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Background and Aims: Patients with acute liver injury or failure (ALI/ALF) experience bleeding complications uncommonly despite an abnormal hemostatic profile. Rotational thromboelastometry (ROTEM), which assesses clot formation in whole blood, was used to determine the nature of abnormal hemostasis and whether it contributes to bleeding events, illness severity, or survival.Approach and Results: A total of 200 patients were recruited from sites of the ALF Study Group. Blood collected daily for up to 5 days was analyzed using ROTEM delta devices. Consistent with standard laboratory evidence of hypocoagulability (median international normalized ratio = 2.9 and platelet count = 144 × 109/L), patients frequently exhibited ROTEM parameters outside the normal range (73% and 62% had abnormalities in clot formation from extrinsic and intrinsic clotting cascades, respectively); however, measures of clot stability were generally normal. Eighteen patients (9%) experienced bleeding events, in whom clot initiation, assembly, and firmness were more severely deranged than patients without bleeding. Abnormal ROTEM parameters were more frequently observed in patients with non-acetaminophen ALI/ALF than those with acetaminophen ALI/ALF (clot initiation [P Conclusions: In patients with ALI/ALF, abnormal ROTEM parameters are frequent and proportional to disease severity. Whether the increased bleeding risk associated with abnormal ROTEM indicates hemostatic failure or is a proxy for disease severity requires additional study.

Objectives The molecular adsorbent recirculating system removes water-soluble and albumin-bound toxins and may be beneficial for acute liver failure patients. We compared the rates of 21-day transplant-free survival in acute liver failure patients receiving molecular adsorbent recirculating system therapy and patients receiving standard medical therapy. Design Propensity score-matched retrospective cohort analysis. Setting Tertiary North American liver transplant centers. Patients Acute liver failure patients receiving molecular adsorbent recirculating system at three transplantation centers (n = 104; January 2009-2019) and controls from the U.S. Acute Liver Failure Study Group registry. Interventions Molecular adsorbent recirculating system treatment versus standard medical therapy (control). Measurements and main results One-hundred four molecular adsorbent recirculating system patients were propensity score-matched (4:1) to 416 controls. Using multivariable conditional logistic regression adjusting for acute liver failure etiology (acetaminophen: n = 248; vs nonacetaminophen: n = 272), age, vasopressor support, international normalized ratio, King's College Criteria, and propensity score (main model), molecular adsorbent recirculating system was significantly associated with increased 21-day transplant-free survival (odds ratio, 1.90; 95% CI, 1.07-3.39; p = 0.030). This association remained significant in several sensitivity analyses, including adjustment for acute liver failure etiology and propensity score alone ("model 2"; molecular adsorbent recirculating system odds ratio, 1.86; 95% CI, 1.05-3.31; p = 0.033), and further adjustment of the "main model" for mechanical ventilation, and grade 3/4 hepatic encephalopathy ("model 3"; molecular adsorbent recirculating system odds ratio, 1.91; 95% CI, 1.07-3.41; p = 0.029). In acetaminophen-acute liver failure (n = 51), molecular adsorbent recirculating system was associated with significant improvements (post vs pre) in mean arterial pressure (92.0 vs 78.0 mm Hg), creatinine (77.0 vs 128.2 µmol/L), lactate (2.3 vs 4.3 mmol/L), and ammonia (98.0 vs 136.0 µmol/L; p ≤ 0.002 for all). In nonacetaminophen acute liver failure (n = 53), molecular adsorbent recirculating system was associated with significant improvements in bilirubin (205.2 vs 251.4 µmol/L), creatinine (83.1 vs 133.5 µmol/L), and ammonia (111.5 vs 140.0 µmol/L; p ≤ 0.022 for all). Conclusions Treatment with molecular adsorbent recirculating system is associated with increased 21-day transplant-free survival in acute liver failure and improves biochemical variables and hemodynamics, particularly in acetaminophen-acute liver failure.

BACKGROUND: Critically ill cirrhotic patients are increasingly transplanted, but there is no consensus about futile liver transplantation (LT). Therefore, the decision to delay or deny LT is often extensively debated. These debates arise from different opinions of futility among transplant team members. This study aims to achieve a multinational and multidisciplinary consensus on the definition of futility in LT and to develop well-articulated criteria for not proceeding with LT due to futility. METHODS: Thirty-five international experts from anesthesiology/intensive care, hepatology, and transplant surgery were surveyed using the Delphi method. More than 70% of similar answers to a question were necessary to define agreement. RESULTS: The panel recommended patient and graft survival at 1 year after LT to define futility. Severe frailty and persistent fever or 1 μg/kg per minute and a serum lactate level >9 mmol/L. CONCLUSIONS: Our expert panel provides a consensus on the definition of futile LT and on specific criteria for postponing or denying LT. A framework that may facilitate the decision if a patient is too sick for transplant is presented., SCOPUS: ar.j, info:eu-repo/semantics/published

Purpose Cirrhotic patients in organ failure are frequently admitted to intensive care units (ICUs) to receive invasive mechanical ventilation (IMV). We evaluated the trends of hospitalizations, in-hospital mortality, hospital costs, and hospital length of stay (LOS) of IMV patients with cirrhosis. Methods We analyzed the United States National Inpatient Sample from 2005–2014. We selected discharges of IMV adult (≥18 years) patients with cirrhosis using the International Classification of Diseases, 9th Edition , Clinical Modification codes. Trends were assessed using linear regression and joinpoint regression. Results Between 2005 and 2014, there were approximately 9,441,605 hospitalizations of IMV adult patients, of which 4.7% had cirrhosis. There was an increasing trend in the total number of IMV cirrhotic patient hospitalizations (annual percent change [APC] 7.0%, 95% confidence interval [CI] 6.4%; 7.6%, Ptrend trend trend = 0.58). The total annual hospital costs of all IMV cirrhotic patients increased from approximately $1.2 billion USD in 2005 to $2.7 billion USD in 2014 ( Ptrend trend trend = 0.01 respectively). Conclusions The total number of hospitalizations and total annual costs of IMV patients with cirrhosis have been increasing over time. However, past hesitancy around admitting cirrhotic patients to the ICU may need to be tempered by the improving mortality trends in this patient population.

Purpose of review Malnutrition is prevalent in critically ill patients and is linked to worse outcomes such as prolonged mechanical ventilation, length of intensive care unit (ICU) stay, and increased mortality. Therefore, nutritional therapy is important. However, it is often difficult to accurately identify those at high malnutrition risk and to optimize nutritional support. Different technological modalities have therefore been developed to identify patients at high nutritional risk and to guide nutritional support in an attempt to optimize outcomes. Recent findings Computed tomography (CT), ultrasound (US), and bioelectrical impedance analysis are tools that allow assessment of lean body mass and detection of sarcopenia, which is a significant marker of poor nutrition. The use of indirect calorimetry allows the determination of resting energy expenditure to serve as a guide to providing optimal nutrition intake in ICU patients. Summary By using CT, US, or bioelectrical impedance analysis, detection of sarcopenia can be undertaken in patients admitted to the ICU. This allows for an accurate picture of underlying nutritional status to help clinicians focus on nutritional support for these patients. Subsequently, indirect calorimetry can be used to guide optimal nutrition therapy and caloric intake in critically ill patients. However, whether these methods result in improved outcomes in critically ill patients remains to be validated.

Liver transplantation (LT) has revolutionized outcomes for cirrhotic patients. Current liver allocation policies dictate patients with highest short-term mortality receive the highest priority, thus, several patients become increasingly ill on the waitlist. Given cirrhosis is a progressive disease, it can be complicated by the occurrence of acute-on-chronic liver failure (ACLF), a syndrome defined by an acute deterioration of liver function associated with extrahepatic organ failures requiring intensive care support and a high short-term mortality. Successfully bridging to transplant includes accurate prognostication and prioritization of ACLF patients awaiting LT, optimizing intensive care support pre-LT, and tailoring immunosuppressive and anti-infective therapies post-LT. Furthermore, predicting futility (too sick to undergo LT) in ACLF is challenging. In this review, we summarize the role of LT in ACLF specifically highlighting (a) current prognostic scores in ACLF, (b) critical care management of the ACLF patient awaiting LT, (c) donor issues to consider in transplant in ACLF, and (d) exploring of recent post-LT outcomes in ACLF and potential opportunities to improve outcomes including current care gaps and unmet research needs.

Background In patients with cirrhosis, progression to acute decompensation (AD) and acute-on-chronic liver failure (ACLF) has been associated with poor prognosis. Differential leucocyte ratios might predict mortality in systemic inflammatory conditions. Aim To evaluate differential leucocyte ratios as prognostic biomarkers in patients with cirrhosis. Methods Patients with AD and ACLF were recruited from four centres in three countries. Peripheral blood differential leucocytes were measured (three centres using flow cytometry) on hospital admission and at 48 hours. Ratios were correlated to model for end-stage liver disease (MELD), chronic liver failure-sequential organ failure (CLIF-SOFA), suspected/culture-positive bacterial infection and survival. Results Nine hundred twenty-six patients (562 (61%) male, median age 55 (25-94) years) were studied. Overall, 350 (37%) did not survive to hospital discharge. Neutrophil-lymphocyte ratio (NLR) and monocyte-lymphocyte ratio (MLR) were elevated in patients with AD and ACLF who died during their hospital stay. On multivariate analysis NLR retained statistical significance independently of CLIF-SOFA or MELD. NLR >30 was associated with an 80% 90-day mortality in patients with ACLF but not AD. On sensitivity analysis for subgroups (alcohol-related liver disease and suspected sepsis), NLR and MLR retained statistically robust accuracy for the prediction of mortality. Significant predictive accuracy was only observed in centres using flow cytometry. Conclusion Leucocyte ratios are simple and robust biomarkers of outcome in ACLF, which are comparable to CLIF-SOFA score but dependent on leucocyte quantification method. NLR and MLR may be used as screening tools for mortality prediction in patients with acutely deteriorating cirrhosis.

Background Acute liver failure is a rare syndrome with significant morbidity and mortality, particularly in absence of transplantation as a rescue therapy. An important mechanism contributing to mortality is hyperammonemia which drives cerebral edema and raised intracranial pressure. Multiple therapies for managing hyperammonemia have been trialed. Continuous renal replacement therapy is effective in treating hyperammonemia in other disease states (notably inborn errors of metabolism). Its efficacy in acute liver failure has been suggested but further investigation is required to prove this. The objective of this systematic review will be to determine the efficacy of continuous renal replacement therapy in patients with acute liver failure and its effect on mortality and transplant-free survival. Methods MEDLINE, EMBASE, Web of Science, and Cochrane Database will be searched. Identified studies will include all patients with acute liver failure in a critical care unit treated with continuous renal replacement therapy. Primary outcome will be effectiveness of ammonia clearance and mortality. Patients treated with any other modality of ammonia lowering therapy (such as plasma exchange or Molecular Adsorbent Recirculating System) will be excluded. Narrative synthesis of the identified studies will occur and if clinical homogeneity is identified, data will be pooled for meta-analysis using a DerSimonian-Laird random effects model. Discussion We present a protocol for a systematic review seeking to establish a link between transplant-free survival in acute liver failure and the use of continuous renal replacement therapy. Given the anticipated paucity of literature on this subject, both narrative and quantitative syntheses are planned. Systematic review registration (PROSPERO) CRD42019122520, registered April 16, 2019.

Liver-type fatty acid binding protein (FABP1) has previously been demonstrated to improve prognostic discrimination in acetaminophen (APAP)-induced ALF but has not been investigated in other etiologies of ALF. AIM: To determine whether FABP1 levels (early: admission or late: days 3-5) are associated with 21-day transplant-free survival in non-APAP ALF. METHODS: FABP1 was measured in serum samples from 384 ALF patients (n = 88 transplant-free survivors (TFS), n = 296 died/LT-NTFS) using solid-phase enzyme-linked immunosorbent assay and analyzed with US ALFSG registry data. RESULTS: Of 384 ALF patients (autoimmune hepatitis n = 125, drug-induced liver injury n = 141, Hepatitis B n = 118), 177 (46%) patients received LT. Early FABP1 levels were significantly higher in ALF patients requiring vasopressor support (203.4 vs. 76.3 ng/mL) and renal replacement therapy (203.4 vs. 78.8 ng/mL; p

Acute kidney injury (AKI) is associated with high perioperative mortality in patients undergoing liver transplantation (LT). In the era of Model of End-stage Liver Disease score-based allocation, more patients with impaired renal function are receiving LT. The majority of preoperative AKI is secondary to azotemia, including hepatorenal syndrome - a progressive form of renal impairment unique to liver failure. Prompt recognition and initiation of cause-directed therapies are central to improving post-transplant survival. Given that, the healthcare providers must develop an expertise in liver failure-related renal complications, specifically their management and perioperative implications. Notably, AKI may complicate intraoperative course, exacerbating hemodynamic instability, metabolic acidosis, and electrolyte and coagulation abnormalities. Adjunctive intraoperative continuous renal replacement therapy has been employed; however, prospective studies remain necessary to validate potential benefits.

Patients with acute-on-chronic liver failure (ACLF) can be listed for liver transplantation (LT) because LT is the only curative treatment option. We evaluated whether the clinical course of ACLF, particularly ACLF-3, between the time of listing and LT affects 1-year post-transplant survival.We identified patients from the United Network for Organ Sharing database who were transplanted within 28 days of listing and categorized them by ACLF grade at waitlist registration and LT, according to the EASL-CLIF definition.A total of 3,636 patients listed with ACLF-3 underwent LT within 28 days. Among those transplanted, 892 (24.5%) recovered to no ACLF or ACLF grade 1 or 2 (ACLF 0-2) and 2,744 (75.5%) had ACLF-3 at transplantation. One-year survival was 82.0% among those transplanted with ACLF-3 vs. 88.2% among those improving to ACLF 0-2 (p 0.001). Conversely, the survival of patients listed with ACLF 0-2 who progressed to ACLF-3 at LT (n = 2,265) was significantly lower than that of recipients who remained at ACLF 0-2 (n = 17,631) at the time of LT (83.8% vs. 90.2%, p 0.001). Cox modeling demonstrated that recovery from ACLF-3 to ACLF 0-2 at LT was associated with reduced 1-year mortality after transplantation (hazard ratio0.65; 95% CI 0.53-0.78). Improvement in circulatory failure, brain failure, and removal from mechanical ventilation were also associated with reduced post-LT mortality. Among patients60 years of age, 1-year survival was significantly higher among those who improved from ACLF-3 to ACLF 0-2 than among those who did not.Improvement from ACLF-3 at listing to ACLF 0-2 at transplantation enhances post-LT survival, particularly in those who recovered from circulatory or brain failure, or were removed from the mechanical ventilator. The beneficial effect of improved ACLF on post-LT survival was also observed among patients60 years of age.Liver transplantation (LT) for patients with acute-on-chronic liver failure grade 3 (ACLF-3) significantly improves survival, but 1-year survival probability after LT remains lower than the expected outcomes for transplant centers. Our study reveals that among patients transplanted within 28 days of waitlist registration, improvement of ACLF-3 at listing to a lower grade of ACLF at transplantation significantly enhances post-transplant survival, even among patients aged 60 years or older. Subgroup analysis further demonstrates that improvement in circulatory failure, brain failure, or removal from mechanical ventilation have the strongest impact on post-transplant survival.

Actes publiés dans le Canadian Liver Journal; vol. 2, no. 4, Fall 2019, p. 137-170.

BACKGROUND AND AIMS Respiratory failure complicating acute liver failure (ALF) may preclude liver transplantation (LT). We evaluated the association between significant lung injury (SLI) and important clinical outcomes. METHODS Retrospective cohort study of 947 ALF patients with chest radiograph (CXR) and arterial blood gas (ABG) data enrolled in the US Acute Liver Failure Study Group (US-ALFSG) from January 1998 to December 2016. SLI was defined by moderate hypoxaemia (Berlin classification; PaO2 /FiO2

To evaluate the feasibility of intraoperative continuous renal replacement therapy (IoCRRT) during liver transplantation (LT), in terms of recruitment, protocol adherence, and ascertainment of follow-up. In this pilot randomized open-label controlled trial in adults receiving LT with a Model for End-Stage Liver Disease (MELD) score ≥ 25 and preoperative acute kidney injury (RIFLE - RISK or higher) and/or estimated glomerular filtration rate < 60 mL·min−1·1.73 m−2, patients were randomized to receive IoCRRT or standard of care (SOC). Primary endpoints were feasibility and adverse events. Primary analysis was intention-to-treat (n = 32) and secondary analysis was per-protocol (n = 28). The trial was stopped early because of slow patient accrual and inadequate funding. Sixty patients were enrolled and 32 (53%) were randomized (n = 15 IoCRRT; n = 17 SOC). Mean (standard deviation) MELD was 36 (8), 81% (n = 26) had cirrhosis; 69% (n = 22) received preoperative RRT; 66% (n = 21) received LT from the intensive care unit. Four patients (n = 2 IoCRRT, n = 2 SOC) did not receive LT post-randomization. Seven patients (41%) allocated to SOC crossed over intraoperatively to IoCRRT. Three patients were lost to follow-up at one year. No adverse events occurred related to IoCRRT. There were no differences in survival at one year (IoCRRT, 71% [n = 10/14] vs SOC, 93% [n = 14/15]; risk ratio, 0.77; 95% confidence interval, 0.54 to 1.1). In the per-protocol analysis (n = 28 received IoCRRT after randomization - n = 20 IoCRRT, n = 8 SOC), one-year survival was 92% and perioperative complications were similar between groups. Only one patient was receiving dialysis one year after LT. In this pilot randomized trial, IoCRRT was feasible and safe with no difference in complications. Crossover rates were high. Despite high preoperative severity of illness, one-year survival was excellent. These data can inform the design of a larger multicentre trial. www.clinicalTrials.gov (NCT01575015); registered 12 April, 2012.

Background/objective Assessing prognosis for acetaminophen-induced acute liver failure (APAP-ALF) patients during the first week of hospitalization often presents significant challenges. Current models such as the King's College Criteria (KCC) and the Acute Liver Failure Study Group (ALFSG) Prognostic Index are developed to predict outcome using only a single time point on hospital admission. Models using longitudinal data are not currently available for APAP-ALF patients. We aim to develop and compare performance of prediction models for outcomes during the first week of hospitalization for APAP-ALF patients. Methods Models are developed for the ALFSG registry data to predict longitudinal outcomes for 1042 APAP-ALF patients enrolled 01/1998–02/2016. The primary outcome is defined as daily low versus high coma grade. Accuracy in prediction of outcome (AC), sensitivity (SN), specificity (SP) and area under the receiver operating curve (AUC) are compared between the following models: classification and regression tree, random forest, frequentist generalized linear mixed model (GLMM), Bayesian GLMM, BiMM tree, and BiMM forest using original and imputed datasets. Results BiMM tree offers predictive (test set) 63% AC, 72% SP and 53% SN for the original dataset, whereas BiMM forest offers predictive (test set) 69% AC, 63% SP and 74% SN for the imputed dataset. BiMM tree has the highest AUC for the original testing dataset (0.697), whereas BiMM forest and standard random forest have the highest AUC for the imputed testing dataset (0.749). The three most important predictors of daily outcome for the BiMM tree are pressor use, bilirubin and creatinine. The BiMM forest model identifies lactate, ammonia and ALT as the three most important predictors of outcome. Conclusions BiMM tree offers a prognostic tool for APAP-ALF patients, which has good accuracy and simple interpretation of predictors which are consistent with clinical observations. BiMM tree and forest models are developed using the first week of in-patient data and are appropriate for predicting outcome over time. While the BiMM forest has slightly higher predictive AC, the BiMM tree model is simpler to use at the bedside.

Patients listed for liver transplantation (LT) as status 1a currently receive the highest priority on the waiting list. The presence of acute on chronic liver failure (ACLF) with three or more organs failing (ACLF-3) portends low survival without transplantation, which may not be reflected by the Model for End-Stage Liver Disease-Sodium (MELD-Na) score. We compared short-term waitlist mortality for patients listed status 1a and those with ACLF-3 at listing. Data were analyzed from the United Network for Organ Sharing database, years 2002–2014, for 3,377 patients listed status 1a and 5,099 patients with ACLF-3. Candidates with ACLF were identified based on the European Association for the Study of the Liver Chronic Liver Failure Consortium criteria. MELD-Na score was treated as a categorical variable of scores 40. We used competing risks regression to assess waitlist mortality risk. Evaluation of outcomes through 21 days after listing demonstrated a rising trend in mortality among ACLF-3 patients at 7 days (18.0%), 14 days (27.7%), and 21 days (32.7%) (P < 0.001) compared to a stable trend in mortality among individuals listed as status 1a at 7 days (17.9%), 14 days (19.3%), and 21 days (19.8%) (P = 0.709). Multivariable modeling with adjustment for MELD-Na category revealed that patients with ACLF-3 had significantly greater mortality (subhazard ratio, 1.45; 95% confidence interval, 1.31–1.61) within 14 days of listing compared to status-1a candidates. Analysis of the interaction between MELD-Na category and ACLF-3 showed that patients with ACLF-3 had greater risk of 14-day mortality than status-1a-listed patients, across all three MELD-Na categories. CONCLUSION: Patients with ACLF-3 at the time of listing have greater 14-day mortality than those listed as status 1a, independent of MELD-Na score; these findings illustrate the importance of early transplant evaluation and consideration of transplant priority for patients with ACLF-3.

Acute kidney injury (AKI) in cirrhosis consists of varying phenotypes, with hepatorenal syndrome (HRS) representing a single entity. Prompt recognition and diagnosis of AKI cause identifies appropriate therapeutic measures. This review provides an overview of AKI definitions, highlights challenges in quantifying renal impairment in cirrhosis, lists novel diagnostic AKI biomarkers, and summarizes transplantation implications.Biomarkers (neutrophil gelatinase-associated lipocalin, kidney injury molecule-1, interleukin-18, and liver-type fatty acid-binding protein) may assist in the identification of underlying acute tubular necrosis. Of these, neutrophil gelatinase-associated lipocalin is the most promising; however, significant overlap occurs among AKI phenotypes, with diagnostic values yet to be defined. Mainstay treatment of HRS consists of albumin and vasopressors. Acute-on-chronic liver failure grade independently predicts response to terlipressin treatment. Many end-stage liver disease patients with AKI have underlying chronic kidney disease with important implications on pre and postliver transplantation mortality. Simultaneous liver-kidney transplant candidacy is based on low likelihood of renal recovery.Novel biomarkers may assist in identification of acute tubular necrosis and persistent/severe AKI. Norepinephrine has been suggested to be inferior to terlipressin, with additional research required. Increasing acute-on-chronic liver failure grade correlates with lower likelihood of vasopressor response in HRS. Severe preliver transplantation AKI confers significantly worse postliver transplantation renal outcomes.

Summary: Cirrhosis is a leading cause of morbidity and mortality throughout the world. Significant complications include variceal bleeding, hepatic encephalopathy, hepatorenal syndrome, and infection. When these complications are severe, admission to the intensive care unit (ICU) is often required for organ support and management. Intensive care therapy can also serve as a bridge to liver transplantation. Along with decompensation of cirrhosis, the concept of acute-on-chronic liver failure (ACLF) has emerged. This involves an acute precipitating event, such as the development of infection in a patient with cirrhosis, which leads to acute deterioration of hepatic function and extrahepatic organ failure. Extrahepatic complications often include renal, cardiovascular, and respiratory failures. Patients with significant extrahepatic and hepatic failures need ICU admission for organ support. Again, in patients who are deemed suitable liver transplant candidates, intensive care management may allow bridging to liver transplantation. However, patients with a Chronic Liver Failure Consortium ACLF score greater than 70 at 48 to 72 hours post-ICU admission do not seem to benefit from ongoing intensive support and a palliative approach may be more appropriate.

Acute kidney injury (AKI) is a common condition following liver transplantation (LT). It negatively impacts patient outcomes by increasing the chances of developing chronic kidney disease and reducing graft and patient survival rates. Multiple definitions of AKI have been proposed and used throughout the years, with the International Club of Ascites definition being the most widely now used for patients with cirrhosis. Multiple factors are associated with the development of post-LT AKI and can be categorized into pre-LT comorbidities, donor and recipient characteristics, operative factors, and post-LT factors. Many of these factors can be optimized in an attempt to minimize the risk of AKI occurring and to improve renal function if AKI is already present. A special consideration during the post-LT phase is needed for immunosuppression as certain immunosuppressive medications can be nephrotoxic. The calcineurin inhibitor tacrolimus (TAC) is the mainstay of immunosuppression but can result in AKI. Several strategies including use of the monoclonoal antibody basilixamab to allow for delayed initiation of tacrolimus therapy and minimization through combination and minimization or elimination of TAC through combination with mycophenolate mofetil or mammalian target of rapamycin inhibitors have been implemented to reverse and avoid AKI in the post-LT setting. Renal replacement therapy may ultimately be required to support patients until recovery of AKI after LT. Overall, by improving renal function in post-LT patients with AKI, outcomes can be improved.

Acute liver failure (ALF) is a rare disease with potentially high mortality. We sought to assess the individual approach to ALF by intensive care unit (ICU) professionals.Cross-sectional survey of ICU professionals. Web-based survey capturing data on respondents' demographics, characteristics of patients with ALF admitted to ICU, and their management.Among 204 participants from 50 countries, 140 (68.6%) worked in Europe, 146 (71.6%) were intensivists, 142 (69.6%) admitted25 patients with ALF per year, and 166 (81.8%) reported25% of patients had paracetamol-related ALF. On patients' outcomes, 126 (75.0%) reported an emergency liver transplantation (ELT) rate25% and 140 (73.3%) a hospital mortality rate50%. The approach to ALF in the ICU varied with age, region, level of training, type of hospital, and etiology (prescribing N-acetylcysteine for paracetamol toxicity, triggers for endotracheal intubation, measurement of and strategies for lowering serum ammonia, extracorporeal device deployment, and prophylactic antibiotics).The management of patients with ALF by ICU professionals differed substantially concerning the relevant clinical measures taken. Further education and high-quality research are warranted.A falência hepatica aguda (ALF) é uma doença rara potencialmente letal. Pretendeu-se avaliar a abordagem individual à ALF por profissionais da Unidade de Cuidados Intensivos (UCI).Inquérito transversal de profissionais da UCI. Inquérito online capturando informação da demografia dos respondedores, características dos doentes com ALF admitidos na UCI e sua abordagem.Entre 204 participantes de 50 países, 140 (68.6%) trabalhavam na Europa, 146 (71.6%) eram inten-sivistas, 142 (62.9%) admitiam25 doentes com ALF por ano, e 166 (81.8%) reportaram25% dos doentes com ALF relacionada com paracetamol. Quanto aos resultados dos doentes, 126 (75.0%) reportaram uma taxa de transplantação hepatica emergente (ELT)25% e 140 (73.3%) uma taxa de mortalidade hospitalar50%. A abordagem da ALF variou com a idade, região, nível de treino, tipo de hospital, ou etiologia nos seguintes tópicos: prescrição de N-acetil-cisteína, critérios de intubação orotraqueal, medição e estratégias de control da amoniémia, uso de técnicas extracorporais, e a prescrição de antibióticos profilácticos.A abordagem de doentes com ALF por profissionais da UCI diferiu substancialmente em aspectos clínicos importantes. Educação e investigação de qualidade adicionais serão necessárias.

Background & Aims Acetaminophen (APAP)-induced acute liver failure (ALF) remains the most common cause of ALF in the Western world. Conventional prognostic models, utilising markers of liver injury and organ failure, lack sensitivity for mortality prediction. We previously identified a microRNA signature that is associated with successful regeneration post-auxiliary liver transplant and with recovery from APAP-ALF. Herein, we aimed to use this microRNA signature to develop outcome prediction models for APAP-ALF. Methods We undertook a nested, case-control study using serum samples from 194 patients with APAP-ALF enrolled in the US ALF Study Group registry (1998-2014) at early (day 1-2) and late (day 3-5) time-points. A microRNA qPCR panel of 22 microRNAs was utilised to assess microRNA expression at both time-points. Multiple logistic regression was used to develop models which were compared to conventional prognostic models using the DeLong method. Results Individual microRNAs confer limited prognostic value when utilised in isolation. However, incorporating them within microRNA-based outcome prediction models increases their clinical utility. Our early time-point model (AUC = 0.78, 95% CI 0.71–0.84) contained a microRNA signature associated with liver regeneration and our late time-point model (AUC = 0.83, 95% CI 0.76–0.89) contained a microRNA signature associated with cell-death. Both models were enhanced when combined with model for end-stage liver disease (MELD) score and vasopressor use and both outperformed the King’s College criteria. The early time-point model combined with clinical parameters outperformed the ALF Study Group prognostic index and the MELD score. Conclusions Our findings demonstrate that a regeneration-linked microRNA signature combined with readily available clinical parameters can outperform existing prognostic models for ALF in identifying patients with poor prognosis who may benefit from transplantation. Lay summary While acute liver failure can be reversible, some patients will die without a liver transplant. We show that blood test markers that measure the potential for liver recovery may help improve identification of patients unlikely to survive acute liver failure who may benefit from a liver transplant.

Background Acute liver failure (ALF) remains a rare but life-threatening condition which requires early prognostication for transplantation (LTx). Existing models such as the King’s College Criteria (KCC) lack sensitivity. We have previously demonstrated the potential for regeneration linked miRNA to perform as biomarkers in acute and chronic liver disease. The aim of this study was to develop a miRNA-based prognostic model for acetaminophen (APAP) ALF. Methods Samples were provided by the US ALF Study Group. We assessed serum miRNA expression from 193 patients (94 survivors, 89 non-survivors) with APAP-ALF at two time points (early; day 1, late; day 3–5). Transplanted patients were excluded. A panel of 24 miRNA identified from our previous studies were analysed. Multiple logistic regression was used to create early and late miRNA outcome prediction models. Clinical data were incorporated to improve prognostication. Results Early up-regulation of miR-150 and down-regulation of -16–2 were associated with mortality. The early detection of miR-20a and absence of miR-149 were associated with mortality. Late up-regulation of miR-30a and down-regulation of -122, 16–2 and -21 were significantly associated with mortality. Late detection of miR-149, -17 and -191 were associated with mortality. Prognostic models were made for early and late miRNA expression. The early model contained miRNA associated with regeneration (miR-20a, -27a, -140, -150, -191) and achieved an area under the receiver operator curve (AUC) of 0.78 (95% CI 0.71–0.84, p Conclusion We demonstrate that specific serum miRNA have prognostic value as biomarkers in ALF. Our early model utilised regeneration linked miRNA whereas our late model utilised cell-death linked miRNA; this may signify mechanistic differences at early and late time points which determine patient survival.

Acute liver failure (ALF) is a rare disease that may lead to cerebral edema and death. An increased optic nerve sheath diameter (ONSD) may reflect an early increase in intracranial pressure. We assessed the feasibility and safety of the ONSD measurement and its association with outcomes in patients with ALF.This was an open-label prospective cohort study including adult patients with ALF admitted to a liver-specialized intensive care unit (ICU) in an academic center between October 2018 and February 2020 (among 24): 20 as intention-to-treat and 17 as per-protocol analyses. The ONSD measurement (primary exposure) used an ultrasound transducer (3 determinations on each eye per patient). The primary outcome was hospital mortality.Among the 20 patients, 11 (55.0%) were females and the mean age was 45 ± 16 years. On the day of ONSD measurement (median 32.4 h post-ICU admission; IQR 19.8-59.8): 8 patients (40.0%) were in a coma, the mean international normalized ratio (INR) was 3.3 ± 1.4, median bilirubin was 12.3 mg/dL (IQR 4.7-24.5), mean ammonia was 163 ± 101 µmol/L, and mean SOFA score was 11 ± 5. The mean bilateral ONSD was 5.6 ± 0.7 mm, with a very good correlation between right and left eyes (Pearson'sIn patients with ALF, a higher ONSD was associated with higher hospital mortality. ONSD measurement is feasible and safe and may have prognostic value.A falência hepatica aguda (ALF) é uma doença rara que pode complicar com edema cerebral e morte. O aumento do diâmetro da bainha do nervo óptico (ONSD) pode reflectir um aumento precose da pressão intracraniana. Avaliámos a viabilidade e segurança da medição do ONSD e a sua associação com os resultados de doentes com ALF.Coorte prospectivo aberto incluindo doentes adultos com ALF admitidos numa unidade de cuidados intensivos (ICU) especializada em fígado entre 10/2018 e 02/2020 (em 24): 20 como análise intenção-de-tratar e 17 como análise por-protocolo. A medição do ONSD (exposição primária) foi realizada com um transdutor ultra-sónico (3 medições em cada olho por doente). O resultado primário foi a mortalidade hospitalar.Entre 20 doentes, 11 (55.0%) eram mulheres e a idade média (SD) foi 45 (16) anos. No dia da medição do ONSD (mediana (IQR) de 32.4 (19.8–59.8) horas pós admissão na ICU): coma em 8 (40.0%) doentes, INR médio (SD) de 3.3 (1.4), bilirrubina mediana (IQR) de 12.3 (4.7–24.5) mg/dL, amónia média (SD) de 163 (101) μmol/L, e SOFA médio (SD) de 11 (5). O ONSD bilateral médio (SD) foi de 5.6 (0.7) mm, com boa correlação entre os olhos (PearsonEm doentes com ALF, maior ONSD esteve associado com maior mortalidade hospitalar. A medição do ONSD é viável, segura, e poderá ter valor prognóstico.

High volume plasmapheresis (HVP) is defined as an exchange of 8-12 L or 15% of ideal body weight with fresh-frozen plasma. It has been reported that HVP can improve outcomes in patients with acute liver failure (ALF) and/or acute-on-chronic liver failure (ACLF). Here, we present a case of a 34-year-old man presenting with ALF that led to multi-organ failure who received HVP in the intensive care unit that improved his biochemical parameters, volume status, and hemodynamics. However, despite objective clinical and biochemical improvements, the patient had developed signs of potential brain injury, and subsequently the family withdrew care. This case and the associated literature review highlight the potential value of HVP in facilities who do not have access to liver transplantation or other means of extracorporeal liver support systems.

Background: Mortality for patients with acute‐on‐chronic liver failure (ACLF) may be underestimated by the model for end‐stage liver disease‐sodium (MELD‐Na) score. / Aim: To assess waitlist outcomes across varying grades of ACLF among a cohort of patients listed with a MELD‐Na score ≥35, and therefore having similar priority for liver transplantation. / Methods: We analysed the United Network for Organ Sharing (UNOS) database, years 2010‐2017. Waitlist outcomes were evaluated using Fine and Gray's competing risks regression. / Results: We identified 6342 candidates at listing with a MELD‐Na score ≥35, of whom 3122 had ACLF‐3. Extra‐hepatic organ failures were present primarily in patients with four to six organ failures. Competing risks regression revealed that candidates listed with ACLF‐3 had a significantly higher risk for 90‐day waitlist mortality (Sub‐hazard ratio (SHR) = 1.41; 95% confidence interval [CI] 1.12‐1.78) relative to patients with lower ACLF grades. Subgroup analysis of ACLF‐3 revealed that both the presence of three organ failures (SHR = 1.40, 95% CI 1.20‐1.63) or four to six organ failures at listing (SHR = 3.01; 95% CI 2.54‐3.58) was associated with increased waitlist death. Candidates with four to six organ failures also had the lowest likelihood of receiving liver transplantation (SHR = 0.61, 95% CI 0.54‐0.68). The Share 35 rule was associated with reduced 90‐day waitlist mortality among the full cohort of patients listed with ACLF‐3 and MELD‐Na score ≥35 (SHR = 0.59; 95% CI 0.49‐0.70). However, Share 35 rule implementation was not associated with reduced waitlist mortality among patients with four to six organ failures (SHR = 0.76; 95% CI 0.58‐1.02). / Conclusion: The MELD‐Na score disadvantages patients with ACLF‐3, both with and without extra‐hepatic organ failures. Incorporation of organ failures into allocation policy warrants further exploration.

KEY POINTS Demand for organs continues to exceed their availability, both in Canada and around the world.[1][1] Optimizing the medical management of potential organ donors is an important strategy for enhancing organ supply. The explicit goals for management of deceased organ donors in the intensive

Recent data have demonstrated >80% 1-year survival probability after liver transplantation (LT) for patients with severe acute-on-chronic liver failure (ACLF). However, longterm outcomes and complications are still unknown for this population. Our aim was to compare longterm patient and graft survival among patients transplanted across all grades of ACLF. We analyzed the United Network for Organ Sharing database for the years 2004-2017. Patients with ACLF were identified using the European Association for the Study of the Liver-Chronic Liver Failure criteria. Kaplan-Meier and Cox regression methods were used to determine patient and graft survival and associated predictors of mortality in adjusted models. A total of 56,801 patients underwent transplantation of which 31,024 (54.6%) had no ACLF, 8757 (15.4%) had ACLF grade 1, 9039 (15.9%) had ACLF grade 2, and 7891 (14.1%) had ACLF grade 3. The 5-year patient survival after LT was lower in the ACLF grade 3 patients compared with the other groups (67.7%; P

Purpose: We aimed to study the effect of FB in the outcomes of critically-ill patients with cirrhosis. Materials: Retrospective analysis of all adult consecutive admissions of patients with cirrhosis and organ failures to the Intensive Care Unit (ICU) at Curry Cabral Hospital (Lisbon, Portugal) and University of Alberta Hospital (Edmonton, Canada) on 08/2013-08/2017. Primary exposure was FB at 3 and 7 days post ICU admission. Primary endpoint was hospital mortality. Results: Amongst 333 patients, median age was 56 years and 67.6% were men. Median MELD, APACHEII, CLIF-SOFA, and CLIF-C-ACLF scores on ICU admission were 27, 28, 14, and 54, respectively. ICU and hospital mortality rates were 33.0% and 49.2%, respectively. While median FB at 3 days post ICU admission (+5.46 l vs. +6.62 l; P = 0.74) was not associated with hospital mortality, higher median FB at 7 days post ICU admission (+13.50 l vs. +6.90 l; P = 0.036) was associated with higher hospital mortality. This association remained significant (OR 95%CI = 1.04 [1.01;1.07] per each l) after adjustment for confounders (age, ascites, infection, lactate, and number of organ failures). Conclusions: FB may be a therapeutic target that helps to improve the outcomes of patients with acute-on-chronic liver failure. This data may inform future clinical trials. info:eu-repo/semantics/publishedVersion

Objectives To develop evidence-based recommendations for clinicians caring for adults with acute or acute on chronic liver failure in the ICU. Design The guideline panel comprised 29 members with expertise in aspects of care of the critically ill patient with liver failure and/or methodology. The Society of Critical Care Medicine standard operating procedures manual and conflict-of-interest policy were followed throughout. Teleconferences and electronic-based discussion among the panel, as well as within subgroups, served as an integral part of the guideline development. Setting The panel was divided into nine subgroups: cardiovascular, hematology, pulmonary, renal, endocrine and nutrition, gastrointestinal, infection, perioperative, and neurology. Interventions We developed and selected population, intervention, comparison, and outcomes questions according to importance to patients and practicing clinicians. For each population, intervention, comparison, and outcomes question, we conducted a systematic review aiming to identify the best available evidence, statistically summarized the evidence whenever applicable, and assessed the quality of evidence using the Grading of Recommendations Assessment, Development, and Evaluation approach. We used the evidence to decision framework to facilitate recommendations formulation as strong or conditional. We followed strict criteria to formulate best practice statements. Measurements and main results In this article, we report 29 recommendations (from 30 population, intervention, comparison, and outcomes questions) on the management acute or acute on chronic liver failure in the ICU, related to five groups (cardiovascular, hematology, pulmonary, renal, and endocrine). Overall, six were strong recommendations, 19 were conditional recommendations, four were best-practice statements, and in two instances, the panel did not issue a recommendation due to insufficient evidence. Conclusions Multidisciplinary international experts were able to formulate evidence-based recommendations for the management acute or acute on chronic liver failure in the ICU, acknowledging that most recommendations were based on low-quality indirect evidence.

Background Acute liver failure (ALF) can result in irreversible shock, cerebral herniation or development of multiple organ failure (MOF). One randomized study and a separate case series have demonstrated the safety and potential improvement in transplant-free survival with the use of high volume plasmapheresis (HVP). HVP is defined as an exchange of 8-12L or 15% of ideal body weight with fresh frozen plasma. In ALF, cytokines are responsible for the progression of MOF and HVP removes these cytokines from the systemic circulation. We report a case of implementing HVP in an adult with ALF in the intensive care unit (ICU) at a tertiary care center. Aims This case and the associated literature review highlight the value of HVP in ALF. Methods Case report and literature review. Results We report a case of a 34-year-old male who presented in ALF secondary to unknown ingestion. He was admitted to the ICU for worsening transaminitis, coagulopathy, hepatic encephalopathy, renal failure and hemodynamic instability which required vasopressor and ventilatory support. A discussion was made with hepatologists at a regional transplant center for potential consideration of either transplant or Molecular Adsorbent Recirculating System (MARS) therapy. However, the patient was too hemodynamically unstable for transport and also began to develop signs of cerebral edema. As a result, they recommended a trial of high volume plasmapheresis. Shortly after initiation, the patient’s hemodynamic, respiratory, and biochemical parameters began to improve, resulting in less vasopressor and ventilator support (Table 1). Despite improvements in these parameters, the patient’s cerebral edema continued to worsen and an electroencephalogram showed signs of a very low likelihood of functional neurological recovery. Given the overall picture, the patient’s spouse decided to withdraw care. Conclusions Presently, liver transplantation remains the only definitive management strategy for ALF patients, but many do not survive to liver transplant or are not candidates for medical or psychosocial reasons such as with this case. As a result, this case demonstrates the potential benefits of conducting HVP in centers without access to MARS or transplantation. However, although HVP did improve certain parameters for this patient, it did not improve overall prognosis. This suggests that prognosis may not improve once a certain threshold of MOF develops. Therefore, in this case and the associated literature review the optimal timing of initiating HVP remains unclear. Funding Agencies None

Patients with cirrhosis are frequently hospitalized with acute decompensation and organ system failure - a syndrome referred to as acute on chronic liver failure (ACLF). These patients often require critical care intervention and experience significant mortality; however, established diagnostic and prognostic criteria are lacking. Given this, it remains imperative for intensivists to develop an expertise in common ACLF complications and management.Liver transplantation serves as the definitive management strategy in ACLF. Traditional organ allocation procedures are based on the Model for Endstage Liver Disease score, which may not correlate with ACLF severity and the associated need for urgent liver transplantation. Recent studies have suggested favorable postliver transplantation outcomes in ACLF patients with multiorgan failure, emphasizing the need for further studies to elucidate optimal timing and candidacy for liver transplantation.Cirrhosis is a chronic and progressive condition leaving patients vulnerable to acute decompensation necessitating the need for critical care intervention. Prompt recognition and implementation of targeted supportive therapies, together with consideration of urgent liver transplantation, are essential to combat the high short-term mortality of ACLF patients.

Acute liver failure (ALF) is a rare syndrome resulting from an acute insult to the liver in patients without known underlying chronic liver disease. It is characterized by loss of synthetic function in the form of jaundice and coagulopathy and development of hepatic encephalopathy. Multiorgan failure (MOF) eventually develops, leading to death. Many different etiologies have been identified, with acetaminophen (APAP) overdose and viral hepatitis being the most common causes worldwide. The pathophysiology of ALF can be divided into cause-specific liver injury pathophysiologies and pathophysiology related to occurrence of secondary MOF. In terms of liver injury pathophysiology, APAP toxicity is the most well known. Secondary MOF is often a result of the initial massive proinflammatory response generating a systemic inflammatory response syndrome followed by a compensatory anti-inflammatory response leading to immune cell dysfunction and sepsis. As the liver is a tremendously important metabolic organ involved in energy metabolism, protein synthesis, fat metabolism, and glycemic control, multiple aspects of nutrition also need to be considered as part of the overall pathophysiology of ALF.

Respiratory complications before and after liver transplant are common, diverse, and potentially have a negative impact on patient outcomes. In this review, we discuss the most frequent respiratory conditions that patients may develop in the perioperative period. Their prevention and/or treatment may help to maximize the benefit these patients may derive from liver transplant. This review examines diagnostic and therapeutic approaches to these complications for hepatologists, surgeons, and critical care physicians. info:eu-repo/semantics/publishedVersion

Tumor necrosis factor-α antagonists (anti-TNF-α) have been associated with drug-induced liver injury. However, cases of anti-TNF-α-associated acute liver failure have only been rarely reported. To identify cases of anti-TNF-α-associated acute liver failure and evaluate patterns of liver injury and common characteristics to the cases. The United States Acute Liver Failure Study Group database was searched from 1998 to 2014. Four subjects were identified. A PubMed search for articles that reported anti-TNF-α-associated acute liver failure identified five additional cases. The majority of individuals affected were female (eight of nine cases). Age of individual ranged from 20 to 53 years. The most common anti-TNF-α agent associated with acute liver failure was infliximab (n = 8). The latency between initial drug exposure and acute liver failure ranged from 3 days to over a year. Of the nine cases, six required emergency LT. Liver biopsy was obtained in seven cases with a preponderance toward cholestatic–hepatitic features; none showed clear autoimmune features. Anti-TNF-α-associated acute liver failure displays somewhat different characteristics compared with anti-TNF-α-induced drug-induced liver injury. Infliximab was implicated in the majority of cases. Cholestatic–hepatitic features were frequently found on pre-transplant and explant histology.

Acetaminophen (APAP)-induced acute liver failure (ALF) is a rare disease associated with high mortality rates. This study aimed to evaluate changes in interventions, psychosocial profile, and clinical outcomes over a 21-year period using data from the ALF Study Group registry.A retrospective review of this prospective, multicenter cohort study of all APAP-ALF patients enrolled during the study period (1998-2018) was completed. Primary outcomes evaluated were the 21-day transplant-free survival (TFS) and neurologic complications. Covariates evaluated included enrollment cohort (early, 1998-2007; recent, 2008-2018), intentionality, psychiatric comorbidity, and use of organ support including continuous renal replacement therapy (CRRT).Of 1190 APAP-ALF patients, recent cohort patients (n = 608) had significantly improved TFS (recent, 69.8% vs early, 61.7%; P = .005). Recent cohort patients were more likely to receive CRRT (22.2% vs 7.6%; P.001), and less likely to develop intracranial hypertension (29.9% vs 51.5%; P.001) or die by day 21 from cerebral edema (4.5% vs 11.6%; P.001). Grouped by TFS status (non-TFS, n = 365 vs TFS, n = 704), there were no differences in psychiatric comorbidity (51.5% vs 55.0%; P = .28) or intentionality (intentional, 39.7% vs 41.6%; P = .58). On multivariable logistic regression adjusting for vasopressor support, development of grade 3/4 hepatic encephalopathy, King's College criteria, and MELD score, the use of CRRT (odds ratio, 1.62; P = .023) was associated with significantly increased TFS (c-statistic, 0.86). In a second model adjusting for the same covariates, recent enrollment was associated significantly with TFS (odds ratio, 1.42; P = .034; c-statistic, 0.86).TFS in APAP-ALF has improved in recent years and rates of intracranial hypertension/cerebral edema have decreased, possibly related to increased CRRT use.

BACKGROUND & AIMS The prevalence of obesity in cirrhosis is rising. The impact of obesity in critically ill cirrhotic patients with sepsis/septic shock has not been evaluated. This study aimed to examine the relationship between obesity and mortality in cirrhotic patients admitted to the intensive care unit with septic shock. METHODS A retrospective cohort study of all cirrhotic patients with septic shock (n = 362) and a recorded body mass index (BMI) from an international, multicentre (CATSS) database (1996-2015) was performed. Patients were classified by BMI as per WHO categories. Primary outcome was in-hospital mortality. Multivariate logistic regression analyses were carried out to determine independent associations with outcome. RESULTS In this analysis, mean age was 56.4 years, and 62% were male. Median BMI was 26.3%, and 57.7% were overweight/obese. In-hospital mortality was 71%. Obese patients were more likely to have comorbidities of cardiac disease, lung disease and diabetes. Compared to survivors (n = 105), non-survivors (n = 257) had significantly higher MELD and APACHEII scores and higher requirements for renal replacement therapy and mechanical ventilation (P

Patients with cirrhosis who are awaiting liver transplantation (LT) are at high risk for developing critical illnesses. Current liver allocation policies that dictate a "sickest first" approach coupled with a mismatch between need and availability of organs result in longer wait times, and thus, patients are becoming increasingly ill while awaiting organ transplantation. Even patients with well-compensated cirrhosis may suffer acute deterioration; the syndrome of acute-on-chronic liver failure (ACLF) results in multisystem organ dysfunction and a marked increase in associated short-term morbidity and mortality. For patients on transplant waiting lists, the development of multisystem organ failure may eliminate candidacy for transplant by virtue of being "too sick" to safely undergo transplantation surgery. The goals of intensive care management of patients suffering ACLF are to rapidly recognize and treat inciting events (eg, infection and bleeding) and to aggressively support failing organ systems to ensure that patients may successfully undergo LT. Management of the critically ill ACLF patient awaiting transplantation is best accomplished by multidisciplinary teams with expertise in critical care and transplant medicine. Such teams are well suited to address the needs of this unique patient population and to identify patients who may be too ill to proceed to transplantation surgery. The focus of this review is to identify the common complications of ACLF and to describe our approach management in critically ill patients awaiting LT in our centers. Liver Transplantation 23 1465-1476 2017 AASLD.

Background Acetaminophen (APAP)-induced acute liver failure (ALF) is associated with significant mortality due to intracranial hypertension (ICH), a result of cerebral edema (CE) and astrocyte swelling. Brain-type fatty acid-binding protein (FABP7) is a small (15 kDa) cytoplasmic protein abundantly expressed in astrocytes. The aim of this study was to determine whether serum FABP7 levels early (day 1) or late (days 3–5) level were associated with 21-day mortality and/or the presence of ICH/CE in APAP-ALF patients. Methods Serum samples from 198 APAP-ALF patients (nested case–control study with 99 survivors and 99 non-survivors) were analyzed by ELISA methods and assessed with clinical data from the US Acute Liver Failure Study Group (ALFSG) Registry (1998–2014). Results APAP-ALF survivors had significantly lower serum FABP7 levels on admission (147.9 vs. 316.5 ng/ml, p = 0.0002) and late (87.3 vs. 286.2 ng/ml, p

Acute liver failure is a rare but potentially devastating disease. Throughout the last few decades, acute liver failure outcomes have been improving in the context of the optimized overall management. This positive trend has been associated with the earlier recognition of this condition, the improvement of the intensive care unit management, and the developments in emergent liver transplantation. Accordingly, we aimed to review the current diagnostic and therapeutic approach to this syndrome, especially in the intensive care unit setting. info:eu-repo/semantics/publishedVersion

Background/Aim Acetaminophen (APAP)-induced Acute Liver Failure (ALF) is associated with significant mortality. Traditional prognostic scores lack sensitivity. Hypothesis: Serum Liver-type Fatty Acid Binding Protein (FABP1) early (day 1) or late (day 3–5) levels are associated with 21-day mortality in the absence of liver transplant. Methods Serum samples from 198 APAP-ALF patients (nested case control study with 99 survivors, 99 non-survivors) were analyzed by ELISA methods and assessed with clinical data from the US Acute Liver Failure Study Group (ALFSG) Registry (1998–2014). Results APAP-ALF survivors had significantly lower serum FABP1 levels early (238.6 vs. 690.8 ng/ml, p 350 ng/ml was associated with significantly higher risk of death at early (p=0.0004) and late (p

Acute liver failure (ALF) caused by hepatitis B virus (HBV) infection can occur after immunosuppressive treatment and be fatal, although it might be preventable. We aimed to characterize the causes, clinical course, and short-term outcomes of HBV-associated ALF after immune-suppressive therapy, compared with patients with HBV-associated ALF without immunosuppression (control subjects).We performed a retrospective multicenter study of 156 consecutive patients diagnosed with HBV-associated ALF (22 with a solid or blood malignancy) enrolled in the Acute Liver Failure Study Group registry from January 1998 through April 2015. We collected data on results of serologic and hepatic biochemistry analyses, grade of hepatic encephalopathy, Model for End-Stage Liver Disease score, and King's College criteria. We also collected data on clinical features, medical therapies, and complications in the first 7 days following study enrollment. Logistic regression was used to identify factors associated with transplant-free survival at 21 days in HBV-associated ALF (the primary outcome).Among patients with HBV-associated ALF, 28 cases (18%) occurred after immunosuppressive therapy (15 patients received systemic corticosteroids and 21 received chemotherapy); and 128 cases did not (control subjects, 82%). Significantly greater proportions of patients with HBV-associated ALF after immunosuppression were nonwhite persons, and had anemia or thrombocytopenia than controls (P.02 for all). The serologic profile of HBV infection, severity of liver failure (based on MELD score), and complications (hepatic encephalopathy or need for mechanical ventilation, vasopressors, or renal replacement therapy) were similar between the groups (P.17 for all). Factors associated with 21 day transplant-free survival were increased MELD score (odds ratio ∼OR, 0.894 (95% confidence interval 0.842-0.949 per increment), requirement for mechanical ventilation (OR 0.111(0.041-0.300), and immunosuppressive therapy (OR 0.274(0.082-0.923)).Within a cohort study of patients with HBV-associated ALF, 18% had received immunosuppressive therapy. Significantly smaller proportions of patients with HBV-associated ALF after immunosuppression survive beyond 21 days than patients with HBV-associated ALF who did not receive immunosuppression. Patients undergoing chemotherapy should be screened for HBV infection and given appropriate antiviral therapies to reduce preventable mortality.

Purpose We evaluated the Chronic Liver Failure–Sequential Organ Failure Assessment (CLIF-SOFA) score to predict survival in a Canadian critically ill cohort with acute-on-chronic liver failure. Methods We retrospectively examined 274 acute-on-chronic liver failure patients admitted to a quaternary level intensive care unit (ICU) between April 1, 2000, and April 30, 2011. We evaluated severity of illness scores, including the Acute Physiology and Chronic Health Evaluation (APACHE) II, model for end-stage liver disease (MELD), Child-Turcotte-Pugh (CTP), SOFA, and CLIF-SOFA. Results On ICU admission, patients had the following median (interquartile range): APACHE II, 23 (19-28); MELD, 26 (19-35); CTP, 12 (10-13); SOFA, 15 (11-18); and CLIF-SOFA, 17 (13-21). In-hospital survival was 40%. There were no significant differences in survival for cirrhosis etiology, reason, or year of admission. The CLIF-SOFA score had the greatest area under receiver operating curve of 0.865 (95% confidence interval, 0.820-0.909) and outperformed the CTP, MELD, SOFA, and APACHE II scores. Sequential Organ Failure Assessment score performance improved on the third day of ICU admission (area under receiver operating curve, 0.935; 95% confidence interval, 0.895-0.975). Conclusions The CLIF-SOFA and SOFA scores during the first 3 days of ICU admission appear to be highly predictive of in-hospital mortality.

Background and aims Hepatic encephalopathy (HE) is a leading contributor to morbidity in liver disease. While hyperammonaemia plays a key role, the mechanisms of cerebral toxicity are unclear. We hypothesized that serum hyperosmolality contributes to HE during acute (ALF) and acute-on-chronic liver failure (ACLF) through mechanisms that affect the water and solute composition of the cerebral environment. Methods We performed a retrospective analysis of serum osmolality, cerebral spinal fluid (CSF) solute density (specific gravity, determined from computed tomography attenuation) and clinical HE severity (Glasgow Coma Score [GCS]) at the time of intensive care admission in a prospectively identified cohort of liver failure patients with overt HE. Results Seventy-three patients (39 ALF and 34 ACLF) were included, of whom 28 (38%) were comatose. Serum osmolality (303.9 ± 15.4 mOsm/kg) was elevated despite normal serum sodium (136.6 ± 6.3 mEq/L). Increased osmolality was independently associated with more severe encephalopathy (ordinal adjusted OR 0.26 [95% CI 0.22, 0.31] for higher GCS per standard deviation increase in osmolality) and lower CSF-specific gravity (linear adjusted β = -0.039 [95% CI -0.069, -0.009] Hounsfield unit per 1 mOsm/kg). Conclusions In the context of related research, these data suggest that hyperosmolality increases brain exposure to metabolic toxins by blood-brain barrier alteration and may be a unique therapeutic target.

Cholecystitis-associated septic shock carries a significant mortality. Our aim was to determine whether timing of source control affects survival in cholecystitis patients with septic shock.We conducted a nested cohort study of all patients with cholecystitis-associated septic shock from an international, multicentre database (1996–2015). Multivariable logistic regression was performed to determine associations between clinical factors and in-hospital mortality. The results were used to inform a classification and regression tree (CART) analysis that modelled the association between disease severity (APACHE II), time to source control and survival.Among 196 patients with cholecystitis-associated septic shock, overall mortality was 37%. Compared with nonsurvivors (n = 72), survivors (n = 124) had lower mean admission APACHE II scores (21 v. 27, p0.001) and lower median admission serum lactate (2.4 v. 6.8 μmol/L, p0.001). Survivors were more likely to receive appropriate antimicrobial therapy earlier (median 2.8 v. 6.1 h from shock, p = 0.012). Survivors were also more likely to undergo successful source control earlier (median 9.8 v. 24.7 h from shock, p0.001). Adjusting for covariates, APACHE II (odds ratio [OR] 1.13, 95% confidence interval [CI] 1.06–1.21 per increment) and delayed source control16 h (OR 4.45, 95% CI 1.88–10.70) were independently associated with increased mortality (all p0.001). The CART analysis showed that patients with APACHE II scores of 15–26 benefitted most from source control within 16 h (p0.0001).In patients with cholecystitis-associated septic shock, admission APACHE II score and delay in source control (cholecystectomy or percutaneous cholecystostomy drainage) significantly affected hospital outcomes.Le choc septique associé à une cholécystite s’accompagne d’une mortalité significative. Notre but était de déterminer si le moment du contrôle de la source affecte la survie chez les patients atteints de cholécystite qui se trouvent en choc septique.Nous avons procédé à une étude de cohorte nichée regroupant tous les patients ayant présenté un choc septique associé à une cholécystite à partir d’une base de données multicentrique internationale (1996–2015). La régression logistique multivariée a été utilisée pour déterminer les liens entre les facteurs cliniques et la mortalité perhospitalière. Les résultats ont été utilisés pour éclairer une analyse par arbre de classification (CART) qui modélisait le lien entre la gravité de la maladie (APACHE II), le temps nécessaire au contrôle de la source et la survie.Parmi 196 patients souffrant d’un choc septique associé à une cholécystite, la mortalité globale a été de 37 %. Comparativement aux patients décédés (n = 72), les survivants (n = 124) présentaient à l’admission des scores APACHE II moyens plus bas (21 c. 27, p0,001) et un taux de lactate sérique médian plus bas (2,4 c. 6,8 μmol/L, p0,001). Les survivants étaient plus susceptibles de recevoir une antibiothérapie adéquate plus hâtive (médiane 2,8 c. 6,1 h suivant le choc, p = 0,012). Les survivants étaient aussi plus susceptibles de bénéficier plus hâtivement d’un contrôle réussi de la source (médiane 9,8 c. 24,7 h suivant le choc, p0,001). L’ajustement pour tenir compte des covariables du score APACHE II (rapport des cotes [RC] 1,13, intervalle de confiance [IC] de 95 % 1,06–1,21 par palier) et le retard du contrôle de la source16 h (RC 4,45, IC de 95 % 1,88–10,70) ont été associés indépendamment à une mortalité plus élevée (tous deux p0,001). L’analyse CART a révélé que les patients ayant des scores APACHE II de 15–26 ont le plus bénéficié d’un contrôle de la source dans les 16 h (p0,0001).Chez les patients présentant un choc septique associé à une cholécystite, le score APACHE II à l’admission et le retard de contrôle de la source (cholécystectomie ou drainage par cholécystotomie percutanée) ont significativement influé sur les résultats hospitaliers.

Nonalcoholic fatty liver disease (NAFLD) prevails in obesity and is linked to several health complications including dyslipidemia and atherosclerosis. How exactly NAFLD induces atherogenic dyslipidemia to promote cardiovascular diseases is still elusive. Here, we identify Tsukushi (TSK) as a hepatokine induced in response to NAFLD. We show that both endoplasmic reticulum stress and inflammation promote the expression and release of TSK in mice. In humans, hepatic TSK expression is also associated with steatosis, and its circulating levels are markedly increased in patients suffering from acetaminophen-induced acute liver failure (ALF), a condition linked to severe hepatic inflammation. In these patients, elevated blood TSK levels were associated with decreased transplant-free survival at hospital discharge, suggesting that TSK could have a prognostic significance. Gain- and loss-of-function studies in mice revealed that TSK impacts systemic cholesterol homeostasis. TSK reduces circulating HDL cholesterol, lowers cholesterol efflux capacity, and decreases cholesterol-to-bile acid conversion in the liver. Our data identify the hepatokine TSK as a blood biomarker of liver stress that could link NAFLD to the development of atherogenic dyslipidemia and atherosclerosis.

Patients with cirrhosis and concomitant coronary/valvular heart disease present a clinical dilemma. The therapeutic outcome of major cardiac surgery is significantly poorer in patients with cirrhosis compared with patients without cirrhosis. To address this, we aimed to identify associations between the severity of cirrhosis and post-cardiac surgical outcomes. A historical cohort analysis of patients undergoing cardiac surgery at the University of Alberta Hospital from January 2004 to December 2014 was used to identify and propensity score-match 60 patients with cirrhosis to 310 patients without cirrhosis. The relationships between cirrhosis and i) mortality, ii) postoperative complications, and iii) requirement of healthcare resources were evaluated. Ten-year mortality was significantly higher in cirrhotic patients compared with propensity score-matched non-cirrhotic patients (40% vs 20%; relative risk [RR], 2.0; 95% confidence interval [CI], 1.3 to 2.9; P = 0.001). Cirrhotic patients had more complications (63% vs 48%; RR, 1.3; 95% CI, 1.05 to 1.7; P = 0.02), longer median [interquartile range (IQR)] intensive care unit stays (5 [3–11] vs 2 [1–4] days; P < 0.001), time on mechanical ventilation (median [IQR] 2 [1–5] vs 1 [0.5–1.2] days; P < 0.001) and more frequently required renal replacement therapy (15% vs 6%; RR, 2.5; 95% CI, 1.2 to 5.2; P = 0.02) postoperatively. After adjusting for other covariates, presence of cirrhosis (adjusted odds ratio, 2.2; 95% CI, 1.1 to 4.1) and intraoperative transfusion (adjusted odds ratio, 3.2; 95% CI, 1.6 to 6.3) were independently associated with increased mortality. Despite having low median model for end-stage liver disease scores, this small series of cirrhotic patients undergoing cardiac surgery had significantly higher mortality rates and required more organ support postoperatively than propensity score-matched non-cirrhotic patients. Impact de la cirrhose chez les patients subissant une chirurgie cardiaque : une etude de cohorte observationnelle et retrospective

Cholangitis-associated septic shock carries significant mortality. There is uncertainty regarding the most appropriate time to achieve biliary decompression.To determine whether the timing of biliary decompression and anti-microbial therapy affect the survival in cholangitis patients with septic shock.Nested retrospective cohort study of all cholangitis-associated septic shock patients (hypotension requiring vasopressors) from an international, multi-centre database between 1996 and 2011.Among 260 patients (mean age 69 years, 57% male), overall mortality was 37%. Compared to nonsurvivors (n = 96), survivors (n = 164) had lower mean admission Acute Physiology And Chronic Health Evaluation (APACHE) II (22 vs. 28, P 0.001) and lower median serum lactate on admission (3.4 vs. 4.6 mmol/L, P 0.001). Survivors were more likely to receive appropriate anti-microbial therapy earlier (median 2.6 vs. 6.8 h from shock, P 0.001). Survivors were also more likely to undergo successful biliary decompression earlier (median 8.8 vs. 22 h, P 0.001). After adjusting for co-variates, APACHE II (odds ratio, OR 1.21 per increment (1.11-1.32), time delay to appropriate anti-microbial therapy [OR 1.15 per hour (1.07-1.25)] and delayed biliary decompression12 h [OR 3.40 (1.12-10.31)] were all significantly associated with increased mortality (P 0.04 for all; c-statistic 0.896).Patients with septic shock secondary to acute cholangitis have significant mortality. Endoscopic biliary decompression12 h after the onset of shock and delayed receipt of appropriate anti-microbial therapy were both significantly associated with adverse hospital outcome. This might suggest that early initiation of anti-microbial therapy and urgent biliary decompression (within 12 h) could potentially improve outcomes in this high-risk patient population.

Artificial (nonbiological) extracorporeal liver support devices aim to remove albumin-bound and water-soluble toxins to restore and preserve hepatic function and mitigate or limit the progression of multiorgan failure while hepatic recovery or liver transplant occurs. The following beneficial effects have been documented: improvement of jaundice, amelioration of hemodynamic instability, reduction of portal hypertension, and improvement of hepatic encephalopathy. The only randomized prospective multicenter controlled trial to show an improvement in transplant-free survival was for high-volume plasmapheresis. Biological (cell-based) extracorporeal liver support systems aim to support the failing liver through detoxification and synthetic function and warrant further study for safety and benefit.