Intestinal and Multivisceral Transplantation 

Updated: Feb 22, 2021
Author: Richard K Gilroy, MBBS, FRACP; Chief Editor: Stuart M Greenstein, MD 

Overview

Practice Essentials

Parenteral nutrition remains the standard of care for most patients with intestinal failure. Currently, only limited numbers of intestinal transplants are performed in pediatric patients, as a result of advancements in intestinal rehabilitation programs and stagnant long-term outcomes of intestinal transplantation.[1] Similarly, in adults, advances in the medical and surgical treatment of intestinal failure have reduced the need for transplantation, and no significant improvement in survival has been seen in transplant recipients since 2005.[2] Nevertheless, intestinal transplants can be lifesaving in patients with severe complications from parenteral nutrition. See the image below.

Revascularized bowel prior to closure. In the lowe Revascularized bowel prior to closure. In the lower right corner the anastomosis between the donor small bowel and recipient remnant colon can be seen.

Total parenteral nutrition (TPN) became available in 1969, with a number of patients relying on it for complete support. At first, all patients on TPN required continuous hospitalization.[3, 4] Currently, TPN is safely used in outpatient management. Pooled data from the North American Home Parenteral and Enteral Patient Registry showed 1- and 4-year survival rates for patients with short bowel syndrome (SBS) who received TPN at home to be 94% and 80%, respectively. Only 5-11% of deaths were directly attributed to TPN, with the vast majority of deaths related to progression of the underlying primary disease.[5]

The success of TPN supplanted the then-urgent need to find solutions for the problems with intestinal transplantation, and TPN became the standard of care. Subsequently, intestinal transplantation has been offered to that minority of the patients on long-term TPN who have severe and life-threatening complications related to this therapy.[6, 7] These TPN-related complications include the following[8] :

  • Impending or overt liver failure related to TPN (parenteral nutrition–associated liver disease [PNALD)
  • Impending loss of vascular access for TPN administration
  • Multiple episodes of catheter-related sepsis
  • A single episode of life-threatening catheter-related sepsis
  • Frequent episodes of significant dehydration despite supplemental fluid administration 

Improvements in surgical technique, the monitoring and diagnosis of rejection, and cytomegalovirus (CMV) prophylaxis and the development of improved immunosuppression have paved the way for signiicant improvements in patient and graft survival rates. Most recipients of intestinal transplants are free from TPN and enjoy an excellent quality of life. Compared with TPN, intestinal transplantation is cost-effective within 1–3 years of graft survival.[7]  

In addition to isolated small bowel transplants, other types of gut transplantation include the following:

  • Liver–small bowel transplants
  • Modified multivisceral transplant with exclusion of the liver
  • Full multivisceral transplant (ie, stomach, duodenum, pancreas, intestine, and liver)

See the images below:

Liver–small bowel transplants address liver failure from prolonged TPN, and post-transplant survival rates may be higher in these patients, compared with recipients of isolated intestine transplants, due to the immunologic benefits of the liver. However, most patients with short bowel syndrome, pseudo-obstruction, and Gardner syndrome receive isolated intestinal or modified multivisceral transplantation Furthermore, regression of liver disease after intestine-only transplant has been reported in patients who had significant liver fibrosis.[7]

Rejection and infection are still the most perplexing problems surrounding intestinal and multivisceral transplantation.  Earlier patient referral, the development of new immunosuppressive agents, and the discovery of a serum marker for graft rejection are the keys to continued improvements in graft and patient survival rates.

Background

At the turn of the 20th century, Alexis Carrel demonstrated the technical feasibility of intestinal transplantation; however, acute allograft rejection was an insurmountable obstacle in the absence of immunosuppressive medications.[9]  In the 1960s, surgeons demonstrated renewed interest in intestinal transplantation following early successes with kidney transplantation. This interest rapidly waned as the inadequacy of the immunosuppressive medications available at the time became apparent.

Intestinal transplantation achieved a clear recognition in the management of complicated total parenteral nutrition (TPN) with Medicare approval (see below). The relatively brief history of intestinal transplantation before then included dismal outcomes prior to 1990 and a moratorium during 1994 as a consequence of the high morbidity and mortality associated with the procedure.

Since 1995, however, rapid improvements in outcomes have been seen. By and large, this success is a consequence of multiple endeavors, including the following:

  • Progress in immunosuppressive therapy; in particular, the introduction of tacrolimus [10]
  • Better understanding of intestinal immunology
  • Refinement of surgical techniques [11]
  • Improvement in post-transplant care
  • Implementation of protocols for monitoring and prophylaxis of infection (primarily  cytomegalovirus [CMV] infection)

On October 4, 2000, the US Health Care Financing Administration (HCFA) approved coverage by Medicare for intestinal transplantation. Medicare agreed to cover all types of intestinal transplants for patients with irreversible intestinal failure who have specific life-threatening complications from long-term intravenous nutrition and TPN. Medicare's criteria for approved centers include an annual volume of at least 10 intestinal transplants and a 1-year actuarial survival of at least 65%. The decision was important because most state Medicaid and other third-party payers in the United States followed suit and provided reimbursement for intestinal transplantation.

However, after steady increases over the preceding decade, the number of intestinal transplantations in the United States peaked in 2007, at 198 transplants, then stabilized at approximately 100 to 120 cases per year. In 2020, only 91 intestinal transplants were performed in the US.[12] See the image below.

Intestinal transplants by year in the United State Intestinal transplants by year in the United States. Data source: Organ Procurement and Transplantation Network https://optn.transplant.hrsa.gov/data/view-data-reports/national-data/#

Along with the decline in intestinal transplants, over the past decade the number of new patients added to the intestine transplant waiting list and the number of intestine donors also decreased. Graft failure plateaued over that period. Patient survival for transplants in 2011-2013 was lowest for adult intestine-liver recipients (1- and 5-year survival 66.7% and 49.1%, respectively) and highest for pediatric intestine recipients (1-and 5-year survival 89.1% and 76.4%, respectively).[13]

Concurrent with the reduction in transplant numbers, transplant programs have placed a greater focus on refining and optimizing the management of patients with rehabilitation and are using multidisciplinary approaches to intestinal failure and short bowel syndrome.[14]  Evidence supports the conclusion that this strategy has reduced these patients' likelihood of developing an indication for intestinal transplantation; when coupled with refinements in the management of TPN-dependent intestinal failure (with novel agents such as teduglutide), continuing reductions in overall listings appear likely.

Relevant Anatomy

Relevant donor anatomy

For isolated intestinal transplantation in patients with normal anatomy, the superior mesenteric artery (SMA) of the donor is procured with the aortic cuff. The portal vein is cut above the confluence of the superior mesenteric and splenic vein. If a right replaced hepatic artery from the SMA is present, the SMA is cut distal to the takeoff of the replaced hepatic artery. The SMA of the donor is anastomosed to the recipient SMA or the abdominal aorta. The portal vein of the donor is anastomosed to the portal vein or the inferior vena cava of the recipient.

For liver and intestinal or multivisceral transplantation, the celiac trunk and SMA are procured with the abdominal aorta and thoracic aorta. The inferior vena cava is procured from the iliac vein bifurcation to above the diaphragm. The anastomosis is performed between the donor abdominal aorta and the recipient abdominal aorta in an end-to-side fashion.

Pathophysiology

Short bowel syndrome is often the result of extensive intestinal resection for multiple pathophysiologies, such as volvulus, trauma, tumor, and thrombosis. An inadequate absorptive surface results in an inadequate energy intake and malabsorption of vitamin B12 and other vitamins. Calcium and magnesium deficiencies can lead to neurologic complications such as encephalopathy, tetany, and convulsions. Intestinal failure with hyperalimentation causes liver failure. Patient on long-term hyperalimentation usually have complications, including line sepsis, thrombosed veins, and liver dysfunction.[15]

Etiology

Intestinal failure is a term applied to individuals who are unable to maintain adequate nutrition with an enteric diet. These patients require TPN to maintain energy (caloric) intake. Most often, intestinal failure occurs secondary to surgical resection, leading to short bowel syndrome (SBS), although functional disorders in motility, mucosal defects, obstruction, and fistulae may also result in intestinal failure.[16] The causes of intestinal failure include anatomic and functional abnormalities and, along with the population affected, are listed below.

In pediatric patients, causes are as follows:

In adult patients, causes are as follows:

Patients with SBS have insufficient small bowel length to support energy (caloric) needs; this typically occurs when at least 80% of the small intestine has been resected. Resection of less than 80% of the length of the bowel is generally followed by intestinal adaptation and subsequent enteral tolerance. Considerable interindividual variability occurs among patients: Some may require TPN despite having less than 80% of their small intestine resected, while others may not require TPN after more extensive resections. This fact emphasizes the importance of trials of enteral tolerance and nutritional rehabilitation while assessing an individual with SBS (see Intestinal rehabilitation).

Additional factors that may increase the likelihood of achieving enteral tolerance include the following:

  • Younger age
  • Presence of an ileocecal valve
  • Presence of an ileum

The functional causes of intestinal failure in those with normal bowel length include the following:

  • Intestinal aganglionosis
  • Chronic idiopathic intestinal pseudo-obstruction
  • Congenital mucosal abnormalities such as microvillous inclusion disease

Indications

Indications for transplantation

The most common cause of death for individuals permanently dependent on TPN is liver failure. Steatohepatitis and cholelithiasis with or without associated cholecystitis are common in patients on TPN and warrant exclusion before the physician makes a diagnosis of TPN-induced liver disease. Advanced TPN-induced liver disease is irreversible; however, when it is identified early it is often reversible with discontinuation of TPN.

Progressive liver disease is more common in young children on TPN and is often associated with a history of multiple resections and recurrent infection. Progressive and irreversible liver disease develops in 2-42% of children and adults with intestinal failure due to SBS.[17, 18, 19, 20, 21] The development of liver disease may be related to enteric stasis, the ability to establish some degree of enteral tolerance, catheter-related sepsis, age, a history of prematurity, the extent of bowel resection, the presence of an underlying inflammatory condition, or the length of time on TPN.[22, 23, 24, 25, 19, 21] The mediators and pathways responsible for the progression of TPN-associated liver disease to end-stage liver disease remain undefined.

Two other causes of life-threatening complications in patients with intestinal failure include recurring sepsis and loss of vascular access due to venous thrombosis.[25, 26] These problems are often concomitant. Sepsis associated with indwelling catheters is more common in children; in some patients, recurrent sepsis is related to gastrointestinal stasis and bacterial overgrowth. Overall, the mortality rate associated with catheter-related sepsis has progressively diminished with the introduction of flexible, silastic, silicone rubber catheters; tunneled, cuffed catheters; and improved line care.[27, 28, 29]

Less common indications for intestinal transplantation include locally invasive desmoid tumors, premalignant conditions (Gardener syndrome), and fluid and electrolyte losses unmanageable with TPN.[30]

In summary, intestinal transplantation is a salvage procedure applied to patients who have either anatomic or functional diseases that preclude enteral tolerance (eg, intestinal failure) and have life-threatening complications of TPN such as progressive liver disease, a history of catheter-related sepsis, or loss of vascular access.[30, 31] It cannot be overemphasized that measures to augment intestinal function and minimize the risk of complications of TPN must be explored in every patient on TPN to avoid the need for this procedure.

There is not an established role for preemptive intestinal transplantation, ie, transplantation in the absence of complications of PN or invasive intra-abdominal desmoid tumor. There is, however, a very clear indication to refer patients early to centers of excellence in intestinal failure and transplantation in the setting of ultrashort bowel or major catheter-related complications.[32]

To illustrate the problems faced in the setting of intestinal transplantation, the following variables and the impact of these variables upon the patient's outcome must be remembered:

  • Patients who are admitted from home for their transplant procedure have better survival rates than those who are inpatients at the time they are taken to the transplant procedure.

  • Central vascular access is required for the procedure and in settings in which access is reduced and technical complications and management of posttransplantation complications is increased. Loss of access complicates the procedure by limiting alternative sites for central access should a catheter need to be removed or repositioned. This central access is important for the provision of perioperative TPN and is essential for resuscitation, perioperative fluids, and medication maintenance required in the peritransplant period.

  • Loss of 2 major access sites is generally an indication for intestinal transplantation. At some centers, however, clinicians have decided that the transplantation cannot be performed if all upper and lower central access is lost, which illustrates the necessity for referral if vascular access loss begins to develop.

  • Advanced liver disease may not preclude isolated intestinal transplantation; however, in the presence of advanced liver disease, isolated intestinal transplantation is generally not possible.

  • Waiting list mortality is higher in those awaiting liver–small bowel transplantation than in those awaiting isolated liver transplantation or isolated bowel transplantation.

  • In patients who undergo intestinal transplantation, then lose their graft and have indications for retransplantation, outcomes in retransplantation are inferior to outcomes for the primary transplantation.[33]

Patient evaluation

The goals of patient evaluation for intestinal transplantation are as follows:

  • Establish the primary diagnosis.

  • Evaluate and document TPN complications experienced by the patient.

  • Establish the length and function of the remnant native intestine.

  • Assess the function of the remnant intestine and potential for establishing enteral tolerance.

  • Determine the degree of liver dysfunction and the potential for reversibility.

  • Identify any comorbid conditions that may impact upon the outcome of intestinal transplantation, and identify potential problems (eg, thrombosis of major vessels).

  • Assess candidate suitability (including families) for the rigors of intestinal transplantation and the ability to comply with the often complex posttransplant regimens.[34]

One critical aspect of the evaluation process is to determine whether the patient's intestinal failure is potentially reversible. Most information regarding nutritional assessment comes from a carefully obtained patient history. Particular attention is given to TPN regimens, prior attempts to achieve enteral tolerance, current enteral feeding protocols, growth, development, and exclusion of nutritional deficiencies. Multidisciplinary consultation with experienced pediatric nutritionists, gastroenterologists, and hepatologists is invaluable before determining the presence or absence of nutritional deficiencies and complications from long-term TPN. Many routine screening studies are listed in Workup.

In addition to a thorough history and review of operative records, evaluation of the length and function of the remnant native bowel is further accomplished through radiographic contrast studies. These studies help delineate the length of the remaining small bowel, its anatomic location, the presence or absence of the ileocecal valve, the caliber of the remaining small and large intestine, and the transit time from the proximal to distal bowel. These studies also may help define surgically correctable diseases that permit enteral tolerance without transplantation. Occasionally, additional motility studies are necessary.

The medical and surgical team must be rigorous when establishing the presence of intestinal failure and when defining its cause because Munchausen syndrome by proxy has been reported in an intestinal transplant recipient.[35] For patients with functional disease, review of histopathologic findings following bowel biopsy is important to confirm the diagnosis and extent of bowel involvement.

During the assessment of TPN complications, the physician must decide whether a patient's TPN-related liver disease is reversible. This decision may be difficult, and considerations include liver biopsy findings and the likelihood of progression during the waiting period. The presence of dense, bridging fibrosis may prompt consideration of LSB transplantation. Minor amounts of fibrosis associated with cholestasis may allow ISB transplantation. However, if rapid progression of the disease is observed and a long waiting period is anticipated (eg, small infants), combined listing for LSB transplantation may be indicated.

An assessment for manifestations of portal hypertension is important, although diminished mesenteric blood flow secondary to the short remnant intestinal length provides protection against varices. Increasing splenomegaly, cytopenia, dilated superficial abdominal veins, and bleeding from gastrostomy sites or stomata provide clues to the presence of portal hypertension. The bilirubin level alone is not a good indicator of whether ISB or LSB transplantation is indicated. ISB transplantation in jaundiced patients has been shown to reverse liver disease, even in patients with a total bilirubin level of 20 mg/dL at the time of transplantation.[36]

Doppler ultrasonography is used to assess venous access and to determine the patency of the central veins. Intestinal transplantation is considered when the patient has lost 2 or more common venous access sites, such as the subclavian or internal jugular veins, or when unconventional sites such as the right atrial, transhepatic, or direct inferior vena caval catheters are required.

Patient history and previous records should reveal the number and type of organisms responsible for previous central venous line infections. Fungal infections requiring mechanical ventilation or vasopressor support are most worrisome.[26, 5] Furthermore, a history of infection with multidrug-resistant organisms should raise concern for future mortality and should be considered in the overall assessment.

Comorbid conditions can greatly increase the likelihood of complications in the posttransplant period. Specific evaluations of other organ systems are dictated by patient history and are further directed by any abnormalities identified from the results of baseline studies. For example, intestinal failure as a consequence of necrotizing enterocolitis may be associated with a history of prolonged neonatal ventilation and bronchopulmonary dysplasia. These conditions are associated with repeated hospitalizations and a propensity for prematurity in infants, which may give rise to behavioral and developmental problems that should be identified and addressed as early as possible. However, controlled trials to support this are lacking. The authors strongly believe that early intervention facilitates posttransplant recovery and that such interventions are important. Portions of these evaluations are incorporated into the psychosocial assessment of the patient and the patient's support system.

Contraindications

Although most contraindications to transplantation are relative, and a collection of factors might present an absolute contraindication, the following is a list of conditions and situations in which transplantation may be contraindicated:

  • Profound disabilities that are not likely to be corrected by transplantation
  • Severe extraintestinal illnesses that are not likely to be corrected by transplantation
  • Uncontrolled sepsisImmunodeficiency (with the possible exception of immunodeficiency associated with multiple intestinal atresia)
  • Nonresectable or disseminated malignancy (including large hepatoma, desmoid tumour)
  • Complete loss of vascular access or insufficient central access sites (lack of central access during transplantation and during the early posttransplantation period)
  • Absence of psychosocial support or willingness to comply with posttransplant regimens
  • Anatomical elements (eg, size of cavity for the allograft, vascular inflow and outflow)

Prognosis

The International Registry for Intestinal Transplantation reports that graft and patient survival rates have improved, with a 69% 1-year patient survival rate and a 55% graft survival rate since 1995.[30]  Trevizol et al studied the procedure over a 5-year period and reported a 1-year patient survival rate of 80%, but survival decreases after the first year to less than 70%.[37]

Of 110 intestinal transplants performed on 101 children from 1994 to 2014, Necker-Enfants malades Hospital in Paris reported graft survival at 5 and 10 years was 44% and 31% for liver-containing graft and 57% and 44% for small bowel transplants.  Among the 55 currently living patients, 21 had a liver-containing graft, 19 a small bowel transplants (17 after induction), and 15 were on parenteral nutrition. Late graft loss occurred in 13 patients, and 7 of 10 retransplanted patients died. The main causes of death and graft loss were sepsis and rejection.[38]

Earlier referral of the patients for intestinal transplantation yields improved survival results. Isolated transplantation is preferable to combined liver-intestinal or multivisceral transplantation from a survival standpoint. Posttransplant prognosis is also improved when transplantation is performed prior to the onset of liver failure and prior to the exhaustion of all routes of vascular access.

Causes of death included the following:

  • Sepsis after rejection
  • Respiratory failure
  • Sepsis
  • Multiple organ failure
  • Arterial graft infection
  • Aspergillosis
  • Posttransplantation lymphoproliferative disorder
  • Intracranial bleeding
  • Fungemia
  • Chronic rejection
  • Graft versus host disease
  • Necrotizing enterocolitis
  • Pancreatitis
  • Pulmonary embolism
  • Viral encephalitis
 

Workup

Laboratory Studies

Perform a complete blood cell count to rule out anemia and thrombocytopenia. Assess electrolyte levels to look for electrolyte imbalance caused by short bowel syndrome. Perform the following liver function tests to rule out cholestatic liver failure and evaluate liver function:

  • Serum aspartate aminotransferase (AST)
  • Serum alanine aminotransferase (ALT)
  • Alkaline phosphatase (ALP)
  • Glucose tolerance test

Measure prothrombin time (PT) and activated partial thromboplastin time (aPTT) to rule out coagulation abnormalities and evaluate liver function. Measure the following to rule out deficiencies as the cause of thrombosis:

  • Protein C
  • Protein S
  • Clotting factors
  • Vitamins B12, K, and D

Perform urinalysis to evaluate renal function and rule out infection. Calculate creatinine clearance to evaluate renal function. Perform a culture to rule out infection. Assess vitamin levels to evaluate nutrition. Perform an absorption test to evaluate intestinal function.

Donor-specific antibodies (DSA) are evaluated to quantify the sensitization.

Citrulline levels are measured to monitor the condition of the intestine.

Additional tests that may be helpful include the following:

  • Total and direct bilirubin
  • Serum albumin
  • Phosphorus and magnesium
  • Cholesterol and triglycerides
  • Zinc and selenium
  • Free and total carnitine
  • Cytomegalovirus (CMV), Epstein-Barr virus (EBV), hepatitis B virus, hepatitis C virus, and human immunodeficiency virus
  • Alpha-fetoprotein
  • Cytotoxic antibody screen

Imaging Studies

Imaging studies include the following[39] :

  • Doppler ultrasonography of the extremities to assess the patency of the veins
  • Doppler ultrasonography of the liver to assess the patency of the vessels
  • Computed tomography scanning of the abdomen
  • Upper gastrointestinal (GI) series with small bowel follow-through
  • Angiography of the abdomen
  • Magnetic resonance imaging/magnetic resonance angiography
  • Echocardiography/stress echocardiography
  • Nuclear medicine studies

Other Tests

Other tests that may be performed include the following:

  • Electrocardiography
  • Motility studies (as indicated)
  • Liver biopsy (as indicated)
  • Upper gastrointestinal endoscopy

If intestinal failure is functional, the diagnosis depends on the pathological findings and exclusion of other etiologies. Biopsy of the intestine is necessary for the final diagnosis. Perform case-by-case evaluations.

 

Treatment

Medical Care

Therapeutic options

At the completion of the evaluation, the physician should recommend one of the following therapies:

  • Continued medical therapy with total parenteral nutrition (TPN)
  • Isolated small bowel (ISB) transplantation
  • Combined liver/small bowel (LSB) transplantation
  • Multivisceral transplantation
  • Isolated liver transplantation

If intestinal failure is not confirmed during the evaluation, intestinal transplantation is not indicated. If the patient does not exhibit evidence of life-threatening complications of TPN administration, risk-benefit and survival analyses support continued TPN.

Isolated intestinal transplantation is the simplest surgical option and offers potential elimination of TPN and its complications. However, ISB transplantation has not supplanted long-term TPN in the management of short bowel syndrome (SBS) in the absence of TPN-associated complications.[40, 41, 31, 30]

Importantly, if the patient shows evidence of potential to advance to enteral nutrition, guidance is offered to such individuals to facilitate this. These patients should be enrolled in an intestinal rehabilitation clinic (see Intestinal rehabilitation). These specialized multidisciplinary clinics optimize TPN regimens, evaluate for complications of TPN, augment intestinal adaptation, and establish timely referral for surgery or transplantation, if needed. Transplantation for intestinal failure, at this point, might be best viewed as a salvage procedure for patients with progressive complications of TPN.

Teduglutide (Gattex), a glucagon-like peptide-2 (GLP-2) analogue, binds to GLP-2R receptors; this promotes local release of intestinal mediators that increase intestinal absorptive capacity, resulting in increased fluid and nutrient absorption.[42] Teduglutide was approved in 2012 for the treatment of adult patients with SBS who are dependent on parenteral support. In 2019, approval was extended to pediatric patients 1 year of age and older with SBS who need additional nutrition or fluids from parenteral support. Use of this agent may reduce the number of patients requiring transplantation for intestinal failure.

Intestinal rehabilitation

Intestinal rehabilitation is an emerging subspecialty. It focuses on measures to optimize enteral tolerance while concurrently assessing, preventing, or managing the complications of TPN. Rehabilitation is most successful when undertaken by multidisciplinary teams with a coordinated approach. These groups use modifications to diet, in association with judicious use of medications, to optimize enteral tolerance of the bowel that is present. In some instances, surgical procedures are performed to remove areas of stasis or to lengthen the bowel. Pivotal to the success of intestinal rehabilitation is the patient's participation within the framework of a multidisciplinary team.[43] . Sudan and others have shown reductions in TPN following these procedures; weaning from TPN has been achieved in several patients following lengthening with step-enteroplasty.[44]

Intestinal failure is defined as a reduction of intestinal absorption so that macronutrient, water, electrolyte supplements, or a combination thereof are needed to maintain health or growth. Severe intestinal failure is when PN, fluid, or both are needed. Mild intestinal failure is when oral supplements or dietary modification suffice. Short bowel syndrome (SBS) is present when failure results from intestinal loss and failure to adapt by 1 month.

Approximately 10,000-20,000 patients with SBS are treated each year in the United States. The incidence is 1-2 cases per 100,000 persons per year, and this accounts for approximately one third of home TPN users. The severity of the disease generally correlates with remnant bowel length and the loss of the ileocecal valve. Over the past decade, the severity of SBS has been better correlated with the absolute function of the intestine that remains, as enormous interindividual variability is present. Of those patients on home TPN, the survival rate is 90% for instances in which TPN was commenced for benign disease as compared with 15% 1-year survival rates in cases in which TPN was commenced for intestinal failure that developed as a consequence of malignant disease.

Intestinal rehabilitation monitors for complications of TPN. These complications include the following:

  • Line infections: Sepsis (frequency 0.4-2 times per year; catheters used for TPN have less catheter colonization than catheters used for other indications.), endocarditis, phlebitis
  • Occlusion: 0.1 times per year
  • TPN-related liver disease
  • Iatrogenic effects (malposition, migration, leaks)
  • Metabolic effects (osteopenia/osteoporosis, diabetes mellitus), electrolyte levels, fluid levels, vitamin deficiencies
  • D-lactic acidosis
  • Manganese and aluminium toxicity
  • Stone disease (renal, biliary)
  • TPN nephropathy

The intestinal rehabilitation program diet involves graduated introduction of a diet from day 5 postresection, when the ileus has resolved. Dietary components may involve some of the following recommendations:

  • Iso-osmolar restriction to 500 cal/d initially, followed by graduated increases to caloric intake
  • Encourage salt and carbohydrate combinations, especially in patients who have a jejunostomy (avoid simple concentrated carbohydrates in isolation)
  • Liquid supplements (gluconate forms)
  • Rice starch products
  • Medium-chain triglycerides
  • Fat restriction: Restrict fat to around 30% of daily intake if colon is in continuity (combined with soluble fibers and complex starches); if the patient has no colon, fat restriction may not be necessary, as fat is felt to be a good energy source in these patients.
  • Glutamine
  • Lactose avoidance
  • Oxalate avoidance
  • Jejunostomies isotonic high sodium (encouraged target is 90 mmol/L)
  • Fiber: Clinical trial data suggest that fiber assists ostomy outputs by modifying the consistency of these outputs; soluble fiber metabolism is an important potential source of nutrition in some patients (fermented to short-chain fatty acids [SFA]). [45, 46]

Medical approaches include the following:

  • Acid suppression (H2 blocker, proton pump inhibitor)
  • Antidiarrheal medications (high dose)
  • Vitamin supplements (high dose)
  • Caution with magnesium and potassium supplements (These supplements may be required to offset losses. However, the physician must recognize that both may contribute to ostomy losses at higher doses and that short transit times may reduce the efficacy of tablet forms.)
  • Cholestyramine (with caution)

Intestinal adaptation postsurgery is generally near completion by 6 months after the procedure. Medical therapies to consider at that time include the following:

  • Bacterial overgrowth management (generally applied as therapeutic trials of antibiotics with clinical responses the end point to be monitored for)
  • Octreotide may be considered to treat refractory diarrhea, although tachyphylaxis develops and use in patients with in situ gallbladders increases the likelihood of cholelithiasis.
  • Clonidine may assist by acting to reduce high outputs for the GI tract (Use caution, as the use of this drug may be associated with hypotension, particularly if initiated in a dehydrated patient.)
  • Pancreatic enzymes (to be used, in particular, in patients with risk for deficiencies of pancreatic enzymes)
  • Bisphosphonates [47]
  • Growth hormone [48]
  • Glucagonlike peptide-2 (GLP-2) [49]

Surgical approaches, in addition to those that restore continuity and manage infections, focus primarily on increasing intestinal length and enhancing function. These surgeries are a form of autologous gastrointestinal reconstruction (AGIR) and include the following:

  • Tapering enteroplasty
  • Bowel plication
  • Reverse segments
  • Creation of intestinal valves
  • Kimura procedure
  • Longitudinal intestinal lengthening [50]
  • Serial transverse enteroplasty (STEP) [51]

These approaches should be explored in an effort to avoid intestinal transplantation. Late referral to centers with clinicians experienced in SBS may limit the alternatives available. In the author's opinion, late referral may also increase the risk of complications related to any of the therapeutic options listed above.

Surgical Care

LSB transplantation is recommended for individuals with irreversible liver injury and intestinal failure. These patients have more severe disease than recipients who receive ISB grafts, and patients waiting for LSB transplantation constitute the majority of intestinal transplant candidates. Waiting list mortality rates are high, and patients are often in intensive care units at the time of transplantation.

Multivisceral transplantation includes transplantation of grafts of other abdominal viscera along with the liver and intestinal grafts. This may include the stomach, pancreas, kidney, and/or colon. This procedure is usually reserved for patients with additional organ system failure (eg, pancreatic insufficiency, diabetes, kidney failure), often on a background of a nonreconstructible gastrointestinal tract.

Multivisceral transplantation is also indicted for patients with duodenal fistulae or locally aggressive tumors that can only be treated with massive abdominal evisceration.[26]  The main drawback with including the stomach appears to be poor emptying, and authorities at some centers completely avoid this by performing a gastrojejunostomy between the allograft and a small native gastric remnant. Surgeons at the University of Pittsburgh have demonstrated that inclusion of the colon diminishes survival and is not recommended.

Although some researchers have demonstrated adequate stomach function after LSB transplantation in patients with motility disorders, Tzakis suggested that multivisceral transplantation with removal of the native stomach at the time of transplantation is indicated for these patients. However, other researchers are not necessarily in agreement with this approach.[5, 52, 40]  Patients who receive multivisceral grafts have lower overall survival rates compared with patients who receive other types of intestinal allografts.[26]

In a small group of predominantly pediatric patients, liver dysfunction related to TPN progresses during the period in which enteral tolerance is being established after intestinal resections. This is usually during the initial evaluation period and, in a select few centers, has been noted to follow aggressive intestinal rehabilitation. If enteral tolerance is likely to be achieved following transplantation, isolated liver transplantation may be recommended.[41, 53]

In patients being considered for isolated liver transplantations, assessment of adequate bowel length is best accomplished by demonstrating enteral tolerance. A history of weight gain during the administration of 50% or more of the energy (caloric) requirements via the enteral route is encouraging. Surrogate markers for the potential of further adaptation include the remaining length of small bowel relative to the patient's age and the presence of the ileocecal valve. The high waiting list mortality rate for LSB transplant candidates makes this is an attractive option for carefully selected patients.

The goal of intestinal transplantation is to eliminate the need for TPN and to reverse or prevent TPN-associated liver disease. The clear disadvantage of intestinal transplantation is the considerable morbidity and mortality associated with the procedure and with the morbidity and cost associated with long-term immunosuppression.

An important publication by Kato et al compared patient and surgical outcomes from intestinal transplantation in which the colon and ileocecal valve was included as part of visceral transplantation procedure with those without.[54]  They identified benefits in stool volume and frequency without additional morbidity or mortality risk. Limitations to this study include its retrospective nature and potential selection biases.

When considered in the context of others reports reviewed by Matsumoto,[55]  the evidence suggests improved stool patterns and potential for fecal continence, potential further improvements in quality of life indices over those already achieved with intestinal transplantation,[56]  and no increase in risk of allograft loss, provided the candidates for this are well selected.

Preoperative Details

Before organ procurement, all the teams, including the liver transplantation team, the kidney transplantation team, the pancreas transplantation team, and the intestinal transplantation team, must discuss the procedure with any organ procurement surgeons present who are unfamiliar with intestinal graft procurement. This discussion addresses any concerns that each team may have regarding the specific organ they are recovering.

Patients referred for intestinal transplantation are evaluated by a multidisciplinary team with representatives from the following specialties:

  • Transplant surgery
  • Gastroenterology
  • Nephrology
  • Cardiology
  • Radiology
  • Nursing
  • Psychology
  • Social work

Pertinent information for evaluation of candidates for intestinal transplantation includes the following:

  • A detailed medical and surgical history
  • Radiologic mapping of GI anatomy
  • Radiologic assessment of the patency of the 6 major routes of central venous access (eg, internal jugular, subclavian, femoral)
  • Assessment of liver, renal, and cardiac function

Precise information regarding previous abdominal surgery and the length of remaining intestine is critical. Liver function test results must be carefully evaluated for derangements that suggest the need for biopsy evaluation. If significant fibrosis, macrosteatosis, or cirrhosis is present on liver biopsy, then liver transplantation is necessary. Evaluation of renal function is critical because of the need for long-term use of tacrolimus postoperatively.

Waiting list mortality

The waiting list mortality rate is nearly 50% for LSB candidates and approximately 10% for ISB candidates although this may have changed in the last 4 years. The lower mortality rate for ISB candidates is principally related to a lesser degree of liver disease. However, the mortality rate for ISB transplantation is underestimated because patients whose disease progresses may require the combined procedure and therefore are not included in ISB mortality figures. At the University of Nebraska, 30% of patients placed on the ISB waiting list develop progressive liver dysfunction and become LSB candidates; half of these patients die while waiting for a transplant.[36] The mean waiting time is more than twice as long for patients whose status has changed compared with those who undergo isolated intestinal transplantation.[36]

Donor selection and organ procurement

Intestinal transplant donors typically include those donors who would be suitable for other forms of organ donation. The donor should be stable and have no evidence of significant metabolic acidosis, and the donor should be matched to the recipient by ABO blood type, size, and medical urgency according to United Network of Organ Sharing status. Approximately two thirds of intestinal transplant recipients have SBS and, as a consequence, have shrinkage of the peritoneal cavity or loss of peritoneal domain.[30]

In order to decrease the number and viability of passenger lymphocytes in the extensive lymphoid tissue of the gut, surgeons at the University of Nebraska typically administer both antithymocyte globulin (Thymoglobulin) and muromonab-CD3 (Orthoclone OKT3) intraoperatively to cadaveric donors.[52] Researchers from the University of Pittsburgh recently presented data that support the use of allograft irradiation. In animal models, the large lymphocyte load of the donor organ has been shown to predispose the transplant recipient to graft versus host disease (GVHD); however, under current regimens the rate is 2-5%. The effect of either regimen on chimerism and long-term rejection is largely unknown and is an area for further investigation.

Primary or recurrent CMV enteritis appears to occur more frequently after intestinal transplantation than after other solid organ transplantation; CMV enteritis is associated with a higher risk of graft loss or patient death.[57, 58] therefore, surgeons at the University of Nebraska select CMV-negative recipients, with the recognition that seropositivity in infants younger than 1 year may be the result of circulating maternal antibodies.[59]

Intraoperative Details

Donor operation

The basic principles of intestinal and multiple intra-abdominal organ procurement have evolved over the past decade, and the operative techniques have been described in detail.[60, 61] If the intestinal graft is to be transplanted alone, the portal vein is cut above the confluence of the superior mesenteric and splenic veins, and the superior mesenteric artery (SMA) is cut with an aortic cuff. If a right replaced hepatic artery is present, the SMA is cut distal to the takeoff of the replaced artery. In multivisceral grafts, both the celiac and superior mesenteric arteries are procured, with the thoracic and abdominal aorta proximal to the origin of the renal arteries.

The graft is flushed with 4°C University of Wisconsin solution via a cannula placed in the distal aorta of the donor. Cold ischemic time is minimized by initiating the recipient operation as soon as the donor graft is harvested. The mean cold ischemic time at the University of Miami is 480 minutes, with 13 hours being the maximum ischemic time to date. 

The portal vein and SMA are dissected and are prepared for isolated transplantation at the back table prior to implantation in the recipient. The composite graft, including thoracic aorta, abdominal aorta, and vena cava, is dissected and prepared for liver-intestinal or multivisceral transplantation.

Recipient operation

Types of transplantation performed for patients with intestinal failure include the following (see the images below):

  • Isolated intestine transplantation
  • Liver and intestine transplantation
  • Liver, intestine, and pancreas transplantation
  • Multivisceral transplantation

Isolated intestine transplantation.

Liver and intestine transplantation.

Liver, intestine, and pancreas transplantation.

Multivisceral transplantation.

 In isolated intestinal transplantation, only the small intestine is transplanted, and the donor SMA is anastomosed to the recipient SMA or aorta, with or without an interposition graft from the donor iliac or carotid arteries. The arterial graft can be anastomosed to the supraceliac or infrarenal aorta of the recipient.

Portal venous anastomosis is performed using either portal or systemic drainage. In portal drainage, the portal vein can be anastomosed to the recipient superior mesenteric vein, to the confluence of the superior mesenteric and splenic veins, or to the side of the recipient portal vein. If access to the recipient portal system is difficult, systemic drainage can be used. In systemic drainage, the donor portal vein is anastomosed to the recipient vena cava in an end-to-side fashion. No survival advantage and no difference with regard to metabolic and immunologic consequences have been reported between portal and systemic drainage.

Combined liver and intestinal transplantation includes the liver and the intestine as a composite graft. The donor and recipient aortas are anastomosed end-to-side with an interposition aortic graft. The vena cava anastomosis is usually performed end-to-side with the recipient hepatic veins for venous outflow (piggyback technique).

Multivisceral transplantation includes the stomach, pancreas, and intestine, with or without the liver or kidney. The arterial and vena caval anastomoses are the same as for combined liver-intestinal transplantation. The proximal end of the isolated intestinal and combined liver-intestinal transplantation is anastomosed side-to-side to the distal end of the native recipient intestine. In multivisceral transplantation, the proximal anastomosis is performed between the donor stomach and the recipient esophagus. A catheter for enteral feeding is placed in the jejunum. The distal end of the transplanted intestine is exteriorized as a stoma to decompress the bowel and to monitor the graft for signs of rejection. The distal part of the intestinal graft just proximal to the ileostomy is anastomosed to recipient colon (if present).

Graft size considerations are important in intestinal transplantation. If the graft is large for the shrunken abdomen of the recipient, resection of intestine and/or liver is performed. Abdominal closure may require mesh or staged approximation. Skin flaps, muscle flaps, or synthetic mesh can be used in cases where significant size discrepancies exist.

Defects of the abdominal wall are an important surgical issue for the patient with multiple surgeries. Abdominal wall transplants have been performed for these patients. The iliac artery and vein were used for vascular anastomosis. Cadaveric fascia grafts have been used for abdominal closure.

Media files 3-9 demonstrate some steps of the surgical procedures.

Intestinal transplantation: Back table operation w Intestinal transplantation: Back table operation with mesenteric vessels held within the forceps and the donor intestine within preservation solution.
Intestinal graft within the abdominal cavity of th Intestinal graft within the abdominal cavity of the recipient at the time of revascularization.
Revascularized bowel prior to closure. In the lowe Revascularized bowel prior to closure. In the lower right corner the anastomosis between the donor small bowel and recipient remnant colon can be seen.
Picture of the liver and small bowel allograft. Th Picture of the liver and small bowel allograft. The liver is to the left of the picture, and the spleen can be seen lying within the loops of the small bowel (spleen is removed later).
Removal of the native liver. Left behind is the ca Removal of the native liver. Left behind is the cavity into which the liver and small bowel allograft will be placed.
Postrevascularization image of the liver and small Postrevascularization image of the liver and small bowel allograft.
The allograft, prior to closure, positioned within The allograft, prior to closure, positioned within the recipient's abdomen. The wedge-shaped excision (biopsy site) seen on the donor organ was performed at organ procurement. These biopsies are selectively performed to review the suitability of organs in instances where issues of suitability are raised.

Postoperative Details

After the operation, the patient is returned to the intensive care unit, where hemodynamic monitoring and mechanical ventilation are performed as needed. Doppler ultrasonography is routinely performed on postoperative day 1 to assess vessel patency or as clinically indicated.

The standard immunosuppression drugs following intestinal transplantation are tacrolimus and steroids. Tacrolimus is administered orally in a dose sufficient to provide a blood level of approximately 20-25 ng/mL by the end of the first postoperative week. Steroids are administered at a dose of approximately 20 mg/d for adults and 0.3 mg/kg for children. No evidence indicates that the routine addition of azathioprine, mycophenolate, cyclophosphamide, or antilymphocyte therapy decreases the frequency or severity of acute rejection, but the addition of these agents may lead to an increased risk for infection and other immunosuppression-related complications.[62, 63]

Some benefit may be achieved with the simultaneous administration of either sirolimus or mycophenolate in patients who receive reduced doses of tacrolimus because of renal toxicity or in patients who experience refractory acute and/or chronic rejection.[64] The protocol at the University of Nebraska Medical Center is to routinely administer basiliximab, an interleukin 2 receptor antagonist, on the day of surgery and on postoperative day 4 to reduce the chance of rejection. This has decreased the rate of rejection from 85% to 35%.

Because of the high rate of infectious complications, broad-spectrum antibacterial and antifungal prophylaxis is administered for 1-2 weeks after transplantation, and prophylactic ganciclovir has been recommended. Other prophylactic regimens target prevention of herpes simplex virus (HSV) infection, EBV infection, and Pneumocystis carinii pneumonia.[36]

The appearance of allograft ostomy and the amount of ostomy output are useful clinical signs of graft dysfunction. Ostomy losses of up to 100 mL/kg/d are acceptable and can be compensated for with supplemental intravenous fluids. Because no serological or biochemical tests are diagnostic for small bowel rejection, the routine protocol is endoscopy with biopsy. A high index of suspicion for rejection and abdominal perforation is warranted in any intestinal transplant recipient with unexplained fever, diarrhea, or gastrointestinal bleeding.

Enteral nutrition is provided as soon as intestinal function returns. In the absence of other clinical complications, enteral feedings are started on the third-to-fifth postoperative day. The concentration and type of enteral nourishment are tailored to the patient's clinical response. A low-fat diet is used in the early posttransplant period. On average, recipients of ISB allografts are successfully weaned from parenteral nutrition by the third or fourth week posttransplant. After 4-6 weeks, an unrestricted diet is allowed.

Occasionally, the recipient does not establish enteral feeding; this is sometimes referred to as food aversion. Ancillary services, including speech therapy, may be helpful in these patients. Enteral feeding can be withdrawn as oral feeding approaches energy (calorie) requirements. The administration of loperamide, often in high doses, may be helpful for reducing ostomy losses and is often used early after transplantation, although no controlled trials support this.

Immunosuppression medications

These agents inhibit immune-mediated responses to the transplanted allograft. By doing so, allograft rejection is prevented. These agents also diminish inflammatory responses.

The cornerstone to a vast majority of immunosuppression protocols is tacrolimus (Prograf). Tacrolimus is a potent antagonist of calcineurin activation and 10-100 times more potent than cyclosporin. To act, tacrolimus binds to the FK binding protein, and this leads to antagonism of calcineurin and through this, inhibition of NF-AT-supported IL-2 gene expression. Tacrolimus also attenuates the response to cytokine stimulation. The effect of these actions leads to suppression of cellular immune responses and T-cell activation. In adults, the dose is 300-500 mcg/kg/d PO/NG divided twice daily. Dosages are subsequently directed by target levels for immunosuppression needed at various times posttransplant; different centers have different protocols (see Table below). The pediatric dose is the same as the adult dose. Tacrolimus must not be coadministered with cyclosporine.

Methylprednisolone (Adlone, Medrol, Solu-Medrol) decreases inflammation by suppressing migration of polymorphonuclear leukocytes and reversing increased capillary permeability. Adult patients are given an intraoperative bolus followed by 200 mg/d IV divided q6h for 4 doses, then 160 mg/d IV divided q6h for 4 doses, then 120 mg/d IV divided q6h for 4 doses, then 80 mg/d IV divided q6h for 4 doses, then 40 mg/d IV divided q12h for 2 doses, then are switched to prednisolone 20 mg PO qd. Children < 20 kg are given 20 mg/kg intraoperatively followed by 10 mg/kg/d IV divided q6h for 4 doses, then 8 mg/kg/d IV divided q6h for 4 doses, then 6 mg/kg/d IV divided q6h for 4 doses, then 4 mg/kg/d IV divided q12h for 2 doses, then 2 mg/kg/d IV divided q12h for 2 doses, then 1 mg/kg/d for 1 dose, and then switched to prednisolone 0.3 mg/kg/d PO qd.

Basiliximab (Simulect) is a chimeric monoclonal antibody that specifically binds to and blocks the interleukin-2 (IL-2) receptor on the surface of activated T cells. Adults dosing depends on body weight. Adults < 20 kg are given 10 mg on days 0 and 4; adults >20 kg are given 20 mg on days 0 and 4. The dosage is not established for children < 2 years. Children aged 2-15 years are given 12 mg/m2 IV, not to exceed 20 mg. The dosage in children >15 years is the same as it is in adults.

Alemtuzumab (Campath) is a monoclonal antibody against CD52, an antigen found on B cells, T cells, and almost all CLL cells. It binds to the CD52 receptor of the lymphocytes, which slows the proliferation of leukocytes. In adults, the dose is 0.3 mg/kg IV preoperatively and then repeated postoperatively. Administer an additional dose on each of postoperative days 3 and 7. The pediatric dose is not established.

Sirolimus (Rapamune) inhibits lymphocyte proliferation by interfering with signal transduction pathways. It binds to immunophilin FKBP to block action of mTOR. It is FDA-approved for prophylaxis of organ rejection in patients receiving allogeneic renal allografts. Dosages and levels should be adjust no more often than twice per wk initially, and monitoring of levels should be started 4 d after initiating medication unless specific indication exists for more frequent monitoring (eg, medication interacting with rapamycin metabolism) In adults, 2-5 mg PO qd is used and loading doses are discouraged. Trough blood concentrations >8 ng/mL are correlated with immunosuppressive activity. The pediatric dose is not established. In patients who develop chronic allograft rejection, sirolimus might initially play an important role. Before a conclusion can be made, additional case reports and case series are needed. Everolimus, a newer mTOR inhibitor, might be equally effective.

Antithymocyte globulin (Thymoglobulin) is a purified concentrated gamma-globulin (primarily monomeric IgG) from hyperimmune horses immunized with human thymic lymphocytes. The mechanism of action is thought to be its effect on lymphocytes responsible in part for cell-mediated immunity and lymphocytes involved in cell immunity. Its immunosuppressive action is generally similar to other antilymphocyte preparations. However, they may differ qualitatively and/or quantitatively in the extent to which they produce specific effects, in part because of factors such as source of antigenic material used, type of animal used to produce antiserum, and method of production. A hematologist or another physician with extensive experience must be involved in the administration and monitoring of antilymphocyte serum because of the many complications and adverse effects of this therapy. Dose and duration of therapy vary with different investigational protocols. In adults, the dose is1.5mg/kgIVondays1,3,5,7.Thepediatricdoseisnot established.

Alemtuzumab is a powerful antilymphocyte antibody that produces profound and long-lasting lymphopenia and has been used at some centers in intestinal transplantation as an induction agent much akin to thymoglobulin. A study, albeit retrospective in nature, demonstrated no difference in bacterial infections with alemtuzumab compared with daclizumab (withdrawn from the market) when used in combination with thymoglobulin. Importantly, the quality of this study and other reports of alemtuzumab use in intestinal transplantation warrants both the need for randomized multicenter studies and caution when considering its use.

Antibiotics

Empiric antimicrobial therapy must be comprehensive and should cover all likely pathogens in the context of the clinical setting.

Piperacillin and tazobactam (Zosyn) is an antipseudomonal penicillin plus a beta-lactamase inhibitor. It inhibits biosynthesis of cell wall mucopeptide and is effective during stage of active multiplication. In adults, the dose is 3.375 g IV q8h for 7 d. The pediatric dose is 200-300 mg/kg IV q8h for 7 d.

Trimethoprim and sulfamethoxazole (Bactrim, Septra) inhibits bacterial growth by inhibiting synthesis of dihydrofolic acid. Its antibacterial activity covers common urinary tract pathogens except Pseudomonas aeruginosa. In adults, the dose is 80 mg TMP/400 mg SMZ PO bid every Monday and Tuesday. Do not administer to children < 2 months. In children >2 months, the dose is 1 mL/kg/d suspension PO divided bid every Monday and Tuesday, not to exceed 10 mL/dose.

Antivirals

Nucleoside analogs are initially phosphorylated by viral thymidine kinase to eventually form a nucleoside triphosphate. These molecules inhibit HSV polymerase with 30-50 times the potency of human alpha-DNA polymerase.

Ganciclovir (Cytovene) is a synthetic guanine derivative active against CMV. It is an acyclic nucleoside analog of 2'-deoxyguanosine that inhibits replication of herpes viruses both in vitro and in vivo. levels of ganciclovir-triphosphate are as much as 100-fold greater in CMV-infected cells than in uninfected cells, possibly because of preferential phosphorylation of ganciclovir in virus-infected cells. In adults, the dose is 5 mg/kg IV bid for 14 d followed by treatment with acyclovir. The pediatric dose in children < 3 months is not established. In children >3 months, administer ganciclovir as in adults.

Acyclovir (Zovirax) inhibits activity of both HSV-1 and HSV-2. It has affinity for viral thymidine kinase. Once phosphorylated, it causes DNA chain termination when acted on by DNA polymerase. Patients experience less pain and faster resolution of cutaneous lesions when it is administered within 48 h of rash onset. It may prevent recurrent outbreaks. Early initiation of therapy is imperative. In adults, the dose is 80 mg/kg/d PO divided qid for 1 y, not to exceed 800 mg/dose. The pediatric dose is the same as the adult dose.

Antifungals

The mechanism of action of antifungals may involve alteration of RNA and DNA metabolism or intracellular accumulation of peroxide that is toxic to fungal cells.

Fluconazole (Diflucan) has fungistatic activity. It is a synthetic oral antifungal (broad-spectrum bistriazole) that selectively inhibits fungal cytochrome P-450 and sterol C-14 alpha-demethylation, which prevents conversion of lanosterol to ergosterol, thereby disrupting cellular membranes. In adults, the dose is 400 mg PO/IV qd for 4 wk. The pediatric dose is 5 mg/kg PO/IV qd for 4 wk. It is critical to remember that the use of antifungals leads to effects on tacrolimus levels. Should these be discontinued or commenced, tacrolimus dosing likely needs to be adjusted and monitoring of levels must be increased.

Prostaglandins

Alprostadil is identical to naturally occurring prostaglandin E1.

Alprostadil (Prostaglandin E1, PGE1) possesses various pharmacologic effects, including vasodilation and inhibition of platelet aggregation. In both adults and children, the dose is 0.2-0.6 mcg/kg IV continuous infusion over 1 h for 7 d.

Proton pump inhibitors

These agents are used in patients who require complete acid suppression. Patients taking omeprazole via NG tube should have granules mixed with an acidic juice. Following administration, the NG tube should be flushed to prevent blockage.

Omeprazole (Prilosec) decreases gastric acid secretion by inhibiting the parietal cell H+/K+ ATP pump. In adults, the dose is 20 mg PO/NG bid. The pediatric dose is 0.5 mg/kg PO/NG q12h.

Salicylates

These agents inhibit prostaglandin synthesis, which prevents formation of platelet-aggregating thromboxane A2.

Aspirin (Anacin, Ascriptin, Bayer Aspirin) is used to treat mild to moderate pain. A low dose may be used to inhibit platelet aggregation and improve complications of venous stasis and thrombosis. In adults, the dose is 80 mg PO/PR qd. The pediatric dose is 40 mg PO/PR qd. Caution when using salicylates; creatinine values must be tracked.

Immune globulins

These agents neutralize circulating myelin antibodies through antiidiotypic antibodies. Immune globulins down-regulate proinflammatory cytokines, including INF-gamma. They also block Fc receptors on macrophages, suppress inducer T and B cells, and augment suppressor T cells. The administration of immune globulins may increase CSF IgG levels by 10%. Immunoglobulins may be used in the setting of rotavirus infection and occasionally in the setting of antibody-mediated rejection.

CMV hyperimmune globulin (CytoGam) is used to prevent CMV disease in immunosuppressed recipients of organ transplants. In both adults and children, the dose is 150 mg/kg IV postoperative day 3, then 100 mg/kg qwk IV for 4 wk, then 50 mg/kg/mo for 1 y.

Table 5. Proposed Immunosuppression Targets (Open Table in a new window)

Medication

Days 2-29

Days 30-89

Days 90-179

Days 180-365

After 1 year

Tacrolimus (monotherapy levels)

15-20 ng/mL

12-15 ng/mL

10-12 ng/mL

7-10 ng/mL

Taper to around 5 ng/mL

Tacrolimus (in combination levels)

10-15 ng/mL

8-12 ng/mL

8-10 ng/mL

5-8 ng/mL

2.5-5 ng/mL

Prednisone (dose)

20 mg

15 mg

10 mg

7.5 mg

5 mg

Rapamycin (to be used only in combination with tacrolimus)

6-10 ng/mL

5-8 ng/mL

5-8 ng/mL

5-8 ng/mL

5-8 ng/mL

Mycophenolic acid (suggested dose as listed and to be used only in combination with tacrolimus; dose listed is adult dose; intolerance may be managed by lowering dose)

1000 mg bid

1000 mg bid

Cease unless renal indication exists

...

...

Complications

Surgical complications

Postoperative bleeding is the most common surgical problem in intestinal transplantation. Most of the patients have borderline liver function and bleeding tendency.

Meticulous surgical hemostasis is necessary. Vascular problems are unusual following intestinal transplantation. The authors have had 3 cases of arterial graft infection, with rupture and death in each case. Attention must be paid to aseptic procedures during the donor and recipient operations. Large-volume antibiotic irrigation is applied in the operating room in an attempt to minimize this complication. Leakage at the intestinal anastomosis has occurred twice. In one case, the patient was explored and the defective anastomosis (esophagogastrostomy) was redone. In another case, the fistula between the colon and the jejunum closed itself. The patients did well in both cases.

Rejection

Rejection episodes occur in 70-90% of recipients following intestinal transplantation, although hyperacute rejection is rare.[30, 36, 65, 66] The median number of rejection episodes per patient is 2.5 and does not differ with the type of allograft.[66] Most episodes respond to steroid bolus therapy, and only 20% of patients require muromonab-CD3 or thymoglobulin for treatment of steroid-resistant rejection. With newer immunosuppressive protocols the incidence of rejection in intestinal transplant recipients has declined markedly in the last 5 years.[53]

Concurrent liver transplantation has been proposed to offer protective benefits, but these effects have not been universal. Recent data, reported by Fishbein and others at the International Small Bowel Transplant Symposium in Stockholm, Sweden have provided optimism that newer immunosuppressive protocols, which include sirolimus and other agents (eg, alemtuzumab [Campath]), may lower the frequency of rejection and may reduce immunosuppression-related adverse effects while improving survival. A more recent review, published in 2008, looked again at the protective effect of a concurrent liver with intestine transplantation versus intestine transplantation alone.[67] This review revealed a trend toward a protective effect and reduced incidence of acute rejection at one year; however, this trend did not reach significance.[67]

The development of moderate or severe acute intestinal graft rejection is a poor prognostic indicator and is associated with a mortality rate of 40%.[36] Graft enterectomy can be performed in ISB recipients with severe rejection; however, removal of the intestinal graft from recipients of composite grafts is technically more challenging and is generally not performed. High mortality occurs in this situation. Salvage therapy with agents such as sirolimus has shown favorable outcomes[68] ; however, no randomized studies have been performed, and a randomized study of sirolimus in intestinal transplantation to assess for a role in chronic or acute rejection is unlikely.

Infection and sepsis

Sepsis is the most frequent cause of death following intestinal transplantation.[30] Frequently involved factors include intra-abdominal infection or abscess, bowel perforation, line infection, wound infection, pulmonary infection, urinary tract infection, and viral enteritis. Sepsis is not uncommon with acute rejection, and this should always be remembered when evaluating a septic patient. Approximately 40% of small bowel transplant recipients require further surgery during their original inpatient stay; additional surgery is usually the result of infectious complications.[63] Furthermore, these complications are primarily responsible for the prolonged hospitalizations of these patients; ISB recipients typically are hospitalized for 3 weeks to 3 months, and LSB recipients typically are hospitalized for 3-6 months.

Following small bowel transplantation, typical pathogens are enteric organisms, fungal species, or staphylococci (associated with central venous line infections). Bacterial infection appears to be far more common if the colon is included in the allograft; thus, inclusion of the colon is not the recommended protocol in many centers.[69] Empiric antibiotic selection is based on the focus of infection and previous resistance patterns of positive isolates. The regimen should be modified based on culture results. In view of the high propensity for translocation of gut-derived bacteria, researchers at the University of Pittsburgh recommend surveillance stool cultures to direct empiric antibiotic selection at the onset of apparent infection.[70]

Cytomegalovirus infection

CMV disease occurs more frequently after intestinal transplantation than after other types of solid organ transplantation. When present, involvement of the allograft occurs in more than 90% of cases.[69] In the past, more than half of intestinal transplant recipients developed symptomatic CMV infection.[69] Recipients of grafts from donors who are seropositive for CMV have a worse outcome than recipients of grafts from seronegative donors.[71, 58] In light of this observation, a policy to avoid donor-positive/recipient-negative transplantations was adopted by the University of Nebraska, which has probably contributed to the reduced incidence of CMV disease observed at this center. Most infections are diagnosed following endoscopic biopsy; the remainder are identified during evaluations of febrile patients.

Lymphoproliferative disease

Posttransplant lymphoproliferative disease (PTLD) is a complication of over-immunosuppression. PTLD is a lymphoma that occurs after transplantation, and it is frequently associated with EBV infection.[72] PTLD occurs in 6-29% of intestinal transplant recipients, and children appear to have an increased frequency of PTLD compared with adults.[63, 30, 73, 36] The peak incidence appears to be at 2 years. Ongoing graft monitoring is essential during therapy for PTLD because graft rejection may occur on a background of reduced immunosuppression, with the potential for graft loss. Recently improved outcomes for those diagnosed with this condition have been demonstrated with treatment with the anti-CD20 antibody, rituximab.[74, 75, 76]

Graft versus host disease

GVHD following intestinal transplantation has been far less common than one might expect considering the substantial volume of lymphoid tissue present in both the mesentery and the Peyer patches of the intestinal allograft. The rate of GVHD after intestinal transplantation is 0-16%.[77, 65, 63, 36] Transplantation programs with higher reported GVHD rates use simultaneous bone marrow infusion, which may contribute to the increased prevalence of GVHD.[77, 78]  Strategies to prevent GVHD include graft irradiation and the administration of antilymphocyte serum.[79] All blood products should be irradiated. Treatment with pulse methylprednisolone generally is effective for controlling mild cases.[80] Unfortunately, a nonspecific presentation and diagnostic delay appear to contribute to the high mortality associated with GVHD.

Chronic rejection

Chronic rejection is becoming more apparent over time. Patients present with failure to thrive, diarrhea, and, occasionally, sepsis. Routine small bowel biopsy results may show mucosal atrophy, although results also may demonstrate minimal, if any, change. This is because obliterative vasculitis and fibrosis, which are often factors involved in chronic rejection, are localized to layers of the small bowel deeper than the biopsy procedure can access. For this reason, biopsy results may be falsely reassuring. Often, at later stages, patients need to be explanted and may later become candidates for repeat intestinal transplantation. As with other forms of transplantation, repeated bouts of acute rejection, duration of the rejection episode, response to steroids, and severity of any rejection episode predict the possibility of developing chronic rejection.

Retransplantation

There has been significant improvements to 1-, 3-, and 5-year survival following intestinal and liver-intestinal transplantation. However, situations arise in which retransplantation needs to be considered. In retransplantation, recipients of a second graft are more commonly adults as recipients of the second allograft compared with the primary transplant. Unfortunately, retransplantation has inferior outcomes in patient survival compared with primary transplantation. The type of retransplanted graft (liver and small bowel vs isolated bowel) does not appear to affect outcome.[33]

Renal dysfunction

As the long-term survival rates of intestinal recipients improve, more complications related to the immunosuppressive management will occur. Among the most serious of these complications is chronic renal disease. The frequency of chronic renal dysfunction among patients who underwent intestinal transplantation appears higher than among recipients of any other form of nonrenal solid organ transplant.[81] The renal dysfunction is multifactorial in origin; intestinal allograft dysfunction likely contributes to the high incidence, although this has never been studied. To reduce the incidence of renal dysfunction, close monitoring of hydration parameters is an important component of posttransplant health maintenance. In the face of chronic renal dysfunction, early nephrology referral and possible revisions to immunosuppression strategies might be considered.

Future and Controversies

Cost

The average cost of intestinal transplantation is $132,285 for ISB transplantation, $214,716 for LSB transplantation, and $219,098 for multivisceral transplantation.[65] As of 1992, the estimated average yearly cost of TPN administration—not including medical equipment, nursing care, or hospitalization—was approximately $150,000 per patient.[82]

Living-related transplantation and reduced-size grafts

Reduced-size LSB grafts have been introduced in an effort to address the high mortality rate due to prolonged waiting times, especially for children younger than 1 year.[83, 84] Living-related (live donor) small bowel transplantation has been performed, although long-term outcome data remain pending for both donor and recipient. Clearly, the number of potential donors would be dramatically increased if live donors or donors who are larger than recipients were routinely considered; however, the functional consequences of bowel reduction for transplantation in humans remain unknown.[85, 86] Another option, which was suggested by researchers at King's College, is sequential transplantation of the liver and, later, the small bowel, in a separate procedure.[87]

The use of reduced-size grafts may not greatly affect waiting list mortality. A shift to targeting prevention of liver disease associated with TPN along with intestinal adaptation measures may provide greater benefits.

Colon inclusion in the transplant

Tzakis and colleagues reported the outcomes of colon inclusion in the primary intestinal transplant procedure. Notable was the finding of improved outcomes over time for the intestinal allograft, as one might expect with a new procedure.[88] Including the colon certainly provides a necessary function in intestinal transplantation as it provides the function of the colon for its physiologic functions of water absorption, residue breakdown, and storage. Currently, increasing clinical evidence supports the efficacy of selective use of the colon in intestinal transplantation.[55]

Obstacles to general application

The primary obstacles to a general application of intestinal transplantation to all patients with benign and irreversible SBS are the consequences of both the procedure and the adverse long-term effects of immunosuppression. Further investigation into the immunology of the intestinal graft and targeted immunosuppression may enable surgeons to offer intestinal transplantation to any patient permanently dependent on TPN. Trials of a variety of immunosuppression regimens and the continued investigations into tolerance induction are being pursued in intestinal transplantation as for all forms of transplantation. The ultimate goal is a functional bowel free of rejection in a recipient without adverse effects of over-immunosuppression or specific medication-related complications. To minimize these complications, tailored regimens involving a variety of medications are being tested.

Although not currently a reality, future patients with uncomplicated intestinal failure may be considered for intestinal transplantation based on quality-of-life issues. Currently, the risks, benefits, and resources limit this procedure to people with complications of TPN, although this restriction is likely to change.

For patient education resources, see the Procedures Center, as well as Liver Transplant.

Bioengineered organs

In recent years, bioengineered intestinal allografts have been made. These have not reached a point of entering into human studies but may significantly reduce the need for multivisceral transplantation.[89, 90, 91]

Long-Term Monitoring

Immunosuppression and rejection monitoring are the main issues after the transplantation.

Tacrolimus (Prograf) levels are checked daily for a month. Then, blood levels are checked twice a week for another month and then once a week depending on the blood level and condition.

Steroids are tapered slowly over several months.

Rejection monitoring by endoscopy is performed twice weekly for the first postoperative month and then weekly for postoperative months 2-4 depending on the clinical situation. After that, periodic endoscopy is performed depending on the clinical signs of rejection

 

Guidelines

Guidelines Summary

A 2001 position paper by the American Society of Transplantation on indications for pediatric intestinal transplantation recommends intestinal transplantation for the subset of children with intestinal failure remaining dependent on parenteral nutrition who develop life‐threatening complications arising from therapy.[92] Life‐threatening complications warranting consideration of intestinal transplantation include the following:

  • Parenteral nutrition–associated liver disease
  • Recurrent sepsis
  • Threatened loss of central venous access

The guidelines note that because a critical shortage of donor organs exists, waiting times for intestinal transplantation are prolonged, so it is essential that children with life‐threatening complications of intestinal failure and parenteral nutrition therapy be identified comparatively early (ie, in time to receive suitable donor organs before they become critically ill). Recommendations are as follows:

  • Children with liver dysfunction should be considered for isolated intestinal transplantation before irreversible, advanced bridging fibrosis, or cirrhosis supervenes, for which a combined liver and intestinal transplant is necessary.
  • Irreversible liver disease is suggested by hyperbilirubinemia persisting beyond 3-4 months of age combined with features of portal hypertension such as splenomegaly, thrombocytopenia, or prominent superficial abdominal veins; esophageal varices, ascites, and impaired synthetic function are not always present.

European Society for Clinical Nutrition and Metabolism (ESPEN) guidelines on chronic intestinal failure in adults, published in 2016, include the following recommendations and suggestions on intestinal transplantation[93] :

ESPEN recommends home parenteral nutrition (HPN) as the primary treatment for patients with chronic intestinal failure CIF and the early referral of patients to intestinal rehabilitation centers with expertise in both medical and surgical treatment for CIF, to maximize the opportunity of weaning off HPN, to prevent HPN failure, and to ensure timely assessment of candidacy for intestinal transplantation.

ESPEN recommends assessment for candidacy for intestinal transplantation when there is failure of HPN, high risk of death attributable to the underlying disease, or intestinal failure with high morbidity or low acceptance of HPN.

Failure of HPN may be indicated by any of the following:

  • Impending liver failure (total bilirubin above 3-6 mg/dL [54-108 mmol/L], progressive thrombocytopenia, and progressive splenomegaly) or overt liver failure (portal hypertension, hepatosplenomegaly, hepatic fibrosis, or cirrhosis) because of intestinal failure-associated liver disease (IFALD).
  • Central venous catheter (CVC)–related thrombosis of two or more central veins (internal jugular, subclavian, or femoral).
  • 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; septic shock and/or acute respiratory distress syndrome.
  • Frequent episodes of severe dehydration despite intravenous fluid in addition to HPN.

High risk of death attributable to the underlying disease may be indicated by any of the following:

  • Invasive intra-abdominal desmoid tumors
  • Congenital mucosal disorders (ie, microvillus inclusion disease, tufting enteropathy)
  • Ultra-short bowel syndrome (gastrostomy, duodenostomy, residual small bowel < 10 cm in infants and< 20 cm in adults)

Intestinal failure with high morbidity or low acceptance of HPN may be indicated by any of the following:

  • Need for frequent hospitalization
  • Narcotic dependency
  • Inability to function (ie, pseudo-obstruction, high-output stoma)
  • Patient's unwillingness to accept long-term HPN (ie, young patients)

Other guideline statements are as follows:

  • ESPEN recommends that patients with impending or overt liver failure due to IFALD and those with an invasive intra-abdominal desmoid tumor be listed for a life-saving intestinal transplantation (with or without liver transplantation).
  • ESPEN suggests that patients with CVC-related thrombosis of two or more central veins (internal jugular, subclavian or femoral) be listed for a life-saving intestinal transplantation on a case-by-case basis.
  • ESPN does not recommend listing for a life-saving intestinal transplantation of patients with CIF having any of the indications for assessment of candidacy other than IFALD-related liver failure, intra-abdominal desmoids, or CVC-related multiple vein thrombosis.
  • ESPEN suggests that patients with CIF with high morbidity or low acceptance of HPN might be listed for a rehabilitative intestinal transplantation on a careful case-by-case basis.
  • ESPEN recommends that, whenever possible, patients listed for intestinal transplantation undergo the procedure while they are in stable clinical condition, as represented by being able to stay at home and not requiring hospitalization while waiting for transplant. For patients listed for a combined intestinal and liver transplantation, mechanisms to prioritize patients on the waiting list for liver transplantation should be adopted in order to minimize the risk of mortality while on waiting list  and after transplantation.