Rounds in the general hospital: qtc prolongation and the use of antipsychotics: a case discussion

ROUNDS IN THE GENERAL HOSPITAL
LESSONS LEARNED AT THEINTERFACE OF MEDICINE QTc Prolongation and the Use of
Antipsychotics: A Case Discussion
Jeff C. Huffman, M.D., and Theodore A. Stern, M.D.
o you wonder about the risk of torsades de pointes (TdP) when Dyou give intravenous (IV) haloperidol to a patient with delirium?
Are you concerned about QT interval prolongation in your patients who Practitioners of medicine and psychiatry are cautioned increasingly about the potential of psychotropic medications to alter the electrocardio- gram (ECG) and to produce ventricular arrhythmias. However, the prev- alence and nature of cardiovascular side effects and electrocardiographic changes associated with specific antipsychotics are not easily discerned.
The following brief clinical vignette and discussion describe our (still- limited) understanding of these relationships. A list of appended refer- Mr. A, a 61-year-old man with coronary artery disease (CAD) and chronic obstructive pulmonary disease, was admitted to the intensive care unit (ICU) for respiratory failure. He was intubated on admission to the hospital; fortunately, his pulmonary function improved, and he was extubated on the third hospital day. Following extubation, he became agitated, and psychiatric consultation was requested. Delirium wasdiagnosed and IV haloperidol was recommended. Despite knowing that Mr. A’s ECG revealed a normal rate and rhythm, that his QTc was 440 ms, and that the rest of his cardiac intervals were normal, the medical resident was uncomfortable with the recommendation. The resident noted that he had seen “lots of problems” with IV haloperidol and that he would rather not use it to treat Mr. A since he had CAD.
What Is the QT Interval?How Is It Related to TdP and Other Cardiac Arrhythmias? The QT interval is an electrocardiographic measure of both depolar- ization and repolarization within the heart. It is measured as the distancebetween the beginning of the QRS complex and the end of the T wave.
The QRS complex represents ventricular depolarization, while the dis-tance from the end of the QRS to the end of the T wave represents repo-larization within the heart. The length of the QT interval decreases asheart rate increases, so, a “corrected” QT value, the QTc, is used to assessthe conduction status within the heart.
The QT interval of healthy persons is generally around 400 ms; the QT interval in women is usually about 20 ms longer than that of men.
QTc values greater than 450 ms are roughly considered to be “borderlineprolonged.” QTc values greater than 500 ms are considered prolongedand appear to be associated with an increased risk of arrhythmias, includ-ing TdP. It should be noted that the QT interval is “only at best modestlyassociated with TdP, but despite its difficulties is the best predictor avail-able (p. 1775).”1 COPYRIGHT 2004 PHYSICIANS POSTGRADUATE
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TdP is a malignant polymorphic ventricular arrhythmia Table 1. Effects of Orally-Administered Antipsychotics on the
with a characteristic pattern seen on the ECG.2 It can be QT Intervala
the result of a genetic long QT syndrome, but it is often associated with drugs that lengthen the QTc. Such drugs include a number of cardiac medications (e.g., quinidine- type compounds—the class IA antiarrhythmics), antibiot- ics or antifungals (e.g., erythromycin and ketoconazole), and other medications (e.g., quinine). A number of medi- cations (e.g., cisapride and terfenadine) have been re- aData adapted from the U.S. Food and Drug Administration’s Center moved from the market because they have been strongly for Drug Evaluation and Research, Psychopharmacological Drugs associated with TdP; many others remain available.
In addition to QTc prolongation, other factors that ap- pear to be associated with an elevated risk of TdP includeabnormal levels of electrolytes. Potassium, sodium, and cant evidence of TdP is linked only to use of thioridazine calcium are associated with repolarization; hypokalemia, (and possibly other low-potency antipsychotics), droperi- in particular, appears to be associated with an elevated dol, and haloperidol. Among antipsychotics, thioridazine risk of drug-associated TdP. Depleted magnesium also is most closely associated with TdP. Other low-potency appears to be associated with an elevated risk of TdP.
antipsychotic medications may also be associated with Other risk factors for TdP include systemic diseases (such TdP; however, thioridazine, unlike the other low-potency as hypothyroidism, renal dysfunction, or hepatic disease), antipsychotic medications, acts as a calcium-channel central nervous system disturbance (such as cerebrovas- blocker, and it may be this property that leads to elevated cular accident or intracranial hemorrhage), cardiac dis- ease (such as ischemic heart disease, congestive heart Haloperidol has been associated with TdP when given failure, bradycardia, and conduction delay), and female orally or intravenously. At least 2 dozen cases of TdP have been documented with intravenous haloperidol.1,5 How-ever, it should be noted that intravenous haloperidol What Effects Do Antipsychotic Medications is used extensively throughout the United States and is of- ten administered to patients who are profoundly ill and It appears that all antipsychotic medications can who may be taking other QT-prolonging medications. So, lengthen the QTc. A study of the effects of antipsychotics while there is a risk of TdP with haloperidol, the risk of in- on the QTc of 154 healthy persons (mostly young men ducing TdP in any given patient appears to be quite low, with QTc values in the normal range) found that different especially if other potential risk factors (like abnormal lev- antipsychotics increased mean QTc values to varying els of potassium and magnesium, a prolonged QT interval degrees.4 In this study,4 medications were titrated to the at baseline, and the coadministration of medications) are highest dose tolerated for each drug; mean increases in QTc values are included in Table 1. However, it is diffi- Recently, droperidol received a “black box warning” cult to extrapolate the results of this study4 to the use of for its association with TdP, despite the fact that the num- antipsychotics in patients with delirium. First, delirious ber of reported episodes of TdP was relatively small, con- patients may be unable to describe discomfort from side sidering the extent of its use in the medically ill. A recent effects; therefore, the doses used in delirious patients may review of intramuscular droperidol used for agitated pa- be higher than those used in the subjects cited in Table 1.
tients found no adverse dysrhythmic effects in over 10,000 Second, delirious patients are often older, have more co- patients.6 There is, as yet, no known association between morbid medical conditions, have more risk factors for ar- the atypical antipsychotics (including ziprasidone and rhythmia, and are more likely to be taking other medica- olanzapine) and TdP. Further study and more prolonged tions that may interact with antipsychotics to extend the use of these medications is required before definitive con- QT interval. Finally, increases in the QTc were detected following use of oral preparations of antipsychotics; It should be noted that QT prolongation with a single the effects on the QT interval after use of an antipsychotic antipsychotic does not necessarily predict QT prolongation intravenously may be different or greater than with the with another agent. On the psychiatric consultation service at Massachusetts General Hospital, when the use of IVhaloperidol led to QT prolongation, IV droperidol was of- Which Antipsychotics Are Associated With TdP? ten substituted for haloperidol; in almost all cases, the sub- Despite the documentation of prolonged QT intervals stitution did not lead to further prolongation of the QT in- with all of the above-mentioned antipsychotics, signifi- terval. Similarly, a switch from droperidol (when it caused COPYRIGHT 2004 PHYSICIANS POSTGRADUATE PRESS, INC. COPYRIGHT 2004 PHYSICIANS POSTGRADUATE PRESS, INC.
Primary Care Companion J Clin Psychiatry 2003;5(6) ROUNDS IN THE GENERAL HOSPITAL
QT prolongation) to haloperidol was also accomplished If the QT interval had become significantly lengthened safely and usually without inducing QT prolongation.
(e.g., > 500 ms, or increased by 60 ms), a number of However, IV droperidol is now rarely used in our institu- other options would have been available. If Mr. A was tion because of the above concerns about QT prolonga- able to open his mouth, wafers of olanzapine or risperi- tion and because of the precautions required for its use.
done could have been dissolved. If he was able to swal-low, any of the antipsychotics could have been admin- istered. Intravenous administration of benzodiazepines could also have been used for sedation; however, these Orthostatic hypotension, as a result of α -receptor agents can worsen confusion or disinhibition in delirious blockade, can result from the use of low-potency typical patients and therefore should be used cautiously.
antipsychotics, as well as from use of clozapine, risperi-done, or quetiapine. Other atypical antipsychotics and Drug names: clozapine (Clozaril and others), droperidol (Inapsine andothers), erythromycin (Benzamycin Pak, Eryc, and others), haloperi- high-potency typical agents have a lower rate of ortho- dol (Haldol and others), ketoconazole (Nizoral, Ketozole, and others), static hypotension; usually this side effect develops only olanzapine (Zyprexa), quetiapine (Seroquel), risperidone (Risperdal), when the patient is significantly volume-depleted. Ortho- stasis can be profound when antipsychotics are combinedwith vasodilatory or antihypertensive drugs.
Tachycardia, as a result of anticholinergic effects, may also result from use of low-potency typical antipsy- Glassman AH, Bigger JT. Antipsychotic drugs: prolonged QTc interval,torsade de pointes, and sudden death. Am J Psychiatry 2001;158: chotics, clozapine, and, to a lesser degree, olanzapine.
When these medications are combined with other anticho- Myerburg RJ, Castellanos A, Kessler KM. Recognition, clinical assess- linergic medications, tachycardia can increase or lead to ment and management of arrhythmias and conduction disturbances.
In: O’Rourke RA, Hurst JW, eds. Hurst’s The Heart. 8th ed. New York: arrhythmias. Therefore, in general, it is best to avoid low- potency antipsychotic medications in patients with car- Piepho RW. Cardiovascular effects of antipsychotics used in bipolar diac disease, given their propensity to lengthen the QT in- illness. J Clin Psychiatry 2002;63(suppl 4):20–23 U.S. Food and Drug Administration. Center for Drug Evaluation and terval and to cause orthostasis and tachycardia.
Research Psychopharmacological Drugs Advisory Committee. MeetingTranscript (for the approval of Zeldox [ziprasidone]), July 19, 2000.
Available at: http://www.fda.gov/ohrms/docket/ac/00/transcripts/3619t1a.pdf, 3619t1b.pdf, and 3619t1c.pdf 5. Sharma ND, Rosman HS, Padhi ID, et al. Torsades de pointes associated Yes. Mr. A was suffering from an acute confusional with intravenous haloperidol in critically ill patients. Am J Cardiology state that required rapid and effective treatment. Given 6. Shale JH, Shale CM, Mastin WD. A review of the safety and efficacy of that the IV route is the most rapid means of administration droperidol for the rapid sedation of severely agitated and violent patients.
of an antipsychotic, as well as the most reliable in a per- son unable to take oral medications, the IV route shouldbe strongly considered. Haloperidol (although not ap- proved for IV use by the Food and Drug Administration)has a long-standing record of efficacy in the symptomatic Review Articles
Alpert JE, Bernstein JG, Rosenbaum JF. Psychopharmacologic issues in the
treatment of delirium when administered intravenously; medical setting. In: Cassem NH, Stern TA, Rosenbaum JF, et al, eds.
empiric dosing can be used to find a dose that rapidly re- Massachusetts General Hospital Handbook of General Hospital duces a patient’s agitation and confusion. Intravenous ad- Psychiatry. 4th ed. St. Louis, Mo: Mosby; 1997:249–303–A very detailed, clearly-written chapter that encompasses virtually all ministration of haloperidol, as opposed to the oral or in- classes of psychotropic medications, with cogent descriptions of their tramuscular routes of administration, has a negligible rate dosing and side effects, as well as a discussion of their use related to of extrapyramidal side effects, which avoids the burden of special issues in the medical setting. The chapter includes extensive dis-cussions of antipsychotics and their cardiovascular side effects (e.g., the this side effect and foregoes the use of concomitant anti- Cassem NH, Murray GB. Delirious patients. In: Cassem NH, Stern TA, With regard to Mr. A’s cardiac status, his QTc was Rosenbaum JF, et al, eds. Massachusetts General Hospital Handbookof General Hospital Psychiatry. 4th ed. St. Louis, Mo: Mosby; 1997: not markedly prolonged. As with all patients receiving IV haloperidol, the QTc should be monitored for QT prolon- –This chapter includes a section on the practical use of intravenous gation. However, neither Mr. A’s history of cardiac dis- haloperidol that describes dosing, cardiac and electrolyte monitoring,drug interactions, and other aspects of the use of intravenous haloperidol ease nor the baseline QTc of 440 ms were contrain- based on a review of the literature and the authors’ extensive clinical dications to the use of haloperidol in this setting. To further reduce the risk of arrhythmia in Mr. A, serum po- Glassman AH, Bigger JT. Antipsychotic drugs: prolonged QTc interval, torsade de pointes, and sudden death. Am J Psychiatry 2001;158: tassium should have been maintained at or above 4 mEq/L –A clear and detailed description of QT prolongation and TdP associated COPYRIGHT 2004 PHYSICIANS POSTGRADUATE
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with antipsychotic medications. A section describes the physiology of the intravenous haloperidol in critically ill patients. Am J Cardiology QT interval, then extensively reviews the literature that has investigated the association between typical antipsychotic medications, TdP, and –This article describes the development of TdP in 8 of 268 patients in an sudden cardiac death. A section on atypical antipsychotics discusses the intensive care unit. In 7 of the cases, the development of TdP was associ- different degrees to which these newer agents appear to prolong the QT ated with doses of haloperidol greater than 35 mg in 24 hours. All of the patients with TdP had QTc intervals greater than 500 ms, and all but 1 Fayek M, Kingsbury SJ, Zada J, et al. Cardiac effects of antipsychotic medi- had QTc greater than 550 ms. The mean maximum QTc among patients cations. Psychiatr Serv 2001;52:607–609 with TdP was 606 ms, while patients who did not have TdP had a mean –A column that discusses the effects of antipsychotics on the QT interval.
maximum QTc interval of 493 ms. This article confirms the association The authors discuss medication-associated and nonpharmacologic causes between QTc prolongation and the development of TdP in patients re- of QT interval prolongation. In addition, they briefly review the literature ceiving IV haloperidol and verifies the need for QTc monitoring with IV regarding the association between antipsychotics and QT interval prolon- haloperidol, especially when high doses are administered.
gation. The column ends with clinical recommendations.
U.S. Food and Drug Administration. Center for Drug Evaluation and Re- Haddad PM, Anderson IM. Antipsychotic-related QTc prolongation, torsade search, Psychopharmacological Drugs Advisory Committee. Meeting de pointes, and sudden death. Drugs 2002;62:1649–1671 Transcript (for the approval of Zeldox [ziprasidone], July 19, 2000.
–Another comprehensive review of the subject. The article describes Available at: http://www.fda.gov/ohrms/docket/ac/00/transcripts/ cardioelectrical physiology, reviews the literature that has investigated an 3619t1a.pdf, 3619t1b.pdf, and 3619t1c.pdf association between antipsychotics and TdP, and outlines risk factors for –This meeting transcript describes Study 054, which compared the effect the development of TdP in persons receiving antipsychotics.
of ziprasidone on the QTc with that of other antipsychotics. In this study, Harrison MO, Krishnan KR. Antipsychotic medications and sudden cardiac 154 healthy subjects were given an antipsychotic medication (thiorid- death. Psychopharmacol Bull 2002;36:91–99 azine, haloperidol, quetiapine, olanzapine, risperidone, or ziprasidone), –A review of the association of antipsychotics with QT-interval prolonga- titrated to the highest tolerated dose. The investigators found that thiorid- tion, TdP, and sudden cardiac death. The authors discuss possible azine resulted in both the greatest mean QTc prolongation and the mechanisms for these events and review data for each class of antipsy- greatest percentage of persons with a QTc increase of greater than 60 ms.
chotics. The authors then make practical recommendations on the use of Ziprasidone caused the next greatest QTc increase among the agents studied; haloperidol caused the smallest QTc increase. Though this study Piepho RW. Cardiovascular effects of antipsychotics used in bipolar illness.
provides useful data, it is not clear that these data can be directly extrapo- J Clin Psychiatry 2002;63(suppl 4):20–23 lated to the administration of antipsychotics by the intravenous route to –A brief, clear discussion of such effects. The article briefly describes the cardiovascular effects of α-adrenergic blockade by antipsychotics, then Hoehns JD, Stanford RH, Geraets DR, et al. Torsades de pointes associated extensively discusses QT interval prolongation and TdP.
with chlorpromazine: case report and review of associated ventricular Al-Khatib SM, Lapointe NM, Kramer JM, et al. What clinicians should know arrhythmias. Pharmacotherapy 2001;21:871–873 about the QT interval. JAMA 2003;289:2120–2127 –A case report of TdP associated with the use of chlorpromazine. The –In this review, the authors provide clinical suggestions regarding medi- authors describe the case and present the results of a review of the Food cations associated with QT interval prolongation and TdP, including and Drug Administration’s Adverse Event Reporting System database antipsychotics. The authors discuss measurement of the QT interval and over a 3-year period. The authors found that 12 cases of ventricular ar- describe medications whose association to QT prolongation appears to be rhythmia associated with chlorpromazine were documented, 5 of which very probable (e.g., thioridazine), probable (e.g., ziprasidone), or possible (e.g., haloperidol). The authors recommend close monitoring of the QT Roe CM, Odell KW, Henderson RR. Concomitant use of antipsychotics and interval and levels of potassium and magnesium in patients receiving drugs that prolong the QT interval. J Clin Psychopharmacol medications associated with QT prolongation.
2003;23:197–200–In this study, approximately 2900 patients being treated with antipsy- Original Articles
chotics were divided into 2 groups: those receiving antipsychotics Mehtonen OP, Aranko K, Malkonen L, et al. A survey of sudden death associ- associated with possible QT prolongation and those receiving antipsy- ated with the use of antipsychotic or antidepressant drugs: 49 cases in chotics not associated with QT prolongation (as delineated by the Finland. Acta Psychiatr Scand 1991;84:58–64 International Registry for Drug-Induced Arrhythmias). The authors found –A retrospective study of 49 sudden deaths among patients taking anti- that both groups of patients had similar rates of concomitant use of non- psychotic or antidepressant drugs in Finland over a 3-year period. Of the psychotropic medications that may increase the QT interval. More than 46 deaths associated with antipsychotics, all but 3 were associated with half of the patients in the QT prolongation group received another medi- phenothiazines; thioridazine was involved in 61% of the cases and it was cation associated with QT prolongation at some point during the 3- to the only antipsychotic drug prescribed in 31%. In contrast, haloperidol 12-month follow-up period (most frequently antidepressants or antibiot- was prescribed in only 13% of the cases and was never the only drug ics). The authors concluded that the use of other QT-prolonging drugs was not being reduced in patients taking antipsychotics that are associ- Sharma ND, Rosman HS, Padhi ID, et al. Torsades de pointes associated with COPYRIGHT 2004 PHYSICIANS POSTGRADUATE PRESS, INC. COPYRIGHT 2004 PHYSICIANS POSTGRADUATE PRESS, INC.
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