Search

Acute liver failure (ALF) is an orphan disease often complicated by acute kidney injury (AKI). We assessed the impact of transient versus persistent AKI on survival in patients with ALF.International multicenter retrospective cohort.U.S. ALF Study Group prospective registry.Patients with greater than or equal to 18 years and ALF in the registry from 1998 to 2016 were included. Patients with less than 3 days of follow-up, without kidney function evaluation on day 3, or with cirrhosis were excluded.AKI was defined by Kidney Disease Improving Global Outcomes guidelines on day 1. Kidney recovery was defined on day 3 as transient AKI, by a return to no-AKI within 48 hours or persistent AKI if no such recovery or renal replacement therapy (RRT) was observed. Primary outcome was transplant-free survival (TFS) at 21 days.Among 1,071 patients with ALF, 339 (31.7%) were males, and median (interquartile range) age was 39 years (29-51 yr). Acetaminophen-related ALF was found in 497 patients (46.4%). On day 1, 485 of 1,071 patients (45.3%) had grade 3-4 hepatic encephalopathy (HE), 500 of 1,070 (46.7%) required invasive mechanical ventilation (IMV), 197 of 1,070 (18.4%) were on vasopressors, and 221 of 1,071 (20.6%) received RRT. On day 1, 673 of 1,071 patients (62.8%) had AKI. On day 3, 72 of 1,071 patients (6.7%) had transient AKI, 601 of 1,071 (56.1%) had persistent AKI, 71 of 1,071 (6.6%) had late onset AKI, and 327 of 1,071 (30.5%) remained without AKI. Following adjustment for confounders (age, sex, race, etiology, HE grade, use of IMV and vasopressors, international normalized ratio, and year), although persistent acute kidney injury (adjusted odds ratio [aOR] [95% CI] 0.62 [0.44-0.88]) or late onset AKI (aOR [95% CI] 0.48 [0.26-0.89]) was associated with lower TFS, transient AKI was not (aOR [95% CI] 1.89 [0.99-3.64]).In a multicenter cohort of patients with ALF, persistent but not transient AKI was independently associated with lower short-term TFS.

To review the surgical and critical care management of liver trauma; one of the most common abdominal injuries sustained due to its size and location.Hepatic injuries range from negligible to life threatening: in the acute phase, the most common cause of morbidity and mortality is hemorrhage; however, severe traumatic hepatic injuries can also lead to biochemical abnormalities, altered coagulation, and ultimately liver failure. This brief review will review the classification of traumatic liver injuries by mechanism, grade, and severity. Most Grades I-III injuries can be managed nonoperatively, whereas the majority of Grades IV-VI injuries require operative management. Therapeutic strategies for traumatic liver injury including nonoperative, operative, radiologic will be described. The primary goal of liver trauma management in the acute setting is hemorrhage control, then the management of secondary factors such as bile leaks. The rapid restoration of homeostasis may prevent further damage to the liver and allow for deferred nonoperative management, which has been shown to be associated with good clinical outcomes.A multidisciplinary approach to the care of these patients at an experienced liver surgery center is warranted.

Background: We applied the Confusion Assessment Method (CAM)-Intensive Care Unit (ICU)-7 delirium scale to patients who underwent liver transplant (LT). Methods: Retrospective cohort including patients who underwent LT for cirrhosis admitted to the ICU from June 2013 to June 2016 at the University of Alberta Hospital, Canada. Delirium was assessed using the CAM-ICU-7 scale (0–7 points) twice daily on days one and 3 post LT, with the highest score being considered. Primary endpoint was hospital mortality. Results: Among all patients, 101/150 (67.3%) were men and mean (SD) age was 52.4 (11.8) years. On days 1 and 3 post LT, mean (SD) CAM-ICU-7 scores were 1.8 (1.3) and 1.6 (1.8), respectively. Therefore, on days 1 and 3 post LT, 38/150 (25.3%) and 26/95 (27.4%) patients had delirium. While delirium on day 3 post LT was associated with higher hospital mortality (11.5% versus 0%; p = 0.019), it was not associated with length-of-hospital stay (29.2 versus 34.4 days; p = 0.36). Following adjustment for APACHEII score, delirium on day 3 post LT was associated with higher odds of hospital mortality (adjusted odds ratio [aOR] (95% confidence interval [CI]) = 1.89 [1.02–3.50]). Following adjustment for Glasgow Coma Scale and mechanical ventilation, serum creatinine was associated with higher odds of delirium on day 3 post LT (aOR [95%CI] = 2.02 [1.08–3.77]). Conclusions: Using the CAM-ICU-7 scale, delirium was diagnosed in a fourth of patients who underwent LT. Delirium on day 3 post LT was associated with higher odds of hospital mortality.

PurposeWhile opioids are part of usual care for analgesia in the intensive care unit (ICU), there are concerns regarding excess use. This is a systematic review of non-steroidal anti-inflammatories (NSAIDs) use in critically ill adult patients.MethodsWe conducted a systematic search of MEDLINE, EMBASE, CINAHL, and Cochrane Library. We included randomized control trials (RCTs) comparing NSAIDs alone or as an adjunct to opioids for analgesia. The primary outcome was opioid utilization. We reported mean difference for continuous outcomes and relative risk for dichotomous outcomes with 95% confidence intervals (CIs). We evaluated study risk of bias using the Cochrane risk of bias tool and evidence certainty using GRADE.ResultsWe included 15 RCTs (n=1621 patients). Adjunctive NSAID therapy to opioids reduced 24-hour oral morphine equivalent consumption by 21.4mg (95% CI: 11.8-31.0mg reduction, high certainty) and probably reduced pain scores (measured by visual analogue scale) by -6.1mm (95% CI: -12.2 to +0.1, moderate certainty). Adjunctive NSAIDs probably had no impact on duration of mechanical ventilation (-1.6 hours, 95% CI: -0.4 to -2.7 hours, moderate certainty) and may have no impact on ICU length of stay (-2.1 hours, 95% CI: -6.1 to +2.0 hours, low certainty). Variability in reporting of adverse outcomes (e.g. gastrointestinal bleeding, acute kidney injury) precluded their meta-analysis.ConclusionIn critically ill adult patients, NSAIDs reduced opioid use, probably reduced pain scores, but were uncertain for duration of mechanical ventilation or ICU length of stay. Further research is required to characterize the prevalence of NSAID-related adverse outcomes.Take-Home MessageIn this systematic review and meta-analysis of 15 randomized control trials that included 1621 critically ill adult patients, the addition of non-steroidal anti-inflammatories to an opioid analgesic strategy reduced 24-hour opioid use and modestly reduced pain with no impact on duration of mechanical ventilation or ICU length of stay.

Liver transplantation remains the only definitive treatment for advanced liver disease and liver failure. Current allocation schemes utilized for liver transplantation mandate a 'sickest first' approach, thus most liver transplants occur in patients with severe systemic illness. For intensive care providers who care for liver transplant recipients, a foundation of knowledge of technical considerations of orthotopic liver transplantation, basic management considerations, and common complications is essential. This review highlights the authors' approach to intensive care management of the postoperative liver transplant recipient with a review of common issues, which arise in this patient population.The number of centers offering liver transplantation continues to increase globally and the number of patients receiving liver transplantation also continues to increase. The number of patients with advanced liver disease far outpaces organ availability and, therefore, patients undergoing liver transplant are sicker at the time of transplant. Outcomes for liver transplant patients continue to improve owing to advancements in surgical technique, immunosuppression management, and intensive care management of liver disease both pretransplant and posttransplant.Given a global increase in liver transplantation, an increasing number of intensive care professionals are likely to care for this patient population. For these providers, a foundational knowledge of the common complications and key management considerations is essential.

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.

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 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.

Patients with acute and chronic liver disease present with a wide range of disease states and severity that may require liver transplantation (LT). Physiologic alterations occur that are dynamic throughout all phases of perioperative care, creating complex management scenarios that necessitate multidisciplinary clinical care. Specifically, alterations in hemostasis in liver disease can be pronounced and evolve with disease progression over time. Recent studies and society guidance address this emerging paradigm and offer recommendations to assist with hemostatic management in patients with liver disease. However, patients undergoing LT are unique and diverse, often with unstable disease that requires specialized approaches. Our aim is to provide a focused review of hemostatic management of the LT patient, distinguish unique aspects of the three main phases of care (before LT, perioperative, and after LT), and identify knowledge gaps and critical areas of future research.

Although liver transplantation (LT) yields survival benefit for patients with acute-on-chronic liver failure grade 3 (ACLF-3), knowledge gaps remain regarding risk factors for post-LT mortality. We retrospectively reviewed data from 10 centers in the United States and Canada for patients transplanted between 2018 and 2019 and who required care in the intensive care unit prior to LT. ACLF was identified using the European Association for the Study of the Liver-Chronic Liver Failure (EASL-CLIF) criteria. A total of 318 patients were studied, of whom 106 (33.3%) had no ACLF, 61 (19.1%) had ACLF-1, 74 (23.2%) had ACLF-2, and 77 (24.2%) had ACLF-3 at transplantation. Survival probability 1 year after LT was significantly higher in patients without ACLF (94.3%) compared with patients with ACLF (87.3%; P = 0.02), but similar between ACLF-1 (88.5%), ACLF-2 (87.8%), and ACLF-3 (85.7%; P = 0.26). Recipients with ACLF-3 and circulatory failure (n = 29) had similar 1-year post-LT survival (82.3%) compared with patients with ACLF-3 without circulatory failure (89.6%; P = 0.32), including those requiring multiple vasopressors. For patients transplanted with ACLF-3 including respiratory failure (n = 20), there was a trend toward significantly lower post-LT survival (P = 0.07) among those with respiratory failure (74.1%) compared with those without (91.0%). The presence of portal vein thrombosis (PVT) at LT for patients with ACLF-3 (n = 15), however, yielded significantly lower survival (91.9% versus 57.1%; P 0.001). Multivariable logistic regression analysis revealed that PVT was significantly associated with post-LT mortality within 1 year (odds ratio, 7.3; 95% confidence interval, 1.9-28.3). No correlation was found between survival after LT and the location or extent of PVT, presence of transjugular intrahepatic portosystemic shunt, or anticoagulation. LT in patients with ACLF-3 requiring vasopressors yields excellent 1-year survival. LT should be approached cautiously among candidates with ACLF-3 and PVT.

Acute liver failure is marked by the rapid deterioration of liver function in a previously well patient over period of days to weeks. Though relatively rare, it is associated with high morbidity and mortality. This makes it a challenging disease to study clinically, necessitating reliance on preclinical models as means to explore pathophysiology and novel therapies. Preclinical models of acute liver failure are artificial by nature, and generally fall into one of three categories: surgical, pharmacologic or immunogenic. This article reviews preclinical models of acute liver failure and considers their relevance in modeling clinical disease.

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.

Clustered binary outcomes and datasets with many predictor variables are frequently encountered in clinical research (e.g. longitudinal studies). Generalized linear mixed models (GLMMs) typically employed for clustered endpoints have challenges for some scenarios, particularly for complex datasets which contain many interactions among predictors and nonlinear predictors of outcome. We propose a new method called Binary Mixed Model (BiMM) forest, which combines random forest and GLMM methodology. BiMM forest offers a flexible and stable method which naturally models interactions among predictors and can be employed in the setting of clustered data. Simulation studies show that BiMM forest achieves similar or superior prediction accuracy compared to standard random forest, GLMMs and its tree counterpart (BiMM tree) for clustered binary outcomes. The method is applied to a real dataset from the Acute Liver Failure Study Group. BiMM forest offers an alternative method for modeling clustered binary outcomes which may be applied in myriad research settings.

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.