Intravenous haloperidol is commonly used in high

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1 TISDALE EFFECT PHARMACOKINETICS OF HALOPERIDOL ANDON PHARMACODYNAMICS QT INTERVAL DISPERSION The Effect of Intravenous Haloperidol on QT Interval Dispersion in Critically Ill Patients: Comparison with QT Interval Prolongation for Assessment of Risk of Torsades de Pointes James E. Tisdale, PharmD, Saeed Rasty, PharmD, I. Desmond Padhi, PharmD, Nagaraja D. Sharma, MD, and Howard Rosman, MD The objective of this study was to determine the effect of intravenous haloperidol on QT interval dispersion in critically ill patients and to compare increases in QT interval dispersion and QTc intervals in patients who developed haloperidolinduced Torsades de Pointes versus those in patients who did not. This was a case-controlled study of 30 critically ill patients who received intravenous haloperidol for delusional agitation. Cases were patients (n = 6) who developed Torsades de Pointes during haloperidol therapy. Controls were patients (n = 24) who did not experience haloperidol-induced Torsades de Pointes. QTc intervals were measured and QT interval dispersion was calculated. Haloperidol prolonged QTc interval compared to pretreatment values in Torsades de Pointes patients (606 ± 61 ms vs. 501 ± 44 ms, p = 0.007) by a greater magnitude than in patients who did not experience Torsades de Pointes (507 ± 60 ms vs. 466 ± 44, p = 0.01). Twelve-lead analysis revealed that QT interval dispersion increased in patients who experienced Torsades de Pointes (from 63 ± 11 to 95 ± 22 ms, p = 0.03) but not in those who did not (62 ± 18 vs. 60 ± 26 ms, p = 0.66). Analysis of precordial leads only showed no significant haloperidol-associated increases in QT interval dispersion in either group. The odds of developing haloperidol-induced Torsades de Pointes were highest in patients with QTc interval > 521 ms during haloperidol therapy (odds ratio = 12.0). It was concluded that intravenous haloperidol prolongs QTc intervals in critically ill patients. The degree of prolongation is greater in patients who experience Torsades de Pointes. QT interval dispersion may be increased in patients who develop haloperidolinduced Torsades de Pointes compared with those who do not. However, these effects are dependent on the method of measurement (12 leads vs. precordial leads). In addition, the odds of haloperidol-induced Torsades de Pointes are higher in patients with QTc interval prolongation compared with increased QT interval dispersion. Therefore, QTc interval determination remains preferable to QT interval dispersion as a means assessment of risk for haloperidol-induced Torsades de Pointes. Journal of Clinical Pharmacology, 2001;41: the American College of Clinical Pharmacology Intravenous haloperidol is commonly used in high doses for managing delusional agitation in critically ill patients. 1 However, high-dose intravenous haloperidol has been reported to cause prolongation of the corrected QT (QTc) interval, 2-4 and Torsades de From the College of Pharmacy and Allied Health Professions, Wayne State University (Dr. Tisdale) and the Department of Pharmacy Services (Dr. Tisdale, Dr. Rasty, Dr. Padhi) and Division of Cardiovascular Medicine (Dr. Sharma, Dr. Rosman), Henry Ford Hospital, Detroit, Michigan. Dr. Rasty and Dr. Padhi are supported in part by an unrestricted investigator-initiated grant from Hoechst Marion Roussel. Address for reprints: James E. Tisdale, PharmD, Associate Professor, College of Pharmacy & Allied Health Professions, Wayne State University, 230 Shapero Hall, Detroit, MI Pointes associated with intravenous haloperidol occurs in up to 3.6% of critically ill patients. 4 QTc interval prolongation 500 ms is known to be a risk factor for drug-induced Torsades de Pointes. 4,5 In recent years, QT interval dispersion has been advocated as a measurement for prediction of risk of arrhythmias. Increased QT interval dispersion has been described in association with monomorphic ventricular arrhythmias 6-9 and has been also associated with drug-induced Torsades de Pointes. 10,11 QT interval dispersion is defined as the difference between the maximum and minimum QT intervals on the surface electrocardiogram (ECG). 12 QT interval dispersion is believed by many to be an accurate noninvasive index J Clin Pharmacol 2001;41:

2 EFFECT OF HALOPERIDOL ON QT INTERVAL DISPERSION of dispersion of ventricular repolarization. 13 The influence of intravenous haloperidol on QT interval dispersion and the predictive value of QT interval dispersion for haloperidol-induced Torsades de Pointes have not been investigated. The objectives of this study were to (1) determine the effect of intravenous haloperidol on QT interval dispersion in critically ill patients, (2) compare the effects of intravenous haloperidol on QT interval dispersion with its effects on QTc interval prolongation, and (3) compare the effects of intravenous haloperidol on QT interval dispersion and QTc interval prolongation in critically ill patients who developed haloperidolinduced Torsades de Pointes with those in patients who received intravenous haloperidol but did not experience Torsades de Pointes. METHODS This was a retrospective analysis of a subgroup of critically ill patients included in a case control study evaluating risk factors for Torsades de Pointes associated with intravenous haloperidol. 4 Briefly, all critically ill adult patients in intensive care units at Henry Ford Hospital who received intravenous haloperidol over a 12-month period were identified from pharmacy and medical records (n = 268). Most of these patients received intravenous haloperidol according to a literature-derived institutional intensive care unit sedation protocol, 14 in which haloperidol doses were doubled every 20 minutes until agitation was controlled, after which the effective dose was administered every 6 hours. Patients with hypokalemia or hypomagnesemia at any time during haloperidol therapy were excluded. In addition, patients who received any other agents known to prolong QTc intervals (class I or III antiarrhythmic agents, macrolide antibiotics, trimethoprim-sulfamethoxazole, nonsedating antihistamines, cisapride, or other antipsychotic agents) were excluded. Finally, patients admitted with head trauma were also excluded, as this is known to cause QTc interval prolongation. 15 Patients were not included if they developed Torsades de Pointes > 24 hours after the last dose of haloperidol. 4 After applying these exclusion criteria, the final patient population was 223 patients, of whom 8 experienced haloperidol-associated Torsades de Pointes. Of the 215 patients who did not develop Torsades de Pointes, 41 patients were selected randomly, using a random numbers table, as the control group for the case control study. 4 For this analysis of QT interval dispersion, only those patients who had at least one complete 12-lead ECG performed both prior to and during therapy with intravenous haloperidol were included, resulting in a final sample size of 30 (6 patients who developed Torsades de Pointes associated with intravenous haloperidol and 24 patients who did not experience Torsades de Pointes). QTc intervals and QT interval dispersion were measured from 12-lead ECGs recorded prior to and during therapy with intravenous haloperidol. In patients who had more than one 12-lead ECG performed prior to initiation of haloperidol therapy, the QT interval measurements were obtained from the ECG taken closest to the time of initiation of intravenous haloperidol. QT intervals were measured manually, using calipers, by a blinded investigator (JET). QT interval measurements were verified subsequently by a second blinded investigator (SR). QT intervals were measured from the earliest QRS deflection to the end of the T wave. In the presence of a U wave, the end of the QT interval was considered to be the nadir between the T and U wave peaks. 12 Corrected QT intervals were determined using lead II of the 12-lead ECG. QT interval dispersion measurements were calculated in two ways: QT interval dispersions were calculated based on measurements from precordial leads only and also based on measurements from all 12 ECG leads. QT intervals were corrected for heart rate using both Bazett s formula (QTc) 16 and the Fridericia correction (QT F ). 17 QT interval dispersion was defined as the maximum QT interval minus the minimum QT interval. 6 Since there is no evidence that QT interval dispersion is dependent on heart rate, QT interval dispersion was not corrected for heart rate, in accordance with published recommendations. 18,19 Statistical analysis was performed using SigmaStatR software (Jandel Corporation, San Rafael, CA). QTc intervals, QT F intervals, and QT interval dispersion measurements prior to and during haloperidol therapy were compared using paired t-tests. If continuous data were not normally distributed, the Mann-Whitney rank sum test was used. Changes in QTc intervals, QT F intervals, and QT interval dispersion in the Torsades de Pointes group versus those in the control group were compared using unpaired t-tests. Nominal data were analyzed using chi-square test or Fisher s exact test as appropriate. The relationship between haloperidol dose and change in QTc interval or QT interval dispersion was analyzed using linear regression. Coefficient of variation (CV) was calculated as standard deviation/ mean 100. Odds ratios for the occurrence of haloperidolinduced Torsades de Pointes were calculated 20 based on QTc intervals, QT F intervals, and QT interval dispersion values. Because no patient with haloperidol- PHARMACOKINETICS AND PHARMACODYNAMICS 1311

3 TISDALE ET AL induced Torsades de Pointes had a maximum QTc interval 500 ms, the odds ratio of developing Torsades de Pointes associated with QTc interval > 500 ms could not be calculated (because of a value of zero in the denominator). Therefore, for purposes of determining the odds of developing Torsades de Pointes associated with QTc interval prolongation, a value of 521 ms was used, as this was the lowest maximum QTc interval in a Torsades de Pointes patient during haloperidol therapy. QT F and QT interval dispersion values for the determination of odds ratios were selected on the basis that these were the values at which the highest odds of Torsades de Pointes occurred. The odds of developing Torsades de Pointes associated with both QTc interval > 521 ms and 12-lead QT interval dispersion > 100 ms could not be calculated, again because of a zero in the denominator. Therefore, for purposes of determining the odds of developing Torsades de Pointes using combined measurements of QTc interval prolongation and QT interval dispersion, a 12-lead QT interval dispersion value of 80 ms was used. RESULTS Individual characteristics of the 6 patients who developed Torsades de Pointes during therapy with haloperidol are presented in Table I. A representative rhythm strip depicting Torsades de Pointes experienced by patient 2 is presented in Figure 1. Demographic characteristics of patients who experienced haloperidol-induced Torsades de Pointes compared with those who did not are presented in Table II. There were no significant differences between the groups in age, sex, or history of ischemic heart disease or heart failure. Patients who developed Torsades de Pointes received a significantly higher mean maximum 24-hour haloperidol dose compared with those who did not develop Torsades de Pointes. Among all 30 patients studied, mean QTc interval increased from a pretreatment value of 473 ± 46 ms to a maximum of 527 ± 72 ms during haloperidol therapy (p < 0.001). QTc intervals prior to and during haloperidol therapy in the group of patients who developed Torsades de Pointes compared with those who did not are presented in Table III. QTc interval during therapy was significantly prolonged compared to pretreatment values in the group of patients who developed Torsades de Pointes. QTc intervals were also significantly prolonged compared to baseline values in the patients who did not experience Torsades de Pointes. The magnitude of QTc interval prolongation was greater in the Torsades de Pointes group of patients Table I Characteristics of Patients Who Experienced Torsades de Pointes Associated with Intravenous Haloperidol Patients Age (years) Sex M F M M M F Haloperidol dose/time 9 mg/ 85 mg/ 70 mg/ 400 mg/ 35 mg/ 75 mg/ 7 hours 27 hours 2.5 hours 24 hours 2 hours 4 hours Pretreatment QTc interval (ms) Maximum QTc interval (ms) on haloperidol Pretreatment QT F interval (ms) Maximum QT F interval (ms) on haloperidol Pretreatment QT interval dispersion (ms) precordial leads Maximum QT interval dispersion (ms) on haloperidol precordial leads Pretreatment QT interval dispersion (ms) 12 leads Maximum QT interval dispersion (ms) on haloperidol 12 leads M, male; F, female; QTc, corrected QT interval using Bazett s equation; QT F, corrected QT interval using the Fridericia equation; ms, milliseconds J Clin Pharmacol 2001;41:

4 EFFECT OF HALOPERIDOL ON QT INTERVAL DISPERSION Figure 1. Rhythm strip (lead II) depicting Torsades de Pointes associated with intravenous haloperidol experienced by patient 2. Table II Demographic Characteristics of 30 Critically Ill Patients Who Received Intravenous Haloperidol Patients Who Experienced Patients Who Did Not Experience Characteristic Torsades de Pointes (n = 6) Torsades de Pointes (n = 24) p Age (years) 56 ± ± Male sex, n (%) 4 (67) 15 (63) 1.0 History of CAD, n (%) 3 (50) 20 (83) 0.12 History of HF, n (%) 4 (67) 21 (88) 0.25 Maximum 24-hour haloperidol dose (mg) 112 ± ± CAD, coronary artery disease; HF, heart failure. compared with the control group (21% vs. 9%), and the maximum QTc interval during haloperidol therapy was significantly longer in the group of patients who developed Torsades de Pointes compared with the control group. There was a significant correlation between haloperidol dose and changes in QTc intervals from pretreatment values (Figure 2). Among all 30 patients studied, mean QT F interval increased from a pretreatment value of 314 ± 53 ms to a maximum of 345 ± 78 ms during haloperidol therapy (p = 0.04). QT F intervals prior to and during haloperidol therapy in the group of patients who developed Torsades de Pointes compared with those who did not are presented in Table III. QT F interval during therapy was not significantly prolonged compared to pretreatment values in the group of patients who developed Torsades de Pointes, although there was a trend toward QT F prolongation in this group. QT F intervals were not significantly prolonged compared to baseline values in the patients who did not experience Torsades de Pointes. The magnitude of QT F interval prolongation was greater in the Torsades de Pointes group of patients compared with the control group (24% vs. 7%). The magnitude of change in the QT F interval in the two groups was similar to the magnitude in change in QTc intervals. The maximum QT F interval during haloperidol therapy was significantly longer in the group of patients who developed Torsades de Pointes compared with the control group. There was a significant correlation between haloperidol dose and changes in QT F intervals from pretreatment values (Figure 3). Among all 30 patients studied, mean QT interval dispersion did not increase significantly from pretreatment values during haloperidol therapy as measured in all leads (pretreatment: 62 ± 17 ms; haloperidol: 67 ± 29 ms, p = 0.46) or as measured using only the precordial leads (pretreatment: 45 ± 21 ms; haloperidol: 47 ± 25 ms, p = 0.82). QT interval dispersion prior to and during haloperidol therapy in the group of patients who developed Torsades de Pointes compared with those who did not are presented in Table III. Analysis of all 12 leads revealed that QT interval dispersion increased significantly compared to pretreatment values in the group of patients who experienced Torsades de Pointes. Twelve-lead analysis revealed that QT interval dispersion was not significantly increased from base- PHARMACOKINETICS AND PHARMACODYNAMICS 1313

5 TISDALE ET AL Table III Effect of Intravenous Haloperidol on QTc Intervals, QT F Intervals, and QT Interval Dispersion in 30 Critically Ill Patients Patients Who Developed Patients Who Did Not Develop Torsades de Pointes (n = 6) Torsades de Pointes (n = 24) Pretreatment QTc a interval (ms) 501 ± ± 44 Maximum QTc interval during haloperidol therapy (ms) 606 ± 61 b 507 ± 60 c,d Pretreatment QT e F interval (ms) 323 ± ± 56 Maximum QT F interval during haloperidol therapy (ms) 400 ± 105 f 333 ± 62 g Pretreatment QTD h (all leads; ms) 63 ± ± 18 QTD during haloperidol therapy (all leads; ms) 95 ± 22 i 60 ± 26 j Pretreatment QTD (precordial leads; ms) 43 ± ± 22 QTD during haloperidol therapy (precordial leads; ms) 61 ± ± 22 a. QTc = corrected QT interval using Bazett s equation. b. p = compared to pretreatment value. c. p = compared to maximum QTc interval in Torsades de Pointes patients. d. p = 0.01 compared to pretreatment value. e. QT F = corrected QT interval using the Fridericia equation. f. p = 0.12 compared to pretreatment value. g. p = compared to maximum QT F in the Torsades de Pointes group. h. QTD = QT interval dispersion. i. p = 0.03 compared to pretreatment value. j. p = compared to Torsades de Pointes patients. Figure 2. Relationship between maximum 24-hour haloperidol dose and change in QTc interval from pretreatment values. p = 0.009; r 2 = Patients who developed haloperidol-induced Torsades de Pointes (open squares); patients who did not develop haloperidolinduced Torsades de Pointes (open circles). Figure 3. Relationship between maximum 24-hour haloperidol dose and change in QT F interval from pretreatment values. p = 0.001; r 2 = Patients who developed haloperidol-induced Torsades de Pointes (open squares); patients who did not develop haloperidolinduced Torsades de Pointes (open circles). line values in the patients who did not develop haloperidol-induced Torsades de Pointes. In contrast, however, analysis of the precordial leads only reveals no significant haloperidol-associated increases in QT interval dispersion in either group of patients. There was no correlation between haloperidol dose and 1314 J Clin Pharmacol 2001;41:

6 EFFECT OF HALOPERIDOL ON QT INTERVAL DISPERSION Table IV Odds Ratios for Development of Haloperidol-Induced Torsades de Pointes in Critically Ill Patients Based on QTc Interval Prolongation, QT F Interval Prolongation, and QT Interval Dispersion Odds Ratio QTc interval > 521 ms 12.1 QT F interval > 370 ms lead QT interval dispersion > 100 ms 11.0 Precordial QT interval dispersion > 50 ms 2.0 QTc interval > 521 ms and 12-lead QT interval dispersion 80 ms 11.0 Figure 4. Relationship between maximum 24-hour haloperidol dose and change in QT interval dispersion from pretreatment values (based on all 12 ECG leads). p = 0.26; r 2 = Patients who developed haloperidol-induced Torsades de Pointes (open squares); patients who did not develop haloperidol-induced Torsades de Pointes (open circles). change in maximum QT interval dispersion from pretreatment values (Figure 4). The mean number of readable leads in the 12-lead analysis was 10.5 ± 1.2 for the pretreatment measurements versus 10.2 ± 1.6 for the on-treatment measurements (p = 0.70). The mean number of readable leads in the precordial lead analysis was 5.5 ± 0.6 for the pretreatment measurements versus 5.6 ± 0.7 for the on-treatment measurements (p = 0.46). Variability in QT interval dispersion measurements was similar in the patients who experienced Torsades de Pointes (pretreatment CV = 35%, on-treatment CV = 54%) compared with that in the patients who did not develop haloperidol-induced Torsades de Pointes (pretreatment CV = 48%, on-treatment CV = 51%) based on precordial lead analysis. Odds ratios for developing Torsades de Pointes associated with intravenous haloperidol based on QTc intervals, QT F intervals, and QT interval dispersion values are presented in Table IV. The greatest odds of developing haloperidol-induced Torsades de Pointes occurred at QTc intervals 521 ms (odds ratio = 12.1). Based on odds ratio calculations, QT F interval was less predictive of the development of haloperidol-induced Torsades de Pointes. The odds of developing Torsades de Pointes were also high (odds ratio = 11.0) in association with 12-lead QT interval dispersion > 100 ms. The odds of developing Torsades de Pointes associated with intravenous haloperidol were similar in patients with both QTc interval > 521 ms and 12-lead QT interval dispersion 80 ms (odds ratio = 11.0). DISCUSSION The results of this study demonstrate that intravenous haloperidol may increase QT interval dispersion in critically ill patients who develop Torsades de Pointes while receiving the drug. This effect was demonstrated only using an analysis of all 12 leads of the ECG but was not apparent using QT interval measurements from the precordial leads alone. Intravenous haloperidol had no influence on QT interval dispersion in critically ill patients who did not develop proarrhythmia. The results of this study also confirm previous findings that intravenous haloperidol prolongs the QTc interval in critically ill patients. The degree of QTc interval prolongation correlated significantly with haloperidol dose. Furthermore, the study confirms that QTc interval is prolonged to a larger degree in patients who experience Torsades de Pointes associated with intravenous haloperidol. Previous studies have shown that haloperidol prolongs the QTc interval and that the degree of prolongation correlates with the risk of developing Torsades de Pointes. 2-5 The effect of intravenous haloperidol on QT interval dispersion has not been previously reported. Some studies have correlated an increase in QT interval dispersion with an increased risk of monomorphic ventricular tachyarrhythmias. 6-9 Fewer reports, however, have associated increased QT interval dispersion with the development of the life-threatening polymor- PHARMACOKINETICS AND PHARMACODYNAMICS 1315

7 TISDALE ET AL phic ventricular tachycardia Torsades de Pointes. In an analysis using precordial leads, Hii and colleagues 10 reported that QT interval dispersion was significantly increased from pretreatment values in 9 patients who experienced Torsades de Pointes associated with class IA antiarrhythmic agents. In contrast, QT interval dispersion did not increase in 29 patients who received class IA antiarrhythmic drugs but did not develop Torsades de Pointes. Similarly, Houltz et al, 11 using all 12 ECG leads, found that QT interval dispersion was significantly greater in 6 patients with atrial fibrillation who developed Torsades de Pointes caused by the class III antiarrhythmic agent almokalant compared with 94 patients who did not. The results of the present study are generally consistent with those of Hii et al 10 and Houltz et al. 11 QT interval dispersion was increased in patients who experienced haloperidol-induced Torsades de Pointes but not in patients who did not experience proarrhythmia. These data suggest that measurement of QT interval dispersion may be used as a factor in assessing the risk of Torsades de Pointes in critically ill patients receiving intravenous haloperidol. However, in the present study, QT interval dispersion was increased in the Torsades de Pointes group only when measured using all 12 ECG leads; when measuring using the precordial leads alone, QT interval dispersion was not significantly increased in the Torsades de Pointes group compared with the control group. Whether it is most appropriate to use all 12 ECG leads or only the precordial leads for determination of QT interval dispersion remains a subject of controversy. It has been recommended that QT interval dispersion measurements be made from the precordial leads only, rather than from all 12 ECG leads, because the chest leads are unipolar and are positioned relatively close to the heart, which more likely reflects regional cardiac activity. 12 However, many studies of QT interval dispersion have used both precordial leads and limb leads for calculation of QT interval dispersion. For this reason, we elected to perform our measurements in both ways. The fact that inconsistency exists in the 12-lead measurements of QT interval dispersion compared with the precordial lead measurements suggests that the use of QT interval dispersion may be somewhat less attractive than simple measurement of QTc interval prolongation as a means of assessing the risk of haloperidol-associated Torsades de Pointes. In the present study, QT intervals were corrected for heart rate using two methods: Bazett s formula 16 and the Fridericia correction. 17 Bazett s formula is the most widely used and therefore currently is the most clinically relevant mode of QT interval correction. However, because some data suggest that the Fridericia correction may be more accurate than Bazett s equation 21-23, we chose to perform heart rate corrections using both methods. Bazett s formula corrects QT interval for heart rate by using the square root of the RR interval (QTc = QT/ 2 /RR), whereas the Fridericia equation uses the cube root of the RR interval (QT F = QT/ 3 /RR). In this study, the magnitude of QT F interval prolongation in patients who developed haloperidol-induced Torsades de Pointes was comparable to the magnitude of QTc interval prolongation in that group. Similarly, the magnitude of QT F interval prolongation in the group of patients who did not experience haloperidol-induced Torsades de Pointes was comparable to the magnitude of QTc interval prolongation. In the population investigated in this study, QTc intervals were prolonged even before patients received intravenous haloperidol. This is likely due to the fact that the patients in this study were critically ill. Patients with hypokalemia or hypomagnesemia at any time during haloperidol therapy were excluded, as were those who received any other agents known to prolong QTc intervals. Based on determination of odds ratios for the development of Torsades de Pointes, measurement of QTc intervals was the best method for determining patients at the highest risk of developing Torsades de Pointes associated with intravenous haloperidol. Measurement associated with QT F interval was less predictive than QTc interval of the development of haloperidol-induced Torsades de Pointes. The odds of haloperidol-associated proarrhythmia were high in patients with 12-lead QT interval dispersion > 100 ms but not so high as the odds associated with QTc interval prolongation > 521 ms. Determination of both QTc interval and 12-lead QT interval dispersion did not identify patients with greater odds of developing Torsades de Pointes associated with intravenous haloperidol. On the basis of these data, determination of QTc interval prolongation appears to be the best method for identification of the highest risk of haloperidol-induced Torsades de Pointes, and additional determination of QT interval dispersion appears to be unnecessary. The prognostic significance of abnormal QT interval dispersion has been disputed and remains unclear. Although some studies have associated increased QT interval dispersion with the occurrence of ventricular tachyarrhythmias in athletes and in patients with coronary artery disease or following acute myocardial in J Clin Pharmacol 2001;41:

8 EFFECT OF HALOPERIDOL ON QT INTERVAL DISPERSION farction, congestive heart failure, or hypertrophic cardiomyopathy, other studies have found that abnormal QT interval dispersion had no prognostic value in patients with acute myocardial infarction, heart failure and left ventricular hypertrophy, and arrhythmogenicity. 24 In view of these conflicting data, it has been suggested that the utility of QT interval dispersion measurement as a clinical decision-making tool remains questionable 24 and requires further investigation. Limitations of the present study warrant discussion. The study was retrospective in design. In addition, the sample size of patients who experienced Torsades de Pointes was sufficiently small that a meaningful receiver-operated characteristics (ROC) analysis for complete characterization of the predictive accuracy of QTc interval prolongation, QT F interval prolongation, and QT interval dispersion for the development of haloperidol-induced Torsades de Pointes could not be performed. However, determination of the odds ratios for the development of haloperidolinduced proarrhythmia provides a valuable estimation of the predictive value of these respective ECG measurements. CONCLUSIONS Intravenous haloperidol prolongs QTc and QT F intervals in critically ill patients. QTc and QT F interval prolongation correlates significantly with haloperidol dose and occurs with greater magnitude in patients who experience Torsades de Pointes compared with those who do not. QT interval dispersion is also increased in critically ill patients who experience Torsades de Pointes during therapy with intravenous haloperidol but is not increased in patients who did not experience this proarrhythmia. However, this finding was demonstrated only in measurements of all ECG leads but not in measurements of the precordial leads alone. The odds of developing haloperidol-induced Torsades de Pointes are highest in patients with QTc interval prolongation, compared with QT F interval prolongation, 12-lead QT interval dispersion, or the combined measurement of QTc interval prolongation and QT interval dispersion. In view of these findings and in view of conflicting data regarding the prognostic significance of QT interval dispersion, measurement of QTc intervals remains preferable to measurement of QT interval dispersion as a means of assessing risk of Torsades de Pointes associated with haloperidol in critically ill patients. 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