Pain, Agitation/Sedation, Delirium, Immobility, Sleep Disruption, and Neuromuscular Blockade

Dexmedetomidine provides a hypnotic and sedative effect by inhibition of norepinephrine release from

the locus coeruleus; dexmedetomidine also produces a weak antinociceptive effect by way of inhibition

of neuronal transmission through presynaptic C-fibers and release of substance P, and hyperpolarization

of postsynaptic α receptors in the dorsal horn of the spinal column. Dexmedetomidine does not

directly affect respiratory drive; therefore, intubation is not required with use. Dexmedetomidine is

considered a weak sedative and would not be appropriate for use when deep sedation is required (e.g.,

in a patient requiring neuromuscular blockade). Both anterograde amnesia and retrograde amnesia have

been described in some patients (20%–50%) in adult and pediatric studies. A benzodiazepine may be

required if full amnesia is desired because of the clinical scenario.

Pharmacokinetics: Hepatic by glucuronidation and renal excretion. Onset with loading dose 15–20

minutes; onset without loading dose greater than 20 minutes to 1 hour; terminal half-life = 3 hours (may

be significantly prolonged in hepatic impairment). Highly protein bound 94%.

Clinical effects: Sedation and weak opiate-sparing antinociceptive effects.

Dosing for ICU sedation: Optional loading dose 0.5–1 mcg/kg intravenously for 10 minutes, followed

by 0.2–0.7 mcg/kg/hour. The loading dose may initially cause severe tachycardia and hypertension, but

it can then quickly lead to significant bradycardia and/or hypotension secondary to receptor saturation.

Because of these untoward hemodynamic effects, the loading dose is rarely administered in clinical

ICU practice on initiation of dexmedetomidine, and the drip is usually initiated at 0.2–0.4 mcg/kg/

hour. For the maintenance infusion dose, randomized trials have safely used dexmedetomidine at

higher than manufacturer-recommended doses, up to 1.5 mcg/kg/hour. Clinical efficacy with doses

greater than 1.5 mcg/kg/hour remains unclear. Other routes of administration have been described for

dexmedetomidine, including intramuscular, subcutaneous, epidural, and intranasal.

Duration of use: Although the package insert recommends a therapy of 24 hours or less, randomized trials

have used dexmedetomidine for up to 5–7 days; thus, ICU clinicians often administer dexmedetomidine

for longer than 24 hours. Safety beyond 7 days of use has not been well established.

Data: The Dexmedetomidine to Lessen ICU Agitation (DahLIA) study was a double-blind placebo-

controlled, parallel-group randomized clinical trial in 15 ICUs in Australia and New Zealand in which 39

patients were randomized to dexmedetomidine and 32 patients to placebo. At 7 days, dexmedetomidine

increased ventilator-free hours compared with placebo (median, 144.8 hours vs. 127.5 hours, 95% CI

4 to 33.2 hours, p=0.01). Patients in the dexmedetomidine group had decreased time to extubation

compared with placebo (median 21.9 hours vs. 44.3 hours, 95% CI 5.3 to 3.1 hours, p<0.001). An

accelerated resolution of delirium was found in the dexmedetomidine group compared with placebo

(median, 23 hours vs. 40 hours, 95% CI, 3 to 28 hours, p=0.01). However, propofol use was common

in both groups after randomization (72% in the dexmedetomidine group vs. 88% in the placebo group)

(median cumulative dose 980 mg (IQR 280–3050) vs. 5390 mg (IQR 1880–10,803), p<0.001).

Data: The DESIRE trial was a open-label, multicenter randomized clinical trial conducted in eight ICUs

in Japan in which 100 patients with sepsis were randomized to dexmedetomidine and 101 patients with

sepsis were randomized to placebo. Mortality at 28 days was not different between the two groups (23%

in the dexmedetomidine group vs. 31% in the placebo group; HR 0.69; 95% CI, 0.38–1.22; p=0.20).

Ventilator-free days over 28 days were not different between groups (median 20 days (IQR 5–24) in the

dexmedetomidine group vs. 18 days (IQR 0.5–23) in the control group (p=0.20).