Midazolam

Midazolam is a short-acting, water-soluble benzodiazepine used for procedural sedation, anaesthetic induction, sedation of ventilated patients, and as a rescue treatment for prolonged seizures by the buccal, intranasal and intramuscular routes. It is a potent respiratory depressant and is given only where monitoring and airway support are available.

Classification. Benzodiazepine, short-acting, imidazobenzodiazepine.

Mechanism. Positive allosteric modulation of GABA-A receptors, which increases chloride channel opening and neuronal inhibition.

Pharmacokinetics. Rapid onset: 1 to 5 minutes intravenously, 5 to 15 minutes intramuscularly, 5 to 10 minutes buccally or intranasally. Extensively metabolised by CYP3A4 to alpha-hydroxymidazolam (active, glucuronidated and renally cleared). Half-life 2 to 6 hours, much longer in the critically ill, older adults, obesity, liver disease and kidney failure, and with infusions over 24 hours.

Procedural sedation, adults (intravenous). Start 0.5 to 1 mg (1 to 2.5 mg in fit adults); titrate in 0.5 to 1 mg steps at intervals of 2 to 3 minutes until the desired effect. Usual total 2.5 to 7.5 mg; do not exceed 5 mg in older adults. Give at a rate not over 1 mg in 30 seconds.

Premedication. Intramuscular 0.07 to 0.1 mg/kg (usual 5 mg) 30 to 60 minutes before surgery; in older adults 0.025 to 0.05 mg/kg.

Induction of anaesthesia. Intravenous 0.1 to 0.2 mg/kg titrated slowly; lower in premedicated, older or frail patients.

Sedation of ventilated patients (continuous intravenous infusion).

• Loading: 0.03 to 0.3 mg/kg slowly, in increments of 1 to 2.5 mg.
• Maintenance: 0.03 to 0.2 mg/kg/hour, adjusted to a sedation target. Reduce in older adults and the critically ill.
• Prolonged infusions: lighten sedation daily and review.

Prolonged seizures, adults and children out of hospital or without intravenous access.

• Intramuscular: 10 mg for over 40 kg; 5 mg for 13 to 40 kg; single dose.
• Buccal solution: aged 3 months to under 1 year 2.5 mg; 1 year to under 5 years 5 mg; 5 years to under 10 years 7.5 mg; 10 years and over 10 mg.
• Intranasal: 0.2 mg/kg (maximum 10 mg), half in each nostril.
• Repeat once after 10 minutes only if a second dose is permitted and respiratory status allows.

Status epilepticus (intravenous). 0.1 to 0.2 mg/kg bolus, then an infusion of 0.05 to 0.4 mg/kg/hour in intensive care.

Dose limits. Older adults, critical illness, liver or kidney impairment, and heart failure: reduce doses by one half or more. Strong CYP3A4 inhibitors (ketoconazole, itraconazole, clarithromycin, ritonavir): reduce doses and avoid oral use.

Contraindications. Acute respiratory failure or severe sleep apnoea without monitoring, myasthenia gravis, hypersensitivity, concurrent strong CYP3A4 inhibitors for oral use. Major warning of respiratory depression and arrest, need for continuous monitoring by trained staff; profound sedation with opioids; neonatal seizures with rapid injection; abuse and dependence.

Serious adverse effects. Respiratory depression and apnoea, hypotension, paradoxical agitation (especially in children and older adults), laryngospasm, hiccups, prolonged sedation after infusion, delirium, withdrawal on abrupt stopping after prolonged infusion, tolerance.

Common adverse effects. Sedation, amnesia, hypotension, nausea, drowsiness, headache.

Interactions. Strong CYP3A4 inhibitors (azole antifungals, macrolides, ritonavir, diltiazem, verapamil) raise levels and prolong effect. Rifampicin, carbamazepine and phenytoin lower them. Opioids, propofol, alcohol and other sedatives add respiratory depression and hypotension. Grapefruit juice raises oral levels.

Common prescribing errors. Giving a fixed dose without titration; using full adult doses in older adults; giving rapidly intravenously; no airway equipment; infusing for several days without sedation breaks; using in neonates without specialist input.

Special groups.

• Pregnancy: avoid unless needed; neonatal sedation and withdrawal with late use.
• Breastfeeding: single doses acceptable; wait 4 hours before feeding after a dose.
• Children: used for sedation and seizures; avoid rapid intravenous injection in neonates; weight-based dosing.
• Older adults: reduce doses by one half or more.
• Kidney impairment: active metabolite accumulates in prolonged infusion.
• Liver impairment: reduce doses.

Formulations. Injection 1 mg/mL, 2 mg/mL and 5 mg/mL; buccal solution 10 mg/mL in pre-filled syringes; oral syrup in some regions. Dilute with sodium chloride 0.9% or glucose 5% for infusion (for example 50 mg in 50 mL as 1 mg/mL). Inject intravenously slowly into a large vein.

Baseline. Airway assessment, oxygen saturation, blood pressure, pulse, sedative and opioid use, liver and kidney function, pregnancy status.

Monitoring. Continuous oxygen saturation, respiratory rate and blood pressure from the first dose until recovered (at least 60 minutes after intravenous procedural sedation). Have oxygen, airway equipment and flumazenil available. Use a sedation score for infusions and review daily. Flumazenil can reverse sedation but may precipitate seizures in dependent patients.

Stopping. After an infusion of more than 3 to 5 days, reduce gradually to avoid withdrawal.

Referral and escalation. Use only in settings with trained staff, resuscitation facilities and monitoring. Apnoea, oxygen saturation under 92%, or a seizure lasting more than 5 minutes after rescue dosing needs immediate airway support and senior help.