BACKGROUND & AIMS: We performed a randomized trial to determine whether albumin should be administered to patients with infections unrelated to spontaneous bacterial peritonitis (SBP). METHODS: We performed a multicenter, open-label trial in which 118 patients with cirrhosis, non-SBP infections, and additional risk factors for poor outcome were randomly assigned to receive antibiotics plus albumin (study group; n = 61) or antibiotics alone (control group; n = 57). The primary outcome was in-hospital mortality; secondary outcomes were effect of albumin on disease course. RESULTS: There were no significant differences at baseline between groups in results from standard laboratory tests, serum markers of inflammation, circulatory dysfunction, or liver severity scores. However, the combined prevalence of acute on chronic liver failure (ACLF) and kidney dysfunction was significantly higher in the study group (44.3% vs 24.6% in the control group; P = .02), indicating greater baseline overall severity. There was no significant difference in the primary outcome between groups (13.1% in the study group vs 10.5% in the control group; P = .66). Circulatory and renal functions improved in only the study group. A significantly higher proportion of patients in the study group had resolution of ACLF (82.3% vs 33.3% in the control group; P = .03). A significantly lower proportion of patients in the study group developed nosocomial infections (6.6% vs 24.6% in the control group; P = .007). CONCLUSIONS: In a randomized trial of patients with advanced cirrhosis and non-SBP infections, in-hospital mortality was similar between those who received albumin plus antibiotics vs those who received only antibiotics (controls). However, patients given albumin were sicker at baseline and, during the follow-up period, a higher proportion had ACLF resolution and a lower proportion had nosocomial infections. ClinicalTrials.gov no: NCT02034279.

OBJECTIVES:In patients with cirrhosis, infections represent a frequent trigger for complications, increasing frequency of hospitalizations and mortality rate. This study aimed to identify predictors of early readmission (30 days) and of mid-term mortality (6 months) in patients with liver cirrhosis discharged after a hospitalization for bacterial and/or fungal infection. METHODS:A total of 199 patients with cirrhosis discharged after an admission for a bacterial and/or fungal infection were included in the study and followed up for a least 6 months. RESULTS:During follow-up, 69 patients (35%) were readmitted within 30 days from discharge. C-reactive protein (CRP) value at discharge (odds ratio (OR)=1.91; P=0.022), diagnosis of acute-on-chronic liver failure during the hospital stay (OR=2.48; P=0.008), and the hospitalization in the last 30 days previous to the admission/inclusion in the study (OR=1.50; P=0.042) were found to be independent predictors of readmission. During the 6-month follow-up, 47 patients (23%) died. Age (hazard ratio (HR)=1.05; P=0.001), model of end-stage liver disease (MELD) score (HR=1.13; P<0.001), CRP (HR=1.85; P=0.001), refractory ascites (HR=2.22; P=0.007), and diabetes (HR=2.41; P=0.010) were found to be independent predictors of 6-month mortality. Patients with a CRP >10 mg/l at discharge had a significantly higher probability of being readmitted within 30 days (44% vs. 24%; P=0.007) and a significantly lower probability of 6-month survival (62% vs. 88%; P<0.001) than those with a CRP ≤10 mg/l. CONCLUSIONS:CRP showed to be a strong predictor of early hospital readmission and 6-month mortality in patients with cirrhosis after hospitalization for bacterial and/or fungal infection. CRP values could be used both in the stewardship of antibiotic treatment and to identify fragile patients who deserve a strict surveillance program.

Acute kidney injury (AKI) is a common and life-threatening complication in patients with cirrhosis. Recently, new criteria for the diagnosis of AKI have been proposed in patients with cirrhosis by the International Club of Ascites. Almost all types of bacterial infections can induce AKI in patients with cirrhosis representing its most common precipitating event. The bacterial infection-induced AKI usually meets the diagnostic criteria of hepatorenal syndrome (HRS). Well in keeping with the "splanchnic arterial vasodilation hypothesis", it has been stated that HRS develops as a consequence of a severe reduction of effective circulating volume related to splanchnic arterial vasodilation and to an inadequate cardiac output. Nevertheless, the role of bacterial infections in precipitating organ failures, including renal failure, is enhanced when their course is characterized by the development of a systemic inflammatory response syndrome (SIRS), thus, when sepsis occurs. Sepsis has been shown to be capable to induce "per se" AKI in animals as well as in patients conditioning also the features of renal damage. This observation suggests that when precipitated by sepsis, the pathogenesis and the clinical course of AKI also in patients with cirrhosis may differentiate to a certain extent from AKI with another or no precipitating factor. The purpose of this review is to describe the features of AKI precipitated by bacterial infections and to highlight whether infection and/or the development of SIRS may influence its clinical course, and, in particular, the response to treatment.

In patients with cirrhosis and hepatorenal syndrome (HRS), terlipressin has been used either as continuous intravenous infusion or as intravenous boluses. To date, these two approaches have never been compared. The goal of this study was to compare the administration of terlipressin as continuous intravenous infusion versus intravenous boluses in the treatment of type 1 HRS. Seventy‐eight patients were randomly assigned to receive either continuous intravenous infusion (TERLI‐INF group) at the initial dose of 2 mg/day or intravenous boluses of terlipressin (TERLI‐BOL group) at the initial dose of 0.5 mg every 4 hours. In case of no response, the dose was progressively increased to a final dose of 12 mg/day in both groups. Albumin was given at the same dose in both groups (1 g/kg of body weight at the first day followed by 20‐40 g/day). Complete response was defined by decrease of serum creatinine (sCr) from baseline to a final value ≤133 μmol/L, partial response by a decrease ≥50% of sCr from baseline to a final value >133 μmol/L. The rate of adverse events was lower in the TERLI‐INF group (35.29%) than in the TERLI‐BOL group (62.16%, P < 0.025). The rate of response to treatment, including both complete and partial response, was not significantly different between the two groups (76.47% versus 64.85%; P value not significant). The mean daily effective dose of terlipressin was lower in the TERLI‐INF group than in the TERLI‐BOL group (2.23 ± 0.65 versus 3.51 ± 1.77 mg/day; P < 0.05). Conclusion : Terlipressin given by continuous intravenous infusion is better tolerated than intravenous boluses in the treatment of type 1 HRS. Moreover, it is effective at doses lower than those required for intravenous bolus administration. (H epatology 2016;63:983–992)

Hepatorenal syndrome (HRS), a serious complication of cirrhosis, is associated with high mortality without treatment. Terlipressin with albumin is effective in the reversal of HRS. Where terlipressin is not available, as in the United States, midodrine and octreotide with albumin are used as an alternative treatment of HRS. The aim was to compare the effectiveness of terlipressin plus albumin versus midodrine and octreotide plus albumin in the treatment of HRS in a randomized controlled trial. Twenty‐seven patients were randomized to receive terlipressin with albumin (TERLI group) and 22 to receive midodrine and octreotide plus albumin (MID/OCT group). The TERLI group received terlipressin by intravenous infusion, initially 3 mg/24 hours, progressively increased to 12 mg/24 hours if there was no response. The MID/OCT group received midodrine orally at an initial dose of 7.5 mg thrice daily, with the dose increased to a maximum of 12.5 mg thrice daily, together with octreotide subcutaneously: initial dose 100 μg thrice daily and up to 200 μg thrice daily. Both groups received albumin intravenously 1 g/kg of body weight on day 1 and 20‐40 g/day thereafter. There was a significantly higher rate of recovery of renal function in the TERLI group (19/27, 70.4%) compared to the MID/OCT group (6/21, 28.6%), P = 0.01. Improvement in renal function and lower baseline Model for End‐Stage Liver Disease score were associated with better survival. Conclusion: Terlipressin plus albumin is significantly more effective than midodrine and octreotide plus albumin in improving renal function in patients with HRS (Hepatology 2015;62:567–574

Acute‐on‐chronic liver failure (ACLF) is characterized by acute decompensation (AD) of cirrhosis, organ failure(s), and high 28‐day mortality. We investigated whether assessments of patients at specific time points predicted their need for liver transplantation (LT) or the potential futility of their care. We assessed clinical courses of 388 patients who had ACLF at enrollment, from February through September 2011, or during early (28‐day) follow‐up of the prospective multicenter European Chronic Liver Failure (CLIF) ACLF in Cirrhosis study. We assessed ACLF grades at different time points to define disease resolution, improvement, worsening, or steady or fluctuating course. ACLF resolved or improved in 49.2%, had a steady or fluctuating course in 30.4%, and worsened in 20.4%. The 28‐day transplant‐free mortality was low‐to‐moderate (6%‐18%) in patients with nonsevere early course (final no ACLF or ACLF‐1) and high‐to‐very high (42%‐92%) in those with severe early course (final ACLF‐2 or ‐3) independently of initial grades. Independent predictors of course severity were CLIF Consortium ACLF score (CLIF‐C ACLFs) and presence of liver failure (total bilirubin ≥12 mg/dL) at ACLF diagnosis. Eighty‐one percent had their final ACLF grade at 1 week, resulting in accurate prediction of short‐ (28‐day) and mid‐term (90‐day) mortality by ACLF grade at 3‐7 days. Among patients that underwent early LT, 75% survived for at least 1 year. Among patients with ≥4 organ failures, or CLIF‐C ACLFs >64 at days 3‐7 days, and did not undergo LT, mortality was 100% by 28 days. Conclusions: Assessment of ACLF patients at 3‐7 days of the syndrome provides a tool to define the emergency of LT and a rational basis for intensive care discontinuation owing to futility. (Hepatology 2015;62:243‐252)

Hyponatremia is common in patients with cirrhosis and ascites. Patients with cirrhosis may develop two types of hyponatremia: (i) hypovolemic hyponatremia, and (ii) hypervolemic hyponatremia. Hypovolemic hyponatremia represents only 10% of all cases of hyponatremia in patients with cirrhosis. In hypervolemic hyponatremia, the extracellular fluid volume is increased, with ascites and edema in the absence of signs of dehydration. The pathogenesis of hypervolemic hyponatremia is complex and involves several factors that negatively affect the renal free water clearance. These factors include: (i) an increased plasma levels of vasopressin (AVP), (ii) a reduced renal synthesis of prostaglandins, and (iii) a reduced delivery of filtrate to the ascending limb of the loop of Henle, the diluting segment of the nephron. The first step in the management of hyponatremia in cirrhosis is to identify whether hyponatremia is hypovolemic or hypervolemic, because the management differs markedly according to the type. The management of hypovolemic hyponatremia is essentially based upon the administration of sodium with the aim of normalizing the depleted body sodium stores, while the key to management of hypervolemic hyponatremia is to increase renal solute-free water excretion. The other electrolyte disorders that can occur in patients with cirrhosis – hypokalemia, hyperkalemia, hypomagnesemia, and hypophosphatemia – are less common. Often, they represent only adverse effects of diuretics, as in the case of hyperkalemia and hypokalemia. Sometimes, their appearance seems to be more related to the etiology than to the severity of liver disease, as in the case of hypophosphatemia. Finally, their impact on the prognosis of cirrhotic patients is largely unknown or, at least, not comparable with that of hyponatremia. For all these reasons, the present chapter concentrates mainly on hypervolemic hyponatremia in cirrhosis.

Background & AimsThe new International Club of Ascites diagnostic criteria to diagnose acute kidney injury at hospital admission suggests the possibility of using a presumed baseline serum creatinine, defined as the last of at least two stable creatinine values during the last 3months. Nevertheless, the possibility of the lack of such a value still remains. In these patients, the KDIGO criteria suggest to use an inverse application of MDRD equation assuming that baseline glomerular filtration rate is 75ml/min per 1.73m(2) (imputed baseline creatinine). We tested the accuracy of this approach to detect acute kidney injury at admission in patients with decompensated cirrhosis and creatinine <1.5mg/dl.MethodsWe analysed 213 patients hospitalized for acute decompensation of cirrhosis. At admission, glomerular filtration rate was estimated using creatinine-based equations and measured by inulin clearance. A diagnosis of acute kidney injury was made using an imputed value of serum creatinine as baseline.ResultsThe diagnosis of AKI based on an imputed baseline creatinine identified only 20.1% of patients with measured glomerular filtration rate 60ml/min/1.73m(2) without any predictive value on 90-day survival.ConclusionsIn patients with cirrhosis and ascites with a creatinine <1.5mg/dl without a baseline value on their records, the diagnosis of acute kidney injury at admission based on an imputed baseline creatinine is not accurate.See Editorial on Page 2079

Spontaneous bacterial peritonitis (SBP) is a common, life‐threatening complication of liver cirrhosis. Third‐generation cephalosporins have been considered the first‐line treatment of SBP. In 2014, a panel of experts suggested a broader spectrum antibiotic regimen for nosocomial SBP, according to the high rate of bacteria resistant to third‐generation cephalosporins found in these patients. However, a broader‐spectrum antibiotic regimen has never been compared to third‐generation cephalosporins in the treatment of nosocomial SBP. The aim of our study was to compare meropenem plus daptomycin versus ceftazidime in the treatment of nosocomial SBP. Patients with cirrhosis and nosocomial SBP were randomized to receive meropenem (1 g/8 hours) plus daptomycin (6 mg/kg/day) or ceftazidime (2 g/8 hours). A paracentesis was performed after 48 hours of treatment. A reduction in ascitic fluid neutrophil count <25% of pretreatment value was considered a treatment failure. The primary outcome was the efficacy of treatment defined by the resolution of SBP after 7 days of treatment. Thirty‐two patients were randomized and 31 were analyzed. The combination of meropenem plus daptomycin was significantly more effective than ceftazidime in the treatment of nosocomial SBP (86.7 vs. 25%; P < 0.001). Ninety‐day transplant‐free survival (TFS) was not significantly different between the two groups. In the multivariate analysis, ineffective response to first‐line treatment (hazard ratio [HR]: 20.6; P = 0.01), development of acute kidney injury during hospitalization (HR: 23.2; P = 0.01), and baseline mean arterial pressure (HR: 0.92; P = 0.01) were found to be independent predictors of 90‐day TFS. Conclusion: The combination of meropenem plus daptomycin is more effective than ceftazidime as empirical antibiotic treatment of nosocomial SBP. Efficacy of the empirical antibiotic treatment is a strong predictor of 90‐day survival in patients with nosocomial SBP. (Hepatology 2016;63:1299–1309)

body weight (42±1.2, vs. 24.6±0.6 grams; p<0.0001) and presence of hepatic steatosis by ORO stain.Splenocytes from HFD mice undergoing IRI demonstrated significant increase in CD4+ T cell activation markers, such as PD1 (p<0.0009),CD69(p<0.01),and CD62L(p<0.001), in addition to higher levels of serum ALT and significant increase in hepatocellular necrosis.The T cell proliferation marker Ki67 (p<0.0089), was significantly higher in HFD IRI as compared to lean IRI.Expression levels of L-selectin (p<0.03) but not P or E-selectin were elevated in HFD IRI.Increased cytokines such as IFNγ, IL-1a, IL-10, IL-6 and IL-17, suggested a pro-inflammatory milieu in HFD IRI.Blockade of L-selectin, lead to a significant attenuation of hepatocellular injury.Conclusion: A steatotic liver undergoing IRI is associated with elevation of adhesion molecule L-selectin along with activation and proliferation of CD4+ T cells, and a pro-inflammatory cytokine milieu.Blocking the adhesion molecule L-selectin leads to mitigation of hepatocellular injury, thus offering an important and clinically relevant therapeutic intervention in the increasingly prevalent clinical condition of IRI of fatty liver disease.

Background & Aims: Acute-on-chronic liver failure (ACLF) is a frequent syndrome (30% prevalence), characterized by acute decompensation of cirrhosis, organ failure(s) and high short-term mortality. This study develops and validates a specific prognostic score for ACLF patients.Methods: Data from 1349 patients included in the CANONIC study were used. First, a simplified organ function scoring system (CLIF Consortium Organ Failure score, CLIF-C OFs) was developed to diagnose ACLF using data from all patients. Subsequently, in 275 patients with ACLF, CLIP-C OFs and two other independent predictors of mortality (age and white blood cell count) were combined to develop a specific prognostic score for ACLF (CLIF Consortium ACLF score [CLIF-C ACLFs]). A concordance index (C-index) was used to compare the discrimination abilities of CLIF-C ACLF, MELD, MELD-sodium (MELD-Na), and Child-Pugh (CPs) scores. The CLIF-C ACLFs was validated in an external cohort and assessed for sequential use.Results: The CLIF-C ACLFs showed a significantly higher predictive accuracy than MELDs, MELD-Nas, and CPs, reducing (19-28%) the corresponding prediction error rates at all main time points after ACLF diagnosis (28, 90, 180, and 365 days) in both the CANONIC and the external validation cohort. CLIF-C ACLFs computed at 48 h, 3-7 days, and 8-15 days after ACLF diagnosis predicted the 28-day mortality significantly better than at diagnosis.Conclusions: The CLIF-C ACLFs at ACLF diagnosis is superior to the MELDs and MELD-Nas in predicting mortality. The CLIP-C ACLFs is a clinically relevant, validated scoring system that can be used sequentially to stratify the risk of mortality in ACLF patients. (C) 2014 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Introduction and aims: Acute on chronic liver failure (ACLF) is a severe complication of cirrhosis characterized by organs failure and a high short-term mortality. Inflammation may be relevant in the pathophysiology and prognosis of ACLF. Inflammasome is a multi-complex protein involved in the inflammatory immune response. We aimed to investigate the expression of genetic effector pathway of inflammasome in peripheral blood mononucleated cells (PBMCs) of patients with ACLF and its prognostic relevance.

Objective Prognostic stratification of patients with cirrhosis is common clinical practice. This study compares the prognostic accuracy (28-day and 90-day transplant-free mortality) of the acute-on-chronic liver failure (ACLF) classification (no ACLF, ACLF grades 1, 2 and 3) with that of acute kidney injury (AKI) classification (no AKI, AKI stages 1, 2 and 3). Design The study was performed in 510 patients with an acute decompensation of cirrhosis previously included in the European Association for the Study of the Liver–Chronic Liver Failure consortium CANONIC study. ACLF was evaluated at enrolment and 48 h after enrolment, and AKI was evaluated at 48 h according to Acute Kidney Injury Network criteria. Results 240 patients (47.1%) met the criteria of ACLF at enrolment, while 98 patients (19.2%) developed AKI. The presence of ACLF and AKI was strongly associated with mortality. 28-day transplant-free mortality and 90-day transplant-free mortality of patients with ACLF (32% and 49.8%, respectively) were significantly higher with respect to those of patients without ACLF (6.2% and 16.4%, respectively; both p<0.001). Corresponding values in patients with and without AKI were 46% and 59%, and 12% and 25.6%, respectively (p<0.0001 for both). ACLF classification was more accurate than AKI classification in predicting 90-day mortality (area under the receiving operating characteristic curve=0.72 vs 0.62; p<0.0001) in the whole series of patients. Moreover, assessment of ACLF classification at 48 h had significantly better prognostic accuracy compared with that of both AKI classification and ACLF classification at enrolment. Conclusions ACLF stratification is more accurate than AKI stratification in the prediction of short-term mortality in patients with acute decompensation of cirrhosis.

The detection of alcohol consumption in liver transplant candidates (LTCs) and liver transplant recipients (LTRs) is required to enable a proper assessment of transplant eligibility and early management of alcohol relapse, respectively. In this clinical setting, urinary ethyl glucuronide (uEtG), the Alcohol Use Disorders Identification Test for Alcohol Consumption (AUDIT-c), serum ethanol, urinary ethanol, carbohydrate-deficient transferrin (CDT), and other indirect markers of alcohol consumption were evaluated and compared prospectively in 121 LTCs and LTRs. Alcohol consumption was diagnosed when AUDIT-c results were positive or it was confirmed by a patient's history in response to abnormal results. Alcohol consumption was found in 30.6% of the patients. uEtG was found to be the strongest marker of alcohol consumption (odds ratio=414.5, P<0.001) and provided a more accurate prediction rate of alcohol consumption [area under receiving operating characteristic (ROC) curve = 0.94] than CDT (area under ROC curve = 0.63, P<0.001) and AUDIT-c (area under ROC curve = 0.73, P<0.001). The combination of uEtG and AUDIT-c showed higher accuracy in detecting alcohol consumption in comparison with the combination of CDT and AUDIT-c (area under ROC curve = 0.98 versus 0.80, P<0.001). Furthermore, uEtG was the most useful marker for detecting alcohol consumption in patients with negative AUDIT-c results. In conclusion, the combination of AUDIT-c and uEtG improves the detection of alcohol consumption in LTCs and LTRs. Therefore, they should be used routinely for these patients. (C) 2014 AASLD.

How to improve care in outpatients with cirrhosis and ascites: A new model of care coordination by consultant hepatologistsJournal of HepatologyVol. 59Issue 2PreviewThe development of ascites in patients with cirrhosis is associated with a high rate of health care utilization. New models of specialized caregiving support are necessary to optimize its management. The aim of the study was to evaluate the efficacy and financial sustainability of the “Care management check-up” as a new model of specialized caregiving support based on a series of diagnostic facilities performed in real time and on the integrated activity of consultant hepatologists at the hospital unit for outpatients, dedicated nurses, physicians in training and primary physicians, compared to standard care in outpatients with cirrhosis and ascites. Full-Text PDF Coordinated care in cirrhosis; the need for further randomized controlled trialsJournal of HepatologyVol. 60Issue 2PreviewTo the Editor: Full-Text PDF Open Access We are making a step forwardTo the Editor:We would like to thank A.J. Wigg et al. for their interest in our study about a new model of care coordination by consultant hepatologists in outpatients with cirrhosis and ascites [[1]Morando F. Maresio G. Piano S. Fasolato S. Cavallin M. Romano A. et al.How to improve care in outpatients with cirrhosis and ascites: a new model of care coordination by consultant hepatologists.J Hepatol. 2013; 59: 257-264Abstract Full Text Full Text PDF PubMed Scopus (114) Google Scholar]. We regret that the Editorialists have not considered their publication but, such is life! Moreover, it should be recognized that the appearance of the two manuscripts on PubMed were very close each to one other. In their letter [[2]Wigg AJ, McCormick R, Wundke R, Woodman RJ. Coordinated care models in cirrhosis; the need for further randomized controlled, trials. J. Hepatol 2014;60:465–466.Google Scholar] A.J. Wigg et al. highlighted once again that our study was not randomized and suggested that the differences in outcomes of the two groups of our work were not linked to the process of management as outpatients, but to confounding factors that were not well balanced between the two groups. The circumstance that our study was not randomized has been already stressed by ourselves and by the editorialists. We also set out to explain the reasons why we decided to perform this type of study. As far as the enrollment and the matching process are concerned, as we stated in the paper, patients were enrolled consecutively on discharge from hospitalization due to acute decompensation of cirrhosis, and subjected to matching for a large number of variables (age, gender, type of ascites, Model for End Stage Liver Disease (MELD) score, Child-Turcotte-Pugh (CTP) score, etiology of cirrhosis, local or not local residences, and co-morbidities evaluated with the Charlson index). Here, it was clear that there were no significant differences in terms of baseline demographic, clinical or laboratory features. We recognize that the propensity score matching may probably be better, but the sample size was too small for its application. However, patients started the assigned care management program at the same time following discharge, as reported in the results.A.J. Wigg et al. have also speculated that there was a lack of process measures performed during the study, for example, regarding the patient’s attendance of scheduled appointments. Our study was not specifically designed to evaluate the compliance of patients, but rather to assess whether the new model “the Care Management Program”, based on an integrated activity of dedicated physicians and nurses and on some facilities such as lab examinations and diagnostic examinations in real time, may improve some outcomes in patients with cirrhosis and ascites as compared to the standard specialized caregiving model in our country. Nonetheless, the patients’ attendance of the scheduled appointments was extremely high in both groups (>90%) with a dropout rate of 2%. This represents a huge difference between our study and that of A.J. Wigg et al., in which the rate of drop out was considerably higher.As regards the relationship between the outcomes and the number of specialist evaluations, it has been clearly reported that the mean global number of specialist evaluations in the care management program was almost double that in the standard program, either when expressed per patient or per patient month of life. We did not introduce this parameter in the univariate analysis because we thought and we continue to think that the philosophy of the new model is more relevant than the single numbers or aspects of the model.Looking to A.J. Wigg et al., they proposed an analysis about the timing of mortality, assuming a too high rate of early and overall mortality in patients followed with the standard of care. Regarding this, we must emphasize the importance of an early intervention in patients with cirrhosis and ascites discharged after a hospitalization related to a complication of cirrhosis: they are a population of frail patients, immunosuppressed and predisposed towards new complications and hospital readmission [[3]Volk M.L. Tocco R.S. Bazick J. Rakoski M.O. Lok A.S. Hospital readmissions among patients with decompensated cirrhosis.Am J Gastroenterol. 2012; 107: 247-252Crossref PubMed Scopus (300) Google Scholar]. Thus, the prompt management of hyponatremia, renal failure and subclinical bacterial infections that was enabled in patients who were assigned to the “Care Management Program”, can definitively account for the definition of an early difference in the survival curve compared to that of patients who were assigned to the standard model. In addition, the standard treatment group presented a mortality rate that is in line with that reported in the literature on the natural history of cirrhosis, namely a rate of 40% one year after the development of ascites [[4]Guevara M. Cárdenas A. Uriz J. Ginès P. Prognosis in patients with cirrhosis and ascites.in: Ginès P. Arroyo V. Rodés J. Schrier R.W. Ascites and renal dysfunction in liver disease: pathogenesis, diagnosis and treatment. Blackwell, Malden2005: 260-270Crossref Scopus (38) Google Scholar]. As regards the probability of hospital readmission, recently, M.L. Volk and colleagues [[3]Volk M.L. Tocco R.S. Bazick J. Rakoski M.O. Lok A.S. Hospital readmissions among patients with decompensated cirrhosis.Am J Gastroenterol. 2012; 107: 247-252Crossref PubMed Scopus (300) Google Scholar] have shown, in a similar type of patients, a one-week readmission rate of 14%, a one-month readmission rate of 37% and an overall readmission of 69% of patients. These results are perfectly comparable with those found in the standard care group in our study, considering 30 day readmission (42%) and the global readmissions (71%). We are sure that these data are sufficient to reject the idea of A.J. Wigg et al. that the standard caregiving model in our study was below the average. We would like to remind A.J. Wigg et al. that we operated in a region of Italy and of Europe with very high parameters of efficiency and quality of health care system [[5]ISTAT, Sistema sanitario e salute della popolazione, Indicatori Regionali: http://www3.istat.it/dati/catalogo/20081112_00/PDF/cap3.pdf.Google Scholar].Concerning the observation that the MELD is not among the predictors of readmission, the following should be noted: (a) only baseline MELD was considered and (b) patients readmitted to the hospital had a MELD more than 2 points higher than not readmitted patients.It isn’t our duty to underline the limitations of the study of A.J. Wigg and colleagues [[6]Wigg A.J. McCormick R. Wundke R. Woodman R.J. Efficacy of a chronic disease management model for patients with chronic liver failure.Clin Gastroenterol Hepatol. 2013; 11 (e1–4): 850-858Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar]. However, a final comment is needed because the authors did not include a day hospital in their model. This is where we performed all the elective invasive procedures, and more importantly all therapeutic paracenteses. As a consequence, an elective paracentesis or another elective invasive procedure was never a cause of hospital readmission in our study, whereas this represented almost 50% of the reasons for readmission in the intervention group in the study of A.J. Wigg et al. We believe that on providing the Day Hospital in our Care Management Program, we have effectively realized the facility that A.J. Wigg et al. suggested in order to reduce almost half of hospitalizations in patients with cirrhosis and ascites. As a result, the inclusion of the Day Hospital in our Care Management Program has been the key to obtain results both in terms of survival and overall economic sustainability. The editorialists may have intercepted this aspect in our new model as a step forward in the management of these patients.Conflict of interestThe authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript. We are making a step forwardTo the Editor:We would like to thank A.J. Wigg et al. for their interest in our study about a new model of care coordination by consultant hepatologists in outpatients with cirrhosis and ascites [[1]Morando F. Maresio G. Piano S. Fasolato S. Cavallin M. Romano A. et al.How to improve care in outpatients with cirrhosis and ascites: a new model of care coordination by consultant hepatologists.J Hepatol. 2013; 59: 257-264Abstract Full Text Full Text PDF PubMed Scopus (114) Google Scholar]. We regret that the Editorialists have not considered their publication but, such is life! Moreover, it should be recognized that the appearance of the two manuscripts on PubMed were very close each to one other. In their letter [[2]Wigg AJ, McCormick R, Wundke R, Woodman RJ. Coordinated care models in cirrhosis; the need for further randomized controlled, trials. J. Hepatol 2014;60:465–466.Google Scholar] A.J. Wigg et al. highlighted once again that our study was not randomized and suggested that the differences in outcomes of the two groups of our work were not linked to the process of management as outpatients, but to confounding factors that were not well balanced between the two groups. The circumstance that our study was not randomized has been already stressed by ourselves and by the editorialists. We also set out to explain the reasons why we decided to perform this type of study. As far as the enrollment and the matching process are concerned, as we stated in the paper, patients were enrolled consecutively on discharge from hospitalization due to acute decompensation of cirrhosis, and subjected to matching for a large number of variables (age, gender, type of ascites, Model for End Stage Liver Disease (MELD) score, Child-Turcotte-Pugh (CTP) score, etiology of cirrhosis, local or not local residences, and co-morbidities evaluated with the Charlson index). Here, it was clear that there were no significant differences in terms of baseline demographic, clinical or laboratory features. We recognize that the propensity score matching may probably be better, but the sample size was too small for its application. However, patients started the assigned care management program at the same time following discharge, as reported in the results.A.J. Wigg et al. have also speculated that there was a lack of process measures performed during the study, for example, regarding the patient’s attendance of scheduled appointments. Our study was not specifically designed to evaluate the compliance of patients, but rather to assess whether the new model “the Care Management Program”, based on an integrated activity of dedicated physicians and nurses and on some facilities such as lab examinations and diagnostic examinations in real time, may improve some outcomes in patients with cirrhosis and ascites as compared to the standard specialized caregiving model in our country. Nonetheless, the patients’ attendance of the scheduled appointments was extremely high in both groups (>90%) with a dropout rate of 2%. This represents a huge difference between our study and that of A.J. Wigg et al., in which the rate of drop out was considerably higher.As regards the relationship between the outcomes and the number of specialist evaluations, it has been clearly reported that the mean global number of specialist evaluations in the care management program was almost double that in the standard program, either when expressed per patient or per patient month of life. We did not introduce this parameter in the univariate analysis because we thought and we continue to think that the philosophy of the new model is more relevant than the single numbers or aspects of the model.Looking to A.J. Wigg et al., they proposed an analysis about the timing of mortality, assuming a too high rate of early and overall mortality in patients followed with the standard of care. Regarding this, we must emphasize the importance of an early intervention in patients with cirrhosis and ascites discharged after a hospitalization related to a complication of cirrhosis: they are a population of frail patients, immunosuppressed and predisposed towards new complications and hospital readmission [[3]Volk M.L. Tocco R.S. Bazick J. Rakoski M.O. Lok A.S. Hospital readmissions among patients with decompensated cirrhosis.Am J Gastroenterol. 2012; 107: 247-252Crossref PubMed Scopus (300) Google Scholar]. Thus, the prompt management of hyponatremia, renal failure and subclinical bacterial infections that was enabled in patients who were assigned to the “Care Management Program”, can definitively account for the definition of an early difference in the survival curve compared to that of patients who were assigned to the standard model. In addition, the standard treatment group presented a mortality rate that is in line with that reported in the literature on the natural history of cirrhosis, namely a rate of 40% one year after the development of ascites [[4]Guevara M. Cárdenas A. Uriz J. Ginès P. Prognosis in patients with cirrhosis and ascites.in: Ginès P. Arroyo V. Rodés J. Schrier R.W. Ascites and renal dysfunction in liver disease: pathogenesis, diagnosis and treatment. Blackwell, Malden2005: 260-270Crossref Scopus (38) Google Scholar]. As regards the probability of hospital readmission, recently, M.L. Volk and colleagues [[3]Volk M.L. Tocco R.S. Bazick J. Rakoski M.O. Lok A.S. Hospital readmissions among patients with decompensated cirrhosis.Am J Gastroenterol. 2012; 107: 247-252Crossref PubMed Scopus (300) Google Scholar] have shown, in a similar type of patients, a one-week readmission rate of 14%, a one-month readmission rate of 37% and an overall readmission of 69% of patients. These results are perfectly comparable with those found in the standard care group in our study, considering 30 day readmission (42%) and the global readmissions (71%). We are sure that these data are sufficient to reject the idea of A.J. Wigg et al. that the standard caregiving model in our study was below the average. We would like to remind A.J. Wigg et al. that we operated in a region of Italy and of Europe with very high parameters of efficiency and quality of health care system [[5]ISTAT, Sistema sanitario e salute della popolazione, Indicatori Regionali: http://www3.istat.it/dati/catalogo/20081112_00/PDF/cap3.pdf.Google Scholar].Concerning the observation that the MELD is not among the predictors of readmission, the following should be noted: (a) only baseline MELD was considered and (b) patients readmitted to the hospital had a MELD more than 2 points higher than not readmitted patients.It isn’t our duty to underline the limitations of the study of A.J. Wigg and colleagues [[6]Wigg A.J. McCormick R. Wundke R. Woodman R.J. Efficacy of a chronic disease management model for patients with chronic liver failure.Clin Gastroenterol Hepatol. 2013; 11 (e1–4): 850-858Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar]. However, a final comment is needed because the authors did not include a day hospital in their model. This is where we performed all the elective invasive procedures, and more importantly all therapeutic paracenteses. As a consequence, an elective paracentesis or another elective invasive procedure was never a cause of hospital readmission in our study, whereas this represented almost 50% of the reasons for readmission in the intervention group in the study of A.J. Wigg et al. We believe that on providing the Day Hospital in our Care Management Program, we have effectively realized the facility that A.J. Wigg et al. suggested in order to reduce almost half of hospitalizations in patients with cirrhosis and ascites. As a result, the inclusion of the Day Hospital in our Care Management Program has been the key to obtain results both in terms of survival and overall economic sustainability. The editorialists may have intercepted this aspect in our new model as a step forward in the management of these patients. To the Editor: We would like to thank A.J. Wigg et al. for their interest in our study about a new model of care coordination by consultant hepatologists in outpatients with cirrhosis and ascites [[1]Morando F. Maresio G. Piano S. Fasolato S. Cavallin M. Romano A. et al.How to improve care in outpatients with cirrhosis and ascites: a new model of care coordination by consultant hepatologists.J Hepatol. 2013; 59: 257-264Abstract Full Text Full Text PDF PubMed Scopus (114) Google Scholar]. We regret that the Editorialists have not considered their publication but, such is life! Moreover, it should be recognized that the appearance of the two manuscripts on PubMed were very close each to one other. In their letter [[2]Wigg AJ, McCormick R, Wundke R, Woodman RJ. Coordinated care models in cirrhosis; the need for further randomized controlled, trials. J. Hepatol 2014;60:465–466.Google Scholar] A.J. Wigg et al. highlighted once again that our study was not randomized and suggested that the differences in outcomes of the two groups of our work were not linked to the process of management as outpatients, but to confounding factors that were not well balanced between the two groups. The circumstance that our study was not randomized has been already stressed by ourselves and by the editorialists. We also set out to explain the reasons why we decided to perform this type of study. As far as the enrollment and the matching process are concerned, as we stated in the paper, patients were enrolled consecutively on discharge from hospitalization due to acute decompensation of cirrhosis, and subjected to matching for a large number of variables (age, gender, type of ascites, Model for End Stage Liver Disease (MELD) score, Child-Turcotte-Pugh (CTP) score, etiology of cirrhosis, local or not local residences, and co-morbidities evaluated with the Charlson index). Here, it was clear that there were no significant differences in terms of baseline demographic, clinical or laboratory features. We recognize that the propensity score matching may probably be better, but the sample size was too small for its application. However, patients started the assigned care management program at the same time following discharge, as reported in the results. A.J. Wigg et al. have also speculated that there was a lack of process measures performed during the study, for example, regarding the patient’s attendance of scheduled appointments. Our study was not specifically designed to evaluate the compliance of patients, but rather to assess whether the new model “the Care Management Program”, based on an integrated activity of dedicated physicians and nurses and on some facilities such as lab examinations and diagnostic examinations in real time, may improve some outcomes in patients with cirrhosis and ascites as compared to the standard specialized caregiving model in our country. Nonetheless, the patients’ attendance of the scheduled appointments was extremely high in both groups (>90%) with a dropout rate of 2%. This represents a huge difference between our study and that of A.J. Wigg et al., in which the rate of drop out was considerably higher. As regards the relationship between the outcomes and the number of specialist evaluations, it has been clearly reported that the mean global number of specialist evaluations in the care management program was almost double that in the standard program, either when expressed per patient or per patient month of life. We did not introduce this parameter in the univariate analysis because we thought and we continue to think that the philosophy of the new model is more relevant than the single numbers or aspects of the model. Looking to A.J. Wigg et al., they proposed an analysis about the timing of mortality, assuming a too high rate of early and overall mortality in patients followed with the standard of care. Regarding this, we must emphasize the importance of an early intervention in patients with cirrhosis and ascites discharged after a hospitalization related to a complication of cirrhosis: they are a population of frail patients, immunosuppressed and predisposed towards new complications and hospital readmission [[3]Volk M.L. Tocco R.S. Bazick J. Rakoski M.O. Lok A.S. Hospital readmissions among patients with decompensated cirrhosis.Am J Gastroenterol. 2012; 107: 247-252Crossref PubMed Scopus (300) Google Scholar]. Thus, the prompt management of hyponatremia, renal failure and subclinical bacterial infections that was enabled in patients who were assigned to the “Care Management Program”, can definitively account for the definition of an early difference in the survival curve compared to that of patients who were assigned to the standard model. In addition, the standard treatment group presented a mortality rate that is in line with that reported in the literature on the natural history of cirrhosis, namely a rate of 40% one year after the development of ascites [[4]Guevara M. Cárdenas A. Uriz J. Ginès P. Prognosis in patients with cirrhosis and ascites.in: Ginès P. Arroyo V. Rodés J. Schrier R.W. Ascites and renal dysfunction in liver disease: pathogenesis, diagnosis and treatment. Blackwell, Malden2005: 260-270Crossref Scopus (38) Google Scholar]. As regards the probability of hospital readmission, recently, M.L. Volk and colleagues [[3]Volk M.L. Tocco R.S. Bazick J. Rakoski M.O. Lok A.S. Hospital readmissions among patients with decompensated cirrhosis.Am J Gastroenterol. 2012; 107: 247-252Crossref PubMed Scopus (300) Google Scholar] have shown, in a similar type of patients, a one-week readmission rate of 14%, a one-month readmission rate of 37% and an overall readmission of 69% of patients. These results are perfectly comparable with those found in the standard care group in our study, considering 30 day readmission (42%) and the global readmissions (71%). We are sure that these data are sufficient to reject the idea of A.J. Wigg et al. that the standard caregiving model in our study was below the average. We would like to remind A.J. Wigg et al. that we operated in a region of Italy and of Europe with very high parameters of efficiency and quality of health care system [[5]ISTAT, Sistema sanitario e salute della popolazione, Indicatori Regionali: http://www3.istat.it/dati/catalogo/20081112_00/PDF/cap3.pdf.Google Scholar]. Concerning the observation that the MELD is not among the predictors of readmission, the following should be noted: (a) only baseline MELD was considered and (b) patients readmitted to the hospital had a MELD more than 2 points higher than not readmitted patients. It isn’t our duty to underline the limitations of the study of A.J. Wigg and colleagues [[6]Wigg A.J. McCormick R. Wundke R. Woodman R.J. Efficacy of a chronic disease management model for patients with chronic liver failure.Clin Gastroenterol Hepatol. 2013; 11 (e1–4): 850-858Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar]. However, a final comment is needed because the authors did not include a day hospital in their model. This is where we performed all the elective invasive procedures, and more importantly all therapeutic paracenteses. As a consequence, an elective paracentesis or another elective invasive procedure was never a cause of hospital readmission in our study, whereas this represented almost 50% of the reasons for readmission in the intervention group in the study of A.J. Wigg et al. We believe that on providing the Day Hospital in our Care Management Program, we have effectively realized the facility that A.J. Wigg et al. suggested in order to reduce almost half of hospitalizations in patients with cirrhosis and ascites. As a result, the inclusion of the Day Hospital in our Care Management Program has been the key to obtain results both in terms of survival and overall economic sustainability. The editorialists may have intercepted this aspect in our new model as a step forward in the management of these patients. Conflict of interestThe authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript. The authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.

The aim of this study was to evaluate the effect and molecular mechanism of albumin infusion on cardiac contractility in experimental cirrhosis with ascites. Cardiac contractility was recorded ex vivo in rats with cirrhosis and ascites and in control rats after the injection in the caudal vein of albumin, saline, or hydroxyethyl starch (HES). Gene and protein expression of beta-receptors and pathways involved in their intracellular signaling such as Gai2 protein (Gai2), adenylate cyclase 3 (Adcy3), protein expression of tumor necrosis factor alpha (TNF-a) and inducible nitric oxide synthase (iNOS), were evaluated in cardiac tissue in both groups. Phosphorylation and membrane-translocation of the cytosolic components of nicotinamide adenine dinucleotide phosphate (NAD(P)H)-oxidase and translocation of nuclear factor kappa B (NF-?B) were also evaluated. After saline intravenous injection, cardiac contractility was significantly reduced in rats with cirrhosis as compared to control rats (P < 0.01). This was associated with: (1) increased expression of protein Gai2 (P < 0.05), TNF-a (P < 0.05), iNOS (P < 0.05); (2) increased NAD(P)H-oxidase activity (P < 0.05); (3) increased nuclear translocation of NF-?B (P < 0.05); and (4) lower expression of Adcy 3 (P < 0.05) in cardiac tissue of rats with cirrhosis. After albumin injection cardiac contractility (P < 0.01), protein expression of TNF-a, iNOS, Gai2, and Adcy3, NAD(P)H-oxidase activity and nuclear translocation of NF-?B in cardiac tissue of rats with cirrhosis were reversed to control levels (P < 0.05). HES injection did not modify cardiac contractility and nuclear translocation of NF-?B in cardiac tissue of rats with cirrhosis. Conclusion: Albumin exerts a positive cardiac inotropic effect in rats with cirrhosis and ascites counteracting the negative effects of oxidative stress- and TNF-a-induced activation of NF-?B-iNOS pathway and oxidative stress-induced alteration of beta-receptor signaling. (HEPATOLOGY 2013; 57:266-276)