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Experience with combined liver–small intestine transplantation at the University of California, Los Angeles
Experience With Combined Liver–Small Intestine Transplantation at the University of California, Los Angeles D.G. Farmer, S.V. McDiarmid, C. Smith, R. Stribling, P. Seu, M.A. Ament, J. Vargas, H. Yersiz, J.F. Markmann, R.M. Ghobriel, J.A. Goss, P. Martin, and R.W. Busuttil
I
RESULTS
(1), pseudo-obstruction (1), and Crohn’s disease (1). Five patients were ICU-bound (status 1) at the time of transplantation. Eight grafts were used in these six recipients. The median donor age was 12 years (range, 8 mo to 61 yr). The mean donor to recipients weight ratio is 0.75 6 0.35. Seven grafts were ABO blood group identical and one was compatible. Actuarial 1-, 2- and 5-year patient survival is 64%. Three patients are currently alive at 3, 8, and 25 months after transplantation. One patient died more than 5 years after transplantation from fungal sepsis. Two others were lost in the early postoperative period from hemorrhage and primary hepatic nonfunction. Adjusted actuarial graft survival at 1-, 2-, and 5-years is 71%, 48%, and 48%. TPN-independence has been achieved with three grafts and partial independence has been accomplished with two others. The causes of graft loss are noncompliance-induced rejection, hepatic artery thrombosis, and primary hepatic graft nonfunction. Acute small intestine rejection was demonstrated 4 times in 2 patients. Treatment included administration of Orthoclone OKT3 (Ortho Biotech Inc., Raritan, NJ) combined with conversion from Sandimmune, (Sandoz Pharmaceuticals, East Hannover, NJ) to Tacrolimus (1), steroid bolus (2), and enterectomy (1). Chronic rejection has not been seen to date. Major mechanical complications have included gastroparesis (2), gastrointestinal bleeding (3), enterocutaneous fistula (2), bowel perforation (1), and incomplete abdominal wall closure. Major infectious complications have included subphrenic abscess (2), urinary tract infection (2), bacteremia (1), enteritis (1), and wound infection (1) with causative organisms identified as Candida species, cytomegalovirus, Proteus mirabilis, and methacillin-resistant Staphalococcus aureus. To date, no episodes of graft-versus-host disease or
Six patients received combined liver–small intestine grafts. The median age of the group was 13.7 years (range, 3.7 to 32.1). Indications for liver transplantation included endstage liver disease secondary to TPN alone (3), TPN plus HCV (1), TPN plus hemachromatosis (1), and chronic rejection after liver transplantation for TPN and primary sclerosing cholangitis. Indications for intestinal transplantation included short gut syndrome secondary to trauma (1), villous atrophy (1), intestinal atresia (1), gastroschisis
From the Dumont–UCLA Transplant Center, Division of Pancreas and Liver Transplantation, UCLA Medical Center (D.G.F., S.V.M., C.N., R.S., P.S., M.P.A., J.V., H.Y., J.F.M., R.M.G., J.A.G., P.M., R.W.B.), Los Angeles, California, USA Address reprint requests to Ronald W. Busuttil, MD, PhD, Dumont Chair of Transplant Surgery, Dumont–UCLA Transplant Center, Division of Pancreas and Liver Transplantation, Room 77-130 CHS, 10833 LeConte Avenue, Los Angeles, CA 90095.
N 1991, a program of small intestine transplantation was initiated at UCLA.1,2 Our current experience is updated herein.
MATERIALS AND METHODS A retrospective review of all recipients undergoing liver–small intestine transplant (L-SIT) at UCLA was undertaken. Data collection consisted of both donor and recipient indications for operation, laboratory data, operative parameters, postoperative complications, survival, and causes of patient death and graft loss. Survival statistics were calculated using life-table analysis. Preoperative assessment included routine screening for extent of liver disease, intestinal length and function, active infection, cardiopulmonary status, and venous access. All patients were reviewed by a multidisciplinary selection committee. Operative techniques have been described elsewhere.1 Briefly, incontinuity liver and intestinal grafts are placed in the orthotopic position with a standard piggyback technique applied to the hepatic graft. Native portal circulation is drained into the donor splenic vein. Arterialization is achieved using a supraceliac aortic conduit. A 40-cm defunctionalized limb of donor small intestine is used to perform a choledochojejunostomy. All patients have a terminal ileostomy as well as a combination gastrojejunostomy tube placed for enteral access and feeding. Postoperative management included immunosuppression based on Tacrolimus (Fujisawa USA, Inc., Deerfield, Ill) and steroids combined with either Cytoxan (Bristol-Myers Squibb Co, Princeton, NJ) or Cellcept (Syntex Puerto Rico, Inc). Early enteral nutrition support is initiated with an elemental diet via a jejunostomy tube, and endoscopy with biopsies through the terminal ileostomy are routinely performed. Infectious prophylaxis includes Diflucan (Pfizer Inc., New York, NY), Cytovene (Syntex Laboratories, Inc., Palo Alto, Calif), Bactrim (Roche Laboratories, Nutley, NJ), and selective gut decontamination.
© 1998 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010
0041-1345/98/$19.00 PII S0041-1345(98)00714-3
Transplantation Proceedings, 30, 2533–2534 (1998)
2533
2534
lymphoproliferative disorder have been encountered. Hospital stays have averaged 69.4 6 41.2 days. DISCUSSION
Our results showing 63% grafts sustaining part or all of the recipients caloric needs and 64% of patients surviving more than 1 year indicate that successful intestinal transplantation can be achieved. We have also demonstrated that successful retransplantation is possible both in the early and late postoperative periods. Hospital courses and complications are, however, formidable. Still, outcomes for intestinal transplantation lag behind those for other solid organs. Although reasons behind this are multifactorial, immunologic obstacles remain the single largest barrier. Optimal immunosuppression regimens remains elusive although Tacrolimus-based therapy appears to have afforded unprecedented success and more widespread application of the procedure.3,4 Rejection, however, still remains a problem prompting the long-term use of significant immunosuppression. The price of this philosophy is paid with infectious complications as demonstrated by this data. Until better immunosuppression is developed,
FARMER, MCDIARMID, SMITH ET AL
success is dependent upon aggressive search for rejection as well as prophylaxis against and treatment of bacterial, fungal and viral infections. Improvement in outcomes is also dependent on early referral for transplantation. Strict intestinal donor criteria translates into long organ waiting times, and late referrals only compound the situation. Without question, transplanting these patients with advanced end-stage liver disease compromises results. Changing physician referral patterns is slow, requires re-education and demonstration of successful outcomes. Finally, diligent patient care by medical teams with experience in intestinal transplantation is essential for long-term graft and patient viability.
REFERENCES 1. Busuttil RW, Farmer DG, Shaked A, et al: West J Med 158:184, 1994 2. Farmer DG, Shaked A, McDiarmid SV, et al: Transplant Proc 28:2724, 1996 3. Furukawa H, Reyes J, Abu-Elmagd K, et al: Transplant Proc 29:688, 1997 4. Grant D: Lancet 347:1801, 1996
I
RESULTS
(1), pseudo-obstruction (1), and Crohn’s disease (1). Five patients were ICU-bound (status 1) at the time of transplantation. Eight grafts were used in these six recipients. The median donor age was 12 years (range, 8 mo to 61 yr). The mean donor to recipients weight ratio is 0.75 6 0.35. Seven grafts were ABO blood group identical and one was compatible. Actuarial 1-, 2- and 5-year patient survival is 64%. Three patients are currently alive at 3, 8, and 25 months after transplantation. One patient died more than 5 years after transplantation from fungal sepsis. Two others were lost in the early postoperative period from hemorrhage and primary hepatic nonfunction. Adjusted actuarial graft survival at 1-, 2-, and 5-years is 71%, 48%, and 48%. TPN-independence has been achieved with three grafts and partial independence has been accomplished with two others. The causes of graft loss are noncompliance-induced rejection, hepatic artery thrombosis, and primary hepatic graft nonfunction. Acute small intestine rejection was demonstrated 4 times in 2 patients. Treatment included administration of Orthoclone OKT3 (Ortho Biotech Inc., Raritan, NJ) combined with conversion from Sandimmune, (Sandoz Pharmaceuticals, East Hannover, NJ) to Tacrolimus (1), steroid bolus (2), and enterectomy (1). Chronic rejection has not been seen to date. Major mechanical complications have included gastroparesis (2), gastrointestinal bleeding (3), enterocutaneous fistula (2), bowel perforation (1), and incomplete abdominal wall closure. Major infectious complications have included subphrenic abscess (2), urinary tract infection (2), bacteremia (1), enteritis (1), and wound infection (1) with causative organisms identified as Candida species, cytomegalovirus, Proteus mirabilis, and methacillin-resistant Staphalococcus aureus. To date, no episodes of graft-versus-host disease or
Six patients received combined liver–small intestine grafts. The median age of the group was 13.7 years (range, 3.7 to 32.1). Indications for liver transplantation included endstage liver disease secondary to TPN alone (3), TPN plus HCV (1), TPN plus hemachromatosis (1), and chronic rejection after liver transplantation for TPN and primary sclerosing cholangitis. Indications for intestinal transplantation included short gut syndrome secondary to trauma (1), villous atrophy (1), intestinal atresia (1), gastroschisis
From the Dumont–UCLA Transplant Center, Division of Pancreas and Liver Transplantation, UCLA Medical Center (D.G.F., S.V.M., C.N., R.S., P.S., M.P.A., J.V., H.Y., J.F.M., R.M.G., J.A.G., P.M., R.W.B.), Los Angeles, California, USA Address reprint requests to Ronald W. Busuttil, MD, PhD, Dumont Chair of Transplant Surgery, Dumont–UCLA Transplant Center, Division of Pancreas and Liver Transplantation, Room 77-130 CHS, 10833 LeConte Avenue, Los Angeles, CA 90095.
N 1991, a program of small intestine transplantation was initiated at UCLA.1,2 Our current experience is updated herein.
MATERIALS AND METHODS A retrospective review of all recipients undergoing liver–small intestine transplant (L-SIT) at UCLA was undertaken. Data collection consisted of both donor and recipient indications for operation, laboratory data, operative parameters, postoperative complications, survival, and causes of patient death and graft loss. Survival statistics were calculated using life-table analysis. Preoperative assessment included routine screening for extent of liver disease, intestinal length and function, active infection, cardiopulmonary status, and venous access. All patients were reviewed by a multidisciplinary selection committee. Operative techniques have been described elsewhere.1 Briefly, incontinuity liver and intestinal grafts are placed in the orthotopic position with a standard piggyback technique applied to the hepatic graft. Native portal circulation is drained into the donor splenic vein. Arterialization is achieved using a supraceliac aortic conduit. A 40-cm defunctionalized limb of donor small intestine is used to perform a choledochojejunostomy. All patients have a terminal ileostomy as well as a combination gastrojejunostomy tube placed for enteral access and feeding. Postoperative management included immunosuppression based on Tacrolimus (Fujisawa USA, Inc., Deerfield, Ill) and steroids combined with either Cytoxan (Bristol-Myers Squibb Co, Princeton, NJ) or Cellcept (Syntex Puerto Rico, Inc). Early enteral nutrition support is initiated with an elemental diet via a jejunostomy tube, and endoscopy with biopsies through the terminal ileostomy are routinely performed. Infectious prophylaxis includes Diflucan (Pfizer Inc., New York, NY), Cytovene (Syntex Laboratories, Inc., Palo Alto, Calif), Bactrim (Roche Laboratories, Nutley, NJ), and selective gut decontamination.
© 1998 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010
0041-1345/98/$19.00 PII S0041-1345(98)00714-3
Transplantation Proceedings, 30, 2533–2534 (1998)
2533
2534
lymphoproliferative disorder have been encountered. Hospital stays have averaged 69.4 6 41.2 days. DISCUSSION
Our results showing 63% grafts sustaining part or all of the recipients caloric needs and 64% of patients surviving more than 1 year indicate that successful intestinal transplantation can be achieved. We have also demonstrated that successful retransplantation is possible both in the early and late postoperative periods. Hospital courses and complications are, however, formidable. Still, outcomes for intestinal transplantation lag behind those for other solid organs. Although reasons behind this are multifactorial, immunologic obstacles remain the single largest barrier. Optimal immunosuppression regimens remains elusive although Tacrolimus-based therapy appears to have afforded unprecedented success and more widespread application of the procedure.3,4 Rejection, however, still remains a problem prompting the long-term use of significant immunosuppression. The price of this philosophy is paid with infectious complications as demonstrated by this data. Until better immunosuppression is developed,
FARMER, MCDIARMID, SMITH ET AL
success is dependent upon aggressive search for rejection as well as prophylaxis against and treatment of bacterial, fungal and viral infections. Improvement in outcomes is also dependent on early referral for transplantation. Strict intestinal donor criteria translates into long organ waiting times, and late referrals only compound the situation. Without question, transplanting these patients with advanced end-stage liver disease compromises results. Changing physician referral patterns is slow, requires re-education and demonstration of successful outcomes. Finally, diligent patient care by medical teams with experience in intestinal transplantation is essential for long-term graft and patient viability.
REFERENCES 1. Busuttil RW, Farmer DG, Shaked A, et al: West J Med 158:184, 1994 2. Farmer DG, Shaked A, McDiarmid SV, et al: Transplant Proc 28:2724, 1996 3. Furukawa H, Reyes J, Abu-Elmagd K, et al: Transplant Proc 29:688, 1997 4. Grant D: Lancet 347:1801, 1996