Children
Adults
Gastroschisis
Ischemia
Volvulus
Crohn’s disease
Necrotizing enterocolitis
Trauma
Pseudo-obstruction
Volvulus
Intestinal atresia
Motility disorders
Aganglionosis/Hirschsprung
Desmoids
Retransplant
Retransplant
Microvillus inclusion
Miscellaneous
Malabsorption
Gardner’s syndrome
Tumors
Contraindications
Contraindications to SBTx include non-resectable or disseminated malignancy, unreconstructable vascular anatomy, diseases that are likely to recur after transplantation, profound disabilities that will not be corrected by transplantation, loss of vascular access sufficient to allow transplantation, or an inability or unwillingness to comply with the post-transplant management plan (Table 41.2) [3].
Table 41.2
Contraindications to small bowel transplant
Absolute contraindications |
Neurological disabilities |
Life-threatening disease unrelated to the digestive system |
Non-resectable malignancy |
Relative contraindications |
Severe immunological deficiencies |
Multisystem autoimmune diseases |
Inadequate vascular anatomy to warrant long-term patency |
Prematurity with lung disease |
Techniques in Small Bowel Transplantation
Operative Technique Summary
Initial step is to assess the patients to ensure that the selection criteria are met (Table 41.3) and to rule out potential contraindications to the transplant procedure.
Table 41.3
Selection criteria for small bowel transplantation
Absence of acute or chronic active infections that are not effectively treated |
Adequate cardiovascular function (ejection fraction greater than or equal to 40 %) |
No active alcohol or chemical dependency that interferes with compliance to a strict treatment regimen |
No uncontrolled and/or untreated psychiatric disorders that interfere with compliance to a strict treatment regimen |
Absence of inadequately controlled HIV/AIDS |
Cadaveric donors are used in most SBTx, although successful procedures have been performed with an allograft from living related donors.
Intestinal grafts are obtained from blood group compatible donors. Selection criteria for cadaveric donors include blood group ABO match, hemodynamic stability without excessive inotropic requirements, and compatible size match enabling placement of the graft within the peritoneal cavity. Some SBTx centers require a negative lymphocytotoxic cross-match and cytomegalovirus serology match.
During procurement intestinal decontamination is done in all donors with amphotericin B, an aminoglycoside, polymyxin, and broad-spectrum antibiotics. In situ perfusion with University of Wisconsin preservation solution is performed with venous bed decompression.
A cold ischemia time of less than 10 h is recommended to avoid preservation injury of the intestinal allograft. Ischemia of the intestinal graft increases the risk of bacterial translocation by disruption of the mucosal barrier and the risk of early rejection. The procurement method and intraluminal washing technique vary among surgical teams [9, 10]. Intraluminal washing at +4 °C with a storage solution containing antibacterial and antifungal agent is useful. Although University of Wisconsin solution is the most widely used solution during procurement, satisfactory preservation of intestinal morphology and enzyme activities after 8 h of cold ischemia was shown in experimental studies using Ringer’s and Euro-Collins solutions. The author of this chapter personally prefers University of solution for all multivisceral organ procurements including small bowel.
The size of the allograft also has to be taken into account. In cases where the recipient has undergone extensive resection of the small bowel, the reduced volume of the abdominal cavity implies the use of allografts from donors with a lower body weight. Length can be reduced according to the size of the abdominal cavity, although the entire small bowel is often transplanted.
Transplant Procedure
Different techniques are required for the vascular reconstruction of each type of intestinal transplant. For isolated SBTx, the arterial supply is established by an end to side anastomosis to the infrarenal aorta; the superior mesenteric vein is anastomosed to the recipient superior mesenteric vein or the inferior vena cava. Routing the venous outflow via portal drainage provides first-pass delivery of hepatotropic substances to the recipient liver and filtering of translocated organisms by the native liver. It is also postulated that portal drainage provides protection from rejection [11].
Combined small bowel-liver grafts are removed en bloc, connected by the portal vein, superior mesenteric vein, and an aortic segment containing the celiac artery and the superior mesenteric artery [12]. The duodenum and the head of the pancreas are included with the graft to avoid the need for biliary reconstruction. The aortic segment is anastomosed to the infrarenal aorta of the recipient. The end of the native portal vein is anastomosed to the side of the donor portal vein or to the inferior vena cava.
There are many variants of intestinal anastomosis [13]. However, two principles must be followed: (1) exteriorization of the graft, (2) permanent flow of gastric and biliopancreatic secretions through the graft which prevent intraluminal stasis and bacterial proliferation/translocation. The proximal end of the intestinal graft is anastomosed to the native bowel. The distal end of the small bowel graft is exteriorized as a stoma or anastomosed to the native colon. A loop ileostomy (i.e., chimney) is created to divert the stool away from the intestinal anastomosis and provide access for biopsies. The ileostomy is closed after 3–6 months. The donor colon is usually removed because it appears to increase the incidence of rejection and sepsis. If recipient has nonfunctional colon due to a primary disease such as intestinal pseudo-obstruction or had a colectomy, it is preferable to limit colon grafting to the cecum and ascending colon only.
Isolated SBTx is done with or without the large intestine and is more commonly performed in adults [14]. With isolated SBTx the entire jejunum and ileum are transplanted in the majority of cases. If the intestine is donated by a living donor or when reduction of the size of the graft is required, a 200 cm segment is usually transplanted. In order to close the abdomen properly, it is important to match sizes of donor and recipient. Native bowel and allograft bowel must be preserved as much as possible because this provides protection from parenteral nutrition associated injury. The rationale behind this is the fact that these patients will need parenteral nutrition until allograft becomes functional. When SBTx is performed en bloc, duodenum with pancreas may be included (Omaha technique) to avoid the need for biliary reconstruction [13].
Multivisceral Transplantation
Multivisceral transplantation (MTx) is the removal and replacement of both native foregut and midgut. In MTx, the native abdominal viscera are resected and the composite graft including the stomach, pancreaticoduodenal complex, and small intestine are transplanted en bloc. The donors for MTx are cadaveric only. The liver, kidneys, and large intestine of the donor may or may not be included depending on the primary disease process.
The use of MTx is increasing and the 1-year graft and patient survival is at least as good as the other forms of SBTx [15].
Combined Liver and Small Bowel Transplantation
Combined small bowel-liver (SLTx) transplantation is recommended for patients with irreversible failure of both the small bowel and the liver [16]. SLTx is more commonly performed in children. The two organs can be transplanted at the same session or sequentially from the same or a different donor. Concomitant liver failure induced by parenteral nutrition is the usual reason for this type of transplant.
Living and Non-heart-Beating Donors
The technical aspects of living donor intestinal transplantation (LDIT) were standardized by Gruessner [17]. The donor operation consists of harvesting 200 cm (150 cm for pediatric recipients) of distal ileum, preserving at least 20 cm of terminal ileum and ileocecal valve. The vascular pedicle of the graft is formed by the distal branches of the superior mesenteric artery and vein and is anastomosed to the infrarenal aorta and cava of the recipient. LDIT has several potential advantages, such as elimination of waiting time, the elective nature of the procedure, better human leukocyte antigen (HLA) matching, and a short cold ischemia time. LDIT is usually performed with well HLA-matched grafts. The significance of HLA matching in SBTx is still to be determined. In fact, experienced programs have obtained good outcomes and low rates of rejection with poorly matched deceased SBTx. A significant risk of antibody-mediated graft injury in settings of positive cross-match has been demonstrated. A significant reduction of ischemia time has been achieved in the settings of LDIT.
When the intestinal graft is harvested from non-heart beating donors (NHBD), the infection-related mortality was higher and the absorptive function was lower secondary to the fact that intestinal mucosa is sensitive to ischemic injury. Histological examinations confirmed a higher grade of ischemic injury in the NHBD grafts that correlated with the clinical data. Experimental studies suggest that non-heart-beating donation may not be indicated for small bowel transplantation [18].
Classical Immunosuppression (IS) in Small Bowel Transplantation
As with other types of solid organ transplants, IS regimens for SBTx vary from center to center [19]. Many therapies and combinations of IS have been used for SBTx, but what remains undefined are the optimal IS regimens to achieve the required goals while preserving graft function and not predisposing the recipient to increased infections or malignancy. Tacrolimus is the drug that allowed the development of a consistently successful intestinal transplant series and today it is the maintenance IS drug of choice.
Most centers manage patients with a triple regimen for baseline IS including a calcineurin inhibitor (tacrolimus), corticosteroids (usually methylprednisolone), and an antiproliferative agent (usually mycophenolate mofetil) [20, 21].
After SBTx, tacrolimus can be administered immediately as a continuous intravenous infusion, at a dose of 0.05–0.1 mg/kg per day and dose is adjusted with blood levels daily. Tacrolimus is administered orally at a dose of 0.2–0.3 mg/kg twice daily after intestines start functioning. Methylprednisolone is always simultaneously prescribed but in variable doses. Mycophenolate mofetil dose is usually given at 1,000 mg twice daily or its counterpart mycophenolic acid with less gastrointestinal side effects at equivalent doses (i.e., 720 mg twice daily).
Newer Immunosuppression Drugs
The most significant difference of IS in SBTx is the prompt use of induction IS therapy in almost 90 % of cases as part of the overall regimen. The most common induction IS agents are anti-IL2-receptor antibody (daclizumab, basiliximab) and monoclonal antibody (alemtuzumab). Their use has been associated with a reduction in the incidence and severity of rejection episodes and an improvement of survival, which allowed use of lower levels of tacrolimus. This latter issue has become important because there is now increasing evidence of calcineurin-inhibitor toxicities in patients receiving non-renal transplants. Conversion to non-calcineurin-inhibitor drugs such as rapamycin, use of steroid sparing protocols, and determination as to which IS therapy best maintains graft acceptance still need explanation.
Sirolimus (rapamycin) was also studied as an additional IS in SBTx. In a study, authors compared 21 patients with SBTx who received daclizumab, tacrolimus, and steroid with 16 SBTx patients who received sirolimus in addition to sirolimus, basiliximab, tacrolimus, and steroids. The addition of sirolimus to the immunosuppressive regimen after SBTx resulted in fewer early rejections (17 % vs. 68 % in the first 30 days) and no exfoliative rejection. Thus sirolimus did not increase morbidity but improved 1-year patient and graft survival [22].
Bone Marrow Infusion and Ex Vivo Radiation
It was shown in 1990s that bone marrow infusion (BMI) was beneficial in augmenting chimerism in both clinical and experimental SBTx studies [23, 24].
Abu-Elmagd et al. recovered bone marrow cells from the thoracolumbar vertebrae of small bowel donors and gave a single intravenous dose of 3–5 × 108 donor cells/kg to the recipients over 20 min within the first 12 h after revascularization. The 1- and 5-year recipient and graft survival rates in the BMI group were 79 % and 74 %, and 68 % and 62 % respectively. Post-transplant lymphoproliferative disease risk in 1 year was also low in BMI group [7].
Recent experimental data suggested that low-dose graft irradiation when combined with donor-specific bone marrow transfusions may have a beneficial effect on graft outcome. In an attempt to prevent graft versus host disease (GVHD), ex vivo intestinal allograft irradiation was also tested at the Pittsburgh program. The intestine of 11 allografts for 10 primary recipients was irradiated with a single dose of 750 cGy prior to the transplant [25].
Post-transplant Care
Postoperative management of intestinal transplant recipients includes three important steps: (a) immunosuppression, (b) anti-infective prophylaxis, and (c) assessment of the graft.
After the initial 2 weeks, it is possible to initiate oral feeding with an isotonic dipeptide solution enriched with medium chain triglycerides and glutamine, changing to a gluten- and lactose-free diet within 2–4 weeks, and eventually progressing to a normal diet [26].
The mean length of stay in hospital for intestinal transplant was reported to be 59.5 ± 56 days for isolated intestinal transplant, 81.8 ± 79 days for intestine-liver transplant, and 83.5 ± 56 days for multivisceral transplant.
After discharge, patients need regular follow-up at transplant clinics and close monitoring. They may need hospital readmission for treatment of complications associated with intestinal transplantation.
Infection After Small Bowel Transplantation
Despite the use of prophylactic antimicrobial agents, infection with uncontrolled sepsis is still the leading cause of morbidity and mortality following intestinal transplant. Intestinal transplant recipients are predisposed to severe bacterial, viral, and fungal infections because of the high levels of immunosuppression, presence of pre-existing infection, and the potential for bacterial translocation from the graft during periods of stress such as ischemia, reperfusion, and rejection. The Intestinal Transplant Registry identified sepsis as the leading cause of post-intestinal transplant deaths worldwide (51.3 %) [27]. This is five times as high as the mortality rate due to rejection, the second most common cause of death. Bacterial and fungal infections are the most common infections with an incidence of 93 %. The most common organisms identified are pseudomonas and candida.
Translocation of microorganisms from the gastrointestinal tract has been demonstrated in human studies and has been suggested to be the mechanism responsible for the high rate of infection occurring after small bowel transplantation. Cicalese et al. studied the correlation of bacterial translocation and various factors in 50 pediatric small bowel transplant recipients with a mean follow-up of 30 ± 10 months (range: 20 days–6 years). Blood, stool, liver biopsies, and peritoneal fluid were collected and cultured using standard microbiologic techniques as part of follow-up or when infection was clinically suspected. A bacteria translocation episode is determined when microorganisms are found simultaneously in blood or liver biopsy and feces. Approximately 4,000 cultures were evaluated in the study. The results showed that acute rejection was not accompanied by an increased bacteria translocation rate. The inclusion of colon in the allograft significantly increased fecal bacterial count (100 % cultures vs. 84.6 % cultures >1 × 106 CFU) and bacterial translocation rate (75 % of patients vs 33 % of patients) compared to transplants without the colon. Bacteria translocation was observed in a significantly higher number when cold ischemia time is longer than 9 h compared to cold ischemia time of less than 9 h (76 % vs. 20.8 %, p = 0.002) [28].
Viral Infections
Cytomegalovirus (CMV) is the most common viral infections in intestinal transplant recipients [29]. The allograft is more susceptible than other organs to viral infections because of the aberrant immune response within the allograft, local graft versus host reaction, or host versus graft reaction. Besides, the intestine contains a large number of donor leukocytes that might contain latent CMV. The 1997 report of the Intestinal Transplant Registry [27] showed that CMV infection rates for ISB, SB-L, and MV transplants were 24 %, 18 %, and 40 %, respectively. It was shown that CMV disease was associated with a significant increase in mortality and shorter survival among SBTx recipients. Time to death was shorter in patients with CMV enteritis and allograft rejection, while CMV prophylaxis with antiviral drug ganciclovir showed a trend to longer time to death. But prophylaxis with antiviral drugs is associated with the potential threat of nephrotoxicity, myelotoxicity, or development of resistance. Thus, it was suggested that low viral infection rates could be achieved without aggressive antiviral prophylaxis.
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