Case Reports

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Patient 1

A 39-year-old woman with bacterial meningitis developed acute congestive heart failure on hospital day 20 and required reintubation and intravenous haloperidol (5-mg increments) and lorazepam (Ativan, Wyeth-Ayerst Laboratories, Philadelphia, Pennsylvania) administration for sedation. Progressive Q-T interval widening was noted (Figure 1). On day 23, torsade de pointes developed Figure 1, and the haloperidol was discontinued (dosage, 580 mg over a 4-day period). Atropine was administered, the QTc interval normalized Figure 1, and no further dysrhythmia was noted. Concurrent medications included furosemide, penicillin G, methylprednisolone, digoxin, terazosin, and nitroglycerin.

View larger version (71K): [in this window] [in a new window]   Figure 1. Sequential tracings for patient 1 with corresponding QTc intervals. Values are expressed in milliseconds (ms). All tracings were averaged at the time of measurement. The baseline strip (A, standard lead II) and tracings at 4 hours (B, standard lead II), 48 hours (C, standard lead II), and 72 hours (D, lead MCL1) after starting intravenous haloperidol are shown. A sample of the torsade de pointes (TdP) is shown in tracing E (lead MCL1). The QTc gradually returned to baseline after discontinuing the haloperidol; a representative strip from 6 days later (F, lead MCL1) is shown.

Patient 2

A 19-year-old woman with status asthmaticus received sedation with intravenous haloperidol (5- or 10-mg increments) and lorazepam. She experienced progressive Q-T interval widening Figure 2 and developed monomorphic ventricular tachycardia that was unresponsive to defibrillation. She responded transiently to intravenous magnesium, isoproterenol, and lidocaine but developed torsade de pointes Figure 2, necessitating right atrial overdrive pacing. Haloperidol was discontinued (dosage, 170 mg/24 h). The QTc interval normalized Figure 2, and she had no further dysrhythmia. Concurrent medications included methylprednisolone, cefuroxime, ranitidine, albuterol, and theophylline.

View larger version (43K): [in this window] [in a new window]   Figure 2. Sequential tracings for patient 2 with corresponding QTc intervals. Values are expressed in milliseconds (ms). Standard lead II is shown in all tracings. All tracings were averaged at the time of measurement. A baseline strip (A) and a tracing at 12 hours (B) after initiating intravenous haloperidol are shown. Note the prolonged QTc interval at baseline. A sample of the torsade de pointes (TdP) is shown in tracing C. Atrial pacing was instituted (D) and eventually discontinued. The QTc interval gradually returned to below baseline; a representative strip from 8 days later (E) is shown.

Patient 3

A 63-year-old woman with status asthmaticus required intravenous haloperidol (5- or 10-mg increments) and lorazepam for sedation. She experienced progressive Q-T interval lengthening after haloperidol administration and developed torsade de pointes (Figure 3). Haloperidol was discontinued (dosage, 489 mg/36 h). She was given atropine, the tracings gradually returned to baseline Figure 3, and she had no further dysrhythmia. Concurrent medications included cefuroxime, methylprednisolone, theophylline, and albuterol.

View larger version (37K): [in this window] [in a new window]   Figure 3. Sequential tracings for patient 3 with corresponding QTc intervals. Values are expressed in milliseconds (ms). Standard lead II is shown in all tracings. All tracings were averaged at the time of measurement. The baseline strip (A) is shown, as are strips at 24 hours (B) and 48 hours (C) after the initiation of intravenous haloperidol. Note that T-U augmentation is seen in strip C and is important in determining Q-T intervals (see reference 3). A sample of the torsade de pointes (TdP) is shown in tracing D. The tracings gradually returned to baseline after discontinuation of haloperidol; a representative strip from 8 days later (E) is shown.

Patient 4

A 74-year-old woman whose medical problems included intermittent atrial fibrillation, hypothyroidism, and renal insufficiency (creatinine, 212.2 µmol/L [2.4 mg/dL]) had a respiratory arrest at home and was found to be in an agonal rhythm with no discernible blood pressure. She responded to resuscitation, including temporary pacing, and eventually recovered her rhythm (Figure 4). She subsequently developed congestive heart failure and required reintubation and intravenous haloperidol (10 mg/4 h). She abruptly developed several salvos of torsade de pointes Figure 4 and had no further dysrhythmia after haloperidol was discontinued. She had an elevated level of thyroid stimulating hormone (22 ng/mL; normal, 0.3 to 5.0 ng/mL) the day before the torsade de pointes, prompting an increased dose of levothyroxine. Concurrent medicines included furosemide, levothyroxine, nifedipine, ampicillin-sulbactam, gentamicin, lorazepam, and famotidine.

View larger version (21K): [in this window] [in a new window]   Figure 4. Sequential tracings for patient 4 with corresponding QTc intervals. Values are expressed in milliseconds (ms). All tracings were averaged at the time of measurement. A baseline strip (A, standard lead II) shows the patient in atrial fibrillation. A sample of the torsade de pointes (TdP) is shown in tracing B, also standard lead II. Note the long-short initiating sequence leading to TdP (see reference 4). A tracing from 8 days later (with the patient in sinus rhythm) is shown in tracing C (standard lead II).

Discussion

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These patients had dysrhythmias consistent with torsade de pointes. The first three exhibited sequential Q-T interval widening, post-pause extrasystoles (data not shown), and degeneration into polymorphic ventricular tachycardia—a pause-dependent torsade de pointes by definition [3]. The fourth patient, although without serial QT interval widening, had the classic long-short initiating sequence and characteristic morphology of torsade de pointes [4].

These four cases occurred over a 3-year period during which approximately 1100 patients were treated with a combination of haloperidol and lorazepam in our intensive care units. Thus, the association was not common. Considerable evidence supports the safety of intravenous haloperidol at doses much higher than those reported in our four patients [1, 2].

Haloperidol was implicated and was discontinued in each case for the following reasons: First, haloperidol and lorazepam were the only new medications in the first three patients' regimens; the fourth patient was already receiving lorazepam. No benzodiazepine has ever been reported to cause torsade de pointes, and no dysrhythmia was seen until haloperidol was added to the regimen. Lorazepam induction is therefore unlikely but cannot be excluded. Second, haloperidol (a butyrophenone) is an antipsychotic agent, and some drugs in this class have been implicated in the development of torsade de pointes [5, 6]. Third, three of these patients were euthyroid, and all had normal electrolytes including calcium, magnesium, and potassium levels. Abnormalities of these metabolic parameters have been implicated in the genesis of torsade de pointes [3, 6]. The fourth patient received levothyroxine and had an elevated level of thyroid stimulating hormone. Hypothyroidism cannot be excluded as an aggravating factor; however, we found a definite temporal relation between the torsade de pointes and the addition of haloperidol. Finally, progressive Q-T interval widening was noted after haloperidol administration, and this widening resolved after removal of the drug in each of the first three cases.

Two patients had prolonged baseline QTc intervals. The adrenergic form of torsade de pointes has a prolonged baseline QTc interval with induction by heightened sympathetic tone [3]. However, torsade de pointes may also occur in clinical settings in which the QTc interval is not significantly prolonged. Each of our patients probably had heightened sympathetic tone before and after haloperidol use, yet none exhibited the dysrhythmia at that time. Also, the asthmatic patients had never previously exhibited torsade de pointes when in status asthmaticus. Thus, adrenergic induction is unlikely.

All of the patients in our series were women. Whether sex is a predisposing factor cannot be determined.

Three patients responded to standard therapy for pause-dependent torsade de pointes, including intravenous magnesium, isoproterenol, atropine, and right atrial overdrive pacing [7]. The fourth patient had no recurrence after haloperidol was discontinued.

Haloperidol has been previously implicated in the development of torsade de pointes [8-10]. Only one other report has been published supporting electrocardiograms, and the route of administration was not specified in any previous report.

Because of the relation to torsade de pointes in our patients, the use of high-dose intravenous haloperidol may not be as safe as previously reported. Women, or patients with elongating QTc intervals, may be at particular risk.