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1.  The Effect of Oral Methadone on the QTc Interval in Advanced Cancer Patients: A Prospective Pilot Study 
Journal of Palliative Medicine  2010;13(1):33-38.
Abstract
Background
Recent reports suggest that high doses of methadone may prolong QTc interval and occasionally cause torsades de pointes; however, few of these studies involved the palliative care population.
Objective
The purpose of this study was to determine the effect of initiation of methadone on QTc interval in patients with cancer pain seen at the palliative care setting.
Methods
We enrolled 100 patients with cancer in this prospective study. Patients were followed clinically and electrocardiographically for QTc changes at baseline, 2, 4, and 8 weeks. Contributing factors for QTc prolongation such as medications, cardiovascular diseases, and electrolytes disturbances were documented. QTc prolongation was defined as greater than 430 ms in males and greater than 450 ms in females, and significant QTc prolongation was defined as QTc interval greater than 25% increase from baseline or 500 ms or more.
Results
Electrocardiographic (ECG) assessments were available for 100, 64, 41, and 27 patients at baseline, 2-, 4-, and 8-week follow-up, respectively. At baseline prior to initiation of methadone, 28 (28%) patients had QTc prolongation. Clinically significant increase in QTc occurred in only 1 of 64 (1.6%) patients at week 2, and none at weeks 4 and 8. There was no clinical evidence of torsades de pointes, ventricular fibrillation, or sudden death. QTc prolongation was more frequent among patients with increased baseline QTc interval.
Conclusions
Baseline QTc prolongation was common, whereas significant QTc interval 500 ms or more after methadone initiation rarely occurred, with no evidence of clinically significant arrhythmias. This study supports the safety of methadone use for pain control in patients with advanced cancer in the palliative care setting.
doi:10.1089/jpm.2009.0184
PMCID: PMC2939847  PMID: 19824814
2.  Antipsychotic Drug Administration Does Not Correlate with Prolonged Rate-Corrected QT Interval in Children and Adolescents: Results from a Nested Case–Control Study 
Abstract
Background
The rate-corrected QT interval (QTc) prolongation is a risk factor for sudden cardiac death and may be induced by antipsychotic drugs.
Objective
To determine the clinical characteristics associated with QTc prolongation (440 msec or greater) in children and adolescents hospitalized for treatment of psychiatric disorders.
Method
We determined the frequency of baseline prolongation of QTc in 811 psychiatric pediatric inpatients (15.5 ± 2.4 years of age). QTc duration was 440 msec or greater (range 441–481 msec) in 16 patients (1.97%). In a 1:5 nested case–control design, the 16 patients with prolonged QTc were age- and gender-matched with 80 patients with QTc of <421 msec.
Results
Patients with normal and prolonged QTc had similar utilization of antipsychotics (43.8% vs. 40.8%) and daily chlorpromazine equivalents (165 ± 110 vs. 168 ± 218 mg). Hypokalemia (p = 0.009) and obesity (p = 0.032) were more common among patients with prolonged QTc. The correlation between obesity and QTc prolongation was confirmed in logistic regression analysis.
Conclusions
In a large cohort of youth hospitalized for treatment of psychiatric disorders, a prolonged QTc on admission was rare and correlated with the presence of obesity, but not with current use of antipsychotic drugs.
doi:10.1089/cap.2011.0024
PMCID: PMC3157748  PMID: 21823910
3.  Dispersion of QT and QTc interval in healthy children, and effects of sinus arrhythmia on QT dispersion 
Heart  1998;80(1):77-79.
Objective—To determine the normal values of QT and QTc dispersion and the effects of sinus arrhythmia on QT dispersion in healthy children.
Patients and setting—The study was carried out in a university hospital on 372 local schoolchildren (200 male, 172 female), aged seven to 18 years.
Methods—The QT and preceding RR intervals of at least one sinus beat were measured manually in a range of nine to 12 leads on standard 12 lead surface ECGs. The corrected QT interval was computed by the method of Bazett. Dispersion of QT and QTc were defined as (1) the difference between the maximum and minimum QT and QTc intervals occurring in any of the 12 leads (QTD and QTcD), (2) the standard deviation of the QT and QTc interval in the measurable leads (QT-SD and QTc-SD).
Results—There was no significant difference in QT, QTc, and RR dispersion between girls and boys. Overall 53% of children had sinus arrhythmia. Although QTD and QT-SD were not affected by sinus arrhythmia, both QTcD and QTc-SD were significantly greater in children with sinus arrhythmia than in those without (QTcD: 52.9 (17.4) v 40.9 (13.1); QTc-SD: 17.5 (5.9) v 13.2 (4.0); p < 0.001).
Conclusions—As calculation of QTc dispersion is affected by sinus arrhythmia, which is common in childhood, we suggest that QT dispersion should not be corrected for heart rate in children.

 Keywords: QT dispersion;  heart rate;  children;  sinus arrhythmia
PMCID: PMC1728755  PMID: 9764065
4.  Analysis of Orders for QTc-Prolonging Medication for Intensive and Cardiac Care Unit Patients with Pre-existing QTc Prolongation (QTIPPP Study) 
Background:
A prolonged QTc interval on electrocardiography is often used as a surrogate marker for ventricular arrhythmia. Medications that can prolong the QTc interval may increase the risk of cardiac complications, although the exact incidence is unknown. It is reasonable to assume that administration of QTc-prolonging medications to patients with pre-existing QTc prolongation will further increase the risk of cardiac consequences. This study was designed to examine the frequency of prescription of QTc-prolonging medications in such patients and to explore the potential for clinical pharmacists to minimize the associated risks.
Objectives:
The primary objective was to identify the number of patients with pre-existing prolonged QTc interval for whom QTc-prolonging medications were prescribed, from among all patients with orders for QTc-prolonging medications. The secondary objectives were to determine patterns of intervention by clinical pharmacists in these cases and to document any further QTc prolongation and occurrence of cardiac events.
Methods:
A prospective, observational, quality assessment study was conducted over 4.5 months. Adult patients admitted to beds with cardiac monitoring by telemetry for whom one or more QTc-prolonging medications were ordered were eligible for inclusion. Patients were included if the QTc interval was longer than 450 ms on the most recent 12-lead electrocardiogram before the QTc-prolonging medication was ordered. These patients were followed to identify outcomes of interest after administration of QTc-prolonging medication.
Results:
Overall, a QTc-prolonging medication was prescribed for 207 patients. Of these, 53 patients (26%) had pre-existing prolongation of the QTc interval. Clinical pharmacists made recommendations related to 28 medication orders; of these, 16 (57%) were accepted by the physician. Fifty-one (96%) of the 53 patients received at least one dose of QTc-prolonging medication and were monitored daily for complications. Nine (18%) of the 51 patients who underwent daily monitoring experienced at least one cardiac event.
Conclusions:
A substantial proportion (26%) of patients for whom QTc-prolonging medications were prescribed had pre-existing prolongation of the QTc interval. Clinical pharmacists may have a role in reducing the risk of subsequent complications.
PMCID: PMC3242574  PMID: 22479096
QTc interval; torsade de pointes; pre-existing prolongation; pharmacist practice; intervalle QTc; torsade de pointes; allongement préexistant de l’intervalle QTc; pratique du pharmacien
5.  QTc Interval Prolongation Predicts Postoperative Mortality in Heart Failure Patients Undergoing Surgical Revascularization 
QTc interval prolongation is associated with increased mortality rates in patients with advanced heart failure. We investigated the predictive value of prolonged QTc interval in 567 patients with heart failure who were undergoing coronary artery bypass graft surgery. The patients were in New York Heart Association class III or IV, with left ventricular ejection fractions of 0.40 or less. Before surgery, the QT interval duration was measured in leads II and V4 of the standard electrocardiogram and corrected by use of the Bazett formula. The QTc interval was prolonged (>440 msec) in 243 patients (43%) and normal in 324 (57%). The 2 study groups—prolonged QTc versus normal QTc—did not differ in terms of age (62 ± 11 years vs 64 ± 10 years, P =0.65), sex (80% male vs 76% male, P =0.31), ejection fraction (0.29 ± 0.08 vs 0.29 ± 0.09, P =0.72), hypertension (82% vs 78%, P =0.34), or diabetes (11% vs 7%, P =0.10).
Within 1 month after coronary artery bypass grafting, 22 of 243 patients (9.1%) in the prolonged QTc group died, compared with 5 of 324 in the normal QTc group (1.5%) (P =0.0001). QTc interval prolongation was the only independent predictor of postoperative mortality on multivariate analysis (P =0.002). We conclude that patients with heart failure and preoperative QTc interval prolongation have increased mortality rates after coronary artery bypass grafting.
PMCID: PMC1413604  PMID: 16572860
Coronary disease/surgery; electrocardiography; heart failure; long QT syndrome; mortality; myocardial revascularization; prognosis; risk factors; treatment outcome
6.  QTc interval prolongation in HIV-infected patients: a case–control study by 24-hour Holter ECG recording 
Background
Aim of the study was to assess QTc interval by a 24-hour ECG recording in a group of HIV-infected individuals with a basal prolonged QTc. The risk factors associated with QTc prolongation and the indices of cardiovascular autonomic control were also evaluated.
Methods
A case–control study was performed using as cases 32 HIV-infected patients with prolonged (>440 msec) QTc interval as assessed by Holter ECG, and as controls 64 HIV-infected subjects with normal QTc interval. Autonomic function was evaluated by heart rate variability analysis during 24-hour recording.
Results
Duration of HIV disease was significantly longer among cases than among controls (p=0.04). Waist/hip ratio was also higher among cases than among controls (p=0.05). Frequency domain analysis showed the absence of physiologic decrease of low frequency (LF) in the night period in both cases and controls. The LF night in cases showed a statistically significant reduction when compared with controls (p=0.007).
Conclusions
In our study group, QTc interval prolongation was associated with a longer duration of HIV infection and with a greater waist/hip ratio. HIV patients with QTc interval prolongation and with a longer duration of HIV infection were more likely to have an impairment of parasympathetic and sympathetic cardiac component.
doi:10.1186/1471-2261-12-124
PMCID: PMC3543166  PMID: 23259665
Cardiac autonomic function; HIV; Holter ECG; QTc interval
7.  Determinants of Prolonged QT Interval and Their Contribution to Sudden Death Risk in Coronary Artery Disease: The Oregon Sudden Unexpected Death Study 
Circulation  2009;119(5):663-670.
Background
In a recent cohort study, prolongation of the corrected QT interval (QTc) was associated with independent, increased risk of sudden cardiac death (SCD). We evaluated determinants of prolonged QTc as well as the relationship of prolonged QTc to SCD risk among patients with coronary artery disease (CAD) in the general population.
Methods and Results
A case-control design was utilized. Cases were SCDs with coronary artery disease (CAD) among a metropolitan area of 1,000,000 residents (2002-06) and controls were area residents with CAD, but no history of SCD. All cases were required to have an ECG suitable for QTc analysis prior and unrelated to the occurrence of SCD. A total of 373 cases and 309 control subjects met criteria for analysis. Mean QTc was significantly longer in cases vs. controls (450±45 vs. 433±37 ms, p<0.0001). In a multivariate model, gender, diabetes mellitus and QTc prolonging drugs were significant determinants of QTc prolongation in control subjects. In a logistic regression model predicting SCD, diabetes [OR 1.97 (1.32 – 2.96)] and use of QTc prolonging drugs [OR 2.90 (1.92 – 4.37)] were significant predictors of SCD among subjects with normal or borderline QTc. However, abnormally prolonged QTc in the absence of diabetes and QT-prolonging medications was the strongest predictor of SCD [OR 5.53, (3.20-9.57)].
Conclusions
Diabetes and QTc-affecting drugs determined QTc prolongation and were predictors of SCD in CAD. However, idiopathic abnormal QTc prolongation was associated with five-fold increased odds of SCD. A continued search for novel determinants of QTc prolongation, such as genomic factors, is likely to enhance risk stratification for SCD in CAD.
doi:10.1161/CIRCULATIONAHA.108.797035
PMCID: PMC2734945  PMID: 19171855
Death; sudden; epidemiology; population; ventricular; repolarization; risk stratification
8.  Pathogenesis of Lethal Cardiac Arrhythmias in Mecp2 Mutant Mice: Implication for Therapy in Rett Syndrome 
Science translational medicine  2011;3(113):113ra125.
Rett Syndrome is a neurodevelopmental disorder typically caused by mutations in Methyl-CpG-Binding Protein 2 (MECP2) in which 26% of deaths are sudden and of unknown cause. To explore the hypothesis that these deaths may be due to cardiac dysfunction, we characterized the electrocardiograms (ECGs) in 379 people with Rett syndrome and found that 18.5% show prolongation of the corrected QT interval (QTc), indicating a repolarization abnormality that can predispose to the development of an unstable fatal cardiac rhythm. Male mice lacking MeCP2 function, Mecp2Null/Y, also have prolonged QTc and show increased susceptibility to induced ventricular tachycardia. Female heterozygous null mice, Mecp2Null/+, show an age-dependent prolongation of QTc associated with ventricular tachycardia and cardiac-related death. Genetic deletion of MeCP2 function in only the nervous system was sufficient to cause long QTc and ventricular tachycardia, implicating neuronally-mediated changes to cardiac electrical conduction as a potential cause of ventricular tachycardia in Rett syndrome. The standard therapy for prolonged QTc in Rett syndrome, β-adrenergic receptor blockers, did not prevent ventricular tachycardia in Mecp2Null/Y mice. To determine whether an alternative therapy would be more appropriate, we characterized cardiomyocytes from Mecp2Null/Y mice and found increased persistent sodium current, which was normalized when cells were treated with the sodium channel-blocking anti-seizure drug phenytoin. Treatment with phenytoin reduced both QTc and sustained ventricular tachycardia in Mecp2Null/Y mice. These results demonstrate that cardiac abnormalities in Rett syndrome are secondary to abnormal nervous system control, which leads to increased persistent sodium current. Our findings suggest that treatment in people with Rett syndrome would be more effective if it targeted the increased persistent sodium current in order to prevent lethal cardiac arrhythmias.
doi:10.1126/scitranslmed.3002982
PMCID: PMC3633081  PMID: 22174313
Rett Syndrome; autonomic nervous system; arrhythmia; ventricular tachycardia; QT interval
9.  Retrospective analysis of low-dose methadone and QTc prolongation in chronic pain patients 
Korean Journal of Anesthesiology  2010;58(4):338-343.
Background
Methadone is a synthetic opioid that is widely used for the treatment of chronic pain. The association between methadone treatment and QT interval prolongation or which can lead to torsades de pointes has been confirmed with larger studies on high dose methadone. The aim of this study was to determine the effect of methadone on the QTc interval in patients, whether the daily dose of methadone should be lower than what has been previously investigated.
Methods
A total of 130 patients were included, with 90 patients in the methadone group and 40 patients in the control group. For each ECG, heart rate, QT interval and corrected QT (QTc) interval were recorded. The patient demographics, methadone dose and serum level, duration of methadone use and past medical history were collected.
Results
The QTc interval was significantly longer in the treatment group than in the control group (443 ± 30.0 ms versus 408 ± 28.0 ms, respectively, P < 0.0001) and more patients in the treatment group had a QTc interval greater than 450 ms (36.7% versus 7.5%, respectively, P = 0.0005). The QTc interval was not associated with methadone dose P = 0.9278), serum level (P = 0.2256) or duration of treatment (P = 0.1822).
Conclusions
This study has shown that methadone use is associated with longer QTc intervals, even among patients with daily doses of less than 80 mg. In this study, no correlation was found between QTc duration and methadone dose, serum levels or duration of use. However, the magnitude of the QTc interval was associated with female gender and the use of antidepressants.
doi:10.4097/kjae.2010.58.4.338
PMCID: PMC2876853  PMID: 20508789
Methadone; Opioid; QT interval
10.  Prevalence and clinical correlates of QT prolongation in patients with hypertrophic cardiomyopathy 
European Heart Journal  2011;32(9):1114-1120.
Aims
Congenital or acquired QT prolongation is a risk factor for life-threatening arrhythmias. In patients with hypertrophic cardiomyopathy (HCM), the QT interval may be intrinsically prolonged. However, the prevalence, cause, and significance of QT prolongation among patients with HCM are unknown.
Methods and results
After exclusion of patients on QT-prolonging drugs, a blinded, retrospective analysis of electrocardiograms, echocardiograms, and genotype status in 479 unrelated patients with HCM [201 females, age at diagnosis 41 ± 18 years, maximal left ventricular wall thickness (MLVWT) 22 ± 6 mm] from two independent centres was performed. The mean QTc was 440 ± 28 ms. The QTc exceeded 480 ms in 13% of patients. Age, gender, family history of HCM or sudden cardiac arrest, and genotype status had no association with QTc. Patients with a QTc over 480 ms were more symptomatic at diagnosis (P < 0.001), had a higher MLVWT (P = 0.03), were more obstructive (P < 0.001), and were more likely to have undergone septal reduction therapy (P = 0.02). There was a weak but significant direct linear relationship between QTc and peak outflow gradient (r2 = 0.05, P < 0.0001).
Conclusions
Compared with <1 in 200 otherwise healthy adults, QT prolongation (QTc > 480 ms) was present in 1 out of 8 patients with HCM. The QTc was partly reflective of the degree of cardiac hypertrophy and left ventricular outflow tract obstruction. Because of its pro-arrhythmic potential and its potential relevance to management and risk stratification, routine QTc assessment should be performed in patients with HCM, particularly when concomitant use of QT-prolonging medications is considered.
doi:10.1093/eurheartj/ehr021
PMCID: PMC3086898  PMID: 21345853
Long QT syndrome; Hypertrophic cardiomyopathy; Sudden death; Ventricular arrhythmia; QT interval
11.  Effect of Dexmedetomidine on the Corrected QT and Tp-e Intervals during Spinal Anesthesia 
Yonsei Medical Journal  2014;55(2):517-522.
Purpose
The aim of this study is to evaluate the effect of dexmedetomidine on corrected QT (QTc) and Tp-e intervals in patients undergoing spinal anesthesia.
Materials and Methods
We studied 50 patients who were scheduled to undergo spinal anesthesia before orthopedic surgeries. Patients were allocated to receive either an infusion of dexmedetomidine or normal saline after spinal anesthesia.
Results
QTc intervals were significantly prolonged after spinal anesthesia, and the prolonged QTc interval returned to baseline values 10 minutes after either normal saline or dexmedetomidine administration in both groups. The QTc interval values after dexmedetomidine administration were significantly shorter compared to the QTc interval values just before dexmedetomidine administration.
Conclusion
Dexmedetomidine could promote the return of a prolonged QTc interval induced by spinal anesthesia and might be helpful in patients who have a prolonged QTc interval.
doi:10.3349/ymj.2014.55.2.517
PMCID: PMC3936610  PMID: 24532526
Dexmedetomidine; electrocardiogram; spinal anesthesia
12.  False sense of safety by daily QTc interval monitoring during methadone IVPCA titration in a patient with chronic pain 
Journal of Pain Research  2013;6:375-378.
It has been proposed that some deaths attributed to methadone are related to prolongation of the QTc interval; however, there are no clear recommendations on electrocardiogram (ECG) monitoring in patients undergoing intravenous methadone infusion. This is a report on a patient receiving methadone intravenous patient-controlled analgesia titration for the treatment of chronic pain. Initially, her daily ECGs showed QTc intervals within normal limits; however, she experienced a rapid increase in QTc interval from 317 ms to 784 ms within a 24-hour period after methadone had been discontinued for excessive sedation. QTc interval greater than 500 ms is considered to be high risk for the fatal arrhythmia Torsades de Pointes. Daily ECGs did not detect a gradual increase in the QTc interval that would have alerted the medical staff of the need to decrease or stop the methadone before reaching a prolonged QTc interval associated with cardiotoxicity. In selected cases where aggressive methadone titration is required, more intensive monitoring, such as telemetry or ECG determinations every 12 hours, might help detect changes in QTc interval duration that might otherwise be missed by daily ECG determinations.
doi:10.2147/JPR.S42487
PMCID: PMC3666877  PMID: 23723717
methadone; QTc prolongation; opioids; opioid side effects; IVPCA methadone
13.  The association of serum testosterone levels and ventricular repolarization 
It is assumed that testosterone is an important regulator of gender-related differences in ventricular repolarization. Therefore, our aim was to study whether serum levels of testosterone are associated with QTc, QT and RR interval variation. Setting: two independent population-based cohort studies. Participants: 445 male participants (≥55 years) from the Rotterdam study cohort and 1,428 male participants from the study of health in Pomerania (SHIP) with an electrocardiogram who were randomly sampled for assessment of serum testosterone at baseline, after exclusion of participants with testosterone altering drugs, QTc prolonging drugs or dig(it)oxin, left ventricular hypertrophy and left and right bundle branch block. Endpoints: length of the QTc, QT and RR intervals. Analysis: linear regression model, adjusted for the two individual studies and a pooled analysis of both studies. The pooled analysis of the Rotterdam study and SHIP showed that the QTc interval gradually decreased among the tertiles (P value for trend 0.024). The third tertile of serum testosterone was associated with a lower QTc interval compared to the first tertile [−3.4 ms (−6.5; −0.3)]. However, the third tertile of serum testosterone was not associated with a lower QT interval compared to the first tertile [−0.7 ms (−3.1; 1.8)]. The RR interval gradually increased among the tertiles (P value for trend 0.002) and the third tertile of serum testosterone showed an increased RR interval compared to the first tertile [33.5 ms (12.2; 54.8)]. In the pooled analysis of two population-based studies, serum testosterone levels were not associated with the QT interval, which could be due to a lack of power. Lower QTc intervals in men with higher serum testosterone levels could be due to the association of serum testosterone with prolongation of the RR interval.
doi:10.1007/s10654-009-9406-z
PMCID: PMC2807939  PMID: 19957021
Serum testosterone; Ventricular repolarization; QTc interval; RR interval
14.  QT Prolongation Complicated with Torsades de Pointes in Prosthetic Mitral Valve Endocarditis: A Case Report 
Case Reports in Medicine  2012;2012:574923.
We present the case of a 49-year-old male patient with prosthetic mitral valve endocarditis associated with QT prolongation and torsades de pointes. He was asymptomatic until the end of January 2012, when he was admitted to our hospital emergency unit because of syncope, fever, and suspicion of endocarditis. Cardiologic evaluation was requested and the transthoracic (TTE) and transesophageal (TEE) echocardiograms revealed vegetations on the prosthetic mitral valve. All cultures were positive for methicillin-sensitive Staphylococcus aureus. The corrected QT (QTc) interval was markedly prolonged upon admission (QTc 540 ms). He experienced torsades de pointes (TdP) several times and he was recovered after bystander cardiopulmonary resuscitation. The clinical course and the long QTc interval with deep inverted T wave were completely normalized 4 weeks after. He continued on triple antibiotic therapy for 45 days with a good revolution. The clinical features and the possible mechanisms of QT prolongation (inflammation, infection) of this patient are discussed.
doi:10.1155/2012/574923
PMCID: PMC3472411  PMID: 23093971
15.  Left cardiac sympathectomy prevents exercise-induced QTc prolongation in congenital long QT syndrome 
Congenital long QT syndrome (LQTS) is a group of ion channel disorders of ventricular myocytes caused by mutations of genes that encode these ion channels. The main clinical features of LQTS are syncope, cardiac arrest and QT prolongation on body surface electrocardiogram. The present study reports on the case of a 42-year-old female patient with a 10-year history of LQTS and syncopal attacks resistant to beta-blocker therapy. Treadmill exercise testing in this patient increased the corrected QT interval (QTc) from 0.48 s to 0.54 s and reduced the amplitude of the T wave. Left cardiac sympathectomy did not affect the resting heart rate or QTc but it prevented exercise-induced T wave reduction and QTc prolongation. Therefore, sympathetic activation plays a key role in exerciseinduced QT prolongation and changes in T wave morphology in patients with congenital LQTS.
PMCID: PMC2716198  PMID: 19644586
Cardiac electrophysiology; Cardiac sympathectomy; Exercise test; Long QT syndrome; Syncope
16.  Highly abnormal thermotests in familial dysautonomia suggest increased cardiac autonomic risk 
OBJECTIVE—Patients with familial dysautonomia have an increased risk of sudden death. In some patients with familial dysautonomia, sympathetic cardiac dysfunction is indicated by prolongation of corrected QT (QTc) interval, especially during stress tests. As many patients do not tolerate physical stress, additional indices are needed to predict autonomic risk. In familial dysautonomia there is a reduction of both sympathetic neurons and peripheral small nerve fibres which mediate temperature perception. Consequently, quantitative thermal perception test results might correlate with QTc values. If this assumption is correct, quantitative thermotesting could contribute to predicting increased autonomic risk.
METHODS—To test this hypothesis, QTc intervals were determined in 12 male and eight female patients with familial dysautonomia, aged 10 to 41 years (mean 21.7 (SD 10.1) years), in supine and erect positions and postexercise and correlated with warm and cold perception thresholds assessed at six body sites using a Thermotest.
RESULTS—Due to orthostatic presyncope, six patients were unable to undergo erect and postexercise QTc interval assessment. The QTc interval was prolonged (>440 ms) in two patients when supine and in two additional patients when erect and postexercise. Supine QTc intervals correlated significantly with thermal threshold values at the six body sites and with the number of sites with abnormal thermal perception (Spearman's rank correlation p<0.05). Abnormal Thermotest results were more frequent in the four patients with QTc prolongation and the six patients with intolerance to stress tests.
CONCLUSION—The results suggest that impaired thermal perception correlates with cardiac sympathetic dysfunction in patients with familial dysautonomia. Thus thermotesting may provide an alternative, albeit indirect, means of assessing sympathetic dysfunction in autonomic disorders.


PMCID: PMC2170226  PMID: 9728945
17.  Analysis of Relationship between Levofloxacin and Corrected QT Prolongation Using a Clinical Data Warehouse 
Objective
The aim of this study was to examine whether or not levofloxacin has any relationship with QT prolongation in a real clinical setting by analyzing a clinical data warehouse of data collected from different hospital information systems.
Methods
Electronic prescription data and medical charts from 3 different hospitals spanning the past 9 years were reviewed, and a clinical data warehouse was constructed. Patients who were both administrated levofloxacin and given electrocardiograms (ECG) were selected. The correlations between various patient characteristics, concomitant drugs, corrected QT (QTc) prolongation, and the interval difference in QTc before and after levofloxacin administration were analyzed.
Results
A total of 2,176 patients from 3 different hospitals were included in the study. QTc prolongation was found in 364 patients (16.7%). The study revealed that age (OR 1.026, p < 0.001), gender (OR 0.676, p = 0.007), body temperature (OR 1.267, p = 0.024), and cigarette smoking (OR 1.641, p = 0.022) were related with QTc prolongation. After adjusting for related factors, 12 drugs concomitant with levofloxacin were associated with QTc prolongation. For patients who took ECGs before and after administration of levofloxacin during their hospitalization (n = 112), there was no significant difference in QTc prolongation.
Conclusions
The age, gender, body temperature, cigarette smoking and various concomitant drugs might be related with QTc prolongation. However, there was no definite causal relationship or interaction between levofloxacin and QTc prolongation. Alternative surveillance methods utilizing the massive accumulation of electronic medical data seem to be essential to adverse drug reaction surveillance in future.
doi:10.4258/hir.2011.17.1.58
PMCID: PMC3092995  PMID: 21818458
Long QT Syndrome; Ofloxacin; Data Mining; Product Surveillance; Post-marketing; Hospital Information Systems
18.  Multivariate analysis of risk factors for QT prolongation following subarachnoid hemorrhage 
Critical Care  2003;7(3):R7-R12.
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.
PMCID: PMC270671  PMID: 12793884
female; hypokalemia; multivariate analysis; QT prolongation; subarachnoid hemorrhage
19.  Highly-Automated QT Measurement Techniques in Seven Thorough QT Studies Implemented under ICH E14 Guidelines 
Thorough QT (TQT) studies are designed to evaluate potential effect of a novel drug on the ventricular repolarization process of the heart using QTc prolongation as a surrogate marker for torsades de pointes. The current process to measure the QT intervals from the thousands of electrocardiograms is lengthy and expensive. In this study, we propose a validation of a highly-automatic QT interval measurement (HA-QT) method. We applied a HA-QT measurement method to the data from seven TQT studies. We investigated both the placebo and baseline-adjusted QTc interval prolongation induced by moxifloxacin (positive control drug) at the time of expected peak concentration. The comparative analysis evaluated the time course of moxifloxacin-induced QTc prolongation in one study as well. The absolute HA-QT data were longer than the FDA-approved QTc data. This trend was not different between ECGs from the moxifloxacin and placebo arms: 9.6±24msec on drug and 9.8±25msec on placebo. The difference between methods vanished when comparing the placebo-baseline-adjusted QTc prolongation (1.4±2.8msec, p=0.4). The differences in precision between the HA-QT and the FDA-approved measurements were not statistically different from zero: 0.1±0.1msec (p=0.7). Also, the time course of the moxifloxacin-induced QTc prolongation adjusted for placebo was not statistically different between measurements methods.
doi:10.1111/j.1542-474X.2010.00402.x
PMCID: PMC3076006  PMID: 21251129
thorough QT study; drug cardiotoxicity; moxifloxacin; QT interval; electrocardiogram; drug safety
20.  Corrected QT Interval in Children With Brain Death 
Pediatric Cardiology  2010;31(7):1064-1069.
Prolongation of the QT interval is a well-documented finding in adults with severe brain injury. However, QT prolongation has not been well documented in the pediatric population with brain injury. Our objective was to determine the range of QT intervals in children with the diagnosis of brain death, hypothesizing that the QT interval corrected for heart rate (QTc) is longer in this population than in a normal population. All previously healthy children (<18 years) dying in our hospital from 1995 to 2007 with a diagnosis of brain death and at least one electrocardiogram (ECG) with normal anatomy by echocardiogram were included. Admission details, past medical and family history, demographic data, and laboratory data were collected. The QT and preceding RR intervals from three sinus beats on a standard 12-lead ECG were measured. The QTc was calculated with the Bazett method, and the values were averaged. Thirty-seven patients met inclusion criteria. Five had event histories concerning for possible underlying rhythm disturbances; data analysis was performed with and without these patients. The QTc data were normally distributed. The mean (SD) QTc for the entire cohort was 452 (61) ms. Excluding the five patients, it was 449 (62) ms. On multivariate analysis, sex (QTc female < male) and hypokalemia were associated with QTc prolongation. QTc in children with brain death is normally distributed but significantly longer than QTc in normal children. Until rapid genetic testing for channelopathies is universally available, our findings suggest that potential pediatric cardiac donors with isolated prolongation of the QTc in this setting may be acceptable in the absence of other exclusionary criteria.
doi:10.1007/s00246-010-9766-x
PMCID: PMC2948159  PMID: 20725721
Brain death; Brain injury; Electrocardiographic changes; Long QT
21.  Prolongation of QTc interval and risk of stroke: the REasons for Geographic and Racial Differences in Stroke (REGARDS) 
Objective
To examine the association between prolongation of heart rate–corrected QT interval (QTc) with incident stroke.
Background
Unlike cardiovascular morbidity and mortality, little is known about the relationship between QTc and risk of stroke.
Methods
A total of 27,411 participants aged ≥ 45 years without prior stroke from the REasons for Geographic and Racial Differences in Stroke (REGARDS) study were included in this analysis. QTc was calculated using Framingham formula (QTcFram). Stroke cases were identified and adjudicated during up to 8.2 years of follow-up (median 5.1 years).
Results
The risk of incident stroke in study participants with prolonged QTcFram was almost three times the risk in those with normal QTcFram [HR (95% CI): 2.88 (2.12, 3.92), p<0.0001]. After adjustment for demographics (age, race, sex), traditional stroke risk factors (antihypertensive medication use, systolic blood pressure, current smoking, diabetes, left ventricular hypertrophy, atrial fibrillation, prior cardiovascular disease), warfarin use, aspirin use, QRS duration and use of QT-prolonging drugs, the risk of stroke remained significantly high [HR (95% CI): 1.67 (1.16, 2.41), p=0.0061)], and was consistent across several subgroups of REGARDS participants. Similar results were obtained when the risk of stroke was estimated per 1-standard deviation increase in QTcFram, [HR (95% CI): 1.12 (1.03, 1.21), p=0.0053 in multivariable-adjusted model], and when other QTc correction formulas including Hodge’s, Bazett’s and Fridericia’s were used.
Conclusions
QTc prolongation is associated with a significantly increased risk of incident stroke independent of traditional stroke risk factors. Examining the risk of stroke associated with QT-prolonging drugs may be warranted.
doi:10.1016/j.jacc.2012.01.025
PMCID: PMC3345207  PMID: 22497826
QTc; stroke; electrocardiogram; QT-prolonging drugs; REGARDS
22.  QT interval and antidepressant use: a cross sectional study of electronic health records 
Objective To quantify the impact of citalopram and other selective serotonin reuptake inhibitors on corrected QT interval (QTc), a marker of risk for ventricular arrhythmia, in a large and diverse clinical population.
Design A cross sectional study using electrocardiographic, prescribing, and clinical data from electronic health records to explore the relation between antidepressant dose and QTc. Methadone, an opioid known to prolong QT, was included to demonstrate assay sensitivity.
Setting A large New England healthcare system comprising two academic medical centres and outpatient clinics.
Participants 38 397 adult patients with an electrocardiogram recorded after prescription of antidepressant or methadone between February 1990 and August 2011.
Main outcome measures Relation between antidepressant dose and QTc interval in linear regression, adjusting for potential clinical and demographic confounding variables. For a subset of patients, change in QTc after drug dose was also examined.
Results Dose-response association with QTc prolongation was identified for citalopram (adjusted beta 0.10 (SE 0.04), P<0.01), escitalopram (adjusted beta 0.58 (0.15), P<0.001), and amitriptyline (adjusted beta 0.11 (0.03), P<0.001), but not for other antidepressants examined. An association with QTc shortening was identified for bupropion (adjusted beta 0.02 (0.01) P<0.05). Within-subject paired observations supported the QTc prolonging effect of citalopram (10 mg to 20 mg, mean QTc increase 7.8 (SE 3.6) ms, adjusted P<0.05; and 20 mg to 40 mg, mean QTc increase 10.3 (4.0) ms, adjusted P<0.01).
Conclusions This study confirmed a modest prolongation of QT interval with citalopram, and identified additional antidepressants with similar observed risk. Pharmacovigilance studies using electronic health record data may be a useful method of identifying potential risk associated with treatments.
doi:10.1136/bmj.f288
PMCID: PMC3558546  PMID: 23360890
23.  QTc and QTd in Children with Type 1 Diabetes Mellitus during Diabetic Ketoacidosis 
ISRN Pediatrics  2012;2012:619107.
Cardiac arrest has been described in children with diabetic ketoacidosis (DKA). Aim. To evaluate QTc and QTd in type 1 diabetic children with DKA. Methods. Twelve-lead ECG was done to 30 type 1 diabetic children with DKA at presentation and recovery. Corrected QT interval and QT dispersion (QTd) were assessed. Results. QTc and QTd mean values were significantly decreased in patients after than before DKA recovery (P < 0.01). Procedure. Sixteen patients (53, 3%) had prolonged QTc during DKA (range 451–538 ms) that dropped to one patient after recovery, his QTc (453 ms) returned to normal 5 days after hospital discharge. Nineteen patients (63.3%) had prolonged QTd (>50 ms) that dropped to three after recovery. The fact that three patients had normal QTc but prolonged QTd increases the privilege of QTd over QTc as a better marker for cardiac risk in those patients. Anion gap was significantly associated with QTc and QTd prolongation (P < 0.0001). Patients had no electrolyte abnormalities or hypoglycemia to account for QTc or QTd prolongation. Conclusion. Prolonged QTc and QTd frequently occur in DKA positively correlated to ketosis. Cardiac monitoring for patients with DKA is mandatory.
doi:10.5402/2012/619107
PMCID: PMC3503306  PMID: 23209932
24.  Evaluation of QT Interval in β Thalassemia Major Patients in Comparison with Control Group 
Background:
Cardiac complications are the primary cause of death in patients with b thalassemia major. QTc interval is an indicator of variability of ventricular repolarization and is supposed to be prominent in high risk patients. The aim of this investigation was to evaluate the relationship between QTc interval in β thalassemia major in comparison with the control group.
Patients and Methods:
Sixty β thalassemia major and intermadia patients were enrolled in this analytical cross-sectional study. Thalassemia major and intermadia patients with no clinical symptoms of cardiac disease underwent echocardiographic and stress tests. QTc interval, blood pressure, heart rate, and average serum ferritin levels were measured. Statistical analysis was performed using version 15 SPSS.
Results:
Although there was no clinical or echocardiographic sign of cardiac disease and QTc intervals measured before the test were not significantly different between patients and control group (421.7 ± 29.6 vs. 412.4 ± 28.2, P = 0.06), we found that, during stress test, QTc intervals (452.7 ± 30.8 vs. 410.2 ± 26.2, P < 0.001) and heart rate (105 ± 15.1 vs. 89.7 ± 12.3, P < 0.001) were notably greater in β thalassemia major patients compared to the control group, respectively.
Conclusion:
We found augmented QTc intervals in this group of thalassemia major patients who have neither clinical nor electrocardiographic and gross echocardiographic signs of cardiac disease. QTc interval can be helpful in the cardiac assessment of thalassemia major patients.
doi:10.4103/1995-705X.99226
PMCID: PMC3424778  PMID: 22919447
Exercise test; QT interval; β thalassaemia major
25.  QTc Prolongation in Patients Acutely Admitted to Hospital for Psychosis and Treated with Second Generation Antipsychotics 
QTc interval prolongation is a side effect of several antipsychotic drugs, with associated risks of torsade de pointes arrhythmias and sudden cardiac death. There is an ongoing debate of whether or not electrocardiogram (ECG) assessments should be mandatory in patients starting antipsychotic drugs. To investigate QTc prolongation in a clinically relevant patient group 171 adult patients acutely admitted to an emergency ward for psychosis were consecutively recruited. ECGs were recorded at baseline and then at discharge or after 6 weeks at the latest (discharge/6 weeks), thus reflecting the acute phase treatment period. The mean QTc interval was 421.1 (30.4) ms at baseline and there was a positive association between the QTc interval and the agitation score whereas the QTc interval was inversely associated with the serum calcium level. A total of 11.6% had abnormally prolonged QTc intervals and another 14.3% had borderline prolongation. At discharge/6 weeks, the corresponding proportions were reduced to 4.2% and 5.3%, respectively. The reduction of the proportion with prolonged QTc intervals reached statistical significance (chi-square exact test: P = 0.046). The finding of about one-quarter of the patients with borderline or prolonged QTc intervals could indicate mandatory ECG recordings in this population. This trial is registered with ClinicalTrials.gov ID: NCT00932529.
doi:10.1155/2013/375020
PMCID: PMC3893875  PMID: 24490070

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