Banwari Agarwal

Development and Validation of a Prognostic Score to Predict Mortality in Patients with Acute on Chronic Liver Failure.

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

Evaluation of coagulation abnormalities in acute liver failure

BACKGROUND & AIMS In acute liver failure (ALF), prothrombin time (PT) and its derivative prothrombin time ratio (PTR) are elevated, and are considered predictors of increased bleeding risk. We aimed at determining whether increased PT/PTR reflects the haemostatic potential and bleeding risk in ALF patients. METHODS Twenty consecutive ALF patients were recruited. Samples were analysed on admission for standard laboratory clotting tests (e.g. PT), thromboelastography (TEG), individual pro and anticoagulant factors and thrombin generation (TG) kinetics with and without Protac, a snake venom protein C activator, and microparticle assay. TG was also measured in 20 age and sex matched healthy volunteers. RESULTS PT was significantly raised (50.7s ± 7.2, p=0.0001) but did not correlate with TEG parameters. TEG tracings were consistent with a hypocoagulable state in 20%, normal in 45%, and hypercoagulable in 35% of the patients. There was a concomitant and proportional reduction in plasma levels of both procoagulants and natural anticoagulant proteins, in conjunction with a significant elevation in plasma levels of factors-VIII (FVIII) and Von Willebrand factor, and microparticles, culminating in an overall efficient, albeit reduced, thrombin generation capacity in comparison with healthy individuals. A heparin-like effect (HLE) was also noted in most patients. No significant clinical bleeding complications occurred and no blood transfusions were required. CONCLUSIONS In ALF, despite grossly deranged PT in all patients, estimation of bleeding risk suggests that the coagulation disturbance in ALF patients is complex and heterogeneous for which an individualised approach is required.

Critical Care Issues in Patients After Liver Transplantation

The majority of patients who undergo liver transplantation (LT) spend some time in the intensive care unit during the postoperative period. For some, this is an expected part of the immediate posttransplant recovery period, whereas for others, the stay is more prolonged because of preexisting conditions, intraoperative events, or postoperative complications. In this review, 4 topics that are particularly relevant to the postoperative intensive care of LT recipients are discussed, with an emphasis on current knowledge specific to this patient group. Infectious complications are the most common causes of early posttransplant morbidity and mortality. The common patterns of infection seen in patients after LT and their management are discussed. Acute kidney injury and renal failure are common in post‐LT patients. Kidney injury identification, etiologies, and risk factors and approaches to management are reviewed. The majority of patients will require weaning from mechanical ventilation in the immediate postoperative period; the approach to this is discussed along with the approach for those patients who require a prolonged period of mechanical ventilation. A poorly functioning graft requires prompt identification and appropriate management if the outcomes are to be optimized. The causes of poor graft function are systematically reviewed, and the management of these grafts is discussed. Liver Transpl 17:511–527, 2011.

Comparison of the sequential organ failure assessment score with the King's College Hospital criteria and the model for end‐stage liver disease score for the prognosis of acetaminophen‐induced acute liver failure

Acetaminophen‐induced acute liver failure (ALF) is a complex multiorgan illness. An assessment of the prognosis is essential for the accurate identification of patients for whom survival without liver transplantation (LT) is unlikely. The aims of this study were the comparison of prognostic models [Kings College Hospital (KCH), Model for End‐Stage Liver Disease, Sequential Organ Failure Assessment (SOFA), and Acute Physiology and Chronic Health Evaluation II (APACHE II)] and the identification of independent prognostic indicators of outcome. We evaluated consecutive patients with severe acetaminophen‐induced ALF who were admitted to the intensive care unit. At admission, demographic, clinical, and laboratory parameters were recorded. The discriminative ability of each prognostic score at the baseline was evaluated with the area under the receiver operating characteristic curve (AUC). In addition, using a multiple logistic regression, we assessed independent factors associated with outcome. In all, 125 consecutive patients with acetaminophen‐induced ALF were evaluated: 67 patients (54%) survived with conservative medical management (group 1), and 58 patients (46%) either died without LT (28%) or underwent LT (18%; group 2). Group 1 patients had significantly lower median APACHE II (10 versus 14) and SOFA scores (9 versus 12) than group 2 patients (P < 0.001). The independent indicators associated with death or LT were a longer prothrombin time (P = 0.007), the inspiratory oxygen concentration (P = 0.005), and the lactate level at 12 hours (P < 0.001). The KCH criteria had the highest specificity (83%) but the lowest sensitivity (47%), and the SOFA score had the best discriminative ability (AUC = 0.79). In conclusion, for patients with acetaminophen‐induced ALF, the SOFA score performed better than the other prognostic scores, and this reflected the presence of multiorgan dysfunction. A further evaluation of SOFA with the KCH criteria is warranted. Liver Transpl 18:405–412, 2012.

Malnutrition and sarcopenia predict post-liver transplantation outcomes independently of the Model for End-stage Liver Disease score

Although malnutrition and sarcopenia are prevalent in cirrhosis, their impact on outcomes following liver transplantation is not well documented.

Continuous renal replacement therapy (CRRT) in patients with liver disease: Is circuit life different?

BACKGROUND/AIMS Clotting of haemofiltration circuits is a major complication of continuous renal replacement therapies (CRRT), yet systemic anticoagulation risks haemorrhage. Traditionally, patients with liver failure are managed with no or minimal anticoagulation, because of abnormal clotting tests and the perceived, increased bleeding risk. METHODS We retrospectively reviewed CRRT circuit life in 50 patients; 3 groups of liver failure patients treated with CRRT (acute liver failure (ALF), acute on chronic liver disease (ACLD) and post-elective liver transplantation (LTx)), with two control groups; systemic sepsis (SS) and haematological malignancy (Haem). RESULTS CCRT circuit life was significantly greater in the Haem group, compared to the others; 24.3+/-23.9h, vs. 11+/-10.5 ALF, 11.6+/-6.6 ACLF, 7.4+/-5.1 LTx and 9.2+/-6.5 SS, p<0.05, with Haem group requiring fewest new CCRT circuits within 48h; 2.4+/-1.0 vs. 4.3+/-1.3 ALF, 4.2+/-2.1 ACLF, 5.3+/-1.5 LTx and 4.6+/-1.5 SS, p<0.05 and least blood transfusions; 1.2+/-1.3 vs. 4.8+/-4.2 ALF, 4.2+/-4.1 ACLF, 2.2+/-2.1 LTx and 3.0+/-1.5 SS. Transmembrane pressures were higher in those CCRT circuits with haemofilter/dialyzer clotting, compared to other causes, such as access dysfunction (123+/-74 vs. 71.8+/-29.3 mm Hg, p=0.009). In those patients in whom anticoagulation was started due to repeated filter clotting, circuit life improved from 5.6+/-3.4 to 19+/-12.7h, p<0.01. CONCLUSION Despite abnormal laboratory coagulation tests and thrombocytopenia, CCRT circuits clot frequently in liver failure patients. Anticoagulation did improve CRRT circuit survival without an obvious increase in bleeding or blood transfusion requirement. Thus anticoagulation should be considered in these patients with repeated circuit clotting.

Hemostasis in patients with acute kidney injury secondary to acute liver failure

Acute kidney injury (AKI) occurs in over half of patients with acute liver failure. Despite prolonged prothrombin times and thrombocytopenia, continuous renal replacement therapy circuits frequently develop clots during patient treatment. Here we assessed factors contributing to this by measuring coagulation parameters (standard coagulation tests, pro- and anticoagulant factors, thromboelastography, and thrombin generation) in 20 consecutive patients with acute liver failure; mean age 42 years. Within 48 h, 10 had developed stage 3 AKI and 9 required continuous renal replacement therapy, of whom 2 had frequent circuit clots. The patients with stage 3 AKI were found to have significantly lower platelet counts and levels of factor V and the natural anticoagulants antithrombin, Protein C and Protein S, but increased extrinsic pathway activation and von Willebrand factor levels. Tissue factor levels were greater in those with stage 3 AKI, as was microparticle activity. Although patients with acute liver failure and advanced AKI requiring continuous renal replacement therapy have an even more marked thrombocytopenia and more prolonged extrinsic pathway activation, this was not associated with increased bleeding. Thus, more frequent circuit clots during continuous renal replacement therapy appear to be due to a combination of increased tissue factor and microparticle release, endothelial activation, and reduction in natural anticoagulants.

Early invasive fungal infections and colonization in patients with cirrhosis admitted to the intensive care unit

Bacterial infections in cirrhosis are common and associated with increased mortality, but little is known about fungal infections. The aim of this study, a sub-analysis of the Fungal Infection Risk Evaluation study, was to assess the incidence and implications of early invasive fungal disease (IFD) in patients with cirrhosis admitted to intensive care units (ICU). Clinical and laboratory parameters collected in the first 3 days of ICU stay for 782 patients with cirrhosis and/or portal hypertension were analysed and compared with those of 273 patients with very severe cardiovascular disease (CVD). The CVD patients had more co-morbidities and higher APACHE II scores. The overall incidence of IFD was similar in the two groups, but the incidence of IFD in ICU was higher in liver patients (1% versus 0.4%; p 0.025) as was fungal colonization (23.8% versus 13.9%; p 0.001). The ICU and in-hospital mortality, and length of stay were similar in the two groups. A higher proportion of liver patients received antifungal therapy (19.2% versus 7%; p <0.0005). There was no difference in mortality between colonized patients who received antifungal therapy and colonized patients who did not. The incidence of IFD in patients with cirrhosis in ICU is higher compared with another high-risk group, although it is still very low. This risk might be higher in patients with advanced liver disease admitted with acute-on-chronic liver failure, and this should be investigated further. Our data do not support prophylactic use of antifungal therapy in cirrhosis.

Role of ammonia, inflammation, and cerebral oxygenation in brain dysfunction of acute-on-chronic liver failure patients

Hepatic encephalopathy (HE) is a common feature of acute‐on‐chronic liver failure (ACLF). Although ammonia, inflammation, and cerebral oxygenation are associated with HE in acute liver failure, their roles in ACLF are unknown. The aim of this prospective, longitudinal study was to determine the role of these pathophysiological variables in ACLF patients with and without HE. We studied 101 patients with ACLF admitted to the intensive care unit. Severity of ACLF and HE, arterial ammonia, jugular venous oxygen saturation (JVO2), white blood cell count (WCC), and C‐reactive protein were measured at days 0, 1, 3, and 7. Patients were followed until death or hospital discharge. Mortality was high (51 patients, 50.5%), especially in patients with HE of whom 35 of 53 (66.0%) died regardless of ACLF severity. At baseline, increased WCC and abnormal JVO2 (high or low) were independent predictors of death. Further deterioration in inflammation, JVO2, and ammonia were also predictive of mortality. JVO2 deviation and hyperammonemia were associated with the presence and severity of HE; improvement in these parameters was associated with a reduction in HE grade. No direct interaction was observed between these variables in regards to mortality or HE. In conclusion, this study describes potential mechanisms of HE in ACLF indicating that ammonia and abnormal cerebral oxygenation are important. The results suggest that ammonia, JVO2, and WCC are important prognostic biomarkers and therapeutic targets. The relative roles of these pathophysiological factors in the pathogenesis of HE in ACLF or guiding therapy to improve survival requires future study. Liver Transplantation 22 732–742 2016 AASLD.

Difficulties in diagnosing acute kidney injury post liver transplantation using serum creatinine based diagnostic criteria

Renal function in patients with advanced cirrhosis is an important prognostic factor for survival both prior to and following liver transplantation. The importance of renal function is reflected by the introduction of the model for end stage liver disease (MELD) score, which includes serum creatinine. The MELD score has been shown to predict the short term risk of death for transplant wait listed patients and is currently used by many countries to allocate liver transplants on the basis of severity of underlying illness. Changes in serum creatinine are also used to stage acute kidney injury. However prior to liver transplantation the serum creatinine typically over estimates underlying renal function, particularly when a colorimetric Jaffe based assay is used, and paradoxically then under estimates renal function post liver transplantation, particularly when immunophyllins are started early as part of transplant immunosuppression. As acute kidney injury is defined by changes in serum creatinine, this potentially leads to over estimation of the incidence and severity of acute kidney injury in the immediate post-operative period.