Doi:10.1016/s0736-4679(03)00044-

The Journal of Emergency Medicine, Vol. 24, No. 4, pp. 441– 447, 2003 doi:10.1016/S0736-4679(03)00044-1
Pharmacology
in Emergency Medicine
DROPERIDOL IN THE EMERGENCY DEPARTMENT: IS IT SAFE?
John R. Richards, MD* and Aaron B. Schneir, MD† *Division of Emergency Medicine and Toxicology, University of California, Davis Medical Center, Sacramento, California and †Department of Emergency Medicine, Division of Medical Toxicology, University of California, San Diego Medical Center, San Diego Division, California Poison Control System, San Diego, California Reprint Address: John R. Richards, MD, Division of Emergency Medicine, UC Davis Medical Center, 2315 Stockton Boulevard, e Abstract—Droperidol is an antipsychotic and antiemetic
was more useful in the treatment of psychosis, and Hal- drug that has been used extensively by Emergency Physi-
operidol was the first agent to be approved for this use in cians, Psychiatrists, and Anesthesiologists worldwide since
1957 Droperidol has been used extensively for the 1967. It also has been used effectively for other diverse
past 30 years by Psychiatrists, Emergency Physicians, conditions, such as treatment of headache and vertigo. As of
and Anesthesiologists. Recently, however, the drug has January 2001, Droperidol was no longer available in Eu-
come under intense scrutiny for its role in prolonging QT rope after its founder, Janssen-Cilag Pharmaceuticals, dis-
continued its distribution. In December 2001, the United
intervals and development of fatal cardiac dysrhythmias States Food and Drug Administration (FDA) placed a black
The Medicines Control Agency of the United box warning on the use of Droperidol in response to an
Kingdom initially raised a safety concern regarding the association between Droperidol and fatal cardiac dysrhyth-
chronic use of high-dose Droperidol in psychiatric pa- mias, such as torsade de pointes, resulting from prolonga-
tients. This may have led its founding firm, Janssen- tion of the QT interval. In this review we closely examine
Cilag Ltd of Belgium, to discontinue production and the pharmacology, indications, use, and complications as-
distribution of Droperidol to most of the world as of sociated with Droperidol, and speculate on its future use in
January 2001 This resulted in an outcry from the Emergency Department.
2003 Elsevier Inc.
physicians in Europe, mainly anesthesiologists, who used Droperidol extensively for postoperative nausea Keywords—Droperidol; Inapsine; antipsychotic; Emer-
gency Department; FDA warning
and vomiting (PONV) and remarked on its efficacy, lowcost, patient satisfaction, and excellent safety profile INTRODUCTION
In December 2001, the United States Food and Drug Administration (FDA) issued a “black box warning” Droperidol is a butyrophenone, a class of antipsychotic (Appendix), its most serious alert, on the use of Droperi- agents that include Haloperidol, and is marketed in the dol The Canadian Health Protection Branch followed United States under the trade name Inapsine™. Butyro- soon thereafter Before these warnings, doses greater phenones were initially studied in the late 1950s at the than 25 mg were considered to put patients at higher risk Janssen laboratories in Belgium as a potential substitute of QT prolongation and dysrhythmia, and it was esti- for Morphine It was soon realized this class of drugs mated Droperidol constituted 30% of the antiemetic mar- Pharmacology in Emergency Medicine is coordinated by Richard F. Clark, MD, of the University of California San
Diego Medical Center, San Diego, California
RECEIVED: 26 April 2002; FINAL SUBMISSION RECEIVED: 9 September 2002;ACCEPTED: 15 October 2002 erate doses During this sedation, the patient isresponsive to commands and is usually indifferent to hisor her surroundings. There is evidence Droperidol inhib-its specific GABA and nicotinic receptors in high doses,which may explain the anxiety, dysphoria, and akathisiathat accompanies high doses in certain patients Droperidol is the shortest acting of the butyrophe- nones, with a half-life of 2 h Peak serum levelsoccur 1 h after intramuscular (i.m.) and intravenous (i.v.)injection, and it is widely protein bound with a volume ofdistribution of 2 L/kg. Droperidol may be administeredorally, i.m., and i.v. Typical antiemetic doses range from0.625 to 2.5 mg i.v./i.m., and doses for chemical restraintbegin at 5 mg i.v./i.m. and higher. It readily crosses theblood-brain barrier and is distributed into the cerebrospi-nal fluid It slowly traverses the placenta, and it isunclear if it is present in breast milk It is exten-sively metabolized in the liver, and excretion is primarilyrenal (75%) with the remainder excreted in the feces. Itsmetabolites, benzimidazolone, p-fluorophenylacetic acid,and p-hydroxypiperidine, are inactive. Roughly 10% isexcreted in the urine unmetabolized Figure 1. Chemical structure of Droperidol.
INDICATIONS
ket, with over 25 million units sold in 2000 North The most common indications for Droperidol use in the American Anesthesiologists, Pharmacists, and Emer- ED are for chemical restraint of acute psychosis and gency Physicians reacted skeptically to these new restric- agitation, and for antiemesis Of interest, tions on the use of Droperidol Now Emergency Droperidol has received FDA approval for only two Physicians (EPs) who still have access to Droperidol indications, as an antiemetic and as an anxiolytic/amnes- must decide the risk/benefit ratio for its use in their tic agent before diagnostic or surgical procedures for particular practice. To aid in this decision, in this article children and adults. Droperidol is a powerful and inex- we extensively review the current and past literature pensive antiemetic, as demonstrated by several studies regarding Droperidol and its potential for adverse drug However, it does not have FDA approval for reactions in the Emergency Department (ED).
hyperemesis gravidarum and chemotherapy-inducednausea and vomiting, despite several studies demonstrat-ing its efficacy when compared to other alternative anti- PHARMACOLOGY
Perhaps the most important use of Droperidol in the Butyrophenones, of which Droperidol is a member, are ED is rapid tranquilization of the violent, agitated patient potent dopamine (D) antagonists with less potent ␣ re- A plethora of studies has proven the efficacy of ceptor effects. Droperidol binds preferentially to the D-2 Droperidol for this particular indication, especially when and ␣-1 receptors, respectively Both its antiemetic compared to other agents, such as benzodiazepines and antipsychotic properties derive from this potent D-2 Furthermore, Droperidol has been effective for treat- antagonism. Unlike the phenothiazines, butyrophenones ing all subsets of agitation, including stimulant abuse, have weaker anticholinergic and antihistaminic proper- head injury, mania or psychosis, and in pediatric patients ties, and greater tendency to produce extrapyramidal side Unlike Haloperidol, Droperidol has never re- effects. Structurally butyrophenones are sim- ceived FDA approval for use in treatment of acute psy- ilar to ␥-aminobutyric acid (GABA) and are concen- trated in the central nervous system (CNS) This may Droperidol, originally synthesized as a potential alter- account for their potent tranquilization properties, in native to Morphine, also has been used for atypical pain which a quiescent state with reduced motor activity, syndromes. Before the FDA warning, Droperidol had anxiety, and apprehension is achieved with low to mod- become increasingly popular for treatment of headache Two recent studies demonstrated Droperidol to be ported with Droperidol, but these phenomena seem to be an effective agent in the treatment of benign headaches very rare events Agranulocytosis was reported in the ED In Europe, there has been interest in in two patients after addition of Droperidol to an existing the use of Droperidol in combination with Fentanyl for phenothiazine regimen, but no further reports exist cardiac chest pain, but results in one study have demon-strated higher 12 month mortality for unstable anginapatients receiving Droperidol and Fentanyl versus those ADVERSE DRUG EFFECTS: CARDIAC
receiving Morphine A case study of Droperidoluse in a patient with neuropathic pain of central origin After administration of Droperidol, tachycardia and mild reported diminished lightning pain after subarachnoid hypotension, presumably from ␣-1 antagonism, have block In another study, patients undergoing anorec- been reported, but these side effects are extremely rare tal surgery received either Droperidol or Butorphanol as Decreased left ventricular end diastolic pres- an adjunct to epidural anesthesia, and the Droperidol sure, but not cardiac contractility or systemic vascular group had improved analgesia One explanation for resistance, was noted after i.v. Droperidol administration this phenomenon may be that Droperidol selectively in a study of nine patients Droperidol’s effects on blocks the fast sodium channels in the dorsal horn neu- the ionic currents of the heart were recognized by rons of the spinal cord Another indication for Hauswirth in 1967 and by Kern and associates in 1971 Droperidol is the emergency treatment of peripheral ver- This was followed by several studies that further tigo, including Meniere’s disease and benign positional defined Droperidol’s site of action The process variants Two studies have demonstrated impressive of repolarization of cardiac cells involves sodium, cal- cium, and several different potassium channels Droperidol and many other antipsychotic drugs seemto delay repolarization of ventricular cells by blocking a ADVERSE DRUG EFFECTS: NON-CARDIAC
specific type of channel, the potassium rectifier (I ) channel This is represented by QT interval Droperidol has several CNS side effects that have been prolongation on the electrocardiogram (EKG).
previously described. Dysphoria, drowsiness, hallucina- Corrected QT intervals less than 440 ms in duration tions, shivering, and anxiety have been reported after are considered normal, and intervals greater than 500 ms Droperidol injection, but are uncommon Extra- are considered high risk Torsade de pointes is a pyramidal side effects from Droperidol’s action on the unique polymorphic ventricular dysrhythmia associated D-2 receptor include akathisia and dystonias, such as with a long QT interval, which is usually unresponsive to torticollis, and oculogyric crisis Neuroleptic standard antidysrhythmic drugs It exists in a malignant syndrome after Droperidol administration has primary congenital form, and in a secondary form that is been described in patients on long-term antipsychotics, most often drug induced Treatment of torsade de such as Lithium and phenothiazines, and during elective pointes typically involves i.v. magnesium and possibly surgery under anesthesia The risk of Droperidol cardioversion or cardiac pacing. Other risk factors in- lowering threshold for seizure seems to be a common clude hypomagnesemia, hypokalemia, pre-existing dys- dogma, but there is little evidence for its support in the rhythmia, history of cardiac or liver disease, or concom- form of case reports or controlled studies One study itant use of drugs known to inhibit hepatic metabolism of in mice demonstrated low to moderate doses of Droperi- Droperidol In a study of 55 patients, Guy and col- dol lowered seizure threshold, whereas high doses para- leagues injected 0.25 mg/kg i.v. Droperidol and noted doxically raised it A report from Russia noted tonic prolongation of the QT interval in 70% of subjects after episodes resembling seizures in patients after receiving 1 min No one developed torsade de pointes in their study, but they recommended caution with administra- One of Droperidol’s most important advantages is its tion of Droperidol. Reilly and associates compared lack of respiratory depression even in high doses EKGs between patients taking antipsychotics and Only one case of respiratory distress has been described healthy subjects Abnormal QT interval was asso- after 5 mg i.v. Droperidol was given to a patient suffer- ciated with older age, use of tricyclic antidepressants, ing from lysergic acid (LSD) toxicity who had been Thioridazine, Droperidol, or high doses of any antipsy- taking Lithium and Risperidone After becoming chotic. Lischke et al., in a series of 40 patients injected rigid and unable to self-ventilate, he was intubated. It with increasing dosages of Droperidol, determined a was postulated by the authors that Droperidol may have direct association between dose and QT interval prolon- induced serotonin syndrome in this patient. Angioedema, laryngospasm, and true allergic reactions have been re- In their review of antipsychotics, Glassman and Big- Table 1. Drugs That Prolong QT Interval or Induce Torsade
de Pointes
Figure 2. Types of receptors involved in the cardiac action
potential and ionic flow. (a) Surface electrocardiogram. The
QT interval is measured from the beginning of the QRS
* associated with prolonged QT and torsade de pointes.
† complex to the return of the T wave to the isoelectric base-
associated with torsade de pointes only.
line. (b) Action potential showing the four phases of cardiac
depolarization and repolarization with the various sites of
the ion channel effects. I
؍ L-type calcium channel; I
T-type calcium channel; I
cardiac deaths per 10,000 person-years in subjects with- ؍ depolarizing sodium channel;
؍ Inwardly rectifying potassium current; I
؍ rapidly
out cardiac disease, or 2.39 times greater risk of death activating delayed rectifier potassium current; I
؍ slowly
than patients not taking antipsychotics. To date there activating delayed rectifier potassium current; I
rapidly activating delayed rectifier potassium current;
have been over 100 reports of cardiovascular events ؍ transient outward potassium currents. (c) Ion
attributed directly to Droperidol reported to the FDA, current directions during activation of various ion channels.
including 20 cases of torsade de pointes, nine cardiac EC, extracellular; IC, intracellular. (Reprinted with permis-
sion, Buckley NA, Sander P. Cardiovascular adverse effects
arrests, and two deaths at doses of 2.5 mg i.v. or less of antipsychotic drugs. Drug Saf. 2000;23:218. ஽ 2000 Adis)
Although evidence exists that Droperidol causes pro- longation of the QT interval based on the aforementioned ger emphasized that most members of this class of drugs studies, it is difficult to ascertain whether Droperidol cause QT interval prolongation Many other drugs alone is at fault for the genesis of subsequent dysrhyth- that prolong the QT interval, such as Amiodarone, are mias, as patients who receive the drug often have con- rarely associated with torsade de pointes Con- comitant medical and psychiatric problems. Many case versely, quinidine is more frequently associated with reports describe patients undergoing elective and emer- torsade de pointes despite less QT interval prolongation gent surgery in the operating room under general anes- The phenothiazine Thioridazine, in particular, seems thesia Many of these patients also may have to be the most dangerous of the antipsychotics for the been taking cardiac and psychotropic medication. For production of torsade de pointes and sudden death instance, a recent case report involves a patient with These dysrhythmias seem to be more pronounced in chronic renal failure on hemodialysis who underwent a elderly patients with heart disease, patients who smoke, total hysterectomy under general anesthesia and devel- and patients on multiple medications. The risk of sudden oped a chaotic ventricular dysrhythmia Another death from antipsychotic drug use was estimated by Ray series involved three critically ill patients with esopha- and associates in their study of half a million subjects geal varices receiving vasopressin and nitroglycerin over 2.5 years Their calculation was 11 sudden The influence of general anesthetic agents combined with Droperidol on development of dysrhythmias is un- on adverse reactions. To avoid any risk of QT interval clear One study reported no dysrhythmias in a prolongation, the Emergency Physician is essentially left group of patients receiving Enflurane and Droperidol for with benzodiazepines and barbiturates as the only alter- surgery compared to those receiving Enflurane and Hy- natives for sedation. Although the FDA has recom- oscine (0 vs. 4.4%, respectively) Furthermore, pa- mended continuous cardiac monitoring for patients re- tients requiring Droperidol may already be under the ceiving Droperidol, our review demonstrates this may be influence of stimulants such as Methamphetamine and an overstatement of the risk. Although patients at higher Cocaine, which are already prodysrhythmogenic In risk for cardiac events, such as those with prior history of their review of case reports involving Droperidol and dysrhthmia and those receiving high doses of Droperidol, Haloperidol, Lawrence and Nasraway found 11 reports warrant consideration of continuous cardiac monitoring, of 18 patients with conduction disturbances linked to buty- many low-risk patients receiving small doses may not rophenone use. Thirteen (72%) had a history of cardiovas- require continuous cardiac monitoring. For those clini- cular disease Of interest, Haloperidol does not have cians who have come to rely on Droperidol and choose to a black box warning by the FDA, even though it has the continue using it, we recommend careful patient selec- same cardiac effects as Droperidol and has been associ- tion and screening for high-risk individuals, adherence to ated with torsade de pointes To date, no case reports the FDA guidelines, and continuous cardiac monitoring involving cardiac dysrhythmia and Droperidol have ap- of the high-risk patient after administration. An under- peared in Emergency Medicine journals.
standing of the potential complications of Droperidol The promise of improved patient safety with second use, such as dystonia, torsade de pointes, and their treat- generation antipsychotics such as Olanzapine, Risperi- ments, will ultimately reduce potential liability and in- done, Ziprasidone and Quetiapine has been questionable Their safety profile may not be fully knownuntil these drugs have achieved widespread use, as ex-emplified by Sertindole, which was withdrawn after be- REFERENCES
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APPENDIX
74. Gomez-Arnau J, Marquez-Montes J, Avello F. Fentanyl and droperi- dol effects on the refractoriness of the accessory pathway in the FDA black box warning for use of Droperidol Wolff-Parkinson-White syndrome. Anesthesiology 1983;58:307–13.
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larizations and triggered activity in rabbit Purkinje fibers. J Phar- pointes have been reported in patients receiving
INAPSINE at doses at or below recommended doses.
77. Drolet B, Zhang S, Deschenes D, et al. Droperidol lengthens cardiac repolarization due to block of the rapid component of the Some cases have occurred in patients with no known
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