The American College of Gastroenterology (ACG) has issued new guidelines for the preferred approach to managing patients with acute-on-chronic liver failure (ACLF), as published in the American Journal of Gastroenterology.

The guidelines consist of clinically relevant statements that were developed with use of the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) process. The quality of evidence is graded as high, moderate, low, or very low, and the strength of recommendation is noted as either strong or conditional.

“These guidelines are established to support clinical practice and suggest preferable approaches to a typical patient with a particular medical problem based on the currently available published literature,” stated the guideline authors. “When exercising clinical judgment, particularly when treatments pose significant risks, healthcare providers should incorporate this guideline in addition to patient-specific medical comorbidities, health status, and preferences to arrive at a patient-centered care approach.”


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The guidelines defined ACLF as “a potentially reversible condition in patients with chronic liver disease with or without cirrhosis that is associated with the potential for multiple organ failure and mortality within 3 months in the absence of treatment of the underlying liver disease, liver support, or liver transplantation.” ACLF involves elevation in serum bilirubin and prolongation of the international normalized ratio (INR).

The first recommendations concern brain failure, which is an independent prognostic marker in hospitalized patients with cirrhosis. The authors suggest use of short-acting dexmedetomidine for sedation and against listing for liver transplant in patients with cirrhosis and ACLF who continue to need mechanical ventilation. Both recommendations were graded as very low quality and conditional. The authors noted that short-acting drugs such as dexmedetomidine are preferred to benzodiazepines, as well as short parenteral boluses instead of infusions in patients with cirrhosis.

For kidney failure, the authors gave high-quality, strong recommendations for using albumin in addition to antibiotics to prevent acute kidney injury (AKI) and organ failure in patients with cirrhosis and spontaneous bacterial peritonitis (SBP); they recommend against using albumin to improve renal function or mortality in patients with cirrhosis and infections other than SBP. The authors noted that kidney failure is the most common organ failure in patients with ACLF, and treatment options for hepatorenal syndrome (HRS)-AKI include pharmacotherapy and liver transplantation with or without intervening renal replacement therapy (RRT).

“Because bacterial infections are a common precipitant of AKI, early diagnosis and treatment of bacterial infections are key to prevent AKI development,” stated the authors.

As laboratory coagulation abnormalities are common in patients with cirrhosis, the authors recommend use of thromboelastography (TEG) or rotational TEG (ROTEM) vs INR to more accurately assess transfusion needs in patients with cirrhosis who require invasive procedures (moderate quality, conditional).

Among precipitating factors, infection occurs in up to 40% of patients with ACLF at initial presentation and is a leading cause of ACLF in Western countries. Patients with cirrhosis who have an infection may not have typical symptoms. Among hospitalized decompensated patients with cirrhosis, the authors recommend assessing for infection, as it is associated with ACLF and increased mortality (moderate quality, strong evidence). Bacterial infections are the most common type of infections in hospitalized patients with cirrhosis. First-line antibiotic therapy should be determined by the etiology and severity of the infection, when and how it was acquired, and local resistance patterns, according to the guideline authors.

Regarding noninfectious precipitating factors, alcohol-associated hepatitis (AAH) is a leading cause of ACLF. In a moderate-quality, strong recommendation for patients with severe AAH (Maddrey discriminant function [MDF] ≥32; model for end‐stage liver disease [MELD] score >20) in the absence of contraindications, the authors recommend use of prednisolone or prednisone (40 mg/d) orally to improve 28-day mortality.

“[S]evere AAH is probably the most common precipitating event for ACLF,” stated the authors. “Infection is common in these patients. Prednisone is the only pharmacological therapy associated with improved survival, but only at 28 days. In addition to prednisone, treatment of infection, nutritional supplementation, and support of failing organs are required. Abstinence from alcohol is essential for survival beyond 6 months.”

Critical care management with a multidisciplinary team approach including expertise in critical care and transplant hepatology is optimal for patients with ACLF, according to the guideline authors.

“It is critical that effective broad-spectrum antibiotics be administered within 1 hour of [intensive care unit] admission in patients with cirrhosis because every hour delay in administration of antibiotics is associated with almost doubling in mortality,” stated the authors. “Empiric therapy with meropenem and vancomycin is recommended in patients with cirrhosis and septic shock. When vancomycin-resistant Enterococcus infection is suspected, linezolid or daptomycin should be used.”

In hospitalized patients with cirrhosis, the guideline authors suggest against the routine use of parenteral nutrition, enteral nutrition, or oral supplements to improve mortality. “Maintaining a daily caloric intake of 35- to 40-cal/kg body weight/day that includes a daily protein intake of 1.2- to 2.0-g/kg body weight/day is recommended,” they stated.

The authors also gave a moderate-quality, strong recommendation against daily infusions of albumin to maintain the serum albumin >3 g/dL to improve mortality and prevent renal dysfunction or infection in hospitalized patients with cirrhosis.

“When rapid volume expansion is required, 5% albumin is used,” noted the authors. “The expansion in volume is approximately equal to the volume of 5% albumin infused and occurs within about 15 minutes. When 25% albumin is used, the volume expansion is 3.5-5 times the volume infused, but takes longer to achieve. In patients with cirrhosis who have longstanding hypervolemia, 25% albumin is preferred.”

The guidelines also offer recommendations regarding transplant and futility in patients with ACLF. For patients with cirrhosis and ACLF who continue to require mechanical ventilation due to adult respiratory distress syndrome or brain-related conditions despite optimal therapy, the authors suggest against listing for liver transplant to improve mortality. In hospitalized patients with end-stage liver disease, the authors suggest early goals of care discussion and, if appropriate, referral to palliative care to improve resource use. Both recommendations were graded as very low evidence, conditional.

“ACLF has emerged as a major cause of mortality in patients with cirrhosis and chronic liver disease worldwide,” the guideline authors commented. “The varying definitions that focused on established organ failure have reduced generalizability and potential for prevention of ACLF in different settings. Prevention of major precipitating factors such as infections and alcohol is critical in improving the prognosis of individual organ failures (brain, circulatory, renal, respiratory, and coagulation), and judicious use of antibiotics and antifungal medications is required. Critical care management strategies and [liver transplant] potential listing should be balanced with futility considerations in those with a poor prognosis.”

The guidelines were developed in collaboration with the Practice Parameters Committee of the American College of Gastroenterology.

Full List of Guidelines From the American College of Gastroenterology for Acute-on-Chronic Liver Failure

Brain Failure

  1. In hospitalized patients with ACLF, the ACG suggests the use of short-acting dexmedetomidine for sedation as compared with other available agents to shorten time to extubation (very low quality, conditional recommendation)
  2. In patients with cirrhosis and ACLF who continue to require mechanical ventilation because of brain conditions or respiratory failure despite optimal therapy, the ACG suggests against listing for liver transplant to improve mortality (very low quality, conditional recommendation)

Kidney Failure

  1. In patients with cirrhosis and stages 2 and 3 AKI, the ACG suggests intravenous albumin and vasoconstrictors as compared with albumin alone, to improve creatinine (low quality, conditional recommendation)
  2. In patients with cirrhosis, the ACG suggests against the use of biomarkers to predict the development of renal failure (very low quality, conditional recommendation)
  3. In patients with cirrhosis and elevated baseline serum creatinine who are admitted to the hospital, the ACG suggests monitoring renal function closely, as elevated baseline creatinine is associated with worse renal outcomes and 30-day survival (but no data that closer monitoring improves these outcomes) (very low quality, conditional recommendation)
  4. In hospitalized patients with cirrhosis and HRS-AKI without high grade ACLF or major cardiopulmonary or vascular disease, the ACG suggests terlipressin (moderate quality, conditional recommendation) or norepinephrine (low quality, conditional recommendation) to improve renal function
  5. In patients with cirrhosis and SBP, the ACG recommends albumin in addition to antibiotics to prevent AKI and subsequent organ failures (high quality, strong recommendation)
  6. In patients with cirrhosis and infections other than SBP, the ACG recommends against albumin to improve renal function or mortality (high quality, strong recommendation)

Respiratory Failure

  1. In ventilated patients with cirrhosis, the ACG suggests against prophylactic antibiotics to reduce mortality or duration of mechanical ventilation (very low quality, conditional recommendation)

Coagulation Failure

  1. In patients with cirrhosis and ACLF, the ACG suggests against INR as a means to measure coagulation risk (very low quality, conditional recommendation)
  2. In patients with cirrhosis as compared with noncirrhotic populations, the ACG suggests there is an increased risk for venous thromboembolism (VTE) (low quality, conditional recommendation)
  3. In patients with ACLF and altered coagulation parameters, the ACG suggests against transfusion in the absence of bleeding or a planned procedure (low quality, conditional recommendation)
  4. In patients with cirrhosis who require invasive procedures, the ACG recommends the use of TEG or ROTEM, compared with INR, to more accurately assess transfusion needs (moderate quality, conditional recommendation)

Infections

  1. In hospitalized decompensated patients with cirrhosis, the ACG recommends assessment for infection, as infection is associated with the development of ACLF and increased mortality (moderate quality, strong evidence)
  2. In patients with cirrhosis and suspected infection, the ACG suggests early treatment with antibiotics to improve survival (very low quality, conditional evidence)

Nosocomial and Fungal Infections

  1. In hospitalized patients with ACLF due to a bacterial infection who have not responded to antibiotic therapy, the ACG suggests suspicion of a multidrug-resistant (MDR) organism or fungal infection to improve detection (very low quality, conditional recommendation)

Medications and Prophylaxis for Infection

  1. In patients with cirrhosis and a history of SBP, the ACG suggests use of antibiotics for secondary SBP prophylaxis to prevent recurrent SBP (unable to comment on specific antibiotic choice) (low quality, conditional recommendation)
  2. In patients with cirrhosis in need of primary SBP prophylaxis, the ACG suggests daily prophylactic antibiotics, although no one specific regimen is superior to another, to prevent SBP (low quality, conditional recommendation)
  3. In patients with cirrhosis, the ACG suggests avoiding proton pump inhibitors (PPI) unless there is a clear indication, as PPIs increase the risk for infection (very low quality, conditional recommendation)

Alcohol-Associated Hepatitis

  1. In patients with severe alcohol-associated hepatitis (MDF ≥32; MELD score >20) in the absence of contraindications, the ACG recommends the use of prednisolone or prednisone (40 mg/d) orally to improve 28-day mortality (moderate quality, strong recommendation)
  2. In patients with severe alcohol-associated hepatitis (MDF ≥32; MELD score >20), the ACG suggests against the use of pentoxifylline to improve 28-day mortality (very low quality, conditional recommendation)

Management Strategies

  1. In patients with cirrhosis who are hospitalized, the ACG suggests against the routine use of parenteral nutrition, enteral nutrition, or oral supplements to improve mortality
  2. In hospitalized patients with cirrhosis, the ACG recommends against daily infusions of albumin to maintain albumin >3 g/dL to improve mortality and to prevent renal dysfunction or infection (moderate quality, strong recommendation)
  3. In patients with cirrhosis and ACLF, the ACG suggests against the use of granulocyte colony-stimulating factor to improve mortality (very low evidence, conditional recommendation)

Transplant vs Futility

  1. In patients with cirrhosis and ACLF who continue to require mechanical ventilation because of adult respiratory distress syndrome or brain-related conditions despite optimal therapy, the ACG suggests against listing for liver transplant to improve mortality (very low evidence, conditional recommendation)
  2. In patients with end-stage liver disease admitted to the hospital, the ACG suggests early goals of care discussion and, if appropriate, referral to palliative care to improve resource utilization (very low evidence, conditional recommendation)

Reference

Bajaj JS, O’Leary JG, Lai JC, et al. Acute-on-chronic liver failure clinical guidelines. Am J Gastroenterol. Published online January 10, 2022. doi: 10.14309/ajg.0000000000001595