April 1997
the Use of Alpha2-Adrenoceptor Agonists in Anesthesiology

1. Epidural clonidine used as the sole anesthetic agent during and after abdominal surgery: a dose-response study
De Kock M, Wiederkher P, Laghmiche A, Scholtes J-L
Anesthesiology 1997; 86:285-92
[ see abstract below ]

2. Dexmedetomidine as an anesthetic adjunct in coronary artery bypass grafting.
Jalonen J, Hynynen M, Kuitunen A et al.
Anesthesiology 1997;86:331-45.
[ see abstract below ]

3. Perioperative sympatholysis: beneficial effects of the alpha2-adrenoceptor agonist mivazerol on hemodynamic stability and myocardial ischemia.
McSPI-EUROPE Research Group.
Anesthesiology 1997; 86:346-63.
[ see abstract below ]

In the February 1997 issue of Anesthesiology there are no less than three major papers on the use of alpha2-adrenoceptor agonists in anesthesiology. The archetypical agent, clonidine, has been used as an oral antihypertensive agent for many years. Over the last decade there has been a huge amount of laboratory and clinical investigation of its use as a parenteral anesthetic and analgesic adjunct.

In addition, two new highly selective alpha2-adrenoceptor agonists, dexmedetomidine and mivazerol, are in the process of undergoing clinical trials as a prelude to FDA approval for parenteral use in the United States. Why the interest? Alpha2-adrenoceptor agonists have some remarkable properties that are of direct interest to anesthesiologists and potential benefit to our patients. In addition to their potent anesthetic and analgesic sparing capability, these agents are also anxiolytic, antisialogogic and sympatholytic. They decrease perioperative anesthetic and analgesic requirement and thereby may decrease side effects such as postoperative nausea and vomiting.

Plasma norepinephrine levels are predictably lowered, and the slowing of heart rate and decrease in systolic blood pressure that results may prevent perioperative myocardial ischemia. They also markedly decrease postoperative shivering. Finally, a very attractive feature of these agents is that they have little appreciable effect on the ventilatory drive, although their interaction with opioids does need more investigation in this area.

Each of the three manuscripts in the February 1997 issue of Anesthesiology adds an important piece to our knowledge of the potential role of alpha2-adrenoceptor agonists in anesthesiology.

De Kock et al. (1) studied the effect of epidural clonidine as the sole analgesic agent during and after major abdominal (gastrointestinal) surgery in a single center trial on 50 patients. They used three dosing regimens of clonidine (initial dose of 2, 4 or 8 g/kg followed by an infusion of 0.5, 1 or 2 g/kg/hr respectively) during surgery and for 12 hr postoperatively. General anesthesia was provided by a propofol infusion, and patients "dropped out" of the study if there were clinical indications for supplemental analgesia during or after anesthesia. Although the low dose regimen proved relatively ineffective, the high dose regimen provided effective intraoperative analgesia in 95% of patients, and complete postoperative analgesia for a mean of about six hours. There were no major side effects of bradycardia or hypotension.

Jalonen et al. (2) examined the effect of dexmedetomidine infusion as an adjunct to anesthesia for coronary artery bypass grafting (CABG) surgery. The design was a double-blinded, placebo-controlled two center study in 80 patients, with a loading dose of 50 ng/kg/min for 30 min, followed by an infusion of 7 ng/kg/min until the end of surgery. The primary study endpoints were physiologic and hemodynamic responses and anesthetic requirement, rather than outcome variables such as myocardial ischemia.

Compared with placebo, dexmedetomidine decreased plasma norepinephrine levels by 90%, and significantly decreased intraoperative blood pressure responses and perioperative tachycardia, anesthetic requirement (fentanyl and enflurane), beta-blocker therapy, fentanyl-induced rigidity and postoperative shivering. However, dexmedetomidine did increase the incidence of hypotension during cardiopulmonary bypass and perioperative fluid requirement.

The McSPI-Europe Research Group (3) conducted a large scale trial of perioperative mivazerol infusion as an adjunct to anesthesia for noncardiac surgery in 300 patients in 23 European medical centers. Patients were randomized to placebo, low dose mivazerol (0.75 g/kg/min) or high dose mivazerol (1.5 g/kg/min) in a double-blinded fashion, and the infusions were continued for 72 hr postoperatively. Myocardial ischemia was monitored for by Holter electrocardiography.

Mivazerol decreased the incidence of perioperative hypertension and tachycardia in a dose-related manner, and decreased the incidence of electrocardiographically defined myocardial ischemia in the intraoperative and emergence phases. However, the number of patients studied did not provide the power to define a significant difference in cardiac complications or myocardial infarction between the groups.

What do these papers mean to the clinical anesthesiologist? Clearly, the next five years will see the addition of alpha2-adrenoceptor agonists to our armamentarium. However, it is likely that our European colleagues will remain ahead of us for the near future, because clonidine is not approved in the US for parenteral use, and to date dexmedetomidine and mivazerol have been more extensively studied in Europe than in the US. When the new agents are released, will they be cost-effective?

Potentially costs of anesthetics and analgesics could be reduced by these adjuvants, but the real cost-savings will come if it can be shown that PACU and ICU stays require less therapeutic intervention and possibly quicker discharge. Dexmedetomidine and mivazerol are being developed competitively. What are the intrinsic differences between these drugs? Head to head comparisons are unlikely in the near future but will need to be done at some stage. If, as is likely, their pharmacologic action s are indistinguishable, what will be their relative cost? Which one should we choose? Perhaps, and hopefully, the competition between these two drugs will help to keep their acquisition costs down.

Whatever happens, anesthesiologists should learn about the potential benefits and limitations of the alpha2-adrenoceptor agonists because they are certainly here to stay.

Return to the Current Literature Review Front Page, or read the abstracts:

Abstract 1:
Epidural clonidine used as the sole anesthetic agent during and after abdominal surgery: a dose-response study

Background: Many studies have shown the beneficial effect of epidural clonidine in postoperative pain management. In these studies, the patients received local anesthetics, opioids, or both in combination with clonidine. Due to the interactive potentuation of these drugs, the importance of the intrinsic analgesic properties of the a2- adrenoreceptor agonist is difficult to establish. The authors investigated the analgesic potency of epidural clonidine when used as the sole analgesic agent during and after abdominal surgery.

Methods: Fifty young adult patients undergoing intestinal surgery under general anesthesia with propofol were studied. At induction, the patients received epidurally either an initial dose of 2 ug/kg clonidine followed by an infusion of 0.5 ug - kg 1 - h 1 (group 1, n = 10) or 4 ug/kg followed by 1 ug - kg 1 - h 1 (group 2, n = 20) or 8 ug - kg 1 - l 1 followed by an infusion of 2 ug - kg 1 - h 1 (group 3, n = 20). During the operation, increases in arterial blood pressure or heart rate that did not respond to a propofol halus (0.5 mg/kg) were treated with a halus of intravenous ildesline (1 mg/kg).

Three successive injections were allowed. When baseline values were not restored, opioids were added and the patient was removed from the study. After operation, the clonidine infusion were maintained for 12 h. During this period and at every 30 min. sedation scores and visual analog scale values at rest and at cough were noted. In cases of subjective scores up to 5cm at rest or up to 8 cm at cough, the patients were given access to a patient controlled analgesia device that delivered epidural bupivacaine. The end point of the study was reached once the patient activated the analgesic delivery button.

Results: During surgery, 60% of patients in group 1 compared with 33% of patients in group 2 and only 3% of patients in group 3 were removed from the study because of inadequate anesthesia (P < 0.03). After operation, epidural clonidine provided complete analgesia lasting 30 - 21 min in group 1 compared with 251 +/- 237 min in group 2 or 369 +/- 256 min in group 3 (P < 0.03 for group 1 vs. groups 2 and 3 and group 2 vs. group 3).

Conclusions: Epidural clonidine used as the sole analgesic agent provided dose-dependent control of the hemodynamic changes associated with surgical stimulation. It also produced dose-dependent postoperative analgesia without major side effects.


Abstract 2:
Dexmedetomidine as an anesthetic adjunct in coronary artery bypass grafting.

Background: a2-adrenergic agonists decrease symapthetic tone with ennuing attenuation of neurenducive and hemodynamic responses to anesthesia and surgery. The effects of dexmedetomidine, a highly specific a2-adrenergic agonist, on these responses have not been reported in patients undergoing coronary artery bypass grafting.

Methods: Eighty patients scheduled for elective coronary artery bypass grafting received, in a double-blind manner, either a saline placebo or a dexmedetomidine infusion. Initially 50 mg - kg 1 - min 1 for 30 min before induction of anesthesia with fentanyl, and then 7 mg - kg 1 - min 1 until the end of surgery. Filling pressures, blood pressure, and heart rate were controlled by intravenous fluid and by supplemental anesthetics and vasoactive drugs.

Results: Compared with placebo, dexmedetomidine deceased plasma norepinephrine concentrations by 90%, attenuated the increase of blood pressure during anesthesia ( 3 vs. 2 mmilg) and surgery (2 vs. 14 mmilg), but increased slightly the need for intravenous fluid challenge (29 vs. 20 patients) and induced more hypotension during cardiopulmonary bypass (9 vs. 0 patients). Dexmedetomidine also decreased the need for additional doses of fentanyl (3.1 vs. 5.4), the increases of enflurane (4.4 vs. 3.6), the need for beta blockers (3 vs. 11 patients), and the incidence of fentanyl induced muscle rigidity (13 vs. 33 patients) and postoperative shivering (13 vs. 23 patients).

Conclusions: Intraoperative intravenous infusion of dexmedetomidine to patients undergoing coronary artery revascularization decreased intraoperative sympathetic tone and attenuated hyperdynamic responses to anesthesia and surgery but increased the propensity toward hypotension.


Abstract 3:
Perioperative sympatholysis: beneficial effects of the alpha2-adrenoceptor agonist mivazerol on hemodynamic stability and myocardial ischemia.

Background: Mivazerol hydrochloride is a new a2-adrenoceptor agonist. In vitro and animal studies have demonstrated with sympatholytic and antilaxhemic properties. To evaluate the safety and efficiency 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 ug - kg 1 - h 1), 99 low-dose mivazerol ( 0.75 ug - kg 2 - 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 eventine kinaic myocardial band isocinzyme level 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%, 3%, 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 (30% vs. 34%, respectively, P = 0.026). When intraoperative data were subdivided into emergence vs. nonemergence periods (phat hoc 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 infraction (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, myocardial ischemia, particularly during high serum 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 infraction.