PRO/CON: Dexmedetomidine Is a Useful Perioperative Adjunct in Patients Undergoing Cardiac Surgery

PRO:

Sheela S. Pai, MD
Fellow, Cardiac Anesthesia
University of Chicago

The Problem

The cardiac surgery patient presents a unique challenge to the anesthesiologist. Typically, the patient population is older and has a higher association of co-morbidities and is thus less forgiving regarding hemodynamic abnormalities. Traditionally, the issues concerning perioperative care of cardiac surgery patients include avoidance of myocardial ischemia and maintaining a stable hemodynamic profile. Furthermore, older patients are more vulnerable to the myocardial depressant effects of volatile anesthetic agents. In the current era of early extubation, maintaining "railroad tracks" on the anesthesia record (i.e. a stable hemodynamic profile), is challenging.

The classic relationship between myocardial oxygen supply and demand indicates that when demand exceeds supply, ischemia results (1). The primary determinants of oxygen demand are heart rate (HR), contractility, preload, and afterload. Of these, HR may be the most important factor that can be clinically manipulated (2). Tachycardia (HR >120/min), a double-edged devil, increases myocardial oxygen demand tremendously and also decrease myocardial oxygen supply by reducing coronary filling time (reduces the duration of diastole). Anxiety, along with the stress response to surgery (likely initiated by cardiopulmonary bypass support), produce intense β-receptor stimulation via release of endogenous catecholamines. Thus, deleterious increases in myocardial oxygen demand may occur during the perioperative period. With worsening coronary stenoses and failure of coronary autoregulation, maintenance of coronary perfusion pressure difference between aortic diastolic pressure and left ventricular end diastolic pressure (LVEDP), becomes clinically important. Left ventricular preload and afterload also affect myocardial oxygen demand by changing end-diastolic and end-systolic wall tension. Lastly, blood rheology, hematocrit, and collateral coronary flow may also play crucial roles in the pivotal balance between myocardial supply and demand.

Perioperative anesthetic plans must be individualized according to each individual patient. The traditional high-dose narcotic anesthetics (usually promote hemodynamic stability) have fallen into disfavor, in this era of early extubation, as they usually extend ventilator dependence and prolong Intensive Care Unit (ICU) stays. One must also remember that emergence from anesthesia is fraught with surges in circulating catecholamines, which may cause tachycardia, agitation, and vulnerability to ischemia, and possibly an increased risk of early graft thrombosis.

The Solution?

Heart rate control may form the central component of the solution. This may be achieved in a variety of ways. Activation of the sympathetic nervous system, specifically β-receptor stimulation, leads to positive inotropy, chronotropy, and norepinephrine release. β-adrenergic antagonists not only attenuate these adverse effects of sympathetic stimulation but also play an antiarrhythmic role. To date, β-blockers are the only well established means of prophylaxis against myocardial ischemia that demonstrate a reduction in morbidity and mortality in this patient population (2-4).

On the other hand, α2-receptor agonists produce a myriad of effects in addition to lowering heart rate, including analgesia, anxiolysis, and sedation. These agents reduce central sympathetic nervous system activity (a potential advantage over β-blockers), possibly attenuating the adverse effects of both peripheral as well as central α-adrenoceptors. α2-receptors are classified into presynaptic or postsynaptic according to their location. Presynaptic activation of α2-receptors inhibits the release of norepinephrine, terminating the propagation of pain signals, whereas activation of postsynaptic receptors in the central nervous system inhibits sympathetic activity and produces a decrease in HR and blood pressure. Sedation and anxiolysis are a result of this last phenomenon in the locus ceruleus (5). Recently, three different α2-isoceptors have been identified (α2A, α2B, α2C). These receptors are distributed ubiquitously and each has unique actions, all of which contribute to clinical physiologic actions. α2B mediates the short-term hypertensive response to α2 agonists while α2A is responsible for the anesthetic and sympatholytic responses. Therefore, agonists may produce hypotension or hypertension. At lower doses, sympatholysis predominates, yet at higher doses hypertension may occur via α2B action. Specific subtype agents have not yet been identified (6). A recent meta-analysis by Nishina et al (7) suggests that clonidine given preoperatively or intraoperatively reduces myocardial ishemia episodes in high risk patients with coronary artery disease (CAD) and those at risk for CAD undergoing both cardiac and noncardiac surgery. These investigators also demonstrated that rates of bradycardia were similar between the clonidine and placebo groups. Furthermore, in other investigations, clonidine has been used preoperatively to attenuate the hyperadrenergic state. Specifically, dexmedetomidine has been registered for use as a sedative-analgesic in the intensive care setting. Dexmedetomidine has α2-to α1-receptor selectivity ratio that is ten times greater than that of clonidine and has a significantly shorter elimination half-life (8). Dexmedetomidine is primarily an α2-agonist that binds to receptors located throughout the body, including the peripheral and central nervous system, vascular smooth muscle, and platelets, as well as tissues supplied by the sympathetic nervous system, such as the liver, pancreas, kidney, and eye. Following intravenous (IV) administration, dexmedetomidine exhibits the following pharmacokinetic parameters: a rapid distribution phase with a distribution half-life of approximately six minutes and a terminal elimination half-life of approximately two hours. The drug exhibits linear kinetics in the dosage range of 0.2-0.7 μg/kg/hr when administered by IV infusion for up to 24 hours. It is highly protein bound and requires dosage adjustments in the patient with hepatic disease. The pharmacokinetic profile is not altered by age.

Studies by Talke et al (8) evaluated the effects of dexmedetomidine (varying plasma concentrations) on HR, blood pressure, and catecholamine concentrations during emergence from anesthesia in the setting of vascular surgery. This study demonstrated that dexmedetomidine (plasma concentrations in the range of 0.18 to 0.35 ng/ml) attenuates the increases in HR and plasma norepinephrine levels observed during emergence from anesthesia. Furthermore, within the plasma concentrations mentioned, dexmedeto-midine did not increase the incidence of either hypotension or bradycardia. At doses of 0.2 to 0.4 μg/kg/hr, with no loading dose, hypotension and bradycardia have not been reported.

Dexmedetomidine, as with all α2-agonists, attenuates the tachycardia associated with endotracheal intubation. The drug also may increase intraoperative hemodynamic stability because of attenuation of the stress-induced sympathoadrenal responses (causing significantly lower plasma norepinephrine levels). These clinical effects may potentially improve graft patency because sympathetic nervous system activation may play a role in early graft thrombosis (secondary to platelet activation). Clonidine has been reported to reduce intraoperative narcotic and inhalational anesthesia requirements. Studies using larger doses of dexmedetomidine have supported this notion as well, with a greater than 90% reduction in anesthetic requirement. Recent studies do not show a statistically significant reduction in volatile anesthetic requirement in the dose ranges mentioned above (8). With fast tracking in cardiac anesthesia achieving popularity, reduced postoperative intubation and ventilator dependence are crucial. In this setting, use of dexmedetomidine is ideal given its pharmacokinetic profile. A study by Arain and Ebert (9) in the setting of noncardiac surgery compares intraoperative sedation with dexmedetomidine (0.4 μg/kg/hr) with propofol (75 μg/kg/min). They noted that patients receiving dexmedetomidine had lower pain scores and decreased morphine requirements in the postoperative period when compared to the propofol group. Following emergence from anesthesia with use of an inhalational anesthetic agent, patients may exhibit a hyperdynamic hemodynamic profile, which can be attenuated with the continued use of dexmedetomidine during the immediate postoperative period. In the unique setting of cocaine-induced coronary syndrome, dexmedetomidine may play a pivotal role in reducing symptoms from withdrawal. This same benefit may be seen in patients with history of alcohol or intravenous drug abuse.

In conclusion, dexmedetomidine is a short acting α2-agonist with many desirable clinical benefits. It reduces myocardial oxygen demand by decreasing HR and provides a stable intraoperative hemodynamic profile. It attenuates the stress response during endotracheal intubation and also during emergence. In the dose range of 0.2 to 0.4 μg/kg/hr, which may be sufficient for sedation, low rates of complications have been reported. Furthermore, it promotes postoperative analgesia (decreases postoperative pain scores) and also lowers plasma norepinephrine levels. With short hospital stays now desirable, dexmedetomidine may be the most desirable single agent to utilize, because it kills many birds with one stone. However, further studies need to be done to prove its efficacy in the perioperative setting.

References

1. Warltier DC, Pagel PS, Kersten JR: Approaches to the prevention of perioperative myocardial ischemia. Anesthesiology 2000; 92: 253-260

2. Raby KE, Brull SJ, Timimi F, et al: The effect of heart rate control on myocardial ishemia among high-risk patients after vascular surgery. Anesth Analg 1999; 88:477-482

3. Mangano DT, Layug EL, Wallace A, Tateo I: Effect of atenolol on mortality and cardiovascular morbidity after noncardiac surgery. N Engl J Med 1996; 335:1713-1720

4. Wallace A, Layug B, Tateo I, et al: Prophylactic atenolol reduces postoperative myocardial ischemia. Anesthesiology 1998; 88:7-17.

5. Ruesch S, Levy JH: Treatment of persistent tachycardia with dexmedetomidine during off-pump coronary artery cardiac surgery. Anesth Analg 2002; 95:316-318

6. Kamibayashi T, Maze M, Weiskopf RB: Clinical uses of  2 adrenergic agonists. Anesthesiology 2000; 93:1345-1349

7. Nishina K, Mikawa K, Uesugi T, et al: Efficacy of clonidine for prevention of perioperative myocardial ischemia. A critical appraisal and meta-analysis of the literature. Anesthesiology 2002; 96:323-329

8. Talke P, Chen R, Thomas B, et al: The hemodynamic and adrenergic effects of perioperative dexmedetomidine infusion after vascular surgery. Anesth Analg 2000; 90:834-839

9. Arain SR, Ebert TJ: The efficacy, side effects, and recovery characteristics of dexmedetomidine versus propofol when used for intraoperative sedation. Anesth Analg 2002;95:461-466


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