Torsades de pointes and myocardial infarction following reversal of supraventricular tachycardia with adenosine: a case report.

Adenosine is an antiarrhythmic drug that slows conduction through the atrioventricular node and acts as a coronary blood vessel dilator. This case report highlights two unusual life-threatening events following the use of adenosine to revert supraventricular tachycardia in a structurally normal heart: non-sustained polymorphic ventricular tachycardia and myocardial infarction. A 46-year-old woman presented to the emergency department with a two-hour history of palpitations and was diagnosed with supraventricular tachycardia. Vagal maneuvers were ineffective, and after intravenous adenosine administration, the patient presented with chest pain and hypotension. The rhythm degenerated into non-sustained polymorphic ventricular tachycardia and spontaneously reverted to sinus rhythm with ST elevation in lead aVR and ST depression in the inferior and anterolateral leads. The patient spontaneously recovered within a few minutes. Despite successful arrhythmia reversal, the patient was admitted to the intensive care unit because of an infarction without obstructive atherosclerosis. This report aims to alert emergency physicians about the potential complications associated with supraventricular tachycardia and its reversal with adenosine.

First generation antipsychotic-associated serious adverse events in women: a retrospective analysis of a pharmacovigilance database.

BACKGROUND: Women have been under-represented in trials of antipsychotic medications. AIM: Our primary objective was to evaluate five adverse events (AE) associated with first-generation antipsychotics (FGAs) among women relative to men through an analysis of the FDA Adverse Event Reporting System (FAERS). METHOD: We queried 24.6 million AE reports from 2000 to 2023 involving FGAs. The study cohort consisted of chlorpromazine (n = 3317), fluphenazine (n = 1124), haloperidol (n = 16,709), loxapine (n = 3151), perphenazine (n = 816), thioridazine (n = 665), thiothixene (n = 244), and trifluoperazine (n = 360). Cases of neuroleptic malignant syndrome (NMS), tardive dyskinesia (TD), Torsades de Pointes (TdP), agranulocytosis (AG), and cerebrovascular adverse events (CVAE) were identified. Reporting odds ratios (ROR) and associated 95% confidence intervals (CI) were calculated with logistic regression for each AE among women relative to men. RESULTS: A total of 2,857 serious AEs were evaluated in the study cohort (NMS = 1810, TD = 434, TdP = 260, AG = 149, CVAE = 204). The ROR for women compared to men was 0.79 (95% CI, 0.71-0.87) for NMS, 0.83 (0.68-1.01) for TD, 1.21 (0.94-1.53) for TdP, 0.71 (0.51-0.98) for AG, and 0.91 (0.68-1.19) for CVAE. A secondary analysis revealed a higher odds in women compared to men of hospitalization associated with reports of TD (ROR = 1.95, 1.29-2.94) and death associated with reports of AG (ROR = 2.46, 1.15-5.24). A subgroup analysis of haloperidol revealed an ROR = 1.67 (1.26-2.21) for women relative to men for TdP. CONCLUSION: The subgroup analysis of haloperidol AEs revealed a significantly higher reporting odds ratio for TdP. Additionally, the secondary study findings suggest that women were more vulnerable to worse outcomes associated with certain AEs of FGAs.

Prevalence of Medication Associated with QTc Prolongation Used Among Critically Ill Patients.

Background: Acquired prolonged corrected QT (QTc) interval can lead to life-threatening Torsade de Pointes (TdP) arrhythmia. Multiple risk factors including medications, comorbidities, and electrolyte imbalances contribute significantly to acquired manifestations of the QTc prolongation. Critically ill patients are particularly more vulnerable to TdP due to complex medical conditions, aging, and polypharmacy. Objective: This study aimed to assess the prevalence of TdP-associated medication prescribing, identify risk factors for QTc prolongation and TdP, and determine primary predictors of high TdP medication usage in critically ill patients in Jordan. Methods: We conducted a retrospective cross-sectional analysis of electronic medical records for patients from King Abdullah University Hospital who were admitted to Intensive Care Unit (ICU) between (July 2012-July 2022). We collected data on patients' demographics, clinical characteristics, comorbidities, laboratory results, and prescribed medications. Medications were categorized into three TdP risk levels according to CredibleMeds® assessment tool. Data were analyzed using descriptive statistics and a binary logistic regression model. Results: Of the 13,300 patients (58.2% male, median age 62 years). Prescribing prevalence for medications with known TdP risk was 19%, possible risk (24.7%), conditional risk (21.6%), and confirmed conditional risk (8.3%). Common comorbidities included hypertension (40.9%), diabetes (33.3%), and cancer (15.4%). Drugs with known TdP risk included citalopram, amiodarone, clarithromycin, and ciprofloxacin. A binary regression model revealed that as age increased, the odds of TdP associated medication prescribing decreased (OR = 0.989, p < 0.001), while patients on more than five medications had higher odds (OR = 4.281, p < 0.001). Conclusion: The study identified a notable prevalence of prescribing for medications with QTc prolongation/TdP risk in critically ill patients. Healthcare providers in the ICU should exercise caution to minimize the inadvertent prescription of TdP associated medications especially among older patients and those with polypharmacy.

Characterization of cardiovascular profile of anti-influenza drug peramivir: A reverse-translational study using the isoflurane-anesthetized dog.

An injectable anti-influenza drug peramivir has been reported to induce QT-interval prolongation in some phase III studies, although its thorough QT/QTc study was negative. We investigated the discrepancy among those clinical studies using isoflurane-anesthetized beagle dogs (n = 4). Peramivir in doses of 1 mg/kg/10 min (sub-therapeutic dose) followed by 10 mg/kg/10 min (clinically-relevant dose) was intravenously administered. Peramivir prolonged QT interval/QTcV and Tpeak-Tend, and tended to delay ventricular repolarization in a reverse-frequency dependent manner, indicating IKr inhibition in vivo. Meanwhile, peramivir did not alter P-wave duration, PR interval or QRS width, indicating a lack of impact on cardiac conduction via Na+ or Ca2+ channel inhibition in vivo. Peramivir prolonged Tpeak-Tend and tended to prolong terminal repolarization period, which would develop substrates for initiating and maintaining spiral reentry, respectively. Meanwhile, peramivir did not prolong J-Tpeakc, which could not induce early afterdepolarization, a trigger inducing torsade de pointes. Thus, our results support that clinical dose exposure of peramivir can delay the ventricular repolarization in influenza patients. Peramivir has only a small potential to induce torsade de pointes in patients with the intact hearts, but caution should be paid on its use for patients formerly having the trigger for torsade de pointes.

A case of short QT-interval postventricular arrhythmia arrest from Torsade De Pointes, a new phenotype, or the result of tachycardia-mediated imbalance.

INTRODUCTION: We report the case of an 18-year-old female with recurrent syncope that was discovered to have congenital long QT syndrome (LQTS) and episodes of a transiently short QT interval after spontaneous termination of polymorphic ventricular tachycardia. METHODS & RESULTS: A cardiac event monitor revealed a long QT interval and initiation of polymorphic ventricular tachycardia by a premature ventricular complex on the preceding T-wave. After 1 minute of ventricular fibrillation, her arrhythmia spontaneously terminated with evidence of a short QT interval. CONCLUSIONS: A transient, potentially artificial, short QT interval following Torsades de Pointes can occur in patients with LQTS.

Right atrial pressure torsades de pointes.

A 39-year-old man with non-ischemic cardiomyopathy presented for routine right heart catheterization.

Antipsychotics and the QTc Interval During Delirium in the Intensive Care Unit: A Secondary Analysis of a Randomized Clinical Trial.

Importance: Antipsychotic medications, often prescribed for delirium in intensive care units (ICUs), may contribute to QTc interval prolongation. Objective: To determine whether antipsychotics increase the QTc interval in patients with delirium in the ICU. Design, Setting, and Participants: An a priori analysis of a randomized clinical trial in medical/surgical ICUs within 16 centers across the US was conducted. Participants included adults with delirium in the ICU with baseline QTc interval less than 550 ms. The study was conducted from December 2011 to August 2017. Data analysis was performed from April 25 to August 18, 2021. Interventions: Patients were randomized 1:1:1 to intravenous haloperidol, ziprasidone, or saline placebo administered twice daily until resolution of delirium, ICU discharge, or 14 days. Main Outcomes and Measures: Twelve-lead electrocardiograms were used to measure baseline QTc before study drug initiation and telemetry was used to measure QTc before each subsequent dose of study drug. Unadjusted day-to-day changes in QTc were calculated and multivariable proportional odds regression was used to estimate the effects of antipsychotics vs placebo on next-day maximum QTc interval, adjusting for prespecified baseline covariates and potential interactions with sex. Safety end points, including the occurrence of torsade de pointes, were evaluated. All analyses were conducted based on the intention to treat principle. Results: A total of 566 patients were randomized to haloperidol (n = 192), ziprasidone (n = 190), or placebo (n = 184). Median age was 60.1 (IQR, 51.4-68.7) years; 323 were men (57%). Baseline median QTc intervals across the groups were similar: haloperidol, 458.0 (IQR, 432.0-479.0) ms; ziprasidone, 451.0 (IQR, 424.0-472.0) ms; and placebo, 452.0 (IQR, 432.0-472.0) ms. From day 1 to day 2, median QTc changed minimally: haloperidol, -1.0 (IQR, -28.0 to 15.0) ms; ziprasidone, 0 (IQR, -23.0 to 20.0) ms; and placebo, -3.5 (IQR, -24.8 to 17.0) ms. Compared with placebo, neither haloperidol (odds ratio [OR], 0.95; 95% CI, 0.66-1.37; P = .78) nor ziprasidone (OR, 1.09; 95% CI, 0.75-1.57; P = .78) was associated with next-day QTc intervals. Effects were not significantly modified by sex (P = .41 for interaction). There were 2 occurrences of nonfatal torsade de pointes, both in the haloperidol group. Neither was associated with study drug administration. Conclusions and Relevance: The findings of this trial suggest that daily QTc interval monitoring during antipsychotic use may have limited value in patients in the ICU with normal baseline QTc and few risk factors for QTc prolongation. Trial Registration: ClinicalTrials.gov Identifier: NCT01211522.

Incidences, risk factors, and clinical correlates of severe QT prolongation after the use of quetiapine or haloperidol.

BACKGROUND: Case reports suggest that quetiapine or haloperidol use is associated with severe QT prolongation (SQTP) and torsades de pointes. OBJECTIVE: The purpose of this study was to examine the incidences, risk factors, and outcomes of SQTP in quetiapine and haloperidol users. METHODS: This study accessed electronic medical records from a multicenter health-care hospital system in Taiwan and included patients who received quetiapine or haloperidol therapy and had both baseline and follow-up electrocardiograms. SQTP was defined as a posttreatment corrected QT (QTc) interval exceeding 500 ms or an increase in QTc interval of >60 ms compared with the baseline value. We analyzed the risk factors and outcomes of SQTP using multivariate logistic regression. RESULTS: Mean increases in QTc interval were +8.3 ± 51.8 and +8.9 ± 44.0 ms after the administration of quetiapine (n = 8832) and haloperidol (n = 2341). Among these users, 1149 (13.0%) and 333 (14.2%) developed SQTP, respectively. Common risk factors for SQTP included old age, heart failure, hypokalemia, amiodarone use, and baseline QTc interval. SQTP in quetiapine users was significantly associated with ventricular arrhythmias (odds ratio 2.84; 95% confidence interval 1.95-4.13) and sudden cardiac death (odds ratio 2.29; 95% confidence interval 1.44-3.66). CONCLUSION: More than 10% of patients receiving quetiapine or haloperidol therapy developed SQTP, and many of them were exposed to risk factors for SQTP. SQTP in quetiapine users was significantly associated with increased risks of ventricular arrhythmias and sudden cardiac death. Clinicians should be vigilant for ventricular arrhythmias in quetiapine users who have risk factors for SQTP.

Assessing proarrhythmic potential of environmental chemicals using a high throughput in vitro-in silico model with human induced pluripotent stem cell-derived cardiomyocytes.

QT prolongation and the potentially fatal arrhythmia Torsades de Pointes are common causes for withdrawing or restricting drugs; however, little is known about similar liabilities of environmental chemicals. Current in vitro-in silico models for testing proarrhythmic liabilities, using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM), provide an opportunity to address this data gap. These methods are still low- to medium-throughput and not suitable for testing the tens of thousands of chemicals in commerce. We hypothesized that combining high-throughput population- based in vitro testing in hiPSC-CMs with a fully in silico data analysis workflow can offer sensitive and specific predictions of proarrhythmic potential. We calibrated the model with a published hiPSC-CM dataset of drugs known to be positive or negative for proarrhythmia and tested its performance using internal cross-validation and external validation. Additionally, we used computational down-sampling to examine three study designs for hiPSC-CM data: one replicate of one donor, five replicates of one donor, and one replicate of a population of five donors. We found that the population of five donors had the best performance for predicting proarrhythmic potential. The resulting model was then applied to predict the proarrhythmic potential of environmental chemicals, additionally characterizing risk through margin of exposure (MOE) calculations. Out of over 900 environmental chemicals tested, over 150 were predicted to have proarrhythmic potential, but only seven chemicals had a MOE < 1. We conclude that a high-throughput in vitro-in silico approach using population-based hiPSC-CM testing provides a reasonable strategy to screen environmental chemicals for proarrhythmic potential.

This article discusses a new method for testing the potential harmful effects of environmental chemicals on the heart. We used human heart cells grown in a lab to test the chemicals and developed a computer model to predict their potential to cause dangerous heart rhythms. This method could help identify harmful chemicals more quickly and accurately than current testing methods. The study has the potential to improve evaluation of chemical risks and protect public health without the use of animals.

Population pharmacokinetic/pharmacodynamic modeling of nifekalant injection with varies dosing plan in Chinese volunteers: a randomized, blind, placebo-controlled study.

Nifekalant hydrochloride is a class III antiarrhythmic agent which could increase the duration of the action potential and the effective refractory period of ventricular and atrial myocytes by blocking the K+ current. Nifekalant is used to prevent ventricular tachycardia/ventricular fibrillation. QT interval prolongation is the main measurable drug effect. However, due to the complicated dosing plan in clinic, the relationship among dosage, time, drug concentration and efficacy is not fully understood. In this study, a single-center, randomized, blind, dose-ascending, placebo-controlled study was conducted to explore the intrinsic characteristics of nifekalant injection in healthy Chinese volunteers by a population pharmacokinetic (PK)-pharmacodynamic (PD) model approach. 42 subjects were enrolled in this study and received one of three dose plans (loading dose on Day 1 (0.15, 0.3 or 0.5 mg/kg), loading dose followed by maintenance dose (0.2, 0.4 or 0.8 mg/kg/h) on Day 4) or vehicle. Blood samples were drawn for PK evaluation, and ECGs were recorded for QTc calculation at the designed timepoints. No Torsades de Pointes occurred during the study. The popPK model of nifekalant injection could be described by a two-compartment model with first-order elimination. The population mean clearance (CL) was 53.8 L/h. The population mean distribution volume of the central (Vc) and peripheral (Vp) compartments was 8.27 L and 45.6 L, respectively. A nonlinear dose-response (Emax) model well described the pharmacodynamic effect (QTc interval prolongation) of nifekalant. The Emax and EC50 from current study were 101 ms and 342 ng/mL, respectively.

Assessment of Quinidine-Induced Torsades de Pointes Risks Using a Whole-Body Physiologically Based Pharmacokinetic Model Linked to Cardiac Ionic Current Inhibition.

The lethality of torsades de pointes (TdP) by drugs is one of main reasons that some drugs were withdrawn from the market. In order to assess drug-induced TdP risks, a model of cardiac ionic current suppression in human ventricular myocytes (ToR-ORd model), combined with the maximum effective free therapeutic plasma concentration or the maximum effective free therapeutic myocyte concentration was often used, with the latter proved to be more relevant and more accurate. We aimed to develop a whole-body physiologically-based pharmacokinetic (PBPK) model, incorporated with a human cardiomyocyte pharmacodynamic (PD) model, to provide a comprehensive assessment of drug-induced TdP risks in normal and specific scenarios. Quinidine served as an example to validate the PBPK-PD model via predicting plasma quinidine concentrations and quinidine-induced changes in QT interval (ΔQTc). The predicted plasma quinidine concentrations and ΔQTc values following oral administration or intravenous administration of quinidine were comparable to clinic observations. Visual predictive checks showed that most of the observed plasma concentrations and ΔQTc values fell within the 5th and 95th percentiles of simulations. The validated PBPK-PD model was further applied to assess the TdP risks using frequencies of early afterdepolarization and long-QT syndrome occurrence in 4 scenarios, such as therapeutic dose, supra-therapeutic dose, alkalosis, and hyperkalemia in 200 human subjects. In conclusion, the developed PBPK-PD model may be applied to predict the quinidine pharmacokinetics and quinidine-induced TdP risks in healthy subjects, but also simulate quinidine-induced TdP risks under disease conditions, such as hypokalemia and alkalosis.

Torsade de pointes secondary to long QT syndrome after intragastric balloon placement. A rare but severe complication

The obesity pandemic is becoming one of the most prevalent diseases nowadays. There is a wide spectrum of treatment, ranging from hygienic-dietary measures to bariatric surgery. Endoscopic intragastric balloon placement is becoming increasingly more frequent, due to its technical simplicity, safety and short-term success(1). Although complications are rare some can be severe, so pre-endoscopic evaluation must be carried out carefully. A 43-year-old woman with a history of grade I obesity (BMI 32.7) had an Orbera® intragastric balloon implanted successfully. After the procedure she presented frequent nausea and vomiting, partially controlled with antiemetics. She attended the Emergency Department(ED) with a persistent emetic syndrome - oral intolerance and short-term loss of consciousness(syncope), for which she was admitted. Lab tests showed metabolic alkalosis with severe hypokalemia(K+ 1.8mmol/L), so fluid therapy was initiated for hydroelectrolytic replacement. During the patient’s stay in the ED, two episodes of polymorphic ventricular tachychardia “Torsades de Pointes” (PVT-TDP) occurred, leading to cardiac arrest and requiring electrical cardioversion to restore sinus rhythm, in addition to a temporary pacemaker placement. Telemetry showed a corrected QT interval of >500ms, compatible with Long QT Syndrome(LQTS). Once the patient was hemodynamically stabilized a gastroscopy was performed. The intragastric balloon located in the fundus was removed using an extraction kit, puncturing and aspirating 500ml of saline solution, and extracting the collapsed balloon without any complications. The patient achieved an adequate oral intake afterwards, and no recurrence of emetic episodes were noticed. Previous ECGs revealed a prolonged QT interval and a genetic study confirmed a congenital type 1 LQTS. Treatment was initiated with beta-blockers and a bicameral automatic defibrillator was implanted in order to prevent recurrences. ... (AU)

Life-Threatening Cardiac Arrhythmias in a Case of Undetected Myxedema Coma: Importance of Early Detection and Medication Adherence.

BACKGROUND Myxedema coma is a rare, life-threatening condition caused by a severe form of hypothyroidism. The dangerously low levels of circulating thyroid hormone can lead to progressive mental status changes and numerous organ dysfunctions, including serious cardiac abnormalities. CASE REPORT We present a case of a 59-year-old woman who presented with altered mental status and fall who was originally thought to have a cerebrovascular accident but was later diagnosed with myxedema coma, after multiple cardiac arrests. It was discovered that the patient had not been taking any of her medications for the last several weeks, after her primary care provider retired from practice. Initial laboratory evaluation was significant for a TSH level of 159.419 mIU/L and an undetectable free T4 level. Complications of the myxedema coma resulted in QTC interval prolongation, causing torsades de pointes and sustained polymorphic ventricular tachycardia, requiring cardioversion. CONCLUSIONS This case demonstrates the importance of early detection and treatment of myxedema coma, as it can cause life-threatening cardiac arrhythmias. It also emphasizes the need to ensure proper medication adherence in patients with chronic medical conditions, as non-compliance can result in dire consequences.

Coeliac axis thrombosis and acute hepatic failure in a patient with dilated cardiomyopathy.

We present the case of a female patient in her 40s who presented with jaundice, orthopnoea, paroxysmal nocturnal dyspnoea and bilateral pedal oedema. After extensive investigations, she was diagnosed with hepatic dysfunction, dilated cardiomyopathy (DCM) and coeliac axis thrombosis. Her case was further complicated with episodes of torsades de pointes due to metabolic disturbance, with consequent sudden cardiac arrest. In this case report, we explore the clinical features, pathophysiology and treatment of acute hepatic failure and coeliac axis thrombosis, secondary to DCM and alcoholic liver disease.

Personalized, intuitive & visual QT-prolongation monitoring using patient-specific QTc threshold with pseudo-coloring and explainable AI.

BACKGROUND: Drug-induced QT-prolongation increases the risk of TdP arrhythmia attacks and sudden cardiac death. However, measuring the QT-interval and determining a precise cut-off QT/QTc value that could put a patient at risk of TdP is challenging and influenced by many factors including female sex, drug-free baseline, age, genetic predisposition, and bradycardia. OBJECTIVES: This paper presents a novel approach for intuitively and visually monitoring QT-prolongation showing a potential risk of TdP, which can be adjusted according to patient-specific risk factors, using a pseudo-coloring technique and explainable artificial intelligence (AI). METHODS: We extended the development and evaluation of an explainable AI-based technique- visualized using pseudo-color on the ECG signal, thus intuitively 'explaining' how its decision was made -to detect QT-prolongation showing a potential risk of TdP according to a cut-off personalized QTc value (using Bazett's ∆QTc > 60 ms relative to drug-free baseline and Bazett's QTc > 500 ms as examples), and validated its performance using a large number of ECGs (n = 5050), acquired from a clinical trial assessing the effects of four known QT-prolonging drugs versus placebo on healthy subjects. We compared this new personalized approach to our previous study that used a more general approach using the QT-nomogram. RESULTS AND CONCLUSIONS: The explainable AI-based algorithm can accurately detect QT-prolongation when adjusted to a personalized patient-specific cut-off QTc value showing a potential risk of TdP. Using ∆QTc > 60 ms relative to drug-free baseline and QTc > 500 ms as examples, the algorithm yielded a sensitivity of 0.95 and 0.79, and a specificity of 0.95 and 0.98, respectively. We found that adjusting pseudo-coloring according to Bazett's ∆QTc > 60 ms relative to a drug-free baseline personalized to each patient provides better sensitivity than using Bazett's QTc > 500 ms, which could underestimate a potentially clinically significant QT-prolongation with bradycardia.