Drug-induced long QT syndrome and fatal arrhythmias in the intensive care unit.

Long QT syndrome (LQTS) is a genetic or acquired condition characterised by a prolonged QT interval on the surface electrocardiogram (ECG) and is associated with a high risk of sudden cardiac death because of polymorph ventricular tachyarrhythmia called Torsade de Pointes arrhythmia. Drug-induced LQTS can occur as a side effect of commonly used cardiac and non-cardiac drugs in predisposed patients, often with baseline QT prolongation lengthened by medication and/or electrolyte disturbances. Hospitalised patients often have several risk factors for proarrhythmic response, such as advanced age and structural heart disease. Patients in the intensive care unit (ICU) are particularly prone to develop drug induced LQTS because they receive several different intravenous medications. Additionally, they might have impaired drug elimination because of reduced kidney and/or liver function, and also drug-drug-interactions. The clinical symptoms and signs of LQTS range from asymptomatic patients to sudden death because of malignant arrhythmias, and it is therefore important to recognise the clinical characteristics and typical ECG changes. Treatment of acquired LQTS is mainly awareness, identification and discontinuation of QT prolonging drugs, in addition to eventually supplement of magnesium and potassium. Overdrive cardiac pacing is highly effective in preventing recurrences, and antiarrhythmic drugs should be avoided. Recent data suggest that QT prolongation is quite common in ICU patients and adversely affects patient mortality. Thus, high-risk patients should be sufficiently monitored, and the use of medications known to cause drug-induced LQTS might have to be restricted.

Radiofrequency catheter ablation of two right Mahaïm-like accessory pathways in a patient with Ebstein's anomaly.

A 17-year-old woman with Ebstein's anomaly and recurrent episodes of antidromic tachycardia with two distinct morphologies is described. The tachycardias were produced by two separate Mahaïm-like accessory pathways. These were localized by their activation potentials at the anterolateral ventricular margin of the tricuspid annulus and ablated in a single session using radiofrequency current.

Evidence of excess hereditary predisposition in women with angiographically documented coronary artery disease.

In a hospital-based case-control study including women and men with angiographically documented coronary artery disease (CAD) admitted to a university hospital during a 6-month period, we observed an excessive hereditary predisposition in women. Clustering of risk factors was more pronounced in women than in men. Thus, the results suggest that hereditary factors as well as multiple risk factors are essential when CAD is expressed in women.

Efficacy and safety of dofetilide, a new class III antiarrhythmic agent, in acute termination of atrial fibrillation or flutter after coronary artery bypass surgery. Dofetilide Post-CABG Study Group.

Ninety-eight patients, who developed atrial fibrillation/flutter after coronary artery bypass grafting within 1-6 days after surgery, were included into a double-blind, placebo-controlled, randomized trial to assess the efficacy and safety of dofetilide. Patients were randomly allocated to dofetilide 4 micrograms/kg i.v. (n = 33), dofetilide 8 micrograms/kg i.v. (n = 32) or placebo (n = 33) given intravenously over 15 min at a constant infusion rate. Responders were defined as patients who converted to sinus rhythm at any time during the initial 3 h after the start of the infusion. The conversion rates were 24% (8/33) on placebo, 36% (12/33) on dofetilide 4 micrograms/kg, and 44% (14/32) on dofetilide 8 micrograms/kg. The P-values (two-tailed) were 0.27 for dofetilide 4 micrograms/kg vs. placebo, 0.11 for dofetilide 8 micrograms/kg vs. placebo, and 0.10 for dose-response relationship. Short episodes of aberrant ventricular conduction and ventricular tachycardia were seen separately in three subjects after dofetilide 8 micrograms/kg. No episodes of torsades de pointes were noted. No negative inotropic effect was noted. In conclusion, dofetilide was well tolerated, but the effects on atrial fibrillation/flutter did not attain statistical significance, possibly due to the high placebo conversion rate.

[Ablation of the bundle of His in atrial arrhythmia. A solution when the drugs fail]. / Ablasjon av His-bunten ved atriale arytmier. En utvei når medikamentene ikke virker.

Radiofrequency ablation of the bundle of His was performed in 33 patients with intractable atrial arrhythmias (fibrillation in 23, flutter in seven, atrial tachycardia in three). Complete AV block was produced in 30 patients, and clinically satisfactory incomplete block in another two. All were subsequently treated by pacemaker. The ablation was a failure in one patient with hypertrophic cardiomyopathy. Today ablation can be targeted at atrial tachycardias and flutter, and ablative modification of the AV node can reduce ventricular rate in chronic atrial fibrillation. However, His bundle ablation is still the treatment of choice in drug refractory atrial fibrillation when no other measure can provide adequate rate control.

[Cardiology education in Norway--does it keep up with the needs?]. / Kardiologutdanningen i Norge--holder den tritt med behovet?

Despite an increase in the number of education positions for cardiologists in Norway in the late 1980s, there is felt to be a marked lack of sub-specialists in cardiology in most types of hospitals. A working group under the Norwegian Society of Cardiology has used a questionnaire in 1993, membership data from the Norwegian Society of Cardiology in 1994, a telephone query to all hospitals in the country, and data from the Norwegian Medical Association in 1995 to examine this apparent lack of specialists and the potentials for educating them. We were able to confirm a current lack of approximately 60 cardiologists. In addition, the capacity for education has been reduced and will not compensate for the predicted retirement of specialists from approximately year 2000. The capacity for educating cardiologists must be increased.

Mortality in patients supported by intra-aortic balloon pump in the course of cardiac surgery was related to perioperative myocardial infarction.

OBJECTIVE: To search for predictors of mortality for patients in need of intra-aortic balloon pump (IABP) support in the course of cardiac surgery. METHODS: A retrospective study of possible pre- and perioperative risk factors in 110 patients with mean age of 62 years (38-79). The IABP was inserted preoperatively in 19 (17%) and perioperatively in 91 (83%). RESULTS: Well known risk factors as advanced age (63.2/61.0; P = 0.25), NYHA functional class (OR = 1.59; 95% CI 0.23 to 13.31), female sex (OR = 2.40; 95% CI 0.81 to 6.73), emergency surgery (OR = 0.63; 95% CI 0.21 to 1.80), low left ventricular ejection fraction (62.9/60.7; P = 0.53), or elevated end diastolic pressure (19.4/21.0; P = 0.48), were not prognostic of death. Perioperative insertion of the balloon pump (OR = 3.83; 95% CI 1.07 to 14.95), perioperative myocardial infarction (OR = 23.3; 95% CI 7.62 to 81.8), low cardiac output (OR = 7.53; 95% CI 2.43 to 24.11), and renal failure (OR = 20.00; 95% CI 3.63 to 145), were strong predictors of death. CONCLUSIONS: Outcome seemed to be determined by perioperative events rather than preoperative risk factors. This could possibly explain the favourable mortality rates seen in patients on IABP support prior to surgery compared to patients who had IABP installed perioperatively.

[Radiofrequency ablation of heart arrhythmias. Results in the first 150 patients treated at the Arrhythmia center in Oslo]. / Radiofrekvensablasjon av hjertearytmier. Resultater hos de første 150 pasienter behandlet ved Arytmisenteret i Oslo.

The authors review the first 150 patients with cardiac arrhythmias who were treated with radio-frequency ablation at a Norwegian arrhythmia centre. The clinical success rate (either electrophysiological cure or a dramatic reduction in the severity and frequency of the attacks) was 97%. 11 patients were treated for two or more arrhythmias. In 27 patients two, occasionally three, sessions were required to obtain a satisfactory clinical result. Repeat ablation is scheduled for three cases where the treatment was unsuccessful. Among 190 ablations, 13 complications occurred, none of which resulted in permanent sequelae. The time spent on each procedure, and particularly the long time spent on fluoroscopy during the earlier procedures, demonstrates the existence of a learning curve for ablation. This lends support to the authorities' restriction of treatment of arrhythmias by ablation to only two laboratories in a population of four million.

[Lipid-lowering medication--indications and possible hazards. Report from a hearing]. / Lipidsenkende medikasjon--indikasjoner og faremomenter. Høringsreferat.

Drug treatment of hyperlipidaemia should be founded on scientific evidence. A hearing was arranged to arrive at practical measures based on reported clinical trials. Several studies during recent years have shown regression of coronary atheromatosis, and some people would say the effect is striking. Studies using clinical endpoints, like morbidity and mortality, have not yielded equally convincing results, but it should be noted that the results of studies with more than 10% reduction in total serum cholesterol levels are not yet available. So far, the trials have been too small to judge effects on total mortality. It is uncertain whether the treatment actually has untoward effects on the incidence of violent deaths and neoplasms. An upper limit for drug treatment of about 8 mmol/l was proposed during the hearing. The limit can be lowered to 7 if established coronary disease is present. For women without coronary disease the limit should be higher than that for men. All in all, this implies an increase in the total number of individuals treated compared with present practice. It was agreed that at present, high risk individuals are undertreated. The new levels have been set partly on the basis of economic considerations.

[What can be achieved by treatment with antihypertensive agents? Report from a hearing]. / Hva er målet ved medikamentell antihypertensiv behandling? Høringsreferat.

Today it is considered a primary goal to reduce morbidity and mortality from stroke. It will probably also be possible to reduce other pressure-related illnesses, such as heart failure and renal failure. Coronary morbidity is influenced to some extent only, and involves risk of over-treatment. There is most probably a J-shaped relationship between achieved reduction of pressure and mortality. Treatment with drugs is considered when diastolic pressures exceed 90 mm Hg, provided that the patient has been observed when treated in other ways than by drugs for several months. If no other risk factors are present, 5-10 mm Hg higher diastolic blood pressure levels can be accepted. However, all patients with diastolic pressure above 100 mm Hg should be treated. In patients with coronary disease it is advisable not to lower diastolic blood pressure below 85 mm Hg. One should hesitate to give antihypertensive drugs to individuals with high pressures at the doctor's and normal pressures at home. They should preferably receive intense non-drug treatment aimed at reducing total cardiovascular risk.

Positive inotropy linked with class III antiarrhythmic action: electrophysiological effects of the cardiotonic agent DPI 201-106 in the dog heart in vivo.

STUDY OBJECTIVE: The aim was to investigate whether the positive inotrope DPI 201-106 prolongs ventricular monophasic action potential duration and refractoriness in vivo without affecting conduction, thus possessing class III antiarrhythmic characteristics in vivo. DESIGN: Electrophysiological and haemodynamic effects of DPI 201-106 (0.5, 1.0, and 2.0 mg.kg-1 intravenously) were studied at spontaneous heart rate and at three different paced cycle lengths (353, 300, and 261 ms). The following were recorded: monophasic action potentials from right ventricular endocardium; intracardiac conduction times by His bundle electrocardiography; refractoriness by programmed electrical stimulation; and left ventricular (LV) pressures. SUBJECTS: Seven mongrel dogs of either sex, weighing 14-24 kg, were studied under sodium pentobarbitone anaesthesia. MEASUREMENTS AND MAIN RESULTS: DPI 201-106 prolonged ventricular monophasic action potential duration and refractoriness dose dependently and most effectively at long cycle lengths, with no effect on intracardiac conduction times. DPI 201-106 increased LV dP/dtmax, while LV systolic and end diastolic pressures were unchanged both during spontaneous and paced heart rate. DPI 201-106 decreased spontaneous heart rate. CONCLUSIONS: Prolonged monophasic action potential duration and increased refractoriness, with no effect on conduction, indicate class III antiarrhythmic action of DPI 201-106 in vivo.

[Drug therapy of acute coronary syndrome. Summary of a hearing arranged by the Norwegian Cardiologic Society and the Institute of pharmacotherapy]. / Medikamentell behandling av akutt koronarsyndrom. Sammenfatning av høring arrangert av Norsk cardiologisk selskap og Institutt for Parmakoterapi.

Acute coronary syndrome is defined as unstable angina or acute myocardial infarction. A discussion on drug treatment of these conditions was arranged by the Norwegian Society of Cardiology and the Department of Pharmacotherapeutics, University of Oslo, soon after preliminary results of the GISSI II study were available. Relatively simple rules were agreed for the use of analgetics, nitrates and fibrinolytic agents. The last are used only after established myocardial injury. Consensus was also reached on the restricted use of calcium antagonists, inotropic agents and diuretics. There was disagreement concerning the dosage of heparin and the exact use of betablockers, aspirin, warfarin, ACE-inhibitors, magnesium and antiarrhythmics.

Alpha-adrenoceptor blockade and class III antiarrhythmic activity combined: hemodynamic and electrophysiological effects of melperone in the dog.

Melperone has been found to possess vasodilating and slight positive inotropic properties in addition to its class III antiarrhythmic action. To determine whether some of these effects might be related to an alpha-adrenoceptor blocking action of melperone, phenoxybenzamine (10 mg/kg) was given as a 2-h infusion to 12 pentobarbital-anesthetized dogs. In addition, six of the dogs were given atenolol 0.5 mg/kg i.v. After a 1-h stabilizing period, melperone (0.5, 2.5, and 12.5 mg/kg) was given i.v. in cumulative doses to both series of dogs. In the presence of alpha-blockade as well as combined alpha- and beta-blockade, atrial, atrioventricular (AV) nodal, and ventricular refractoriness increased and heart rate and AV nodal conduction time decreased, as previously reported after addition of melperone alone. A slight increase in left ventricular (dP/dt)max occurred after the addition of melperone (2.5 mg/kg) in the presence of alpha- and beta-blockade, but only after the highest dose of melperone were small decreases in blood pressure and total peripheral resistance induced. The present study indicates that melperone combines the properties of class III antiarrhythmic action, slight positive inotropy, and alpha-adrenoceptor mediated vasodilation.

Class III antiarrhythmic action linked with positive inotropy: antiarrhythmic, electrophysiological, and hemodynamic effects of the sea-anemone polypeptide ATX II in the dog heart in situ.

Most antiarrhythmic drugs are more or less negatively inotropic. Positively inotropic properties, however, have been demonstrated for some class III antiarrhythmic drugs. To test the hypothesis that class III antiarrhythmic effect and positive inotropy may be linked, we used the sea-anemone polypeptide ATX II, which in isolated heart muscle preparations has been shown to specifically inhibit the inactivation of the sodium channel and thereby increase action potential duration and inotropy. We used 12 pentobarbital-anesthetized dogs. Atrial arrhythmias were induced by high-rate stimulation of the right atrium in 5 dogs. Cardiac electrophysiological effects were studied by His-bundle electrography, programmed electrical stimulation, and monophasic action potential (MAP) recordings in 7 autonomically blocked dogs. ATX II (1.0-5.0 micrograms/kg i.v.) converted the arrhythmias, and in the autonomically blocked dogs markedly increased atrial and ventricular refractoriness and ventricular MAP duration without influencing atrial or ventricular conduction velocities, heart rate, or AV-nodal refractoriness. ATX II induced a marked increase in left ventricular dP/dt max. The study indicates that ATX II has class III antiarrhythmic effect, and that the electrophysiological and positive inotropic effects of ATX II have a common mechanism.

Acute electrophysiologic and blood pressure effects of amiodarone and its solvent in the dog.

Amiodarone has repeatedly been shown to have potent class III antiarrhythmic properties. It has, however, been questioned whether the acute and chronic effects of the drug are due to the same mechanism. In order to investigate the acute electrophysiologic and blood pressure effect of the drug, amiodarone (Cordarone) was given intravenously in cumulative doses of 2.5, 5.0 and 10.0 mg/kg to seven pentobarbital (mebumalum NFN) anaesthetized dogs. Corresponding volumes of the solvent, polysorbatum 80 (Tween 80), were given to two dogs. Cardiac electrophysiologic effects were studied by His bundle electrography and programmed electrical stimulation. Amiodarone decreased heart rate and AV nodal conduction velocity and increased atrial, AV nodal and ventricular refractoriness. A pronounced but transient fall in mean aortic blood pressure (MABP) occurred after the first injection of amiodarone. No fall in MABP occurred, however, after the subsequent two doses. Intravenous injection of the solvent exactly reproduced the effects on MABP, but not the electrophysiologic effects. The present study supports the concept that amiodarone also has acute class III antiarrhythmic effect. After the initial injection, a pronounced fall in blood pressure due to the solvent may be seen, but rapid tachyphylaxis occurs.