Karvellas, Constantine

Acute-on-chronic liver failure (ACLF) has been associated with excellent post-liver transplant (LT) outcomes at 1 year; however, the impact of alcohol as ACLF precipitant, specifically alcohol-associated hepatitis (AH), and as etiology of chronic liver disease remains uncertain. This study aimed to assess the effect of alcohol as ACLF precipitant and chronic liver disease etiology (alcohol-associated liver disease vs. non–alcohol-associated liver disease) on posttransplant outcomes. We performed a retrospective study using the Multi-Organ Dysfunction and Evaluation for LT Consortium database and included 640 patients with ACLF who underwent LT across 15 transplant centers in North America. The primary outcome was 1-year posttransplant survival. We used logistic regression and Cox proportional hazards to compare posttransplant survival, mortality risk, and health care utilization, adjusting for age, ACLF grade, comorbid diabetes mellitus, chronic kidney disease, and HCC. The median follow-up from LT was 2.8 years (P25–P75, 2.2–5.5 y) for patients with AH-ACLF (n=42) and 3.1 years (P25–P75, 1.6–4.9 y) for patients without AH (n=598). No significant difference was observed in 1-year survival after LT in patients with AH-ACLF versus those without AH ( p =0.36). Patients with AH had significantly higher health care utilization evidenced by greater length of stay (28.5 vs. 19.0 d, p =0.004; adjusted linear estimate 16.89, 95% CI: 7.66–26.11, p <0.001), higher rates of rehabilitation placement (71.4% vs. 41.8%, p =0.002; adjusted odds ratio: 4.13, 95% CI: 2.04–8.89, p <0.001), and non-ambulatory status (39.0% vs. 21.0%, p =0.005; adjusted odds ratio: 4.54, 95% CI: 1.90–10.79, p <0.001). Compared with other etiologies, alcohol-associated liver disease was not associated with differences in 1-year mortality, mortality risk over time, or health care utilization, after excluding patients with AH as ACLF precipitant. While there were no differences in 1-year survival, AH-ACLF was associated with higher health care resource utilization compared with other ACLF precipitants. LT centers should ensure adequate resources are allocated for the management of these patients.

Key Points In patients with cirrhosis and AKI requiring renal replacement therapy (RRT), hepatorenal syndrome-AKI was not associated with an increased 90-day mortality when compared with other AKI etiologies. Etiology of AKI may not be a critical factor regarding decisions to trial RRT in acutely ill patients with cirrhosis and AKI. Although elevated, mortality rates in this study are comparable with those reported in general hospitalized patients with AKI requiring RRT. Background While AKI requiring renal replacement therapy (AKI-RRT) is associated with increased mortality in heterogeneous inpatient populations, the epidemiology of AKI-RRT in hospitalized patients with cirrhosis is not fully known. Herein, we evaluated the association of etiology of AKI with mortality in hospitalized patients with cirrhosis and AKI-RRT in a multicentric contemporary cohort. Methods This is a multicenter retrospective cohort study using data from the HRS-HARMONY consortium, which included 11 US hospital network systems. Consecutive adult patients admitted in 2019 with cirrhosis and AKI-RRT were included. The primary outcome was 90-day mortality, and the main independent variable was AKI etiology, classified as hepatorenal syndrome (HRS-AKI) versus other (non–HRS-AKI). AKI etiology was determined by at least two independent adjudicators. We performed Fine and Gray subdistribution hazard analyses adjusting for relevant clinical variables. Results Of 2063 hospitalized patients with cirrhosis and AKI, 374 (18.1%) had AKI-RRT. Among them, 65 (17.4%) had HRS-AKI and 309 (82.6%) had non–HRS-AKI, which included acute tubular necrosis in most cases (62.6%). Continuous renal replacement therapy was used as the initial modality in 264 (71%) of patients, while intermittent hemodialysis was used in 108 (29%). The HRS-AKI (versus non–HRS-AKI) group received more vasoconstrictors for HRS management (81.5% versus 67.9%), whereas the non–HRS-AKI group received more mechanical ventilation (64.3% versus 50.8%) and more continuous renal replacement therapy (versus intermittent hemodialysis) as the initial RRT modality (73.9% versus 56.9%). In the adjusted model, HRS-AKI (versus non–HRS-AKI) was not independently associated with increased 90-day mortality (subdistribution hazard ratio, 1.36; 95% confidence interval, 0.95 to 1.94). Conclusions In this multicenter contemporary cohort of hospitalized adult patients with cirrhosis and AKI-RRT, HRS-AKI was not independently associated with an increased risk of 90-day mortality when compared with other AKI etiologies. The etiology of AKI appears less relevant than previously considered when evaluating the prognosis of hospitalized adult patients with cirrhosis and AKI requiring RRT.

OBJECTIVES: To develop evidence-based recommendations for clinicians caring for adults with acute liver failure (ALF) or acute on chronic liver failure (ACLF) in the ICU. DESIGN: The guideline panel comprised 27 members with expertise in aspects of care of the critically ill patient with liver failure or methodology. We adhered to the Society of Critical Care Medicine standard operating procedures manual and conflict-of-interest policy. Teleconferences and electronic-based discussion among the panel, as well as within subgroups, served as an integral part of the guideline development. INTERVENTIONS: In part 2 of this guideline, the panel was divided into four subgroups: neurology, peri-transplant, infectious diseases, and gastrointestinal groups. We developed and selected Population, Intervention, Comparison, and Outcomes (PICO) questions according to importance to patients and practicing clinicians. For each PICO question, we conducted a systematic review and meta-analysis where applicable. The quality of evidence was assessed 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: We report 28 recommendations (from 31 PICO questions) on the management ALF and ACLF in the ICU. Overall, five were strong recommendations, 21 were conditional recommendations, two were best-practice statements, and we were unable to issue a recommendation for five questions due to insufficient evidence. CONCLUSIONS: Multidisciplinary, international experts formulated evidence-based recommendations for the management ALF and ACLF patients in the ICU, acknowledging that most recommendations were based on low quality and indirect evidence.

There has been a growing interest in identifying prognostic biomarkers that alone or with available prognostic models (King’s College Criteria, KCC; MELD and ALFSG Prognostic Index) would improve prognosis in acute liver failure (ALF) patients being assessed for liver transplantation. The Acute Liver Failure Study Group (ALFSG) has evaluated 15 potential prognostic biomarkers: serum AFP; apoptosis-associated proteins; serum actin-free Gc-globulin; serum glycodeoxycholic acid; sRAGE/RAGE ligands; plasma osteopontin; circulating MBL, M-, L-, H-ficolin and CL-1; plasma galectin-9; serum FABP1; serum Lct2; miRNAs; factor V; thrombocytopenia, and sCD163. The ALFSG also has reported on 4 susceptibility biomarkers: keratins 8 and 18 (K8/K18) gene variants; polymorphisms of genes encoding putative APAP-metabolizing enzymes ( UGT1A1 , UGT 1A0 , UGT 2B15 , SULT1A1 , CYP2E1 , and CYP3A5 ) as well as CD44 and BHMT1 ; single nucleotide polymorphisms (SNPs) of genes associated with human behavior, rs2282018 in the arginine vasopressin ( AVP ) gene and rs11174811 in the AVP receptor 1A gene. Finally, rs2277680 of the CSCL16 gene in HBV-ALF patients. In conclusion, we have reviewed the prognostic and susceptibility biomarkers studied by the ALFSG. We suggest that a better approach to predicting the clinical outcome of an ALF patient will require a combination of biomarkers of pathogenic processes such as cell death, hepatic regeneration, and degree of inflammation that could be incorporated into prognostic models such as KCC, MELD or ALFSG PI.

Liver transplantation (LT) is a life‐saving treatment for patients with acute liver failure (ALF). Currently, there are few detailed data regarding long‐term outcomes after LT for ALF. We combined prospective data from the Acute Liver Failure Study Group (ALFSG) Registry with those of the Scientific Registry of Transplant Recipients (SRTR) to assess outcomes among consecutive patients with ALF listed for LT. Cohort analysis of detailed pretransplantation data for patients listed for LT for ALF in the ALFSG Registry between January 1998 and October 2018 matched with transplantation‐related data from the SRTR. Primary outcomes were 1‐ and 3‐year post‐LT patient survival. Secondary outcome was receipt of LT; independent associations with successful receipt of LT were determined using multivariable logistic regression. Of 624 patients with ALF listed for LT, 398 (64%) underwent LT, 100 (16%) died without LT, and 126 (20%) recovered spontaneously. Among LT recipients, etiologies included seronegative/indeterminate (22%), drug‐induced liver injury (18%), acetaminophen overdose (APAP; 16%), and viral hepatitis (15%). The 1‐ and 3‐year post‐LT patient survival rates were 91% and 90%, respectively. Comparing those dying on the waiting list versus with those who received LT, the former had more severe multiorgan failure, reflected by increased vasopressor use (65% vs. 22%), mechanical ventilation (84% vs. 57%), and renal replacement therapy (57% vs. 30%; p < 0.0001 for all). After adjusting for relevant covariates, age (adjusted odds ratio [aOR] 1.02, 95% confidence interval [CI] 1.00–1.04), APAP etiology (aOR 2.72, 95% CI 1.42–5.23), requirement for vasopressors (aOR 4.19, 95% CI 2.44–7.20), Grade III/IV hepatic encephalopathy (aOR 2.47, 95% CI 1.29–4.72), and Model for End‐Stage Liver Disease (MELD) scores (aOR 1.05, 95% CI 1.02–1.09; p < 0.05 for all) were independently associated with death without receipt of LT. Post‐LT outcomes for ALF are excellent in this cohort of very ill patients. The development of multiorgan failure while on the transplantation list and APAP ALF etiology were associated with a lower likelihood of successful receipt of LT.

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 <72 hours of appropriate antimicrobial therapy in case of ongoing sepsis were considered reasons to delay LT. A simple assessment of the number of organs failing was considered the most appropriate way to decide whether LT should be delayed or denied, with respiratory, circulatory and metabolic failures having the most influence in this decision. The thresholds of severity of organ failures contraindicating LT for which a consensus was achieved were a Pa o 2 /FiO2 ratio<150 mm Hg, a norepinephrine dose >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.

Acute on chronic liver failure (ACLF) is the culmination of chronic liver disease and extrahepatic organ failures, which is associated with a high short‐term mortality and immense health care expenditure. There are varying definitions for organ failures and ACLF in Europe, North America, and Asia. These differing definitions need to be reconciled to enhance progress in the field. The pathogenesis of ACLF is multifactorial and related to interactions between the immunoinflammatory system, microbiota, and the various precipitating factors. Individual organ failures related to the kidney, brain, lungs, and circulation have cumulative adverse effects on mortality and are often complicated or precipitated by infections. Strategies to prevent and rapidly treat these organ failures are paramount in improving survival. With the aging population and paucity of organs for liver transplant, the prognosis of ACLF patients is poor, highlighting the need for novel therapeutic strategies. The role of liver transplant in ACLF is evolving and needs further investigation across large consortia. A role for early palliative care and management of frailty as approaches to alleviate disease burden and improve patient‐reported outcomes is being increasingly recognized. Conclusion: ACLF is a clinically relevant syndrome that is epidemic worldwide and requires a dedicated multinational approach focused on prognostication and management; investigations are underway worldwide to prepare ACLF for prime time. (Hepatology 2018; 00:000‐000)

Objective: Acute kidney injury requiring renal replacement therapy in severe vasodilatory shock is associated with an unfavorable prognosis. Angiotensin II treatment may help these patients by potentially restoring renal function without decreasing intrarenal oxygenation. We analyzed the impact of angiotensin II on the outcomes of acute kidney injury requiring renal replacement therapy. Design: Post hoc analysis of the Angiotensin II for the Treatment of High-Output Shock 3 trial. Setting: ICUs. Patients: Patients with acute kidney injury treated with renal replacement therapy at initiation of angiotensin II or placebo ( n = 45 and n = 60, respectively). Interventions: IV angiotensin II or placebo. Measurements and Main Results: Primary end point: survival through day 28; secondary outcomes included renal recovery through day 7 and increase in mean arterial pressure from baseline of ≥ 10 mm Hg or increase to ≥ 75 mm Hg at hour 3. Survival rates through day 28 were 53% (95% CI, 38%–67%) and 30% (95% CI, 19%–41%) in patients treated with angiotensin II and placebo ( p = 0.012), respectively. By day 7, 38% (95% CI, 25%–54%) of angiotensin II patients discontinued RRT versus 15% (95% CI, 8%–27%) placebo ( p = 0.007). Mean arterial pressure response was achieved in 53% (95% CI, 38%–68%) and 22% (95% CI, 12%–34%) of patients treated with angiotensin II and placebo ( p = 0.001), respectively. Conclusions: In patients with acute kidney injury requiring renal replacement therapy at study drug initiation, 28-day survival and mean arterial pressure response were higher, and rate of renal replacement therapy liberation was greater in the angiotensin II group versus the placebo group. These findings suggest that patients with vasodilatory shock and acute kidney injury requiring renal replacement therapy may preferentially benefit from angiotensin II.