Non-invasive alloimmune risk stratification of long-term liver transplant recipients.

BACKGROUND & AIMS: Management of long-term immunosuppression following liver transplantation (LT) remains empirical. Surveillance liver biopsies in combination with transcriptional profiling could overcome this challenge by identifying recipients with active alloimmune-mediated liver damage despite normal liver tests, but this approach lacks applicability. Our aim was to investigate the utility of non-invasive tools for the stratification of stable long-term survivors of LT, according to their immunological risk and need for immunosuppression. METHODS: We conducted a cross-sectional multicentre study of 190 adult LT recipients assessed to determine their eligibility to participate in an immunosuppression withdrawal trial. Patients had stable liver allograft function and had been transplanted for non-autoimmune non-replicative viral liver disease >3 years before inclusion. We performed histological, immunogenetic and serological studies and measured the intrahepatic transcript levels of an 11-gene classifier highly specific for T cell-mediated rejection (TCMR). RESULTS: In this cohort, 35.8% of patients harboured clinically silent fibro-inflammatory liver lesions (13.7% had mild damage and 22.1% had moderate-to-severe damage). The severity of liver allograft damage was positively associated with TCMR-related transcripts, class II donor-specific antibodies (DSAs), ALT, AST, and liver stiffness measurement (LSM), and negatively correlated with serum creatinine and tacrolimus trough levels. Liver biopsies were stratified according to their TCMR transcript levels using a cut-off derived from biopsies with clinically significant TCMR. Two multivariable prediction models, integrating ALT+LSM or ALT+class II DSAs, had a high discriminative capacity for classifying patients with or without alloimmune damage. The latter model performed well in an independent cohort of 156 liver biopsies obtained from paediatric liver recipients with similar inclusion/exclusion criteria. CONCLUSION: ALT, class II DSAs and LSM are valuable tools to non-invasively identify stable LT recipients without significant underlying alloimmunity who could benefit from minimisation of immunosuppression. LAY SUMMARY: A large proportion of liver transplant patients with normal liver tests have inflammatory liver lesions, which in 17% of cases are molecularly indistinguishable from those seen at the time of rejection. ALT, class II donor-specific antibodies and liver stiffness are useful in identifying patients with this form of subclinical rejection. We propose these markers as a useful tool to help clinicians determine if the immunosuppression administered is adequate.

Impact of hepatic encephalopathy on liver transplant waiting list mortality in regions with different transplantation rates.

Overt hepatic encephalopathy (OHE) negatively impacts the prognosis of liver transplant candidates. However, it is not taken into account in most prioritizing organ allocation systems. We aimed to assess the impact of OHE on waitlist mortality in 3 cohorts of cirrhotic patients awaiting liver transplantation, with differences in the composition of patient population, transplantation policy, and transplantation rates. These cohorts were derived from two centers in the Netherlands (reference and validation cohort, n = 246 and n = 205, respectively) and one in Spain (validation cohort, n = 253). Competing-risk regression analysis was applied to assess the association of OHE with 1-year waitlist mortality. OHE was found to be associated with mortality, independently of MELD score, other cirrhosis-related complications and hepatocellular carcinoma (HCC; sHR = 4.19, 95% CI = 1.9-9.5, P = 0.001). The addition of extra MELD points for OHE counteracted its negative impact on survival. These findings were confirmed in the Dutch validation cohort, whereas in the Spanish cohort, containing a significantly greater proportion of HCC and with higher transplantation rates, OHE was not associated with mortality. In conclusion, OHE is an independent risk factor for 1-year waitlist mortality and might be a prioritization rule for organ allocation. However, its impact seems to be attenuated in settings with significantly higher transplantation rates.

An objective definition for clinical suspicion of T-cell-mediated rejection after liver transplantation.

A uniform definition of clinical suspicion of T-cell-mediated rejection (TCMR) in liver transplantation (LT) is needed to homogenize clinical decisions, especially within randomized trials. This multicenter study included a total of 470 primary LT recipients. The derivation cohort consisted of 142 patients who had clinically driven liver biopsies at any time after LT. The external validation cohort included 328 patients who underwent protocol biopsies at day 7-10 after LT. The rates of moderate-severe histological TCMR were 33.8% in the derivation cohort and 43.6% in the validation cohort. Independent predictors (ie, risk factors) of moderate-severe TCMR in the derivation cohort were as follows: serum bilirubin >4 mg/dL (OR=5.83; P<.001), rising bilirubin within the 4 days prior to liver biopsy (OR=4.57; P=.003), and blood eosinophils count >0.1×109 /L (OR=3.81; P=.004). In the validation cohort, the number of risk factors was an independent predictor of moderate-severe TCMR (OR=1.74; P=.001), after controlling for hepatitis C status. The number of risk factors paralleled the rates of moderate-severe TCMR in the derivation and validation cohorts (P<.001 in both comparisons). In conclusion, increased serum bilirubin, rising bilirubin and eosinophilia are validated risk factors for moderate-severe histological TCMR and could be used as objective criteria to select candidates for liver biopsy.

Use of artificial intelligence as an innovative donor-recipient matching model for liver transplantation: results from a multicenter Spanish study.

BACKGROUND & AIMS: There is an increasing discrepancy between the number of potential liver graft recipients and the number of organs available. Organ allocation should follow the concept of benefit of survival, avoiding human-innate subjectivity. The aim of this study is to use artificial-neural-networks (ANNs) for donor-recipient (D-R) matching in liver transplantation (LT) and to compare its accuracy with validated scores (MELD, D-MELD, DRI, P-SOFT, SOFT, and BAR) of graft survival. METHODS: 64 donor and recipient variables from a set of 1003 LTs from a multicenter study including 11 Spanish centres were included. For each D-R pair, common statistics (simple and multiple regression models) and ANN formulae for two non-complementary probability-models of 3-month graft-survival and -loss were calculated: a positive-survival (NN-CCR) and a negative-loss (NN-MS) model. The NN models were obtained by using the Neural Net Evolutionary Programming (NNEP) algorithm. Additionally, receiver-operating-curves (ROC) were performed to validate ANNs against other scores. RESULTS: Optimal results for NN-CCR and NN-MS models were obtained, with the best performance in predicting the probability of graft-survival (90.79%) and -loss (71.42%) for each D-R pair, significantly improving results from multiple regressions. ROC curves for 3-months graft-survival and -loss predictions were significantly more accurate for ANN than for other scores in both NN-CCR (AUROC-ANN=0.80 vs. -MELD=0.50; -D-MELD=0.54; -P-SOFT=0.54; -SOFT=0.55; -BAR=0.67 and -DRI=0.42) and NN-MS (AUROC-ANN=0.82 vs. -MELD=0.41; -D-MELD=0.47; -P-SOFT=0.43; -SOFT=0.57, -BAR=0.61 and -DRI=0.48). CONCLUSIONS: ANNs may be considered a powerful decision-making technology for this dataset, optimizing the principles of justice, efficiency and equity. This may be a useful tool for predicting the 3-month outcome and a potential research area for future D-R matching models.

Hemodynamic response to propranolol in patients with recurrent hepatitis C virus-related cirrhosis after liver transplantation: a case-control study.

Cirrhosis recurrence is frequent after orthotopic liver transplantation for hepatitis C virus (HCV). Because transplantation causes liver denervation, we hypothesized that the response to propranolol might differ in transplant patients versus nontransplant patients with cirrhosis and portal hypertension. Twenty-one patients with cirrhosis recurrence after orthotopic liver transplantation with portal hypertension were compared to 20 nontransplant patients with cirrhosis, HCV, and portal hypertension, and they were matched by sex, age, presence of varices, and Child-Pugh score. The patients underwent systemic and hepatic hemodynamic measurements at the baseline and 20 minutes after intravenous propranolol (0.15 mg/kg). At the baseline, the transplant patients with cirrhosis had a lower hepatic venous pressure gradient (HVPG) than the nontransplant patients with cirrhosis (14.8 ± 2.9 versus 17.3 ± 4.4 mm Hg, P = 0.03) but a higher mean arterial pressure (MAP; 100.3 ± 12.3 versus 91.8 ± 11.6 mm Hg, P = 0.04) and higher systemic vascular resistance (2253 ± 573 versus 1883 ± 525 dyn/second/cm(-5) , P = 0.03). There were no differences in the cardiac index (CI). Propranolol significantly decreased HVPG to similar extents in transplant patients and nontransplant patients with cirrhosis (-14.1% ± 8.0% versus -16.9% ± 9.5%, P > 0.99). MAP tended to increase in transplant patients with cirrhosis, whereas it slightly decreased in nontransplant patients (5.1% ± 14.2% versus -4.8% ± 6.4%, P = 0.007); however, the reduction in CI was less marked in transplant patients with cirrhosis (-18.6% ± 7.6% versus -26.9% ± 9.0%, P = 0.005). In conclusion, patients with HCV-related cirrhosis and portal hypertension after orthotopic liver transplantation have lower baseline HVPG values but similar HVPG responses to propranolol infusions in comparison with nontransplant patients with cirrhosis. In contrast to nontransplant patients, propranolol increases the systemic vascular resistance and arterial pressure in transplant patients with cirrhosis and attenuates the fall in CI.

Prospective evaluation of single-operator peroral cholangioscopy in liver transplant recipients requiring an evaluation of the biliary tract.

In this descriptive study, we examined the role of single-operator cholangioscopy (SOC) in the evaluation of biliary complications after liver transplantation (LT). We prospectively included adult recipients of deceased donor LT who were referred for endoscopic retrograde cholangiopancreatography between June 2009 and July 2011. All patients underwent SOC with biopsy of the biliary anastomosis. Sixteen patients were included: 12 with biliary anastomotic strictures (ASs), 2 with common bile duct stones, 1 with a bile leak, and 1 with sphincter of Oddi dysfunction. Patients with ASs displayed 1 of 2 patterns: (A) mild erythema (n = 9) or (B) edema, ulceration, and sloughing (n = 3). Those without ASs displayed a pale mucosa with mild edema at the anastomosis. Patients with ASs and pattern B required a longer period of stenting than patients with pattern A (457 versus 167 days, P = 0.02). In addition, patients with pattern A had a better response and better resolution of their strictures with endoscopic therapy than those with pattern B (66% versus 33%, P = 0.13). Histological examinations of ASs showed nonspecific intraepithelial inflammation in patients with patterns A and B. Biopsy samples from patients without ASs showed normal columnar epithelial bile duct cells. The total cholangioscopy time for all procedures was 26.8 ± 10.1 minutes. In conclusion, SOC in LT recipients is feasible and allows adequate visualization and tissue sampling of ASs and bile ducts. Two distinct visual patterns that are easily identified with SOC may help to predict the outcomes of endoscopic therapy in patients with biliary complications after LT.

Risk factors and outcomes of failed endoscopic retrograde cholangiopancreatography in liver transplant recipients with anastomotic biliary strictures: a case-control study.

Anastomotic strictures (ASs) of the biliary duct after liver transplantation (LT) are primarily managed with endoscopic retrograde cholangiopancreatography (ERCP), but in some cases, this fails because of difficulties in passing the strictures. The aim of this case-control study was to examine specific risk factors for initial ERCP failure and the outcomes of percutaneous transhepatic cholangiography (PTC) as a second-line approach in LT recipients with ASs. Between January 2002 and December 2010, we identified LT recipients with ASs who experienced initial ERCP failure (which was defined as the inability to traverse the AS with guidewires in 2 or more consecutive procedures). A period-matched control group (ratio = 1:2) with ASs and initial ERCP success was analyzed. Preoperative, intraoperative, postoperative, and endoscopic variables were evaluated as risk factors. The outcomes of PTC and the need for hepaticojejunostomy (HJ) or retransplantation were evaluated. Seventeen cases who experienced initial ERCP failure were compared with 34 controls. The median times from LT to ERCP were similar (8.7 months for cases and 8.6 months for controls, P = not significant). A multivariate analysis revealed that previous bile leaks [odds ratio (OR) = 6.07, 95% confidence interval (CI) = 1.0-36.5] and more than 4 U of intraoperatively transfused red blood cells (OR = 11.51, 95% CI = 1.9-71.2) were independent risk factors for failure. PTC was an effective second-line treatment in only 3 of 12 cases (25%). The need for HJ was more frequent for the cases (13/17 or 76.5%) versus the controls (7/34 or 20.6%, P < 0.001). One patient in each group underwent retransplantation (P = not significant). In conclusion, previous bile leaks and high packed red blood cell transfusion requirements during surgery are risk factors for initial ERCP failure in LT recipients with ASs. A high proportion of these patients will need surgery as their final therapy.

Bacterial DNA translocation is associated with systemic circulatory abnormalities and intrahepatic endothelial dysfunction in patients with cirrhosis.

UNLABELLED: Presence of bacterial DNA in noninfected patients with cirrhosis and ascites is associated with a marked inflammatory response including activation of the inducible form of nitric oxide synthase and release of nitric oxide, similar to that observed in patients with spontaneous bacterial peritonitis. Although presence of bacterial DNA is associated with an impaired prognosis, no information is available regarding its hemodynamic consequences. Systemic and hepatic hemodynamics before and after a liquid test meal were assessed in a series of 75 noninfected patients with cirrhosis (55 with ascites). Bacterial DNA was measured by polymerase chain reaction. Bacterial DNA was detected only in patients with ascites. Clinical data and liver function were similar in ascitic patients with presence (n = 21) or absence of bacterial DNA (n = 34). Bacterial-DNA(+) patients had significantly lower mean arterial pressure (P = 0.002) and systemic vascular resistance (P = 0.03) than bacterial-DNA(-) patients. Cardiac output, cardiopulmonary pressures, hepatic venous pressure gradient (HVPG), and hepatic blood flow were similar in both groups. Thirty minutes after the test meal, in response to increased blood flow caused by postprandial hyperemia, there was a significantly greater increase in HVPG and impaired hepatic vasorelaxation in bacterial-DNA(+) as compared with bacterial-DNA(-) patients, which indicates hepatic endothelial dysfunction. Indeed, the increase in HVPG after the test meal significantly correlated with serum bacterial DNA concentration. CONCLUSION: Presence of bacterial DNA, a marker of bacterial translocation, is associated with aggravation of peripheral vasodilation and with worsening of intrahepatic endothelial dysfunction.

Complications after ERCP in liver transplant recipients.

BACKGROUND: Complications of the biliary tract after liver transplantation are successfully managed with ERCP; however, the incidence and risk factors for post-ERCP complications remain unknown. OBJECTIVE: To examine the incidence, risk factors, and short-term outcome of post-ERCP complications in liver transplant (LT) recipients. DESIGN: Retrospective evaluation of all ERCPs performed in LT recipients at our institution during a 7-year, 4-month period. SETTING: Tertiary referral center. PATIENTS: A total of 243 ERCPs performed in 121 LT recipients with duct-to-duct anastomosis. MAIN OUTCOME MEASUREMENTS: Incidence of post-ERCP complications. Predictive factors were determined by univariate and multivariate analyses. RESULTS: Overall complications occurred in 22 procedures (9%) (13 mild, 9 moderate): pancreatitis in 9 patients (3.7%), cholangitis in 8 patients (3.3%), postsphincterotomy bleeding in 4 patients (1.6%), and subcapsular hematoma in 1 patient (0.4%). The mean hospitalization for post-ERCP complications was 4.8 days (range 2-11 days). Logistic regression identified mammalian target of rapamycin inhibitors (odds ratio [OR], 4.65; 95% CI, 1.01-21.81; P = .049), serum creatinine level greater than 2 mg/dL (OR, 4.17; 95% CI, 1.07-16.26; P = .04), biliary sphincterotomy (OR, 3.03; 95% CI, 1.07-8.53; P = .037), and more than 2 pancreatic duct contrast injections (OR, 2.95; 95% CI, 1.10-7.91; P = .032) as independent risk factors for post-ERCP complications, whereas steroid therapy (OR, 0.23; 95% CI, 0.08-0.63; P = .004) was an independent protective factor. LIMITATIONS: Single-center retrospective study. CONCLUSIONS: The rate of complications after ERCP in LT recipients seems to be similar to that of non-LT recipients. Complications in this analysis were more common in LT recipients receiving mammalian target of rapamycin inhibitors and those with renal failure, biliary sphincterotomy, and more than 2 pancreatic duct injections, whereas they were less common in those patients on steroid therapy.

Current management of biliary complications after liver transplantation: emphasis on endoscopic therapy.

Biliary complications occur in 5-25% of patients after liver transplantation and represent a major source of morbidity in this group of individuals. The major risk factor for most of these complications is ischemia of the bile tree usually due to obstruction or vascular insufficiency of the hepatic artery. The most common complications include biliary strictures (anastomostic and nonanastomotic), bile leaks, and biliary filling defects. The initial diagnostic approach starts with a high index of suspicion along with an abdominal ultrasound and Doppler exam. Magnetic resonance imaging is highly sensitive and is usually reserved for confirmation. The vast majority of these complications can be successfully treated with endoscopic retrograde cholangiography, however if this procedure cannot be performed a percutaneous approach or surgery is recommended. Nonanastomotic strictures and living donor recipients present a less favorable response to endoscopic management. This review focuses on the current diagnostic and therapeutic approaches for the management of biliary complications after liver transplantation.

Hepatitis C virus superinfection of liver grafts: a detailed analysis of early exclusion of non-dominant virus strains.

Liver transplantation (LT) of hepatitis C virus (HCV)-infected grafts into HCV-infected recipients leads to superinfection with two different virus strains. To characterize the virological outcomes of HCV superinfection immediately after LT, we performed phylogenetic analysis of a fragment of the NS5B gene in donor and recipient serum samples prospectively collected before and after LT, starting on day 1. In four of six cases, the donor strain finally prevailed, while in the remaining two cases, the native recipient strain overtook the donor quasispecies. Clonal sequence analysis showed that, in three cases, the expelled strain was undetectable 1 day after LT. Our study shows that superinfection with a different HCV strain can lead to the exclusion of one strain by the other as soon as the first day after LT. This would suggest that competition might not be limited to the replication level, but could also take place during virus entry.

[The value of MELD in the allocation of priority for liver transplantation candidates]. / Utilidad del MELD (Model for End-stage Liver Disease) para asignar prioridades en el trasplante hepático.

Liver transplantation is the most effective treatment for many patients with chronic end-stage liver disease. The discrepancy between the number of donor organs and potential recipients causes marked pre-transplantation mortality and consequently optimal rationalization of organ allocation is essential. The Model for End-Stage Liver Disease (MELD) is an objective and easily reproducible prognostic index of mortality based on three simple analytical variables: bilirubin and serum creatinine and the prothrombin time/International Normalized Ratio (INR) of protrombine time. The implementation of MELD as an organ allocation system has reduced mortality on the waiting list without affecting post-transplantation survival. Nevertheless, this model has some limitations and consequently further investigations should be performed to improve the organ allocation policy in liver transplantation.

Monitoring of miR-181a-5p and miR-155-5p Plasmatic Expression as Prognostic Biomarkers for Acute and Subclinical Rejection in de novo Adult Liver Transplant Recipients.

Background and Aims: News strategies for the accurate assessment of the state of immunosuppression (IS) in liver transplant recipients are needed to prevent rejection and minimize drug-related side effects. miRNAs can potentially be used as diagnostic or prognostic biomarkers in transplant patients. This study evaluated the capacity of a plasmatic miRNA panel (miR-155-5p, miR-122-5p, miR-181a-5p, and miR148-3p) as an early non-invasive prognostic and diagnostic biomarker for T cell-mediated acute rejection (TCMAR) and subclinical rejection (SCR) in adult liver recipients. Methods: A total of 145 liver recipients were included. All patients received a calcineurin inhibitor with or without mycophenolate mofetil and methylprednisolone. Plasmatic miRNA expression was assessed by qPCR before and at different time-points after liver transplantation. Results: Seventeen patients experienced TCMAR, and eight were diagnosed with SCR during the protocol biopsy at the 3rd month post-transplantation. Pre-transplantation, miR-155-5p expression was significantly higher in TCMAR patients and in SCR patients than in non-rejectors, and miR-181a-5p expression was also significantly higher in SCR patients than in non-rejectors. Post-transplantation, before transaminase-level modification, significantly increased miR-181a-5p, miR-155-5p, and miR-122-5p expression was observed in TCMAR and SCR patients. Binary logistic regression analyses showed, post-transplantation, that TCMAR risk was better predicted by individual expression of miR-181a-5p (LOGIT = -6.35 + 3.87*miR-181a-5p), and SCR risk was better predicted by the combination of miR-181a-5p and miR-155-5p expression (LOGIT = -5.18 + 2.27*miR-181a-5p+1.74*miR-155-5p). Conclusions: Pre-transplantation plasmatic miR-155-5p expression may be useful for stratifying low-immunologic-risk patients, and post-transplantation miR-181a-5p and miR-155-5p may be candidates for inclusion in early, non-invasive prognostic biomarker panels to prevent TCMAR or SCR and better identify patient candidates for IS minimization. Large prospective randomized multicenter trials are needed to refine the cut-off values and algorithms and validate the clinical usefulness of these biomarkers.

Microbiologic features and outcome of pneumonia in transplanted patients.

We prospectively evaluated lower respiratory tract infections in solid organ transplantation (SOT) patients to determine the microbiologic diagnosis and clinical outcomes. We diagnosed 83 cases of pneumonia, 38 of which were community acquired and 45 were nosocomial. Those with bilateral infiltrates or absence of improvement after 3 days of treatment underwent fiberoptic bronchoscopy. Bacterial pneumonia was the most frequent diagnosis and mixed infection predominated in the nosocomial group (11/45 nosocomial versus 1/38 community). Fiberoptic bronchoscopy with bronchoalveolar lavage had higher diagnostic yield in nosocomial pneumonia (77% versus 47%). Mortality differences between the 2 groups were 58% nosocomial versus 8% community-acquired infections (P < 0.001). SOT patients with nosocomial pneumonia, or those who needed mechanical ventilation, had a high mortality rate and benefits from the fiberoptic diagnostic techniques.

Cell culture replication of a genotype 1b hepatitis C virus isolate cloned from a patient who underwent liver transplantation.

The introduction of the genotype 2a isolate JFH1 was a major breakthrough in the field of hepatitis C virus (HCV), allowing researchers to study the complete life cycle of the virus in cell culture. However, fully competent culture systems encompassing the most therapeutically relevant HCV genotypes are still lacking, especially for the highly drug-resistant genotype 1b. For most isolated HCV clones, efficient replication in cultured hepatoma cells requires the introduction of replication-enhancing mutations. However, such mutations may interfere with viral assembly, as occurs in the case of the genotype 1b isolate Con1. In this study, we show that a clinical serum carrying a genotype 1b virus with an exceptionally high viral load was able to infect Huh7.5 cells. Similar to previous reports, inoculation of Huh7.5 cells by natural virus is very inefficient compared to infection by cell culture HCV. A consensus sequence of a new genotype 1b HCV isolate was cloned from the clinical serum (designated Barcelona HCV1), and then subjected to replication studies. This virus replicated poorly in a transient fashion in Huh7.5 cells after electroporation with in vitro transcribed RNA. Nonetheless, approximately 3 weeks post electroporation and thereafter, core protein-positive cells were detected by immunofluorescence. Surprisingly, small amounts of core protein were also measurable in the supernatant of electroporated cells, suggesting that HCV particles might be assembled and released. Our findings not only enhance the current method of cloning in vitro HCV replication-competent isolates, but also offer valuable insights for the realization of fully competent culture systems for HCV.

MELD score and serum sodium in the prediction of survival of patients with cirrhosis awaiting liver transplantation.

BACKGROUND/AIMS: Serum sodium predicts prognosis in cirrhosis and may improve the prognostic accuracy of the model for end-stage liver disease (MELD) score, but the available information is limited. The aim of the present study was to assess the prognostic value of serum sodium in the prediction of survival at 3 and 12 months after listing in patients with cirrhosis awaiting liver transplantation, and to compare its predictive value with that of the MELD score. PATIENTS AND METHODS: 308 consecutive patients with cirrhosis listed for transplantation during a 5-year period were included in the study. The end-point was survival at 3 and 12 months before transplantation. Variables obtained at the time of listing were analysed for prognostic value using multivariable analysis. Accuracy of prognostic variables was analysed by receiver operating characteristic (ROC) curves. RESULTS: The MELD score and serum sodium concentration were the only independent predictors of survival at 3 and 12 months after listing. Low serum sodium was associated with an increased risk of death in all subpopulations of patients with cirrhosis categorised according to the major complication developed before listing. The area under the ROC curves for serum sodium and MELD score was not significantly different both at 3 months (0.83 vs 0.79, respectively) and at 12 months (0.70 vs 0.77, respectively). The addition of serum sodium did not significantly improve the accuracy of the MELD score in the prediction of survival at 3 and 12 months. CONCLUSION: In patients with cirrhosis awaiting liver transplantation, serum sodium and MELD were found to be independent predictors of survival. Larger studies are needed to determine whether the addition of serum sodium to MELD can improve its prognostic accuracy.

Norfloxacin vs ceftriaxone in the prophylaxis of infections in patients with advanced cirrhosis and hemorrhage.

BACKGROUND & AIMS: Oral norfloxacin is the standard of therapy in the prophylaxis of bacterial infections in cirrhotic patients with gastrointestinal hemorrhage. However, during the last years, the epidemiology of bacterial infections in cirrhosis has changed, with a higher incidence of infections caused by quinolone-resistant bacteria. This randomized controlled trial was aimed to compare oral norfloxacin vs intravenous ceftriaxone in the prophylaxis of bacterial infection in cirrhotic patients with gastrointestinal bleeding. METHODS: One hundred eleven patients with advanced cirrhosis (at least 2 of the following: ascites, severe malnutrition, encephalopathy, or bilirubin >3 mg/dL) and gastrointestinal hemorrhage were randomly treated with oral norfloxacin (400 mg twice daily; n = 57) or intravenous ceftriaxone (1 g/day; n = 54) for 7 days. The end point of the trial was the prevention of bacterial infections within 10 days after inclusion. RESULTS: Clinical data were comparable between groups. The probability of developing proved or possible infections, proved infections, and spontaneous bacteremia or spontaneous bacterial peritonitis was significantly higher in patients receiving norfloxacin (33% vs 11%, P = .003; 26% vs 11%, P = .03; and 12% vs 2%, P = .03, respectively). The type of antibiotic used (norfloxacin), transfusion requirements at inclusion, and failure to control bleeding were independent predictors of infection. Seven gram-negative bacilli were isolated in the norfloxacin group, and 6 were quinolone resistant. Non-enterococcal streptococci were only isolated in the norfloxacin group. No difference in hospital mortality was observed between groups. CONCLUSIONS: Intravenous ceftriaxone is more effective than oral norfloxacin in the prophylaxis of bacterial infections in patients with advanced cirrhosis and hemorrhage.

Adrenal insufficiency in patients with cirrhosis and septic shock: Effect of treatment with hydrocortisone on survival.

Relative adrenal insufficiency is frequent in patients with severe sepsis and is associated with hemodynamic instability, renal failure, and increased mortality. This study prospectively evaluated the effects of steroids on shock resolution and hospital survival in a series of 25 consecutive patients with cirrhosis and septic shock (group 1). Adrenal function was evaluated by the short corticotropin test within the first 24 hours of admission. Patients with adrenal insufficiency were treated with stress doses of intravenous hydrocortisone (50 mg/6 h). Data were compared to those obtained from the last 50 consecutive patients with cirrhosis and septic shock admitted to the same intensive care unit in whom adrenal function was not investigated and who did not receive treatment with steroids (group 2). Incidence of adrenal insufficiency in group 1 was 68% (17 patients). Adrenal dysfunction was frequent in patients with advanced cirrhosis (Child C: 76% vs. Child B: 25%, P = .08). Resolution of septic shock (96% vs. 58%, P = .001), survival in the intensive care unit (68% vs. 38%, P = .03), and hospital survival (64% vs. 32%, P = .003) were significantly higher in group 1. The main causes of death in group 1 were hepatorenal syndrome or liver failure (7 of 9 patients). In contrast, refractory shock caused most of the deaths in group 2 (20 of 34 patients). In conclusion, relative adrenal insufficiency is very frequent in patients with advanced cirrhosis and septic shock. Hydrocortisone administration in these patients is associated with a high frequency of shock resolution and high survival rate.

A randomized unblinded pilot study comparing albumin versus hydroxyethyl starch in spontaneous bacterial peritonitis.

The administration of albumin improves circulatory function, prevents hepatorenal syndrome, and reduces hospital mortality in patients with cirrhosis and spontaneous bacterial peritonitis. This randomized unblinded pilot study compared the effect of albumin (10 patients) and the synthetic plasma expander hydroxyethyl starch 200/0.5 (10 patients) on the systemic hemodynamics of patients with spontaneous bacterial peritonitis. Baseline measurements were performed within 12 hours after diagnosis of infection. Patients then received 2 doses of the volume expander (1.5 g/kg body weight after baseline measurements and 1 g/kg body weight on day 3). Measurements were repeated after infection resolution. Treatment with albumin was associated with a significant increase in arterial pressure and a suppression of plasma renin activity, indicating an improvement in circulatory function. This occurred in the setting of a significant expansion of central blood volume (increase in cardiopulmonary pressures and atrial natriuretic factor) and an increase in systolic volume and systemic vascular resistance. In contrast, no significant changes were observed in these parameters in patients treated with hydroxyethyl starch. Von Willebrand-related antigen plasma levels significantly decreased in patients treated with albumin but not in those treated with hydroxyethyl starch. Serum nitrates and nitrites increased in patients treated with hydroxyethyl starch but not in those treated with albumin. These data suggest an effect of albumin on endothelial function. In conclusion, albumin but not hydroxyethyl starch improves systemic hemodynamics in patients with spontaneous bacterial peritonitis. This effect is due not only to volume expansion but also to an action on the peripheral arterial circulation.