Version October 2024
| Agent | Pharmacology | Dosing (adult) | Role in palliative sedation |
| Benzodiazepines | |||
| Midazolam | Short-acting GABAA agonist Rapidly penetrates CNS Brief duration of action Continuous infusion is generally required to maintain effect | Acute: 1 to 5 mg IV or 2.5 to 10 mg SUBQ; may repeat every 5 minutes (IV) or every 20 minutes (SUBQ) as needed until calm.¶ Continuous infusion: Initially 1 mg/hour IV or SUBQ titrated every 1 to 2 hours to calm; repeat boluses may be administered as needed. Usual effective dose: 0.5 to 5 mg/hour. Consider an additional agent (eg, an antipsychotic) or switching medications before exceeding 10 mg/hour. A ceiling effect can occur. | Role: First-line choice. Often given in combination with an antipsychotic to relieve accompanying symptoms of agitated delirium. Advantages: Rapid onset. Water soluble and compatible with most drugs given by CSQI. Potent sedative and anxiolytic also useful for control of seizures, muscle spasms, nausea, vomiting, and intractable central pruritus. Reversal agent available (flumazenil). Disadvantages: Risk of paradoxical agitation and delirium. Risk of apnea with large individual doses in combination with opioid or if low cardiac output. Accumulation, prolonged sedation, and tolerance can occur after several days of continuous use. Subject to drug interactions with CYP3A4 inhibitors and inducers. Clearance is reduced in severe kidney or liver impairment. |
| Lorazepam | Intermediate-acting GABAA agonist Relatively slow onset Longer duration of effect compared with midazolam | Intermittent: 1 to 3 mg IV or SUBQ every 2 to 4 hours. Continuous infusion: 0.01 to 0.1 mg/kg/hour IV or SUBQ. Usual effective dose: 1 to 5 mg/hour. Doses of up to 10 mg/hour have been used. A ceiling effect can occur. | Role: An alternative to midazolam for patients likely to require a longer period of sedation or receiving care where midazolam continuous infusion is unavailable. Often given in combination with an antipsychotic. Advantages: Potent sedative and anxiolytic also useful for control of seizures (IV/SUBQ but not orally), muscle spasms, nausea, and vomiting. Prolonged onset and duration of effect may permit management with intermittent IV or SUBQ injections in some patients. Reversal agent available (flumazenil). Clearance is not altered by kidney or liver impairment. Disadvantages: Relatively slow onset. Risk of oversedation when titrating due to delayed response. Risk of paradoxical agitation and delirium. IV and CSQI line incompatibilities, risk of line precipitate, tissue injury, and phlebitis. Accumulation of toxic propylene glycol solvent; risk is increased with high doses, prolonged use, and in kidney impairment. Drug accumulation, prolonged sedation, and tolerance can occur after several days of continuous use. |
| First-generation antipsychotics | |||
| Levomepromazine (methotrimeprazine) | Sedating dopamine D2, 5HT2A, H1, alpha1, alpha2, and muscarinic antagonist with analgesic and amnestic effects Usual onset within 20 to 40 minutes | Initial loading dose: 12.5 to 25 mg SUBQ, or IV. Continuous infusionΔ: 0.5 to 8 mg/hour SUBQ; usual effective dose: 50 to 200 mg/day. IntermittentΔ: 12.5 to 25 mg SUBQ daily in 1 or 2 divided doses; may administer additional 6.25 mg doses every hour as needed (titrate scheduled dose based on as-needed dose requirements). | Role: Sedating antipsychotic for control of delirium and/or agitation in imminently dying patient. Often given when large doses of benzodiazepine (eg, midazolam 30 mg/day) do not provide sufficient anxiolysis or calm. NOTE: Not available in the United States. Advantages: Effective sedative, analgesic, and anxiolytic with rapid onset and useful for control of nausea, vomiting, delirium, and agitation. Flexible delivery options include CSQI that is compatible for delivery with analgesics and anticholinergics often used in palliative care. Disadvantages: Anticholinergic effects, orthostatic hypotension with rapid IV administration, akathisia, acute dystonic reactions, seizures, and cardiotoxicity associated with QT prolongation. |
| Chlorpromazine | See levomepromazine | Intermittent: 12.5 to 25 mg IV (over 30 to 60 minutes) or IM every 4 to 12 hours. Usual effective dose: 37.5 to 150 mg/day. Continuous infusion: 3 to 5 mg/hour IV. Usual effective dose 37.5 to 150 mg/day. Rectal◊: 25 to 100 mg every 4 to 12 hours. Usual effective dose: 75 to 300 mg/day. | Role: A sedating antipsychotic alternative in settings where levomepromazine is not available. Advantages: Effective sedative and anxiolytic with rapid onset; also useful for control of delirium, agitation, nausea, vomiting, and intractable hiccups. Wide availability. Disadvantages: SUBQ administration is not an option due to tissue damage and pain. Anticholinergic effects, orthostatic hypotension (which can be severe) with rapid IV administration, akathisia, acute dystonic reactions, seizures, and cardiotoxicity associated with QT prolongation. |
| Barbiturate | |||
| Phenobarbital | Enhances GABA and inhibits glutamate, providing long-acting sedative, hypnotic, and anticonvulsant actions (higher doses) Onset in 5 minutes, peak effect may take up to 30 minutes (parenteral) | Initial loading dose: 200 mg IV or IM; repeat after 30 minutes if needed. Continuous infusion: 30 mg/hour IV or SUBQ (~800 mg/day). Usual effective dose: 30 to 50 mg/hour (~800 to 1200 mg/day); doses of up to 160 mg/hour (~3800 mg/day) have been used. | Role: A second-line option for refractory agitation in imminently dying patients who have not adequately responded to full doses of midazolam with either levomepromazine or chlorpromazine. Advantages: Provides effective sedation to patients who have developed extreme tolerance to benzodiazepines and antipsychotics; controls refractory seizures. Maintenance dose may be administered by CSQI. Disadvantages: Paradoxical excitement, especially among older adults. Other adverse effects include hypotension, bradycardia, nausea, vomiting, and serious cutaneous allergic reactions. Subject to numerous drug interactions; increases metabolism of other drugs via CYP3A4 induction. It should not be abruptly discontinued due to occurrence of rebound seizures. Difficult to titrate due to long half-life and accumulation. CSQI not compatible for delivery with other drugs. |
| Short-acting anesthetic | |||
| Propofol | Ultra rapid-acting general anesthetic providing global CNS depression by GABAA potentiation and possibly inhibition of glutamate | Continuous infusion: Initial: 1 mg/kg/hour IV; increase by 0.5 mg/kg/hour every 30 minutes as needed. Usual effective dose: 1 to 2 mg/kg/hour; long-term use of doses greater than 4 mg/kg/hour is not recommended. Administration under the supervision of an anaesthesiologist is advisable. | Role: A second-line option for refractory intolerable agitation and delirium in imminently dying patient who has not adequately responded to full doses of benzodiazepines and antipsychotics receiving care in a specialty setting (ie, critical care unit) with access to necessary expertise and equipment. Advantages: Produces reliable and rapid unconsciousness. Useful in patients who have developed extreme tolerance to benzodiazepines and antipsychotics; controls refractory nausea, vomiting, and seizures. Disadvantages: Infusion site pain and phlebitis if given via peripheral vein. Delivered in an oil-in-water emulsion that can support bacterial growth, requiring strict adherence to aseptic technique and frequent bottle and tubing changes. Requires computer-controlled infusion pump. Other adverse effects: apnea with bolus injection, hypotension, allergic reactions, and bradycardia. |
5HT: serotonin; CNS: central nervous system; CSQI: continuous subcutaneous infusion; CYP3A4: cytochrome P450 isoenzyme 3A4; GABA: gamma aminobutyric acid; IM: intramuscular; IV: intravenous; SUBQ: subcutaneous.
* The medications listed in this table for palliative sedation in general do NOT provide analgesia. Analgesia must be provided prior to and during use of palliative sedation with appropriate opioid and non-opioid options. For additional information, refer to UpToDate topic reviews of pain assessment and management at end of life.
¶ Immediate deep sedation is rarely needed, ie, for sudden massive hemorrhage.
Δ After 3 days, the dose should be reduced by half to minimize accumulation.
◊ Not commercially available in most countries, however may be obtained from a compounding pharmacy.Do you want to add Medilib to your home screen?
