Updated: May 19, 2022
Annatasha Bartel DVM DACVAA
Dexmedetomidine is a highly selective alpha-2 agonist, often used in veterinary medicine for its excellent sedative and analgesic effects. Dexmedetomidine is the dextrorotatory isomer of medetomidine and is the active component of the racemic drug. Peak sedation occurs ~10 minutes after IV administration and peak analgesia ~20 minutes in dogs and cats. Both sedation and analgesia can last 40-90 minutes, although there are reports of sedation persisting for up to three hours in some patients. Dexmedetomidine also has a profound effect on MAC reduction; it can reduce the amount of inhalant required for dogs by 59-88% when given as an infusion or as a high dose IV bolus. Cats also demonstrate dose-dependent reduction in MAC values when dexmedetomidine is infused, although this may not result in improved hemodynamics in this species.
Mechanism of Action
Dexmedetomidine is an agonist of the alpha-2 adrenoceptor, a transmembrane G-protein coupled receptor. Activation of the alpha-2 adrenoceptor inhibits adenylyl cyclase, which causes an intracellular decrease of cAMP and activation of the inwardly rectifying potassium channel. This leads to an efflux of K+ and inhibition of voltage-gated Ca2+channels, causing cell membrane hyperpolarization. This in turn suppresses neuronal firing and ascending noradrenergic activity. Fundamentally, the occupancy of the alpha-2 receptors by dexmedetomidine reduces the release of norepinephrine presynaptically through a negative feedback loop mechanism. This prevents firing of the pathways that contribute to consciousness and nociception and is the mechanism by which sedation and analgesia are achieved.
A classic biphasic cardiovascular response is described following administration of alpha-2 agonists. Binding of the alpha-2 agonist to post synaptic alpha-2 receptors in the vasculature causes peripheral vasoconstriction, which is often observed as acute blanching of the mucous membranes and transient loss of distal peripheral pulses. Vasoconstriction extends to the pulmonary and coronary vasculature as well. The increase in systemic vascular resistance leads to a reflex decrease in heart rate and therefore cardiac output. Myocardial contractility is not directly affected. With time, peripheral vasoconstriction fades and the central sympatholytic effects predominate leading to continued bradycardia and vasodilation.
Dexmedetomidine administration slows conduction through the atrioventricular node which is why one may observe 1st or 2nd degree atrioventricular block with the use of dexmedetomidine. The cardiovascular effects of alpha-2 agonists are only partially dose-dependent, reaching maximal effect at relatively low IV doses (probably ~2-3 mcg/kg). As such, a higher dose does not induce a proportionally higher impedance of cardiac output, e.g. a 3 mcg/kg IV dose would result in the same cardiovascular effects as a 10 mcg/kg IV dose. However, “micro” doses (0.5 mcg/kg IV or less) and slow IV infusions (up to 1 mcg/kg/hr) do not cause bradycardia or confer a drop in cardiac output.
Blood flow to the brain, heart, kidneys, and liver is not directly impacted by dexmedetomidine, i.e. blood is not shunted away from these vascular beds. There is, however, an overall reduction in local organ circulation and perfusion secondary to the fall in cardiac output, e.g. hepatic and renal blood flow can be reduced as a consequence of cardiac impedance. As there is also a general fall in oxygen demand in a stable sedated or anesthetized patient, an oxygen debt is not incurred subsequent to the changes in tissue perfusion. Dexmedetomidine does shunt blood away from the gastrointestinal circulation, however, and should be used with caution in patients with severe GI compromise.
Ventilatory drive can be affected in patients administered dexmedetomidine. Although dexmedetomidine does not directly cause changes in minute and tidal volume in dogs and cats, it does obtund the normal reflexes to hypoxemia and hypercapnia that a healthy, non-sedated patient demonstrates. Care must also be taken when recovering a patient from sedation or anesthesia with dexmedetomidine as they cannot change their ventilatory pattern appropriately in recovery to meet their physiological oxygen demands. A patient sedated with dexmedetomidine should always be monitored for its ventilation and oxygenation and provided with intervention as needed, i.e. supplemental oxygen. Moreover, a primary compensation for hypoxemia is tachycardia and dexmedetomidine will suppress this compensatory mechanism, possibly fatally.
Other Organ Effects
Care should be taken with the use of dexmedetomidine in patients with altered intracranial hemodynamics. Intracranial pressure is largely unaffected although there is some increase in cerebral perfusion pressure. Some studies have shown a decrease in cerebral blood flow and therefore, oxygen delivery. There are no specific neurological contraindications as long as the delivery of oxygen to the brain is both understood and maintained. There is an increase in circulating glucose levels due to insulin antagonism at the level of the pancreas and often subsequent osmotic diuresis in the form of large volume and frequent urinations is observed. Dexmedetomidine also increases uterine motor activity, i.e. contractions, and impedes uterine blood flow, which is proportional to fetal oxygen delivery. Dexmedetomidine should be used cautiously, if at all, in pregnant and laboring patients.
Reversal of Dexmedetomidine
Atipamezole (Antisedan) is the most commonly used reversal agent for dexmedetomidine. However, reversal is not a benign process, nor does it always achieve the desired clinical outcome. Atipamezole, given IV in cats, has shown to cause acute and significant hypotension, which could be catastrophic in an unstable patient. When given IV, it can also cause seizure-like activity. This is why we primarily administer it via the intramuscular route. However, in cases of very low cardiac output or cardiopulmonary arrest, atipamezole should be given IV as there will be little uptake from an IM injection to central circulation. Often times, atipamezole is given to patients sedated with dexmedetomidine when their heart rate becomes inappropriately low. However, giving atipamezole often reverses the central effects of the drug, e.g. sedation and analgesia, but may not change the cardiovascular parameters. As such, the patient may stay bradycardic but become lighter.
A better course of action for treating the bradycardia is to raise the heart rate with either a lidocaine bolus or an anticholinergic. An anticholinergic is indicated if the patient is both hypotensive and bradycardic or more than 30 minutes have passed since the initial dose of dexmedetomidine; this helps mitigate the risk of hypertension.