Dexmedetomidine

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current role of dexmedetomidine in anaesthesia & intensive care

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Dexmedetomidine Current Role in Anaesthesia & Intensive care: 

Dexmedetomidine Current Role in Anaesthesia & Intensive care Dr. Gagan pal Singh MBBS, MD, FNB (Cardiac Anaesthesia ) Consultant, Dept of Cardiothoracic Anaesthesia Max superspeciality Hospital Bathinda Sept 14, 2012

Objectives: 

Objectives Pharmacology of D ex alpha 2 agonist Molecular targets + neural substrates L ocus Ceruleus N atural sleep pathways Clinical paradigms for use of Dex in Anaesthesia S edation + analgesia w/o respiratory depression A ttenuation of tachycardia S mooth emergence + weaning from mech vent

α2 Receptors: 

α 2 Receptors Central – Peripheral Effector organs liver, kidney, pancreas, eye, vascular smooth muscles and platelets Presynaptic – Postsynaptic Extrasynaptic (peripheral) Vascular Coronary

α2 Receptors: 

α 2 Receptors Isoreceptors (A, B and C) Subtype A, the predominant subtype in CNS responsible for the sedative, analgesic and sympatholytic effect Subtype B, found mainly in the peripheral vasculature responsible for the short-term hypertensive response Subtype C, found in the CNS responsible for the anxiolytic effect

α2 Adrenergic Receptor Pharmacology: 

α 2 A drenergic R eceptor Pharmacology Adrenergic receptors Regulate release of neurotransmitters Control epinephrine, norepinephrine release Modulate sympathetic response “negative feedback loop”

Dexmedetomidine - Mechanism of Action: 

Dexmedetomidine - Mechanism of Action

Dexmedetomidine, α2 receptors and CNS: 

Dexmedetomidine , α 2 receptors and CNS Sites of action Brain (locus ceruleus ) Spinal cord Autonomic nerves CNS Sedation/hypnosis Anxiolysis Analgesia Autonomic nerves  Sympathetic activity  BP,  HR Dexmedetomidine Spinal Cord LOCUS CERULEUS FOURTH VENTRICLE PONS CEREBRUM CEREBELLUM

Protein Binding and Brain: 

94% Protein Bound Dexmedetomidine 6% Free Blood Brain Barrier Blood Brain Protein Binding and B rain

α2 Adrenoceptor Mediated Responses: 

α 2 Adrenoceptor Mediated Responses Central nervous system Sedation Anxiolysis Analgesia Renal Diuresis Cardiovascular Vasoconstriction Bradycardia Respiratory  ventilation Bronchodilation Endocrine  NE release  Insulin release  C ortisol release  GH release Gastrointestinal  Salivation  Bowel motility

Pharmacodynamics: 

Pharmacodynamics Sedation/hypnosis Anxiolysis Analgesia Sympatholysis (BP/HR, NE) Reduces shivering Neuroprotective effects No effect on ICP No respiratory depression

Sedation/ Hypnosis: 

Sedation/ Hypnosis Dose dependent Minimal respiratory depression Arousable Reduced anesthetic/analgesic use Reversible ( A tipamezole ) Amnesia?

Mechanism for the Hypnotic Effect: 

Mechanism for the Hypnotic Effect Hyperpolarization of locus ceruleus neurons –  2 A-Adrenoreceptor subtype Activation of K + channels Inhibition of Ca ++ channels Inhibition of adenylyl cyclase  Firing rate of locus ceruleus neurons  Activity in ascending noradrenergic pathway

Restorative Properties of Sleep: 

Restorative Properties of Sleep Activates natural sleep pathways Increased rate of healing Promotes anabolism Facilitates growth hormone release Counteracts catabolism Inhibits cortisol release Inhibits catecholamine release

Harmful Effects of Sleep Deprivation: 

Harmful Effects of Sleep Deprivation  pressor response to sympathetic stimulation Impaired CV response to positioning change Immune dysfunction  ability of lymphocytes to synthesize DNA  leukocyte phagocytic activity  interferon production by lymphocytes Cognitive dysfunction Impaired memory, communication skills Impaired decision-making Confusional state, delirium

Mechanisms for Analgesic Effect: 

Mechanisms for Analgesic Effect Disinhibit A5/A7 noradrenergic pathways Activate noradrenergic pathways Descending inhibitory pathways Decrease emotive aspects Decrease emotive aspects Subcortical + cortex Inhibit firing Inhibit firing Second order neurons Inhibit release of SP and glutamate Inhibit release of SP and glutamate Primary afferent neurons Inhibit sympathetic- mediated pain   inflammation [e.g., bradykinin , other kinins ] Peripheral nociceptors  2 Agonists Opioids

Effect on Ventilation : 

Effect on Ventilation Clonidine , dexmedetomidine Minimal effect on RR, V E , Pa CO 2  in V E /ET CO 2 No potentiation of opioid -induced respiratory depression

Side Effects: 

Side Effects Sinus pause/arrest Orthostatic hypotension Dry mouth Vasoconstriction

Benefits of α2 Agonists: 

Benefits of α 2 Agonists No respiratory depression Decrease anesthetic requirements Decrease analgesic requirements Blood pressure control without tachycardia Sedation, anxiolysis , analgesia Decrease oxygen demand Decrease shivering

Pharmacokinetics: 

Pharmacokinetics Rapid distribution ( t 1/2 α ): 6 minutes Steady-state volume of distribution ( Vss ): 118 liters Clearance: 39 L/hr Terminal elimination half-life ( t 1/2  ): 2 hours

Metabolism: 

Metabolism Active d -isomer of medetomidine Metabolized in liver Eliminated via kidney

2 Agonists: 

 2 Agonists Clonidine Selectivity :  2 : 1 200:1 t 1/2  - 8 hrs PO, patch, epidural Antihypertensive Analgesic adjunct Dexmedetomidine Selectivity :  2 : 1 1620:1 t 1/2  - 2 hrs Intravenous Sedative-analgesic Primary sedative

Perioperative use of Dexmedetomidine: 

Perioperative use of Dexmedetomidine Premedication Possesses anxiolytic , sedative, analgesic, antisialogogue and sympatholytic properties. Potentiates the anesthetic effects of all intraoperative anesthetics (intravenous, volatile or regional block). Bohrer et al (1994) showed that preoperative administration of i.v . or i.m . dexmedetomidine resulted in a decrease in induction dose of thiopentone by up to 30%.

Premedication: 

Premedication Indications Patients susceptible to preoperative and perioperative stress Drug addicts and alcoholics, chronic opioid users Hypertensive patients.

Intraoperative uses : 

Intraoperative uses As Adjunct to General Anesthesia Increase hemodynamic stability Attenuation of the stress-induced sympathoadrenal responses to intubation, during surgery and during emergence from anesthesia . Reduces the vasoconstriction threshold and the shivering threshold Lower incidence of shivering. Produces a anesthetic -sparing effect.

As Adjunct to General Anesthesia: 

As Adjunct to General Anesthesia Aho et al (1991) showed 25% reduction of maintenance concentrations of isoflurane in patients undergoing hysterectomy. Fragen et al (1999) noted 17% reduction in sevoflurane requirement for maintenance of anaesthesia in elderly patients. Talke et al (1999) investigated the muscle relaxant effects of dexmedetomidine on the neuromuscular junction and found no clinically relevant effects.

For Regional Anesthesia: 

For Regional Anesthesia Its use as adjuvant in regional anesthesia is still not validated. Maroof et al found in 60 patients undergoing orthopaedic surgery that the addition of 100 μg of dexmedetomidine to 20 ml 0.5% bupivacaine resulted in lower incidence of postoperative shivering when compared to patients who received epidural bupivacaine alone (10% vs. 36%).

For Regional Anesthesia: 

For Regional Anesthesia Memis et al (2004) noted that the addition of 0.5 μg /kg dexmedetomidine to lidocaine for intravenous regional anesthesia improves the quality of anesthesia and perioperative analgesia without causing side effects. Kanazi et al (2006) investigated the effect of adding a small dose of 3 μg of intrathecal dexmedetomidine to 12 mg bupivacaine . They found a significant prolongation of sensory and motor block as compared to bupivacaine alone. In this study, the effect of 3 μg intrathecal dexmedetomidine was similar to that produced by the addition of 30 μg of intrathecal clonidine .

In Monitored Anesthesia Care: 

In Monitored Anesthesia Care Dexmedetomidine in MAC was used successfully in many situations: when patient arousability needed to be preserved for awake craniotomy for awake carotid endarterectomy for vitreoretinal surgey . For sedation in difficult airway patients During fiberoptic intubation For sedation of a patient with difficult airway undergoing lumbar laminectomy surgery in the prone chest position under spinal anesthesia .

As a Sole Anaesthetic Agent: 

As a Sole Anaesthetic Agent Ramsay has used dexmedetomidine as a sole anesthetic agent. The report describes three patients who presented for surgery with potential airway management challenges. Dexmedetomidine was infused in increasing doses (up to 10 μg /kg/h) until general anesthesia was attained. No respiratory depression was noted, only one patient required chin lift. Also no hypotension or severe bradycardia were noted. The rationale for this new, off-label use of dexmedetomidine is based on its known properties to provide sedation, analgesia while avoiding respiratory depression at low doses. These effects were maintained at higher doses without hemodynamic instability.

In Postoperative Period: 

In Postoperative Period Its special properties favor its use in recovery room in the extubated , spontaneously breathing patient. Care should be taken in patients who depend on a high level of sympathetic tone or in patients with reduced myocardial function who cannot tolerate the decrease in sympathetic tone. Perioperative administration of dexmedetomidine could be beneficial in chronic opioid users and alcoholics, in high-risk patients as well as in cardiac patients with good to moderately decreased left ventricular function.

In Postoperative Period: 

In Postoperative Period In a study conducted by Talke , high-risk patients who received dexmedetomidine from 1 h before until 48 h after vascular surgery experienced significantly fewer ischemic episodes than did patients in the placebo group (8% vs 29%). During emergence from anesthesia , NE levels in the placebo group were 2 to 3 times higher than those in the dexmedetomidine group. Patients who received intraoperative dexmedetomidine needed more fluids to avoid hypotension, a side effect that may be unfavorable in volume-sensitive patients with reduced left ventricular function.

Clinical Uses in Anaesthesia: 

Clinical Uses in Anaesthesia Bariatric surgery Sleep apnea patients Craniotomy: aneurysm, AVM [hypothermia] Cervical spine surgery Off-pump CABG Vascular surgery Thoracic surgery Conventional CABG Back surgery Head injury Burn Trauma Alcohol withdrawal Awake intubation

Sleep Apnea Patients: 

Ogan OU, Plevak DJ: Mayo Clinic; www.sleepapnea.org Sleep Apnea Patients Anesthesia considerations Morbid obesity, at risk for aspiration Difficult IV access Systemic + pulm HTN, cor pulmonale Postop airway obstruction + ventilatory arrest with anesthetic drugs  upper airway muscle activity inhibition of normal arousal patterns upper airway swelling from laryngoscopy , surgery, intubation Dexmedetomodine Anesthetic adjunct to minimize opioid + sedative use

Gastric Bypass Surgery Patients: 

Craig MG et al: IARS abstract, 2002. Baylor Gastric Bypass Surgery Patients Anesthesia considerations Morbidly obese patients Prone to hypoxemia Sleep apnea is common Respiratory depression with opioids Dexmedetomidine 0.1 to 0.7 ug /kg/hr, prospectively studied in 32 pts  opioid use in dex group 1 pt in control gp needed reintubation Dex pts more likely to be normotensive with  HR

Dex Improves Postop Pain Mgt after Bariatric SX: 

Ramsay MA, et al: Anesthesiology, 2002: A-910 and A-165. Baylor Dex Improves Postop Pain Mgt after Bariatric S X Double blind RCT , n= 25. Dex started at 0.5 to 0.7 ug /kg/hr 1 hr prior to end of surgery [ vs.saline ]. Infusion adjusted according to need Dex continued in PACU Pain control with PCA with morphine Dexmedetomidine Morphine use  in dex gp (P < 0.03) Pain score better in dex gp : 1.8 vs 3.4 (P < 0.01) % time pain free in PACU  in dex gp : 44 % vs 0 (P < 0.002) Better control of HR in dex gp

Craniotomy for Aneurysm / AVM: 

Doufas AG et al: Stroke 2003;34. Louisville, KY Craniotomy for Aneurysm / AVM Anesthesia considerations Smooth induction + emergence Prevent rupture Avoid cerebral ischemia Hypothermia (33 o C )  CMRO 2 , CBF, CSF , ICP Dexmedetomodine  sympathetic stimulation  or no change in ICP  shivering w/o respiratory depression Preserved cognitive function reliable serial neuro exams

Coronary Artery Bypass Surgery : 

Herr DL: Crit Care Med 2000;28:M248. Washington Hospital Coronary Artery Bypass Surgery Herr study n=300: Dex vs. controls [ propofol ] RCT, dex started at sternal closure, 0.4 ug /kg/hr after loading dose, and 0.2 to 0.7 ug /kg/hr for 6-24 hrs after extubation Ramsay > 3 before extub , Ramsay 2 after extub Dexmedetomidine Faster time to extub in dex gp by 1 hr 94% did not require propofol 70% did not require morphine (vs. 34% controls) Dex pts had less Afib (7 vs 12 pts)

CABG and Lung Disease: 

Sumping ST: CCM 2000;28:M249. Duke CABG and Lung Disease Anesthesia considerations Often delays tracheal extubation RCT, n= 20. Dex started at end of surgery, 0.2 to 0.7 ug /kg/hr, + continued 6 hr after extubation vs. controls ( propofol ) Ramsay > 3 before extub , Ramsay 2 after extubation Dexmedetomidine Faster time to extubation : 7.8 + 4.6 h v. 16.5 + 11.8 h No difference in PaCO2 between baseline & 30 min after extub : 37.9 v. 34.9 mmHg

Thoracotomy + Thoracoscopy : 

Thoracotomy + Thoracoscopy Anesthesia considerations COPD , pleural effusion, marginal pulmonary function  pCO 2 +  pO 2 with opioids for analgesia Thoracic epidural: mainly for thoracotomy Dex : mainly for thoracoscopy Dexmedetomidine Patients are arousable , but sedated Does not  ventilatory drive Greatly  need for opioids Alternative to thoracic epidural Continue after extubation

Vascular Surgery : 

Talke et al: Anesth Analg 2000;90:834. Multicenter Vascular Surgery Anesthesia considerations Usually at risk for CAD, ischemia, HTN, tachycardia Dex attenuates periop stress response Dex attenuates  BP w AXC, especially thoracic aorta Dexmedetomidine RCT , n=41. Dex continued 48 hr postop HR  in dex gp at emergence 73 + 11 v. 83 + 20 bpm Better control of HR in dex gp Plasma NE levels  in dex gp

Meta- Analysis of Alpha-2 Agonists : 

Wijeysundera , Am J Med 2003;114:742. Univ of Toronto Meta- Analysis of Alpha-2 Agonists 23 trials, n=3395. All surgeries:  mortality + ischemia Vascular:  MI + mortality Cardiac:  ischemia Cardiac:  BP (more hypotension) Conclusions: Not class 1 evidence yet, but trials look promising Especially vascular surgery

Other Surgical Procedures: 

Other Surgical Procedures Neck + back surgery Dex causes minimal effect on SSEP monitoring Smooth emergence, especially cervical spine Easy to evalute neuro function prior to + after extubation Abdominal surgery Dexmedetomidine provides analgesia without respiratory depression Especially useful in elderly undergoing colon resections, TAH, + other stressful procedures

Burn Unit: 

Burn Unit  2 agonist effect assists in the management of burn patients Blunts catecholamine surge Use in intubated and non- intubated burn patients Administer as a standard load once patient is normovolemic (range: 0.4 to 0.7 mcg/kg/hr)  dose for less severe burns and non- intubated patients 0.2 to 0.4 mcg/kg/hr for routine burn care outpatient dressing changes, instead of ketamine

Alcohol Withdrawal and Trauma : 

Alcohol Withdrawal and Trauma Trauma often occurs in males who are intoxicated Trauma pt may experience agitation and is at risk for exacerbating underlying injuries Benzodiazepines typically used Intubation and ventilation often required if extreme agitation Dexmedetomidine is an alternative Spontaneous breathing Hemodynamic stability Adequate sedation Prevention of autonomic effects of withdrawal Pain control

In Pediatric-age Group: 

In Pediatric -age Group Only few cases about the use of dexmedetomidine in the pediatric age group are found in the literature. Tobias used dexmedetomidine for ICU sedation in a 10-week old infant requiring mechanical ventilation and in a 14-y old patient after posterior spinal fusion for scoliosis at a dose of 0.25 μg /kg/h for 24 h which resulted in acceptable sedation without significant hemodynamic changes. Dexmedetomidine was also used for sedation and anesthesia in an 11-y old patient undergoing gastroscopy ; however, it resulted in insufficient sedation. Another study conducted in pediatric -age group explored the use of intraoperative dexmedetomidine at different doses with the goal of reducing the post sevoflurane agitation in children aged 1-10 y. The optimal dose of dexmedetomidine was 0.3 μg /kg and its use did not result in adverse effects.

Considerations With Use of Dexmedetomidine: 

Considerations With Use of Dexmedetomidine Dilute in 0.9% saline: 4 mcg/ mL Requires infusion pump: mcg/kg/h Transient HTN: with rapid bolus H ypotension may occur, especially if hypovolemia  HR (attenuation of tachycardia): usually desirable  conc of inhaled agents: BIS monitoring Continue infusion after extubation for 30 min [PACU] Geriatrics : more hypotension + bradycardia :  dose

Summary: 

Summary Short acting alpha 2 agonist FDA approval in 1999 for use as a short-term (less than 24 h) sedative analgesic in the ICU. Good premedication agent Dex can help optimize anesthesia via: Sedation, analgesia +  sympathetic activity Attenuation of stress response +  HR Smooth emergence + tracheal extubation Unique mechanism of action on natural sleep pathway permits sedation + analgesia w/o respiratory depression Effective agent for pts with compromised airway, postoperative extubated pt.

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