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Intestinal transplantation

            Dr. Richard S. Mangus, MD MS FACS
              Assistant Professor of Surgery
               Contact: rmangus@iupui.edu

09/25/12                                        1
Intestinal Failure
           Definition and Etiologies




09/25/12                               2
Intestinal Failure - Definition

• Failure of digestion and absorption
• Inability of the intestinal tract to maintain adequate
  nutritional status and fluid / electrolyte balance
• Results from a loss or absence of sufficient
  functional intestinal area




09/25/12                                              3
Intestinal Failure - Etiology
                         Children
  • Short gut (necrotizing enterocolitis, others)
  • Intestinal atresia
  • Midgut volvulus
  • Gastroschisis
  • Hirschprung’s disease
  • Microvillus inclusion disease

09/25/12                                            4
Intestinal Failure - Etiology
                     Adults
  • Short gut
  • Mesenteric thrombosis (arterial or venous)
  • Trauma
  • Inflammatory bowel disease / Crohn’s
    disease
  • Pseudo-obstruction
  • Tumors (desmoid, neuroendocrine tumors)

09/25/12                                         5
Intestinal Failure
           Management issues




09/25/12                        6
Intestinal Failure - Management

  • Medically or surgically alter the remaining
    intestine to compensate for inadequate
    absorptive surface area
  • Meet caloric and nutritional requirements via
    an alternate route (parenteral nutrition (PN))
  • Intestinal transplantation



09/25/12                                             7
Parenteral nutrition (PN)

    •       First line therapy
    •       Requires long term central venous access
    •       Labor intensive
    •       Expensive (total costs up to $1000/day)
    •       Associated with serious and frequent
           complications
           –   Infections
           –   Loss of vascular access
           –   Electrolyte abnormalities
           –   Nutritional deficiencies (trace metals, other)
           –   Liver disease
09/25/12                                                        8
Parenteral nutrition – complications
 • Catheter related sepsis:
           – Standard site infection
           – Seeding from compromised intestine
             • Bacterial translocation
 • Avoiding catheter infections
           – Meticulous site care
           – 70% alcohol dwell
           – Antibiotic dwell


09/25/12                                          9
Parenteral nutrition – complications
  • Loss of vascular access

           – 6 primary sites for vascular access
              • Jugular, subclavian, femoral

           – Thrombus formation
              • May require anticoagulation
              • Heparin dwell

           – Vein sclerosis / narrowing


09/25/12                                           10
Parenteral nutrition – complications
  • Cholestatic liver disease
           – Progressive cholestasis and cirrhosis
           – Rate of progression may be associated with
             length of remaining intestine
              • Full intestinal length – liver failure slow onset
              • Short intestinal length – more rapid
                progression
           – Low lipid strategies
              • <1g/kg per day
              • Every other day or 3x/week lipids

09/25/12                                                            11
Parenteral nutrition – complications
  • Cholestatic liver disease (continued)
           – Liver function tests in short gut patients are
             altered after 6 months in 15% to 40% of
             adults and 95% of children
           – Chronic cholestasis related to short gut,
             bacterial overgrowth, lipid infusion > 1g/kg,
             overfeeding , lack of oral feedings, infections
           – Liver dysfunction is the ultimate cause of
             death in 30 to 40% of PN patients


09/25/12                                                       12
Parenteral nutrition – FAILURE
  • Medicare approved criteria for PN failure:
           – Impending/overt liver failure due to PN-induced liver
             injury
           – Thrombosis of 2 or more central venous access sites
           – The development of 2 or more episodes of systemic
             sepsis secondary to line infection, in one year, that
             requires hospitalization indicates failure of PN therapy
           – A single episode of line-related fungemia, septic shock,
             and/or acute respiratory distress syndrome is
             considered an indicator of TPN failure
           – Frequent episodes of severe dehydration despite
             intravenous fluid supplementation in addition to TPN.
09/25/12                                                                13
Intestinal Transplantion
           Transplant options




09/25/12                          14
Intestinal transplantation
  • Advantages:
           – Replace normal intestinal anatomy, continuity
           – Patient able to eat and drink
           – Chance for definitive cure of disease
           – Able to stop PN
             • Remove central venous catheters
                – Decrease infection risk
                – Decrease risk of loss of vascular access
             • Reversal of liver injury


09/25/12                                                     15
Intestinal transplantation
  • Disadvantages:
           – Risks of major surgery
           – Risk of rejection
           – Risks of life-long immunosuppression
             •   Infections
             •   Cancers
             •   Renal failure
             •   Graft versus host disease



09/25/12                                            16
Intestinal Transplantation - surgery
  • Intestinal transplant options:
           – Isolated intestinal transplant
             • Small intestine only
           – Modified multivisceral transplant
             • Small intestine + pancreas + stomach
           – Full multivisceral transplant
             • Small intestine + pancreas + stomach + liver
           – Can add in other organs, as indicated
             • +/- kidney


09/25/12                                                      17
Intestinal Transplantation - surgery

           • Surgical considerations:
             – Organs to include
             – Composite or separate
             – Whole or reduced size
             – Arterial inflow
             – Venous outflow
             – Enteric connection



09/25/12                                   18
Intestinal Transplantation
  • Intestinal transplant : Recipient
    operation




09/25/12                                19
Intestinal Transplantation
  • Isolated intestinal transplant
           – Indication: Intestinal failure in the absence of
             any other organ failure
              • Normal function of liver, stomach, pancreas




09/25/12                                                        20
Intestinal Transplantation
  • Isolated intestinal
    transplant




09/25/12                         21
Intestinal Transplantation
  • Isolated intestinal
    transplant




09/25/12                         22
Intestinal Transplantation
  • Isolated intestinal
    transplant




09/25/12                         23
Intestinal Transplantation
  • Modified multivisceral transplant
           – Indication: Intestinal failure in the absence of
             liver failure
              • Normal function of liver
              • Dysfunction of stomach, intestine, +/- pancreas




09/25/12                                                          24
Intestinal Transplantation
  • Modified
    multivisceral
    transplant




09/25/12                         25
Intestinal Transplantation
  • Modified multivisceral transplant




09/25/12                                26
Intestinal Transplantation
  • Multivisceral transplant
           – Indication: Intestinal failure with liver failure
              • Dysfunction of liver and intestine
              • +/- dysfunction of stomach and pancreas




09/25/12                                                         27
Intestinal Transplantation
  • Multivisceral
    transplant




09/25/12                         28
Intestinal Transplantation
• Multivisceral transplant:
  – Liver / intestine
    transplant (+/- pancreas)




09/25/12                         29
Intestinal Transplantation
  • Multivisceral
    transplant




09/25/12                         30
Intestinal Transplantation
  • Multivisceral
    transplant




09/25/12                         31
Intestinal Transplantation
  • Multivisceral
    transplant




09/25/12                         32
Intestinal Transplantation

  • Non-traditional indications:
           – Diffuse mesenteric thrombosis
           – Benign/ low grade malignant tumors involving the
             mesenteric root
                • Neuroendocrine tumors (carcinoid, insulinoma, others)
                • Desmoid tumors
           –   Abdominal catastrophes / fistulas
           –   Radiation enteritis
           –   Trauma
           –   Enteropathies / dysmotility disorders

09/25/12                                                                  33
Post-transplant care
           Complications




09/25/12                          34
Intestinal Transplantation - Rejection
  • Rejection
           – Isolated and modified multivisceral (liver
             excluded)
              • 1-year risk of rejection      45-50%
           – Multivisceral (liver included)
              • 1-year risk of rejection      15%


  • Liver known to be protective against rejection



09/25/12                                                  35
Intestinal Transplantation - Complications

  • Other complications
           – Graft versus host disease (GVHD)
           – Post transplant lymphoproliferative disorder
             (PTLD)
           – Disease recurrence
             • Pseudoobstruction
           – Obstruction
           – Chronic rejection
           – Narcotic addiction (chronic pain)

09/25/12                                                    36
Post-transplant
           Outcomes




09/25/12                     37
Intestinal Transplantation - Volume
           U.S. intestinal transplant volume for last
           decade200
                180
                160
                140
                120
                100
                 80
                 60
                 40
                 20
                  0
                      2001 2002 2003 2004 2005 2006 2007 2008 2009 2010




09/25/12                                                                  38
Intestinal Transplantation - Volume
  • World Intestinal Transplant Registry (ITR)
           – Worldwide database of all intestinal
             transplants
           – Between 2005 and 2007, 28 centers
             wordwide reporting to the ITR performed 389
             intestinal transplants on 377 patients
  • In U.S. (Year 2010):
           – 151 transplants (-16% from previous year)
           – 17 centers with at least one transplant
           – 6 centers with 10 or more transplants
09/25/12                                                   39
Intestinal Transplantation - Outcomes
  • U.S. Adult intestinal transplant outcomes
                                     Patient Survival

             Age group               1-year   5-years
                 18 to 34 years      81%      70%


                 35 to 49 years      80%      63%

                 50 to 64 years      93%      38%


                 65+ years           100%     N/A




           From the Organ Procurement and Transplant Network (U.S.), 2002-2007




09/25/12                                                                    40
Intestinal Transplantation – Costs
• Cost to maintain a patient on PN ranges from $75,000-$200,000 per
  year
   – Added costs of home nursing, support, equipment
• PN related complications result in an average of 1 major
  hospitalization per year, and catheter related complications are
  common and costly
• Intestinal transplantation has been shown to be a cost effective
  therapy and is superior to continued PN in appropriately selected
  patients
• Costs for intestinal transplantion, including the initial hospitalization
  for the transplant range from $200,000-$500,000
• There are frequent hospital readmissions post-transplant, but these
  admissions decrease markedly after the second year post-transplant
• The cost-benefit of transplantation reaches parity with PN after 2-3
  years post-transplant and is more cost-effective thereafter

09/25/12                                                                  41

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Intestinal Transplantation Options and Complications

  • 1. Intestinal transplantation Dr. Richard S. Mangus, MD MS FACS Assistant Professor of Surgery Contact: rmangus@iupui.edu 09/25/12 1
  • 2. Intestinal Failure Definition and Etiologies 09/25/12 2
  • 3. Intestinal Failure - Definition • Failure of digestion and absorption • Inability of the intestinal tract to maintain adequate nutritional status and fluid / electrolyte balance • Results from a loss or absence of sufficient functional intestinal area 09/25/12 3
  • 4. Intestinal Failure - Etiology Children • Short gut (necrotizing enterocolitis, others) • Intestinal atresia • Midgut volvulus • Gastroschisis • Hirschprung’s disease • Microvillus inclusion disease 09/25/12 4
  • 5. Intestinal Failure - Etiology Adults • Short gut • Mesenteric thrombosis (arterial or venous) • Trauma • Inflammatory bowel disease / Crohn’s disease • Pseudo-obstruction • Tumors (desmoid, neuroendocrine tumors) 09/25/12 5
  • 6. Intestinal Failure Management issues 09/25/12 6
  • 7. Intestinal Failure - Management • Medically or surgically alter the remaining intestine to compensate for inadequate absorptive surface area • Meet caloric and nutritional requirements via an alternate route (parenteral nutrition (PN)) • Intestinal transplantation 09/25/12 7
  • 8. Parenteral nutrition (PN) • First line therapy • Requires long term central venous access • Labor intensive • Expensive (total costs up to $1000/day) • Associated with serious and frequent complications – Infections – Loss of vascular access – Electrolyte abnormalities – Nutritional deficiencies (trace metals, other) – Liver disease 09/25/12 8
  • 9. Parenteral nutrition – complications • Catheter related sepsis: – Standard site infection – Seeding from compromised intestine • Bacterial translocation • Avoiding catheter infections – Meticulous site care – 70% alcohol dwell – Antibiotic dwell 09/25/12 9
  • 10. Parenteral nutrition – complications • Loss of vascular access – 6 primary sites for vascular access • Jugular, subclavian, femoral – Thrombus formation • May require anticoagulation • Heparin dwell – Vein sclerosis / narrowing 09/25/12 10
  • 11. Parenteral nutrition – complications • Cholestatic liver disease – Progressive cholestasis and cirrhosis – Rate of progression may be associated with length of remaining intestine • Full intestinal length – liver failure slow onset • Short intestinal length – more rapid progression – Low lipid strategies • <1g/kg per day • Every other day or 3x/week lipids 09/25/12 11
  • 12. Parenteral nutrition – complications • Cholestatic liver disease (continued) – Liver function tests in short gut patients are altered after 6 months in 15% to 40% of adults and 95% of children – Chronic cholestasis related to short gut, bacterial overgrowth, lipid infusion > 1g/kg, overfeeding , lack of oral feedings, infections – Liver dysfunction is the ultimate cause of death in 30 to 40% of PN patients 09/25/12 12
  • 13. Parenteral nutrition – FAILURE • Medicare approved criteria for PN failure: – Impending/overt liver failure due to PN-induced liver injury – Thrombosis of 2 or more central venous access sites – The development of 2 or more episodes of systemic sepsis secondary to line infection, in one year, that requires hospitalization indicates failure of PN therapy – A single episode of line-related fungemia, septic shock, and/or acute respiratory distress syndrome is considered an indicator of TPN failure – Frequent episodes of severe dehydration despite intravenous fluid supplementation in addition to TPN. 09/25/12 13
  • 14. Intestinal Transplantion Transplant options 09/25/12 14
  • 15. Intestinal transplantation • Advantages: – Replace normal intestinal anatomy, continuity – Patient able to eat and drink – Chance for definitive cure of disease – Able to stop PN • Remove central venous catheters – Decrease infection risk – Decrease risk of loss of vascular access • Reversal of liver injury 09/25/12 15
  • 16. Intestinal transplantation • Disadvantages: – Risks of major surgery – Risk of rejection – Risks of life-long immunosuppression • Infections • Cancers • Renal failure • Graft versus host disease 09/25/12 16
  • 17. Intestinal Transplantation - surgery • Intestinal transplant options: – Isolated intestinal transplant • Small intestine only – Modified multivisceral transplant • Small intestine + pancreas + stomach – Full multivisceral transplant • Small intestine + pancreas + stomach + liver – Can add in other organs, as indicated • +/- kidney 09/25/12 17
  • 18. Intestinal Transplantation - surgery • Surgical considerations: – Organs to include – Composite or separate – Whole or reduced size – Arterial inflow – Venous outflow – Enteric connection 09/25/12 18
  • 19. Intestinal Transplantation • Intestinal transplant : Recipient operation 09/25/12 19
  • 20. Intestinal Transplantation • Isolated intestinal transplant – Indication: Intestinal failure in the absence of any other organ failure • Normal function of liver, stomach, pancreas 09/25/12 20
  • 21. Intestinal Transplantation • Isolated intestinal transplant 09/25/12 21
  • 22. Intestinal Transplantation • Isolated intestinal transplant 09/25/12 22
  • 23. Intestinal Transplantation • Isolated intestinal transplant 09/25/12 23
  • 24. Intestinal Transplantation • Modified multivisceral transplant – Indication: Intestinal failure in the absence of liver failure • Normal function of liver • Dysfunction of stomach, intestine, +/- pancreas 09/25/12 24
  • 25. Intestinal Transplantation • Modified multivisceral transplant 09/25/12 25
  • 26. Intestinal Transplantation • Modified multivisceral transplant 09/25/12 26
  • 27. Intestinal Transplantation • Multivisceral transplant – Indication: Intestinal failure with liver failure • Dysfunction of liver and intestine • +/- dysfunction of stomach and pancreas 09/25/12 27
  • 28. Intestinal Transplantation • Multivisceral transplant 09/25/12 28
  • 29. Intestinal Transplantation • Multivisceral transplant: – Liver / intestine transplant (+/- pancreas) 09/25/12 29
  • 30. Intestinal Transplantation • Multivisceral transplant 09/25/12 30
  • 31. Intestinal Transplantation • Multivisceral transplant 09/25/12 31
  • 32. Intestinal Transplantation • Multivisceral transplant 09/25/12 32
  • 33. Intestinal Transplantation • Non-traditional indications: – Diffuse mesenteric thrombosis – Benign/ low grade malignant tumors involving the mesenteric root • Neuroendocrine tumors (carcinoid, insulinoma, others) • Desmoid tumors – Abdominal catastrophes / fistulas – Radiation enteritis – Trauma – Enteropathies / dysmotility disorders 09/25/12 33
  • 34. Post-transplant care Complications 09/25/12 34
  • 35. Intestinal Transplantation - Rejection • Rejection – Isolated and modified multivisceral (liver excluded) • 1-year risk of rejection 45-50% – Multivisceral (liver included) • 1-year risk of rejection 15% • Liver known to be protective against rejection 09/25/12 35
  • 36. Intestinal Transplantation - Complications • Other complications – Graft versus host disease (GVHD) – Post transplant lymphoproliferative disorder (PTLD) – Disease recurrence • Pseudoobstruction – Obstruction – Chronic rejection – Narcotic addiction (chronic pain) 09/25/12 36
  • 37. Post-transplant Outcomes 09/25/12 37
  • 38. Intestinal Transplantation - Volume U.S. intestinal transplant volume for last decade200 180 160 140 120 100 80 60 40 20 0 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 09/25/12 38
  • 39. Intestinal Transplantation - Volume • World Intestinal Transplant Registry (ITR) – Worldwide database of all intestinal transplants – Between 2005 and 2007, 28 centers wordwide reporting to the ITR performed 389 intestinal transplants on 377 patients • In U.S. (Year 2010): – 151 transplants (-16% from previous year) – 17 centers with at least one transplant – 6 centers with 10 or more transplants 09/25/12 39
  • 40. Intestinal Transplantation - Outcomes • U.S. Adult intestinal transplant outcomes Patient Survival Age group 1-year 5-years 18 to 34 years 81% 70% 35 to 49 years 80% 63% 50 to 64 years 93% 38% 65+ years 100% N/A From the Organ Procurement and Transplant Network (U.S.), 2002-2007 09/25/12 40
  • 41. Intestinal Transplantation – Costs • Cost to maintain a patient on PN ranges from $75,000-$200,000 per year – Added costs of home nursing, support, equipment • PN related complications result in an average of 1 major hospitalization per year, and catheter related complications are common and costly • Intestinal transplantation has been shown to be a cost effective therapy and is superior to continued PN in appropriately selected patients • Costs for intestinal transplantion, including the initial hospitalization for the transplant range from $200,000-$500,000 • There are frequent hospital readmissions post-transplant, but these admissions decrease markedly after the second year post-transplant • The cost-benefit of transplantation reaches parity with PN after 2-3 years post-transplant and is more cost-effective thereafter 09/25/12 41