Development Of Torsade De Pointes Research Articles

The Incidence of Torsades de Pointes With Perioperative Triple Antiemetic Administration.

The safety of triple antiemetic therapy consisting of ondansetron, haloperidol, and a steroid, to surgical patients is unknown. To determine the incidence of torsade de pointes (TdP) or death following perioperative administration of triple antiemetic therapy. A retrospective cohort study identified 19,874 patients who received 22,202 doses of triple antiemetics during the 2.5-year time frame from March 4, 2020 to September 7, 2022 for surgical nausea prophylaxis or treatment of nausea. These patients above were cross-matched with an electrocardiogram and adverse outcome database; this identified 226 patients with documentation of a QTc > 450 ms, all ventricular tachycardias including TdP within 48 hours of receiving triple antiemetic therapy, or death within 7 days of receiving ondansetron. There were 3 patients who had documented VT (n = 3), but there were no documented incidents of TdP (n = 0). There were 9 codes called on patients within 48 hours of medication administration, and none of them were due to ventricular arrythmias (n = 0). A total of 11 patients died within 7 days of triple antiemetic therapy. Ten of the 11 deaths were determined to not be from the triple antiemetic. One patient died at home within 24 hours of the procedure of an unknown cause (n = 1). No episodes of TdP were identified in patients receiving triple antiemetic therapy perioperatively, though the cause of death in 1 patient could not be determined. This suggest that low-dose triple antiemetic therapy is low risk for the development of TdP.

The Antiarrhythmic Action of the Na+/Ca2+ Exchanger Inhibitor SEA0400 on Drug-Induced Long QT Syndrome Depends on the Severity of Proarrhythmic Conditions in Anesthetized Atrioventricular Block Rabbits.

To clarify the pharmacological properties of the Na+/Ca2+ exchanger (NCX) inhibitor SEA0400 as an antiarrhythmic agent, we assessed its effects on rapid component of delayed rectifier K+ current (IKr) blocker-induced torsade de pointes (TdP) in isoflurane-anesthetized rabbits. Atrioventricular block was induced in rabbits using a catheter ablation technique, and the monophasic action potential (MAP) of the right ventricle was measured under electrical pacing at 60 beats/min. In non-treated control animals, intravenous administration of low-dose (0.3 mg/kg) or high-dose nifekalant (3 mg/kg) prolonged the MAP duration (MAP90) by 113 ± 11 ms (n = 5) and 237 ± 39 ms (n = 5), respectively, where TdP was induced in 1/5 animals treated with a low dose and in 3/5 animals treated with a high dose of nifekalant. In SEA0400-treated animals, low- and high-dose nifekalant prolonged the MAP90 by 65 ± 13 ms (n = 5) and 230 ± 20 ms (n = 5), respectively. No TdP was induced by the low dose but 1/5 animals treated with a high dose of nifekalant developed TdP. In verapamil-treated animals, low-dose and high-dose nifekalant prolonged MAP90 by 50 ± 12 ms (n = 5) and 147 ± 30 ms (n = 5), respectively, without inducing TdP. These results suggest that SEA0400 has the potential to inhibit low-dose nifekalant-induced TdP by suppressing the MAP-prolonging action of nifekalant, whereas the drug inhibited high-dose nifekalant-induced TdP without affecting the MAP-prolonging action of nifekalant. This may reveal that, in contrast to verapamil, the antiarrhythmic effects of SEA0400 on IKr blocker-induced TdP may be multifaceted, depending on the severity of the proarrhythmogenic conditions present.

IKs Activator ML277 Mildly Affects Repolarization and Arrhythmic Outcome in the CAVB Dog Model

Long QT syndrome type 1 with affected IKs is associated with a high risk for developing Torsade de Pointes (TdP) arrhythmias and eventually sudden cardiac death. Therefore, it is of high interest to explore drugs that target IKs as antiarrhythmics. We examined the antiarrhythmic effect of IKs channel activator ML277 in the chronic atrioventricular block (CAVB) dog model. TdP arrhythmia sensitivity was tested in anesthetized mongrel dogs (n = 7) with CAVB in series: (1) induction experiment at 4 ± 2 weeks CAVB: TdP arrhythmias were induced with our standardized protocol using dofetilide (0.025 mg/kg), and (2) prevention experiment at 10 ± 2 weeks CAVB: the antiarrhythmic effect of ML277 (0.6-1.0 mg/kg) was tested by infusion for 5 min preceding dofetilide. ML277: (1) temporarily prevented repolarization prolongation induced by dofetilide (QTc: 538 ± 65 ms at induction vs. 393 ± 18 ms at prevention, p < 0.05), (2) delayed the occurrence of the first arrhythmic event upon dofetilide (from 129 ± 28 s to 180 ± 51 s, p < 0.05), and (3) decreased the arrhythmic outcome with a significant reduction in the number of TdP arrhythmias, TdP score, arrhythmia score and total arrhythmic events (from 669 ± 132 to 401 ± 228, p < 0.05). IKs channel activation by ML277 temporarily suppressed QT interval prolongation, delayed the occurrence of the first arrhythmic event and reduced the arrhythmic outcome in the CAVB dog model.

The Effects of Moxifloxacin and Gemifloxacin on the ECG Morphology in Healthy Volunteers: A Phase 1 Randomized Clinical Trial

Moxifloxacin and gemifloxacin are the two newer broad-spectrum 8-methoxy-quinolone derivatives that are used to treat various bacterial infections in cardiac patients. In this research study, we assessed the impact of moxifloxacin and gemifloxacin on the QT intervals of electrocardiograms in normal adult doses and draw a comparison, in a controlled environment, on healthy volunteers. Additionally, the effect of both test drugs on the QRS complex was checked. Sixty healthy volunteers were randomly assigned to two groups via R-software, and each respectively received moxifloxacin and gemifloxacin for five days. The research ethics committee approved the research, and it was registered for clinical trial under NCT04692623. The participants' electrocardiograms were obtained before the start of the dose (baseline) and on the fifth day. Significant prolongation of QT interval was noted in moxifloxacin (p < 0.0001) as compared to gemifloxacin treated groups. There were no cases of QTc prolongation over the usual limits (450-470 ms) in the gemifloxacin-treated group, however, QTc prolongations at the rate of 30 and 60 ms from the baseline were noted, interpreted as per the EMEA guidelines. These findings indicate that moxifloxacin caused significant (p < 0.0001) QT interval prolongation (QTIP) as compared to gemifloxacin. In contrast to the previously reported literature, the prominent effect of moxifloxacin on the widening of the QRS-complex was noted with no such effect on QRS-widening in the gemifloxacin-treated group. It is concluded that both drugs have the potential for considerable QT interval prolongation (QTIP) effects, which is one of the risk factors for developing torsade de pointes (TdPs) in cardiac patients. Thus, clinicians should exercise caution when prescribing moxifloxacin and gemifloxacin to cardiac patients and should consider alternate treatment options.

Adverse reactions to antiarrhythmic drugs

There are various types of adverse reactions to antiarrhythmic drugs (AADs). Proarrhythmia, which refers to an exacerbation of the preexisting arrhythmia or occurrence of a new arrhythmia, may occur under the therapeutic concentration of an AAD. Bradyarrhythmia is the most common type of proarrhythmia due to AADs, and prior myocardial infarction and old age are known risk factors. Atrial flutter with 1:1 atrioventricular conduction usually occurs during rhythm control of atrial fibrillation with class IC AADs. QT prolongation due to AADs, mainly class III AADs, elevates the risk of torsade de pointes by triggered activity due to early afterdepolarization. The addition of clinical factors that promote QT prolongation, such as hypokalemia, hypomagnesemia, female sex, and bradycardia, increases the risk of developing torsade de pointes. Proarrhythmic monomorphic ventricular tachycardia usually occurs as a result of slow conduction and disparity of refractoriness due to class IC AADs. In patients with preexisting left ventricular systolic dysfunction or structural heart disease, the risk of hypotension or cardiogenic shock caused by negative inotropic effects due to AADs should be considered. To prevent these major adverse reactions to AADs, we need to understand the electrophysiologic properties of AADs in detail. Furthermore, the risk of proarrhythmia could be heightened by interplay with clinical factors, such as electrolyte unbalances, heart rate, and hepatic/renal or myocardial dysfunction. Sufficient awareness about drug-drug interactions, which may affect the metabolism of AADs, will improve patient safety during the management of arrhythmia.

Abstract 9267: Modified Protocol of Niferidil Administration for Rhythm Restoration in Patients With Paroxysm of Atrial Fibrillation

Introduction: Niferidil is a new Russian class III antiarrhythmic drug, which in clinical trials has shown a high efficiency of restoration of sinus rhythm (SR) in persistent AF (87%), not inferior to electrical cardioversion. Currently, a three-stage scheme of drug administration is used (10 μg / kg - 10 μg / kg - 10 μg / kg). In a number of patients, SR is restored before the end of the first dose of the drug, which indicates the effectiveness of an even lower dose (5 μg / kg) of the drug, which has not been studied in clinical trials. Objective: To evaluate the effectiveness and safety of the modified protocol of niferidil administration in patients with paroxysmal AF. Methods: Included 87 patients with paroxysmal, 42 of them were men, mean age 63 [57;70]. After exclusion of contraindications, all patients received niferidil according to the following scheme. The initial dose of niferidil was 5 μg/kg of body weight, if AF did not terminate after 15 minutes (min.), niferidil was additionally administered at a dose of 5 μg/kg (total dose of 10 μg/kg). If SR was not restored patients received subsequent injections of niferidil 10 μg/kg, each after 15 min. (maximal total dose of 30 μg/kg). Injections were discontinued in case of SR restoration, QTc&gt;500ms or proarrhythmia. All patients underwent continuous ECG monitoring within 24 hours to assess effectiveness and safety of niferidil. Results: SR was restored in 81 out of 87 patients (cumulative effectiveness of niferidil in doses up to 30 μg / kg was 93,1 %. 49,4 % of them restored SR after administration of 5 μg/kg dose, 66 (77 %) - after 10 μg/kg dose, 77 (88,5 %) - after 20 μg/kg dose, 81 (93,1 %) - after 30 μg/kg dose. In none of the cases was there any development of life-threatening ventricular arrhythmias. Prolongation of the QTc&gt;500 ms was recorded in 14 patients (16%). Bradyarrhythmias after SR recovery were reported in 6 patients (6,8 %). In all cases sinus bradycardia was asymptomatic. Conclusions: The modified protocol of cardioversion allows SR to be restored in a significant number of AF patient’s lower doses of niferidil. The drug is highly effective in the treatment of paroxysmal AF, while in almost half of the cases, SR is restored after the administration after drug dose - 5 μg / kg. None of the patients developed Torsades de pointes.

Methadone-Induced QT Interval Prolongation and Torsades de Pointes

: The most common cause of acquired long QT syndrome in patients without physiological and structural cardiovascular disease is the use of medications. Chronic high-dose methadone usage can cause prolongation of QT interval that may provoke the life-threatening arrhythmia Torsades de Pointes. In this study, we present a 41-year-old man with chronic high-dose methadone usage who developed Torsades de Pointes triggered by short-coupled premature ventricular contraction.

EPH107 An Evaluation of the Relationship between QTc Prolonging Medications, Tisdale Risk Scores and Mortality Using a Nationally Representative Electronic Health Records Database

QTc prolongation is associated with the risk of developing Torsade de Pointes (TdP), a serious and life-threatening arrhythmia. Some medications are associated with QTc prolongation. The purpose of this study was to examine the relationship between mortality and medications known to prolong the QTc while accounting for other risk factors that comprise the Tisdale QTc risk score.

Efficiency and safety of the modified protocol for cardioversion of atrial fibrillation using the antiarrhythmic drug niferidil. First results of clinical use

Abstract Introduction Atrial fibrillation (AF) is one of the most common forms of arrhythmia. Niferidil is a new russian class III antiarrhythmic drug that has shown high efficiency in restoration of sinus rhythm (SR) in persistent AF (87%) in clinical trials that is non-inferior to direct current cardioversion. Currently, a three-stage scheme of drug administration is used (10 μg/kg – 10 μg/kg – 10 μg/kg). In a number of patients, SR restored before the end of injection of the first dose of the drug, which suggests the effectiveness of an even lower dose (5 μg/kg) of the drug, which has not been studied in clinical trials. Objective To evaluate the effectiveness and safety of the modified protocol of niferidil administration in patients with paroxysmal and persistent AF. Materials and methods This study included 100 patients with paroxysmal (n=20) and persistent AF (n=80), 53 of them were men, mean age 63±12 years. After exclusion of contraindications, all patients received niferidil according to the following scheme. The initial dose of niferidil was 5 μg/kg of body weight, if AF did not terminate after 15 minutes (min.), niferidil was additionally administered at a dose of 5 μg/kg (total dose of 10 μg/kg). If SR was not restored patients received subsequent injections of niferidil 10 μg/kg, each after 15 min. (maximal total dose of 30 μg/kg). Injections were discontinued in case of SR restoration, QTc &amp;gt;500 ms or proarrhythmia. All patients underwent continuous ECG monitoring within 24 hours to assess effectiveness and safety of niferidil. Results SR was restored in 94 out of 100 patients (cumulative effectiveness of niferidil in doses up to 30 μg/kg was 94%). 37% of patients restored SR after a dose of 5 μg/kg. All 20 patients with paroxysmal AF restored SR within 24 hours. Niferidil restored SR in 74 of 80 patients with persistent AF (92,5%). 26 (32,5%) of them restored SR after administration of 5 μg/kg dose, 62% – after 10 μg/kg dose and 92,5% – after 30 μg/kg dose. In none of the cases was there any development of life-threatening ventricular arrhythmias. Prolongation of the QTc &amp;gt;500 ms was recorded in 16 patients (16%). In all patients, prolongation of the QTc interval to the maximum values was noted within the first 6 hours from the start of drug administration. Bradyarrhythmias after SR recovery were reported in 11 patients (11%). In all cases sinus bradycardia was asymptomatic and resolved within a few minutes without any therapeutic intervention. Conclusions The modified protocol of cardioversion allows SR to be restored in a significant number of AF patients lower doses of niferidil. The drug is highly effective in the treatment of paroxysmal AF, while in many patients, SR recovery occurs after injection of lowest (5 μg/kg and 10 μg/kg) doses of the drug. Despite the prolongation of the QTc interval &amp;gt;500 ms in a number of patients, in none of the cases the development of Torsades de pointes observed. Funding Acknowledgement Type of funding sources: None.

Efficiency and safety of using the modified protocol for the administration of the domestic class III antiarrhythmic drug for the relief of paroxysmal atrial fibrillation

Evaluation of the efficacy and safety of the modified refralon administration protocol for the relief of paroxysmal atrial fibrillation (AF). The study included 39 patients (19 men, mean age 6312.8 years). All patients, after excluding contraindications in the intensive care unit, were injected intravenously with refralon at an initial dose of 5 mg/kg. If AF was preserved and there were no contraindications, after 15 min, repeated administration was performed at a dose of 5 mg/kg (total dose of 10 mg/kg). After another 15 min, while maintaining AF and the absence of contraindications, the third injection of the drug was performed at a dose of 10 mg/kg (total dose of 20 mg/kg). In the absence of relief and the absence of contraindications, another injection of refralon at a dose of 10 mg/kg was performed after another 15 min (in this case, the maximum total dose of 30 mg/kg was reached). After each injected bolus and before the introduction of the next one, the ECG parameters and the general condition of the patient were assessed. The patient was monitored for 24 hours to exclude the arrhythmogenic effect and other possible adverse events. Restoration of sinus rhythm (SR) was noted in 37 patients out of 39 (95%). Of these, 19 people (48.7%) had SR recovery after the administration of a minimum dose of refralone of 5 mg/kg. The effectiveness of the total dose of 10 mg/kg was 76.9%, the dose of 20 mg/kg was 89.7%, and the dose of 30 mg/kg was 95%. Only two patients did not recover HR after administration of the maximum dose of refralon 30 mg/kg. Pathological prolongation of the QTc interval (500 ms) was recorded in 5% of patients. Not a single case of ventricular arrhythmogenic action (induction of Torsade de pointes) has been reported. Bradyarrhythmias (pauses, bradycardia) were registered in 13% of cases, were of a transient nature. Refralon has a high efficiency of relief (95%) of paroxysmal AF, while in almost half of cases (48.7%), SR recovery is achieved using the minimum dose of refralon 5 mg/kg. Despite the prolongation of the QTc500 ms recorded in 5% of cases, none of the patients developed Torsade de pointes after administration of the drug.

Genetic and Molecular Aspects of Drug-Induced QT Interval Prolongation.

Long QT syndromes can be either acquired or congenital. Drugs are one of the many etiologies that may induce acquired long QT syndrome. In fact, many drugs frequently used in the clinical setting are a known risk factor for a prolonged QT interval, thus increasing the chances of developing torsade de pointes. The molecular mechanisms involved in the prolongation of the QT interval are common to most medications. However, there is considerable inter-individual variability in drug response, thus making the application of personalized medicine a relevant aspect in long QT syndrome, in order to evaluate the risk of every individual from a pharmacogenetic standpoint.

Safety and Efficacy of Ibutilide for Acute Pharmacological Cardioversion of Rheumatic Atrial Fibrillation

Introduction: Ibutilide is indicated for acute cardioversion of nonvalvular atrial fibrillation (AF). However, its efficacy and safety in the pharmacological cardioversion of rheumatic AF are unknown. Methods: Patients with mild-to-moderate rheumatic mitral valve (MV) disease with symptomatic, paroxysmal, or persistent AF were included in the analysis. Intravenous ibutilide was administered at doses tailored to body weight (0.5–2.0 mg) for over 10 min. The primary end point was efficacy, assessed as the rate of conversion of AF to sinus rhythm. The secondary end point was safety, including arrhythmic events and death within 24 h of drug initiation. Results: From June 2016 to October 2018, 165 patients (94 with mitral stenosis, 23 with mitral regurgitation, 11 with mixed MV disease, and 37 with MV replacement) received ibutilide (mean dose 0.90 ± 0.54 mg). Ibutilide successfully converted AF to sinus rhythm in 127/165 (76.9%) patients, with a conversion time of 7.9 ± 4.1 min. The QTc increased from 419.9 ± 15.8 to 487.5 ± 34 ms after ibutilide administration (p < 0.001). The mean change in QTc after ibutilide administration (∆QTc) was 72.01 ± 36.03. There were no deaths, but 3 patients (1.8%) developed torsades de pointes (TdP) requiring defibrillation 55 ± 37 min after infusion. Conclusion: Ibutilide cardioverted 77% of rheumatic AF to sinus rhythm, indicating its potential as a clinically useful option for pharmacological cardioversion of rheumatic AF. TdP is a potentially serious adverse event that requires careful monitoring.

Electrical Features of the Diabetic Myocardium. Arrhythmic and Cardiovascular Safety Considerations in Diabetes.

Diabetes is a chronic metabolic disease characterized by hyperglycemia in the absence of treatment. Among the diabetes-associated complications, cardiovascular disease is the major cause of mortality and morbidity in diabetic patients. Diabetes causes a complex myocardial dysfunction, referred as diabetic cardiomyopathy, which even in the absence of other cardiac risk factors results in abnormal diastolic and systolic function. Besides mechanical abnormalities, altered electrical function is another major feature of the diabetic myocardium. Both type 1 and type 2 diabetic patients often show cardiac electrical remodeling, mainly a prolonged ventricular repolarization visible in the electrocardiogram as a lengthening of the QT interval duration. The underlying mechanisms at the cellular level involve alterations on the expression and activity of several cardiac ion channels and their associated regulatory proteins. Consequent changes in sodium, calcium and potassium currents collectively lead to a delay in repolarization that can increase the risk of developing life-threatening ventricular arrhythmias and sudden death. QT duration correlates strongly with the risk of developing torsade de pointes, a form of ventricular tachycardia that can degenerate into ventricular fibrillation. Therefore, QT prolongation is a qualitative marker of proarrhythmic risk, and analysis of ventricular repolarization is therefore required for the approval of new drugs. To that end, the Thorough QT/QTc analysis evaluates QT interval prolongation to assess potential proarrhythmic effects. In addition, since diabetic patients have a higher risk to die from cardiovascular causes than individuals without diabetes, cardiovascular safety of the new antidiabetic drugs must be carefully evaluated in type 2 diabetic patients. These cardiovascular outcome trials reveal that some glucose-lowering drugs actually reduce cardiovascular risk. The mechanism of cardioprotection might involve a reduction of the risk of developing arrhythmia.

Safety of pharmacotherapy in a psychiatric inpatient setting and the QT interval

Background; Events associated with a risk of death are the most serious complications of pharmacotherapy; One of these complications is prolongation of the QT interval leading to Torsades de Pointes, a life-threatening condition that can result in asystole and sudden death. Factors contributing to the development of the long QT syndrome include heredity, structural abnormalities of the heart, electrolyte disorders, female gender, advanced age, use of drugs with certain electrophysiological properties, and drug-drug interactions. Consideration of all these factors can help achieve the most accurate and objective assessment of the risk of these rhythm disturbances.&#x0D; Aims to assess the risk of prolongation of the QT interval and the development of Torsades de Pointes in psychiatric inpatients.&#x0D; Methods. The study enrolled 500 patients who received medical care in a psychiatric inpatient setting. The risk of QT interval prolongation and development of Torsades de Pointes was assessed using the MedSafety Scan medical decision support system.&#x0D; Results. Of the 500 patients treated in the psychiatric inpatient setting, 224 had a risk of QT interval prolongation and developing Torsades de Pointes; the incidence was highest in the group of elderly patients. The mean risk score was 7.59 3.29 in general, 6.02 3.14 in patients aged under 65 years, and 9.16 2.62 in subjects over 65 years of age. An analysis of the frequencies of risk factors for prolongation of the QT interval and Torsades de Pointes revealed that patients aged over 65 years most commonly had atrial fibrillation, chronic heart failure, heart valve disorders, hypertension, and a history of myocardial infarction. Patients under 65 years of age more commonly received medicinal products prolonging the QT interval and drug combinations that can lead to potential drug-drug interactions of relevant clinical significance.&#x0D; Conclusion. The obtained results indicate the importance of assessing the risk of QT interval prolongation and development of Torsades de Pointes in psychiatric inpatients as an affordable preventive tool that can increase the safety of drug therapy.

Comprehensive Cardiotoxicity Assessment of COVID-19 Treatments Using Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes.

Coronavirus disease 2019 (COVID-19) continues to spread across the globe, with numerous clinical trials underway seeking to develop and test effective COVID-19 therapies, including remdesivir. Several ongoing studies have reported hydroxychloroquine-induced cardiotoxicity, including development of torsade de pointes (TdP). Meanwhile, human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are expected to serve as a tool for assessing drug-induced cardiotoxicity, such as TdP and contraction impairment. However, the cardiotoxicity of COVID-19 treatments has not been fully assessed using hiPSC-CMs. In this study, we focused on drug repurposing with various modes of actions and examined the TdP risk associated with COVID-19 treatments using field potential using multi-electrode array system and motion analysis with hiPSC-CMs. Hydroxychloroquine induced early after depolarization, while remdesivir, favipiravir, camostat, and ivermectin had little effect on field potentials. We then analyzed electromechanical window, which is defined as the difference between field potential and contraction-relaxation durations. Hydroxychloroquine decreased electromechanical window of hiPSC-CMs in a concentration-dependent manner. In contrast, other drugs had little effect. Our data suggest that hydroxychloroquine has proarrhythmic risk and other drugs have low proarrhythmic risk. Thus, hiPSC-CMs represent a useful tool for assessing the comprehensive cardiotoxicity caused by COVID-19 treatments in nonclinical settings.

QT interval in patients receiving HCQ in SARS-CoV-2- A study on risk factors and correlation of baseline QTc with delta QTc in Pakistani population

Funding AcknowledgementsType of funding sources: None.IntroductionHydroxychloroquine(HCQ) use alone or in combination with Azithromycin (AZM) in SARS-CoV-2 infection is associated with QTc prolongation and risk of arrhythmias.ObjectivesTo determine changes in QTc interval and factors predictive of extreme QTc prolongation in patients receiving HCQ alone or in azithromycin combination in Pakistani patients.MethodologyRetrospective review of records of hospitalized patients with SARS-Cov2 RT-PCR positive result who received HCQ or HCQ/Azithromycin in combination from March-May 2020. Baseline ECGs as well as post drug use ECGs data was recorded. Tisdale score was calculated for predicting risk of QTc prolongation,QTc interval was calculated using Bazett formula. Data entry and analysis was done in SPSS version 23. ResultsA total of 134 patients were included in the study. 82.1%(110) were males and 17.9%(24) were females, mean age was 54.9 ± 13.7 years. 61.2% (82) had severe disease and 38.8 %(52) had non-severe disease. 14.2%(19) had history of cardiac disease, 35.8%(48) had hypertension and 35.1%(47) had diabetes mellitus. 70.1% (94) patients had received HCQ, AZM, or HCQ/AZM in combination. 40(29.9%) patients had not received any drug. Median baseline QTc among controls and non-control group was 383.5 (IQR 342.25-413.75)msec and 379(IQR 358-402)msec respectively. HCQ alone was administered to 26.9%(36) and HCQ/AZM to 33.6%(45) patients. 55.6% (45/81) developed QTc prolongation(QTc> 480 msec) or delta QTc increase > 60 msec. 6.2%(5/81) had absolute QTc > 500 msec post-drug administration. 55.6%(25/45) and 30.6%(11/36) (p-value 0.024) developed QTc prolongation in combination and HCQ alone groups respectively. Delta QTc increased to >60msec in 42.0% (34/81); 53.3%(24/45) in combination group and in 27.8%(10/36) of those receiving HCQ alone( p-value 0.021). Median delta change was 63( IQR 25-81) and 48.5(IQR 26.25-66.75) msec; Median Day 2 QTc was 413.5 msec (IQR 377.5-436) and 413 msec (IQR361-447); and median maximum QTc was 447(IQR391-471) and 429.8(IQR401.5-45.75) msec in those receiving HCQ/AZM combination and HCQ alone respectively. 9%(12/134) had arrhythmias during hospital stay, in 8.9% (4) and 5.6%(2) patients of those receiving HCQ/AZM combination and HCQ alone respectively, no patient developed torsade de pointes, one patient had non-sustained VT. There was no statistically significant association of QTc prolongation with mortality, acute kidney injury, myocardial injury or severity of disease. Diuretic use was found to be statistically significant association with QTc prolongation(p-value 0.038). There was a weak correlation of baseline QTc with Δ QTc(r = 0.207 and p-value 0.017)ConclusionQTc prolongation was observed in a significant population of patients receiving HCQ and HCQ/AZM combination, however, no significant life threating arrhythmias occurred.

Rotatory nystagmus after granisetron administration

Background: Granisetron is a popular antiemetic medication used in the emergency department to control nausea and vomiting with an excellent side effect profile among adults and pediatric, in both healthy and oncology patients. Case Presentation: Our patient received granisetron for nausea and vomiting then developed torsional nystagmus, asymmetrical abnormal muscle contractions, and electrocardiography showed QTc prolongation 487 ms. The patient did improve after IV lorazepam and magnesium sulphate administration. Conclusion: QTc prolongation increases the risk of developing Torsades de Pointes and sudden death. Extrapyramidal syndrome caused by granisetron is rare and should not be confused with seizure. Both are significant effects associated with 5-HT3 antagonists administration to be aware of and if they occurred, should be managed in a timely fashion.

Evaluation of intramuscular olanzapine and ziprasidone in the medically ill.

IntroductionDespite the paucity of studies evaluating short-acting parenteral second-generation antipsychotics in the medically ill, their use in this population has increased. The purpose of this study was to characterize the use of IM olanzapine and ziprasidone in the medically ill at an academic medical center.MethodsThis is a retrospective medical record review of all patients who received IM olanzapine or ziprasidone on nonpsychiatric inpatient units at a large academic medical center from August 1, 2015 to July 31, 2017. The primary endpoint characterized the indication for use. Secondary endpoints included safety, effectiveness, and prescribing patterns.ResultsAfter exclusion criteria, a total of 100 patients were included in this study, predominantly white males with a mean age of 56 years. Seventy-four percent of patients received IM ziprasidone and 26% received IM olanzapine. The most common indications for use were agitation of nonpsychotic origin (40%) and delirium (33%). Patients received IM olanzapine and ziprasidone when their use was contraindicated (26.9% vs 9.5%, respectively).DiscussionIntramuscular second-generation antipsychotics are increasingly being used in the medically ill for delirium and agitation. Our study confirms these were the most common indications for IM second-generation antipsychotic use in this population. Additionally, their use appeared to be well-tolerated, and no patient developed Torsades de Pointes even when combined with other agents that putatively increase QTc. Given the retrospective, single-center, nonrandomized design of this study, the safety and effectiveness of these parenteral second-generation antipsychotics in common causes of acute agitation should continue to be further evaluated.

Torsade de pointes caused by hydroxychloroquine use in a patient with a severe form of COVID-19.

We report the case of a previously healthy patient who was severely affected by COVID-19 and developed torsade de pointes after hydroxychloroquine-azithromycin administration. Critically ill COVID-19 patients have multiple abnormalities that lead to an unsteady state in heart electricity, and can potentiate hydroxychloroquine cardiotoxicity. In light of this clinical observation, and until the efficacy of this association is proven, we plead against its use in critically ill COVID-19 patients.

In silico models for evaluating proarrhythmic risk of drugs.

Safety evaluation of drugs requires examination of the risk of generating Torsade de Pointes (TdP) because it can lead to sudden cardiac death. Until recently, the QT interval in the electrocardiogram (ECG) has been used in the evaluation of TdP risk because the QT interval is known to be associated with the development of TdP. Although TdP risk evaluation based on QT interval has been successful in removing drugs with TdP risk from the market, some safe drugs may have also been affected due to the low specificity of QT interval-based evaluation. For more accurate evaluation of drug safety, the comprehensive in vitro proarrhythmia assay (CiPA) has been proposed by regulatory agencies, industry, and academia. Although the CiPA initiative includes in silico evaluation of cellular action potential as a component, attempts to utilize in silico simulation in drug safety evaluation are expanding, even to simulating human ECG using biophysical three-dimensional models of the heart and torso under the effects of drugs. Here, we review recent developments in the use of in silico models for the evaluation of the proarrhythmic risk of drugs. We review the single cell, one-dimensional, two-dimensional, and three-dimensional models and their applications reported in the literature and discuss the possibility of utilizing ECG simulation in drug safety evaluation.