Dexmedetomidine might be the sedative agent of choice.
Introduction: ED physicians regularly perform procedural sedation for painful or invasive procedures. Many factors influence the choice of sedating agent, such as safety and efficacy, but also drug shortages, a push to reduce use of opioid analgesia and the need to quickly see rising patient volumes. The “ideal” sedative agent should have rapid onset, short duration, predictable efficacy, minimal adverse effect and simple administration. Unfortunately, no such perfect agent exists. All agents require a careful balance of understanding of efficacy, intended effects, and potential harm.
The 2014 ACEP Clinical Policy on Procedural Sedation and Analgesia (PSA) offers several evidence-based recommendations on selecting an agent for use in the ED. Routine agents for procedural sedation in the ED include: propofol, ketamine, etomidate, opiates and benzodiazepines. Short-acting sedative agents are ideal, as they provide shorter periods of impaired consciousness, less potential for respiratory depression and reduction in necessary monitoring time.[1] Current literature suggests some of the most commonly used agents are associated with respiratory adverse events leading to an interventions up to 50% of the time. The desire for minimal respiratory depression has led to interest in recent years in short-acting sedatives with novel mechanisms of action, such as dexmedetomidine. Though a potent sedative with anxiolytic and analgesic effects, potential for respiratory depression is virtually nonexistent.[2]
Notable history: Dexmedetomidine was initially approved by the FDA in 1999 as a short-term sedative for mechanically ventilated, critically ill patients. It has been widely used and studied in the anesthesia and critical care practice arenas since that time for a variety of indications including: continuous sedation and analgesia, ICU delirium prevention and management, alcohol and drug withdrawal syndromes, attenuation of cardiovascular effects of acute stimulant intoxication, neuroaxial and regional anesthesia, and to enhance ventilator synchrony in awake intubation. Recently, there is growing interest in expanding its use for sedation and analgesia in adult and pediatric patients undergoing short, minimally invasive surgical and diagnostic procedures.
How it works: Dexmedetomidine is an imidazole compound that is a highly selective central alpha-2 adrenergic agonist that binds all three subtypes (A, B and C) of the alpha-2 adrenergic receptors in the brain. It is similar to clonidine, but 8-10 times more specific for the central alpha-2 receptor. Dexmedetomidine induces sedation by in the locus ceruleus, thus increasing the activity of inhibitory GABA neurons in the CNS. Its selectivity for CNS receptors allows it to provide moderate semi-arousable sedation that mirrors the non-REM phase of natural sleep, without excessive respiratory depression or vasodilation. It has minimal amnestic effect in comparison to some other sedatives.
Unlike other hypnotic agents like propofol, dexmedetomidine can be used as an adjunct medication to help decrease the opioid requirements of people in pain while still providing similar analgesia. Intravenous dexmedetomidine exhibits linear pharmacokinetics with a half-life of six minutes and a terminal elimination half-life of approximately two hours. [3-5]
Use in conjunction with ketamine: Dexmedetomidine monotherapy may not be ideal for procedural sedation because of the delayed recovery time, and it has limited analgesia and amnesia. There is growing interest in combination of dexmedetomidine with ketamine, sometimes called “ketadex.” Both anecdotal experience and few pilot studies demonstrate the utility and rationale for combination therapy. When used in combination, dexmedetomidine may limit the tachycardia, hypertension, sialorrhea and dissociative side effects associated with ketamine. [6-9] The rapid onset of ketamine allows for quick sedation, while its stimulation of increased sympathetic nervous system outflow prevents the bradycardia and hypotension that has been reported with dexmedetomidine. [10] Literature on a dexmedetomidine-ketamine combination is limited, but promising. A recent pilot study showed high rates of procedural success with minimal adverse effect. [11] Additional randomized-control trials with direct comparison to other sedation regimens will assist in further delineating the role for dexmedetomidine-ketamine combinations in procedural sedation.
Dosing and administration: Initial trials and product labeling of dexmedetomidine alone call for a loading dose 1mcg/kg over 10 minutes, followed by a 0.2-0.7mcg/kg/hr infusion for continuous sedation. The limited dosing recommendations within the labeling exist due to lack of studies outside this range, rather than due to evidence of safety concerns.
Procedural sedation dosing is variable in the literature, but is most commonly done as a 1mcg/kg bolus dose, followed by infusion if additional sedation is needed. When combined with ketamine, the most common regimen is a 1 mg/kg bolus of ketamine and 1 mcg/kg bolus of dexmedetomidine. These may be combined in 100 mL of normal saline and administered over 10 minutes. If further sedation is needed, a dexmedetomidine infusion at 1 mcg/kg/hr and intermittent 0.25-0.5 mg/kg ketamine boluses may be administered as needed every 10-15 minutes until the procedure is complete.
Adverse Events: The most commonly reported adverse reaction with intravenous dexmedetomidine is bradycardia and hypotension. These effects may be dose dependent or cumulative when the drug is used in conjunction with other sedatives that share these adverse effects. Several studies and case reports have shown both bolus and continuous infusion at the doses described above to be safe and efficacious with minimal potential for adverse effects. Use should be avoided in patients taking beta blockers and those with significant hepatic dysfunction.
The bottom line: As a short acting sedative with minimal potential for adverse effect, dexmedetomidine has promising potential for use in ED procedural sedation, particularly in combination with ketamine. Additional studies are warranted, but it could be considered as a viable alternative, particularly when there are shortages of alternative drugs.
Cost: Dexmedetomidine 200mcg vials cost $40 to $100.
References
- Godwin SA, et al. Clinical Policy: Procedural Sedation and Analgesia in the Emergency Department. Ann Emerg Med. 2014;63:2.247-58.
- Jewett J, Phillips WJ. Dexmedetomidine for procedural sedation in the emergency department. Eur J Emerg Med. 2010;17:60.
- Kaur M, Singh PJ. Current role of dexmedetomidine in clinical anesthesia and intensive care. Anesth Essays Res. 2011;5(2): 128–133.
- Gerlach A, Dasta J. Dexmedetomidine: An Updated Review. Annals of Pharmacotherapy 2007; 41:245-253.
- Nelson LE, Lu, J, Guo T, et al. The alpha2-adrenoceptor agonist dexmedetomidine converges on an endogenous sleep-promoting pathway to exert its sedative effects. Anesthesiology. 98 (2): 428–436
- Upadhyay SP, Singh AK, Varma M, et al. Procedural Sedation and Analgesia in Emergency Department: A Review and Update. J Pain Relief. 2016;5(5):270.
- Joseph DT (2012) Dexmedetomidine and Ketamine An Effective Alternative for Procedural Sedation? PediatrCrit Care Med 13: 423-427
- Mahmoud M, Tyler T, Sadhasivam S (2008) Dexmedetomidine and ketamine for large anterior mediastinal mass biopsy. PaediatrAnaesth 18: 1011-1013
- Tobias J. Dexmedetomidine and Ketamine: An Effective Alternative for Procedural Sedation? Pediatric Crit Care Med 2012; 13(4):423-27.
- Levänen J, Mäkelä ML, Scheinin H (1995) Dexmedetomidine premedication attenuates ketamine-induced cardiostimulatory effects and postanesthetic delirium. Anesthesiology 82: 1117-1125.
- Woods RM, Miller PT, Prater NI, et al. Ketadex for adult procedural sedation in the emergency department: a pilot study. Annals of Emergency Medicine 2016;68:4 S80
