Highly specific and selective α 2 -adrenergic agonist with sedative, anxiolytic, and analgesic effects.
Pharmacologically active dextro-isomer of medetomidine.
1 st synthesized in late 1980’s,
Phase 1 studies in early 1990’s,
Clinical trials late 1990’s.
Approved by FDA at the end of 1999 for use in humans as a short-term medication (<24 hours) for analgesia and sedation in the intensive care unit (ICU).
Alpha 2 Alpha 1 Dexmedetomidine is 8 times more selective than Clonidine α2:α1 = 1600:1 vs 200:1 Alpha-Adrenoceptor Agonists
Mechanism of Action
Central nervous system stimulation of parasympathetic outflow and inhibition of sympathetic outflow from the locus ceruleus in the brainstem -> sedation and anxiolysis.
Primary analgesic effects and potentiation of opioid-induced analgesia result from the activation of α 2 -adrenergic receptors in the dorsal horn of the spinal cord and the inhibition of substance P release.
α 2 -Adrenergic Receptors & Effects
Inhibition of norepinephrine release appears to be equally affected by all three alpha-2 receptor subtypes
BUMC PROCEEDINGS 2001;14:13–21. Goodman & Gilman. .The pharmacological Basis of therapeutics. 11th edition . Dexmedetomidine, US FDA approved prescribing information. Receptor Type Agonism causes Alpha 2 A - Presynaptic sedation, hypnosis, analgesia, sympatholysis, neuroprotection and inhibition of insulin secretion Alpha 2 B - Postsynaptic suppresses shivering centrally, promotes analgesia at spinal cord sites, and induces vasoconstriction in peripheral arteries Alpha 2 C modulation of cognition, sensory processing and regulation of epinephrine outflow from the adrenal medulla
BUMC PROCEEDINGS 2001;14:13–21 Clinical Effects
Route: Intravenous infusion (recommended route)
Loading: 1mcg/kg over 10 min
Maintenance: 0.2-0.7 mcg/kg/hr
Short distribution half-life (6 min): Rapid onset of sedation
Short elimination half-life (2 hr): Facilitates clearance
Protein binding: 94%
There are no active or toxic metabolites.
It undergoes hepatic metabolism with limited unchanged drug excreted in the urine or stool.
Drugs 2000 Feb; 59(2): 263-268 Critical Care Nurse 2010 Feb;30(1):29-39
Hepatic clearance may be ↓ by as much as 50% of normal with severe liver disease.
Pk is not significantly altered in patients with severe renal impairment, but patients remained sedated for longer than normal controls, suggesting an enhanced pharmacodynamic effect.
Dosages should be ↓ in the presence of either hepatic or renal disease.
De Wolf AM, Fragen RJ, Avram MJ, et al. Anesth Analg 2001;93: 1205–9.
Pharmacokinetic profile in children :
Pharmacokinetics of dexmedetomidine in children are similar to adults with no dose-dependent kinetics.
Petroz GC et al: . Anesthesiology 2006;105:1098–110.
Infants (1 to 24 months):
appear to clear dexmedetomidine more quickly than adults or older children -> (median clearance of 27.2mL/kg/min).
need larger initial doses of dexmedetomidine than the older children to reach a certain plasma concentration -> (young children have a larger volume of distribution of the drug).
similar rates of infusion can be used to maintain a steady-state concentration of dexmedetomidine in plasma -> (total plasma clearance of dexmedetomidine is independent of age).
Su F et al: Abstr. Crit Care Med 2005.
End-Organ Effects :
Hypotension and bradycardia have been reported in adults
presence of comorbid cardiac disease,
when administered with other medications that possess negative chronotropic effects
during vagotonic procedures (laryngoscopy) or following large or rapid bolus doses.
High-dose boluses may result in a biphasic response
with bradycardia and hypertension consequent to initial stimulation of peripheral alpha-2B vascular receptors,
followed by central sympatholysis and a decline in blood pressure.
At clinically effective doses, dexmedetomidine causes minimal respiratory depression.
Central Nervous System Effects:
Anxiolysis and Sedation:
through activation of α 2 -adrenergic in the locus cerulus.
An unusually cooperative form of sedation
have significant analgesic effects.
reduces opioid requirements by 30 to 50%.
ICP and CPP:
Slight decrease in the mean for ICP and a slight corresponding increase in CPP.
Aryan HE et al. Brain Injury, July 2006.
CBF and CMRO 2 :
Dose-related reduction in both CBF and CMR in healthy subjects.
The anticipated adverse effects on the cerebral oxygen supply–demand relation, i.e. , the CBF/CMR ratio, were not apparent during either normocapnia or hypocapnia.
Drummond JC et al . Anesthesiology 2008.
Effect on EEG
The EEG during dexmedetomidine sedation resembled stage II NREM sleep.
Spike frequency increased by 47% during sedation but no new spike foci or seizures were observed.
Mason KP et. Pediatric Anesthesia, Dec 2009.
Effect on Evoked Potentials
Use of dexmedetomidine as an anesthetic adjunct at target plasma concentrations up to 0.6 ng/ml does not change somatosensory or motor evoked potential responses during complex spine surgery by any clinically significant amount.
Bala E., et al. Anesthesiology. 2008 Sep;109(3):417-25.
decreases the peripheral catecholamine levels thus balancing the ratio between cerebral oxygen supply & demand and improving the perfusion in the ischemic penumbra .
Engelhard et al., Anesthesiology 96:450-7, 2002.
inhibits isoflurane induced capsase-3 expression in hippocampal slice cultures suggesting that dexmedetomidine may be an important adjunct to prevent isoflurane-induced neurotoxicity in the growing brain
Sanders et al., Anesthesiology 110:1077-85, 2009
Potential adverse effect profile of dexmedetomidine
The most common adverse reactions are
Transient hypertension may be seen during a loading dose.
Central nervous system side effects:
Ineffective sedation and/or analgesia
Proconvulsant effect (animal study).
WARNINGS AND PRECAUTIONS
Avoid in patients with:
Low BP/ Shock not responding to vasopressors
SBP < 90mmHg or a mean BP < 60 mmHg in spite of significant vasopressor support:
(Vasopressin > 2 U/hr Noradrenaline or Adrenaline > 0.2 µg/kg/min or Dobutamine > 10 µg/kg/min)
HR<55 BPM, not induced by beta-blocker
Severe ventricular dysfunction
High grade AV block in the absence of pacemaker
Crit Care Nurse. 2010;30: 29-38. Crit Care & Shock (2010) 13:40-50
Intubated and mechanically ventilated patients in ICU
Non-intubated patients prior to and/or during surgical and other procedure
Off Label Use
To control agitation in patients receiving noninvasive ventilatory support
As Anesthetic Adjuvant
Adjunct to general & regional (IVRA) anesthesia
Supplement to regional block in patients undergoing carotid endarterectomy or during awake craniotomy / fiberoptic intubation.
To treat shivering
To minimize withdrawal phenomena in patients who have received long-term BDZ and Opioids during their hospitalization.
Trials in ICU Sedation:
SEDCOM Trial: DXMD vs Midazolam:
A double-blind, RCT in 68 centers in 5 countries
375 medical/surgical ICU patients with expected MV for >24 hours
Dexmedetomidine @ 0.2-1.4 µg/kg/hr (n=244) or Midazolam @ 0.02-0.1mg/kg/hr (n=122) titrated to achieve light sedation (RASS −2 to 1) until extubation or 30 days.
SEDCOM Trial: DXMD vs Midazolam P= 0 .01 SEDCOM (Safety and Efficacy of Dexmedetomidine COmpared With Midazolam).
Early Extubation: Median time reduced by 1.9 days
3.7days with DXMD vs 5.6 days with Midazolam ( P= 0 .01)
Shorter LOS in ICU (1.3 days)
Bradycardia 42%, only 4.9% needed intervention
Significantly less Tachycardia & HTN
3.7 days 5.6 days 0 2 4 6 Time to extubation in days Dexmedetomidine-treated patients spend less time on ventilator Dexmedetomidine Midazolam
DEXCOM study: DXMD vs Morphine-based regimen after Cardiac Surgery
DXMD promoted early extubation
Required less propofol (total dose)
Less systolic hypotension (23% vs 38.1%, P= 0.006),
Required less norepinephrine ( P < 0.001)
More bradycardia than morphine treatment.
DXMD produced effective analgesia/sedation, less hypotension, less vasopressor requirement, vs morphine regimen, and reduced the duration of delirium.
DEXCOM: DEXmedetomidine COmpared to Morphine . DEXCOM Study: Anaesthesiology 2009,111:1075-84.
Evaluating the use of dexmedetomidine in neurocritical care patients. Grof TM., Neurocritical care: 2010 Jun;12(3):356-61.
The mean initial dexmedetomidine infusion rate and mean maximum infusion rate were 0.67 +/- 0.2 and 1.3 +/- 0.5 mcg/kg/h, respectively.
Two patients (33%) experienced a significant change in HR and SBP after starting dexmedetomidine infusion.
Neurocritically ill patients may require high doses of dexmedetomidine to achieve desired levels of sedation.
The high rates and long duration of dexmedetomidine infusion had a statistically, but not clinically, significant impact on hemodynamic parameters.
Use of Dexmedetomidine in paediatric patients.
Tobias JD. Dexmedetomidine: applications in pediatric critical care and pediatric anesthesiology . Pediatr Crit Care Med 2007; 8:115–31
Shukry M et al. Does dexmedetomidine prevent emergence delirium in children after sevoflurane-based general anesthesia? Paediatr Anaesth 2005; 15:1098–1104.
Guler G et al. Single-dose dexmedetomidine reduces agitation and provides smooth extubation after pediatric adenotonsillectomy . Paediatr Anaesth 2005;15: 762–6
Al-Zaben KR et al. Intraoperative administration of dexmedetomidine reduces the analgesic requirements for children undergoing hypospadius surgery. Eur J Anaesthesiol 2010; 27: 247–52
Olutoye OA et al . The effect of intraoperative dexmedetomidine of postoperative analgesia and sedation in pediatric patients undergoing tonsillectomy and adenoidectomy. Anesth Analg 2010; 111: 490-5.
Sadhasivam S, et al. Comparison of patient-controlled analgesia with and without dexmedetomidine following spine surgery in children. J Clin Anesth 2009; 21: 493–501
Patel A,et al. Dexmedetomidine Infusion for analgesia and prevention of emergence agitation in children with obstructive sleep apnea syndrome undergoing tonsillectomy and adenoidectomy Anesth Analg 2010 ;111:1004–10.
Sato M et al. Effect of single-dose dexmedetomidine on emergence agitation and recovery profiles after sevoflurane anesthesia in pediatric ambulatory surgery. J Clin Anesth 2010 ; 24:675–682 .
THE EFFECT OF INTRAOPERATIVE DEXMEDETOMIDINE ON POSTOPERATIVE RECOVERY PROFILE OF PEDIATRIC NEUROSURGICAL PATIENTS UNDERGOING SPINAL SURGERY Principal Investigator: Dr. Nidhi Gupta Guide: Dr. Girija Prasad Rath Co-Guide: Dr. Hemanshu Prabhakar
AIMS AND OBJECTIVES
PRIMARY OUTCOME VARIABLES:
Objective pain score (OPS) - for postoperative pain.
Modified aldrete score – time to attain full modified aldrete score.
5 point agitation scale as described by Cole for emergence delirium.
SECONDARY OUTCOME VARIABLES:
Total Sevoflurane consumption.
Intraoperative and postoperative fentanyl requirement.
Postoperative complications- nausea, vomiting and shivering.
Children with American Society of Anesthesiologists (ASA) physical status I-II, aged between 1-12 years undergoing elective surgery for spinal dysraphism at thoracic, lumbar and sacral level.
METHODOLOGY: ( Salient Points)
Induction - sevoflurane 8% in oxygen with spontaneous ventilation, in all the patients. Intravenous (IV) access will be established when the eyelash reflex is lost. Fentanyl (2 µg/kg) will be given intravenously followed by rocuronium (1 mg/kg) to facilitate endotracheal intubation.
Computer generated randomization table will be used to assign each patient to either the dexmedetomidine group (Group D, n=13) or placebo group (Group P, n=13).
Group D will receive IV dexmedetomidine (1µg/kg over 10 minutes, followed by 0.5µg/kg/hr until beginning of skin closure). Group P will receive volume matched saline.
In postanesthesia care unit:
Pain and emergence agitation will be evaluated and treated with fentanyl (1-2µg/kg) for pain (score equal or more than 4) or severe agitation (score 4 or 5) lasting more than 5 minutes.