MIDAZOLAM 

MECHANISM OF ACTION

• Acts on GABA-A receptor
• Enhances frequency of chloride channel opening → neuronal hyperpolarization

Effects:

• Sedation
• Hypnosis
• Anxiolysis
• Anticonvulsant action
• Anterograde amnesia

PHARMACOKINETICS

1. Absorption

• IV (most common in ICU)
• IM, oral, intranasal (procedural use)

2. Distribution

• Highly lipophilic
• Rapid CNS penetration → quick onset
• Protein bound (~95%)

3. Metabolism

• Hepatic via Cytochrome P450 3A4
• Active metabolite: 1-hydroxymidazolam

4. Elimination

• Renal excretion (as conjugates)

Context-Sensitive Half-Time

• Short after single dose
• Markedly prolonged in infusion
• Accumulation in:
• Renal failure
• Hepatic failure
• Obesity
• Elderly

Midazolam → unpredictable awakening in prolonged ICU sedation

PHARMACODYNAMICS

ICU INDICATIONS

1. Sedation in Mechanically Ventilated Patients

• Short-term sedation
• When hemodynamic instability present (relative advantage vs propofol)

2. Status Epilepticus

• IV bolus or infusion
• Alternative to diazepam/lorazepam

3. Procedural Sedation

• Intubation
• Central line insertion
• Bronchoscopy

4. Alcohol Withdrawal

• Severe cases (DTs)

DOSING (ICU)

Bolus

• 0.01–0.05 mg/kg IV

Infusion

• 0.02–0.1 mg/kg/hr

 Titrate to sedation target:

• RASS: −2 to 0 (preferred modern target)

 ADVERSE EFFECTS

 Respiratory

• Respiratory depression
• Apnea (especially with opioids)

 Cardiovascular

• Hypotension (more in hypovolemia)

 Neurological

• Delirium (important ICU issue)
• Prolonged sedation
• Withdrawal syndrome

 Metabolic

• Accumulation → delayed awakening

 ICU DELIRIUM & SEDATION CONTROVERSY

According to:

• Society of Critical Care Medicine PADIS Guidelines (2018)

Recommendations:

 Avoid benzodiazepines (including midazolam) for routine sedation
 Prefer:

• Propofol
• Dexmedetomidine

 Why?

• ↑ ICU delirium
• ↑ ventilator days
• ↑ ICU stay

WITHDRAWAL & TOLERANCE

Seen in:

• Prolonged infusion (>5–7 days)

Features:

• Agitation
• Tachycardia
• Hypertension
• Seizures

 Prevention:

• Gradual taper
• Switch to longer-acting benzo (e.g., diazepam)

 CONTRAINDICATIONS / CAUTION

• Severe respiratory depression
• Shock (relative)
• Hepatic failure
• Renal failure (metabolite accumulation)
• Elderly (increased sensitivity)

 REVERSAL AGENT

 Flumazenil

Mechanism:

• Competitive antagonist at GABA-A receptor

Dose:

• 0.2 mg IV increments

 Risks:

• Seizures (especially in chronic benzo users)

 MIDAZOLAM VS OTHER ICU SEDATIVES