Decompensated Chronic Liver Failure

Chronic liver failure can lead to several acute complications.5 Limited evidence suggests hospital-based liver failure care bundles (i.e., checklist for patients admitted with decompensated liver failure) may help reduce readmission.15,16 The chart below defines and reviews signs and symptoms, prophylaxis, and treatment of some acute complications of chronic liver failure including ascites, hepatic encephalopathy, spontaneous bacterial peritonitis, and variceal bleeding. It also defines and provides a list of medications that should be avoided in patients who develop hepatorenal syndrome. See our chart, Drug Therapy for Severe Alcoholic Hepatitis, for more on its management.

Abbreviations: HE = hepatic encephalopathy; HRS = hepatorenal syndrome; IV = intravenously; TMP/SMX = trimethoprim/sulfamethoxazole.

Question

Pertinent Information/Clinical Pearls

Ascites: The accumulation of fluid within the abdomen due to sodium retention and high pressure in the veins of the liver.5,10 Ascites is the most common complication of cirrhosis, affecting more than 50% of patients within ten years of diagnosis.4 There are three grades of ascites:12

  • Grade 1: abdominal fluid only detectable by ultrasound.
  • Grade 2: moderate and symmetrical abdominal distention.
  • Grade 3: large volume ascites with gross abdominal distention.


What are complications associated with ascites?

Complications of ascites include:12

Certain medications should generally be avoided in patients with cirrhosis and ascites, including angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), and nonsteroidal anti-inflammatory drugs (NSAIDs).4


How can the risk of ascites be reduced?

Patients with cirrhosis should abstain from alcohol and some experts recommend limiting sodium intake to reduce the risk of developing ascites.4,10,12 Recommended maximums for sodium intake vary among the guidelines, ranging from about 2,000 to 3,000 mg sodium/day.12

Fluid restriction is not routinely recommended in patients with normal serum sodium levels.12

  • Some experts recommend restricting fluid intake in patients with hypervolemic hyponatremia, though more studies are needed to confirm benefit.12


What medications are used to treat ascites?

Spironolactone, with or without furosemide (added to counteract spironolactone-induced hyperkalemia), is used in the chronic management of ascites.4,5,11

  • Start with spironolactone 50 to 100 mg once daily. Doses can be adjusted about every three to five days to achieve weight loss of about 0.5 kg/day (no edema present) to ≥1 kg/day (edema present).12
  • The ratio of spironolactone to furosemide is typically 100 mg of spironolactone to 40 mg of furosemide.4,5,12
  • Max recommended doses are spironolactone 400 mg/day and furosemide 160 mg/day.5,10-12
  • Monitor electrolytes and renal function at least weekly during the first month of therapy and as necessary with dosage adjustments, especially for hyponatremia, hypo or hyperkalemia, or increased serum creatinine.5,11

Amiloride may be an alternative option in patients with intolerable painful gynecomastia from spironolactone.11

  • Recommend an initial amiloride dose of 20 mg/day. Amiloride can be titrated to a max of 60 mg/day.11


When is paracentesis used to treat ascites?

Paracentesis is the removal of fluid from the abdomen with a needle.

Experts recommend paracentesis for:4,11

Albumin should be administered to patients who have >5 L of fluid removed during paracentesis (e.g., large volume paracentesis) to prevent low blood pressure and maintain blood flow to the kidneys.4,10,12

  • Recommend intravenous albumin 6 to 8 g/L of fluid removed during paracentesis.4,11


When is transjugular intrahepatic portosystemic shunting (TIPS) used to treat ascites?

TIPS involves inserting a shunt to lower hepatic venous pressure. TIPS can be used for ascites refractory to medication and paracentesis therapies.12

TIPS is not routinely recommended, but can be considered for patients requiring frequent paracentesis (e.g., every one to two weeks) or patients who have a Child-Pugh score ≤11.11

  • Avoid TIPS in some patients (e.g., patients with bilirubin >3 mg/dL, Child-Pugh score >11, age >70, or heart failure).11

TIPS appears to be more effective than large volume paracentesis [Evidence Level A-1].12

Possible complications associated with TIPS include hepatic encephalopathy and stent thrombosis.12

  • Hepatic encephalopathy may occur in up to 25% of patients that receive a TIPS and incidence appears to be higher in patients older than 60 years old.12


Hepatic Encephalopathy (HE): There is no specific test to diagnose HE.9 HE is a complication of liver failure involving key features including high ammonia levels, inflammation, and cerebral hemodynamic dysfunction.7 HE affects about 20% of patients with liver failure each year.8

What are signs and symptoms of hepatic encephalopathy?

Symptoms can be divided into two categories: mental and physical.9

  • Mental symptoms of HE include:9
    • Anxiety and confusion.
    • Decreased attention span and difficulty with basic or simple math.
    • Disorientation or forgetfulness.
    • Mood swings or personality changes.
  • Physical symptoms of HE include:9
    • Change in sleeping patterns (e.g., sleeping in the day, awake during the night) or extreme sleepiness.
    • Difficulty with fine motor skills (e.g., writing, small hand movements).
    • Slowed or sluggish movements or speech, can progress to coma.


What things can trigger or worsen hepatic encephalopathy?

Several conditions, medications, or procedures can trigger or worsen HE:9


How is lactulose used to treat hepatic encephalopathy?

Lactulose is the corner stone of treatment of HE, by reducing ammonia levels.4

  • Lactulose reduces HE episodes, but has no impact on survival.4

Lactulose is used to treat acute episodes of and prevent future episodes of HE.8

  • Initial treatment: oral lactulose 10 to 30 g every one to two hours until a bowel movement occurs.4,11
  • Ongoing treatment and prevention: reduce dosing frequency to about twice daily.4,6
    • Monitor patients closely and aim for about three soft bowel movements per day. Doses should be adjusted as needed.4,6

If oral administration is not possible (e.g., coma), lactulose can be given rectally.3,4,6

Dosing: Lactulose 300 mL in 700 mL normal saline given as an enema and retained for 30 to 60 minutes.3,4,6

  • Rectal dosing can be repeated about every four to six hours.3
  • Resume oral therapy as soon as able, giving the first dose before stopping rectal administration.3


How are antibiotics used to treat hepatic encephalopathy?

Certain oral antibiotics (e.g., rifaximin, neomycin) can be added to lactulose therapy in patients with continued HE episodes despite lactulose therapy.4,8 Antibiotics are proposed to reduce ammonia levels by minimizing ammonia producing bacteria in the gut.8

  • Rifaximin is used more commonly than neomycin.4,8
    • Dosing options include rifaximin 400 mg three times daily or 550 mg twice daily.4
  • Neomycin is considered a second-line alternative, due to nephrotoxicity, ototoxicity, and neurotoxicity, especially with long-term use.4
    • Neomycin dosing ranges from 1 to 3 grams given every six hours for about five to six days.3,4


What are long-term considerations for patients with hepatic encephalopathy?

It is no longer recommended to limit dietary protein intake as a way to decrease ammonia production and ultimately reduce the risk of HE.8,11

Instead, encourage patients to get 1.2 to 1.5 g/kg of protein divided in small meals throughout the day and have a late night snack with complex carbohydrates (e.g., an apple, cereal with milk, whole grain crackers).8


Hepatorenal Syndrome (HRS): Reduced renal blood flow, due to vasodilation within the abdomen in cirrhosis and ascites, leads to the inability to eliminate toxins and electrolytes.5 HRS is a strong predictor of mortality in patients with cirrhosis. Patients with HRS should be expedited for possible liver transplation.12 The following are required to diagnose HRS:5,12

  • Cirrhosis with ascites.
  • Serum creatinine >1.5 mg/dL.
  • No improvement in renal function after two days of volume expansion therapy with albumin and without any diuretics.
  • Absence of shock.
  • No current or recent nephrotoxic medications and absence of parenchymal kidney disease (e.g., proteinuria, hematuria).


Which medications should be avoided to prevent hepatorenal syndrome?

All diuretics should be stopped in patients diagnosed with HRS.12

  • However, furosemide can be used to maintain urine output and treat volume overload.12

Avoid drugs that have been associated with precipitating HRS in patients with cirrhosis.14 Examples include:14

  • Blood pressure meds: alpha-blockers (e.g., terazosin), angiotensin-converting enzyme inhibitors (e.g., lisinopril).
  • Drugs that reduce kidney perfusion: nonsteroidal anti-inflammatory drugs (NSAIDs), including the cyclo-oxygenase-2 (COX-2) inhibitors (e.g., celecoxib), dipyridamole.
  • Nephrotoxic meds: aminoglycosides, amphotericin.


Spontaneous Bacterial Peritonitis: an infection of ascitic fluid with a neutrophil count of ≥250 cell/mm3 or an ascitic fluid culture positive for bacteria, without an existing surgically treatable source.2 Spontaneous bacterial peritonitis affects about 30% of patients with cirrhosis and has a mortality rate of about 20%.4


When and how should a first episode of spontaneous bacterial peritonitis be prevented (primary prophylaxis)?

Consider primary prophylaxis for patients with cirrhosis that are at high-risk for developing spontaneous bacterial peritonitis (e.g., history of variceal bleeding, ascitic fluid protein levels <1 g/dL).1,2

  • First-line: TMP/SMX double-strength tablet orally once daily.1,2
  • Alternative (e.g., allergic or resistance to TMP/SMX): Ciprofloxacin 500 mg orally once daily.1
  • Rifaximin has limited data and inconsistent results for use as primary prevention.1
    • Avoid rifaximin unless TMP/SMX and ciprofloxacin are not options (e.g., allergies, adverse effects).1


How is spontaneous bacterial peritonitis diagnosed?

Spontaneous bacterial peritonitis should be suspected in patients with ascites and one or more of the following:

  • Abdominal pain or tenderness
  • Ascitic fluid neutrophil count ≥250 cells/mm3
  • Fever (e.g., 100℉ [37.8℃])
  • Mental status changes
  • OR

  • Patients presenting with a variceal bleeding.

If possible, perform paracentesis, send ascitic fluid for a neutrophil count and cultures, and draw blood cultures BEFORE starting antibiotics.4

  • Antibiotic therapy is still warranted if spontaneous bacterial peritonitis is suspected (e.g., fever, abdominal pain) and patients have an elevated ascitic neutrophil count, even with negative cultures.2,4


How should spontaneous bacterial peritonitis be treated?

When selecting antibiotic therapy, review antibiograms for coverage of pathogens that commonly cause spontaneous bacterial peritonitis (e.g., Escherichia coli [E.coli], Streptococcus, Klebsiella).

Treat with antibiotics for five days.1,2 Treatment for more than five days has not been shown to improve cure rates, recurrence, or hospital mortality.11,12

Start with empiric antibiotics outlined below and adjust therapy based on cultures and sensitivities.1

  • First-line options for community-acquired spontaneous bacterial peritonitis include:1,2,4
    • Cefotaxime 2 g IV every eight hours.
    • Ceftriaxone 1 g IV every 12 hours or 2 g IV every 24 hours.
    • For patients with penicillin allergies: ciprofloxacin 400 mg IV or levofloxacin 500 to 750 mg IV every 24 hours.
  • For hospital-acquired (symptoms begin >48 hours after hospital admission) spontaneous bacterial peritonitis consider:1
    • Piperacillin/tazobactam 3.375 g IV every six hours PLUS vancomycin 1 g IV every 12 hours.
    • For suspected vancomycin-resistant enterococcus consider linezolid 600 mg IV every 12 hours or daptomycin 4 to 6 mg/kg IV every 24 hours.
    • For suspected extended-spectrum beta-lactamase Enterobacteriaceae consider meropenem 1 g IV every eight hours.
  • Consider transitioning patients that are improving (e.g., afebrile, tolerating oral intake, white blood cells [WBCs] trending down) from IV to oral antibiotics after about 48 hours of IV therapy using cultures and sensitivities.1,11


When should albumin be used in the treatment of spontaneous bacterial peritonitis?

Albumin may reduce renal failure and mortality in some patients with spontaneous bacterial peritonitis.1

  • Albumin is not necessary for all patients with spontaneous bacterial peritonitis.1
  • Albumin WITH antibiotic therapy prevents one renal injury AND in-hospital death for every five patients treated [Evidence Level A-1].13 Recommend albumin for patients with the following:1,4
    • Serum creatinine >1 mg/dL.
    • Total bilirubin >4 mg/dL.
    • Blood urea nitrogen (BUN) >30 mg/dL.

When treating patients with spontaneous bacterial peritonitis with albumin, recommend albumin 25% with the following dosing:1,4

  • Day one (within six hours of diagnosis): 1.5 g/kg
  • Day three: 1 g/kg


What are the most appropriate ways to prevent subsequent episodes of spontaneous bacterial peritonitis (secondary prophylaxis)?

The risk of recurrence of spontaneous bacterial peritonitis is about 70% within two years of initial episode.1

Recommend secondary prophylaxis against spontaneous bacterial peritonitis.1 Options include:1

  • TMP/SMX double-strength tablet orally once daily five to seven days/week.
  • Ciprofloxacin 500 mg orally daily.

Risk factors for recurrent episodes of spontaneous bacterial peritonitis include:1

  • Total bilirubin >4 mg/dL.
  • Prothrombin ≤45%.
  • Low ascitic fluid protein levels (e.g., <1g/dL).


Variceal Bleeding: See our chart, Esophageal Variceal Bleeding FAQs, for specifics on prevention and treatment options.


Levels of Evidence

In accordance with our goal of providing Evidence-Based information, we are citing the LEVEL OF EVIDENCE for the clinical recommendations we publish.

Level

Definition

Study Quality

A

Good-quality patient-oriented evidence.*

  1. High-quality RCT
  2. SR/Meta-analysis of RCTs with consistent findings
  3. All-or-none study

B

Inconsistent or limited-quality patient-oriented evidence.*

  1. Lower-quality RCT
  2. SR/Meta-analysis with low-quality clinical trials or of studies with inconsistent findings
  3. Cohort study
  4. Case control study

C

Consensus; usual practice; expert opinion; disease-oriented evidence (e.g., physiologic or surrogate endpoints); case series for studies of diagnosis, treatment, prevention, or screening.

*Outcomes that matter to patients (e.g., morbidity, mortality, symptom improvement, quality of life).

RCT = randomized controlled trial; SR = systematic review [Adapted from Ebell MH, Siwek J, Weiss BD, et al. Strength of Recommendation Taxonomy (SORT): a patient-centered approach to grading evidence in the medical literature. Am Fam Physician 2004;69:548-56. http://www.aafp.org/afp/2004/0201/p548.pdf.]

Project Leader in preparation of this clinical resource (340820): Beth Bryant, Pharm.D., BCPS, Assistant Editor

References

  1. Dever JB, Sheikh MY. Review article: spontaneous bacterial peritonitis – bacteriology, diagnosis, treatment, risk factors and prevention. Aliment Pharmacol Ther 2015;41:1116-31.
  2. Perri GA, Khosravani H. Complications of end-stage liver disease. Can Fam Physician 2016;62:44-50.
  3. Clinical Pharmacology powered by ClinicalKey. Tampa (FL): Elsevier. 2018. http://www.clinicalkey.com. (Accessed July 12, 2018).
  4. Long B, Koyfman A. The emergency medicine evaluation and management of the patient with cirrhosis. Am J Emerg Med 2018;36:689-98.
  5. McPherson S, Lucey MR, Moriarty KJ. Decompensated alcohol related liver disease: acute management. BMJ 2016;352:i124.
  6. Patidar KR, Bajaj JS. Covert and overt hepatic encephalopathy: diagnosis and management. Clin Gastroenterol Hepatol 2015;13:2048-61.
  7. Lee GH. Hepatic encephalopathy in acute-on-chronic liver failure. Hepatol Int 2015;9:520-6.
  8. Ellul MA, Gholkar SA, Cross TJ. Hepatic encephalopathy due to liver cirrhosis. BMJ 2015;351:h4187.
  9. American Liver Foundation. Diagnosing hepatic encephalopathy. https://liverfoundation.org/for-patients/about-the-liver/diseases-of-the-liver/hepatic-encephalopathy/diagnosing-hepatic-encephalopathy/#what-are-the-symptoms-of-he. (Accessed July 16, 2018).
  10. University of Michigan. Liver cirrhosis: a toolkit for patients. Revised October 2011. http://www.med.umich.edu/1libr/Hepatology/CirrhosisToolkit.pdf. (Accessed July 16, 2018).
  11. Garcia-Tsao G, Lim J, members of the Veterans Affairs Hepatitis C Resource Center Program. Management and treatment of patients with cirrhosis and portal hypertension: recommendations from the Department of Veterans Affairs Hepatitis C Resource Center Program and the National Hepatitis C Program. Am J Gastroenterol 2009;104:1802-29.
  12. Pericleous M, Sarnowski A, Moore A, et al. The clinical management of abdominal ascites, spontaneous bacterial peritonitis and hepatorenal syndrome: a review of current guidelines and recommendations. Eur J Gastroenterol Hepatol 2016;28:e10-8.
  13. Sort P, Navasa M, Arroyo V, et al. Effect of intravenous albumin on renal impairment and mortality in patient with cirrhosis and spontaneous bacterial peritonitis. N Engl J Med 1999;341:403-9.
  14. Davenport A, Ahmad J, Al-Khafaji A, et al. Medical management of hepatorenal syndrome. Nephrol Dial Transplant 2012;27:34-41.
  15. McPherson S, Dyson J, Austin A, Hudson M. Response to the NCEPOD report: development of a care bundle for patients admitted with decompensated cirrhosis – the first 24 h. Frontline Gastroenterol 2016;7:16-23.
  16. Tapper EB, Finkelstein D, Mittleman MA, Piatkowski G, et al. A quality improvement initiative decreases 30-day readmission rates for patients with cirrhosis: a prospective trial. Clin Gastroenterol Hepatol 2016;14:753-9.

Cite this document as follows: Clinical Resource, Decompensated Chronic Liver Failure. Hospital Pharmacist’s Letter/Prescriber’s Letter. August 2018.

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