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From the Departments of Surgery and Anesthesia, Montreal Heart Institute, Montreal, Quebec.
Address correspondence to: Louis P. Perrault MD PhD, Research Center, Montreal Heart Institute, 5000 Belanger Street East, Montreal, Quebec, HIT I C8 Canada. Phone: 514-376-3330; Fax: 514-376-1355; E-mail: lpperrau{at}icm.umontreal.ca
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Clinical features: The patient reported underwent uneventful triple bypass surgery. Administration of large intravenous doses of haloperidol was necessary for control of psychomotor agitation due to delirium. Torsades de pointes occurred in the absence of QT prolongation on the third postoperative day following use of the drug with no other obvious etiological factor.
Conclusion: Awareness of this rare complication is key to judicious use of this drug in the post CABG patient in whom such an arrhythmia may have very deleterious consequences because of the underlying cardiac condition.
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A 64-yr-old woman underwent triple coronary artery bypass grafting surgery for class 2 angina for a three vessel disease with moderate left ventricular dysfunction. She had a history of tobacco smoking, obesity and hypertension treated with nifedipine and enalapril. The immediate postoperative period was uneventful with no evidence of myocardial infarction, arrhythmia, heart failure or stroke. The first postoperative electrocardiogram (ECG) 30 min after surgery was normal including a Q-T interval of 372ms (QTc of 418msec). Weaning from mechanical ventilation was delayed until the third postoperative day because of hypoxemia from shunting secondary to atelectasis. Concurrently, she began presenting symptoms of delirium with aggressive and paranoid behaviour. The trachea was extubated and blood gas analyses thereafter were normal. Intravenous haloperidol was administered to control psychomotor agitation that hindered chest physiotherapy. A total of 175 mg was used over 14 hr. After a few premature ventricular complexes, a long-short sequence was followed by an R on T phenomenon (Figure 1
), a 29 beat sequence of wide complex ventricular tachycardia with polymorphous configuration of torsades de pointes developed (Figure 2). She converted back to sinus rhythm spontaneously, haloperidol was discontinued and 2 g of magnesium sulfate were administered intravenously. At that time, the ECG was unchanged compared with the first postoperative ECG. The QT interval was 356msec (QTc 413msec). Calcium and potassium concentrations were within the normal range. Plasma magnesium concentrations, obtained during and shortly after surgery, were normal. Concurrent medication included: sucralfate, furosemide, lorazepam, enalapril, nifedipine, metoclopramide and salbutamol. There was no recurrence of ventricular complexes or arrhythmias following cessation of haloperidol. She subsequently recovered uneventfully and was discharged on the 10th postoperative day.
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). The torsades de pointes sequence was preceded by a pause then followed by a premature beat occurring on the T wave of the previous beat ® on T phenomenon). This was referred to as the pause-dependent "long-short" initating sequence.
Antipsychotic drugs are usually considered to be safe and are frequently used in the intensive care unit (ICU) for the treatment of delirium. Haloperidol a butyrophenone, is the most commonly used antipsychotic in the ICU. Apart from mild hypotension through an alpha-blocking action and the neuroleptic malignant syndrome, butyrophenone does not cause any hemodynamic alterations.1 However, there have been reports of major cardiac arrhythmias in patients receiving psychotropic; drugs and some authors have suggested that the use of haloperidol was directly related to the genesis of torsades de pointes.2–10 Initially described during haloperidol overdoses,2 torsades de pointes appeared following conventional doses of haloperidol .3,4 Wilt et al. observed this type of arrhythmia in four women who received large doses of intravenous haloperidol.5 In Kay's series of 32 patients and Di Salva's, torsades de pointes occurred mostly in patients with underlying heart disease,6,7 most frequently ischemic heart disease, in 53% of patients in some series6 but it is also described in patients with liver diseases8,9 and in critically ill patients.10 It has also been described with doses as small as 4 mg.11 In more than 90% of patients, the initiating event is a premature ventricular beat occurring following an R on T phenomenon as observed in this report. Most patients also show a long-short cycle length sequence, as in Figure 2. Appearance of a labile T wave following a post-extrasystolic pause configuration is a warning sign preceding torsades de pointes, and was present in this patient (Figures 1,2). The Q-T interval (356 msec) during the arrhythmia, is not considered to be prolonged12 and was unchanged from the first postoperative days. A new and significant flattening of the T wave was present the day prior to the arrhythmia compared with the first postoperative ECG. These abnormalities of the Q-T interval and T wave illustrate the pathophysiology of torsades de pointes which is due to abnormal and prolonged ventricular repolarization.13 Animal models have shown a concentration dependency prolongation of the QT interval with the use of antipsychotics.14 Droperidol which is a butyrophenone can also prolong the QT interval but so far has not been associated with the development of torsades de pointes.15
Torsades de pointes arrhythmias are classified as pause-dependent and adrenergic-dependent types.13 The former, related to drugs and electrolyte abnormalities that prolong the Q-T interval, is best treated by removing the cause and by agents or maneuvers, such as pacing, isoproterenol or magnesium, that increase conduction velocity and shorten the Q-T interval. The latter type, of familial origin, is best treated with beta-adrenergic blocking agents or left stellate ganglion block. In the present case, the torsades de pointes observed was of the pause-dependent type. The large dose of haloperidol administered was the most likely cause of torsades de pointes in the case presented in this report since there was no recurrence of rhythm disturbances after haloperidol withdrawal. Hypomagnesemia could not be completely ruled out as the cause of this life-threatening tachyarrythmia. However, plasma magnesium concentrations were normal 72 hr earlier and there were no recurrences despite administration of a suboptimal dose of magnesium for replenishment of stores. Considering that magnesium deficiency is usually treated with doses of 5 g per day for three to five days. Moreover, if magnesium deficiency were the primary cause of torsades in this case, we would have expected an associated hypokalemia, progressive Q-T prolongation or recurrence following the initial therapy. In the absence of hypokalemia, there is some controversy as whether hypomagnesemia is arrythmogenic. Finally, most cases of magnesium deficiency-related torsades de pointes occur in chronically malnourished patients and are not reversed by the sole administration of 2 g of magnesium sulfate. The combination of ischemic heart disease, electrolyte abnormality and haloperidol operating simultaneously cannot be excluded in the pathogenesis of this arrhythmia. However, the time-sequence and the high cumulative amount of haloperidol administered and development of torsades de pointes argues for a link of causality.
In summary, delirium after CABG surgery requiring treatment with antipsychotic drugs is frequent. The administration of haloperidol in large amounts in this setting mandates use of caution because of the risk of inducing torsades de pointes in patients susceptible to myocardial electrical instability. This type of drug related complication can occur without the warning sign of a prolonged QT interval and should be promptly recognized and treated since the consequences of such an arrhythmia may be extremely deleterious in patients with an already compromised myocardial function and reserve.
Accepted for publication November 26, 1999.
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2 Zee-Cheng C-S, Mueller CE, Seifert CF, Gibbs HR. Haloperidol and torsades de pointes (Letter). Ann Intern Med 1985; 102: 418.
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Kriwisky M, Peny GY, Tarchitsky D, Gutman Y, Kishon Y. Haloperidol-induced torsades de pointes. Chest 1990; 98: 482–4.
4 Metzger E, Friedman R. Prolongation of the corrected QT and torsades de pointes cardiac arrhythmia associated with intravenous haloperidol in the medically ill. J Clin Psychopharmacol 1993; 13: 128–32.[Medline]
5
Wilt A, Minnema AM, Johnson RF, Rosenblum AM. Torsade de pointes associated with the use of intravenous haloperidol. Ann Intern Med 1993; 119: 391–4.
6 Kay GN, Plumb VJ, Arciniegas JG, Henthorn RW, Waldo AL. Torsade de pointes: the long-short initiating sequence and other clinical features: observations in 32 patients. J Am Coll Cardiol 1983; 2: 806–17.[Abstract]
7 Di Salvo TG, O'Gara PT. Torsades de pointes caused by high-dose intravenous cardiac haloperidol in cardiac patients. Clin Cardioll 1995; 18: 285–90.
8 Faigel DO, Metz DC, Kochman ML. Torsades de pointes complicating the treatment of bleeding oesophageal varices: association with neuroleptics, vasopressm, and electrolite imbalance. Am J Gastroenterol 1995; 90: 822–4.[Medline]
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Hunt N, Stern TA. The association between intravenous haloperidol and torsades de pointes. Psychosomatics 1995; 36: 541–9.
10 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.[Medline]
11 Jackson T, Ditmanson L, Phibbs B. Torsades de pointes and low-dose oral haloperidol. Arch Intern Med 1997; 157: 2013–5.[Abstract]
12 Marriott HJL. Practical Electrocardiography, 7th ed. Baltimore: Williams & Wilkins 1983: 22.
13 Jackman WM, Friday KJ, Anderson JL, Aliot EM, Clark M, Lazzara R. The long QT syndromes: a critical review, new clinical observations and a unifying hypothesis. Prog Cardiovasc Dis 1988; 31: 115–72.[Medline]
14 Drici M-D, Wang WX, Liu X-K, Woosley RL, Flockhart DA. Prolongation of QT interval in isolated feline hearts by antipsychotic drugs. J Clin Psychopharmacol 1998; 18: 477–81.[Medline]
15 Lawrence KR, Nasraway SA. Conduction disturbances associated with the administration of butyrophenones antipsychotics in the critically ill: a review of the literature. Pharmacotherapy 1997; 17: 531–7.[Medline]
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