Introduction
Alpha-2 receptor agonists have many desirable effects such as minimum alveolar concentration (MAC) reduction, analgesia, anxiolysis, sedation, and sympatholysis. Adding to this list the possibility of perioperative myocardial protection makes the perioperative use of alpha-2 agonists very appealing in patients with known or suspected coronary artery disease. It is well-known that drugs that positively affect myocardial oxygen supply and demand are beneficial in the perioperative period for myocardial protection. Perioperative beta-blockade is an excellent example of this. The ability of alpha-2 agonists to modulate sympathetic tone may similarly offer perioperative myocardial protection.
Options/Therapies
The most widely studied alpha-2 agonists are clonidine, mivazerol, and dexmedetomidine. Clonidine is available in oral, transdermal, and parenteral forms and is a partial agonist. Mivazerol is an intravenous alpha-2 agonist, and dexmedetomidine is a shorter-acting intravenous alpha-2 agonist. The selectivity ratios for all three are shown in Table 32-1 . All three alpha-2 agonists have been shown to cause dose-dependent sympatholysis, but clonidine and mivazerol have been most extensively studied with regard to perioperative cardiac protection. Unfortunately, mivazerol is not available in the United States.
| Alpha-2 Agonist | Alpha-2:Alpha-1 Specificity |
|---|---|
| Dexmedetomidine | 1300 : 1 |
| Mivazerol | 119 : 1 |
| Clonidine | 39 : 1 |
Evidence
Several studies have been published investigating alpha-2 agonists and their role in perioperative myocardial protection. In addition, many studies have evaluated the hemodynamic stabilizing effects and sympatholysis produced by alpha-2 agonists. It is important to understand the endpoints in these investigations because many used myocardial ischemia as a surrogate marker for myocardial infarction and cardiac death. Although several studies have linked perioperative myocardial ischemia to subsequent increased cardiac morbidity and mortality rates, most of the studies to date have not linked the use of perioperative alpha-2 agonists to decreased rates of myocardial infarction and death.
Randomized Controlled Trials: Clonidine
The perioperative use of clonidine for myocardial protection in noncardiac surgery has been studied in three well-designed small, randomized trials. Ellis and colleagues studied the use of transdermal clonidine combined with oral clonidine in a randomized, double-blind, placebo-controlled clinical trial of 61 patients undergoing elective major noncardiac surgery. The treatment group received premedication with the transdermal clonidine system (0.2 mg/day) the night before surgery, which was left in place for 72 hours, and 0.3 mg oral clonidine 60 to 90 minutes before surgery. The incidence of intraoperative electrocardiographic (ECG) ischemia was diminished in the clonidine group (4% versus 21%, p = 0.05). There was no difference, however, between the two groups in the incidence of postoperative ischemia. Later, Stuhmeier and colleagues studied 297 patients scheduled for vascular surgery in a randomized, double-blind fashion. They evaluated the effect of 2 mcg/kg of oral clonidine 90 minutes before induction of anesthesia. Patients receiving oral clonidine demonstrated a decreased incidence of intraoperative myocardial ischemia (24% versus 39%, p < 0.01). However, no statistical difference was noted in the number of patients who had a nonfatal myocardial infarction or who died of major cardiac events. In 2004 Wallace and colleagues conducted a prospective, double-blind, randomized clinical trial of 190 patients at risk of coronary artery disease scheduled for noncardiac surgery. All patients in the clonidine group ( n = 125) received 0.2 mg orally the night before and 1 hour before surgery. A transdermal patch (0.2 mg/day) was placed the night before surgery and removed on postoperative day 4. The incidence of myocardial ischemia in the clonidine group was reduced on days 0 to 3 versus the placebo group (14% versus 31%, p < 0.01). Long-term follow-up revealed that the clonidine group had a reduced mortality rate at 30 days (0.8% versus 6.5%, p = 0.048) and at 2 years (15% versus 29%, p = 0.035), but this benefit lost statistical significance after removing all patients who received preoperative or intraoperative beta-blockers.
Randomized Controlled Trials: Mivazerol
Mivazerol, an intravenous alpha-2 agonist administered by continuous infusion, has been studied in larger trials. A European multicenter group studied mivazerol in a phase II, placebo-controlled, double-blind, randomized trial. Three hundred patients with known coronary artery disease (CAD) were placed into three groups: high-dose mivazerol (1.5 mcg/kg/hr), low-dose mivazerol (0.75 mcg/kg/hr), or placebo. High-dose mivazerol had significantly less intraoperative myocardial ischemia versus placebo (20% versus 34%, p = 0.026), but no differences were observed for perioperative myocardial infarction or death. In addition, there was no difference in postoperative myocardial ischemia. In 1999 Oliver and colleagues conducted a large double-blind, randomized, placebo-controlled study of 2854 patients (1897 with known CAD and 957 with risk factors for CAD). Patients received perioperative mivazerol at 1.5 mcg/kg/hr for 72 hours or placebo. On subgroup analysis, in the group of 1897 patients with known CAD, there were fewer cardiac deaths in the mivazerol group versus placebo (13 of 956 versus 25 of 941, p = 0.037). The rates of myocardial infarction and all-cause death were not statistically different between the two groups. In the subgroup of patients undergoing vascular procedures ( n = 904), mivazerol afforded significant myocardial protection. The cardiac death rate was 6% versus 18% ( p = 0.009), and the combined cardiac death and myocardial infarction rate was 10% versus 14% ( p = 0.02). The myocardial infarction rate alone was not significantly different.
Randomized Controlled Trials: Dexmedetomidine
No large randomized controlled trials have studied the infusion of dexmedetomidine for reduction of perioperative cardiac morbidity and mortality rates in noncardiac surgical patients. Dexmedetomidine has been investigated in small studies for its hemodynamic effects. Talke and colleagues evaluated the hemodynamic effects of four different doses of dexmedetomidine in 22 vascular surgery patients at risk of CAD. Although patients at the higher doses of dexmedetomidine appeared to have greater hemodynamic stability (less tachycardia and systolic hypertension), they needed more intraoperative vasopressor and fluid support. Because of the study size, no statistical significance could be determined regarding myocardial ischemia and perioperative myocardial infarction. A second study by Jalonen and colleagues looked at 80 patients scheduled for elective coronary artery bypass grafting. Again, dexmedetomidine produced less tachycardia and was associated with lower blood pressures, but the study patients needed more fluid challenges and pharmacologic treatment for hypotension. No statistical significance was determined with respect to myocardial ischemia and infarction. Table 32-2 summarizes all of the randomized controlled trials.
| Author, Year | Procedure | No. of Subjects | Study Design | Intervention | Ischemia | MI | Cardiac Death |
|---|---|---|---|---|---|---|---|
| Ellis, 1994 | Noncardiac | Control 31 Treated 30 | Double-blind placebo | TD clonidine 0.2 mg night prior (72 hr); clonidine 0.3 mg PO preoperatively | D: 1/28 (4%) C: 5/24 (21%) p = 0.05 | ||
| Stuhmeier, 1996 | Vascular | Control 152 Treated 145 | Double-blind placebo | Clonidine 2 mcg/kg PO preoperatively | D: 35/145 (24%) C: 59/152 (39%) p < 0.01 | D: 0/145 (0%) C: 4/152 (3%) NS | D: 2/145 (1%) C: 1/152 (1%) NS |
| McSPI, 1997 | Noncardiac | Control 103 Treated 98 | Double-blind placebo | Mivazerol 1.5 mcg/kg/hr (high dose); started 20 min before induction; continued for 72 hr | D: 17/87 (20%) C: 34/99 (34%) p = 0.026 (high dose only) | D: 2/98 (2%) C: 6/103 (6%) NS (high dose only) | D: 1/98 (1%) C: 1/98 (1%) NS (high dose only) |
| Oliver, 1999 | Noncardiac with known CAD | Control 941 Treated 946 | Double-blind placebo | Mivazerol 1.5 mcg/kg/hr; started 20 min before induction; continued for 72 hr | D: 78/946 (8%) C: 79/941 (8%) NS | D: 13/946 (3%) C: 25/941 (1%) p = 0.037 | |
| Oliver, 1999 | Vascular | Control 450 Treated 454 | Double-blind placebo | Mivazerol 1.5 mcg/kg/hr; started 20 min before induction; continued for 72 hr | D: 42/454 (9%) C: 53/450 (12%) NS | D: 6/454 (1%) C: 18/450 (4%) p = 0.009 | |
| Wallace, 2004 | Noncardiac | Control 65 Treated 125 | Double-blind placebo | TD clonidine 0.2 mg night prior (4 days); clonidine 0.2 mg PO preoperatively and night prior | D: 18/125 (14%) C: 20/65 (31%) p = 0.01 | D: 5/125 (4%) C: 3/65 (5%) NS | D: 19/125 (15%) C: 19/65 (29%) p = 0.035 |
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