clinical use of dexmedetomidine

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Clinical Use of Dexmedetomidine Clinical Use of Dexmedetomidine Charles E. Smith, MD Charles E. Smith, MD Professor of Anesthesia Professor of Anesthesia Director, Cardiothoracic Director, Cardiothoracic Anesthesia Anesthesia MetroHealth Medical Center MetroHealth Medical Center Case Western Reserve University Case Western Reserve University Cleveland, Ohio, USA Cleveland, Ohio, USA October 7, 2003 October 7, 2003

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Clinical Use of Dexmedetomidine. Charles E. Smith, MD Professor of Anesthesia Director, Cardiothoracic Anesthesia MetroHealth Medical Center Case Western Reserve University Cleveland, Ohio, USA October 7, 2003. Objectives. Pharmacology of dex alpha 2 agonist - PowerPoint PPT Presentation

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Page 1: Clinical Use of Dexmedetomidine

Clinical Use of DexmedetomidineClinical Use of Dexmedetomidine

Charles E. Smith, MDCharles E. Smith, MDProfessor of AnesthesiaProfessor of AnesthesiaDirector, Cardiothoracic Director, Cardiothoracic

AnesthesiaAnesthesiaMetroHealth Medical CenterMetroHealth Medical CenterCase Western Reserve UniversityCase Western Reserve UniversityCleveland, Ohio, USACleveland, Ohio, USAOctober 7, 2003October 7, 2003

Page 2: Clinical Use of Dexmedetomidine

ObjectivesObjectives

• Pharmacology of dexPharmacology of dex– alpha 2 agonistalpha 2 agonist

• Molecular targets + neural substratesMolecular targets + neural substrates– locus caeruleuslocus caeruleus– natural sleep pathwaysnatural sleep pathways

• Clinical paradigms for use of dex in anesthesiaClinical paradigms for use of dex in anesthesia– sedation + analgesia w/o resp depressionsedation + analgesia w/o resp depression– attenuation of tachycardiaattenuation of tachycardia– smooth emergence + weaning from mech ventsmooth emergence + weaning from mech vent

Page 3: Clinical Use of Dexmedetomidine

PharmacologyPharmacology

• Establish and maintain adequate drug Establish and maintain adequate drug concentration at effector site to produce concentration at effector site to produce desired effect desired effect – sedationsedation– hypnosishypnosis– analgesiaanalgesia– paralysisparalysis

• Predict the time course of drug onset + Predict the time course of drug onset + offsetoffset

Page 4: Clinical Use of Dexmedetomidine

PharmacodynamicsPharmacodynamics

• Relationship between drug conc + effectRelationship between drug conc + effect• Interaction of drug with receptorInteraction of drug with receptor• ReceptorReceptor

– cell componentcell component– interacts with drug interacts with drug – biochemical changebiochemical change

• Examples of receptors: Examples of receptors: – AchR, GABA, opioid, AchR, GABA, opioid, + + adrenergic adrenergic

Page 5: Clinical Use of Dexmedetomidine

ReceptorsReceptors

• Coupled to ion channels Coupled to ion channels – neural signaling, 2nd messenger effectsneural signaling, 2nd messenger effects

• Drug effects at receptorDrug effects at receptor– agonist, antagonist or mixed effectsagonist, antagonist or mixed effects– stereospecificity, racemic mixture of isomersstereospecificity, racemic mixture of isomers

• Receptor alterations Receptor alterations – upregulated or downregulated (e.g., CHF)upregulated or downregulated (e.g., CHF) or or number (e.g., burns, myasthenia number (e.g., burns, myasthenia

gravis)gravis)

Page 6: Clinical Use of Dexmedetomidine

PharmacodynamicsPharmacodynamics

• Sedation/hypnosisSedation/hypnosis• AnxiolysisAnxiolysis• AnalgesiaAnalgesia• Sympatholysis (BP/HR, NE)Sympatholysis (BP/HR, NE)• Reduces shiveringReduces shivering• Neuroprotective effectsNeuroprotective effects• No effect on ICPNo effect on ICP• No respiratory depressionNo respiratory depression

Page 7: Clinical Use of Dexmedetomidine

PharmacokineticsPharmacokinetics

• Rapid redistribution: 6 minRapid redistribution: 6 min• Elimination half-life: 2 hElimination half-life: 2 h• Vd steady state: 118 LVd steady state: 118 L• Clearance: 39 L/hClearance: 39 L/h• Protein binding: 94%Protein binding: 94%• Metabolism: biotransformation in liver to inactive Metabolism: biotransformation in liver to inactive

metabolites + excreted in urinemetabolites + excreted in urine• No accumulation after infusions 12-24 hNo accumulation after infusions 12-24 h• Pharmacokinetics similar in young adults + Pharmacokinetics similar in young adults +

elderlyelderly

Page 8: Clinical Use of Dexmedetomidine

2 2 AgonistsAgonists

ClonidineClonidine• Selectivity: Selectivity: 22::11 200:1 200:1• tt1/21/2 8 hrs 8 hrs11

• PO, patch, epiduralPO, patch, epidural• AntihypertensiveAntihypertensive• Analgesic adjunctAnalgesic adjunct• IV formulation not IV formulation not

available in USavailable in US

DexmedetomidineDexmedetomidine• Selectivity: Selectivity: 22::11 1620:1 1620:1• tt1/21/2 2 hrs 2 hrs• IntravenousIntravenous• Sedative-analgesicSedative-analgesic• Primary sedativePrimary sedative• Only IV Only IV 22 available for available for

use in the USuse in the US

Page 9: Clinical Use of Dexmedetomidine

Mechanism for the Hypnotic EffectMechanism for the Hypnotic Effect

• Hyperpolarization of locus ceruleus neuronsHyperpolarization of locus ceruleus neurons–– 2A2A-Adrenoreceptor subtype-Adrenoreceptor subtype– Activation of KActivation of K++ channels channels– Inhibition of CaInhibition of Ca++++ channels channels– Inhibition of adenylyl cyclaseInhibition of adenylyl cyclase

Firing rate of locus caeruleus neuronsFiring rate of locus caeruleus neurons Activity in ascending noradrenergic Activity in ascending noradrenergic

pathwaypathway

Page 10: Clinical Use of Dexmedetomidine

Restorative Properties of SleepRestorative Properties of Sleep

• Activates natural sleep pathwaysActivates natural sleep pathways• Increased rate of healing Increased rate of healing

– Promotes anabolismPromotes anabolism• Facilitates growth hormone releaseFacilitates growth hormone release

– Counteracts catabolismCounteracts catabolism• Inhibits cortisol releaseInhibits cortisol release• Inhibits catecholamine releaseInhibits catecholamine release

Page 11: Clinical Use of Dexmedetomidine

Harmful Effects of Sleep Harmful Effects of Sleep DeprivationDeprivation

pressor response to sympathetic stimulationpressor response to sympathetic stimulation• Impaired CV response to positioning changeImpaired CV response to positioning change BP, HR + urine norepinephrineBP, HR + urine norepinephrine• Immune dysfunctionImmune dysfunction

ability of lymphocytes to synthesize DNAability of lymphocytes to synthesize DNA leukocyte phagocytic activityleukocyte phagocytic activity interferon production by lymphocytesinterferon production by lymphocytes

• Cognitive dysfunctionCognitive dysfunction– Impaired memory, communication skillsImpaired memory, communication skills– Impaired decision-makingImpaired decision-making– Confusional state [ICU]: Confusional state [ICU]: apathy, delirium apathy, delirium

Page 12: Clinical Use of Dexmedetomidine

Mechanisms for Analgesic EffectMechanisms for Analgesic Effect

Disinhibit A5/A7 Disinhibit A5/A7 noradrenergic noradrenergic pathwayspathways

Activate PAG; Activate PAG; activate activate noradrenergic noradrenergic pathwayspathways

Descending Descending inhibitory pathwaysinhibitory pathways

Decrease emotive Decrease emotive aspectsaspects

Decrease emotive Decrease emotive aspectsaspects

Subcortical + cortexSubcortical + cortex

Inhibit firingInhibit firingInhibit firingInhibit firingSecond order Second order neuronsneurons

Inhibit release of Inhibit release of SP and glutamateSP and glutamate

Inhibit release of Inhibit release of SP and glutamateSP and glutamate

Primary afferent Primary afferent neuronsneurons

Inhibit sympathetic- Inhibit sympathetic- mediated painmediated pain

inflammation [e.g., inflammation [e.g., bradykinin, other bradykinin, other kininskinins]]

Peripheral Peripheral nociceptorsnociceptors

2 2 AgonistsAgonistsOpioidsOpioids

Page 13: Clinical Use of Dexmedetomidine

Dex: Package Insert InfoDex: Package Insert Info• Indications Indications

– Sedation of intubated and ventilated patients during Sedation of intubated and ventilated patients during treatment in an ICU setting x 24 htreatment in an ICU setting x 24 h

• ContraindicationsContraindications– Caution in patients with advanced heart block, severe Caution in patients with advanced heart block, severe

ventricular dysfunction, shockventricular dysfunction, shock• Drug interactionsDrug interactions

– Vagal effects can be counteracted by atropine / glycoVagal effects can be counteracted by atropine / glyco• Clearance is lower w hepatic impairmentClearance is lower w hepatic impairment• Withdrawal sx after discontinuation: not seen after 24 h Withdrawal sx after discontinuation: not seen after 24 h

useuse• Adrenal insufficiency: no effect on cortisol response to Adrenal insufficiency: no effect on cortisol response to

ACTHACTH

Page 14: Clinical Use of Dexmedetomidine

Clinical Uses of Dex in AnesthesiaClinical Uses of Dex in Anesthesia

• Bariatric surgeryBariatric surgery• Sleep apnea patientsSleep apnea patients• Craniotomy: Craniotomy:

aneurysm, AVM aneurysm, AVM [hypothermia][hypothermia]

• Cervical spine Cervical spine surgerysurgery

• Off-pump CABGOff-pump CABG• Vascular surgeryVascular surgery• Thoracic surgeryThoracic surgery

• Conventional CABG Conventional CABG • Back surgery, evoked Back surgery, evoked

potentialspotentials• Head injuryHead injury• BurnBurn• TraumaTrauma• Alcohol withdrawalAlcohol withdrawal• Awake intubationAwake intubation

Page 15: Clinical Use of Dexmedetomidine

Ogan OU, Plevak DJ: Mayo Clinic; www.sleepapnea.org

Sleep Apnea PatientsSleep Apnea Patients

Anesthesia considerationsAnesthesia considerations• Morbid obesity, at risk for aspirationMorbid obesity, at risk for aspiration• Difficult IV accessDifficult IV access• Systemic + pulm HTN, cor pulmonaleSystemic + pulm HTN, cor pulmonale• Postop airway obstruction + ventilatory arrest with Postop airway obstruction + ventilatory arrest with

anesthetic drugsanesthetic drugs upper airway muscle activityupper airway muscle activity– inhibition of normal arousal patternsinhibition of normal arousal patterns– upper airway swelling from laryngoscopy, surgery, upper airway swelling from laryngoscopy, surgery,

intubationintubationDexmedetomodineDexmedetomodine• Anesthetic adjunct to minimize opioid + sedative Anesthetic adjunct to minimize opioid + sedative

useuse

Page 16: Clinical Use of Dexmedetomidine

Craig MG et al: IARS abstract, 2002. Baylor

Gastric Bypass Surgery PatientsGastric Bypass Surgery Patients

Morbidly obese patientsMorbidly obese patients• Prone to hypoxemiaProne to hypoxemia• Sleep apnea is commonSleep apnea is common• Respiratory depression w opioidsRespiratory depression w opioids

Dexmedetomidine, 0.1 to 0.7 ug/kg/hr, Dexmedetomidine, 0.1 to 0.7 ug/kg/hr, prospectively studied in 32 pts prospectively studied in 32 pts

opioid use in dex groupopioid use in dex group• 1 pt in control gp needed reintubation1 pt in control gp needed reintubation• Dex pts more likely to be normotensive w Dex pts more likely to be normotensive w HR HR

Page 17: Clinical Use of Dexmedetomidine

Ramsay MA, et al: Anesthesiology, 2002: A-910

and A-165. Baylor

Dex Improves Postop Pain Mgt Dex Improves Postop Pain Mgt after Bariatric Surgeryafter Bariatric Surgery

RCT, n= 25. Dex started at 0.5 to 0.7 ug/kg/hr 1 hr RCT, n= 25. Dex started at 0.5 to 0.7 ug/kg/hr 1 hr prior to end of surgery [vs.saline]. Double- blindprior to end of surgery [vs.saline]. Double- blind

• Infusion adjusted according to needInfusion adjusted according to need• Dex continued in PACUDex continued in PACU• PACU pain control with PCAPACU pain control with PCA

DexmedetomidineDexmedetomidine• Morphine use Morphine use in dex gp (P < 0.03) in dex gp (P < 0.03)• Pain score better in dex gp: 1.8 vs 3.4 (P < 0.01)Pain score better in dex gp: 1.8 vs 3.4 (P < 0.01)• % time pain free in PACU % time pain free in PACU in dex gp: in dex gp:

– 44% vs 0 (P < 0.002)44% vs 0 (P < 0.002)• Better control of HR in dex gpBetter control of HR in dex gp

Page 18: Clinical Use of Dexmedetomidine

Doufas AG et al: Stroke 2003;34. Louisville, KY

Craniotomy for Aneurysm / AVMCraniotomy for Aneurysm / AVM

Anesthesia considerationsAnesthesia considerations• Smooth induction + emergenceSmooth induction + emergence• Prevent rupturePrevent rupture• Avoid cerebral ischemiaAvoid cerebral ischemia• Hypothermia (33 Hypothermia (33 ooC) C) CMRO CMRO22, CBF, CBV, CSF, ICP, CBF, CBV, CSF, ICP

DexmedetomodineDexmedetomodine sympathetic stimulationsympathetic stimulation or no change in ICPor no change in ICP shivering w/o resp depressionshivering w/o resp depression• Preserved cognitive fct Preserved cognitive fct

– reliable serial neuro examsreliable serial neuro exams

Page 19: Clinical Use of Dexmedetomidine

Herr DL: Crit Care Med 2000;28:M248. Washington

Hospital

Coronary Artery Surgery PatientsCoronary Artery Surgery PatientsHerr study, n=300: Dex vs. controls [propofol]Herr study, n=300: Dex vs. controls [propofol]• RCT, dex started at sternal closure, 0.4 ug/kg/hr 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- after loading dose, and 0.2 to 0.7 ug/kg/hr for 6- 24 hrs after extubation24 hrs after extubation

• Ramsay Ramsay >> 3 before extub, Ramsay 2 after extub 3 before extub, Ramsay 2 after extub

DexmedetomidineDexmedetomidine• Faster time to extub in dex gp Faster time to extub in dex gp

– by 1 hrby 1 hr• 94% did not require propofol94% did not require propofol• 70% did not require morphine 70% did not require morphine

– (vs. 34% controls)(vs. 34% controls)• Dex pts had less Afib (7 vs 12 pts)Dex pts had less Afib (7 vs 12 pts)

Page 20: Clinical Use of Dexmedetomidine

Sumping ST: CCM 2000;28:M249. Duke

CABG and Lung DiseaseCABG and Lung Disease

Lung DiseaseLung Disease• Often delays tracheal extubationOften delays tracheal extubation• RCT, n= 20. Dex started at end of surgery, 0.2 RCT, n= 20. Dex started at end of surgery, 0.2

to 0.7 ug/kg/hr, + continued 6 hr after to 0.7 ug/kg/hr, + continued 6 hr after extubation vs. controls (propofol)extubation vs. controls (propofol)

• Ramsay Ramsay >> 3 before extub, Ramsay 2 after extub 3 before extub, Ramsay 2 after extub

DexmedetomidineDexmedetomidine• Faster time to extub: Faster time to extub:

– 7.8 7.8 ++ 4.6 h v. 16.5 4.6 h v. 16.5 ++ 11.8 h 11.8 h• No difference in PaCO2 between gps 30 min No difference in PaCO2 between gps 30 min

after extub: after extub: 37.9 v. 34.9 mmHg37.9 v. 34.9 mmHg

Page 21: Clinical Use of Dexmedetomidine

Thoracotomy + Thoracoscopy Thoracotomy + Thoracoscopy Thoracotomy + thoracoscopy patientsThoracotomy + thoracoscopy patients• COPD, pleural effusion, marginal pulmonary fctCOPD, pleural effusion, marginal pulmonary fct pCOpCO22 + + pO pO22 with opioids for analgesia with opioids for analgesia• Thoracic epidural: mainly for thoracotomyThoracic epidural: mainly for thoracotomy• Dex: mainly for thoracoscopyDex: mainly for thoracoscopy

DexmedetomidineDexmedetomidine• Patients are arousable, but sedatedPatients are arousable, but sedated• Does not Does not ventilatory drive ventilatory drive• Greatly Greatly need for opioids need for opioids• Alternative to thoracic epidural Alternative to thoracic epidural • Continue after extubationContinue after extubation

Page 22: Clinical Use of Dexmedetomidine

Talke et al: Anesth Analg 2000;90:834. Multicenter

Vascular Surgery Vascular Surgery

Vascular surgery patientsVascular surgery patients• Usually at risk for CAD, ischemia, HTN, tachycardiaUsually at risk for CAD, ischemia, HTN, tachycardia• Dex attenuates periop stress responseDex attenuates periop stress response• Dex attenuates Dex attenuates BP w AXC, especially thoracic BP w AXC, especially thoracic

aortaaorta

DexmedetomidineDexmedetomidine• RCT, n=41. Dex continued 48 hr postopRCT, n=41. Dex continued 48 hr postop• HR HR in dex gp at emergence in dex gp at emergence

– 73 73 ++ 11 v. 83 11 v. 83 ++ 20 bpm 20 bpm• Better control of HR in dex gpBetter control of HR in dex gp• Plasma NE levels Plasma NE levels in dex gp in dex gp

Page 23: Clinical Use of Dexmedetomidine

Wijeysundera, Am J Med 2003;114:742. Univ of

Toronto

Meta- Analysis of Alpha-2 Agonists Meta- Analysis of Alpha-2 Agonists

23 trials, n=3395.23 trials, n=3395.• All surgeries: All surgeries: mortality + ischemia mortality + ischemia• Vascular:Vascular: MI + mortality MI + mortality • Cardiac: Cardiac: ischemia ischemia• Cardiac: Cardiac: BP (more hypotension) BP (more hypotension)

Conclusions:Conclusions:• Not class 1 evidence yet, but trials look Not class 1 evidence yet, but trials look

promisingpromising– Especially vascular surgeryEspecially vascular surgery

Page 24: Clinical Use of Dexmedetomidine

Other Surgical ProceduresOther Surgical Procedures

•Neck + back surgery Neck + back surgery – Dex causes minimal effect on SSEP monitoringDex causes minimal effect on SSEP monitoring– Smooth emergence, especially cervical spineSmooth emergence, especially cervical spine– Easy to evalute neuro fct prior to + after extub Easy to evalute neuro fct prior to + after extub

•Abdominal surgeryAbdominal surgery– Dexmedetomidine provides analgesia without Dexmedetomidine provides analgesia without

respiratory depressionrespiratory depression– Especially useful in elderly undergoing colon Especially useful in elderly undergoing colon

resections, TAH, + other stressful proceduresresections, TAH, + other stressful procedures

Page 25: Clinical Use of Dexmedetomidine

Perioperative Dex Infusion Perioperative Dex Infusion ProtocolProtocol

Example: 70 kg patient. Assess BP, HR, volume status

2 mL Dex in 48 mL 0.9% saline= 200 ug/50 mL, or 4 ug/ml

Hypovolemic

Start at 40 mL/hr

Stop load if HR

Usual load: 25 to 35 ug or 6 to 9 mL over 10-15 min

Monitor BP/HRthroughout

If bradycardia, infusion

Maintenance: 0.2 to 0.7 ug/kg/hr [4 to 12 mL/hr]

Volume preload500 to 1000 cc LR

Normovolemic

Dex=dexmedetomidine.

Page 26: Clinical Use of Dexmedetomidine

Considerations With AnesthesiaConsiderations With AnesthesiaUse of DexmedetomidineUse of Dexmedetomidine

• Dilute in 0.9% saline: 4 mcg/mLDilute in 0.9% saline: 4 mcg/mL• Requires infusion pump: mcg/kg/h Requires infusion pump: mcg/kg/h • Transient HTN: with rapid bolus Transient HTN: with rapid bolus • Hypotension may occur, especially if hypovolemiaHypotension may occur, especially if hypovolemia HR (attenuation of tachycardia): usually desirableHR (attenuation of tachycardia): usually desirable conc of inhaled agents: BIS monitoringconc of inhaled agents: BIS monitoring• Continue infusion after extubation for 30 min [PACU]Continue infusion after extubation for 30 min [PACU]• L + D: not studiedL + D: not studied• Pediatrics: abstracts + case reports Pediatrics: abstracts + case reports [Lerman, Toronto][Lerman, Toronto]• Geriatrics: more hypotension + bradycardia: Geriatrics: more hypotension + bradycardia: dose dose

Page 27: Clinical Use of Dexmedetomidine

Use of Dexmedetomidine in Use of Dexmedetomidine in the Burn Unitthe Burn Unit

22 agonist effect assists in the management of agonist effect assists in the management of burn patients; blunts catecholamine surgeburn patients; blunts catecholamine surge

• Use in intubated and non-intubated burn Use in intubated and non-intubated burn patientspatients

• Administer as a standard load once patient is Administer as a standard load once patient is normovolemic (range: 0.4 to 0.7 mcg/kg/hr)normovolemic (range: 0.4 to 0.7 mcg/kg/hr)

dose for less severe burns and non-intubated dose for less severe burns and non-intubated patientspatients

– 0.2 to 0.4 mcg/kg/hr for routine burn care0.2 to 0.4 mcg/kg/hr for routine burn care– outpatient dressing changes, instead of ketamineoutpatient dressing changes, instead of ketamine

Page 28: Clinical Use of Dexmedetomidine

Alcohol Withdrawal and Trauma Alcohol Withdrawal and Trauma

• Trauma often occurs in males who are intoxicatedTrauma often occurs in males who are intoxicated• Trauma pt may experience agitation and is at risk for Trauma pt may experience agitation and is at risk for

exacerbating underlying injuries (e.g., SCI)exacerbating underlying injuries (e.g., SCI)• Benzodiazepines typically usedBenzodiazepines typically used

– Intubation and ventilation often required if extreme agitationIntubation and ventilation often required if extreme agitation• Dexmedetomidine is an alternativeDexmedetomidine is an alternative

– Spontaneous breathingSpontaneous breathing– Hemodynamic stabilityHemodynamic stability– Adequate sedationAdequate sedation– Prevention of autonomic effects of withdrawalPrevention of autonomic effects of withdrawal– Pain controlPain control

Page 29: Clinical Use of Dexmedetomidine

SummarySummary• Goal is to establish + maintain adequate drug Goal is to establish + maintain adequate drug

conc at effector site to produce desired effect conc at effector site to produce desired effect • Dex can help optimize anesthesia via:Dex can help optimize anesthesia via:

– Sedation, analgesia + Sedation, analgesia + sympathetic activity sympathetic activity– Attenuation of stress response + Attenuation of stress response + HR HR– Smooth emergence + tracheal extubationSmooth emergence + tracheal extubation

• Unique mechanism of action on natural sleep Unique mechanism of action on natural sleep pathway permits sedation + analgesia w/o pathway permits sedation + analgesia w/o respiratory depressionrespiratory depression

• Adjunct agent of choice for many surgeriesAdjunct agent of choice for many surgeries