Assessing risk of a prolonged QT interval–a survey of emergency physicians

Background

Although QT prolongation is associated with an increased risk of torsades de pointes (TdP), it is unclear how clinicians determine risk in individual patients with prolonged QT.

Aims

To investigate physicians’ interpretation of electrocardiogram (ECG) values in patients with a prolonged QT in reference to risk of TdP.

Methods

A survey was sent to Australasian emergency physicians (EPs) to investigate interpretation of ECG data in risk assessment for TdP. The survey contained three sections: demographic information, questions on heart rate correction and six sets of ECG data which the clinician ranked from low to high risk. Risk analysis for ECG values was performed by producing histograms of the distribution of responses for each of the six sets of ECG parameters. These distributions were compared to predicted distributions based on Bazett’s corrected QT>500 ms and the QT nomogram. The QT nomogram is a recently developed method for assessing whether QT-HR pairs are associated with increased risk of TdP by plotting them to determine if they are above an at risk line—the nomogram.

Results

Of 720 surveys sent out, 249 were returned (35%). A heart rate correction was used by 90% of respondents and the median “at risk” QTc judged by EPs was 450 ms [interquartile range (IQR): 440–500 ms]. Respondents were divided as to whether bradycardia increased the risk of TdP, with equal numbers responding “no change” and “more caution”. In four of the six sets of ECG parameters, EPs had a similar risk distribution to that predicted by Bazett. For one point predicted to be high risk by the QT nomogram, there was a uniform (undecided) risk distribution by EPs.

Conclusions

EPs mainly relied on Bazett’s correction as their method of TdP risk assessment, which may be problematic for bradycardic patients.     

Clinical assessment of drug-induced QT prolongation in association with heart rate changes

BACKGROUND: The formulas for heart rate (HR) correction of QT interval have been shown to overcorrect or undercorrect this interval with changes in HR. A Holter-monitoring method avoiding the need for any correction formulas is proposed as a means to assess drug-induced QT interval changes. METHODS: A thorough QT study included 2 single doses of the alpha1-adrenergic receptor blocker alfuzosin, placebo, and a QT-positive control arm (moxifloxacin) in 48 healthy subjects. Bazett, Fridericia, population-specific (QTcN), and subject-specific (QTcNi) correction formulas were applied to 12-lead electrocardio-graphic recording data. QT1000 (QT at RR = 1000 ms), QT largest bin (at the largest sample size bin), and QT average (average QT of all RR bins) were obtained from Holter recordings by use of custom software to perform rate-independent QT analysis. RESULTS: The 3 Holter end points provided similar results, as follows: Moxifloxacin-induced QT prolongation was 7.0 ms (95% confidence interval [CI], 4.4-9.6 ms) for QT1000, 6.9 ms (95% CI, 4.8-9.1 ms) for QT largest bin, and 6.6 ms (95% CI, 4.6-8.6 ms) for QT average. At the therapeutic dose (10 mg), alfuzosin did not induce significant change in the QT. The 40-mg dose of alfuzosin increased HR by 3.7 beats/min and induced a small QT1000 increase of 2.9 ms (95% CI, 0.3-5.5 ms) (QTcN, +4.6 ms [95% CI, 2.1-7.0 ms]; QTcNi, +4.7 ms [95% CI, 2.2-7.1 ms]). Data corrected by "universal" correction formulas still showed rate dependency and yielded larger QTc change estimations. The Holter method was able to show the drug-induced changes in QT rate dependence. CONCLUSIONS: The direct Holter-based QT interval measurement method provides an alternative approach to measure rate-independent estimates of QT interval changes during treatment.     

Utility of QT interval corrected by Rautaharju method to predict drug-induced torsade de pointes

Introduction: New QT correction formulae derived from large populations are available such as Rautaharju’s [QTcRTH?=?QT * (120?+?HR)/180] and Dmitrienko’s [QTcDMT?=?QT/RR^0.413]. These formulae were derived from 57,595 and 13,039 cases, respectively. Recently, a study has shown that they did not experience errors across a wide range of heart rates compared to others.

Objectives: (1) To determine the best cut-off value of QTcRTH and QTcDMT as a predictor of torsade de pointes (TdP) and (2) to compare the sensitivity and specificity using the cut-off value of QTcRTH with those of the QTcBazett (QTcBZT), QTcFridericia (QTcFRD), and QT nomogram.

Methods: Data were derived from two data sets. All cases aged over 18 years with an exposure to QT-prolonging drugs. Group-1, all cases developed TdP. Data in Group-1 were obtained from systematic review of reported cases from Medline since its establishment until 10 December 2015. Group-2 is composed of those who overdosed on QT prolonging drugs but did not develop TdP. This data set was previously extracted from a chart review of three medical centers from January 2008 to December 2010. Data from both groups were used to calculate QTcRTH and QTcDMT. The cut-off values from QTcRTH and QTcDMT that provided the best sensitivity and specificity to predict TdP were then selected. The same method was applied to find those values from QTcBZT, QTcFRD, and QT nomogram. The receiver operating characteristic curve (ROC) was applied where appropriate.

Results: Group-1, 230 cases of drug-induced TdP were included from the systematic review of Medline. Group-2 (control group), which did not develop TdP, consisted of 292 cases. After applying all of the correction methods to the two datasets, the best cut-off values that provided the best accuracy (Ac) with the best sensitivity (Sn) and specificity (Sp) for each formula were as follows: QTcRTH at 477 milliseconds (ms), Ac?=?89.08%, Sn?=?91.30% (95%CI?=?86.89–94.61), Sp?=?87.33%(95%CI?=?82.96–90.92); QTcDMT at 475?ms, Ac?=?88.31%, Sn?=91.30% (95%CI?=?86.89–94.61), Sp?=?85.96%(95%CI?=?81.44–89.73); QTcBZT at 490?ms, Ac?=?86.97%, Sn?=?88.26% (95%CI?=?83.38–92.12), Sp?=?85.96% (95%CI?=?81.44–89.73); QTcFRD at 473?ms, Ac?=?88.89%, Sn?=?89.13% (95%CI?=?84.37–92.84), Sp =88.70% (95%CI?=?84.50–92.09). We found a significant difference (p-value?=?0.0020) between area under the ROC of the QTcRTH (0.9433) and QTcBZT (0.9225) but not QTcFRD (0.9338). The Ac, Sn, and Sp of the QT nomogram were 89.08%, 91.30% (95%CI?=?86.89–94.61), and 87.33% (95%CI?=?82.96–90.92), respectively, and they were all equal to those of QTcRTH.

Conclusion: Rautaharju method not only produced minimal errors for QT interval correction but also at QTcRTH 477?ms, it could predict TdP as accurately as QT nomogram and was better than the QTcBZT.     

Dynamic beat-to-beat modeling of the QT-RR interval relationship: analysis of QT prolongation during alterations of autonomic state versus human ether a-go-go-related gene inhibition

Methods to correct the QT interval for heart rate are often in disagreement and may be further confounded by changes in autonomic state. This can be problematic when trying to distinguish the changes in QT interval by either drug-induced delayed repolarization or from autonomic-mediated physiological responses. Assessment of the canine dynamic QT-RR interval relationship was visualized by novel programming of the dynamic beat-to-beat confluence of data or "clouds". To represent the nonuniformity of the clouds, a bootstrap sampling method that computes the mathematical center of the uncorrected beat-to-beat QT value (QTbtb) with upper 95% confidence bounds was adopted and compared with corrected QT (QTc) using standard correction factors. Nitroprusside-induced reflex tachycardia reduced QTbtb by 43 ms, whereas an increase of 55 and 16 ms was obtained using the Bazett (QTcB) and Fridericia (QTcF) formulae, respectively. Phenylephrine-induced reflex bradycardia increased QTbtb by 3 ms but decreased QTcB by 20 ms and QTcF by 12 ms. Delayed repolarization with E-4031 (1-[2-(6-methyl-2-pyridyl)ethyl]-4-methylsulfonylaminobenzoyl)-piperidine), an inhibitor of rectifier potassium current, increased QTbtb by 26 ms but QT prolongation calculations using QTcF and QTcB were between 12 and 52% less, respectively, when small decreases in heart rate (5-8 beats per minute) were apparent. Dynamic assessment of beat-to-beat data, using the bootstrap method, allows quantification of QT interval changes under varying conditions of heart rate, autonomic tone, and direct repolarization that may not be distinguishable with use of standard correction factors.     

Clinical characteristics of patients with drug-induced QT interval prolongation and torsade de pointes: identification of risk factors

The present study aimed to investigate the causative medications and underlying risk factors that predispose to drug-induced QT interval prolongation. Twenty-one patients with drug-induced long QT (90% females, mean age 64.3 ± 14.1 years) were included in the study. Transthoracic echocardiography as well as continuous or ambulatory 48-h electrocardiographic monitoring was carried out in all patients during their hospitalization. The mean corrected QT (QTc) interval was 542 ± 56.8 ms. Known cardiac agents (mainly class III antiarrhythmics) were implicated in 13/21 (62%), antipsychotics in 8/21 (38%), and antibiotics in 5/21 patients (24%). Potential drug-interactions through inhibition of cytochrome P450 isoenzymes were considered responsible in 5/21 cases (24%). The underlying cardiovascular diseases included hypertension (57%) with left ventricular hypertrophy (29%), paroxysmal atrial tachyarrhytmias (48%), heart failure (14%), valvular heart disease (10%), and coronary artery disease (5%). Torsade de pointes (TdP) was recorded in 6/21 of patients, and cardiac arrest necessitating resuscitation occurred in five of them. A significant correlation was observed between administration of cardiac agents and TdP events (P < 0.05). TdP and cardiac arrest events were both associated with a QTc interval >510 ms (P < 0.05). Advanced age (>60 years), female gender, hypertension and paroxysmal atrial tachyarrhytmias were the most common identifiable pre-existing factors for drug-induced long QT in our patient cohort. Marked QTc interval prolongation should be considered of prognostic significance for TdP and cardiac arrest events.     

四硫化四砷对急性早幼粒细胞白血病患者心电图QTc问期的影响

目的探讨四硫化四砷(As4S4)对急性早幼粒细胞白血病(APL)患者心电图校正后QT(QTc)间期的影响.方法复方柏子仁(主要成分As4S4)治疗的90例患者分为诱导缓解组和巩固维持治疗组.诱导缓解组测定并记录患者服药前及缓解后的血砷浓度及同步12导联心电图;巩固维持治疗组测定并记录患者服药前及第2,4,6,8,10疗程后的血砷浓度及心电图.测量每份心电图的QT间期值,以Bazett公式校正,计算出QTc,观察血砷浓度与QTc间期的关系.结果无论诱导缓解组还是巩固维持治疗组,口服As4S4均能引起QTc间期的延长,QTc与As4S4的剂量及血砷浓度有关,随着As4S4的累积剂量或血砷浓度增大,QTc值及其延长的幅度也增大.在巩固维持治疗组服药的10个疗程中,QTc值异常(≥440 ms)率平均为 37.7%,随服用As4S4累积剂量的增加,各疗程血砷浓度缓慢上升,但各疗程之间的变化差异无显著性(P>0.05).各疗程中QTc间期虽逐步延长,但QTc值异常率在各疗程中无显著性差异(P>0.05).QTc异常的患者均无临床症状,未出现室性心动过速或尖端扭转型室性心动过速等病变,无一例患者因QTc间期延长而终止治疗.结论 As4S4治疗APL虽可引起QTc间期延长,且QTc间期的变化与血砷浓度呈正相关,但As4S4仍为一种安全的治疗APL的药物.     

Literature review and pilot studies of the effect of QT correction formulas on reported beta2-agonist-induced QTc prolongation

BACKGROUND: Drugs that stimulate the beta2-adrenergic receptor have been reported to prolong the QT interval corrected for heart rate (QTc interval), a potential mechanism for cardiac toxicity. OBJECTIVE: This study evaluated whether beta2-adrenergic agonist drugs prolong the QTc interval when different correction formulas for the effect of heart rate are used. METHODS: Healthy subjects of both sexes aged 19 to 33 years were recruited with advertisements. In pilot studies, subjects took a preparation containing the beta2-agonist ephedrine, or they participated in a postural study of the effect of endogenous beta-agonists. The study-drug group took 3 pills of the ephedra preparation per day for 2 days and then 6 pills per day for the next 2 days. Electrocardiograms (ECGs) were recorded before and at 1, 3, and 82 hours after the first study-drug dose and both before and after standing in the standing-up group. QT intervals obtained by automatic measurement were corrected for heart rate with 3 formulas: Bazett (QTc[B]), Framingham (QTc[F]), and Fridericia (QTc[Fr]). For the literature review, PubMed was searched using the search terms beta2-agonist drugs, QT, QTc, EKG, ECG, or electrocardiogram for studies that reported prolongation of the QTc by beta2-agonist drugs. We analyzed the method by which 11 different studies corrected QT interval for heart rate after the use of formoterol, salmeterol, terbutaline, salbutamol, and fenoterol. RESULTS: The ephedra study included 20 healthy subjects (35% men; mean [SD] age, 25 [4] years). Two hours after the last dose, QTc[B] had increased significantly from baseline by 19 ms (P=0.02). QTc[F] and QTc[Fr] did not change significantly. In the postural study, 19 healthy subjects (68% men; mean [SD] age, 32 [8] years) stood up and QTc[B] increased by a mean (SD) of 8 (15) ms (P=0.03). In these subjects, the QTc[B]/RR regression slope was significantly different from 0 (r=0.60, P=0.002), and the Bazett formula did not eliminate the dependence of QTc on heart rate. However, QTc[F] and QTc[Fr] did not change significantly, meaning that these formulas eliminated the dependence of QTc on heart rate. Eleven publications reported prolongation of QTc[B] by 5 beta2-adrenergic agonists for asthma. The change in QTc[B] interval from these publications was still dependent on the change in heart rate (r=0.63, P=0.004), but this dependence was eliminated after using QTc[F] and QTc[Fr]. The increase in QTc[B] would have been up to 30 ms less if QTc[F] or QTc[Fr] had been reported instead. CONCLUSIONS: The Bazett correction is the one typically reported by computerized ECG machines and the medical literature. This review suggests that QTc[B] may overestimate QTc when heart rate increases. Because the beta2-adrenergic agonist drugs increase heart rate, a systematic bias may have implicated these drugs in prolongation of cardiac repolarization. Prospective, large studies with a placebo and active control group are needed to evaluate the effect of beta2 agonists on QTc using formulas other than Bazett.     

The imprecision in heart rate correction may lead to artificial observations of drug induced QT interval changes

Because of the known limitations of the Bazett and other heart rate correction formulas, it has been proposed that studies of drug induced QT interval changes should use several different heart rate correction formulas and that the consistency of findings by a majority of such formulas should be considered as valid. The aim of this article was to show that such an approach is inappropriate. Using the database of the EMIAT trial, data of QT and RR intervals were taken from electrocardiograms of the first postrandomization visit of 1,402 patients. Of these, 309 were on amiodarone and beta-blockers, 395 on amiodarone and off beta-blockers, 318 on beta-blockers and off amiodarone, and 380 off amiodarone and off beta-blockers. An investigation of drug induced QT interval changes was modeled by evaluating the corrected QT (QTc) interval differences between patients on and off amiodarone, and on and off beta-blockers. A set of 31 previously published heart rate correction formulas was used. In addition to calculating the QTc difference between on and off drug for each formula, the success of heart rate correction was judged by computing correlation coefficients between QTc and RR intervals (ideally corrected QTc values should be independent of heart rate). The difference between on and off drug QT intervals was also evaluated by logarithmic regression models between uncorrected QT and RR intervals in data taken from patients on and off treatment. The QTc interval prolongation on amiodarone was confirmed by all heart rate correction formulas but the extent of the prolongation differed from formula to formula and ranged from 13.6 to 30.9 ms. Of the 31 formulas, 3 reported QTc interval shortening on beta-blockers (up to -11.8 ms) and 28 reported QTc interval prolongation (up to +16.8 ms). The distribution of the results provided by the different formulas suggested that beta-blocker treatment led to a QTc interval prolongation by approximately 7 ms (e.g., +7.4 ms by the Fridericia formula, P = 0.002). The on treatment QTc changes obtained by different formulas were closely correlated to their correction success. Formulas that provided QTc intervals almost independent of the RR intervals estimated approximately 20 ms QTc prolongation on amiodarone and no QTc change on beta-blockers. QT/RR regression analysis confirmed that while amiodarone led to substantial QT prolongation, there was no change of QT interval on beta-blockers beyond the change in heart rate. The study showed that the concept of "majority voting" by different heart rate correction formulas is inappropriate and may lead to erroneous conclusions.     

Multivariate analysis of risk factors for QT prolongation following subarachnoid hemorrhage

Background

Subarachnoid hemorrhage (SAH) often causes a prolongation of the corrected QT (QTc) interval during the acute phase. The aim of the present study was to examine independent risk factors for QTc prolongation in patients with SAH by means of multivariate analysis.

Method

We studied 100 patients who were admitted within 24 hours after onset of SAH. Standard 12-lead electrocardiography (ECG) was performed immediately after admission. QT intervals were measured from the ECG and were corrected for heart rate using the Bazett formula. We measured serum levels of sodium, potassium, calcium, adrenaline (epinephrine), noradrenaline (norepinephrine), dopamine, antidiuretic hormone, and glucose.

Results

The average QTc interval was 466 ± 46 ms. Patients were categorized into two groups based on the QTc interval, with a cutoff line of 470 ms. Univariate analyses showed significant relations between categories of QTc interval, and sex and serum concentrations of potassium, calcium, or glucose. Multivariate analyses showed that female sex and hypokalemia were independent risk factors for severe QTc prolongation. Hypokalemia (<3.5 mmol/l) was associated with a relative risk of 4.53 for severe QTc prolongation as compared with normokalemia, while the relative risk associated with female sex was 4.45 as compared with male sex. There was a significant inverse correlation between serum potassium levels and QTc intervals among female patients.

Conclusion

These findings suggest that female sex and hypokalemia are independent risk factors for severe QTc prolongation in patients with SAH.     

Q-T interval (QT(C)) in patients with cirrhosis: relation to vasoactive peptides and heart rate

OBJECTIVE: Prolonged Q-T interval (QT) has been reported in patients with cirrhosis who also exhibit profound abnormalities in vasoactive peptides and often present with elevated heart rate (HR). The aim of this study was to relate QT to the circulating level of endothelins (ET-1 and ET-3) and calcitonin gene-related peptide (CGRP) in patients with cirrhosis. In addition, we studied problems with HR correction of QT. MATERIAL AND METHODS: Forty-eight patients with cirrhosis and portal hypertension were studied during a haemodynamic investigation. Circulating levels of ETs and CGRP were determined by radioimmunoassays. Correction of QT for HR above 60 beats per min was performed using the methods described by Bazett (QT(C)) and Fridericia (QT(F)). RESULTS: Prolonged QT(C) (above 440 ms), found in 56% of the patients, was related to the presence of significant portal hypertension and liver dysfunction (p < 0.05 to 0.001), but not to elevated ET-1, ET-3 or CGRP. When corrected according to Bazett, QT(C) showed no significant relation to differences in HR between patients (r = 0.07, ns). QTF showed some undercorrection of HR (r = -0.36; p < 0.02). During HR variation in the individual patient, QT(C) revealed a small but significant overcorrection (2.6 ms per heartbeat per min; p < 0.001). This value was significantly (p < 0.02) smaller with QTF (1.2 ms per heartbeat per min). CONCLUSIONS: The prolonged QT(C) in cirrhosis is related to liver dysfunction and the presence of portal hypertension, but not to the elevated powerful vasoconstrictor (ET-1) or vasodilator (CGRP, ET-3) peptides. The problems with correction of the QT for elevated HR in cirrhosis are complex, and the lowest HR should be applied for determination of the QT.     

Epinephrine-induced QT interval prolongation: a gene-specific paradoxical response in congenital long QT syndrome

OBJECTIVE: To determine the effect of epinephrine on the QT interval in patients with genotyped long QT syndrome (LQTS). PATIENTS AND METHODS: Between May 1999 and April 2001, 37 patients (24 females) with genotyped LQTS (19 LQT1, 15 LQT2, 3 LQT3, mean age, 27 years; range, 10-53 years) from 21 different kindreds and 27 (16 females) controls (mean age, 31 years; range, 13-45 years) were studied at baseline and during gradually increasing doses of intravenous epinephrine infusion (0.05, 0.1, 0.2, and 0.3 microg x k(-1) x min(-1)). The 12-lead electrocardiogram was monitored continuously, and heart rate, QT, and corrected QT interval (QTc) were measured during each study stage. RESULTS: There was no significant difference in resting heart rate or chronotropic response to epinephrine between LQTS patients and controls. The mean +/- SD baseline QTc was greater in LQTS patients (500+/-68 ms) than in controls (436+/-19 ms, P<.001). However, 9 (47%) of 19 KVLQT1-genotyped LQT1 patients had a nondiagnostic resting QTc (<460 milliseconds), whereas 11 (41%) of 27 controls had a resting QTc higher than 440 milliseconds. During epinephrine infusion, every LQT1 patient manifested prolongation of the QT interval (paradoxical response), whereas healthy controls and patients with either LQT2 or LQT3 tended to have shortened QT intervals (P<.001). The maximum mean +/- SD change in QT (AQT [epinephrine QT minus baseline QT]) was -5+/-47 ms (controls), +94+/-31 ms (LQT1), and -87+/-67 ms (LQT2 and LQT3 patients). Of 27 controls, 6 had lengthening of their QT intervals (AQT >30 milliseconds) during high-dose epinephrine. Low-dose epinephrine (0.05 microg x kg(-1) x min(-1)) completely discriminated LQT1 patients (AQT, +82+/-34 ms) from controls (AQT, -7+/-13 ms; P<.001). Epinephrine-triggered nonsustained ventricular tachycardia occurred in 2 patients with LQTS and in 1 control. CONCLUSIONS: Epinephrine-induced prolongation of the QT interval appears pathognomonic for LQT1. Low-dose epinephrine infusion distinguishes controls from patients with concealed LQT1 manifesting an equivocal QTc at rest. Thus, epinephrine provocation may help unmask some patients with concealed LQTS and strategically direct molecular genetic testing.     

Effect of Combined Fluoroquinolone and Azole Use on QT Prolongation in Hematology Patients

QTc prolongation is a risk factor for development of torsades de pointes (TdP). Combination therapy with fluoroquinolones and azoles is used in patients with hematologic malignancies for prophylaxis and treatment of infection. Both drug classes are implicated as risk factors for QTc prolongation. The cumulative effect on and incidence of QTc prolongation for this combination have not been previously described. A retrospective chart review was performed with hospitalized inpatients from 1 September 2008 to 31 January 2010 comparing QTc interval data from electrocardiogram (ECG) assessment at baseline and after the initiation of combination therapy. Ninety-four patients were eligible for inclusion. The majority, 88 patients (93.6%), received quinolone therapy with levofloxacin. Fifty-three patients (56.4%) received voriconazole; 40 (42.6%) received fluconazole. The overall mean QTc change from baseline was 6.1 (95% confidence interval [CI], 0.2 to 11.9) ms. Twenty-one (22.3%) of the studied patients had clinically significant changes in the QTc while receiving combination fluoroquinolone-azole therapy. Statistically significant risk factors for clinically significant changes in QTc were hypokalemia (P = 0.03) and a left-ventricular ejection fraction of <55% (P = 0.02). Low magnesium (P = 0.11), exposure to 2 or more drugs with the potential to prolong the QTc interval (P = 0.17), and female sex (P = 0.21) trended toward significance. Combination therapy with fluoroquinolone and azole antifungals is associated with increased QTc from baseline in hospitalized patients with hematologic malignancies. One in five patients had a clinically significant change in the QTc, warranting close monitoring and risk factor modification to prevent the possibility of further QTc prolongation and risk of TdP.     

Greater quinidine-induced QTc interval prolongation in women

BACKGROUND: Prolongation of the electrocardiographic QT interval by drugs is associated with the occurrence of a potentially lethal form of polymorphic ventricular tachycardia termed torsades de pointes. Women are at greater risk than men for development of this adverse event when taking drugs that prolong the QT interval. To determine whether this may be the result of gender-specific differences in the effect of quinidine on cardiac repolarization, we compared the degree of quinidine-induced QT interval lengthening in healthy young men and women. METHODS: Twelve women and 12 men received a single intravenous dose of quinidine (4 mg/kg) or placebo in a single-blind, randomized crossover trial. Total plasma and protein-free concentrations of quinidine and 3-hydroxyquinidine were measured in serum. QT intervals were determined and corrected for differences in heart rate with use of the method of Bazett (QTc = QT/RR1/2). RESULTS: As expected, the mean QTc interval at baseline was longer for women than for men (mean +/- SD; 407 +/- 7 versus 395 +/- 9 ms, P < .05). The slope of the relationship between change in the QTc interval (delta QTc) from baseline to the serum concentration of quinidine was 44% greater for women than for men (mean +/- SE; 42.2 +/- 3.4 versus 29.3 +/- 2.6 ms/microg per mL, P < .001). These results were not influenced by analysis of 3-hydroxyquinidine, free concentrations of quinidine and 3-hydroxyquinidine, or the JT interval. CONCLUSIONS: Quinidine causes greater QT prolongation in women than in men at equivalent serum concentrations. This difference may contribute to the greater incidence of drug-induced torsades de pointes observed in women taking quinidine and has implications for other cardiac and noncardiac drugs that prolong the QTc interval. Adjustment of dosages based on body size alone are unlikely to substantially reduce the increased risk of torsades de pointes in women.     

Correlation between QTc interval and clinical severity of subarachnoid hemorrhage depends on the QTc formula used

OBJECTIVES: Subarachnoid hemorrhage (SAH) frequently prolongs QT interval in the acute phase. The purpose of our study is to investigate whether the correlation between electrocardiographic corrected QT interval and the clinical severity of SAH depends on QTc formula used. METHODS: We retrospectively studied 52 consecutive subjects with nontraumatic SAH (extravasation of blood into the spaces covering the central nervous system that are filled with cerebrospinal fluid) who were admitted within the first day of SAH. QT intervals were measured on a standard 12-lead electrocardiography and corrected by Bazett and Hodges formulae. All patients were evaluated according to clinical condition on admission by Hunt-Hess grades. The patients were grouped in two different categories according to QT interval corrected by Bazett and Hodges and scored by Hunt-Hess (HH) grades. RESULTS: Mean age of the study patients was 54 +/- 12 years and of those 31 (60%) were female. Mean values of heart rate and RR interval were 82 +/- 21 bpm and 777 +/- 163 msec, respectively. The mean QTc interval by Bazett and Hodges were 456 +/- 59 msec and 438 +/- 48 msec, respectively (P < 0.001). Twenty-three patients according to Bazett and fifteen according to Hodges had prolonged QTc. Correlation analyses showed relation between HH and QTc and prolonged QTc by Bazett (r = 0.278, P = 0.04 and r = 0.314, P = 0.024; respectively). There was no correlation between HH and QTc and prolonged QTc by Hodges (r = 0.204, P = 0.14 and r = 0.115, P = 0.41; respectively). CONCLUSIONS: In our study, correlation between QTc interval and clinical severity of SAH depended on the QTc formula used.     

Comparison of Formulae for Heart Rate Correction of QT Interval in Exercise Electrocardiograms

The study investigated the differences in five different formulae for heart rate correction of the QT interval in serial electrocardiograms recorded in healthy subjects subjected to graded exercise. Twenty-one healthy subjects (aged 37+/-10 years, 15 male) were subjected to graded physical exercise on a braked bicycle ergometer until the heart rate reached 120 beats/min. Digital electrocardiograms (ECG) were recorded on baseline and every 30 seconds during the exercise. In each ECG, heart rate and QT interval were measured automatically (QT Guard package, Marquette Medical Systems, Milwaukee, WI, USA). Bazett, Fridericia, Hodges, Framingham, and nomogram formulae were used to obtain QTc interval values for each ECG. For each formula, the slope of the regression line between RR and QTc values was obtained in each subject. The mean values of the slopes were tested by a one-sample t-test and the comparison of the baseline and peak exercise QTc values was performed using paired t-test. Bazett, Hodges, and nomogram formulae led to significant prolongation of QTc intervals with exercise, while the Framingham formula led to significant shortening of QTc intervals with exercise. The differences obtained with the Fridericia formula were not statistically significant. The study shows that the practical meaning of QT, interval measurements depends on the correction formula used. In studies investigating repolarization changes (e.g., due to a new drug), the use of an ad-hoc selected heart rate correction formula is highly inappropriate because it may bias the results in either direction.     

Termination of drug-induced torsades de pointes with overdrive pacing

Drug-induced prolongation of the QT interval is frequently encountered after medication overdose. Such toxicity can result in degeneration to torsades de pointes (TdP) and require overdrive pacing. We present 3 cases in which intentional medication overdose resulted in QTc prolongation with subsequent degeneration to TdP. Despite appropriate care, including magnesium therapy, each case required overdrive pacing for resolution of TdP. Although rarely encountered, patients with drug-induced TdP can be successfully managed with overdrive pacing.     

Institution-Wide QT Alert System Identifies Patients With a High Risk of Mortality

ObjectivesTo determine the phenotype and outcome of patients with QTc of at least 500 ms and to create a pro-QTc risk score for mortality.Patients and MethodsAn institution-wide computer-based QT alert system was developed and implemented at Mayo Clinic in Rochester, Minnesota. This system screens all electrocardiograms (ECGs) performed and alerts the physician if the QTc is 500 ms or greater. Between November 10, 2010, and June 30, 2011, 86,107 ECGs were performed in 52,579 patients. Clinical diagnoses, laboratory abnormalities, and medications known to influence the QT interval were collected from the medical records and summarized in a new pro-QTc score. Survival was compared with that of the 51,434 Mayo Clinic patients with a QTc less than 500 ms during the same period.ResultsQT alerts were sent for 1145 patients (2%); of these, 470 (41%) had no other identifiable ECG reason for QT prolongation (eg, pacing). All-cause mortality during a mean ± SD of 224±174 days of follow-up was 19% in those with QTc of 500 ms or greater compared with 5% in patients with QTc less than 500 ms (log-rank P<.001). The pro-QTc score was an age-independent predictor of mortality (pro-QTc score: hazard ratio, 1.18; 95% CI, 1.05-1.32; P=.006; age: hazard ratio, 1.02; 95% CI, 1.01-1.03; P=.004.). QT-prolonging medications accounted for 37% of the pro-QTc score.ConclusionThis novel institution-wide QT alert system identified patients with a high risk of mortality. The pro-QTc score, reflecting patients’ multimorbidity and multipharmacy, was an independent predictor of mortality. The QT alert system may increase a physician’s awareness of a high-risk patient. Potentially lifesaving interventions can be facilitated by reducing the modifiable factors of the pro-QTc score.     

Sex differences in ventricular repolarization: from cardiac electrophysiology to Torsades de Pointes

A number of non-cardiovascular drugs have been withdrawn from clinical use due to unacceptable adverse cardiac side-effects involving drug-induced Torsades de Pointes (TdP)--a rare, life-threatening polymorphic ventricular tachycardia associated with prolongation of the action potential duration of ventricular myocytes and, hence, prolongation of the QT interval, of the electrocardiogram (ECG), which measures the total time for activation of the ventricles and their recovery to the resting state. Research has suggested that women are more prone to develop TdP than men during administration of medicines that share the potential to prolong the QT interval, with 65-75% of drug-induced TdP occurring in women. Clinical and experimental studies show that female sex demonstrate differences in the electrocardiographic pattern of ventricular repolarization in human and other animal species and is associated with a longer rate-corrected QT (QTc) interval at baseline than males. Reports of a similar propensity towards drug-induced TdP in both premenopausal and postmenopausal women support factors in addition to those of female sex hormones eliciting sex-based differences in ventricular repolarization. However, conflicting evidence suggests sex hormones may have a role in increasing the susceptibility of women or ultimately reducing the susceptibility of men to TdP. Cyclical variations in hormone levels during the menstrual cycle have been associated with an increased and reduced risk of TdP. In contradiction to this finding, the male sex hormone is thought to be beneficial. Modulation of the ventricular repolarization by testosterone may explain why the QTc interval shortens at puberty, and might account for the tendency towards an age-dependent reduction in the incidence of drug-induced TdP in men. Mechanisms underlying these differences are not fully understood but a case for the involvement of gonadal steroids is obviously strong. Therefore, further non-clinical/clinical investigations ought to be a necessary step to elucidate any sex differences in cardiac repolarization characteristics, QT interval prolongation and susceptibility to cardiac arrhythmias. This may have implications for the development of the safest medicinal products and for the clinical management of cardiac arrhythmias.     

Assessment of corrected QT interval in sickle-cell disease patients who undergo erythroapheresis

Extension of the QT interval is characterized by syncope and cardiac arrest and often occurs in association with medical therapies and procedures. Whether erythroapheresis (EPH) could influence the QT interval duration in patients with sickle cell disease (SCD) is not known. We aimed to investigate the effects of EPH on the heart rate-corrected QT (QTc) interval. The study included 25 patients with SCD who underwent 34 EPH procedures. Two independent observers measured QTc interval duration from electrocardiograms performed continuously for 3 min at three different points during the EPH procedures (prior to EPH, after completion of 50% EPH and 15 min after EPH). Multiple regression analysis was used to determine if the ionized plasma calcium, the level of plasma magnesium, citrate infusion rate and painful crisis significantly contributed to the QTc interval. There was a non-significant trend (P = 0.184) towards increased QTc in sickle cell patients during EPH compared with pre-EPH values. QTc prolongation (>440 ms) occurred in 72% of the procedures. Fifty percent QTc values returned to baseline after the procedure. The independent variables were not significantly associated with QTc interval. Exchange procedures can induce QTc prolongation in patients with SCD.