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Table 1 Characteristics of included studies

From: Uncertainty in the impact of liver support systems in acute-on-chronic liver failure: a systematic review and network meta-analysis

First author, publication year Eligibility criteria Etiology of the underlying disease and baseline characteristics Intervention(s) and/or comparison Outcomes
Banares (2013) Inclusion: presumptive diagnosis of cirrhosis with an identifiable triggering event; an increase of TBIL > 5 mg/dl and at least one of the following: HRS, HE ≥ grade II, rapidly progressive hyperbilirubinemia (> 50% increase from TBIL levels at admission) > 20 mg/dl at admission
Exclusion: progressive jaundice as a consequence of the natural course of cirrhosis; extrahepatic cholestasis; PLT < 50,000/mm3; INR > 2.3; suspected or evident DIC; need for RRT; intrinsic renal disease; uncontrolled infection; active bleeding; HCC > 4 cm in diameter; portal vein thrombosis; severe cardiopulmonary disease; MAP < 60 mmHg despite vasopressor therapy; major surgical procedure within the last 4 weeks; HIV infection
Mostly alcoholic; viral, autoimmune, drug-induced, NASH, etc.
Age (years)a: 51.8/50.0
Males (%): 66.7/70.8
MELDa:25.6/24.1
MARS/SMT Survival, HE, laboratory parameters, AEs
Duan (2018) Inclusion: 15–65 years; clinical diagnosis of ACLF; obvious gastrointestinal and/or systemic toxic symptoms; TBIL > 5 times upper limit of normal or daily increase > 1 mg/dl; prothrombin activity of 10–50%; INR 1.6–4.0, or prothrombin time > 5 s longer than the control but < 20 s, HE absent or grade I–II; no or mild ascites/pleural effusion
Exclusion: primary or metastatic liver cancer; uncontrolled severe infection; shock; active bleeding within 3 days; grade III–IV HE; PLT < 40 × 109/l; creatinine > 1.5 mg/ml; severe esophageal varices
Mostly alcoholic and viral; drug-induced, autoimmune, unknown, “acute/subacute”
Agea (years): 39.5/39.2
Males (%): 96.9/88.2
MELDa: 28.0/30.8
ELAD/SMT Survival, AEs
Ellis (1999) Inclusion: acute alcoholic hepatitis, HE ≥ grade II
Exclusion: pregnancy; MAP < 50 mmHg despite adequate volume loading and appropriate use of inotropes; respiratory failure; cerebrovascular event within the previous 12 months, a recent upper gastrointestinal hemorrhage; poorly controlled epilepsy; recent myocardial infarction/ischemia
Alcoholic
Ageb (years): 46/43
Males (%): 60/80
MELD/CTP: NR
BioLogic-DT/SMT Survival, HE, physical and laboratory parameters, AEs
Hassanein (2007) Inclusion: ≥ 18 years, manifestations of cirrhosis and HE grade III–IV
Exclusion: active hemorrhage; hemodynamic instability; acute cardiopulmonary complications (pulmonary edema, massive aspiration pneumonia, heart failure); pregnancy; active RRT; drug intoxication or irreversible brain damage or nonhepatic causes of altered mental status; acute liver failure; HCC; received transplant
Mostly alcoholic or viral; autoimmune, drug induced, unknown
Ageb (years): 49/56
Males (%): 61.5/48.4
MELDb: 33/38
MARS/SMT HE, AEs, laboratory parameters (survival is additional)
Heemann (2002) Inclusion: 18–65 years; cirrhosis (CTP ≥ 7) and a superimposed acute liver injury leading to decompensation and severe hyperbilirubinemia (TBIL ≥ 20 mg/dl)
Exclusion: hepatobiliary obstruction; active bleeding or sepsis causing hemodynamic instability; comorbid conditions associated with a poor outcome; coma of nonhepatic origin; extensive surgery 30 days preceding admission; HRS; pregnancy
Mostly alcoholic; viral, drug induced
Ageb (years): 48/57
Males (%): 50/63.6
CTPb: 11.5/12
MARS/SMT Survival, HE, AEs, laboratory parameters
Hillebrand (2010) Inclusion: acute decompensation of cirrhosis; SOFA score ≥ 9; and either a MELD score of ≥ 32, or MELD ≥ 24 and at least one of HE grade III–IV or type I HRS
Exclusion: NR
Etiology, age, sex NR
MELDa: 34.3/40.8
ELAD/SMT Survival, AEs
Huang (2012) Inclusion: chronic severe hepatitis B with HE ≥ grade II
Exclusion: late stage disease; previous irreversible respiratory failure; severe brain edema with hernia; severe systemic circulation disorder accompanied by DIC; serious active bleeding
HBV
Ageb (years): 43/42
Males (%): 78.3/75
MELD/CTP: NR
MARS ± PE Survival, HE, AEs, laboratory parameters, cost of treatment
Kramer (2001) Inclusion: documented cirrhosis and encephalopathy grade II or III had not improved with conventional treatment
Exclusion: renal failure; hypotension (MAP < 55 mmHg); respiratory or multiorgan failure; fever of > 38.5 °C; bleeding requiring transfusion of > 2 units within the preceding 24 h; insulin-dependent diabetes mellitus; administration of sedatives within the preceding 2 days
Alcoholic, viral, autoimmune, unknown
Ageb (years): 55/56
Malesc (%): 65%
CTPb: 14/14.5
BioLogic-DT/SMT HE, laboratory and physical parameters, AEs (survival is additional)
Kribben (2012) Inclusion: 18–70 years; severe deterioration of chronic liver disease; CTP ≥ 10 (over 72 h); TBIL ≥ 5 mg/dl (over 72 h)
Exclusion: pregnancy/lactation; HIV infection, intracranial bleeding; cerebrovascular disease; ARDS; circulatory shock with vasopressor therapy; persistent bleeding needing perfusion; chronic renal failure stage V; acute necrotizing pancreatitis; HCC, malignancy; INR > 3.0 or PLT < 30,000/l; extrahepatic cholestasis; liver resections or major hepatobiliary surgery in the previous 6 months except laparoscopic cholecystectomy; LT within 2 years, ALSS therapy within 7 days; participation in another clinical trial or this study priorly
Mostly alcoholic and viral; others not specified
Agea (years): 50/51
Males (%): 62/65
MELDb: 28/27
Prometheus/SMT Survival, laboratory parameters; AEs
Mitzner (2000) Inclusion: 18–60 years; HRS (serum creatinine > 1.5 mg/dl, oliguria < 500 ml/d, urine sodium < 20 mmol/l, central venous pressure > 8 cmH2O); need of hemodialysis/filtration treatment; chronic liver failure (3 of 4 criteria): ultrasonic signs of chronic damage or impaired synthesis function (hypoalbuminemia, 30 g/l, prolonged prothrombin time (quick value < 70%), AT III < 70%, serum cholinesterase < 40 umol/s/l) or hyperbilirubinemia (> 15 mg/dl) or grade III–IV HE
Exclusion: fulminant hepatic failure; sepsis unresponsive to antibiotics; severe acute hemorrhages; malignancies; obstructive/chronic renal failure; pregnancy; severe cardiopulmonary disease
Mostly alcoholic; HBV, primary and secondary biliary cirrhosis
Agea (years): 49.6/43.8
Males (%): 37.5/40
CTPa: 12.5/12.2
MARS/SMT Survival
Pyrsopoulos (2019) Inclusion: SAH, age 18–50 years, total bilirubin ≥ 16 mg/dl, Maddrey score ≥ 32, not eligible for transplant
Exclusion: PLT < 40,000/mm3; INR > 2.5; serum creatinine ≥ 1.3 mg/dl; MELD score ≥ 30; AST > 500 IU/l; infection unresponsive to antibiotics; reduction in TBIL ≥ 20% in the previous 72 h; hemodynamic instability; active bleeding; major hemorrhage; liver size reduction due to cirrhosis; occlusive portal vein thrombosis; bile duct obstruction; life expectancy of less than 3 months due to concomitant diseases; subject on hemodialysis; Wilson’s disease; NAFLD; Budd-Chiari syndrome; active viral hepatitis; pregnancy; received liver transplant
Alcoholic hepatitis
Agea (years): 39.1/39.5
Males (%): 60.3/60.3
MELDa: 24.8/25.6
ELAD/SMT Survival, AEs
Qin (2014) Inclusion: 18–70 years; presumptive diagnosis of chronic hepatitis B infection, HBV-associated cirrhosis, or hepatitis B surface antigen (HBsAg) carrier; rapidly progressive hyperbilirubinemia with TBIL > 10 mg/dl, within 28 days from symptom onset; INR > 1.5 or plasma prothrombin activity < 40%
Exclusion: acute HBV infection; hepatitis E, A, D, or HIV superinfection; alcohol- or drug-induced liver injury; severe gastrointestinal bleeding; HCC; pregnancy
HBV
Agea (years): 44.1/48.7
Males (%): 82.7/72.3
MELDa: 28.6/29.5
PE/SMT Survival, AEs
Sen (2004) Inclusion: 18–75 years old; alcoholic liver disease; acute deterioration in liver function over 2–4 weeks leading to severe progressive clinical deterioration despite supportive care (over 48 h); jaundice (TBIL > 100 mol/l) and either HE Grade II or HRS; cirrhosis
Exclusion: prior enrollment in another study; known hepatic/extrahepatic malignancy; uncontrolled infection or upper gastrointestinal bleeding over the previous 48 h; pregnancy; prior treatment with terlipressin for HRS; coexisting HIV infection; severe cardiorespiratory disease
Alcoholic
Ageb (years): 45/44
Males (%): 78/67
MELDb: 16.5/19.4
MARS/SMT Survival, HE, laboratory and physical parameters
Teperman (2012) Inclusion: acute alcoholic hepatitis or acute decompensation of cirrhosis, MELD 18–35
Exclusion: NR
Alcoholic and not specified (baseline only given for PP subjects) ELAD/SMT Survival, time to progression, AEs
Thompson (2018) Inclusion: ≥ 18 years, history of heavy alcohol abuse, maximum of 6 weeks between the last consumption, rapid onset of jaundice (TBIL ≥ 8 mg/dl), and coagulopathy (Maddrey's DF ≥ 32), stratum A: liver biopsy confirmed SAH/ 2 of the following: AST > ALT, leukocytosis, ascites stratum B: SAH + underlying chronic liver disease confirmed by biopsy, laboratory findings, and/or medical history
Exclusion: end-stage cirrhosis; portal vein thrombosis; MELD > 35, PLT < 40,000/mm3; severe concomitant disease; uncontrolled bleeding; infection unresponsive to antibiotics; hemodynamic instability; chronic dialysis
Alcoholic hepatitis (superimposed or primary)
Agea (years): 46.5/44.8
Males%: 57.3/60.7
MELDa: 27.6/27.1
ELAD/SMT Survival, laboratory parameters, AEs
Yu (2008) Inclusion: acute-on-chronic hepatitis B liver failure (HBV-DNA ≥ 10,000 copies/mL); defined as severe jaundice (TBIL > 171 mmol/l), coagulopathy, and/or HE > grade II; previous lamivudine treatment; MELD > 30
Exclusion: obstructive and hemolytic jaundice; prolonged prothrombin time due to hematologic diseases; drug-induced hepatitis; Wilson's disease; alcoholic liver disease; autoimmune hepatitis; hepatitis C or D or HIV infection
HBV
Agea (years): 45.2/46.4
Males (%): 80/78.6
MELDa,d: 41.4
PE/SMT Survival, laboratory parameters
He (2000)* Inclusion: severe viral hepatitis according to the criteria of the 1995 national symposium
Exclusion: NR
Mostly viral; alcoholic
Age, sex, MELD/CTP: NR
PE, PP, DHP/SMT Survival, laboratory parameters, HE, AEs
Hu (2005)* Inclusion: chronic severe hepatitis complicated with multiorgan failure
Exclusion: NR
NR MARS/SMT Survival, HE, laboratory parameters
Krisper (2005)* Inclusion: ACLF
Exclusion: NR
Mostly alcoholic; HCV
Agec (years): 57
Malesc (%): 67%
MELDb: 35.4
MARS and Prometheus, crossover Laboratory parameters, AEs
Laleman (2006)* Inclusion: 18–75 years; histologically proven alcoholic cirrhosis with superposed alcoholic hepatitis; portal hypertension with associated hyperdynamic circulation and ACLF (persistent deterioration in liver function despite treatment of the precipitating event and elevated bilirubin > 12 mg%)
Exclusion: extrahepatic cholestasis; coma of nonhepatic origin; active gastrointestinal bleeding in the past 5 days; comorbidities associated with poor outcome (acute necrotizing pancreatitis, neoplasia, severe cardiopulmonary disease, oxygen-dependent or steroid-dependent COPD); ongoing infection; HRS type I
Alcoholic
Agea (years): 54.5/43.2/55.8
Males (%): 83.3/66.7/50
MELDa: 22.7/29.7/24.3
MARS/Prometheus /SMT Laboratory parameters, AEs
Meijers (2012)* Inclusion: ≥ 18 years, compensated chronic liver disease; developed intrahepatic cholestasis (TBIL > 5 mg/dl); at least one of the following complications within 4–8 weeks after a potential identifiable acute superposed hepatic insult: (a) a progressive hyperbilirubinemia ≥ 50% increase of TBIL > 20 mg/dl, (b) HE grade  ≥ II, (c) de novo development of ascites, and/or (d) HRS
Exclusion: extrahepatic cholestasis; severe hypocalcemia (Ca2+ < 0.9 mmol·l−1); acidosis (pH < 7.25)
Mostly alcoholic; HCV, NASH, and others
Agec (years): 54.6
Males (%): NR
MELDa,c: 32.1
MARS ± citrate, crossover Laboratory parameters, AEs
Wilkinson (1998)* Inclusion: decompensated chronic liver disease and grade III–IV encephalopathy
Exclusion: NR
Alcoholic, HCV, HBV, autoimmune, unknown
Agea (years): 58.3/42.7
Males (%): 60/100
MELD/CTP: NR
BioLogic-DT/SMT Physiologic and neurologic improvement, AEs
You (2011)* Inclusion: ACLF defined by the Chinese Medical Association’s definition (2006)
Exclusion: NR
Viral (?)
Agea (years): 42.7/43.5
Males (%): 100/83
MELDa: 23/24.1
HBALSS/PE Survival, AEs, laboratory parameters
  1. Articles included in the quantitative and qualitative synthesis (indicated by *) are listed here
  2. TBIL total bilirubin, HRS hepatorenal syndrome, HE hepatic encephalopathy, PLT platelet, INR international normalized ratio, DIC disseminated intravascular coagulation, RRT renal replacement therapy, HCC hepatocellular carcinoma, MAP mean arterial pressure, HIV human immunodeficiency virus, NASH non-alcoholic steatohepatitis, MELD Model for end-stage liver disease, MARS molecular adsorbent and recirculating system, SMT standard medical therapy, AEs adverse events, ACLF acute-on-chronic liver failure, ELAD extracorporeal liver assist device, CTP Child–Turcotte–Pugh, NR not reported, SOFA sequential organ failure assessment, HBV hepatitis B virus, PE plasma exchange, ARDS adult respiratory distress syndrome, SAH severe alcoholic hepatitis, AST aspartate aminotransferase, ALT alanine aminotrasferase, NAFLD nonalcoholic fatty liver disease, PP plasma perfusion, DHP direct hemoperfusion, HCV hepatitis C virus, COPD chronic obstructive pulmonary disease
  3. aMean values
  4. bMedian values
  5. cAll patients
  6. dOnly reported in the intervention group