Acute-on-chronic liver failure: Objective admission and support criteria in the intensive care unit

  • Victor Dong
    Affiliations
    Division of Gastroenterology, University of Alberta, Edmonton, Canada
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  • Constantine J. Karvellas
    Correspondence
    Corresponding author. Address: Department of Critical Care Medicine, Division of Gastroenterology (Liver Unit), University of Alberta, 1-40 Zeidler Ledcor Building, Edmonton, Alberta, Canada T6G 2X8.
    Affiliations
    Division of Gastroenterology, University of Alberta, Edmonton, Canada

    Department of Critical Care Medicine, University of Alberta, Edmonton, Canada
    Search for articles by this author
Open AccessPublished:April 03, 2019DOI:https://doi.org/10.1016/j.jhepr.2019.02.005

      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.

       Key points

      • Acute on chronic liver failure (ACLF, cirrhosis with organ failure) often requires intensive care (ICU) support.
      • The most common reason for ICU admission in ACLF is infection.
      • Prognosis in ACLF is dependent on candidacy for liver transplantation and the burden of multiorgan failure.
      • In patients who are not transplant candidates who have persistent organ failure after a brief period of support (72 hours), a palliative approach may be more appropriate.

      Introduction

      Liver cirrhosis is a progressive disease characterised histologically by formation of regenerative nodules and bridging fibrous bands.
      • Schuppan D
      • Afdhal NH
      Liver cirrhosis.
      It continues to be a leading cause of morbidity and death throughout the world. The most common aetiologies of cirrhosis in the Western world are non-alcoholic fatty liver disease, alcohol abuse, and chronic hepatitis C infection.
      • Tsochatzis EA
      • Bosch J
      • Burroughs AK
      Liver cirrhosis.
      Within Asia and sub-Saharan Africa, chronic hepatitis B infection remains the most common aetiology.
      • Tsochatzis EA
      • Bosch J
      • Burroughs AK
      Liver cirrhosis.
      Although patients may remain asymptomatic with normal liver function and compensated disease, morbidity and mortality from cirrhosis occur because of decompensation, which is driven by portal hypertension and systemic inflammation and their complications.
      • Bernardi M
      • Moreau R
      • Angeli P
      • Schnabl B
      • Arroyo V
      Mechanisms of decompensation and organ failure in cirrhosis: From peripheral arterial vasodilation to systemic inflammation hypothesis.
      These complications include development of and bleeding from oesophageal and gastric varices, hepatic encephalopathy (HE), ascites, infection, hepatorenal syndrome (HRS), portopulmonary hypertension, and hepatopulmonary syndrome.
      • Olson JC
      Acute-on-chronic and Decompensated Chronic Liver Failure: Definitions, Epidemiology, and Prognostication.
      Development of decompensated liver disease is significant as it results in a decline in median survival from 12 years to only 2 years in patients with cirrhosis.
      • D'Amico G
      • Garcia-Tsao G
      • Pagliaro L
      Natural history and prognostic indicators of survival in cirrhosis: a systematic review of 118 studies.
      In recent years, the concept of acute-on-chronic liver failure (ACLF) has been recognised as a separate clinical presentation from hepatic decompensation in cirrhotic patients. ACLF is characterised by acute and rapid deterioration of hepatic function, after an acute precipitating event, resulting in liver failure and extrahepatic organ failures.
      • Jalan R
      • Gines P
      • Olson JC
      • Mookerjee RP
      • Moreau R
      • Garcia-Tsao G
      • et al.
      Acute-on chronic liver failure.
      It is associated with significant short-term mortality.
      • Arroyo V
      • Moreau R
      • Kamath PS
      • Jalan R
      • Ginès P
      • Nevens F
      • et al.
      Acute-on-chronic liver failure in cirrhosis.
      Although the exact definition lacks standardisation around the world, it is accepted that ACLF leads to the involvement of a variety of extrahepatic organs, including the renal, cardiovascular, and respiratory systems.
      • Bajaj JS
      • Moreau R
      • Kamath PS
      • Vargas HE
      • Arroyo V
      • Reddy KR
      • et al.
      Acute-on-Chronic Liver Failure: Getting Ready for Prime Time?.
      The 3 most widely used definitions are region specific (Asia, Europe, and North America). The World Gastroenterology Organization has proposed that ACLF be defined as a syndrome in patients with chronic liver disease characterised by an acute hepatic decompensation leading to liver failure in the form of jaundice and elevated international normalized ratio (INR), along with at least one extrahepatic organ failure as a way of unifying the definition of ACLF across regions.
      • Jalan R
      • Yurdaydin C
      • Bajaj JS
      • Acharya SK
      • Arroyo V
      • Lin HC
      • et al.
      Toward an improved definition of acute-on-chronic liver failure.
      Currently, the most widely used definition of ACLF is based on the European Association for the Study of the Liver-Chronic Liver Failure Consortium (EASL-CLIF) Acute-on-Chronic Liver Failure in Cirrhosis (CANONIC) study.
      • Moreau R
      • Jalan R
      • Gines P
      • Pavesi M
      • Angeli P
      • Cordoba J
      • et al.
      Acute-on-chronic liver failure is a distinct syndrome that develops in patients with acute decompensation of cirrhosis.
      ACLF is an important syndrome since it is relatively common and often necessitates intensive care unit (ICU) admission for intensive organ support. Its prevalence is about 31% in patients presenting with acute decompensation of cirrhosis.
      • Moreau R
      • Jalan R
      • Gines P
      • Pavesi M
      • Angeli P
      • Cordoba J
      • et al.
      Acute-on-chronic liver failure is a distinct syndrome that develops in patients with acute decompensation of cirrhosis.
      Its incidence in stable outpatients with cirrhosis is 14% after 12 months.
      • Piano S
      • Tonon M
      • Vettore E
      • Stanco M
      • Pilutti C
      • Romano A
      • et al.
      Incidence, predictors and outcomes of acute-on-chronic liver failure in outpatients with cirrhosis.
      It even carries a greater mortality risk than decompensated cirrhosis, as demonstrated by a recent study showing a 90-day mortality rate of 34% in patients with ACLF compared to 1.9% in patients with decompensated cirrhosis.
      • Moreau R
      • Jalan R
      • Gines P
      • Pavesi M
      • Angeli P
      • Cordoba J
      • et al.
      Acute-on-chronic liver failure is a distinct syndrome that develops in patients with acute decompensation of cirrhosis.
      ACLF is divided into 3 grades depending on the number of extrahepatic organ failures present, as defined by the chronic liver failure-sequential organ failure assessment (CLIF-SOFA) score (Table 1). Grade 1 ACLF involves patients with only renal failure, patients with a single organ failure combined with renal dysfunction (creatinine between 1.5 mg/dl to 1.9 mg/dl) and/or mild to moderate HE (West Haven grade 1 or 2 [Table 2]), or patients with HE and renal dysfunction. Grade 2 ACLF involves patients with 2 organ failures and grade 3 ACLF involves at least 3 organ failures (Table 3).
      • Moreau R
      • Jalan R
      • Gines P
      • Pavesi M
      • Angeli P
      • Cordoba J
      • et al.
      Acute-on-chronic liver failure is a distinct syndrome that develops in patients with acute decompensation of cirrhosis.
      The relevance of grading ACLF based on the number of organ failures is based on studies showing that mortality significantly increases as the number of organ failures increase in patients with ACLF, as shown in a study where 28-day mortality based on ACLF grade was 22%, 32%, and 77% for grade 1, grade 2, and grade 3 ACLF, respectively.
      • Moreau R
      • Jalan R
      • Gines P
      • Pavesi M
      • Angeli P
      • Cordoba J
      • et al.
      Acute-on-chronic liver failure is a distinct syndrome that develops in patients with acute decompensation of cirrhosis.
      Table 1Chronic liver failure-sequential organ failure assessment (CLIF-SOFA) score.
      System0 Points1 Point2 Points3 Points4 Points
      Bilirubin (mg/dl)<1.21.2 to <2.02.0 to <6.06.0 to <12.012.0
      Creatinine (mg/dl)<1.21.2 to <2.02.0 to <3.53.5 to <5.05.0 or dialysis
      Hepatic encephalopathy grade01234
      International normalized ratio<1.11.1 to <1.251.25 to <1.51.5 to <2.52.5 or platelet count <20 x 109/L
      Mean arterial pressure (mmHg)70<70Dopamine ≤5 or dobutamine or terlipressinDopamine >5 or epinephrine ≤0.1 or norepinephrine ≤0.1Dopamine >15 or epinephrine >0.1 or norepinephrine >0.1
      PaO2/FiO2>400>300 to 400>200 to 300>100 to 200100
      Coloured areas indicate diagnostic criteria for organ failures.
      FiO2, fraction of inspired oxygen; PaO2, partial pressure of arterial oxygen.
      Table 2West Haven Grade for hepatic encephalopathy.
      StageClinical features
      0No abnormalities
      1Alterations in behaviour

      Mild confusion

      Disordered sleep
      2Lethargy

      Moderate confusion

      Asterixis
      3Somnolent but arousable
      4Coma
      Table 3Grading of acute-on-chronic liver failure.
      Grade of ACLFClinical features
      0No organ failure

      Single non-renal organ failure, creatinine <1.5 mg/dl, no HE
      1Single renal failure

      Single non-renal organ failure, creatinine 1.5-1.9 mg/dl, and/or grade 1-2 HE
      2Two organ failures
      3Three or more organ failures
      ACLF, acute-on-chronic liver failure; HE, hepatic encephalopathy.
      Patients with cirrhosis who require hospitalisation are often managed in a non-intensive care setting. However, when complications of decompensated liver disease (variceal bleeding, HE, infection, or HRS) are severe or when ACLF develops with extrahepatic organ failure (renal, cardiac, or pulmonary failure) ICU admission is often required for organ support and attempts at reversal of organ dysfunction, especially as a bridge to liver transplant (LT) in patients who are candidates. However, consideration of ICU admission in cirrhotic patients can be a challenge. This is due to the often irreversible nature of the disease course without LT and the need to balance limited resources, cost, and benefit against futility. Therefore, scores like the Chronic Liver Failure Consortium ACLF (CLIF-C ACLF) score have been proposed and utilised to determine the prognosis of patients with ACLF and to determine when initiating and continuing intensive care treatment in patients with cirrhosis and ACLF is futile.
      However, presently, there are no objective criteria for refusal of ICU admission in patients with cirrhosis based solely on initial prognostic scores or severity of illness.
      • Gustot T
      • Fernandez J
      • Garcia E
      • Morando F
      • Caraceni P
      • Alessandria C
      • et al.
      Clinical Course of acute-on-chronic liver failure syndrome and effects on prognosis.
      Neither the CLIF-C ACLF score nor the severity of ACLF at initial diagnosis demonstrate any absolute cut-off level for which there is complete futility in intensive care management. Thus, careful consideration is required when deciding on ICU admission.

      Complications indicating intensive care unit admission

      As stated, patients with cirrhosis may develop decompensated disease with portal hypertension and functional impairment of the liver, resulting in numerous complications including infection, variceal bleeding, HE, and HRS.
      • D'Amico G
      • Morabito A
      • D'Amico M
      • Pasta L
      • Malizia G
      • Rebora P
      • et al.
      Clinical states of cirrhosis and competing risks.
      Patients with cirrhosis may also develop ACLF, leading to renal, cardiovascular, and respiratory failures. Such complications, when severe, represent indications for management in an intensive care setting (Table 4).
      Table 4Objective criteria for ICU admission in patients with cirrhosis.
      Type of complicationCriteria for ICU admission
      InfectionSeptic shock

      Change in SOFA score ≥2

      qSOFA score ≥2
      Variceal bleedingHaemorrhagic shock

      Tracheal intubation for airway protection

      Need for balloon tamponade
      Hepatic encephalopathyGrade 4
      Renal failureDevelopment of hepatorenal syndrome not responsive to medical management (withdrawal of nephrotoxic medications and volume replacement with albumin)

      Acute need for renal replacement therapy
      Respiratory failurePaO2/FiO2 <200
      Cardiovascular compromiseRefractory hypotension
      FiO2, fraction of inspired oxygen; ICU, intensive care unit; PaO2, partial pressure of arterial oxygen; qSOFA, quick SOFA; SOFA, sequential organ failure assessment.

       Infection

      Bacterial infections are a leading complication in patients with decompensated liver disease. Bacterial infections are present in around one-third of patients with decompensated cirrhosis and account for up to 50% of deaths.
      • Strauss E
      The impact of bacterial infections on survival of patients with decompensated cirrhosis.
      • Taneja SK
      • Dhiman RK
      Prevention and management of bacterial infections in cirrhosis.
      Patients with cirrhosis have a relative immunodeficiency that puts them at risk of developing infections. A lack of complement and protein C production by the liver impairs the adaptive immune response.
      • Bunchorntavakul C
      • Chamroonkul N
      • Chavalitdhamrong D
      Bacterial infections in cirrhosis: A critical review and practical guidance.
      Splenomegaly as a consequence of portal hypertension leads to sequestration of immune cells, further reducing the activity of the cellular immune system.
      • Nanchal RS
      • Ahmad S
      Infections in Liver Disease.
      Along with a weakened immune system, altered gut microflora and translocation of intestinal bacteria also contribute to the development of infection.
      • Bruns T
      • Zimmermann HW
      • Stallmach A
      Risk factors and outcome of bacterial infections in cirrhosis.
      Major clinical risk factors for development of infection include recent infection within the past 12 months, malnutrition, and a model for end-stage liver disease (MELD) score of 15 or more.
      • Merli M
      • Lucidi C
      • Giannelli V
      • Giusto M
      • Riggio O
      • Falcone M
      • et al.
      Cirrhotic patients are at risk for health care-associated bacterial infections.
      Overall, the most common types of infection encountered by decompensated cirrhotic patients are spontaneous bacterial peritonitis (SBP), urinary tract infections, bacteraemia, pneumonia, and skin infections.
      • Jalan R
      • Fernandez J
      • Wiest R
      • Schnabl B
      • Moreau R
      • Angeli P
      • et al.
      Bacterial infections in cirrhosis: a position statement based on the EASL Special Conference 2013.
      Bacterial infections are also a major precipitant of ACLF and patients with ACLF not triggered by infection are at high risk of developing bacterial infections. In a study by Fernandez and colleagues, 37% of patients with ACLF had a bacterial infection at the time of ACLF diagnosis.
      • Fernández J
      • Acevedo J
      • Wiest R
      • Gustot T
      • Amoros A
      • Deulofeu C
      • et al.
      Bacterial and fungal infections in acute-on-chronic liver failure: prevalence, characteristics and impact on prognosis.
      The severity of ACLF, as measured by the prevalence of organ failures and the need for critical care and organ support, was greater when ACLF was caused by infection than if it developed from non-infectious aetiologies.
      • Fernández J
      • Acevedo J
      • Wiest R
      • Gustot T
      • Amoros A
      • Deulofeu C
      • et al.
      Bacterial and fungal infections in acute-on-chronic liver failure: prevalence, characteristics and impact on prognosis.
      Bacterial infections also conferred increased mortality in patients with ACLF, leading to a 90-day transplant free mortality of 51% compared with 38% in patients who did not have an infectious trigger.
      • Fernández J
      • Acevedo J
      • Wiest R
      • Gustot T
      • Amoros A
      • Deulofeu C
      • et al.
      Bacterial and fungal infections in acute-on-chronic liver failure: prevalence, characteristics and impact on prognosis.
      Infectious complications developed in 46% of patients with ACLF who did not initially present with an infection and were significantly more frequent in patients with acute decompensation The development of infection also resulted in a significant 90-day transplant free mortality rate of 51%.
      • Fernández J
      • Acevedo J
      • Wiest R
      • Gustot T
      • Amoros A
      • Deulofeu C
      • et al.
      Bacterial and fungal infections in acute-on-chronic liver failure: prevalence, characteristics and impact on prognosis.
      Cirrhotic patients have a hyperdynamic circulation with elevated cardiac output, decreased arterial pressure, and reduced systemic vascular resistance. If infection occurs, these patients develop an even more hyperdynamic circulation and become less responsive to alpha-adrenergic agonists.
      • Moreau R
      • Hadengue A
      • Soupison T
      • Kirstetter P
      • Mamzer MF
      • Vanjak D
      • et al.
      Septic shock in patients with cirrhosis: hemodynamic and metabolic characteristics and intensive care unit outcome.
      Therefore, cirrhotics are more likely to develop sepsis and progress to septic shock with multiorgan failure from infection, which is a strong indication for ICU admission.
      • Gustot T
      • Felleiter P
      • Pickkers P
      • Sakr Y
      • Rello J
      • Velissaris D
      • et al.
      Impact of infection on the prognosis of critically ill cirrhotic patients: results from a large worldwide study.
      • Piano S
      • Bartoletti M
      • Tonon M
      • Baldassarre M
      • Chies G
      • Romano A
      • et al.
      Assessment of Sepsis-3 criteria and quick SOFA in patients with cirrhosis and bacterial infections.
      Currently the use of the Sepsis-3 criteria involving an acute change in the SOFA score (Table 5) of 2 or more points and the simplified quick SOFA (qSOFA) score (Table 6) of at least 2 is advocated for the early identification of cirrhotic patients with sepsis and those who need to be admitted to the ICU.
      • Piano S
      • Bartoletti M
      • Tonon M
      • Baldassarre M
      • Chies G
      • Romano A
      • et al.
      Assessment of Sepsis-3 criteria and quick SOFA in patients with cirrhosis and bacterial infections.
      EASL Clinical Practice Guidelines for the management of patients with decompensated cirrhosis.
      Overall these patients have higher mortality rates when compared to septic shock patients without cirrhosis.
      • Moreau R
      • Hadengue A
      • Soupison T
      • Kirstetter P
      • Mamzer MF
      • Vanjak D
      • et al.
      Septic shock in patients with cirrhosis: hemodynamic and metabolic characteristics and intensive care unit outcome.
      Table 5Sequential organ failure assessment score.
      System01234
      Respiratory
       PaO2/FiO2 (mmHg)400<400<300<200<100
      Coagulation
       Platelets (x109/L)150<150<100<50<20
      Liver
       Bilirubin (mg/dl)<1.21.2–1.92.0–5.96.0–11.912.0
      Cardiovascular
       Mean arterial pressure (mmHg)70<70Dopamine <5

      Dobutamine
      Dopamine 5.1–15

      Epinephrine ≤0.1

      Norepinephrine ≤0.1
      Dopamine >15

      Epinephrine >0.1

      Norepinephrine >0.1
      Central Nervous System
       Glasgow coma score1513–1410–126–9<6
      Renal
       Creatinine (mg/dl)<1.21.2–1.92.0–3.43.5–4.9>5.0
       Urine output (ml/d)<500<200
      FiO2, fraction of inspired oxygen; PaO2, partial pressure of arterial oxygen.
      Table 6Quick sequential organ failure score.
      SystemValue
      Respiratory
      Respiratory rate22/min
      Central Nervous System
      Glasgow coma score13
      Cardiovascular
      Systolic blood pressure100 mmHg
      One major goal of therapy is the early initiation of appropriate empiric broad spectrum antibiotics.
      • Fernández J
      • Acevedo J
      • Wiest R
      • Gustot T
      • Amoros A
      • Deulofeu C
      • et al.
      Bacterial and fungal infections in acute-on-chronic liver failure: prevalence, characteristics and impact on prognosis.
      The presence of multidrug-resistant (MDR) bacteria needs to be considered as the global prevalence of MDR bacterial infections in cirrhotics is 34% with variations in prevalence and type of bacteria depending on geographical location.
      • Piano S
      • Singh V
      • Caraceni P
      • Maiwall R
      • Alessandria C
      • Fernandez J
      • et al.
      Epidemiology and Effects of Bacterial Infections in Patients With Cirrhosis Worldwide.
      Usage of an empiric antibiotic regimen with appropriate antimicrobial coverage resulted in improved clinical outcomes and mortality.
      • Fernández J
      • Acevedo J
      • Wiest R
      • Gustot T
      • Amoros A
      • Deulofeu C
      • et al.
      Bacterial and fungal infections in acute-on-chronic liver failure: prevalence, characteristics and impact on prognosis.
      • Piano S
      • Singh V
      • Caraceni P
      • Maiwall R
      • Alessandria C
      • Fernandez J
      • et al.
      Epidemiology and Effects of Bacterial Infections in Patients With Cirrhosis Worldwide.
      Other goals of therapy include attaining euvolemia and maintaining adequate tissue perfusion.
      • Fernández J
      • Acevedo J
      • Wiest R
      • Gustot T
      • Amoros A
      • Deulofeu C
      • et al.
      Bacterial and fungal infections in acute-on-chronic liver failure: prevalence, characteristics and impact on prognosis.
      • Fernández J
      • Gustot T
      Management of bacterial infections in cirrhosis.
      As such, treatment often requires ICU admission to allow for adequate resuscitation and management of the underlying infection through the use of fluids, vasopressors, and antibiotics.
      • Gustot T
      • Durand F
      • Lebrec D
      • Vincent JL
      • Moreau R
      Severe sepsis in cirrhosis.
      This enables clinicians to target a mean arterial pressure (MAP) of at least 65 mmHg for sufficient organ perfusion.
      • Levy MM
      • Evans LE
      • Rhodes A
      The Surviving Sepsis Campaign Bundle: 2018 update.

       Variceal bleeding

      Oesophageal and gastric varices are porto-systemic collaterals that develop as a consequence of portal hypertension and are present in about 50% of cirrhotic patients with the frequency increasing with worsening liver function.
      • Garcia-Tsao G
      • Sanyal AJ
      • Grace ND
      • Carey W
      • Diseases PGCotAAftSoL, Gastroenterology PPCotACo
      Prevention and management of gastroesophageal varices and variceal hemorrhage in cirrhosis.
      Acute variceal bleeding occurs at a rate of up to 15% per year with the greatest risk factor being variceal size.
      • Varices NIECftSaToE
      Prediction of the first variceal hemorrhage in patients with cirrhosis of the liver and esophageal varices. A prospective multicenter study.
      As a varix enlarges, vessel wall tension increases significantly, making it more likely to rupture. Mortality from variceal haemorrhage ranges from 30% to 50% and is a result of exsanguination or progressive hepatic failure.
      • Chalasani N
      • Kahi C
      • Francois F
      • Pinto A
      • Marathe A
      • Bini EJ
      • et al.
      Improved patient survival after acute variceal bleeding: a multicenter, cohort study.
      Due to the significant mortality associated with variceal bleeding, intensive care management is often required.
      Given the massive amount of haemorrhaging that may occur, airway protection from aspiration through tracheal intubation is often needed.
      • Olson JC
      • Saeian K
      Gastrointestinal Issues in Liver Disease.
      Tracheal intubation may prevent fatal episodes of massive aspiration and is an indication for ICU admission.
      • Rudolph SJ
      • Landsverk BK
      • Freeman ML
      Endotracheal intubation for airway protection during endoscopy for severe upper GI hemorrhage.
      Rapid resuscitation is also required given the potential nature of the bleed with a conservative haemoglobin transfusion threshold of 70 g/L conferring a higher survival rate than that of a more liberal haemoglobin transfusion threshold of 90 g/L.
      • Villanueva C
      • Colomo A
      • Bosch A
      • Concepción M
      • Hernandez-Gea V
      • Aracil C
      • et al.
      Transfusion strategies for acute upper gastrointestinal bleeding.
      Immediate initiation of vasoactive agents such as somatostatin, terlipressin, or octreotide allows for a decline in portal pressures to help reduce the amount of bleeding. Antibiotic prophylaxis usually with norfloxacin or ceftriaxone is required as it has been shown to reduce the rates of infection, rebleeding, and mortality.
      • Bernard B
      • Grangé JD
      • Khac EN
      • Amiot X
      • Opolon P
      • Poynard T
      Antibiotic prophylaxis for the prevention of bacterial infections in cirrhotic patients with gastrointestinal bleeding: a meta-analysis.
      Depending on the amount of bleeding that occurs, haemorrhagic shock may arise necessitating ICU transfer and use of vasopressor agents to maintain a MAP of 65 mmHg.
      • Katsounas A
      • Canbay A
      Intensive Care Therapy for Patients with Advanced Liver Diseases.
      Endoscopic therapy is standard treatment for variceal bleeding and should be undertaken within 12 hours of the bleeding presentation, once adequate resuscitation is achieved.
      • de Franchis R
      • Faculty BV
      Expanding consensus in portal hypertension: Report of the Baveno VI Consensus Workshop: Stratifying risk and individualizing care for portal hypertension.
      For oesophageal varices, the preferred endoscopic management is variceal band ligation, which has been shown to be superior to sclerotherapy in terms of rates of haemostasis, adverse events, and 6-week survival.
      • Villanueva C
      • Piqueras M
      • Aracil C
      • Gómez C
      • López-Balaguer JM
      • Gonzalez B
      • et al.
      A randomized controlled trial comparing ligation and sclerotherapy as emergency endoscopic treatment added to somatostatin in acute variceal bleeding.
      Regarding bleeding gastric varices, the preferred endoscopic therapy is cyanoacrylate injection as it results in less rebleeding, treatment-induced ulcer bleeding, and mortality compared to band ligation.
      • Lo GH
      • Lai KH
      • Cheng JS
      • Chen MH
      • Chiang HT
      A prospective, randomized trial of butyl cyanoacrylate injection versus band ligation in the management of bleeding gastric varices.
      Despite adequate standard therapy, 20% of patients may have failure of haemostasis and require rescue therapy.
      • Olson JC
      • Saeian K
      Gastrointestinal Issues in Liver Disease.
      Balloon tamponade with either a Sengstaken-Blakemore or Minnesota tube is often utilised as a way of rapidly achieving haemostasis in patients who have massive bleeding or who fail standard endoscopic therapy. Studies have shown that with balloon tamponade, 59% of patients survive to discharge from hospital and 1-year survival is 41%, which makes it an effective rescue therapy.
      • Nadler J
      • Stankovic N
      • Uber A
      • Holmberg MJ
      • Sanchez LD
      • Wolfe RE
      • et al.
      Outcomes in variceal hemorrhage following the use of a balloon tamponade device.
      Intensive care admission is mandatory when balloon tamponade is being implemented. Balloon tamponade is often used as a bridge to more definitive therapy in the form of early transjugular intrahepatic portosystemic shunt (TIPS) insertion (within 72 hours post admission). Early TIPS has been shown to reduce 1-year rebleeding and mortality rates compared to pharmacotherapy with endoscopic variceal band ligation and should be strongly considered in cirrhotics admitted to the ICU for variceal bleeding.
      • García-Pagán JC
      • Caca K
      • Bureau C
      • Laleman W
      • Appenrodt B
      • Luca A
      • et al.
      Early use of TIPS in patients with cirrhosis and variceal bleeding.

       Hepatic encephalopathy

      HE is a common complication of chronic liver disease in up to 45% of cirrhotic patients and is manifested by impaired cognition, confusion, and a decreased level of consciousness.
      • Wijdicks EF
      Hepatic Encephalopathy.
      It occurs as a result of impaired hepatic metabolic function leading to reduced removal of nitrogen-based waste products such as ammonia.
      • Katsounas A
      • Canbay A
      Intensive Care Therapy for Patients with Advanced Liver Diseases.
      Ammonia crosses the blood-brain-barrier and is combined with glutamate to form glutamine, which leads to cerebral oedema.
      • Wijdicks EF
      Hepatic Encephalopathy.
      Most instances of HE are precipitated by reversible factors including infection, gastrointestinal bleeding, acute kidney injury (AKI), sedating medications, and constipation.
      • Kandiah PA
      • Kumar G
      Hepatic Encephalopathy-the Old and the New.
      With the onset of HE, mortality at 1 year is greater than 50%.
      • Fichet J
      • Mercier E
      • Genée O
      • Garot D
      • Legras A
      • Dequin PF
      • et al.
      Prognosis and 1-year mortality of intensive care unit patients with severe hepatic encephalopathy.
      Although the presence of HE in the setting of acute liver failure is often an indication for intensive care admission, occurrence of severe HE in patients with chronic liver disease also calls for ICU management. Grading of HE occurs with the use of the West Haven grading scale (Table 2). Patients who are grade 4 generally have a Glasgow coma score less than 7 and tend to be comatose.
      • Kandiah PA
      • Kumar G
      Hepatic Encephalopathy-the Old and the New.
      Therefore, the presence of severe HE in cirrhotic patients is an indication for management in the ICU, with patients often requiring tracheal intubation for airway protection. Judicious use of sedation should be carried out with the avoidance of benzodiazepines.
      • Bakti G
      • Fisch HU
      • Karlaganis G
      • Minder C
      • Bircher J
      Mechanism of the excessive sedative response of cirrhotics to benzodiazepines: model experiments with triazolam.
      In terms of specific management options for HE, the initial step is to identify and reverse any precipitating causes such as infection or bleeding. Ammonia-lowering therapies are the standard of care and the most frequently utilised agent is lactulose, a nonabsorbable disaccharide that is converted into short-chain fatty acids by the colonic microbiome creating an acidic environment in the colonic lumen. This leads to inactivation of ammonia producing colonic bacteria and conversion of ammonia to nonabsorbable ammonium.
      • Gerber T
      • Schomerus H
      Hepatic encephalopathy in liver cirrhosis: pathogenesis, diagnosis and management.
      Lactulose can be given orally or via nasogastric tube as well as rectally. The antibiotic rifaximin is also a widely used therapy for management of HE, often in combination with lactulose, as its addition to lactulose was found to reduce mortality and length of hospital stay when compared to lactulose alone.
      • Sharma BC
      • Sharma P
      • Lunia MK
      • Srivastava S
      • Goyal R
      • Sarin SK
      A randomized, double-blind, controlled trial comparing rifaximin plus lactulose with lactulose alone in treatment of overt hepatic encephalopathy.

       Acute kidney injury

      AKI results in renal dysfunction in up to 50% of hospitalised cirrhotic patients.
      • Garcia-Tsao G
      • Parikh CR
      • Viola A
      Acute kidney injury in cirrhosis.
      The definition of AKI has been modified in recent years by the International Club of Ascites (ICA) based on ICA-AKI criteria, which split AKI into 3 different stages (Table 7). AKI in cirrhotic patients is now defined as an increase in serum creatinine (sCr) by at least 0.3 mg/dl within 48 hours or an increase in baseline sCr by at least 50% within the last 7 days.
      • Angeli P
      • Ginès P
      • Wong F
      • Bernardi M
      • Boyer TD
      • Gerbes A
      • et al.
      Diagnosis and management of acute kidney injury in patients with cirrhosis: revised consensus recommendations of the International Club of Ascites.
      Stage 1 AKI involves an increase in baseline sCr by at least 0.3 mg/dl or an increase in sCr by 1.5-fold to 2-fold. Stage 2 AKI results in an increase in sCr by 2-fold to 3-fold from baseline. Stage 3 AKI is defined as an increase in sCr by more than 3-fold from baseline or an increase in sCr to more than 4.0 mg/dl with an acute rise by at least 0.3 mg/dl.
      • Angeli P
      • Ginès P
      • Wong F
      • Bernardi M
      • Boyer TD
      • Gerbes A
      • et al.
      Diagnosis and management of acute kidney injury in patients with cirrhosis: revised consensus recommendations of the International Club of Ascites.
      Table 7International Club of Ascites: acute kidney injury definition and staging.
      Definition of acute kidney injuryIncrease in serum creatinine ≥0.3 mg/dl within 48 hours

      Increase in serum creatinine ≥50% from baseline within the last 7 days
      Staging of acute kidney injury
      Stage 1Increase in serum creatinine ≥0.3 mg/dl

      Increase in serum creatinine ≥1.5 to 2-fold from baseline
      Stage 2Increase in serum creatinine >2 to 3-fold from baseline
      Stage 3Increase in serum creatinine >3-fold from baseline

      Serum creatinine ≥4.0 mg/dl with an acute increase ≥0.3 mg/dl

      Initiation of renal replacement therapy
      Hepatorenal syndrome (HRS) is a particular form of AKI in patients with cirrhosis. It occurs in up to 40% of patients within the first 5 years of being diagnosed with cirrhosis.
      • Ginès A
      • Escorsell A
      • Ginès P
      • Saló J
      • Jiménez W
      • Inglada L
      • et al.
      Incidence, predictive factors, and prognosis of the hepatorenal syndrome in cirrhosis with ascites.
      In the past, HRS was divided into 2 types. Type 1 HRS was regarded as a rapidly progressing renal failure defined as the doubling of baseline sCr in less than 2 weeks to a value of greater than 2.5 mg/dl.
      • Colle I
      • Laterre PF
      Hepatorenal syndrome: the clinical impact of vasoactive therapy.
      Type 2 HRS was seen as a less progressive renal failure with elevation of sCr to greater than 1.5 mg/dl.
      • Colle I
      • Laterre PF
      Hepatorenal syndrome: the clinical impact of vasoactive therapy.
      More recently, the ICA has defined HRS as meeting the following criteria: i) presence of cirrhosis and ascites; ii) diagnosis of AKI in accordance with the ICA-AKI criteria; iii) absence of shock; iv) no improvement with 2 days of diuretic stoppage and plasma volume expansion with 1 g/kg body weight of albumin; v) absence of nephrotoxic drug use; vi) absence of macroscopic signs of structural renal disease (lack of proteinuria, haematuria, and abnormalities on renal ultrasonography).
      • Angeli P
      • Ginès P
      • Wong F
      • Bernardi M
      • Boyer TD
      • Gerbes A
      • et al.
      Diagnosis and management of acute kidney injury in patients with cirrhosis: revised consensus recommendations of the International Club of Ascites.
      Risk factors for the development of HRS include gastrointestinal bleeding, bacterial infection, spontaneous bacterial peritonitis, large-volume paracentesis, and alcoholic hepatitis.
      • EAftSot Liver
      EASL clinical practice guidelines on the management of ascites, spontaneous bacterial peritonitis, and hepatorenal syndrome in cirrhosis.
      Development of HRS is significant as it carries a poor prognosis. Previous studies have indicated median survival in patients with type 1 HRS of 2 weeks while patients with type 2 HRS have a median survival of 6 months.
      • Ginès P
      • Guevara M
      • Arroyo V
      • Rodés J
      Hepatorenal syndrome.
      Therefore, it is imperative to identify and treat patients who develop HRS early in the disease course as some reversal of renal dysfunction may be possible. Vasoconstrictors and albumin are the mainstays of medical therapy for HRS and often necessitate ICU admission, especially when HRS occurs in the setting of severe and refractory hypotension. Renal replacement therapy may be considered in the setting of LT candidates.
      Terlipressin is a vasopressin analogue that has been studied extensively in HRS. Multiple studies have shown that treatment with terlipressin and albumin leads to significant renal recovery in up to 50% of patients with type 1 HRS.
      • Martín-Llahí M
      • Pépin MN
      • Guevara M
      • Díaz F
      • Torre A
      • Monescillo A
      • et al.
      Terlipressin and albumin vs albumin in patients with cirrhosis and hepatorenal syndrome: a randomized study.
      Survival has also been shown to increase with the use of terlipressin and albumin.
      • Facciorusso A
      • Chandar AK
      • Murad MH
      • Prokop LJ
      • Muscatiello N
      • Kamath PS
      • et al.
      Comparative efficacy of pharmacological strategies for management of type 1 hepatorenal syndrome: a systematic review and network meta-analysis.
      When utilizing terlipressin, monitoring of central venous pressure is encouraged to help guide albumin use, which requires ICU admission and is not strongly recommended by current international guidelines.
      • Nadim MK
      • Durand F
      • Kellum JA
      • Levitsky J
      • O'Leary JG
      • Karvellas CJ
      • et al.
      Management of the critically ill patient with cirrhosis: A multidisciplinary perspective.
      Aside from terlipressin, norepinephrine can also be used along with albumin for the treatment of HRS. Norepinephrine has been shown to be as effective and as safe as terlipressin for type 1 HRS and is an alternative when terlipressin is unavailable.
      • Nassar Junior AP
      • Farias AQ
      • D' Albuquerque LA
      • Carrilho FJ
      • Malbouisson LM
      Terlipressin versus norepinephrine in the treatment of hepatorenal syndrome: a systematic review and meta-analysis.
      Norepinephrine can only be used in an ICU setting. In North America, terlipressin is not available so norepinephrine is the vasopressor of choice for the intensive management of HRS.
      Renal failure in the setting of ACLF represents a severe form of AKI and can be precipitated by infection, hypovolemia, or structural renal disease.
      • Bajaj JS
      • Moreau R
      • Kamath PS
      • Vargas HE
      • Arroyo V
      • Reddy KR
      • et al.
      Acute-on-Chronic Liver Failure: Getting Ready for Prime Time?.
      Based on the CLIF-organ failure (CLIF-OF) scoring system, renal failure is defined as a creatinine greater than 2 mg/dl or need for renal replacement therapy.
      • Jalan R
      • Saliba F
      • Pavesi M
      • Amoros A
      • Moreau R
      • Ginès P
      • et al.
      Development and validation of a prognostic score to predict mortality in patients with acute-on-chronic liver failure.
      Occurrence is a result of inflammation and hemodynamic compromise. Renal failure in the ACLF population has been associated with increased mortality with studies showing a 28-day mortality of close to 19%.
      • Moreau R
      • Jalan R
      • Gines P
      • Pavesi M
      • Angeli P
      • Cordoba J
      • et al.
      Acute-on-chronic liver failure is a distinct syndrome that develops in patients with acute decompensation of cirrhosis.
      Renal failure in patients with ACLF is also more likely to be prolonged and progressive compared to renal failure occurring in cirrhotic patients with acute decompensation. Patients with ACLF who develop AKI and renal failure are also more likely to require renal replacement therapy.
      • Maiwall R
      • Kumar S
      • Chandel SS
      • Kumar G
      • Rastogi A
      • Bihari C
      • et al.
      AKI in patients with acute on chronic liver failure is different from acute decompensation of cirrhosis.
      In terms of management of AKI in patients with ACLF, the first step is to address any potential underlying cause. This involves withholding any nephrotoxic drugs, treating potential infections, reducing or withdrawing diuretics, and plasma volume expansion in the presence of hypovolemia.
      • Angeli P
      • Ginès P
      • Wong F
      • Bernardi M
      • Boyer TD
      • Gerbes A
      • et al.
      Diagnosis and management of acute kidney injury in patients with cirrhosis: revised consensus recommendations of the International Club of Ascites.
      Like AKI in decompensated cirrhotic patients, the mainstay of volume expansion therapy in patients with ACLF and renal dysfunction is the colloid solution albumin.
      • Bernardi M
      • Ricci CS
      • Zaccherini G
      Role of human albumin in the management of complications of liver cirrhosis.
      No other colloids such as starch should be used because of the risk of nephrotoxicity.
      • Myburgh JA
      • Finfer S
      • Bellomo R
      • Billot L
      • Cass A
      • Gattas D
      • et al.
      Hydroxyethyl starch or saline for fluid resuscitation in intensive care.
      • Perner A
      • Haase N
      • Guttormsen AB
      • Tenhunen J
      • Klemenzson G
      • Åneman A
      • et al.
      Hydroxyethyl starch 130/0.42 versus Ringer's acetate in severe sepsis.
      However, when these measures do not provide an adequate response and HRS or refractory hypotension develops, ICU admission is often indicated for therapy with vasoactive agents including terlipressin or norepinephrine. Terlipressin may be the vasoactive agent of choice in patients with ACLF who develop HRS, as a recent study by Arora et al. demonstrated greater response rates and lower mortality with the use of terlipressin compared to norepinephrine in this patient population.
      • Arora V
      • Maiwall R
      • Vijayaraghavan R
      • Jindal A
      • Saggere Muralikrishna S
      • Kumar G
      • et al.
      Terlipressin is superior to noradrenaline in the management of acute kidney injury in acute on chronic liver failure.
      Overall, it appears that the ACLF grade prior to the initiation of treatment for HRS, with terlipressin and albumin, is the greatest predictor of response.
      • Piano S
      • Schmidt HH
      • Ariza X
      • Amoros A
      • Romano A
      • Hüsing-Kabar A
      • et al.
      Association Between Grade of Acute on Chronic Liver Failure and Response to Terlipressin and Albumin in Patients With Hepatorenal Syndrome.
      In patients who are awaiting a LT, renal replacement therapy in the ICU may be required as a bridge to LT or combined kidney-liver transplant if renal impairment does not respond to vasopressor and colloid support.
      • Nadim MK
      • Durand F
      • Kellum JA
      • Levitsky J
      • O'Leary JG
      • Karvellas CJ
      • et al.
      Management of the critically ill patient with cirrhosis: A multidisciplinary perspective.
      In the ICU setting, continuous renal replacement therapy is preferred over haemodialysis as it offers greater haemodynamic stability.
      • Bellomo R
      • Cass A
      • Cole L
      • Finfer S
      • Gallagher M
      • Lo S
      • et al.
      Intensity of continuous renal-replacement therapy in critically ill patients.
      Other indications for ICU admission in cirrhotics with renal failure include metabolic derangements such as refractory hyperkalemia, metabolic acidosis, severe uraemia, and fluid overload.

       Respiratory failure

      Respiratory failure in the context of ACLF often occurs secondary to the inflammatory sequelae of ACLF or because of lung infection. Within this patient population, respiratory failure is defined by the CLIF-OF scoring system as a partial pressure of arterial oxygen (PaO2) to fraction of inspired oxygen (FiO2) ratio (P/F ratio) of less than 200 mmHg.
      • Jalan R
      • Saliba F
      • Pavesi M
      • Amoros A
      • Moreau R
      • Ginès P
      • et al.
      Development and validation of a prognostic score to predict mortality in patients with acute-on-chronic liver failure.
      Pulmonary infiltrates are also often seen on chest radiography. Overall this demonstrates significant lung injury and a need for ICU admission to facilitate tracheal intubation and use of mechanical ventilation for respiratory support.
      • Ranieri VM
      • Rubenfeld GD
      • Thompson BT
      • Ferguson ND
      • Caldwell E
      • Fan E
      • et al.
      Acute respiratory distress syndrome: the Berlin Definition.
      Management requires ventilation with low tidal volumes that are typical of lung protective ventilation strategies in acute respiratory distress syndrome.
      • Brower RG
      • Matthay MA
      • Morris A
      • Schoenfeld D
      • Thompson BT
      • Wheeler A
      • et al.
      Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome.
      Despite such supportive efforts, respiratory failure requiring mechanical ventilation is a poor prognostic sign in patients with ACLF, with 1-year mortality as high as 89%.
      • Levesque E
      • Saliba F
      • Ichaï P
      • Samuel D
      Outcome of patients with cirrhosis requiring mechanical ventilation in ICU.
      Nonetheless, ICU management with mechanical ventilation is often used to bridge patients with ACLF to transplant in those who are candidates for LT.

       Cardiovascular failure

      Patients with chronic liver disease often have baseline hyperdynamic circulation with low systemic vascular resistance.
      • Gustot T
      • Fernandez J
      • Garcia E
      • Morando F
      • Caraceni P
      • Alessandria C
      • et al.
      Clinical Course of acute-on-chronic liver failure syndrome and effects on prognosis.
      With the development of ACLF, release of proinflammatory cytokines leads to systemic inflammation and peripheral vascular vasodilation, which results in worsening of systemic vascular resistance and mean arterial blood pressure.
      • Stadlbauer V
      • Krisper P
      • Aigner R
      • Haditsch B
      • Jung A
      • Lackner C
      • et al.
      Effect of extracorporeal liver support by MARS and Prometheus on serum cytokines in acute-on-chronic liver failure.
      This leads to reduced end-organ tissue perfusion and a requirement for ICU admission for management with vasoactive agents for haemodynamic support, which defines cardiovascular failure according to the CLIF-OF scoring system.
      • Jalan R
      • Saliba F
      • Pavesi M
      • Amoros A
      • Moreau R
      • Ginès P
      • et al.
      Development and validation of a prognostic score to predict mortality in patients with acute-on-chronic liver failure.
      A complicating factor in patients with ACLF is the presence of adrenal insufficiency, which is fairly common in patients with chronic liver disease. Overall this leads to reduced serum cortisol levels and a decreased peripheral response to vasoconstrictor therapy.
      • Fernández J
      • Escorsell A
      • Zabalza M
      • Felipe V
      • Navasa M
      • Mas A
      • et al.
      Adrenal insufficiency in patients with cirrhosis and septic shock: Effect of treatment with hydrocortisone on survival.
      Also, the existence of cirrhotic cardiomyopathy is present in up to 50% of patients with cirrhosis and can further worsen haemodynamic stability if ACLF develops.
      • Møller S
      • Hove JD
      • Dixen U
      • Bendtsen F
      New insights into cirrhotic cardiomyopathy.

       Prognostication in patients with ACLF

      ACLF is a dynamic process and patients may require admission and management in an ICU setting as there is potential for improvement. At the same time, patients with ACLF may significantly worsen. Despite the potential for clinical improvement, mortality is high in this patient population, especially in those with multiorgan failure and septic shock.
      • Weil D
      • Levesque E
      • McPhail M
      • Cavallazzi R
      • Theocharidou E
      • Cholongitas E
      • et al.
      Prognosis of cirrhotic patients admitted to intensive care unit: a meta-analysis.
      Continued utilisation of intensive care therapies may become futile as the prognosis for patients with ACLF admitted to the ICU remains fairly poor. Overall, it appears that the early clinical course in patients with ACLF helps to determine the prognosis. Different prognostication models including the Acute Physiology and Chronic Health Evaluation (APACHE) II score, the MELD score, and the Child-Turcotte-Pugh (CTP) score have been used to identify patients with ACLF who are at the highest risk of death.
      • Jalan R
      • Saliba F
      • Pavesi M
      • Amoros A
      • Moreau R
      • Ginès P
      • et al.
      Development and validation of a prognostic score to predict mortality in patients with acute-on-chronic liver failure.
      More recently, the CLIF-C ACLF score was developed by the CANONIC study group as a diagnostic and prognostic tool that can be used to determine the risk of mortality in patients with ACLF.
      • Jalan R
      • Saliba F
      • Pavesi M
      • Amoros A
      • Moreau R
      • Ginès P
      • et al.
      Development and validation of a prognostic score to predict mortality in patients with acute-on-chronic liver failure.
      Overall, the CLIF-C ACLF score is calculated based on bilirubin, creatinine, HE grade, INR, MAP, and PaO2, which gives an overview of the number of organ failures present, along with age and white cell count. The CLIF-C ACLF score was found to be more accurate at predicting poor outcomes in all patients with ACLF than the older models such as APACHE II, MELD, and CTP scores, regardless of the care setting.
      • Jalan R
      • Saliba F
      • Pavesi M
      • Amoros A
      • Moreau R
      • Ginès P
      • et al.
      Development and validation of a prognostic score to predict mortality in patients with acute-on-chronic liver failure.
      However, it remained unclear how well the CLIF-C ACLF score predicted mortality in patients with ACLF requiring ICU admission.
      A recent study by Karvellas et al. assessed the performance of the CLIF-C ACLF score in critically ill patients with ACLF who were admitted to the ICU. CLIF-C ACLF scores and ACLF grades on ICU admission and at day 3 post-ICU admission were evaluated for their ability to differentiate non-survivors and survivors at 28 and 90 days. These scores were also compared directly with APACHE II and CTP scores in terms of their ability to predict survival in patients admitted to the ICU.
      • Karvellas CJ
      • Garcia-Lopez E
      • Fernandez J
      • Saliba F
      • Sy E
      • Jalan R
      • et al.
      Dynamic Prognostication in Critically Ill Cirrhotic Patients With Multiorgan Failure in ICUs in Europe and North America: A Multicenter Analysis.
      Patients with a CLIF-C ACLF score of greater than 70 either on ICU admission or at day 3 post-ICU admission were identified as having 90% mortality at 90 days. The CLIC-C ACLF score also had a c-index of 0.75 in terms of separating survivors from non-survivors and performed significantly better than APACHE II and CTP scores.
      • Karvellas CJ
      • Garcia-Lopez E
      • Fernandez J
      • Saliba F
      • Sy E
      • Jalan R
      • et al.
      Dynamic Prognostication in Critically Ill Cirrhotic Patients With Multiorgan Failure in ICUs in Europe and North America: A Multicenter Analysis.
      Patients who had an improvement in their ACLF grade at day 3 post-ICU admission had improved survival at 28 and 90 days.
      • Karvellas CJ
      • Garcia-Lopez E
      • Fernandez J
      • Saliba F
      • Sy E
      • Jalan R
      • et al.
      Dynamic Prognostication in Critically Ill Cirrhotic Patients With Multiorgan Failure in ICUs in Europe and North America: A Multicenter Analysis.
      A separate study by Engelmann and colleagues also examined the CLIF-C ACLF score as a way to identify patients admitted to the ICU who were not expected to benefit from continued intensive therapies and compared its prognostic value to other scores of chronic liver disease. CLIF-C ACLF and other chronic liver disease scores were calculated at 48 hours post-ICU admission and mortality at 28 days was observed.
      • Engelmann C
      • Thomsen KL
      • Zakeri N
      • Sheikh M
      • Agarwal B
      • Jalan R
      • et al.
      Validation of CLIF-C ACLF score to define a threshold for futility of intensive care support for patients with acute-on-chronic liver failure.
      All patients with a CLIF-C ACLF score of greater than 70 at 48 hours post-ICU admission died within 28 days.
      • Engelmann C
      • Thomsen KL
      • Zakeri N
      • Sheikh M
      • Agarwal B
      • Jalan R
      • et al.
      Validation of CLIF-C ACLF score to define a threshold for futility of intensive care support for patients with acute-on-chronic liver failure.
      Regarding the importance of the early clinical course of ACLF in determining prognosis and futility of care, Gustot and colleagues also demonstrated that prognosis correlated better with the clinical course in patients with ACLF (final ACLF grade post diagnosis) than with the ACLF grade at diagnosis.
      • Gustot T
      • Fernandez J
      • Garcia E
      • Morando F
      • Caraceni P
      • Alessandria C
      • et al.
      Clinical Course of acute-on-chronic liver failure syndrome and effects on prognosis.
      The 28-day mortality rate steadily increased depending on the final ACLF grade with rates of 5.8%, 18.2%, 41.7%, and 91.8% for final ACLF grades of 0, 1, 2, and 3 respectively.
      • Gustot T
      • Fernandez J
      • Garcia E
      • Morando F
      • Caraceni P
      • Alessandria C
      • et al.
      Clinical Course of acute-on-chronic liver failure syndrome and effects on prognosis.
      This was independent of what the initial ACLF grade was. The authors found that the final ACLF grade was defined between days 3 to 7 post diagnosis in the vast majority of patients (81%) and that the day 3 to 7 ACLF grade could be used to define the early clinical course.
      • Gustot T
      • Fernandez J
      • Garcia E
      • Morando F
      • Caraceni P
      • Alessandria C
      • et al.
      Clinical Course of acute-on-chronic liver failure syndrome and effects on prognosis.
      Day 3 to 7 ACLF grade had a c-index of 0.85 in predicting 28-day mortality and was significantly better than ACLF grade at diagnosis.
      • Gustot T
      • Fernandez J
      • Garcia E
      • Morando F
      • Caraceni P
      • Alessandria C
      • et al.
      Clinical Course of acute-on-chronic liver failure syndrome and effects on prognosis.
      Based on these studies, it could be suggested that limits to further aggressive therapy and organ support may need to be placed on patients with ACLF, who are admitted to the ICU and have poor prognostic scores, especially in patients who do not respond to a trial of short-term therapy and who are not LT candidates. Patients who continue to have a CLIF-C ACLF score of greater than 70 at 48 to 72 hours post-ICU admission should be considered for palliative care instead of ongoing intensive care therapies, especially if deemed to not be transplant candidates. Another algorithm proposed by Gustot and colleagues suggests that for patients not appropriate for LT, withdrawal of care should be considered if the day 3 to 7 ACLF grade is 3, with 4 or more organ failures present, or if the CLIF-C ACLF score is greater than 64 at 3 to 7 days post diagnosis with an ACLF grade of 3 at diagnosis.
      • Gustot T
      • Fernandez J
      • Garcia E
      • Morando F
      • Caraceni P
      • Alessandria C
      • et al.
      Clinical Course of acute-on-chronic liver failure syndrome and effects on prognosis.
      For patients who have reasonable prognostic scores or who are appropriate transplant candidates, ongoing aggressive therapy could potentially prevent further deterioration and serve as a bridge to LT.
      Although patients with ACLF may be too ill to ultimately undergo LT, it remains an important consideration in appropriate candidates. A recent study by Thuluvath and colleagues demonstrated excellent survival post-LT in patients with ACLF, even with a high number of organ failures prior to LT. Patient survival was 90% at 90 days post-LT and 81% at 1-year post-LT for patients with ACLF and 5 to 6 organ failures.
      • Thuluvath PJ
      • Thuluvath AJ
      • Hanish S
      • Savva Y
      Liver transplantation in patients with multiple organ failures: Feasibility and outcomes.
      Without LT, 30-day survival was only up to 8% in patients with ACLF and 3 or more organ failures.
      • Thuluvath PJ
      • Thuluvath AJ
      • Hanish S
      • Savva Y
      Liver transplantation in patients with multiple organ failures: Feasibility and outcomes.
      Within this patient population, there may be a narrow window for LT and LT candidacy should be considered early in the clinical course. Continued intensive therapy in the ICU while awaiting LT may allow these patients to survive to LT.

      Conclusions

      Although the majority of cirrhotic patients can be managed in a non-critical care environment, acute decompensation or the development of ACLF may necessitate transfer to an ICU setting for more intensive support. Complications of variceal bleeding, HE, HRS, and respiratory, renal, and cardiovascular failures, often require critical care management in the ICU. This is especially true in patients who are LT candidates, where intensive management can serve as a bridge to transplantation. However, frequent reassessment and utilisation of prognostic scores such as the CLIF-C ACLF score are required to identify patients who will not benefit from continued intensive care therapies, particularly for patients who are not LT candidates. LT candidacy needs to be evaluated early on. For patients who are not LT candidates, if clinical improvement is not seen within 48 to 72 hours post-ICU admission, serious consideration should be given to palliation as opposed to continued aggressive ICU management. For those patients who are LT candidates continued aggressive therapy may allow bridging to LT.

      Financial support

      The authors received no financial support to produce this manuscript.

      Conflict of interest

      The authors declare no conflicts of interest that pertain to this work.
      Please refer to the accompanying ICMJE disclosure forms for further details.

      Authors’ contributions

      VD and CJK both drafted and significantly revised the final manuscript.

      Supplementary data

      References

        • Schuppan D
        • Afdhal NH
        Liver cirrhosis.
        Lancet. 2008; 371: 838-851
        • Tsochatzis EA
        • Bosch J
        • Burroughs AK
        Liver cirrhosis.
        Lancet. 2014; 383: 1749-1761
        • Bernardi M
        • Moreau R
        • Angeli P
        • Schnabl B
        • Arroyo V
        Mechanisms of decompensation and organ failure in cirrhosis: From peripheral arterial vasodilation to systemic inflammation hypothesis.
        J Hepatol. 2015; 63: 1272-1284
        • Olson JC
        Acute-on-chronic and Decompensated Chronic Liver Failure: Definitions, Epidemiology, and Prognostication.
        Crit Care Clin. 2016; 32: 301-309
        • D'Amico G
        • Garcia-Tsao G
        • Pagliaro L
        Natural history and prognostic indicators of survival in cirrhosis: a systematic review of 118 studies.
        J Hepatol. 2006; 44: 217-231
        • Jalan R
        • Gines P
        • Olson JC
        • Mookerjee RP
        • Moreau R
        • Garcia-Tsao G
        • et al.
        Acute-on chronic liver failure.
        J Hepatol. 2012; 57: 1336-1348
        • Arroyo V
        • Moreau R
        • Kamath PS
        • Jalan R
        • Ginès P
        • Nevens F
        • et al.
        Acute-on-chronic liver failure in cirrhosis.
        Nat Rev Dis Primers. 2016; 216041
        • Bajaj JS
        • Moreau R
        • Kamath PS
        • Vargas HE
        • Arroyo V
        • Reddy KR
        • et al.
        Acute-on-Chronic Liver Failure: Getting Ready for Prime Time?.
        Hepatology. 2018; 68: 1621-1632
        • Jalan R
        • Yurdaydin C
        • Bajaj JS
        • Acharya SK
        • Arroyo V
        • Lin HC
        • et al.
        Toward an improved definition of acute-on-chronic liver failure.
        Gastroenterology. 2014; 147: 4-10
        • Moreau R
        • Jalan R
        • Gines P
        • Pavesi M
        • Angeli P
        • Cordoba J
        • et al.
        Acute-on-chronic liver failure is a distinct syndrome that develops in patients with acute decompensation of cirrhosis.
        Gastroenterology. 2013; 144 (1437.e1421-1429): 1426-1437
        • Piano S
        • Tonon M
        • Vettore E
        • Stanco M
        • Pilutti C
        • Romano A
        • et al.
        Incidence, predictors and outcomes of acute-on-chronic liver failure in outpatients with cirrhosis.
        J Hepatol. 2017; 67: 1177-1184
        • Gustot T
        • Fernandez J
        • Garcia E
        • Morando F
        • Caraceni P
        • Alessandria C
        • et al.
        Clinical Course of acute-on-chronic liver failure syndrome and effects on prognosis.
        Hepatology. 2015; 62: 243-252
        • D'Amico G
        • Morabito A
        • D'Amico M
        • Pasta L
        • Malizia G
        • Rebora P
        • et al.
        Clinical states of cirrhosis and competing risks.
        J Hepatol. 2018; 68: 563-576
        • Strauss E
        The impact of bacterial infections on survival of patients with decompensated cirrhosis.
        Ann Hepatol. 2013; 13: 7-19
        • Taneja SK
        • Dhiman RK
        Prevention and management of bacterial infections in cirrhosis.
        Int J Hepatol. 2011; 2011784540
        • Bunchorntavakul C
        • Chamroonkul N
        • Chavalitdhamrong D
        Bacterial infections in cirrhosis: A critical review and practical guidance.
        World J Hepatol. 2016; 8: 307-321
        • Nanchal RS
        • Ahmad S
        Infections in Liver Disease.
        Crit Care Clin. 2016; 32: 411-424
        • Bruns T
        • Zimmermann HW
        • Stallmach A
        Risk factors and outcome of bacterial infections in cirrhosis.
        World J Gastroenterol. 2014; 20: 2542-2554
        • Merli M
        • Lucidi C
        • Giannelli V
        • Giusto M
        • Riggio O
        • Falcone M
        • et al.
        Cirrhotic patients are at risk for health care-associated bacterial infections.
        Clin Gastroenterol Hepatol. 2010; 8: 979-985
        • Jalan R
        • Fernandez J
        • Wiest R
        • Schnabl B
        • Moreau R
        • Angeli P
        • et al.
        Bacterial infections in cirrhosis: a position statement based on the EASL Special Conference 2013.
        J Hepatol. 2014; 60: 1310-1324
        • Fernández J
        • Acevedo J
        • Wiest R
        • Gustot T
        • Amoros A
        • Deulofeu C
        • et al.
        Bacterial and fungal infections in acute-on-chronic liver failure: prevalence, characteristics and impact on prognosis.
        Gut. 2018; 67: 1870-1880
        • Moreau R
        • Hadengue A
        • Soupison T
        • Kirstetter P
        • Mamzer MF
        • Vanjak D
        • et al.
        Septic shock in patients with cirrhosis: hemodynamic and metabolic characteristics and intensive care unit outcome.
        Crit Care Med. 1992; 20: 746-750
        • Gustot T
        • Felleiter P
        • Pickkers P
        • Sakr Y
        • Rello J
        • Velissaris D
        • et al.
        Impact of infection on the prognosis of critically ill cirrhotic patients: results from a large worldwide study.
        Liver Int. 2014; 34: 1496-1503
        • Piano S
        • Bartoletti M
        • Tonon M
        • Baldassarre M
        • Chies G
        • Romano A
        • et al.
        Assessment of Sepsis-3 criteria and quick SOFA in patients with cirrhosis and bacterial infections.
        Gut. 2018; 67: 1892-1899
      1. EASL Clinical Practice Guidelines for the management of patients with decompensated cirrhosis.
        J Hepatol. 2018; 69: 406-460
        • Piano S
        • Singh V
        • Caraceni P
        • Maiwall R
        • Alessandria C
        • Fernandez J
        • et al.
        Epidemiology and Effects of Bacterial Infections in Patients With Cirrhosis Worldwide.
        Gastroenterology. 2019; ([Epubed ahead of print])
        • Fernández J
        • Gustot T
        Management of bacterial infections in cirrhosis.
        J Hepatol. 2012; 56: S1-12
        • Gustot T
        • Durand F
        • Lebrec D
        • Vincent JL
        • Moreau R
        Severe sepsis in cirrhosis.
        Hepatology. 2009; 50: 2022-2033
        • Levy MM
        • Evans LE
        • Rhodes A
        The Surviving Sepsis Campaign Bundle: 2018 update.
        Intensive Care Med. 2018; 44: 925-928
        • Garcia-Tsao G
        • Sanyal AJ
        • Grace ND
        • Carey W
        • Diseases PGCotAAftSoL, Gastroenterology PPCotACo
        Prevention and management of gastroesophageal varices and variceal hemorrhage in cirrhosis.
        Hepatology. 2007; 46: 922-938
        • Varices NIECftSaToE
        Prediction of the first variceal hemorrhage in patients with cirrhosis of the liver and esophageal varices. A prospective multicenter study.
        N Engl J Med. 1988; 319: 983-989
        • Chalasani N
        • Kahi C
        • Francois F
        • Pinto A
        • Marathe A
        • Bini EJ
        • et al.
        Improved patient survival after acute variceal bleeding: a multicenter, cohort study.
        Am J Gastroenterol. 2003; 98: 653-659
        • Olson JC
        • Saeian K
        Gastrointestinal Issues in Liver Disease.
        Crit Care Clin. 2016; 32: 371-384
        • Rudolph SJ
        • Landsverk BK
        • Freeman ML
        Endotracheal intubation for airway protection during endoscopy for severe upper GI hemorrhage.
        Gastrointest Endosc. 2003; 57: 58-61
        • Villanueva C
        • Colomo A
        • Bosch A
        • Concepción M
        • Hernandez-Gea V
        • Aracil C
        • et al.
        Transfusion strategies for acute upper gastrointestinal bleeding.
        N Engl J Med. 2013; 368: 11-21
        • Bernard B
        • Grangé JD
        • Khac EN
        • Amiot X
        • Opolon P
        • Poynard T
        Antibiotic prophylaxis for the prevention of bacterial infections in cirrhotic patients with gastrointestinal bleeding: a meta-analysis.
        Hepatology. 1999; 29: 1655-1661
        • Katsounas A
        • Canbay A
        Intensive Care Therapy for Patients with Advanced Liver Diseases.
        Visc Med. 2018; 34: 283-289
        • de Franchis R
        • Faculty BV
        Expanding consensus in portal hypertension: Report of the Baveno VI Consensus Workshop: Stratifying risk and individualizing care for portal hypertension.
        J Hepatol. 2015; 63: 743-752
        • Villanueva C
        • Piqueras M
        • Aracil C
        • Gómez C
        • López-Balaguer JM
        • Gonzalez B
        • et al.
        A randomized controlled trial comparing ligation and sclerotherapy as emergency endoscopic treatment added to somatostatin in acute variceal bleeding.
        J Hepatol. 2006; 45: 560-567
        • Lo GH
        • Lai KH
        • Cheng JS
        • Chen MH
        • Chiang HT
        A prospective, randomized trial of butyl cyanoacrylate injection versus band ligation in the management of bleeding gastric varices.
        Hepatology. 2001; 33: 1060-1064
        • Nadler J
        • Stankovic N
        • Uber A
        • Holmberg MJ
        • Sanchez LD
        • Wolfe RE
        • et al.
        Outcomes in variceal hemorrhage following the use of a balloon tamponade device.
        Am J Emerg Med. 2017; 35: 1500-1502
        • García-Pagán JC
        • Caca K
        • Bureau C
        • Laleman W
        • Appenrodt B
        • Luca A
        • et al.
        Early use of TIPS in patients with cirrhosis and variceal bleeding.
        N Engl J Med. 2010; 362: 2370-2379
        • Wijdicks EF
        Hepatic Encephalopathy.
        N Engl J Med. 2016; 375: 1660-1670
        • Kandiah PA
        • Kumar G
        Hepatic Encephalopathy-the Old and the New.
        Crit Care Clin. 2016; 32: 311-329
        • Fichet J
        • Mercier E
        • Genée O
        • Garot D
        • Legras A
        • Dequin PF
        • et al.
        Prognosis and 1-year mortality of intensive care unit patients with severe hepatic encephalopathy.
        J Crit Care. 2009; 24: 364-370
        • Bakti G
        • Fisch HU
        • Karlaganis G
        • Minder C
        • Bircher J
        Mechanism of the excessive sedative response of cirrhotics to benzodiazepines: model experiments with triazolam.
        Hepatology. 1987; 7: 629-638
        • Gerber T
        • Schomerus H
        Hepatic encephalopathy in liver cirrhosis: pathogenesis, diagnosis and management.
        Drugs. 2000; 60: 1353-1370
        • Sharma BC
        • Sharma P
        • Lunia MK
        • Srivastava S
        • Goyal R
        • Sarin SK
        A randomized, double-blind, controlled trial comparing rifaximin plus lactulose with lactulose alone in treatment of overt hepatic encephalopathy.
        Am J Gastroenterol. 2013; 108: 1458-1463
        • Garcia-Tsao G
        • Parikh CR
        • Viola A
        Acute kidney injury in cirrhosis.
        Hepatology. 2008; 48: 2064-2077
        • Angeli P
        • Ginès P
        • Wong F
        • Bernardi M
        • Boyer TD
        • Gerbes A
        • et al.
        Diagnosis and management of acute kidney injury in patients with cirrhosis: revised consensus recommendations of the International Club of Ascites.
        J Hepatol. 2015; 62: 968-974
        • Ginès A
        • Escorsell A
        • Ginès P
        • Saló J
        • Jiménez W
        • Inglada L
        • et al.
        Incidence, predictive factors, and prognosis of the hepatorenal syndrome in cirrhosis with ascites.
        Gastroenterology. 1993; 105: 229-236
        • Colle I
        • Laterre PF
        Hepatorenal syndrome: the clinical impact of vasoactive therapy.
        Expert Rev Gastroenterol Hepatol. 2018; 12: 173-188
        • EAftSot Liver
        EASL clinical practice guidelines on the management of ascites, spontaneous bacterial peritonitis, and hepatorenal syndrome in cirrhosis.
        J Hepatol. 2010; 53: 397-417
        • Ginès P
        • Guevara M
        • Arroyo V
        • Rodés J
        Hepatorenal syndrome.
        Lancet. 2003; 362: 1819-1827
        • Martín-Llahí M
        • Pépin MN
        • Guevara M
        • Díaz F
        • Torre A
        • Monescillo A
        • et al.
        Terlipressin and albumin vs albumin in patients with cirrhosis and hepatorenal syndrome: a randomized study.
        Gastroenterology. 2008; 134: 1352-1359
        • Facciorusso A
        • Chandar AK
        • Murad MH
        • Prokop LJ
        • Muscatiello N
        • Kamath PS
        • et al.
        Comparative efficacy of pharmacological strategies for management of type 1 hepatorenal syndrome: a systematic review and network meta-analysis.
        Lancet Gastroenterol Hepatol. 2017; 2: 94-102
        • Nadim MK
        • Durand F
        • Kellum JA
        • Levitsky J
        • O'Leary JG
        • Karvellas CJ
        • et al.
        Management of the critically ill patient with cirrhosis: A multidisciplinary perspective.
        J Hepatol. 2016; 64: 717-735
        • Nassar Junior AP
        • Farias AQ
        • D' Albuquerque LA
        • Carrilho FJ
        • Malbouisson LM
        Terlipressin versus norepinephrine in the treatment of hepatorenal syndrome: a systematic review and meta-analysis.
        PLoS One. 2014; 9e107466
        • Jalan R
        • Saliba F
        • Pavesi M
        • Amoros A
        • Moreau R
        • Ginès P
        • et al.
        Development and validation of a prognostic score to predict mortality in patients with acute-on-chronic liver failure.
        J Hepatol. 2014; 61: 1038-1047
        • Maiwall R
        • Kumar S
        • Chandel SS
        • Kumar G
        • Rastogi A
        • Bihari C
        • et al.
        AKI in patients with acute on chronic liver failure is different from acute decompensation of cirrhosis.
        Hepatol Int. 2015; 9: 627-639
        • Bernardi M
        • Ricci CS
        • Zaccherini G
        Role of human albumin in the management of complications of liver cirrhosis.
        J Clin Exp Hepatol. 2014; 4: 302-311
        • Myburgh JA
        • Finfer S
        • Bellomo R
        • Billot L
        • Cass A
        • Gattas D
        • et al.
        Hydroxyethyl starch or saline for fluid resuscitation in intensive care.
        N Engl J Med. 2012; 367: 1901-1911
        • Perner A
        • Haase N
        • Guttormsen AB
        • Tenhunen J
        • Klemenzson G
        • Åneman A
        • et al.
        Hydroxyethyl starch 130/0.42 versus Ringer's acetate in severe sepsis.
        N Engl J Med. 2012; 367: 124-134
        • Arora V
        • Maiwall R
        • Vijayaraghavan R
        • Jindal A
        • Saggere Muralikrishna S
        • Kumar G
        • et al.
        Terlipressin is superior to noradrenaline in the management of acute kidney injury in acute on chronic liver failure.
        Hepatology. 2018 Aug 3; ([Epubed ahead of print])https://doi.org/10.1002/hep.30208
        • Piano S
        • Schmidt HH
        • Ariza X
        • Amoros A
        • Romano A
        • Hüsing-Kabar A
        • et al.
        Association Between Grade of Acute on Chronic Liver Failure and Response to Terlipressin and Albumin in Patients With Hepatorenal Syndrome.
        Clin Gastroenterol Hepatol. 2018; 16: 1792-1800.e1793
        • Bellomo R
        • Cass A
        • Cole L
        • Finfer S
        • Gallagher M
        • Lo S
        • et al.
        Intensity of continuous renal-replacement therapy in critically ill patients.
        N Engl J Med. 2009; 361: 1627-1638
        • Ranieri VM
        • Rubenfeld GD
        • Thompson BT
        • Ferguson ND
        • Caldwell E
        • Fan E
        • et al.
        Acute respiratory distress syndrome: the Berlin Definition.
        JAMA. 2012; 307: 2526-2533
        • Brower RG
        • Matthay MA
        • Morris A
        • Schoenfeld D
        • Thompson BT
        • Wheeler A
        • et al.
        Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome.
        N Engl J Med. 2000; 342: 1301-1308
        • Levesque E
        • Saliba F
        • Ichaï P
        • Samuel D
        Outcome of patients with cirrhosis requiring mechanical ventilation in ICU.
        J Hepatol. 2014; 60: 570-578
        • Stadlbauer V
        • Krisper P
        • Aigner R
        • Haditsch B
        • Jung A
        • Lackner C
        • et al.
        Effect of extracorporeal liver support by MARS and Prometheus on serum cytokines in acute-on-chronic liver failure.
        Crit Care. 2006; 10: R169
        • Fernández J
        • Escorsell A
        • Zabalza M
        • Felipe V
        • Navasa M
        • Mas A
        • et al.
        Adrenal insufficiency in patients with cirrhosis and septic shock: Effect of treatment with hydrocortisone on survival.
        Hepatology. 2006; 44: 1288-1295
        • Møller S
        • Hove JD
        • Dixen U
        • Bendtsen F
        New insights into cirrhotic cardiomyopathy.
        Int J Cardiol. 2013; 167: 1101-1108
        • Weil D
        • Levesque E
        • McPhail M
        • Cavallazzi R
        • Theocharidou E
        • Cholongitas E
        • et al.
        Prognosis of cirrhotic patients admitted to intensive care unit: a meta-analysis.
        Ann Intensive Care. 2017; 7: 33
        • Karvellas CJ
        • Garcia-Lopez E
        • Fernandez J
        • Saliba F
        • Sy E
        • Jalan R
        • et al.
        Dynamic Prognostication in Critically Ill Cirrhotic Patients With Multiorgan Failure in ICUs in Europe and North America: A Multicenter Analysis.
        Crit Care Med. 2018; 46: 1783-1791
        • Engelmann C
        • Thomsen KL
        • Zakeri N
        • Sheikh M
        • Agarwal B
        • Jalan R
        • et al.
        Validation of CLIF-C ACLF score to define a threshold for futility of intensive care support for patients with acute-on-chronic liver failure.
        Crit Care. 2018; 22: 254
        • Thuluvath PJ
        • Thuluvath AJ
        • Hanish S
        • Savva Y
        Liver transplantation in patients with multiple organ failures: Feasibility and outcomes.
        J Hepatol. 2018; 69: 1047-1056