Are benzodiazepines (BZDs) safe to use in patients with cirrhosis?

Benzodiazepines Are Contraindicated in Cirrhosis with Decompensation

Benzodiazepines should be contraindicated in patients with decompensated cirrhosis due to the significant risk of precipitating or worsening hepatic encephalopathy, increased falls and injuries, and altered mental status. 1

Guideline Recommendations

The French guidelines explicitly recommend contraindication of benzodiazepines in patients with decompensated cirrhosis. 1 This represents the strongest position among major hepatology societies and should guide clinical practice.

• The EASL (European Association for the Study of the Liver) states that in patients with advanced cirrhosis, psychoactive drugs and particularly benzodiazepines are associated with increased risk of falls, injuries, and altered mental status, recommending great caution when using them in patients with cirrhotic liver dysfunction. 1

• The FDA drug label for lorazepam explicitly warns that "as with all benzodiazepines, the use of lorazepam may worsen hepatic encephalopathy; therefore, lorazepam should be used with caution in patients with severe hepatic insufficiency and/or encephalopathy." 2

• Korean guidelines identify psychoactive medications, including benzodiazepines, as precipitating factors for hepatic encephalopathy that must be recognized and managed by discontinuation. 3

The Critical Time Window of Risk

The highest risk period for hepatic encephalopathy occurs between days 3-10 of benzodiazepine use in cirrhotic patients with ascites, with a five-fold increased risk. 4 This finding from a study of 865 cirrhosis patients with ascites provides crucial timing information:

• Days 1-2: No significantly increased risk of hepatic encephalopathy 4
• Days 3-10: Five-fold increased risk of first-time hepatic encephalopathy 4
• Beyond 28 days: Risk returns to baseline (though this does not justify chronic use) 4

The Exception: Alcohol Withdrawal

Benzodiazepines remain the treatment of choice for alcohol or benzodiazepine withdrawal, even in cirrhotic patients, but require careful dose adjustment and monitoring. 1, 3, 5

For alcohol withdrawal in cirrhotic patients:

• Start with 2-5 mg IV diazepam rather than the standard 10 mg in patients with severe liver disease. 5
• Use symptom-triggered dosing (CIWA-Ar scale) rather than fixed-schedule dosing to prevent drug accumulation while ensuring adequate withdrawal control. 5
• Lorazepam may be preferred over diazepam in severe hepatic impairment because lorazepam undergoes glucuronidation (relatively preserved in cirrhosis) while diazepam undergoes oxidative metabolism (significantly impaired in cirrhosis). 6
• Monitor continuously for the first 24 hours even without symptoms in patients with severe liver disease and respiratory compromise. 5
• Have flumazenil available as an antidote, though it should be administered gradually due to seizure risk. 5

Alternative Sedation Strategies

When sedation is required in cirrhotic patients:

• Propofol is preferred in intubated cirrhotic patients due to its short half-life. 3
• Dexmedetomidine (alpha-2 adrenergic agonist) can reduce ventilation duration and preserve cognitive function while reducing the need for benzodiazepines in substance withdrawal. 3
• Flumazenil can temporarily improve consciousness in patients with hepatic encephalopathy caused by benzodiazepines, though it does not improve survival. 1, 3

Pharmacokinetic Considerations

The metabolism of benzodiazepines is significantly affected by hepatic insufficiency:

• All benzodiazepines' metabolism is affected by hepatic insufficiency, and the value of using short-acting benzodiazepines in hepatic insufficiency has not been validated by controlled trials. 5
• Diazepam blood levels are substantially elevated in liver cirrhosis, while lorazepam levels are less affected due to different metabolic pathways. 6
• Bioavailability increases and hepatic clearance decreases for drugs with high hepatic extraction (like most benzodiazepines) in cirrhotic patients. 7

Critical Pitfalls to Avoid

• Do not combine benzodiazepines with high-dose olanzapine, as fatalities have been reported with concurrent use. 1, 5
• Do not assume altered mental status is primary delirium without first ruling out hepatic encephalopathy and its precipitants (infections, GI bleeding, constipation, dehydration, electrolyte imbalances). 3
• Do not use fixed-schedule dosing in cirrhotic patients requiring benzodiazepines for withdrawal; symptom-triggered approaches prevent dangerous drug accumulation. 5
• Do not overlook that benzodiazepines in transfused blood can precipitate hepatic encephalopathy in transplant recipients with preexisting encephalopathy. 8