Midazolam (Versed)

Benzodiazepine - Short-Acting Sedative-Hypnotic

Overview

Midazolam is a short-acting benzodiazepine that was first approved by the FDA in 1985. It is unique among benzodiazepines due to its rapid onset of action, short duration of effect, and water-soluble formulation at acidic pH that becomes lipophilic at physiologic pH. Midazolam is widely used in medical settings for sedation, anxiolysis, amnesia, and seizure control. Available in multiple formulations including intravenous, intramuscular, oral, intranasal (Nayzilam), and buccal routes, it serves as a versatile medication for procedural sedation, anesthesia induction, seizure emergencies, and ICU sedation. Its pharmacokinetic profile allows for predictable onset and recovery, making it a preferred choice in acute care settings.

Mechanism of Action

Midazolam acts as a positive allosteric modulator of the GABAA receptor complex, enhancing the inhibitory effects of gamma-aminobutyric acid (GABA), the brain's primary inhibitory neurotransmitter. By binding to the benzodiazepine binding site on the GABAA receptor, midazolam increases the frequency of chloride channel opening, leading to neuronal hyperpolarization and reduced excitability. This mechanism produces the characteristic effects of sedation, anxiolysis, muscle relaxation, anterograde amnesia, and anticonvulsant activity. Midazolam also has some activity at glycine receptors, contributing to its muscle-relaxing effects. The drug's unique pH-dependent solubility allows for rapid CNS penetration and onset of action, while its metabolism to active metabolites contributes to its overall pharmacological profile.

Indications

  • Procedural Sedation: Sedation, anxiolysis, and amnesia prior to or during diagnostic, therapeutic, or endoscopic procedures.
  • Anesthesia Induction: Induction of general anesthesia before administration of other anesthetic agents.
  • Anesthesia Supplementation: Component of intravenous supplementation for balanced anesthesia.
  • ICU Sedation: Continuous intravenous infusion for sedation of mechanically ventilated patients.
  • Status Epilepticus: Intramuscular injection for treatment of status epilepticus (approved 2018).
  • Seizure Clusters: Intranasal spray (Nayzilam) for acute treatment of intermittent, stereotypic seizure episodes in patients ≥12 years (approved 2019).
  • Acute Agitation: Rapid control of agitation in psychiatric emergencies.
  • Alcohol Withdrawal: Management of severe alcohol withdrawal symptoms.
  • Premedication: Anxiolysis before surgical procedures.
  • Pediatric Sedation: Procedural sedation in children for various medical procedures.
  • End-of-Life Care: Palliative sedation for refractory symptoms.

Dosing and Administration

Indication Route Adult Dose Pediatric Dose
Procedural Sedation IV 1-2.5 mg slowly; titrate to effect 0.05-0.15 mg/kg; max 10 mg
Anesthesia Induction IV 0.15-0.35 mg/kg 0.15-0.3 mg/kg
Premedication IM 0.07-0.08 mg/kg (≈5 mg) 0.1-0.15 mg/kg; max 10 mg
ICU Sedation IV Infusion 0.01-0.05 mg/kg/hr; titrate 0.05-0.2 mg/kg/hr; titrate
Status Epilepticus IM 10 mg (single dose) 0.2 mg/kg; max 10 mg
Seizure Clusters Intranasal 5 mg (may repeat once) 5 mg (≥12 years)
  • IV Administration: Administer slowly over 2-3 minutes; wait 2-3 minutes between doses to assess effect.
  • Monitoring Required: Continuous respiratory and cardiac monitoring essential; resuscitation equipment must be available.
  • Titration: Start with lowest effective dose and titrate to desired clinical effect.
  • Onset Times: IV: 1-3 minutes; IM: 15 minutes; Intranasal: 5-10 minutes.
  • Elderly (>60 years): Reduce dose by 20-50%; increased sensitivity to CNS effects.
  • Hepatic Impairment: Reduce dose and expect prolonged duration; avoid in severe hepatic impairment.
  • Renal Impairment: No dose adjustment for single doses; use caution with repeated dosing.
  • Obesity: Dose based on ideal body weight; prolonged elimination possible.
  • Pregnancy: Category D; use only if potential benefit justifies risk.
Clinical Pearl: Midazolam has a "context-sensitive half-time" - with prolonged infusions, the recovery time increases significantly due to redistribution and active metabolite accumulation.

Pharmacokinetics

Parameter Details
Absorption Variable oral bioavailability (15-50%); rapid IM/IV absorption
Distribution Highly lipophilic at physiologic pH; rapid CNS penetration
Metabolism Hepatic via CYP3A4 to 1-hydroxymidazolam (active metabolite)
Half-Life 1.8-6.4 hours (mean ~3 hours); prolonged in elderly and hepatic impairment
Protein Binding 97% protein bound
Excretion Primarily urine as glucuronide conjugates; <0.5% unchanged drug
Clinical Pearl: The active metabolite 1-hydroxymidazolam is at least as potent as the parent compound and contributes significantly to prolonged effects, especially in renal impairment or with repeated dosing.

Side Effects

  • Respiratory: Respiratory depression, hiccoughs, cough, apnea
  • Cardiovascular: Hypotension, decreased cardiac output, arrhythmias
  • Neurological: Oversedation, confusion, amnesia, headache, dizziness
  • Gastrointestinal: Nausea, vomiting, increased salivation
  • Local: Pain at injection site, thrombophlebitis, tissue irritation
  • Respiratory Arrest: Life-threatening respiratory depression, especially with opioid combinations - FDA Boxed Warning
  • Cardiovascular Collapse: Severe hypotension, cardiac arrest, particularly in elderly or debilitated patients
  • Paradoxical Reactions: Agitation, combativeness, confusion, especially in children and elderly
  • Prolonged Sedation: Unexpected duration of effects, particularly with hepatic impairment
  • Withdrawal Syndrome: Seizures, delirium, life-threatening withdrawal after prolonged use
  • Allergic Reactions: Anaphylaxis, bronchospasm, laryngospasm
Clinical Pearl: Midazolam has a higher risk of respiratory depression than other benzodiazepines, particularly when combined with opioids. Deaths have occurred in non-critical care settings without adequate monitoring.

Interactions

  • CYP3A4 Inhibitors: Ketoconazole, itraconazole, erythromycin, clarithromycin, diltiazem, verapamil significantly increase midazolam levels
  • CYP3A4 Inducers: Rifampin, phenytoin, carbamazepine, phenobarbital decrease midazolam effectiveness
  • Opioids: Profound synergistic respiratory depression with fentanyl, morphine, oxycodone - reduce doses of both
  • CNS Depressants: Additive effects with alcohol, barbiturates, antipsychotics, antihistamines
  • Grapefruit: Increases oral bioavailability; avoid consumption
  • H2 Antagonists: Cimetidine (not ranitidine) increases midazolam levels
  • Protease Inhibitors: Ritonavir, nelfinavir contraindicated due to severe interaction
Clinical Pearl: The combination of midazolam with fentanyl is particularly dangerous and has been associated with numerous deaths. Always reduce doses of both agents when used together.

Contraindications and Warnings

  • Hypersensitivity: Known allergy to midazolam, other benzodiazepines, or benzyl alcohol
  • Acute Narrow-Angle Glaucoma: May precipitate acute angle closure
  • Severe Respiratory Depression: Unless mechanically ventilated
  • Shock or Coma: May worsen hemodynamic status
  • Respiratory Depression: FDA Boxed Warning - must use only in monitored settings with resuscitation capability
  • Dedicated Monitoring: Pediatric patients require dedicated personnel for monitoring during procedures
  • Benzyl Alcohol Toxicity: Avoid benzyl alcohol-containing formulations in neonates
  • Dependency Risk: Schedule IV controlled substance; potential for abuse and dependence
  • Withdrawal: Gradual tapering required after prolonged use to prevent life-threatening withdrawal
  • Myasthenia Gravis: May worsen muscle weakness
  • Sleep Apnea: Increased risk of severe respiratory depression

Evidence and Guidelines

  • Procedural Sedation: Multiple studies demonstrate superior patient and physician satisfaction compared to other sedatives for endoscopic procedures
  • Status Epilepticus: RAMPART trial showed IM midazolam non-inferior to IV lorazepam for prehospital seizure termination
  • Nayzilam Efficacy: Phase 3 trials showed superior seizure termination compared to placebo with rapid onset (median 3 minutes)
  • ICU Sedation: Studies demonstrate effective sedation with faster wake-up times compared to longer-acting agents
  • Pediatric Use: Extensive safety and efficacy data for various pediatric procedures and seizure management
  • ASA Guidelines: Recommended for procedural sedation with appropriate monitoring standards
  • AES Guidelines: First-line IM treatment for status epilepticus when IV access unavailable
  • Society for Pediatric Sedation: Preferred agent for many pediatric procedures with dedicated monitoring
  • ICU Guidelines: Recommended for short-term sedation with daily interruption protocols
  • Standardize 4 Safety: Standard concentrations established for patient safety

Monitoring Parameters

  • Respiratory Function: Continuous monitoring of respiratory rate, oxygen saturation, and airway patency
  • Cardiovascular Status: Blood pressure, heart rate, ECG monitoring during administration
  • Level of Consciousness: Sedation scales (RASS, Richmond) for appropriate depth of sedation
  • Airway Reflexes: Gag reflex, ability to maintain airway protection
  • Recovery Assessment: Return to baseline mental status, protective reflexes, and ambulation ability
  • Injection Site: Monitor for signs of extravasation, thrombophlebitis, or tissue damage
  • Paradoxical Reactions: Watch for agitation, combativeness, especially in elderly or pediatric patients
  • Long-term Use: Monitor for tolerance, dependence, and withdrawal symptoms

Patient Education

  • Amnesia Effects: Inform that memory of the procedure may be impaired or absent - this is expected
  • Post-Procedure Care: Arrange for responsible adult supervision for 24 hours after administration
  • Activity Restrictions: No driving, operating machinery, or making important decisions for 24 hours
  • Alcohol Avoidance: Do not consume alcohol for 24 hours due to dangerous additive effects
  • Nayzilam Training: Caregivers must be trained on proper administration technique for seizure emergencies
  • Emergency Recognition: Know signs of respiratory depression requiring immediate medical attention
  • Storage Safety: Keep in secure location away from children; controlled substance with abuse potential
  • Drug Interactions: Inform all healthcare providers about midazolam use due to significant interactions
  • Seizure Action Plan: Develop clear plan for seizure cluster management with Nayzilam use
  • When to Seek Help: Contact emergency services if breathing problems, excessive sedation, or allergic reactions occur