Timothy Gayowski

Tolerogenic immunosuppression for organ transplantation

BACKGROUND Insight into the mechanisms of organ engraftment and acquired tolerance has made it possible to facilitate these mechanisms, by tailoring the timing and dosage of immunosuppression in accordance with two therapeutic principles: recipient pretreatment, and minimum use of post-transplant immunosuppression. We aimed to apply these principles in recipients of renal and extrarenal organ transplants. METHODS 82 patients awaiting kidney, liver, pancreas, or intestinal transplantation were pretreated with about 5 mg/kg of a broadly reacting rabbit antithymocyte globulin during several hours. Post-transplant immunosuppression was restricted to tacrolimus unless additional drugs were needed to treat breakthrough rejection. After 4 months, patients on tacrolimus monotherapy were considered for dose-spacing to every other day or longer intervals. FINDINGS We frequently saw evidence of immune activation in graft biopsy samples, but unless this was associated with graft dysfunction or serious immune destruction, treatment usually was not intensified. Immunosuppression-related morbidity was virtually eliminated. 78 (95%) of 82 patients survived at 1 year and at 13-18 months. Graft survival was 73 (89%) of 82 at 1 year and 72 (88%) of 82 at 13-18 months. Of the 72 recipients with surviving grafts, 43 are on spaced doses of tacrolimus monotherapy: every other day (n=6), three times per week (11), twice per week (15), or once per week (11). INTERPRETATION The striking ability to wean immunosuppression in these recipients indicates variable induction of tolerance. The simple therapeutic principles are neither drug-specific nor organ-specific. Systematic application of these principles should allow improvements in quality of life and long-term survival after organ transplantation.

Long-term survival after liver transplantation in 4,000 consecutive patients at a single center

ObjectiveTo evaluate the long-term survival outcomes of a large cohort of liver transplant recipients and to identify static and changing factors that influenced these outcomes over time. Summary Background DataLiver transplantation has been accepted as a therapeutic option for patients with end-stage liver disease since 1983, with continual improvements in patient survival as a result of advances in immunosuppression and medical management, technical achievements, and improvements in procurement and preservation. Although many reports, including registry data, have delineated short-term factors that influence survival, few reports have examined factors that affect long-term survival after liver transplantation. MethodsFour thousand consecutive patients who underwent liver transplantation between February 1981 and April 1998 were included in this analysis and were followed up to March 2000. The effect of donor and recipient age at the time of transplantation, recipient gender, diagnosis, and year of transplantation were compared. Rates of retransplantation, causes of retransplantation, and cause of death were also examined. ResultsThe overall patient survival for the entire cohort was 59%; the actuarial 18-year survival was 48%. Patient survival was significantly better in children, in female recipients, and in patients who received transplants after 1990. The rates of retransplantation for acute or chronic rejection were significantly lower with tacrolimus-based immunosuppression. The risk of graft failure and death was relatively stable after the first year, with recurrence of disease, malignancies, and age-related complications being the major factors for loss. ConclusionSignificantly improved patient and graft survival has been observed over time, and graft loss from acute or chronic rejection has emerged as a rarity. Age-related and disease-related causes of graft loss represent the greatest threat to long-term survival.

Hepatic Resection for Metastatic Colorectal Adenocarcinoma: A Proposal of a Prognostic Scoring System

BACKGROUND Hepatic resection for metastatic colorectal cancer provides excellent longterm results in a substantial proportion of patients. Although various prognostic risk factors have been identified, there has been no dependable staging or prognostic scoring system for metastatic hepatic tumors. STUDY DESIGN Various clinical and pathologic risk factors were examined in 305 consecutive patients who underwent primary hepatic resections for metastatic colorectal cancer. Survival rates were estimated by the Cox proportional hazards model using the equation: S(t) = [So(t)]exp(R-Ro), where So(t) is the survival rate of patients with none of the identified risk factors and Ro = 0. RESULTS Preliminary multivariate analysis revealed that independently significant negative prognosticators were: (1) positive surgical margins, (2) extrahepatic tumor involvement including the lymph node(s), (3) tumor number of three or more, (4) bilobar tumors, and (5) time from treatment of the primary tumor to hepatic recurrence of 30 months or less. Because the survival rates of the 62 patients with positive margins or extrahepatic tumor were uniformly very poor, multivariate analysis was repeated in the remaining 243 patients who did not have these lethal risk factors. The reanalysis revealed that independently significant poor prognosticators were: (1) tumor number of three or more, (2) tumor size greater than 8 cm, (3) time to hepatic recurrence of 30 months or less, and (4) bilobar tumors. Risk scores (R) for tumor recurrence of the culled cohort (n = 243) were calculated by summation of coefficients from the multivariate analysis and were divided into five groups: grade 1, no risk factors (R = 0); grade 2, one risk factor (R = 0.3 to 0.7); grade 3, two risk factors (R = 0.7 to 1.1); grade 4, three risk factors (R= 1.2 to 1.6); and grade 5, four risk factors (R > 1.6). Grade 6 consisted of the 62 culled patients with positive margins or extrahepatic tumor. Kaplan-Meier and Cox proportional hazards estimated 5-year survival rates of grade 1 to 6 patients were 48.3% and 48.3%, 36.6% and 33.7%, 19.9% and 17.9%, 11.9% and 6.4%, 0% and 1.1%, and 0% and 0%, respectively (p < 0.0001). CONCLUSIONS The proposed risk-score grading predicted the survival differences extremely well. Estimated survival as determined by the Cox proportional hazards model was similar to that determined by the Kaplan-Meier method. Verification and further improvements of the proposed system are awaited by other centers or international collaborative studies.

High-Dose Acyclovir Compared with Short-Course Preemptive Ganciclovir Therapy To Prevent Cytomegalovirus Disease in Liver Transplant Recipients: A Randomized Trial

Cytomegalovirus (CMV) is a major pathogen in liver transplant recipients. Although recent progress in the treatment of CMV disease has led to decreased mortality from this virus, a substantial number of patients still die of CMV-related complications, such as superinfection with bacterial and fungal agents in association with CMV infection [1-3], CMV-associated atherosclerosis in heart transplant recipients [4], bronchiolitis obliterans in lung transplant recipients [5], and chronic rejection (the vanishing bile duct syndrome) in liver transplant recipients [6]. Cytomegalovirus disease also substantially increases the cost of transplantation because it prolongs hospitalization [7]. In 1989, Balfour and colleagues [8] reported that high-dose oral acyclovir decreased the rate of CMV disease in kidney transplant recipients. Despite a small number of patients and an unusually high attack rate (100%) in the control patients, acyclovir-treated seronegative recipients of grafts from seropositive donors had the greatest protection from CMV disease. Based on this study, high-dose oral acyclovir is now also routinely used as prophylaxis for CMV in other organ transplant recipients, including liver recipients. Acyclovir, however, is inactive against CMV in vitro, its long-term administration is expensive, and CMV disease continued to occur at our institution despite such prophylaxis. Another potential problem with continuous, long-term administration of acyclovir is the possible emergence of CMV strains resistant to its closely related nucleoside analog, ganciclovir. Ganciclovir is several times more active against CMV in vitro than is acyclovir. Ganciclovir prophylaxis has been administered in various ways in organ transplant recipients [9], either as prophylaxis in all post-transplant patients, thereby unnecessarily exposing a large number of patients to the drug (most of whom do not develop CMV infection [10-12]) or as prolonged therapy (100 to 120 days), which causes hematologic toxicity, expense, and possibly a prolonged hospital stay [13, 14]. In this study, our approach was to identify or target the patients at highest risk for CMV disease. Viral excretion or shedding precedes CMV disease in transplant recipients [15]. Assuming that viral excretion is a predictor of CMV disease, we hypothesized that a short course (7 days) of ganciclovir instituted as preemptive antiviral therapy in patients shedding the virus would prevent progression of early asymptomatic CMV infection to more severe, invasive CMV disease. Thus, we did a randomized, controlled trial of standard high-dose acyclovir compared with short-course, pulse ganciclovir to be given only if CMV shedding was documented in asymptomatic patients using a CMV surveillance protocol. Methods Study Design All patients having liver transplantation at our institution were randomly assigned to one of the two prophylactic groups. Randomization was stratified by the CMV antibody status of the recipient and the donor. Patients in the control group received 800 mg of acyclovir orally, four times daily, beginning immediately after transplantation as described by Balfour and colleagues [8]; patients continued receiving acyclovir (Zovirax; Burroughs Wellcome, Research Triangle Park, North Carolina) for 24 weeks postoperatively. The dosage of acyclovir was adjusted for impaired renal function as follows: If the creatinine clearance was greater than 50 mL/min, then patients received 800 mg of acyclovir four times a day; if the creatinine clearance was 25 to 50 mL/min, they received 800 mg of acyclovir three times a day; if the clearance was 10 to 25 mL/min, they received 800 mg of acyclovir twice a day; and if the clearance was less than 10 mL/min, they received 800 mg of acyclovir once daily. Surveillance cultures for CMV (buffy coat and urine) were obtained at 2, 4, 6, 8, 12, 16, and 24 weeks postoperatively for all study patients using the shell vial culture method. The experimental group did not receive acyclovir, but intravenous ganciclovir (Cytovene; Syntex, Palo Alto, California), 5 mg/kg twice daily, was administered for 7 days only if surveillance cultures yielded CMV (Figure 1). Ganciclovir dosage was modified for abnormal creatinine clearance as follows: If the creatinine clearance was 80 mL/min or more, then patients received 5 mg/kg of ganciclovir twice daily; if the creatinine clearance was 50 to 79 mL/min, they received 2.5 mg/kg of ganciclovir twice daily; if the clearance was 25 to 49 mL/min, they received 2.5 mg of ganciclovir daily; if the clearance was less than 25 mL/min, they received 1.25 mg/kg of ganciclovir daily. The study was continued for 24 weeks postoperatively. Figure 1. Flow chart representing the study design. Immunosuppression All patients received 0.10 mg/kg of tacrolimus (Fujisawa, Deerfield, Illinois) as a continuous drip for 24 hours, until they were able to take oral medications. The oral dosage of tacrolimus was 0.10 mg/kg every 12 hours. Subsequent dosage adjustments were made as indicated by clinical course and plasma levels of tacrolimus. Methylprednisolone, 1 g, was given immediately after revascularization of the graft. Methylprednisolone, 20 mg, was given intravenously immediately after transplantation and daily thereafter until the oral route was established, at which time 20 mg of prednisone was administered daily. During the subsequent months, prednisone was slowly tapered. Rejection episodes were treated with boluses of 1 g of methylprednisolone with or without steroid recycles (prednisone decreasing daily by 40 mg from an initial starting dose of 200 mg). Muromonab-CD3 (Orthoclone OKT3, Ortho Pharmaceuticals, Raritan, New Jersey) was used for steroid-resistant rejection. Definition of Viral Infections Cytomegalovirus Infection Serologic test results for cytomegalovirus were determined using an enzyme immunosorbent assay, and titers of 0.79 or more were considered positive. All patients received blood products that were neither tested nor screened for CMV antibody. Primary infection was defined as isolation of virus or seroconversion in a patient who was seronegative before transplantation. Reactivation infection was diagnosed by isolation of virus in a seropositive recipient. Cytomegalovirus Disease Clinical diseases caused by CMV included the viral syndrome, localized CMV disease, and disseminated CMV disease. Identification of the viral syndrome caused by CMV required the following: 1) positive culture for CMV; 2) temperature of 38 C or more with no other source to account for it; and 3) one of the following findings: leukocyte count 4000/mm3 or less, atypical lymphocytes 3% or more, and platelets 100 000/mm3 or less. Localized CMV disease was defined as tissue invasion of a single organ determined histopathologically with or without culture of the virus from tissue. Disseminated disease was defined as tissue involvement of two or more noncontiguous organ sites. Identification of Other Viruses Antibodies against viral capsid antigen, early antigen, and Epstein-Barr virus (EBV) nuclear antigen were determined preoperatively in all patients. Patients were defined as having a symptomatic EBV infection if they had EBV-associated lymphoproliferative disease identified by the presence of EBV DNA in tissue using nucleic acid hybridization. Antibody titers to detect asymptomatic increases in EBV were not routinely determined. Herpes simplex virus infection was defined as the presence of typical symptomatic oral or genital ulcers. Varicella zoster virus infection was determined clinically by the presence of typical dermatomal lesions with or without viral isolation. Statistical Analysis Analysis was done using the Prophet System (BBN Systems and Technologies, Division of Research Resources, National Institutes of Health, Bethesda, Maryland). Baseline characteristics (age, Child-Pugh score) were compared using the Fisher exact or t-test. We estimated that at least 20 patients in each group would be needed to detect a decrease in CMV disease from 35% with standard acyclovir prophylaxis to 5% with ganciclovir ( = 0.05, power = 0.8). The incidence of infection or disease was compared using a two-tailed Fisher exact test. A Kaplan-Meier estimate was used to examine the number of days from transplant until first CMV infection for each group. The two curves were compared using the Mantel-Cox log-rank test. Similar curves were constructed for CMV disease. Results The study sample consisted of 47 consecutive adult male patients who received liver transplants at the Pittsburgh Veterans Affairs Medical Center during a 2-year period and who survived at least 72 hours postoperatively. These included 44 patients who had primary transplants and 3 who had re-transplants (2 transplanted once previously and another twice previously). Of 47 patients enrolled in the study, 24 were randomly assigned to the acyclovir group and 23, to the experimental group. The two patient groups were similar at entry in terms of all baseline characteristics measured (Table 1). The Child-Pugh scoring system was used to assess the severity of liver disease in the two groups before transplantation [16]. Table 1. Characteristics of the Study Group at the Time of Enrollment Cytomegalovirus Infection and Disease Shedding of CMV before the onset of CMV disease occurred in 25% (6 of 24) of patients receiving acyclovir prophylaxis and in 22% (5 of 23) of patients receiving no prophylaxis (experimental group) (Figure 2). Seventeen percent (4 of 24) of the patients in the acyclovir group and 4% (1 of 23) in the experimental group did not have previous shedding and developed CMV disease as the first manifestation of CMV infection. Thus, 42% (10 of 24) in the acyclovir group and 26% (6 of 23) in the experimental group had CMV infection (16% difference; 95% CI, 10% to 42%; P > 0.2). All CMV infections were diagnosed by viral isolation. One of 6 infections in the experimental group wa

Infectivity of hepatic allografts with antibodies to hepatitis B virus

BACKGROUND Since suitable recipients for hepatic allografts from donors with antibodies to hepatitis B virus (HBV) have not been determined, a review of our 7-year experience with donors positive for hepatitis B surface antibody (anti-HBs), hepatitis B core antibody (anti-HBc), or both was undertaken. METHODS Recipients of hepatic allografts from donors with antibodies to HBV were identified by a retrospective review of procurement records and screened for HBV infection. RESULTS From January 1, 1990, to January 1, 1997, 2578 liver transplants were performed and 140 (5.4%) recipients received an allograft from a donor with antibodies to HBV. Twenty-five of 48 recipients of a hepatic allograft from a donor positive only for anti-HBs were screened and none developed HBV infection. Twenty-five of 41 naive recipients of a hepatic allograft from an anti-HBc positive donor were screened and 18/25 (72%) developed HBV infection. Four of these 18 naive recipients with HBV infection received an allograft from a donor positive for both anti-HBc and anti-HBs. Seven of 13 anti-HBs-positive recipients of an allograft from an anti-HBc-positive donor were screened and none developed HBV infection. Fifteen of 16 recipients positive only for anti-HBc who received a hepatic allograft from an anti-HBc-positive donor were screened and 2/15 (13%) developed HBV infection. CONCLUSIONS Hepatic allografts from donors positive only for anti-HBs do not transmit HBV infection. Hepatic allografts from anti-HBc-positive donors frequently transmit HBV infection to naive recipients regardless of the donor anti-HBs status, and antiviral prophylaxis may be indicated. Anti-HBs-positive recipients appear resistant to HBV infection after orthotopic liver transplantation with an allograft from an anti-HBc-positive donor. Recipients positive only for anti-HBc infrequently develop HBV infection when transplanted with an allograft from an anti-HBc-positive donor; however, HBV prophylaxis may be justified.

Trimethoprim-sulfamethoxazole for the prevention of spontaneous bacterial peritonitis in cirrhosis : a randomized trial

Spontaneous bacterial peritonitis is a serious complication that occurs in 8% to 25% of patients with cirrhosis and ascites [1]. The overall mortality rate is 30% to 50%. Antibiotic prophylaxis for the prevention of spontaneous bacterial peritonitis has been attempted using selective intestinal decontamination with nonabsorbable antibiotics [2] and partially absorbable antibiotics (for example, norfloxacin) [3-6]. Use of these antibiotics was not only ineffective against gram-positive (streptococcal) infections but was associated with the selection of highly resistant gram-negative isolates and with the emergence of streptococci as pathogens, not only in patients with cirrhosis but also in other clinical situations (for example, myelosuppressed patients, patients receiving mechanical ventilation, and transplant recipients) [3, 7-10]. Trimethoprim-sulfamethoxazole is a systemically absorbed antibiotic with in vitro activity against enteric gram-negative bacteria and streptococci, including pneumococci. Trimethoprim-sulfamethoxazole has been extensively used as a prophylactic agent in diverse patient populations (for example, patients with granulocytopenia [7], transplant recipients [11], and patients with human immunodeficiency virus infection [12]). We did a randomized trial to assess the efficacy and safety of trimethoprim-sulfamethoxazole for the prevention of spontaneous bacterial peritonitis in patients with cirrhosis and ascites, using the Bactec culture method to detect spontaneous bacterial peritonitis. Methods All patients with documented cirrhosis and ascites were considered eligible. Patients were excluded if they 1) were allergic to sulfonamides; 2) had renal failure with a creatinine clearance of less than 15 mL/min [use of trimethoprim-sulfamethoxazole is not recommended for patients with a creatinine clearance of <15 mL/min unless the patient is receiving dialysis]; or 3) had active spontaneous bacterial peritonitis or extraperitoneal infection at the time of enrollment. The patients were randomly assigned to receive either trimethoprim-sulfamethoxazole (one double-strength tablet five times a week, Monday through Friday) or no prophylaxis. Entry was stratified by serum bilirubin level, renal function, and ascitic fluid protein level. Patients at risk for spontaneous bacterial peritonitis or mortality have ascitic fluid protein levels less than 1 g/dL [13], serum bilirubin levels greater than 51 mol/L (>3 mg/dL) [14], and renal dysfunction (serum creatinine levels >177 mol/L [72 mg/dL]) [3, 15]. These criteria were selected so that high-risk patients would not be disproportionately allocated to one group. Paracentesis was done in both groups when ascitic fluid infection was suspected (that is, for the evaluation of fever, abdominal pain or tenderness, leukocytosis, or worsening encephalopathy). The primary end points were development of spontaneous bacteremia or spontaneous bacterial peritonitis, which was defined as either an ascitic fluid polymorphonuclear cell count of 250/mm3 or more and a positive ascitic fluid culture (culture-positive neutrocytic ascites) or as an ascitic fluid polymorphonuclear cell count of 250/mm3 or more and a negative ascitic fluid culture (culture-negative neutrocytic ascites). Ascitic fluid was cultured using the Bactec culture system (Becton Dickinson Diagnostic Instrument System, Sparks, Maryland) as previously described [16]. Extraperitoneal infections (for example, pneumonia and mortality) were also assessed. Clinical and laboratory data were entered into a database (Prophet, BBN Systems and Technologies, Cambridge, Massachusetts). Continuous variables (age and bilirubin, albumin, and cholesterol levels) were compared using the Student t-test or the Mann-Whitney test. Categorical variables (such as underlying liver disease, comorbid illnesses, and infections) were compared using the chi-square or the Fisher exact tests. Results Patient Characteristics Sixty-seven consecutive patients with cirrhosis and ascites were evaluated, but 7 were excluded on the basis of preset criteria; thus, 60 patients were ultimately enrolled. Of the 60 patients, 30 were randomly assigned to the group receiving trimethoprim-sulfamethoxazole and 30 were assigned to the group not receiving prophylaxis. The underlying causes of liver disease in the 30 patients in the trimethoprim-sulfamethoxazole group were hepatitis C virus (HCV) (n = 11), alcohol (n = 8), alcohol and HCV (n = 4), and hepatitis B virus (n = 5); cause was indeterminate in 2 patients. Liver diseases in the 30 patients not receiving prophylaxis were caused by HCV (n = 12), alcohol (n = 11), alcohol and HCV (n = 1), hepatitis B virus (n = 1), -1-antitrypsin deficiency (n = 2), hepatocellular carcinoma (n = 1), and autoimmune hepatitis (n = 1); cause was indeterminate in 1 patient. The two study groups were similar at baseline for all clinical and laboratory data outlined in Table 1, except that more patients in the trimethoprim-sulfamethoxazole group had anasarca (P = 0.09) and more had a history of encephalopathy before enrollment (P = 0.04) (Table 1). The median duration of follow-up was 90 days (range, 7 to 682 days). Table 1. Clinical and Laboratory Characteristics of Patients at Baseline* Incidence and Type of Infections Overall, infectious complications developed in 9 patients (30%) not receiving prophylaxis and in 1 patient (3%) receiving trimethoprim-sulfamethoxazole (P = 0.012) (Table 2). Spontaneous bacterial peritonitis or spontaneous bacteremia developed in 8 patients (27%) receiving no prophylaxis and in 1 patient (3%) receiving trimethoprim-sulfamethoxazole (P = 0.025). Table 2. Incidence and Types of Infections The eight episodes of spontaneous bacterial peritonitis or spontaneous bacteremia in the group not receiving prophylaxis comprised Escherichia coli peritonitis with bacteremia (two episodes), spontaneous Klebsiella pneumoniae bacteremia (one episode), enterococcal peritonitis (two episodes), and culture-negative neutrocytic ascites (three episodes). These infections developed a mean of 37 days (range, 3 to 114 days) after enrollment. Only one patient in the trimethoprim-sulfamethoxazole group developed an episode of culture-negative neutrocytic ascites 111 days after enrollment. Only one patient in the group not receiving prophylaxis developed an extraperitoneal infection (Haemophilus influenzae pneumonia). Adverse Effects None of the patients developed adverse effects; hematologic toxicity caused by trimethoprim-sulfamethoxazole was notably absent. Diarrhea possibly related to trimethoprim-sulfamethoxazole was seen in one patient; Clostridium difficile colitis was not evident, and the diarrhea resolved despite continuing therapy with trimethoprim-sulfamethoxazole. Mortality Two patients (7%) receiving trimethoprim-sulfamethoxazole and 6 patients (20%) not receiving prophylaxis died (P = 0.15). The median time to death after enrollment was 45 days in the group not receiving prophylaxis (range, 7 to 509 days). The cause of death in these patients was gastrointestinal bleeding (two patients), hepatic insufficiency (three patients), and hepatic insufficiency with respiratory failure (one patient). Although none of the deaths could be directly attributed to spontaneous bacterial peritonitis, two of six patients died during the hospitalization in which spontaneous bacterial peritonitis was diagnosed. Two patients in the trimethoprim-sulfamethoxazole group died 85 and 167 days after enrollment because of gastrointestinal bleeding and hepatic insufficiency, respectively. Discussion Several studies [3-5] have shown that norfloxacin reduces the incidence of spontaneous bacterial peritonitis in patients with cirrhosis, and this antibiotic is now commonly used as prophylaxis in these patients [3]. However, prolonged use of norfloxacin and quinolones has been associated with the selection of gram-positive isolates and with the eventual emergence of methicillin-resistant Staphylococcus aureus and enterococci as pathogens. In fact, it has been proposed that long-term prophylaxis with norfloxacin would probably shift the spectrum of microbial agents causing peritonitis from gram-negative aerobic bacilli to gram-positive organisms [17]. Dupeyron and colleagues [6] showed that the use of norfloxacin to prevent spontaneous bacterial peritonitis in cirrhosis led to colonization with gram-negative bacilli that were resistant to fluoroquinolones and with staphylococci that were resistant to methicillin in 52% of patients a median of 25 days after therapy. All isolates of Enterobacteriaceae after therapy were also resistant to aminoglycosides and -lactams [6]. Another study [18] also reported that quinolones can promote cross-resistance to unrelated classes of antibiotics. Although acquisition of resistance to trimethoprim-sulfamethoxazole has also been reported, the selection of streptococci appears to be uniquely more prevalent with quinolones. In a study [7] of patients with granulocytopenia, bacteremia caused by gram-positive isolates occurred significantly more often in patients receiving norfloxacin (29%) than in those receiving trimethoprim-sulfamethoxazole (6%). Therefore, we selected trimethoprim-sulfamethoxazole as a potentially useful agent for the prophylaxis of spontaneous bacterial peritonitis. In this randomized trial, trimethoprim-sulfamethoxazole was compared with no prophylaxis for the prevention of spontaneous bacterial peritonitis in 60 consecutive patients with documented cirrhosis and ascites. The incidence of spontaneous bacterial peritonitis or spontaneous bacteremia (3% compared with 27%) and overall infection (3% compared with 30%) was lower in patients receiving trimethoprim-sulfamethoxazole compared with patients not receiving prophylaxis (P < 0.05 for both values). Emergence of enterococci as pathogens did not occur in any patient receiving trimethoprim-sulfamethoxazole, whereas enterococci cau

Tissue-arterial PC02 difference is a better marker of ischemia than intramural pH (pHi) or arterial pH-pHi difference

Gastric intramucosal pH (pHi) is often calculated by the Henderson-Hasselbalch equation, using arterial plasma [HCO3-]ap and PCO2 measured in saline obtained from a silastic balloon tonometer after equilibration in the lumen of the stomach. A pHi value less than approximately 7.3 pH units is often taken as evidence of intestinal ischemia. An alternative measure is tissue PCO2 (PtCO2)-PaCO2 difference [P(t-a)CO2]. The idea is that PtCO2 will increase slightly relative to PaCO2 as O2 supply decreases, and then increase strikingly when flow decreases to a critical value, because of liberation of CO2 from tissue Hco3- by anaerobically generated strong acid. A third method is arterial plasma pH (pHap)-pHi difference [pH(ap-i)]. We used mathematical simulations to test the hypotheses that calculated pHi is independent of arterial acid-base status; and pH(ap-i) provides the same information as does P(t-a) CO2. Using the Van Slyke version of the arterial whole blood [standard base excess] ([SBE]aWB) equation, it was found that a change in [SBE]aWB at constant PaCO2 and constant PtCO2 produces a change in calculated pHi (P = 0), such that the relation between changing [SBE]aWB and changing pHi is predictable by a single polyomial equation (R2 = .999). pH(ap-i) avoids this confounding influence of [SBE]aWB. However, it was further shown that pH(ap-i) can be associated with a wide range of P(t-a)CO2, depending on the magnitude of pH(ap-i), and on the PaCO2 at which P(t-a)CO2 is measured. We conclude that P(t-a)CO2 is a more reliable index of gastric oxygenation than is pHi alone or pH(ap-i).

Interferon-α for prophylaxis of recurrent viral hepatitis C in liver transplant recipients : A prospective, randomized, controlled trial

BACKGROUND In a randomized, controlled trial, we sought to determine whether prophylaxis with interferon-alpha for 6 months had an impact on rate, severity, and timing of onset of recurrent hepatitis C virus (HCV) hepatitis in liver transplant recipients and to assess whether interferon use was associated with rejection in liver transplant recipients. METHODS Twenty-four consecutive liver transplant recipients with HCV were randomized after transplantation to receive either interferon-alpha (3 million U three times weekly) for 6 months or no prophylaxis; median follow-up was 874 days. RESULTS Recurrent HCV hepatitis (histopathologically proven) developed in 50% (6 of 12) of the interferon-alpha patients versus 42% (5 of 12) of the control patients (P=NS). Severity of recurrence (as assessed by Knodell score on liver biopsies) also did not differ between the two groups (mean 4.0 for interferon-alpha patients versus 3.5 for control patients, P=NS). Interferon-alpha, however, significantly delayed the timing of occurrence of HCV hepatitis; recurrent HCV hepatitis developed a median of 408 days after transplant in the interferon-alpha group versus 193 days in the control group (P=0.05). No difference in graft or patient survival was demonstrated in the two groups. Rejection episodes, treated with corticosteroids, occurred in 50% (6 of 12) of patients in the interferon-alpha group versus 42% (5 of 12) in the control group (P=NS). Corticosteroid resistant rejection (requiring OKT3) occurred in only one study patient (in the control group). CONCLUSIONS Interferon-alpha in liver transplant recipients for 6 months delayed the occurrence of HCV hepatitis, but did not decrease the incidence nor the severity of HCV hepatitis after transplantation. Interferon-alpha use was not associated with a higher incidence of rejection compared with the control patients.

The hepatoadrenal syndrome: a common yet unrecognized clinical condition.

Objective:Adrenal failure is common in critically ill patients, particularly those with sepsis. As liver failure and sepsis are both associated with increased circulating levels of endotoxin and proinflammatory mediators and reduced levels of apoprotein-1/high-density lipoprotein, we postulated that adrenal failure may be common in patients with liver disease. Design:Clinical study. Setting:Liver transplant intensive care unit. Patients:The study cohort included 340 patients with liver disease. Interventions:Based on preliminary observational data, all patients admitted to our 28-bed liver transplant intensive care unit (LTICU) undergo adrenal function testing. An honest broker system was used to extract clinical, hemodynamic, medication, and laboratory data on patients admitted to the LTICU from March 2002 to March 2004. A random (stress) cortisol level <20 &mgr;g/dL in a highly stressed patient (respiratory failure, hypotension) was used to diagnose adrenal insufficiency. In all other patients, a random cortisol level <15 &mgr;g/dL or a 30-min level <20 &mgr;g/dL post-low-dose (1 &mgr;g) cosyntropin was considered diagnostic of adrenal insufficiency. Patients were grouped as follows: a) chronic liver failure; b) fulminant hepatic failure; c) patients immediately status post-orthotopic liver transplantation receiving a steroid-free protocol of immunosuppression; and d) patients status post-remote liver transplant (≥6 months). The decision to treat patients with stress doses of hydrocortisone was at the discretion of the treating intensivist and transplant surgeon.. Measurements and Main Results:Two-hundred and forty-five (72%) patients met our criteria for adrenal insufficiency (the hepatoadrenal syndrome). Eight (33%) patients with fulminant hepatic failure, 97 (66%) patients with chronic liver disease, 31(61%) patients with a remote history of liver transplantation, and 109 (92%) patients who had undergone liver transplantation under steroid-free immunosuppression were diagnosed with adrenal insufficiency. The high-density lipoprotein level at the time of adrenal testing was the only variable predictive of adrenal insufficiency (p < .0001). In vasopressor-dependent patients with adrenal insufficiency, treatment with hydrocortisone was associated with a significant reduction (p = .02) in the dose of norepinephrine at 24 hrs, whereas the dose of norepinephrine was significantly higher (p = .04) in those patients with adrenal failure not treated with hydrocortisone. In vasopressor-dependent patients without adrenal insufficiency, treatment with hydrocortisone did not affect vasopressor dose at 24 hrs. One hundred and forty-one patients (26.4%) died during their hospitalization. The baseline serum cortisol was 18.8 ± 16.2 &mgr;g/dL in the nonsurvivors compared with 13.0 ± 11.8 &mgr;g/dL in the survivors (p < .001). Of those patients with adrenal failure who were treated with glucocorticoids, the mortality rate was 26% compared with 46% (p = .002) in those who were not treated. In those patients receiving vasopressor agents at the time of adrenal testing, the baseline cortisol was 10.0 ± 4.8 &mgr;g/dL in those with adrenal insufficiency compared with 35.6 ± 21.2 &mgr;g/dL in those with normal adrenal function. Vasopressor-dependent patients who did not have adrenal failure had a mortality rate of 75%. Conclusions:Patients with liver failure and patients post-liver transplantation have an exceedingly high incidence of adrenal failure, which may be pathophysiologically related to low levels of high-density lipoprotein. Treatment of patients with adrenal failure may improve outcome. High baseline serum cortisol levels may be a maker of disease severity and portend a poor prognosis.

Use of Alemtuzumab and Tacrolimus Monotherapy for Cadaveric Liver Transplantation: With Particular Reference to Hepatitis C Virus

We have proposed that the mechanisms of alloengraftment and variable acquired tolerance can be facilitated by minimum posttransplant immunosuppression. It was further suggested that the efficacy of minimalistic treatment could be enhanced by preoperative recipient conditioning with an antilymphoid antibody preparation. A total of 76 adults (38 hepatitis C virus [HCV]−, 38 HCV+) were infused with 30 mg alemtuzumab before primary cadaveric liver transplantation and maintained afterward on daily monotherapy unless breakthrough rejection mandated additional agents. In stable patients, the intervals between tacrolimus doses were lengthened (“spaced weaning”) after approximately 4 months. Eighty-four contemporaneous nonlymphoid-depleted liver recipients (58 HCV−, 26 HCV+) were treated with conventional postoperative immunosuppression. The overall incidence of rejection was similar with the two strategies of immunosuppression. With follow-ups of 14 to 22 months, patient and primary graft survival in HCV− cases are 97% and 90%, respectively, with alemtuzumab depletion plus minimal immunosuppression versus 71% and 70%, respectively, under conventional immunosuppression. In HCV+ recipients, current patient and graft survival in the alemtuzumab-pretreated group are 71% and 70% versus 65% and 54%, respectively, under conventional treatment. With both strategies of immunosuppression, the adverse effect of preexisting HCV on survival parameters and graft function already was significant at the 1-year milestone, but its extent was not evident until the second year. With or without HCV, 62% of the 64 surviving lymphoid-depleted patients are on spaced immunosuppression, and four patients receive no immunosuppression. Lymphoid depletion with alemtuzumab and minimalistic maintenance immunosuppression is a practical strategy of liver transplantation in HCV− recipients but not HCV+ recipients.