Small Bowel Transplantation

Intestinal Transplantation Indications include: Short-bowel syndrome with complications associated with parenteral nutrition Irreversible intestinal failure End-stage liver disease for combined liver and small-intestine transplantation Congenital mucosal disorders Chronic pseudo-obstruction of intestine Locally invasive tumors at the base Transplant options include: Isolated intestinal (cadaveric or living-related) Multivisceral transplantation (combined liver and multivisceral) 4/21/2017 Dr .yekehfallah-phd of nursing-2015

Contraindications of Small Bowel Transplant Presence of Active Infection Aggressive Malignancy Multi-System Organ Failure Cerebral Edema AIDS 4/21/2017 Dr .yekehfallah-phd of nursing-2015

History of the Procedure Lillehei et al reported the first case of human bowel transplantation in October 1967 Alexis Carrel was the first one to perform it in an animal model Before 1970, 8 clinical cases of small-intestine transplantation were reportedly performed worldwide maximum graft survival time was 79 days All patients died of technical complications, sepsis, or rejection 4/21/2017 Dr .yekehfallah-phd of nursing-2015

Intestinal Transplantation - Etiology Worldwide, the leading cause of intestinal failure is short-bowel syndrome caused by surgical removal ~10-20cm of small bowel needed with an ileocecal valve 40cm without a ileocecal valve Conditions leading to short-bowel syndrome include Midgut volvulus Gastroschisis Trauma Necrotizing enterocolitis (NEC) Ischemia Crohn’s disease 4/21/2017 Dr .yekehfallah-phd of nursing-2015

Dr .yekehfallah-phd of nursing-2015 Short Bowel Syndrome In patients with short bowel syndrome, absorption of nutrients is significantly altered, leading to electrolyte and mineral imbalances and inadequate delivery of calories (severe dehydration and malnourishment) Symptoms are common: persistent diarrhea, muscle wasting, poor growth, frequent infections, weight loss, fatigue, and dehydration 4/21/2017 Dr .yekehfallah-phd of nursing-2015

Preoperative evaluation and selection Preoperative evaluation requires a complete multidisciplinary assessment to clearly define the cause of isolated intestinal or intestinal/hepatic failure Evaluation of comorbidities and organ dysfunction Optimization of preoperative morbid conditions (infection, malnutrition) can significantly affect outcome 4/21/2017 Dr .yekehfallah-phd of nursing-2015

Preoperative evaluation and selection Referring patients before the onset of hepatic dysfunction is important Progression of liver injury, as manifested by jaundice, significantly influences life expectancy Bilirubin concentrations >3 mg/dL have 1- and 2-year survival rates of 42% and 20% Bilirubin <3 mg/dL have a survival rate of 80% pT >15 and pTT >40 also associated with poorer outcomes 4/21/2017 Dr .yekehfallah-phd of nursing-2015

Isolated Intestinal Transplantation 4/21/2017 Dr .yekehfallah-phd of nursing-2015

Multivisceral transplantation Pts with permanent intestinal dysfunction, those with TPN dependency with complications, and those with a systemic motility disorder (e.g., chronic pseudo-obstruction, traumatic loss of the stomach or duodenum) Can receive a stomach, duodenum, pancreas, and small intestine, with or without the liver 4/21/2017 Dr .yekehfallah-phd of nursing-2015

Dr .yekehfallah-phd of nursing-2015 4/21/2017 Dr .yekehfallah-phd of nursing-2015

Dr .yekehfallah-phd of nursing-2015 An isolated intestine being prepared on the back table prior to implantation 4/21/2017 Dr .yekehfallah-phd of nursing-2015

Transplantation – Intra-operative Details Transplantation surgical therapy Carefully preservation of the vascular pedicle comprising the ileocolic artery & vein with end-to-side anastomoses to the recipient's infrarenal aorta & vena cava For cadaveric intestinal grafting, arteries are anastomosed directly to the infrarenal aorta with a Carrel patch Venous drainage through an anastomosis or patch to the recipient's IVC (combined) Isolated cadaveric intestinal grafting -> preferred venous drainage =portal vein In addition, a gastrostomy or jejunostomy is usually performed for continuous enteral feeding Graft ileostomy permits frequent endoscopic and histologic postoperative monitoring 4/21/2017 Dr .yekehfallah-phd of nursing-2015

Dr .yekehfallah-phd of nursing-2015 4/21/2017 Dr .yekehfallah-phd of nursing-2015

Dr .yekehfallah-phd of nursing-2015 4/21/2017 Dr .yekehfallah-phd of nursing-2015

Intestinal Transplantation – Follow-up care At regular intervals, perform CMV antigenemia Quantitative EBV polymerase chain reaction (PCR) surveillance Routine cultures Transplant ileostomal endoscopy & biopsy (as often as twice weekly) Additionally, monitor fluid status, stool losses, and serum electrolytes 4/21/2017 Dr .yekehfallah-phd of nursing-2015

Major Post Operative Complications Bleeding Thrombosis Anastomatic Leaks Sepsis from bacterial translocation of Graft GVHD Acute Rejection 4/21/2017 Dr .yekehfallah-phd of nursing-2015

Intestinal Transplantation - Complications Infectious complications account for ~60% of intestinal graft losses Bacterial and fungal infections in intestinal transplantation are similar to those found in other solid-organ transplantations Rejection and technical errors accounting for a further 36% An autopsy series found 94% had a coexisting infection, even in cases in which sepsis was not the immediate cause of death Post-transplant lymphoproliferative disease and graft rejection can lead to breakdown of the mucosal barrier, resulting in bacteremia or fungemia 4/21/2017 Dr .yekehfallah-phd of nursing-2015

Intestinal Transplantation - Complications CMV infection Immunosuppression is maintained to avoid breakthrough rejection but is decreased if the patient's condition worsens. ~ 15-30% of patients (most often involves an allograft intestine) One of the most serious infections that can occur, because it can lead to loss of the transplanted organ and even death Incidence is highest in CMV-negative recipients who receive CMV-positive grafts (thus avoided) Infection is diagnosed by measuring CMV antigenemia and by findings on endoscopic examination Endoscopy shows superficial ulcers, and histopathology confirms CMV inclusion bodies 4/21/2017 Dr .yekehfallah-phd of nursing-2015

Intestinal Transplantation - Complications CMV infection Treatment consists of IV ganciclovir in combination with CMV immune globulin (CytoGam) and valganciclovir (Valcyte) tablets Valganciclovir is the oral prodrug of ganciclovir (ester prodrug converted by intestinal & hepatic esterases) Valganciclovir delivers the same active drug ingredient with up to 10 times more bioavailability Ganciclovir is a synthetic analogue of 2'-deoxyguanosine, which inhibits replication of human CMV 4/21/2017 Dr .yekehfallah-phd of nursing-2015

Intestinal Transplantation - Complications EBV-associated lymphoproliferative disease Posttransplantation lymphoproliferative disease occurs more often in children > adults (29% vs. 11%) Occurs more commonly within 24 months after multivisceral transplantation than after isolated intestinal transplantation Linked to EBV infection in association with the use of anti-CD3 monoclonal antibody (OKT3) and steroids The high incidence in small-intestine recipients is presumably caused by the large amount of immunosuppression necessary to prevent transplant rejection EBV may lead to a wide spectrum of clinical disease, ranging from a benign mononucleosis syndrome to a polyclonal proliferative tumor or monoclonal type lymphoma. Present with fever, abdominal pain, & either lymphadenopathy or masses on abdominal imaging In addition, low-grade EBV infections often precede posttransplantation lymphoproliferative disease 4/21/2017 Dr .yekehfallah-phd of nursing-2015

Intestinal Transplantation - Complications EBV-associated lymphoproliferative disease Treatment of posttransplantation lymphoproliferative disease involves Reduction of immunosuppression Administration of ganciclovir (10 mg/kg/d) Mortality has decreased with improved early diagnosis In situ hybridization staining for EBV Early ribonucleic acid (RNA) and EBV PCR surveillance Combined with early intervention 4/21/2017 Dr .yekehfallah-phd of nursing-2015

Intestinal Transplantation - Complications Acute allograft rejection Rejection is diagnosed by endoscopic intestinal biopsy Diagnosis can be difficult because of the patchy nature of rejection and the presence of bleeding & perforation complications Histologic evidence -> mucosal necrosis and loss of villous architecture with transmural cellular infiltrate Histopathology -> crypt cell apoptosis, cryptitis or crypt loss, necrosis, and endotheliitis Treatment -> IV bolus of methylprednisolone (10 mg/kg), followed by steroid recycle and optimization of the tacrolimus level OKT3 therapy may be used to treat steroid-resistant rejection Some centers report that combined liver-intestine transplantation provides a greater protective benefit (i.e., lower incidence and severity of acute rejection) than intestinal transplantation. OKT3 ( also called muromonab) is an immunosuppressant drug given to reduce acute rejection in transplant patients. A major milestone in the prevention of acute allograft rejection was achieved with the development of the mAb OKT3, the first mAb to be approved for clinical use in humans. OKT3 is a murine monoclonal IgG2a antibody that specifically reacts with the T cell receptor-CD3 complex on the surface of circulating human T cells.[13] The T cell has 2 molecules on its surface which function primarily in antigen recognition. These antigen recognition structures are associated with 3 polypeptide chains (the CD-3 complex). The CD-3 complex transduces the signal for the T cell to react to the foreign antigen, proliferate, and attack the foreign matter. OKT3 is a monoclonal antibody that specifically reacts with the T-3 complex by blocking the function of T cells 4/21/2017 Dr .yekehfallah-phd of nursing-2015

Intestinal Transplantation - Complications Chronic allograft rejection With improvements in immunosuppressive drugs, chronic rejection has become an increasingly important cause of late allograft dysfunction Little is known of the clinical and pathophysiologic course of chronic intestinal rejection In 1990, Goulet reported muscular fibrosis & chronic infiltrate with intact mucosal and epithelial structures in a small-intestine transplant removed from a 17-month-old infant Obliterative arteritis, atrophic Peyer patches and mesenteric lymph nodes Possibly caused by injury to the vascular endothelium, with a complex inflammatory cascade occurring in the vessel wall Therefore, prevention and treatment of chronic intestinal rejection are difficult 4/21/2017 Dr .yekehfallah-phd of nursing-2015

Intestinal Transplantation - Complications Graft versus host disease Small intestine = immunocompetent organ Population of lymphoid cells can mount an immunologic response to the host—a GVHD reaction Although animal models have shown that GVHD is a common occurrence and GVHD has not been a significant clinical problem Acute GVHD presents 1-8 weeks post-transplantation with Fever Leukopenia Diarrhea Rash Other symptoms may include malaise, anorexia, arthralgia, and abdominal pain. Confirm diagnosis by biopsy Treatment -> high-dose steroids & antithrombocyte globulin or with OKT3 4/21/2017 Dr .yekehfallah-phd of nursing-2015

Intestinal Transplantation - Complications Technical errors (up to 50%) More common in children than in adults May cause graft loss The errors include Anastomotic leaks Hepatic artery thrombosis Biliary anastomosis leaks or stricture Intra-abdominal hemorrhage Intra-abdominal abscess Chylous ascites 4/21/2017 Dr .yekehfallah-phd of nursing-2015

Intestinal Transplantation - Outcome and Prognosis In 1999, Mazariegos reported a 55% patient survival rate and 52% graft survival rate at 5 years following intestinal transplantation Matched group of patients (no transplantation) demonstrated 30% 1-year and 22% 2-year survival rates Isolated intestinal grafts reportedly provide better patient and graft survival rates than multivisceral grafts Graft and patient survival rates are improving as centers gain experience (51 worldwide centers) Main centers – U of Pittsburgh, U of Nebraska, U of Miami, Hopital Necker-Enfants-Malades, & London Health Sciences Center 4/21/2017 Dr .yekehfallah-phd of nursing-2015

Intestinal Transplantation - Outcome and Prognosis Small-intestine transplantation has higher incidences of rejection, sepsis, and post-transplantation lymphoproliferative disease than other organ transplantations These outcomes may be secondary to bacterial translocation Overall, 78% of intestinal transplant patients can be expected to be free of TPN and to tolerate oral nutrition following surgery 4/21/2017 Dr .yekehfallah-phd of nursing-2015

Intestinal Transplantation – Outcome and Prognosis The introduction of tacrolimus immunosuppression, in combination with decontamination protocols, antibiotic regimens, and antiviral measures against CMV and EBV, has improved patient and graft survival rates Survival rates at 1 year as high as 90% have been achieved for patients receiving isolated intestinal grafts 3 year survival > 70% 4/21/2017 Dr .yekehfallah-phd of nursing-2015

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