Chronic pancreatitis results in irreversible morphologic and functional changes in the pancreas from persistent or recurrent inflammation. Although an uncommon disease in childhood and adolescence, with an incidence of 4 to 13 cases per 100,000, the incidence of chronic pancreatitis in children is comparable to that seen in adults. The general concepts regarding presentation and management of this disease are well covered in Chapter 82 . The clinical presentation and course of chronic pancreatitis are similar to that seen in adults. Thus, the presentation in younger years is also one of abdominal pain, and definitive management focuses on elimination of pain to improve quality of life. There is a particular form of idiopathic chronic pancreatitis, termed tropical pancreatitis, which can present as recurrent abdominal pain in adolescence and occurs in endemic regions. An important consideration in management should focus on causes of pancreatitis that can be eliminated to avoid ongoing inflammation. The etiology of pancreatitis is of particular interest when considering the differences between adult and pediatric patients. In adults, the principal causes are alcohol use and biliary tract disease, whereas in children hereditary and idiopathic causes predominate, especially in patients who require surgery. Pancreatitis in children includes a preponderance of patients with trauma and congenital anatomic variations including pancreatic divisum, annular pancreas, and choledochocysts. The natural history of chronic pancreatitis would be of great interest in the pediatric population. The conflicting outcome variables of possible interest would include eventual relief of pain as a consequence of so-called “burn-out” versus the risk of developing narcotic dependence and the development of irreversible exocrine and endocrine insufficiency during the period of medical management. These competing outcomes are expected to likely play out over the course of a longer life expectancy in children than in the adult population. The natural history data for chronic pancreatitis in adults are illustrative for their shortcomings. The results from some European centers that have tried to investigate the long-term success of complete pain relief with medical management alone have not been confirmed elsewhere. Data from these centers suggest that any sustained pain relief for chronic pancreatitis requires decades to achieve, requires removal of the initiators of pancreatitis (alcohol in adults), is likely dependent on the type of pancreatic pain experienced (type A vs type B), and will occur predominantly at only the expense of addiction and complete functional insufficiency. This has not led to a groundswell to treat adults with medical therapy alone where durable pain relief without substantial quality of life consequences has been the general experience of patients and experienced treating physicians. The differences in etiology are of importance when considering the natural history. In adults, the major causes of chronic pancreatitis are potentially mutable, especially the elimination of alcohol. In the pediatric population, the most common causes of chronic pancreatitis cannot be altered because they include idiopathic and hereditary etiologies. Chronic idiopathic pancreatitis when it develops in juveniles may be characterized more frequently by early onset of severe type of pain but with better preservation of pancreatic function over time compared to adults. Hereditary pancreatitis is better characterized and is of greater concern for long-term consequences. Multiple germline mutations have been determined to cause pancreatitis, with the most common being a mutation in the cationic trypsinogen gene ( PRSS1 ) which has a penetrance of greater than 90%. The median age of symptom onset in hereditary pancreatitis is 10 years, yet the median age of diagnosis is at 19 years. There are no clinical or morphologic differences in patients with hereditary chronic pancreatitis, but half will ultimately die of pancreatic adenocarcinoma. Long-term follow-up of patients with hereditary pancreatitis is important when considering total pancreatectomy and islet autotransplantation in terms of β-cell function. Chronic pancreatitis in children is rarely complicated by diabetes, which is present in only 5% of patients. With hereditary pancreatitis, 5% of patients will develop diabetes by 10 years after onset of symptoms and 18% by 20 years. Therapeutic interventions, endoscopic or surgical, should be considered when an accurate diagnosis has been established, and significant alterations in quality of life are occurring, which in children includes inability to remain in school. In children, narcotic dependence is not required as a criterion, and intervention to prevent addiction is advisable. Long-term success with endoscopic therapy has been demonstrated in selected patients, including in the pediatric population. Patients with pancreatic divisum have shown reintervention for pain in 39% and no need for surgical salvage in 48 patients followed for a median of 67 months. Similarly, endoscopic stenting specifically in pediatric patients has shown an 81% improvement in pain and subsequent surgery in 12% at a median follow-up of 61 months, although objective measures of pain assessment were lacking.
There are numerous surgical options available to treat patients who have failed to respond to medical management of chronic pancreatitis. The plethora of surgical options should highlight the need to tailor the appropriate operation for each patient, and is not a reflection of uncertainty as to how to surgically manage the disease, including in children. All surgical options available in adults are options for the pediatric population, and entail one of two categories: resectional or drainage. The drainage procedures are aimed at decompressing the ductal system either by ablating any sphincter obstruction or surgical bypass to the duct directly. Surgical procedures of the sphincter include both the minor or major ampullae; the former is classically associated with pancreatic divisum, and the latter with sphincter of Oddi dysfunction. Endoscopic sphincterotomy has substantially reduced the frequency of surgical sphincteroplasty, although surgery may still be necessary for recurrent stenosis post endoscopic drainage, or when the orifice is too small to allow access for endoscopic therapy. Paramount in determining if a patient is a candidate for surgical therapy directed at a sphincter is the character of the pancreatic duct and length of sphincter stenosis. Multiple strictures in the main duct will not respond to sphincter-directed procedures alone, thus the length of obstruction at the sphincter must be short. The length of obstruction and diameter of the dorsal duct are critically important for therapy directed at the minor sphincter where it enters the duodenum at a right angle making entry difficult without coring out the sphincter complex. The maximal size of the opening is no larger than the diameter of the duct. In properly selected patients, the results of surgical sphincteroplasty are acceptable, making it an appropriate initial operative approach for some pediatric patients with pancreatic divisum. Decompression by suturing the main pancreatic duct, with or without incorporating a chronic pseudocyst, is more commonly done and includes lateral longitudinal pancreaticojejunostomy (Partington-Rochelle modification of the Puestow procedure). The modified Puestow procedure is the most frequently decompressive procedure, including in children, and is applicable to patients with firm fibrotic glands with a dilated duct due to multiple strictures without an inflammatory mass. Initial results from this operation in children are good, but long-term pain control is difficult to assess due to both poor and unbiased follow-up. In some series, follow-up is absent in half of the cohort of operated patients. At best, pain relief is achieved in 50% to 80% of patients, and this result is better than what can be achieved in comparable patients managed with endoscopic therapy. Unfortunately, should duct decompression fail and total pancreatectomy with islet autotransplantation (TP-IAT) be required, the islet yield and therefore the likelihood of insulin independence are significantly impaired. In pediatric patients, endoscopic treatment is associated with more admissions for recurrent pancreatitis, with comparable pain response compared to a tailored surgical approach. Resectional treatment inherently includes a component of ductal decompression, but some component of parenchymal loss is inherent. These procedures involve a proportional loss of the body and tail of the gland, or the pancreatic head. The most limited type of pancreatic resection is the Duvall procedure, wherein a small portion of the tail is removed and the remaining gland is sutured to a defunctionalized limb of jejunum principally for ductal drainage. This procedure is done infrequently, but may be indicated for distal outflow obstruction where the duct is uniformly dilated and a sphincteroplasty is not technically achievable. Distal pancreatectomy up to and including subtotal pancreatectomy can be considered for focal pancreatitis of that portion of the gland. Focal pancreatitis is not a common indication for distal pancreatectomy. In one series, only 12% of patients undergoing distal pancreatectomy had the procedure for that indication, which resulted in a substantial loss of gland volume. Expected loss of insulin secretion from 50% to 55% is expected for major resections of the pancreas, either body or head. Pancreatic head resections involve complex operations that either preserve the duodenum (Beger, Bern, or Frey procedures) or remove the duodenum and distal bile duct (Whipple procedure). All remove an inflammatory head mass, considered to be the location responsible for the elicitation of pain, the “pancreatic pain pacemaker.” They all achieve excellent pain relief in patients with head-centric disease, and the Whipple procedure removes areas secondarily affected such as duodenal and biliary strictures. These procedures have been used in appropriately selected children with chronic pancreatitis.
The ultimate option for management of pancreatic pain in chronic pancreatitis is total pancreatectomy. This has the advantage of removing completely the offending source of pain and leaves no potential for recurrent disease. Clearly irrevocable, it has immediate and long-term consequences. Fortunately the operative consequences of total pancreatectomy have improved so that it is comparable to pancreaticoduodenectomy (Whipple procedure), but the long-term metabolic morbidity of metabolic bone disease, exocrine, and endocrine insufficiency appropriately cautions its application. The major endocrine insufficiency of diabetes mellitus in the setting of no islet cell mass is meant to be ameliorated by the use of islet-auto beta-cell transplantation. Although the clear indication for total pancreatectomy and auto-islet transplantation is to improve quality of life through pain reduction and return to normal activity, this is supplemented by return of islet cell mass, which may prevent the onset of diabetes or improve glucose control by some insulin production.
Paramount in importance is proper patient selection, particularly in affected children with chronic pancreatitis, where decisions regarding their long-term success in medical management of chronic pancreatitis and durability of islet cell function are incompletely known. A multidisciplinary team assessment of prospective candidates is ideal, and at the Cleveland Clinic, this includes involvement of the primary treating physician or pediatrician, gastroenterologist, surgeon, clinical psychologist specializing in chronic pain, and endocrinologist. A decision to proceed with TP-AIT assumes consensus by all members of the team as well as the patient and family. Although the chief indication is for pain relief, it is important to realize that degree of symptoms does not clearly correlate with morphologic changes in the pancreas. Indeed, patients who are typically candidates for this procedure have “minimal change pancreatitis,” which belies their incapacitation and frequent hospitalizations despite a clear lack of radiologic abnormalities. Minimal change pancreatitis can therefore be difficult to diagnose and requires an appreciation of the entity, as well as investigational tests beyond endoscopic retrograde cholangiopancreatography (ERCP), magnetic resonance cholangiopancreatography (MRCP), and computed tomography (CT) imaging, which may not be as commonly available as endoscopic ultrasound (EUS) and pancreatic function testing. EUS allows the identification of specific parameters used to grade the extent of chronic pancreatitis in a reproducible manner and is less dependent on subjective interpretation. EUS findings include hyperechoic parenchymal foci, strands, hypoechoic lobules, cysts, main duct irregularity, ductal dilation, hyperechoic duct walls, visible side branches, and calcifications. The standard diagnosis of chronic pancreatitis is made when five of these nine features are found. Some authors believe a better sensitivity to specificity balance to diagnose minimal change chronic pancreatitis may require finding only three of the nine features. Pancreatic function testing is aimed at quantifying pancreatic bicarbonate secretion into the duodenum with secretin stimulation. This has progressed at our institution to endoscopic duodenal aspiration, and a bicarbonate level of less than 80 mEq/L is suggestive of exocrine dysfunction. Supportive objective data are valuable in making the diagnosis of minimal change chronic pancreatitis that must also be supported by clinical features of chronic pancreatic type pain. This may be difficult in the pediatric population where the incidence of chronic pancreatitis is low and familiarity with the disease is uncommon. The indications for TP-IAT in patients with chronic pancreatitis are the same in children as in adults, with pain being responsible for all reported cases to date. There is a heightened need to correctly identify pediatric patients for consideration of all surgical options, since the associated narcotic dependence can impair normal growth and development as well as important childhood activities such as school attendance. It may be difficult to know what time frame prior to surgical intervention is appropriate, but the reported median time to surgical intervention in pediatric patients is 4 years. Patients who have failed to respond to prior surgical treatment are candidates for TP-IAT, given the understanding that the islet yield is less than that for an unaltered gland. A key factor in selecting patients for TP-IAT is assessing the extent of islet dysfunction. Patients with diabetes are candidates for the operation, providing their beta cell mass is sufficient to produce C peptide.
Surgical Procedure of Total Pancreatectomy
There have been various approaches to the pancreatectomy for TP-IAT, which deal primarily with the extent of pancreatic resection and length of duodenum removed. Initial enthusiasm to preserve a small rim of pancreatic head has been supplanted at most centers with complete gland removal and removal of some portion of the duodenum. This ensures no possibility for recurrent symptoms, and does not compromise the perfusion of the duodenum, which is interrupted with division of the pancreaticoduodenal arterial arcade. To reduce the length of warm ischemia time, the gland is mobilized completely without dividing any of the major blood supply ( Figure 83-1 ). Thus, the division of the uncinate process, and division of the gastroduodenal and splenic arteries constitute the final steps of the resection. Precise hemostasis is important throughout the resection, since full heparinization will be necessary at the time of re-infusion of the islet cells. Some centers have favored a limited resection of the duodenum to preserve local endocrine interactions, whereas most have performed complete duodenal resection with or without maintaining the pylorus. Splenic preservation has not been a common feature of the operation, but it may be of greater importance in pediatric patients. The main splenic artery and vein are often densely adherent to the pancreas in advanced forms of chronic pancreatitis, and therefore are not often able to be safely removed from the gland. The need to avoid prolonged warm ischemia may also limit the enthusiasm for the tedious dissection of small vessels from the pancreatic body and tail. Preservation of the spleen is therefore typically done where the main vessels are sacrificed at the hilum and the spleen is meant to survive on the short gastric vessels. This can lead to immediate ischemia requiring removal or delayed complications such as gastric varices and splenic abscesses. Reconstruction following resection requires reconstitution of the gastrointestinal tract by advancement of the jejunum to the duodenum or stomach, and a bile duct to jejunum anastomosis. Feeding tube access is favored by most groups, since many of these patients have nutritional deficiencies and altered motility, and can be accomplished by nasojejunal or jejunostomy tube.
Islet Isolation and Reintroduction
Islet purification must be performed in a U.S. Food and Drug Administration (FDA)–approved biolaboratory under sterile conditions and quality control measures for processing of human tissues. The pancreas undergoes both enzymatic and mechanical digestion to yield islet isolates. Enzymatic digestion is the first step, with collagenase infused under pressure into the main pancreatic duct ( Figure 83-2 ). This initiates tissue digestion and dissolution of the intact gland. This process is continued in an isolation chamber until the islets are separated from acinar tissue, as detected by dithizone staining ( Figure 83-3 ). The extent of islet purification is imprecise. A balance must be achieved between purifying the islets away from surrounding tissue to reduce the volume of the infusate and lessen the thrombogenic particulate matter versus reducing the absolute number of islets with successive purification cycles. Up to 40% of islet cell mass can be lost during purification, which tempers the enthusiasm for extended purification. Most centers further purify the islet preparation if the crude tissue digest exceeds 15 cc. Before transplantation, islet preparations are suspended in a 50:50 solution of 20% human serum albumin and transplant media, and antibiotics are added.
Islets preparations are currently introduced into the liver via the portal venous system to achieve islet engraftment ( Figure 83-4 ). The major complications of this route of access are portal hypertension, venous thrombosis, and infarction. Intrasplenic, renal capsule, peritoneal cavity, and omental transplantation have been attempted experimentally to reduce the incidence of these complications, but have not been successful in humans. The current methods used to reduce these complications include limiting the volume and rate of infusion, and transient heparinization (70 mg/kg). There are multiple routes to access the portal system; these include catheterization of the splenic vein, mesenteric vein, umbilical vein in the falciform ligament, and transhepatic direct portal puncture. Most centers, including our own, favor portal reinfusion via a major portal branch at the time of laparotomy, either during the same or subsequent operation depending on the time of islet purification and transport. The portal pressures must be monitored periodically throughout the infusion, and should not exceed 25 to 30 cm of water.
Results of Islet Autotransplantation
Total pancreatectomy and islet autotransplantation was first successfully performed at the University of Minnesota in 1977 for a patient with chronic pancreatitis. The patient recovered from the operation, and lived a pain-free, insulin-independent life for 6 years, which spurred interest in the procedure as well as the outcomes. Outcomes of interest would include surgical morbidity, islet graft function, and improvement in pain and quality of life. Operative mortality rates of 0% to 4% have been reported for TP-AIT, with a current 5-year survival rate of 93%, both for adults and children. Most series report a major operative complication rate of between 15% and 25%, and one comprehensive series reports a complication rate of 56% in 27 patients, but no perioperative mortality. This would be similar to large series of patients undergoing pancreaticoduodenectomy for any indication where operative mortality is rare, but complications are frequent, even at high volume centers. Operative variables notable from several centers performing TP-AIT are summarized in Table 83-1 .
| Center | Minnesota | Leicester | Cincinnati |
|---|---|---|---|
| Operative duration (hours) | Mean 9 (1- to 1.5) | Median 8 (4 to 11) | Mean 9 (5 to 12) |
| Blood loss (mL) | Median 2000 | Median 400 | Mean 563 |
| Length of stay (days) | Median 25 (9 to 82) | Median 20 (8 to 144) | Mean 15 (5 to 40) |
| Major complication (%) | 25 | 15 | 18 |
| Mortality (%) | 2 | 4 | 4 |
| References | Sutherland 2008 | Garcea 2009 Clayton 2003 | Ahmad 2005 |
Autotransplantation of islets recovered from the resected pancreas aims to preserve a proportion of beta-cell mass and result in endogenous insulin production. The success and durability of the transplanted islets is therefore of great interest. It would appear intuitive that a higher number of islets transplanted correlates with insulin independence, and this indeed is generally found. This correlation is not straightforward, or linear, as long-term insulin independence has been demonstrated in patients who received as few as 882 islet equivalents per kilogram body weight (IEQ/kg). Although not as high as what can be achieved by harvesting allo-islets, the islet yields for auto-islets are robust; the current median transfused islets transplanted across multiple sites range from 2245 to 6635 IEQ/kg ( Table 83-2 ). The largest experience from the University of Minnesota showed that islet function as defined by partial or total insulin independence was significantly correlated with islet yield ( p < 0.05). Recipients with yields less than 2500 IEQ/kg showed islet function at 1 year in 32% of patients, those with yields of 2501 to 5000 IEQ/kg were functioning in 79% of patients, and those with yields greater than 5000 IEQ/kg showed function in 86% of patients. As suspected, insulin independence also correlated with C-peptide levels at 3 to 12 months posttransplantation with mean levels of 3.9 ± 1.5 ng/mL in insulin-independent subjects and 2.7 ± 1.3 ng/mL in those with partial graft function ( p = 0.017). Recent follow-up data from the Minnesota Group show at 3-year follow-up insulin independence in 30%, partial function in 33%, and insulin dependence in 37%. The outcomes in children treated at Minnesota are better compared to adults. Representing 13% of their total TP-IAT experience, the 1-, 5-, and 10-year patient survival rates are 98%, 98%, and 79%. Islet function in children showed that at 3 years, 55% are insulin dependent. The proportion of patients achieving insulin independence was higher in preadolescent patients; 68% of children younger than 13 years of age were insulin independent. Islet yield greater than 2000 IEQ/kg was an important predictor of pediatric insulin independence. A longer duration of disease (>7 years), moderate to severe fibrosis, and severe acinar atrophy were associated with lower islet yield in children, highlighting the need to appropriately select patients by disease and age. Insulin independence of 29% at a median follow-up of 9 months has been shown in adolescents treated in Cincinnati. No single factor is predictive of insulin independence. A combination of preoperative factors can predict islet mass and increased insulin independence following IAT: normal fasting glucose level, peak stimulated C-peptide greater than 4 ng/mL with Mixed Meal Tolerance test, and no prior history of Puestow procedure.
| Center | Minnesota | Leicester | Cincinnati |
|---|---|---|---|
| Number of Patients | 173 | 50 | 45 |
| Islet yield (median IEQ/kg) | 1977-1990: 1375 (49 to 12,470) 1990-2007: 3588 (23 to 17,035) | 2245 (405 to 20,385) | Insulin independent: 6635 ± 229 Insulin dependent 3799 ± 629 |
| Glucose control | Insulin independence 32% Partial dependence 33% | Insulin independence: 24% C-peptide positive: 100% | Insulin independence 40% |
| Factors influencing outcome | Islet function correlates with islet mass (IEQ/kg) p < 0.05 | Nonsignificant trend for increased insulin requirement over time | Higher IEQ/kg islet shows insulin independence p = 0.04 |
| References | Sutherland 2008 | Garcea 2009 Webb 2008 | Ahmad 2005 |
The ability to achieve relief of chronic pain is a critical outcome variable. There are many factors that can affect this outcome such as duration and etiology of disease, etiology of pain in chronic pancreatitis, and confounding opioid-induced hyperalgesia. Objective measures of pain response are often poorly studied in retrospective series of surgical patients treated for chronic pancreatitis. Common parameters studied that can give some measure of success include opiate requirements and pain scores. These results are summarized in Table 83-3 . Fortunately, improvement in pain, whether measured as a global assessment, mean morphine equivalents required, or by pain scales, show improvement across multiple sites. Improvement in pain results was seen in the Cincinnati group to be associated with time from surgery; patients likely require at least 6 months to wean from their narcotics. They also demonstrated in adolescents followed for a median of 9 months that 79% were narcotic independent. Objective pain scale measurements all show significant reductions in pain. In pediatric patients undergoing TP-IAT, 61% had discontinued all narcotic pain medication, with 67% reporting no pain symptoms and 27% reporting pain improvement postoperatively. In addition, 80% were able to attend school or work, and 73% reported their overall quality of life as excellent or good. Similarly, objective measures of quality of life are important to quantify. Significant improvements have clearly been demonstrated following TP-IAT. This has also been realized in the pediatric population, although the data are incomplete due to lack of follow-up of patients.
| Center | Minnesota | Leicester | Cincinnati |
|---|---|---|---|
| Number of Patients | 112 | 50 | 45 |
| Opiate requirement |
| 16% require opiates at 60 months |
|
| Pain score |
|
|
|
| References |
| Garcea 2009 | Ahmad 2005 |
It appears apparent that total pancreatectomy with auto-islet transplantation is an appropriate treatment for highly selected adult patients with chronic pancreatitis. This similarly appears appropriate in pediatric patients with chronic pancreatitis, although the data are preliminary. Total pancreatectomy is effective in reducing pain and dependence on opioid analgesia in patients with chronic pancreatitis. The addition of an islet-cell transplant results in reduction in exogenous insulin requirements, as well as potential insulin independence.
Whole Organ Pancreas Allotransplantation
Whole organ and isolated islet allotransplantation remain largely theoretical options for children with either type 1 diabetes mellitus or acquired insulin dependent diabetes mellitus secondary to chronic pancreatitis or other diseases. The safety and success of both of these therapies continue to limit their use. Both therapies subject the patient to the potential risks of long-term immunosuppression, and although whole organ pancreas transplantation can provide long-term insulin independence with relative normoglycemia in adults, the isolation of islets of Langerhans in adequate quantities to achieve either of these therapeutic goals remains elusive and expensive in the allotransplantation setting.
Indications for pancreas transplantation in adults include end-stage renal disease (ESRD), hypoglycemic unawareness, diabetic neuropathy and retinopathy, gastroparesis, and labile blood sugars. Although these diabetic complications may occur in children, only labile blood sugars and hypoglycemic unawareness typically occur with any frequency in children, who have not had the disease as long. In addition, ESRD in children is often due to hemolytic-uremic syndrome (HUS), glomerulonephritis, or congenital urologic conditions rather than diabetic nephropathy. Only 56 kidney pancreas transplants and 502 pancreas transplants alone have been done in children as of the end of 2013 in the United States. Many of these pancreas transplants alone were in fact not done in diabetics but rather as part of an intestinal or multivisceral transplant for intestinal failure.
The goals of pancreas transplantation are to normalize glucose metabolism and to halt or reverse secondary diabetic complications. An additional aspiration of pancreas transplantation alone (PTA) in adults is to preemptively halt the progression of diabetic nephropathy and eliminate the need for a future kidney transplantation, thereby freeing scarce kidney allografts for allocation to patients with nondiabetic causes of renal failure. PTA in children has been performed primarily for labile blood sugars, frequent hypoglycemic unawareness with complications such as seizure and coma, and diabetic ketoacidosis requiring frequent emergency room visits and hospital stays.
Organ Procurement
Whether intended for whole organ or islet transplantation, donor pancreata are procured in a standard fashion. At the donor hospital, a total, en bloc, pancreatectomy and splenectomy is performed leaving the duodenum and proximal jejunum attached to the graft. The spleen is generally left attached during the procurement operation to minimize the risk of injury to the tail of the pancreas and intraoperative hemorrhage from the spleen. This could result in hemodynamic instability and threaten the suitability of the pancreas and other organs for transplantation. The duodenum is transected, generally with a stapler, just distal to the pylorus, and the proximal jejunum and small bowel mesentery are transected with a stapler in the area of the first superior mesenteric branch. After transport to the recipient hospital, the pancreas is prepared for whole organ transplantation on a sterile “back table” in a basin containing chilled sterile preservative solution. The jejunum and a variable amount of distal duodenum are removed. The spleen is usually removed also at this point, since the splenic vessels can now be carefully dissected and ligated with good visibility and low risk of injury to the pancreas allograft ( Figure 83-5 ). Routinely in the past, however, and currently according to surgeon preference, the spleen may be left attached until the graft is implanted, re-perfused and warmed, theoretically serving as a low-resistance vascular sink to minimize the risk of acute graft thrombosis.
The whole organ implantation operation proceeds transabdominally through a midline laparotomy or retroperitoneally through a lateral lower quadrant incision parallel to the iliac crest, similar to the incision for kidney transplantation. Ultimately the pancreas is implanted heterotopically (i.e., in a different location than the native organ like a kidney transplant, as opposed to orthotopically as in heart, lung, and liver transplantation). Its artery is sewn to a recipient artery, its portal vein to a recipient vein, and its duodenum to the recipient bowel or bladder for exocrine drainage. The pancreas is implanted typically in one of three ways named for the type of venous and exocrine drainage: systemic-bladder; systemic-enteric; or porto-enteric. In the former, the graft artery and vein are sewn to the recipient external iliac vessels (so secreted insulin is drained through the graft portal vein into the systemic venous circulation) and the graft duodenum is sewn to the recipient bladder ( Figure 83-6 ). This was the first routinely successful technique. It allows measurement of urinary amylase and lipase to monitor for rejection, evidenced by a fall in the concentration of these enzymes, and avoids the life-threatening complications of enteric leak or pancreatic fistula (leak from the pancreatic duct into the abdomen or out through the incision). In this case, the graft is positioned in a so-called “head-down” position with the head of the pancreas directed inferiorly into the pelvis and the tail superiorly into the mid-abdomen. In systemic-enteric drainage, the arterial inflow is via the recipient external or common iliac artery, and the venous drainage is to a systemic vein of the recipient (either the external or common iliac vein, or the inferior vena cava) with the graft lying in a “head-down” or “head-up” (head of the pancreas directed superiorly into the mid-abdomen and the tail inferiorly into the pelvis) orientation. The graft duodenum is then sewn or stapled to a Roux limb of recipient jejunum, a loop of recipient jejunum, or more recently (and our preferred approach for the last 2 years) the recipient duodenum. Finally, using the portoenteric technique ( Figure 83-7 ), the portal vein of the graft is sewn to a major tributary to the superior mesenteric vein in the small bowel mesentery just inferior to the transverse mesocolon and the middle colic vein. The arterial inflow to the pancreas comes from the recipient common iliac artery to which a segment of donor iliac artery, brought back with the organ from the donor, is sewn. This so-called “donor conduit” is then sewn to the graft’s arteries after being tunneled up through the small bowel mesentery to the graft from the recipient common iliac artery in the retroperitoneum. The exocrine drainage passes from the graft duodenum, which, as for the systemic-enteric technique, is sewn to a Roux limb or loop of recipient jejunum. The graft lies in a “head-up” orientation. A newer technique for portoenteric drainage places the pancreas transplant graft entirely in the retroperitoneum behind the right colon, again in a “head-up” orientation, with the portal vein sewn to the backside of the superior mesenteric vein and the graft duodenum sewn to the first part of the native duodenum, while the arterial inflow continues to come from the right common iliac artery.
Advantages of the systemic bladder drainage are ease of implantation, since it requires less dissection; an excellent source of arterial inflow and low resistance venous outflow in the iliac vessels or vena cava; safety of exocrine drainage, since leaks from recipient bowel cannot occur; and the ability to measure urinary amylase and lipase to monitor for rejection (with decreased concentration of these enzymes in the urine suggesting rejection). The problems with this technique include dehydration and other metabolic derangements from the loss of pancreatic exocrine secretions from the patient’s system into the urine (at times requiring chronic intravenous hydration), hemorrhagic cystitis, urethritis, urethral stricture, urinary tract infection, and reflux pancreatitis. These complications often result in the need for reoperation to convert from bladder exocrine drainage to enteric exocrine drainage. Advantages of the systemic-enteric technique are ease of implantation particularly from the vascular standpoint and elimination of the risk of dehydration and urologic complications associated with the bladder-drained technique. The disadvantage of intestinal leak has diminished over time with experience. Although the portoenteric method is technically more challenging, it may confer some immunologic advantage in limiting rejection as shed graft antigen may be cleared by the liver and it avoids the hyperinsulinemia of systemic venous drainage and the associated hyperlipidemia.
Immunosuppression for pancreas transplantation generally parallels that of kidney transplantation, partly because of similarly high immunogenicity of the kidney and pancreas, and minimal interest in or ability to perform prospective randomized trials in pancreas transplantation due to relatively low numbers of cases compared with other solid organs. An “induction” agent is given at the time of transplant, often in the operating room, to create a state of immediate “immunoparalysis” to promote early acceptance of the graft. During the postoperative hospitalization, a “maintenance” regimen is instituted, typically a “triple-drug” regimen including a steroid (intravenous methylprednisolone in the immediate postoperative period followed by oral prednisone), a calcineurin inhibitor (cyclosporine or tacrolimus), and an anti-metabolite (azathioprine or mycophenolate mofetil). Although a three-drug regimen is most common, some “double-drug” or “steroid-free” regimens may be employed successfully, thereby avoiding exposure to steroids. Sirolimus, an mTOR inhibitor immunosuppressant, is also occasionally used in pancreas transplantation for its renal-sparing effect. The great variety of specific induction, two-drug, and three-drug maintenance regimens is demonstrated in Tables 83-4 and 83-5 , taken from the Organ Procurement and Transplantation Network (OPTN) 2008 Annual Report.
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