Introduction
The successful clinical introduction of intestinal and multivisceral transplantation in the 1990s fueled a great interest in the management of patients with short gut syndrome (SGS) and gastrointestinal failure. With the early restricted utilization of transplantation as a rescue therapy, the concept of gut rehabilitation was introduced as a new therapeutic dimension to restore the nutritional autonomy of the native digestive system. These nontransplant rehabilitative measures include advanced nutritional care, new biologic therapy, and novel surgical techniques including autologous gut reconstruction and bowel lengthening. Adopting a multidisciplinary team approach, these therapeutic modalities have been successful in restoring nutritional autonomy in properly selected groups of patients without the need for visceral transplantation. Creative efforts have also been made to treat certain gastrointestinal malignancies with ex-vivo tumor resection and gut autotransplantation.
When attempts to restore nutritional autonomy fail, intestinal and multivisceral transplantation should be promptly considered, particularly for patients who can no longer be maintained on total parenteral nutrition (TPN). The procedure also offers a valid therapeutic option for patients with complex abdominal disease that is not amenable to conventional medical and surgical treatment. With the continual improvement in survival, intestinal and multivisceral transplantation has become the standard of care for gut failure in both children and adults. In 2000, Medicare and other commercial health insurances approved the procedure, particularly for patients who no longer can be maintained on TPN. Similar waves of clinical interest were witnessed across North America and Europe with an increase in the worldwide clinical practicality of the procedure, which is currently available in all continents but Africa. Such an achievement has been the result of surgical innovations, novel immunosuppressive protocols, and better postoperative management.
This chapter is designed to address the comprehensive strategic management of gut failure, including medical therapy, surgical rehabilitation, and intestinal transplantation. The newly introduced treatment algorithm is discussed in the setting of recent therapeutic advances with special reference to innovative surgical techniques. In addition, the current status of intestinal and multivisceral transplantation, including survival, graft function, and quality of life, are highlighted, with new insights to further improve the long-term therapeutic efficacy of the transplant procedures.
Gut Adaptation
Soon after each small bowel resection, the natural process of gut adaptation is initiated in both adults and children and continues for at least the next 2 years. The dynamic process includes structural and functional changes in the residual visceral organs with enhanced nutrient and fluid absorption. The extent of gut adaptation is commonly influenced by the site and extent of bowel resection, the presence of active intrinsic gastrointestinal disorders such as Crohn disease, early initiation of enteral feeding, growth of beneficial intestinal microbiota, and stimulation of the endogenous enterotropic factors, including glucagon-like peptide 2 (GLP-2). The different phases of such a natural phenomenon and its triggering mechanisms, including the potent stimulatory effect of luminal nutrients with upregulation of the colonic peptide transporter Pep T1, are discussed elsewhere. It is also our speculation that changes in the gut-brain neural circuit activities with altered gut neuropeptides may play an important role, with enhancement of intestinal gluconeogenesis and gut homeostasis.
Medical Management
Prompt comprehensive medical management and optimal nutritional care are the foundations of successful restoration of nutritional autonomy. In addition to TPN, treatment includes dietary modification, antidiarrheal medication, and oral hydration with vitamin, mineral, and trace element replacement. Since its inception in the 1960s, TPN has undergone several modifications to reduce associated life-threatening complications. For example, antibiotic-impregnated central indwelling catheters and ethanol-lock therapy were introduced to reduce risk of line infection, and more recently, a short-chain lipid formulation has been prescribed to reduce risk of hepatic injury.
Since its clinical introduction in 2005, omega-3 lipid formulation replaced the standard omega-6 storage-based lipids for children in many intestinal failure programs across both Europe and Canada. However, despite a reported significant reduction in serum bilirubin, there has been no noticeable effect on the degree of hepatic fibrosis, and the formulation has yet to become the standard of care in the United States. Efforts to optimize TPN are crucial to the interval and long-term management of patients with gut failure, particularly those who are not candidates for transplantation.
Pharmacologic manipulation of the gut adaptation process has been used increasingly in recent years. In addition to growth hormone, teduglutide (Gattex), a recombinant analog of human GLP-2, has recently been approved in the United States for the treatment of adult patients with intestinal failure due to SGS, including those with quiescent Crohn disease. Approval for the pediatric population is pending the results of a recently initiated clinical trial. The synthetic protease-resistance analogue, with a longer half-life, has been shown to promote changes in intestinal structure with increased villous height and crypt depth and a subsequent increase in the intestinal absorptive capacity. In addition, GLP-2 inhibits gastric emptying, increases intestinal transit time, suppresses gastric acid secretion, improves bone mineral density, protects intestinal barrier function, and increases intestinal blood flow. Nonetheless, there is a current need to establish standard criteria and practical guidelines to optimize the utilization and cost-effectiveness of such an expensive medical therapy.
Surgical Rehabilitation
Strategy
Along with visceral transplantation, other innovative surgical modalities have been introduced to treat patients with intestinal failure due to SGS and complex abdominal pathology. Other innovative operations have been comprehensively addressed in one of our recent review articles. Such surgical rehabilitative efforts have been fueled by the limited indications and potential complications of transplantation. Two of the most commonly used rehabilitative surgical techniques are autologous gut reconstruction and bowel lengthening.
The therapeutic benefits of these multidisciplinary rehabilitative measures are largely determined by the ability to control the primary disease, restore continuity, slow transit time, prevent intraluminal bacterial overgrowth, and enhance overall gut absorptive capacity. Failure to restore nutritional autonomy should prompt early consideration for transplantation.
Autologous Reconstruction
Preoperative planning with in-depth understanding of the underlying surgical disease and the residual gut anatomy is essential to achieve a successful outcome and minimize risk of postoperative complications. Each operation is an organ salvage procedure with conservative techniques guided by the embryonic development of the alimentary canal ( Fig. 73-1 ). Of crucial importance is complete awareness of any abnormal vascular and structural anatomy that may dictate the need for technical modifications to avoid injury of the residual native organs, particularly in patients with prior multiple abdominal operations and complex anatomy.
All surgical procedures should be performed with an open approach with placement of bilateral external ureteric stents in patients with frozen abdomens to avoid incidental ureteric injury. Sharp tissue dissection with use of thermal hemostatic tools is advisable. Excision of all scar and granulation tissues is essential to identify the residual organs with careful preservation of the segmental blood supply and any aberrant vasculature, particularly of the liver. All anastomoses must be tension-free and hand sewn in two layers using fine surgical techniques. Pyloroplasty is required with foregut reconstruction for drainage of a denervated stomach. Complete removal of any abdominal wall surgical mesh is necessary to avoid postoperative abdominal infection and recurrent enterocutaneous fistulae. Safe abdominal wall closure can be performed simply in a single layer using nonabsorbable material, particularly in patients with an infected abdomen.
Autologous reconstruction has frequently been used for patients with complex enterocutaneous and genitourinary fistulae, recurrent strictures, and loss of gut continuity ( Fig. 73-2 ). Most of these patients have hostile abdomens with loss of the main domain. Common operative findings in these patients with complex disease include a recalcitrant gut disorder, technically flawed surgery, and infected abdominal wall synthetic mesh. Foregut reconstruction is commonly indicated for patients with bariatric surgery–associated gut failure and other patients with complicated gastric surgery ( Fig. 73-3 ). With residual gastric segments, primary gastrogastric reconstruction is performed at levels dictated by the size and integrity of the segmental blood supply of the retained gastric portion(s). Proximal gastrogastric anastomosis ( Fig. 73-3, A ) is commonly performed with esophagogastric reconstruction ( Fig. 73-3, B ), which is often needed in patients with a small fibrotic gastric fundus and those with a disrupted esophagogastric junction. Complete salvage of residual portions of the stomach often requires two-level anastomoses, particularly in patients with combined high and low gastric disruption ( Fig. 73-3, C ). With proximal and mid gastric reconstruction, takedown of the short gastric vessels is often necessary, and a pyloroplasty is required for drainage. In addition, all efforts should be made to avoid disruption of the angle of His.
In patients with massive gastric necrosis and a prior gastrectomy, maintenance of the normal alimentary flow is crucial to restore full nutritional autonomy, particularly in patients with SGS. Therefore, innovative surgical techniques should be used to create a neostomach with a visceral conduit ( Fig. 73-4 ) to avoid exclusion of the duodenal from the alimentary flow and the accelerated exposure of the intestine to undigested nutrients. Interposition of a vascularized jejunal segment ( Fig. 73-4, A ) or colonic segment ( Fig. 73-4, B ) between the abdominal esophagus and gastric antrum or duodenum ( Fig. 73-4, C ) is effective in restoring gut continuity and optimizing absorptive capacity with achievement of full nutritional autonomy in patients with sufficient residual intestine. A pyloroplasty should be performed in patients with a retained antrum.
Midgut reconstruction has been the most common rehabilitative procedure, particularly in patients with mesenteric ischemia, Crohn disease, and adhesive disorders ( Fig. 73-5, A ). All efforts should be made to restore continuity of the hindgut, particularly in patients with residual large bowel and a spared anorectum ( Fig. 73-5, B ). When extensive hindgut resection is indicated—particularly in patients with Crohn disease, dysmotility, familial adenomatous polyposis, and colonic ischemia—it is our recommendation that the anal sphincters be preserved for a future pull-though operation using the donor colon at the time of transplantation. These genuine and technically challenging autologous reconstructive procedures have evolved as a result of our cumulative surgical experience in the field of abdominal visceral transplantation.
Intestinal Lengthening
Bowel lengthening increasingly has been used for patients with SGS who have normal structural and vascular anatomy of the residual gut. Figure 73-6 illustrates the technical steps of both the longitudinal (Bianchi; Fig. 73-6 ) and serial transverse enteroplasty ( Fig. 73-7 ) procedures, with full details described elsewhere. Both operations can be successfully performed in patients with dilated bowel loops to enhance gut absorption by reducing transit time and eliminating the risk of bacterial overgrowth. With nutritional and pharmacologic support, nutritional autonomy is achievable in properly selected patients within the first few months of surgery, particularly in those with residual small and large bowel. The procedure could also be repeated at a later time, particularly in patients who continue to require TPN with redilated intestinal loops.
Intestinal and Multivisceral Transplantation
Types
The main “icons” of abdominal visceral transplantation are intestine alone ( Fig. 73-5, A ), combined liver-intestine ( Fig. 73-5, B ), and multivisceral with ( Fig. 73-5, C ) and without ( Fig. 73-5, D ) inclusion of the liver. The combined liver-intestinal graft commonly includes the pancreas to maintain continuity of the axial blood supply and the biliopancreatic system. The multivisceral graft includes the stomach, duodenum, pancreas, and intestine with (full) and without (modified) the liver. Inclusion of the donor colon is recommended for a selected group of patients, in particular those who are suitable candidates for a pull-through operation ( Fig. 73-9 ) or other innovative reconstructive procedures. In patients with concomitant failure of other organs, the needed organ such as the kidney or pancreas is either added en bloc to the visceral allograft or rarely implanted separately.
When native hepatic functions are preserved, patients with irreversible intestinal failure undergo isolated intestinal transplantation. A pancreas or kidney is simultaneously transplanted for those with insulin-dependent diabetes and renal failure, respectively, and a composite liver-intestinal allograft is given to patients with combined liver and intestinal failure. Full multivisceral transplantation is indicated for patients with liver failure and diffuse end-stage gastrointestinal disorders. The procedure is also applied for patients with a hostile abdomen and complex surgical disease, particularly those who require retransplantation with more complex visceral allografts. Modified multivisceral transplantation is commonly used for patients with combined foregut and midgut organ loss or failure with preserved hepatic function. With the recent broadening of indications for transplantation and the diversity of the underlying gastrointestinal disorders, various innovative surgical techniques have recently been introduced to the originally described donor and recipient operations.
Indications
Small bowel and multivisceral transplantation is currently indicated for patients with irreversible intestinal failure who experience significant complications of TPN. It is also required for patients with complex abdominal pathology who failed conventional surgical intervention. SGS is the most common cause of intestinal failure and the leading indication for transplantation in both children and adults. The main causes in adults are mesenteric vascular occlusion, recalcitrant Crohn disease, dysmotility syndromes, neoplastic disorders, adhesive disease, and impaired enterocyte functions. Mesenteric vascular thrombosis is most commonly precipitated by a prothrombotic state including protein C, S, and antithrombin III deficiencies, factors V/II and Jake-2 mutations, myeloproliferative disorders, essential thrombocytosis, lupus anticoagulant, and anticardiolipin antibodies. Crohn disease is the second most common indication, and candidates are those either with type 3 intestinal failure or type 2 with failure of surgical rehabilitation. In children, the precipitating causes of SGS are commonly gastroschisis, volvulus, intestinal atresia, and necrotizing enterocolitis.
Dysmotility and neoplastic syndromes are common indications for transplantation among both children and adults. The spectrum of the gastrointestinal motility disorders include enteric dysmotility, hollow visceral myopathy and neuropathy, total intestinal aganglionosis, and secondary syndromes due to viral illnesses, autoimmune diseases, and other unknown causes. The main hereditary neoplastic disorder is familial adenomatous polyposis, although other, rarer dysplastic conditions also exist. End stage deficiencies of enterocyte absorptive capacity are commonly seen in children with microvillus inclusion disease and in adults with irradiation enteritis, autoimmune enteropathy, lymphangiectasia, and inflammatory bowel disease. The extent and severity of the disease process commonly dictate the necessity for spontaneous en-bloc replacement of more than one of the abdominal visceral organs.
Of the recently emergent indications for transplantation are gut failure after bariatric surgery and diffuse portomesenteric venous hrombosis inpatients with liver failure. The catastrophic loss of the gastrointestinal organs after the weight reduction procedures (type 1) and the unsuccessful surgical rehabilitation of type 2 (chronic technical complication) and type 3 (functional disorders) commonly dictate the need for intestinal and multivisceral transplantation. In the presence of diffuse thrombosis of the portomesenteric venous system, replacement of a failing liver can only be successfully achieved in most patients with full multivisceral transplantation.
Despite continual improvement in survival after transplantation, failure of TPN has continued to be a prerequisite for intestinal and multivisceral transplantation. In our formal request for national coverage in 2000, TPN failure was defined as “significant biochemical or histologic evidence of hepatic injury, loss of central venous access with occlusion of at least two central veins, frequent line sepsis or single episode of fungal infection, and recurrent episodes of severe dehydration despite intravenous fluid supplementation.” In addition, ultra-SGS and end stage gastrointestinal disorders that are not amenable to medical and surgical rehabilitative measures are legitimate indications for visceral transplantation.
Retransplantation with an intestinal or multivisceral graft is indicated as a life-saving procedure in about 10% of the patients. With intestine-alone allografts, a two-stage surgical strategy with a time interval between allograft enterectomy and retransplantation may achieve a better outcome. Despite a satisfactory outcome, novel strategies are required to reduce the risk of recurrent intractable rejection, particularly of a liver-free allograft. Recipient pretreatment with lymphoid-depleting agents, anti–B cell therapy, better human leukocyte antigen (HLA) match, and simultaneous replacement of the native liver utilizing the domino procedure are such novel approaches that could potentially improve outcome after retransplantation.
Contraindications
Significant cardiopulmonary insufficiency, incurable malignancy, persistent life-threatening intra-abdominal or systemic infections, and severe immune deficiency syndromes are absolute contraindications to an intestinal transplant. The coexistence of acquired immune deficiencies dictates the need for a stem cell transplantation first to avoid the inevitable risk of graft-versus-host disease after visceral transplantation.
Recently, poor psychosocial support has been identified as a major risk factor for compromising a long-term successful outcome, and thus the lack of adequate social support should be considered a relative contraindication for transplantation. Meanwhile, all multidisciplinary efforts should be made to improve the psychosocial support of these unfortunate patients, particularly children. However, the presence of long-standing neuropsychiatric disorders should not preclude transplantation because successful rehabilitation after transplantation has recently been documented.
A history of gastrointestinal malignancy, loss of central venous access, and older age should not exclude candidacy for transplantation. Chemical dependency, psychosomatic disorders, active abdominal infection, and the presence of locally advanced desmoids or stroma cell tumors should be addressed before the patients are considered unsuitable for transplantation.
Early Referral
Early consideration for transplantation before the development of TPN failure or progression of complex abdominal disease is not yet the standard of care. However, recently published data favor early transplantation with increased candidacy and survival ( Fig. 73-10 ) and better quality of life. The native liver can be saved with reduction or elimination of the potential prohibitive risk of dying while patients are on the United Network for Organ Sharing (UNOS) waiting list for an allograft that contains a liver. An additional advantage is the ability to perform allograft enterectomy to rescue the intestine-alone recipients with reinstitution of TPN.
