Transcript Pharmacologic Agents Used for the Sedative and Analgesic

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
• Molecular targets + neural substrates
– locus caeruleus
– natural sleep pathways
• Clinical paradigms for use of dex in anesthesia
– sedation + analgesia w/o resp depression
– attenuation of tachycardia
– smooth emergence + weaning from mech vent
Pharmacology
• Establish and maintain adequate drug
concentration at effector site to produce
desired effect
– sedation
– hypnosis
– analgesia
– paralysis
• Predict the time course of drug onset + offset
Pharmacodynamics
• Relationship between drug conc + effect
• Interaction of drug with receptor
• Receptor
– cell component
– interacts with drug
– biochemical change
• Examples of receptors:
– AchR, GABA, opioid,  +  adrenergic
Receptors
• Coupled to ion channels
– neural signaling, 2nd messenger effects
• Drug effects at receptor
– agonist, antagonist or mixed effects
– stereospecificity, racemic mixture of isomers
• Receptor alterations
– upregulated or downregulated (e.g., CHF)
–  or  number (e.g., burns, myasthenia gravis)
Pharmacodynamics
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Sedation/hypnosis
Anxiolysis
Analgesia
Sympatholysis (BP/HR, NE)
Reduces shivering
Neuroprotective effects
No effect on ICP
No respiratory depression
Pharmacokinetics
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Rapid redistribution: 6 min
Elimination half-life: 2 h
Vd steady state: 118 L
Clearance: 39 L/h
Protein binding: 94%
Metabolism: biotransformation in liver to inactive
metabolites + excreted in urine
• No accumulation after infusions 12-24 h
• Pharmacokinetics similar in young adults + elderly
2 Agonists
Clonidine
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Selectivity: 2:1 200:1
t1/2  8 hrs1
PO, patch, epidural
Antihypertensive
Analgesic adjunct
IV formulation not
available in US
Dexmedetomidine
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Selectivity: 2:1 1620:1
t1/2  2 hrs
Intravenous
Sedative-analgesic
Primary sedative
Only IV 2 available for use
in the US
Mechanism for the Hypnotic Effect
• Hyperpolarization of locus ceruleus neurons
– 2A-Adrenoreceptor subtype
– Activation of K+ channels
– Inhibition of Ca++ channels
– Inhibition of adenylyl cyclase
•  Firing rate of locus caeruleus neurons
•  Activity in ascending noradrenergic pathway
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
 pressor response to sympathetic stimulation
Impaired CV response to positioning change
 BP, HR + urine norepinephrine
Immune dysfunction
–  ability of lymphocytes to synthesize DNA
–  leukocyte phagocytic activity
–  interferon production by lymphocytes
• Cognitive dysfunction
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– Impaired memory, communication skills
– Impaired decision-making
– Confusional state [ICU]: apathy, delirium
Mechanisms for Analgesic Effect
Opioids
2 Agonists
Peripheral nociceptors
 inflammation [e.g.,
bradykinin, other kinins]
Inhibit sympatheticmediated pain
Primary afferent
neurons
Inhibit release of
SP and glutamate
Inhibit release of
SP and glutamate
Second order neurons
Inhibit firing
Inhibit firing
Subcortical + cortex
Decrease emotive
aspects
Decrease emotive
aspects
Descending inhibitory
pathways
Activate PAG; activate
noradrenergic
pathways
Disinhibit A5/A7
noradrenergic
pathways
Dex: Package Insert Info
• Indications
– Sedation of intubated and ventilated patients during
treatment in an ICU setting x 24 h
• Contraindications
– Caution in patients with advanced heart block, severe
ventricular dysfunction, shock
• Drug interactions
– Vagal effects can be counteracted by atropine / glyco
• Clearance is lower w hepatic impairment
• Withdrawal sx after discontinuation: not seen after 24 h use
• Adrenal insufficiency: no effect on cortisol response to ACTH
Clinical Uses of Dex in Anesthesia
• Bariatric surgery
• Sleep apnea patients
• Craniotomy: aneurysm,
AVM [hypothermia]
• Cervical spine surgery
• Off-pump CABG
• Vascular surgery
• Thoracic surgery
• Conventional CABG
• Back surgery, evoked
potentials
• Head injury
• Burn
• Trauma
• Alcohol withdrawal
• Awake intubation
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
Ogan OU, Plevak DJ: Mayo Clinic;
www.sleepapnea.org
Gastric Bypass Surgery Patients
Morbidly obese patients
• Prone to hypoxemia
• Sleep apnea is common
• Respiratory depression w 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 w  HR
Craig MG et al: IARS abstract,
2002. Baylor
Dex Improves Postop Pain Mgt after
Bariatric Surgery
RCT, n= 25. Dex started at 0.5 to 0.7 ug/kg/hr 1 hr
prior to end of surgery [vs.saline]. Double- blind
• Infusion adjusted according to need
• Dex continued in PACU
• PACU pain control with PCA
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
Ramsay MA, et al: Anesthesiology,
2002: A-910 and A-165. Baylor
Craniotomy for Aneurysm / AVM
Anesthesia considerations
• Smooth induction + emergence
• Prevent rupture
• Avoid cerebral ischemia
• Hypothermia (33 oC)  CMRO2, CBF, CBV, CSF, ICP
Dexmedetomodine
•  sympathetic stimulation
•  or no change in ICP
•  shivering w/o resp depression
• Preserved cognitive fct
– reliable serial neuro exams
Doufas AG et al: Stroke 2003;34.
Louisville, KY
Coronary Artery Surgery Patients
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)
Herr DL: Crit Care Med
2000;28:M248. Washington
CABG and Lung Disease
Lung Disease
• 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 extub
Dexmedetomidine
• Faster time to extub:
– 7.8 + 4.6 h v. 16.5 + 11.8 h
• No difference in PaCO2 between gps 30 min after
extub: 37.9 v. 34.9 mmHg
Sumping ST: CCM 2000;28:M249.
Duke
Thoracotomy + Thoracoscopy
Thoracotomy + thoracoscopy patients
• COPD, pleural effusion, marginal pulmonary fct
•  pCO2 +  pO2 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
Vascular surgery patients
• 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
Talke et al: Anesth Analg
2000;90:834. Multicenter
Meta- Analysis of Alpha-2 Agonists
23 trials, n=3395.
• All surgeries:
• Vascular:
• Cardiac:
• Cardiac:
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mortality + ischemia
MI + mortality
ischemia
BP (more hypotension)
Conclusions:
• Not class 1 evidence yet, but trials look promising
– Especially vascular surgery
Wijeysundera, Am J Med
2003;114:742. Univ of Toronto
Other Surgical Procedures
• Neck + back surgery
– Dex causes minimal effect on SSEP monitoring
– Smooth emergence, especially cervical spine
– Easy to evalute neuro fct prior to + after extub
• Abdominal surgery
– Dexmedetomidine provides analgesia without
respiratory depression
– Especially useful in elderly undergoing colon
resections, TAH, + other stressful procedures
Perioperative Dex Infusion Protocol
Example: 70 kg patient. Assess BP, HR, volume status
Hypovolemic
Normovolemic
Volume preload
500 to 1000 cc LR
2 mL Dex in 48 mL 0.9% saline= 200 ug/50 mL, or 4 ug/ml
Start at 40 mL/hr
Usual load: 25 to 35 ug or 6 to 9 mL over 10-15 min
Stop load if  HR
Maintenance: 0.2 to 0.7 ug/kg/hr [4 to 12 mL/hr]
Dex=dexmedetomidine.
Monitor BP/HR
throughout
If bradycardia,
 infusion
Considerations With Anesthesia
Use of Dexmedetomidine
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Dilute in 0.9% saline: 4 mcg/mL
Requires infusion pump: mcg/kg/h
Transient HTN: with rapid bolus
Hypotension 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]
L + D: not studied
Pediatrics: abstracts + case reports [Lerman, Toronto]
Geriatrics: more hypotension + bradycardia:  dose
Use of Dexmedetomidine in
the 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
• Trauma often occurs in males who are intoxicated
• Trauma pt may experience agitation and is at risk for
exacerbating underlying injuries (e.g., SCI)
• Benzodiazepines typically used
– Intubation and ventilation often required if extreme agitation
• Dexmedetomidine is an alternative
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Spontaneous breathing
Hemodynamic stability
Adequate sedation
Prevention of autonomic effects of withdrawal
Pain control
Summary
• Goal is to establish + maintain adequate drug conc at
effector site to produce desired effect
• 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
• Adjunct agent of choice for many surgeries