Is a viable alternative sedative/hypnotic agent for procedural sedation in the ED?
Mark Estrellado MD, PGY3
Given the regularity of noninvasive and minimally invasive procedures that emergency physicians must perform on a daily basis, proficiency in the art of procedural sedation remains an indispensable component of their already broad repertoire of skills. And while every discussion on the topic of procedural sedation most often begins with the description of the “ideal sedative” as an inexpensive agent that is easily administered, has a rapid and predictable onset and dissipation of effect without prolonged accumulation despite repeated dosing, and is free of adverse side effects and drug interactions, no such agent exists. Instead, the ED physician’s current armamentarium consists of a handful of agents–namely benzodiazepines, opioids, propofol, ketamine, and etomidate–each of which have proven useful when taking into account each individual patient’s comorbidities and when utilized in the appropriate setting.3 Nevertheless, the issue of respiratory depression remains a constant concern, and this is where dexmedetomidine has garnered increasing attention over the last two decades as a potential addition to the current set of sedation agents.
Unlike its other sedative counterparts, dexmedetomidine exerts its effects primarily via presynaptic α-2 agonism resulting in lower levels of norepinephrine, and consequently, decreased sympathetic drive.1-2 This manifests in profound analgesia and sedation with decreased heart rate and blood pressure. Associated respiratory depression is virtually nonexistent, with maintenance of both rate and depth of ventilation.4 Given its respiratory profile, dexmedetomidine was originally used as a short-term sedative for mechanically vented critically ill patients.5 More recently, however, there seems to be a growing trend towards expanding its use for sedation and analgesia in adult and pediatric patients undergoing small, minimally invasive surgical and diagnostic procedures.
While evidence in the current literature is still modest at best, several experimental and observational studies suggest that dexmedetomidine may be just as efficacious, if not superior when compared to other sedative agents. Several case reports highlight the successful use of dexmedetomidine during airway surgical procedures (e.g. microlaryngeal surgery, bronchoscopy, laryngoscopy), where dexmedetomidine was either the sole anesthetic agent or supplemented with small doses of fentanyl and topical lidocaine. Recovery times in these reports were not prolonged compared to conventional anesthetics.6-7
A randomized, double-blind study compared dexmedetomidine with midazolam for intravenous sedation during dental surgery under local anesthesia. The study concluded that sedation with dexmedetomidine was comparable to midazolam, but also provided more “predictability” as it was associated with less “restlessness” and “disinhibition among patients.” While the majority of patients in the study did rate dexmedetomidine’s analgesic effect as satisfactory, however, researchers found its amnestic effects to be unreliable.8-10
In 56 patients undergoing endarterectomy with regional anesthesia, dexmedetomidine proved an acceptable alternative to sedation using midazolam and fentanyl, without showing superiority to conventional sedation techniques used during awake carotid endarterectomy.11
In another study by Kaygusus et al., the combination of dexmedetomidine with a small dose of fentanyl was used safely and effectively when compared to the standard propofol regimen used during extracorporeal shockwave lithotripsy.12
In the pediatric setting, dexmedetomidine has been garnering popularity as an alternative to propofol among nonanesthesiologists for sedation of children during diagnostic CT and MRI imaging. Comparative studies have seen an association between using higher doses of dexmedetomidine and higher rates of completion of imaging without the need to administer another sedative. One study found that utilizing higher doses of dexmedetomidine even resulted in shorter recovery times, which the authors attributed to the lower use of barbiturates for rescue sedation.13-14
Nevertheless, several controversies surrounding dexmedetomidine’s efficacy and safety profile have hindered its universal acceptance. Despite a growing number of positive studies, dexmedetomidine’s effectiveness as a sedative agent has not been uniformly successful, particularly for invasive procedures. For instance, in a prospective study where dexmedetomidine was used as the sole agent during cardiac catheterization in pediatric patients, investigators found that, not only did dexmedetomidine have a longer time of onset, but also more than half of the subjects required additional propofol boluses in order to facilitate successful cannulae placement.15 Concerns have also arisen regarding dexmedetomidine’s hemodynamic effects, especially when used in higher doses. As a case in point, in a randomized, single-blind study comparing the use of dexmedetomidine and fentanyl versus midazolam and meperidine for outpatient colonoscopies, Jalowiecki et al. reported a higher incidence of hypotension and bradycardia in the dexmedetomidine group, prompting the investigators to terminate the study prematurely.16 Given these issues, the addition of a second agent–ketamine–in conjunction with dexmedetomidine has been proposed by some as a more preferable alternative. An NMDA receptor antagonist, ketamine causes dose dependent direct stimulation of the CNS that leads to increased sympathetic nervous system outflow, manifesting as increases in systemic and pulmonary blood pressure, heart rate, and cardiac output without producing any significant respiratory depression.17 As such, ketamine may complement the limitations of dexmedetomidine as a sole anesthetic agent.
Current literature regarding the use of a dexmedetomidine-ketamine combination is severely limited at present, but the preliminary findings show some promise. A prospective randomized trial by Tosun et al. compared dexmedetomidine-ketamine to propofol-ketamine for pediatric patients with acyanotic congenital heart disease undergoing cardiac catheterization found that sedation was effective in both regimens without any clinically significant differences in hemodynamic stability or respiratory status between the two.18 However, the dexmedetomidine-ketamine group required more supplemental boluses of ketamine. Koruk et al. conducted a similar prospective investigation comparing dexmedetomidine-ketamine versus midazolam-ketamine during extracorporeal shockwave lithotripsy for pediatric patients, again showing that sedation was equally effective in both groups, with the incidence of nausea and vomiting significantly lower in the dexmedetomidine-ketamine group.19 Additional evidence regarding the potential utility of the dexmedetomidine-ketamine combination comes by way of small retrospective case series and anecdotal case reports, several of which attest to the achievement of a satisfactory level of sedation even in patients with significant comorbid conditions–e.g. obstructive sleep apnea, pulmonary hypertension–with minimal adverse effects observed.20-27
Overall, while the existing data is still insufficient to make any definitive conclusions at this time, the potential for the dexmedetomidine-ketamine combination to be a viable sedative/hypnotic alternative for procedural sedation is undeniable. From a theoretical standpoint, the two agents have the capacity to complement each other’s limitations. When used in tandem, dexmedetomidine may limit the tachycardia, hypertension, and “emergence phenomenon” commonly associated with ketamine. Conversely, ketamine may counteract the bradycardia and hypotension seen with dexmedetomidine and may help achieve a more rapid time of onset of sedation compared to dexmedetomidine alone. Ultimately, more large randomized-control trials must be conducted with direct comparisons to other commonly used regimens in order to gain a better sense of the impact, if any, that dexmedetomidine-ketamine will have in the practice of procedural sedation in the ED.
1) Scholz J, Tonner PH. α2-Adrenoceptor anesthesia: a new paradigm. Curr Opin Anaesthesiol 2000;13:437-42.
2) Chiu TH, Chen MJ, Yang YR, Yang JJ, Tang FL. Action of dexmedetomidine on rat locus coerleus neurons: intracellular recording in vitro. Eur J Pharmacol 1995;285:261-8.
3) Jacobi J, Fraser GL, Coursin DB, et al. Clinical practice guidelines for the sustained use of sedatives and analgesics in the critically ill adult. Crit Care Med. 2002;30:119–141
4) Bhana N, Goa KL, McClellan K. Dexmedetomidine. Drugs 2000;59: 263-8.
5) Dyck JB, Shafer SL. Dexmedetomidine pharmacokinetics and pharmacodynamics. Anaesthetic Pharmacology Review. 1993;1:238–245.
6) Jense RJ, Souter K, Davis J, Romig C, Panneerselvam A, Maronian N. Dexmedetomidine sedation for laryngeal framework surgery. Ann Otol Thinol Laryngol. 2008;117:659–664.
7) Ohata H, Tanemura E, Dohi S. Use of high-dose dexmedetomidine infusion for anesthesia and sedation in a patient for microlaryngeal surgery maintained with spontaneous breathing. Masui. 2008;57:428–432.
8) Ogawa S, Seino H, Ito H, Yamazaki S, Ganzberg S, Kawaai H. Intravenous sedation with low-dose dexmedetomidine: its potential for use in dentistry. Anesth Prog. 2008;55:82–88.
9) Cheung CW, Ying CLA, Chiu WK, Wong GTC, Ng KFJ, Irwin MG. A comparison of dexmedetomidine and midazolam for sedation in third molar surgery. Anaesthesia. 2007;62:1132–1138.
10) Ustun Y, Gunduz M, Erdogan O, Benlidayi ME. Dexmedetomidine versus midazolam in outpatient third molar surgery. J Oral Maxillofac Surg. 2006;64:1353–1358.
11) McCutcheon CA, Orme RM, Scott DA, Davies MJ, McGlade DP. A comparison of dexmedetomidine versus conventional therapy for sedation and hemodynamic control during carotid endarterectomy performed under regional anesthesia. Anesth Analg. 2006;102:668–675.
12) Kaygusuz K, Gokce G, Gursoy S, Ayan S, Mimaroglu C, Gultekin Y. A comparison of sedation with dexmedetomidine or propofol during shockwave lithotripsy: a randomized controlled trial. Anesth Analg. 2008;106:114–119.
13) Mason KP, Zurakowski D, Zgleszewski SE, et al. High dose dexmedetomidine as the sole sedative for pediatric MRI. Pediatr Anesth. 2008;18:403–411.
14) Koroglu A, Demirbilek S, Teksan H, Sagir O, But AK, Ersoy OM. Sedative, haemodynamic and respiratory effects of dexmedetomidine in children undergoing magnetic resonance imaging examination: preliminary results. Br J Anaesth. 2005;94:821–824.
15) Munro HM, Tirotta CF, Felix DE, et al. Initial experience with dexmedetomidine for diagnostic and interventional cardiac catheterization in children. Pediatr Anesth. 2007;17:109–112.
16) Jalowiecki P, Rudner R, Gonciarz M, Kawecki P, Petelenz M, Dziurdzik P. Sole use of dexmedetomidine has limited utility for conscious sedation during outpatient colonoscopy. Anesthesiology 2005;103:269-75.
17) J Albanèse, S Arnaud, M Rey, L Thomachot, B Alliez, C Martin Ketamine decreases intracranial pressure and electroencephalographic activity in traumatic brain injury patients during propofol sedation. Anesthesiology: 1997, 87(6);1328-34
18) Tosun Z, Akin A, Guler G, et al: Dexmedetomidine-ketamine and propofol-ketamine combinations for anesthesia in spontaneously breathing pediatric patients undergoing cardiac catheterization. J Cardiothor Vasc Anesth 2006; 20:515–519
19) Koruk S, Mizrak A, Gul R, et al: Dexmedetomidine-ketamine and midazolam-ketamine combinations for sedation in pediatric patients undergoing extracorporeal shock wave lithotripsy: A randomized prospective study. J Anesth2010; 24:858–863
20) Bozdogan N, Sener M, Caliskan E, et al: A combination of ketamine and dexmedetomidine sedation with caudal anesthesia during incarcerated inguinal hernia repair in three high-risk infants. Pediatr Anesth 2008; 18:1009–1011
21) Barton KP, Munoz R, Morell VO, et al: Dexmedetomidine as the primary sedative during invasive procedures in infants and toddlers with congenital heart disease. Pediatr Crit Care Med 2008; 9:612–615
22) Luscri N, Tobias JD: Monitored anesthesia care with a combination of ketamine and dexmedetomidine during magnetic resonance imaging in three children with trisomy 21 and obstructive sleep apnea. Pediatr Anesth 2006; 16:782–786
23) Iravani M, Wald SH: Dexmedetomidine and ketamine for fiberoptic intubation in a child with severe mandibular hypoplasia. J Clin Anesth 2008; 20:455–457
24) Mahmoud M, Tyler T, Sadhasivam S: Dexmedetomidine and ketamine for large anterior mediastinal mass biopsy.Pediatr Anesth 2008; 18:1011–1013
25) Munro HM, Felix DE, Nykanen DG: Dexmedetomidine/ketamine for diagnostic cardiac catheterization in a child with idiopathic pulmonary hypertension. J Clin Anesth 2009; 21:435–438
26) Rozmiarek A, Corridore M, Tobias JD: Dexmedetomidine-ketamine sedation during bone marrow aspirate and biopsy in a patient with duchenne muscular dystrophy. Saudi J Anaesth 2011; 5:219–222
27) Corridore M, Phillips A, Rabe A, et al: Dexmedetomidine-ketamine sedation in a child with a mediastinal mass.World J Pediatr Cong Heart Surg (in press)28)
28) Shukry M, Miller J: Update on dexmedetomidine: use in nonintubated patients requiring sedation for surgical procedures. Therapeutics and Clinical Risk Management 2010; 6:111-121
29) Gerlach A, Dasta J: Dexmedetomidine: An Updated Review. Annals of Pharmacotherapy 2007; 41:245-253
30) Tobias J: Dexmedetomidine and Ketamine: An Effective Alternative for Procedural Sedation? Pediatric Crit Care Med 2012; 13(4):423-27