Title: Clinical Use of Dexmedetomidine
1Clinical 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
2Objectives
- 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
3Pharmacology
- 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
4Pharmacodynamics
- 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
5Receptors
- 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)
6Pharmacodynamics
- Sedation/hypnosis
- Anxiolysis
- Analgesia
- Sympatholysis (BP/HR, NE)
- Reduces shivering
- Neuroprotective effects
- No effect on ICP
- No respiratory depression
7Pharmacokinetics
- 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
8?2 Agonists
- Clonidine
- Selectivity ?2?1 2001
- t1/2 ? 8 hrs1
- PO, patch, epidural
- Antihypertensive
- Analgesic adjunct
- IV formulation not available in US
- Dexmedetomidine
- Selectivity ?2?1 16201
- t1/2 ? 2 hrs
- Intravenous
- Sedative-analgesic
- Primary sedative
- Only IV ?2 available for use in the US
9Mechanism 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
10Restorative 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
11Harmful 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
12Mechanisms for Analgesic Effect
?2 Agonists
Opioids
Inhibit sympathetic- mediated pain
?? inflammation e.g., bradykinin, other kinins
Peripheral nociceptors
Inhibit release of SP and glutamate
Inhibit release of SP and glutamate
Primary afferent neurons
Inhibit firing
Inhibit firing
Second order neurons
Decrease emotive aspects
Decrease emotive aspects
Subcortical cortex
Disinhibit A5/A7 noradrenergic pathways
Activate PAG activate noradrenergic pathways
Descending inhibitory pathways
13Dex 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
14Clinical 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
15Sleep 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
16Gastric 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
17Dex 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 lt 0.03)
- Pain score better in dex gp 1.8 vs 3.4 (P lt
0.01) - time pain free in PACU ? in dex gp
- 44 vs 0 (P lt 0.002)
- Better control of HR in dex gp
18Craniotomy 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
19Coronary Artery Surgery Patients
- Herr study, n300 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 gt 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)
20CABG 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 gt 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
21Thoracotomy 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
22Vascular 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, n41. 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
23Meta- Analysis of Alpha-2 Agonists
- 23 trials, n3395.
- 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
24Other 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
25Perioperative Dex Infusion Protocol
Example 70 kg patient. Assess BP, HR, volume
status
Hypovolemic
Normovolemic
Monitor BP/HR throughout If bradycardia, ?
infusion
Volume preload500 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
Dexdexmedetomidine.
26Considerations With AnesthesiaUse 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
27Use 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
28Alcohol 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
29Summary
- 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