What are the considerations for using lorazepam (Ativan) in patients with impaired renal function?

Lorazepam Use in Renal Impairment

Lorazepam does not require dose adjustment in patients with renal impairment, as the parent drug is primarily metabolized hepatically and its clearance remains unchanged in renal disease. 1, 2

Key Pharmacokinetic Principles

Lorazepam itself is safe in renal impairment because:

• The parent drug undergoes hepatic glucuronidation to an inactive metabolite (lorazepam-glucuronide), not renal elimination 2, 3
• Total body clearance of lorazepam remains approximately 85 ml/min in renal patients versus 71 ml/min in normal subjects—a non-significant difference 2
• Only 2% of the dose is excreted as unchanged drug in urine and feces 2
• The elimination half-life of lorazepam (11.3 hours in renal failure vs 11.1 hours in normals) is essentially unchanged 3
• Oral absorption exceeds 90% and is not impaired by renal disease 2

Critical Safety Concern: Propylene Glycol Toxicity

The major risk with IV lorazepam in renal patients is propylene glycol toxicity from the diluent, not the drug itself. 4

Mechanism and Risk Factors

• IV lorazepam formulations contain propylene glycol as a diluent, which accumulates in critically ill patients 4
• Toxicity manifests as metabolic acidosis and acute kidney injury 4
• Doses as low as 1 mg/kg/day can cause propylene glycol toxicity—much lower than previously recognized 4
• These effects may be overlooked because metabolic acidosis and kidney injury are common in critically ill patients 4

Monitoring Strategy

• Use serum osmol gap as a screening tool for propylene glycol accumulation 4
• An osmol gap >10-12 mOsm/L suggests significant propylene glycol accumulation 4

Metabolite Accumulation Considerations

While lorazepam clearance is unchanged, the inactive glucuronide metabolite accumulates significantly in renal failure: 3, 5

• Lorazepam-glucuronide has a prolonged half-life (20.7 hours in normals) and accumulates to high plasma concentrations in renal failure 3
• This metabolite is pharmacologically inactive and nontoxic 2
• The glucuronide is dialyzable (40% removed by 6-hour hemodialysis) with 39.5-43.4% plasma protein binding 2, 5
• CVVH contributes significantly to removal of lorazepam-glucuronide (sieving coefficient 0.48) 5

Practical Dosing Recommendations

For oral or IM lorazepam: No dose adjustment is necessary in renal impairment 1, 2, 6

For IV lorazepam in critically ill patients with renal impairment:

• Consider alternative sedatives, especially for prolonged sedation 4
• If IV lorazepam is used, monitor serum osmol gap for propylene glycol toxicity 4
• Be particularly cautious in elderly patients who have decreased benzodiazepine clearance 4, 1

FDA Labeling Guidance

The FDA label states: "The usual precautions for treating patients with impaired renal or hepatic function should be observed" and recommends monitoring elderly or debilitated patients frequently with careful dosage adjustment (initial dosage should not exceed 2 mg). 1

Common Pitfalls to Avoid

• Assuming lorazepam requires dose reduction in renal failure—the parent drug clearance is unchanged 2
• Failing to recognize that IV formulation risks are from propylene glycol, not lorazepam itself 4
• Overlooking propylene glycol toxicity signs (metabolic acidosis, AKI) as they mimic common critical illness findings 4
• Using high-dose IV lorazepam without monitoring osmol gap in renally impaired patients 4