Protein C activity and postoperative metabolic liver function after liver transplantation.

BACKGROUND: Protein C is a natural thrombin antagonist produced by hepatocytes. Its levels are low in liver failure and predispose patients to increased risk for thrombosis. Little is known about the relationship between protein C activity and hepatic function after orthotopic liver transplantation (OLT). METHODS: We measured protein C activity of 41 patients undergoing liver transplantation by the Staclot method (normal range, 70%-130%) preoperatively and then daily on postoperative days (POD) 0-5. RESULTS: The mean protein C activity was low before OLT (34.3 ± 4.3%) and inversely correlated with the preoperative Model for End-Stage Liver Disease score (Spearman's r = -0.643; P < .0001). Mean activity increased significantly on POD 1 (58.9 ± 4.5%), and remained above preoperative levels through POD 5. Ten patients developed metabolic liver dysfunction defined by a serum total bilirubin >5 mg/dL on POD 7. These patients had significantly lower protein C activity from POD 3 (47.2 ± 9.6% vs 75.9 ± 5.8%; P = .01) to POD 5. Preoperative protein C activity correlated inversely with the severity of liver failure as indicated by preoperative MELD score. CONCLUSION: Protein C activity recovered rapidly in patients with good allograft function but remained significantly lower in patients who had limited metabolic function as evidenced by increased total bilirubin levels.

Hypothermic machine preservation in human liver transplantation: the first clinical series.

Hypothermic machine perfusion (HMP) is widely used to preserve kidneys for transplantation with improved results over cold storage (CS). To date, successful transplantation of livers preserved with HMP has been reported only in animal models. In this, the first prospective liver HMP study, 20 adults received HMP-preserved livers and were compared to a matched group transplanted with CS livers. HMP was performed for 3-7 h using centrifugal perfusion with Vasosol solution at 4-6 degrees C. There were no cases of primary nonfunction in either group. Early allograft dysfunction rates were 5% in the HMP group versus 25% in controls (p = 0.08). At 12 months, there were two deaths in each group, all unrelated to preservation or graft function. There were no vascular complications in HMP livers. Two biliary complications were observed in HMP livers compared with four in the CS group. Serum injury markers were significantly lower in the HMP group. Mean hospital stay was shorter in the HMP group (10.9 +/- 4.7 days vs. 15.3 +/- 4.9 days in the CS group, p = 0.006). HMP of donor livers provided safe and reliable preservation in this pilot case-controlled series. Further multicenter HMP trials are now warranted.

Select utilization of obese donors in living donor liver transplantation: implications for the donor pool.

Living donor liver transplantation evolved in response to donor shortage. Current guidelines recommend potential living donors (LD) have a body mass index (BMI) <30. With the current obesity epidemic, locating nonobese LD is difficult. From September 1999 to August 2003, 68 LD with normal liver function test (LFTs) and without significant comorbidities underwent donor hepatectomy at our center. Post-operative complications were collected, including wound infection, pneumonia, hernia, fever, ileus, biliary leak, biliary stricture, thrombosis, bleeding, hepatic dysfunction, thrombocytopenia, deep venous thrombosis, pulmonary embolism, difficult to control pain, depression and anxiety. Complication rates for LD with BMI >30 (n = 16) and BMI <30 (n = 52) were compared. The incidence of wound infection increased with BMI, 4% for nonobese and 25% for obese LD (p = 0.024). There were no statistically significant differences for all other complications. No LD died. Recipient survival was 100% with obese LD and 80% with nonobese LD (p = 0.1). Select donors with a BMI >30 may undergo donor hepatectomy with acceptable morbidity and excellent recipient results. Updating current guidelines to include select LD with BMI >30 has the potential to safely increase the donor pool.

Improved outcome after intestinal transplantation at a single institution over 12 years.

PURPOSE: To evaluate the outcomes of patients undergoing intestinal transplantation (IT). METHODS: Retrospective review was undertaken using existing medical records and database. RESULTS: Between November 1991 and May 2003, 114 patients were referred for consideration for IT, of which 33 patients received 37 intestinal allografts. All patients had intestinal failure and all patients had significant complications from total parenteral nutrition (TPN). TPN was the predominant cause of liver failure (63%). Combined liver intestinal grafts were used in the majority of patients. Overall 1- and 3-year patient survival is 77% and 52% with patients transplanted since 1999 having a 1- and 3-year survival of 94% and 73%, respectively. The most common cause of death was sepsis. No graft or patient was lost to cytomegalovirus or Epstein-Barr virus disease. Twenty-seven percent of allografts were lost to rejection. Long-term TPN independence is 82% for grafts more than 30 days after IT. Statistical analysis revealed several important factors impacting outcome. CONCLUSIONS: Successful IT defined as prolonged patient and graft survival and TPN independence can be readily achieved in select patients with IF and complications related to TPN therapy. Outcomes have improved with experience gained and control of viral infections and rejection.

Application of combined liver-intestinal transplantation as a staged procedure.

Liver-intestinal transplantation is a complex surgical procedure that historically has required prolonged operative periods. This report is the first series where liver-intestinal transplantation was performed as a staged procedure. Specifically, allograft reperfusion was followed by resuscitation and stabilization in an intensive care unit before completion of the transplant procedure. Triage of recipients to the intensive care unit following allograft reperfusion was determined at the time of operation and was based upon the clinical condition of the recipient including hemodynamic stability, evidence of coagulopathy, and assessment of early liver function. Medical stabilization was followed by completion of the transplant procedure and definitive abdominal closure within 72 hours. The application of combined liver-intestinal transplantation as a staged procedure demonstrated no effect upon early graft function, incidence of complications, or ability to perform a definitive abdominal closure.

Induction therapy with interleukin-2 receptor antagonist after intestinal transplantation is associated with reduced acute cellular rejection and improved renal function.

PURPOSE: To determine the effectiveness of induction immunotherapy with interleukin-2 receptor antagonists (IL2RA) after intestinal transplantation (IT). METHODS: A single-center, retrospective study was undertaken of all patients undergoing IT using existing medical records and database. Immunotherapy was either triple (standard maintenance triple therapy [SMTT]) or IL2RA [induction IL2RA plus SMTTx] or OKT3 [induction antilymphocyte preparations plus SMTTx]). Data was collected for the first 175 postoperative days. Outcomes included pretransplant renal function, posttransplant serum creatinine normalized to age (nl-sCR), rejection (ACR), and survival. Standard statistical analysis was undertaken. RESULTS: There were no significant differences in the groups: triple (n = 10, median age 3.5 years, cGFR 106 +/- 44 mL/min), IL2RA (n = 13, median age 3.2 years, cGFR 101 +/- 61 mL/min), OKT3 (n = 4, median age 7.7 years, cGFR 104 +/- 27 mL/min). nl-sCR was significantly (P <.01) lower in IL2RA at most postoperative weeks. IL2RA had significantly fewer rejection and infectious episodes than the other two groups. Three-year patient survival was 92% in IL2RA versus 50% triple and OKT3. CONCLUSIONS: IL2RA immunotherapy after IT is associated with a lower incidence of renal dysfunction as compared with historical controls. Furthermore, IL2RA therapy resulted in a lower incidence of rejection and improved survival. IL2RA should be considered in select patients undergoing IT.

Infectious enteritis after intestinal transplantation: incidence, timing, and outcome.

AIM: To review the incidence, timing, and outcome of infectious enteritis after intestinal transplantation (IT). METHOD: A retrospective review of all patients undergoing IT at a single institution between 1991 and 2003 was analyze with standard statistical tools. RESULTS: Among 33 IT recipients, 13 (39%) developed 20 culture- or biopsy-proven episodes of infectious enteritis. The recipient demographics were 77% men and median age 2.6 years. Infections were diagnosed at a median of 76 days (32 to 1800) after IT. There were 14 viral (CMV one, rotavirus eight, adenovirus four, EBV one, three bacterial (Clostridium difficile), and three other infections (Giardia lamblia one, cryptosporidium two). Complete resolution was achieved in 17 (94%) infectious after appropriate antimicrobial or conservative therapy. Interestingly, there were six rejection episodes following infectious enteritis. Grafts were lost to rejection after rotaviral enteritis (n = 1) and adenoviral enteritis misdiagnosed as rejection (n = 1). Patient and graft survival were not adversely affected by infections. CONCLUSIONS: Infectious enteritis occurs frequently after IT. Viral agents are the cause in two-thirds of cases. With supportive care and appropriate treatment, resolution is possible in the majority of cases. Differentiating rejection and infection by histopathology can be difficult.

Posttransplantation growth in pediatric liver recipients.

The aim of this retrospective analysis was to evaluate the growth of 96 pediatric liver transplant recipients from February 1988 to June 1999. Inclusion criteria were the following: age younger than 18 years, follow-up longer than 1 year, transplantation for a nontumor indication, and no retransplantation. Linear height and growth velocity SD scores were correlated to age, sex, indication for transplantation, immunosuppression, and graft type. Transplant recipients of all ages and indications and both sexes were growth retarded at transplantation. Recipients aged younger than 24 months showed growth within the first year to achieve a height distribution equal to that of an age-matched population. Posttransplantation growth inversely correlated with height standard score at transplantation. Children older than 2 years at transplantation established new growth curves, but remained growth retarded. As children approached the prepubertal growth acceleration, growth deficits frequently were erased. Transplant recipients with biliary atresia and alpha(1)-antitrypsin deficiency showed increased growth performance compared with those who underwent transplantation for chronic hepatitis or fulminant hepatic failure. Boys were less growth retarded at transplantation and showed improved posttransplantation growth performance versus girls. No correlation to immunosuppression or graft type was identified. We conclude that early transplantation of children who show growth retardation is optimal for restoration of growth potential, whereas delaying transplantation in older children impedes potential growth.

Functional venous anatomy for right-lobe grafting and techniques to optimize outflow.

Right-lobe living donor liver transplantation has emerged as an alternative to cadaveric transplantation. An appreciation of the unique anatomy and behavior of the right lobe has emerged and has precipitated technical modifications. Living donors underwent right lobectomy, including preservation of significant inferior hepatic veins. The parenchyma was divided following a plane approximating the right border of the posterior two thirds of the midhepatic vein (MHV), but deviating anteriorly to include the distal one third of the MHV with the graft. Large venous tributaries from segment VIII were preserved. Anastomosis in the recipient was accomplished by means of complete cavoplasty. Significant inferior veins, tributaries to the MHV, and the distal portion of the MHV were reconstructed when technically possible. Forty-eight right-lobe resections and transplantations were performed in the manner described. There were no donor complications attributable to the technique. Forty-six of the 48 recipients are alive, and 44 of the 46 surviving patients have their original graft. Venous tributaries from segment VIII and/or the distal portion of the MHV were reconstructed in only 3 patients. Outflow obstruction was recognized intraoperatively in 2 patients; 1 patient had a caval web excised and the other patient required revision of the main anastomosis. Neither organ was lost. There were no other significant venous complications. The incidence of ascites was the same as that in recipients of whole organs. These methods of parenchymal transection and venous reconstruction resulted in a low rate of complications. The wide anastomosis and collateral pathways between the MHV and right hepatic vein seem to be more critical than reconstruction of tributaries from segment VIII or the distal MHV.

Surgical anatomy of the left lateral segment as applied to living-donor and split-liver transplantation: a clinicopathologic study.

OBJECTIVE: To evaluate intrahepatic vascular and biliary anatomy of the left lateral segment (LLS) as applied to living-donor and split-liver transplantation. SUMMARY BACKGROUND DATA: Living-donor and split-liver transplantation are innovative surgical techniques that have expanded the donor pool. Fundamental to the application of these techniques is an understanding of intrahepatic vascular and biliary anatomy. METHODS: Pathologic data obtained from cadaveric liver corrosion casts and liver dissections were clinically correlated with the anatomical findings obtained during split-liver, living-donor, and reduced-liver transplants. RESULTS: The anatomical relation of the left bile duct system with respect to the left portal venous system was constant, with the left bile duct superior to the extrahepatic transverse portion of the left portal vein. Four specific patterns of left biliary anatomy and three patterns of left hepatic venous drainage were identified and described. CONCLUSIONS: Although highly variable, the biliary and hepatic venous anatomy of the LLS can be broadly categorized into distinct patterns. The identification of the LLS duct origin lateral to the umbilical fissure in segment 4 in 50% of cast specimens is significant in the performance of split-liver and living-donor transplantation, because dissection of the graft pedicle at the level of the round ligament will result in separate ducts from segments 2 and 3 in most patients, with the further possibility of an anterior segment 4 duct. A connective tissue bile duct plate, which can be clinically identified, is described to guide dissection of the segment 2 and 3 biliary radicles.

Long-term complications of living donor liver transplantation.

1. Donor outcome after living donor liver transplantation (LDLT) is related to type of liver resection. Left lateral segmentectomy is used in pediatric cases and right lobectomy is used in adult cases. 2. Biliary complications occur in 5% to 10% of both pediatric and adult cases. 3. Three donors, 2 in pediatric LDLT and 1 in adult LDLT, have died. Estimated mortality is 0.13% for pediatric donation and 0.2% for adult donation. 4. Postoperative cholestasis occurs commonly in donors, but clinically relevant jaundice occurs in less than 5%. 5. Other donor morbidity may be related to incisional hernias, postoperative gastric dysfunction, and pain. 6. Donors report overall satisfaction with LDLT, and 88% believed that the role of LDLT should be increased. 7. All donors returned to predonation activities; 25% by 1 month, 75% by 3 months, 88% by 6 months, and 100% by 1 year.

Adult-to-adult living-donor liver transplantation: a critical analysis.

Adult-to-adult living-donor liver transplantation is the most recent achievement in the evolution of strategies to increase donor organ supply. Justification of the procedure has evolved from increased organ-waiting times, wait-list morbidity and mortality of adult transplant candidates. Successful application of adult-to-adult living-donor liver transplantation mandates unique surgical, medical, and donor considerations as these procedures predispose to unique complications resulting from anatomic variations, technical considerations, and the transplantation of "partial" grafts. Additionally, because the magnitude of the donor operation is greater and potentially fraught with serious short and long term morbidity and possibly mortality, the utilization of living-donors for adult liver transplantation raises bio-ethical concerns heretofore not encountered. This review explores the current state of adult-to-adult living-donor liver transplantation.

Mycophenolate mofetil, microemulsion cyclosporine, and prednisone as primary immunosuppression for pediatric liver transplant recipients.

Triple immunosuppressive therapy using mycophenolate mofetil (MMF), microemulsion cyclosporine (me-CsA), and prednisone offers the potential for potent immunosuppression without intravenous drug therapy or anti-T-cell antibody induction therapy. This report describes the application of an immunosuppressive protocol (CNp) using MMF, me-CsA, and prednisone as primary immunosuppression for pediatric liver transplant recipients at the University of California at San Francisco. From August 1995 through December 1996, 26 children (17 boys, 9 girls) aged 1 month to 16 years (mean +/- standard deviation, 58 +/- 62 months; median, 31 months) underwent liver transplantation at our institution, receiving CNp as primary immunosuppression. Posttransplantation renal function, incidence of leukopenia, and drug tolerance within the group receiving CNp as primary immunosuppression were compared with those of 19 children who received primary immunosuppression consisting of azathioprine, oil-based gel-encapsulated cyclosporine, and prednisone with anti-T-cell antibody induction therapy at the same institution from October 1993 through July 1995. No significant difference was observed between immunosuppressive protocols in serum creatinine level or incidence of leukopenia requiring medical therapy during the first year posttransplantation. Whereas gastrointestinal symptoms were observed in approximately 30% of CNp recipients during initial immunotherapy, tolerance of CNp primary immunotherapy was routinely achieved by the dose reduction of MMF. At 1 year posttransplantation, 20 children (77%) remained on CNp primary immunotherapy, 5 children (19%) were receiving tacrolimus-based immunotherapy secondary to rejection, and 1 patient (4%) converted to tacrolimus-based immunotherapy secondary to persistent gastrointestinal intolerance. In conclusion, CNp provides an alternative immunosuppressive protocol that eliminates the necessity of intravenous and induction immunosuppressive therapy with no increased incidence of posttransplantation renal dysfunction or leukopenia and is well tolerated in children.

Biliary complications of reduced-organ liver transplantation.

Reduced-organ liver transplantation for children is effective in lowering pretransplantation morbidity and mortality. Improvements in surgical technique have reduced vascular complications; however, biliary complications continue to account for significant posttransplantation morbidity. This investigation chronicles the incidence and type of biliary complications encountered with reduced-organ liver transplantation. Retrospective review of reduced-organ liver recipients over a 59-month period was performed, and biliary complications were classified as (1) missed biliary radicle, (2) anastomotic leak requiring revision, and (3) biliary stricture. From July 1992 to May 1997, 42 children received reduced-organ grafts: 32 living-donor, 8 cadaveric-reduced, 1 split-liver, and 1 auxiliary orthotopic liver transplant. Of the 42 grafts, 41 were Couinaud segments II/III and 1 was segments II/III/IV. Ten biliary complications were identified in 9 recipients (24%). Biliary complications included parenchymal radicle leaks, 5 (50%); biliary strictures, 3 (30%); and anastomotic leaks, 2 (20%). Although technical advances have reduced the incidence of biliary complications secondary to organ ischemia, parenchymal radicle leaks continue to be a source of morbidity for reduced-organ recipients. Planned exploration on posttransplantation day 7 was performed on the most recent 26 of the 42 total reduced-organ procedures as a mechanism to identify and treat early technical complications. Planned exploration as a routine component of reduced-organ transplantation has yielded a 15% incidence of discovered parenchymal leaks and a 5% incidence of discovered anastomotic leaks. This series underscores the necessity for improved anatomical studies to correctly identify duct territories and the development of accurate noninvasive methods to assess the biliary system preoperatively and intraoperatively in the application of reduced-organ liver transplantation.

Planned exploration of pediatric liver transplant recipients reduces posttransplant morbidity and lowers length of hospitalization.

BACKGROUND: Pediatric liver transplantation (eg, orthotopic liver transplantation) has been associated with decreased graft survival compared with adult transplantation; this has been attributed to the increased difficulty of the procedure in small children and the increased number of technical variants that have been used to increase the supply of small livers. OBJECTIVES: To adopt a policy of planned exploration (PLANEX) of children on the seventh day after orthotopic liver transplantation, to obtain a liver biopsy specimen, to identify and treat potential technical problems at that time, and to evaluate the effect of this strategy on the length of hospitalization and morbidity rate in 60 children who underwent orthotopic liver transplantation. DESIGN: The PLANEX was adopted progressively during a 3-year period. A retrospective study was conducted that compared outcomes between patients who did and did not undergo PLANEX. Data were collected from chart review with a complete follow-up of patients. SETTING: A university medical center at which 130 liver transplantations are performed annually in adults and children. PATIENTS: Sixty children who received primary transplants between October 1992 and December 1996 were studied. INTERVENTIONS: Standard, partial, and living-donor transplantations were performed. Routine procedures performed at PLANEX included hematoma evacuation, tissue culture, inspection of all anastomoses, intraoperative ultrasonographic verification of vessel patency, open liver biopsy, and definitive abdominal closure. MAIN OUTCOME MEASURES: The duration of the primary hospitalization was the main outcome measure. Surgical complications and graft and patient survival rates were also analyzed. RESULTS: The mean +/- SD length of hospitalization for 24 recipients who underwent PLANEX was 16.5 +/- 5.7 days compared with 19.2 +/- 4.7 days for 6 patients (25%) who had significant findings at exploration (P = .34). In the 36 patients who did not undergo PLANEX, 10 patients (28%) required unplanned explorations (on median posttransplant day 13) that identified the following 13 complications: biliary (n = 4), undiscovered enterotomy (n = 6), hemoperitoneum (n = 2), and partial vascular thrombosis (n = 1). The mean length of hospitalization for recipients who did not require exploration was 19.3 +/- 3.9 days (PLANEX, P = .28); however, in patients who required unplanned exploration, the mean length of hospitalization increased to 41.2 +/- 15.5 days (median, 43 days). The mean length of hospitalization of recipients who underwent unplanned exploration was significantly increased compared with recipients who underwent PLANEX with significant intraoperative findings (P = .02). CONCLUSIONS: In this series, early identification and repair of surgical problems in asymptomatic patients on day 7 significantly decreased the hospital stay and morbid consequences of surgical problems. This aggressive approach may improve overall graft and patient survival.