesiology team might help decrease the risks or morbidity. A major operation such as a pancreas transplant or combined kidney–pancreas transplant is often prolonged and can be associated with significant blood loss. Prompt replacement with blood or colloids should be instituted to avoid hypoperfusion after significant blood loss. Before and after revascularization of the pancreas, careful blood glucose monitoring, along with continuous intravenous (IV) insulin therapy to maintain tight control of blood glucose levels, is essential. Perioperative β-blockade should be considered for long-standing diabetic patients with a cardiac history.
BACK-TABLE PREPARATION OF THE DONOR PANCREAS
Once the donor pancreas has been opened in the recipient operating room, some back-table work is necessary to prepare it for the transplant, including these steps (98):
- Donor splenectomy (taking care to avoid injury to the pancreatic tail)
- Trimming down of the donor duodenum to the shortest length without damage to the main or accessory duct (especially important with BD to minimize bicarbonate loss)
- Oversewing or individual vessel ligation of the mesocolic and mesenteric stumps on the anterior aspect of the pancreas
- Excision of lymphatic and ganglionic tissue in the periportal area
- Reconstruction of the splenic and superior mesenteric arteries with a Y graft of the donor iliac A bifurcation (to provide for a single arterial anastomosis in the recipient).
Several techniques have been described for the recipient operation (32,99). The techniques vary based on whether a solitary pancreas transplant (PTA, PAK) or a combined transplant (SPK) is done.
Solitary Pancreas Transplant
Choice of Exocrine Secretion of the Pancreas—Drainage of Bowel or Bladder?
Currently, for pancreas transplants in the United States, 86% of PAK, 79% of PTA, and 87% of SPK transplants are drained enterically (5,6). ED is more physiologic and does away with the complications of BD (e.g., acidosis, pancreatitis, urinary infections, hematuria). Between 10% and 20% of BD recipients are ultimately converted to ED because of such complications once they are 6 to 12 months posttransplant and their rejection risk is lower. BD, however, allows for direct measurement of urinary amylase as a marker of exocrine function. A decrease in urine amylase is sensitive, but not very specific, for acute rejection of the pancreas (100,101). Hyperglycemia is a late event in the rejection, and a decrease in urine amylase occurs early. Thus, rejection episodes are detected early with BD, and the rejection loss rate is lower with BD than with other techniques (55). In clinical practice, the choice of exocrine drainage varies. Some groups always use ED, while some always use BD (101,102). Others base it on the individual recipient’s immunologic risk versus the risk of urologic complications (28). The surgical risks and short-term outcome with both techniques are comparable (74,103). ED is likely to predominate as the major technique in the future as immunologic strategies to eliminate rejection are developed (102).
Choice of Venous Drainage—Portal or Systemic?
Currently in the United States, of all ED transplants, 20% of SPK, 10% of PAK, and 12% of PTA cases are drained to the portal vein (5,6). Portal drainage is more physiologic than systemic drainage (104,105). Theoretically, portal drainage preserves the first-pass metabolism of insulin in the liver. Therefore, portally drained recipients will have lower systemic insulin levels (106). However, there is no evidence of any detrimental effect on lipid levels (107) or on risk of vascular disease (62) as seen in de novo hyperinsulinemia (syndrome X). Portal venous drainage is difficult to perform with exocrine BD (45). Portal drainage had gained in popularity after initial reports that rejection rates are lower in this category (103,108). It appears, however, based on registry data (5,6) that the immunologic advantage is much smaller than initially found. Recent modifications include a retroperitoneal portal-ED technique (109).
Transplantation Portion—Whole Organ or a Segment?
Almost all cadaveric pancreas transplants performed today use whole-organ grafts. Segmental grafts have little role to play in this group, except when a rare anatomic abnormality is noted such that the head of the pancreas cannot be used. A rare instance of a split cadaveric pancreas transplanted into two different recipients has been described (110). All living-donor pancreas transplants use segmental grafts (body and tail); doing so maintains normoglycemia in the recipient (12).
SPK transplants have a lower rejection rate than do solitary pancreases. Further, rejection episodes are rarely isolated to the pancreas alone. Most pancreas rejection episodes can be indirectly detected by monitoring serum creatinine as a marker for kidney rejection. Therefore, most SPK transplants are done using ED, as advocated by the Stockholm group (111) (Fig. 73.5). With ED, the risk of acute technical complications is slightly higher, but the chronic complication rate is lower (112). Choice of venous drainage varies by center. Because ED is the choice for exocrine drainage, there is no impediment to performing portal venous drainage.
After an uncomplicated pancreas transplant, the recipient is transferred to the postanesthesia care unit (PACU) or the surgical intensive care unit (SICU). Centers that have a specialized monitored transplant unit (with central venous and arterial monitoring capabilities) transition the postoperative recipients through the PACU to the transplant unit. Others transfer directly to the SICU for the first 24 to 48 hours. Care during the first few hours after transplant is similar to care after any major operative procedure. Careful monitoring of vital signs, central venous pressure, oxygen saturation, and hematologic and laboratory parameters is crucial. The factors below are unique to pancreas recipients and should be attended to.
Blood Glucose Levels
Any sudden, unexplained increase in glucose levels should raise the suspicion of graft thrombosis. An immediate ultrasound examination must be done to assess blood flow to the graft. Maintenance of tight glucose control (<150 mg/dL) using an IV insulin drip is important to “rest” the pancreas in the early postoperative period.
Because the pancreas is a “low-flow” organ, intravascular volume must be maintained to provide adequate perfusion to the graft. Central venous pressure monitoring is used to monitor intravascular volume status. In some cases, such as patients with depressed cardiac function, pulmonary artery catheter monitoring may be required during the first 24 to 48 hours. If the hypovolemia is associated with low hemoglobin levels, then washed packed red blood cell transfusions should be given. Otherwise, colloid or crystalloid replacement can be used.
Maintenance IV Fluid Therapy
The choice of IV fluid is usually 5% dextrose in 0.45% saline solution. The use of dextrose is not contraindicated and may be of benefit, as long as IV insulin is used to maintain good blood glucose control. In SPK recipients, whose IV rate is based on urine output, dextrose should be eliminated if the urine output is high (>500 mL/hr). Maintenance solution for BD recipients should include 10 mEq of HCO3 added to each liter to account for the excess HCO3 loss (113,114); sodium lactate can be used as an alternative (115).
Broad-spectrum antibiotic therapy (with strong gram-negative coverage) and antifungal therapy are instituted before the incision is made in the operating room, then continued for 3 (for antibiotics) and 7 days (for antifungal). At the University of Minnesota, since the introduction of this protocol, we have noted a decrease in postoperative abdominal infections (74). Cytomegalovirus (CMV) and antiviral prophylaxis are similar to that for other solid organs.
The use of octreotide in pancreas recipients helps reduce the incidence of technical complications (116). This benefit should be weighed against evidence from rat studies that shows decreased pancreatic islet blood flow with octreotide use (117), although clinically no detrimental effects of octreotide use have been documented. A dose of 100 to 150 μg IV or subcutaneously three times a day is administered for 5 days posttransplant. Dose adjustments may be made for nausea, which is the predominant side effect.
The use of low-dose heparin in the early postoperative period (days 0 to 5) decreases the risk of graft thrombosis (118). An intraoperative dose of 70 units/kg is given, followed by an IV infusion of 3 units/kg started at 4 hours postoperatively and gradually increased up to 7 units/kg (depending on hemodynamic stability and hemoglobin levels). Enteric-coated aspirin (80 mg) is started on day 1 and continued for 6 months. At the University of Minnesota, this protocol decreased the thrombosis rate from about 12% to 6%, but increased the relaparotomy rate due to bleeding from 4% to 6%. Segmental pancreas transplants (as in living-donor transplants) have a higher thrombosis risk and therefore therapeutic heparinization (with a target-activated partial thromboplastin time [aPTT] of 50 seconds) for 5 days and Coumadin therapy (with a target international normalized ratio [INR] of 2 to 2.5) are recommended for 6 months. The higher risk of thrombosis is due to the smaller vessels in a segmental graft (119,120).
Immunosuppression is essential to thwart rejection in all allotransplant recipients (17). Before the advent of cyclosporine in the early 1980s (121), azathioprine and prednisone were the mainstays of immunosuppression. From the early 1980s to the mid-1990s, cyclosporine was added to the mix and resulted in significant improvement in immunologic outcomes (122). Since the mid-1990s, tacrolimus and mycophenolate mofetil have replaced cyclosporine and azathioprine as the main drugs, resulting in even better pancreas graft survival rates (122–124). In addition, steroids have been successfully withdrawn from some pancreas recipients (125) and, in some cases, avoided (126). With a recently introduced drug, rapamycin, used in combination with tacrolimus, steroids have been successfully avoided in some pancreas recipients (127,128).
Anti–T-cell therapy has always remained a part of the induction protocol for pancreas recipients. With the recent emphasis on steroid withdrawal or avoidance, anti–T-cell therapy has taken on added importance to avoid rejection. Anti-CD25 antibodies are also used frequently as induction therapy (129). Avoidance of calcineurin inhibitors has been attempted in pancreas transplantation. When combined with steroid avoidance, this required prolonged anti–T-cell therapy, which increases the risk of infection without adequately controlling rejection (130). Table 73.2 presents the immunosuppressive protocol for pancreas transplant recipients at the University of Minnesota.
For PTA recipients, whose rejection rates are the highest of all categories, pretransplant immunosuppression has decreased rejection rates and graft loss from rejection (31). Heavy use of immunosuppression may increase the infection rate, but effective antimicrobial prophylaxis has helped ameliorate this problem (131,132).
|TABLE 73.2 University of Minnesota Standard Immunosuppression Pancreas Program|