session4 1300 qunintini ddi nursing conference · infections nearly all patients (>95%) develop...

Intestinal TransplantationCristiano Quintini, MD

Intestinal Rehabilitation and Transplant ProgramCleveland Clinic

History ofHistory ofIntestinal TransplantationIntestinal Transplantation

• Initially attempted in early 1960’s• Only a few unsuccessful cases until the late

1980’s• With the development of Cyclo/Tacrolimus

successful transplantation has been achieved• Guidelines for intestinal transplantation

adopted by United States Department of Health and Human Services in 2000

Intestinal Transplantation Under Cyclosporine

• Pittsburgh Nov ’ 87 Multivisceral 6.5 mos

• Kiel Aug ’88 Intestine 61 mos

• Ontario Nov ’88 Liver/Intestine 66 mos

• Paris Mar ’89 Intestine still alive!

• Ontario Nov ’89 Multivisceral 58 mos

• Innsbruck Dec ’89 Multivisceral 7.5 mos

Causes Of Intestinal Failure

ADULTS– Vascular occlusion– Crohn’s disease– Abdominal trauma– Radiation enteritis– Surgical adhesions– Pseudo-obstruction– Desmoid tumor

• CHILDREN– Gastroschisis– Necrotizing enterocolitis– Volvulus– Intestinal atresia– Microvillus disease– Pseudo-obstruction– Familial polyposis

Treatment Of Intestinal FailureTreatment Of Intestinal Failure

• Medical/Pharmacological• Surgical restoration • TPN• Transplantation

Tapering

Strictureplasty

LengtheningValve

Reversed Segment

Surgical Management of Short Bowel Syndrome

STEP procedure

HPNHPN

•The ‘artificial gut’ for Intestinal failure and represent the treatment of choice for irreversible CIF

•The first patient was discharged on HPN by Shils et al. in the late 1960s

•About 20–50% of patients who starts HPN has a reversible CIF and are able to stop treatment after 1–2 years

•2-year PN represents the limit between transient and permanent intestinal failure.

HPN complicationsHPN complications

• Line sepsis

• Venous access thrombosis

• TPN-induced liver disease

• Psychological and economic factors

31%–68% of HPN have short bowel syndrome

•Analysis on 124 consecutive adults with nonmalignant SBS enrolled from 1980 to 1992 at 2 home PN centers.

•Analyzed for survival and PN dependence probabilities

Messing B. et AlGastroenterology 1999;117:1043–1050


HPNOverall survival


HPNPrimary diagnosis survival curve


HPN Effect of remnant bowel


HPN Colon and ICV

Mayo Clinic Proc; Volume 74(3), March 1999, pp 217-222

HPNPrimary diagnosis survival curve

100% mortality at an average of 10.8 ± 7.1 months after the initial bilirubin elevation.

Indications for Referring Adults to Indications for Referring Adults to Intestinal Tx CenterIntestinal Tx Center•• Liver disease despite expert PN managementLiver disease despite expert PN management•• Loss of all but 2 major venous access routes (1 should be Loss of all but 2 major venous access routes (1 should be

above diaphragm)above diaphragm)•• Recurrent or life threatening central line sepsisRecurrent or life threatening central line sepsis•• Inability to maintain hydration/nutrition with PNInability to maintain hydration/nutrition with PN•• Dismotility disorders Dismotility disorders •• Need for extensive evisceration (desmoid, trauma or rare Need for extensive evisceration (desmoid, trauma or rare

selected malignancies)selected malignancies)

Nightingale and Woodward. Gut 55:1-12, 2006.

From Jonathan Fryer MD. Northwestern University September 2006

Annual Waiting List Death Rates All organsAnnual Waiting List Death Rates All organs

((per 1,000 Patientper 1,000 Patient--Years at Risk WaitingYears at Risk Waiting))

Acceptance CriteriaAcceptance Criteria

•• Age 1 Age 1 –– 6565•• Irreversible intestinal failureIrreversible intestinal failure•• Failure / complication of TPNFailure / complication of TPN•• Early referral to avoid associated need Early referral to avoid associated need

for combined intestine & liver transplantfor combined intestine & liver transplant•• No contraindication to surgeryNo contraindication to surgery•• Patient readiness and caregiver supportPatient readiness and caregiver support

Liver and intestine

Liver, intestine and pancreas Multivisceral

Isolated Intestine

Multivisceral transplantation

Types of Grafts in Clinical Types of Grafts in Clinical Intestinal TransplantIntestinal Transplant

Isolated bowel graft plus:Isolated bowel graft plus:Stomach, duodenum and pancreas Stomach, duodenum and pancreas LiverLiverColonColonSpleenSpleen

Intestinal Tx

TechnicalTechnical datadata

•Operative time: 10:40 (± 2:10)

•Average Blood loss: 10-25 PRBCs

•Cold ischemia time: 6:20 (± 1:10)

Induction and Maintenance TherapyInduction and Maintenance Therapy

SteroidsSteroidsTacrolimusTacrolimusSirolimusSirolimusMonoclonal AntibodiesMonoclonal Antibodies

CampathCampathMuromonab CD3 (OKT3)Muromonab CD3 (OKT3)

Polyclonal AntibodiesPolyclonal AntibodiesThymoglobulinThymoglobulinATGAMATGAM

ILIL--2 Receptor Blockers2 Receptor BlockersDaclizumab (Zenapax)Daclizumab (Zenapax)

Induction

Treatment of rejection episodesTreatment of rejection episodes

Intestinal transplantIntestinal transplantMild rejection: Steroid bolus and cycle; increase in Mild rejection: Steroid bolus and cycle; increase in baseline immunosuppression; if no response in 2 days, baseline immunosuppression; if no response in 2 days, OKT3 (7OKT3 (7--14 days)14 days)Moderate and severe rejection: Moderate and severe rejection: Thymoglobuline/Infliximab/AlefaceptThymoglobuline/Infliximab/Alefacept//

Abdominal Closure

Intestinal Transplant

Past history of complete midgut removal with the loss of the abdominal cavity domain

Many patients undergoing intestinal or multivisceral transplantation have:

Severely damaged abdominal wall(from repeated laparotomies, tumors, enterocutaneous fistulae)

Intestinal Transplant ProgramAbdominal wall reconstruction

Difficult abdominal ClosureDifficult abdominal Closure

MESH CLOSUREMESH CLOSURE

FLAP CLOSURE FLAP CLOSURE

Abdominal wall flap- skin and subcutaneous tissue

- muscolar fascia

- rectus abdominis muscles

- parietal peritoneum

CombinedCombined intestinalintestinal and and abdominalabdominal wallwalltransplantationtransplantation

Donor: preDonor: pre--op drawingop drawing

Abdominal wall flapAbdominal wall flap

Abdominal wall flap Abdominal wall flap in perfusion with in perfusion with

Celsior sol.Celsior sol.

Immediate postImmediate post--opop 6 months post6 months post--opop

•Four pediatric recipient -Left lateral segment -Averages of 160 cm (150–180 cm) of terminal ileum•The mother was always the donor!

The decision to proceed with a single- or a two-stage procedure was dictated by the presence of a positive cross-match and preformed antibodies against the donor in one case and by advanced end-stage liver disease in two cases. The rationale in the latter was to re-establish quasinormal liver function before submitting the child to the intestine transplant.

Donor anatomy

Donor operation

Rejection

Intestinal TransplantComplications

Intestinal TransplantIntestinal TransplantRejectionRejection

Kidney: Renal failure, HDKidney: Renal failure, HDPancreas: Endocrine failure/Pancreas: Endocrine failure/InsulineInsulineLiver: Increased LFTs, Liver failure (Days), Liver: Increased LFTs, Liver failure (Days), DeathDeathIntestine: Disruption of Blood/Enteric barrier Intestine: Disruption of Blood/Enteric barrier and SEPSISand SEPSIS

RejectionRejectionPatient Symptoms Patient Symptoms

Symptoms are very Symptoms are very aspecificaspecific ((nausea,vomitingnausea,vomiting, , increased stoma output, fever)increased stoma output, fever)Target: small intestine, distal ileumTarget: small intestine, distal ileumLiver is protective!Liver is protective!

MILD/MODERATEMILD/MODERATEChest pain, Nausea, Vomiting, DiarrheaChest pain, Nausea, Vomiting, DiarrheaSEVERESEVEREFever, STFever, ST--elevation and seizures elevation and seizures

RejectionRejectionSurgeon Symptoms Surgeon Symptoms

HISTOLOGICAL ANALYSISHISTOLOGICAL ANALYSIS

Biopsy of the affected organ is still the gold standard. Biopsy of the affected organ is still the gold standard. Try to get results same dayTry to get results same dayExperienced pathologistsExperienced pathologists

No rejection: normal tissueNo rejection: normal tissueIndeterminateIndeterminate (Grade IND) (Grade IND) MildMild acute cellular rejection (Grade 1) acute cellular rejection (Grade 1) ModerateModerate acute cellular rejection (Grade 2)acute cellular rejection (Grade 2)SevereSevere acute cellular rejection (Grade 3)acute cellular rejection (Grade 3)

ZOOM ENDOSCOPYZOOM ENDOSCOPY

Magnifies > 100 foldsMagnifies > 100 foldsMinute analysis of mucosaMinute analysis of mucosaOnly in adult/older childrenOnly in adult/older children

Endoscopy protocolEndoscopy protocol

Twice/week endoscopy in the first 4 Twice/week endoscopy in the first 4 weeks after transplant weeks after transplant Once weekly for 3 months, then monthlyOnce weekly for 3 months, then monthlyDaily or every other day when rejection Daily or every other day when rejection diagnosed until resolution of clinical and diagnosed until resolution of clinical and histological signs histological signs

““Endoscopy dogmaEndoscopy dogma””

You are never wrong to do a scope!You are never wrong to do a scope!If there is something suspicious, scope!If there is something suspicious, scope!Scope at the drop of a hat!Scope at the drop of a hat!If you do not know what to do, scope first, then think If you do not know what to do, scope first, then think about it!about it!Cleveland winters are good for scopes!!Cleveland winters are good for scopes!!

Height

Erythema

Normal mucosaNormal mucosa

Mild rejectionMild rejection

Moderate rejectionModerate rejection

Severe rejectionSevere rejection

SEVERE REJECTIONSEVERE REJECTION

• ZOOM VIDEO ENDOSCOPY&

INTESTINAL BIOPSY

Twice a week (up to 15 POD)Weekly (up to 2nd month)Monthly or ACR suspicion

• INTRAVITAL POLARIZEDLIGHT MICROSCOPE.

CYTOSCAN® (after endoscopy)

MUCOSAL SURVEILLANCE

OPS IMAGINGSevere acute ACR

CITRULLINECITRULLINECurrently no biochemical markers of Currently no biochemical markers of

intestinal rejectionintestinal rejection

Citrulline is an aminoCitrulline is an amino--acid whose serum level is acid whose serum level is solely dependent on enterocyte metabolismsolely dependent on enterocyte metabolismLow levels of citrulline are seen in patients with Low levels of citrulline are seen in patients with bowel dysfunction or short gutbowel dysfunction or short gutWorking hypothesis: could citrulline levels vary in Working hypothesis: could citrulline levels vary in serum of intestinal transplant patients according to serum of intestinal transplant patients according to graft function? graft function?

0

5

10

15

20

25

30

35

40

45

Pre-Trans

0 1 2 2.5 - 4.0

Grade of Rejection

Seru

m C

itrul

line

[u

mol

es/m

l]

Mean + SD

No Rejection

Correlation of citrulline with rejection gradeCorrelation of citrulline with rejection grade

Infections


InfectionsInfectionsNearly all patients (>95%) develop one or more episodes of Nearly all patients (>95%) develop one or more episodes of documented infections after transplantdocumented infections after transplantAverage number of infection episodes: 5 per patientAverage number of infection episodes: 5 per patientMore common early after transplant: 50% 1More common early after transplant: 50% 1--3 months, 25% 33 months, 25% 3--12 12 months, 25% > 12 monthsmonths, 25% > 12 monthsCausative agents:Causative agents:

90% bacterial90% bacterial6% fungal6% fungal4% viral4% viralMany episodes of mixed infections (viral/bacterial or bacterial/Many episodes of mixed infections (viral/bacterial or bacterial/fungal)fungal)

Location:Location:BloodBloodRespiratory tractRespiratory tractWoundWoundIntraIntra--abdominalabdominalUrineUrineCentral venous catheterCentral venous catheter

PTLDPost-Transplant

Lymphoproliferative Disoreder


DefinitionDefinition--PathogenesisPathogenesisPostPost--transplant lymphoproliferative disorders transplant lymphoproliferative disorders (PTLD) are a spectrum of diseases in which there (PTLD) are a spectrum of diseases in which there is abnormal proliferation of lymphocytes (most is abnormal proliferation of lymphocytes (most cases: Epstein Barr Viruscases: Epstein Barr Virus--infected Binfected B--lymphocytes) in all tissues and organs where lymphocytes) in all tissues and organs where lymphocytes are presentslymphocytes are presentsFor most cases of PTLD, EBV infection of the BFor most cases of PTLD, EBV infection of the B--cells is the first stepcells is the first step

Intestinal ulcer from PTLD lesion

Microscopic appearance of intestinal PTLD

TreatmentTreatmentReduction or complete discontinuation of Reduction or complete discontinuation of

immunosuppressionimmunosuppression

Antiviral medications (Gancyclovir, Acyclovir), Antiviral medications (Gancyclovir, Acyclovir), hyper immune immunoglobulins (Cytogam)hyper immune immunoglobulins (Cytogam)AntiAnti-- B cell antibody therapy B cell antibody therapy (Rituximab)(Rituximab)Surgical resection/local irradiationSurgical resection/local irradiationInterferon alphaInterferon alphaConventional chemotherapy Conventional chemotherapy

GVHDGraft Versus Host Disease


GVHDGVHD

GraftGraft--versusversus--host diseasehost disease (GVHD) is a rare but (GVHD) is a rare but potentially fatal complication of solid organ potentially fatal complication of solid organ transplant in which functional immune cells transplant in which functional immune cells (mature T and B cells) in the transplanted organ (mature T and B cells) in the transplanted organ recognize the recipient as "foreign" and mount recognize the recipient as "foreign" and mount an immunologic attack. an immunologic attack.

TreatmentTreatment

Increase/decrease ISP????Increase/decrease ISP????Prognosis is POOR (70Prognosis is POOR (70--90% death rate)90% death rate)

, ITR Complete Data Set, Interim Analysis Sept 5, 2007

Intestine Transplant Registry

Supported by an unrestricted educational grant from Astellas, Canada, Inc.

www.IntestineTransplant.org


Database Profile1

1. Database includes ~95% of the world experience.2. The longest surviving recipient was transplanted 18 years ago and

she still has a functioning graft!

Number of centres 69Number of transplants 1720

SBT 746SB/Liv 594MVT 380 (281/99)

Number of Patients 1608

Current Survivors2 909


BirminghamBoston (2)CharlestonChicago (4)DallasHoustonIndianapolisIowa CityKansas CityLos Angeles (2)MadisonMiamiMinneapolisNew OrleansNew York (2)Oklahoma CityOmahaPittsburghRochesterSeattleSt. LouisStanfordWashington, DC

Geneva

BirminghamCambridgeLeedsLondon

LondonToronto (2)Edmonton

Torreon

GöteborgStockholmUppsala

Innsbruck

NeumünsterTübingenBerlin, KeilCologne

KyotoOsakaSendai

NanjingTianjinWuhanXi’an

Coimbra

BrusselsLeuven

Buenos Aires(2)

Madrid

Sao Paulo

Groningen Tehran

ParisVillejuif

BergamoMilanoRomeBologna

Santiago

Participating Countries

Complete Data Set

Medellin


69 Participating Programs Ordered by Case Volume

Complete Data Set

0

100

200

300

400

500


* -Jan 1 to May 31

Intestinal Transplants by Year


Demographics

0 20 40

<=2

6 - 18

> 5018‐50

2‐6

Age at TransplantGender Distribution

Males52%

Females48%


Indications in Children


Indications in Adults


Pre Tx Status by Era


Median Hospital Stay 2005 – 2007


Tx Type N

Intestine 384

Intestine + Liver 242

Mod. MV 60

MV 192

Overall 878

p = 0.171 p = 0.112

Tx Type N

Intestine 384

Intestine + Liver 242

Mod. MV 60

MV 192

Overall 878

Graft and Patient Survival 2002/07


Rejection @ 3 months

Intestinal Transplant Registry March 31, 20055yr ITR Data Set

p = 0.024

Rej_3M Total N

Rejection 103

No Rejection 242

Overall 345


Alive Patient Status > 6 Months Post Tx2005 - 2007

Graft Function (N=178)

Modified Karnofsky

Performance Score

(N=163)


Cause of Death Distribution 2005 - 07

Intestinal Transplant Registry May 31, 2

Univariate Analysis of Factors Affecting Survival

0.0000nsTx Type

0.03520.0000Tx Era

0.00000.0000Maintenance Rx

0.00070.0000Induction Rx

0.00000.0000Centre Size

0.00100.0005Re-Tx

0.00000.0000Pre Tx Status

PatientGraftp values

Not significant: recipient gender; recipient age, PRA, donor type, portal vein, and donor blood group compatibility

Intestinal transplant is cost effective within first two years of transplant

Cost and Benefit analysisCost and Benefit analysis

•• Cost of TPN per yearCost of TPN per year $150,000$150,000Does not include: HPN support, Does not include: HPN support, equipment, equipment, matherialsmatherials and 0.5and 0.5--1 1 admission per year (0admission per year (0--$140,000)$140,000)

•• Intestinal Transplant is Cost/Effective after the Intestinal Transplant is Cost/Effective after the 11--2 years2 years

•• MulticenterMulticenter survey in 41 HPN centers from 9 survey in 41 HPN centers from 9 European countriesEuropean countries

•• 688 adult and 166 pediatric patients688 adult and 166 pediatric patients•• Potential candidates based on Medicare and Potential candidates based on Medicare and

Medicaid and USA transplantation society Medicaid and USA transplantation society recommendationsrecommendations

•• Physician attitudes based on if they would refer Physician attitudes based on if they would refer potential candidates for transplant potential candidates for transplant

Pironi et al. Am J Gastroenterol. 101:1633-1643, 2006

Candidates for Intestinal Transplantation

Candidates for Intestinal Candidates for Intestinal TransplantationTransplantation

0

100

200

300

400

500

600

700

ADULT PED

Total ptsCandidatesMD refer

15.7%

2.3% 34

.3%

5.4%

Pironi et al. Am J Gastroenterol. 101:1633-1643, 2006

Conclusions

• A low percentage of candidate patients were considered to be immediate candidates for ITx, suggesting physician reticence toward ITx, a factor which may cause late referral to the waiting list;

• The rate of candidacy differed greatly among the HPN centers, appearing lower in centers taking care of a higher number of HPN patients, whereas data within countries were more homogeneous.

• Better Survival Outcome• Save Organs• Speed Recovery • Avoid Narcotic Dependence• Full Rehabilitation

Early referral

Trends and future developmentsTrends and future developments

New immunosuppression drugsNew immunosuppression drugsRejection Monitoring (Citrulline, Rejection Monitoring (Citrulline, CalprotectinCalprotectin))Infections prophylaxis and treatmentInfections prophylaxis and treatmentContinue studies on Continue studies on ‘‘tolerogenicitytolerogenicity’’ of of multivisceral graftmultivisceral graft

Conclusions

• HPN offers the best survival in patients with IF

• Transplant offers the best survival in patients that have developed life threatening complications sec to HPN/IF

• Early referral will prevent HPN related deaths, improve Intestinal Tx outcomes and expand indications

Thank you for all you do for these patients!

session4 1300 qunintini ddi nursing conference · infections nearly all patients (>95%) develop...

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