1. Clinical Use of Dexmedetomidine
Pharmacologic Agents Used for the Sedative and Analgesic Management of ICU Patients
Module 3
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
Good morning. My name is ___ + I am an attending anesthesiologist at metro. MHMC is a level 1 trauma center in cleveland + is the regional center for burns in Northeast Ohio. I will be spending the next 40 min or so discussing the use of dex in anesthesia + I will share w you some of my experiences w this agent. I would like to thank Abbott for their generous donation to the anesthesia research + education fund. thank you to tony cooper + brian radesic for encouraging me to use this drug 6 mos ago

2. Objectives Pharmacology of dex Molecular targets + neural substrates
Pharmacologic Agents Used for the Sedative and Analgesic Management of ICU Patients
Module 3
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
I would like to go over some basic pharmacology of dex- its an alpha 2 agoinst with a fairly short half-life- : the t 1/2 alpha is 6 min and the t 1/2 beta is 2 hr
we will then look at how this agent works- mostly at the locus caeruleus which is where alot of noradrenergic neurons are located in the CNS- this is the so-called "blue spot " b/c of a high conc of blue staining neurons; and we will go over some of the uses for dex in anesthesia- sed + analg w/o resp depression, atten of tachy, + smooth emerg + weaning from mech vent.

3. Pharmacologic Agents Used for the Sedative and Analgesic Management of ICU Patients
Module 3
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
as far as goals of anesthesia go, you need to establish and maintain adequate drug concentration at effector site to produce desired effect : whether its sedation, or hypnosis; analgesia orparalysis
basic pharmacologic principles will allow you to predict the time course of drug onset + offset

4. Pharmacodynamics Relationship between drug conc + effect
Pharmacologic Agents Used for the Sedative and Analgesic Management of ICU Patients
Module 3
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
Pharmacodynamics describes what the drug does to the body- most drugs bind to receptors to initiate a chain of events that results in the desired action-
for example- NMBA bind to the AchR + block neuromuscular transmission; thiopental ,propofol + midaz alter chloride channel gating fct of GABA; opioids act as agonists at stereospecific opioid receptors

5. Receptors Coupled to ion channels Drug effects at receptor
Pharmacologic Agents Used for the Sedative and Analgesic Management of ICU Patients
Module 3
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)
Receptors are components of the cell.
they are coupled to ion channels + result in
neural signaling + 2nd messenger effects
Depending on stereospecificity + other factors such as potency + mixtures of isomers, a A drug can act as agonist, antagonist or have mixed effects. Also, receptors may be downregulated as occurs w beta adrenergic receptors in CHF, upregulated + increased in # as occurs w AchR in burns + denervation; or destroyed as w AchR + myasthenia gravis)

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

7. Pharmacokinetics 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 h
Pharmacokinetics similar in young adults + elderly

8. 2 Agonists Clonidine Selectivity: 2:1 200:1 t1/2  8 hrs1
PO, patch, epidural
Antihypertensive
Analgesic adjunct
IV formulation not available in US
Dexmedetomidine
Selectivity: 2: :1
t1/2  2 hrs
Intravenous
Sedative-analgesic
Primary sedative
Only IV 2 available for use in the US

9. 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

10. Restorative Properties of Sleep
Pharmacologic Agents Used for the Sedative and Analgesic Management of ICU Patients
Module 3
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

11. 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
Impaired memory, communication skills
Impaired decision-making
Confusional state [ICU]: apathy, delirium

12. Mechanisms for Analgesic Effect
Opioids
2 Agonists
Peripheral nociceptors
 inflammation [e.g., bradykinin, other kinins]
Inhibit sympathetic- mediated 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

13. 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

14. Clinical Uses of Dex in Anesthesia
Pharmacologic Agents Used for the Sedative and Analgesic Management of ICU Patients
Module 3
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
The first surgeries i used dex in were morbidly obese patients w sleep apnea- dex allowed me to dec the opioids + get the tracheal tube out early + safely- cooperative with a sedated pain free patient w/o resp depression
The next series of pts i used dex for were the crani for aneurysm- we use hypothermia to 33 C, + dex really helps prevent shivering during rewarming while at the same time allowing for a cooperative pt to do neuro exams on. then i started w cervical spine surgery- again for the smooth emergence.

15. Ogan OU, Plevak DJ: Mayo Clinic; www.sleepapnea.org
Pharmacologic Agents Used for the Sedative and Analgesic Management of ICU Patients
Module 3
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
Anesthesia considerations, sleep apnea patients
Morbid obesity, at risk for aspiration
Difficult IV access
Systemic + pulm HTN
Cor pulmonale
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 of choice to minimize opioid + sedative use
Ogan OU, Plevak DJ: Mayo Clinic;

16. Gastric Bypass Surgery Patients
Pharmacologic Agents Used for the Sedative and Analgesic Management of ICU Patients
Module 3
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
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
v bpm
Better control of HR in dex gp
Plasma NE levels  in dex gp
Craig MG et al: IARS abstract, Baylor

17. Dex Improves Postop Pain Mgt after Bariatric Surgery
Pharmacologic Agents Used for the Sedative and Analgesic Management of ICU Patients
Module 3
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
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

18. 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

19. 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 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 Hospital

20. Sumping ST: CCM 2000;28:M249. Duke
Pharmacologic Agents Used for the Sedative and Analgesic Management of ICU Patients
Module 3
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:
h v h
No difference in PaCO2 between gps 30 min after extub: 37.9 v mmHg
Lung Disease
Often delays tracheal extubation
RCT, n= 20. Dex started at end of surgery, 0.2 to 0.7 ug/kg/min, + continued 6 hr after extubation vs. controls (propofol)
Ramsay > 3 before extub, 2 after extub
Dexmedetomidine
Faster time to extub: h v h
No difference in PaCO2 between gps 30 min after extub: 37.9 v mmHg
Sumping ST: CCM 2000;28:M249. Duke

21. Thoracotomy + Thoracoscopy
Pharmacologic Agents Used for the Sedative and Analgesic Management of ICU Patients
Module 3
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
Thoracotomy + thoracoscopy patients
COPD, pleural effusion, marginal pulmonary fct
Thoracic epidural: mainly for thoracotomy
Dex: excellent for thoracoscopy
Dexmedetomidine
Patients are arousable, but sedated
Does not dec ventilatory drive
Greatly dec need for opioids
Alternative to thoracic epidural
Continue in PACU/ ICU

22. Talke et al: Anesth Analg 2000;90:834. Multicenter
Pharmacologic Agents Used for the Sedative and Analgesic Management of ICU Patients
Module 3
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
v bpm
Better control of HR in dex gp
Plasma NE levels  in dex gp
Vascular surgery patients
Usually at risk for CAD, ischemia, HTN, tachycardia
Dex attenuates periop stress response
Dex attenuates  BP w aortic cross clamp
Dexmedetomidine
RCT, n=41. Dex started 20 min before surgery + continued 48 hr after surgery, v. controls
HR  in dex gp at emergence: v bpm
Better control of HR in dex gp
Plasma NE levels  in dex gp
Talke et al: Anesth Analg 2000;90:834. Multicenter

23. Meta- Analysis of Alpha-2 Agonists
Pharmacologic Agents Used for the Sedative and Analgesic Management of ICU Patients
Module 3
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
23 trials, n=3395.
 mortality, all surgeries
 ischemia, all surgeries
 MI + mortality after vascular surgery
 ischemia during cardiac surgery
 BP during cardiac surgery (more hypotension)
My Conclusions:
Not class 1 evidence yet but trials look promising, especially vascular surgery
Wijeysundera, Am J Med 2003;114:742. Univ of Toronto

24. Other Surgical Procedures
Pharmacologic Agents Used for the Sedative and Analgesic Management of ICU Patients
Module 3
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
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

25. Perioperative Dex Infusion Protocol
Example: 70 kg patient. Assess BP, HR, volume status
Hypovolemic
Normovolemic
Monitor BP/HR
throughout
If bradycardia,  infusion
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 min
Stop load if  HR
Maintenance: 0.2 to 0.7 ug/kg/hr [4 to 12 mL/hr]
Dex=dexmedetomidine.

26. Considerations With Anesthesia Use of Dexmedetomidine
Pharmacologic Agents Used for the Sedative and Analgesic Management of ICU Patients
Module 3
Considerations With Anesthesia Use of Dexmedetomidine
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
Transient hypertension: with rapid bolus
Hypotension may occur, especially if hypovolemia
 HR (attenuation of tachycardia): usually desirable
 conc inhaled agents: BIS monitoring
Potentiates benzodiazepines
 narcotic use
Continue infusion in PACU / ICU

27. Use of Dexmedetomidine in the Burn Unit
Pharmacologic Agents Used for the Sedative and Analgesic Management of ICU Patients
Module 3
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
The alpha-2 agonist effect of dexmedetomidine has been used to manage burn patients in several centers
This agent can be used in both intubated and nonintubated burn patients
The standard loading dose of dexmedetomidine is 0.4 to 0.7 mcg/kg
Lower doses can be used for less severe burns and nonintubated patients and for outpatient burn care

28. Alcohol Withdrawal and Trauma
Pharmacologic Agents Used for the Sedative and Analgesic Management of ICU Patients
Module 3
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
Spontaneous breathing
Hemodynamic stability
Adequate sedation
Prevention of autonomic effects of withdrawal
Pain control
Many trauma patients are intoxicated males with uncleared spines. They are at risk for serious injury if they move or thrash. Typically, an alcohol withdrawal regimen uses benzodiazepines, but patients often require intubation and ventilation due to extreme agitation
The use of dex allows patients to breathe spontaneously, controls their heart rate and blood pressure, prevents the autonomic effects of withdrawal, and provides adequate sedation

29. Pharmacologic Agents Used for the Sedative and Analgesic Management of ICU Patients
Module 3
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
Overall goal of anesthesia is to establish + maintain adequate drug concentration at effector site to produce desired effect
Dex can help optimize anesthesia via:
Sedation/hypnosis, analgesia +  sympathetic activity
Attenuation of stress response with  HR
Smooth emergence + tracheal extubation
Unique mechanism of action on natural sleep pathway permits patients to be well rested yet easily aroused
Pain control w/o respiratory depression
Adjunct agent of choice for many surgeries