Effects of Low and High Plasma Concentrations of Dexmedetomidine on Myocardial Perfusion and Cardiac Function in Healthy Male Subjects

Background: Dexmedetomidine, a selective [alpha]2-adrenoceptor agonist, has counteracting effects on the cardiovascular system. It mediates sympatholysis by activating [alpha]2 adrenoceptors in the central and peripheral nervous system, and vasoconstriction and vasorelaxation by activating postsynaptic [alpha]2 adrenoceptors in blood vessels. The goal of this study was to determine the effects of therapeutic and high concentrations of dexmedetomidine on myocardial perfusion and cardiac function in healthy subjects.

Methods: The authors studied 12 healthy young men. Myocardial blood flow (assessed with positron emission tomography), myocardial function (by echocardiography), and hemodynamic data were collected before and during low (measured mean plasma concentration, 0.5 ng/ml) and high (5 ng/ml) plasma concentrations of dexmedetomidine.

Results: The low concentration of dexmedetomidine reduced myocardial perfusion (mean difference, -27% from baseline [95% confidence interval, -31 to -23%], P < 0.001) in parallel with a reduction in myocardial oxygen demand (estimated by the rate-pressure product (-23% [-28 to -18%], P < 0.001). The high dexmedetomidine plasma concentration did not further attenuate myocardial perfusion (-3% [-12 to +6%] from low dexmedetomidine, P > 0.05; -29% [-39 to -18%] from baseline, P < 0.001) or statistically significantly affect the rate-pressure product (+5% [0 to +10%], P > 0.05). Systolic myocardial function was attenuated by sympatholysis during the low infusion rate and was further attenuated by a combination of the sustained sympatholysis and increased afterload during the high infusion rate.     

Comparison of the effects of dexmedetomidine and esmolol on myocardial oxygen consumption in dogs

BACKGROUND AND OBJECTIVE: The beta-adrenergic blocker esmolol and the alpha 2-adrenergic agonist dexmedetomidine have the potential to decrease perioperative myocardial ischaemia. The pathophysiological mechanisms involved in these anti-ischaemic properties have not been thoroughly studied. We compared the effects of esmolol and dexmedetomidine on two indices of overall myocardial oxygen demand and on directly measured myocardial oxygen consumption of the left anterior coronary artery territory. METHODS: Eleven mongrel dogs were instrumented to measure aortic and left ventricular pressure, aortic and left anterior coronary artery flow and myocardial wall thickening. Variables related to myocardial oxygen metabolism were also determined. Measurements were performed during four sequential experimental conditions in each dog (Control 1: esmolol; Control 2: dexmedetomidine). RESULTS: Esmolol and dexmedetomidine decreased haemodynamic indices of myocardial oxygen demand to a similar extent: esmolol decreased the rate-pressure product by 16+/-3% and the pressure-work index (PWI) by 16+/-3%, dexmedetomidine decreased the rate-pressure product by 26+/-3% and the PWI by 16+/-7%. However, these similar decreases resulted from different haemodynamic effects of the two study drugs. Dexmedetomidine had a more pronounced bradycardic effect than esmolol (P = 0.01) and increased systolic aortic pressure (SAP) by 15+/-4% while esmolol decreased SAP by 8+/-2% (P < 0.01). dP/dt(max) and regional myocardial area decrease were lower after esmolol than after dexmedetomidine. Neither drug had an effect on myocardial oxygen consumption. CONCLUSIONS: Esmolol and dexmedetomidine decreased two haemodynamic indices of overall myocardial oxygen demand to a similar extent but neither drug decreased directly measured myocardial oxygen consumption in the territory of the left anterior descending artery.     

Reversal of the Sedative and Sympatholytic Effects of Dexmedetomidine with a Specific [Greek small letter alpha]2-Adrenoceptor Antagonist Atipamezole: A Pharmacodynamic and Kinetic Study in Healthy Volunteers

Background: Specific and selective [Greek small letter alpha]2-adrenergic drugs are widely exploited in veterinary anesthesiology. Because [Greek small letter alpha]2-agonists are also being introduced to human practice, the authors studied reversal of a clinically relevant dexmedetomidine dose with atipamezole, an [Greek small letter alpha]2-antagonist, in healthy persons.

Methods: The study consisted of two parts. In an open dose-finding study (part 1), the intravenous dose of atipamezole to reverse the sedative effects of 2.5 [micro sign]g/kg of dexmedetomidine given intramuscularly was determined (n = 6). Part 2 was a placebo-controlled, double-blinded, randomized cross-over study in which three doses of atipamezole (15, 50, and 150 [micro sign]g/kg given intravenously in 2 min) or saline were administered 1 h after dexmedetomidine at 1-week intervals (n = 8). Subjective vigilance and anxiety, psychomotor performance, hemodynamics, and saliva secretion were determined, and plasma catecholamines and serum drug concentrations were measured for 7 h.

Results: The mean +/- SD atipamezole dose needed in part 1 was 104 +/- 44 [micro sign]g/kg. In part 2, dexmedetomidine induced clear impairments of vigilance and psychomotor performance that were dose dependently reversed by atipamezole (P < 0.001). Complete resolution of sedation was evident after the highest (150 [micro sign]g/kg) dose, and the degree of vigilance remained high for 7 h. Atipamezole dose dependently reversed the reductions in blood pressure (P < 0.001) and heart rate (P = 0.009). Changes in saliva secretion and plasma catecholamines were similarly biphasic (i.e., they decreased after dexmedetomidine followed by dose-dependent restoration after atipamezole). Plasma norepinephrine levels were, however, increased considerably after the 150 [micro sign]g/kg dose of atipamezole. The pharmacokinetics of atipamezole were linear, and elimination half-lives for both drugs were approximately 2 h. Atipamezole did not affect the disposition of dexmedetomidine. One person had symptomatic sinus arrest, and another had transient bradycardia approximately 3 h after receiving dexmedetomidine.     

Effects of Perioperative Dexmedetomidine Infusion in Patients Undergoing Vascular Surgery

Background: Dexmedetomidine, a highly selective alpha2 -adrenergic agonist, increases perioperative hemodynamic stability in healthy patients but decreases blood pressure and heart rate. The goal of this study was to evaluate, in a preliminary manner, the hemodynamic effects of perioperatively administered dexmedetomidine in surgical patients at high risk for coronary artery disease.

Methods: Twenty-four vascular surgery patients received a continuous infusion of placebo or one of three doses of dexmedetomidine, targeting plasma concentrations of 0.15 ng/ml (low dose), 0.30 ng/ml (medium dose), or 0.45 ng/ml (high dose) from 1 h before induction of anesthesia until 48 h postoperatively. All patients received standardized anesthesia and hemodynamic management. Blood pressure, heart rate, and Holter ECG were monitored; additional monitoring included continuous 12-lead ECG preoperatively, anesthetic concentrations and myocardial wall motion (echocardiography) intraoperatively, and cardiac enzymes postoperatively.

Results: Preoperatively, there was a decrease in heart rate (low dose 11%, medium dose 5%, high dose 20%) and systolic blood pressure (low dose 3%, medium dose 12%, high dose 20%) in patients receiving dexmedetomidine. Intraoperatively, dexmedetomidine groups required more vasoactive medications to maintain hemodynamics within predetermined limits. Postoperatively, dexmedetomidine groups had less tachycardia (minutes/monitored hours) than the placebo group (placebo 23 min/h; low dose 9 min/h, P = 0.006; medium dose 0.5 min/h, P = 0.004; high dose 2.3 min/h, P = 0.004). Bradycardia was rare in all groups. There were no myocardial infarctions or discernible trends in the laboratory results.     

Dexmedetomidine Increases the Cocaine Seizure Threshold in Rats

Background: Central [alpha] adrenoceptors have been demonstrated to play an important role in the control of seizure activity; moreover, [alpha]2 adrenoceptors have been linked to electroencephalogram changes associated with cocaine. The purpose of this study was to determine if dexmedetomidine, a highly selective [alpha]2-adrenoceptor agonist, alters the threshold for cocaine-induced seizure activity in rats.

Methods: Sprague-Dawley rats received a cocaine infusion (1.25 mg [middle dot] kg-1 [middle dot] min-1) followed 15 min later by the coinfusion of either dexmedetomidine (20-[mu]g/kg intravenous bolus followed by an infusion of 1 [mu]g [middle dot] kg-1 [middle dot] min-1, CD group, n = 8) or an equal volume of saline (CS group, n = 8). Dexmedetomidine or saline were coinfused with cocaine until the onset of cocaine-induced seizures. Dopamine concentrations in the nucleus accumbens were measured by microdialysis paired with chromatography. To determine if changes in extracellular dopamine were related to the seizures, dopamine (1 [mu]m) was continuously delivered to the nucleus accumbens in a separate group (DACD group, n = 6) via retrograde microdialysis. These rats then received an intravenous cocaine infusion followed by dexmedetomidine in the same manner as the CD group.

Results: Dexmedetomidine significantly increased the dose of cocaine necessary to produce seizures. Seizures occurred at 25.0 +/- 7.7 and 49.3 +/- 14.8 min in CS and CD, respectively (P < 0.001). The ratio of the percent increase in accumbal dopamine to the cocaine dose at the onset of seizure activity was significantly lower in CD, 39.9 +/- 16.5, compared to CS, 82.2 +/- 46.5 (P = 0.04). Intraaccumbal administration of dopamine prevented the effects of dexmedetomidine on the cocaine seizure threshold.     

The hemodynamic and adrenergic effects of perioperative dexmedetomidine infusion after vascular surgery

We tested dexmedetomidine, an alpha(2) agonist that decreases heart rate, blood pressure, and plasma norepinephrine concentration, for its ability to attenuate stress responses during emergence from anesthesia after major vascular operations. Patients scheduled for vascular surgery received either dexmedetomidine (n = 22) or placebo (n = 19) IV beginning 20 min before the induction of anesthesia and continuing until 48 h after the end of surgery. All patients received standardized anesthesia. Heart rate and arterial blood pressure were kept within predetermined limits by varying anesthetic level and using vasoactive medications. Heart rate, arterial blood pressure, and inhaled anesthetic concentration were monitored continuously; additional measurements included plasma and urine catecholamines. During emergence from anesthesia, heart rate was slower with dexmedetomidine (73 +/- 11 bpm) than placebo (83 +/- 20 bpm) (P = 0.006), and the percentage of time the heart rate was within the predetermined hemodynamic limits was more frequent with dexmedetomidine (P < 0.05). Plasma norepinephrine levels increased only in the placebo group and were significantly lower for the dexmedetomidine group during the immediate postoperative period (P = 0.0002). We conclude that dexmedetomidine attenuates increases in heart rate and plasma norepinephrine concentrations during emergence from anesthesia. IMPLICATIONS: The alpha(2) agonist, dexmedetomidine, attenuates increases in heart rate and plasma norepinephrine concentrations during emergence from anesthesia in vascular surgery patients.     

Systemically Administered α2-Agonist-induced Peripheral Vasoconstriction in Humans

Background: [alpha]2-Adrenoceptors mediate both sympatholytic and vasoconstrictive hemodynamic effects. The goal of this study was to profile the peripheral vasoconstrictive effects of a selective [alpha]2-adrenoceptor agonist in isolation from the sympatholytic effects it also induces.

Methods: The authors administered increasing plasma target concentrations of dexmedetomidine (0.075, 0.15, 0.3, and 0.6 ng/mL) or saline placebo to healthy young volunteers in whom the sympatholytic effects of the drug were attenuated in one of two ways: general anesthesia (propofol-alfentanil-nitrous oxide) or axillary brachial plexus block. Measurements were made of finger blood volume (an indicator of vasoconstriction) by photoplethysmographic determination of light transmitted through a finger (LTF) and hemodynamic variables. Measurements made before and during the four steps of infusion were compared by repeated-measures ANOVA.

Results: In anesthetized volunteers, all concentrations of dexmedetomidine increased LTF (vasoconstriction) and systolic blood pressure (P < 0.001 for both), whereas placebo did not. In awake volunteers, all concentrations decreased systolic blood pressure (P < 0.001). Concentrations of 0.15, 0.3, and 0.6 ng/mL decreased LTF (vasodilation) in the neurally intact hand; in contrast, the same concentrations increased LTF (vasoconstriction) in the sympathectomized hand (P < 0.001 for both).     

Effects of dexmedetomidine on isoflurane requirements in healthy volunteers. 2: Auditory and somatosensory evoked responses

The anaesthetic-sparing activity of dexmedetomidine during isoflurane anaesthesia was examined, using the end-point of lack of response to tetanic nerve stimulation. Nine subjects were given two doses of dexmedetomidine (target plasma concentrations of 0.3 ng ml-1 and 0.6 ng ml-1, respectively) and saline on separate occasions. We measured auditory (AER) and somatosensory (SER) evoked responses at end-tidal isoflurane concentrations of 0.2-1.4%. Pa and P25-N35 amplitudes increased as isoflurane concentration was reduced (P < 0.001). Dexmedetomidine had no significant effect on this relationship. In contrast, P15-N20 (SER) amplitude increased (P < 0.001) as isoflurane concentration was reduced. The dose of dexmedetomidine had a significant interaction with this trend (P < 0.002). Decreasing the concentration of isoflurane at the high dose of dexmedetomidine had less impact on P15-N20 amplitude than decreasing isoflurane at the low dose or with saline. The mechanism by which dexmedetomidine spares isoflurane is discussed in the light of these evoked response changes.      

Dexmedetomidine decreases perioperative myocardial lactate release in dogs

The sympatholytic effect of the alpha(2)-adrenergic agonist dexmedetomidine may decrease emergence-related myocardial ischemic load in patients. However, a direct measure of myocardial ischemia, such as myocardial lactate release, is difficult to obtain in patients. Therefore, we studied mongrel dogs and measured myocardial lactate release, myocardial oxygen supply, hemodynamic variables, and neurohumoral indices of the stress response. After the induction of a standardized degree of borderline myocardial ischemia, either dexmedetomidine (dexmed group, n = 9) or normal saline (control group, n = 9) was infused. Measurements were repeated at the end of the anesthetic period and every 10 min during the 90-min emergence period. In the dexmed group, the cumulative emergence-related lactate release was 46% less than in the control group (95% confidence interval, 20%-80%; P = 0.02). Simultaneously, dexmedetomidine increased the endo-/epicardial blood flow ratio by 35% (control group, 0.4 +/- 0.1; dexmed group, 0.6 +/- 0.1; P = 0.03). These antiischemic effects of dexmedetomidine were accompanied by reduced plasma concentrations of norepinephrine (126 versus 577 pg/mL) and epinephrine (158 versus 1909 pg/mL) and a slower heart rate (123 +/- 6 versus 160 +/- 10 bpm, dexmed versus control). The antiischemic effect of dexmedetomidine started before emergence, as evidenced by a decreased prevalence of myocardial lactate release at that time (zero of eight dogs in the dexmed group and four of seven dogs in the control group had lactate release before emergence; P = 0.03). IMPLICATIONS: Dexmedetomidine decreases plasma catecholamines and heart rate during emergence from anesthesia. In dogs with a coronary stenosis, these sympatholytic effects decrease myocardial lactate release and, therefore, minimize emergence-related myocardial ischemia.     

Dexmedetomidine increases the cocaine seizure threshold in rats

BACKGROUND: Central alpha adrenoceptors have been demonstrated to play an important role in the control of seizure activity; moreover, alpha adrenoceptors have been linked to electroencephalogram changes associated with cocaine. The purpose of this study was to determine if dexmedetomidine, a highly selective alpha -adrenoceptor agonist, alters the threshold for cocaine-induced seizure activity in rats. METHODS: Sprague-Dawley rats received a cocaine infusion (1.25 mg x kg(-1) x min(-1)) followed 15 min later by the coinfusion of either dexmedetomidine (20-microg/kg intravenous bolus followed by an infusion of 1 microg x kg(-1) x min(-1), CD group, n = 8) or an equal volume of saline (CS group, n = 8). Dexmedetomidine or saline were coinfused with cocaine until the onset of cocaine-induced seizures. Dopamine concentrations in the nucleus accumbens were measured by microdialysis paired with chromatography. To determine if changes in extracellular dopamine were related to the seizures, dopamine (1 microm) was continuously delivered to the nucleus accumbens in a separate group (DACD group, n = 6) retrograde microdialysis. These rats then received an intravenous cocaine infusion followed by dexmedetomidine in the same manner as the CD group. RESULTS: Dexmedetomidine significantly increased the dose of cocaine necessary to produce seizures. Seizures occurred at 25.0 +/- 7.7 and 49.3 +/- 14.8 min in CS and CD, respectively (P < 0.001). The ratio of the percent increase in accumbal dopamine to the cocaine dose at the onset of seizure activity was significantly lower in CD, 39.9 +/- 16.5, compared to CS, 82.2 +/- 46.5 (P = 0.04). Intraaccumbal administration of dopamine prevented the effects of dexmedetomidine on the cocaine seizure threshold. CONCLUSIONS: These data suggest that dexmedetomidine increases the cocaine-induced seizure threshold possibly a mechanism related to the attenuation of the extracellular dopaminergic neurotransmitter response to cocaine.     

Effect of α2B-Adrenoceptor Polymorphism on Peripheral Vasoconstriction in Healthy Volunteers

Background: Alpha-2B adrenoceptor is the vasoconstrictive subtype in the mouse. Human [alpha]2B-AR deletion (D) allele has been associated with loss of short-term agonist-promoted receptor desensitization, which may lead to increased vasoconstriction on [alpha]2 activation. The goal of this study was to test the hypothesis that [alpha]2B-adrenoceptor activation induces enhanced vasoconstriction in carriers of the DD genotype, compared with carriers of the insertion/insertion (II) genotype.

Methods: The authors administered increasing doses of dexmedetomidine (targeting plasma concentrations of 0.15, 0.3, 0.6, and 1.2 ng/ml) to 16 healthy young volunteers (8 carrying the [alpha]2B DD genotype, 8 carrying the II genotype) in whom sympatholytic effects of the drug were attenuated by general anesthesia. Measurements were made of finger blood volume (an indicator of vasoconstriction) by photoplethysmographic determination of light transmitted through a finger, finger blood flow by venous occlusion plethysmography, and hemodynamic variables.

Results: All concentration of dexmedetomidine increased light transmitted through the finger (vasoconstriction) and systolic blood pressure and decreased heart rate in both groups (P < 0.001 for all). Dexmedetomidine reduced finger arterial inflow only in the DD group (P < 0.001). Dexmedetomidine had no effect on finger venous outflow or venous capacitance. There were no significant differences between the II and DD groups in any of the variables.     

Desensitization to the Behavioral Effects of alpha sub 2 -Adrenergic Agonists in Rats

Background: The analgesic and sedative-hypnotic utility of the alpha2 agonists clonidine and dexmedetomidine are currently being investigated. Both compounds exert their behavioral responses by activating central alpha2 adrenoceptors, albeit with different selectivities and efficacies. Furthermore, the analgesic and hypnotic behavioral responses are produced at different sites and may be affected independently of one another. A series of studies was conducted in rats to determine (1) whether tolerance and cross-tolerance develop to the analgesic actions of clonidine or dexmedetomidine; (2) how the number of available alpha2 adrenoceptors affects the analgesic response to dexmedetomidine and clonidine; and (3) how the number of available alpha sub 2 adrenoceptor affects the hypnotic response to dexmedetomidine.

Methods: Rats were administered equianalgesic doses of dexmedetomidine or clonidine continuously, subcutaneously by osmotic minipumps. After 7 days the analgesic response to acutely administered dexmedetomidine or clonidine at median effective analgesic doses was assessed by the tail-flick latency response. The number of alpha2 adrenoceptors in the spinal cord was diminished in a dose-dependent manner by covalent modification with a noncompetitive receptor blocker, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ). Recovery of the tail-flick latency response to clonidine and dexmedetomidine was determined and correlated to the recovery of receptor density as assessed by radiolabeled-ligand binding studies. The alpha2 adrenoceptor population in the locus ceruleus of rats was depleted with EEDQ, and recovery of the hypnotic response (as assessed by the loss of righting reflex) to dexmedetomidine was determined and correlated to the recovery of receptor density.

Results: After 7 days of chronic treatment with dexmedetomidine, analgesic responses to dexmedetomidine and clonidine remained unaltered. However, chronic treatment with clonidine significantly decreased the analgesic effect of clonidine, whereas the analgesic effect to dexmedetomidine was unaffected. In the EEDQ experiments, the analgesic response to dexmedetomidine was restored to normal when 44% of the alpha sub 2 adrenoceptors in the spinal cord were available for agonist binding; comparatively more alpha2 adrenoceptors (77%) were required for the analgesic response to clonidine to be restored. The recovery of the hypnotic response to dexmedetomidine after EEDQ treatment was retarded when compared with the recovery of the analgesic response to that compound. Greater than 77% of alpha2 adrenoceptors in the locus ceruleus must be available for the hypnotic response to alpha2 agonists to be expressed.     

The effects of dexmedetomidine on neuromuscular blockade in human volunteers

The neuromuscular effects of dexmedetomidine in humans are unknown. We evaluated the effect of dexmedetomidine on neuromuscular block and hemodynamics during propofol/alfentanil anesthesia. During propofol/alfentanil anesthesia, the rocuronium infusion rate was adjusted in 10 volunteers to maintain a stable first response (T1) in the train-of-four sequence at 50% +/- 3% of the pre-rocuronium value. Dexmedetomidine was then administered by computer-controlled infusion, targeting a plasma dexmedetomidine concentration of 0.6 ng/mL for 45 min. The evoked mechanical responses of the adductor pollicis responses (T1 response and T4/T1 ratio), systolic blood pressure (SBP), heart rate (HR), and transmitted light through a fingertip were measured during the dexmedetomidine infusion and compared with predexmedetomidine values using repeated-measures analysis of variance and Dunnett's test. Plasma dexmedetomidine levels ranged from 0.68 to 1.24 ng/mL. T1 values decreased during the infusion, from 51% +/- 2% to 44% +/- 9% (P < 0.0001). T4/T1 values did not change during the infusion. Plasma rocuronium concentrations increased during the infusion (P = 0.02). Dexmedetomidine increased SBP (P < 0.001) and decreased HR (P < 0.001) (5-min median values) during the infusion compared with values before the infusion. Dexmedetomidine increased the transmitted light through the fingertip by up to 41% +/- 8% during the dexmedetomidine infusion (P < 0.001).We demonstrated that dexmedetomidine (0.98 +/- 0.01 microg/kg) increased the plasma rocuronium concentration, decreased T1, increased SBP, and decreased finger blood flow during propofol/alfentanil anesthesia. We conclude that dexmedetomidine-induced vasoconstriction may alter the pharmacokinetics of rocuronium. IMPLICATIONS: We studied the effect of an alpha2-agonist (dexmedetomidine) on rocuronium-induced neuromuscular block during propofol/alfentanil anesthesia. We found that the rocuronium concentration increased and the T1 response decreased during the dexmedetomidine administration. Although these effects were statistically significant, it is unlikely that they are of clinical significance.     

The effects of increasing plasma concentrations of dexmedetomidine in humans

BACKGROUND: This study determined the responses to increasing plasma concentrations of dexmedetomidine in humans. METHODS: Ten healthy men (20-27 yr) provided informed consent and were monitored (underwent electrocardiography, measured arterial, central venous [CVP] and pulmonary artery [PAP] pressures, cardiac output, oxygen saturation, end-tidal carbon dioxide [ETCO2], respiration, blood gas, and catecholamines). Hemodynamic measurements, blood sampling, and psychometric, cold pressor, and baroreflex tests were performed at rest and during sequential 40-min intravenous target infusions of dexmedetomidine (0.5, 0.8, 1.2, 2.0, 3.2, 5.0, and 8.0 ng/ml; baroreflex testing only at 0.5 and 0.8 ng/ml). RESULTS: The initial dose of dexmedetomidine decreased catecholamines 45-76% and eliminated the norepinephrine increase that was seen during the cold pressor test. Catecholamine suppression persisted in subsequent infusions. The first two doses of dexmedetomidine increased sedation 38 and 65%, and lowered mean arterial pressure by 13%, but did not change central venous pressure or pulmonary artery pressure. Subsequent higher doses increased sedation, all pressures, and calculated vascular resistance, and resulted in significant decreases in heart rate, cardiac output, and stroke volume. Recall and recognition decreased at a dose of more than 0.7 ng/ml. The pain rating and mean arterial pressure increase to cold pressor test progressively diminished as the dexmedetomidine dose increased. The baroreflex heart rate slowing as a result of phenylephrine challenge was potentiated at both doses of dexmedetomidine. Respiratory variables were minimally changed during infusions, whereas acid-base was unchanged. CONCLUSIONS: Increasing concentrations of dexmedetomidine in humans resulted in progressive increases in sedation and analgesia, decreases in heart rate, cardiac output, and memory. A biphasic (low, then high) dose-response relation for mean arterial pressure, pulmonary arterial pressure, and vascular resistances, and an attenuation of the cold pressor response also were observed.     

Premedication with oral dexmedetomidine alters hemodynamic actions of intravenous anesthetic agents in chronically instrumented dogs.

Dexmedetomidine (the D-stereoisomer of medetomidine), a highly selective alpha 2-adrenoceptor agonist, has been demonstrated to produce analgesia and sedation and attenuate hemodynamic responses to emergence from inhalational anesthetics, which suggests a potential use for this drug as a premedicant for general anesthesia. The authors examined hemodynamic interactions between dexmedetomidine and three commonly used intravenous anesthetic agents with markedly different hemodynamic effects. Conscious, chronically instrumented dogs received intravenous induction doses of ketamine, propofol, or etomidate, followed by continuous infusions of each drug at four different doses for 15-min intervals on different days. Studies in six separate groups (range, 9-12 dogs/group) with and without pretreatment with oral dexmedetomidine (20 micrograms/kg) were completed. Heart rate, arterial pressure, left ventricular pressure, rate of increase of left ventricular pressure at 50 mmHg (dP/dt50), and cardiac output were continuously recorded. Dexmedetomidine administration caused a significant (P less than 0.05) decrease in heart rate, rate-pressure product, left ventricular dP/dt50, and cardiac output. Dexmedetomidine abolished or attenuated the increase in heart rate, rate-pressure product, cardiac output, and arterial pressure produced during induction of anesthesia with ketamine. After the dexmedetomidine pretreatment, continuous infusion of ketamine caused no increase in heart rate or rate-pressure product. However, ketamine significantly reduced left ventricular dP/dt50 compared to control in dogs premedicated with dexmedetomidine. Except for a significant reduction in systemic vascular resistance, dexmedetomidine did not significantly affect the hemodynamic response to induction of anesthesia with propofol. Similarly, dexmedetomidine did little to alter the hemodynamic response to induction of anesthesia with etomidate.(ABSTRACT TRUNCATED AT 250 WORDS)     

Comparative Analgesic and Mental Effects of Increasing Plasma Concentrations of Dexmedetomidine and Alfentanil in Humans

Background: In animals, systemic and intrathecal administration of the [alpha]2 -adrenergic receptor agonist dexmedetomidine results in robust antinociceptive effects in models of heat pain. In humans, systemically administered dexmedetomidine is approved for sedating patients in the intensive care unit. However, whether systemic administration of dexmedetomidine in humans produces significant analgesia at doses causing sedation but not unconsciousness remains controversial.

Methods: This study in human volunteers used a placebo-controlled, double-blind, and randomized design to examine whether dexmedetomidine at doses causing mild to severe sedation produces analgesia in experimental models of heat and electrical pain. Results were compared to the effects of the [mu]-opioid receptor agonist alfentanil. A computer-controlled infusion provided four median step-up plasma concentrations of dexmedetomidine (0.09, 0.24, 0.54, and 1.23 ng/ml) and alfentanil (13.4, 33.8, 67.8, and 126.1 ng/ml).

Results: Sedative and cognitive effects of dexmedetomidine were dose-dependent, resulting in a median sedation score of 95 of 100 and slowing of cognitive speed (reaction time, trail-making test) by a factor of about two at the highest plasma concentration. Dexmedetomidine did not attenuate heat or electrical pain. Alfentanil caused severe sedation (median sedation score 88 of 100) and slowed cognitive speed by a factor of approximately 1.4 at the highest plasma concentration. Alfentanil attenuated heat and electrical pain dose dependently.     

Systemically administered alpha2-agonist-induced peripheral vasoconstriction in humans

BACKGROUND: alpha(2)-Adrenoceptors mediate both sympatholytic and vasoconstrictive hemodynamic effects. The goal of this study was to profile the peripheral vasoconstrictive effects of a selective alpha(2)-adrenoceptor agonist in isolation from the sympatholytic effects it also induces. METHODS: The authors administered increasing plasma target concentrations of dexmedetomidine (0.075, 0.15, 0.3, and 0.6 ng/mL) or saline placebo to healthy young volunteers in whom the sympatholytic effects of the drug were attenuated in one of two ways: general anesthesia (propofol-alfentanil-nitrous oxide) or axillary brachial plexus block. Measurements were made of finger blood volume (an indicator of vasoconstriction) by photoplethysmographic determination of light transmitted through a finger (LTF) and hemodynamic variables. Measurements made before and during the four steps of infusion were compared by repeated-measures ANOVA. RESULTS: In anesthetized volunteers, all concentrations of dexmedetomidine increased LTF (vasoconstriction) and systolic blood pressure (P < 0.001 for both), whereas placebo did not. In awake volunteers, all concentrations decreased systolic blood pressure (P < 0.001). Concentrations of 0.15, 0.3, and 0.6 ng/mL decreased LTF (vasodilation) in the neurally intact hand; in contrast, the same concentrations increased LTF (vasoconstriction) in the sympathectomized hand (P < 0.001 for both). CONCLUSIONS: The results of this study are the first to characterize the lower end of the dose-response curve for vasoconstriction induced by dexmedetomidine. By denervating the vascular bed of interest or by decreasing sympathetic nervous system activity, the authors were able to observe vasoconstriction induced by a systemically administered alpha(2)-agonist with minimal interference from the sympatholytic effects of the drug.     

Dexmedetomidine Does Not Alter the Sweating Threshold, But Comparably and Linearly Decreases the Vasoconstriction and Shivering Thresholds

Background: Clonidine decreases the vasoconstriction and shivering thresholds. It thus seems likely that the alpha2 agonist dexmedetomidine will also impair control of body temperature. Accordingly, the authors evaluated the dose-dependent effects of dexmedetomidine on the sweating, vasoconstriction, and shivering thresholds. They also measured the effects of dexmedetomidine on heart rate, blood pressures, and plasma catecholamine concentrations.

Methods: Nine male volunteers participated in this randomized, double-blind, cross-over protocol. The study drug was administered by computer-controlled infusion, targeting plasma dexmedetomidine concentrations of 0.0, 0.3, and 0.6 ng/ml. Each day, skin and core temperatures were increased to provoke sweating and then subsequently reduced to elicit vasoconstriction and shivering. Core-temperature thresholds were computed using established linear cutaneous contributions to control of sweating, vasoconstriction, and shivering. The dose-dependent effects of dexmedetomidine on thermoregulatory response thresholds were then determined using linear regression. Heart rate, arterial blood pressures, and plasma catecholamine concentrations were determined at baseline and at each threshold.

Results: Neither dexmedetomidine concentration increased the sweating threshold from control values. In contrast, dexmedetomidine administration reduced the vasoconstriction threshold by 1.61 +/- 0.80 [degree sign] Celsius [center dot] ng sup -1 [center dot] ml (mean +/- SD) and the shivering threshold by 2.40 +/- 0.90 [degree sign] Celsius [center dot] ng sup -1 [center dot] ml. Hemodynamic responses and catecholamine concentrations were reduced from baseline values, but they did not differ at the two tested dexmedetomidine doses.     

Effects of alpha(2)-adrenoceptor agonists on perinatal excitotoxic brain injury: comparison of clonidine and dexmedetomidine.

BACKGROUND: A growing number of children have severe neurologic impairment related to very premature birth. Experimental data suggest that overstimulation of cerebral N-methyl-d-aspartate (NMDA) receptors caused by excessive glutamate release may be involved in the genesis of perinatal hypoxic-ischemic brain injury. alpha(2)-Adrenoceptor agonists are protective in models of brain ischemia in adults. The authors sought to determine whether they prevent perinatal excitotoxic neuronal damage. METHODS: Five-day-old mice were allocated at random to clonidine (4-400 microg/kg), dexmedetomidine (1-30 microg/kg), or saline injected intraperitoneally before an intracerebral stereotactic injection of the NMDA receptor agonist ibotenate; cortical and white matter lesions were quantified 5 days later by histopathologic examination. Cortical neuron cultures exposed to 300 microm NMDA were used to evaluate the effects of clonidine or dexmedetomidine on neuronal death assessed by counting the number of pycnotic nuclei after fluorescent chromatin staining. RESULTS: In vivo, both clonidine and dexmedetomidine induced significant concentration-dependent reductions in the size of ibotenate-induced lesions in the cortex and white matter. In vitro, the number of neurons damaged by NMDA exposure was significantly decreased by both dexmedetomidine (-28 +/- 12% at 10 microm; P < 0.01) and clonidine (-37 +/- 19% at 100 microm; P < 0.01) as compared with controls. In both models, the selective alpha2-adrenoceptor antagonist yohimbine abolished the neuroprotective effect of clonidine and dexmedetomidine. CONCLUSIONS: Clonidine and dexmedetomidine are potent neuroprotectors that act by stimulating the alpha(2) adrenoceptors. These results obtained in a murine model of perinatal excitotoxic injury may be relevant to some forms of neonatal brain damage in humans.     

The Effects of Increasing Plasma Concentrations of Dexmedetomidine in Humans

Background: This study determined the responses to increasing plasma concentrations of dexmedetomidine in humans.

Methods: Ten healthy men (20-27 yr) provided informed consent and were monitored (underwent electrocardiography, measured arterial, central venous [CVP] and pulmonary artery [PAP] pressures, cardiac output, oxygen saturation, end-tidal carbon dioxide [ETCO2], respiration, blood gas, and catecholamines). Hemodynamic measurements, blood sampling, and psychometric, cold pressor, and baroreflex tests were performed at rest and during sequential 40-min intravenous target infusions of dexmedetomidine (0.5, 0.8, 1.2, 2.0, 3.2, 5.0, and 8.0 ng/ml; baroreflex testing only at 0.5 and 0.8 ng/ml).

Results: The initial dose of dexmedetomidine decreased catecholamines 45-76% and eliminated the norepinephrine increase that was seen during the cold pressor test. Catecholamine suppression persisted in subsequent infusions. The first two doses of dexmedetomidine increased sedation 38 and 65%, and lowered mean arterial pressure by 13%, but did not change central venous pressure or pulmonary artery pressure. Subsequent higher doses increased sedation, all pressures, and calculated vascular resistance, and resulted in significant decreases in heart rate, cardiac output, and stroke volume. Recall and recognition decreased at a dose of more than 0.7 ng/ml. The pain rating and mean arterial pressure increase to cold pressor test progressively diminished as the dexmedetomidine dose increased. The baroreflex heart rate slowing as a result of phenylephrine challenge was potentiated at both doses of dexmedetomidine. Respiratory variables were minimally changed during infusions, whereas acid-base was unchanged.