First clinical experience with the rapid-, short-acting amiodarone derivative E 047/1 after cardiac surgery.
OBJECTIVE
Amiodarone is very effective against a variety of dysrhythmias but has poor pharmacodynamic properties and many undesired side-effects. Its short- and rapid-acting derivative E 047/1 may circumvent some of these drawbacks. It is easier to titrate while retaining the high efficacy of amiodarone and may have acceptable influences on haemodynamics and cardiac conduction in patients who develop serious, destabilizing ventricular tachydysrhythmias after cardiac surgery.


METHODS
Testing E 047/1 was performed prospectively in two consecutive phase II open, clinical studies. Out of 504 patients scheduled for surgery using cardiopulmonary bypass for coronary artery grafting and/or valve repair, 35 developed serious, haemodynamically destabilizing ventricular dysrhythmias (Lown 2-Lown 4b) after surgery and were treated with a 1 mg kg(-1) (pilot study, n = 15) or randomized to a 2 or 3 mg kg(-1) bolus of E 047/1, followed by a 1 mg kg(-1) h(-1) continuous infusion for 2 h (n = 10 in each group). Dysrhythmias, PQ, QTc intervals and haemodynamics using the thermodilution technique were evaluated for up to 24 h after drug initiation.


RESULTS
At the time of final inclusion the patients had between 6 and 12 (or more) ventricular ectopics per minute. Within the first 2-3 min of application in the pilot trial E 047/1 induced a decrease of ventricular dysrhythmias to between 0 and 4 per min, a decrease that held for the duration of treatment. The area under the curve decreased from 434 (322, 855; median, quartiles) to 114 (9, 477, P < 0.01) events per hour. In the randomized trial, E 047/1 administered in either dose rapidly reduced ventricular dysrhythmias at least as effectively as in the pilot trial 565 (478, 701) to 33 (8, 238, P < 0.05) after a 2 mg bolus; 482 (339, 482) to 95 (13, 540, P < 0.01) events per hour after a 3 mg bolus. Approximately 4-6 h after drug termination, dysrhythmias reappeared in the majority of patients. In only three patients did the incidence of dysrhythmias return to inclusion criteria levels. In contrast to the pilot trial, in the randomized trial there was a slight increase of mean pulmonary artery pressure, central venous pressure and pulmonary arterial wedge pressure and a slight decrease of LCWI in both groups. E 047/1 did not cause QTc prolongation.


CONCLUSIONS
E 047/1 appears to be a safe alternative to amiodarone in the perioperative setting of cardiac surgery when serious, destabilizing dysrhythmias occur.
Gombotz
H
H
University of Graz, Department of Anaesthesiology and Intensive Care Medicine, Austria. hans.gombotz@kfunigraz.ac.at
Vicenzi
M
M
Mahla
E
E
Rehak
P
P
Metzler
H
H
D000368:Aged; D000638:Amiodarone / Q000031:analogs & derivatives*; D000704:Analysis of Variance; D000889:Anti-Arrhythmia Agents / Q000627:therapeutic use*; D019540:Area Under Curve; D001145:Arrhythmias, Cardiac / Q000188:drug therapy*; D001572:Benzofurans / Q000627:therapeutic use*; D002315:Cardiopulmonary Bypass; D002318:Cardiovascular Diseases / Q000188:drug therapy* / Q000601:surgery*; D005260:Female; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D008297:Male; D019990:Perioperative Care; D011446:Prospective Studies; D013997:Time Factors
C402242:((2-butyl-3-benzofuranyl)-(5-(2-diethylamino)ethoxy)-2-thienyl)methanone; D000889:Anti-Arrhythmia Agents; D001572:Benzofurans; D000638:Amiodarone