Midazolam (Versed)

Indications

Intensive Care Unit Sedation (see Sedation, [[Sedation]])

Clinical Efficacy

  • Dexmedetomidine (Precedex) Compared to Midazolam (Versed) (2009) (see Dexmedetomidine, [[Dexmedetomidine]] and Midazolam, [[Midazolam]]) [MEDLINE]
    • Dexmedetomidine is Similarly Effective for Sedation, as Compared to Midazolam
    • Dexmedetomidine Shortened the Time to Extubation, as Compared to Midazolam
    • Dexmedetomidine was Associated with Less Delirium, as Compared to Midazolam
    • Dexmedetomidine was Associated with Less Tachycardia/Hypotension, but More Bradycardia, as Compared to Midazolam
  • Dexmedetomidine (Precedex) Compared to Midazolam (Versed) (2010) (see Dexmedetomidine, [[Dexmedetomidine]] and Midazolam, [[Midazolam]]) [MEDLINE]
    • Dexmedetomidine Resulted in Less Cost in the ICU, as Compared to Midazolam: due to decreased length of ICU stay and decreased ventilator days
  • MIDEX and PRODEX Trials: Dexmedetomidine (Precedex) Compared to Midazolam (Versed) and Propofol (Diprivan) (2012) (see Dexmedetomidine, [[Dexmedetomidine]], Midazolam, [[Midazolam]], and Propofol, [[Propofol]]) [MEDLINE]: data from randomized MIDEX (Midazolam vs. Dexmedetomidine) and PRODEX (Propofol vs. Dexmedetomidine) trials
    • Dexmedetomidine was Equivalent in Maintaining Light-Moderate Sedation
    • Dexmedetomidine Decreased the Duration of Mechanical Ventilation, as Compared to Midazolam (But Not When Compared to Propofol)
    • Dexmedetomidine Improved Patients’ Ability to Communicate Pain, as Compared with Midazolam and Propofol
    • Dexmedetomidine Demonstrated More Adverse Effects (Bradycardia/Hypotension), as Compared with Midazolam and Propofol
    • In the First 24 hrs of PRODEX Trial, Discontinuation of Dexmedetomidine was More Frequent Due to Lack of Efficacy: this suggests that adequate sedation may not be possible in all patients with dexmedetomidine alone (and it is likely that dexmedetomidine is not equivalent to propofol)
  • Comparison of Non-Benzodiazepine Sedation (Dexmedetomidine, Propofol) vs Benzodiazepine Sedation in Mechanically Ventilated ICU Patients (Crit Care Med, 2013) [MEDLINE]
    • Use of Dexmedetomidine/Propofol-Based Sedation Regimen Decreased ICU Length of Stay and Duration of Mechanical Ventilation, as Compared to a Benzodiazepine-Based Regimen
  • Propofol (Diprivan) Compared to Midazolam/Lorazepam (2014) (see Propofol, [[Propofol]], Midazolam, [[Midazolam]], and Lorazepam, [[Lorazepam]]) [MEDLINE]
    • Propofol Decreased Mortality Rate, as Compared to Benzodiazepines (Midazolam/Lorazepam)
    • Propofol Increased Probability of ICU Discarge at 28 Days, as Compared to Benzodiazepines (Midazolam/Lorazepam)
    • Propofol Decreased Ventilator Days at 28 Days, as Compared to Benzodiazepines (Midazolam/Lorazepam)

Intoxication/Withdrawal

  • Ethanol Withdrawal (see Ethanol, [[Ethanol]])

Procedural Sedation (see Sedation, [[Sedation]])

  • Bone Marrow Biopsy (see Bone Marrow Biopsy, [[Bone Marrow Biopsy]])
  • Bronchoscopy (see Bronchoscopy, [[Bronchoscopy]])
  • Cardioversion for Atrial Fibrillation (see Atrial Fibrillation, [[Atrial Fibrillation]])
  • Dental Procedures
  • Endoscopy
  • Fine Needle Aspiration (FNA) of Mass/Lesion
  • Foreign Body Extraction: particularly in pediatric populations
  • Surgery

Other

  • Anxiety (see Anxiety, [[Anxiety]])

Pharmacology

  • Benzodiazepine (see Benzodiazepines, [[Benzodiazepines]])
    • Benzodiazepines are GABA-A Receptor Agonists: bind to post-synaptic receptors on GABA neurons in the central nervous system (limbic system, reticular formation)
      • GABA has an Inhibitory Effect

Pharmacokinetics

  • Midazolam is Lipophilic: rapidly crosses the blood brain barrier
  • Onset of Action (IV Dose): 2-5 min
  • Peak Effect (IV Dose): 5-7 min
  • Half-Life: 3-11 hrs (Typical Range: 1.8-6.4 hrs)
    • Prolonged Infusion Results in Accumulation of the Active Metabolite
    • Half-Life is Prolonged in Cirrhosis, Congestive Heart Failure, Obesity, Renal Failure, and the Elderly

Metabolism

  • Hepatic Oxidation (CYP3A4): 60-70% is 1-Hydroxy-Midazolam (Active Metabolite) or Alpha-Hydroxymidazolam
    • Renal Excretion of 1-Hydroxy-Midazolam (Active Metabolite) and Alpha-Hydroxymidazolam

Administration

  • PO
  • Intranasal
  • IV (Load): 1-5 mg
  • IV (Maintenance): 1-5 mg/hr

Dose Adjustment

  • Hepatic: use with caution in liver disease (due to prolonged duration)
  • Renal: although no dose adjustment is specified in manufacturer labeling, renal failure patients on a continuous midazolam infusion are unable to eliminate the active metabolite 1-hydroxymidazolam, resulting in accumulation and prolonged sedation after discontinuation (sometimes for days)

Adverse Effects

Cardiovascular Adverse Effects

  • Hypotension (see Hypotension, [[Hypotension]])
    • Epidemiology: hypotension may be more common in patients with hemodynamic instability or who have received opiates

Gastrointestinal Adverse Effects

Neurologic Adverse Effects

  • Anterograde Amnesia
  • Central Nervous System Depression
  • Increased Risk of Delirium/Tolerance (see Delirium, [[Delirium]]): compared to short-acting sedative agents (such as propofol and dexmedetomidine)
  • Paradoxical Agitation (see Agitation, [[Agitation]])
    • Epidemiology: increased risk in pediatrics/adolescents and patients with psychiatric disease
    • Treatment: agitation may be responsive to flumazenil (see Flumazenil, [[Flumazenil]])

Pulmonary Adverse Effects


References

  • Sedation with intranasal midazolam in adults undergoing upper gastrointestinal endoscopy. J Clin Gastroenterol. 2002 Aug;35(2):133-7 [MEDLINE]
  • Clinical pharmacokinetic monitoring of midazolam in critically ill patients. Pharmacotherapy. 2007 Mar;27(3):389-98 [MEDLINE]