CONTROVERSIAL DRUGS IN CLINICAL PRACTICE
From the 61st Postgraduate Assembly in Anesthesiology, sponsored by the New York State Society of Anesthesiologists,
December 7-11, 2007, New York, NY
Educational Objectives
| The goal of this program is to improve anesthesia management by reevaluating the usefulness of older agents such as
droperidol and succinylcholine. After hearing and assimilating this program, the clinician will be better able to:
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 | 1. Describe the potentially life-threatening adverse reactions associated with the use of droperidol.
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| 2. Review the history of the United States Food and Drug Administration actions on droperidol and the contents
of the “black box” warning label.
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| 3. Summarize the clinical pharmacology and pharmacokinetics of droperidol and succinylcholine.
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| 4. Identify problems associated with the use of succinylcholine.
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| 5. List alternatives to succinylcholine and identify potential future replacements.
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Faculty Disclosure
In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and members of the planning
committee 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 following has been disclosed: Dr. Lebowitz
is a consultant to Organon Pharmaceuticals. Dr. Kopman is on the Speakers’ Bureau of Organon Pharmaceuticals.
The planning committee reported nothing to disclose.
Acknowledgements
Drs. Lebowitz and Kopman spoke in New York, NY, at the 61st Annual Postgraduate Assembly in Anesthesiology, held
December 7-11, 2007, and sponsored by the New York State Society of Anesthesiologists, Inc. The Audio-Digest
Foundation thanks the speakers and the NYSSA for their cooperation in the production of this program.
| DROPERIDOL: BLACK BOX WARNING REVISITED —Philip W. Lebowitz, MD, Professor of Clinical Anesthesiology,
Albert Einstein College of Medicine, and Attending Anesthesiologist, Montefiore Medical Center, Bronx,
NY
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| Clinical pharmacology: droperidol one of butyrophenones; phenothiazine derivative; haloperidol synthesized first
(in 1950s; treatment for psychosis in Europe); first marketed in United States in 1967; droperidol then synthesized
and marketed; combined with fentanyl (eg, Sublimaze) to produce Innovar (no longer on market); central nervous
system (CNS) depressant; reduces central dopaminergic neurotransmission relative to cholinergic neurotransmission;
creates dissociative state; when combined with opioid, creates neuroleptanalgesia; addition of nitrous oxide results
in neuroleptanesthesia; also has powerful antiemetic properties
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| Neuroleptanalgesia: “unusual state”; patient sedated and psychically indifferent to environmental stimuli; with nitrous
oxide and muscle relaxant, “nothing else need be added”; produces total anesthetic; however, when given to
otherwise awake patient as preoperative sedative or tranquilizer, dysphoria can occur; has resulted in patient refusing
surgery and walking out of operating room
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| Neuroleptanesthesia: recommended induction dose of Innovar was 0.1 mg/kg (combination of droperidol, 2.5 mg,
and fentanyl, 50 µg in 1 mL); as antiemetic, 0.625 to 1.25 mg; inject slowly
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| Side effects: include hypotension, bradycardia, chest wall rigidity, and respiratory depression; little effect on breathing;
tracheal secretions not problematic; 10% incidence of nausea, retching, or vomiting; 5% incidence of persistent
grogginess; 1% incidence of extrapyramidal movements; cardiovascular (CV) effects include vasodilation due
to α-adrenergic blockade (myocardial contractility preserved); no cardiac rhythm disturbances
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| History: in 1970, droperidol (2.5 mg intramuscular [IM] or intravenous [IV] dosing) received Food and Drug Administration
(FDA) approval as treatment for preoperative anxiety or postoperative nausea and vomiting; by 2000,
anesthesia providers had marginalized droperidol use as neuroleptanesthetic, but had widely adopted it in small
doses for prophylaxis against nausea and vomiting; in 2001, 11 million doses sold in United States; in January
2001, following notification that distribution of droperidol worldwide being stopped, FDA began to reexamine database
and consider information available and why worldwide distribution had ceased
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| FDA investigation: greater CV risk than had been appreciated; 273 cases gathered from November 1, 1997, to January
2, 2002; 127 serious adverse outcomes (38 cases of CV events; 25 cases of cardiac or sudden death; 9 cases of
torsades de pointes; 4 cases of extrasystole or syncope); 12 of 28 serious CV events occurred at doses <2.5 mg; one
death, one cardiac arrest, and one case of torsades de pointes at doses <1.0 mg; etiology of deaths and arrhythmias
unknown; in 1991—Guy and colleagues reported droperidol-induced QT prolongation associated with torsades de
pointes; in 1994—Lischke and colleagues demonstrated droperidol causes dose-dependent prolongation of QT interval;
by 1999—Drolet and colleagues showed droperidol blocks human ether a-go-go-related gene (HERG) channel
in guinea pigs that underlies QT interval duration; FDA concluded QT prolongation surrogate for “something
that was rare, but very dangerous” (ie, torsades de pointes and related arrhythmias); determined that droperidol significant
culprit; since torsades de pointes occurred at and below labeled dose, droperidol considered serious risk with
no margin of safety; after discussing concerns with Akorn Pharmaceuticals (US holder of marketing application)—
FDA changed labeling, designating ≤2.5 mg the maximum initial adult dose, and dictating inclusion of a “black
box” warning; November 18, 2003—FDA Center for Drug Evaluation and Research held meeting of Anesthetic and
Life Support Drugs Advisory Committee; involved FDA scientists, anesthesiologists, cardiologists, and industry representatives;
discussed data available to FDA about droperidol and process by which black box warning established;
several anesthesiologists avidly advocated eliminating or modifying black box warning; argued that most adverse effects
reported to FDA related to large doses (sometimes as high as 250 mg) and predominantly outside United States;
FDA decided not to remove warning, but requested new information to support contention that droperidol safe; nothing
submitted to FDA to change viewpoint
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| Contents of black box warning: droperidol should be reserved for use in patients who do not show response to
other adequate treatments; patient should undergo 12-lead electrocardiography (ECG) before administration of droperidol
to determine whether prolonged QT interval present; if potential benefits outweigh risk, ECG monitoring
must be performed before treatment and continued for 2 to 3 hr after treatment; use droperidol with extreme caution
in patients at risk of developing prolonged QT syndrome or with congestive heart failure (CHF), in bradycardia,
and when used with diuretic or other drugs known to increase QT interval; use carefully in patients >65 yr of age,
patients who drink alcohol, and with benzodiazepines, volatile anesthetics, and IV opioids; initiate at low dose and
adjust upward, with caution, when necessary, to achieve desired effect
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| Studies: White (2005) —60 patients; those receiving 0.625 or 1.25 mg droperidol, and those in saline group had increased
QT interval corrected for heart rate (QTc) by small amount; 2 of 40 patients who received droperidol had
significant QT prolongation; Charbit (2005)—demonstrated significant (>60 ms) QTc prolongation with droperidol
0.75 mg; QT change occurred within 3 min and disappeared by 90 min; some patients “set up” for increased QT
prolongation, due to prolonged QT at baseline; as safe and effective as 5-HT3 receptor antagonists in clinical use,
but because of FDA labeling, many anesthesia providers have stopped using droperidol and instead use ondansetron
or alternative; 5-HT3 antagonists also appear to block HERG channel; Nuttall at el—found greater incidence
of torsades de pointes after droperidol discontinuation; Charbit editorial—risk for torsades de pointes with
QT-prolonging drugs justifies placing warning boxes on these drugs; therefore, study by Nuttall does not in itself
justify removal of warning for droperidol use; instead, results should prompt FDA to reconsider and lessen warning;
FDA— stated that “doses of droperidol <2.5 mg are off-label”; black box warning does not address doses <2.5
mg; in general, FDA has no specific comment on off-label uses of approved drugs, but expects physicians to exercise
judgment when doing so; droperidol can cause QT prolongation; torsades de pointes rare event that appears to
be associated with increased QT interval; droperidol black box warning will continue to address dosing ≥2.5 mg;
discussions expected regarding “tweaking” labeling for dosing <2.5 mg
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| Important questions: is droperidol too dangerous to use? should it be eliminated? if used, must anesthesia provider
follow FDA labeling, or is it permissible to pursue off-label use? if using droperidol at doses of 0.625 to 1.25
mg IV (for antiemesis), “can we then, with impunity, proceed”? if anesthesia provider not following labeling, does
he or she face departmental sanctions or state disciplinary action? If anesthesia provider not following labeling and,
eg, cardiac arrest occurs, can provider be held liable for negligence? however, if anesthesia provider believes droperidol
has merit and wants to continue use, can studies be conducted to confirm safety (and define situations in
which it might or might not be safe), and therefore convince FDA to change labeling?
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| SUCCINYLCHOLINE: A MARVEL WHOSE TIME HAS PASSED ?—Aaron F. Kopman, MD, Professor of Clinical
Anesthesiology, New York Medical College, Valhalla, NY, and Vice Chair and Director of Research, Department
of Anesthesiology, St. Vincent Catholic Medical Centers, New York, NY
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| Recent editorial: “after more than 50 years of dramatic advances in anesthesia, a pharmacologically dirty and dangerous
drug (succinylcholine) is still the ‘gold standard’ for producing paralysis during rapid-sequence induction of
anesthesia and endotracheal intubation—arguably one of the most dangerous moments in anesthesia practice”
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| Pharmacology: succinylcholine consists of 2 molecules of acetylcholine; breaks down into succinic acid and choline;
ED95 (ie, dose that produces 95% suppression of single twitch) ≈0.25-0.30 mg/kg; usual intubating dose of 1
mg/kg 3 to 4 times greater than ED95 (comparable dose of rocuronium 1.2 mg/kg); any drug can be made fast-acting
if “industrial” dose given; best test of onset time is to give ED95 to determine when peak effect occurs; if patient
given 0.25 mg/kg succinylcholine, 90% of peak effect seen in ≈75 sec, and maximum effect not seen until ≈2 min;
slower time to peak effect for cisatracurium (90% at ≈5 min, maximum at ≈7 min), and vecuronium and atracurium
(for both, 90% at 2.5-3 min); with rocuronium, initial onset “about the same” as with succinylcholine, but peak effect
much later; many consider duration of action of succinylcholine shorter than in actuality; with 1 mg/kg succinylcholine,
90% recovery of twitch height occurs in 9 to 13 min; in majority of patients, administration of 0.6 mg/
kg results in similar onset time (compared to 1 mg/kg) and somewhat faster recovery (90-120 sec faster); speaker
finds combination of propofol (2.0 mg/kg) “a little bit of narcotic”, and succinylcholine (0.5-0.6 mg/kg) “works
just fine”; review of literature by Benumof discovered succinylcholine (1 mg/kg) produces apnea and significant
life-threatening desaturation before recovery of respiratory mechanism occurs; Heier looked at recovery of spontaneous
ventilation after succinylcholine-induced apnea; 4 in 12 patients required intervention, due to O2 saturation
<80%; individuals aware, despite 5 mg/kg thiopental
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| Problems associated with succinylcholine: unpredictable—atypical or low plasma cholinesterase levels; if patient
heterozygous for atypical plasma cholinesterase, succinylcholine, 1 mg/kg, produces duration of action of ≈20
min and >10 min of apnea; incidence of modestly, but significantly clinically prolonged, responses to succinylcholine
in general population much higher than most people realize; miscellaneous morbidity—includes bradycardia,
ventricular ectopy (especially with repeat doses), anaphylactic and anaphylactoid reactions, and triggering of malignant
hyperthermia; postoperative myalgia—“fairly high incidence”; true incidence probably ≈50%; possible to
reduce incidence by using nonsteroidal anti-inflammatory drugs, or with precurarization, but “you can’t eliminate
it”; potentially fatal hyperkalemia—motor neuron injuries; peripheral neuropathies (eg, multiple sclerosis, amyotrophic
lateral sclerosis, critical illness polyneuropathy); thermal injuries; direct muscle trauma; disuse atrophy; immobilization;
various myopathies (eg, muscular dystrophy; correct precurarization dose of nondepolarizing muscle
relaxant 10% of ED95 [eg, for rocuronium, 2-3 mg {0.03 mg/kg}]; doses that are 10% of intubating dose cause significant
weakness; black box warning in children; reserved for emergency intubation or instances in which immediate
securing of airway necessary [eg, laryngospasm, difficult airway, full stomach, IM use where suitable vein
inaccessible]); cost—vial of succinylcholine inexpensive, but total cost equals acquisition cost, plus cost of treating
complications, plus cost of adverse outcomes; study estimated overall cost of single dose of succinylcholine,
over long term, may be $35; hidden costs (eg, discarding opened vial of rocuronium)
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| Alternatives to succinylcholine: laryngeal mask airway (LMA)—increased use of LMA resulting in decreased
use of succinylcholine; however, not always appropriate; even in experienced hands, <100% successful placement
of LMA; less secure than endotracheal tube; avoidance of muscle relaxants—propofol, 2.0 mg/kg plus alfentanil, 40
to 50 µg; propofol, 2.0 mg/kg plus remifentanil, 2 to 4 µg/kg; high incidence (90%) of excellent intubating conditions;
may not be wise approach in hemodynamically unstable patient or octogenarian (causes profound drop in
blood pressure); nondepolarizing muscle relaxants—with most intermediate-acting drugs, eg, atracurium, cisatracurium,
vecuronium, 4 times ED95 required for endotracheal intubation within 60 to 90 sec; with rocuronium, however,
only 2 times ED95 required for intubation in 60 to 90 sec; for rapid sequence intubation and profound
relaxation (intubation in <60 sec), use rocuronium 1.0 to 1.2 mg/kg; none of above options allow for immediate reversal
of deep neuromuscular blockade
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| Future possibilities: rocuronium, 1.2 mg/kg, followed 3 min later by sugammadex, 12 to 16 mg/kg, results in recovery
to train-of-four ratio of 0.9 in <2 min; economic realities may limit use of combination (200-mg ampule of
sugammadex unlikely to be <$20); unlikely to replace succinylcholine for routine use; gantacurium proof that nondepolarizing
drugs with onset-offset profiles similar to succinylcholine possible; histamine release may be problematic;
commercial development uncertain
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| Summary: unclear whether succinylcholine should be retired; speaker believes pharmacoeconomics cannot be
ignored; speed with which succinylcholine eventually abandoned depends not just on theoretic advantages of replacement
drugs, but on actual cost of drugs
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Suggested Reading
Benumof JL et al: Critical hemoglobin desaturation will occur before return to an unparalyzed state following 1
mg/kg intravenous succinylcholine. Anesthesiology 87:979, 1997; Charbit B et al: Droperidol-induced proarrhythmia:
the beginning of an answer? Anesthesiology 107:524, 2007; Charbit B et al: Prolongation of QTc interval after
postoperative nausea and vomiting treatment by droperidol or ondansetron. Anesthesiology 102:1094, 2005; Dershwitz
M: Droperidol: should the black box be light gray? J Clin Anesth 14:598, 2002; Dexter F et al: Cost identification
analysis for succinylcholine. Anesth Analg 92:693, 2001; Drolet B et al: Droperidol lengthens cardiac
repolarization due to block of the rapid component of the delayed rectifier potassium current. J Cardiovasc Electrophysiol
10:1597, 1999; Guy JM et al: Torsades de pointes and prolongation of the duration of QT interval after injection
of droperidol. Ann Cardiol Angeiol (Paris) 40:541, 1991 (French); Kopman AF et al: An alternate method
for estimating the dose-response relationships of neuromuscular blocking drugs. Anesth Analg 90:1191, 2000; Erratum
in: Anesth Analg 91:67, 2000; Kopman AF et al: The "intubating dose" of succinylcholine: the effect of decreasing
doses on recovery time. Anesthesiology 99:1050, 2003; Kopman AF: Rocuronium versus succinylcholine
for rapid tracheal intubation. Anesth Analg 102:1912; author reply 1912, 2006; Lischke V et al: Droperidol causes a
dose-dependent prolongation of the QT interval. Anesth Analg 79:983, 1994; Mazze RI et al: Hyperkalemia and
cardiovascular collapse following administration of succinylcholine to the traumatized patient. Anesthesiology 31:540,
1969; Miller R: Will succinylcholine ever disappear? Anesth Analg 98:1674, 2004; Nuttall GA et al: Does low-
dose droperidol administration increase the risk of drug-induced QT prolongation and torsade de pointes in the general
surgical population? Anesthesiology 107:531, 2007; Pace NL: Prevention of succinylcholine myalgias: a meta-
analysis. Anesth Analg 70:477, 1990; White PF et al: Drug-induced prolongation of the QT interval: what's the
point? Anesthesiology 104:386, 2006; White PF: Droperidol: a cost-effective antiemetic for over thirty years. Anesth
Analg 95:789, 2002.
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