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.

Electrophysiological effects of thoracic epidural analgesia in the dog heart in situ.

To investigate cardiac electrophysiological effects of thoracic epidural analgesia, a local anaesthetic solution, 0.5% bupivacaine, was administered into the thoracic epidural space in twelve pentobarbital anaesthetised dogs. Intracardiac conduction times were measured by His bundle electrography and refractoriness was determined by programmed electrical stimulation. Monophasic action potentials were recorded from the right ventricle by a suction electrode technique. Thoracic epidural analgesia increased the ventricular effective and functional refractory period, as well as the duration of the monophasic action potential. The intra-atrial and His-Purkinje conduction times and the QRS-width were not significantly influenced. AV nodal conduction time and AV nodal functional refractory period were markedly prolonged by thoracic epidural analgesia. Thoracic epidural analgesia induced AV block of the second degree in most experiments after a second dose of bupivacaine during pacing at higher frequencies. We conclude that thoracic epidural analgesia has significant cardiac electrophysiological effects which may be both antiarrhythmic and arrhythmogenic. Thoracic epidural analgesia should be used with care in patients with atrioventricular conduction disturbances.

Influence of beta-adrenergic and cholinergic blockade on the electrophysiological effects of melperone in the dog heart in situ.

Melperone (0.5 to 12.5 mg.kg-1) reduced mean aortic blood pressure in pentobarbital anaesthetised dogs to a greater extent after beta1-adrenergic receptor blockade with atenolol than after cholinergic blockade with atropine. Electrophysiological studies demonstrated that increased heart rate and decreased atrioventricular nodal refractoriness after lower doses of melperone (0.5 to 2.5 mg.kg-1), could be prevented by pretreatment with atenolol. The melperone-induced decrease in atrioventricular nodal conduction time was, however, not affected by pretreatment with atenolol or atropine. Intra-atrial and His-Purkinje conduction times and QRS width were not affected by atenolol or atropine plus melperone. Melperone caused a dose-dependent and very pronounced increase in ventricular and, even more, atrial refractoriness after atenolol. The ventricular and atrial refractoriness increased less after pretreatment with atropine. Some of the cardiac electrophysiological effects of melperone thus depend on the degree of beta-adrenergic stimulation. The overall cardiac electrophysiological effects of melperone results from a combination of direct and indirect actions of the drug.

Haemodynamic and metabolic effects of the antiarrhythmic drug melperone during acute left ventricular failure in dogs.

Haemodynamic and metabolic effects of the new antiarrhythmic drug melperone were studied during acute ischaemic left ventricular failure in closed-chest anaesthetized dogs. Embolisation of the left main coronary artery with 50 micrometer plastic microspheres induced severe depression of left ventricular performance as evidenced by a marked increase in left ventricular end-diastolic pressure and a marked reduction in the maximum rate of left ventricular pressure rise (LVdP/dtmax), cardiac output, and stroke volume. Six dogs received intravenous melperone 1.0 and 2.5 mg . kg-1 (cumulative dose) 90 and 115 min after the embolisation, respectively. Six other dogs received no treatment and served as controls. Melperone effected a marked reduction in left ventricular end-diastolic pressure, a slight but transient increase in LVdP/dtmax, a moderate reduction in heart rate, a moderate reduction in mean aortic blood pressure and total peripheral resistance and a moderate increase in stroke volume. Melperone moderately decreased myocardial O2-consumption, while myocardial lactate uptake remained unchanged. In conclusion, in contrast to commonly used antiarrhythmic drugs which may all induce cardiodepression, melperone improved left ventricular function in dogs with acute ischaemic left ventricular failure.

Electrophysiological effects of melperone in the dog heart in situ - a new antiarrhythmic drug.

In pentobarbital anaesthetised dogs, melperone (a neuroleptic butyrophenone) reduced mean aortic blood pressure and at lower doses (0.5 and 2.5 mg . kg-1) increased the heart rate. By means of His bundle electrography and programmed electrical stimulation, conduction velocity and refractoriness were measured at different frequencies of stimulation (170, 200, 230 and 260 beats.min-1). Melperone 0.5 and 2.5 mg.kg-1 decreased the atrioventricular nodal conduction time and refractoriness. Melperone (0.5 to 12.5 mg.kg-1) did not affect the intra-atrial or His-Purkinje conduction times or the QRS width. However, melperone increased the functional and effective refractory period of the right atrium and ventricle dose-dependently at all frequencies studied. This suggests that melperone may be a valuable drug in treating selected cardiac arrhythmias.

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.

Plasma levels and cardiac electrophysiological effects of melperone in the dog.

The butyrophenone neuroleptic melperone has recently been shown to possess antiarrhythmic properties in man and animals. We studied the correlation between plasma concentration of melperone and the electrophysiological and blood pressure effects of the drug in 20 pentobarbital-anaesthetized dogs. Linear correlations were found between the log melperone plasma concentration and decreases in mean aortic blood pressure and heart rate, and increases in atrial and AV nodal refractoriness. The correlations were better after pretreatment with the beta 1-blocker atenolol. There was a linear correlation between log melperone plasma concentration and increases in ventricular refractoriness only after atenolol. No correlation was found between log melperone plasma concentration and decreases in AV nodal conduction time. Apart from the effect on AV nodal conduction time, the relationship between plasma concentration of melperone and the electrophysiological and blood pressure effects after beta 1-blockade fits well into an overall log concentration-effect relationship. The poorer correlation without beta 1-blockade was probably due to a combination of direct and indirect effects of the drug.

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.

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 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.

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.

Class III antiarrhythmic action in experimental atrial fibrillation and flutter in dogs.

Progress in the pharmacological treatment of atrial fibrillation and flutter has been achieved by the introduction of the class III antiarrhythmic drug amiodarone. In the present study we tested amiodarone and a new class III antiarrhythmic drug, melperone, in experimentally induced atrial fibrillation and flutter in pentobarbital-anesthetized dogs. By high-rate stimulation in the right atrium, atrial fibrillation was induced in 4, and atrial flutter in 10 out of 22 dogs. Atrial flutter rate was 496 +/- 13 min-1 (median +/- 95% confidence interval). Both drugs converted the arrhythmias at doses from 2.5 to 10 mg . kg-1 and reduced that atrial flutter rate before conversion. Average ventricular rate during arrhythmias (261 +/- 16 min-1) decreased after amiodarone, and was unchanged or, in three out of nine dogs, increased after melperone. The doses of amiodarone converting the arrhythmias increased atrial refractoriness, whereas the effects on AV nodal conduction and refractoriness were variable. The results support the concept that atrial flutter is due to circus movement where the flutter rate is dependent upon atrial refractoriness. The class III antiarrhythmic drugs amiodarone and melperone seem to be equally potent in converting atrial arrhythmias.

Cardiac electrophysiological and hemodynamic effects of beta-adrenoceptor blockade and thoracic epidural analgesia in the dog.

To investigate whether thoracic epidural analgesia (TEA) has additional cardiac electrophysiological and hemodynamic effects when induced after beta-adrenergic blockade, bupivacaine (0.7-1.2 mg/kg) was injected into the epidural space at T2-3 after intravenous injection of atenolol (1.0 mg/kg) in anesthetized dogs. Cardiac electrophysiology was studied by His bundle electrography, programmed electrical stimulation, and monophasic action potential recordings. Atenolol reduced heart rate, prolonged atrio-ventricular (AV) nodal impulse conduction time and refractoriness, prolonged ventricular refractoriness and action potential duration, and decreased left ventricular (LV) dP/dt max. Addition of TEA further reduced heart rate, prolonged AV nodal conduction time and refractoriness, decreased LV dP/dt max and arterial blood pressure, but had no effect on atrial and ventricular electrophysiology. Induction of TEA during beta-blockade may thus have additive depressive effects on sinoatrial and AV nodal functions, as well as on left ventricular inotropy. The study indicates that the cardiac electrophysiological effects induced by TEA are mainly caused by decreased beta-receptor stimulation, but increased vagal activity may also contribute.

A method for simultaneous epicardial monophasic action potential recordings from the dog heart in situ.

In order to record epicardial monophasic action potentials (MAP) simultaneously from different regions of intact beating hearts, we developed a tripodal suction electrode device (total weight 1.5 g, distance between the flexible silicone legs 25 mm) which we tested in pentobarbital anaesthetized open chest dogs. The device was easy to apply and gave stable and reproducible recordings. Repolarization times for epicardial left ventricular and endocardial right ventricular MAPs correlated well (r = 0.97, P less than 0.001). There was no correlation between MAP amplitude and repolarization times. The beta 1-adrenergic agonist prenalterol decreased MAP duration, while the new class III antiarrhythmic drug melperone increased MAP duration. Mild ischaemia effected MAP prolongation and severe ischaemia MAP shortening, compared to simultaneous recordings from non-ischaemic ventricular regions. We conclude that the new tripodal suction electrode is a simple device for simultaneous recording of multiple MAPs. The method should be suitable for studies of electrophysiological effects of drugs and other interventions in intact beating hearts.

Effects of thoracic epidural analgesia on cardiovascular function and plasma concentration of free fatty acids and catecholamines in the dog.

Increased plasma levels of free fatty acids (FFA), leading to increases in the myocardial oxygen demand, are seen after, for example, surgical stress, traumas and myocardial infarction. The present study was undertaken to investigate the cardiovascular effects of thoracic epidural analgesia (TEA) and the effect of TEA on the plasma concentration of FFA and catecholamines. In 10 sodium-pentobarbital-anaesthetized dogs the local anaesthetic agent bupivacaine was injected into the thoracic epidural space via a surgically introduced catheter. TEA markedly reduced heart rate, mean aortic blood pressure, left ventricular systolic blood pressure and dP/dtmax. TEA reduced the plasma concentration of FFA. The FFA-lowering effect was greatest when the FFA values were high. The effect of TEA on the plasma concentration of noradrenaline and adrenaline was inconsistent and seemed to be of minor importance for the haemodynamic and FFA effects of TEA. The study indicates that TEA, by its haemodynamic and FFA-lowering effects, may reduce myocardial oxygen demand.

[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.

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.

[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.