PRO/CON: Dexmedetomidine Is a Useful Perioperative Adjunct in Patients Undergoing Cardiac Surgery
Kyung W. Park, MD
Beth Israel Deaconess Medical Center
Dexmedetomidine (DME), a selective α-2 agonist, has been touted for its anxiolytic, analgesic, and anesthetic-sparing properties in the absence of respiratory depression. Although it may have a niche application in the postoperative period, there is insufficient literature evidence that warrants its routine application during cardiac surgery.
Classically, a adrenergic receptors were classified as postsynaptic α-1 receptors and presynaptic α-2 receptors. With discovery of postsynaptic and extrasynaptic α-2 receptors, the classification is now based on binding affinity of the antagonists prazosin for α-1 antagonism and yohimbine for α-2 antagonism (1). α-2 receptors are further subdivided into 3 subtypes, α-2A, α-2B, and α-2C receptors. All the α-2 adrenoreceptors are coupled to pertussis toxin-sensitive G protein and the coupling may lead to inhibition of adenylate cyclase, inhibition of calcium conductance through N-type voltage-gated calcium channels, stimulation of phospholipase A2 activity, increase in Na+/H+ exchange, increase in K+ conductance, and increase in polyphosphoinositide hydrolysis. The α-2 adrenoceptors are found at various sites throughout the body and this accounts for the diversity of effects. Stimulation of the α-2A receptors in the locus ceruleus, the predominant noradrenergic nucleus in the brainstem, reduces neuronal firing and elicits the sedative and hypnotic response. Stimulation of the α-2 receptors in the medullary dorsal motor nucleus of the vagus may elicit the bradycardic and hypotensive effects. The intermediolateral cell column and substantia gelatinosa of the spinal cord have a high density of α-2 receptors; stimulation of these spinal and supraspinal α-2 receptors inhibits release of the nociceptive mediator substance P and mediates the analgesic effect. In the peripheral tissues, α-2 receptors are found on sympathetic nerve endings and their target cells. Stimulation of postsynaptic α-2B receptors on arterial and venous smooth muscle cells mediates vasoconstriction. DME is a significant cerebral vasoconstrictor and decreases cerebral blood flow out of proportion to any reduction in metabolism (2, 3). In the coronary circulation, α-2 receptor stimulation with DME causes a dose-dependent increase in coronary vascular resistance and oxygen extraction (4), but the oxygen supply: demand ratio is unaltered (5). In addition, stimulation of α-2 receptors may mediate bronchodilation, decreased salivation, reduction in intestinal motility, increased diuresis, platelet aggregation, decreased intraocular pressure, inhibition of lipolysis, and decreased shivering. Finally, α-2 agonists administered prior to onset of cerebral ischemia may confer a neuroprotective effect (6).
DME is a highly selective α-2 agonist (α2:α1=1620:1 compared to 220:1 for clonidine), though without any selectivity among the three α-2 receptor subtypes. As may be expected from the above list of α-2 adrenergic effects, trials of DME in healthy volunteers and in gynecologic surgeries (7-12) have demonstrated that DME provides a dose-dependent increase in sedation and analgesia with a reduction in requirement for other anesthetics and postoperative analgesics and a reduction in the level of stress hormones such as cortisol, norepinephrine, and epinephrine during surgery. These effects are achieved with minimal respiratory depression and a minimal decrease in hypercapnic respiratory drive, so that PaCO2 increases by 4 - 5 mmHg 10 minutes after 1 - 2 μg/kg boluses (7). The doses of DME used in these trials were about 0.2 - 2.5 μg/kg in boluses and/or 3-14 ng/kg/min (0.2-0.9 μg/kg/hr) in infusions. In particular, the sedation provided by DME has been branded "cooperative" or "arousable" sedation, to distinguish it from the sedation produced by drugs acting on the γ-amino butyric acid (GABA) system, such as midazolam or propofol. Whereas the latter produce a clouding of consciousness, DME sedates patients by decreasing sympathetic activity and the level of arousal. Patients sedated with DME are calm, but are easily arousable to full consciousness and cooperation.
These properties of DME confer two potential uses of the medication (and perhaps other α-2 agonists) for the cardiovascular anesthesiologists. First, cooperative sedation produced by DME may be useful in the postoperative intensive care unit. Two recent placebo-controlled, double-blind studies looked at the requirement for rescue midazolam and morphine (reference 13, N=353) or rescue propofol and morphine (reference 14, N=401) in ICU patients randomized to DME or saline infusions. About 60 % of the DME patients in both studies did not require any rescue sedation and the overall propofol and midazolam requirement was seven- and four-fold lower, respectively, compared to control. Similarly, nearly half the DME patients did not require any morphine rescue and the overall morphine requirement was about halved compared to control. With the use of DME, patients were easily maintained at a Ramsay sedation scale of 3 3 (sedated, but responsive to commands) while intubated and 3 2 (cooperative and tranquil) after extubation. Nurses reported ease of management of patients on DME and, because of lack of respiratory depression, did not have to discontinue the medication for weaning from the ventilator. Similar experience was reported in a multi-center study from the United Kingdom (15). Postoperative sedation is a FDA-approved indication for DME and may be useful even for post-cardiac surgical patients. At the present time, sedation with DME is allowed for up to a maximum of 24 hours, because of concern for possible rebound hypertension after a longer use. Second, DME may be useful in blunting perioperative stress responses and associated tachycardia and possibly myocardial ischemia in susceptible, high-risk patients. Talke et al. (16) used DME infusions perioperatively in vascular surgical patients and found that DME blunted emergence-associated tachycardia and prevented increases in plasma norepinephrine levels. In a European study of mivazerol, an α-2 agonist not available in the U.S., the medication was used for 72 hours perioperatively in high-risk noncardiac surgery (17). In a subgroup analysis of vascular surgical patients, mivazerol was shown to reduce the rate of myocardial infarction or death (RR of 0.67, P < 0.04). In a meta-analysis of the literature on clonidine, another α-2 agonist, the pooled odds ratio for perioperative myocardial ischemia was 0.49 (95 % confidence interval 0.34-0.71) (18). At present, there is insufficient data to state whether DME reduces myocardial ischemia or infarction in high-risk noncardiac surgery.
Application of DME in cardiac surgery, however, poses several potential or real problems without any real benefits over conventional, less expensive alternatives. First, the state of arousable sedation as may be produced with DME is not a preferable state during cardiac surgery. The patient needs to be rendered fully anesthetized, unaware, and unarousable during conventional cardiac surgery. There may certainly be intraoperative applications for arousable sedation such as awake craniotomy (19), wake-up test during spine surgery, and plastic surgery in the head and neck, when supplemental oxygen cannot be used in an awake, but sedated patient. But cardiac surgery, as it is practiced today, is not one of such applications. Second, the hemodynamic effect of DME may be deleterious to certain cardiac surgical patients. DME, when given as a bolus or a loading dose, produces transient hypertension due to direct vasoconstriction of arteries and veins, followed by more enduring hypotension and bradycardia. In the above-mentioned volunteer studies, the blood pressure drop was in the range of 14-27 % of the baseline (e.g., reference 9). Use of DME usually requires more vasoactive medications to maintain hemodynamics within desirable limits (20). Hypotension, as may be produced with DME (especially, pre-induction hypotension produced with DME premedication), if left untreated, could be detrimental in certain cardiac surgical patients such as patients with left main disease, aortic stenosis, significant left ventricular hypertrophy, asymmetrical septal hypertrophy, and pericardial tamponade physiology. Bradycardia, as may be produced by DME, could be detrimental in patients with severe mitral, aortic or tricuspid regurgitation or with pericardial tamponade physiology. Heart rate is decreased by a mean of 27 % after the loading dose of DME and there may be rare cases of sinus arrest or severe vasovagal reaction (21). Third, DME may compromise compensatory mechanisms in response to acute bleeding or hypovolemia, which is not infrequently encountered in cardiac surgery. In a rabbit study, Blake et al. found that the vasoconstrictive and tachycardiac response to gradual inflation of an inferior vena cava cuff was blunted by DME, and decompensation occurred earlier with DME (22). Fourth, a significant fraction of cardiac surgical patients are on antidepressants. The tricyclic antidepressants, because of their ability to inhibit norepinephrine reuptake, may interact with DME. Guo et al. found that desipramine blunted the antinociceptive and anesthetic actions of DME (23). Fifth and perhaps most importantly, our experience with DME in cardiac surgical patients is very limited and DME has not demonstrated a clear advantage over a placebo in these patients. Jalonen et al. (24) reported the first (and, to my knowledge, the only) study of the use of DME in coronary bypass surgery (CABG). They randomized 80 patients to receive either a saline placebo or DME, initially 1.5 μg/kg given over 30 minutes followed by 7 ng/kg/min until the end of surgery. They found that compared with placebo, DME decreased plasma norepinephrine concentrations by 90 % and blunted the hemodynamic response to intubation and surgery. DME, however, was also associated with more episodes of hypotension during the pre-bypass period and the bypass period and greater fluid challenges to maintain blood pressure. There was no difference in outcome, although the study, as the authors admitted, was not powered to show a difference in outcome. With clonidine, the findings of hemodynamic benefit in CABG have not been uniform, either (25,26).
In summary, DME produces a state of arousable sedation and has analgesic, anxiolytic, and anesthetic-sparing properties, as well as causing variable degrees of bradycardia and hypo/hypertension. These properties of the medication may prove useful in certain niche applications such as in the postoperative intensive care unit. However, during cardiac surgery, the medication has several potential shortcomings. And as of now, there is insufficient evidence in the literature, indicating the superiority of DME over other anesthetic or adjunctive agents during cardiac surgery. Further studies on the topic are indicated, as well as development of a more subtype-selective and site-specific α2-agonist without the hypotensive side effects.
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