Drug-Induced QT/QTc Interval Shortening: Lessons from Drug-Induced QT/QTc Prolongation

There is a paucity of information regarding QTc prolongation in critically ill patients. A prospective observational study was conducted to assess the incidence and predictors of QTc prolongation associated with medications in intensive care unit (ICU) patients. Consecutive adult patients prescribed prespecified QTc-prolonging medications were assessed for development of the combined incidence of QTc >500 ms at anytime and QTc increase >60 ms above baseline. Over 3 months, 200 consecutive patients (63 ± 18 years; 52% female; 73% Caucasian; baseline QTc 447.3 ± 51.5 ms) were evaluated. The primary end point occurred in 48% of the patients (QTc >500 ms 40%, QTc increase >60 ms 29%). The majority of patients experienced a QTc >470 or 450 ms (60.5%). Mean increase in QTc at 48 hours was 20 ± 35 ms. Upon multivariate analysis, length of stay [odds ratio 1.30, 95% confidence interval (1.15, 1.47)] and baseline QTc [1.01 (1.01, 1.02)] were associated with an increased risk for the primary end point, while beta-blockers [0.41 (0.20, 0.81)] were associated with a risk reduction. In conclusion, increased risk of proarrhythmia, as assessed by QTc prolongation, occurs in the majority of ICU patients when prescribed medications with electrophysiologic properties. Increased vigilance is warranted. The possible protective effect of beta-blockers requires confirmation.

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The Use of Intravenous Lidocaine in the Setting of Chronic Dofetilide Overdose: A Case Report

Journal of Pharmacy Practice ◽

10.1177/08971900211015053 ◽

2021 ◽

pp. 089719002110150

Author(s):

Eric Zhu ◽

Michael Gabriele ◽

May Thuy Nguyen

Keyword(s):

Life Support ◽

Management Strategies ◽

Advanced Cardiac Life Support ◽

Qtc Interval ◽

Intravenous Lidocaine ◽

Qtc Prolongation ◽

Prescription Error ◽

Drug Induced ◽

Multiple Factors ◽

Electrolyte Disturbances

Managing the risks and consequences of long QT syndrome can be challenging. Multiple factors contribute to the prolongation of the heart-rate corrected QT (QTc) interval including many drug-drug and drug-disease state interactions. Current literature is often focused on avoiding dysrhythmias with limited guidance on acute management strategies. Here we describe a case of QTc prolongation to 616 msec (Bazett’s formula) in the setting of chronic dofetilide overdose due to a possible prescription error. Our case was complicated by alcohol withdrawal and electrolyte disturbances that progressed to patient cardiac arrest in the emergency department. Dofetilide overdose was identified through pharmacist-initiated medication reconciliation and lidocaine was recommended as an alternative to amiodarone during advanced cardiac life support (ACLS). This case highlights the importance of reviewing outpatient medication records as well as avoiding drug-drug interactions during ACLS. Due to the potential for additive QTc prolongation, we recommend using lidocaine as the preferred antiarrhythmic in ACLS algorithms where drug induced QTc prolongation is suspected.

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A SYSTEMS PHARMACOLOGY MODEL TO EXPLAIN DEVELOPMENTAL DIFFERENCES IN SENSITIVITY TO DRUG-INDUCED QT PROLONGATION

Archives of Disease in Childhood ◽

10.1136/archdischild-2015-310148.24 ◽

2015 ◽

Vol 101 (1) ◽

pp. e1.17-e1

Author(s):

Verena Gotta ◽

Marc Pfister ◽

John van den Anker ◽

Piet van der Graaf

Keyword(s):

Ion Channel ◽

Developmental Change ◽

Qtc Interval ◽

Receptor Density ◽

Qtc Prolongation ◽

Drug Induced ◽

Channel Density ◽

Adults And Children

BackgroundNeonates have been reported to be more sensitive to drugs prolonging the QT-interval than adults. As explanation a developmental change in myocardial ion-channel density has been proposed. Here we explore changes in ion-channel density using a mechanistic pharmacodynamic model and clinical sotalol literature data.Materials and MethodsThe applied model relates in vitro and in vivo drug potency (regarding IKr-receptor occupancy and QTc-prolongation, respectively) by a system-specific transducer function. We characterized this function first for preclinical dog and in vitro data (moxifloxacin, sotalol, dofetilide). From a corresponding dofetilide model in adults we derived scaling factors for the system-specific parameters (maximal in vivo QTc-effect Em,dog/Em,adults, transducer ratio τ,dog/τ,adults; τ is proportional to the receptor density in vivo). The derived relationship was used to predict clinical sotalol pharmacodynamics in adults. Literature data was used to evaluate this scaling approach. Simulations of different τ values were performed to explore pharmacodynamic differences in neonates.ResultsIn adults, the agonistic activity of dofetilide was higher than in dogs (τ,adults≈2x τ,dogs), while the estimated maximal in vivo QTc-prolongation was similar (Em≈27% from baseline). This relationship could also predict clinical sotalol pharmacodynamics in adults and children. The steeper PD profile in neonates could be explained by a higher IKr-receptor density (τ, neonates≈2x τ, adults).ConclusionThis model-based approach allowed to integrate and scale in vitro and in vivo (preclinical, clinical adult and neonate) drug effects on the QTc-interval. The preliminary results confirm the hypothesis that IKr-receptor density is higher (≈2 times) in neonates than in adults and children.

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An Online Module to Evaluate the Validity of an Algorithm to assess the Risk for DrugInduced Qtc Prolongation in the Psychiatric Population

University of the Future: Re-Imagining Research and Higher Education ◽

10.29117/quarfe.2020.0231 ◽

2020 ◽

Author(s):

Iman Ashraf Qubaiah ◽

Waad Abubaker Elamin ◽

Doaa Elsayed Mahmoud ◽

Shorouk Akram Homs ◽

Enge Sherif Tawfik ◽

...

Keyword(s):

Risk Assessment ◽

Online Education ◽

Qtc Interval ◽

Pilot Test ◽

Interval Prolongation ◽

Qtc Prolongation ◽

Drug Induced ◽

Qtc Interval Prolongation ◽

Assessment Guidelines ◽

Psychiatric Population

Introduction: QTc interval prolongation leads to serious complications making it a concern for all clinicians. Assessing the risk of QTc interval prolongation, especially in the psychiatric population, can be challenging for pharmacists due to the complexity of regimens in this population and the difficulty in retrieving the needed information for the risk assessment. Guidelines and protocols for QTc prolongation risk assessment may vary among clinicians and few algorithms exist that address the prevention, management or monitoring of drug-induced QTc prolongation in the psychiatric population. Hence, there is a need for a validated comprehensive algorithm that helps clinicians in with the assessment of the risk of QTc prolongation. Aim: The study aims to pilot an educational module that guides experts through an algorithm for the assessment, management and monitoring of drug-induced QTc prolongation in the psychiatric population. Methods: This study involved developing an online education module using Articulate Presenter® to introduce a comprehensive literature-based algorithm to subject-matter experts. The orientation was followed by an anonymous, self-administered survey with quantitative and qualitative components to assess the content validity of the QTc Prolongation Algorithm. Results: Feedback from the first pilot test with faculty members indicated that the module’s interface was crowded. The module was updated accordingly. The results from the second pilot test with cardiologists were that the module provided a thorough explanation of the algorithm steps and rationale. Furthermore, some cardiologists commented that the algorithm was time consuming, however, most supported the implementation of the algorithm saying that it is easy to use, systematic, stepbased and would be helpful if implemented. Conclusion/Future directions: The results show that the module was helpful in introducing cardiologists to the algorithm and that the implementation of the algorithm after minor alterations can prove to be useful as a tool for risk assessment of QTc prolongation

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Antipsychotics in routine treatment are minor contributors to QT prolongation compared to genetics and age

Journal of Psychopharmacology ◽

10.1177/02698811211003477 ◽

2021 ◽

pp. 026988112110034

Author(s):

Leif Hommers ◽

Maike Scherf-Clavel ◽

Roberta Stempel ◽

Julian Roth ◽

Matthias Falter ◽

...

Keyword(s):

Qt Interval ◽

Multivariate Regression Analysis ◽

Cardiac Repolarization ◽

Qtc Interval ◽

Serum Concentrations ◽

Drug Induced ◽

Individual Level ◽

Main Determinants ◽

The Individual ◽

Polygenic Variation

Background: Drug-induced prolongation of cardiac repolarization limits the treatment with many psychotropic drugs. Recently, the contribution of polygenic variation to the individual duration of the QT interval was identified. Aims: To explore the interaction between antipsychotic drugs and the individual polygenic influence on the QT interval. Methods: Retrospective analysis of clinical and genotype data of 804 psychiatric inpatients diagnosed with a psychotic disorder. The individual polygenic influence on the QT interval was calculated according to the method of Arking et al. Results: Linear regression modelling showed a significant association of the individual polygenic QT interval score (ßstd = 0.176, p < 0.001) and age (ßstd = 0.139, p < 0.001) with the QTc interval corrected according to Fridericia’s formula. Sex showed a nominal trend towards significance (ßstd = 0.064, p = 0.064). No association was observed for the number of QT prolonging drugs according to AZCERT taken. Subsample analysis ( n = 588) showed a significant association of potassium serum concentrations with the QTc interval (ßstd = −0.104, p = 0.010). Haloperidol serum concentrations were associated with the QTc interval only in single medication analysis ( n = 26, ßstd = 0.101, p = 0.004), but not in multivariate regression analysis. No association was observed for aripiprazole, clozapine, quetiapine and perazine, while olanzapine and the sum of risperidone and its metabolite showed a negative association. Conclusions: Individual genetic factors and age are main determinants of the QT interval. Antipsychotic drug serum concentrations within the therapeutic range contribute to QTc prolongation on an individual level.

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Drug-induced QTc interval prolongation: A proposal towards an efficient and safe anticancer drug development

European Journal of Cancer ◽

10.1016/j.ejca.2007.10.001 ◽

2008 ◽

Vol 44 (4) ◽

pp. 494-500 ◽

Cited By ~ 30

Author(s):

Giuseppe Curigliano ◽

Gianluca Spitaleri ◽

Howard J. Fingert ◽

Filippo de Braud ◽

Cristiana Sessa ◽

...

Keyword(s):

Drug Development ◽

Anticancer Drug ◽

Qtc Interval ◽

Interval Prolongation ◽

Drug Induced ◽

Qtc Interval Prolongation ◽

Anticancer Drug Development

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Coronavirus disease 2019 (COVID-19) and QTc prolongation

BMC Cardiovascular Disorders ◽

10.1186/s12872-021-01963-1 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Khalid Changal ◽

David Paternite ◽

Sean Mack ◽

Spiro Veria ◽

Rehana Bashir ◽

...

Keyword(s):

Cardiovascular Disease ◽

Enzyme Inhibitors ◽

Cardiac Injury ◽

Angiotensin Converting Enzyme Inhibitors ◽

Qtc Interval ◽

Qtc Prolongation ◽

Converting Enzyme Inhibitors ◽

Stage Renal Disease ◽

End Stage ◽

Relationship Of

Abstract Introduction The cause-and-effect relationship of QTc prolongation in Coronavirus disease 2019 (COVID-19) patients has not been studied well. Objective We attempt to better understand the relationship of QTc prolongation in COVID-19 patients in this study. Methods This is a retrospective, hospital-based, observational study. All patients with normal baseline QTc interval who were hospitalized with the diagnosis of COVID-19 infection at two hospitals in Ohio, USA were included in this study. Results Sixty-nine patients had QTc prolongation, and 210 patients continued to have normal QTc during hospitalization. The baseline QTc intervals were comparable in the two groups. Patients with QTc prolongation were older (mean age 67 vs. 60, P 0.003), more likely to have underlying cardiovascular disease (48% versus 26%, P 0.001), ischemic heart disease (29% versus 17%, P 0.026), congestive heart failure with preserved ejection fraction (16% versus 8%, P 0.042), chronic kidney disease (23% versus 10%, P 0.005), and end-stage renal disease (12% versus 1%, P < 0.001). Patients with QTc prolongation were more likely to have received hydroxychloroquine (75% versus 59%, P 0.018), azithromycin (18% vs. 14%, P 0.034), a combination of hydroxychloroquine and azithromycin (29% vs 7%, P < 0.001), more than 1 QT prolonging agents (59% vs. 32%, P < 0.001). Patients who were on angiotensin-converting enzyme inhibitors (ACEi) were less likely to develop QTc prolongation (11% versus 26%, P 0.014). QTc prolongation was not associated with increased ventricular arrhythmias or mortality. Conclusion Older age, ESRD, underlying cardiovascular disease, potential virus mediated cardiac injury, and drugs like hydroxychloroquine/azithromycin, contribute to QTc prolongation in COVID-19 patients. The role of ACEi in preventing QTc prolongation in COVID-19 patients needs to be studied further.

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Translating the gap in the evaluation of drug-induced QTc-interval prolongation from in vivo to the clinic

Journal of Pharmacological and Toxicological Methods ◽

10.1016/j.vascn.2014.03.055 ◽

2014 ◽

Vol 70 (3) ◽

pp. 324

Author(s):

Vincent F.S. Dubois ◽

Piet van der Graaf ◽

Derek Leishman ◽

David Gallacher ◽

Nick McMahon ◽

...

Keyword(s):

Qtc Interval ◽

Interval Prolongation ◽

Drug Induced ◽

Qtc Interval Prolongation

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Predictive Role of QTc Prolongation in Carbon Monoxide Poisoning-Related Delayed Neuropsychiatric Sequelae

BioMed Research International ◽

10.1155/2018/2543018 ◽

2018 ◽

Vol 2018 ◽

pp. 1-8

Author(s):

Shu-Chen Liao ◽

Yan-Chiao Mao ◽

Yao-Min Hung ◽

Ching-Hsing Lee ◽

Chen-Chang Yang

Keyword(s):

Carbon Monoxide ◽

Roc Curve ◽

Carbon Monoxide Poisoning ◽

Chang Gung Memorial Hospital ◽

Qtc Interval ◽

Continuous Variables ◽

Co Poisoning ◽

Qtc Prolongation ◽

Roc Curve Analysis ◽

Delayed Neuropsychiatric Sequelae

Objective. Delayed neuropsychiatric sequelae (DNS) are serious complications of carbon monoxide (CO) poisoning that adversely affect poisoned patients’ quality of life as well as socioeconomic status. This study aimed to determine clinical predictors of DNS in patients with CO poisoning. Methods. This retrospective study included all CO-poisoned patients admitted to the emergency department (ED) of Linkou Chang Gung Memorial Hospital in Taiwan from 1 January 2009 to 31 December 2015. The medical records of all patients with CO poisoning were carefully reviewed, and relevant data were abstracted into a standardised form. Univariate and multivariate logistic regression models were used to identify predictors of DNS after CO poisoning. Receiver operating characteristic (ROC) curve analysis was used to determine the ideal cut-off value for continuous variables that predict the development of DNS. Results. A total of 760 patients with CO poisoning were identified during the study period. Among them, 466 were eligible for the analysis of predictors of DNS. In multivariate analysis, Glasgow Coma Scale <9 (odds ratio [OR], 2.74; 95% confidence interval [CI], 1.21–6.21), transient loss of consciousness (OR, 3.59; 95% CI, 1.31–9.79), longer duration from CO exposure to ED presentation (OR, 1.05; 95% CI, 1.03–1.08), and corrected QT (QTc) prolongation (OR, 2.61; 95% CI, 1.21–5.61) were found to be associated with a higher risk of DNS. The area under the ROC curve (AUC) for QTc interval measured within 6 h after exposure best predicted the development of DNS, with a result of 0.729 (95% CI 0.660–0.791). Moreover, the best cut-off value of the QTc interval was 471 ms, with a sensitivity of 53.3% and a specificity of 85.1%. Conclusions. We identified several potential predictors of DNS following CO poisoning. Among them, QTc prolongation found within 6 h after exposure is a novel predictor of DNS, which may be helpful in the future care of patients with CO poisoning.

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