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QTc Prolongation and Risk of Torsades de Pointes in Hospitalized Pediatric Oncology Patients
ORIGINAL ARTICLES QTc Prolongation and Risk of Torsades de Pointes in Hospitalized Pediatric Oncology Patients Tiffany R. Lim, MD1, Arun A. Rangaswami, MD2, Anne M. Dubin, MD3, Kristopher I. Kapphahn, MS4, Charlotte Sakarovitch, PhD4, Jin Long, PhD4, Kara S. Motonaga, MD3, Tony Trela, PNP-BC3, and Scott R. Ceresnak, MD3 Objective To evaluate the prevalence of torsades de pointes and to identify risk factors associated with QTc prolongation of ³500 milliseconds in hospitalized pediatric oncology patients. A QTc prolongation of ³500 milliseconds is associated with higher mortality in hospitalized adults but has not been demonstrated in pediatrics. Study design A single-center, retrospective review of all hospitalized oncology patients £21 years of age was performed from 2014 to 2016. Patients with long/short QT syndrome or a QRS interval of ³120 ms were excluded. Rapid response events were reviewed to determine the prevalence of torsades. In patients with ECGs for review, data were compared between patients with a QTc of <500 and ³500 ms via logistic regression. Results There were 1934 hospitalized patients included. Rapid response events occurred in 90 patients (4.7%) with 2 torsades events (0.1%). There were 1412 electrocardiograms performed in 287 unique patients (10.6 6.3 years of age; 43% female). The mean QTc was 448 31 ms; 25 patients (8.7%) had ³1 ECG with a QTc of ³500 ms. The prevalence of torsades was greater in patients with a QTc of ³500 ms (8% vs 0%; P<.01). In multivariate analysis, factors associated with a QTc of ³500 ms included female sex, (OR 2.95) and ³2 QT-prolonging medications (OR, 2.95). Conclusions The prevalence of torsades in hospitalized pediatric oncology patients was low (0.1%), although the risk was significantly greater in patients with a QTc of ³500 ms. Routine monitoring of electrocardiograms and electrolytes is essential in patients with risk factors predisposing to QTc prolongation. (J Pediatr 2019;-:1-6).
P
rolongation of the QTc interval is frequently identified in hospitalized pediatric oncology patients, often secondary to a combination of factors including antineoplastic and antiemetic medications and electrolyte abnormalities.1-3 Although electrocardiograms (ECGs) are often recommended in these patients for surveillance of the QTc interval, the risk of prolongation of the QTc, life threatening arrhythmias and torsades de pointes (torsades) has not been clearly identified in this population. In hospitalized adults, a QTc interval of ³500 ms has been associated with a higher risk of torsades, a lifethreatening, malignant ventricular arrhythmia, as well as increased overall mortality.4-6 This risk of torsades has not been well-described in the pediatric population.7-10 In this investigation, we sought to determine the prevalence of torsades de pointes in hospitalized pediatric oncology patients, determine the prevalence of marked QT prolongation (a QTc of ³500) in pediatric oncology patients with ECGs, and to assess if a QTc of ³500 ms was associated with a higher risk of torsades de pointes or death. In addition, we sought to identify other factors, including electrolyte abnormalities, number of QT-prolonging medications and/or primary oncologic diagnoses, associated with significant prolongation of the QTc (³500 ms) in this particular at-risk population.
Methods A single-center, retrospective cohort study of hospitalized pediatric oncology patients from January 2014 through August 2016 was performed. This study included all patients £21 years of age admitted to a single, large-volume pediatric oncology service (Lucile Packard Children’s Hospital at Stanford University) with a primary oncologic diagnosis who had an ECG performed for QTc surveillance. During this time period, ECGs were typically performed at the discretion of the pediatric oncology team. Throughout the study period, there were not set institutional guidelines detailing the necessity of an ECG, but common indications and group practice patterns for obtaining an ECG during this time included initiation of a new chemotherapeutic medication or From the Department of Pediatrics; Division of Hematology and Oncology, Lucile Packard Children’s regimen, standard workup for a new oncologic diagnosis, history of QTc prolongaHospital; Division of Cardiology, Lucile Packard Children’s Hospital; and Quantitative Science Unit, tion, use of multiple QT-prolonging medications, significant electrolyte wasting, or Stanford University, Stanford, CA 1
2
3
4
Sponsored in part by a grant from the Stanford Cardiovascular Institute. The authors declare no conflicts of interest.
ECG EF LV MS
Electrocardiogram Ejection fraction Left ventricular Milliseconds
Portions of this study were presented at the American Heart Association’s Scientific Sessions, November 13, 2017, Anaheim, California. 0022-3476/$ - see front matter. ª 2019 Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.jpeds.2019.10.018
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a history of other electrolyte abnormalities. Patients with known long QT syndrome, short QT syndrome, and those with prolongation of the QRS interval of >120 ms were excluded, because these factors would affect the QTc calculations and risk of torsades. Rapid response and code blue records of all hospitalized pediatric oncology patients were reviewed to determine the prevalence of torsades. The following data were obtained and reviewed for each patient: demographics, primary oncologic diagnoses, QTprolonging medications, electrolyte levels obtained within 24 hours of an ECG, ECG data (including QTc), and outcome. QTc measurements were performed by a pediatric electrophysiologist and retrieved from a hospital-wide database. A subset of 10% of the QTc measurements were recalculated by a second pediatric electrophysiologist who was blinded to the subject classification and database QTc values to confirm the validity of the QTc intervals from the database. The QTc interval was measured using the Bazett formula in the standard manner described by Bazett.11 In patients with a QTc of ³500 ms, echocardiogram reports were reviewed and left ventricular (LV) ejection fraction (EF) was recorded from the echocardiogram at the time closest to the time that the ECG of ³500 ms was noted. QT-prolonging medications were defined as those listed in the most commonly used clinical database of QT-prolonging medications, Credible Meds (qtdrugs.org, list date updated as of September 1, 2017). Electrolyte abnormalities were defined as a potassium of <3.5 mmol/L, ionized calcium of <1.2 mmol/L or serum calcium of <8.5 mg/dL, and magnesium of <1.5 mg/dL.4,12-14 Torsades events were classified as >3 beats of polymorphic ventricular tachycardia with characteristic fluctuation of the QRS complex around the electrocardiographic baseline.15-17 Statistical Analyses Categorical variables are expressed as numbers and percentages whereas continuous variables are expressed as mean SD or median (IQR) if not normally distributed. The prevalence of torsades de pointes was determined by dividing the number of patients with documented torsades de pointes by the total number of pediatric oncology patients admitted to the hospital over the same period. The remainder of the analysis focused on those patients in whom an ECG had been obtained during hospitalization. In those patients with an ECG available for review, the number of torsades events in patients with ³1 ECG during admission with a QTc of ³500 ms was compared with those with a QTc of <500 ms using the Fisher exact test to determine if prolongation of the a QTc of ³500 ms was associated with torsades. All-cause mortality was also compared in patients with a QT of <500 ms and a QT of ³500 ms using the Fisher exact test. In addition, in those patients with an ECG available for review, a univariable generalized linear mixed model with a binary distribution and a logit link function was used to determine variables associated with the finding of a QTc of ³500 ms. Variables significantly associated with a QTc prolongation of ³500 ms were 2
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included in a multivariable generalized linear mixed model. All ECGs from the database were confirmed by a pediatric electrophysiologist. To verify the accuracy of the QTc measurements in the database, the Spearman correlation was used to compare repeated measurements performed by a blinded pediatric electrophysiologist to the ECG database with remeasurement of a random sample of 10% of the ECGs. Two-sided P values of <.05 were considered significant. Statistical analysis was performed using SAS version 9 (SAS Institute, Cary, North Carolina) and R version 3.1.3 (R Core Team, Vienna, Austria).
Results Of the 1934 patients admitted to the pediatric oncology service, a total of 1412 ECGs were performed in 287 unique patients (mean age, 10.7 6.3 years; 41% female) (Figure). In those patients who had an ECG performed (n = 287), the mean QTc was 448 31 ms (Table I). The random sampling of ECGs from the database showed strong correlation with reading of a blinded pediatric electrophysiologist (rs of 0.83; P<.001). In patients who had an ECG, the most common primary oncologic diagnoses included T-cell acute lymphoblastic leukemia (n = 85 [35%]), acute myelogenous leukemia (n = 27 [14%]), and rhabdomyosarcoma (n = 11 [4%]). The most common QT-prolonging medications administered to patients included diphenhydramine (n = 68 [24%]) and ondansetron (n = 107 [37%]). A total of 123 rapid responses and code blues occurred in 90 inpatient oncology patients (4.7% of the entire 1934 hospitalized oncology patients) with 6 events (6.7%) secondary to clinically significant cardiac arrhythmias. These arrhythmias included 3 supraventricular tachycardia (2 reentrant supraventricular tachycardia and 1 ectopic atrial tachycardia), 1 ventricular tachycardia, and 2 torsades events. The 2 torsades events occurred in 2 unique patients, yielding a torsades prevalence of 0.1% (2 of 1934 patients) in all inpatient oncology patients during the study period. Of those patients that had an ECG for review (n = 287), the prevalence of torsades was significantly greater in those with a QTc of ³500 ms (8% vs 0%; P<.01) (Table I). In the 2 patients (both females) with torsades events, the QTcs at the time of their events were 532 and 639 ms, respectively (Table II). Both patients experienced cardiopulmonary arrest, required emergent defibrillation, and had multiple episodes of torsades requiring treatment with intravenous magnesium. Patient 1 had a baseline QTc of 488 ms and patient 2 had a baseline QTc of 447 ms. Neither patient had a family history of sudden death or of implantable cardioverter-defibrillator placement. Genetic testing for long QT syndrome was performed in both patients and both were negative, although it is possible that one or both could be gene-negative long QT syndrome. Patient 1 had an echocardiogram 3 days before the arrest with normal LV systolic function with an EF of 72%. After the arrest, the Lim et al
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Figure. Flow diagram of patient cohort including ECGs and RRTs/code blues. SVT, supraventricular tachycardia.
LV systolic function was noted to be mildly diminished with an EF of 49%. Patient 2 had an echocardiogram 3 months before cardiac arrest at the LV systolic function was normal (EF of 62%). Immediately after arresting, the LV systolic function was severely diminished (EF of 15%), although by 1 week after the arrest the LV systolic function was normal (LV EF of 66%). In patients with an ECG during hospitalization (n = 287), a total of 25 patients (8.7%) had ³1 ECG with a QTc of ³500 ms, with a total of 63 ECGs (4.4% of total ECGs) with a QTc of ³500 ms. In univariate analysis, factors associated with a QTc of ³500 ms included female sex, diphenhydramine, the use of ³2 QT-prolonging medications, and hypocalcemia (Table I). On multivariate analysis, female sex and the use of ³2 QT-prolonging medications independently contributed to QT prolongation (Table III). The use of a higher cut-off QTc (such as 550 ms) was considered, although of the 1412 ECGs there were only 16 ECG in 12 unique patients and analysis of this small sample was limited. Echocardiograms were performed in all patients with a QTc of ³500 ms, with all but 2 performed within 3 months of the time their ECG was noted to be ³500 ms. The remaining 2 patients had echocardiograms 4 months after and 5 months before the date of their ECG identifying prolongation of the QTc. All echocardiograms in patients with a QTc of ³500 ms demonstrated normal biventricular function with a mean EF of 64.5 6.5% (mean time from ECG, 23 37 days). All-cause mortality was compared in patients with an ECG and there was no significant difference in all-cause mortality in those patients with a QTc of ³500 ms compared with those with a QTc of <500 ms (13 ³ 500 ms [22%] vs 347 < 500 ms [25%]; P = .96).
Discussion Hospitalized pediatric oncology patients may be particularly susceptible to acquired prolongation of the QTc and life-threatening torsades de pointes.1-3 The use of QTprolonging medications and frequent electrolyte abnormalities in this patient population may predispose patients to significant prolongation of the QTc to >500 ms. In this cohort of hospitalized children from a large tertiary care center, the overall prevalence of torsades was quite low at 0.1%. In this study, we discovered that patients with a significant QTc prolongation of ³500 ms had a higher rate of torsades, were female, and were on ³2 QT-prolonging medications. These findings may help providers assess to risk and develop screening algorithms in this vulnerable population. An association between significant prolongation of the QTc and mortality has been reported in adult populations. In a recent investigation of 41 649 hospitalized adults, Yu et al identified a risk of torsades of 0.7%.10 In that cohort, patients with acquired long QT had a higher risk of syncope and life-threatening arrhythmias. Haugaa et al also recently reported on the Mayo clinic experience with acquired long QT and demonstrated that hospitalized adult patients with prolongation of the QTc and a higher pro-QTc score had higher all-cause mortality.9 The oncology patient population may be a particularly vulnerable population for acquired QTc prolongation, and in a recent meta-analysis targeting the adult oncology population specifically, Porta-Sanchez et al showed the prevalence of significant prolongation of the a QTc of ³500 ms to be £22%.18 In the pediatric population, the group at Mayo clinic also evaluated the risk of QT prolongation in all hospitalized children and determined the prevalence of acquired QT prolongation to be 5%, although
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Table I. Patient population, demographics, and clinical data Characteristics Age (years) Female sex Primary oncologic diagnosis T-cell acute lymphoblastic leukemia Acute myelogenous leukemia Rhabdomyosarcoma Medulloblastoma Lymphoma Sarcoma Wilms’ tumor Other Mean QTc (ms) QT-prolonging medications Furosemide Diphenhydramine Ondansetron Granisetron Hydroxyzine Trimethoprim-sulfamethoxazole Metronidazole Metoclopramide Pentamadine Promethazine Posaconazole Voriconazole Fluconazole Other ³2 QT-prolonging meds Electrolyte abnormalities Hypokalemia (K <3.5 mmol/L) Hypocalcemia (iCal <1.2 mmol/L or serum calcium <8.5 g/dL) Hypomagnesemia (<1.5 mg/dL) Cardiac arrhythmias Torsades de pointes SVT (reentry) Ventricular tachycardia Ectopic atrial tachycardia All-cause mortality
All patients (n = 287)
QTc <500 (n = 262)
QTc ‡ 500 (n = 25)
P value
10.7 6.4 124 (43)
10.6 6.5 109 (42)
11.1 6.4 15 (60)
.08 .09
85 (30) 27 (9) 11 (4)
78 (30) 22 (8) 11 (4)
7 (28) 5 (20) 0 (0)
1.00 .07 .61
202 (70) 448 31
184 (70) 439 23
18 (72) 461 37
.85 <.01
26 (9) 68 (24) 107 (37) 14 (5) 9 (3) 7 (2) 14 (5) 3 (1) 6 (2) 6 (2) 10 (3) 33 (12) 9 (3) 202 (70) 104 (36)
19 (7) 59 (23) 94 (36) 10 (4) 5 (2) 6 (2) 10 (4) 1 (0.4) 5 (2) 6 (2) 9 (3) 25 (10) 5 (2) 184 (70) 88 (34)
7 (28) 9 (36) 13 (52) 4 (16) 4 (16) 1 (4) 4 (16) 2 (8) 1 (4) 0 (0) 1 (4) 8 (32) 4 (16) 18 (72) 16 (64)
<.01 .14 .11 .02 <.01 .48 .02 .02 .42 1.00 .60 <.01 <.01 .85 <.01
58 (20) 85 (30)
45 (17) 72 (27)
13 (52) 13 (52)
<.0001 .01
23 (8) 5 (2) 2 (0.7) 2 (0.7) 1 (0.3) 1 (0.3) 62 (22)
18 (7) 1 (0.4) 0 (0) 0 (0) 0 (0) 0 (0) 56 (21)
5 (20) 5 (19) 2 (8) 2 (8) 1 (4) 1 (4) 6 (24)
.04 <.01 <.01 <.01 .09 .09 .80
SVT, supraventricular tachycardia. Values are number (%) or mean SD. Bolded values indicate P < .05.
they could not demonstrate a mortality or arrhythmia risk owing to the low number of cardiac events.19 In our cohort of hospitalized pediatric oncology patients with ECGs available for review, 9% (25 total patients) were noted to have significant prolongation of the QTc (³500 ms). Although we did not identify an all-cause mortality difference, we did identify
a higher risk of developing torsades with a significant QTc prolongation (³500 ms). Modulation of the cardiac hERG (human ether-a-go-go related gene) potassium channel function, renal or gastrointestinal dysfunction resulting in electrolyte disturbances, and cardiac dysfunction may all play a role in the high prevalence
Table II. Demographic and clinical data in patients with torsades (n = 2) Characteristics Sex Age (years) Diagnoses QTc duration (ms) QT-prolonging medications (n) Electrolytes Potassium (mmol/L) Calcium (mmol/L) Magnesium (mg/dL) Genetic testing for long QT syndrome
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Patient 1
Patient 2
Female 21 Acute lymphoblastic leukemia 639 2 (trimethoprim/sulfamethoxazole, vorinostat)
Female 13 Acute myelogenous leukemia 532 2 (diphenhydramine, ondansetron)
2.9 1.1 2.6 Negative
5 1.3 2.4 Negative
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Table III. Factors associated with QT prolongation of ‡500 ms Univariate analysis
Multivariate analysis
Factors
OR
CI
P value
OR
CI
P value
Age Sex (female) Diagnosis QT-prolonging medications Diphenhydramine (vs no) Ondansetron (vs no) Furosemide (vs no) 1 QT-prolonging medication (vs 0) ³2 QT-prolonging medications (vs 0) Electrolytes Hypokalemia Hypocalcemia Hypomagnesemia
1.05 3.06
0.99-1.11 1.50-6.24
.08 .002
1.05 2.95
0.99-1.11 1.44-6.06
.11 .003
2.41 1.06 1.34 0.33 3.15
1.05-5.55 0.45-2.47 0.44-4.09 0.08-1.44 1.48-6.68
.04 .90 0.34 2.95
0.08-1.49 1.39-6.26
.15 .005
5.07 4.23 1.29
0.43-59.6 1.88-9.50 0.58-2.86
.20 .0005 .54
.14 .003
Only 3 variables were used in multivariable analysis owing to the number of patients in the cohort with a QTc of ³500 ms (n = 27). Hypocalcemia was not used as only a small fraction of patients (n = 111 [38.7% of the total cohort]), had data available for this variable. Bolded values indicate P < 0.05.
of QT prolongation in the critically ill patient.3,6,9,10 A small subset of these patients may have a particular susceptibility to QTc prolongation secondary to subclinical mutations in genes associated with congenital long QT syndrome that can further exacerbate prolongation of the QTc when exposed to QT-prolonging medication.20-22 This unmasking of congenital long QT with QT-prolonging medications has been demonstrated by Sesti et al; they identified several patients with no clinical signs of congenital long QT syndrome before drug exposure who then developed drug-induced long QT syndrome.23 In that series, genetic testing revealed common variations in the KNE2 gene associated with inherited long QT syndrome. Similarly, Weeke et al compared whole exome sequencing in 65 drug-induced patients with long QT to 148 drug-exposed controls and found rare variants in known long QT genes in 37% of these patients.20 In this investigation, we did not have genomic data available, although it is likely that a small subset of the pediatric patients in this series may have a genetic predisposition to prolongation of the QT interval that is further exacerbated with exposure to medications and electrolyte disturbances. As we enter the age of genomics and precision medicine, we may be able to identify patients that are genetically susceptible to drug-induced QTc prolongation and further prevent torsades and life-threatening cardiac events. In the absence of whole exome or genomic sequencing on all patients, identifying and screening patients at risk for torsades and life-threatening events with 12-lead ECGs remains challenging. In the 2010 Joint Scientific Statement from the American Heart Association and American College of Cardiology regarding prevention of torsades de pointes in a hospital setting, factors reportedly associated with the development of torsades included a QTc of ³500 ms, ³1 QT-prolonging medications, heart disease, electrolyte abnormalities, diuretic use, bradycardia, impaired hepatic drug metabolism, advanced age, and female sex.4 Other studies in adults have also demonstrated a 2-fold greater risk of torsades in females compared with males.24-27 In our pediatric cohort, we also identified female sex and use of ³2 QT-
prolonging drugs as factors associated the development of torsades. Although the overall risk of life-threating cardiac arrhythmias was low in our pediatric cohort, selective screening of at-risk hospitalized children with the above risk factors may be warranted to prevent torsades and lifethreatening ventricular arrhythmias. There are several limitations to this investigation and analysis. During this time period, no formal protocol existed to guide clinicians in determining which patients should have screening or monitoring ECGs. Although clinical practice in oncology attendings at this institution was fairly uniform during the study period, the frequency of ECG attainment was ultimately limited by the ordering clinician’s discretion, likely affected by patient factors including history of arrhythmias or electrolyte abnormalities, QT prolongation, and/or number of concurrent QT-prolonging medications. As a result, there may have been patients with a QTc of ³500 ms that were not identified on a formal 12-lead ECG. We therefore cannot report an exact prevalence of a QTc of ³500 ms in these hospitalized oncology patients. Although 9% of the patients in our series had a QTc of ³500, the patients in this cohort with ECGs could have had more serious illness and been considered a “high-risk” population, resulting in an over-estimation owing to the cohort biases. The same holds true for analyzing the effect of electrolyte abnormalities, as some electrolyte derangements may not have been captured through routine testing on all patients. Patients with significant electrolyte disturbances may have been more likely to have screening ECGs, again potentially biasing the cohort. In addition, when analyzing the prevalence of torsades, brief, nonsustained, and/or clinically silent episodes of torsades may not have triggered a code blue or rapid response and therefore may not have been captured by this study. Clinically identified torsades events were rare in our population, with only 2 patients experiencing events of 287 patients who had an ECG obtained. This small sample size makes it difficult to identify additional risk factors associated with the development of torsades. Finally, genetic testing for ion channelopathies causing congenital long QT syndrome or
QTc Prolongation and Risk of Torsades de Pointes in Hospitalized Pediatric Oncology Patients
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predisposition to more significant lengthening of the QT interval with pharmacologic agents was not performed routinely, and it is unknown whether some of these oncology patients had underlying mutations in any known long QT genes. Further investigation into the direct effects of QTprolonging medications and electrolyte abnormalities on QTc lengthening and the corresponding risk of torsades de pointes may be helpful in further guiding clinical decision making for ECG and laboratory surveillance. n Submitted for publication May 7, 2019; last revision received Sep 9, 2019; accepted Oct 9, 2019. Reprint requests: Tiffany R. Lim, MD, C.S. Mott Children’s Hospital, University of Michigan, Department of Cardiology, 1540 E Hospital Dr, Ann Arbor, MI 48109. E-mail: [email protected]
Data Statement Data sharing statement available at www.jpeds.com.
References 1. Buyukavci M, Olgun H, Ceviz N. The effects of ondansetron and granisetron on electrocardiography in children receiving chemotherapy for acute leukemia. Am J Clin Oncol 2005;28:201-4. 2. Pinarli FG, Elli M, Dagdemir A, Baysal K, Acar S. Electrocardiographic findings after 5-HT3 receptor antagonists and chemotherapy in children with cancer. Pediatr Blood Cancer 2006;47:567-71. 3. Roden DM. Drug-induced prolongation of the QT interval. N Engl J Med 2004;350:1013-22. 4. Yap YG, Camm AJ. Drug induced QT prolongation and torsades de pointes. Heart 2003;89:1363-72. 5. Tisdale JE. Drug-induced QT interval prolongation and torsades de pointes: role of the pharmacist in risk assessment, prevention and management. Can Pharm J 2016;149:139-52. 6. Trinkley KE, Page RL 2nd, Lien H, Yamanouye K, Tisdale JE. QT interval prolongation and the risk of torsades de pointes: essentials for clinicians. Curr Med Res Opin 2013;29:1719-26. 7. Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, et al. Prevention of torsade de pointes in hospital settings: a scientific statement from the American Heart Association and the American College of Cardiology Foundation, Endorsed by the American Association of Critical-Care Nurses and the International Society for Computerized Electrocardiology. J Am Coll Cardiol 2010;55: 934-47. 8. Sauer AJ, Moss AJ, McNitt S, Peterson DR, Zareba W, Robinson JL, et al. Long QT syndrome in adults. J Am Coll Cardiol 2007;49:329-37.
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9. Haugaa KH, Bos JM, Tarrell RF, Morlan BW, Caraballo PJ, Ackerman MJ. Institution-wide QT alert system identifies patients with a high risk of mortality. Mayo Clin Proc 2013;88:315-25. 10. Yu H, Zhang L, Liu J, Liu Y, Kowery PR, Zhang Y, et al. Acquired long QT syndrome in hospitalized patients. Heart Rhythm 2017;14:974-8. 11. Bazett HC. An analysis of the time-relations of electrocardiograms. Ann Noninvas Electro 1997;2:177-94. 12. Gennari FJ. Hypokalemia. N Engl J Med 1998;339:451-8. 13. Cardenas-Rivero N, Chernow B, Stoiko MA, Nussbaum SR, Todres ID. Hypocalcemia in critically ill children. J Pediatr 1989;114:946-51. 14. Satur CM, Stubington SR, Jennings A, Newton K, Martin PG, Gebitekin C, et al. Magnesium flux during and after open heart operations in children. Ann Thorac Surg 1995;59:921-7. 15. Dessertenne F. Ventricular tachycardia with 2 variable opposing foci. Arch Mal Coeur Vaiss 1966;59:263-72. 16. Smith WM, Gallagher JJ. “Les torsades de pointes”: an unusual ventricular arrhythmia. Ann Intern Med 1980;93:578-84. 17. Krikler DM, Curry PV. Torsade De Pointes, an atypical ventricular tachycardia. Br Heart J 1976;38:117-20. 18. Porta-Sanchez A, Gilbert C, Spears D, Amir E, Chan J, Nanthakumar K, et al. Incidence, diagnosis, and management of QT prolongation induced by cancer therapies: a systematic review. J Am Heart Assoc 2017;6:007724. 19. Anderson HN, Bos JM, Haugaa KH, Morlan BW, Tarrell RF, Caraballo PJ, et al. Phenotype of children with QT prolongation identified using an institution-wide QT alert system. Pediatr Cardiol 2015;36: 1350-6. 20. Weeke P, Mosley JD, Hanna D, Delaney JT, Shaffer C, Wells QS, et al. Exome sequencing implicates an increased burden of rare potassium channel variants in the risk of drug-induced long QT interval syndrome. J Am Coll Cardiol 2014;63:1430-7. 21. Ramirez AH, Shaffer CM, Delaney JT, Sexton DP, Levy SE, Rieder MJ, et al. Novel rare variants in congenital cardiac arrhythmia genes are frequent in drug-induced torsades de pointes. Pharmacogenomics J 2013;13:325-9. 22. Kaab S, Crawford DC, Sinner MF, Behr ER, Kannankeril PJ, Wilde AA, et al. A large candidate gene survey identifies the KCNE1 D85N polymorphism as a possible modulator of drug-induced torsades de pointes. Circ Cardiovasc Genet 2012;5:91-9. 23. Sesti F, Abbott GW, Wei J, Murray KT, Saksena S, Schwartz PJ, et al. A common polymorphism associated with antibiotic-induced cardiac arrhythmia. Proc Natl Acad Sci U S A 2000;97:10613-8. 24. Drici MD, Clement N. Is gender a risk factor for adverse drug reactions? The example of drug-induced long QT syndrome. Drug Saf 2001;24:57585. 25. Drici MD, Knollmann BC, Wang WX, Woosley RL. Cardiac actions of erythromycin: influence of female sex. JAMA 1998;280:1774-6. 26. Ebert SN, Liu XK, Woosley RL. Female gender as a risk factor for druginduced cardiac arrhythmias: evaluation of clinical and experimental evidence. J Womens Health 1998;7:547-57. 27. Makkar RR, Fromm BS, Steinman RT, Meissner MD, Lehmann MH. Female gender as a risk factor for torsades de pointes associated with cardiovascular drugs. JAMA 1993;270:2590-7.
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rolongation of the QTc interval is frequently identified in hospitalized pediatric oncology patients, often secondary to a combination of factors including antineoplastic and antiemetic medications and electrolyte abnormalities.1-3 Although electrocardiograms (ECGs) are often recommended in these patients for surveillance of the QTc interval, the risk of prolongation of the QTc, life threatening arrhythmias and torsades de pointes (torsades) has not been clearly identified in this population. In hospitalized adults, a QTc interval of ³500 ms has been associated with a higher risk of torsades, a lifethreatening, malignant ventricular arrhythmia, as well as increased overall mortality.4-6 This risk of torsades has not been well-described in the pediatric population.7-10 In this investigation, we sought to determine the prevalence of torsades de pointes in hospitalized pediatric oncology patients, determine the prevalence of marked QT prolongation (a QTc of ³500) in pediatric oncology patients with ECGs, and to assess if a QTc of ³500 ms was associated with a higher risk of torsades de pointes or death. In addition, we sought to identify other factors, including electrolyte abnormalities, number of QT-prolonging medications and/or primary oncologic diagnoses, associated with significant prolongation of the QTc (³500 ms) in this particular at-risk population.
Methods A single-center, retrospective cohort study of hospitalized pediatric oncology patients from January 2014 through August 2016 was performed. This study included all patients £21 years of age admitted to a single, large-volume pediatric oncology service (Lucile Packard Children’s Hospital at Stanford University) with a primary oncologic diagnosis who had an ECG performed for QTc surveillance. During this time period, ECGs were typically performed at the discretion of the pediatric oncology team. Throughout the study period, there were not set institutional guidelines detailing the necessity of an ECG, but common indications and group practice patterns for obtaining an ECG during this time included initiation of a new chemotherapeutic medication or From the Department of Pediatrics; Division of Hematology and Oncology, Lucile Packard Children’s regimen, standard workup for a new oncologic diagnosis, history of QTc prolongaHospital; Division of Cardiology, Lucile Packard Children’s Hospital; and Quantitative Science Unit, tion, use of multiple QT-prolonging medications, significant electrolyte wasting, or Stanford University, Stanford, CA 1
2
3
4
Sponsored in part by a grant from the Stanford Cardiovascular Institute. The authors declare no conflicts of interest.
ECG EF LV MS
Electrocardiogram Ejection fraction Left ventricular Milliseconds
Portions of this study were presented at the American Heart Association’s Scientific Sessions, November 13, 2017, Anaheim, California. 0022-3476/$ - see front matter. ª 2019 Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.jpeds.2019.10.018
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a history of other electrolyte abnormalities. Patients with known long QT syndrome, short QT syndrome, and those with prolongation of the QRS interval of >120 ms were excluded, because these factors would affect the QTc calculations and risk of torsades. Rapid response and code blue records of all hospitalized pediatric oncology patients were reviewed to determine the prevalence of torsades. The following data were obtained and reviewed for each patient: demographics, primary oncologic diagnoses, QTprolonging medications, electrolyte levels obtained within 24 hours of an ECG, ECG data (including QTc), and outcome. QTc measurements were performed by a pediatric electrophysiologist and retrieved from a hospital-wide database. A subset of 10% of the QTc measurements were recalculated by a second pediatric electrophysiologist who was blinded to the subject classification and database QTc values to confirm the validity of the QTc intervals from the database. The QTc interval was measured using the Bazett formula in the standard manner described by Bazett.11 In patients with a QTc of ³500 ms, echocardiogram reports were reviewed and left ventricular (LV) ejection fraction (EF) was recorded from the echocardiogram at the time closest to the time that the ECG of ³500 ms was noted. QT-prolonging medications were defined as those listed in the most commonly used clinical database of QT-prolonging medications, Credible Meds (qtdrugs.org, list date updated as of September 1, 2017). Electrolyte abnormalities were defined as a potassium of <3.5 mmol/L, ionized calcium of <1.2 mmol/L or serum calcium of <8.5 mg/dL, and magnesium of <1.5 mg/dL.4,12-14 Torsades events were classified as >3 beats of polymorphic ventricular tachycardia with characteristic fluctuation of the QRS complex around the electrocardiographic baseline.15-17 Statistical Analyses Categorical variables are expressed as numbers and percentages whereas continuous variables are expressed as mean SD or median (IQR) if not normally distributed. The prevalence of torsades de pointes was determined by dividing the number of patients with documented torsades de pointes by the total number of pediatric oncology patients admitted to the hospital over the same period. The remainder of the analysis focused on those patients in whom an ECG had been obtained during hospitalization. In those patients with an ECG available for review, the number of torsades events in patients with ³1 ECG during admission with a QTc of ³500 ms was compared with those with a QTc of <500 ms using the Fisher exact test to determine if prolongation of the a QTc of ³500 ms was associated with torsades. All-cause mortality was also compared in patients with a QT of <500 ms and a QT of ³500 ms using the Fisher exact test. In addition, in those patients with an ECG available for review, a univariable generalized linear mixed model with a binary distribution and a logit link function was used to determine variables associated with the finding of a QTc of ³500 ms. Variables significantly associated with a QTc prolongation of ³500 ms were 2
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included in a multivariable generalized linear mixed model. All ECGs from the database were confirmed by a pediatric electrophysiologist. To verify the accuracy of the QTc measurements in the database, the Spearman correlation was used to compare repeated measurements performed by a blinded pediatric electrophysiologist to the ECG database with remeasurement of a random sample of 10% of the ECGs. Two-sided P values of <.05 were considered significant. Statistical analysis was performed using SAS version 9 (SAS Institute, Cary, North Carolina) and R version 3.1.3 (R Core Team, Vienna, Austria).
Results Of the 1934 patients admitted to the pediatric oncology service, a total of 1412 ECGs were performed in 287 unique patients (mean age, 10.7 6.3 years; 41% female) (Figure). In those patients who had an ECG performed (n = 287), the mean QTc was 448 31 ms (Table I). The random sampling of ECGs from the database showed strong correlation with reading of a blinded pediatric electrophysiologist (rs of 0.83; P<.001). In patients who had an ECG, the most common primary oncologic diagnoses included T-cell acute lymphoblastic leukemia (n = 85 [35%]), acute myelogenous leukemia (n = 27 [14%]), and rhabdomyosarcoma (n = 11 [4%]). The most common QT-prolonging medications administered to patients included diphenhydramine (n = 68 [24%]) and ondansetron (n = 107 [37%]). A total of 123 rapid responses and code blues occurred in 90 inpatient oncology patients (4.7% of the entire 1934 hospitalized oncology patients) with 6 events (6.7%) secondary to clinically significant cardiac arrhythmias. These arrhythmias included 3 supraventricular tachycardia (2 reentrant supraventricular tachycardia and 1 ectopic atrial tachycardia), 1 ventricular tachycardia, and 2 torsades events. The 2 torsades events occurred in 2 unique patients, yielding a torsades prevalence of 0.1% (2 of 1934 patients) in all inpatient oncology patients during the study period. Of those patients that had an ECG for review (n = 287), the prevalence of torsades was significantly greater in those with a QTc of ³500 ms (8% vs 0%; P<.01) (Table I). In the 2 patients (both females) with torsades events, the QTcs at the time of their events were 532 and 639 ms, respectively (Table II). Both patients experienced cardiopulmonary arrest, required emergent defibrillation, and had multiple episodes of torsades requiring treatment with intravenous magnesium. Patient 1 had a baseline QTc of 488 ms and patient 2 had a baseline QTc of 447 ms. Neither patient had a family history of sudden death or of implantable cardioverter-defibrillator placement. Genetic testing for long QT syndrome was performed in both patients and both were negative, although it is possible that one or both could be gene-negative long QT syndrome. Patient 1 had an echocardiogram 3 days before the arrest with normal LV systolic function with an EF of 72%. After the arrest, the Lim et al
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Figure. Flow diagram of patient cohort including ECGs and RRTs/code blues. SVT, supraventricular tachycardia.
LV systolic function was noted to be mildly diminished with an EF of 49%. Patient 2 had an echocardiogram 3 months before cardiac arrest at the LV systolic function was normal (EF of 62%). Immediately after arresting, the LV systolic function was severely diminished (EF of 15%), although by 1 week after the arrest the LV systolic function was normal (LV EF of 66%). In patients with an ECG during hospitalization (n = 287), a total of 25 patients (8.7%) had ³1 ECG with a QTc of ³500 ms, with a total of 63 ECGs (4.4% of total ECGs) with a QTc of ³500 ms. In univariate analysis, factors associated with a QTc of ³500 ms included female sex, diphenhydramine, the use of ³2 QT-prolonging medications, and hypocalcemia (Table I). On multivariate analysis, female sex and the use of ³2 QT-prolonging medications independently contributed to QT prolongation (Table III). The use of a higher cut-off QTc (such as 550 ms) was considered, although of the 1412 ECGs there were only 16 ECG in 12 unique patients and analysis of this small sample was limited. Echocardiograms were performed in all patients with a QTc of ³500 ms, with all but 2 performed within 3 months of the time their ECG was noted to be ³500 ms. The remaining 2 patients had echocardiograms 4 months after and 5 months before the date of their ECG identifying prolongation of the QTc. All echocardiograms in patients with a QTc of ³500 ms demonstrated normal biventricular function with a mean EF of 64.5 6.5% (mean time from ECG, 23 37 days). All-cause mortality was compared in patients with an ECG and there was no significant difference in all-cause mortality in those patients with a QTc of ³500 ms compared with those with a QTc of <500 ms (13 ³ 500 ms [22%] vs 347 < 500 ms [25%]; P = .96).
Discussion Hospitalized pediatric oncology patients may be particularly susceptible to acquired prolongation of the QTc and life-threatening torsades de pointes.1-3 The use of QTprolonging medications and frequent electrolyte abnormalities in this patient population may predispose patients to significant prolongation of the QTc to >500 ms. In this cohort of hospitalized children from a large tertiary care center, the overall prevalence of torsades was quite low at 0.1%. In this study, we discovered that patients with a significant QTc prolongation of ³500 ms had a higher rate of torsades, were female, and were on ³2 QT-prolonging medications. These findings may help providers assess to risk and develop screening algorithms in this vulnerable population. An association between significant prolongation of the QTc and mortality has been reported in adult populations. In a recent investigation of 41 649 hospitalized adults, Yu et al identified a risk of torsades of 0.7%.10 In that cohort, patients with acquired long QT had a higher risk of syncope and life-threatening arrhythmias. Haugaa et al also recently reported on the Mayo clinic experience with acquired long QT and demonstrated that hospitalized adult patients with prolongation of the QTc and a higher pro-QTc score had higher all-cause mortality.9 The oncology patient population may be a particularly vulnerable population for acquired QTc prolongation, and in a recent meta-analysis targeting the adult oncology population specifically, Porta-Sanchez et al showed the prevalence of significant prolongation of the a QTc of ³500 ms to be £22%.18 In the pediatric population, the group at Mayo clinic also evaluated the risk of QT prolongation in all hospitalized children and determined the prevalence of acquired QT prolongation to be 5%, although
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Table I. Patient population, demographics, and clinical data Characteristics Age (years) Female sex Primary oncologic diagnosis T-cell acute lymphoblastic leukemia Acute myelogenous leukemia Rhabdomyosarcoma Medulloblastoma Lymphoma Sarcoma Wilms’ tumor Other Mean QTc (ms) QT-prolonging medications Furosemide Diphenhydramine Ondansetron Granisetron Hydroxyzine Trimethoprim-sulfamethoxazole Metronidazole Metoclopramide Pentamadine Promethazine Posaconazole Voriconazole Fluconazole Other ³2 QT-prolonging meds Electrolyte abnormalities Hypokalemia (K <3.5 mmol/L) Hypocalcemia (iCal <1.2 mmol/L or serum calcium <8.5 g/dL) Hypomagnesemia (<1.5 mg/dL) Cardiac arrhythmias Torsades de pointes SVT (reentry) Ventricular tachycardia Ectopic atrial tachycardia All-cause mortality
All patients (n = 287)
QTc <500 (n = 262)
QTc ‡ 500 (n = 25)
P value
10.7 6.4 124 (43)
10.6 6.5 109 (42)
11.1 6.4 15 (60)
.08 .09
85 (30) 27 (9) 11 (4)
78 (30) 22 (8) 11 (4)
7 (28) 5 (20) 0 (0)
1.00 .07 .61
202 (70) 448 31
184 (70) 439 23
18 (72) 461 37
.85 <.01
26 (9) 68 (24) 107 (37) 14 (5) 9 (3) 7 (2) 14 (5) 3 (1) 6 (2) 6 (2) 10 (3) 33 (12) 9 (3) 202 (70) 104 (36)
19 (7) 59 (23) 94 (36) 10 (4) 5 (2) 6 (2) 10 (4) 1 (0.4) 5 (2) 6 (2) 9 (3) 25 (10) 5 (2) 184 (70) 88 (34)
7 (28) 9 (36) 13 (52) 4 (16) 4 (16) 1 (4) 4 (16) 2 (8) 1 (4) 0 (0) 1 (4) 8 (32) 4 (16) 18 (72) 16 (64)
<.01 .14 .11 .02 <.01 .48 .02 .02 .42 1.00 .60 <.01 <.01 .85 <.01
58 (20) 85 (30)
45 (17) 72 (27)
13 (52) 13 (52)
<.0001 .01
23 (8) 5 (2) 2 (0.7) 2 (0.7) 1 (0.3) 1 (0.3) 62 (22)
18 (7) 1 (0.4) 0 (0) 0 (0) 0 (0) 0 (0) 56 (21)
5 (20) 5 (19) 2 (8) 2 (8) 1 (4) 1 (4) 6 (24)
.04 <.01 <.01 <.01 .09 .09 .80
SVT, supraventricular tachycardia. Values are number (%) or mean SD. Bolded values indicate P < .05.
they could not demonstrate a mortality or arrhythmia risk owing to the low number of cardiac events.19 In our cohort of hospitalized pediatric oncology patients with ECGs available for review, 9% (25 total patients) were noted to have significant prolongation of the QTc (³500 ms). Although we did not identify an all-cause mortality difference, we did identify
a higher risk of developing torsades with a significant QTc prolongation (³500 ms). Modulation of the cardiac hERG (human ether-a-go-go related gene) potassium channel function, renal or gastrointestinal dysfunction resulting in electrolyte disturbances, and cardiac dysfunction may all play a role in the high prevalence
Table II. Demographic and clinical data in patients with torsades (n = 2) Characteristics Sex Age (years) Diagnoses QTc duration (ms) QT-prolonging medications (n) Electrolytes Potassium (mmol/L) Calcium (mmol/L) Magnesium (mg/dL) Genetic testing for long QT syndrome
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Patient 1
Patient 2
Female 21 Acute lymphoblastic leukemia 639 2 (trimethoprim/sulfamethoxazole, vorinostat)
Female 13 Acute myelogenous leukemia 532 2 (diphenhydramine, ondansetron)
2.9 1.1 2.6 Negative
5 1.3 2.4 Negative
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Table III. Factors associated with QT prolongation of ‡500 ms Univariate analysis
Multivariate analysis
Factors
OR
CI
P value
OR
CI
P value
Age Sex (female) Diagnosis QT-prolonging medications Diphenhydramine (vs no) Ondansetron (vs no) Furosemide (vs no) 1 QT-prolonging medication (vs 0) ³2 QT-prolonging medications (vs 0) Electrolytes Hypokalemia Hypocalcemia Hypomagnesemia
1.05 3.06
0.99-1.11 1.50-6.24
.08 .002
1.05 2.95
0.99-1.11 1.44-6.06
.11 .003
2.41 1.06 1.34 0.33 3.15
1.05-5.55 0.45-2.47 0.44-4.09 0.08-1.44 1.48-6.68
.04 .90 0.34 2.95
0.08-1.49 1.39-6.26
.15 .005
5.07 4.23 1.29
0.43-59.6 1.88-9.50 0.58-2.86
.20 .0005 .54
.14 .003
Only 3 variables were used in multivariable analysis owing to the number of patients in the cohort with a QTc of ³500 ms (n = 27). Hypocalcemia was not used as only a small fraction of patients (n = 111 [38.7% of the total cohort]), had data available for this variable. Bolded values indicate P < 0.05.
of QT prolongation in the critically ill patient.3,6,9,10 A small subset of these patients may have a particular susceptibility to QTc prolongation secondary to subclinical mutations in genes associated with congenital long QT syndrome that can further exacerbate prolongation of the QTc when exposed to QT-prolonging medication.20-22 This unmasking of congenital long QT with QT-prolonging medications has been demonstrated by Sesti et al; they identified several patients with no clinical signs of congenital long QT syndrome before drug exposure who then developed drug-induced long QT syndrome.23 In that series, genetic testing revealed common variations in the KNE2 gene associated with inherited long QT syndrome. Similarly, Weeke et al compared whole exome sequencing in 65 drug-induced patients with long QT to 148 drug-exposed controls and found rare variants in known long QT genes in 37% of these patients.20 In this investigation, we did not have genomic data available, although it is likely that a small subset of the pediatric patients in this series may have a genetic predisposition to prolongation of the QT interval that is further exacerbated with exposure to medications and electrolyte disturbances. As we enter the age of genomics and precision medicine, we may be able to identify patients that are genetically susceptible to drug-induced QTc prolongation and further prevent torsades and life-threatening cardiac events. In the absence of whole exome or genomic sequencing on all patients, identifying and screening patients at risk for torsades and life-threatening events with 12-lead ECGs remains challenging. In the 2010 Joint Scientific Statement from the American Heart Association and American College of Cardiology regarding prevention of torsades de pointes in a hospital setting, factors reportedly associated with the development of torsades included a QTc of ³500 ms, ³1 QT-prolonging medications, heart disease, electrolyte abnormalities, diuretic use, bradycardia, impaired hepatic drug metabolism, advanced age, and female sex.4 Other studies in adults have also demonstrated a 2-fold greater risk of torsades in females compared with males.24-27 In our pediatric cohort, we also identified female sex and use of ³2 QT-
prolonging drugs as factors associated the development of torsades. Although the overall risk of life-threating cardiac arrhythmias was low in our pediatric cohort, selective screening of at-risk hospitalized children with the above risk factors may be warranted to prevent torsades and lifethreatening ventricular arrhythmias. There are several limitations to this investigation and analysis. During this time period, no formal protocol existed to guide clinicians in determining which patients should have screening or monitoring ECGs. Although clinical practice in oncology attendings at this institution was fairly uniform during the study period, the frequency of ECG attainment was ultimately limited by the ordering clinician’s discretion, likely affected by patient factors including history of arrhythmias or electrolyte abnormalities, QT prolongation, and/or number of concurrent QT-prolonging medications. As a result, there may have been patients with a QTc of ³500 ms that were not identified on a formal 12-lead ECG. We therefore cannot report an exact prevalence of a QTc of ³500 ms in these hospitalized oncology patients. Although 9% of the patients in our series had a QTc of ³500, the patients in this cohort with ECGs could have had more serious illness and been considered a “high-risk” population, resulting in an over-estimation owing to the cohort biases. The same holds true for analyzing the effect of electrolyte abnormalities, as some electrolyte derangements may not have been captured through routine testing on all patients. Patients with significant electrolyte disturbances may have been more likely to have screening ECGs, again potentially biasing the cohort. In addition, when analyzing the prevalence of torsades, brief, nonsustained, and/or clinically silent episodes of torsades may not have triggered a code blue or rapid response and therefore may not have been captured by this study. Clinically identified torsades events were rare in our population, with only 2 patients experiencing events of 287 patients who had an ECG obtained. This small sample size makes it difficult to identify additional risk factors associated with the development of torsades. Finally, genetic testing for ion channelopathies causing congenital long QT syndrome or
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predisposition to more significant lengthening of the QT interval with pharmacologic agents was not performed routinely, and it is unknown whether some of these oncology patients had underlying mutations in any known long QT genes. Further investigation into the direct effects of QTprolonging medications and electrolyte abnormalities on QTc lengthening and the corresponding risk of torsades de pointes may be helpful in further guiding clinical decision making for ECG and laboratory surveillance. n Submitted for publication May 7, 2019; last revision received Sep 9, 2019; accepted Oct 9, 2019. Reprint requests: Tiffany R. Lim, MD, C.S. Mott Children’s Hospital, University of Michigan, Department of Cardiology, 1540 E Hospital Dr, Ann Arbor, MI 48109. E-mail: [email protected]
Data Statement Data sharing statement available at www.jpeds.com.
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9. Haugaa KH, Bos JM, Tarrell RF, Morlan BW, Caraballo PJ, Ackerman MJ. Institution-wide QT alert system identifies patients with a high risk of mortality. Mayo Clin Proc 2013;88:315-25. 10. Yu H, Zhang L, Liu J, Liu Y, Kowery PR, Zhang Y, et al. Acquired long QT syndrome in hospitalized patients. Heart Rhythm 2017;14:974-8. 11. Bazett HC. An analysis of the time-relations of electrocardiograms. Ann Noninvas Electro 1997;2:177-94. 12. Gennari FJ. Hypokalemia. N Engl J Med 1998;339:451-8. 13. Cardenas-Rivero N, Chernow B, Stoiko MA, Nussbaum SR, Todres ID. Hypocalcemia in critically ill children. J Pediatr 1989;114:946-51. 14. Satur CM, Stubington SR, Jennings A, Newton K, Martin PG, Gebitekin C, et al. Magnesium flux during and after open heart operations in children. Ann Thorac Surg 1995;59:921-7. 15. Dessertenne F. Ventricular tachycardia with 2 variable opposing foci. Arch Mal Coeur Vaiss 1966;59:263-72. 16. Smith WM, Gallagher JJ. “Les torsades de pointes”: an unusual ventricular arrhythmia. Ann Intern Med 1980;93:578-84. 17. Krikler DM, Curry PV. Torsade De Pointes, an atypical ventricular tachycardia. Br Heart J 1976;38:117-20. 18. Porta-Sanchez A, Gilbert C, Spears D, Amir E, Chan J, Nanthakumar K, et al. Incidence, diagnosis, and management of QT prolongation induced by cancer therapies: a systematic review. J Am Heart Assoc 2017;6:007724. 19. Anderson HN, Bos JM, Haugaa KH, Morlan BW, Tarrell RF, Caraballo PJ, et al. Phenotype of children with QT prolongation identified using an institution-wide QT alert system. Pediatr Cardiol 2015;36: 1350-6. 20. Weeke P, Mosley JD, Hanna D, Delaney JT, Shaffer C, Wells QS, et al. Exome sequencing implicates an increased burden of rare potassium channel variants in the risk of drug-induced long QT interval syndrome. J Am Coll Cardiol 2014;63:1430-7. 21. Ramirez AH, Shaffer CM, Delaney JT, Sexton DP, Levy SE, Rieder MJ, et al. Novel rare variants in congenital cardiac arrhythmia genes are frequent in drug-induced torsades de pointes. Pharmacogenomics J 2013;13:325-9. 22. Kaab S, Crawford DC, Sinner MF, Behr ER, Kannankeril PJ, Wilde AA, et al. A large candidate gene survey identifies the KCNE1 D85N polymorphism as a possible modulator of drug-induced torsades de pointes. Circ Cardiovasc Genet 2012;5:91-9. 23. Sesti F, Abbott GW, Wei J, Murray KT, Saksena S, Schwartz PJ, et al. A common polymorphism associated with antibiotic-induced cardiac arrhythmia. Proc Natl Acad Sci U S A 2000;97:10613-8. 24. Drici MD, Clement N. Is gender a risk factor for adverse drug reactions? The example of drug-induced long QT syndrome. Drug Saf 2001;24:57585. 25. Drici MD, Knollmann BC, Wang WX, Woosley RL. Cardiac actions of erythromycin: influence of female sex. JAMA 1998;280:1774-6. 26. Ebert SN, Liu XK, Woosley RL. Female gender as a risk factor for druginduced cardiac arrhythmias: evaluation of clinical and experimental evidence. J Womens Health 1998;7:547-57. 27. Makkar RR, Fromm BS, Steinman RT, Meissner MD, Lehmann MH. Female gender as a risk factor for torsades de pointes associated with cardiovascular drugs. JAMA 1993;270:2590-7.
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