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.     

Dexmedetomidine reduces seizure threshold during enflurane anaesthesia in cats

Dexmedetomidine is an alpha 2 agonist and has been reported to have proconvulsant actions. To investigate the interaction of dexmedetomidine with convulsant anaesthetics, we studied effects on seizure threshold in cats during enflurane anaesthesia. Cats were prepared with chronic implantation of electrodes for recording of the cortical electroencephalogram (EEG) and midbrain reticular formation multi-unit activity (R-MUA). Seizure threshold, the reciprocal of the number of electrical stimuli required to induce generalized EEG seizure activity x 1000 (seizure induction index (SII)), was assessed. The effects of dexmedetomidine 1, 10 and 100 micrograms kg-1 i.v. and yohimbine 500 micrograms kg-1, an alpha 2 antagonist, on SII during 3.5% enflurane anaesthesia were investigated. Dexmedetomidine significantly increased SII at 10 and 100 micrograms kg-1, and this effect was reversed by yohimbine. We found that high-dose dexmedetomidine reduced seizure threshold during enflurane anaesthesia.      

The pharmacokinetics of dexmedetomidine in volunteers with severe renal impairment.

Dexmedetomidine, an alpha2-adrenergic agonist with sedative and analgesic properties, is mainly cleared by hepatic metabolism. Because the pharmacokinetics of dexmedetomidine have not been determined in humans with impaired renal function, we studied them in volunteers with severe renal disease and in control volunteers. Six volunteers with severe renal disease and six matched volunteers with normal renal function received dexmedetomidine, 0.6 microg/kg, over 10 min. Venous blood samples for the measurement of plasma dexmedetomidine concentrations were drawn before, during, and up to 12 h after the infusion. Two-compartmental pharmacokinetic models were fit to the drug concentration versus time data. We also determined its hemodynamic, respiratory, and sedative effects. There was no difference between Renal Disease and Control groups in either volume of distribution at steady state (1.81 +/- 0.55 and 1.54 +/- 0.08 L/kg, respectively; mean +/- SD) or elimination clearance (12.5 +/- 4.6 and 8.9 +/- 0.7 mL x min(-1) x kg(-1), respectively). However, elimination half-life was shortened in the Renal Disease group (113.4 +/- 11.3 vs 136.5 +/- 13.0 min; P < 0.05). A mild reduction in blood pressure occurred in most volunteers. Although most volunteers were sedated by dexmedetomidine, renal disease volunteers were sedated for a longer period of time. IMPLICATIONS: The pharmacokinetics of dexmedetomidine in volunteers with severe renal impairment differed little from those in volunteers with normal renal function. In addition, there were no clinically significant differences in the hemodynamic responses to dexmedetomidine. However, dexmedetomidine resulted in more prolonged sedation in subjects with renal disease.     

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.     

Dexmedetomidine decreases the convulsive potency of bupivacaine and levobupivacaine in rats: involvement of alpha2-adrenoceptor for controlling convulsions

Dexmedetomidine, a highly selective alpha(2)-adrenoceptor agonist, is used in combination with local anesthetics for sedation and analgesia. We tested the hypothesis that dexmedetomidine used for sedation alters the convulsive potency of racemic bupivacaine and levobupivacaine in awake, spontaneously breathing rats. In the first experiments, male Sprague-Dawley rats were randomly divided into six groups: bupivacaine with no dexmedetomidine (bupivacaine control; BC), bupivacaine with small-dose dexmedetomidine (BS), bupivacaine with large-dose dexmedetomidine (BL), levobupivacaine with no dexmedetomidine (levobupivacaine control; LC), levobupivacaine with small-dose dexmedetomidine (LS), and levobupivacaine with large-dose dexmedetomidine (LL) (n = 10 for each group). Continuous infusion of dexmedetomidine (Groups BC and LC, 0 microg x kg(-1) x h(-1); Groups BS and LS, 3.6 microg x kg(-1) x h(-1); and Groups BL and LL, 10.8 microg x kg(-1) x h(-1)) was started after bolus injection (Groups BC and LC, 0 microg/kg; Groups BS and LS, 0.5 microg/kg; and Groups BL and LL, 1.5 microg/kg). Fifteen minutes after the start of the dexmedetomidine infusion, continuous infusion of bupivacaine (Groups BC, BS, and BL) or levobupivacaine (Groups LC, LS, and LL) at 1 mg x kg(-1) x min(-1) was started and continued until tonic/clonic convulsions occurred. Dexmedetomidine achieved significantly different sedation levels both in Groups BC, BS, and BL and in Groups LC, LS, and LL (P < 0.05). Convulsive doses of bupivacaine and levobupivacaine were significantly larger in Groups BL and LL than in Groups BC and LC, respectively (P < 0.01 for both). Concentrations of bupivacaine and levobupivacaine in plasma and in brain at the onset of convulsions were also larger in Groups BL and LL than in Groups BC and LC (P < 0.01 for both). In the second experiment, yohimbine (1 mg/kg) administered 10 min before and 5 min after the start of dexmedetomidine infusion completely reversed the sedative effect of dexmedetomidine (bolus 1.5 microg/kg, followed by 10.8 microg x kg(-1) x h(-1)). Convulsive doses and plasma and brain concentrations of bupivacaine and levobupivacaine at the onset of convulsions in rats receiving yohimbine and dexmedetomidine were significantly smaller than in those receiving only dexmedetomidine (P < 0.05 for all) and were similar to those without dexmedetomidine or yohimbine. We conclude that dexmedetomidine used for sedation decreases the convulsive potency of both bupivacaine and levobupivacaine in rats. Alpha(2)-adrenoceptor agonism may be involved in this anticonvulsant potency.     

Effect of dexmedetomidine on hemodynamics in pediatric patients following cardiac surgery

BACKGROUND: Dexmedetomidine (DEX), a highly selective alpha2-adrenergic receptor agonist, has sedative and analgesic properties with minimal respiratory depression. We retrospectively evaluated the hemodynamic effects of dexmedetomidine in pediatric patients following cardiac surgery. METHODS: The subjects were twenty children aged 4 months to 15 years who had undergone cardiac surgery. After hemodynamics were stabilized in ICU, DEX was infused at a rate of 0.3-0.5 microg x kg(-1) min(-1), following initial loading (0.5 microg x kg(-1) over 10 min). Heart rate and blood pressure were analyzed just before starting infusion, following 1, 3, 6 hours during infusion, and at the end of the infusion. RESULTS: There was no change in blood pressure during measurement. HR was slightly decreased during DEX infusion but not significantly. After discontinuation of DEX, HR was significantly increased from 109 +/- 17 to 124 +/- 19 beats x min(-1) (mean +/- SD) (P < 0.05). Two patients were excluded from the study, because clinically significant bradycardia developed during DEX infusion. CONCLUSIONS: DEX had little effect on blood pressure in patients after cardiac surgery. DEX, however, had a tendency to decrease HR. Therefore, it shoud be used with caution in patients with low heart rate.     

Dexmedetomidine does not reduce epileptiform discharges in adults with epilepsy

There are limited data on the effect of dexmedetomidine on epileptiform electroencephalogram (EEG). The aim of this study was to investigate if dexmedetomidine will abolish epileptiform discharges in patients with medically refractory seizure disorders who were candidates for surgery to resect foci of epileptic activity. With approval from the Institutional Review Board and written informed consent, we enrolled 5 patients with medically intractable seizures who were undergoing continuous video/EEG monitoring. EEG and hemodynamic values were recorded from 15 minutes before, during, and for 60 minutes after a 60-minute dexmedetomidine infusion. Epileptiform discharges were counted for each 15-minute epoch during the study. Two of the 5 patients had a discrete spike focus in each hemisphere. Thus, we analyzed the activity of 7 distinct foci. Epileptiform activity did not decrease in any individual focus during dexmedetomidine infusion. Although dexmedetomidine did not have a statistically significant effect on interictal epileptiform activity for the group as a whole, the activity of 4 foci increased during dexmedetomidine infusion. Dexmedetomidine did not reduce seizure focus activity and thus may be a suitable anesthetic adjunct during seizure surgery.     

Dexmedetomidine prevents epinephrine-induced arrhythmias through stimulation of central alpha 2 adrenoceptors in halothane-anesthetized dogs.

Since alpha 2-adrenergic agonists have important effects on the adrenergic system that have recently been applied to the anesthetic setting, we investigated the effect of stimulation of alpha 2 adrenoceptors on epinephrine-induced arrhythmias in halothane-anesthetized dogs. The arrhythmogenic threshold for epinephrine was determined during halothane anesthesia in the presence of dexmedetomidine, a selective alpha 2 agonist, and L-medetomidine, a stereoisomer of medetomidine that lacks alpha 2-agonist activity. Dexmedetomidine increased the arrhythmogenic threshold for epinephrine in a dose-dependent manner during halothane anesthesia. At the highest dose of dexmedetomidine, 0.5 microgram.kg-1.min-1, there was a three-fold increase in both the arrhythmogenic dose of epinephrine and the plasma epinephrine concentration that was reached at this dose. On the other hand, L-medetomidine over the same dose range did not effect the arrhythmogenic dose of epinephrine. Atipamezole, a central alpha 2 antagonist that crossed the blood-brain barrier, blocked the antiarrhythmic action of dexmedetomidine. L-659,066 a peripheral alpha 2 antagonist that does not penetrate the blood-brain barrier, did not affect the antiarrhythmic action of dexmedetomidine. Thus, dexmedetomidine's antiarrhythmic effect on epinephrine-induced arrhythmias during halothane anesthesia appears to be mediated at least in part by stimulation of central alpha 2 adrenoceptors.     

The effects of esmolol and dexmedetomidine on myocardial oxygen consumption during sympathetic stimulation in dogs

OBJECTIVE: The purpose of this study was to compare the potential of the beta(1)-adrenergic receptor blocker esmolol and the alpha(2)-adrenergic receptor agonist dexmedetomidine to suppress the cardiovascular and neuroendocrine response to a sympathetic stimulus. DESIGN: Experimental study. SETTING: Laboratory of university. PARTICIPANTS: Eleven anesthetized dogs. INTERVENTIONS: Catheters for arterial and coronary venous blood sampling and calculation of myocardial oxygen consumption were inserted. Pressure sensors were placed in the aorta, left ventricle, and a carotid artery. Flow probes were placed around the aortic root and around the left anterior descending coronary artery. Esmolol was infused (loading dose of 1 mg/kg, infusion of 0.3 mg/kg/h), and the adequacy of beta-blockade was checked. Thirty minutes after stopping esmolol, dexmedetomidine infusion was started (loading dose of 1 microg/kg, infusion of 1.5 microg/kg/min). Occlusion of both carotid arteries was used as a sympathetic stimulus before and during infusion of esmolol and before and during infusion of dexmedetomidine. MEASUREMENTS AND MAIN RESULTS: The variables were measured just before and during sympathetic stimulation, and changes were calculated. Both drugs suppressed the increase in dPdT(max). Dexmedetomidine suppressed the increase in plasma norepinephrine and the increase in systemic vascular resistance (dexmedetomidine 4% +/- 4% and esmolol 25% +/- 19% increase, p = 0.02). Esmolol attenuated the heart rate response (esmolol 2% +/- 2% and dexmedetomidine 20% +/- 18% increase, p = 0.02). However, dexmedetomidine decreased baseline heart rate more than esmolol; therefore, the absolute maximal heart rate during sympathetic stimulation was lower in the presence of dexmedetomidine (dexmedetomidine 119 +/- 14 and esmolol 141 +/- 15 beats/min, p = 0.01). Neither drug suppressed the increase in myocardial oxygen consumption. CONCLUSIONS: Both esmolol and dexmedetomidine have the potential to suppress some of the cardiovascular and neuroendocrine changes to a sympathetic stimulus but neither drug abolished the increase in myocardial oxygen consumption.     

Dexmedetomidine-induced sedation in volunteers decreases regional and global cerebral blood flow

Dexmedetomidine is a selective alpha(2)-agonist approved for sedation of critically ill patients. There is little information on the effects of dexmedetomidine on cerebral blood flow (CBF) or intracranial hemodynamics, despite considerable other pharmacodynamic data. We hypothesized that therapeutic doses of dexmedetomidine would decrease CBF. Therefore, nine supine volunteers, aged 24-48 yr, were infused with a 1 micro g/kg IV loading dose of dexmedetomidine, followed by an infusion of 0.2 micro g. kg(-1). h(-1) (LOW DEX) and 0.6 micro g. kg(-1). h(-1) (HIGH DEX). Hemodynamic and CBF (via positron emission tomography) measurements were determined at each experimental time point. Dexmedetomidine decreased both cardiac output and heart rate during and 30 min after drug administration. Blood pressure decreased from 12% to 16% during and after the dexmedetomidine administration. Global CBF was decreased significantly from baseline (91 mL. 100 g(-1). min(-1) [95% confidence interval, 72-114] to 64 mL. 100 g(-1). min(-1) [51-81] LOW DEX and 61 mL. 100 g(-1). min(-1) [48-76] HIGH DEX). This decrease in CBF remained constant for at least 30 min after the dexmedetomidine infusion was discontinued, despite the plasma dexmedetomidine concentration decreasing 40% during this same time period (628 pg/mL [524-732] to 380 pg/mL [253-507]). IMPLICATIONS: Dexmedetomidine-induced sedation decreased cerebral blood flow (CBF) by congruent with 33%, which could be due to direct alpha(2)-receptor cerebral smooth muscle vasoconstriction or to compensatory CBF changes caused by dexmedetomidine-induced decreases in the cerebral metabolic rate.     

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.     

右美托咪啶对切口痛大鼠中脑导水管去甲肾上腺素释放的影响

目的 探讨右美托咪啶对切口痛大鼠中脑导水管去甲肾上腺素(NE)释放的影响.方法 成功植入微透析系统的雄性Wistar大鼠24只,采用随机数字表法,将大鼠随机分为4组(n=6),对照组(C组):腹腔注射0.9%生理盐水2 ml,15 min后吸入2%异氟醚;切口痛组(IP组):腹腔注射0.9%生理盐水2 ml,15 min后制备切口痛模型;D组:腹腔注射右美托咪啶30 μg/kg,15 min后制备切口痛模型;拮抗组(DY组):腹腔注射右美托咪啶30 μg/kg和育亨宾0.5 mg/kg,15 min后制备切口痛模型.除DY组外,其余各组于术前30 min(基础状态)、术后4 h内每30 min收集微透析液10μl,DY组于术前30 min、术后30、60 min时收集微透析液,采用高效液相色谱仪和电化学检测器测定微透析液NE浓度;DY组于术前30 min(基础状态)、术后1 h,其余各组于术前30 min(基础状态)、术后1、2、3、4h时测定机械缩足反应阈值(MWT).结果 与C组比较,IP组和DY组术后MWT降低,微透析液NE浓度升高,D组术后微透析液NE浓度升高(P＜0.05),MWT差异无统计学意义(P＞0.05);与IP组比较,D组和DY组术后MWT升高,微透析液NE浓度降低(P＜0.05);与D组比较,DY组术后MWT降低,微透析液NE浓度升高(P＜0.05).结论 右美托咪啶可抑制切口痛大鼠中脑导水管NE的释放,从而产生中枢镇痛作用.

Abstract：

Objective To investigate the effect of dexmedetomidine on norepinephrine(NE)release in midbrain periaqueductal gray(PAG)in a rat model of incisional pain.Methods Twenty-four male Wistar rats in which microdialvsis catheter was successfully placed in the ventrolateral region of PAG without complications were randomly divided into 4 groups(n=6 each):group control(group C);group incisional pain(group IP);group dexmetomidine(group D)and group dexmedetomidine+yohimbine(group DY).Incisional pain was induced by an incision made into the plantar surface of left hindpaw in IP,D,DY groups.Dexmedetomidine 30 μg/kg and dexmedetomidine 30 μg/kg+yohimbine 0.5 mg/kg were given intraperitoneally at 15 min before plantar incision in group D and group DY respectively.Mechanical paw withdrawal threshold(MWT)to von Frey filament stimulation was measured at 30 min before(baseline)and 1,2,3,4 h after operation in C,IP,D groups,and at 30 min before(baseline),and 1 h after operation in group DY.Dialysate samples were collected at 30 min before(baseline)and at evcry 30 min after operation for 4 h via cerebral microdialysis catheter for determination of the NE concentration in C,IP,D groups,and at 30 min before(baseline),30,60 min after operation in group DY.Results Incisional pain significantly decreased MWT and increased the NE concentration in dialysate in group IP.Dexmedetomidine premedication significantly inhibited mechanical hyperalgesia and attenuated incisional pain-induced increase in the NE concentration in dialysate in group D.Yohimbine counteracted effects of dexmedetomidine.Conclusion Dexmedetomidine has analgesic effect though inhibition of NE release from PAG.     

Rescue sedation with dexmedetomidine for diagnostic imaging: a preliminary report

BACKGROUND: Sedation is frequently required during noninvasive radiological imaging in children. Although commonly used agents such as chloral hydrate and midazolam are generally effective, failures may occur. The authors report their experience with dexmedetomidine for rescue sedation during magnetic resonance imaging. METHODS: A retrospective chart review was undertaken. RESULTS: The cohort included five patients ranging in age from 11 months to 16 years. Following the failure of other agents (chloral hydrate and/or midazolam), dexmedetomidine was administered as a loading dose of 0.3-1.0 microg x kg(-1) x min(-1) over 5-10 min followed by an infusion of 0.5-1.0 microg x kg(-1) x h(-1). The dexmedetomidine loading dose required to induce sedation was 0.78 +/- 0.42 microg x kg(-1) (range 0.3-1.2). The maintenance infusion rate was 0.57 +/- 0.06 microg x kg(-1) x h(-1) (range 0.48-0.69). The imaging procedures were completed without difficulty. No patient required additional bolus administrations or changes in the infusion rate. The duration of the dexmedetomidine infusion ranged from 30 to 50 min. The mean decrease in heart rate was 13.6 +/- 5.1 b x min(-1) (14.3 +/- 5.0% from baseline; P = 0.02), the mean decrease in systolic blood pressure was 26.4 +/- 15.2 mmHg (24.6 +/- 12.4% decrease from baseline; P = 0.004), and the mean decrease in respiratory rate was 1.4 +/- 1.5 min(-1) (7.5 +/- 7.9% decrease from baseline; P = NS). P(E)CO2 exceeded 6.5 kPa (50 mmHg) in one patient [maximum 6.6 kPa (51 mmHg)] with a maximum value of 6.0 +/- 0.4 kPa (46 +/- 3 mmHg). Oxygen saturation decreased from 98 +/- 1 to 95 +/- 1%; P = 0.001. No patient developed hypoxemia (oxygen saturation less than 90%). Mean time to recovery to baseline status was 112.5 +/- 50.6 min and time to discharge was 173.8 +/- 83.8 min. CONCLUSIONS: Our preliminary experience suggests that dexmedetomidine may be an effective agent for procedural sedation during radiological imaging. Its potential application in this setting is discussed and other reports regarding its use in pediatric patients are reviewed.     

The effect of intravenous dexmedetomidine premedication on the dose requirement of propofol to induce loss of consciousness in patients receiving alfentanil

Dexmedetomidine reduces the dose requirements for opioids and anaesthetic agents. We conducted a single-centre, open-label, noncomparative phase II study of the effect of intravenous dexmedetomidine on the dose requirement of propofol to induce loss of consciousness in 49 ASA I and II patients. The initial dexmedetomidine infusion scheme was reduced twice because of adverse events. Forty patients who received the final infusion scheme were randomly allocated to receive one of five stepped propofol infusions; loss of consciousness was assessed after 21 min. The ED50 for the final infusion rate of propofol to suppress consciousness was 3.45 mg x kg(-1) x h(-1) (95% CL 2.7-4.2): ED95 was 6.68 mg x kg(-1) x h(-1) (95% CL 5.1-19.1), EC50 was 1.69 microg x ml(-1) (95% CL 0.95-2.5) and EC95 was 5.7 microg x ml(-1) (95% CL 3.2 to > 10). Our final dose of dexmedetomidine of 0.63 microg x kg(-1) caused a reduction in the overall concentration and dose of propofol required to produce loss of consciousness, but no significant shift in the dose-response curve compared with other studies.     

Dexmedetomidine improves neurologic outcome from incomplete ischemia in the rat. Reversal by the alpha 2-adrenergic antagonist atipamezole.

Dexmedetomidine is an alpha 2-adrenergic agonist that decreases central sympathetic activity and reduces the anesthetic requirement for halothane. We evaluated the effect of dexmedetomidine on neurologic and histopathologic outcome from incomplete cerebral ischemia in the rat. Anesthesia was maintained with a 25-micrograms.kg-1.h-1 fentanyl infusion combined with 70% nitrous oxide. Incomplete ischemia was produced by unilateral carotid artery ligation combined with hemorrhagic hypotension to 35 mmHg for 30 min. Arterial blood gas tensions, pH, and head temperature were maintained at normal levels during the experiment. Four ischemic groups were tested: group 1 (n = 15) received an intraperitoneal (ip) saline injection (control); group 2 (n = 10) received an ip injection of 10 micrograms/kg dexmedetomidine 30 min before ischemia; group 3 (n = 10) received 100 micrograms/kg dexmedetomidine; and group 4 (n = 10) received 100 micrograms/kg dexmedetomidine plus 1 mg/kg atipamezole (an alpha 2-adrenergic antagonist). Neurologic outcome was evaluated for 3 days using a graded deficit score. Histopathology was evaluated in coronal section in caudate and hippocampal tissue segments. Dexmedetomidine (10 and 100 micrograms/kg) significantly decreased plasma catecholamines and improved neurologic and histopathologic outcome in a dose-dependent manner compared to control rats (P less than 0.05). Atipamezole abolished the decrease in catecholamines and the improvement in outcome seen with dexmedetomidine, confirming that these effects were mediated by alpha 2-adrenergic receptors. It is concluded that alpha 2-adrenoreceptor stimulation decreases sympathetic activity and decreases ischemic injury in a model of incomplete cerebral ischemia.     

Effects of low and high plasma concentrations of dexmedetomidine on myocardial perfusion and cardiac function in healthy male subjects

BACKGROUND: Dexmedetomidine, a selective alpha2-adrenoceptor agonist, has counteracting effects on the cardiovascular system. It mediates sympatholysis by activating alpha2 adrenoceptors in the central and peripheral nervous system, and vasoconstriction and vasorelaxation by activating postsynaptic alpha2 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. CONCLUSIONS: In healthy subjects, plasma concentrations of dexmedetomidine that significantly exceed the recommended therapeutic level do not seriously attenuate myocardial perfusion below the level that is observed with usual therapeutic concentrations and do not induce evident myocardial ischemia.     

Effects of dexmedetomidine on hippocampal focal adhesion kinase tyrosine phosphorylation in physiologic and ischemic conditions

BACKGROUND: Dexmedetomidine is a potent and selective alpha2-adrenoceptor agonist that exhibits a broad pattern of actions, including sedation, analgesia, and neuroprotection. Some of these actions (e.g., neuroprotection) may require targets involved in long-term cellular changes. The authors hypothesized that dexmedetomidine increases the expression of active (autophosphorylated) focal adhesion kinase (FAK), a nonreceptor tyrosine kinase playing a pivotal role in cellular plasticity and survival. Therefore, we examined the cellular mechanisms involved in this effect and its sensitivity to oxygen-glucose deprivation (OGD) in rat hippocampal slices. METHODS: The effects of dexmedetomidine on phospho-tyrosine FAK phosphorylation were studied first with or without various pharmacologic agents in normoxic conditions, and second in a model of pharmacologic preconditioning of slices subjected to 30 min of OGD followed by 1 h of reperfusion. FAK phosphorylation and caspase-3 activation were examined by immunoblotting. Neuronal death was assessed by propidium iodide fluorescence. RESULTS: Dexmedetomidine produced a dose-related increase in FAK phosphorylation (187 +/- 4%, mean +/- SD, from basal level, EC50 = 0.2 microm; 95% confidence interval, 0.09-0.5 microm). This effect was stereoselective and was completely blocked by yohimbine and the combination of the cyclic monophosphate permeant analog 8 bromo cyclic monophosphate and the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine. It was mimicked by the protein kinase A inhibitor H 89. In contrast, prazosin and the protein kinase C inhibitors chelerythrine and bisindolylmaleimide I were ineffective. OGD induced a significant increase in immunoreactivity of the cleaved caspase-3 17-kd fragment (417 +/- 22; P < 0.001), a decrease in FAK phosphorylation (78 +/- 12% of control; P < 0.05), and production of significant neuronal death. In OGD conditions, a preconditioning application of dexmedetomidine (0.2 microm, 20-min application, 3 h before anoxia) significantly reduced neuronal death and cleaved caspase-3 expression and significantly attenuated the decrease in phosphorylated FAK content. The dexmedetomidine-induced reduction in caspase-3 expression was significantly decreased by the Src tyrosine kinase inhibitor PP2. CONCLUSION: Dexmedetomidine exhibits a preconditioning effect against ischemic injury in hippocampal slices subjected to OGD. Increase in phosphorylation of FAK via stimulation of alpha2 adrenoceptors and decrease in cleaved caspase-3 expression correlate with dexmedetomidine-induced cell survival.     

Preservation of the cortical somatosensory-evoked potential during dexmedetomidine infusion in rats

Successful somatosensory-evoked potential (SEP) monitoring has been performed during the administration of dexmedetomidine to patients, but a systematic investigation of the dose response of the SEP to dexmedetomidine has not been reported. In this study, we evaluated the effect of a range of dexmedetomidine doses on the cortical SEP in rats. Twelve rats were initially anesthetized with ketamine and the lungs were mechanically ventilated. Femoral arterial and venous catheters were placed. Anesthesia was maintained with constant infusions of remifentanil (5-15 microg. kg(-1). min(-1)) and vecuronium (56 microg. kg(-1). min(-1)). Dexmedetomidine was infused at 0.1, 0.25, 0.5, 1.0, and 2.0 microg. kg(-1). min(-1) in a stepwise manner with 10-min infusion periods at each step. In eight rats, an additional large-dose infusion of dexmedetomidine at 10 microg. kg(-1). min(-1) was administered for 30 min. The cortical SEPs were recorded after stimulation of the tibial nerve. At all infusion rates, there was a statistically insignificant increase in the SEP amplitude. Dexmedetomidine consistently increased the SEP latency, but these increases were not statistically significant. These data demonstrate that dexmedetomidine maintains technically adequate conditions for SEP monitoring in rats and provides support for future studies of the effect of dexmedetomidine on SEP monitoring in humans. IMPLICATIONS: In rats, the administration of a wide range of infusion rates of dexmedetomidine did not significantly affect the somatosensory-evoked potential. These results suggest that dexmedetomidine might be a useful adjunctive drug in patients undergoing intraoperative somatosensory-evoked potential monitoring.     

Experience in postoperative sedation with dexmedetomidine for mandibular osteotomy

BACKGROUND: Dexmedetomidine may be suitable for postoperative sedation of patients with mandibular osteotomy. METHODS: Twenty patients were sedated with dexmedetomidine (group D) employing loading infusion at 1.0 microg x kg(-) x hr(-1) and then continuous infusion at 0.7 mg x kg(-1) x hr(-1). Other twenty patients were sedated with midazolam 0.1 mg x kg(-1) (group C). Ramsay score was recorded at 3 hours and 12 hours after infusing sedative drugs. Then, we questioned patients, nurses and doctors. RESULTS: Ramsay score in the group D was higher than that in the group C (P < 0.01). Hypotension and respiratory depression did not occur. But bradycardia occurred in two cases. By adding propofol, group D showed more effective sedation. CONCLUSIONS: This study shows that sedation with dexmedetomidine is more suitable than that with midazolam.     

Dexmedetomidine infusion is associated with enhanced renal function after thoracic surgery

STUDY OBJECTIVE: To test the hypothesis that dexmedetomidine, a selective alpha-2 agonist, enhances urine flow rate and perioperative renal function, a post hoc analysis was conducted on a recently completed study of dexmedetomidine used as an adjunct to epidural analgesia after thoracotomy. DESIGN: Post hoc analysis of a randomized, placebo-controlled, double-blind clinical trial. SETTING: Tertiary-care university medical center. PATIENTS: 28 patients undergoing elective thoracotomy. INTERVENTIONS: Patients were prospectively randomized to receive a supplemental 24-hour intravenous infusion of either dexmedetomidine (0.4 microg kg(-1) h(-1), n = 14) or saline placebo (equivalent infusion rate, n = 14). MEASUREMENTS: Available renal parameters including urine output, calculated creatinine clearance (cCl(Cr)), daily serum creatinine level (S(Cr)), and the fractional change in S(Cr) level (DeltaS(Cr)%, [peak postoperative S(Cr) - baseline S(Cr)] / baseline S(Cr)) x 100) were recorded. MAIN RESULTS: Values are expressed as means +/- SD. There were no significant differences in baseline values between the groups. The dexmedetomidine group had significantly greater cumulative urine output at postoperative hour 4 (473 +/- 35 vs 290 +/- 122 mL, P = 0.001) and 12 (1033 +/- 240 vs 822 +/- 234 mL, P = 0.02), although only 14% of the group received diuretic agents, compared with 43% in the control group. The dexmedetomidine group had significantly better preserved perioperative renal function compared with the control group, as assessed by DeltaS(Cr)% (0.04% decrease vs 21% increase, P = 0.0007) and cCl(Cr) (75.3 +/- 13.2 vs 62.5 +/- 15.5 mL/min, P = 0.02). CONCLUSION: Dexmedetomidine infusion administered as a supplement to epidural analgesia induced diuresis in postthoracotomy patients with normal preoperative renal function and undergoing fluid restriction. Although this finding may represent simple reversal of a tubular antidiuresis, the lower DeltaS(Cr)% and preservation of cCl(Cr) suggest a beneficial effect on glomerular filtration compared with controls.