SPECIAL ARTICLE Alpha-2 Adrenergic Agonists to Prevent Perioperative Cardiovascular Complications: A Meta-analysis Duminda N. Wijeysundera, MD, Jennifer S. Naik, MD, W. Scott Beattie, MD, PhD ␣ ϭ ϭ PURPOSE: To investigate the effects of 2-adrenergic agonists 0.99; P 0.05) and ischemia (RR 0.76; 95% CI: 0.63 to 0.91; on perioperative mortality and cardiovascular complications in P ϭ 0.003) significantly. They also reduced mortality (RR ϭ adults undergoing surgery. 0.47; 95% CI: 0.25 to 0.90; P ϭ 0.02) and myocardial infarction METHODS: MEDLINE (1966 to May 2002), EMBASE (1980 (RR ϭ 0.66; 95% CI: 0.46 to 0.94; P ϭ 0.02) during vascular to May 2002), the Cochrane Clinical Trials Register, the Science ␣ surgery. During cardiac surgery, 2-adrenergic agonists re- Citation Index, and bibliographies of included articles were duced ischemia (RR ϭ 0.71; 95% CI: 0.54 to 0.92; P ϭ 0.01) and searched without language restriction. Randomized trials com- were associated with trends toward lower mortality (RR ϭ 0.49; paring preoperative, intraoperative, or postoperative (first 48 95% CI: 0.12 to 1.98; P ϭ 0.3) and a reduced risk of myocardial hours) administration of clonidine, dexmedetomidine, or infarction (RR ϭ 0.83; 95% CI: 0.35 to 1.96; P ϭ 0.7). mivazerol with controls were included. Studies had to report CONCLUSION: Alpha-2 adrenergic agonists reduce mortality any of the following outcomes: mortality, myocardial infarc- and myocardial infarction following vascular surgery. During tion, ischemia, or supraventricular tachyarrhythmia. Treat- cardiac surgery, they reduce ischemia and may also have effects ment effects were calculated using the fixed-effects model. Het- on mortality and myocardial infarction. Large randomized erogeneity was assessed using the Q test. RESULTS: Twenty-three trials comprising 3395 patients were trials are needed to evaluate these agents during cardiac and ␣ vascular surgery. Am J Med. 2003;114:742–752. ©2003 by included. Overall, 2-adrenergic agonists reduced mortality (relative risk [RR] ϭ 0.64; 95% confidence interval [CI]: 0.42 to Excerpta Medica Inc. ␣ ardiovascular complications following cardiac diovascular complications. Unlike 1-antagonists (e.g., and noncardiac surgery increase mortality, mor- prazosin), which act on peripheral adrenergic receptors bidity, and health care costs (1–4). Approxi- ␣ C to inhibit vasoconstriction directly, 2-agonists act on mately 4.5% of patients undergoing cardiac surgery will central and presynaptic receptors to inhibit central sym- have a perioperative myocardial infarction (1), whereas pathetic outflow (7) and reduce peripheral norepineph- about 30% of patients undergoing noncardiac surgery rine release (8). Alpha-2 agonists dilate poststenotic have, or are at risk of, coronary artery disease (3). The coronary vessels (9) and attenuate the severity of periop- direct health care costs of these complications have been erative hemodynamic abnormalities (10,11), and conse- estimated at U.S. $20 billion (3). quently were conferred a grade IIb recommendation in The surgical stress response is important in the patho- the 2002 American College of Cardiology/American ␣ genesis of cardiovascular complications (5,6). The 2-ad- Heart Association Guideline Update on Perioperative renergic agonists currently used in clinical practice— Cardiovascular Evaluation for Noncardiac Surgery (12). clonidine, dexmedetomidine, and mivazerol—attenuate This recommendation, however, was based on one study the stress response and therefore potentially reduce car- (13). A prior meta-analysis concluded that clonidine re- From the Department of Anesthesia (DNW, JSN, WSB), University of duced perioperative ischemia significantly (14). How- Toronto, and Toronto General Hospital (WSB), University Health Net- work, Toronto, Ontario, Canada. ever, the review was underpowered (664 patients in seven Dr. Wijeysundera is the recipient of the Dr. Allan K. Laws Clinician studies), searched only English-language literature, and Scientist Fellowship from the University of Toronto, Ontario, Canada. reported effects only on ischemia, a surrogate outcome. It Requests for reprints should be addressed to W. Scott Beattie, MD, PhD, Department of Anesthesia, University of Toronto, EN 3-453, To- did not include trials of mivazerol or dexmedetomidine, ronto General Hospital, 200 Elizabeth Street, Toronto, Ontario, M5G which have enrolled up to 1900 patients (13). A system- 2C4, Canada, or [email protected]. ␣ Manuscript submitted September 11, 2002, and accepted in revised atic review of perioperative 2-agonists is therefore justi- form February 11, 2003. fied. 742 © 2003 by Excerpta Medica Inc. 0002-9343/03/$–see front matter All rights reserved. doi:10.1016/S0002-9343(03)00165-7 Table 1. Characteristics of Included Studies First Author Number of Coronary Concealed Jadad (Reference) Patients Artery Disease Procedure Alpha-2 Agonist Control Blinding Allocation Score* Cardiac surgery Abi-Jaoude (21) 24 ϩ Coronary bypass grafting Oral clonidine 5 ␮g/kg 120 minutes before surgery Placebo ϩ Unclear 3 Boldt (22) 44 ϩ Coronary bypass grafting Intravenous clonidine 0.05 ␮g/kg/min from induction Placebo ϩ Unclear 3 Alpha-2 adrenergic agonists to prevent perioperative cardiovascular complications/Wijeysundera et al to cardiopulmonary bypass Dorman (23) 43 ϩ Coronary bypass grafting Oral clonidine 5 ␮g/kg 90 minutes before surgery, and Placebo ϩ Unclear 3 5 ␮g/kg before cardiopulmonary bypass Ghignone (24) 24 ϩ Coronary bypass grafting Oral clonidine 5 ␮g/kg 90 minutes before surgery Control Ϫ Unclear 1 Helbo-Hansen 40 ϩ Coronary bypass grafting Intravenous clonidine 7 ␮g/kg in three divided Placebo Ϫ Unclear 1 (26) intraoperative bolus doses Jalonen (27) 80 ϩ Coronary bypass grafting Intravenous dexmedetomidine 50 ng/kg/min before Placebo ϩ Unclear 3 surgery for 30 minutes, 7 ng/kg/min intraoperatively Loick (29) 45 ϩ Coronary bypass grafting Intravenous clonidine 4 ␮g/kg before surgery, 1 ␮g/kg/ Control Ϫ Unclear 2 min intraoperatively, and 0.2–0.5 ␮g/kg/min for 48 hours postoperatively Myles (31) 150 ϩ Coronary bypass grafting Oral clonidine 5 ␮g/kg 90 minutes before surgery, and Placebo ϩ Unclear 4 ␮ June 15, 2003 T 5 g/kg before coronary bypass grafting Quintin (33) 26 ϩ Coronary bypass grafting Oral clonidine 2.5 ␮g/kg 90 minutes before surgery Placebo ϩ Unclear 3 Venn (38) 105 ϩ Mixed (83% cardiac) Intravenous dexmedetomidine 1 ␮g/kg within 1 hour Placebo ϩ Unclear 4 after surgery, and 0.2–0.7 ␮g/kg/h for 6–24 hours Noncardiac surgery ϩ ϩϩ HE Ellis (8) 61 Noncardiac surgery Transdermal clonidine (0.2 mg/d) for 72 hours from Placebo 4 A (82% vascular) night before surgery, and 0.3 mg orally 60–90 minutes MERICAN before surgery Ghignone (25) 30 ϩ Nonvascular surgery Oral clonidine 5 ␮g/kg 90 minutes before surgery Control Ϫ Unclear 2 ϩ ␮ ϩ J Lipszye (28) 40 Carotid artery surgery Oral clonidine 4 g/kg 90 minutes before surgery Placebo Unclear 2 OURNAL OF Mangano (10) 317 ϩ Vascular surgery Two intravenous mivazerol regimens: low (2 ␮g/kg Placebo ϩ Unclear 4 bolus and 0.75 ␮g/kg/h), high (4 ␮g/kg bolus and 1.5 ␮g/kg/h). Bolus given 20 minutes before surgery; M EDICINE infusion until 72 hours after surgery Matot (30) 36 Unclear Airway surgery Oral clonidine 300 ␮g 90 minutes before surgery Placebo ϩ Unclear 3 Oliver (13) 1897† ϩ Noncardiac surgery Intravenous mivazerol 4 ␮g/kg 20 minutes before Placebo ϩϩ4 ௡ surgery, and 1.5 ␮g/kg/h for 72 hours Volume 114 Pluskwa (32) 30 ϩ Carotid artery surgery Oral clonidine 300 ␮g 90 minutes before surgery Placebo ϩϩ5 Quintin (34) 24 ϩ Aortic surgery Oral clonidine 6 ␮g/kg 120 minutes before surgery, Placebo ϩ Unclear 4 and 3 ␮g/kg intravenously after surgery Stuhmeier (35) 297 ϩ Vascular surgery Oral clonidine 2 ␮g/kg 90 minutes before surgery Placebo ϩ Unclear 5 743 Alpha-2 adrenergic agonists to prevent perioperative cardiovascular complications/Wijeysundera et al METHODS Jadad Score* This review adhered to the recommendations of the Quality of Reporting of Meta-analyses (QUOROM) group (15). Unclear 4 Unclear 2 Unclear 4 Unclear 4 Allocation Concealed Inclusion and Exclusion Criteria Eligible studies were published, randomized controlled ϩ Ϫ ϩ ϩ trials that enrolled adults (age Ͼ18 years) who were un- dergoing surgery under general or neuroaxial (spinal or epidural) anesthesia. Trials that recruited patients under- going local anesthesia or peripheral nerve blockade alone were excluded. We also excluded trials that recruited pa- 3 mg/kg/ – propofol 1 mg/kg and 1 h infusion tients who were pregnant, organ transplant recipients, or Placebo Intravenous Placebo Placebo suffering from substance withdrawal. The interventions assessed were preoperative (within g/ 24 hours), intraoperative, or postoperative (within 48 ␮ hours) administration of clonidine, dexmedetomidine, or mivazerol via intravenous, intramuscular, oral, or 24 hours – transdermal routes. Trials had to report any of the follow- g intraoperative ing outcomes: death, myocardial infarction, myocardial g/kg within 1 hour ␮ ␮ g/kg within 6 hours ischemia, or supraventricular tachyarrhythmia. We did ␮ g/kg), high (8.03 ␮ not employ a uniform definition of myocardial infarc- g/kg/h for 6 ␮ tion given the lack of a standardized criterion in the liter- g/kg/h for 72 hours 0.5 ␮ – ature. Ischemia was defined as ST-segment deviation on g/min until 48 hours after surgery ␮ an electrocardiogram or new wall motion abnormalities on a transesophageal echocardiogram. Supraventricular tachyarrhythmias included atrial fibrillation, atrial flut- ter, and supraventricular tachycardia. g/kg), medium (5.31 ␮ Search Strategy (2.64 after surgery, and 0.2 infusion, and 0.15 kg)] as 48-hour infusion from start of surgery after surgery, and 0.4 We identified eligible trials using MEDLINE (1966 to May 2002), EMBASE (1980 to May 2002), and the Cochrane Clinical Trials Register (The Cochrane Library, Issue 2, 2002) (16).