Perioperative sympatholysis. Beneficial effects of the alpha 2-adrenoceptor agonist mivazerol on hemodynamic stability and myocardial ischemia. McSPI--Europe Research Group.
BACKGROUND
Mivazerol hydrochloride is a new alpha 2-adrenoceptor agonist. In vitro and animal studies have demonstrated both sympatholytic and antiischemic properties. To evaluate the safety and efficacy of mivazerol in patients during perioperative stress, this multicenter phase II clinical trial studied hemodynamic stability and myocardial ischemia in patients with coronary artery disease undergoing noncardiac surgery.


METHODS
Three hundred patients, from twenty-three European medical institutions, participated in this placebo-controlled, double-blind, randomized, parallel-group trial. Ninety-eight were given high-dose mivazerol (1.5 micrograms.kg-1.h-1); 99, low-dose mivazerol (0.75 microgram.kg-1.h-1); and 103, placebo, continuously intraoperatively and for 72 h postoperatively. Blood pressure and heart rate were monitored for 96 h. Myocardial ischemia was assessed by Holter electrocardiography for at least 8 h before induction of anesthesia until 96 h after surgery. Twelve-lead electrocardiograms and creatine kinase myocardial band isoenzyme levels were obtained before and serially after surgery. Adverse cardiac events were assessed for the intraoperative, early postoperative (0-24 h), and late postoperative (24-72 h) periods.


RESULTS
The incidence of tachycardia was significantly lower with high-dose mivazerol (vs. placebo) during the intraoperative (30% vs. 51%; P = 0.002), early postoperative (29% vs. 50%; P = 0.002), and late postoperative periods (46% vs. 70%; P = 0.001). Also, the percentage of patients treated for tachycardia was significantly lower with the high dose (vs. placebo) during the early (10% vs. 20%; P = 0.043) and late (6% vs. 15%; P = 0.024) postoperative periods. The incidence of hypertension was significantly lower with both high and low doses (vs. placebo) 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, vs. 46%; P = 0.066). The incidence of bradycardia was significantly higher at both dose levels than with placebo during 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 incidence of, and treatment for, hypotension were similar for the three groups. Intraoperative myocardial ischemia was significantly lower with high-dose mivazerol than with placebo (20% vs. 34%, respectively, P = 0.026). When intraoperative data were subdivided into emergence vs. nonemergence periods (post boc analysis), the incidence of myocardial ischemia was significantly lower with high-dose mivazerol than with placebo during emergence (11% vs. 30%; P = 0.001). Regarding blood pressure, heart rate, and ischemia, no rebound response occurred in the 12 h after discontinuation of mivazerol. The high-dose, low-dose, and placebo groups did not differ in the incidence of adverse cardiac outcomes (3%, 2%, and 8%, respectively) or the diagnosis of myocardial infarction (2%, 1%, and 6%, respectively).


CONCLUSIONS
Continuous, 72-h perioperative administration of mivazerol to high-risk patients appears to be relatively safe, producing no significant hypotension or adverse events but some evidence of bradycardia not associated with adverse clinical events. Mivazerol decreased the incidence of, and treatment for, tachycardia, hypertension, and myocardial ischemia, particularly during high stress periods. Therefore, these salutary effects of mivazerol indicate further study in large-scale trials that assess mivazerol's effects on adverse cardiac outcomes, including death and myocardial infarction.
D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D000368:Aged; D000700:Analgesics / Q000008:administration & dosage; D000777:Anesthetics / Q000008:administration & dosage; D001794:Blood Pressure / Q000187:drug effects; D003000:Clonidine / Q000494:pharmacology; D004311:Double-Blind Method; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects*; D006801:Humans; D007093:Imidazoles / Q000009:adverse effects / Q000097:blood / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D017202:Myocardial Ischemia / Q000517:prevention & control*; D013564:Sympathetic Nervous System / Q000187:drug effects*
D000316:Adrenergic alpha-Agonists; D000700:Analgesics; D000777:Anesthetics; D007093:Imidazoles; D003000:Clonidine; C087969:mivazerol