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Introduction

  1. Pharmacology
    1. Dexmedetomidine is a potent alpha2-adrenergic receptor agonist. It shares structural and functional similarities with clonidine; however, the alpha2:alpha1 specificity ratio is eight times higher for dexmedetomidine. In addition, dexmedetomidine has more affinity for the alpha2A and alpha2C receptor subtypes, making it more effective than clonidine for sedation and analgesia. It can provide sedation with limited effects on respiratory function. The sympatholytic effects are mediated via neuronal presynaptic alpha2 receptors that provide negative feedback to reduce synaptic transmission.
    2. When given as an intravenous loading dose, followed by continuous infusion, the onset of action is 5-10 minutes and peak concentrations are achieved within 1 hour.
    3. The drug is rapidly distributed in a two-compartment model to a steady-state volume of distribution (Vd) of 118-152 L. Dexmedetomidine is 94% protein bound and has a distributional half-life of approximately 6 minutes following IV bolus and an elimination half-life of 2-2.67 hours.
    4. Dexmedetomidine undergoes complete biotransformation to inactive metabolites via N-glucuronidation, N-methylation, and hydroxylation primarily via CYP P450 2A6.
  2. Indications
    1. Sedation of intubated and mechanically ventilated adults. While labeling indicates use should not exceed 24 hours, safety and efficacy has been demonstrated during infusion of up to 5 days.
    2. Sedation of non-intubated patients prior to and/or during surgical and other procedures.
    3. Common uses include sedation for critically ill patients; sedation for minimally invasive procedures; premedication for surgery; opioid, benzodiazepine, ethanol and cocaine withdrawal states; fentanyl or sufentanil-induced cough; postanesthetic shivering; and awake craniotomy. It may have potential neuroprotective use in neurological surgery due to its stable hemodynamics.
  3. Contraindications
    1. No specific contraindications exist. However, dose reductions and caution are advised in patients with impaired liver function, those older than 65 years and patients with advanced heart block and/or severe ventricular dysfunction.
  4. Adverse effects
    1. Bradycardia and hypotension are the most common dose-dependent and clinically important adverse effects. Hypotension may be preceded by a brief phase of hypertension.
    2. Most adverse effects occur during or shortly after the loading dose and may be minimized by slowing or omitting the loading dose. More pronounced effects may occur in patients older than 65 years and those with diabetes mellitus, advanced heart block, chronic hypertension, hypovolemia, and/or ventricular dysfunction.
    3. There are post-marketing reports of other cardiovascular (atrial fibrillation, AV block, ventricular arrhythmias), CNS (agitation, confusion, delirium, convulsions), and respiratory (apnea, bronchospasm, pulmonary congestion) adverse effects.
    4. Abrupt cessation of dexmedetomidine infusion may result in rebound tachycardia and/or hypertension. Other drug withdrawal symptoms including nausea, vomiting, and agitation have been reported.
    5. Administration greater than 24 hours may lead to tachyphylaxis requiring higher doses.
    6. Use in pregnancy. FDA Category C. No human data exists for use during labor, pregnancy, or lactation.
  5. Drug or laboratory interactions
    1. Use caution when administering dexmedetomidine with other drugs known to cause bradycardia or hypotension.
    2. Despite the high protein binding of dexmedetomidine, no significant displacement of warfarin, phenytoin, digoxin, theophylline, or propranolol was evident when studied.
  6. Dosage and method of administration
    1. Intravenous loading dose is 1 mcg/kg (children: 0.25-1 mcg/kg) over 10 minutes (procedural sedation: 0.5 mcg/kg), followed by continuous infusion of 0.2-0.7 mcg/kg/h.
      1. Note: Significant dosing errors have occurred due to misinterpretation of dosing units. Manufacturer's continuous infusion recommendations are expressed in mcg/kg per hour, not per minute.
      2. Reduce dose in patients older than 65 years or with hepatic impairment.
    2. Intranasal doses for procedural or preoperative sedation is 1 mcg/kg (children: 1-2.5 mcg/kg) administered bilaterally (one half in each nostril). Onset is 45-60 minutes, although faster when using an atomizer.
    3. Intramuscular doses of 0.5-1.5 mcg/kg are used as adjunct therapy 1 hour prior to surgery.
    4. Intrathecal doses of 10 mcg have been used as a sensory and motor nerve block for abdominal and lower limb surgery.
    5. Epidural administration for postoperative pain is 0.5-1.5 mcg/kg.