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disease. Thus far, dexmedetomidine has been administered only to healthy volunteers and healthy surgical patients. Therefore, to perform a preliminary evaluation of the feasibility and effects of perioperative administration of dexmedetomidine in high-risk surgical patients, we studied three consecutively increasing doses of an infusion of dexmedetomidine in vascular surgery patients, a population with a high incidence of coronary artery disease (CAD) who might benefit significantly from increased perioperative hemodynamic stability. With approval from our Human Research Committee and written informed consent, we studied 25 patients with or at high risk for CAD who were scheduled for vascular surgery at the San Francisco Veterans Affairs Medical Center. Study entry criteria included one or more of the following: a history of classic angina pectoris; a history of myocardial infarction; electrocardiographic (ECG) evidence of Q waves typical of infarction without a history; CAD detected by angiography; or the presence of two or more risk factors for CAD, including cigarette smoking, treatment for hypertension, treated diabetes mellitus, or hypercholesterolemia (> 240 mg/dL). Excluded from study were patients with unstable angina, uninterpretable preoperative ECGs (left bundle branch block), patients taking clonidine or tricyclic antidepressants, and those who did not receive the study drug continuously for at least the first 24 postoperative hours. Cardiac medications were continued until the night of surgery. The study was a double-blind, randomized, dose-escalation trial using three different doses of dexmedetomidine and placebo. Twenty-four patients were divided into three groups of eight to form low-, medium-, and high-dose test groups, each having six patients who received dexmedetomidine and two who received placebo. Thus, six patients received placebo during the study. The number of patients used in this study was not based on power calculations. Study began with the low-dose group, and once this dose was determined to be tolerable, proceeded to the medium-dose group, then, after the same determination, the high-dose group. Initially, 25 patients were enrolled in the study, but one (high-dose group) was excluded when dexmedetomidine was discontinued within 24 h of administration to permit an emergent return to surgery. Dexmedetomidine was administered by a computer-controlled infusion pump (CCIP) targeting plasma concentrations of 0.15 ng/ml (low-dose), 0.30 ng/ml (medium-dose), and 0.45 ng/ml (high-dose). STAN-PUMP software (Steve Shafer, Stanford University, Palo Alto, CA) was used to run the infusion pump (Harvard Apparatus 22, Harvard Apparatus, South Natick, MA). The STANPUMP software updated the infusion rate at 10-s intervals using dexmedetomidine pharmacokinetic data [19] to allow drug delivery to targeted plasma concentrations. The infusion rate data were stored in the laptop computer, which was used to run the STANPUMP program. To study the effect of dexmedetomidine in awake and anesthetized patients, infusion was begun 1 h before induction of anesthesia and continued throughout the intraoperative period and for 48 h postoperatively. The average amount of dexmedetomidine infused was 2.64 micro gram/kg (range 2.30–3.75 micro gram/kg), 5.31 micro gram/kg (range 4.40–5.97 micro gram/kg), and 8.03 micro gram/kg (range 5.57–9.87 micro gram/kg) for the low-, medium-, and high-dose groups, respectively. Patients were not permitted to ambulate during study drug infusion. The night before surgery, patients received 2 mg lorazepam orally. In the operating room, study drug infusion was started 1 h before induction of anesthesia. Patients then breathed oxygen while anesthesia was induced with alfentanil (up to 30 micro gram/kg) and thiopental (up to 3 mg/kg). Vecuronium (0.1 mg/kg) was administered to achieve muscle relaxation before tracheal intubation and as needed thereafter. Anesthesia was maintained with a continuous alfentanil infusion of 0.5 micro gram *symbol* kg sup -1 *symbol* min sup -1 and 70% N2O in oxygen. Isoflurane (0–2%) was administered to maintain hemodynamics within
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