Does Low-Dose Droperidol Administration Increase the Risk of Drug-Induced QT Prolongation and Torsade De Pointes in the General Surgical Population? Gregory A

Ⅵ CLINICAL INVESTIGATIONS

Anesthesiology 2007; 107:531–6 Copyright © 2007, the American Society of Anesthesiologists, Inc. Lippincott Williams & Wilkins, Inc. Does Low-dose Droperidol Administration Increase the Risk of Drug-induced QT Prolongation and Torsade de Pointes in the General Surgical Population? Gregory A. Nuttall, M.D.,* Karen M. Eckerman, C.R.N.A. M.N.A.,† Kelly A. Jacob, C.R.N.A. M.N.A.,† Erin M. Pawlaski, C.R.N.A. M.N.A.,† Susan K. Wigersma, C.R.N.A. M.N.A.,† Mary E. Shirk Marienau, C.R.N.A., M.S.,‡ William C. Oliver, M.D.,* Bradly J. Narr, M.D.,§ Michael J. Ackerman, M.D., Ph.D.࿣

Background: The US Food and Drug Administration issued a DROPERIDOL, a butyrophenone, is most often used as a Downloaded from http://pubs.asahq.org/anesthesiology/article-pdf/107/4/531/365099/0000542-200710000-00006.pdf by guest on 27 September 2021 black box warning regarding the use of droperidol and the premedication for anesthesia, treatment for nausea and potential for torsade de pointes (TdP). vomiting after anesthesia, and sedation of agitated pa- Methods: The primary objective of this retrospective study was to determine whether low-dose droperidol administration tients. The maximum recommended initial dose for pre- increased the incidence of TdP in the general surgical popula- vention or treatment of postoperative nausea and vom- tion during a 3-yr time period before and after the Food and iting (PONV) is 2.5 mg intravenous or intramuscular. Drug Administration black box warning. A random sample of Additional 1.25-mg doses of droperidol may be adminis- 150 surgical patients during each time interval was selected to tered to achieve desired effect.1 Droperidol has been estimate the droperidol use for each time period. used successfully by anesthesiologists for the treatment Results: During the time period before the black box warning (July 1, 1998 to June 30, 2001), 2,321/139,932 patients (1.66%) had and prevention of PONV in millions of patients for more 2,3 QT prolongation, TdP, or death within 48 h after surgery. We could than 30 yr. A review of the literature reveals conflict- identify no patients who clearly developed TdP before the black ing facts regarding the administration of droperidol and box warning. There was one patient for whom the cause of death compounding factors that may be associated with the could not positively be ruled out as due to TdP. In the time period potential for drug-induced long QT syndrome (LQTS).4 after the black box warning (July 1, 2002 to June 30, 2005), 2,207 In December 2001, the US Food and Drug Administra- patients (1.46%) had documented QT prolongation, TdP, or death within 48 h after surgery, including only two cases (<0.1%) of tion (FDA) issued a black box warning regarding the use TdP. The incidence of droperidol exposure was approximately of droperidol and the potential for drug-induced QT 12% (exact 95% confidence interval, 7.3–18.3%) before the black prolongation and torsade de pointes (TdP). The warning box warning and 0% after placement of the black box warning on stated that “cases of QTc prolongation and/or TdP have droperidol. Therefore, we estimate that approximately 16,791 pa- been reported in patients receiving droperidol at doses tients (95% confidence interval, 10,173–25,607) were exposed to at or below recommended doses.”1 The warning was droperidol, none of whom experienced documented TdP. Conclusions: This indicates that the Food and Drug Administra- based on 10 reported cases in association with droperi- tion black box warning for low dose droperidol is excessive and dol use (1.25 mg or below) over the approximately 30 yr unnecessary. that droperidol has been available on the market world- wide. Before this warning, 0.625–1.25 mg intravenous droperidol had been accepted widely as a first-line therapy This article is featured in “This Month in Anesthesiology.” for management of PONV with a 30-yr history of low side ᭛ Please see this issue of ANESTHESIOLOGY, page 5A. effects and high cost-effectiveness. A comparably effective rescue drug for PONV does not currently exist, although 5 ᭜ This article is accompanied by an Editorial View. Please see: promethazine and dimenhydrinate have been used. Charbit B, Funck-Brentano C: Droperidol-induced proarrhyth- After the black box warning on droperidol, 5-hydroxy- mia: The beginning of an answer? ANESTHESIOLOGY 2007; 107:524–6. tryptamine type 3 (5-HT3) antagonists (ondansetron, granisetron, and dolasetron) became the first-line treatment both for prevention and treatment of PONV.6 In-

* Professor of Anesthesiology, § Associate Professor of Anesthesiology, terestingly, these 5-HT3 antagonists are listed among QT ࿣ Professor of Medicine, Pediatrics, and Molecular Pharmacology & Experi- interval–prolonging drugs with possible risk of TdP.# mental Therapeutics, Mayo Clinic College of Medicine, Rochester, Minnesota. † Nurse Anesthetist, ‡ Nurse Anesthesia Program Director, Mayo School of The FDA case reports, MedWatch reports, and data Health Sciences, Rochester, Minnesota. from the manufacturer have been examined, and both Received from the Departments of Medicine, Pediatrics, and Molecular Phar- literature reviews and editorial comments have sug- macology & Experimental Therapeutics, Mayo Clinic College of Medicine, Roch- ester, Minnesota. Submitted for publication January 24, 2007. Accepted for gested the black box warning on droperidol is unwar- publication May 9, 2007. Support was provided solely from institutional and/or ranted. At this time, no published studies have conclu- departmental sources. sively related the recommended low-dose droperidol Address correspondence to Dr. Nuttall: Department of Anesthesiology, Mayo Foundation, 200 First Street Southwest, Rochester, Minnesota 55905. administration used in prevention or treatment of PONV [email protected]. This article may be accessed for personal use at no to the development of drug-induced LQTS consisting of charge through the Journal Web site, www.anesthesiology.org. 6 # http://www.qtdrugs.org/medical-pros/drug-lists/drug-lists.htm#. Accessed either QT prolongation or development of TdP. Because May 7, 2007. the FDA black box warning was based on case reports, we

Anesthesiology, V 107, No 4, Oct 2007 531 532 NUTTALL ET AL. sought to determine the true incidence of TdP associated with droperidol use in a large anesthesia practice.

Materials and Methods

After institutional review board approval (Rochester, Minnesota), we performed a retrospective study of patients who had undergone surgery with general anesthesia or central neuraxial blockade at Mayo Clinic Roches-

ter during the 3-yr time period from July 1, 1998 to June Downloaded from http://pubs.asahq.org/anesthesiology/article-pdf/107/4/531/365099/0000542-200710000-00006.pdf by guest on 27 September 2021 30, 2001 (before the black box warning) and the 3-yr time period from July 1, 2002 to June 30, 2005 (after the black box warning). These time frames were expected to capture a realistic use of droperidol before the black box warning and the decreased use after the warning. The primary endpoint for this investigation was the occurrence of TdP within 2 days after surgery. The frequency of TdP was estimated separately for each calendar period and compared between periods using descriptive analysis. The frequency of droperidol use was extrapolated for each time period using data from random sampling. Using the electronic Anesthesia Quality Assurance system (Performance Improvement Database) database, we identified 139,932 patients who underwent surgery with general anesthesia or central neuraxial blockade at the Mayo Clinic Rochester during the earlier time window ؍ and 151,256 patients who underwent surgery during the Fig. 1. The methods used to identify high-risk patients. QTc ؍latter time period. All patients who require anesthesia heart rate–corrected QT interval using Bazett formula7;VT services are included: Inpatients, outpatients, and all ventricular tachycardia. procedures (radiologic imaging, such as magnetic reso- nance imaging and/or computerized axial tomography within 48 h of surgery and reviewed these charts for scanning; bronchoscopy, endoscopy, and other inter- evidence of TdP. ventional procedures including cardiac catheterizations) The charts of these 4,528 patients with documented at Mayo Clinic Rochester are entered into our electronic QTc prolongation, TdP, or death within 2 days after their Anesthesia Quality Assurance system. The electronic sys- surgical procedure were reviewed to determine whether tem became effective on November 1, 1988. By merging the patient had an adverse cardiac event afterward, no- the anesthesia database patient’s data with an electrocar- tably TdP. For all patients who had TdP, a thorough chart diogram database, we determined that 2,321 (1.66%) review was performed to collect demographic and po- patients in the earlier time period and 2,207 (1.46%) tential risk factor information, including droperidol use patients in the latter time period had documented QTc within 2 days of surgery and other drugs or medical prolongation, TdP, or death within 2 days after their conditions known to increase the risk of TdP. A descrip- surgical procedure (fig. 1). The electrocardiographic re- tive analysis of the cases of TdP for the time periods sults of all patients who have a 12-lead electrocardio- before and after the December 2001 black box warning gram or Holter performed at Mayo Clinic Rochester are was conducted. entered into the electrocardiogram database, and start- In addition to the aforementioned data, a random sam- ing in 1982, the electrocardiograms were recorded in ple of 150 surgical patients during each time interval was electronic format. The QTc calculation was performed selected to estimate the droperidol use for each time according to the method of Bazett.7 To identify patients period (fig. 2). With the sample size of 150 patients, we who developed TdP, we reviewed the charts of patients would be able to estimate the percentage of droperidol with prolonged QTc and/or any ventricular tachycardia. use before the black box warning with precision of Further, to ensure that patients who did not have an approximately plus or minus 5% based on the width of electrocardiogram performed in the perioperative pe- the 95% confidence interval (CI). Timing of droperidol riod who nevertheless developed TdP were captured, administration as well as amount of droperidol given we used a database to identify patients who had a death were recorded.

Anesthesiology, V 107, No 4, Oct 2007 DROPERIDOL AND TORSADE DE POINTES 533

uneventful. She was transferred to the floor. She was evaluated around 9:30 PM and found to be in no distress. She was found at approximately 10 PM to be unresponsive and pulseless. Therefore, this event occurred at least 10 h after her exposure to droperidol. None of her notes indicated TpD. She was resuscitated from asystole to rapid atrial fibrillation with epinephrine and atropine then controlled with amiodarone. After resuscitation, a presumptive diagnosis of pulmonary embolism was made and treated with antifibrinolytics and heparin. A

pulmonary embolism was ruled out subsequently by Downloaded from http://pubs.asahq.org/anesthesiology/article-pdf/107/4/531/365099/0000542-200710000-00006.pdf by guest on 27 September 2021 rapid chest computed tomography. Computed tomography of her head revealed diffuse cerebral edema. She remained unresponsive and died 2 days later. The au- Fig. 2. The methods used to identify incidence of exposure to topsy report listed the immediate cause of death as acute droperidol. hypoperfusion injury and acute pneumonitis. She did not have a baseline electrocardiogram to identify her QT Results interval (table 1). The time period before the black box warning (July 1, In the time period after the black box warning (July 1, 1998 to June 30, 2001) included 2,321 patients (1.66%) 2002 to June 30, 2005), we identiﬁed 2,207 patients who died within 48 h after surgery, experienced TdP, or (1.46%) who died within 48 h after surgery, experienced exhibited QT interval prolongation. We could identify TdP, or exhibited QT interval prolongation. In this no patients who clearly developed TdP before the black group, there were two cases of documented TdP (table box warning. Of the 456 patients who died within 48 h 1). One patient was a 6-week-old infant who underwent after surgery in the time period before the black box repair of congenital cardiac anomalies and experienced warning, there was only one patient for whom the cause TdP postoperatively. The other patient was a 74-yr-old of death could not positively be ruled out as due to TpD. woman undergoing aortic valve repair. She experienced This patient was a 48-yr-old, obese (104-kg, 165-cm) multiple arrhythmias, including TdP, perioperatively and woman, status-post orthopedic surgery, who was found postoperatively. Neither patient received droperidol; unresponsive and pulseless in bed. She had received however, they had many other confounding, TdP-predis- 1.25 mg intravenous droperidol at 11:30 AM in surgery posing risk factors, such as cardiac surgery. and 4 mg ondansetron at 5:00 PM in the postanesthesia Other occurrences of TdP were identiﬁed. They were care unit. Her operative and postoperative course was excluded for the following reasons: TdP occurring be-

Table 1. Patients Experiencing Torsade de Pointes

Date of Preoperative Postoperative Other Causes of Droperidol Surgery QTc, ms QTc, ms Long QT Administration, mg Comments

April 28, No ECG No ECG 4 mg ondansetron 1.25 intraoperative 48-yr-old female orthopedic surgery patient 2001 in recovery found unresponsive and pulseless in bed. Pulmonary embolism ruled out. Cardiac rhythm before event unknown. December 23, No ECG 413, 419, 542 Congenital cardiac None 6-wk-old patient with failure to thrive, 2002 anomalies hypoplastic aortic arch, and juxtaductal coarctation repair. NSR and stable hemodynamics off-pump. Postoperative day 1, two episodes of TdP treated successfully with magnesium, propranolol, and digoxin. August 7, 459 397, 551 Cardiac surgery None 74-yr-old female aortic valve repair patient. 2004 Postoperative day 2 of redo coronary anastomosis and right ventricular assist device inserted. Ventricular tachycardia, TdP, and atrial ﬁbrillation perioperatively and postoperatively. Support withdrawn.

Other occurrences of torsade de pointes (TdP) were identiﬁed. They were excluded for the following reasons: TdP occurring before surgery, TdP occurring more than 48 h postoperatively, and TdP occurring in a setting unrelated to anesthesia. ECG ϭ electrocardiogram; NSR ϭ normal sinus rhythm.

Anesthesiology, V 107, No 4, Oct 2007 534 NUTTALL ET AL. fore surgery or droperidol exposure (n ϭ 1), TdP occur- coded by KCNH2. Among these drugs, antiarrhythmic ring more than 48 h postoperatively (n ϭ 2), and TdP agents such as quinidine, sotalol, dofetilide, and ibutilide occurring in a setting unrelated to anesthesia (n ϭ 3). have the greatest potential to induce fatal TdP. There are None of the excluded patients received droperidol nine structurally unrelated drugs that were marketed in within 48 h before their event. the United States or elsewhere for a range of noncardiovas- Based on a random sampling of 150 surgical cases, the cular indications that have been removed from the market incidence of droperidol exposure at our institution during or had their availability severely restricted because of this the time period before the black box warning was esti- rare disastrous effect.9 Along with droperidol, these drugs mated to be 12% (exact 95% CI, 7.3–18.3%). Therefore, of include terfenadine, astemizole, grepaﬂoxacin, terodiline, 139,932 patients in the time period before the black box lidoﬂazine, sertindole, levomethadyl, and cisapride. Many

warning, we estimate that approximately 16,791 (95% CI, Downloaded from http://pubs.asahq.org/anesthesiology/article-pdf/107/4/531/365099/0000542-200710000-00006.pdf by guest on 27 September 2021 antipsychotic and antiemetic drugs, including the 5-HT3 10,173–25,607) patients were exposed to droperidol, none antagonists, are listed among QT interval–prolonging drugs of whom experienced documented TdP. Using the conser- with possible risk of TdP.6,10 Curiously, droperidol is the vative estimate of 10,173 exposed patients, the upper only antiemetic that has received the black box warning. bound (based on a 95% CI) for the rate of TdP in patients Recently, it has been suggested that QT prolongation is receiving droperidol is 3.6 per 10,000. The incidence of not the significant effect per se for TdP, but rather the droperidol exposure approached 0%, with none of the 150 risk factor is transmural dispersion of repolarization that randomly sampled surgical cases associated with droperi- is manifested by a widened T wave.11 Whyte et al.12 has dol use after the placement of the black box warning on suggested that the time interval from the peak to the end droperidol. of the T wave would be a good measure of transmural dispersion of repolarization. Whyte et al.12 also has pointed out that QTc prolongation is a poor predictor of Discussion the actual risk of TdP, because 40% of patients congenital QT prolongation are asymptomatic at the time of We found no evidence supporting the black box warn- diagnosis, and there are many drugs that are known to ing placed on droperidol by the FDA when used to treat prolong the QT interval but have not been shown to PONV in the surgical population. Droperidol use as an induce TdP. antiemetic in the perioperative period decreased from There have been several well-controlled, randomized, 12% to 0% after the December 2001 FDA black box comparative clinical trials where droperidol has been warning for droperidol because of concerns regarding demonstrated to be as safe and effective as the more drug-induced LQTS. There was no change in the inci- costly 5-HT antagonists.13–15 One large-scale study, in- dence of TdP with the commonly used low-dose droperi- 3 volving more than 2,000 outpatients, conducted by the dol versus no droperidol use in a large number of surgi- ® cal patients. This indicates that the incidence of TdP is at manufacturer of ondansetron (Zofran ; Glaxo Smith most 1 in 16,791 (95% CI, 10,173–25,607) droperidol Kline, Research Triangle Park, NC), did not find any exposures, with that 1 patient also having received 1.25 safety or efficacy advantages of 4 mg intravenous ondansetron over 0.625 or 1.25 mg intravenous droperidol.14 mg droperidol 10 h before the event and having received 9 ondansetron, another implicated drug for possible drug- In a review article by Roden on the subject of drug- induced TdP 5 h before the event. Given the short induced LQTS, he noted that “Rare, poorly understood half-life of droperidol, it is unlikely that droperidol con- side effects occur with many highly-effective drugs, and tributed to this patient’s dysrhythmia. This indicates that the withdrawal of these medications from the market the FDA black box warning is excessive and unnecessary probably harm more patients than it helps.” for low-dose droperidol therapy. The data suggest that In high doses, droperidol certainly can cause severe 16,17 the guidelines initiated by the FDA for mandatory elec- dysrhythmias. Many of the adverse cases were found trocardiographic screening before administration of within the FDA database, and such cases undoubtedly droperidol are also unnecessary for patient safety. caught the attention of the FDA officials. However, such There are many confounding factors that can be asso- large doses of droperidol are not needed to prevent ciated with both QTc prolongation and TdP. Approxi- emesis in surgical patients. In 2000, Hill et al.15 per- mately 1 in 3,000 persons have congenital LQTS caused formed a randomized, double-blind, placebo-controlled, chiefly by genetic mutations in cardiac potassium and multicenter study including 50 institutions in North sodium channels. For acquired LQTS, there is a long list America, where patients were randomized to one of four of drugs and medical conditions that are reported to intravenous treatments: 4 mg ondansetron, 0.625 mg prolong the QT interval and predispose patients to droperidol, 1.25 mg droperidol, or placebo (normal sa- TdP.1,8,9 Most of these drugs precipitate drug-induced line). They found that the use of 1.25 mg intravenous LQTS by inhibiting cardiac potassium channels, particu- droperidol was associated with greater effectiveness, larly the LQT2-associated IKr potassium channel en- lower costs, and similar patient satisfaction compared

Anesthesiology, V 107, No 4, Oct 2007 DROPERIDOL AND TORSADE DE POINTES 535 with 0.625 mg intravenous droperidol and 4 mg intrave- rescue with 6.25–25 mg promethazine (78%) than after nous ondansetron. rescue with 4 mg ondansetron (46%). Further, for those But is droperidol given at the usual antiemetic doses patients who failed prophylaxis with 0.625 and 1.25 mg “QT safe”? Our data would certainly suggest that it is. droperidol, the complete response rate was significantly 18 White et al. performed a randomized, double-blind, higher after rescue with 6.25–25 mg promethazine (77%; placebo-controlled trial to evaluate the intraoperative P ϭ 0.02) and 25–50 mg dimenhydrinate (78%; P ϭ and postoperative effects of low-dose droperidol (0.625 0.04) than after rescue with 0.625–1.25 mg droperidol and 1.25 mg intravenous) on the QT interval when used (56%). These results suggest that drugs acting at a differ- for antiemetic prophylaxis during a standardized general ent receptor sites might be more efficacious for the anesthetic. They found that the use of a small dose of treatment of established PONV for patients who have droperidol (0.625–1.25 mg intravenous) for antiemetic failed prophylaxis with an antiemetic agent compared Downloaded from http://pubs.asahq.org/anesthesiology/article-pdf/107/4/531/365099/0000542-200710000-00006.pdf by guest on 27 September 2021 prophylaxis during general anesthesia was not associ- with a repeat dose of the same agent used for prophy- ated with a statistically significant increase in the QT laxis. This observation suggests that it would be benefi- interval compared with saline. Further, there was no cial to have droperidol as a rescue therapy. evidence of any droperidol-induced QT prolongation A potential weakness of this study was the difficulty of immediately after surgery. capturing TdP with the standard 12-lead electrocardio- There has been a suggestion that there should be a threshold dose of droperidol, such as 5 or 10 mg, gram due to the brevity of the cardiac rhythm. For this beyond which the stipulations of the black box warn- reason, we were forced to rely on notation in the patient ing would apply.16 Chan et al.19 performed a prospec- records by the physician to provide a diagnosis after the tive trial where 400 patients scheduled to undergo cardiac event had occurred. In addition, not all patients laparoscopic gynecologic surgery were assigned ran- undergoing surgery had an electrocardiogram preopera- domly to receive intravenous saline, 4 mg intravenous tively. By capturing patients who died within 48 h after ondansetron, 1.25 mg intravenous droperidol, or a surgery, we expected to identify those with fatal TdP. It combination of 1.25 mg intravenous droperidol and 4 is conceivable that a patient could have had transient, mg intravenous ondansetron 5 min before induction nonfatal TdP, and this was not noted in the record and of anesthesia. They used a standardized anesthetic therefore not captured in our study. Further, in the technique and postoperative analgesic regimen. They period before the black box warning, the event rate for noted a modest increase in the QT interval after ad- documented QTc prolongation, TdP, or death within 2 ministration of ondansetron, droperidol, or their com- days after their surgical procedure was 1.66% (2,321 of bination that resolved by 2–3 h after drug administra- 139,932). After the black box warning, and the virtual tion. There was no difference between drugs in elimination of droperidol use, this event rate was re- change of QT interval. They concluded that a combi- duced to 1.46% (2,207 of 151,256). This relatively small nation of 4 mg ondansetron and 1.25 mg droperidol 0.2% absolute reduction (approximately 12% relative risk produced an additive effect for preventing PONV after reduction) was statistically different from zero (P Ͻ laparoscopic gynecologic surgery. 0.001). Although this event rate was not driven by TdP A panel of experts was convened in 2002 to develop 20 events, it was hopefully due to practice improvements consensus guidelines for the management of PONV. because the rate of death improved from 456 (0.33%) They stated, “If it were not for the ‘black-box’ warning, before the black box warning to 425 (0.28%) after the black droperidol would have been the panel’s overwhelming box warning (P ϭ 0.025). A final potential weakness of our first choice for PONV prophylaxis.” They recommended study was the use of a sample population versus the entire the use of antiemetics from different classes for the population to estimate the frequency of droperidol use. treatment of established PONV in patients who failed This limitation is inherent to retrospective studies, because prophylaxis. In the absence of available data, this recom- mendation was based on expert opinion. In a prospec- of the vast number of patients required to identify the TdP tive study, patients were randomly assigned to receive 4 cases and the fact that use of droperidol was not available mg ondansetron, 1.25 mg droperidol, 0.625 mg droperi- in the database. dol, or placebo.5 Patients who developed PONV re- The findings of our study indicate that despite nearly ceived rescue antiemetics at the discretion of the attend- 17,000 patient exposures to droperidol before the FDA ing anesthesiologist in the postanesthesia care unit. The warning, no patient experienced documented TdP. antiemetics used for rescue therapy were 4 mg ondan- Therefore, our data suggests that droperidol’s black box setron, 0.625–1.25 mg droperidol, 10 mg metoclopra- warning is excessive and unnecessary and that the guide- mide, 6.25–25 mg promethazine, and 25–50 dimenhy- lines initiated by the FDA for mandatory electrocardio- drinate mg. They found that among those patients who graphic screening before administration of low-dose failed prophylaxis with 4 mg ondansetron, the complete droperidol are likely to have a negligible effect on pa- response rate was significantly higher (P ϭ 0.02) after tient safety.

Anesthesiology, V 107, No 4, Oct 2007 536 NUTTALL ET AL.

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