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BJA Education, 16 (7): 242–246 (2016

)

doi: 10.1093/bjaed/mkv047
Advance Access Publication Date: 26 September 2015
Matrix reference 1A02,
2C05, 2A10, 3C00

Dexmedetomidine: its use in intensive care medicine
and anaesthesia
VL Scott-Warren MBChB (Hons) FRCA1 and J Sebastian BSc MBBS MRCP FRCA2,*
1
ST5 Anaesthesia, University Hospital of South Manchester NHS Foundation Trust, Manchester, UK
and 2Consultant Neuroanaesthetist, Salford Royal NHS Foundation Trust, Stott Lane, Salford M6 8HD, UK
*To whom correspondence should be addressed. Tel: +44 161 206 5107; E-mail: joe.sebastian@srft.nhs.uk

dose-dependent inhibition of norepinephrine release. It is pos-
Key points tulated that this results in disinhibition of the ventrolateral pre-
optic nucleus which then releases inhibitory neurotransmitters.
• Dexmedetomidine provides a unique quality of
This pathway is part of the complex circuitry governing natural
conscious sedation which resembles natural sleep.
sleep, resulting in a quality of sedation with dexmedetomidine
• Its administration does not result in respiratory which more closely resembles normal physiological sleep than
depression. the more familiar GABA-ergic sedatives ( propofol and the
benzodiazepines). This sedation is characterized by preserved
• It is licensed for intensive care sedation in the UK.
muscle tone and ventilation, by spontaneous and evoked
• Its use as a perioperative sedative is growing. movements, and by awakening by external stimuli. Once
roused, patients are cooperative and can typically obey simple
• The use of dexmedetomidine as a sole agent for
instructions. Once the external stimulus is discontinued, pa-
general anaesthesia in specific circumstances has
tients resume the previous level of sedation. Electroencephalo-
been reported.
gram studies have further confirmed that the sedative effects of
dexmedetomidine mimic stage 2 non-rapid eye movement
sleep.1
Dexmedetomidine is a relatively new drug to the UK having been
launched in October 2011 with marketing authorization for sed- Analgesia
ation of adult intensive care unit (ICU) patients only. Despite this,
It is likely that dexmedetomidine exerts effects at various sites in
its unique pharmacological profile has led to its unlicensed use in
the pain pathway, but its main site of action is at the level of the
a number of areas of anaesthetic and critical care practice where
spinal cord where stimulation of α2-receptors in the substantia
evidence for its efficacy is mounting.
gelatinosa of the dorsal horn reduces the release of nociceptive
neurotransmitters such as substance P.
Drug actions
Dexmedetomidine is the S-enantiomer of the veterinary sedative Effects on organ systems
medetomidine. It is a highly selective α2-adrenoceptor agonist
demonstrating an α2:α1 selectivity ratio of 1620:1. This makes The cardiovascular effects of the drug are biphasic (Fig. 1). At
it eight times more selective for the α2-adrenoceptor than higher rates of infusion, such as during administration of a load-
clonidine. ing dose, the predominant effect is hypertension due to acti-
vation of α2B receptors on vascular smooth muscle. This is
superseded by hypotension and bradycardia as a result of
Sedation and anxiolysis
the centrally mediated inhibition of sympathetic outflow. Case
These properties are mediated via agonism of α2-adrenoceptors reports of bradycardia leading to asystole after loading dose
primarily in the locus coeruleus of the pons where it results in administration of the drug in conjunction with multiple other

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0 to −3. It exerts a diuretic effect by inhi. with the current maximum dose. tomidine than with midazolam. Contraindications Uncontrolled hypotension and second.com/bjaed/article-abstract/16/7/242/2196362 by guest on 10 June 2018 . although with no increase in the rate of drug discontinuation due to adverse effects. and N-methylation in the liver to inactive metabolites which are then renally excreted. The rates of hypotension and bradycardia with dexmedetomidine and propo- Pharmacokinetics fol were comparable. those receiving the other sedatives. It may propofol. hydroxyl- ation. dexmedetomidine has not hypotension and bradycardia with dexmedetomidine when been found to cause any clinically significant adrenal suppression. with a distribu- tion half-life of 6 min. Number 7. level of light to moderate sedation. No difference in ICU length of stay. 4. However.9% and can be administered centrally or peripherally. while renal impairment and renal replacement therapy requires no dose adjustment. Hepatic impairment therefore should prompt a dose reduction due to decreased protein binding and metabolism. with a bioavail. human studies have de- monstrated a maintenance of flow-metabolism coupling with decreased rate of metabolic consumption in the brain matching the decreased cerebral blood flow. however. but not when compared with midine also has decongestant and antisialagogue effects. even when given in doses 10 midazolam (MIDEX). The presence of ‘acute cerebrovascular conditions’ is also considered a contraindication as research in animals has shown a decrease in cerebral blood flow with dexmedetomidine. stay. colour- less solution containing 100 µg ml−1 concentrate. Its steady-state volume of distribution (118 litres) is increased in patients with low plasma albumin concentration. Dexme. MRI studies effective as propofol and midazolam in maintaining the target have shown that the airway remains patent during dexmedeto. It has a terminal elimin- ation half-life of ∼2 h with clearance estimated at 39 litre h−1.2 Cardiovascular [corresponding to Richmond Agitation-Sedation Scale6 (RASS) adverse effects associated with dexmedetomidine may be ex. double-blind trials7 erly and in those with high vagal tone. more receptors in the hypothalamus. randomized. The median duration of midine sedation.or third-degree heart block (unless a pacemaker is fitted) may potentially be worsened by administration of dexmedetomidine. 65% nasally. the formulation of dexmedetomidine marketed in the UK by Orion Pharma (UK) Limited. compared with midazolam. It is diluted before administration to a concentration of 4 µg ml−1 using glucose 5% or sodium chloride 0. Drug discontinuation due to lack of efficacy Administration is possible via multiple routes. and better able to communicate their pain than biting the action of ADH at the collecting duct. Dexmedetomidine was found to be as times the maximum recommended. It is available in ampoules of 2 ml and vials of 2. It is not suitable for patients requiring deep pected to be more pronounced in hypovolaemic patients. there have been no reports of associated complications. lack of efficacy can be expected It is 94% protein bound with the unbound drug freely crossing in ∼1 in every 8 to 10 patients. or mortality was seen with 45 day follow-up. It undergoes glucuronidation. propofol (PRODEX) and is its minimal effect on ventilation. compared dexmedetomidine for the sedation of intubated A defining feature of the sedative action of dexmedetomidine patients with the established sedatives. ceiving dexmedetomidine were found to be more rousable. Two phase III multicentre.3 In addition. was higher with dexmedetomidine and the authors state that ability of 16% when given orally.4 Pharmaceutical information Dexdor®. patients re- detomidine suppresses shivering. is presented as a clear. Sedation in the ICU Dexmedetomidine is indicated for patients requiring a sedation level not deeper than arousal in response to verbal stimulation anaesthetic agents can be found in the literature. and 10 ml.7 BJA Education | Volume 16. possibly due to agonism of α2B. In keeping with its unique mechanism of action. although to our knowledge. those with diabetes mellitus or chronic hypertension. in sedation. and 82% buccally. Use of dexmedetomidine the blood–brain barrier to exert its central effects. cooperative. prolonging the terminal half-life and context-sensitive half-time in such patients.5 Fig 1 Effects of dexmedetomidine on organ systems. hospital length of theoretically reduce bowel motility. 2016 243 Downloaded from https://academic. Table 1]. There was. more Despite its imidazole structure. dexmedeto.oup. in the eld. mechanical ventilation was significantly shorter with dexmede- Owing to actions on peripheral α2-adrenoecptors.

In contrast to its use in anaesthe- SEDCOM. with which critical care staff may be failed to successful extubation with the introduction of dexme. on the basis of the marketing company’s cost- Where propofol sedation is contraindicated (e. group (and again found a significantly shorter time to extubation ation. After dose adjustment. co-prescribed med- with midazolam would be potentially detrimental. The dexmedetomidine infusion is begun at an infusion rate of 0. including pharmacoeconomic communicative. As a bridge to extubation Dexmedetomidine does not cause respiratory depression or air- way compromise. these indications is not available. due to hypertri. The frequency of the use of dexmedetomidine is anecdotally cheal tolerance when compared with other sedatives.7 µg kg−1 h−1 and is then adjusted according to response within the Patients at particular risk of critical care delirium dose range 0. 2016 Downloaded from https://academic. but has sustained (>10 s) awakening. but any movement to physical stimulation −5 Unrousable No response to voice or physical stimulation A recent Cochrane review8 supported the finding of reduced prevalence and duration of delirium in the dexmedetomidine duration of mechanical ventilation with dexmedetomidine sed.4 µg kg−1 h−1. of dexmedetomidine with an application of its specific pharma- There is early interest in a possible benefit of dexmedetomi- cological properties suggest the following indications. for respiratory depression or airway obstruction. is also 70 kg patient at the dose range of 0.10 a phase IV trial comparing dexmedetomidine and sia. clinical situations in which they feel dexmedetomidine will pro- vide additional benefits. It also depresses the gag reflex and improves tra. and better able to follow commands than with analysis other agents. March As an alternative sedative 2015). the acquisition costs of the drug are detomidine has been demonstrated in small trials. and also found a reduced ICU length of stay. in this group). This is in-keeping with the Intensive Where sedation is required to tolerate non-invasive ventilation in the Care Society’s position that ‘the [sedative] agents chosen should ICU be individualized to the patient’s requirements.g. Use of dexmedetomidine Table 1 The Richmond Agitation-Sedation Scale. as an ultra-short-acting opioid. However. which would have an up-front drug cost of £10–130 (costs and dose ranges as listed in the British National Formulary. First. minimization analysis exploring costs associated with drug glyceridaemia) but in whom the delayed extubation associated preparation. found a reduction in the for sedation in the ICU. to voice −2 Light sedation Briefly (<10 s) awakens with eye contact to voice −3 Moderate sedation Any movement (but no eye contact) to voice −4 Deep sedation No response to voice. higher than other agents—dexmedetomidine sedation of a While remifentanil. with many units reserving therapeutic profile makes it suitable for continuing infusion it for the above clinical situations where it may be specifically in- through the period of extubation in patients who deteriorate dicated. The improved specificity of dexmedetomidine for Drug administration the α2-receptor makes it a more effective sedative than clonidine.12 Where the clinician feels an α2-agonist would be beneficial (e. dine sedation in patients with sepsis via attenuation of immunosuppression. the agitated patient). dexmedetomidine would cost £26–184. clinical experience of the use Small trial evidence of its efficacy in this situation is available. This reduction in delirium confirms findings from previous trials (although not a universal finding)8 and has led to guidance from the Society of Critical Care Medicine11 recom- Potential indications mending dexmedetomine be used for sedation of patients with While non-inferiority to established sedatives for the licensed in. characteristics Lack of respiratory depression and provision of ‘rousable sed- and the clinical situation’.4 µg kg−1 h−1 for 24 h sometimes used as a bridge to extubation. This is likely to be due to a combination of factors. immediate danger to staff +3 Very agitated Pulls on or removes tube(s) or catheter(s) or has aggressive behaviour towards staff +2 Agitated Frequent non-purposeful movement or patient–ventilator dyssynchrony +1 Restless Anxious or apprehensive but movements not aggressive or vigorous 0 Alert and calm −1 Drowsy Not fully alert. sedation or drug withdrawal) but in whom clonidine is not efficacious. icines. and reduced costs associated with earlier extubation.2–1.3–4 mg kg−1 h−1. allow. unlike ing for a smooth and non-combative extubation.9 This much lower than the other sedatives.9 While robust large trial evidence for ation’ might make it particularly suitable for such patients. In addition. Number 7.2–1. This compares with sedation of a 70 kg pa- sedation can be continued post-extubation with less potential tient with propofol at the dose range of 0. a new steady- 244 BJA Education | Volume 16. Patients sedated with it are more cooperative. dexmedetomidine provides a novel. once sedatives are discontinued (e. Conversion of that of the other sedatives.6 Dexmedetomidine is indicated for patients requiring sedation levels corresponding to levels 0 to −3 as shaded Points Classification Description +4 Combative Overtly combative or violent. Barriers to use on ICU. management of adverse events. most UK ICUs currently reserve this drug for preference to benzodiazepines. ‘conscious sedation’.com/bjaed/article-abstract/16/7/242/2196362 by guest on 10 June 2018 . it is recommended that no loading dose is given when used midazolam for light sedation. delirium not related to benzodiazepine or alcohol withdrawal in dication is proven. with eye contact.g.oup. less familiar.g. the Scottish Medicines Consortium considers the economic case for Where the clinician feels an α2-agonist would be beneficial the use of dexmedetomidine to be demonstrated.

oup. they were unable to conduct a tage in paediatric premedication where intranasal administra. in the USA.7 µg kg−1 h−1 is advised when perform. effects of other sedatives. No Dexmedetomidine decreases anaesthetic requirements and is significant differences were seen between the treatment and opioid sparing. an increase in perioperative hypotension not be administered in this way. duce cerebral blood flow leading to ischaemia.2 and 1. report of ongoing trials. These properties are particularly useful in certain control groups in terms of airway obstruction. It does not suppress epileptiform procedures are to be undertaken (e. Many small randomized controlled trials have reported Sympatholysis benefits when using dexmedetomidine for sedation for invasive A Cochrane review in 200914 examined the theoretical benefits of procedures compared with standard techniques. patients found less supplemental epidural opioid was needed The recommended dosing regimens when using dexmedeto- in the group who also received an i. and normal saline. shockwave litho- complications of surgery. Many ICUs α2-agonists reduced mortality and myocardial ischaemia. that A reduced loading infusion of 0. Similarly.6 µg kg−1 h−1 and titrated to the de.13 propofol. Number 7. full meta-analysis. and cerebral metabolic rate. dicated. fentanyl. The drug also acts as an A recently published Cochrane review15 examined the use of dex- anaesthetic-sparing agent and obtunds the pressor response to medetomidine for awake fibreoptic intubation. or cardio- patient populations where the respiratory-depressant properties vascular adverse events. however. Although there were initial concerns that it may re- sired clinical effect between doses of 0. The monitored for symptoms and if apparent should prompt a drug also offers effective prevention and treatment of emergence more gradual dose reduction. nidine infusion and has occasionally been reported with dexme. anaesthetics. However. but it is important to note that dexmedetomidine should There was. awake craniotomy for supratentorial tumour resection or deep mended for patients over 65 years of age and when less invasive brain stimulator implantation. and further studies were called for. the greatest benefit seen in patients undergoing vascular surgery. They concluded that dexmedetomi- dine significantly reduced the participants discomfort with Anaesthetic and opioid-sparing agent awake fibreoptic intubation compared with control groups. if a patient is being converted to dexmedetomidine models. Dexmedetomidine enhances the pharmacodynamic scoliosis surgery. with have protocols in place to allow nurses to bolus sedation when in. hypnotics. of the drug on α2A-receptors and at imidazoline receptors. The authors found that perioperative tripsy. phenomena.5 When stopping the drug. and antisialagogue prop- erties. Owing to the het- intubation. Overall. erogeneity of the available studies.5 mg kg−1 orally.g. the authors note that these of opioids may be particularly detrimental. and opioids Experimental studies show dexmedetomidine has neuropro- and concomitant use therefore should also prompt a dose reduc. and dental procedures. sions about the safety and efficacy of perioperative α2-agonists hypertension. dexmedetomidine is approved for oid-induced respiratory depression would be potentially deleteri- sedation of non-intubated patients before and/or during surgical ous.v. sympatholytic. multiple studies Maintenance infusion at 0. Its versatility in route of administration is an advan. useful anaesthetic-sparing agent and analgesic supplement in pairment.5 It does not affect somatosensory- A reduction in the loading and maintenance dose are recom.5 µg kg−1 over 10 min is recom- is. with modest lowed by infusion with controls of midazolam. dexmedetomidine infusion. Neuroanaesthesia A loading infusion of 1 µg kg−1 over 10 min Dexmedetomidine is routinely used in our centre for neurosurgi- cal procedures requiring intraoperative patient cooperation. This neuroprotection appears to be afforded by the action from another sedative. hypoxia. 2016 245 Downloaded from https://academic.com/bjaed/article-abstract/16/7/242/2196362 by guest on 10 June 2018 . and tachycardia is recognized after prolonged clo. BJA Education | Volume 16. The clinical relevance of these findings is yet to be fully evaluated. Awake fibreoptic intubation detomidine suitable for premedication. There is no published experience and bradycardia with drug administration.0 µg kg−1 h−1. activity in patients undergoing electrocorticography and so is useful in epilepsy surgery. such as in bariatric conclusions are based on weak evidence and they await the surgery. a loading dose may not be necessary. awake carotid endarterectomy. midine for periprocedural sedation in the USA are described below. Dexmedetomidine in anaesthetic practice Postoperative analgesia Postoperative dexmedetomidine infusions have been used to Although unlicensed for use other than for intensive care sed- supplement other forms of analgesia in patients in whom opi- ation in the UK. nial pressure. have demonstrated a matched reduction in cerebral blood flow ing awake fibreoptic intubation until the tracheal tube is secured. along with a lack of respiratory depression make dexme. investigated include radiological and gastrointestinal endoscopic crease in sympathetic activity. evoked potentials or motor-evoked potentials and so may be a mended when administering the drug to patients with hepatic im. A maintenance infusion Dexmedetomidine administration has no effect on intracra- This is generally initiated at 0. the data with infusions lasting >14 days. ophthalmic). Procedures α-agonists in obtunding the perioperative stress-induced in. tective effects in hypoxic–ischaemic and traumatic brain injury tion. and thereby reducing cardiac procedures. available to the authors were insufficient to make firm conclu- A discontinuation syndrome manifest as rebound agitation. Perioperative use Sedative premedication Sedation for invasive procedures Its anxiolytic. patients should be tubation period has been used for emergence smoothing. haemodynamic effects. Use of dexmedetomidine state sedation level may not be reached for up to 1 h. Continuous infusion of dexmedetomidine throughout the ex- detomidine. A small randomized controlled trial of thoracic surgical and other procedures. The review considered four randomized con- tion of 1 µg kg−1 dexmedetomidine was shown to be as trolled trials examining dexmedetomidine given by bolus fol- effective a sedative as midazolam 0. sedative.

Romera Ortega MA. Indications of dexmedeto- A limited number of studies have shown a prolongation of midine in the current sedoanalgesia trends in the critical regional nerve block when dexmedetomidine was added to the patient. Huupponen E. agitation.oup. Maksimov A. although its superiority to cloni. Shehabi Y. Clonidine remains popular as an adjunct to 6. 41: 263–306 12. Cochrane Database Syst physiological sleep. The Richmond local anaesthetic for caudal epidural in children. Szumita PM. Available from http://www. Lipperheide Regional anaesthesia adjuncts Vallhonrat I. 11. 52: 289–94 Rev 2014. Chen K. 307: 1151–60 There have been case reports of the use of dexmedetomidine as 8. Shi X. He Q. Sedation patients and analgesia in the intensive care unit: evaluating the role of dexmedetomidine. 7. care patients. Grap MJ et al. Use of dexmedetomidine Sedation for non-invasive procedures in challenging 2. J Am Med Assoc 2009. Gaspari R. 1: CD009798 246 BJA Education | Volume 16. a tracheal debridement with stenting and bronchopulmonary 2014 lavage. and Best Practice for Analgesia and Sedation in the Critical Care. 1: mended for procedural sedation) to be adequately anaesthetized. those with obstructive sleep apnoea or an of dexmedetomidine during long-term sedation in intensive anterior mediastinal mass. Arcangeli A. prolonged neuraxial analgesia. 4: CD004126 1. Xin YC. It is of particular use in patients in whom the eral anaesthesia. The use of dex. Wechsler ME. 2015) 13. Grounds RM et al. 10: 687–95 respiratory-depressant effects of other sedatives should be mini- 4. Am J Respir Crit Care Med 2002. CD010269 The authors chose this technique in two of the cases due to the 9. Yuen VM. Lapinlampi P. laser ablation of a tracheal stenosis. Med Intensiva 2014. Anger KE. Number 7. Alpha-2 agonists a sole agent for general anaesthesia. Irwin MG. The Intensive Care Society. Beattie WS. Hui TW. 106: 1715–21 http://www. He X. Chen Y. There was no haemodynamic compromise in mized trial. Intensive Care Society Review of nature of the surgery. 166: 1338–44 dine for this indication has not been proven.oxfordjournals. (784/12). 301: 489–99 this small group of patients. 2016 Downloaded from https://academic. Puntillo K et al. for example. D’Alò C.org. 14.01. Gosnell MS. Wijeysundera DN. Iirola T. Barr J. None declared. Electrocardiogram 15. Agitation-Sedation Scale: validity and reliability in adult medetomidine has been described as efficacious in providing intensive care unit patients. Jakob SM. Pan SM. Cao J. UK. Crit Care Med 2013. Chamorro Jambrina C. Ihmsen H. 108: 460–8 5.org/podcasts/ceaccp_16. Dexmedetomidine vs midazolam or propofol for sedation during prolonged General anaesthesia single-agent case reports mechanical ventilation: two randomised controlled trials. A comparison of intranasal dexmedetomidine and oral midazolam for Podcasts premedication in pediatric anesthesia: a double-blinded This article has an associated podcast which can be accessed at randomized controlled trial. Anesth Analg 2008.mp3. Sessler CN.pdf (accessed 14 April BJA Education. J Am Med Assoc 2012. Cochrane Database Syst Rev References 2009. Curr Drug Targets 2009. Scottish Medicines Consortium. Lu Z. Bender JS. Dexmedetomidine 100 micrograms/mL concentrate for solution for infusion MCQs (Dexdor®) SMC No. Cochrane Database Syst Rev 2015. Am J Health Syst Pharm 2007.07.com/bjaed/article-abstract/16/7/242/2196362 by guest on 10 June 2018 . Laitio R et al. Bokesch PM et al.org by subscribers to Dexdor_FINAL_May_2012_for_website. Ruokonen E. Yuen MK. Population pharmacokinetics mized. Baroletti SA. Dexmedetomdine use in gen- investigations. 38: 41–8 local anaesthetic. Fraser GL. These patients required for long-term sedation during mechanical ventilation in doses of 5–10 µg kg−1 h−1 (5 to 10 times the maximum recom- critically ill patients. Cai Y. The associated MCQs (to support CME/CPD activity) can be scottishmedicines. Riker R. Alpha-2 adrenergic agonists for the prevention of cardiac complications among patients undergoing surgery.uk/files/advice/dexmedetomidine_ accessed at https://access. Dexmedetomidine vs drive with easy maintenance of a patent airway (one patient re- midazolam for sedation of critically ill patients: a rando- quired a chin lift). Dexmedetomidine for the manage- spindle activity during dexmedetomidine sedation and ment of awake fibreoptic intubation.oxfordjournals. 64: The pharmacotherapeutic properties of dexmedetomidine have 37–44 led to its use for paediatric and adult sedation for radiological 3. Fernández Simón I. and delirium in Declaration of interest adult patients in the intensive care unit. Br J Anaesth 2012. Acta Anaesthesiol Scand 2008. Clinical practice guidelines for the management of pain. Dexmedetomidine allowed preservation of respiratory 10.