Intestinal failure

Intestinal failure in children is defined as the reduction of functional gut mass below the minimum needed for digestion and absorption of nutrients and fluids required for growth. Causes of intestinal failure that lead to IT are outlined in Box 1 , with short bowel syndrome as the leading cause, followed by motility and mucosal disorders. The important role of dedicated multidisciplinary and professional gut failure programs has become evident in the last decade. Children who are treated by such programs have improved survival rates, expedited intestinal adaptation, faster weaning from PN, a lower incidence and severity of intestinal failure-associated complications, and a reduced requirement for IT.

A combined medical and surgical treatment is a key factor in successful intestinal adaptation. Surgical interventions include early stoma closure and lengthening procedures that can improve the absorptive capacity of the failing gut and shorten the duration of PN. Reports on the novel STEP bowel lengthening procedure have shown a 50% to 60% increase in small bowel length and a significant improvement in oral tolerance. Medical strategies to improve intestinal adaptation include prevention of infections by careful central line care and control of bacterial overgrowth; early and continuous enteral feeding; use of elemental formulas; optimization of PN treatment; and prevention of intestinal failure-associated liver disease (IFALD). Uncontrolled studies suggest that treatment with a fish oil-based lipid emulsion often corrects the hyperbilirubinemia associated with soy-based lipid emulsions. Although more studies are needed to define the efficacy and optimal balance of lipid sources, it seems that fish oil-based emulsions have the potential to substantially reduce the frequency of IFALD. Although most patients with chronic intestine failure do well with these treatments, a small proportion are refractory to standard therapies and this is where IT plays a role.

Historical notes

IT has had a slower genesis than other solid-organ transplants. In 1959, Richard Lillehei and coworkers published a landmark paper describing the techniques for orthotopic IT in dogs, which demonstrated absorptive function for up to 7 days before the grafts were lost to rejection. Subsequent early attempts at clinical IT using antilymphocyte products, azathioprine, and steroids failed because of graft rejection. In 1989, Goulet’s group, at the Hôpital Necker-Enfants Malades, Paris, performed the first deceased-donor clinical isolated IT to achieve long-term survival in an infant who was initially treated with cyclosporine. Around the same time, Grant and colleagues (London, Ontario, Canada) reported the first successful combined liver and intestine transplant. The techniques for IT and MVTx using tacrolimus were subsequently developed, refined, and reported by Sudan and colleagues (Omaha, NA), Abu-Almagd and colleagues (Pittsburgh, PA), and Selvaggi and Tzakis (Miami, FL). In the early 1990s, the results of live-donor IT with tacrolimus were reported by Benedetti and colleagues and Gruessner and Sharp. From the late 1990s until today, these groups along with Beath and colleagues (Birmingham, AL), Venick and colleagues (Los Angeles, CA), Fishbein (Washington, DC), and others have continued to advance the field through a reemphasis on the development of multidisciplinary teams to treat intestine failure; earlier referral and listing for transplantation; the use of anti-interleukin 2 (anti-IL-2) agents for induction immune suppression; the use of more aggressive methods to prevent and preemptively treat viral infections; the introduction of rapamycin for IT; and early detection and treatment of acute rejection (AR).

Historical notes

IT has had a slower genesis than other solid-organ transplants. In 1959, Richard Lillehei and coworkers published a landmark paper describing the techniques for orthotopic IT in dogs, which demonstrated absorptive function for up to 7 days before the grafts were lost to rejection. Subsequent early attempts at clinical IT using antilymphocyte products, azathioprine, and steroids failed because of graft rejection. In 1989, Goulet’s group, at the Hôpital Necker-Enfants Malades, Paris, performed the first deceased-donor clinical isolated IT to achieve long-term survival in an infant who was initially treated with cyclosporine. Around the same time, Grant and colleagues (London, Ontario, Canada) reported the first successful combined liver and intestine transplant. The techniques for IT and MVTx using tacrolimus were subsequently developed, refined, and reported by Sudan and colleagues (Omaha, NA), Abu-Almagd and colleagues (Pittsburgh, PA), and Selvaggi and Tzakis (Miami, FL). In the early 1990s, the results of live-donor IT with tacrolimus were reported by Benedetti and colleagues and Gruessner and Sharp. From the late 1990s until today, these groups along with Beath and colleagues (Birmingham, AL), Venick and colleagues (Los Angeles, CA), Fishbein (Washington, DC), and others have continued to advance the field through a reemphasis on the development of multidisciplinary teams to treat intestine failure; earlier referral and listing for transplantation; the use of anti-interleukin 2 (anti-IL-2) agents for induction immune suppression; the use of more aggressive methods to prevent and preemptively treat viral infections; the introduction of rapamycin for IT; and early detection and treatment of acute rejection (AR).

Referral criteria and indications for listing

Despite optimal treatment of intestinal failure, about 10% to 15% of patients develop life-threatening complications. Early and timely referral of these patients for a pretransplant assessment is a crucial determinant for their survival because (1) the waiting list mortality is higher for IT than for other solid-organ transplants; and (2) patients who are transplanted while waiting at home have an approximately 15% higher survival rate than those who are transplanted while waiting in hospital (Intestinal Registry Report, Bologna 2009). Early reports assessing the mortality of patients on the waiting list for IT during the late 1990s showed a significantly higher mortality compared with other solid-organ recipients, with mortality of 50% in some series. A variety of reasons contribute to this high incidence, including late referrals of patients for transplant, scarcity of size-matched donors in the young age group, and allocation criteria (United Network for Organ Sharing [UNOS] and others) that did not account for the unique risk factors of IT candidates. To reduce waiting list mortality, UNOS criteria were recently revised, adding 23 points to the MELD (Model for End-stage Liver Disease) or PELD (Pediatric End-stage Liver Disease) score of patients needing liver transplantation and IT.

Criteria for referral for pretransplant assessment are provided in Table 1 . Unlike the restricted listing criteria, the referral criteria are more inclusive to ensure timely referral and listing with better patient outcome. Many patients who are referred for transplant assessment can be treated by other means and do not necessarily require listing for IT.

Listing for transplant based on the following criteria is considered only when all treatment options directed to achieve intestinal adaptation have failed. The American Society of Transplantation (AST) recommends that listing should be considered for the complications outlined in Table 1 . When considering listing for IT, intestinal adaptation is not simply length dependent, and under some circumstances adaptation can be achieved in children with intestinal length as short as 10 to 15 cm. In addition, there is a wide spectrum of disease severity with many of the congenital causes of gut failure, and expert management can significantly improve the outcome in these cases. Thus, each child requires an individualized assessment to evaluate the unique circumstances of their disease with judicious use of the listing criteria.

The survival advantage of IT for patients with liver failure as a result of PN has recently been confirmed by Pironi and colleagues. This group conducted a 3-year prospective European multicenter study to assess the validity of the AST listing criteria by comparing the 3-year outcome of adults (n = 357) and children (n = 114) with intestinal failure who were either candidates (n = 153) or noncandidates (n = 320) for IT. Three-year survival was lower in candidates without transplantation compared with noncandidates (87% vs 94%, respectively), supporting the view that IT is the standard of care for children and adults with chronic intestine failure who are doing poorly on PN. However, unlike patients who were listed for liver failure or central line-related complications, patients who were listed for QOL reasons alone or for high-risk disease (microvillus inclusion disease, tufting enteropathy) had a higher mortality after transplantation than those patients who were not transplanted. Thus, great caution should be exercised when considering IT for treatment of a poor QOL on PN or high-risk disease.

The contraindications to IT are similar to other solid-organ transplants: severe neurologic disabilities, life-threatening systemic diseases, severe immunologic deficiencies, nonresectable malignancies, and specifically for IT, multisystem autoimmune disease and insufficient vascular patency to guarantee vascular access for up to 6 months after transplant.

Pretransplant evaluation of recipient

As in other solid-organ recipients, the goals of the pretransplant assessment are to achieve a comprehensive evaluation of the patient’s clinical status before transplant; to exclude patients with contraindication for transplant; to stabilize and improve the candidate’s nutritional and clinical status to improve their posttransplant outcome; and to ensure that the child and family understand and are able to manage the requirements after transplant.

In the authors’ center, pretransplant assessment includes viral serology (hepatitis A virus, hepatitis B virus, hepatitis C virus, herpes simplex virus, CMV, EBV, human immunodeficiency virus, varicella-zoster virus, measles, rubella) and toxoplasmosis; anthropometric and laboratory nutritional assessment with optimization of pretransplant nutrition; cardiology and nephrology assessment including glomerular filtration rate (GFR) measurement to assess kidney reserve before transplant and the need for renal transplantation; imaging studies (Doppler survey of central veins, abdominal ultrasound, and for selected patients gastrointestinal follow-through, gastric emptying studies, and abdominal computed tomography scan); and assessments by an oral therapist for eating behavior, by a physiotherapist for motor skills, and by a social worker for the family and the child’s ability to cope with the challenges after transplant. During the assessment process the candidate and the family are informed by the medical and surgical team about the pre- and posttransplant process, the related risks, and the possible outcome of IT. Further studies and consultations are tailored to the specific patient according to their medical history and clinical status. In addition to this comprehensive assessment the patient is followed routinely every 3 to 6 months by the transplant team until transplantation.

Transplant surgery and techniques

There are 3 major types of grafts: isolated intestine transplants; intestine plus liver transplants, which usually include the duodenum and head of pancreas to avoid the need for a biliary anastomosis; and MVTx, which can include any of the abdominal organs along with the small intestine ( Fig. 1 ). Partial intestine and liver grafts can be procured from living donors, although these techniques are not routinely used as in liver or kidney transplantation.

Surgical techniques of IT and MVTx: ( A ) Isolated IT, ( B ) combined liver transplantation and IT, ( C ) MVTx including the colon. AC, aortic conduit; CBD, common bile duct; D, donor; HA, hepatic artery; IVC, inferior vena cava; P, pancreas; PV, portal vein; R, recipient; SMA, superior mesenteric artery; SMV, superior mesenteric vein; SV, splenic vein.

Isolated intestine grafting is indicated for patients with limited venous access, recurrent line infections, reversible liver dysfunction as a result of PN, and unmanageable fluid and electrolyte problems associated with PN. An isolated intestine graft is the preferred surgical option because there is no shortage of deceased-donor organs and the graft can be removed, if necessary, without compromising the function of other intra-abdominal organs.

The liver should be added to an intestine graft when the recipient has irreversible liver damage as a result of PN, usually manifested by severe fibrosis with or without portal hypertension and liver dysfunction.

MVTx are indicated for children with severe motility disorders; locally aggressive but nonmetastazing tumors; or patients with extensive abdominal pathology that cannot be safely removed without an evisceration or reconstruction with multiple organs (eg, children with multiple previous operations and severe portal hypertension). Inclusion of colon in the graft is controversial. The allografted colon has been shown experimentally to slow intestinal transit time and improve absorption. However, early clinical studies suggest that it may also increase the bacterial load in the terminal ileum, leading to bacterial translocation and an increased rate of sepsis. A recent report by Kato and colleagues has shown that inclusion of colon had no additional effect on morbidity or on poor graft survival.

With isolated intestinal grafts, the donor superior mesenteric artery (SMA) is anastamosed to the recipient’s SMA or native aorta. It does not seem to matter whether the portal venous drainage of the graft is directed to the inferior vena cava or into the portal system of the recipient. For composite grafts, a donor aortic conduit is usually anastomosed to the recipient’s infrarenal aorta. The proximal bowel is anastamosed to the native bowel. The distal bowel is brought out as an end ileostomy or anastamosed end to end with the recipient bowel, with creation of a proximal, diverting loop ileostomy.

Graft dysfunction

Nutrition after transplant

Discontinuation of PN and oral autonomy are major goals of IT. The optimal nutritional treatment after transplant has not been studied in large randomized studies and is currently based on expert opinion and individual center experience. Key management questions such as polymeric versus elemental diet, timing of introduction and type of solid foods to be used after transplant, and rate of PN weaning have not been fully answered yet.

Tolerance of tube feeding or solids in the early phase after transplant is frequently hampered by graft malfunction as a result of infection, rejection, or PTLD and by the physiologic changes in the intestine after transplant, including extrinsic denervation, dysmotility, lymphatic disruption, and fat malabsorption. Prevention of these posttransplant complications promotes PN weaning and oral tolerance. PN is commonly initiated 1 to 3 days after transplant and enteral feeding is started at postoperative day 5 to 7 following resolution of the postsurgical ileus. Some centers start feeding with an elemental, low-fat, low-osmolality formula, whereas others use polymeric formula. Introduction of solids, which can be started as early as 2 weeks after transplant, is often challenging in children who have been dependent on PN for years, have not acquired eating habits, or suffer from food aversion. Solids are usually limited initially to low-fat, low-osmolarity, low-sugar, and low-lactose feeds to avoid high stoma output. The diet is advanced as tolerated. Augmentation of solid-food diet with overnight tube feeding and extra fluids is frequently required in young children to avoid dehydration and to promote growth.