Download Small Bowel Transplantation

Small Bowel
Transplantation
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Intestinal Transplantation
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Small-intestine transplantation continues to
evolve as a surgical procedure used in the
management of intestinal failure in children and
adults
Intestinal transplantation offers the hope of
increased longevity & improved quality of life to
patients with intestinal failure and lifethreatening complications of chronic TPN
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Intestinal Transplantation
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Over the last three decades, intestinal transplantation
has evolved from experimental to a standard
therapeutic option for intestinal failure patients
Primarily a pediatric procedure with ~2/3s performed
on children
Remains less successful to other solid organ
transplantation -> presumably due to the
preponderance of lymphocytes in the bowel (strong
stimulus for rejection)
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Intestinal Transplantation
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Indications include:
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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:
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Isolated intestinal (cadaveric or living-related)
Multivisceral transplantation (combined liver and
multivisceral)
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Intestinal Transplantation
Contraindications
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Absolute contraindications
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Relative contraindications are evolving, but concern about
transplantation from CMV- or EBV-positive donors to CMV- or
EBV-negative recipients, weight (<5kg) and elderly pts
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Congenital immunodeficiency syndromes, systemic malignancy,
metastatic disease, AIDs, cardiopulmonary insufficiency & overwhelming
sepsis
Because of the risk of unrestrained graft versus host disease (GVHD)
High morbidity & mortality rates associated with the development of
CMV or lymphoproliferative disease in pediatric intestinal transplants
Although critically ill patients should be excluded, a history of multiple
abdominal surgeries is not a contraindication for transplantation
No clear lower age limit for pediatric patients (better results
>2yrs of age)
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Indications for Small Bowel
Transplant as recommend by the
American Gastroenterology
Association
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AGA recommends SBT on patients who have
Short Bowel Syndrome ( Functional Small
Intestine of less than 200 cm) and have
developed severe complications from Total
Parental Nutrion.
Small Bowel transplants have been performed
on children with motility disorders and
malignancy
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Common Causes of Short Bowel
Syndrome
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Neonates: Necrotizing enterocolitis
Children: Congenital abnormalities such as
necrotizing entercolitis, intestinal atresia, mid gut
volvulus, gastrochisis
Adults: Chron’s Disease, Mesenteric
Thrombosis, Trauma, Desmoid Tumors,
mesenteric occlusion, midgut volvulus,
traumatic disruption of SMA/SMV
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Complications of TPN requiring
Small Bowel Transplant
1.Frequent Central- Line related Sepsis: 2 episodes of
systemic sepsis secondary to line infection per year, 1
episode of line related fungemia, 1 episode of septic
shock, or Acute Respiratory Distress Syndrome
2. Liver Failure : Increased Billirubin, Increased Liver
enzymes, splenomegaly, gastroesophageal varcices,
thrombocytopenia, coagulopthy, hepatic fibrosis, or
cirrhosis
3. More than ½ of the sites used for TPN ( jugular,
subclavain, femoral) have become inaccessible due to
thrombosis
4. Severe Dehydration
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Contraindications of Small Bowel
Transplant
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Presence of Active Infection
Aggressive Malignancy
Multi-System Organ Failure
Cerebral Edema
AIDS
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History of the Procedure
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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
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History of the Procedure
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This continued until the early 1980s, with the advent of cyclosporine,
immunosuppressive medications (azathioprine), steroids, and
antilymphocyte globulin (ALG)
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Deltz reported the first successful long-term transplantation in
Germany
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However, clinical results with cyclosporine were disappointing (most grafts lost
to rejection)
1988 - 42-year-old woman received a segment of her sister's jejunum and ileum
The graft survived until 1992 -> lost to chronic rejection
Goulet reported on 9 patients in 1990 (including a 9-month-old
infant who received 2 intestinal transplants) with poor success rates
under cyclosporine-based immunosuppression
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Graft survival time ranged from 10 days to 49 months.
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History of the Procedure
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The most significant advance in the development of
intestinal transplantation was the introduction of
TACROLIMUS (1990)
The Starzl group (1998) reported that in 55 children
who underwent small-intestine transplantations with
tacrolimus
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28 girls and 27 boys
Median age = 3.2 years of age
Patient survival rates were 55%
Graft survival rates were 52%
Greater understanding of the unique immunologic
properties of the intestine has furthered the
advancement of small-intestine
transplantation
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History of the Procedure
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As a result of these advances and a growing
appreciation of the phenomenon of chimerism,
the number of intestinal transplants has steadily
increased
More than 100 intestinal transplants being
performed each year in the United States
Most active programs in North America:
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Univ of Pittsburgh, Univ of Nebraska, Univ of
Miami, and the Toronto Hospital
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Intestinal Transplantation - Etiology
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TPN = current standard of care for patients
unable to maintain adequate nutrition via the
intestinal tract alone
Patients with poor intestinal function who
cannot be maintained on TPN are potential
candidates for transplantation
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Intestinal Transplantation - Etiology
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Intestinal failure—defined as the inability to
maintain sufficient electrolyte, nutrient, and fluid
balance for more than 1 month without TPN
and no adaptive potential to meet these needs in
the future
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May result from surgical short-bowel syndrome or
intestinal dysfunction in children
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Intestinal Transplantation - Etiology
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Worldwide, the leading cause of intestinal failure is
short-bowel syndrome caused by surgical removal
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~10-20cm of small bowel needed with an ileocecal valve
40cm without a ileocecal valve
Conditions leading to short-bowel syndrome include
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Midgut volvulus
Gastroschisis
Trauma
Necrotizing enterocolitis (NEC)
Ischemia
Crohn’s disease
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Short Bowel
Syndrome
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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
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Intestinal Transplantation - Etiology
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Other causes of intestinal dysfunction are
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Absorptive disorders
Microvillus inclusion
 Secretory diarrhea
 Autoimmune enteritis
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Dysmotiliy disorders
Pseudo-obstruction
 Hirschsprung disease
 Visceral neuropathy
 A tumor (desmoid tumor and familial polyposis (eg,
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Intestinal Transplantation - Etiology
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Leading causes of
intestinal failure in
children (in order of
decreasing frequency)
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Leading causes of
intestinal failure in adults
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Crohn’s disease
Superior mesenteric artery
thrombosis
Superior mesenteric vein
thrombosis
Trauma
Desmoid tumor
Volvulus
Pseudo-obstruction
Massive resection secondary to
tumor
Radiation enteritis
Intestinal atresia
Gastroschisis
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Crohn’s disease
Microvillus involution disease
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NEC
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Midgut volvulus (leading to
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infarction)
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Chronic intestinal pseudo
obstruction
Massive resection secondary to
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tumor
Hirschsprung diseasel.yekehfallah-phd student of nursing
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Intestinal Transplantation - Etiology
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Intestinal transplantation is reserved for TPNdependent patients with permanent intestinal
insufficiency
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Pts become intolerant of TPN -> which manifests in
potentially fatal complications
Recurrent sepsis
 Thrombosis of access sites
 Metabolic disorders
 Cholestasis
 Hepatic dysfunction
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Intestinal Transplantation
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Isolated intestinal grafting
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Combined small-intestine and liver transplantation
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Poor venous access or moderate hepatic dysfunction and for
those who develop severe fluid and electrolyte abnormalities
that cannot be managed with TPN
Intestinal insufficiency & irreversible hepatic failure or
coagulopathy
Multivisceral transplants (ie, combined stomach,
duodenum, pancreas, small intestine)
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Following extensive surgical resection of abdominal organs
for aggressive tumor or severe abdominal trauma
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Preoperative evaluation and selection
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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
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Optimization of preoperative morbid conditions
(infection, malnutrition) can significantly affect
outcome
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Preoperative evaluation and selection
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Referral criteria:
Intestinal failure with impending life-threatening
complications (i.e. end-stage liver disease)
 Recurrent sepsis (bacterial translocation 2ndary
chronic TPN)
 Impending loss of central venous access
 Locally invasive tumors of the abdomen (desmoid)
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Rescue therapy for visceral vascular thrombosis,
primary intestinal graft loss, and poor quality of
life secondary to intestinal failure
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Preoperative evaluation and selection
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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 2year 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
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Isolated intestinal transplantation
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Transplantation may not be indicated for
patients who have complications of their disease
but maintain a borderline length of intestine
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May respond to intensive medical management
Medical management may involve
Modified administration of TPN
 Selective gut decontamination
 Optimized enteral feedings ( at least 20-30% caloric
needs)
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Isolated intestinal transplantation
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Must evaluate liver function
Suspected progression of liver dysfunction
requires prompt evaluation for intestinal
transplantation and a liver biopsy to determine
whether a combined liver and small-intestine
transplantation is needed
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Isolated Intestinal Transplantation
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Combined liver and small-intestine
transplantation
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Patients with end-stage liver disease (often TPN-related
liver disease) & intestinal failure
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The highest mortality rate of all patients on the waiting lists
for organ transplantations
Chronic TPN -> cholestatic liver disease (esp. children)
Very few size-match quality organs are available, and
these patients are competing for organs with patients
on longer waiting lists who are waiting for an isolated
liver transplantation
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Represent only 2% of the patients on the liver waiting list
Do not rank well in the MELD (model for end-stage liver
disease) and PELD (pediatric end-stage liver disease) scoring
system
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Multivisceral transplantation
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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
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Intestinal Transplantation - Workup
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Preoperative workup:
All potential transplant recipients require a
review of
Comorbidities
 Relevant laboratory
 Imaging studies
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Intestinal Transplantation - Workup
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Laboratory studies include the following:
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CBC
Chem-20
Prothrombin time (PT)
Activated partial thromboplastin time (aPTT)
Blood group and screen
Serologic testing for HIV, hepatitis B virus (HBV), hepatitis
C virus (HCV), CMV, EBV, syphilis, blood group system
(ABO), and human leukocyte antigen (HLA) status
When indicated, a hypercoagulable workup (i.e., protein C,
protein S, antithrombin III, factor V mutation)
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Intestinal Transplantation - Workup
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Imaging Studies:
Perform angiography and or additional Duplex
studies
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Assess the vascular supply for potential isolated living-related
intestine donors
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Angiography helps evaluate the SMA to ensure a normal vascular
intestinal distribution
Duplex and Doppler studies help asses for possible inflow/outflow
stenosis
Adequate assessment & preservation of the descending
branch of the right colic artery are important to provide
adequate blood supply to the areas of the terminal ileum
and ileocecal valve
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Intestinal Transplantation - Workup
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Diagnostic Procedures:
Dysmotility disorders require assessment of the
stomach to exclude functional abnormalities
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Pediatric pseudo-obstruction pts require urologic
assessment
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Up to 1/3 may have a dysfunctional urinary tract
NEC -> full neurologic and pulmonary workup
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Manometry of the stomach, esophagus, and rectum may be
required to exclude sphincter achalasia and gastroparesis
Exclude the possibility of associated intraventricular
hemorrhage & bronchopulmonary dysplasia
Liver biopsy in patients with intestinal failure and
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Transplantation – Preoperative Details
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Cadaveric small-intestine procurement
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Perform selective gut decontamination with antibiotic and
antifungal preparations administered via a NGT along with
standard IV antibiotic prophylaxis
Use University of Wisconsin Universal Organ Preservation
(UW) solution for both in situ flushing and cold storage
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Choose smaller donors than the intended recipient
Preferentially direct CMV– donors to CMV– recipients
Polyethylene glycol electrolyte solution
Obtain wide exposure to the abdominal cavity, and encircle
the abdominal aorta distally for subsequent insertion of the
infusion cannula and proximally above the celiac axis for
cross-clamping
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Transplantation – Preoperative Details
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Cadaveric small-intestine procurement
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Perform dissection, in situ cooling of abdominal organs, and
exsanguination before removing the organs to the back table
for preparation.
Mobilize and devascularize the cecum and ascending colon
with care to preserve the ileal branches of the ileocolic artery.
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Divide and close the ileum with the GIA stapler near the ileocecal
valve
Devascularize the colon by ligating and dividing the middle
colic, left colic, and inferior mesenteric arteries near their
origin
After transection of the gastrocolic ligament and transection
of the stapled sigmoid colon, remove the large bowel and
greater omentum
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Transplantation – Preoperative Details
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Cadaveric small-intestine procurement
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Free the small-bowel mesentery from its retroperitoneal
attachments
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Preserve the vascular supply to the fourth part of the
duodenum and the proximal part of the jejunum.
Transect the proximal jejunum after mobilizing and dividing
the ligament of Treitz and the IMV
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Expose the mesenteric root, abdominal aorta, and infrahepatic vena
cava (including renal veins entry)
Divide the highest jejunal vascular arcades
Suture the jejunal end of the intestine to help orient the allograft
At this stage, the intestine is attached to the donor only
by the superior mesenteric pedicle (SMA & SMV)
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Divide the mesenteric root distal to the level of the ligated middle
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Transplantation – Intra-operative
Details
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In situ organ cooling and removal
Transaortic cooling requires perfusion with UW
solution, 50-100 mL/kg, for pediatric donors
 Remove the small-intestine graft by dissection of the
SMA & SMV below the origin of the inferior
pancreaticoduodenal artery
 Excise a large Carrel patch from the anterior aortic
wall containing the celiac axis and superior
mesenteric artery.
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Procure iliac and carotid arteries and veins as potential
vascular grafts
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Transplantation – Intra-operative
Details
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Back-table preparation of organs
Small-intestine grafts require little revision
 If the pedicle of the superior mesenteric artery is too
short, it may be lengthened with free vascular grafts
 The anastomoses are made to the recipient
aorta and portal vein or vena cava
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An isolated intestine being prepared on the back table
prior to implantation
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Transplantation – Intra-operative
Details
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Transplantation surgical therapy
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Isolated living-related intestinal grafting requires as
much as 150-200 cm of distal jejunum and ileum
to ensure that the recipient has a sufficient amount
of small bowel to be completely free of TPN
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Transplantation – Intra-operative
Details
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Transplantation surgical therapy
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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
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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
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Transplantation – Postoperative
Details
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Require ICU monitoring postoperatively
Induction therapy with tacrolimus and steroids is
typically begun most often in conjunction with an
interleukin-2 (IL-2) receptor antibody
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Maintain high levels of immunosuppression early in the
postoperative period (risk of rejection is greatest)
Then follow with a lower dose for maintenance therapy
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Consider the variable absorption and bioavailability of whichever immunosuppression regimen is
used (ie, tacrolimus, cyclosporine microemulsion)
Because the bioavailability of these drugs depends on intestinal surface area and transit time, the
function of the grafts directly affects drug availability
In addition, multiple immunosuppressive agents are used (as in other organ
transplants) to minimize toxicity and to maximize therapeutic efficacy
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Intestinal Transplantation –
Follow-up care
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At regular intervals, perform
CMV antigenemia
 Quantitative EBV polymerase chain reaction (PCR)
surveillance
 Routine cultures
 Transplant ileostomal endoscopy & biopsy (as often
as twice weekly)
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Additionally, monitor fluid status, stool losses,
and serum electrolytes
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Major Post Operative Complications
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Bleeding
Thrombosis
Anastomatic Leaks
Sepsis from bacterial translocation of Graft
GVHD
Acute Rejection
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Intestinal Transplantation Complications
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Infectious complications account for ~60% of
intestinal graft losses
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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
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Monitoring Intestinal Function PostTransplant
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D-xlyose absorption Test: Decreased absorption
might indicate rejection, or CMV infection
Fecal Fat Determination
Intestinal Motility: Assessed via Bowel Sounds
and Stoma Output
TPN is continued post-transplant until intestinal
function and motility return to baseline, enteral
feeds begin, and TPN is tapered over a 4-6week
period.
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Intestinal Transplantation Complications
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CMV infection
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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
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Endoscopy shows superficial ulcers, and histopathology confirms
CMV inclusion bodies
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Intestinal Transplantation Complications
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CMV infection
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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
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Ganciclovir is a synthetic analogue of 2'deoxyguanosine, which inhibits replication of human
CMV
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Intestinal Transplantation Complications
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EBV-associated lymphoproliferative disease
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Posttransplantation lymphoproliferative disease occurs more
often in children > adults (29% vs. 11%)
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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.
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Present with fever, abdominal pain, & either lymphadenopathy or
masses on abdominal imaging
In addition, low-grade EBV infections often precede
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Intestinal Transplantation Complications
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EBV-associated lymphoproliferative disease
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Treatment of posttransplantation
lymphoproliferative disease involves
Reduction of immunosuppression
 Administration of ganciclovir (10 mg/kg/d)
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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
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Intestinal Transplantation Complications
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Acute allograft rejection
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Early diagnosis of allograft rejection, a major contributor to both the high
morbidity and the high mortality associated with small-intestine
transplantation, is essential
Allograft rejection incidence rates as high as 87% have been reported
Manifests clinically
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Fever
abdominal pain
increased output from the ostomy
abdominal distention
Acidosis
Malabsorption and electrolyte abnormalities occur in some patients
Bacterial & fungal sepsis can be life threatening because of the intestine's
loss of barrier function, making early diagnosis and effective treatment of
the rejection vital
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Intestinal Transplantation Complications

Acute allograft rejection

Rejection is diagnosed by endoscopic intestinal biopsy


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 ->



Diagnosis can be difficult because of the patchy nature of rejection
and the presence of bleeding & perforation complications
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
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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
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Intestinal Transplantation Complications

Graft versus host disease

Small intestine = immunocompetent organ



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







Population of lymphoid cells can mount an immunologic response to the
host—a GVHD reaction
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
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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
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 Chylous ascites
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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
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Intestinal Transplantation Outcome and Prognosis
Author
Transplant
type
Graft 1 Yr % Patient 1 Yr
%
Lagnas(Neb)
Liver & S.I.
61
76
Reyes (Pitt)
All
63
73
Grant
S.I.
55
69
Liver & S.I.
63
66
Multivisceral
63
63
Mazariegos
All
Graft 5 Yr % Patient 5 Yr
%
52
Control
55
30
Madariaga
Multivisceral
54
Farmer
All
77
42
90
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Intestinal Transplantation Outcome and Prognosis

Small-intestine transplantation has higher
incidences of rejection, sepsis, and posttransplantation 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
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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%
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Intestinal Transplantation

Patient survival & graft survival rates have
improved with
The introduction of tacrolimus (FK506)–based
immunosuppression (calcineurin inhibitor)
 Used in combination with

Decontamination protocols
 Antibiotic regimens
 Antiviral measures against cytomegalovirus (CMV) and
Epstein-Barr virus (EBV).

Pre-tacrolimus – pt survival 0-28% and graft survival
0-11%
 With tacrolimus – pt & graft survival exceed 50%
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