Background: Sirolimus is a potent immunosuppressive medication that acts by inhibiting T-cell proliferation. It has been used in kidney transplantation because of its lack of nephrotoxicity. It is now being investigated in liver transplantation, but there are concerns about safety and long-term side effects such as dyslipidaemia. Hypertriglyceridaemia is a common adverse event seen with sirolimus use, and often does not respond to dose reduction or anti-lipemic drugs.Method: We report six patients who have developed significant hyperlipidaemia while receiving sirolimus, in spite of therapeutic trough levels.Conclusion: All six patients showed either resolution or improvement in lipid levels with discontinuation of sirolimus.

OBJECTIVEThe authors determined the long-term outcome of patients undergoing hepatic retransplantation at their institution. Donor, operative, and recipient factors impacting on outcome as well as parameters of patient resource utilization were examined.SUMMARY BACKGROUND DATAHepatic retransplantation provides the only available option for liver transplant recipients in whom an existing graft has failed. However, such patients are known to exhibit patient and graft survival after retransplantation that is inferior to that expected using the same organs in naiive recipients. The critical shortage of donor organs and resultant prolonged patient waiting periods before transplantation prompted the authors to evaluate the results of a liberal policy of retransplantation and to examine the factors contributing to the inferior outcome observed in retransplanted patients.METHODSA total of 2053 liver transplants were performed at the UCLA Medical Center during a 13-year period from February 1, 1984, to October 1, 1996. A total of 356 retransplants were performed in 299 patients (retransplant rate = 17%). Multivariate regression analysis was performed to identify variables associated with survival. Additionally, a case-control comparison was performed between the last 150 retransplanted patients and 150 primarily transplanted patients who were matched for age and United Network of Organ Sharing (UNOS) status. Differences between these groups in donor, operative, and recipient variables were studied for their correlation with patient survival. Days of hospital and intensive care unit stay, and hospital charges incurred during the transplant admissions were compared for retransplanted patients and control patients.RESULTSSurvival of retransplanted patients at 1, 5, and 10 years was 62%, 47%, and 45%, respectively. This survival is significantly less than that seen in patients undergoing primary hepatic transplantation at the authors' center during the same period (83%, 74%, and 68%). A number of variables proved to have a significant impact on outcome including recipient age group, interval to retransplantation, total number of grafts, and recipient UNOS status. Recipient primary diagnosis, cause for retransplantation, and whether the patient was retransplanted before or after June 1, 1992, did not reach statistical significance as factors influencing survival. In the case-control comparison, the authors found that of the more than 25 variables studied, only preoperative ventilator status showed both a significant difference between control patients and retransplanted patients and also was a factor predictive of survival in retransplanted patients. Retransplant patients had significantly longer hospital and intensive care unit stays and accumulated total hospitalization charges more than 170% of those by control patients.CONCLUSIONSHepatic retransplantation, although life-saving in almost 50% of patients with a failing liver allograft, is costly and uses scarce donor organs inefficiently. The data presented define patient characteristics and preoperative variables that impact patient outcome and should assist in the rational application of retransplantation.

(Sopher, Braunfeld, Sangwan) Associate Professor, Department of Anesthesiology, University of California Los Angeles.(Shackleton) Associate Professor, Department of Surgery, University of California Los Angeles.(Busittil) Professor, Department of Surgery, University of California Los Angeles.(Csete) Associate Professor, Department of Anesthesiology, University of California Irvine.Received from the University of California Los Angeles School of Medicine, Los Angeles, California. Submitted for publication October 11, 1996. Accepted for publication March 24, 1997.Address reprint requests to Dr. Csete: Caltech Biology, Mail Code 156–29, Pasadena, California 91125. Address electronic mail to: csetem@starbase1.caltech.edu.Fatal pulmonary embolism is a very rare intraoperative complication of orthotopic liver transplantation (OLT), despite the use of antifibrinolytic agents in cirrhotic patients prone to hyperfibrinolysis in the setting of clotting activation and thrombin generation. [1] We report two such fatal complications to which aprotinin may have contributed.The patient was a 38-yr-old man with Laennec's cirrhosis and hepatitis C. Eight months before transplantation he presented with esophageal variceal bleeding and spontaneous bacterial peritonitis. He became progressively encephalopathic and short of breath and was admitted to the hospital. Laboratory studies included hematocrit, 21%; leukocyte count, 18.5 x 103/mm3; platelet count, 103,000/mm sup 3; and prothrombin time (PT) 16.3 s (INR, 1.6). The patient was hyponatremic, hyperkalemic, and oliguric, with creatinine level of 4.6 mg/dl, and required hemodialysis. Thoracentesis and paracentesis revealed negative bacterial cultures. He was treated with ciprofloxacin, and his leukocyte count fell to 9.4 x 103/mm3.The patient underwent an uncomplicated rapid sequence induction of anesthesia, after which a radial arterial catheter and two 9-French introducers were placed in the right internal jugular vein. Anesthesia was maintained with isoflurane and fentanyl, and dopamine was infused at 3 micro gram [center dot] kg sup -1 [center dot] min sup -1. The first hemodynamics recorded (before incision) were pulmonary artery (PA) pressure of 23/10 mmHg; CVP, 10 mmHg; and cardiac output (CO), 9.8 l/min. On FIO2of 0.6, first arterial blood gas (ABG) analysis revealed pH, 7.34; PaCO2, 35 mmHg; PaO2, 109 mmHg; base deficit, -5.7. Hct was 25%; PT, 19.1 s; and fibrinogen, 135 mg/dl. TEG is not used in our center. Before incision, 1 g/h infusion of epsilon-aminocaproic acid (EACA) was started after a 5-g bolus. Thirty minutes after incision, the patient experienced acute hypotension (systolic blood pressure, 65 mmHg) associated with rapid blood loss, which responded quickly to transfusion with 2 U packed red cells, 4 U fresh frozen plasma (FFP), 250 cc 5% albumin, and administration of CaCl sub 2 (500 mg) and phenylephrine (400 micro gram). After this episode, blood pressure was 130/75 mmHg, and PA was 41/23 mmHg; CVP, 14 mmHg; and CO, 12.7 l/min. The patient was hemodynamically stable through the rest of the dissection phase. Venovenous bypass with a heat exchanger and nonheparinized tubing was instituted without problems (flows, 2.1–2.5 l/min). Thirty minutes later, after hepatectomy, the surgeons noted extremely poor hemostasis and requested that aprotinin be given. The EACA infusion was discontinued, and after a test dose of aprotinin (10,000 KIU), the patient received a loading dose of 2 million KIU, followed by infusion of 200,000 KIU/h. Blood gas level a few minutes later (FIO20.45) was pH, 7.4; PaCO2, 28 mmHg; PaO2, 218 mmHg, Hct, 25%; platelets, 37,000/mm3; PT, 16 s, and fibrinogen 154 mg/dl. Venous anastomoses were completed, and portal bypass was discontinued. Approximately 20 min after aprotinin was first given, the patient's blood pressure dropped acutely to 45/20 mmHg. Dopamine was increased to 10 micro gram [center dot] kg sup -1 [center dot] min sup -1, and boluses of epinephrine, neosynephrine, CaCl2, sodium bicarbonate, and intravenous fluids were given with only transient improvement in blood pressure. PA pressures were also noted to be elevated to 50/29 mmHg, CVP to 29 mmHg, and CO could not be measured. End-tidal CO2dropped, and ABG on FIO21.0 was pH, 7.49; Pa sub CO2, 27 mmHg; PaO2, 47 mmHg, base deficit, -1.7. Venovenous bypass was discontinued, and the aprotinin infusion stopped. Large doses of pressors were administered without improvement.A transesophageal echocardiographic (TEE) probe was placed and revealed a large right atrium and ventricle, with a large thrombus in the right atrium, through the tricuspid valve, and into the right ventricle. The right ventricle was severely hypocontractile, and the left ventricle appeared empty but normally contractile. Despite pharmacologic interventions, blood pressure continued to fall, and chest compression was begun, followed by direct myocardial compression for several minutes. One hour into the resuscitation, ABG on FIO21.0 was pH, 7.12; PaCO2, 33 mmHg; PaO2, 75 mmHg; base deficit, -16.5. Systolic blood pressure never increased above 45 mmHg. The new liver was grafted and reperfused without any improvement in the patient's blood pressure. Cardiac surgeons were called and removed a large thrombus from the right atrium and pulmonary artery, without bypass. Nonetheless, the patient died 2 h after the onset of hypotension.A 37-yr-old man with subacute hepatic failure of unknown cause presented 1 month before transplantation with fever, weakness, nausea, and vomiting. Hematocrit was 32%, platelets, 289,000/mm3; glucose, 57 mg/dl; creatinine, 1.4 mg/dl; albumin, 2.0 g/dl; and total bilirubin, 27.7 mg/dl. PT was 19.2 s; aspartate aminotransferase, 556 U/l; and alanine aminotransferase, 321 U/l-all significantly higher than 1 month previous. The patient's hospital course was significant for septic arthritis of the knee and bacteremia, managed with multiple antibiotics, and for spontaneous bacterial peritonitis. The patient's renal function deteriorated, and he was transferred to University of California, Los Angeles. He required hemodialysis, which was complicated by hypotension. Dopamine was administered for 8 days in dosages ranging from 3.5 to 7.5 micro gram [center dot] kg sup -1 [center dot] min sup -1. Dobutamine stress echo showed an ejection fraction of 55–60%.The patient underwent an uncomplicated liver transplantation, during which 10 U packed cells, 17 U FFP, 20 U platelets, and 10 U of cryoprecipitate were given. He received aprotinin (2 million KIU bolus, 500,000 KIU/h) from the dissection phase through the end of surgery. The postoperative course was complicated by renal failure requiring dialysis and poor graft function. Two days later, the patient underwent a second liver transplantation for primary nonfunction.After induction of anesthesia, aprotinin was administered in the same dose as for the first transplantation. Dissection and institution of venovenous bypass were uncomplicated. After hepatectomy, the patient developed acute systemic hypotension, and PA pressures rose suddenly to 40/30 mmHg. The surgeons noted a poorly contracting right ventricle (compared with normal hyperdynamic contractions), and PA pressures remained increased. The hypotension was unresponsive to dopamine, 8 micro gram [center dot] kg sup -1 [center dot] min sup -1, atropine given when the heart rate fell to 45 beats/min, and boluses of epinephrine. For these reasons, TEE was placed. A large thrombus was seen in the inferior vena cava and right atrium. Cardiac surgery consultants elected to remove the thrombus, and the patient was placed on cardiopulmonary bypass with heparin anticoagulation. Cardiotomy was performed, and large clots (some appearing fibrinous and likely to be days old, some appearing newly formed or gelatinous) were removed from the inferior vena cava, right atrium and ventricle, and pulmonary artery. After cardiopulmonary bypass, the patient required large doses of epinephrine, and then norepinephrine, to maintain blood pressure. The liver graft was placed without improvement in the pressor requirement. Hemostasis in the neohepatic phase was poor despite administration of cryoprecipitate, FFP, and 100 mg of protamine. New thrombus was noted on TEE in the RA and RV and attached to the PA catheter, and so, further protamine and antifibrinolytics were not given (despite partial thromboplastin time [PTT] > 180 s). Cardiac surgeons did not believe a second procedure was indicated. The patient received 36 U each of packed cells and FFP. The patient was transported to the intensive care unit on a norepinephrine infusion (2 micro gram [center dot] kg sup -1 [center dot] min sup -1). He never regained consciousness and was declared brain dead on the second postoperative day.The two cases presented here occurred within 1 month of each other, at a time just after the introduction of aprotinin into clinical use during OLT; 15 patients before these received aprotinin during OLT. Before this time, the standard antifibrinolytic regimen during OLT at our center was EACA, given to more than 600 patients without evidence of abnormal clot formation. The proximity of these cases in our center is striking and should motivate reevaluation of antifibrinolytic therapy during liver transplantation.Liver transplantation centers vary in their practice of administration of procoagulant drugs. EACA is probably the most commonly administered antifibrinolytic drug in the United States for patients undergoing OLT. A combination of release of tissue plasminogen activator (t-PA) from graft endothelium and decreased hepatic clearance of t-PA generally is accepted as one contributor to enhanced fibrinolysis during liver transplantation. [2] Thus, EACA is used during liver transplantation for its effect of interfering with plasmin(ogen) binding to fibrin. Almost a decade ago, the drug was reported to reverse thromboelastographic evidence of fibrinolysis without causing thrombotic complications during liver transplantation. [3] Although EACA was not rigorously, prospectively studied, such reports influenced clinical practice tremendously. A prospective study on EACA was reported at a national meeting [4] and greatly influenced our local practice. In this blinded study, transfusion requirements were significantly decreased when EACA was given to patients undergoing liver transplantation (5-g bolus, then 1- g/h infusion). This study caused our center to standardize the administration and dose of EACA.Several reports from outside the United States suggested that the antifibrinolytic drug, aprotinin, was effective in reducing transfusion requirements during OLT. A 50% reduction in transfusion requirements was reported when aprotinin (2 million KIU bolus, then 500,000 KIU/h infusion) was given during liver transplantation. [5] However, this study was small and used retrospective control subjects. Similar problems plague other reports, [6–9] and further, drug dose is not standardized from report to report. [10,11] Recent studies have helped elucidate some of the mechanisms of aprotinin action during liver transplantation, such as its antikallikrein effect, [12] but the number of patients prospectively studied against either placebo or EACA has not been large. Nonetheless, aprotinin is used routinely in many European liver transplantation centers, and some authors report that they will not study the drug with a control arm because withholding aprotinin would be unethical. [13] Not all studies support a role for aprotinin in reducing transfusion requirements during OLT. [14]One case report increased concern that aprotinin contributed to a fatal pulmonary embolism during OLT. [15] This patient (after receiving a bolus of aprotinin 1.6 million KIU and an infusion at 0.5 million KIU/h) developed a large thrombus attached to the pulmonary artery catheter, spanning the superior vena cava into the pulmonary artery. The authors suggested that the complication may have been a result of very low antithrombin III levels and of two introducers in the internal jugular vein leading to endothelial activation. Further, in a report of six perioperative liver transplantation deaths attributed to pulmonary platelet aggregates, three of the six patients received aprotinin, and two of these died during surgery. [16]Rare cases of pulmonary embolism during OLT have been reported before the use of aprotinin. [17–19] Another report increased concern that EACA may contribute to rare pulmonary embolism. [20] Two of 12 patients who had received EACA experienced massive thromboembolism during transplantation. Of note, both patients were critically ill and intubated before surgery.In the two cases reported here, several factors may have contributed to abnormal clot formation. The first patient received EACA followed by aprotinin, and it is possible that the drugs had a synergistic action on clot formation. The second patient was septic in the weeks before transplantation. If he had ongoing infection, disseminated intravascular coagulation (DIC) may have contributed to clot formation. In addition, patients with acute liver disease may be more prone to DIC than those with chronic disease. [21] Drug dosage may be a factor. A recent prospective study of aprotinin suggests that much lower dosages (0.2 million KIU/h infusion without a bolus) than originally reported may be sufficient to decrease fibrinolytic activity during liver transplantation, [22] increasing concern that high- dose aprotinin may be an unnecessary risk. The timing of the second transplantation may have placed the second patient at risk for clotting complications because there may be a relative abundance of procoagulants (such as plasminogen activator inhibitor) and slow recovery of protein C and S several days after OLT. [23]In summary, the complicated coagulopathy in liver disease combined with an equally complex superimposed coagulopathy during surgery are inherently difficult to study. For example, there often is insufficient clinical information to clearly distinguish between primary and secondary fibrinolysis in these patients. Large prospective trials to determine optimal antifibrinolytic therapy are needed to determine minimal effective doses and to carefully document the balance between thrombogenic factors and antifibrinolytic parameters after drug administration. In experienced transplantation centers, aggressive transfusion therapy of coagulopathy combined with potent procoagulant drugs may lead to increased thrombotic complications. These cases highlight the need for a reevaluation of procoagulant therapy during liver transplantation.The authors thank Dr. Hillel Laks for his contributions.

The effect of ganciclovir prophylaxis on reinfection of hepatic allografts by hepatitis B virus (HBV) was studied in 26 patients undergoing orthotopic liver transplantation (OLT) for decompensated cirrhosis due to HBV. Patients were randomized to receive either ganciclovir (6 mg/kg/day intravenously for a total of 100 days) or acyclovir (10 mg/kg every 8 hours intravenously until discharged and then 800 mg orally every 6 hours) for a total of 100 days after OLT as part of a study of prophylaxis against cytomegalovirus infection. All patients received hepatitis B immunoglobulin (HBIG), 10,000 units intravenously, during the anhepatic phase, daily for the first 7 days, after OLT, and then every 4 weeks for 6 months, Seven of 12 (58%) patients in the ganciclovir group developed recurrent HBV, compared with 6/14 (46%) of the acyclovir group (nonsignificant). No significant difference was observed in time to recurrent HBV in the ganciclovir group (mean 13.2 months) compared to the acyclovir group (mean 11 months). Our results suggest that ganciclovir administered prophylactically for 100 days after OLT does not prevent or delay graft reinfection by HBV.

We have observed an increased rate of delayed non-function (DNF) of liver grafts procured from older donors. The aim of this study was to correlate donor age and the patterns of graft failure after transplantation. Pattern of liver injury, synthetic function, and graft survival in recipients receiving liver grafts from donor older than age 50 (group I, n=95) were compared with matched cohort of recipients transplanted with grafts from donors age 20–30 (group III, n=50). Primary nonfunction (PNF) of the graft was defined as non-recoverable hepatocellular function necessitating emergency retransplantation within 72 hr. DNF was defined as marginal graft function necessitating re-transplantation within one month. Recipient characteristics, including age and preoperative UNOS status, were similar between groups. Ischemic/reperfusion injury, reflected by SGOT and SGPT was more severe in older donors. PNF occurred at similar frequencies for all groups (7%). Normal liver function was regained in 76% of recipients in group I, and in 92% in group II. However, cholestatic pattern was observed in recipient of grafts from group I donors. Rapid rise in bilirubin, despite normalization of prothrombin time and liver transaminases, was the hallmark of DNF. DNF resulted in higher retransplantation rate in group I (24% vs. 8% in group II). Donor age did not affect patient survival. Liberalizing criteria for donor selection, and acceptance of older donors is a calculated risk. Over 75% of the recipients will regain normal liver function. However, a higher number of these grafts will exhibit slow recovery after transplantation, and a significant rate of DNF. Recognition of such