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Cardiac K+ channels are membrane-spanning proteins that allow the passive movement of K+ ions across the cell membrane along its electrochemical gradient. They regulate the resting membrane potential, the frequency of pacemaker cells and the shape and duration of the cardiac action potential. Additionally, they have been recognized as potential targets for the actions of neurotransmitters and hormones and class III antiarrhythmic drugs that prolong the action potential duration (APD) and refractoriness and have been found effective to prevent/suppress cardiac arrhythmias. In the human heart, K+ channels include voltage-gated channels, such as the rapidly activating and inactivating transient outward current (Ito1), the ultrarapid (IKur), rapid (IKr) and slow (IKs) components of the delayed rectifier current and the inward rectifier current (IK1), the ligand-gated channels, including the adenosine triphosphate-sensitive (IKATP) and the acetylcholine-activated (IKAch) currents and the leak channels. Changes in the expression of K+ channels explain the regional variations in the morphology and duration of the cardiac action potential among different cardiac regions and are influenced by heart rate, intracellular signalling pathways, drugs and cardiovascular disorders. A progressive number of cardiac and noncardiac drugs block cardiac K+ channels and can cause a marked prolongation of the action potential duration (i.e. an acquired long QT syndrome, LQTS) and a distinct polymorphic ventricular tachycardia termed torsades de pointes. In addition, mutations in the genes encoding IKr (KCNH2/KCNE2) and IKs (KCNQ1/KCNE1) channels have been identified in some types of the congenital long QT syndrome. This review concentrates on the function, molecular determinants, regulation and, particularly, on the mechanism of action of drugs modulating the K+ channels present in the sarcolemma of human cardiac myocytes that contribute to the different phases of the cardiac action potenti, Depto. de Farmacología y Toxicología, Fac. de Medicina, TRUE, pub

BackgroundThe short-coupled variant of torsade de pointes (sc-TdP) is a malignant arrhythmia that frequently presents with ventricular fibrillation (VF) electrical storm. Verapamil is considered the first-line therapy of sc-TdP while catheter ablation is not widely adopted. The aim of this study was to determine the origin of sc-TdP and to assess the outcome of catheter ablation using 3D-mapping.Methods and resultsWe retrospectively analyzed five patients with sc-TdP who underwent 3D-mapping and ablation of sc-TdP at five different institutions. Four patients initially presented with sudden cardiac arrest, one patient experienced recurrent syncope as the first manifestation. All patients demonstrated a monomorphic premature ventricular contraction (PVC) with late transition left bundle branch block pattern, superior axis, and a coupling interval of less than 300 ms. triggering recurrent TdP and VF. In four patients, the culprit PVC was mapped to the free wall insertion of the moderator band (MB) with a preceding Purkinje potential in two patients. Catheter ablation using 3D-mapping and intracardiac echocardiography eliminated sc-TdP in all patients, with no recurrence at mean 2.7 years (range 6 months to 8 years) of follow-up.Conclusion3D-mapping and intracardiac echocardiography demonstrate that sc-TdP predominantly originates from the MB free wall insertion and its Purkinje network. Catheter ablation of the culprit PVC at the MB free wall junction leads to excellent short- and long-term results and should be considered as first-line therapy in recurrent sc-TdP or electrical storm.

BackgroundThe short-coupled variant of torsade de pointes (sc-TdP) is a malignant arrhythmia that frequently presents with ventricular fibrillation (VF) electrical storm. Verapamil is considered the first-line therapy of sc-TdP while catheter ablation is not widely adopted. The aim of this study was to determine the origin of sc-TdP and to assess the outcome of catheter ablation using 3D-mapping.Methods and resultsWe retrospectively analyzed five patients with sc-TdP who underwent 3D-mapping and ablation of sc-TdP at five different institutions. Four patients initially presented with sudden cardiac arrest, one patient experienced recurrent syncope as the first manifestation. All patients demonstrated a monomorphic premature ventricular contraction (PVC) with late transition left bundle branch block pattern, superior axis, and a coupling interval of less than 300 ms. triggering recurrent TdP and VF. In four patients, the culprit PVC was mapped to the free wall insertion of the moderator band (MB) with a preceding Purkinje potential in two patients. Catheter ablation using 3D-mapping and intracardiac echocardiography eliminated sc-TdP in all patients, with no recurrence at mean 2.7 years (range 6 months to 8 years) of follow-up.Conclusion3D-mapping and intracardiac echocardiography demonstrate that sc-TdP predominantly originates from the MB free wall insertion and its Purkinje network. Catheter ablation of the culprit PVC at the MB free wall junction leads to excellent short- and long-term results and should be considered as first-line therapy in recurrent sc-TdP or electrical storm.

Introduction: Long QT syndrome (LQTS) is an uncommon disorder that can lead to potentially life-threatening dysrhythmias. LQTS can be genetic, acquired, or both.Case Report: A 44-year-old female with well-controlled hypertension and asthma presented with chest tightness. An initial electrocardiogram yielded a normal corrected QT interval of 423 milliseconds (ms) (normal <480 ms in females). Albuterol was administered and induced agitation, tremulousness, and tachycardia. Follow-up electrocardiograms demonstrated extreme prolongation of the corrected QT interval to 633 ms and morphology change of the T wave. Lab values were later notable for hypokalemia and hypomagnesemia, attributable to a recently started thiazide diuretic. The patient was ultimately diagnosed with congenital LQTS after initial unmasking by albuterol in the emergency department.Conclusion: LQTS can be unmasked or exacerbated by electrolyte abnormalities and QT prolonging medications.

BackgroundEpileptic seizures can be difficult to distinguish from other etiologies that cause cerebral hypoxia, especially cardiac diseases. Long QT syndrome (LQTS), especially LQTS type 2 (LQT2), frequently masquerades as seizures because of the transient cerebral hypoxia caused by ventricular arrhythmia. The high rate of sudden death in LQTS highlights the importance of accurate and early diagnosis; correct diagnosis of LQTS also prevents inappropriate treatment with anti-epileptic drugs (AEDs).Case presentationWe report a case of congenital LQT2 with potassium voltage-gated channel subfamily H member 2 gene (KCNH2) mutation misdiagnosed as refractory epilepsy and treated with various AEDs for 22 years. The possibility of cardiac arrhythmia was suspected after the patient presented to the emergency room and the electrocardiograph (ECG) monitor showed paroxysmal ventricular tachycardia during attacks. Atypical seizure like attacks with prodromal uncomfortable chest sensation and palpitation, triggered by auditory stimulation, and typical ventricular tachycardia monitored by ECG raised suspicion for LQT2, which was confirmed by exome sequencing and epileptic seizure was ruled out by 24-h EEG monitoring. Although the patient rejected implantation of an implantable cardioverter defibrillator, β blocker was given and the syncope only attacked 1-2 per year when there was an incentive during the 5 years follow up.ConclusionsOur case illustrates how long LQTS can masquerade convincingly as epilepsy and can be treated wrongly with AEDs, putting the patient at high risk of sudden cardiac death. Careful ECG evaluation is recommend for both patients with first seizure and those with refractory epilepsy.

Introduction: Long QT syndrome (LQTS) is an uncommon disorder that can lead to potentially life-threatening dysrhythmias. LQTS can be genetic, acquired, or both.Case Report: A 44-year-old female with well-controlled hypertension and asthma presented with chest tightness. An initial electrocardiogram yielded a normal corrected QT interval of 423 milliseconds (ms) (normal <480 ms in females). Albuterol was administered and induced agitation, tremulousness, and tachycardia. Follow-up electrocardiograms demonstrated extreme prolongation of the corrected QT interval to 633 ms and morphology change of the T wave. Lab values were later notable for hypokalemia and hypomagnesemia, attributable to a recently started thiazide diuretic. The patient was ultimately diagnosed with congenital LQTS after initial unmasking by albuterol in the emergency department.Conclusion: LQTS can be unmasked or exacerbated by electrolyte abnormalities and QT prolonging medications.

This project aims to support pharmacovigilance, the science and activities relating to drug-safety and prevention of adverse drug reactions (ADRs). We focus on a specific ADR called QT prolongation, a serious reaction affecting the heartbeat. Our main goal is to group medicinal ingredients that might cause QT prolongation. This grouping can be used in safety analysis and for exclusion lists in clinical studies. It should preferably be ranked according to level of suspected correlation. We wished to create an automated and standardised process. Drug safety-related reports describing patients' experienced ADRs and what medicinal products they have taken are collected in a database called VigiBase, that we have used as source for ingredient extraction. The ADRs are described in free-texts and coded using an international standardised terminology. This helps us to process the data and filter ingredients included in a report that describes QT prolongation. To broaden our project scope to include uncoded data, we extended the process to use free-text verbatims describing the ADR as input. By processing and filtering the free-text data and training a classification model for natural language processing released by Google on VigiBase data, we were able to predict if a free-text verbatim is describing QT prolongation. The classification resulted in an F1-score of 98%. For the ingredients extracted from VigiBase, we wanted to validate if there is a known connection to QT prolongation. The VigiBase occurrences is a parameter to consider, but it might be misleading since a report can include several drugs, and a drug can include several ingredients, making it hard to validate the cause. For validation, we used product labels connected to each ingredient of interest. We used a tool to download, scan and code product labels in order to see which ones mention QT prolongation. To rank our final list of ingredients according to level of suspected QT prolongation correlation, we used

Torsade de Pointes (TdP), a rare but lethal ventricular arrhythmia, is a toxic side effect of many drugs. To assess TdP risk, safety regulatory guidelines require quantification of hERG channel block in vitro and QT interval prolongation in vivo for all new therapeutic compounds. Unfortunately, these have proven to be poor predictors of torsadogenic risk, and are likely to have prevented safe compounds from reaching clinical phases. Although this has stimulated numerous efforts to define new paradigms for cardiac safety, none of the recently developed strategies accounts for patient conditions. In particular, despite being a well-established independent risk factor for TdP, female sex is vastly under-represented in both basic research and clinical studies, and thus current TdP metrics are likely biased toward the male sex. Here, we apply statistical learning to synthetic data, generated by simulating drug effects on cardiac myocyte models capturing male and female electrophysiology, to develop new sex-specific classification frameworks for TdP risk. We show that (i) TdP classifiers require different features in females vs. males; (ii) male-based classifiers perform more poorly when applied to female data; and (iii) female-based classifier performance is largely unaffected by acute effects of hormones (i.e., during various phases of the menstrual cycle). Notably, when predicting TdP risk of intermediate drugs on female simulated data, male-biased predictive models consistently underestimate TdP risk in women. Therefore, we conclude that pipelines for preclinical cardiotoxicity risk assessment should consider sex as a key variable to avoid potentially life-threatening consequences for the female population.

Hydroxychloroquine has been widely prescribed to treat patients with COVID-19 pneumonia. A 73-year-0ld woman with COVID-19 pneumonia was treated with dexamethasone and hydroxychloroquine. Her home medications, citalopram and donepezil, were continued. The ECG prior to starting hydroxychloroquine showed normal sinus rhythm with prolonged corrected QT (QTc) of 497 ms, due to citalopram and donepezil therapy. Repeat ECG on days 3 and 4 of hydroxychloroquine therapy showed significantly prolonged QTc of 557 ms and 538 ms, respectively, despite normal serum electrolytes. All QT-prolonging medications including hydroxychloroquine were discontinued on day 4; however, she suffered a transient torsades de pointes lasting for about 15 s, which resolved before any intervention. QTc improved to 477 ms, after discontinuation of QT-prolonging medications. The patient had QTc prolongation and torsades de pointes due to therapy with multiple QT-prolonging medications. Medicine reconciliation and careful monitoring of QTc may help prevent cardiac complications in patients with COVID-19 treated with hydroxychloroquine.

This project aims to support pharmacovigilance, the science and activities relating to drug-safety and prevention of adverse drug reactions (ADRs). We focus on a specific ADR called QT prolongation, a serious reaction affecting the heartbeat. Our main goal is to group medicinal ingredients that might cause QT prolongation. This grouping can be used in safety analysis and for exclusion lists in clinical studies. It should preferably be ranked according to level of suspected correlation. We wished to create an automated and standardised process. Drug safety-related reports describing patients' experienced ADRs and what medicinal products they have taken are collected in a database called VigiBase, that we have used as source for ingredient extraction. The ADRs are described in free-texts and coded using an international standardised terminology. This helps us to process the data and filter ingredients included in a report that describes QT prolongation. To broaden our project scope to include uncoded data, we extended the process to use free-text verbatims describing the ADR as input. By processing and filtering the free-text data and training a classification model for natural language processing released by Google on VigiBase data, we were able to predict if a free-text verbatim is describing QT prolongation. The classification resulted in an F1-score of 98%. For the ingredients extracted from VigiBase, we wanted to validate if there is a known connection to QT prolongation. The VigiBase occurrences is a parameter to consider, but it might be misleading since a report can include several drugs, and a drug can include several ingredients, making it hard to validate the cause. For validation, we used product labels connected to each ingredient of interest. We used a tool to download, scan and code product labels in order to see which ones mention QT prolongation. To rank our final list of ingredients according to level of suspected QT prolongation correlation, we used

Introduction Hydroxychloroquine (HCQ) has been proposed as a SARS-CoV-2 treatment but the frequency of long QT (LQT) during use is unknown.Objective To conduct a meta-analysis of the frequency of LQT in patients with SARS-CoV-2 infection treated with HCQ.Data Sources PubMed, EMBASE, Google Scholar, the Cochrane Database of Systematic Reviews and preprint servers (medRxiv, Research Square) were searched for studies published between December 2019 and June 30, 2020.Methods Effect statistics were pooled using random effects. The quality of observational studies and randomized controlled trials was appraised with STROBE and the Cochrane Risk of Bias Assessment tools, respectively.Outcomes Critical LQT was defined as: (1) maximum QT corrected (QTc) >= 500 ms (if QRS = 550 ms (if QRS >= 120 ms), and (2) QTc increase >= 60 ms.Results In the 28 studies included (n = 9124), the frequency of LQT during HCQ treatment was 6.7% (95% confidence interval [CI]: 3.7-10.2). In 20 studies (n = 7825), patients were also taking other QT-prolonging drugs. The frequency of LQT in the other 8 studies (n = 1299) was 1.7% (95% CI: 0.3-3.9). Twenty studies (n = 6869) reported HCQ discontinuation due to LQT, with a frequency of 3.7% (95% CI: 1.5-6.6). The frequency of ventricular arrhythmias during HCQ treatment was 1.68% (127/7539) and that of arrhythmogenic death was 0.69% (39/5648). Torsades de Pointes occurred in 0.06% (3/5066). Patients aged 60 years were at highest risk of HCQ-associated LQT (P <0.001).Conclusions HCQ-associated cardiotoxicity in SARS-CoV-2 patients is uncommon but requires ECG monitoring, particularly in those aged > 60 years and/or taking other QT-prolonging drugs. (C) 2020 Elsevier Ltd and International Society of Antimicrobial Chemotherapy. All rights reserved.

BackgroundLong QT syndrome 3 (LQT3) is caused by SCN5A mutations. Late sodium current (late I Na) inhibitors are current-specific to treat patients with LQT3, but the mechanisms underlying mexiletine (MEX) -sensitive (N1325S and R1623Q) and -insensitive (M1652R) mutations remains to be elucidated.MethodsLQT3 patients with causative mutations were treated with oral MEX following i.v. lidocaine. Whole-cell patch-clamp techniques and molecular remodeling were used to determine the mechanisms underlying the sensitivity to MEX.ResultsIntravenous administration of lidocaine followed by MEX orally in LQT patients with N1325S and R1623Q sodium channel mutation shortened QTc interval, abolished arrhythmias, and completely normalized the ECG. In HEK293 cells, the steady-state inactivation curves of the M1652R channels were rightward shifted by 5.6 mV relative to the WT channel. In contrast, the R1623Q mutation caused a leftward shift of the steady-state inactivation curve by 15.2 mV compared with WT channel, and N1325S mutation did not affect steady-state inactivation (n = 5-13, P < 0.05). The extent of the window current was expanded in all three mutant channels compared with WT. All three mutations increased late I Na with the greatest amplitude in the M1652R channel (n = 9-15, P < 0.05). MEX caused a hyperpolarizing shift of the steady-state inactivation and delayed the recovery of all three mutant channels. Furthermore, it suppressed late I Na in N1325S and R1623Q to a greater extent compared to that of M1652R mutant channel. Mutations altered the sensitivity of Nav1.5 to MEX through allosteric mechanisms by changing the conformation of Nav1.5 to become more or less favorable for MEX binding. Late I Na inhibitors suppressed late I Na in N1325S and R1623Q to a greater extent than that in the M1652R mutation (n = 4-7, P < 0.05).ConclusionThe N1325S, R1623Q, and M1652R mutations are associated with a variable augmentation of late I Na, which was reversed by MEX. M16

Acquired long QT syndrome is typically caused by medications, electrolyte disturbances, bradycardia, or catastrophic central nervous system events. We report a case of myocardial infarction-related acquired long QT syndrome in a 58-year-old woman that had no clear cause and progressed to torsades de pointes requiring treatment with isoproterenol and magnesium. Despite negative results of DNA testing against a known panel of genetic mutations and polymorphisms associated with long QT syndrome, the patient's family history of fatal cardiac disease suggests a predisposing genetic component. This report serves to remind clinicians of this potentially fatal ventricular arrhythmia after myocardial infarction.

BackgroundLong QT syndrome 3 (LQT3) is caused by SCN5A mutations. Late sodium current (late I Na) inhibitors are current-specific to treat patients with LQT3, but the mechanisms underlying mexiletine (MEX) -sensitive (N1325S and R1623Q) and -insensitive (M1652R) mutations remains to be elucidated.MethodsLQT3 patients with causative mutations were treated with oral MEX following i.v. lidocaine. Whole-cell patch-clamp techniques and molecular remodeling were used to determine the mechanisms underlying the sensitivity to MEX.ResultsIntravenous administration of lidocaine followed by MEX orally in LQT patients with N1325S and R1623Q sodium channel mutation shortened QTc interval, abolished arrhythmias, and completely normalized the ECG. In HEK293 cells, the steady-state inactivation curves of the M1652R channels were rightward shifted by 5.6 mV relative to the WT channel. In contrast, the R1623Q mutation caused a leftward shift of the steady-state inactivation curve by 15.2 mV compared with WT channel, and N1325S mutation did not affect steady-state inactivation (n = 5-13, P < 0.05). The extent of the window current was expanded in all three mutant channels compared with WT. All three mutations increased late I Na with the greatest amplitude in the M1652R channel (n = 9-15, P < 0.05). MEX caused a hyperpolarizing shift of the steady-state inactivation and delayed the recovery of all three mutant channels. Furthermore, it suppressed late I Na in N1325S and R1623Q to a greater extent compared to that of M1652R mutant channel. Mutations altered the sensitivity of Nav1.5 to MEX through allosteric mechanisms by changing the conformation of Nav1.5 to become more or less favorable for MEX binding. Late I Na inhibitors suppressed late I Na in N1325S and R1623Q to a greater extent than that in the M1652R mutation (n = 4-7, P < 0.05).ConclusionThe N1325S, R1623Q, and M1652R mutations are associated with a variable augmentation of late I Na, which was reversed by MEX. M16

ObjectivesThis study sought to determine the relationship between long QT syndrome (LQTS) subtype (LTQ1, LTQ2, LTQ3) and postnatal cardiac events (CEs).BackgroundLQTS presenting with 2:1 atrioventricular block or torsades de pointes in the fetus and/or neonate has been associated with risk for major CEs, but overall outcomes and predictors remain unknown.MethodsA retrospective study involving 25 international centers evaluated the course of fetuses/newborns diagnosed with congenital LQTS and either 2:1 atrioventricular block or torsades de pointes. The primary outcomes were age at first CE after dismissal from the newborn hospitalization and death and/or cardiac transplantation during follow-up. CE was defined as aborted cardiac arrest, appropriate shock from implantable cardioverter-defibrillator, or sudden cardiac death.ResultsA total of 84 fetuses and/or neonates were identified with LQTS (12 as LQT1, 35 as LQT2, 37 as LQT3). Median gestational age at delivery was 37 weeks (interquartile range: 35 to 39 weeks) and age at hospital discharge was 3 weeks (interquartile range: 2 to 5 weeks). Fetal demise occurred in 2 and pre-discharge death in 1. Over a median of 5.2 years, there were 1 LQT1, 3 LQT2, and 23 LQT3 CEs (13 aborted cardiac arrests, 5 sudden cardiac deaths, and 9 appropriate shocks). One patient with LQT1 and 11 patients with LQT3 died or received cardiac transplant during follow-up. The only multivariate predictor of post-discharge CEs was LQT3 status (LQT3 vs. LQT2: hazard ratio: 8.4; 95% confidence interval: 2.6 to 38.9; p < 0.001), and LQT3, relative to LQT2, genotype predicted death and/or cardiac transplant (p < 0.001).ConclusionsIn this large multicenter study, fetuses and/or neonates with LQT3 but not those with LQT1 or LQT2 presenting with severe arrhythmias were at high risk of not only frequent, but lethal CEs.

Torsade de pointes is a clinically important ventricular tachyarrhythmia that typi-cally appears in the presence of a long QT interval and which, without prompt identification and treatment, can lead to sudden cardiac death. The prolongation of QT and corrected QT intervals significantly increases the chance of this arrhyth-mia to appear in congenital or acquired long QT syndromes. In almost all patients, these intervals are markedly long in the period prior to the arrhythmic event. We describe a case of a female patient with a pacemaker who presented this arrhyth-mia and suffered several syncopal events., La torsade de pointes es una taquiarritmia ventricular de gran importancia clínica que aparece típicamente en presencia de un intervalo QT prolongado y que, sin identificación y tratamiento puntual, puede conducir a la muerte súbita cardíaca. La prolongación de los intervalos QT y QT corregido aumenta significativamente la posibilidad de que aparezca esta arritmia en los síndromes de QT largo congénitos o adquiridos. En casi todos los pacientes, dichos intervalos se encuentran marca-damente prolongados en el período previo al evento arrítmico. Se describe un caso de una paciente con marcapasos que presentó esta arritmia y sufrió varios episodios sincopales.

Congenital long QT syndrome is a primary electrical disorder of the heart which predisposes to the occurrence of malignant ventricular arrhythmias. It is charac-terized by a prolongation of the QT interval on the electrocardiogram and the tor-sade de pointes is the main associated arrhythmia, resulting in syncope and sud-den cardiac death. Pregnancy and puerperium increase the incidence of those events. We present the case of a patient who suffered from this disorder, and dur-ing the post-delivery period, she had events of faint and anxiety interpreted as psychogenic. Torsades de pointes without response to the available antiarrhyth-mic drugs was documented and she was transferred to the reference center (Insti-tuto de Cardiología y Cirugía Cardiovascular), where the pacemaker stimulation frequency was increased and, subsequently, an implantable cardioverter defibril-lator was implanted. This is an infrequent case that was a real challenge for the comprehensive and emergent treatment, all of which enabled the survival of the patient., El síndrome de QT largo congénito es una enfermedad eléctrica primaria del cora-zón que predispone a la ocurrencia de arritmias ventriculares malignas. Se tradu-ce en una prolongación del intervalo QT en el electrocardiograma y la torsión de puntas es la arritmia que ocasiona síncope y, en ocasiones, muerte súbita. El em-barazo y el puerperio aumentan la incidencia de estos eventos. Se presenta el caso de una puérpera afectada que presentó crisis de ansiedad y desmayos inter-pretados como psicógenos. Se documentó torsión de puntas sin respuesta a los fármacos antiarrítmicos diponibles y se trasladó al centro de referencia (Instituto de Cardiología y Cirugía Cardiovascular), donde se aumentó la frecuencia de esti-mulación del marcapasos y, posteriormente, se implantó un desfibrilador automá-tico. Se trata de un caso infrecuente que constituyó un verdadero reto en el trata-miento integral y emergente, todo lo cual posibilitó la supervivencia de la pacien-te.

Torsade de Pointes (TdP) is a type of ventricular tachycardia that is generally related to a QT interval prolongation due to congenital/ acquired causes or is associated to drugs. It is usually observed in the presence of corrected QT (cQT) above 440 milliseconds. It can also appear in patients without prolongation of this interval. TdP is usually characterized by a less disorganized rhythm than ventricular fibrillation (VF), appearing as paroxysmal episodes. The relevance of this case arises from the customary use of haloperidol in emergency services in agitated or aggressive patients or in patients with some kind of psychopathy. According to the literature, there are numerous investigations that have described a direct relationship in the appearance of TdP during intravenous administration of haloperidol. The objective of the case is to know the possible appearance of this arrhythmia in connection with the use of intravenous haloperidol and the development of a care plan focused on the patient. In order to carry out the study, an individualized care plan and a bibliographic search in different nursing methodology databases were performed. We present the case of a 28-year-old male with a psychiatric history who, after sedation with intravenous haloperidol, presented several self-limited TdP episodes. Following Virginia Henderson‘s conceptual model and the NANDA taxonomy by which we highlight the main diagnoses (00151) Self-mutilation, (00240) Risk of decreased cardiac output and (00062) Risk of exhaustion from the caregiver‘s role, and the results and interventions according to NOC and NIC taxonomies., La Torsade de Pointes (TdP) es un tipo de taquicardia ventricular que generalmente se relaciona con la prolongación del intervalo QT debido a causas congénitas/adquiridas o asociado a fármacos. Normalmente, se observa en presencia de QT corregidos (QTc) por encima de 440 milisegundos. También puede aparecer en pacientes sin prolongación de este intervalo. La TdP suele caracterizarse por ser un ritmo menos desorganizado que la fibrilación ventricular (FV), presentándose como episodios paroxísticos. La relevancia de este caso viene dada por el habitual uso del haloperidol en los servicios de urgencias en pacientes agitados, agresivos o con algún tipo de psicopatía. Según la bibliografía, existen numerosas investigaciones que han descrito una relación directa en la aparición de la TdP durante la administración intravenosa de haloperidol. El objetivo del caso es conocer la posible aparición de esta arritmia relacionada al uso de haloperidol intravenoso y la elaboración de un plan de cuidados dirigidos al paciente. Para realizar el estudio se desarrolló un plan de cuidados individualizado y una búsqueda bibliográfica en diferentes bases de datos de metodología enfermera. Presentamos un caso clínico de un varón de 28 años con antecedentes psiquiátricos que tras sedación con haloperidol intravenoso presentó varios episodios autolimitados de TdP. Siguiendo el modelo conceptual de Virginia Henderson y la taxonomía NANDA mediante la cual destacamos los diagnósticos principales (00151) Automutilación, (00240) Riesgo de disminución del gasto cardiaco y (00062) Riesgo de cansancio del rol del cuidador, y los resultados e intervenciones, según las taxonomías NOC y NIC.

BACKGROUND Long QT syndrome (LQTS) is an arrhythmogenic heart condition that can be congenital or acquired. Prolonged ventricular repolarizations in individuals with the disorder can cause fatal arrhythmias. Abnormal functioning of cardiac ion channels leads to arrhythmias such as torsades de pointes (TdP) and may be triggered by stress or medications. Many medications used in the perioperative period are triggers for the arrythmia. CASE REPORT A 7-year-old patient with known congenital LQTS type 2 presented for bilateral myringotomy and tube placement. The patient was otherwise healthy and taking propranolol daily. Preoperative midazolam was administered for anxiolysis, and induction of anesthesia was uneventful. He sustained an episode of TdP immediately following general anesthetic induction after failure of an in situ automatic implantable cardioverter-defibrillator (AICD). External defibrillation succeeded, and the patient was stabilized in the Postanesthesia Recovery Unit before transfer to the Pediatric Intensive Care Unit. Interrogation of the AICD revealed several undelivered defibrillation attempts. A chest X-ray showed an area suggestive of an epicardial electrode fracture. The following day, the AICD was replaced with no arrythmias noted. The patient had an uneventful recovery. CONCLUSIONS In patients with a known history of LQTS, preparation and prevention are cornerstones of anesthesia care. Minimizing the use of triggering medications and emotional stress in the perioperative period, combined with ready equipment and medications to respond to arrythmias, are essential. In children, there is a greater chance of lead fracture and resulting device failure. Preoperative history of device function or interrogation of the AICD and possibly a chest X-ray are essential to ensure the integrity of the leads.

Introduction Hydroxychloroquine (HCQ) has been proposed as a SARS-CoV-2 treatment but the frequency of long QT (LQT) during use is unknown.Objective To conduct a meta-analysis of the frequency of LQT in patients with SARS-CoV-2 infection treated with HCQ.Data Sources PubMed, EMBASE, Google Scholar, the Cochrane Database of Systematic Reviews and preprint servers (medRxiv, Research Square) were searched for studies published between December 2019 and June 30, 2020.Methods Effect statistics were pooled using random effects. The quality of observational studies and randomized controlled trials was appraised with STROBE and the Cochrane Risk of Bias Assessment tools, respectively.Outcomes Critical LQT was defined as: (1) maximum QT corrected (QTc) >= 500 ms (if QRS = 550 ms (if QRS >= 120 ms), and (2) QTc increase >= 60 ms.Results In the 28 studies included (n = 9124), the frequency of LQT during HCQ treatment was 6.7% (95% confidence interval [CI]: 3.7-10.2). In 20 studies (n = 7825), patients were also taking other QT-prolonging drugs. The frequency of LQT in the other 8 studies (n = 1299) was 1.7% (95% CI: 0.3-3.9). Twenty studies (n = 6869) reported HCQ discontinuation due to LQT, with a frequency of 3.7% (95% CI: 1.5-6.6). The frequency of ventricular arrhythmias during HCQ treatment was 1.68% (127/7539) and that of arrhythmogenic death was 0.69% (39/5648). Torsades de Pointes occurred in 0.06% (3/5066). Patients aged 60 years were at highest risk of HCQ-associated LQT (P <0.001).Conclusions HCQ-associated cardiotoxicity in SARS-CoV-2 patients is uncommon but requires ECG monitoring, particularly in those aged > 60 years and/or taking other QT-prolonging drugs. (C) 2020 Elsevier Ltd and International Society of Antimicrobial Chemotherapy. All rights reserved.

BACKGROUND: Male hypogonadism, arising from a range of etiologies including androgen-deprivation therapies (ADTs), has been reported as a risk factor for acquired long-QT syndrome (aLQTS) and torsades de pointes (TdP). A full description of the clinical features of aLQTS associated with ADT and of underlying mechanisms is lacking. METHODS: We searched the international pharmacovigilance database VigiBase for men (n=6 560 565 individual case safety reports) presenting with aLQTS, TdP, or sudden death associated with ADT. In cardiomyocytes derived from induced pluripotent stem cells from men, we studied electrophysiological effects of ADT and dihydrotestosterone. RESULTS: Among subjects receiving ADT in VigiBase, we identified 184 cases of aLQTS (n=168) and/or TdP (n=68; 11% fatal), and 99 with sudden death. Of the 10 ADT drugs examined, 7 had a disproportional association (reporting odds ratio=1.4-4.7; P<0.05) with aLQTS, TdP, or sudden death. The minimum and median times to sudden death were 0.25 and 92 days, respectively. The androgen receptor antagonist enzalutamide was associated with more deaths (5430/31 896 [17%]; P<0.0001) than other ADT used for prostate cancer (4208/52 089 [8.1%]). In induced pluripotent stem cells, acute and chronic enzalutamide (25 µM) significantly prolonged action potential durations (action potential duration at 90% when paced at 0.5 Hz; 429.7±27.1 (control) versus 982.4±33.2 (acute, P<0.001) and 1062.3±28.9 ms (chronic; P<0.001), and generated afterdepolarizations and/or triggered activity in drug-treated cells (11/20 acutely and 8/15 chronically). Enzalutamide acutely and chronically inhibited delayed rectifier potassium current, and chronically enhanced late sodium current. Dihydrotestosterone (30 nM) reversed enzalutamide electrophysiological effects on induced pluripotent stem cells. CONCLUSIONS: QT prolongation and TdP are a risk in men receiving enzalutamide and other ADTs. CLINICAL TRIAL REGISTRATION: URL: https://ww

OBJECTIVES:Methadone is often used in pediatric patients to prevent or treat opioid withdrawal after prolonged sedation. Prolonged corrected QT interval is an important adverse effect of methadone because it can progress to torsades de pointes, a potentially fatal dysrhythmia. The prevalence of corrected QT interval prolongation and contributing risk factors are not well defined in hospitalized pediatric patients receiving methadone. The study purpose was to identify the frequency and risk factors of corrected QT interval prolongation in hospitalized pediatric patients receiving methadone. DESIGN:Retrospective cohort study. SETTING:Tertiary academic pediatric hospital, University of California Davis Children's Hospital, Sacramento, CA. PATIENTS:Cohort of 89 pediatric patients (birth to 18 yr) who received at least one dose of methadone while hospitalized. INTERVENTIONS:Retrospective data over 7.5 years were obtained from the electronic health record. MEASUREMENTS AND MAIN RESULTS:From the cohort, 45 patients (50.6%) had documented corrected QT interval prolongation (≥ 450 ms) during the study period. No episodes of torsades de pointes were identified. In univariate analyses, higher maximum methadone doses were associated with a prolonged corrected QT interval (0.98 vs 0.59 mg/kg/d; odds ratio, 2.56; 1.15-5.70). Corrected QT interval prolongation occurred more frequently in patients with cardiac disease (63% vs 41%; p = 0.10). No factors were statistically significant in the multivariate analysis. CONCLUSIONS:In hospitalized pediatric patients receiving methadone, corrected QT interval prolongation was common, but no episodes of torsades de pointes were documented. Risk factors that have been identified in adults were not associated with prolongation in our study population.

AimThe aim of the study was to examine mortality risk associated with use of antidepressants and antipsychotics classified with torsades de pointes (TdP) risk in elderly. MethodsA matched case-control register study was conducted in people 65 years and older dying outside hospital from 2008-2013 (n=286092) and matched controls (n=1430460). The association between prescription of antidepressants and antipsychotics with various TdP risk according to CredibleMeds () and all-cause mortality was studied by multivariate conditional logistic regression adjusted for comorbidity and several other confounders. ResultsUse of antidepressants classified with known or possible TdP risk, was associated with higher adjusted risk for mortality (OR 1.53, 95% CI 1.51, 1.56 and OR 1.63, 95% CI 1.61, 1.67, respectively) compared with antidepressants classified with conditional TdP risk (OR 1.25, 95% CI 1.22, 1.28) or without TdP classification (OR 0.99, 95% CI 0.94, 1.05). Antipsychotics classified with known TdP risk were associated with higher risk (OR 4.57, 95% CI 4.37, 4.78) than antipsychotics with possible risk (OR 2.58, 95% CI 2.52, 2.64) or without TdP classification (OR 2.14, 95% CI 2.03, 2.65). The following risk ranking was observed for commonly used antidepressants: mirtazapine > citalopram > sertraline > amitriptyline and for antipsychotics: haloperidol > risperidone >olanzapine > quetiapine. ConclusionThe CredibleMeds system predicted drug-associated risk for mortality in the elderly at the risk class level. Among antipsychotics, haloperidol, and among antidepressants, mirtazapine and citalopram, were associated with the highest risks. The results suggest that the TdP risk with antidepressants and antipsychotics should be taken into consideration when prescribing to the elderly.

Female sex is an independent risk factor for development of torsade de pointes (TdP) arrhythmias not only in congenital long QT syndromes but also in acquired long QT syndromes. Clinical and experimental evidences suggest that the gender differences may be due to, at least in part, gender differences in regulation of rate-corrected QT (QTC) interval between men and women. In adult women, both QTC interval and arrhythmic risks in TdP alter cyclically during menstrual cycle, suggesting a critical role of female sex hormones in cardiac repolarization process. These gender differences in fundamental cardiac electrophysiology result from variable ion channel expression and diverse sex hormonal regulation via long term genomic and acute non-genomic actions, and sex differences in drug responses and metabolisms. In particular, non-genomic actions of testosterone and progesterone on cardiac ion channels are likely to contribute to the gender differences in cardiac repolarization processes. This review summarizes current knowledge on sex hormonal regulation of cardiac ion channels which contribute to cardiac repolarization processes and its implication for gender differences in drug-induced long QT syndromes.

BackgroundVentricular dysrhythmias are a serious consequence associated with drug overdose and chemical poisoning. The risk factors for the type of ventricular dysrhythmia and the outcomes by drug class are not well documented.ObjectiveThe aim of this study was to determine the most common drugs and chemicals associated with ventricular dysrhythmias and their outcomes.MethodsWe reviewed all human exposures reported to a statewide poison control system between 2002 and 2011 that had a documented ventricular dysrhythmia. Cases were differentiated into two groups by type of arrhythmia: (1) ventricular fibrillation and/or tachycardia (VT/VF); and (2) torsade de pointes (TdP).ResultsAmong the 300 potential cases identified, 148 cases met the inclusion criteria. Of these, 132 cases (89%) experienced an episode of VT or VF, while the remaining 16 cases (11%) had an episode of TdP. The most commonly involved therapeutic classes of drugs associated with VT/VF were antidepressants (33/132, 25%), stimulants (33/132, 25%), and diphenhydramine (16/132, 12.1%). Those associated with TdP were antidepressants (4/16, 25%), methadone (4/16, 25%), and antiarrhythmics (3/16, 18.75%). Drug exposures with the greatest risk of death in association with VT/VF were antidepressant exposure [odds ratio (OR) 1.71; 95% confidence interval (CI) 0.705-4.181] and antiarrhythmic exposure (OR 1.75; 95% CI 0.304-10.05), but neither association was statistically significant. Drug exposures with a statistically significant risk for TdP included methadone and antiarrhythmic drugs.ConclusionsAntidepressants and stimulants were the most common drugs associated with ventricular dysrhythmias. Patients with suspected poisonings by medications with a high risk of ventricular dysrhythmia warrant prompt ECG monitoring.

Torsades de Pointes is an extremely rare arrhythmia in children associated to LQT syndrome. Pheochromocytomas are also extremely rare tumours in the paediatric age. We present a case of a young patient with an acquired long QT syndrome complicating with Torsades de Pointes as first clinical manifestation of a pheochromocytoma.

BackgroundVentricular dysrhythmias are a serious consequence associated with drug overdose and chemical poisoning. The risk factors for the type of ventricular dysrhythmia and the outcomes by drug class are not well documented.ObjectiveThe aim of this study was to determine the most common drugs and chemicals associated with ventricular dysrhythmias and their outcomes.MethodsWe reviewed all human exposures reported to a statewide poison control system between 2002 and 2011 that had a documented ventricular dysrhythmia. Cases were differentiated into two groups by type of arrhythmia: (1) ventricular fibrillation and/or tachycardia (VT/VF); and (2) torsade de pointes (TdP).ResultsAmong the 300 potential cases identified, 148 cases met the inclusion criteria. Of these, 132 cases (89%) experienced an episode of VT or VF, while the remaining 16 cases (11%) had an episode of TdP. The most commonly involved therapeutic classes of drugs associated with VT/VF were antidepressants (33/132, 25%), stimulants (33/132, 25%), and diphenhydramine (16/132, 12.1%). Those associated with TdP were antidepressants (4/16, 25%), methadone (4/16, 25%), and antiarrhythmics (3/16, 18.75%). Drug exposures with the greatest risk of death in association with VT/VF were antidepressant exposure [odds ratio (OR) 1.71; 95% confidence interval (CI) 0.705-4.181] and antiarrhythmic exposure (OR 1.75; 95% CI 0.304-10.05), but neither association was statistically significant. Drug exposures with a statistically significant risk for TdP included methadone and antiarrhythmic drugs.ConclusionsAntidepressants and stimulants were the most common drugs associated with ventricular dysrhythmias. Patients with suspected poisonings by medications with a high risk of ventricular dysrhythmia warrant prompt ECG monitoring.

Many drugs can significantly inf luence cardiac repolarisation causing an increased duration of this repolarisation phase, challenging the repolarisation reserve. This may set the stage for life-threatening ventricular arrhythmias such as torsades de pointes (TdP). TdP generally occurs in conjunction with a prolonged QT interval (QT) on the electrocardiogram. The Dutch Poisons Information Centre (NVIC) often receives information requests about drugs that can influence the QT already at therapeutic dosages. Drug-induced QT prolongation is dose dependent and hence can be particularly pronounced in overdose situations. Also, additional risk factors for the development of life-threatening arrhythmias are often present in intoxicated patients. This review focuses on identification and management of drug-intoxicated patients who are at risk for a reduction in their repolarisation reserve, measured by their QT interval. The QT interval is strongly dependent on heart rate, which has led to the introduction of different methods to adjust the QT interval, i.e. the QTc. Bazett's formula, which has been used for decades, lacks accuracy concerning QTc calculation at higher and lower heart rates, situations often relevant when dealing with intoxicated patients. Additionally, we highlight drugs with QT-prolonging potential that are commonly associated with an overdose setting in Netherlands. Finally, standard treatment options specifically pointed toward the intoxicated patient at risk of QT prolongation and TdP will be discussed.

Introduction: Domperidone is a dopamine D2-receptor antagonist developed as an antiemetic and prokinetic agents. Oral domperidone is not approved in the US, but is used in many countries to treat nausea and vomiting, gastroparesis, and as a galactogogue (to promote lactation). The US Food and Drug Administration (FDA) have issued a warning about the cardiac safety of domperidone. Areas covered: The authors undertook a review of the cardiac safety of oral domperidone. Expert opinion: The data from preclinical studies are unambiguous in identifying domperidone as able to produce marked hERG channel inhibition and action potential prolongation at clinically relevant concentrations. The compound’s propensity to augment instability of action potential duration and action potential triangulation are also indicative of proarrhythmic potential. Domperidone should not be administered to subjects with pre-existing QT prolongation/LQTS, subjects receiving drugs that inhibit CYP3A4, subjects with electrolyte abnormalities or with other risk factors for QT-prolongation. With these provisos, it is possible that domperidone may be used as a galactogogue without direct risk to healthy breast feeding women but more safety information should be sought in this situation. Also, more safety information is required regarding risk to breast feeding infants or before domperidone is routinely used in gastroparesis or gastroesphageal reflux in children.

Pharmacovigilance in healthcare is essential for safe drug treatment. Spontaneous reporting is the most common source of information in the context of implementing label changes and taking a drug off the market. However, underreporting is found to be very prevalent. One way to decrease underreporting is to include different categories of healthcare professionals in such reporting and to investigate attitudes towards and incentives for reporting adverse drug reaction (ADR)s. As nurses form the largest group of health professionals, a sample of nurses were allowed and encouraged to report ADR during a 12 month period after they had received training in pharmacovigilance. A questionnaire posted to physicians and nurses investigated their knowledge and attitudes towards reporting. Spontaneous reports of torsade de pointes (TdP) and erectile dysfunction (ED) were scrutinized with respect to the reported drugs, risk factors and if the reaction was listed in the summary of product characteristics (SPC). After training, the nurses produced relevant reports and three years after the introduction of nurses in the reporting scheme, more than half of the responding nurses were aware of their role as reporters. Both nurses and physicians stated that the most important factor for reporting a suspected ADR was the severity of the ADR and an ADR arising in response to a newly approved drug. A web-based reporting system was deemed to facilitate the reporting. In spontaneous reports of TdP, citalopram was reported as a suspected drug. However, neither QT prolongations, nor TdP, were labelled in the SPC. ED was reported for all antihypertensive drugs including angiotensin II type I blockers. A positive information component (IC), assessing the disproportionality between the observed and the expected number of reports, was found indicating that ED was reported more often in association with antihypertensive drug classes, except for angiotensinconverting enzyme inhibitors. This thesis d

BackgroundA secondary rise of intracellular Ca(2+) (Cai) and an upregulation of apamin-sensitive K(+) current (I(KAS)) are characteristic findings of failing ventricular myocytes. We hypothesize that apamin, a specific I(KAS) blocker, may induce torsades de pointes (TdP) ventricular arrhythmia from failing ventricles exhibiting secondary rises of Cai.ObjectiveTo test the hypothesis that small conductance Ca(2+) activated IKAS maintains repolarization reserve and prevents ventricular arrhythmia in a rabbit model of heart failure (HF).MethodsWe performed Langendorff perfusion and optical mapping studies in 7 hearts with pacing-induced HF and in 5 normal control rabbit hearts. Atrioventricular block was created by cryoablation to allow pacing at slow rates.ResultsThe left ventricular ejection fraction reduced from 69.1% [95% confidence interval 62.3%-76.0%] before pacing to 30.4% [26.8%-34.0%] (N = 7; P < .001) after pacing. The corrected QT interval in failing ventricles was 337 [313-360] ms at baseline and 410 [381-439] ms after applying 100 nmol/L of apamin (P = .01). Apamin induced early afterdepolarizations (EADs) in 6 ventricles, premature ventricular beats (PVBs) in 7 ventricles, and polymorphic ventricular tachycardia consistent with TdP in 4 ventricles. The earliest activation site of EADs and PVBs always occurred at the site with long action potential duration and large amplitude of the secondary rises of Ca(i). Apamin induced secondary rises of Ca(i) in 1 nonfailing ventricle, but no EAD or TdP were observed.ConclusionsIn HF ventricles, apamin induces EADs, PVBs, and TdP from areas with secondary rises of Ca(i). I(KAS) is important in maintaining repolarization reserve and preventing TdP in HF ventricles.

Introduction: Ondansetron is a 5-HT3 receptor antagonist commonly used as an anti-emetic to prevent the nausea and vomiting associated with anti-cancer drugs, cancer radiotherapy, or postoperatively. Recently, the US Food and Drug Administration (FDA) issued a warning for ondansetron due to a potential for prolongation of the QT interval of the electrocardiogram (ECG), a phenomenon that is associated with an increased risk of the potentially fatal arrhythmia torsade de pointes. Areas covered: We undertook a review of the cardiac safety of ondansetron. Our primary sources of information were PubMed (with downloading of full articles), and the internet. Expert opinion: The dose of ondansetron that the FDA has concerns about is 32 mg iv (or several doses that are equivalent to this), which is only used in preventing nausea and vomiting associated with cancer chemotherapy. This suggests that ondansetron may be safe in the lower doses used to prevent the nausea and vomiting in radiation treatment or postoperatively. However, as there is a report that a lower dose of ondansetron prolonged the QT interval in healthy volunteers, this needs to be clarified by the FDA. More research needs to be undertaken of the relationship between QT prolongation and torsades in order that the FDA can produce clear-cut evidence of pro-arrhythmic risk when introducing warnings for this.

We present the case of a patient with initially insignificant coronary atherosclerosis with rapid progression revealed by dobutamine stress echocardiography, despite the absence of a major risk factor. A 61-year-old woman, complaining of chest pain, palpitations and dyspnoea on exertion, was referred to our department for outpatient assessment. Coronary angiography performed two months earlier revealed an insignificant stenosis of the proximal left anterior descending coronary artery. Holter monitoring revealed malignant ventricular arrhythmias during angina episodes.The results of maximal treadmill exercise testing were negative, but those of the dobutamine stress echocardiography were positive. The angiographic re-evaluation revealed a rapid progression of stenosis of the proximal left anterior descending coronary artery. Percutaneous coronary angioplasty with stenting was successfully performed.The outcome of patients with insignificant angiographic stenosis and no major risk factor is not necessarily favourable. Therefore, these patients should receive intensive therapy for the management of risk factors and careful clinical monitoring, including dobutamine stress echocardiography.

BackgroundA secondary rise of intracellular Ca(2+) (Cai) and an upregulation of apamin-sensitive K(+) current (I(KAS)) are characteristic findings of failing ventricular myocytes. We hypothesize that apamin, a specific I(KAS) blocker, may induce torsades de pointes (TdP) ventricular arrhythmia from failing ventricles exhibiting secondary rises of Cai.ObjectiveTo test the hypothesis that small conductance Ca(2+) activated IKAS maintains repolarization reserve and prevents ventricular arrhythmia in a rabbit model of heart failure (HF).MethodsWe performed Langendorff perfusion and optical mapping studies in 7 hearts with pacing-induced HF and in 5 normal control rabbit hearts. Atrioventricular block was created by cryoablation to allow pacing at slow rates.ResultsThe left ventricular ejection fraction reduced from 69.1% [95% confidence interval 62.3%-76.0%] before pacing to 30.4% [26.8%-34.0%] (N = 7; P < .001) after pacing. The corrected QT interval in failing ventricles was 337 [313-360] ms at baseline and 410 [381-439] ms after applying 100 nmol/L of apamin (P = .01). Apamin induced early afterdepolarizations (EADs) in 6 ventricles, premature ventricular beats (PVBs) in 7 ventricles, and polymorphic ventricular tachycardia consistent with TdP in 4 ventricles. The earliest activation site of EADs and PVBs always occurred at the site with long action potential duration and large amplitude of the secondary rises of Ca(i). Apamin induced secondary rises of Ca(i) in 1 nonfailing ventricle, but no EAD or TdP were observed.ConclusionsIn HF ventricles, apamin induces EADs, PVBs, and TdP from areas with secondary rises of Ca(i). I(KAS) is important in maintaining repolarization reserve and preventing TdP in HF ventricles.

Pharmacovigilance in healthcare is essential for safe drug treatment. Spontaneous reporting is the most common source of information in the context of implementing label changes and taking a drug off the market. However, underreporting is found to be very prevalent. One way to decrease underreporting is to include different categories of healthcare professionals in such reporting and to investigate attitudes towards and incentives for reporting adverse drug reaction (ADR)s. As nurses form the largest group of health professionals, a sample of nurses were allowed and encouraged to report ADR during a 12 month period after they had received training in pharmacovigilance. A questionnaire posted to physicians and nurses investigated their knowledge and attitudes towards reporting. Spontaneous reports of torsade de pointes (TdP) and erectile dysfunction (ED) were scrutinized with respect to the reported drugs, risk factors and if the reaction was listed in the summary of product characteristics (SPC). After training, the nurses produced relevant reports and three years after the introduction of nurses in the reporting scheme, more than half of the responding nurses were aware of their role as reporters. Both nurses and physicians stated that the most important factor for reporting a suspected ADR was the severity of the ADR and an ADR arising in response to a newly approved drug. A web-based reporting system was deemed to facilitate the reporting. In spontaneous reports of TdP, citalopram was reported as a suspected drug. However, neither QT prolongations, nor TdP, were labelled in the SPC. ED was reported for all antihypertensive drugs including angiotensin II type I blockers. A positive information component (IC), assessing the disproportionality between the observed and the expected number of reports, was found indicating that ED was reported more often in association with antihypertensive drug classes, except for angiotensinconverting enzyme inhibitors. This thesis d

Pharmacovigilance in healthcare is essential for safe drug treatment. Spontaneous reporting is the most common source of information in the context of implementing label changes and taking a drug off the market. However, underreporting is found to be very prevalent. One way to decrease underreporting is to include different categories of healthcare professionals in such reporting and to investigate attitudes towards and incentives for reporting adverse drug reaction (ADR)s. As nurses form the largest group of health professionals, a sample of nurses were allowed and encouraged to report ADR during a 12 month period after they had received training in pharmacovigilance. A questionnaire posted to physicians and nurses investigated their knowledge and attitudes towards reporting. Spontaneous reports of torsade de pointes (TdP) and erectile dysfunction (ED) were scrutinized with respect to the reported drugs, risk factors and if the reaction was listed in the summary of product characteristics (SPC). After training, the nurses produced relevant reports and three years after the introduction of nurses in the reporting scheme, more than half of the responding nurses were aware of their role as reporters. Both nurses and physicians stated that the most important factor for reporting a suspected ADR was the severity of the ADR and an ADR arising in response to a newly approved drug. A web-based reporting system was deemed to facilitate the reporting. In spontaneous reports of TdP, citalopram was reported as a suspected drug. However, neither QT prolongations, nor TdP, were labelled in the SPC. ED was reported for all antihypertensive drugs including angiotensin II type I blockers. A positive information component (IC), assessing the disproportionality between the observed and the expected number of reports, was found indicating that ED was reported more often in association with antihypertensive drug classes, except for angiotensinconverting enzyme inhibitors. This thesis d

Pharmacovigilance in healthcare is essential for safe drug treatment. Spontaneous reporting is the most common source of information in the context of implementing label changes and taking a drug off the market. However, underreporting is found to be very prevalent. One way to decrease underreporting is to include different categories of healthcare professionals in such reporting and to investigate attitudes towards and incentives for reporting adverse drug reaction (ADR)s. As nurses form the largest group of health professionals, a sample of nurses were allowed and encouraged to report ADR during a 12 month period after they had received training in pharmacovigilance. A questionnaire posted to physicians and nurses investigated their knowledge and attitudes towards reporting. Spontaneous reports of torsade de pointes (TdP) and erectile dysfunction (ED) were scrutinized with respect to the reported drugs, risk factors and if the reaction was listed in the summary of product characteristics (SPC). After training, the nurses produced relevant reports and three years after the introduction of nurses in the reporting scheme, more than half of the responding nurses were aware of their role as reporters. Both nurses and physicians stated that the most important factor for reporting a suspected ADR was the severity of the ADR and an ADR arising in response to a newly approved drug. A web-based reporting system was deemed to facilitate the reporting. In spontaneous reports of TdP, citalopram was reported as a suspected drug. However, neither QT prolongations, nor TdP, were labelled in the SPC. ED was reported for all antihypertensive drugs including angiotensin II type I blockers. A positive information component (IC), assessing the disproportionality between the observed and the expected number of reports, was found indicating that ED was reported more often in association with antihypertensive drug classes, except for angiotensinconverting enzyme inhibitors. This thesis d

Pharmacovigilance in healthcare is essential for safe drug treatment. Spontaneous reporting is the most common source of information in the context of implementing label changes and taking a drug off the market. However, underreporting is found to be very prevalent. One way to decrease underreporting is to include different categories of healthcare professionals in such reporting and to investigate attitudes towards and incentives for reporting adverse drug reaction (ADR)s. As nurses form the largest group of health professionals, a sample of nurses were allowed and encouraged to report ADR during a 12 month period after they had received training in pharmacovigilance. A questionnaire posted to physicians and nurses investigated their knowledge and attitudes towards reporting. Spontaneous reports of torsade de pointes (TdP) and erectile dysfunction (ED) were scrutinized with respect to the reported drugs, risk factors and if the reaction was listed in the summary of product characteristics (SPC). After training, the nurses produced relevant reports and three years after the introduction of nurses in the reporting scheme, more than half of the responding nurses were aware of their role as reporters. Both nurses and physicians stated that the most important factor for reporting a suspected ADR was the severity of the ADR and an ADR arising in response to a newly approved drug. A web-based reporting system was deemed to facilitate the reporting. In spontaneous reports of TdP, citalopram was reported as a suspected drug. However, neither QT prolongations, nor TdP, were labelled in the SPC. ED was reported for all antihypertensive drugs including angiotensin II type I blockers. A positive information component (IC), assessing the disproportionality between the observed and the expected number of reports, was found indicating that ED was reported more often in association with antihypertensive drug classes, except for angiotensinconverting enzyme inhibitors. This thesis d

Two cases of liver cirrhosis complicated with QT interval prolongation syndrome are reported. The first case was a 64-year-old female. She was admitted to our hospital because of pleural effusion and hypoalbuminemia, and diagnosed as having decompensated liver cirrhosis. DB-cAMP was administered for liver cirrhosis. Eighteen days later, QT interval prolonged and ventricular tachycardia occurred. Laboratory tests revealed hypopotassemia and hypocalcemia. The second case was a 76-year-old female. She had been treated with glycyrrhizin for liver cirrhosis since ten years before. She was admitted because of QT interval prolongation and ventricular tachycardia. Laboratory tests revealed hypopotassemia, hypocalcemia and hypomagnesemia. In both of these cases, electrocardiogram showed Torsades de Pointes and cardioversion were not effective. Torsades de Pointes returned to sinus rhythm by right ventricular pacing and correction of both hypopotassemia and hypocalcemia. Based on the study of these cases, it is concluded that electrocardiogram is sometimes necessary for the management of liver cirrhosis.

QT interval prolongation on the electrocardiogram is a marker of abnormal ventricular repolarization and is associated with Torsades de Pointes, sudden death, and all-cause mortality in outpatient samples. This is the first inpatient study of acutely ill adults performed to determine the: 1) need for QT monitoring as outlined in American Heart Association (AHA) guidelines, 2) prevalence and predictors of QT prolongation, 3) association of QT prolongation with hospital length of stay and all-cause mortality and 4) ability of acute care nurses to perform accurate QT measurement by routine manual methods. Methods: Special study software (Philips Healthcare, Andover, MA) was installed to measure the QT and heart-rate-corrected QT (QTc) interval every minute in all patients admitted to 5 hospital units over a 2-month period. Patient data were abstracted directly from the medical record. Nurses' knowledge and skills were assessed by pre-post tests conducted during QT-related classes repeated 44 times on all nursing shifts. Nurses were taught how to measure the QT interval from a rhythm strip using hand-held calipers and to calculate the QTc using the Bazett formula. Results: Patients. 67,648 hours of QT data were obtained from 1039 patients. 73% of patients had at least 1 AHA indication for QT monitoring. 24% had an episode of dangerous QT interval prolongation > 500 milliseconds lasting 15 minutes or more. In a multivariate logistic regression analysis, predictors of QT prolongation were female sex, number of proarrhythmic drugs, low potassium or calcium, high glucose or creatinine, and history of stroke or hypothyroidism. An episode of QT prolongation was associated with longer length of stay (11.53 v 5.52 days, p <.0005) and greater all-cause mortality (8.7% v 2.6%, Fishers exact p < .0005). Patients with QT prolongation had 3 times the odds for all-cause mortality than those without (OR 2.99; 95% C.I., 1.1 - 8.1). Nurses. 391 participated in the classes (81.5

QT interval prolongation on the electrocardiogram is a marker of abnormal ventricular repolarization and is associated with Torsades de Pointes, sudden death, and all-cause mortality in outpatient samples. This is the first inpatient study of acutely ill adults performed to determine the: 1) need for QT monitoring as outlined in American Heart Association (AHA) guidelines, 2) prevalence and predictors of QT prolongation, 3) association of QT prolongation with hospital length of stay and all-cause mortality and 4) ability of acute care nurses to perform accurate QT measurement by routine manual methods. Methods: Special study software (Philips Healthcare, Andover, MA) was installed to measure the QT and heart-rate-corrected QT (QTc) interval every minute in all patients admitted to 5 hospital units over a 2-month period. Patient data were abstracted directly from the medical record. Nurses' knowledge and skills were assessed by pre-post tests conducted during QT-related classes repeated 44 times on all nursing shifts. Nurses were taught how to measure the QT interval from a rhythm strip using hand-held calipers and to calculate the QTc using the Bazett formula. Results: Patients. 67,648 hours of QT data were obtained from 1039 patients. 73% of patients had at least 1 AHA indication for QT monitoring. 24% had an episode of dangerous QT interval prolongation > 500 milliseconds lasting 15 minutes or more. In a multivariate logistic regression analysis, predictors of QT prolongation were female sex, number of proarrhythmic drugs, low potassium or calcium, high glucose or creatinine, and history of stroke or hypothyroidism. An episode of QT prolongation was associated with longer length of stay (11.53 v 5.52 days, p <.0005) and greater all-cause mortality (8.7% v 2.6%, Fishers exact p < .0005). Patients with QT prolongation had 3 times the odds for all-cause mortality than those without (OR 2.99; 95% C.I., 1.1 - 8.1). Nurses. 391 participated in the classes (81.5

This study adds the dimension of a T-wave morphology composite score (MCS) to the QTc interval-based evaluation of drugs that affect cardiac repolarization. Electrocardiographic recordings from 62 subjects on placebo and 400 mg moxifloxacin were compared with those from 21 subjects on 160 and 320 mg D,L-sotalol. T-wave morphology changes, as assessed by DeltaMCS, are larger after 320 mg D,L-sotalol than after 160 mg D,L-sotalol; and the changes associated with 160 mg D,L-sotalol are, in turn, larger than those associated with moxifloxacin and placebo. Covariate analyses of DeltaQTc and DeltaMCS showed that changes in T-wave morphology are a significant effect of D,L-sotalol. By contrast, moxifloxacin was found to have no significant effect on T-wave morphology (DeltaMCS) at any given change in QTc. This study offers new insights into the repolarization behavior of a drug associated with low cardiac risk vs. one associated with a high risk and describes the added benefits of a T-wave MCS as a covariate to the assessment of the QTc interval.

Recent research suggests that other surrogate markers than QTc, including QTc dispersion and Tpeak-Tend, may better correlate with cardiac arrhythmia risk. While sertindole significantly prolongs the QTc interval, the effects on other markers of arrhythmia risk, such as QTc dispersion and Tpeak-Tend are unknown.

This study adds the dimension of a T-wave morphology composite score (MCS) to the QTc interval-based evaluation of drugs that affect cardiac repolarization. Electrocardiographic recordings from 62 subjects on placebo and 400 mg moxifloxacin were compared with those from 21 subjects on 160 and 320 mg D,L-sotalol. T-wave morphology changes, as assessed by DeltaMCS, are larger after 320 mg D,L-sotalol than after 160 mg D,L-sotalol; and the changes associated with 160 mg D,L-sotalol are, in turn, larger than those associated with moxifloxacin and placebo. Covariate analyses of DeltaQTc and DeltaMCS showed that changes in T-wave morphology are a significant effect of D,L-sotalol. By contrast, moxifloxacin was found to have no significant effect on T-wave morphology (DeltaMCS) at any given change in QTc. This study offers new insights into the repolarization behavior of a drug associated with low cardiac risk vs. one associated with a high risk and describes the added benefits of a T-wave MCS as a covariate to the assessment of the QTc interval.