Benzodiazepine · Sedative · Antiepileptic
Midazolam (Versed)
Also called Versed
Indications
- Procedural sedation, anxiolysis and amnesia
- Premedication and induction of anesthesia
- Sedation of intubated patients, now second-line to propofol or dexmedetomidine (PADIS 2018)
- Status epilepticus without IV access, IM (RAMPART); intranasal or buccal (off-label)
- Refractory status epilepticus by infusion (off-label)
- Acute agitation (off-label)
Dosing
Midazolam drip card and mL/h converterStart: 1–2 mg/h (0.02–0.1 mg/kg/h)
| Where | Dose |
|---|---|
| Airway and RSI | Midazolam: 0.1–0.3 mg/kg (slow onset; hypotension) |
| Seizures and neuro | Midazolam: 10 mg IM (over 40 kg) when no IV |
| Benzodiazepine equivalence | Midazolam: 2 mg IV (fast, short; accumulates in infusion) |
| Other ICU drugs | Midazolam: Active metabolite accumulates with infusions |
On the quick cards
Mechanism of action
Midazolam binds the benzodiazepine site in the GABA-A receptor's extracellular domain, at the interface of an α subunit (α1, α2, α3 or α5) and the γ2 subunit. It raises GABA affinity, so the chloride channel opens more often, but it cannot open the channel without GABA, which gives benzodiazepines alone a ceiling. α1 receptors mediate sedation, amnesia and anticonvulsant effects; α2 and α3 mediate anxiolysis and muscle relaxation. Flumazenil competes for this site; propofol, etomidate and barbiturates bind elsewhere.
Pharmacology
- CNS: anxiolysis, sedation and strong anterograde amnesia; anticonvulsant; no analgesia; paradoxical agitation in some older adults and children
- Respiratory: dose-related depression, airway obstruction and apnea, much worse with opioids, age, COPD or sleep apnea
- Cardiovascular: modest fall in BP and SVR, more with hypovolemia or opioids
- Other: a modifiable ICU delirium risk factor (PADIS 2018); tolerance and withdrawal after long infusions
Pharmacokinetics
| Onset | IV 1.5–5 min; IM about 15 min, peaking at 30–60 min (label) |
|---|---|
| Duration | Recovery usually within 2 h of procedural doses, up to 6 h (label) |
| Context-sensitive half-time | Rises with infusion length; waking after days of infusion can take days |
| Half-life | About 3 h (1.8–6.4 h); doubled or more in older adults, heart failure and obesity (label) |
| Distribution | Vd 1–3.1 L/kg, larger in obesity; lipophilic at body pH |
| Protein binding | About 97% |
| Metabolism | CYP3A4 to α-hydroxymidazolam, at least as potent as midazolam (label), which is then glucuronidated |
| Elimination | Urine as the glucuronide; under 0.5% unchanged |
| Kidney failure | The glucuronide accumulates (half-life 12 h to over 25 h, label) and prolongs sedation |
| Bioavailability | IM over 90% (label); oral low (first-pass CYP3A4) |
Chemistry
- An imidazobenzodiazepine, 8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine; the fused imidazole makes it a weak base, pKa about 6.2
- pH-dependent ring opening: in the acidic vial (pH about 3) the diazepine ring is partly open (up to 25%, label) and the protonated drug is water-soluble; at body pH the ring closes and the un-ionized drug is highly lipophilic
- Water-based, so little injection pain or phlebitis and reliable IM and intranasal absorption, unlike diazepam
- Comes as 1 and 5 mg/mL; some vials contain 1% benzyl alcohol
Adverse effects and cautions
In the one-pagers
- Sedation, Pain and Delirium ScalesPharmacology and ICU pitfalls: Midazolam: 0.02–0.1 mg/kg/h: Active metabolite builds up in renal failure
- Pediatric Assessment and EmergenciesFebrile seizures and dehydration: Over 5 min or seizing on arrival: airway, O₂, glucose, benzodiazepine (paramedic: midazolam 0.2 mg/kg IM/IN, max 10 mg, per protocol)
- Airway and RSIRSI drugs: Midazolam: 0.15–0.35 mg/kg: 1.5–2.5 min: Slow onset; hypotension
- End of Life, Brain Death and Organ DonationWithdrawing life support: Midazolam: 0.02–0.1 mg/kg: 1–5 mg/h
- Mental Health: Meds and CommunicationBenzodiazepines and sedative withdrawal: Midazolam: About 2–6 h; longer in obesity, AKI: CYP3A4 inhibitors prolong it
- Neuro: ICP and StrokeStatus epilepticus: No IV: Midazolam 10 mg IM
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Sources
- FDA label: Midazolam injection (2023)
- PubChem: midazolam
- Devlin 2018 (PADIS)
- Silbergleit 2012 (RAMPART)
For education and exam preparation only. Follow your institution’s protocols. Typical adult values for study. Follow the order, the label and your institution's protocols.