Dexmedetomidine

Reviewed and revised 25 August 2016

CLASS

  • alpha 2 agonist

MECHANISM OF ACTION

  • selective alpha 2 agonist in CNS
    • 8 times more selective than clonidine)
    • binds all 3 subtypes of alpha2 receptor (A, B, C)
  • Sedation
    • reduces sympathetic activity and agitation, causing a state resembling the non-REM phase of sleep without impairing cognitive function
    • sedation is induced by inhibition of noradrenergic activity  via activation of alpha-2 receptors at the locus coeruleus
    • produces a patient who is sedated but can be easily roused with minimal stimulation
    • minimal respiratory depression (RR, PaCO2, SpO2, and higher PF ratios)
  • Analgesia
    • posterior horns of the spinal cord where the modulation of pain impulses is mediated by the noradrenergic bulbar/spinal pathway
    • peripheral nerve mechanisms also implicated
    • reduce need for opioid analgesia
  • Neuroprotective effects
    • decreases circulating and cerebral catecholamines and CNS glutamate
  • Other effects
    • decreases CBF, CNS VO2, and mild decrease in ICP
    • decreases shivering
    • suppression of stress response to surgery and other noxious stimuli

DOSE

  • loading dose 1mcg/kg over 10 minutes (optional)
  • 0.2-0.7mcg/kg/hr infusion

INDICATIONS

  • sedoanalgesia
  • analgesia sparing post operation
  • delirium prevention and management
  • ventilator dysynchrony due to discomfort
  • withdrawal syndromes
  • awake intubation
  • peri-operative sympatholysis
  • neuraxial and regional anesthesia
  • SVT (use described in children)

DISADVANTAGES

  • only licensed for use in mechanically ventilated patients for < 24 hrs (data emerging of safety in using post this period)
  • decrease dose in liver dysfunction

Adverse effects

  • bradycardia and hypotension
  • nausea
  • dry mouth
  • initial transient hypertension with reflex bradycardia (stimulation of α2B subtypes of receptors present in vascular smooth muscles)
  • discontinuation syndrome: tachycardia, nervousness, agitation, headaches, and hypertensive crisis (e.g. if prolonged use due to upregulation of alpha2 receptors)

PHARMACOKINETICS

  • Absorption – IV
  • Distribution – t1/2 alpha = 6 minutes; VD = 118 L; 94% protein bound
  • Metabolism – hepatic: complete biotransformation by glucuronidation and by cytochrome P-450 mediated aliphatic hydroxylation to inactive metabolites
  • Elimination – metabolites excreted renally (95%) and in faeces (4%); context-sensitive half-life varies from 4 min for a 10 min infusion to 250 min for an 8 h infusion

EVIDENCE

Pandharipande PP, et al. Effect of sedation with dexmedetomidine vs lorazepam on acute brain dysfunction in mechanically ventilated patients: the MENDS randomized controlled trial. JAMA. 2007 Dec 12;298(22):2644-53. PubMed PMID: 18073360.

  • DB RCT
  • n = 103
  • Dexmedetomidine compared with lorazepam IV infusion
  • Improved coma-free days and time at target level of sedation in mechanically ventilated patients
  • required more open-label fentanyl, higher incidence of bradycardia

Pandharipande PP, et al; MENDS investigators. Effect of dexmedetomidine versus lorazepam on outcome in patients with sepsis: an a priori-designed analysis of the MENDS randomized controlled trial. Crit Care. 2010;14(2):R38. PMC2887145.

  • re-analysis with regard to sepsis of MENDS trial given the different effects of dex and lorazepam on immune function
  • patients with sepsis and dexmedetomidine did better: less delirum, more coma free days, higher survival

Riker RR, Shehabi Y, Bokesch PM, Ceraso D, Wisemandle W, Koura F, Whitten P, Margolis BD, Byrne DW, Ely EW, Rocha MG; SEDCOM (Safety and Efficacy of Dexmedetomidine Compared With Midazolam) Study Group. Dexmedetomidine vs midazolam for sedation of critically ill patients: a randomized trial. JAMA. 2009 Feb 4;301(5):489-99. PMID: 19188334.

  • DB RCT, 68 centers in 5 countries
  •  375 medical/surgical ICU patients with expected mechanical ventilation for >24 hours
  • Dexmedetomidine compared with midazolam
  • Comparable in achieving sedation targets in MV patients
  • Reduced ICU delirium and MV duration in the dexmedetomidine group

Jakob SM, et al; Dexmedetomidine for Long-Term Sedation Investigators. Dexmedetomidine vs midazolam or propofol for sedation during prolonged mechanical ventilation: two randomized controlled trials. JAMA. 2012 Mar 21;307(11):1151-60. PMID: 22436955.

  • DB MC RCT; mixed non-inferiority and superiority trial
  • n = 1000, mechanically ventilated
  • Dexmedetomidine (0.2 – 1.4mcg/kg/hr) versus propofol (PRODEX) or midazolam (MIDEX)
  • Exclusion criteria: narrow, reasonable (pregnancy, shock, pre-existing bradycardia etc)
  • Dexmed vs propofol – NO difference in:
    • Time within goal of sedation
    • Duration of MV: extubated sooner with dexmed however required NIV post
    • ICU or hospital LOS
    • Incidence of hypotension / bradycardia (13% each)
  • Dexmed compared with midazolam:
    • No difference ICU or hospital LOS
    • Shorter MV duration: extubated 2 days sooner
    • Patients more alert and communicative
    • Better able to communicate pain
    • Significantly more hypotension
    • Significantly more bradycardia (14% vs 5%)
  • Commentary
    • Non-inferiority trial powered (90%) to test the hypothesis that dexmedetomide is no more than 15% worse than propofol (PRODEX) or midazolam (MIDEX) for time to reach sedation target using per-protocol analysis
    • Other endpoints (e.g. MV duration) tested as part of a superiority trial using intention-to-treat analysis
    • Trial designed and controlled by Orion Pharma (patent holders of dexmedetomidine), including statistical analyses and manuscript preparation (listed as co-author)
    • One author (not a lead) disclosed personal payment from Orion
    • Dose utilised up to twice the maximum 0.7mcg/kg/hr dosing approved by FDA in US

DahLIA trial, 2016

  • MCRCT (15 Australasian ICUs)
  • n =71 adult ICU patients who needed to remain mechanically ventilated because their degree of agitation was considered so severe as to make lessening their sedation and extubation unsafe
  • Intervention: Dexmedetomidine started at 0.5mcg/kg/hr and then titrated to rates between 0 and 1.5mcg/kg/hr to achieve RASS 0 or  a physician-prescribed goal; clinical-directed option for bolus of 1.0mcg/kg over 20 minutes
  • Control: placebo
  • Outcomes
    • Primary outcome
      • increase in median ventilator free hours at 7 days in the dexmedetomidine group: 144.8 vs. 127.5 hours, P=0.01
    • Multiple secondary outcomes, some favoured dexmedetomidine and none favoured the control arm
  • Commentary
    • underpowered (did not reach the calculated n=96 sample size), yet still found a difference
    • Patients in the dexmedetomidine group were ventilated for longer prior to enrolment in the study (median times were 63 hours vs 43.5 hours)
    • Sedation received prior to randomisation was not well characterised
    • Clinicians could use dexmedetomidine as a rescue agent in the control arm
    • few patients enrolled despite screening >20,000 patients, which may limit external validity
  • Conclusion
    • Among patients with agitated delirium receiving mechanical ventilation in the Intensive Care Unit, the addition of dexmedetomidine to standard care compared with standard care alone resulted in more ventilator-free hours at 7 days.

References and Links

FOAM and web resources

Journal articles

  • Bajwa S, Kulshrestha A. Dexmedetomidine: an adjuvant making large inroads into clinical practice. Ann Med Health Sci Res. 2013 Oct;3(4):475-83. doi: 10.4103/2141-9248.122044. Review. PubMed PMID: 24379995; PubMed Central PMCID: PMC3868110.
  • He XY, Cao JP, He Q, Shi XY. Dexmedetomidine for the management of awake fibreoptic intubation. Cochrane Database Syst Rev. 2014 Jan 19;1:CD009798. doi: 10.1002/14651858.CD009798.pub2. Review. PubMed PMID: 24442817.
  • Keating GM. Dexmedetomidine: A Review of Its Use for Sedation in the Intensive Care Setting. Drugs. 75(10):1119-30. 2015. [pubmed]
  • Jakob SM, et al; Dexmedetomidine for Long-Term Sedation Investigators. Dexmedetomidine vs midazolam or propofol for sedation during prolonged mechanical ventilation: two randomized controlled trials. JAMA. 2012 Mar 21;307(11):1151-60. doi: 10.1001/jama.2012.304. PubMed PMID: 22436955.
  • Mo Y, Zimmermann AE. Role of dexmedetomidine for the prevention and treatment of delirium in intensive care unit patients. Ann Pharmacother. 2013 Jun;47(6):869-76. doi: 10.1345/aph.1AR708. Review. PubMed PMID: 23719785.
  • Pandharipande PP, et al. Effect of sedation with dexmedetomidine vs lorazepam on acute brain dysfunction in mechanically ventilated patients: the MENDS randomized controlled trial. JAMA. 2007 Dec 12;298(22):2644-53. PubMed PMID: 18073360.
  • Pandharipande PP, et al; MENDS investigators. Effect of dexmedetomidine versus lorazepam on outcome in patients with sepsis: an a priori-designed analysis of the MENDS randomized controlled trial. Crit Care. 2010;14(2):R38. doi: 10.1186/cc8916. Epub 2010 Mar 16. Erratum in: Crit Care. 2011;15(1):402. PubMed PMID: 20233428; PubMed Central PMCID: PMC2887145.
  • Reade MC, Eastwood GM, Bellomo R. Effect of Dexmedetomidine Added to Standard Care on Ventilator-Free Time in Patients With Agitated Delirium: A Randomized Clinical Trial. JAMA. 315(14):1460-8. 2016. [pubmed]
  • Riker RR, Shehabi Y, Bokesch PM, Ceraso D, Wisemandle W, Koura F, Whitten P, Margolis BD, Byrne DW, Ely EW, Rocha MG; SEDCOM (Safety and Efficacy of Dexmedetomidine Compared With Midazolam) Study Group. Dexmedetomidine vs midazolam for sedation of critically ill patients: a randomized trial. JAMA. 2009 Feb 4;301(5):489-99. doi: 10.1001/jama.2009.56. Epub 2009 Feb 2. PubMed PMID: 19188334.
  • Wujtewicz1 M, et al. Use of dexmedetomidine in the adult intensive care unit. Anaesthesiol Intensive Ther 2013, vol. 45, no 4, 235–240 [Free Full Text]

CCC 700 6

Critical Care

Compendium

Chris is an Intensivist and ECMO specialist at the Alfred ICU in Melbourne. He is also the Innovation Lead for the Australian Centre for Health Innovation at Alfred Health and Clinical Adjunct Associate Professor at Monash University. He is a co-founder of the Australia and New Zealand Clinician Educator Network (ANZCEN) and is the Lead for the ANZCEN Clinician Educator Incubator programme. He is on the Board of Directors for the Intensive Care Foundation and is a First Part Examiner for the College of Intensive Care Medicine. He is an internationally recognised Clinician Educator with a passion for helping clinicians learn and for improving the clinical performance of individuals and collectives.

After finishing his medical degree at the University of Auckland, he continued post-graduate training in New Zealand as well as Australia’s Northern Territory, Perth and Melbourne. He has completed fellowship training in both intensive care medicine and emergency medicine, as well as post-graduate training in biochemistry, clinical toxicology, clinical epidemiology, and health professional education.

He is actively involved in in using translational simulation to improve patient care and the design of processes and systems at Alfred Health. He coordinates the Alfred ICU’s education and simulation programmes and runs the unit’s education website, INTENSIVE.  He created the ‘Critically Ill Airway’ course and teaches on numerous courses around the world. He is one of the founders of the FOAM movement (Free Open-Access Medical education) and is co-creator of litfl.com, the RAGE podcast, the Resuscitology course, and the SMACC conference.

His one great achievement is being the father of two amazing children.

On Twitter, he is @precordialthump.

| INTENSIVE | RAGE | Resuscitology | SMACC

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