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Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, Wisconsin
Address correspondence and reprint requests to Alexander Kulier, MD, LKH Graz, Department of Anesthesiology, Auenbruggerplatz 15, A-8036 Graz, Austria.
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Abstract |
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Implications: Life-threatening arrhythmias of the heart after myocardial infarction or ischemia may be treated quickly and efficiently by the new drug E 047/1.
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Introduction |
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Drug regimens that are recommended for IV bolus administration are not always successful in suppressing ventricular ectopic beats (2,3,8,9). Also, currently available drugs may not have immediate effects and may even be proarrhythmic (3,8–10). Because of delayed onset of action, slow plasma elimination, and serious side effects, some potent antiarrhythmics, such as amiodarone, are not ideal for acute management of life-threatening ventricular tachyarrhythmias and are, therefore, only recommended for treatment of arrhythmias refractory to other regimens (8).
The new antiarrhythmic benzofurane compound E 047/1 (EBEWE Pharmaceuticals, Unterach, Austria; Figure 1) has been shown to suppress postischemic ventricular tachyarrhythmias efficiently and quickly in preliminary studies in different canine models (7,11,12) as well as in human patients after open heart surgery (13). Electrophysiologic studies in isolated cardiac tissue have confirmed distinct antiarrhythmic effects. In addition to possible Na+ channel antagonism, E 047/1 counteracts the proarrhythmic impulses and regional conduction disparities originating from ischemic areas and borderline zones (14). E 047/1 has an immediate onset of action, short plasma and elimination half-times, and no known active metabolites (11,13,14). Thus, E 047/1 would not be expected to preclude the subsequent use of other drugs affecting cardiac conduction, unlike amiodarone (8).
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Preliminary studies have been performed on E 047/1 dissolved in polysorbate (Tween 60) (11,14). Because this solvent is known to produce temporary hypotension in dogs (17), we chose to administer E 047/1 in a preparation without polysorbate. To provide direct comparison of plasma levels and pharmacokinetics of E 047/1 preparations with and without polysorbate, we performed a pilot study with an additional set of animals.
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Methods |
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A pilot study was performed comparing plasma levels and pharmacokinetics of E 047/1 preparations, with and without the carrier substance polysorbate, which produced substantial hypotension in previous studies (11,17). Six dogs were anesthetized, and an arterial catheter with a vascular access port was implanted into the right femoral artery. Five days later, each dog received IV E 047/1 (6 mg/kg-1 bolus for 60 s plus 6 mg · kg-1 · h-1 infusion for 1 h in one of three different forms: 1) 15 mg/mL E 047/1 in 5% polysorbate, 2) 8 mL of 15 mg/mL-1 E 047/1 with 2.5 mL intralipid solution, or 3) 15 mg/mL E 047/1 in saline only; all were taken and diluted to a total volume of 2.5 mL/kg with saline solution. Each dog received each preparation of E 047/1 in a randomized balanced order, with rest periods of 5 days between experiments. Blood samples were drawn from the arterial line before each experiment, at 15, 30, 60, and 120 min after the bolus, and analyzed by high-performance liquid chromatography. Arterial blood pressure and a 2-lead surface electrocardiogram (ECG) were monitored continuously.
Forty-seven adult mongrel dogs (19–22 kg) entered the main study protocol. After a 60-min ECG control reading, each animal was anesthetized by isoflurane (1.25 minimum alveolar anesthetic concentration) in 100% oxygen, tracheally intubated, and mechanically ventilated. Atracurium was used for muscle relaxation and buprenorphine for analgesia. After a left thoracotomy, the left anterior descending coronary artery was ligated in two stages, by first applying a critical stenosis for 60 min, followed by a total and permanent occlusion, which resulted in acute myocardial infarction (15,16). Additionally, an indwelling heparinized arterial catheter was inserted from the femoral artery into the abdominal aorta. A vascular port was attached and implanted subcutaneously for continuous measurement of the arterial blood pressure. After chest closure and tracheal extubation, the dogs were transferred to a specialized cage unit and monitored overnight.
Twenty-two hours later, 40 of the 47 dogs had survived the acute postinfarct phase and randomly received one of five antiarrhythmic drug regimens at doses previously demonstrated to be effective in this preparation (2,9,11,18–22): 1) E 047/1 6 mg/kg plus 6 mg · kg-1 · h-1 in saline solution, 2) lidocaine: 1 mg/kg plus 4.8 mg · kg-1 · h-1, 3) flecainide 1 mg/kg plus 0.05 mg · kg-1 · h-1, 4) amiodarone 10 mg/kg plus 1.8 mg · kg-1 · h-1, or 5) bretylium 10 mg/kg plus 20 mg · kg-1 · h-1 (60-s bolus plus 1-h infusion; n = 8 for each group). Each drug was diluted with saline to a volume of 10 mL for the bolus and 46 mL for the continuous infusion.
Measurements were obtained before (control) and immediately after (0 min) the bolus, during (15, 30, and 60 min) and 1 h after (120 min) the infusion. At each time, 5 min of 2-lead surface ECG and mean arterial blood pressure (MAP) were recorded. MAP readings were averaged, and ECG was evaluated for the following variables: 1) total number of premature ventricular contractions (PVC) per minute, irrespective of whether these beats occurred as single PVC, couplets, triplets, or runs of ventricular tachycardia (VT; more than three consecutive PVCs); 2) number of regularly conducted, normal sinoatrial (SA) beats per minute, from which the arrhythmic ratio (PVCs/all beats) was calculated; 3) total duration of all episodes of VT, regardless of their length, in seconds per minute; and 5) the average rate within these runs of VT. This beat-by-beat evaluation of the ECG recordings was blinded, i.e., investigators scoring the data were not present during the experiment and did not know which drug had been administered.
After the experiment, the animals were killed with a euthanasia solution, and the heart was examined to confirm that all animals had a similar size and area of the myocardial infarction.
After confirmation of the normal distribution, the obtained values were evaluated by analysis of variance for repeated measures. Mean values at each observation point were compared using appropriate denominator-adjusted t-tests, whenever P values were significant. Arrhythmic ratio was analyzed by nonparametric analyses of variance (Kruskal-Wallis test for between group comparisons, Friedmann’s test for repeated measures over time). Significance was accepted at P < 0.05. Data are shown as mean ± SEM where applicable.
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Results |
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Figure 2 shows E 047/1 plasma levels obtained in the pilot study. With all three preparations, E 047/1 plasma levels remained stable throughout the infusion period (15–60 min) and decreased markedly after the termination of the infusion. During the continuous infusion, E 047/1 with Tween 60 produced plasma levels 30%–40% higher than both preparations without Tween 60 (1.90 ± 0.28 ng/mL versus 1.41 ± 0.13 ng/mL for lipid and 1.20 ± 0.18 ng/mL with saline at 15 min, P < 0.01). Control values for MAP (111 ± 17 mm Hg; data not shown) and heart rate did not differ between experiments and remained unchanged by E 047/1 in lipid or saline. However, E 047/1 in Tween 60 decreased MAP markedly to a minimum of 51 ± 13.6 mm Hg at 15 min (P < 0.01), and heart rate simultaneously increased from 95 ± 8 to 155 ± 13 bpm. Thereafter, MAP gradually increased, returning toward baseline only after 120 min.
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Total duration of VT runs was reduced by 40% after the bolus administration of E 047/1 (Table 1), and the underlying rate of ventricular contractions within these runs was also decreased. This effect lessened, and values returned to a consistent range of 75%–80% of the control values during the following infusion period. Amiodarone and flecainide induced a similar response, but with considerably slower onset showing maximal efficacy after 60 min. The administration of bretylium dramatically increased the rate of beats during VT.
MAP control values were comparable for all treatment groups and ranged from 76 to 98 mm Hg (Figure 4). MAP increased gradually during the administration of E 047/1 to levels approximately 20% above control. In contrast, amiodarone decreased MAP to a minimum of 43 ± 5 mm Hg (48% of the control) after 15 min, subsequently returning toward baseline. Flecainide and lidocaine did not change MAP, whereas bretylium caused an immediate and sustained increase.
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Discussion |
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The Harris dog infarction model we used provides a reliable and well established setting commonly used for identification of antiarrhythmic pharmacological effects (15,16,20,21,23). The experimental infarction results in abnormal impulses that originate from surviving Purkinje fibers situated at the endocardial surface of the transmural infarct (24). Enhanced automaticity leads to spontaneous ventricular depolarizations, reaching a maximal incidence one day after infarction, such that 80%–100% of all contractions are ventricular in origin (15,16,23). Because of the similar pathogenic mechanism, these experimental arrhythmias accurately reproduce the incidence, time course, and ECG characteristics of the delayed phase of subacute arrhythmias associated with human myocardial cell injury (1,5,15,16,25,26). Hence, this model closely reflects the mechanism leading to delayed arrhythmias after repetitive myocardial ischemia or infarction (15,16,25,26). However, the high rate of ventricular beats, which is necessary for adequately assessing and quantifying antiarrhythmic drug effects, and the stable uniformity of the ventricular depolarizations produced by this model may not completely mirror a clinical arrhythmia, which often results from a heterogenous mix of pathogenic mechanisms. Other manifestations of postischemic arrhythmias or outcome by sudden cardiac death cannot be tested with this model because the underlying arrhythmic mechanisms may be different (5,7,15,16). However, this conscious dog model serves the main purpose of this study in establishing the antiarrhythmic quality of a new drug.
In our study, the administration of E 047/1 induced an immediate and potent decrease of arrhythmia. E 047/1 suppressed ventricular ectopic beats, increased both the absolute number and the relative fraction of SA beats, and decreased the rate of ventricular contractions within runs of VT. The rapid onset of action indicates that E 047/1 may be a most appropriate tool for short-term IV therapy. The results of the present animal investigation are consistent with a preliminary human study after coronary artery bypass grafting surgery showing antiarrhythmic efficiency and safety (13). In patients with significant ventricular arrhythmia within 48 hours after cardiac surgery, the administration of 1 mg/kg plus 1 mg · kg-1 · h-1 of E 047/1 reduced PVCs by 55% after 15 minutes and by 93% after one hour. Thus, extensive dose-response trials to find the optimal E 047/1 regimen seem warranted.
MAP progressively increased over the entire infusion period, presumably because coordinated contractions originating from the SA node resulted in augmented cardiac output. Effects of E 047/1 on (systemic) vascular resistance, cardiac filling pressures, or cardiac output could contribute to supporting MAP, but these are unknown and were not measured.
The time course of the effects of E 047/1 may be explained by its specific pharmacokinetic and pharmacodynamic properties. E 047/1 has a relatively short and predictable plasma half-life (11), which is confirmed by the acute drop of plasma levels found in the pilot study upon discontinuation of the administration. Accordingly, all observed antiarrhythmic effects obeyed a consistent time pattern, reaching a maximum shortly after the bolus, followed by a slight decrease in antiarrhythmic activity during the subsequent infusion period. E 047/1 does not require a specific solvent or carrier substance, but it is very sensitive to pH shifts and increasing adherence to the surface of the syringe and afferent IV lines (Dr. M. Windisch, Ebewe Co., personal communication, 1996). The solvent Tween 60 generates stabilizing effects on the solution (11), leading to higher E 047/1 plasma levels both in the pilot study and in previous reports (11). However, at this time, the use of Tween 60 to enhance pharmacokinetic efficiency of E 047/1 is undesirable because it has caused a strong decrease of MAP, both in the present and in previous investigations (11), and with amiodarone (17). Initial studies (unpublished) in different types of tissue, as well as in whole animals and humans, have not revealed toxic adverse effects of E 047/1. Accordingly, no clinically relevant side effects were observed in the dogs of this study, apart from a slight increase in salivation.
The interactions of electrophysiological mechanisms producing the antiarrhythmic effect of E 047/1 are not completely clear. In healthy dogs, E 047/1 increases the effective refractory period of SA and arterioventricular node and prolongs QRS complex duration (14), indicating possible Na+ channel antagonism. In infarcted dog myocardium, E 047/1 decreases atrial-His conduction time, thereby counteracting the infarct-induced prolongation of conduction (14). However, in vitro, Purkinje fiber action potential duration is decreased, more so in nonischemic than in ischemic areas, correcting the preexisting regional disparity of infarcted hearts (14). Additionally, E 047/1 slows conduction in the infarcted region by reducing the maximal rate of Phase 0 depolarization (14). Because of these partly divergent findings, E 047/1 cannot be clearly assigned to any single antiarrhythmic drug class.
Our main goal was to investigate the efficacy of E 047/1 in suppressing malignant ventricular tachyarrhythmia. To put these pharmacological effects in a comparative context, control animals were given available potent IV antiarrhythmics from different classes to reflect diverse mechanisms of action. For this purpose, we used single doses of each drug selected to have optimal effect, as determined in our preliminary investigations (11,12), or from recommendations for antiarrhythmic therapy and similar experimental protocols in other studies (2,9,18–22). Different administration regimens using other doses for each drug could alter our findings. Similarly, E 047/1 plasma levels produced by the preparation used for this study may not provide optimal pharmacological efficacy. Thus, our data do not provide a full comparison of relative efficacy of E 047/1 to other drugs. Such a comprehensive trial with extensive dose-response analyses of each drug may be justified by the results of our investigation.
Current guidelines for antiarrhythmic therapy recommend the Class I drug lidocaine as the first choice for the acute IV treatment of malignant ventricular ectopies (2,8,9). Lidocaine is not always effective, but it is familiar to most physicians and generally safe to use. Although the value of lidocaine for the prophylaxis of ventricular ectopies in cardiac surgery patients is questionable, it is highly effective against ventricular arrhythmias of the early and late phases after myocardial ischemia (18). However, for subacute delayed arrhythmias that are largely present in the postoperative phase, it may exhibit only weak antiarrhythmic or even proarrhythmic effects (27). This selective efficacy was also found in our study and may be caused by a different origin and mechanism of the ectopic beats (23,27). Thus, lidocaine showed only a slight tendency toward an antiarrhythmic effect under our protocol. Larger doses (21) consistently produced seizures and vomiting in the animals.
Flecainide is not recommended for treatment of ventricular arrhythmias in patients with structural heart disease because of its proarrhythmic potential (10), but has potent antiarrhythmic effects in several different dog models (21). Consistently, flecainide reduced ectopies and both duration and frequency of tachycardic runs in our study. Bretylium, which was for a long time the only Class III drug approved for IV use (9,28), is now considered a second-line drug for the treatment of ventricular tachyarrhythmia because of its tendency to cause prolonged hypotension (9,28). In this study, bretylium caused immediate and strong proarrhythmic effects associated with continued arterial hypertension, conceivably a result of acute release of norepinephrine from nerve endings (28). The subsequent decline of these sympathoadrenergic actions during our experimental protocol suggests that the time course of bretylium effects may differ substantially between dogs and humans and that potential hypotensive or antiarrhythmic effects occurred either beyond the observation period or not at all.
Amiodarone is a potentially valuable drug for perioperative patients experiencing life-threatening ventricular arrhythmias refractory to conventional antiarrhythmic drugs (8,9). In our study, amiodarone showed antiarrhythmic effects in a time-dependent manner similar to previous reports (20), gradually reducing the total number and the rate of ventricular ectopies and increasing SA beats. However, the slow onset of action makes amiodarone less suitable for immediate and effective abolition of ventricular ectopies. Unlike E 047/1, amiodarone has an unpredictable duration of action and plasma elimination, and the compound is degraded to active metabolites (8). For these reasons, it is often recommended only as a drug of second choice (8,9).
In summary, the antiarrhythmic E 047/1 has desirable features that make it potentially useful. In a canine model of subacute postoperative ischemia, E 047/1 is highly antiarrhythmic immediately after IV administration. Conclusions regarding the application of these findings to humans must be drawn carefully, but our results indicate that the experimental drug E 047/1 may become a valuable addition to current drug regimens for the treatment of malignant ventricular arrhythmias. Our findings should encourage further testing in different experimental and clinical models.
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Acknowledgments |
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We are grateful for the valuable technical assistance of John Krolikowski.
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Footnotes |
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