dexmed

Dexmedetomidine

Overview

Dexmedetomidine is the d-enantiomer of medetomidine
It is an a₂-adrenergic agonist that provides sedation, anxiolysis, hypnosis, analgesia, and sympatholysis with minimal respiratory depression
Dexmedetomidine has a 1600 greater selectivity for the a₂ receptor than for the a₁ receptor
Unique effects
o Titratable sedation
o Sympatholysis
o Analgesia
Dexmedetomidine is used for
o short-term sedation of mechanically ventilated patients in the ICU
o off-label use in the OR for sedation and analgesia
o off-label use for withdrawal/detoxification amelioration
Major Side Effects
o limited respiratory depression
o Hypotension
o Bradycardia

Pharmacokinetics

The pharmacokinetic profile of dexmedetomidine is best described using a three-compartment model
Important Pharmacokinetic Variables
o Vd_ss = 2-3 L/kg
o Clearance = 10-30 mL/kg/min
o Alpha Elimination Half-life = 8-9 min
o Beta Elimination Half-life = 2-3 hours
o 94% protein bound
Metabolism
o extensively metabolized in the liver ® it undergoes conjugation, n-methylation or hydroxylation followed by conjugation, and is excreted in the urine and feces
Dexmedetomidine is freely soluble in water, and is rapidly distributed
Dexmedetomidine may alter its own pharmacokinetics ® large doses cause marked vasoconstriction, thus reducing its V_d
Pharmacokinetic parameters are unaltered by age, weight, or renal failure
Context sensitive half-time ranges from 4 min after a 10 min. infusion to 250 min. after an 8 hour infusion

Pharmacodynamics

CNS
o Dexmedetomidine causes sedation and hypnosis by acting on a₂ receptors in the locus caeruleus, and analgesia by acting on a₂ receptors in the locus caeruleus and spinal cord (primary site of analgesic action). Dexmedetomidine also acts through endogenous sleep-promoting pathways to induce LOC
o Sedation from dexmedetomidine is different from that caused by sedatives acting on GABA receptors ® patients on dexmedetomidine are
§ Easy to wake up
§ Have the ability to follow commands and cooperate while being intubated
§ if undisturbed will fall back asleep immediately
o Dexmedetomidine is narcotic sparing when used systemically. Postoperative ICU patients on a dexmedetomidine drip have a 50% reduction in opiate requirements
§ HOWEVER, analgesia may be confounded by sedation, as several studies show conflicting results regarding the analgesic properties of dexmedetomidine. Therefore, opiates should be co-administered with dexmedetomidine if analgesia is required
o Patients on a₂ agonists exhibit tolerance after prolonged administration
o Dexmedetomidine may be used for addiction treatment
§ rapid opioid detoxification
§ cocaine withdrawal
§ iatrogenic induced BDZ and opioid tolerance after prolonged sedation
Respiratory system_•o Dexmedetomidine slighty reduces minute ventilation, but maintains hypercarbic ventilatory response
o Respiratory rate may increase
o In healthy volunteers, there was no change in arterial oxygenation or pH with administration of dexmedetomidine
Cardiovascular system
o There is a biphasic response to the administration of dexmedetomidine ® initial increase in BP and a decrease in HR due to vasoconstrictive effects of dexmedetomidine by stimulating peripheral a₂ receptors. Initial effects are followed by a gradual decrease in BP to below baseline by 1 hour post injection, and HR returns to baseline by 15 min.
§ Giving a loading dose over a 20 min. period decreases the transient hypertension
o Rarely dexmedetomidine can cause severe bradycardia and even sinus arrest, but both are either spontaneously resolved or can be reversed by anticholinergics

Uses

Sedation in the ICU
o Advantages over propofol for sedation in intubated patients in the ICU
§ Patients on dexmedetomidine required significantly less narcotics (>50% reduction)
§ HR was slower in the dexmedetomidine group, but MAP was similar
§ The PaO₂/FIO₂ ratio was higher in the dexmedetomidine group
§ Time to extubation after d/c of infusion was similar at 28 min.
§ Patients on dexmedetomidine had greater recall of their stay in the ICU, but their stay was "pleasant"
§ More stable hemodynamics with weaning of sedation on dexmedetomidine
§ Dexmedetomidine was associated with less delirium than lorazepam in sedated ICU patients
o Can be used for successful weaning of patients from the ventilator due to its adequate sedation without respiratory depression
o Dose: infusion rate of 0.1-1 mg/kg/hr
Treatment of Withdrawal
o Dexmedetomidine has been used successfully in the treatment of withdrawal from BDZs, narcotics, alcohol, and recreational drugs.
o It is especially useful in ICU patients who develop withdrawal symptoms from prolonged use of BDZs and narcotics while in the ICU
Anesthesia
o Premedication dose ® 0.33-0.67 mg/kg IV given 15 min. before surgery (this dose minimizes side effects of hypotension and bradycardia)
o It reduces the requirements of volatile anesthetics by about 25% and more effectively attenuates the hemodynamic response to endotracheal intubation than fentanyl
o Intraoperative sedation ® dexmedetomidine had slower onset and termination of effect than propofol but had similar cardiorespiratory effects
o Maintenance of anesthesia
§ Balanced anesthesia with desflurane or propofol plus dexmedetomidine (0.5-0.8 mg/kg bolus then 0.4 mg/kg/hr) reduces postoperative pain scores and morphine consumption and improves hemodynamics when compared to desflurane-fentanyl or propofol-fentanyl
§ Dexmedetomidine is a promising anesthetic adjunct or sedative agent in patients who are susceptible to narcotic-induced respiratory depression or sleep apena (obese patients)

Side Effects/Contraindications

Common Side Effects
o Transient HTN and bradycardia
o Mild respiratory depression
o Patients may develop tolerance to dexmedetomidine after prolonged administration
o Rare Side Effects
o Severe bradycardia or sinus arrest
o Severe Hypotension

Anesthesiology Rotation & Elective

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Last modified on March 30, 2010