Intestinal and Multivisceral Transplantation Treatment & Management

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

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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.

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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.

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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]

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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.
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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

...

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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.

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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]

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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

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