Intestinal and Multivisceral Transplantation

198 Intestinal and Multivisceral Transplantation



The ongoing development of intestinal and multivisceral transplantation remains a dynamic process moved forward by advances in multidisciplinary care of intestinal failure, surgical technique, innovative immunosuppressive strategies, and an improved understanding of intestinal transplantation immunology. Recognition of intestinal transplantation as an established modality for select intestinal failure patients and better outcomes over the past decade have led to an increasing number of candidates referred for intestinal transplantation each year (Figure 198-1) and allowed more patients to benefit. In the United States alone, nearly 700 patients are alive with a functioning intestinal allograft as of December 2007.1 Although the time interval between listing and intestinal transplant has decreased over the past decade (Figure 198-2), waitlist mortality remains high, particularly for infants and adults with concomitant liver failure.2 Immunosuppression for intestinal and multivisceral transplantation now commonly involves perioperative antibody induction. The inability to prevent and treat chronic rejection in isolated intestinal allografts continues to be a fundamental barrier to achieving successful long-term outcomes and is the subject of rigorous investigation. Long-term data on nutritional outcomes and transplantation morbidity will help further define the optimal timing and role of intestinal and multivisceral transplantation in patients with intestinal failure.





image Management of Intestinal Failure


Intestinal failure is clinically defined as the loss of nutritional autonomy secondary to bowel dysfunction. Patients with intestinal failure are initially managed by administration of total parenteral nutrition (TPN) through central venous access. The duration of intestinal failure is variable and in certain patients unpredictable, from short-term to lifelong, and depends largely on the adaptation capacity of the remaining viable intestine. Improved long-term outcomes in TPN-dependent pediatric patients have been reported recently by single centers.3,4,5 Nonetheless, there remains a significant subset of patients who develop irreversible intestinal failure and require indefinite TPN therapy with its attendant complications. Intestinal transplantation may be lifesaving in this group of patients.6


Optimal management of the patient with intestinal failure is achieved after a detailed multidisciplinary evaluation.7,8 Obtaining a comprehensive history is critical and must include birth and disease history, past surgical procedures, infections, number and location of previous central venous lines, presence of central venous thrombosis, a detailed nutrition history including duration of TPN, details of TPN prescriptions and maximal enteral feeding tolerance, as well as medication history and frequency/volume of stools. A careful history and physical examination by the intestine rehabilitation team is critical to the process of achieving a complete pretransplant workup. Further investigations may include upper gastrointestinal (GI) contrast study with small-bowel follow-through, contrast enema if indicated, abdominal sonogram, ultrasound exam of central venous anatomy, endoscopy with small-intestinal aspiration for quantitative microbial culture and mucosal biopsy, and liver biopsy if there is evidence of liver dysfunction or portal hypertension.


Management of the patient with intestinal failure focuses on optimization of gut adaptation and recovery of intestinal function to achieve enteral autonomy. Surgical therapies that have a role in adaptation after intestinal failure include serial transverse enteroplasty (STEP).9 Alternatively, if gut dysfunction is considered irreversible, management of these patients concentrates on maintaining optimal growth in children and nutritional repletion in adults to prepare them for eventual intestinal transplantation.


Small-bowel bacterial overgrowth (SBBO) is a common clinical problem in patients with intestinal failure and is treated with a variety of antibiotic regimens. To date, there are no comparative studies available to enable an evidence-based approach to treatment of SBBO. The use of metronidazole for anaerobic overgrowth, combined with trimethoprim and sulfamethoxazole or an oral aminoglycoside for gram-negative organisms, is a common theme. Metronidazole monotherapy is used if the dominant symptoms suggest predominantly anaerobic overgrowth (such as bloating, increasing diarrhea, and D-lactic acidemia). The extreme sensitivity of anaerobes to oxygen makes the use of small-bowel aspirate cultures relatively unreliable as a means of microbial surveillance or indication to treat for SBBO. Probiotics such as Lactobacillus and Saccharomyces have been used in an attempt to limit SBBO. Given the absence of randomized evidence to support the efficacy of probiotics, coupled with reasonable concerns about impurities and possible contamination with other bacteria (e.g., Leuconostoc), the use of probiotics has been discouraged in patients with intestinal failure.


Parenteral nutrition–associated liver disease (PNALD), also referred to as intestinal failure–associated liver disease (IFALD), remains a critical problem in this patient population, affecting infants disproportionately. The 1-year mortality of patients with PNALD exceeds 80% in the absence of TPN weaning or transplantation. Although not always feasible, the best strategy to prevent and treat PNALD involves a commitment to the advancement of enteral nutrition. Despite a conscientious approach to TPN therapy, many children and adults still develop cholestasis relatively early in their clinical course. Prevention and timely treatment of infection, minimizing SBBO, preventing overfeeding with dextrose, providing adequate amino acids, cycling TPN, providing TPN-free days when possible, and providing taurine to neonates are probably all important measures to slow the progression of PNALD.10 Stasis of bile in the non-stimulated biliary system and gallbladder can lead to sludge buildup and cholelithiasis. In the authors’ experience, cholecystectomy rarely improves liver function and is not indicated for PNALD alone. None of the components of standard parenteral nutrition solutions have been conclusively shown to cause or contribute to PNALD, but excessive glucose and improper ratios of glucose to amino acid have been associated with hepatic steatosis. Recently, interest in the manipulation of the lipid component of TPN has led some to advocate for the removal of soy-based lipid solutions or their substitution with Omegaven (a fish-oil-based, intravenous [IV] lipid solution rich in omega-3 fatty acids); however, substantive evidence that these measures retard or reverse the progression of liver disease has not yet been demonstrated.11,12,13 Many clinicians will add but not entirely substitute fish-oil-based lipids for soy-based solutions only after liver function tests demonstrate abnormalities.


In addition to PNALD, patients on long-term parenteral nutrition are also at risk of developing metabolic bone disease (MBD). Associated with an insidious onset of bone pain that can become quite severe, patients with MBD will present with normal serum calcium, phosphorus, vitamin D and parathyroid hormone, but with hypercalciuria. Nontraumatic spinal and rib fractures have been reported in these patients. To optimize bone maintenance in patients on TPN, it is important to include calcium in parenteral formulations, prevent metabolic acidosis, and minimize aluminum contamination. Symptoms of MBD tend to resolve only after stopping parenteral nutrition.


Most intestinal transplant recipients will require intensive care unit (ICU) care during the pretransplant period; in fact, more than 10 % of intestinal and multivisceral recipients are in intensive care at the time of transplantation. Sepsis and GI hemorrhage are common reasons for ICU admission in patients with intestinal failure. Blood products, though necessary in the resuscitation of GI hemorrhage, should be used judiciously in the absence of acute bleeding. Pretransplant exposure to blood products, particularly platelets, can predispose intestinal transplant recipients to developing antibody-mediated rejection. Leukoreduced blood products may be preferable in patients awaiting transplant.


Catheter-associated bloodstream infections are common in TPN-dependent patients and often necessitate removal of a tunneled central venous catheter. Smaller pediatric patients and patients with a history of thrombosis may have limited venous access, necessitating preservation of an infected line. Percutaneous lines should be placed with caution in these patients; great vessels may no longer be patent, and trauma to remaining vessels may have serious consequences. Ultrasonic evaluation of deep veins to guide percutaneous central line placement is occasionally necessary.


Nutritionally deplete patients are relatively immune suppressed and prone to a severe course with community acquired infections. Pediatric patients with intestinal failure and IFALD are at increased risk of respiratory failure even with common viral infections. Because children have a compliant chest wall, increased abdominal girth creates a mechanical disadvantage even during normal tidal volume breathing. In the setting of pulmonary infection, volume overload, or decreased cardiac output, the work of breathing can lead to fatigue.



Indications For Transplant


In October 2000, the Center for Medicare and Medicaid Services approved intestinal, combined liver-intestine, and multivisceral transplantation as a standard of care for patients with irreversible intestinal failure who could no longer be maintained with TPN. Intestinal and multivisceral transplantation are now considered for patients with irreversible intestinal failure who fail TPN therapy due to complications, who cannot tolerate quality-of-life limitations associated with TPN therapy, or who must undergo native bowel resection for potentially life-limiting indications. The myriad causes of bowel dysfunction can be subcategorized into acute and chronic pathophysiologies. Common causes of acute dysfunction include necrotizing enterocolitis, volvulus, and mesenteric thrombosis. Common causes of chronic dysfunction include Crohn’s disease and radiation enteritis. These disease processes can alternatively be classified as either surgical due to resection leading to short bowel syndrome (SBS) or nonsurgical due to congenital enterocyte disorders leading to dysmotility or malabsorption. Unlike patients with SBS, patients with nonsurgical causes of intestinal failure may have native intestine which demonstrates normal gross morphology and anatomic length. Table 198-1 lists the already well-described indications for intestinal and multivisceral transplantation.


TABLE 198-1 Indications for Intestinal and Multivisceral Transplantation







































Pediatric Patients Adult Patients
Volvulus Superior mesenteric artery thrombosis
Gastroschisis Crohn’s disease/irritable bowel disease (IBD)
Necrotizing enterocolitis Desmoid tumor
Pseudo-obstruction Volvulus
Microvillus inclusion disease Trauma
Intestinal polyposis Familial polyposis
Hirschsprung’s disease Gastrinoma
Trauma Budd-Chiari disease
  Intestinal adhesions
  Pseudo-obstruction
  Radiation enteritis

Owing to the particularly high morbidity and mortality of children with PNALD, increasing efforts have been made by the pediatric medical community to optimize timing of referral of these patients to specialized intestine-failure rehabilitation centers and transplant centers to improve overall outcomes. A recent expert consensus panel14 recommended the following pediatric criteria for consultation or referral for small-bowel transplant assessment: (1) children with massive small-bowel resection, (2) children with severely diseased bowel and unacceptable morbidity, (3) continuing prognostic or diagnostic uncertainty, (4) microvillus inclusion disease or intestinal epithelial dysplasia, (5) persistent hyperbilirubinemia (>6 g/dL), (6) thrombosis of 2 of 4 upper body central veins, (7) the request of the patient or family.


Determining which type of allograft to use in a patient with intestinal failure involves a comprehensive evaluation of the function and anatomy of the remaining bowel along with other abdominal organs. Intestinal failure patients are considered candidates for isolated intestinal transplant, combined liver and intestine transplant, multivisceral transplant (includeing liver, stomach, duodenum, pancreas, and small-bowel), or modified multivisceral transplant which excludes the liver. Whether to perform simultaneous hepatic replacement remains a challenging decision even to experienced transplant surgeons, particularly for patients with asymptomatic portomesenteric venous thrombosis and significant liver injury. The key factors in determining whether to perform liver transplant in patients with intestinal failure are the extent of portal hypertension and the severity of parenchymal liver disease. In general, patients with mild portal hypertension should be cautiously considered for isolated intestinal transplant. It is preferable under these circumstances that venous outflow from the intestinal allograft bypass the portal circulation and be drained to the recipient systemic circulation through the inferior vena cava.




image Transplantation Procedures


Brief descriptions of recipient operations are provided. The multivisceral donor procurement operation has already been well described.15



Isolated Intestinal Transplant


For isolated intestinal transplant (Figure 198-3), the donor intestinal graft (jejunum and ileum) is procured along with donor vascular conduits, including an artery (iliac and/or carotid) and a vein (iliac). The donor superior mesenteric vessels are occasionally anastomosed directly to the recipient superior mesenteric artery and vein if adequate length is achieved. More commonly, interposition vascular conduits are anastomosed to the recipient infrarenal aorta and recipient superior mesenteric vein (portal drainage) or inferior vena cava (systemic drainage) to provide sufficient length and proper orientation for the allograft.



The intestinal reconstruction involves a proximal duodeno- or jejunojejunostomy, depending on individual recipient considerations of remnant bowel viability and anatomy. The distal length of intestinal allograft may end as a permanent end ileostomy if the recipient has no remaining viable colon or may be anastomosed to the remnant colon, leaving a short portion of allograft distal to the enterocolic anastomosis to bring out as a temporary end ileostomy that allows access to the bowel for endoscopic surveillance and mucosal biopsies. Single or multiple feeding tubes may be placed based on multiple considerations including recipient pretransplant oral intake capacity as well as donor bowel length.



Combined Small-Bowel And Liver Transplant


For combined small-bowel and liver transplant (Figure 198-4), the recipient hepatectomy is performed with preservation of the native retrohepatic inferior vena cava. The recipient foregut including stomach, native pancreas, and proximal duodenum is also preserved, and its outflow maintained with a permanent end-to-side portocaval shunt. The composite donor allograft includes the primary organs (liver and small bowel) as well as the donor duodenum and pancreas, allowing for maintenance of donor hepatobiliary continuity. Arterial inflow to the composite donor allograft is achieved using an arterial interposition conduit from the recipient infrarenal aorta. Liver venous outflow commonly involves the well-described “piggyback” technique, anastomosing donor suprahepatic inferior vena cava to the confluence of the recipient hepatic veins and cava. Intestinal reconstruction is performed in a similar fashion to an isolated intestinal transplant. Feeding tubes are placed as indicated.




Full Multivisceral Transplant


In the full multivisceral transplant procedure (Figure 198-5), prior to implantation, the recipient distal stomach, duodenum, pancreas, liver, and remaining small bowel are resected. The recipient inferior vena is meticulously preserved. The absence of remaining foregut or midgut precludes the need for portocaval shunt. Vascular inflow is similar to composite liver-bowel transplant but now includes celiac inflow to the stomach as well. Vascular outflow is identical to composite liver-bowel transplant. The donor spleen is removed from the composite allograft on the backtable prior to reperfusion.



Intestinal reconstruction is performed proximally with a gastrogastrostomy anastomosis, and the distal anatomosis is similar to previously described intestinal transplants. To avoid gastric outlet obstruction due to vagal denervation, a Heineke-Mikulicz pyloroplasty is routinely performed after reperfusion. Feeding tubes are placed as indicated.


A “modified” multivisceral transplant (Figure 198-6) involves transplantation of a full composite allograft without a liver. The recipient liver is preserved along with its vasculature and extrahepatic biliary system. Vascular conduits are used routinely (Figure 198-7). This procedure involves disruption of hepatobiliary continuity, commonly requiring in children a recipient-to-donor Roux-en-Y hepatojejunostomy, and in adults a choledochocholedochostomy (duct-to-duct) anastomosis, as well as vascular anastomoses to the recipient common hepatic artery and portal vein.





image Immunosuppression


Although a variety of combinations of immunosuppressive drugs have been used in intestinal transplant recipients, most patients are maintained on tacrolimus (Prograf [Astellas, Tokyo, Japan]) therapy along with other adjunctive medications. Organ Procurement and Transplantation Network (OPTN) data show that 99% of intestinal transplant recipients receive tacrolimus as part of for maintenance immunosuppression at the time of posttransplant discharge. Moreover, during the first posttransplant year, only a select number of patients are taken off tacrolimus, with nearly 97% remaining on tacrolimus-based therapy. The most common regimen at 1-year post transplant is currently tacrolimus in combination with steroids, with the second most common being tacrolimus monotherapy.


Two classes of immunomodulatory drugs have recently been introduced for intestinal transplantation and have been associated with improvements in 1-year patient and graft survival. Depleting antilymphocyte antibody therapies include rabbit antithymocyte globulin (rATG, Thymoglobulin [Genzyme Corp., Cambridge, Massachusetts]) and alemtuzumab (Campath-1H [Genzyme Corp.]). The individual use of these agents by high-volume single centers has demonstrated improved short-term survival and decreased rejection rates as well as severity.16,17,18 Associated with similar improvements in survival and decreased incidence of acute rejection and severity, induction with nondepleting interleukin (IL)-2 receptor antagonists, daclizumab (Zenapax) and basiliximab (Simulect), has also gained increasing acceptance by many intestinal transplant programs. Immunosuppression for intestinal and multivisceral transplantation now involves perioperative antibody induction in 60% of cases.



Immunologic Monitoring


The gold standard for monitoring and diagnosing rejection in intestinal and multivisceral transplant recipients remains routine ileoscopy and proximal enteroscopy with histopathologic examination of multiple random mucosal biopsies. Significant investigation is underway toward the development of tools to guide and monitor the immunologic state of the intestinal transplant recipient. Ideally, noninvasive markers such as serologic, proteomic, or genomic markers may identify those patients who are at increased risk of rejection and, conversely, those who might benefit from decreased levels of immunosuppression.19,20 Preformed antibody and de novo antidonor-specific antibody measurement may be of assistance in determining risk of rejection.21,22 When technically feasible, the presence of circulating donor cells in the recipient peripheral blood should be serially evaluated after transplantation by either flow cytometry or polymerase chain reaction (PCR). Monoclonal antibodies specific for donor HLA class I molecules are used for single-color immunofluorescence analysis. The presence of donor-specific antibodies in intestinal transplant recipients at the University of Pittsburgh prompts aggressive therapy with serial plasmapheresis and intravenous immunoglobulin (IVIG) until clearance of antibodies has been confirmed. For PCR analysis, primers specific for donor HLA class II alleles or else the sex-determining region of the Y chromosome (in male donor to female recipients) can be used. The use of fecal calprotectin or serum citrulline as noninvasive biochemical markers of allograft rejection does not appear to be warranted based upon currently available data.23,24


In recipients of intestinal or multivisceral transplants, surveillance endoscopy (esophagogastroduodenoscopy [EGD], ileoscopy, colonoscopy) is performed biweekly for the first 4 to 6 weeks post transplant, and then weekly for an additional 4 to 6 weeks to monitor for rejection. After the first 3 months post transplant, the frequency of surveillance endoscopies performed in recipients is based upon individual clinical assessments.

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Jul 7, 2016 | Posted by in CRITICAL CARE | Comments Off on Intestinal and Multivisceral Transplantation

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