Current role of dexmedetomidine in clinical anesthesia and intensive care.

Dexmedetomidine is a new generation highly selective α2-adrenergic receptor (α2-AR) agonist that is associated with sedative and analgesic sparing effects, reduced delirium and agitation, perioperative sympatholysis, cardiovascular stabilizing effects, and preservation of respiratory function. The aim of this review is to present the most recent topics regarding the advantages in using dexmedetomidine in clinical anesthesia and intensive care, while discussing the controversial issues of its harmful effects.

INTRODUCTION

α2-adrenergic receptor (α2-AR) agonists have been successfully used in several clinical settings in view of diverse actions which include sedation, analgesia, anxiolysis, perioperative sympatholysis, cardiovascular stabilizing effects, reduced anesthetic requirements, and preservation of respiratory function.[1] Dexmedetomidine is a relatively new drug approved at the end of 1999 by the Food and Drug Administration (FDA) for humans use for short-term sedation and analgesia (<24 hours) in the intensive care unit (ICU). Dexmedetomidine is a useful sedative agent with analgesic properties, hemodynamic stability and ability to recover respiratory function in mechanically ventilated patients facilitating early weaning.[2] Besides being a new modality of sedation and analgesia in ICU patient management,[3] it has been studied in several other perioperative settings, which will be discussed.

CHEMICAL STRUCTURE

Dexmedetomidine is the dextrorotatory S-enantiomer of medetomidine, an agent used in veterinary medicine.[4] It is chemically (S)-4-[1-(2,3-dimethylphenyl) ethyl]-3H-imidazole [Figure 1].

Figure 1

Chemical structure of dexmedetomidine

MECHANISM OF ACTION

α2-AR agonists produce clinical effects after binding to G-Protein-coupled α2-AR, of which there are three subtypes (α2A, α2B, and α2C) with each having different physiological functions and pharmacological activities. These receptor subtypes are found ubiquitously in the central, peripheral, and autonomic nervous systems, as well as in vital organs and blood vessels.[5] Dexmedetomidine is 8 to 10 times more selective towards α2-AR than clonidine.[6] Neither clonidine nor dexmedetomidine is totally selective for any one of the α2-AR subtypes, but dexmedetomidine seems to have higher α2A-AR and α2C-AR affinity than clonidine.[7] Major differences in the pharmacology of clonidine and dexmedetomidine have been described in [Table 1].

Table 1

Comparison of clonidine with dexmedetomidine

Locus ceruleus of the brain stem is the principal site for the sedative action and spinal cord is the principal site for the analgesic action, both acting through α2A-AR. In the heart, the dominant action of α2-AR agonists is a decrease in tachycardia (through blocking cardioaccelerator nerve) and bradycardia via α2A-AR (through a vagomimetic action). In the peripheral vasculature, there is sympatholysis-mediated vasodilatation and smooth muscle cells receptor-mediated vasoconstriction.[8] The mechanism for the antishivering and diuretic actions has yet to be established firmly[9] [Figure 2].

Figure 2

Physiology of various α2-adrenergic receptors

The responses to activation of the receptors in other areas include decreased salivation, decreased secretion, and decreased bowel motility in the gastrointestinal tract; contraction of vascular and other smooth muscle; inhibition of renin release, increased glomerular filtration, and increased secretion of sodium and water in the kidney; decreased intraocular pressure; and decreased insulin release from the pancreas.[10] Combining all these effects, dexmedetomidine avoids some of the side effects of multiagent therapies.

PHARMACOKINETICS

Absorption and distribution

Dexmedetomidine exhibits linear pharmacokinetics in the recommended dose range of 0.2 to 0.7 μg/ kg/ hr administered as intravenous infusion up to 24 hours. The distribution phase is rapid, with a half-life of distribution of approximately 6 minutes and elimination half life of 2 hours. The steady-state volume of distribution is 118 L. The average protein binding is 94% and is constant across the different plasma concentrations and also similar in males and females. It has negligible protein binding displacement by drugs commonly used during anesthesia and in the ICU like fentanyl, ketorolac, theophylline, digoxin, and lidocaine.[10] Context-sensitive half life ranges from 4 minutes after a 10-minute infusion to 250 minutes after an 8-hour infusion. Oral bioavailability is poor because of extensive first-pass metabolism. However, bioavailability of sublingually administered dexmedetomidine is high (84%), offering a potential role in pediatric sedation and premedication.[11]

Metabolism and excretion

Dexmedetomidine undergoes almost complete biotransformation through direct N-glucuronidation and cytochrome P-450 (CYP 2A6)-mediated aliphatic hydroxylation to inactive metabolites. Metabolites are excreted in the urine (about 95%) and in the feces (4%).[10] Dose adjustments are required in patients with hepatic failure because of lower rate of metabolism.

CLINICAL PHARMACOLOGY

Cardiovascular system

Dexmedetomidine evokes a biphasic blood pressure response: A short hypertensive phase and subsequent hypotension. The two phases are considered to be mediated by two different α2-AR subtypes: the α-2B AR is responsible for the initial hypertensive phase, whereas hypotension is mediated by the α2A-AR.[12] In younger patients with high levels of vagal tone, bradycardia and sinus arrest have been described which were effectively treated with anticholinergic agents (atropine, glycopyrrolate).

Central nervous system

Dexmedetomidine reduces cerebral blood flow and cerebral metabolic requirement of oxygen but its effect on intracranial pressure (ICP) is not yet clear. Dexmedetomidine modulates spatial working memory, enhancing cognitive performance besides having sedative, analgesic, and anxiolytic action through the α2-AR.[13] Studies suggest the likelihood of its neuroprotective action by reducing the levels of circulating and brain catecholamines and thus balancing the ratio between cerebral oxygen supplies, reducing excitotoxicity, and improving the perfusion in the ischemic penumbra. It reduces the levels of the glutamate responsible for cellular brain injury, especially in subarachnoid hemorrhage.[14] It has been shown to limit the morphologic and functional effects after ischemic (focal and global) and traumatic injury to the nervous system.

Respiratory effects

Dexmedetomidine affect on respiration appears to be similar in order of magnitude to those seen in the heavy sleep state.[15] Dexmedetomidine does not suppress respiratory function, even at high doses.[16] It has no adverse effects on respiratory rate and gas exchange when used in spontaneously breathing ICU patients after surgery.[15] It helps in maintaining sedation without cardiovascular instability or respiratory drive depression and hence may facilitate weaning and extubation in trauma/surgical ICU patients who have failed previous attempts at weaning because of agitation and hyperdynamic cardiopulmonary response.[217]

Endocrine and renal effects

Dexmedetomidine activates peripheral presynaptic α2- AR which reduces the release of catecholamines, and hence reduces sympathetic response to surgery.[18] Animal studies have demonstrated the occurrence of natriuresis and diuresis. Dexmedetomidine is an imidazole agent but unlike etomidate, it does not appear to inhibit steroidogenesis when used as an infusion for short-term sedation.[19]

ADVERSE EFFECTS

The various reported side effects are hypotension, hypertension, nausea, vomiting, dry mouth, bradycardia, atrial fibrillation, pyrexia, chills, pleural effusion, atelectasis, pulmonary edema, hyperglycemia, hypocalcaemia, acidosis, etc. Rapid administration of dexmedetomidine infusion (Loading dose of 1 μ/ kg/ hr if given in less than 10 minutes) may cause transient hypertension mediated by peripheral α2B- AR vasoconstriction.[5] But hypotension and bradycardia may occur with ongoing therapy mediated by central α2A-AR, causing decreased release of noradrenaline from the sympathetic nervous system. Long-term use of dexmedetomidine leads to super sensitization and upregulation of receptors; so, with abrupt discontinuation, a withdrawal syndrome of nervousness, agitation, headaches, and hypertensive crisis can occur.[20] Dexmedetomidine is not recommended in patients with advanced heart block and ventricular dysfunction.[5] FDA has classified it as a category C pregnancy risk, so the drug should be used with extreme caution in women who are pregnant.

CLINICAL APPLICATIONS OF DEXMEDETOMIDINE

Premedication

Dexmedetomidine is used as an adjuvant for premedication, especially in patients susceptible to preoperative and perioperative stress because of its sedative, anxiolytic, analgesic, sympatholytic, and stable hemodynamic profile. Dexmedetomidine decreases oxygen consumption in intraoperative period (up to 8%) and in postoperative period (up to 17%).[21] Premedication dose is 0.33 to 0.67 mg/kg IV given 15 minutes before surgery (this dose minimizes side effects of hypotension and bradycardia).

Intraoperative use

Dexmedetomidine attenuates hemodynamic stress response to intubation and extubation by sympatholysis.[1522-24] In view of absent respiratory depression, it can be continued at extubation period unlike other drugs. Dexmedetomidine potentiates anesthetic effect of all the anesthetic agents irrespective of the mode of administration (intravenous, inhalation, regional block). Intraoperative administration of dexmedetomidine in lower concentrations has reduced the requirement of other anesthetic agents; fewer interventions to treat tachycardia; and a reduction in the incidence of myocardial ischemia.[23] However, side effects like bradycardia and hypotension are limitations to its use necessitating need for pharmacological rescue therapy. These effects may be attributed to the combined properties of volatile anesthetics such as vasodilatation and myocardial depression. Dexmedetomidine administered in high concentrations may cause systemic and pulmonary hypertension because of direct peripheral vascular effects or may compromise myocardial function and blood pressure.

Locoregional analgesia

Highly lipophilic nature of dexmedetomidine allows rapid absorption into the cerebrospinal fluid and binding to α2-AR of spinal cord for its analgesic action. It prolongs the duration of both sensory and motor blockade induced by local anesthetics irrespective of the route of administration (e.g., epidural,[25] caudal,[26] or spinal[27] ). Dexmedetomidine though enhances both central and peripheral neural blockade by local anesthetics;[27] however, the peripheral neural blockade is due to its binding to α2A-AR.[28] Dexmedetomidine has been successfully used in intravenous regional anesthesia (IVRA),[29] brachial plexus block,[30] and intraarticularly.[3132] Addition of 0.5 μg/kg dexmedetomidine to lidocaine for IVRA improves quality of anesthesia and improves intraoperative-postoperative analgesia without causing side effects.[29] Dexmedetomidine added to levobupivacaine for axillary brachial plexus block shortens the onset time and prolongs the duration of the block and postoperative analgesia.[30] Intraarticular dexmedetomidine in patients undergoing arthroscopic knee surgery improves the quality and duration of postoperative analgesia.[3132]

Sedation in intensive care unit

Dexmedetomidine has become popular sedative agent in ICU because of its ability to produce cooperative sedation, i.e., patients remain awake, calm, and are able to communicate their needs. It does not interfere with the respiratory drive or produce any agitation, hence facilitating early weaning from ventilator, thereby reducing overall ICU stay costs.[33] The maintenance of natural sleep during sedation might speed recovery time in the ICU. Dexmedetomidine currently is approved by FDA for use in ICU for not more than 24 hours; though many studies have reported its safe use for longer duration.[34] Dexmedetomidine, when compared with conventional sedatives and opiates [Table 2], has been demonstrated to be associated with both sedative and analgesic sparing effects, reduced delirium and agitation, minimal respiratory depression, and desirable cardiovascular effects.[23536]

Table 2

Comparison of dexmedetomidine with other ICU sedatives

Procedural sedation

Dexmedetomidine is an attractive agent for short-term procedural sedation and has been safely used in transesophageal echocardiography,[37] colonoscopy,[38] awake carotid endarterectomy,[39] shockwave lithotripsy,[34] vitreoretinal surgery,[40] elective awake fiberoptic intubation,[41] pediatric patients undergoing tonsillectomy,[42] and pediatric MRI.[43] The usual dose of dexmedetomidine for procedural sedation is 1 μg/ kg, followed by an infusion of 0.2 μg/kg/h. Its onset of action is less than 5 minutes and the peak effect occur within 15 minutes. As the pharmacologic effects of dexmedetomidine can be reversed by the α2-AR antagonist atipamezole,[44] dexmedetomidine provides a titratable form of hypnotic sedation that can be readily reversed.

Controlled hypotension

Dexmedetomidine is an effective and safe agent for controlled hypotension mediated by its central and peripheral sympatholytic action. Its easy administration, predictability with anesthetic agents, and lack of toxic side effect while maintaining adequate perfusion of the vital organs makes it a near-ideal hypotensive agent. Spinal fusion surgery for idiopathic scoliosis,[45] septoplasty and tympanoplasty operations,[46] and maxillofacial surgery[47] have been safely done with dexmedetomidine-controlled hypotension.

Analgesia

Dexmedetomidine activates α2-AR in the spinal cord reducing transmission of nociceptive signals like substance P. It has significant opioid sparing effect and is useful in intractable neuropathic pain.[14]

Cardiac surgery

Dexmedetomidine in addition to blunting the hemodynamic response to endotracheal intubation also reduces the extent of myocardial ischemia during cardiac surgery.[48] Dexmedetomidine has been successfully used to manage patients with pulmonary hypertension undergoing mitral valve replacement, with reduction in pulmonary vascular resistance, pulmonary artery pressure, and pulmonary capillary wedge pressures.[5]

Neurosurgery

Dexmedetomidine provides stable cerebral hemodynamics without sudden increase in ICP during intubation, extubation, and head pin insertion. It attenuates neurocognitive impairment (delirium and agitation) allowing immediate postoperative neurological evaluation. It exerts its neuroprotective effects through several mechanisms which make the usage of this drug a promising tool during cerebral ischemia.[14] It does not interfere with neurological monitors[5] and has an upcoming role in “functional” neurosurgery. This includes awake craniotomy for the resection of tumors or epileptic foci in eloquent areas, and the implantation of deep brain stimulators for Parkinson's disease.[5]

Obesity

Dexmedetomidine does not cause respiratory depression and has been infused at a dose of 0.7 μg/kg intraoperatively to avoid respiratory depression due to narcotic usage in a morbidly obese patient.[49]

Obstetrics

Dexmedetomidine has been successfully used as an adjunct to unsatisfactory analgesia by systemic opioids in laboring parturients who could not benefit from epidural analgesia.[50] It provides maternal hemodynamic stability, anxiolysis, and stimulation of uterine contractions. It is retained in placental tissue and passes less readily into the fetal circulation than clonidine because of high lipophilicity and thereby has less susceptibility to cause fetal bradycardia.

Pediatrics

It is currently being used off-label as an adjunctive agent in pediatric patients for sedation and analgesia in the critical care unit and for sedation during noninvasive procedures in radiology like computed tomography and magnetic resonance imaging.[43]

Other uses

The literature suggests other potential uses for dexmedetomidine, for example

Dexmedetomidine has been used successfully in the treatment of withdrawal from benzodiazepines, opioids, alcohol, and recreational drugs.

As an adjunct in otorhinolaryngology anesthesia for middle ear surgery and rhinoplasty.

As an adjunct in the repair of aortic aneurysms.

Management of tetanus in ICU.

As an antishivering agent.

Dexmedetomidine is effective in preventing ethanol-induced neurodegeneration.

CONCLUSION

Dexmedetomidine because of its unique properties offers its promising use in wide spectrum of clinical settings and ICUs. It is a part of fast-tracking anesthesia regimens and offers anesthetic sparing and hemodynamic stabilizing effects. As pharmacological effects of dexmedetomidine can be reversed by α2-AR antagonist atipamezole, combination of dexmedetomidine and atipamezole can provide titratable form of sedation in the future.