PERIOPERATIVE SYMPATHOLYSIS - BENEFICIAL-EFFECTS OF THE ALPHA(2)-ADRENOCEPTOR AGONIST MIVAZEROL ON HEMODYNAMIC STABILITY AND MYOCARDIAL-ISCHEMIA

Background: Mivazerol hydrochloride is a new alpha(2)-adrenoceptor ago nist, In vitro and animal studies have demonstrated both sympatholytic and antiischemic properties. To evaluate the safety and efficacy of m ivazerol in patients during perioperative stress, this multicenter pha se II clinical trial studied hemodynamic stability and myocardial isch emia in patients with coronary artery disease undergoing noncardiac su rgery. Methods: Three hundred patients, from twenty-three European med ical institutions, participated in this placebo-controlled, double-bli nd, randomized, parallel-group trial. Ninety-eight were given high-dos e mivazerol (1.5 mu g . kg(-1) . h(-1)); 99, low-dose mivazerol (0.75 mu g . kg(-1) . h(-1)); and 103, placebo, continuously intraoperativel y and for 72 h postoperatively. Blood pressure and heart rate were mon itored for 96 h. Myocardial ischemia was assessed by Holter electrocar diography for at least 8 h before induction of anesthesia until 96 h a fter surgery, Twelve-lead electrocardiograms and creatine kinase myoca rdial band isoenzyme levels were obtained before and serially after su rgery, Adverse cardiac events were assessed For the intraoperative, ea rly postoperative (0-24 h), anal late postoperative (24-72 h) periods. Results: The incidence of tachycardia was significantly lower with hi gh-dose mivazerol (vs. placebo) during the intraoperative (30% vs. 51% ; P = 0.002), early postoperative (29% is. 50%; P = 0.002), and late p ostoperative periods (46% ys. 70%; P = 0.001). Also, the percentage of patients treated for tachycardia was significantly lower with the hig h dose (vs, placebo) during the early (10% vs. 20%; P = 0.043) and lat e (6% vs. 15%; P = 0.024) postoperative periods. The incidence of hype rtension was significantly lower with both high and low doses (vs. pla cebo) during the intraoperative period (46% and 43%, respectively, vs. 63%; P = 0.010); treatment was similar at both high and low doses (33 % and 34%, respectively, ris. 46%; P = 0.066). The incidence of bradyc ardia was significantly higher at both dose levels than with placebo d uring and after drug administration (intraoperatively-3%, 7%, and 9%; early postoperative-0%, 5%, and 6%; late postoperative-0%, 4%, and 6%; after drug-0%, 6%, and 6%; placebo, low-dose, high-dose, respectively ), but the need for treatment did not differ for the groups. The incid ence of and treatment for, hypotension were similar for the three grou ps. Intraoperative myocardial ischemia was significantly lower with hi gh-dose mivazerol than with placebo (20% vs. 34%, respectively, P = 0. 026). When intraoperative data were subdivided into emergence vs. none mergence periods (post hoc analysis), the incidence of myocardial isch emia was significantly lower with high-dose mivazerol than with placeb o during emergence (11% vs. 30%; P = 0.001). Regarding blood pressure, heart rate, and ischemia, no rebound response occurred in the 12 In a fter discontinuation of mivazerol. The high-dose, low-dose, and placeb o groups did not differ in the incidence of adverse cardiac outcomes ( 3%, 2%, and 8%, respectively) or the diagnosis of myocardial infarctio n (2%, 1%, and 6%, respectively). Conclusions: Continuous, 72-h periop erative administration of mivazerol to high-risk patients appears to b e relatively safe, producing no significant hypotension or adverse eve nts but some evidence of bradycardia not associated with adverse clini cal events. Mivazerol decreased the incidence of, and treatment for, t achycardia, hypertension, and myocardial ischemia, particularly during high stress periods. Therefore, these salutary effects of mivazerol i ndicate further study in large scale trials that assess mivazerol's ef fects on adverse cardiac outcomes, including death and myocardial infa rction.