ADVANCES IN ANESTHETIC PHARMACOLOGY
| DEXMEDETOMIDINE —John B. Leslie, MD, Professor of Anesthesiology, Mayo Clinic College of Medicine, Rochester,
MN, and Consultant in Anesthesia, Mayo Clinic, Scottsdale, AZ
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| Sedation of mechanically ventilated patient in intensive care unit (ICU): dexmedetomidine designed to alleviate
anxiety, relieve pain, control ventilation, modulate and reduce stress response, and provide hormonal value vs
other options for sedating and controlling intubated, ventilated, semianesthetized patient
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| Target results for ICU sedation and analgesia: patient characteristics include calm (free of anxiety), comfortable
(free of pain), cooperative (facilitating medical procedures), and communicative (with clinician and family);
dexmedetomidine dramatically different from propofol or benzodiazepines
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| Effect of α2 -agonists (eg, dexmedetomidine): stimulate growth hormone, decrease cortisol, massively reduce catecholamines,
and improve protein synthesis; no effect on chemotaxis, phagocytosis, superoxide anions, or metabolic
parameters; tissue repair, immune function, and sleep pathways appear to mimic nature
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| Role of anesthesia provider: before ICU administration, have anesthesia team administer drug, stabilize patient on
appropriate dose, then transfer to nursing care; anesthesia provider has best understanding of autonomic nervous system
and adrenergic receptors (α2 receptors presynaptic and inhibit norepinephrine release); dexmedetomidine sympatholytic
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| α2 -agonist selection: clonidine—antihypertensive; prolongs effects of analgesics, so used in blocks; slightly sedating;
dexmedetomidine—sedative-analgesic; hemodynamic effect antihypertensive, antitachycardic like clonidine, but
greater selectivity and shorter half-life; in United States, available only as intravenous (IV) infusion for sedation and
analgesia; not approved as antihypertensive
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| Central pharmacology of dexmedtomidine: sites of action include brain, spinal cord, and periphery; produces
sedation/hypnosis, anxiolysis, and analgesia; major sympathectomy effect (used as adjunct for general anesthesia); reduces
shivering; no effect on intracranial pressure (ICP); no respiratory depression (as measured by minute ventilation,
elevated CO2 , or hypoxia under deep sedation)
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| Dexmedetomidine: advantages—sedative and analgesic effects; respiratory stability; predictable hemodynamic response;
activates natural sleep pathways; unnecessary to discontinue before extubation; strong anti-shivering effect;
limitations—reduces heart rate (HR) and blood pressure (BP; in hypovolemic patient, produces hypotension); potentiates
effects of anesthetic drugs (use less anesthetic); metabolic pathway—metabolized in liver; potential for hepatic
accumulation in patient with liver dysfunction or liver transplant; pharmacokinetic properties—short α half-life (rapidly
equilibrates during titration with IV infusion); quick onset of dynamic effects if given as bolus or loading bolus;
half-life 2 hr; no rebound hemodynamics; high protein binding; adverse effects—does not require prolonged weaning;
does not cause respiratory depression, constipation, or lack of orientation; may cause hypotension and arrhythmias
(eg, bradycardia); clinical effects—alleviates anxiety, relieves pain, stimulates natural sleep, promotes
arousability during sedation, facilitates ventilation during weaning, and promotes respiratory stability; controls emergent
delirium
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| Phase 3 studies: dexmedetomidine given in loading dose of 1 µg/kg over 10 min; started drug at end of coronary artery
bypass graft (CABG), craniotomy, and major vascular procedures; idea to have patient respond to commands without
being completely awake; majority of patients undergoing cardiac surgery; minimum 6 hr mechanical ventilation; sedation
occurred in ICU, although started drug in operating room (OR); 83% of patients receiving placebo required add-
on morphine in first 24 hr; ≈50% of patients receiving dexmedetomidine required no other opiates for 24 hr; in placebo
group, average additional dose of morphine ≈12 mg for adequate analgesia, in dexmedetomidine group, ≈6 mg;
in two thirds of patients, dexmedetomidine alone adequate; recommendation of 0.7 µg/kg per hour good guideline; infusion
also recommended; mean HR during infusion of dexmedetomidine 75 to 80 beats per minute; mean HR within
2 to 3 hr after infusion indistinguishable from placebo; mean systolic BP also indistinguishable after infusion
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| Costs: $57.20 per 200-µg vial; loading dose (1 µg/kg) $20 for 70-kg patient; infusion rate $4 to $14 per hour; cost similar
to propofol infusion; studies of use as routine sedative-hypnotic-analgesic in CABG procedures show significantly
reduced length-of-stay and faster extubation, compared to propofol
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| Recommended uses: preoperative sedation; off-pump CABG; conventional CABG; prompt extubation; failure-to-
wean from ventilator; transition from long-term propofol infusion; thoracotomy; back and neck surgery; awake craniotomy;
head injury; burns; trauma; alcohol withdrawal; detoxification; painful procedures; prevention of emergence
delirium; awake bronchoscopy; awake intubation; certain blocks; transurethral resection of prostate; difficult airway;
monitoring evoked potentials; major vascular surgery; endoscopy; bariatric surgery; complicated radiologic procedures
in children; prevention of postoperative shivering; serotonin syndrome
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| Procedural considerations in perioperative use: decrease inhaled anesthetic agents; be vigilant for hypotension
(if patient hypovolemic); if infusion started after induction, consider extending or avoiding loading dose; decrease narcotic
use; replace fluid loss; remember potentiation of benzodiazepines (avoid lorazepam as premedicant)
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| Dexmedetomidine in outpatient anesthesia (studies): awake fiberoptic intubation (per package insert, gave
loading dose 1 µg/kg over 10 min, then infusion 0.3 to 0.7 µg/kg per hour; reduction of stress response to extubation
(hemodynamic stability at extubation); sedation in monitored anesthesia care (MAC) and regional cases (0.7 µg/kg per
hour of dexmedetomidine equal to propofol, ≈35 µg/kg per minute; improvements seen in hemodynamics and respiratory
depression with dexmedetomidine); facial rejuvenation surgery (no respiratory depression, no desaturation, and
no postoperative nausea and vomiting [PONV], despite no preoperative antiemetics); minor gynecologic surgery (improves
desflurane induction; no effect on quality of recovery or hospital discharge times; fewer complications and
complaints of foul smell; higher satisfaction scores); effects on PONV (incidence 9% with dexmedetomidine vs 40%
without); speaker advises against use as total IV anesthetic (not amnestic); magnetic resonance imaging and computed
tomography in children 5 mo to 16 yr of age (sedation achieved within 10 min; no hypoxia or hypercarbia; reduction
of sevoflurane emergence delirium); postoperative pain (0.1 µg/kg given preoperatively reduces pain for 24 hr);
conclusions—potential value in outpatient anesthesia; downsides include “wicked” pharmacology (eg, significant hypotension,
bradycardia), poor amnesia, inadequate study and dosing information, not approved by the Food and Drug
Administration (FDA), and too expensive
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| How speaker does it: supplied in 200-µg vial; dilution in 50- mL bag; speaker removes 5 mL from infusion and injects
20 µg initially, then starts infusion at appropriate reasonable dose; hypotension and bradycardia most frequent
side effects; outcomes—enhanced sleep; less ileus; fewer negative inotropic effects, compared to propofol; reduced
shivering; reduced postoperative myocardial ischemia; improved spontaneous ventilation; improved management of
difficult cases
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| Conclusions: consider loading patient with 20-µg bolus of dexmedetomidine in OR; use of selected α2 -agonists in OR
and ICU eliminates or reduces need for opiates and provides respiratory stability; modest but predictable changes in
hemodynamics
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| CLINICAL APPLICATION OF INTRAVENOUS ANESTHETICS —Talmage D. Egan, MD, Professor and K.C.
Wong Presidential Endowed Chair, Department of Anesthesiology, University of Utah School of Medicine, Salt Lake
City
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| Introduction: control of duration and magnitude of drug effect critical; must be able to anesthetize patient rapidly,
then “get all of those profound effects to go away quickly” at end of surgery to transfer patient to less intense environment;
anesthesia provider faces unique challenges in clinical pharmacology
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| Approaches for controlling drug effect
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 | Surfing analogy: useful in conceptualizing approaches to rational drug selection and administration; concentration-effect
relationship like wave; as drug concentration increases, effect rises rapidly then levels off; target upper portion of steep
part of wave because in this portion of concentration-effect relationship, relatively small changes in concentration
translate into bigger changes in effect
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| Pharmacodynamic approach: uses drug-effect measurement to titrate dosage (eg, processed electroencephalography
[EEG] to titrate propofol; peripheral nerve stimulator to titrate neuromuscular blocking agent)
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| Pharmacokinetic approach: irrespective of drug effect, target specific drug concentration or level known to be appropriate
(therapeutic window; eg, agent-specific vaporizer to deliver some multiple of agent’s minimum alveolar concentration
[MAC]; target-controlled infusion system to infuse to specified concentration)
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| Pharmaceutic (“forgiving drug”) approach: takes advantage of responsive pharmacokinetic profiles of modern anesthetic
agents; unnecessary to hit target with as much precision and accuracy as with other approaches (eg, short-acting
opioid, remifentanil; short-acting intravenous [IV] agent, propofol; inhalation anesthetics, sevoflurane and
desflurane)
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| Pharmacokinetic and pharmacodynamic advances
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| Pharmacogenomic (pharmacogenetic) knowledge: advances may eventually explain observed variation in anesthetic
and analgesic response; pharmacogenetics study of role of inheritance on individual variation in drug response;
>60,000 polymorphisms in coding regions of human genome; basis for most differences in drug response; to date,
>60 pharmacogenetic differences of clinical importance identified (mostly pharmacokinetic differences); differences
observed only with administration of drug; pseudocholinesterase deficiency and malignant hyperthermia prototypical
kinetic and dynamic pharmacogenetic conditions; codeine—prodrug; converted to morphine (active drug)
by cytochrome P450 CYP2D6 enzyme; ≈10% of white population has polymorphism that prevents codeine-to-morphine
conversion (poor metabolizers; codeine has no therapeutic effect or side effects); certain ethnic groups (eg,
≈30% of Ethiopians) have polymorphisms that increase codeine-to-morphine conversion (ultraextentive metabolizers;
codeine produces more pronounced analgesia and side effects); red hair phenotype—marker for increased anesthetic
requirement (red hair results from mutations of melanocortin-1 receptor)
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| Covariate effects: changes in demographics or physiology (eg, age, weight) that can change drug response; from earliest
days of anesthesia, providers recognized profound influence of hemorrhagic shock on drug behavior, ie, patients
in shock have low tolerance for IV anesthesia; Halford observed that IV anesthetics “ideal form of euthanasia”; animal
study looking at influence of hemorrhagic shock on propofol (kinetic and dynamic analysis) found higher levels and
increased potency for bolus and infusion; propofol doses must be reduced on kinetic and dynamic basis during shock;
patient in shock rarely taken to OR for anesthesia without resuscitation; study in pigs looked at effect of crystalloid resuscitation
on clinical pharmacology of propofol after episode of shock; pharmacokinetic alterations produced by
hemorrhage largely reversed with resuscitation, but pharmacodynamic alterations persist, even after fluid resuscitation
(increased potency in shocked animals); summary by Shafer—without resuscitation, 90% reduction in propofol dosage
required in hemorrhagic shock, with resuscitation 50% dosage reduction; ≈50% dosage reduction required for opiates;
etomidate requires no dosage reduction and is drug of choice for induction of anesthesia in hemorrhagic shock
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| Pharmaceutic considerations
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| Propofol formulation: currently marketed in Intralipid-type formulation; associated with pain on injection, allergic reactions
to egg-type components of formulation, and support of microbial growth; investigational propofol formulations
include lipid-based emulsions, prodrug, and water-soluble solutions; changes in formulation, (eg, droplet size)
may alter clinical behavior of propofol, eg, peak levels, time course of peaks; examples of new propofol formulations
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| Sugammadex: designer reversal agent (investigational); cyclodextrin that forms tight one-to-one, noncovalent
bonds with steroid-type neuromuscular blockers; pharmacologically inert by itself; does not have cardiovascular
effects and, possibly, nauseating effects associated with neostigmine and glycopyrrolate; rapidly reverses profound
neuromuscular blockade
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| Remifentanil: esterase-metabolized opioid; loses mu receptor agonist activity upon ester hydrolysis; produces sedation,
analgesia, and side effects associated with mu agonists (eg, respiratory depression, bradycardia, muscle rigidity);
reversible with naloxone; potency similar to fentanyl; dramatically decreases minimum alveolar concentration;
rapid metabolism (first true ultra-short-acting opioid); time independent context-sensitive half-time (≈5 min) and
rapid effect-side equilibration; clinical features include rapid recovery, rapid control of degree of opioid effect, minimal
concerns about special populations, and less clinical penalty for overdosage
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Educational Objectives
| The goal of this program is to educate the listener about clinical uses of dexmedetomidine and the application of intravenous
anesthetics. After hearing and assimilating this program, the participant will be better able to:
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| 1. Summarize the effects of sedative agents.
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| 2. Review the pharmacokinetic properties and clinical effects of dexmedetomidine.
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| 3. Discuss the recommended inpatient and outpatient uses of dexmedetomidine.
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| 4. Identify the various approaches for controlling drug effect of intravenous (IV) anesthetics.
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| 5. Describe the importance of covariate effects associated with IV anesthesia.
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Suggested Reading
Bekker AY et al: Dexmedetomidine for awake carotid endarterectomy: efficacy, hemodynamic profile, and side effects.
J Neurosurg Anesthesiol 16:126, 2004; Cascorbi I: Pharmacogenetics of cytochrome p4502D6: genetic background
and clinical implication. Eur J Clin Invest 33 Suppl 2:17, 2003; Doufas AG et al: Dexmedetomidine and
meperidine additively reduce the shivering threshold in humans. Stroke 34:1218, 2003; Ebert T et al: Dexmedetomidine:
another arrow for the clinician's quiver. Anesthesiology 101:568, 2004; Eckhardt K et al: Same incidence of adverse
drug events after codeine administration irrespective of the genetically determined differences in morphine
formation. Pain 76:27, 1998; Egan TD et al: Remifentanil versus alfentanil: comparative pharmacokinetics and pharmacodynamics
in healthy adult male volunteers. Anesthesiology 84:821, 1996; Egan TD et al: Target-controlled infusions
for intravenous anesthetics: surfing USA not! Anesthesiology 99:1039, 2003; Egan TD et al: The
pharmacokinetics and pharmacodynamics of propofol in a modified cyclodextrin formulation (Captisol) versus propofol
in a lipid formulation (Diprivan): an electroencephalographic and hemodynamic study in a porcine model. Anesth Analg
97:72, 2003; Egan TD: Remifentanil pharmacokinetics and pharmacodynamics. A preliminary appraisal. Clin Pharmacokinet
29:80, 1995; Egan TD: Target-controlled drug delivery: progress toward an intravenous "vaporizer" and automated
anesthetic administration. Anesthesiology 99:1214, 2003; Grant SA et al: Dexmedetomidine infusion for
sedation during fiberoptic intubation: a report of three cases. J Clin Anesth 16:124, 2004; Halford FJ: A critique of intravenous
anesthesia in war surgery. Anesthesiology 4:67, 1943; Hofer RE et al: Anesthesia for a patient with morbid
obesity using dexmedetomidine without narcotics. Can J Anaesth 52:176, 2005; Johnson KB et al: The influence of
hemorrhagic shock on etomidate: a pharmacokinetic and pharmacodynamic analysis. Anesth Analg 96:1360, 2003;
Johnson KB et al: The influence of hemorrhagic shock on propofol: a pharmacokinetic and pharmacodynamic analysis.
Anesthesiology 99:409, 2003; Laxenaire MC et al: Life-threatening anaphylactoid reactions to propofol (Diprivan).
Anesthesiology 77:275, 1992; Liem EB et al: Anesthetic requirement is increased in redheads. Anesthesiology
101:279, 2004; Liem EB et al: Increased sensitivity to thermal pain and reduced subcutaneous lidocaine efficacy in
redheads. Anesthesiology 102:509, 2005; Liem EB et al: Women with red hair report a slightly increased rate of bruising
but have normal coagulation tests. Anesth Analg 102:313, 2006; Mack PF et al: Dexmedetomidine and neurocognitive
testing in awake craniotomy. J Neurosurg Anesthesiol 16:20, 2004; Maze M et al: New agents for sedation in the
intensive care unit. Crit Care Clin 17:881, 2001; Shafer SL: Shock values. Anesthesiology 101:567, 2004.
Faculty Disclosure
In adherence to ACCME guidelines, the Audio-Digest Foundation requests all lecturers to disclose any significant financial
relationship with the manufacturer or provider of any commercial product or service discussed. The following
has been disclosed: Dr. Leslie has received research grants from GlaxoSmithKline, Baxter International Inc., and
Helsinn Healthcare. Dr. Egan has indicated he has relationships with the following companies as noted: GlaxoSmithKline
(consulting, research support, speaking), Abbott Labs (research support, speaking), Scott Labs (consulting,
stock options), Aspect Medical (consulting), Cydex (research support, consulting), Johnson & Johnson (consulting),
Guilford Pharmaceuticals (consulting), Theravance (research support, consulting), Alaris Medical (research support,
consulting), ZARS (consulting, stock options), and Medvis (consulting).
Drs. Leslie and Egan were recorded at the Annual Meeting and Anesthesiology Review Course, jointly presented May
18-21, 2006, by the California Society of Anesthesiologists and the University of California, San Diego, School of
Medicine, and held in Rancho Mirage, CA. The Audio-Digest Foundation thanks the speakers and the sponsors for
their cooperation in the production of this program.
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