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DEXMEDETOMIDINE
Intern SunderIntern Ghanshyam
(Dhulikhel Hospital, Dhulikhel, Nepal)
Dexmedetomidine
• INTRODUCTION -Novel drug FDA approved in 1999 for short
term sedation and analgesia(<24hours) - New generation alfa-2 AR agonist. - Diverse action - Category C drug
DexmedetomidineMOA
Dexmedetomidine
Dexmedetomidine
Dexmedetomidine
Dexmedetomidine
Dexmedetomidine
• CNS - effects of action on alfa 2 AR --- Sedetives
analgesics, anxiolytics -enhances cognitive performance - decrease cerebral blood flow - decreases cerebral metabolic 02 requirements - Neuroprotective
Dexmedetomidine
• CVS -BP- biphasic response transient
hypertension (alpha 2B-AR) followed by hypotension (alpha 2A-AR) - HR –decrease tachycardia (block cardio-
acceleratory nerve)– Bradycardia (vagomimetic action)
Dexmedetomidine
• CVS -Peripheral Vasculature vasodilation – sympatholytic mediated vasoconstriction –smooth muscle cell
receptor mediated
Dexmedetomidine
• Respiratory system - does not suppress respiratory centre - no effects on RR and gaseous exchange• Endocrine System -decrease catecholamine release - no inhibition of steroidogenesis - decrease insulin release from pancreas
Dexmedetomidine• Renal system
– Diuresis– increase GFR– inhibition of Renin release– Natriuresis
• Eye – Decrease IOP• GIT-decrease secretions
– decrease GI motility– decrease salivation
• Anti shivering –CNS based thermoregulatory inhibition(alfa 2B –AR)
Dexmedetomidine• Pharmacokinetics - linear pharmacokinetics iv – distribution t1/2 6 min -elimination t1/2 2 hours - volume of distribution 118 litres( 94% ppb) IM-Peak plasma concentration variable -bioavailability 70%Enteral –gastric 16-20% bioavailibility - buccal – 80% bioavailability contest sensetive half life - 4 min in infusion over 10 min - 250 min in infusion over 8 hours
Dexmedetomidine
• Pharmacokinetics Metabolism –in liver direct n- glucoronidation and via cytochrome p450 mediated
alipathic hydroxylation inactive metabolites Excretion- 95% urinary 4% fecal
Dexmedetomidine
Dexmedetomidine
USES•ICU sedation:• Loading dose: 1mcg/kg over 10 minutes• Maintenance dose: 0.2-0.7 mcg/kg/hr• Burns• Trauma• Alcohol withdrawal• Delirium• Seizure
•Procedural sedation:• Loading dose: 1 mcg/kg over 10 minutes• Maintenance dose: initiated at 0.6 mcg/kg/hr and then
titrated between 0.2-1 mcg/kg/hr• UGI endoscopy, Clonoscopy, MRI, ERCP
•Stress response to laryngoscopy and intubation
•Perioperative anesthesia• Premedication• Regional• Intravenous regional• General anesthesia• Postoperative pain management
•Use in operation theatre• Craniotomy: aneurysm, AV Malformation• Cervical spine surgery• Conventional CABG• Vascular surgery• Thoracic surgery• Bariatric surgery• Back surgery• Awake fiberoptic intubation
ICU Patients•Dexmedetomidine as a Sedative Agent in Critically Ill Patients: A Meta-Analysis of Randomized Controlled Trials:• Dexmedetomidine could help
to reduce ICU stay and time to extubation, in critically ill patients.
•does NOT produce respiratory depression•decreases opioid requirement by about 50%
Laura Pasin et. al ; PLOS ONE, December 2013, Volume 8, Issue 12, e82913 ;; BJA
BURNS• Deeper and better sedation.• Blunts catecholamine surge.• Prevent hypertension related to burn procedures.• Can be used in both intubated and non-intubated burn patients• Dexmedetomidine decreases requirements of propofol and ketamine.
Asmussen S,et al. burns. 2013 & PMCID: PMC4050928
Alcohol withdrawal syndrome• Benefits:• Inhibition of norepinephrine release, sympatholysis,
decreases autonomic hyperactivity associated with alcohol withdrawal syndrome• Rapid onset, lack of respiratory depression, and short
duration of action• Can be used in delirium tremens
• Clinical outcomes and efficacy • Case series comparing pre- and post-Dexmedetomidine
show rapid response : 1. Improved CIWA-Ar score 2. Decrease in blood pressure and heart rate 3. Decrease in benzodiazepines and haloperidol usage
Kalabalik and Sullivan. Int J Crit Care Emerg Med 2014, 1:1
Delirium• As compared with lorazepam and midazolam, Dexmedetomidine resulted in less delirium and a decreased duration of mechanical ventilation but not reduced stays in the ICU or hospital
•Dexmedetomidine administration spent less time in patients undergoing mechanical ventilation
Michael C. Reade et. al; N Eng J 2013,370;5
Delirium Percentage Comparison
Seizure•Dexmedetomidine increases the seizure threshold possibly via a mechanism related to the attenuation of the extracellular dopaminergic neurotransmitter response to cocaine administered to rats.
•Decreased bupivacaine toxicity in ratsPMCID: PMC7992911
Procedural Sedation•UGI endoscopy, Colonoscopy, MRI, ERCP•As compared to Midazolam:• More efficacy than than midazolam and faster onset
of action(19 min vs 35 min)•As compared to Propofol:• No hypoxia with dexmedetomidine• Onset of action : 10-20 min as compared to
propofol: 4 min• Similar efficacy• Greater recovery time with dexmedetomidine
Demiraran Y, Can J Gastroenter 2007(Dex good alternative for UGI endoscopy)Mason K, Ped Anesth 2008; Koroglu A, Anesth Analg 2006(sedation in MRI
Intravenous regional anesthesia
• Shortened sensory and motor block onset time
• Prolonged sensory and motor block recovery times
• Prolonged tolerance for the tourniquet• Decreased intra-postoperative analgesic
requirements• Longer time-to-first analgesic requirement
March 2004 - Volume 98 - Issue 3 - pp 835-840
Dexmedetomidine & Cardiovascular Surgery
• Decrease the risk of ventricular tachycardia andhyperglycemia
•Perioperative Dexmedetomidine use is associated with a decrease in postoperative mortality up to 1 year and decreased incidence of postoperative complications and delirium in patients undergoing cardiac surgery
•Dexmedetomidine : Herr et al. study, n=300: Dexmedetomidine vs. controls [propofol]
Faster time to extubate in Dexmedetomidine group - by 1 hr 70% did not require morphine vs. 34% controls Dexmedetomidine patients had less A. Fib (7 vs 12 pts)
PMCID: PMC3682268
Use in Thoracotomy and Thoracoscopy
•Patients are arousable, but sedated•Does NOT decrease ventilatory drive•Greatly decrease need for opioids•Alternative to thoracic epidural •Continue after extubation
Talke et al: Anesth Analg 2000;90:834. Multicenter
Use in Neuro anesthesia Mean CBF velocity decreasedPulsatility index increased (indicates an increase in CVR)
Zornow MH et al, J Cereb Blood Flow Metab; 1993 NO effect on CMRO2 Zornow MH, et al. anesth Analg. 1990
Increase prefrontal cortical function (PFC)Arnstein et el. Arch Gen Psychiatry 1996
No effect on lumbar CSF pressure Talke P et al. Anesth Analg 1997
Dexmedetomidine decreased total ischemic volume by 40% compared to placebo Jolkkonen J et al. Euro J Pharm 1999
NEUROPROTECTION Dexmedetomidine prevents delayed neuronal death
after focal ischemia Jolkkonen J et al. Euro J Pharm 1999
Dexmedetomidine enhances glutamine disposal by oxidative metabolism in astrocytes Huang R et al. J Cereb Blood Metab 2000
Use in Ophthalmology• Rise of IOP with Succinylcholine & endotracheal intubation can be blunted with I.V. Dexmedetomidine premedication.
• Hemodynamic stability
• Beneficial premedication in open globe injuries
• Single I.V. dose of Dexmedetomidine 0.6 mcg/kg decrease IOP by 34%
British Journal of Anaesthesia 100 (4): 485–9 (2008) February 19, 2008
Effect of perioperative dexmedetomidine on stress response• Laryngoscopy and intubation• Perioperative use of dexmedetomidine reduces serum catecholamine, IL-10 and cortisol levels but the decrease in cortisol levels was not statistically different from the comparator anaesthetics.
Clinical Administration•Onset of action: about 5 minutes as compared to that of midazolam 3-5 minutes and that of propofol 30-50 seconds can be decreased by infusion of standard loading dose of 1µg/kg, over 10 minutes
Anesth Essays Res. 2011 Jul-Dec; 5(2): 128-133
•Offset of sedative action in 5 minutes, while midazolam has about 2 to 6 hours and propofol has 3-8 minutes.
•Duration of analgesic action of about 4 hours as compared to that of Fentanyl up to 60-80 minutes
alpha 2 Adrenergic Receptor Antagonist
Atipamezole• Effectively reverses Psychomotor side-effects• Reverses Sedation & Sympatholysis• Reverses Analgesia• t ½ is 1 ½ - 2 hours.
Anesth Essays Res. 2011 Jul-Dec; 5(2): 128-133
CONCLUSION
• OPERATION THEATRE:– Suitable agent for preanesthetic anxiolysis,
preoperative sedation and intra-,post-operative analgesia.
• PROCEDURE ROOM:– Useful in procedural sedation and conscious
sedation.• ICU:– Better and cost effective for sedation in ICU patients.
THANK YOU