Small Bowel Transplantation

FIGURE 74.1 Causes of short bowel syndrome (SBS) leading to intestinal transplantation in children (A) and adults (B).

There are no clear definitions of intestinal failure that allow patient status quantification. The use of PN can potentially be tracked; short-term PN, whether in the hospital or ambulatory, is commonly used for nutritional support, but it does not necessarily imply intestinal failure. Furthermore SBS does not, in every case, necessarily result in intestinal failure. Patients may be on PN for a prolonged period, only to reestablish enteral nutrition after rehabilitation that may include surgery. Although population data is lacking in the United States, the Dutch registry recently reported a prevalence (per million) of 12.24 for adults and 9.56 for children with intestinal failure (6). If we were to apply these data to the United States United Network of Organ Sharing (UNOS) wait-list, data indicate that only a small proportion of patients with intestinal failure are wait-listed (2). In a multicenter study of children on continuous PN for more than 60 days, 29% were referred for SBTx (7).

TRANSPLANTATION

Patient Selection

Broadly similar to the use of dialysis for renal failure, PN is the immediate therapy for intestinal failure. In general, transplantation of the kidney is the preferred option for end-stage kidney disease so that patients, though on dialysis, will be wait-listed for kidney transplant.

Patients with intestinal failure have specific features that determine a poor outcome, including loss of central venous line access, recurrent episodes of dehydration while on intravenous therapy, systemic bacterial and fungal infection, and progressive liver disease. Not surprisingly these features have been determined by the United States Centers for Medicare and Medicaid Services to be indications for SBTx.

Evaluation of SBTx candidates for suitability for transplantation has developed over time as with other abdominal organ transplant recipients, and the necessity for a liver graft in a proportion of these patients puts them in competition with those on the liver transplant (alone) wait-list. Contraindications to transplant include the presence of a systemic infection; a history of malignancy is also a contraindication to transplantation, at least until a designated follow-up period has determined a state of cure; unstable cardiac status and primary immune deficiency present challenges to the success of operative and early posttransplant outcome and therefore may be deemed as relative contraindications. Patients with static neurologic injury are candidates and transplantation may simplify their overall care by reducing the need for support with PN and intravenous fluids. Age is not a usual limitation, but the general health of patients and their ability to tolerate the rigors of transplant are of importance. It has been noted that individuals with intestinal failure transplanted from home, as compared to inpatients, have a better outcome and is a statement on the importance of the patient’s condition and the lack of reserve in more severely ill patients (1).

Malnutrition is a factor in poor perioperative outcome in general so that, in all SBTx candidates, nutritional deficiency must be addressed. Detailed imaging of the intra-abdominal vascular and enteric anatomy with computed tomography (CT) or magnetic resonance imaging (MRI) is a prerequisite, as is assessment for patency of central venous access sites. A liver biopsy and evaluation for portal hypertension will determine whether a patient is a candidate for a simultaneous liver graft. Additionally, SBTx candidates with a history of vascular thrombosis should be evaluated thoroughly for an underlying hypercoagulability disorder.

Graft Selection

The operative procedure of SBTx is still performed according to the “cluster” concept originally proposed by Thomas Starzl (8). The SB can be combined with the liver or with any of the abdominal viscera, including the abdominal wall if necessary. Isolated SBTx is the basic graft necessary to reconstitute primary SB function and comprises the SB from jejunum to ileum. The liver-small bowel transplant (L-SBTx) includes part or all of the liver. In practice, most of these transplants are a composite that includes the duodenum and the pancreas primarily to avoid the need for bile duct reconstruction. In a similar fashion, a multivisceral transplant (MVTx) of the small bowel includes most of the gastric cavity, liver, duodenum, pancreas, transplanted en bloc, especially for small children. A modified MVTx includes all the organs in MVTx excluding the liver.

Apart from the need for a liver graft, other organs selected are based on specific indications. For instance, in the case of pseudo-obstruction or total aganglionosis, the gastric cavity may be included as part of a modified MVTx. The inclusion of the pancreas as part of a multiorgan graft is a technical indication so that all the organs are effectively procured and transplanted as one unit, avoiding the need for multiple anastomoses.

Graft Procurement

Deceased donor graft selection is predicated upon obtaining an immunologic and physical size match, with an ideal donor being approximately 50% to 60% of the size of the recipient. The immunogenicity of the small bowel has led some to advocate antithymocyte treatment of the donor. Technically this may be a challenge given that multiple organs are usually procured from the youngest donors; the quality of the graft for SBTx is highly critical, and procurements after “brain death”—and not after “cardiac death”—are the ones most often considered suitable for Tx. A clinical history of gastrointestinal disease or bowel surgeries in the donor may be clues to inadequacy of the bowel as a graft.

Cannulation of the distal abdominal aorta to set up for the University of Wisconsin (UW) solution flush is the initial step in the donor operation. In preparation for cross-clamping, the supraceliac aorta is circumscribed, taking care that it should be as proximal as possible in pediatric donors in order to use the descending thoracic aorta for necessary conduits. Isolated small bowel graft procurement proceeds with dissection of the base of the mesentery followed by dissection of the portal vein and superior mesenteric artery (SMA) just below the pancreatic uncinate process; thereby facilitating pancreatic and small intestinal grafts from the same donor. In these cases, the inferior pancreatico-duodenal artery stays with the simultaneously procured donor pancreas. The small bowel is stapled just below the ligament of Treitz, and distally the colon is stapled at the level of left branch of middle colic vessel. The SMA is dissected free and looped at its origin and the pancreatic neck is then divided to remove the small bowel graft.

The liver-small bowel and multivisceral graft procurement commences as for an isolated small bowel graft. The tail of the pancreas and spleen is dissected, and the proximal duodenum is dissected and divided at the level of the pylorus. A patch containing the origins of the celiac axis and SMA is included with the potential of creating an aortic conduit if necessary. The graft is then removed en bloc including the pancreas, spleen, small bowel, liver, an intact inferior vena cava and duodenum. For a multivisceral graft, modified or otherwise, the stomach is included. A similar dissection is performed for the modified multivisceral graft with the exception that the liver is not included. The distal pancreas is resected or stapled off to the right of the mesenteric vessels. The left gastric artery and splenic arteries are ligated while the gastroduodenal and inferior pancreatico-duodenal arteries are preserved.

The Recipient Operative Procedure

The recipient procedure comes with challenges that depend on the underlying disorder that caused the intestinal failure. A recipient with functional bowel disease may have a surgically virgin abdomen, representing the most straight-forward scenario. Conversely, SBS or extensive Crohn disease are often associated with multiple prior surgeries and therefore intra-abdominal adhesions are likely. The abdominal domain is frequently limited, especially when there is small bowel atresia in small children or loss of a large amount of bowel. Similarly, the abdominal wall may be inadequate to complete closure in patients with a history of repeated abdominal surgeries or trauma. Major venous access sites may be reduced from sepsis and thrombosis.

Isolated Small Bowel Transplant

After a midline incision, the recipient superior mesenteric vein (SMV) and SMA are dissected at the base of mesentery and with or without conduits, the respective graft SMV and SMA are anastomosed. The small bowel is anastomosed proximally end-to-side or side-to-side to the recipient jejunum or distal duodenum (Fig. 74.2). A stoma, “chimney” or loop ileostomy is created and distal intestinal continuity is established either end-to-end or side-to-end with the recipient colon. If the mesentery is scarred and primary portal drainage is not possible, the portal flow is drained systemically; the SMV is anastomosed end-to-side to the inferior vena cava, similarly the SMA may be anastomosed end-to-side to the infrarenal aorta.

Liver-Small Bowel Transplant

A midline incision is performed with bilateral subcostal extensions facilitating dissection of the liver hilum, and ligation of the hepatic artery and common bile duct. The portal vein is then dissected and prepared for construction of a native portocaval shunt to the infrahepatic vena cava. This is followed by dissecting the liver from the cava as for a “piggyback” liver transplant exposing the infrarenal aorta for anastomosis. A thoracic aortic donor conduit is then placed on the infrarenal aorta to facilitate inflow to the graft; in some cases the supraceliac aorta is used. The hepatic veins are now clamped and the liver removed. An end-to-side, “native,” portocaval shunt is constructed. The graft is then brought into the field and the suprahepatic caval anastomosis is performed in a piggyback fashion. In children, the entire aorta with the origin of celiac and SMA is used for inflow. In adults, an iliac-Y-graft can be used to establish inflow. Enteral continuity is reestablished with a side-to-side graft duodeno-jejunal junction anastomosis with the recipient distal duodenum or proximal jejunum depending on the recipient anatomy. The distal anastomosis is as with an isolated SBTx; a gastrostomy or a gastrojejunostomy tube is placed to facilitate nutrition.

FIGURE 74.2 Endoscopic view of the proximal small bowel graft anastomosis (side-to-side).

Multivisceral Transplant

Radical surgery is performed to remove the entire splanchnic circulation with associated viscera including the pancreas and spleen, the root of the small bowel mesentery, the stomach, and the liver. The celiac and SMA are ligated, and the organs are removed together, preserving the inferior vena cava for piggyback liver transplant. Vascular anastomoses and enteral continuity is reestablished as for liver-small bowel graft implantation. A pyloroplasty is usually performed to improve gastric emptying.

Operative Caveats

Size-matched organ availability is an issue for small children, and the use of larger donors may be necessary. In adults and children, loss of abdominal domain may result in an inability to obtain primary closure of the abdominal wall. Alternatives for abdominal closure include abdominal expansion, nonbiologic or biologic mesh, acellular dermal matrix, human skin, a rotational flap, and/or a donor abdominal wall graft implanted into the recipient’s iliac or epigastric vessels (9–11).

Living Donor Small Bowel Transplant

Early attempts at living donor (LD) SBTx were not successful long-term because of technical issues and/or ongoing need for TPN. In the 1990s, a successful, standardized technique was developed by Rainer Gruessner at the University of Minnesota, using 150 to 200 cm of the distal jejunum and ileum, leaving 40 cm of prececal ileum and the ileocecal valve; the arterial supply was limited to only one artery and vein of the superior mesenteric vessels (12). Using this technique, Enrico Benedetti, at the University of Illinois, subsequently reported the combination of LD liver and small bowel grafts (13). Apart from the obvious advantages of human leukocyte antigen (HLA) matching, there is shorter graft ischemia time, reduction in wait-list numbers and avoidance of a simultaneous liver graft if advanced PNALD is not yet present. Selection of the donor for LD is not dissimilar to other solid organs with particular attention to the arterial supply a necessity (14).

Posttransplant Management

The general issues related to global care of the postoperative patient after major surgery apply to the SBTx patient. The common issues include respiratory support, fluid balance and nutrition, and pain relief. Initial nutritional rehabilitation of the donor small bowel in the recipient is based on the premise that the small bowel is in a denervated state and that lymphatic channels will take several weeks to form. A low fat, predigested formula is therefore standard for adults and children and antimotility drugs are necessary to reduce fluid and electrolyte losses. Anticipatory management of the SBTx patient in the posttransplant period is centered on certain areas that are discussed below.

Posttransplant surgical complications require vigilance in the first several days after transplantation and include the possibility of thrombosis of vascular conduits, dehiscence of anastomoses and perforation of the graft from loss of integrity or from indwelling feeding tubes. Surveillance for arterial vascular compromise with frequent visual examination of the ostomy site and regular Doppler ultrasound evaluation are routine. Similarly, abdominal ultrasound is performed for the examination of hepatic vessels.

The second potential source of morbidity in the early posttransplant period is infection, either bacterial or fungal; prophylaxis for both is routine for the first several days. As noted, hospitalized patients at the time of transplant have the highest morbidity in the posttransplant period, in part related to control of sepsis in the peritransplant period, and will be further dependent on complications during surgery. Tailoring the antimicrobial regimen to specific pathogens based on laboratory findings may be necessary under these circumstances.

The third major issue is acute cellular rejection (Fig. 74.3). Not surprisingly, immunosuppressive regimens are more aggressive in this group of patients as compared to other abdominal organ transplants. In order to preempt the development of severe rejection, serial small bowel biopsies are taken routinely through the distal stoma. Acute rejection is typically heralded by the onset diarrhea or increased ostomy output. The presentation is the same for enteric viral infections, particularly with adenovirus, rotavirus and norovirus; these must be differentiated from acute rejection.

Immunosuppression

Current induction regimens consist of high-dose steroids along with interleukin (IL)-2 receptor blockade and/or antithymocyte globulin (1); maintenance immunosuppression is based on tacrolimus. A second agent is considered by most to be necessary for several months and often much longer. Commonly used agents include mycophenolate and sirolimus (15,16). Alemtuzumab has also been an induction agent historically though it has been less commonly used in children (17). Consistent with the notion that the small bowel is a highly immunogenic organ, acute cellular rejection after SBTx has been shown to occur more aggressively than rejection of any other abdominal organ and is seen in up to 70% of recipients (18). However, more recent data indicate that rates of acute cellular rejection have improved with current regimens. Treatment regimens for established acute cellular rejection are based on the same agents as used for induction. Apart from severe acute cellular rejection, graft loss occurs from chronic allograft dysfunction, the nature and precise etiology of which remains to be elucidated (19). Monoclonal antibodies to tumor necrosis factor (TNF)-α have been shown to be effective for treating acute rejection especially for intractable cases (20). Antibody-mediated acute rejection is a risk in patients with high circulating levels of antibody as determined by panel-reactive antibody (PRA) testing (21). Similar to renal transplant patients, a high PRA level is of great concern in retransplant cases. Our center has previously demonstrated that mutations in the gene coding for nucleotide-binding oligomerization domain containing 2 (NOD2) may also have a role in rejection (22). This finding may be of significance given the relationship of the mutation and Crohn disease and may also explain the response to anti–TNF-α treatment.