Retransplantation of patients with severe posttransplant hepatitis B in the first allograft.

BACKGROUND: The outcome of orthotopic liver transplantation (OLTX) in patients retransplanted for severe hepatitis B virus (HBV) in the first allograft has been poor due to high rates of HBV reinfection and even more aggressive disease in the second graft. Recent data suggest that hepatitis B immunoglobulin (HBIg) given after transplantation can be successful in delaying or preventing HBV reinfection in patients transplanted for chronic hepatitis B cirrhosis. We report the successful retransplantation of patients who developed recurrent or de novo hepatitis B after OLTXY. METHODS: Using similar HBIg regimens, two centers retransplanted seven patients after they developed recurrent or de novo hepatitis B in the first allograft. At retransplantation all seven patients were HBs antigen (Ag) positive; four patients were positive for HBeAg and HBV DNA by immunoblot assay, two patients were negative for HBeAg and HBV DNA, and one patient was positive for HBV DNA and negative for HBeAg. All patients were either HDV Ag or anti-HDV negative. One patient was anti-HCV positive. All patients received HBIg infusions after retransplantation to maintain serum anti-HBs levels >500 IU/L indefinitely. RESULTS: After retransplantation, six of seven patients are alive (86%): all are without evidence of HBV recurrence with serum negative for HBsAg, HBeAg, and HBV DNA by immunoblot assay. Liver biopsies are normal on routine studies with immunohistochemical stains for HBcAg and HBsAg also being negative. Mean follow-up of these six patients is 40.1 months (range 21-63 months). One patient (14%) developed HBV reinfection 7 months after his second transplant, in spite of maintaining target anti-HBs levels. He maintained stable liver function with minimal evidence of clinical hepatitis B, but died 8 months later from an unrelated stroke. CONCLUSIONS: We conclude that patients with recurrent or de novo hepatitis B after OLTX can be successfully retransplanted using aggressive immunoprophylaxis to prevent HBV reinfection. The failure of HBIg therapy in one patient underscores the need for other effective adjunctive anti-HBV modalities.

Oral ganciclovir dosing in transplant recipients and dialysis patients based on renal function.

BACKGROUND: An oral formulation of ganciclovir (GCV) was recently approved for the prevention of cytomegalovirus disease in solid organ transplant recipients. This study was designed to determine the bioavailability of GCV and to test a dosing algorithm in transplant and dialysis patients with different levels of renal function. METHODS: Pharmacokinetic studies were carried out in 23 patients who were either a recipient of an organ transplant or on hemodialysis. Drug dosing was established by the following algorithm based on calculated creatinine clearance (CrCl): CrCl = [(140-age) x body weight]/(72 x Cr) x 0.85 for women that is, CrCl >50 ml/min, 1000 mg every 8 hr; CrCl of 25-50 ml/min, 1000 mg every 24 hr; CrCl of 10-24 ml/ min, 500 mg every day; CrCl < 10 ml/min (or on dialysis), 500 mg every other day after dialysis. GCV was taken within 30 min after a meal. The patients received oral GCV for between 12 days and 14 weeks. Serum specimens (or plasma from patients on hemodialysis) obtained at steady state were analyzed for GCV concentrations by high-performance liquid chromatography. In nine of the transplant recipients, absolute bioavailability was determined by comparing GCV levels after single oral and intravenous doses of GCV. RESULTS: The following GCV concentrations (mean +/-SD) were determined: with CrCl of > or =70 ml/min, the minimum steady-state concentration (Cmin) and maximum concentration (Cmax) were 0.78+/-0.46 microg/ml and 1.42+/-0.37 microg/ml, respectively, with a 24-hr area under the concentration time curve (AUC0-24) of 24.7+/-7.8 microg x hr/ml; with CrCl of 50-69 ml/min, the Cmin and Cmax were 1.93+/-0.48 and 2.57+/-0.39 microg/ml, respectively, with an AUC0-24 of 52.1+/-10.1 microg x hr/ml; with CrCl of 25-50 ml/min, the Cmin and Cmax were 0.41+/-0.27 and 1.17+/-0.32 microg/ml, respectively, with an AUC0-24 of 14.6+/-7.4 microg x hr/ml. For one patient with a CrCl of 23.8 ml/min, the Cmin and Cmax were 0.32 and 0.7 microg/ml, respectively, with an AUC0-24 of 10.7 microg x hr/ml. With CrCl of <10 ml/min, the mean Cmin and Cmax were 0.75+/-0.42 and 1.59+/-0.55 microg/ml, respectively, with a mean AUC0-24 of 64.6+/-18.8 microg x hr/ml. Absolute bioavailability, for the nine patients so analyzed, was 7.2+/-2.4%. For those patients with end-stage renal failure, GCV concentrations fell during dialysis from a mean of 1.47+/-0.48 microg/ml before dialysis to 0.69+/-0.38 microg/ml after dialysis. CONCLUSIONS: The bioavailability of oral GCV in transplant patients was similar to that observed in human immunodeficiency virus-infected patients. However, levels between 0.5 and 1 microg/ml (within the IC50 of most cytomegalovirus isolates) could be achieved with tolerable oral doses. The proposed dosing algorithm resulted in adequate levels for patients with CrCl greater than 50 ml/min and for patients on dialysis. For patients with CrCl between 10 and 50 ml/min, the levels achieved were low and these patients would likely benefit from increased doses.

Improved outcome of orthotopic liver transplantation for chronic hepatitis B cirrhosis with aggressive passive immunization.

Passive immunization with hepatitis B surface antibody (anti-HBs) is important to prevent hepatitis B virus (HBV) recurrence after orthotopic liver transplantation for chronic HBV cirrhosis. Hepatitis B immune globulin (HBIG) dosing regimens have been poorly defined, utilize numerous routes of administration, and result in a high rate of HBV relapse and mortality. Twenty-five of 27 (93%) patients transplanted (four retransplants) for chronic HBV cirrhosis show no evidence of recurrent HBV (range, 2-55 months). Anti-HBs titers necessary to minimize the risk of hepatitis B surface antigen detectability were >500 IU/L for days 0 to 7, >250 IU/L for days 8 to 90, and >100 IU/L thereafter. Pretransplant HBV E antigen (HBeAG)-positive patients required more HBIG to achieve these goals than HBeAG-negative individuals. The elimination of anti-HBs changed continually for the initial 3 posttransplant months. The anti-HBs half-life increased from 0.7 days to 14.1 days. Anti-HBs elimination was significantly different in HBeAG+ and HBeAG- patients for the first week, but was subsequently indistinguishable after week 1. After 3 months, the half-life was statistically less for HBeAG+ patients, but the difference did not influence the clinical treatment regimens. Quantitative hepatitis B DNA levels did not predict the amount of HBIG required. HBV recurrence after orthotopic liver transplantation can be reduced by aggressive passive immunization. Pharmacokinetic analysis of anti-Hbs elimination can improve immunoglobulin therapy and prevent recurrence of clinical hepatitis.

Pharmacokinetic considerations.

Limited studies of the pharmacokinetics of pain medication suggest altered serum elimination when the liver is hypoperfused or affected by severe cirrhosis. Drugs that are eliminated by Phase I oxidation reactions are sensitive to changes in hepatic blood flow, while drugs eliminated by Phase II glucuronidation are more affected by diseased hepatocytes. Additionally, alterations in renal function decrease elimination of both parent drugs and metabolites, resulting in toxicity for selected opioids such as meperidine and morphine. Caution is suggested in drawing general conclusions from pharmacokinetic patterns of opioid elimination discussed in this review. Practitioners should be aware that drugs with short duration of action may have long half-lives and accumulate in end-stage liver and renal disease. While pharmacokinetic differences have been described in various populations, the clinical effects and adverse outcomes are greatly influenced by numerous independent physiologic alterations seen in critical care patients. Patients with severe alterations in liver and renal function should be administered pain medications judiciously because these patients are predisposed to metabolic disarrays. These patients should not be denied pain care, but they may benefit from smaller, less frequently administered doses, rather than continuous infusion of opioid drugs. Titration of doses to clinical effects with careful patient assessment for adverse effects is crucial for achieving desired therapeutic outcomes with analgesic agents in the ICU.

Safety profile, pharmacokinetics, and pharmacodynamics of siplizumab, a humanized anti-CD2 monoclonal antibody, in renal allograft recipients.

BACKGROUND: We report the safety profile, pharmacokinetics (PK), and pharmacodynamics (PD) of siplizumab, a humanized IgG1 anti-CD2 monoclonal antibody and potential agent for preventing renal allograft rejection, in a phase 1 study in renal allograft recipients. METHODS: Subjects on conventional immunosuppressive regimens received 2 infusions (4-6 and 60-72 hours postsurgery) of siplizumab (0.012, 0.06, or 0.12 mg/kg per dose). Adverse events (AEs) were recorded for 33 days. Serum siplizumab concentrations were measured and PD was assessed by flow cytometry and NK in vitro cytotoxicity. RESULTS: Thirteen renal allograft recipients were enrolled. Two patients had mild infusion reactions with single temperature elevations of 38.2 degrees C and 38.6 degrees C, respectively. Eight patients had siplizumab-related AEs: lymphopenia (7 patients), anemia (3), chills (2), and nausea (2). Mean natural killer (NK) cell cytotoxicity decreased after the first dose, but exceeded pretreatment values by day 33 in all patients. No anti-siplizumab antibodies were detected. The 0.012 mg/kg group did not achieve quantifiable siplizumab serum concentrations. By the second dose, mean peak concentrations were 958 ng/mL, with mean T(1/2) of 29 hours, in the 0.06 mg/kg group, and 2870 ng/mL, with mean T(1/2) of 49 hours, in the 0.12 mg/kg group. Mean total lymphocyte and CD2(+) lymphocyte counts declined after the first infusion and rose by day 8 in all groups despite a second infusion of siplizumab. Lymphocyte counts returned to pretreatment levels by day 60. CONCLUSION: Siplizumab exhibited an acceptable safety profile in this study. Detectable siplizumab concentrations were maintained for 3 days after the second dose at the 2 highest dose levels.

Pharmacoeconomic analysis of HBV liver transplant therapies.

The outcome of liver transplantation for patients infected with the hepatitis B virus (HBV) has greatly improved over the last several years. The rate of allograft infection has decreased from 85 to 25%, while the post-transplant mortality rate due to HBV has decreased from 50% at 18 months to nearly nonexistent. For the most part, this result has been due to the increased dose and extended use of hepatitis B immunoglobulin (HBIg). Current lack of knowledge of the amount of HBIg monotherapy that is necessary to suppress residual virus has led to an expensive therapy. In our early experience, no alternative existed at the time of transplant for this group of recipients. Administration of HBIg was directed toward patient safety and optimal outcome rather than cost containment. The significance of the economic impact of this decision is discussed in this article. Analysis of institutional expenses revealed that the cost of HBIg to establish viral control was fairly consistent over time, despite the increased purchase price of the drug. Individualized dosing of HBIg was more expensive in the first year after transplantation compared to typical monthly administration protocols, but was substantially less expensive after 12 months due to decreased dosage needs. In addition to HBIg acquisition price, factors that affect expenditure for HBIg maintenance include time intervals between doses, purchase contracts, overhead of drug administration, and methods employed in determining charge structures. Combination therapies with nucleoside analogues may have a beneficial effect on future costs. Controlled trials to identify the optimum and most cost-effective therapy need to be performed.

Hepatitis B immune globulin: the US experience.

The increasingly aggressive use of hepatitis B immune globulin (HBIg) in liver transplantation for hepatitis B infected patients has led to a great improvement in this procedure by lowering the incidence of allograft infection. In this article, major US studies on the use of HBIg are reviewed, including clinical results, clinical failures and problems, and the remaining information still needed for optimal therapy. Several major clinical findings have resulted from these studies. (1) With a high dose of HBIg and continuous use of this agent, it is possible to prevent recurrence in hepatitis B virus DNA-positive patients. (2) It is difficult to predict the required post-transplant dose of HBIg or the recurrence of hepatitis B in allografts. (3) While passive immunization of HBIg can help achieve successful transplants of patients suffering from hepatitis B cirrhosis, there are two typical patterns of failure: allograft infection with wild-type hepatitis B virus in the early perioperative period and with a mutant virus more than 6 months post-transplantation. These problems appear to arise only in patients with pre-transplant viral replication. (4) Combination therapy of HBIg and lamivudine seems promising for further improvement of liver transplantation. (5) There are still unanswered questions concerning the combination strategy: optimal timing, patient selection, duration of therapy, and the risk of viral mutations and adverse events. In addition, the role of changing immunosuppression protocols in improving transplantation of hepatitis B infected patients has not been determined.

Magnesium repletion and its effect on potassium homeostasis in critically ill adults: results of a double-blind, randomized, controlled trial.

OBJECTIVES: The aims of this study were to evaluate the safety and efficacy of magnesium replacement therapy and to determine its effect on potassium retention in hypokalemic, critically ill patients. DESIGN: A prospective, double-blind, randomized, placebo-controlled trial. SETTING: A surgical intensive care unit (ICU). PATIENTS: A total of 32 adult surgical ICU patients were admitted to the study on the basis of documented hypokalemia (potassium of < 3.5 mmol/L) within the 24-hr period before entering the study. Patients were randomized to receive either placebo (n = 15) or magnesium sulfate (n = 17). One patient from each group was excluded from the study due to failure to complete the full series of doses. INTERVENTIONS: Patients received a "test dose" of either magnesium sulfate (2 g, 8 mmol) or placebo (5% dextrose in water) infused over 30 mins every 6 hrs for eight doses. The next schedule test dose was held if hypermagnesemia (magnesium of > 2.8 mg/dL [> 1.15 mmol/L]) was documented at any time during the study. Routine replacements of potassium and magnesium continued during the duration of the study, when clinically indicated, for serum potassium concentrations of 3.5 mmol/L or serum magnesium concentrations of < 1.8 mg/dL (< 0.74 mmol/L). MEASUREMENTS AND MAIN RESULTS: Age, weight, and Acute Physiology and Chronic Health Evaluation II scores were recorded on entry into the study. Just before administration of each test dose, blood was drawn for magnesium and potassium, bicarbonate, pH, and glucose determinations, and an aliquot of the preceding 6 hrs urine collection was sent for magnesium and potassium determinations. Serum calcium, phosphate, urea nitrogen, and creatinine concentrations were measured daily. The amounts of magnesium and potassium administered via parenteral nutrition, tube feeding, and replacement infusions were calculated for each 6-hr interval. The amounts of magnesium and potassium excreted in the urine were similarly assessed. The groups showed no differences with regard to age, weight, Acute Physiology and Chronic Health Evaluation II scores, or initial serum magnesium concentration. Initial potassium, bicarbonate, pH, calcium, phosphate, glucose, blood urea nitrogen, and creatinine values were not different between groups. Patients receiving magnesium sulfate showed a statistically significant increase in serum magnesium concentration at 6 hrs when compared with placebo, as well as with itself at time 0 (p < .0001), a difference maintained throughout the study. Compared with the placebo group, the total amount of elemental magnesium administered was significantly greater in the treatment group (1603 +/- 124 vs. 752 +/- 215 mg [65.7 +/- 5.8 vs. 30.8 +/- 8.8 mmol], p < .0001), as was urine magnesium excretion (1000 +/- 156 vs. 541 +/- 68 mg [41.0 +/- 6.4 vs. 22.2 +/- 2.8 mmol] p < .0001). However, the net magnesium balance (total magnesium in - total urine magnesium) was significantly more positive in the treatment group (612 +/- 180 vs. 216 +/- 217 mg [25.1 +/- 7.4 vs. 8.9 +/- 8.9 mmol], p < .005). The treatment and control groups had the same serum potassium concentrations and did not receive different amounts of potassium (245 +/- 39 vs. 344 +/- 45 mmol, respectively, p = .06), although the treatment group required less potassium replacement/6 hrs by 30 hrs compared with itself at time 0 (p < .05). Despite the same serum potassium values, the net potassium balance for 48 hrs was positive in the treatment group (+ 72 +/- 32 mmol) and negative in the control group (-74 +/- 95 mmol, p < .05). There were no complications associated with the magnesium sulfate administration. CONCLUSIONS: Magnesium sulfate administered according to the above regimen safety and significantly increases the circulating magnesium concentration. Despite greater urine magnesium losses in the treatment group, this group exhibited significantly better magnesium retention.

Pharmacokinetics of vancomycin in patients with various degrees of renal function.

The pharmacokinetics of vancomycin were characterized in 56 patients with different degrees of renal function after an intravenous dose of 18.4 +/- 4.7 mg kg-1 (mean +/- standard deviation). Seven subjects had a creatinine clearance (CLCR) of greater than 60 ml min-1 (group I), 13 had a CLCR of 10 to 60 ml min-1 (group II), and 36 had a CLCR of less than 10 ml min-1 (group III). Serial serum samples (range, 3 to 8) were collected during the 168 h after drug administration. The serum concentration-time profile in all patients demonstrated monoexponential decay. The mean half-lives were 9.1, 32.3, and 146.7 h in groups I, II, and III, respectively. A significant decline in serum clearance (CLS) was also noted (62.7 to 28.3 to 4.87 ml min-1 in groups I, II, and III, respectively). The steady-state volume of distribution varied from 0.72 to 0.90 liter kg-1. There was no significant relationship between the steady-state volume of distribution and CLCR. The observed relationship between CLS and CLCR (CLS = 3.66 + 0.689 CLCR; r = 0.8807) can be utilized to devise dosage schedules for patients with any degree of renal impairment. This relationship was utilized to develop a nomogram for initial and maintenance dosing of vancomycin.

Hemodialysis clearance of total and unbound lidocaine.

The hemodialysis clearance and protein binding of lidocaine was determined in two acutely ill patients with end-stage renal disease. Patient A was a 74-year-old white man admitted for severe thrombocytopenia; lidocaine was started to control ventricular tachycardia. Patient B was a 66-year-old white man admitted for a myocardial infarction (MI); prophylactic treatment with lidocaine was begun after a second MI. Lidocaine hemodialysis clearance was evaluated during a five-hour dialysis procedure. Paired arterial and venous blood samples for lidocaine concentrations were collected at the midpoint of each hour of dialysis. Before dialysis and two hours after dialysis, venous samples were collected and assayed for alpha-1-acid glycoprotein (AAG) and lidocaine. The hemodialysis clearance of total and unbound lidocaine was calculated. The total amount of lidocaine removed was 8.9 and 12.5 mg for patients A and B, respectively. These amounts represented the removal of 5.6 and 2.8% of the total lidocaine dose administered to patients A and B, respectively, during the dialysis procedure. For patient A, the mean plasma dialysis clearance (Clp) was 28.2 +/- 6.3 ml/min for total lidocaine and 41.3 +/- 15.6 ml/min for unbound lidocaine. The Clp could not be calculated for patient B. The mean dialysate clearance (Cld) of total lidocaine was 28.6 +/- 7.8 and 26.3 +/- 6.5 ml/min for patients A and B, respectively. The Cld of unbound lidocaine was 42.7 +/- 6.7 and 44.5 +/- 9.9 for patients A and B, respectively. Although both patients A and B had substantial elevations in AAG concentrations (254 and 247 mg/dl, respectively), they exhibited high lidocaine unbound fractions of 0.55 and 0.68 before dialysis. The lidocaine unbound fraction was further increased in patient A after fat emulsion infusion to 0.80 and in patient B after heparin administration to 0.90. The clearance of lidocaine by hemodialysis in these two patients was negligible and clinically unimportant. No dose adjustment or supplementation was required after hemodialysis.

Hemodynamic effects of rapid vancomycin infusion in critically ill patients.

The rapid infusion of vancomycin produces histamine release resulting in rash ("red-man's" syndrome) and hypotension. Because this phenomenon has been described primarily in healthy subjects, we prospectively studied the rapid infusion of vancomycin in 16 critically ill patients after open heart surgery in an attempt to document histamine release with resulting hemodynamic changes, and to see if there is any correlation with vancomycin levels. After establishing baseline hemodynamic stability and histamine levels, 1 g vancomycin diluted in 50 mL of 5% dextrose was infused over 30 min. Cardiac index, heart rate, blood pressure, pulmonary venous pressures, and systemic and pulmonary vascular resistances remained unchanged during the infusion. Although the mean plasma vancomycin level increased to a peak of 69 +/- 20 micrograms/mL after 20 min of the infusion before declining, mean plasma histamine levels in 15 of the 16 patients remained within the normal range during the infusion. In one patient a baseline histamine level (2.8 ng/mL) more than three times the normal before the vancomycin infusion increased further during the infusion (3.0, 4.9, and 5.0 ng/mL at t = 10, 20, and 30 min, respectively), and remained elevated (2.9 ng/mL) 30 min after the infusion. This patient developed the red-man's syndrome, although there were no hemodynamic changes. There was no evidence of myocardial depression in any of the patients. In conclusion, we safely infused a concentrated solution of vancomycin into critically ill patients over 30 min without any adverse hemodynamic changes. One patient developed the red-man's syndrome. There was no correlation between peak vancomycin levels and the release of histamine in this patient population.

Liver transplantation for hepatitis B cirrhosis: clinical sequela of passive immunization.

UNLABELLED: Aggressive administration of hepatitis B immune globulin (HBIg) has been shown to prevent hepatitis B viral (HBV) infection of the allograft; however, the clinical sequela of such therapy has not been previously described. We reviewed our experience with high dose, intravenous infusion of an intramuscular HBIg preparation to assess the effectiveness and complications of such therapy. Thirty three orthotopic liver transplants (OLTx) were performed in 32 patients with chronic HBV cirrhosis at the University of Virginia between March 1990 and June 1995. Twenty-nine of 32 (91%) patients remain free of HBV recurrence (defined by undetectable serum HBsAg and HBV-DNA) after a mean of 21 months (2-54 months), with one patient requiring retransplantation. Three (10%) patients died of non-HBV causes (two vascular events, one infectious event). Twenty episodes of acute cellular rejection were treated in 18 patients (two had two episodes). Sixteen rejections occurred within 18 d of transplant, 19 by day 120, and one late rejection occurred at 18 months owing to medication non-compliance. Eighteen patients had at least one documented infection. Six patients were treated for CMV infection (five empirically). Eight patients were treated for HSV infections (seven mild herpetic labialis and one herpetic keratitis). Four patients had documented fungal infection (one mucormycosis pneumonia and three minor superficial mucosal infections). With the exception of one necrotizing pneumonia, 11 bacterial infections were successfully treated with conventional antimicrobial agents. No patient developed post-transplant lymphoproliferative disorder. Symptoms associated with HBIg infusion were intermittent but frequent and consisted of myalgias, predominantly back pain (90%), headache (20%) and flushing (5%). No patient experienced anaphylaxis, fever, rash, arthritis or hypotension. Despite the potential for mercury toxicity and HCV transmission in the HBIg formulations currently available in the United States, serum mercury levels remained below standards for industrial exposure (60 micrograms/ml), and only one individual developed post-transplant HCV infection after receiving multiple units of unscreened blood prior to 1991. SUMMARY: High-dose HBIg prevented HBV infection of the allograft in 29 of 32 patients transplanted for HBV cirrhosis with three non-HBV associated deaths. The intravenous infusion of HBIg was frequently associated with minor side effects that were safely tolerated by patients. The risk of HCV transmission and mercury toxicity are minimal, but support the need for a new intravenous formulation of HBIg. HBIg therapy successfully decreased post-OLTx HBV recurrence with no clinical events associated with immunosuppression. Patients did non experience allergic or infusion-related complications that altered or terminated therapy. Manufacturing modifications of HBIg may allow for improved patient tolerance and decreased risks.

Prostaglandin E1 administration following orthotopic liver transplantation: a randomized prospective multicenter trial.

BACKGROUND & AIMS: Prostaglandin E1 (PGE1) has been used after orthotopic liver transplantation (OLT) based on limited clinical data suggesting PGE1 infusion improves immediate hepatic allograft function. The aim of this study was to conduct a randomized double-blinded multicenter trial to evaluate the effect of PGE1 on early hepatic and renal function in patients undergoing OLT. METHODS: One hundred eighteen patients were randomized to receive either PGE1 or crystalloid placebo intravenously after allograft revascularization. Primary end points were incidence of primary allograft nonfunction (PNF) or severe renal dysfunction. RESULTS: The incidence of PNF was 6.7% (4 of 60) and 6.9% (4 of 58) in the control and PGE1 groups, respectively. PGE1 infusion was, however, associated with improved early renal function (mean peak creatinine level of 1.4 +/- 1.0 and 2.0 +/- 1.0 in patients treated with PGE1 and placebo, respectively; P < 0.001). Severe renal dysfunction occurred more frequently in the placebo group (26.7%) than in the PGE1 group (13.8%; P = 0.65). Additionally, dialysis treatments were more frequent in the placebo group (0.7 +/- 2.0 per patient) than in the PGE1 group (0.2 +/- 1.0 per patient; P = 0.10). Initial intensive care unit stay was shorter in patients treated with PGE1 (4.0 +/- 3.6 days) compared with controls (10.5 +/- 17.1 days) (P < 0.01). CONCLUSIONS: PGE1 administration after OLT resulted in improved renal function and decreased initial postoperative intensive care unit stay but did not affect the incidence of PNF.

Improved clinical outcomes with liver transplantation for hepatitis B-induced chronic liver failure using passive immunization.

OBJECTIVE: The goals were to summarize the results of liver transplantation for chronic hepatitis B disease (HBV) at the University of Virginia, correlate pretransplant viral markers with posttransplant hepatitis B immunoglobulin (HBIg) requirements, and identify the relation between viral protein in the liver and clinical reinfection. SUMMARY BACKGROUND DATA: Liver transplantation is an accepted treatment for end-stage liver disease from chronic HBV infection, although lifelong antiviral treatment (with HBIg or antiviral agents) is still necessary. Patients with evidence of active viral replication (detectable serum HBV-DNA or e antigen) at the time of transplant have a higher rate of allograft infection. Whether clinically stable patients receiving HBIg immunoprophylaxis have detectable viral products in their grafts remains unknown. METHODS: Forty-four transplants performed for HBV disease at the University of Virginia since March 1990 were reviewed. Most patients underwent aggressive passive immunoprophylaxis with HBIg to maintain serum HBV surface antibody (HBsAb) levels > or =500 IU/l for the first 6 months after the transplant, and > or =150 IU/l thereafter. Patients had viral markers quantified, underwent pharmacokinetic analysis of HBsAb levels to adjust dosing, and were biopsied routinely every 3 to 6 months and when indicated. RESULTS: Forty-four transplants were performed in 39 patients. Actual 1-year and 3-year graft survival was 95% and 81%, respectively, and 1-year and 3-year patient survival was 98% and 96%, respectively. After the adoption of indefinite HBIg prophylaxis, nine grafts became infected (all in recipients positive for HBV e antigen). Three occurred within 8 weeks of transplantation and were associated with a short HBsAb half-life and a wild-type virus. Six occurred >8 months after the transplant, and most of these were associated with viral mutation. Quantification of pretransplant markers was an overall poor predictor of HBIg requirements after the transplant. Immunohistochemistry demonstrated transient low-level expression of core protein in the liver in 23% of patients without serum or clinical evidence of recurrent hepatitis. CONCLUSIONS: An excellent outcome is possible after liver transplantation for chronic HBV disease using HBIg dosed by pharmacokinetic parameters. Currently, quantification of pretransplant serum markers of the HBV antigen load does not predict the intensity of posttransplant treatment required for good clinical outcomes. Because HBV is not eradicated from the patient, some form of indefinite antiviral therapy continues to be warranted.