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Anesth Analg 2004;98:551-552
© 2004 International Anesthesia Research Society
doi: 10.1213/01.ANE.0000077705.55641.6B

LETTERS TO THE EDITOR

Safety of Patients Reason for FDA Black Box Warning on Droperidol

Steven L. Shafer, MD

Anesthesiology Service (112A), PAVAHCS, Palo Alto, CA

To the Editor:

I appreciate the brief report by Drs. Habib and Gan on the case reports examining perioperative use of droperidol (1). Their letter adds useful insight into the cases that prompted the FDA to issue a black box warning about droperidol. I wish to raise several issues in defense of the FDA decision about the black box warning on droperidol:

  1. Let us assume briefly that droperidol was responsible for the arrhythmias in the 10 case reports. Since we know that droperidol is safe in the overwhelming majority of patients, we can reasonably assume that patients in whom droperidol precipitates an arrhythmia must be susceptible to ventricular arrhythmias. In fact, this has been clearly documented (2). It is therefore entirely to be expected that in reviewing case reports for droperidol associated arrhythmias, one would identify multiple risk factors, exactly as done by Drs. Habib and Gan. Thus, we don’t really learn anything about whether droperidol caused these patients to experience arrhythmias by the identification of additional risk factors for ventricular arrhythmias, since such factors would be expected covariates of droperidol-induced arrhythmias.
  2. Having explained away several of the cases by identifying other risk factors, and noting the lack of detailed information in the other cases, Drs. Habib and Gan conclude that in no case "was there evidence of a cause and effect relationship." This is expected. This was not a double blind, randomized trial. Lacking appropriate controls, case reports of rare events can almost always be explained away (3). Individuals who published case reports appeared more convinced of the causative role of droperidol (4–6) or its chemical cousin haloperidol (7–9).
  3. The important question is whether there is any mechanistic basis for concern. Here the data are unequivocal. First, droperidol causes dose-dependent QT prolongation in patients (10,11) and the effect is readily demonstrated in vitro (12). As nicely summarized by Prielipp and Balser (13), droperidol blocks the I(k)r potassium channel encoded by the HERG gene at concentrations of 10 nmol/L (14). Given a volume of distribution of 2.04 L/kg (15) and a molecular weight of 369 daltons, we can readily calculate that a droperidol dose of 0.625 mg would yield a plasma concentration of 12 nmol/L. The genetics of long QT syndrome are complex, but clearly place a small number of patients at risk of drug-induced arrhythmias (16,17). Rare mutations of the MiRP1 gene predispose patients to arrhythmias from drugs that affect HERG-encoded potassium channels (18). Genetic predisposition towards long QT has low penetrance, but those individuals with the genetic trait and without clinically evident QT prolongation are still at increased risk of arrhythmias from drugs that block potassium channels (19).
  4. The genetic, cellular, and animal data paint a convincing story of genuine risk from droperidol for a very small numbers of patients. When combined with suggestive case reports, this is a legitimate concern. The package insert is the appropriate instrument for communicating legitimate concerns to physicians.
  5. Habib and Gan suggest an incidence of torsade of about 1 in 1 million doses. Individual physicians will have a different perspective on such risk from a regulatory agency. If I’m throwing up, please give me droperidol—the risk sounds vanishingly small. However, if I am a regulatory agency, that same small risk translates into a handful of preventable deaths.
  6. Unfortunately, the true causal relationship between low-dose droperidol and torsade will probably never be established in humans. The incidence is too low for any feasible study to establish the safety of droperidol. Lacking the definitive study, we will be forced to continue examining inconclusive case reports, looking carefully at animal and cellular data, and drawing the best conclusions we can for our patients. Since the FDA has to think about the safety of many millions of patients, their position is likely to be more conservative than the conclusions of individual physicians.

References

  1. Habib AS, Gan TJ. Food and drug administration black box warning on the perioperative use of droperidol: a review of the cases. Anesth Analg 2003; 96: 1377–9.[Free Full Text]
  2. Haddad PM, Anderson IM. Antipsychotic-related QTc prolongation, torsade de pointes and sudden death. Drugs 2002; 62: 1649–71.[ISI][Medline]
  3. Naranjo CA, Busto U, Sellers EM, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther 1981; 30: 239–45.[ISI][Medline]
  4. Shigeyama T, Yanagidani T. Droperidol causes multifocal ventricular dysrhythmias [in Japanese]. Masui 2002; 51: 53–5.[Medline]
  5. Michalets EL, Smith LK, Van Tassel ED. Torsade de pointes resulting from the addition of droperidol to an existing cytochrome P450 drug interaction. Ann Pharmacother 1998; 32: 761–5.[Abstract]
  6. Faigel DO, Metz DC, Kochman ML. Torsade de pointes complicating the treatment of bleeding esophageal varices: association with neuroleptics, vasopressin, and electrolyte imbalance. Am J Gastroenterol 1995; 90: 822–4.[ISI][Medline]
  7. O’Brien JM, Rockwood RP, Suh KI. Haloperidol-induced torsade de pointes. Ann Pharmacother 1999; 33: 1046–50.[Abstract]
  8. Sharma ND, Rosman HS, Padhi ID, Tisdale JE. Torsades de Pointes associated with intravenous haloperidol in critically ill patients. Am J Cardiol 1998; 81: 238–40.[ISI][Medline]
  9. Jackson T, Ditmanson L, Phibbs B. Torsade de pointes and low-dose oral haloperidol. Arch Intern Med 1997; 157: 2013–5.[Abstract]
  10. Lischke V, Behne M, Doelken P, et al. Droperidol causes a dose-dependent prolongation of the QT interval. Anesth Analg 1994; 79: 983–6.[Abstract/Free Full Text]
  11. Guy JM, Andre-Fouet X, Porte J, et al. Torsades de pointes and prolongation of the duration of QT interval after injection of droperidol [in French]. Ann Cardiol Angeiol (Paris) 1991; 40: 541–5.
  12. Adamantidis MM, Kerram P, Dupuis BA. In vitro electrophysiological detection of iatrogenic arrhythmogenicity. Fundam Clin Pharmacol 1994; 8: 391–407.[ISI][Medline]
  13. Prielipp RC, Balser JR. Providers need to take warning seriously. APSF Newsletter, Spring 2002.
  14. Drolet B, Zhang S, Deschenes D, et al. Droperidol lengthens cardiac repolarization due to block of the rapid component of the delayed rectifier potassium current. J Cardiovasc Electrophysiol 1999; 10: 1597–604.[ISI][Medline]
  15. Fischler M, Bonnet F, Trang H, et al. The pharmacokinetics of droperidol in anesthetized patients. Anesthesiology 1986; 64: 486–9.[ISI][Medline]
  16. Priori SG, Barhanin J, Hauer RN, et al. Genetic and molecular basis of cardiac arrhythmias: impact on clinical management parts I and II. Circulation 1999; 99: 518–28.[Abstract/Free Full Text]
  17. Priori SG, Barhanin J, Hauer RN, et al. Genetic and molecular basis of cardiac arrhythmias: impact on clinical management part III. Circulation 1999; 99: 674–81.[Free Full Text]
  18. Abbott GW, Sesti F, Splawski I, et al. MiRP1 forms IKr potassium channels with HERG and is associated with cardiac arrhythmia. Cell 1999; 97: 175–87.[ISI][Medline]
  19. Priori SG, Napolitano C, Schwartz PJ. Low penetrance in the long-QT syndrome: clinical impact. Circulation 1999; 99: 529–33.[Abstract/Free Full Text]
 

Response

Ashraf S. Habib, MBBCh MSc, FRCA, and Tong J. Gan, MB FRCA, FFARCS(I)

Department of Anesthesiology, Duke University Medical Center, Durham, NC

In Response:

We thank Dr. Shafer for his interest in our article (1) and for raising some important issues in defense of the FDA decision about the Black Box warning on droperidol.

We agree with many points raised by Dr. Shafer, however, we have reservations regarding some of the arguments presented:

  1. The data presented regarding blockade of the rapid delayed rectifier cardiac potassium channel (Ikr) at concentrations of 10 nmol/L come from an in vitro animal study involving eight isolated, buffer-perfused guinea pig hearts (2). While in vitro animal data provide useful information, such extrapolation of data to humans need to be interpreted cautiously. We therefore have reservations about the calculation provided by Dr. Shafer leading to the conclusion that the administration of 0.625 mg droperidol results in dangerous plasma concentrations of that drug.
  2. We agree with Dr. Shafer that individuals genetically predisposed towards long QT are at increased risk of arrhythmias from drugs that block potassium channels. It should, however, be noted that prolongation of the QTc secondary to potassium channel blockade has been reported with sevoflurane, halothane, and isoflurane (3–6). A number of other drugs routinely used in anesthesia also prolong the QT interval including thiopentone (7), succinyl choline (8), atropine (9), neostigmine (10,11), glycopyrrolate (10) , ondansetron, dolasetron, and granisetron (12).

We believe that there is good evidence to support the efficacy, safety, and cost-effectiveness of low-dose droperidol (0.625–1.25 mg) for PONV prophylaxis (13–16). Data showing QT prolongation with droperidol involved larger doses of this drug (17,18). While a warning about the risk of arrhythmias in high-risk patients is appropriate, the "Black Box" warning is not justified based on the available evidence. As a result of the "Black Box" warning, many hospitals removed droperidol from their formulary. Using the more expensive 5-HT3receptor antagonists as first line agents for antiemetic prophylaxis has significant cost implications, with no evidence that these agents are any safer than droperidol.

We, therefore, urge the FDA to consider reexamining the available evidence and lifting this "Black Box" warning on antiemetic doses of droperidol.

References

  1. Habib AS, Gan TJ. Food and drug administration black box warning on the perioperative use of droperidol: a review of the cases. Anesth Analg 2003; 96: 1377–9.
  2. Drolet B, Zhang S, Deschenes D, et al. Droperidol lengthens cardiac repolarization due to block of the rapid component of the delayed rectifier potassium current. J Cardiovasc Electrophysiol 1999; 10: 1597–604.
  3. Park WK, Pancrazio JJ, Suh CK, Lynch C 3rd. Myocardial depressant effects of sevoflurane: mechanical and electrophysiologic actions in vitro. Anesthesiology 1996; 84: 1166–76.[ISI][Medline]
  4. Kuenszberg E, Loeckinger A, Kleinsasser A, et al. Sevoflurane progressively prolongs the QT interval in unpremedicated female adults. Eur J Anaesthesiol 2000; 17: 662–4.[ISI][Medline]
  5. Pancrazio JJ, Frazer MJ, Lynch C 3rd. Barbiturate anesthetics depress the resting K+ conductance of myocardium. J Pharmacol Exp Ther 1993; 265: 358–65.[Abstract/Free Full Text]
  6. Schmeling WT, Warltier DC, McDonald DJ, et al. Prolongation of the QT interval by enflurane, isoflurane, and halothane in humans. Anesth Analg 1991; 72: 137–44.[ISI][Medline]
  7. McConachie I, Keaveny JP, Healy TE, et al. Effect of anaesthesia on the QT interval. Br J Anaesth 1989; 63: 558–60.[Abstract/Free Full Text]
  8. Saarnivaara L, Lindgren L. Prolongation of QT interval during induction of anaesthesia. Acta Anaesthesiol Scand 1983; 27: 126–30.[ISI][Medline]
  9. Annila P, Yli-Hankala A, Lindgren L. Effect of atropine on the QT interval and T-wave amplitude in healthy volunteers. Br J Anaesth 1993; 71: 736–7.[Abstract/Free Full Text]
  10. Saarnivaara L, Simola M. Effects of four anticholinesterase-anticholinergic combinations and tracheal extubation on QTc interval of the ECG, heart rate and arterial pressure. Acta Anaesthesiol Scand 1998; 42: 460–3.[ISI][Medline]
  11. Pleym H, Bathen J, Spigset O, Gisvold SE. Ventricular fibrillation related to reversal of the neuromuscular blockade in a patient with long QT syndrome. Acta Anaesthesiol Scand 1999; 43: 352–5.[ISI][Medline]
  12. White PF. Droperidol: a cost-effective antiemetic for over thirty years. Anesth Analg 2002; 95: 789–90.[Free Full Text]
  13. Fortney JT, Gan TJ, Graczyk S, et al. A comparison of the efficacy, safety, and patient satisfaction of ondansetron versus droperidol as antiemetics for elective outpatient surgical procedures. S3A-409 and S3A-410 Study Groups. Anesth Analg 1998; 86: 731–8.[Abstract]
  14. Hill RP, Lubarsky DA, Phillips-Bute B, et al. Cost-effectiveness of prophylactic antiemetic therapy with ondansetron, droperidol, or placebo. Anesthesiology 2000; 92: 958–67.[ISI][Medline]
  15. Tang J, Watcha MF, White PF. A comparison of costs and efficacy of ondansetron and droperidol as prophylactic antiemetic therapy for elective outpatient gynecologic procedures. Anesth Analg 1996; 83: 304–13.[Abstract]
  16. Henzi I, Sonderegger J, Tramer MR. Efficacy, dose-response, and adverse effects of droperidol for prevention of postoperative nausea and vomiting. Can J Anaesth 2000; 47: 537–51.[Abstract/Free Full Text]
  17. Lischke V, Behne M, Doelken P, et al. Droperidol causes a dose-dependent prolongation of the QT interval. Anesth Analg 1994; 79: 983–6.
  18. Guy JM, Andre-Fouet X, Porte J, et al. Torsades de pointes and prolongation of the duration of QT interval after injection of droperidol [in French]. Ann Cardiol Angeiol (Paris) 1991; 40: 541–5.




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Right arrow Articles by Shafer, S. L.
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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press