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.

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