Midazolam for Procedural Sedation

Midazolam is a short-acting water-soluble benzodiazepine used for anxiolysis, sedation and anterograde amnesia during procedures. It has rapid onset and a short effect after a single dose, but respiratory depression is the main hazard, especially with opioids, in older adults and in children given a rapid dose. A reversal agent exists, but it is shorter-acting than midazolam.

Class. Benzodiazepine (short-acting).

Mechanism. Positive allosteric modulation of GABA-A receptors, increasing the frequency of chloride channel opening.

Pharmacokinetics. Intravenous onset 1 to 3 minutes, peak effect 3 to 5 minutes, duration 30 to 60 minutes after a single dose. Oral onset 15 to 30 minutes, intranasal 5 to 10 minutes. Oral bioavailability about 40 to 50%. Protein binding about 97%. Elimination half-life 1.5 to 2.5 hours, prolonged in older adults, obesity, liver failure and critical illness. Metabolised by CYP3A4 to alpha-hydroxymidazolam (active), which is glucuronidated and accumulates in kidney failure.

Indications are premedication, procedural sedation (endoscopy, dental, minor surgery, imaging), sedation before painful procedures in children, and amnesia.

Adults

• Intravenous, under 60 years: 1 to 2.5 mg over 2 minutes, then 1 mg every 2 to 3 minutes until the desired level; usual total 2.5 to 5 mg (rarely more than 5 mg).
• Intravenous, over 60 years, debilitated or ASA 3 and 4: 0.5 to 1.5 mg initially, then 0.5 to 1 mg increments after 2 to 5 minutes; usual total up to 3.5 mg.
• With an opioid: reduce the midazolam dose by 30 to 50%.
• Intramuscular: 0.07 to 0.1 mg/kg (usually 5 mg) 30 to 60 minutes before the procedure.
• Wait at least 2 minutes after each dose for full effect before giving more.
• Maximum: about 5 mg in a healthy adult for sedation (3.5 mg in older adults), unless under specialist care.

Children

• Oral premedication: 0.25 to 0.5 mg/kg (maximum 20 mg), 20 to 30 minutes before the procedure.
• Intranasal: 0.2 to 0.3 mg/kg (maximum 10 mg).
• Buccal: 0.2 to 0.3 mg/kg.
• Intravenous, 6 months to 5 years: 0.05 to 0.1 mg/kg, titrated, with a total up to 0.6 mg/kg (maximum 6 mg).
• Intravenous, 6 to 12 years: 0.025 to 0.05 mg/kg, titrated, with a total up to 0.4 mg/kg (maximum 10 mg).
• Intramuscular: 0.05 to 0.1 mg/kg.
• Neonates: avoid rapid injection, which causes severe hypotension and seizures.

Reversal. Flumazenil 0.2 mg intravenously over 15 seconds, then 0.1 mg every 60 seconds to a total of 1 mg (specialist use up to 2 mg); in children 10 micrograms/kg (maximum 200 micrograms), repeated every minute to 50 micrograms/kg or 1 mg. Re-sedation can occur after 30 to 60 minutes.

Contraindications. Hypersensitivity to benzodiazepines; severe respiratory insufficiency or untreated sleep apnoea; myasthenia gravis; acute alcohol or drug intoxication; shock or coma; acute narrow-angle glaucoma; ritonavir and other strong CYP3A4 inhibitors with oral use (reduce intravenous doses if they are present); absence of airway equipment and trained staff.

Boxed-warning-level risks. Respiratory depression and arrest, especially with opioids and rapid injection; hypotension and seizures in neonates after rapid injection; concurrent opioid or other central nervous system depressant use causing profound sedation; dependence with prolonged use.

Adverse effects. Common: drowsiness, amnesia, mild hypotension, hiccups. Serious: apnoea, airway obstruction, paradoxical agitation (children, older adults), hypotension, respiratory arrest, delirium, aspiration.

Interactions. Opioids, propofol, alcohol and other sedatives add respiratory depression. CYP3A4 inhibitors (erythromycin, clarithromycin, azole antifungals, diltiazem, verapamil, protease inhibitors, grapefruit juice) increase and prolong effect. Rifampicin, carbamazepine and phenytoin reduce it. Flumazenil reverses it but can precipitate seizures in dependent patients.

Common prescribing errors. Giving an opioid and midazolam at full dose each; giving repeat doses before the peak; confusing 1 mg/mL and 5 mg/mL ampoules; a fixed dose of 5 to 10 mg in an older adult; relying on flumazenil and discharging early; rapid injection in neonates.

Special groups

• Pregnancy: limited data; avoid regular use, and note that late exposure can cause a floppy infant and neonatal withdrawal.
• Breastfeeding: single doses are acceptable; watch the infant for drowsiness.
• Older adults: reduce the dose by 50% and titrate slowly.
• Kidney impairment: reduce repeat doses; the active glucuronide accumulates.
• Liver impairment: reduce the dose; half-life is prolonged.
• Regional: flumazenil is often not available in district settings, so give small titrated doses, ensure oxygen, suction and a bag-valve-mask, and observe patients until fully awake.

Formulations. Injection 1 mg/mL and 5 mg/mL, oral syrup 2 mg/mL, buccal and intranasal preparations.

Administration. Give intravenous doses slowly over at least 2 minutes into a large vein; dilute the 5 mg/mL concentrate with 0.9% sodium chloride or 5% glucose. Use a separate syringe for each patient.

Baseline. Airway assessment, oxygen saturation, respiratory disease, sleep apnoea, alcohol and drug use, current opioids and CYP3A4 inhibitors, fasting status, age and weight.

Monitoring. Continuous pulse oximetry, with capnography if available, heart rate and blood pressure. Sedation scoring every 5 minutes. Continue observation for at least 60 minutes after the last dose.

Therapeutic drug monitoring. Not used.

Dose reduction and stopping thresholds. Stop giving doses when speech is slurred, drowsiness is obvious or the oxygen saturation is under 94% on air. Reduce doses by 50% in older adults, with opioids and in liver or kidney impairment. Withhold in respiratory rate under 10 breaths/minute.

Referral and escalation. Apnoea or oxygen saturation under 90% needs airway opening, oxygen, assisted ventilation and flumazenil 0.2 mg intravenously, repeated every minute to a total of 1 mg. Paradoxical agitation needs stopping the drug and calm supportive care. Seizures after flumazenil need a benzodiazepine and airway support.