Significant advances have been made in the management of patients with intestinal failure, including pediatric patients. These advances include medical gut rehabilitation, autologous reconstruction, bowel lengthening, and visceral transplantation. Gut replacement is one of the most important milestones in the recent history of organ transplantation. Significant progress in donor management, technical advances, new immunosuppressive protocols, and follow-up care has led to improvement in patient and graft survival. Accordingly, intestinal and multivisceral transplantation should be considered an essential component of the algorithm in the management of these unique patients. This chapter focuses on recent developments in the diagnosis and surgical management of pediatric patients with short gut syndrome, particularly those patients who failed to respond to conservative medical management. Special emphasis is directed toward the recent advances in the field of intestinal and multivisceral transplantation.
Pathophysiology of Gut Failure
Short gut syndrome includes a constellation of symptoms related to reduction in the length of small bowel below a threshold that is specific for every patient. Associated symptoms include chronic diarrhea, electrolyte imbalances, malnutrition, weight loss, stunted growth, kidney injury, and impaired immune system. Most of these patients need total parenteral nutrition and are at risk for venous access–related complications, hepatic injury, and other related morbidities. Reduction in functional gut length is anatomic , resulting from bowel resection, or physiologic, as a consequence of mucosal pathologies such as tufting enteropathy, microvillus inclusion disease, or neurologic disorders such as pseudo-obstruction. There is a considerable overlap in the factors leading to anatomic intestinal failure. Neonates are more affected by congenital malformations, whereas volvulus, trauma, and desmoid tumors can lead to short gut syndrome and intestinal failure in adolescents ( Box 36-1 ). The symptomatology is a function of whether resection led to loss of proximal or distal small bowel. Loss of proximal jejunum is associated with high output losses if patients have an ostomy. However, if the intestinal continuity has been restored, the distal bowel reabsorbs and helps to reduce chronic losses. Distal small bowel resection leads to fat malabsorption, diarrhea, electrolyte loss, and reduction in bile salt reabsorption, thereby interrupting enterohepatic circulation. Loss of ileum and ileocecal valve (“ileal brake”) results in shortened transit time and reduction in glucagon-like peptide 1 (GLP1) and other peptides.
Short gut syndrome
Gastroschisis
Necrotizing enterocolitis
Intestinal atresia
Volvulus
Trauma
Radiation enteritis
Crohn’s disease
Dysmotility syndrome
Neoplastic disorders
Tumor-like desmoids associated with familial adenomatous polyposis
Enterocyte dysfunction
Aganglionosis
Microvillus inclusion disease
Tufting enteropathy
Portomesenteric thrombosis
Residual intestinal length and its functional characteristics determine the propensity to develop intestinal failure. In general, the threshold below which patients will need parenteral nutrition is residual intestinal length of 30% or less. Above this, patients can be supplemented with enteral nutrition, increased caloric intake, and forced hyperphagia. Following an acute loss in the length of functioning bowel, the remaining bowel undergoes hyperplastic response. The degree of hyperplasia is dependent on the health of the residual bowel, blood supply to the remaining bowel, and optimum nutrient intake. Enterocyte hyperplasia leads to lengthening of villus-crypt units and increase in absorptive surface area. At the molecular level, there is increase in the level of enzyme and transport molecules per crypt. Rising plasma citrulline levels following the start of enteral feeding indicate enterocyte proliferation and adaptation. Enterocyte and myocyte proliferation results in intestinal thickening, thereby increasing the absorptive surface of the residual bowel. In pediatric patients, the gut takes longer to adapt because of its linear growth as well, and enteral feeding should be continued for at least 3 to 4 years before committing pediatric patients to lifelong total parenteral nutrition (TPN) therapy. Patients with mucosal abnormalities or pseudo-obstruction have limited capacity to adapt, and changes seen in patients with reduction in bowel length may not apply to patients with these disorders.
Complications of Short Gut Syndrome
Interruption of enterohepatic circulation from small bowel resection results in progressive liver disease compared to patients who are receiving parenteral nutrition without short gut. Enteral calories and intravenous lipid derived from fish oil may prevent cholestasis and liver injury. Recent data have demonstrated that omega-3 fatty acids are associated with chemical reversal of parenteral nutrition–associated cholestatic liver disease. Bacterial overgrowth results from excessive bacterial proliferation because of blind loop or absence of ileocecal valve. Symptoms include excessive bloating, flatulence resulting from enterocyte injury, and inactivation of bile acids via deconjugation. It leads to a deficiency of vitamins, especially B 12 , A, D, E, and K. Therapy includes gut decontamination with oral Flagyl or trimethoprim-sulfamethoxazole and gentamycin. Pancreatitis is a well-known complication of TPN that is exacerbated by the development of gallstones. Consequently, patients can develop endocrine and exocrine dysfunction and require replacement therapy with insulin and pancreatic enzymes. Patients develop progressive gut organ failure. Venous thrombosis and sepsis is a known complication of maintenance therapy with TPN. These include catheter-related bloodstream infections, septic endocarditis, thromboembolism, and microinfarctions in the brain. In addition, central venous thrombosis can occur in patients with hypercoagulable disorders. All of the preceding complications including metabolic derangement and renal insufficiency due to frequent dehydration can be an indication for gut rehabilitation including transplantation.
Principles of Gut Rehabilitation
In the early phase following loss of bowel length or function, therapy is focused on fluid and electrolyte replacement. Early restoration of intestinal continuity, liberal use of continuous gastrostomy feedings, administration of hypocaloric elemental formulas to optimize enterocyte absorption, use of operative bowel-lengthening techniques in dilated bowel, and aggressive antibiotic treatment of bacterial overgrowth are mainstays of intestinal rehabilitation.
Medical Management
In the early postoperative period, patients require parenteral nutrition via a peripheral or a central line. After resolution of ileus and if there are no confounding factors, enteral feeding is started in the form of formulas and breast milk for infants. Depending on age, nutritional requirements, and ability to take orally, formula and amount of tube feeding are modified with the help of nutritionists who are instrumental in the management of these patients. A well-hydrated patient with rising albumin, weight, reduction in fecal volume, and normal laboratory values on enteral nutrition indicates that TPN weaning is warranted. Care is taken to ensure oral replacements include trace elements and vitamins, and therapy is guided by periodic testing of laboratory values of these. Failure of TPN withdrawal is usually seen in patients with diseased remaining bowel, ultra short gut length (less than 40 cm), absence of ileocecal valve, and loss of colon. Thus, failure of enteral therapy, total loss of small bowel, dysmotility, and mucosal disorders are absolute indications for long-term parenteral nutrition at home. This is supported by a multidisciplinary team of providers that includes home nursing, pharmacists, nutritionists, and the gastrointestinal physician.
A multidisciplinary approach is essential to the success of any intestinal rehabilitation program. Patients are evaluated by pediatric gastroenterologists, pediatric general surgeons, intestinal failure nutritionists, pharmacists with advanced training in parenteral nutrition, and social workers ( Figure 36-1 ). Depending on residual intestinal length, patients may require antimotility agents such as loperamide, diphenoxylate, atropine, or tincture of opium. Cholestyramine and octreotide are of limited benefit. In addition to the standard nutritional measures, enterocyte growth factors have been utilized increasingly to promote gut adaptation. Teduglutide, a recombinant analog of human glucagon-like peptide 2 (GLP2) has been recently approved in the United States (Gattex) and Europe (Revestive) as the first targeted treatment of short bowel syndrome–associated intestinal failure and to increase fluid absorption and reduction in the need for parenteral nutrition. Parameters of success include enteral autonomy (discontinuation of TPN for more than 3 consecutive months), reduction in caloric requirement for TPN, and reduction in serum-conjugated bilirubin.
Surgical Interventions
Failure of supportive and medical therapy, especially in patients with dilated small bowel, is an indication for surgical intervention to enhance gut adaptation of intestinal failure. These interventions include the following.
Autologous Reconstruction and Bowel Lengthening
Patients with atretic bands, obstructed bowel loops, and dilated bowel segments need surgical exploration. Oftentimes patients develop enterocutaneous fistulae or intraabdominal abscesses that need to be surgically repaired or drained, respectively. Successful, calculated surgical intervention can restore native gut function and preclude the need for intestine transplantation.
The technical feasibility of visceral transplantation and improved outcomes has stimulated the introduction of different nontransplantation surgical procedures to treat intestinal failure and complex abdominal pathology. Of these are autologous reconstructive and bowel-lengthening procedures ( Figure 36-2, A-E ). With transplantation being utilized as a rescue therapy, surgical reconstruction has been increasingly applied in patients with multiple enterocutaneous fistulae and residual bowel function. Dilated segments of the bowel can be lengthened by one of the two well-known and innovative techniques. Both modalities can be successfully performed in patients with dilated bowel loops to reduce transit time, eliminate bacterial overgrowth, and enhance gut absorption. These include longitudinal intestinal lengthening and tailoring (LILT) introduced by Bianchi and serial transverse enteroplasty (STEP) reported by Kim et al. Indications, selection criteria, and outcome measures are summarized in Table 36-1 . In general, the Bianchi procedure requires a minimum of 20 cm of small bowel, whereas the STEP procedure can be performed on any length of bowel. Future reports of the STEP registry ( www.stepoperation.org ) may shed some light on the proper indications and long-term outcomes of this procedure.
| Longitudinal Intestinal Lengthening and Tailoring (LILT), Bianchi | Serial Transverse Enteroplasty (STEP), Kim et al. | |
|---|---|---|
| Indication | Loss of Nutritional Autonomy | |
| Age | Any age, preferably after 6 months | Any age |
| Recommended anatomy | 20-40 cm dilated bowel | Any length |
| Minimal intestinal diameter and length | 3-5 cm along a length of 20 cm | 4 cm, any length |
| Associated liver disease | Can be done in the presence of early fibrosis | Can be done in the presence of early fibrosis |
| Intestinal lengthening | 1.25- to 2-fold | 1.4- to 2.2-fold |
| Reversal of liver disease | Yes | Yes |
| Ability to repeat procedure | None | Possible |
| Complications | Perforation, ischemia | Bleeding, microperforation |
In addition, creative efforts have been made to treat abdominal malignancy including ex vivo tumor resection with gut auto-transplantation. However, failure of autologous intestinal rehabilitation should prompt the need for early transplantation with expected better outcomes. The indications for early referral and transplantation to prevent irreversible neurologic and psychosocial impairments that may have a significant impact on the procedure’s rehabilitative therapeutic indices are summarized in Box 36-2 .
Massive small bowel resection
Severely diseased bowel and unacceptable morbidity
Microvillus inclusion disease
Persistent hyperbilirubinemia
Venous thrombosis of upper body veins
Dysmotility
Portomesenteric thrombosis
Intestinal and Multivisceral Transplantation
Evolution of small bowel transplantation is the result of continual interplay between new advances in surgical techniques, novel immunosuppressive strategies, and better postoperative management. With new insights into the mechanisms of allograft acceptance and other important predictors of long-term functional survival, further progress has been made. Improved postoperative management and better long-term therapeutic efficacy, particularly of the liver-free visceral allograft, has led to improved results.
With U.S. Food and Drug Administration (FDA) approval of tacrolimus and the initial encouraging results with intestinal and multivisceral transplantation, there was a resurgence of clinical interest in the field across major transplant centers. Clinical application of the procedure has gradually increased, with promising outlook especially after the 2000 approval of Centers for Medicare & Medicaid Services (CMS) considering intestinal, liver–intestinal, and multivisceral transplantation procedures as standard of care for patients with irreversible intestinal failure who no longer can be maintained on parenteral nutrition.
Current Clinical Practice
Nomenclature
The three main procedures include intestine, liver–intestine, and multivisceral transplantation with the adoption of a new sub-classification according to the type of added organs introduced by the senior author of this article, Kareem Abu-Elmagd. This nomenclature set the stage for future reporting metrics and outcome analysis. It has been accepted by major professional transplant societies ( Figure 36-3 ).
Indications
CMS has approved reimbursement for Intestinal Transplant (ITx) when life-threatening complications related to TPN occur. The American Society of Transplantation position paper on pediatric ITx also considers patients with high risk of death or with very poor quality of life (QoL) related to the underlying intestinal failure as candidates for ITx. Late referral for ITx is associated with increased perioperative mortality and late postoperative morbidity.
Common indications for visceral transplantation include and are not limited to the following:
- 1.
Failure of TPN therapy
- a.
TPN-associated liver injury: Impending (total bilirubin above 3 to 6 mg/dL, progressive thrombocytopenia, and progressive splenomegaly) or overt liver failure (portal hypertension, hepatosplenomegaly, hepatic fibrosis, or cirrhosis) because of parenteral nutrition–liver injury, stomal bleeding, and liver cirrhosis on biopsy.
- b.
Central venous catheter (CVC)–related thrombosis of two or more central veins (subclavian, internal jugular, or femoral vein).
- c.
Frequent central line sepsis: Two or more episodes per year of systemic sepsis secondary to line infections requiring hospitalization; a single episode of line-related fungemia associated with septic shock and/or acute respiratory distress syndrome.
- d.
Frequent episodes of severe dehydration despite intravenous fluids over and above TPN.
- a.
- 2.
High risk of morbidity and mortality due to the underlying disease
- a.
Desmoid tumors associated with familial adenomatous polyposis.
- b.
Congenital mucosal disorders (i.e., microvillus inclusion disease, tufting enteropathy).
- c.
Ultra short bowel syndrome (gastrostomy, duodenostomy, residual small bowel less than 10 cm in infants and less than 40 cm in older children).
- a.
- 3.
Poor quality of life with socioeconomic concerns
- a.
Intestinal failure with high morbidity (frequent hospitalization, narcotic dependency) or inability to function (i.e., pseudo-obstruction, high output stoma) or family’s unwillingness to accept long-term TPN
- a.
New Trends
Indications for Transplantation
In a series published by Abu-Elmagd, the causes of intestinal failure and indications for transplantation are outlined. Figure 36-4 shows indications for transplantation in children as reported in a biannual report of the Intestine Transplant Association. The reported series evaluated 376 patients who underwent ITx and multivisceral transplantations at a single center. A total of 163 (43.4%) of the 376 patients in the series were pediatric patients younger than 18 years of age at the time of transplantation, with the mean age at transplantation being 26 years. With increased awareness, more patients are being referred for transplantation before development of TPN-associated liver failure and thus receive liver-free allografts. Combined liver small bowel transplantation is only indicated for patients with advanced liver damage and severe cholestasis. Several patients have undergone isolated intestinal or modified multivisceral transplantation with preservation of native liver including those with short bowel, pseudo-obstruction, and Gardner syndrome. In contrast, isolated liver transplantation has been used for liver failure in highly selected patients with short bowel syndrome. Multivisceral transplantation with inclusion of the liver has evolved to be an effective therapeutic modality for patients with hepatic failure and diffuse portomesenteric venous thrombosis who are not suitable candidates for isolated hepatic replacement. Patients with preserved hepatic functions should be considered for portal hypertensive surgery as a permanent therapy or bridge to multivisceral transplantation.
Early Transplantation
Early transplantation before the development of nutritional failure or progression of liver disease is becoming the standard of care. Recently published data favor early transplantation with better outcomes and improved quality of life ( Figure 36-5 ). Cholestatic disease progression in the native liver can be forestalled, leading to a reduction in end-stage liver disease and death on the liver transplantation waiting list. An added advantage of isolated ITx is that allograft enterectomy can be undertaken should the graft reject or thrombose, reverting the patient back to TPN. Occasionally, isolated liver transplantation can be lifesaving in patients who have short gut syndrome. Survival after transplantation is comparable to that in patients with TPN-dependent intestinal failure despite the use of the procedure as a rescue therapy. Successful transplantation leads to nutritional autonomy with better quality of life and improved value of health care.
