Sedatives in Liver Disease

Sedatives in liver disease carry a high risk of precipitating or worsening hepatic encephalopathy because of reduced clearance, increased free drug and increased cerebral GABA receptor sensitivity. Sedation should be used only for clear indications such as alcohol withdrawal, procedures, severe agitation or ventilated care, at the lowest effective dose.

Benzodiazepine kinetics. Diazepam and chlordiazepoxide undergo oxidation and have long-acting metabolites that accumulate. Lorazepam, oxazepam and temazepam are glucuronidated and safer.

Encephalopathy mimic. New confusion in cirrhosis is encephalopathy until proven otherwise. Treat precipitants before sedating.

Alcohol withdrawal. Benzodiazepines remain first line. In cirrhosis use lorazepam or oxazepam, symptom-triggered rather than fixed schedules.

Insomnia. Sleep hygiene and treatment of pruritus, nocturia and pain come first. Melatonin is preferred. Zopiclone at low dose is acceptable in compensated disease. Avoid zolpidem in Child-Pugh C. Hydroxyzine has some evidence for sleep in compensated cirrhosis.

Agitation and delirium. Low-dose haloperidol or quetiapine. Avoid benzodiazepines unless alcohol withdrawal is the cause.

Procedural sedation. Propofol is preferred for endoscopy because of rapid offset. Use midazolam at reduced doses if propofol is unavailable.

Intensive care. Propofol or dexmedetomidine with dose reduction. Avoid prolonged midazolam infusion.

Avoid. Diazepam and chlordiazepoxide in decompensated disease, sedating antihistamines in encephalopathy, and opioids used for sedation.

Alcohol withdrawal in cirrhosis. Lorazepam 1 to 2 mg orally hourly when the withdrawal score is 8 to 10 or more, reassessing before each dose; or oxazepam 15 to 30 mg orally. Maximum lorazepam usually 8 to 10 mg in 24 hours outside intensive care.

Thiamine. 100 mg orally three times daily for prevention. If Wernicke encephalopathy is suspected, give 200 to 500 mg intravenously three times daily for 3 to 5 days, before any glucose.

Insomnia. - Melatonin modified-release 2 mg orally 1 to 2 hours before bed. - Zopiclone 3.75 mg orally at night, maximum 7.5 mg, for up to 2 to 4 weeks.

Agitation. - Haloperidol 0.5 to 1 mg orally or intramuscularly, repeated after 1 to 2 hours if needed; maximum usually 5 mg in 24 hours in older or frail patients. Check QTc first. - Quetiapine 12.5 to 25 mg orally at night or twice daily.

Procedural sedation. Propofol titrated in small boluses by a trained operator. Midazolam 0.5 to 1 mg intravenously, repeated after 2 to 3 minutes; total usually under 2 to 3 mg.

Special groups. - Older adults: halve starting doses. - Kidney impairment: reduce oxazepam and avoid accumulation of active metabolites. - Pregnancy: lorazepam may be used for withdrawal; avoid regular use near delivery because of neonatal sedation. - Breastfeeding: lorazepam is preferred over diazepam; observe the infant for sedation.

Monitoring. Sedation score, withdrawal score, respiratory rate, oxygen saturation and encephalopathy grade with each dose.

Reversal. Flumazenil 0.2 mg intravenously, repeated to a maximum of 1 mg, may reverse benzodiazepine sedation. Avoid in long-term benzodiazepine use or seizure risk.

Stopping. Stop sedatives if encephalopathy develops or worsens, and treat with lactulose.

Referral and escalation. Escalate to high dependency care for withdrawal needing high benzodiazepine doses, delirium tremens, seizures or grade 3 encephalopathy.