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Clinical Use of DexmedetomidineClinical Use of Dexmedetomidine
Charles E. Smith, MDCharles E. Smith, MD
Professor of AnesthesiaProfessor of Anesthesia
Director, Cardiothoracic AnesthesiaDirector, Cardiothoracic Anesthesia
MetroHealth Medical CenterMetroHealth Medical Center
Case Western Reserve UniversityCase Western Reserve University
Cleveland, Ohio, USACleveland, Ohio, USAOctober 7, 2003October 7, 2003
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 Clinical paradigms for use of dex in anesthesiaanesthesia– 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
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
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
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)
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
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 Metabolism: biotransformation in liver to
inactive metabolites + excreted in urineinactive metabolites + 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
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
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
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
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
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 kininsbradykinin, other kinins]]
Peripheral Peripheral nociceptorsnociceptors
2 2 AgonistsAgonistsOpioidsOpioids
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
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
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 Postop airway obstruction + ventilatory arrest
with anesthetic drugswith anesthetic 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,
intubationintubation
DexmedetomodineDexmedetomodine• Anesthetic adjunct to minimize opioid + sedative Anesthetic adjunct to minimize opioid + sedative
useuse
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
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
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
Herr DL: Crit Care Med 2000;28:M248. Washington Hospital
Coronary Artery Surgery PatientsCoronary Artery Surgery Patients
Herr 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)
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
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
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
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
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
Perioperative Dex Infusion Perioperative Dex Infusion ProtocolProtocol
Example: 70 kg patient. Assess BP, HR, volume statusExample: 70 kg patient. Assess BP, HR, volume status
2 mL Dex in 48 mL 0.9% saline= 200 ug/50 mL, or 4 ug/ml2 mL Dex in 48 mL 0.9% saline= 200 ug/50 mL, or 4 ug/ml
HypovolemicHypovolemic
Start at 40 mL/hrStart at 40 mL/hr
Stop load if HRStop load if HR
Usual load: 25 to 35 ug or 6 to 9 mL over 10-15 minUsual load: 25 to 35 ug or 6 to 9 mL over 10-15 min
Monitor BP/HRthroughout
If bradycardia, infusion
Monitor BP/HRthroughout
If bradycardia, infusion
Maintenance: 0.2 to 0.7 ug/kg/hr [4 to 12 mL/hr]Maintenance: 0.2 to 0.7 ug/kg/hr [4 to 12 mL/hr]
Volume preload500 to 1000 cc LRVolume preload
500 to 1000 cc LR
NormovolemicNormovolemic
Dex=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
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
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 Trauma pt may experience agitation and is at risk
for exacerbating underlying injuries (e.g., SCI)for exacerbating underlying injuries (e.g., SCI)• Benzodiazepines typically usedBenzodiazepines typically used
– Intubation and ventilation often required if extreme Intubation and ventilation often required if extreme agitationagitation
• 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
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