Adrian Casavilla

The Incidence, Timing, and Management of Biliary Tract Complications After Orthotopic Liver Transplantation

ObjectiveThis study analyzed the incidence and timing of biliary tract complications after orthotopic liver transplantation (OLTx) in 1792 consecutive patients. These results were then compared with those of previously reported series. Finally, recommendations were made on appropriate management strategies. Summary Background DataTechnical complications after OLTx have a significant impact on patient and graft survival. One of the principle technical advances has been the standardization of techniques for biliary reconstruction. Nonetheless, biliary complications still occur. A 1983 report from the University of Pittsburgh reported biliary complications in 19% of all transplants, and an update in 1987 reported biliary complications in 13.2% of transplants. MethodsThe medical records of all patients who underwent liver transplantation and were hospitalized between January 1, 1988 and July 31, 1991 were reviewed. The case material consisted of the medical records of 217 patients treated for 245 biliary complications. ResultsPrimary biliary continuity was established by either choledochocholedochostomy over a T-tube (C-C, n = 129) or a Roux-en-Y choledochojejunostomy with an internal stent (C-RY, n = 85). The overall incidence for biliary complication in this large series was 11.5%. Strictures (n = 93) and bile leak (n = 58) were the most common complications (69.6%). Most billary complications (n = 143, 66%) occurred within the first 3 months after surgery. In general, leaks occurred early, and strictures developed later. Bile leaks were equally frequent in both C-C and C-RY (27.1% and 25.9%, respectively); strictures were more common after a C-RY type of reconstruction (36.4% and 52.9%, respectively). Twenty-one patients died, an incidence of 9.6%. Fifteen of the 21 biliary-related deaths were among patients treated for rejection before the recognition of biliary tract pathologic findings. ConclusionsProgress has been made on improving the result of biliary reconstruction after OLTx. Nonetheless, patients continue to experience biliary complications after OLTx, and these complications cause considerable loss of grafts and life. If significant additional improvement in patient and graft survival are to be obtained, the technical performance of OLTx must continue to improve.

EXPERIENCE WITH LIVER AND KIDNEY ALLOGRAFTS FROM NON-HEART-BEATING DONORS

Given the shortage of cadaveric organs, we began a study utilizing NHBD for OLTx and KTx. There were 24 NHBD between January 1989 and September 1993. These donors were divided into 2 groups: uncontrolled NHBD (G1) (n=14) were patients whose organs were recovered following a period of CPR; and controlled NHBD (G2) (n=10) were patients whose organs were procured after sustaining cardiopulmonary arrest (CA) following extubation in an operating room setting. Eight kidneys and 5 livers were discarded because of macroscopic or biopsy findings. In G1, 22/27 (81.5%) kidneys were transplanted; 14/22 (64%) developed ATN; 20/22 (95%) recipients were off dialysis at the time of discharge. With a mean follow-up of 32.7± 21.1 months, sixteen (73%) kidneys are still functioning, with a mean serum creatinine of 1.7±0.6 mg/dl. The one-year actuarial patient and graft survivals are 95% and 86%. In G2, 17/20 (85%) kidneys were transplanted; 13/17 (76%) kidneys experienced ATN. All patients were off dialysis by the time of discharge. With a mean follow-up of 17.6±15.4 months, twelve (70%) kidneys are still functioning, with a mean serum creatinine of 2.5±2.1 mg/dl. The one-year actuarial patient and graft survivals are 94% and 82%, respectively. In G1, 6/10 (60%) livers were transplanted; 3/6 (50%) livers functioned, the other 3 patients required ReOLTx in the first week postoperatively because of PNF(n=2) and inadequate portal flow (n=1). Two functioning livers were lost due to HAT (n=1) and CMV hepatitis (n=1). In G2, 6/7 (85.7%) livers were transplanted. All the livers (100%) functioned. 2 patients required ReOLTx for HAT at 0.9 and 1.0 months. Both patients eventually died. One patient with a functioning liver died 2 months post OLTx. The remaining 3 patients are alive and well at 27 months of follow-up. This study shows that the procurement of kidneys from both uncontrolled and controlled NHBD leads to acceptable graft function despite a high incidence of ATN. The function of liver allografts is adequate in the controlled NHBD but suboptimal in the uncontrolled NHBD, with a high rate of PNF.

Effect of cold ischemia time on the early outcome of human hepatic allografts preserved with UW solution

Five hundred ninety-three cadaveric livers were used for primary liver transplantation between October 24, 1987, and May 19, 1989. The grafts were procured with a combined method, using in situ cooling with cold electrolyte solution and backtable flushing with UW solution. The mean cold-ischemia time was 12.8 (range 2.4–34.7) hr. The cases were divided into 5 groups according to the cold-ischemia time: group 1: <10 hr (n=223); group 2:10–14 hr (n=188); group 3:15–19 hr (n=101); group 4: 20–24 hr (n=52); and group 5: ≥25 hr (n=29). There was no difference between the 5 groups in 1-year patient survival, highest SGOT in first week after operation, and SGOT and total bilirubin during the first month after operation. However, with a logistic regression model, the retransplantation rate (P=0.001) and primary nonfunction rate (P=0.006) significantly rose as cold-ischemia time increased, meaning that the equivalency of patient survival was increasingly dependent on aggressive retransplantation.

The spectrum of portal vein thrombosis in liver transplantation

Thrombosis of the portal vein with or without patency of its tributaries used to be a contraindication to orthotopic liver transplantation (OLTX) until quite recently. Rapid progress in the surgical technique of OLTX in the last few years has demonstrated that most patients with portal vein thrombosis can be safely and successfully transplanted. Presented here is a series of 34 patients with portal vein thrombosis transplanted at the University of Pittsburgh since 1984. The various techniques used to treat various forms of thrombosis are described. The survival rate for this series was 67.6% (23 of 34 patients). Survival was best for patients who underwent phlebothrombectomy or placement of a jump graft from the superior mesenteric vein. The survival rate also correlated with the amount of blood required for transfusion during surgery. Overall it is concluded that a vast majority of the patients with thrombosis of the portal system can be technically transplanted and that their survival rate is comparable to that of patients with patent portal vein.

Intestinal transplantation in composite visceral grafts or alone.

Under FK 506-based immunosuppression, the entire cadaver small bowel except for a few proximal and distal centimeters was translated to 17 randomly matched patients, of whom two had antigraft cytotoxic antibodies (positive cross-match). Eight patients received the intestine only, eight had intestine in continuity with the liver, and one received a full multivisceral graft that included the liver, stomach, and pancreas. One liver-intestine recipient died after an intestinal anastomotic leak, sepsis, and graft-versus-host disease. The other 16 patients are alive after 1 to 23 months, in one case after chronic rejection, graft removal, and retransplantation. Twelve of the patients have been liberated from total parenteral nutrition, including all whose transplantation was 2 months or longer ago. The grafts have supported good nutrition, and in children, have allowed growth and weight gain. Management of these patients has been difficult and often complicated, but the end result has been satisfactory in most cases, justifying further clinical trials. The convalescence of the eight patients receiving intestine only has been faster and more trouble free than after liver-intestine or multivisceral transplantation, with no greater difficulty in the control of rejection.

CADAVERIC SMALL BOWEL AND SMALL BOWEL–LIVER TRANSPLANTATION IN HUMANS

Five patients had complete cadaveric small bowel transplants under FK506 immunosuppression, one as an isolated graft and the other 4 in continuity with a liver. Three were children and two were adults. The five patients are living 2-13 months posttransplantation with complete alimentation by the intestine. The typical postoperative course was stormy, with sluggish resumption of gastrointestinal function. The patient with small intestinal transplantation alone had the most difficult course of the five, including two severe rejections, bacterial and fungal translocation with bacteremia, renal failure with the rejections, and permanent consignment to renal dialysis. The first four patients (studies on the fifth were incomplete) had replacement of the lymphoreticular cells in the graft lamina propria by their own lymphoreticular cells. Although the surgical and after-care of these patients was difficult, the eventual uniform success suggests that intestinal transplantation has moved toward becoming a practical clinical service.

Small intestinal transplantation in humans with or without the colon.

Under FK506-based immunosuppression, 16 cadaveric small bowel transplantations were performed in 15 recipients with (n=5) or without (n=11) the large bowel. Twelve (80%) patients are alive after 1.5 to 19 months, 11 bearing their grafts, of which 4 include colon. The actuarial one-year patient and graft survivals are 87.5% and 65.9%, respectively. Five grafts were lost to acute (n=4) or chronic (n=l) rejection, and 3 of these patients subsequently died after 376, 440, and 776 days total survival. Six recipients developed severe CMV infection that was strongly associated with seronegative status preoperatively and receipt of grafts from CMV positive donors; 3 died, and the other 3 required prolonged hospitalization. Currently, 9 patients are free from TPN 1–18 months postoperatively, 2 require partial TPN, and one has returned to TPN after graft removal. The results show the feasibility of small bowel transplantation but emphasize the difficulty of managing these recipients not only early but long after their operation.

Single-center experience with primary orthotopic liver transplantation with FK 506 immunosuppression.

OBJECTIVE The efficacy for primary orthotopic liver transplantation of a new immunosuppressive agent, FK 506 (tacrolimus, Prograf, Fujisawa USA, Deerfield, IL), was determined. SUMMARY BACKGROUND DATA After 3 years of preclinical research, a clinical trial of FK 506 for orthotopic liver transplantation was begun in February 1989, first as a rescue therapy for patients with intractable rejection with conventional immunosuppression, then as a primary drug. METHODS Between August 1989 and December 1993, 1391 recipients (1188 adult and 203 pediatric) of primary liver allografts were treated with FK 506 from the outset. Results from these patients were analyzed and compared with those of 1212 historical control patients (971 adult and 241 pediatric) given cyclosporine-based immunosuppression. RESULTS Actuarial survival at 4 years was 86.2% with FK 506 versus 65.5% with cyclosporine in the pediatric patients (p < 0.0000) and 71.4% versus 65.5% in the adults (p < 0.0005). The need for retransplantation was reduced significantly for FK 506 patients. Four-year graft survival was 77.0% with FK 506 versus 48.4% with cyclosporine in the pediatric patients (p < 0.0000), and 61.9% with FK 506 versus 51.4% with cyclosporine in the adult recipients (p < 0.0000). Regression analysis revealed that reduction in mortality or graft loss from uncontrollable rejection, sepsis, technical failure, and recurrent original liver disease were responsible for the improved results with FK 506 therapy. CONCLUSIONS FK 506 is a potent and superior immunosuppressive agent for orthotopic liver transplantation.

Logistics and technique for combined hepatic-intestinal retrieval

During a 13-month period, en bloc liver-small bowel cadaveric grafts were procured for seven children and one adult. All liver grafts functioned immediately, and all but one of the recipient patients recovered. Return of absorptive small bowel function was slow, but the integrity of the bacterial intestinal barrier was not disrupted. The described technique allows the procurement of other abdominothoracic organs, with the exception of the whole pancreas.

Liver transplantation in patients over sixty years of age.

Orthotopic liver transplantation has been considered the accepted form of therapy for a number of end-stage liver diseases for several years (1). Until the early 1980s, the unofficially accepted limit for OLTX candidates was 50 years of age. Although a recent UNOS report seems to suggest that the survival of older patients with OLTX is poorer than that of the general adult transplant population (2), we have previously reported excellent preliminary results with OLTX in patients over 50 years of age (3). We have now expanded our series to 156 patients over 60 years of age at the time they received their transplant, and the results are reported here. Our study indicates that results after liver transplantation in patients over 60 years of age are comparable to the results obtainable in other age groups and that advanced age per se is not a contraindication to liver transplantation. Between January 1, 1985 and November 30, 1989, 1475 patients underwent OLTX at the University of Pittsburgh. There were 125 (8.5%) infants (under 2 years of age), 229 (15.5%) children (between 2 and 18 years of age), 965 (65.4%) adults, and 156 (10.6%) seniors (over 60 years of age) (Fig. 1A). Figure 1 (A) OLTX by age group; (B) senior OLTX population distribution by class; (C) senior OLTX population distribution by graft number; and (D) senior OLTX population distribution by diagnosis. Of the 156 senior patients, 80 were males (51.3%), and 76 were females (48.7%). One hundred fifty-two patients (97.4%) were in the seventh decade of their life, while 4 patients (2.6%) were in the eighth decade. Forty-nine patients (31.4%) were UNOS class 1 (out of hospital) at the time of the operation, 62 (39.7%) were class 2 (in the hospital), 24 (15.4%) were class 3 (in the intensive care unit), and 21 (13.5%) were class 4 (urgent) (Fig. 1B). Of the entire group, 129 patients (82.7%) received one graft, 26 patients (16.7%) 2 grafts, and 1 patient (0.6%) received 3 grafts (Fig. 1C). The indications for transplantation were: postnecrotic cirrhosis (PNC)* 65 (41.7%); primary biliary cirrhosis (PBC) 40 (25.6%); primary hepatic malignancy (CA) 19 (12.2%); alcoholic cirrhosis (ETOH) 17 (10.9%); primary sclerosing cholangitis (PSC) 6 (3.8%); metabolic disorders (MET) 5 (3.2%); acute hepatic failure (AHF) 2 (1.3%); and miscellaneous (OTH) 2 (1.3%) (Fig. 1D). Actuarial survival analysis was performed using the 1L module of BMDP/PC, 1988 release (BMDP Statistical Software, Los Angeles, CA) on an IBM-PC compatible microcomputer. Differences were considered significant if P <0.05 and highly significant if P<0.01. The actuarial survival rates (life-table method) for patients with primary grafts was 71.3% after 1 year and 65.5% after 3 years. By comparison, the adult survival ranges were 78% and 71.4%, respectively (Fig. 2A). Figure 2 (A) Patient survival (primary graft); (B) patient survival (retransplants); and (C) senior OLTX population survival by UNOS class. For retransplantations, the senior survival rates were 50% at 1 year and 30.7% at 3 years. By comparison, the adult survival rates were 56% and 43.1%, respectively (Fig. 2B). When the UNOS status was considered, the survival was significantly worse for class 4 (P <0.02) (Fig. 2C). Of the survivors, 66 (66.7%) are fully functional (status I); 27 (27.3%) are functional with some limitation (status II); 5 (5.0%) are partially disabled and in need of some assistance (status III); and 1 (1.0%) is disabled and needing full-time assistance (status IV) (Fig. 3A). Figure 3 (A) Senior OLTX population; functional status; and (B) senior OLTX population by year. The senior group had characteristics similar to the general adult liver transplant population, with the exception of age. This includes primary liver disease, male/female ratio, and medical urgency status (UNOS class). The overall survival for the senior group compared favorably with that of the infant and adult groups. The adult group was used for comparison as a “standard” for survival, while the infants were used as another “high-risk” group. The positive results with the older age population may come as a surprise at first glance, but to us it is clear that the physiological age is vastly more important than the chronological age toward survival. Our oldest recipient was 76 years old when she was given a transplant for PBC, and is still well and an active grandmother at 4 years later. In fact, over the years, the number of transplants in older patients has proportionally increased, compared to those in the adult population, as we have become more confident of achieving good results in this patient population (Fig. 3B). As anticipated, the survival for the much sicker patients in class 4 was statistically poorer. This is consistent with previous observations of a correlation between preoperative patient condition and survival with OLTX (4,5). The preoperative evaluation of the older OLTX candidates is similar to that of the general population, although sometimes it may be more complex, as it is more frequently necessary to study the cardiopulmonary condition in greater detail. But once severe concurrent conditions have been ruled out, the prognosis is as good as that for the general adult population. Many of these patients, especially those with primary biliary cirrhosis, present with advanced hepatic osteopathy that is often the rate-limiting pathology for recuperation after liver transplantation. This is one of the reasons for which we advocate early referral and transplantation for such patients, before the crippling effects of advanced and irreversible bone disease have set in. It is frequently possible and often important to use less-aggressive steroid regimens for immunosuppression in these older patients, in order to avoid worsening of the osteopathy, onset of steroid-dependent diabetes, and cataracts. As in the rest of the surgical population, early mobilization is extremely important. Otherwise, the postoperative care does not differ significantly from the “standard.” A large percentage of the older patients do recuperate completely or almost completely (93.9% of the survivors in our series have a functional status I or II) and can be active and productive again. Besides assuring them satisfactory quality for the rest of their lives, liver transplantation has the potential to increase the pool of productive population, in an era in which there will be an ever-higher percentage of elderly persons who retire late or reenter the job market. We conclude that advanced age is not a contraindication to liver transplantation. The results after liver transplantation in patients over the age of 60 were comparable to results for the general transplant population. These statistics were in contrast to the recent UNOS report for the calendar year 1988, during which the 1-year mortality rate was 50% for patients 65 years or older (2).