MORE ON DRUGS IN CLINICAL PRACTICE
Educational Objectives
| The goal of this program is to improve general anesthesia, local anesthesia, and pediatric anesthesia management. After
hearing and assimilating this program, the clinician will be better able to:
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 | 1. Review the clinical characteristics of local anesthetics.
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| 2. Examine the use of vasoconstrictors and α2 -agonists in anesthesia practice.
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| 3. Determine methods to help avoid cardiovascular toxicity and methemoglobinemia during local anesthesia.
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| 4. Develop resuscitation techniques for local anesthetic toxicity, including intravenous lipid and cardiopulmonary
bypass.
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| 5. Summarize the beneficial and adverse effects and indications and contraindications for clonidine and dexmedetomidine
in pediatric anesthesia practice.
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Faculty Disclosure
In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and planning committee members
to disclose relevant financial relationships within the past 12 months that might create any personal conflicts of interest.
Any identified conflicts were resolved to ensure that this educational activity promotes quality in health care and not a proprietary
business or commercial interest. For this program, the faculty and planning committee reported nothing to disclose.
Acknowledgements
Dr. Butterworth spoke in Asheville, NC, at the North Carolina and South Carolina Societies of Anesthesiologists’
Fall Session XXVII, jointly sponsored by the Wake Forest University School of Medicine and the North Carolina Society
of Anesthesiologists, held September 28-30, 2007; Dr. Mason, in Universal City, CA, at the California Society of
Anesthesiologists’ Annual Meeting and Clinical Anesthesia Update, held May 30 to June 1, 2008. The Audio-Digest
Foundation thanks the speakers and the sponsors for their cooperation in the production of this program.
| LOCAL ANESTHETIC DRUGS, ADDITIVES, AND CONTROVERSIES —John F. Butterworth IV, MD, Robert K.
Stoelting Professor and Chair, Department of Anesthesia, Indiana University School of Medicine, Indianapolis
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| Clinical characteristics of local anesthesia: lipid solubility—correlates with greater potency, higher degree of protein
binding, longer delays in onset, and longer duration of action; consistent across all types of local anesthetics; bupivacaine
most lipid soluble of local anesthetics; longest onset and duration; protein binding—local anesthetics bound to α1 -
acid glycoprotein and albumin; more potent local anesthetics more protein bound than less potent local anesthetics; more
potent local anesthetics also more highly lipid soluble; protein binding declines during pregnancy; as local anesthetics become
more lipid soluble, they also get more highly protein bound; therefore, bupivacaine more protein bound than
mepivacaine and lidocaine; no relationship between protein binding of local anesthetics and onset or duration of block;
highly lipid-soluble agents more potent and produce longer-acting block; onset of block—slowest onset occurs with
bupivacaine, compared to lidocaine or mepivacaine; textbooks indicate PKa controls onset of local anesthesia (however,
this is incorrect); duration of action—appears to correlate with potency of agent; sensory analgesia—goal to avoid motor
block; effective in labor analgesia and postoperative analgesia; differential onset of block occurs with some drugs; no
consistent differential block when fully set up; smaller nerve fibers more sensitive to local anesthetics than larger fibers
(pain fibers [eg, A-Ä fibers] more sensitive to local anesthetics than A-α motor fibers)
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| Vasoconstrictors: ischemic finger one concern when using procaine and epinephrine in digital nerve block; medical literature
contains only 48 published cases of gangrene after digital nerve block; almost all occurred with procaine or cocaine;
most also included hot soaks, tourniquet, and infection; in 21 of 48 cases, gangrene occurred when epinephrine
used; no reports of gangrene with lidocaine and epinephrine; cases of digital ischemia reported with accidental administration
of epinephrine with EpiPen; no evidence that currently used local anesthetics plus epinephrine cause digital
necrosis
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| α2 -agonists: clonidine produces local anesthesia when applied to peripheral nerve in sufficiently high concentration; can
be used to intensify regional blockade; adding to intermediate-acting agent, eg, mepivacaine, results in longer duration
of action (both analgesia and anesthesia); also effective in prolonging spinal anesthesia; studies also show oral clonidine
(eg, 150-300 µg) prolongs spinal anesthesia
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| Cardiovascular: early on, noticed that local anesthetics associated with severe cardiovascular toxicity; deaths mostly associated
with tetracaine; modern era of cardiovascular toxicity from local anesthetics begins with Albright article in 1979
on unexpected cardiac arrest without previous central nervous system (CNS) toxicity in patients who received bupivacaine
or etidocaine; as result of much concern, in 1983 Food and Drug Administration (FDA) added black box warning
to bupivacaine package insert; recently, ropivacaine and levobupivacaine introduced; neither has black box warning for
cardiotoxicity; laboratory reports suggest longer-acting agents predispose to cardiac arrest; single S(-) isomer less potent
in producing cardiotoxicity; speaker’s hypothesis that mechanism of cardiac arrest with local anesthetics dependent on
which drug administered; most potent agents predispose to arrhythmias; Groban study in dogs found fewer arrhythmias
with lidocaine than with bupivacaine, levobupivacaine, or ropivacaine; infusions were continued to point of cardiac arrest,
at which time advanced cardiac life support (ACLS)–style resuscitation given; more epinephrine-induced ventricular
fibrillation and death seen among dogs receiving bupivacaine, than among those given ropivacaine or lidocaine;
curiously, almost all dogs who received lidocaine required infusion of epinephrine thereafter to support blood pressure
(BP); suggests that with lidocaine, cardiac arrest associated with severe left ventricular (LV) depression; with bupivacaine,
infusion of epinephrine usually not needed
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| Methemoglobinemia: examination question suggests methemoglobin forms with >600-mg dose of prilocaine in adults;
however, recent study in European literature suggests severe methemoglobin levels (≤15%) possible with doses ≤400
mg; younger patients more likely to have high levels of methemoglobin than older patients given same dose of
prilocaine; benzocaine more problematic than prilocaine in North America; study found dapsone most common cause
of methemoglobinemia; most severe cases caused by use of benzocaine (Hurricane) spray; Department of Veterans Affairs
(VA) has removed benzocaine from system; treat with O2 and methylene blue, 1 to 2 mg/kg
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| Resuscitation: ACLS resuscitation should include, eg, vasopressin, epinephrine, O2 , chest compressions, defibrillation,
and amiodarone; inamrinone, milrinone, or isoproterenol “doesn’t make a lot of sense” for treatment of shock after receiving
bupivacaine; speaker suggests using drugs supported in ACLS guidelines, eg, amiodarone, vasopressin, and
epinephrine; use other drugs and techniques as support (if evidence indicates usefulness)
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| Intravenous (IV) lipid: counteracts bupivacaine cardiotoxicity; Weinberg showed if lipid given before toxic dose of bupivacaine,
animals did not develop toxicity; animals unable to be resuscitated using standard ACLS protocol recovered
after administration of lipid; mechanism of action unclear; www.lipidrescue.org contains case reports and testimonials
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| Cardiopulmonary bypass (CPB): consider if lipid infusion and standard drugs fail; numerous case reports of CPB used to
support circulation until toxin cleared
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| AN UPDATE ON α2 -AGONISTS IN PEDIATRIC ANESTHESIA PRACTICE— Linda J. Mason, MD, Professor of Anesthesiology
and Pediatrics, Loma Linda University School of Medicine, and Director, Pediatric Anesthesiology, Loma
Linda University Medical Center, Loma Linda, CA
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| α2 -receptors: both α and β groups in adrenergic nervous system; α receptors include α1 -postsynaptic and α2 -presynaptic;
α2 -receptors have a, b, and c subgroups that inhibit neurotransmitter release; presynaptic—suppress release of norepinephrine
(causes circulatory, minimum alveolar concentration [MAC], and sedation effects); locus ceruleus—largest noradrenergic
cell group in brain; modulates wakefulness; α2 -adrenoreceptors have no direct cardiac effect, but block release of
neurotransmitters
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Clonidine
| Introduction: supplied as oral tablets, injectable solution, and transdermal patch (for hypertension); selectivity ratio 39
(partial agonist); causes sedation via oral and neuraxial routes; cardiac—decreases BP; resets baroreflex (decreases heart
rate [HR] for given increase in BP); inhibits sinoatrial (SA) node firing, prolonging PR, AV, and QT intervals (via vagal
effects); respiratory—minimal respiratory depression; renal—decreases secretion of vasopressin; analgesia—blocks afferent
fibers; modulates release of substance P; modulates afferent pain responses
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| Premedication: slowly absorbed orally (60-90 min); dissolve parenteral formulation in apple juice; long elimination
half-life; studies—Mikawa found reduced pain scores and fewer rescue medications in clonidine patients, but slow onset
and increased sedation; study comparing clonidine to midazolam found more anxiety, lower intraoperative BP, decreased
need for supplemental O2 , larger postoperative opioid requirements, higher pain scores, and more excitement on emergence
with clonidine, but equal discharge readiness, postoperative emesis, and 24-hr analgesic requirement; another
study compared clonidine with midazolam and found clonidine had shorter onset time (38-40 min), improved level of sedation,
less emergence agitation, and more parental satisfaction; study of nasal route of administration found time to sedation
“a little longer” with nasal clonidine; steal-induction possible in 60% of patients; in another study, success with
intranasal clonidine seen in children with preoperative agitation and hallucination after midazolam premedication, in
children who refused oral midazolam, and in 3-mo-old with posterior urethral valves with hypertension; another study
found oral clonidine attenuates hyperglycemic response to surgical stress
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| Nausea and vomiting: clonidine shown to decrease incidence, but children in study remained hospitalized overnight after
strabismus surgery, rather than traveling home in car
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| Shivering and emergence delirium: dexmedetomidine more effective (shorter duration of action); clonidine, 2 to 3
µg/kg, IV or caudal, decreases emergence delirium
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| Controlled hypotension: reports of clonidine premedication causing decreased HR and BP; less inhalational agent and
β-blocker required to maintain BP; faster recovery and shorter stay in recovery room; opioid requirement decreased
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| Bradycardia and myocardial depression: study showed severe bradycardia and myocardial depression from combination
of clonidine (in extreme doses) and sevoflurane; successfully treated with atropine and epinephrine
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| Epidural analgesia: study adding clonidine to bupivacaine found dramatic decrease in duration of action; equal duration
of action when compared with fentanyl, but higher incidence of vomiting and O2 desaturation with fentanyl; little benefit
from increasing dose of clonidine from 1 to 2 µg/kg; addition of clonidine to ropivacaine 0.1% produced better analgesia
than with ropivacaine 0.2% alone; no motor block or sedation; good evidence from study of nonopioid additives given
with local anesthetics for caudal blockade that addition of clonidine prolongs duration; associated side effects (eg, mild sedation)
with doses <2 µg/kg appear to be minimal or beneficial for pediatric patient; 2 studies found no enhancement of
postoperative analgesia with lower concentration of bupivacaine plus epinephrine and clonidine; however, more recent
study found longer duration of action, even with lower concentration of bupivacaine
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| When to use: reports of apnea in neonates; avoid administration until infant at least 6 mo to 1 yr of age; can be added to
epidural (good results with lidocaine and ropivacaine; decreased time to first supplemental analgesia in first 48 hr without
increased side effects); study of children undergoing peripheral nerve blockade found adding clonidine (1 µg/kg) to bupivacaine
or ropivacaine extended sensory block by 4 to 5 hr, but also increased incidence of motor block
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Dexmedetomidine
| Introduction: 8 times more specific for α2 -adenoreceptors than clonidine; first used for sedation in intensive care unit
(ICU); IV use only; original dose 1 µg/kg for 10 min, then 0.2 to 0.7 µg/kg per hour; distribution half-life 9 min; elimination
half-life 2 hr
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| Actions: CNS sedation (decreases MAC); minimal effect on respiratory depression; analgesic properties
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| Pharmacology in children: study in which children given bolus of dexmedetomidine 1 µg/kg per hour over 10 min; HR
and BP examined; elimination half-life of 1.8 hr (similar to adults) observed
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| Adverse effects: bradycardia; decreased cardiac output; hypotension; hypertension (during bolus); decreased sympathetic
nervous system activity; increased pulmonary vascular resistance (animal study); respiratory—minimal increase
in resting PACO2 ; minimal effect on respiratory physiology (unless patient obstructed); CNS—ineffective sedation; proconvulsant
effect (animal study); decreased cerebral perfusion due to effect on mean arterial pressure
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| Applications: upper gastrointestinal (GI) endoscopy; adjunct for controlled hypotension; noninvasive radiologic imaging;
cardiac catheterization; fiberoptic tracheal intubation; treatment of withdrawal from substance abuse; treatment of
emergence delirium; treatment of shivering after general anesthesia; awake craniotomy; oral administration for premedication;
decreases use of opioid narcotics and other sedatives that cause respiratory depression
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| Studies: dexmedetomidine, smaller dose (0.5 µg/kg over 10 min), in continuous infusion until separation from CPB; resulted
in decreased stress response; after cardiac and thoracic surgery, rescue medications needed less frequently with dexmedetomidine;
younger patients required more dexmedetomidine than older patients; good sedation and analgesia; occurrence of
hypotension, with trend toward lower HR
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| Premedication: study of oral dexmedetomidine, 2.5 µg/kg; sedation occurred in 11 of 13 patients; patient accepted mask in
20 to 30 min; good for neurobehavioral disorders; larger dose may be necessary; study of intranasal dexmedetomidine, 1.0
to 1.5 µg/kg; onset 45 min; both doses produced equal sedation with decreases in bispectral index (BIS), systolic BP, diastolic
BP, and HR; another study looked at midazolam, clonidine, and dexmedetomidine; no difference found in preanesthesia
level of sedation or separation from parents; clonidine and dexmedetomidine associated with less perioperative
sympathetic stimulation and postoperative pain; glycopyrrolate used to prevent vagal effects, and still lower HR seen with
sevoflurane; use with caution, especially in younger patient with bradycardia
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| Awake craniotomy: advantages with dexmedetomidine include fast onset and offset and no respiratory depression; patient
more quickly conversant
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| Controlled hypotension: for spine surgery, speaker starts infusion without giving loading dose; continue at low dose
into postanesthesia recovery (provides good analgesia)
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| Motor evoked potentials: some studies show dexmedetomidine less effective in preserving motor evoked potentials;
necessary to watch evoked potential carefully after onset of drug; may be more effective with somatosensory evoked potential
(SSEP) alone
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| Awake intubation: infrequently used in children; effective in adults (maintains respiration; titrate midazolam, if necessary);
provides baseline level of sedation and avoids respiratory depression
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| Total IV anesthesia: for infants; used with topical drugs, but may sometimes require extra bolus of propofol
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| Cardiac catheterization: timing crucial to cover stimulus during vascular access; effective with midazolam oral premedication
followed by bolus dose; higher doses of dexmedetomidine may cause bradycardia
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| Computed tomography (CT) and magnetic resonance imaging (MRI): use carefully in child who does not
tolerate decrease in HR or BP; 3 µg/kg over 10 min likely necessary to achieve rapid onset and greater efficacy; study
looked at dexmedetomidine, 1 µg/kg, followed by continuous infusion of 0.5 µg/kg per hour, and induction with sevoflurane;
movement necessitated addition of midazolam; use selectively in difficult airway, larger child who may be difficult,
and for congenital cardiac anomalies requiring MRI of thorax
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Suggested Reading
Almenrader N et al: Premedication in children: a comparison of oral midazolam and oral clonidine. Paediatr Anaesth
17:1143, 2007; Almenrader N et al: Steal-induction after clonidine premedication: a comparison of the oral and nasal
route. Paediatr Anaesth 17:230, 2007; Ash-Bernal R et al: Acquired methemoglobinemia: a retrospective series of 138
cases at 2 teaching hospitals. Medicine (Baltimore) 83:265, 2004; Butterworth J et al: Differential onset of median
nerve block: randomized, double-blind comparison of mepivacaine and bupivacaine in healthy volunteers. Br J Anaesth
81:515, 1998; Butterworth JF 4th: Potency ratios for local anesthetics in regional blocks: how long must we wait? Reg
Anesth Pain Med 33:1, 2008; Butterworth JF 4th: Which actions of local anesthetics are relevant to the medical care of
humans? Reg Anesth Pain Med 32:459, 2007; Goldfinger MM et al: Cardiac arrest in a child with cerebral palsy undergoing
sevoflurane induction of anesthesia after preoperative clonidine. Paediatr Anaesth 17:270, 2007; Groban L et al:
Cardiac resuscitation after incremental overdosage with lidocaine, bupivacaine, levobupivacaine, and ropivacaine in anesthetized
dogs. Anesth Analg 92:37, 2001; Groban L et al: Does local anesthetic stereoselectivity or structure predict myocardial
depression in anesthetized canines? Reg Anesth Pain Med 27:460, 2002; Mason KP et al: Dexmedetomidine for
pediatric sedation for computed tomography imaging studies. Anesth Analg 103:57, 2006; Meininger D et al: Intrathecal
fentanyl, sufentanil, or placebo combined with hyperbaric mepivacaine 2% for parturients undergoing elective cesarean
delivery. Anesth Analg 96:852, 2003; Mikawa K et al: Oral clonidine premedication reduces postoperative pain in children.
Anesth Analg 82:225, 1996; Rhee K et al: Intravenous clonidine prolongs bupivacaine spinal anesthesia. Acta Anaesthesiol
Scand 47:1001, 2003; Rosenblatt MA et al: Successful use of a 20% lipid emulsion to resuscitate a patient
after a presumed bupivacaine-related cardiac arrest. Anesthesiology 105:217, 2006; Shukry M et al: Dexmedetomidine
as a total intravenous anesthetic in infants. Paediatr Anaesth 17:581, 2007; Stella MJ et al: Intranasal clonidine as a premedicant:
three cases with unique indications. Paediatr Anaesth 18:71, 2008; Weinberg GL et al: Resuscitation with
lipid versus epinephrine in a rat model of bupivacaine overdose. Anesthesiology 108:907, 2008; Young B: Intraoperative
detection of methemoglobinemia in a patient given benzocaine spray to relieve discomfort from a nasogastric tube: a case
report. AANA J 76:99, 2008.
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