解读“院内获得性TdP防治(2010)专家共识”

<正>抗心律失常药物的致心律失常作用及安全性问题严重干扰着临床用药,临床医师唯恐发生意外,尤其担心药物引发尖端扭转型室速(TdP)及室颤。本文解读"院内获得性TdP防治(2010)专家共识",通过讨论几个关键性问题,希望能提高对这一问题的认识水平。     

贝达喹啉药代动力学和药物相互作用研究进展

贝达喹啉作为抗结核新药,多与其他二线抗结核药物联合使用。鉴于目前有关贝达喹啉药代动力学文献逐渐增加,以及部分临床医生对其药代动力学尤其药物相互作用方面内容了解有限,本综述对药代动力学参数、协变量对药代动力学影响、暴露-反应关系、药物相互作用等内容进行总结,为指导临床医生用药和科研人员开展研究提供帮助。     

间歇依赖性长QT综合征扭转型室速/室颤(附八例报告)

间歇依赖性LQTS患者发生TdP后少数可恶化成VF。对心脏病患者凡心动过缓，特别是伴低血钾、低血镁者，使用可引起QT间期延长药物者，有晕厥史，尤其有TdP史者，均应视为TdP高危患者，而行严密心电及血电解质监测，注意TdP的预兆性征象以期早诊断、早防治。当有关致病因素合并存在时可致病情复杂化及病程绵延。强调综合治疗，予镁盐、钾盐治疗时疗程宜长，以防病情反复。     

伊布利特致心律失常及安全性评价

目的:探讨静脉应用伊布利特的安全性。方法:结合2例心房颤动射频消融术后患者于静脉推注伊布利特后出现的心律失常并复习相关文献。结果:伊布利特的最严重不良反应为多形性室性心动过速,尖端扭转性室性心动过速(TdP)为表现之一,发生率为1%～8%,TdP一般发生于用药40min内。其防治措施如下:用药前电解质异常患者应纠正电解质;用药期间进行心电监测;女性患者较男性更易出现心律失常,应予以注意;一旦出现TdP应立即停药,给予电复律,同时给予药物异丙基肾上腺素、阿托品、钾镁及β受体阻滞剂。结论:伊布利特引起心室肌复极异常与早期后除极致触发活动有关。     

获得性长QT间期综合征的防治建议

前言 长QT间期综合征(long QT syndrome,LQTS)亦称QT间期延长综合征,是一种心室复极时程延长、不均一性增大的疾病.心电图上表现为QT间期延长、T波和(或)U波异常、早搏后的代偿间歇及心率减慢时易于发生尖端扭转型室性心动过速(torsade de pointes,TdP).临床表现以晕厥、搐搦或猝死为特征的临床综合征.LQTS可以是先天性,也可以是获得性.先天性LQTS是一种由基因缺陷引起复极异常的遗传性心脏病.获得性LQTS是指由药物、心脏疾病[心力衰竭(心衰)、心肌缺血、心动过缓等]或者代谢异常等因素引起的以可逆性QT间期延长伴TdP发作的临床综合征,其中药物性LQTS最常见.本建议重点放在药物引起的获得性QT间期延长伴TdP的防治.     

重庆市临床医生丙型病毒性肝炎防治知识知晓率调查北大核心CSCD

目的 了解临床医务人员对丙型病毒性肝炎（简称丙肝）防治知识认知现状,为下一步防治工作提供参考。方法 采用问卷调查的方式对重庆市4家医院的临床医生开展丙肝防治基本知识及专业知识知晓率调查,并对调查结果进行统计分析。结果 共调查413名临床医生,医生对丙肝防治基本知识知晓率为94.4%,三级医院医生知晓率高于二级医院（OR=6.078,95%CI:2.339～15.791）,其中医生对“丙肝可以治愈”知晓率最低（83.3%）。医生对丙肝防治专业知识知晓率为35.6%,三级医院（OR=11.581,95%CI:5.819～23.051）、内科医生（OR=1.898,95%CI:1.009～3.572）、工作年限6～10年（OR=2.976,95%CI:1.655～5.351）及10年以上（OR=2.737,95%CI:1.524～4.913）者知晓率更高。医生对丙肝病例的诊断分类及临床病例的诊断依据认知最低,完全正确认知率分别为24.2%和29.1%;仅有40.7%的医生能完全认知感染HCV的高风险人群,61.7%的医生能完全正确认知HCV筛查的实验室检测项目,49.6%的医生认为治疗丙肝最有效的药物是直接抗病毒药物（DAAs）。结论 重庆市临床医生对丙肝防治专业知识知晓率较低,今后应加强医务人员丙肝防治专业知识的培训,从而提高丙肝病例发现率和诊治水平。     

湖南省县级医院支气管哮喘防控现状分析

目的了解湖南省基层地区哮喘防控现状。方法采用问卷调查方式,于2009年4月共调查湖南省72家县级医院,每家医院抽取1名哮喘归口科室医生,共72名医生接受调查。结果仅有20.83%(15/72)的医院开展肺通气功能检查,但均未开展支气管激发试验或舒张试验。仅有48.61%的医生选择吸入型糖皮质激素作为一线药物,而30.56%和9.72%的医生分别将口服激素和静脉应用激素作为一线药物。中(成)药、肾上腺素等非常规药物被部分医生作为一线药物应用。仅有19.44%的医生表示了解并且执行了哮喘指南,多数医生处于"听说过但不了解(50%)"及"了解但从未执行(26.39%)"的状态。91.67%(66/72)的医生对哮喘的防控现状不满意,其中86.36%(57/66)的医生认为其主要原因是经济因素。结论推出适合基层应用的改良哮喘防治方案势在必行。     

浙江省基层医生高血压防治知识知晓情况调查分析

目的了解浙江省基层医院社区医生对《中国高血压防治指南》知识的知晓情况,为进一步开展基层医生高血压防治知识培训工作提供参考。方法于2005—2008年,对全省91区/县基层医院11200名基层医生进行了为期3 d的《中国高血压防治指南》培训。培训前采用不记名、闭卷笔试,并在规定时间内完成的方式,进行高血压病相关新知识,临床治疗新观念的调查。结果培训前仅有27.3%基层医生读过《中国高血压防治指南》;高血压危险因素回答正确率为33.2%,仅8.5%和15.7%的基层医生能正确回答高血压诊断标准、血压水平分级,24.4%的基层医生正确回答高血压的非药物治疗措施,同时仅有44.6%和39.4%的基层医生能正确回答降压治疗原则和降压药物的主要不良反应和禁忌证;培训后基层医生高血压防治知识和临床诊治理念有了明显改善,高血压危险因素、高血压诊断、血压水平分级、非药物治疗内容、药物治疗原则和降压药物的不良反应和禁忌证的回答正确率分别提高到82.2%、84.2%、87.2%、79.8%和76.3%、82.3%。结论基层医生关于高血压的新知识和临床诊治新理念处于较低的水平,开展《中国高血压防治指南》普及培训十分必要。     

北京市不同级别医院医生冠心病临床诊断和处理能力的评价

目的:了解北京市二级医院、一级医院和社区卫生服务中心(站)医生诊断和处理冠心病临床病例的能力。方法:2006年4月至2006年12月,采用不记名闭卷笔试的方法对北京市3个城区和6个郊区共671名医生实施"医务人员冠心病防治知识及能力"问卷调查。结果:1.51%的医生把症状和心电图疑似冠心病的诊断为冠心病;64%的医生把症状和心电图疑似稳定性心绞痛的按照冠心病进行处理。2.36%的医生能够为急性心肌梗死患者采取正确的院前急救处理措施,仅有16%的医生为冠心病患者选择的二级预防药物完全符合冠心病指南的规定。3.医生的冠心病诊疗水平总体上没有明显的城乡和学历差异。结论:医生在诊断和处理临床常见的冠心病过程中存在较多问题,应该采取相应措施提高医生的诊治水平。     

药物诱导的自身免疫性肝炎的研究进展

药物诱导的自身免疫性肝炎是由药物触发自身免疫系统导致的肝损伤,约占药物性肝损伤的6%~22%。目前,药物诱导的自身免疫性肝炎的发病机制尚未完全阐明,亦无特异性的诊断标准,临床诊断困难。重点介绍药物诱导的自身免疫性肝炎的发病情况、危险因素、发病机制、临床特征等方面的研究进展,以增强临床医生对这一特殊类型肝损伤的认识,提高对药物诱导的自身免疫性肝炎的诊断及治疗水平。     

尖端扭转型室性心动过速的院内预防

药物引起的获得性长QT综合征中由于尖端扭转型室性心动过速引发的心脏骤停尽管罕见但却是致命的,尤其对于住院病人。现综述尖端扭转型室性心动过速的心电图特征、即将发生心律失常的征兆、获得性长QT综合征的细胞学机制、当前对于遗传易感性的认识、最容易引起尖端扭转型室性心动过速的药物、医院内监测QT间期的方法、QT显著延长和尖端扭转型室性心动过速的即刻处理策略等,为尖端扭转型室性心动过速的院内预防提供参考。     

Drugs that cause torsades de pointes and increase the risk of sudden cardiac death

Torsades de pointes (TdP) is a potentially life-threatening arrhythmia associated with not only antiarrhythmic drugs, but noncardiac drugs of many different classes. All these drugs prolong the QT interval by their blocking of the potassium channel IKr, and many are metabolized by the cytochrome P450 isoenzyme CYP3A4. Polypharmacy with other drugs utilizing the same enzyme, or inhibiting CYP3A4, can lead to TdP. A consistent finding of all the QT-prolonging drugs is predominance of TdP in women. Other risk factors for QT prolongation and TdP include hypokalemia, congestive heart failure, and structural heart disease. Knowledge of potential drug interactions and other risk factors for TdP can help in reducing the number of adverse events associated with the use of QT-prolonging drugs.     

Torsades de pointes: Prevention and therapy

Torsades de pointes (TdP) is a life-threatening ventricular tachycardia that occurs in the setting of a prolonged QT interval and is most frequently related to administration of antiarrhythmic drugs. Patients with organic heart disease, with low serum electrolyte levels, with a previous episode of TdP and with bradycardia or baseline QT prolongation may be at increased risk of developing TdP. After initiation of a QT prolonging therapy, the dosage should be modified if the QT interval reaches 560-600 ms. Cessation of medication and immediate hospitalization are indicated in the presence of lightheadedness, syncope, or increased frequency and complexity of ventricular premature beats. The conventional therapy of TdP with isoproterenol or cardiac pacing, although usually effective, has certain disadvantages. Isoproterenol is contraindicated in patients with hypertension or ischemic heart disease, whereas institution of cardiac pacing requires skilled personnel and fluoroscopy. Recently, infusion of magnesium sulfate has been shown to abolish TdP both in the clinical and experimental setting. Compared with conventional therapy, magnesium sulfate has the advantage of safety and simplicity of its administration. In doubtful cases, if does not aggravate a ventricular tachycardia that is not TdP, as may occur with isoproterenol. This advantage and the prompt effectiveness of the drug in four clinical series, including 31 patients, support the use of magnesium sulfate as the first line of therapy for TdP.     

Double jeopardy

Torsades de pointes (“twisting of points”) (TdP) is a broad complex tachyarrhythmia which was first described in 1966 by Francois Dessertenne and usually results from prolongation of the QT interval.¹ A wide variety of drugs have been shown to prolong the QT interval in susceptible individuals.² We present the case of a former intravenous heroin user presenting with several episodes of TdP which were caused by QT prolongation due to methadone treatment and exacerbated by hepatitis B/C infection. Despite aggressive medical treatment and withdrawal of methadone, he had recurrent episodes of TdP which required continuous temporary cardiac pacing for six days. He was found to have moderate LV dysfunction on his echocardiogram and unobstructed coronary arteries on coronary angiography. He underwent implantation of a defibrillator due to concerns about further episodes of ventricular arrhythmias which could recur even in the absence of further methadone use.     

Role of a KCNH2 polymorphism (R1047 L) in dofetilide-induced Torsades de Pointes

Various drugs are reported to prolong the QT-interval on the surface ECG, thereby increasing the risk of developing a potentially fatal arrhythmia known as Torsades de Pointes (TdP). TdP case reports for these drugs have often been associated with risk factors such as overdosing, concomitant drugs and/or existing pathophysiological conditions. A few cases appear to be devoid of these factors. To determine what role genetic variation in the hERG gene plays in drug-induced arrhythmias, we screened DNA samples collected from 105 atrial-fibrillation patients treated with dofetilide for polymorphisms, seven of whom developed TdP. An uncommon missense change, R1047L, was identified in two of seven patients who experienced TdP as compared with five of 98 individuals who were free of TdP. Included in the affected individuals was the only subject homozygous for this SNP. Cellular electrophysiological studies revealed a 10-mV positive shift in the steady-state activation curve of the 1047L hERG channel stably expressed in HEK-293 cells as compared with the wild-type (WT) channel. The activation and inactivation kinetics of the 1047L current were significantly slower than the WT (P < 0.05) at given membrane potentials. A computer simulation using a rabbit ventricular myocyte model indicated that same extent of changes in the I(Kr) channel may result in an approximately 15% prolongation in the action potential duration. Our study suggests that 1047L leads to a functional impairment of the hERG channel, which may contribute to the higher incidence of TdP in 1047L carriers when challenged with a channel blocker.     

Current concepts in the mechanisms and management of drug-induced QT prolongation and torsade de pointes

Drug-induced long QT syndrome is characterized by a prolonged corrected QT interval (QTc) and increased risk of a polymorphic ventricular tachycardia known as torsade de pointes (TdP). We review mechanisms, predispositions, culprit agents, and management of this potentially fatal phenomenon. Virtually all drugs that prolong QTc block the rapid component of the delayed rectifier current (I(kr)). Some drugs prolong QTc in a dose-dependent manner, others do so at any dose. Most patients that develop drug-induced TdP have underlying risk factors. Female sex is the most common. Implicated drugs include class 1A and III antiarrhythmics, macrolide antibiotics, pentamidine, antimalarials, antipsychotics, arsenic trioxide, and methadone. Treatment for TdP includes immediate defibrillation for hemodynamic instability and intravenous magnesium sulfate. Potassium levels should be maintained in the high normal range, and all QT prolonging agents must be promptly discontinued.     

Iatrogenic QT Abnormalities and Fatal Arrhythmias: Mechanisms and Clinical Significance

Severe and occasionally fatal arrhythmias, commonly presenting as Torsade de Pointes [TdP] have been reported with Class III-antiarrhythmics, but also with non-antiarrhythmic drugs. Most cases result from an action on K⁺ channels encoded by the HERG gene responsible for the IKr repolarizing current, leading to a long QT and repolarization abnormalities. The hydrophobic central cavity of the HERG-K+ channels, allows a large number of structurally unrelated drugs to bind and cause direct channel inhibition. Some examples are dofetilide, quinidine, sotalol, erythromycin, grepafloxacin, cisapride, dolasetron, thioridazine, haloperidol, droperidol and pimozide. Other drugs achieve channel inhibition indirectly by impairing channel traffic from the endoplasmic reticulum to the cell membrane, decreasing channel membrane density (pentamidine, geldalamicin, arsenic trioxide, digoxin, and probucol). Whereas, ketoconazole, fluoxetine and norfluoxetine induce both direct channel inhibition and impaired channel trafficking. Congenital long QT syndrome, subclinical ion-channel mutations, subjects and relatives of subjects with previous history of drug-induced long QT or TdP, dual drug effects on cardiac repolarization [long QT plus increased QT dispersion], increased transmural dispersion of repolarization and T wave abnormalities, use of high doses, metabolism inhibitors and/or combinations of QT prolonging drugs, hypokalemia, structural cardiac disease, sympathomimetics, bradycardia, women and older age, have been shown to increase the risk for developing drug-induced TdP. Because most of these reactions are preventable, careful evaluation of risk factors and increased knowledge of drugs use associated with repolarization abnormalities is strongly recommended. Future genetic testing and development of practical and simple provocation tests are in route to prevent iatrogenic TdP.     

Dispersion of repolarisation and the autonomic system-can we predict torsade de pointes?

Prediction of the onset of Torsade de Pointes (TdP) is a challenge for clinicians, because the list of drugs affecting myocardial repolarisation is continuously increasing. Alterations in the activity of autonomic nervous system and abnormalities in ventricular repolarisation are key features both as triggers and as markers for vulnerability to TdP. Recent molecular genetic studies have shown that autonomic nervous system has channel and gene specific influences on vulnerability to TdP. New analysis techniques in quantifying the dispersion of repolarisation have also been developed. QT interval dispersion, defined as a difference between the maximum and minimum QT interval measured from the standard 12-lead electrocardiogram (ECG), is one such method. In preliminary studies, QT dispersion has provided more accurate information on the risk for TdP than the measurement of the length of QT interval from a single ECG lead. Unfortunately, QT dispersion is entailed with some conceptual and methodological problems, which impairs its widespread clinical utility in risk stratification. Despite advances in the understanding of the role of autonomic nervous system as a trigger of TdP in specific gene mutations and improved clinical methods in detecting repolarisation abnormalities, accurate and reliable prediction of the onset of TdP still remains an unresolved clinical problem in individual cases.     

Blinded validation of the isolated arterially perfused rabbit ventricular wedge in preclinical assessment of drug-induced proarrhythmias

BACKGROUND: The development of preclinical models with high predictive value for the identification of drugs with a proclivity to induce Torsade de Pointes (TdP) in the clinic has long been a pressing goal of academia, industry and regulatory agencies alike. The present study provides a blinded appraisal of drugs, in an isolated arterially-perfused rabbit ventricular wedge preparation, with and without the potential to produce TdP. METHODS AND RESULTS: Thirteen compounds were tested for their potential for TdP using the rabbit left ventricular wedges. All investigators were blinded to the names, concentrations and molecular weights of the drugs. The compounds were prepared by the study sponsor and sent to the investigator as 4 sets of 13 stock solutions with the order within each set being assigned by a random number generator. Each compound was scored semi-quantitatively for its relative potential for TdP based on its effect on ventricular repolarization measured as QT interval, dispersion of repolarization measured as T(p-e)/QT ratio and early afterdepolarizations. Disclosure of the names and concentrations after completion of the study revealed that all compounds known to be free of TdP risk received a score of less or equal to 0.25, whereas those with known TdP risk received a score ranging from 1.00 to 7.25 at concentrations less than 100X their free therapeutic plasma C(max). CONCLUSIONS: Our study provides a blinded evaluation of the isolated arterially-perfused rabbit wedge preparation demonstrating both a high sensitivity and specificity in the assessment of 13 agents with varying propensity for causing TdP.