Dexmedetomidine Concentration Research Articles

A high dose of dexmedetomidine using the BIS monitor™ for diagnostic and interventional cardiac catheterization in a toddler with congenital heart disease

Dexmedetomidine (DEX) for sedation in diagnostic and interventional cardiac catheterization (DICC) has been reported to require other drugs or rescue drugs because of its insufficient sedative effect when used alone. We administered DEX and adjusted its dose according to the bispectral index (BIS) monitor™ for DICC in a toddler; consequently, a high dose of DEX had to be administered. The patient was a 1-year and 4-month-old boy who was scheduled to undergo DICC after intracardiac repair. We used DEX alone as the sedative because this was expected to avoid oxygen supply and mechanical ventilation and to produce a safe situation for procedures around the neck. DEX was administered at the dose of 1-15μg/kg/h according to BIS monitor™; administration of cardiovascular drugs or oxygen supply or assist ventilation, except chin lift, were not needed. The maximum predicted plasma concentration (pCp) of DEX and mean pCp were calculated as 6.1 and 4.1ng/mL, respectively. A high dose of DEX may be required for DICC sedation, as for MRI sedation, in many cases. Although further studies should be conducted to reveal the merits and demerits of DEX in cardiac catheterization, a high dose of DEX may be useful in some cases.

Hemodynamic effects of dexmedetomidine in isoflurane-anesthetized cats

ObjectiveTo characterize the hemodynamic effects of dexmedetomidine in isoflurane-anesthetized cats. Study designProspective experimental study. AnimalsSix healthy adult female cats weighing 4.6 ± 0.8 kg. MethodsDexmedetomidine was administered intravenously using target-controlled infusions to maintain nine plasma concentrations between 0 and 20 ng mL−1 in isoflurane-anesthetized cats. The isoflurane concentration was adjusted for each dexmedetomidine concentration to maintain the equivalent of 1.25 times the minimum alveolar concentration, based on a previous study. Heart rate, systemic and pulmonary arterial pressures, central venous pressure, pulmonary artery occlusion pressure, body temperature, and cardiac output were measured at each target plasma dexmedetomidine concentration. Additional variables were calculated. Arterial and mixed-venous blood samples were collected for blood gas, pH, and (on arterial blood only) electrolyte, glucose and lactate analysis. Plasma dexmedetomidine concentration was determined for each target. Pharmacodynamic models were fitted to the data. ResultsHeart rate, arterial pH, arterial bicarbonate concentration, mixed-venous PO2, mixed-venous pH, mixed-venous hemoglobin oxygen saturation, cardiac index, stroke index, and venous admixture decreased following dexmedetomidine administration. Arterial blood pressure, central venous pressure, pulmonary arterial pressure, pulmonary arterial occlusion pressure, packed cell volume, PaO2, PaCO2, arterial hemoglobin concentration, mixed-venous PCO2, mixed-venous hemoglobin concentration, ionized calcium concentration, glucose concentration, rate-pressure product, systemic and pulmonary vascular resistance indices, left ventricular stroke work index, arterial oxygen concentration, and oxygen extraction increased following dexmedetomidine administration. Most variables changed in a dexmedetomidine concentration-dependent manner. Conclusion and clinical relevanceThe use of dexmedetomidine as an anesthetic adjunct is expected to produce greater negative hemodynamic effects than a higher, equipotent concentration of isoflurane alone.

Calcium sensitization involved in dexmedetomidine-induced contraction of isolated rat aorta

Dexmedetomidine, a full agonist of the α2B-adrenoceptor that is mainly involved in vascular smooth muscle contraction, is primarily used for analgesia and sedation in intensive care units. High-dose dexmedetomidine produces hypertension in children and adults. The goal of this in vitro study was to investigate the role of the calcium (Ca(2+)) sensitization mechanism involving Rho-kinase, protein kinase C (PKC), and phosphoinositide 3-kinase (PI3-K) in mediating contraction of isolated rat aortic smooth muscle in response to dexmedetomidine. The effect of dexmedetomidine on the intracellular Ca(2+) level ([Ca(2+)]i) and tension was measured simultaneously. Dexmedetomidine concentration-response curves were generated in the presence or absence of the following antagonists: rauwolscine, Y 27632, LY 294002, GF 109203X, and verapamil. Dexmedetomidine-induced phosphorylation of PKC and membrane translocation of Rho-kinase were detected with Western blotting. Rauwolscine, Y 27632, GF 109203X, LY 294002, and verapamil attenuated dexmedetomidine-induced contraction. The slope of the [Ca(2+)]i-tension curve for dexmedetomidine was higher than that for KCl. Dexmedetomidine induced phosphorylation of PKC and membrane translocation of Rho-kinase. These results suggest that dexmedetomidine-induced contraction involves a Ca(2+) sensitization mechanism mediated by Rho-kinase, PKC, and PI3-K that is secondary to α2-adrenoceptor stimulation in rat aortic smooth muscle.

Administration of dexmedetomidine alone during diagnostic cardiac catheterization in adults with congenital heart disease: two case reports

We report the clinical management of 2 adults with mental retardation because of trisomy 21 who were sedated with high-dose dexmedetomidine (DEX) alone during diagnostic cardiac catheterization (DCC). The first patient was a 25-year-old man with aortic regurgitation and ventricular septal defect. DEX increased his Ramsay sedation score; however, a high dose and bolus injection of DEX were required to perform an invasive procedure. Cardiovascular drugs were not administered and heart rate was maintained in the low 40s. The maximum predicted plasma concentration (pCp) of DEX was 2.3ng/mL. The second patient was a 26-year-old woman who had developed hypoxia 20years after palliative surgery for tetralogy of Fallot. High-dose DEX was administered to keep the bispectral index value below 70 and maintain an immobile state; her maximum pCp of DEX was 4.3ng/mL. Percutaneous oxygen saturation was kept above 83%, because of the suspicion that DEX may increase the ratio of pulmonary artery flow to systemic artery flow. In both cases, no respiratory system complications occurred despite inspiration of room air, indicating the usefulness of DEX for DCC. However, because of DEX may affect DCC data, it is necessary to pay careful attention to the use of DEX during DCC.

Effect of dexmedetomidine on the minimum alveolar concentration of isoflurane in cats

This study reports the effects of dexmedetomidine on the minimum alveolar concentration of isoflurane (MAC(iso) ) in cats. Six healthy adult female cats were used. MAC(iso) and dexmedetomidine pharmacokinetics had previously been determined in each individual. Cats were anesthetized with isoflurane in oxygen. Dexmedetomidine was administered intravenously using target-controlled infusions to maintain plasma concentrations of 0.16, 0.31, 0.63, 1.25, 2.5, 5, 10, and 20 ng/mL. MAC(iso) was determined in triplicate at each target plasma dexmedetomidine concentration. Blood samples were collected and analyzed for dexmedetomidine concentration. The following model was fitted to the concentration-effect data: [Formula in text] where MAC(iso.c) is MAC(iso) at plasma dexmedetomidine concentration C, MAC(iso.0) is MAC(iso) in the absence of dexmedetomidine, I(max) is the maximum possible reduction in MAC(iso), and IC(50) is the plasma dexmedetomidine concentration producing 50% of I(max). Mean ± SE MAC(iso.0), determined in a previous study conducted under conditions identical to those in this study, was 2.07 ± 0.04. Weighted mean ± SE I(max), and IC(50) estimated by the model were 1.76 ± 0.07%, and 1.05 ± 0.08 ng/mL, respectively. Dexmedetomidine decreased MAC(iso) in a concentration-dependent manner. The lowest MAC(iso) predicted by the model was 0.38 ± 0.08%, illustrating that dexmedetomidine alone is not expected to result in immobility in response to noxious stimulation in cats at any plasma concentration.

Dexmedetomidine was safely used for sedation during spinal anesthesia in a very elderly patient

We safely administered dexmedetomidine (DEX) for sedation during spinal anesthesia in a very elderly patient. The patient was a 98-year-old woman who had hypertension, renal failure, and first-grade atrioventricular block. She was scheduled to undergo internal fixation for fracture of the femoral neck. Initially, DEX (6.0μg/kg/h) was administered over 10min, followed by continuous infusion at a dose of 0.7μg/kg/h. Consequently, her Ramsay sedation score (RSS) increased to 5, and the patient did not grimace in pain while being turned to the lateral position. Epidural catheterization and spinal anesthesia were performed under sedation without any problem. The DEX dose was adjusted to maintain the RSS within 3-4. The surgical operation was performed smoothly without any problem. Since the hemodynamic condition was stable, administration of ephedrine (5mg) was required only once during surgery. Percutaneous oxygen saturation was maintained at 98% or more; respiratory rate was within 15-21tpm, and no ventilatory assistance was required. The maximum predicted plasma concentration (pCp) of DEX was 1.56ng/mL, and the mean pCp of DEX during surgery was approximately 0.45ng/mL. We found that DEX can be safely used for sedation during spinal anesthesia in a very elderly patient.

Deterioration of myocardial injury due to dexmedetomidine administration after myocardial ischaemia

Aim Dexmedetomidine is a highly selective α-2 adrenergic agonist used perioperatively. Dexmedetomidine's cardioprotective effect after myocardial ischaemia remains unknown. In this study, we administered dexmedetomidine after ischaemia to investigate its ability to protect the cardiac muscle from ischaemia-reperfusion injury in isolated rat hearts. Methods After a 30-min stop of perfusion, isolated rat hearts underwent reperfusion for 120 min. At the initiation of reperfusion, dexmedetomidine was administered for 25 min at concentrations of 0 nM (control group), 1 nM (Dex 1 group), and 10 nM (Dex 10 group). Yohimbine (an α-2 adrenergic antagonist) was administered in the manner as above in another group of isolated rat hearts at a concentration of 1 μM without dexmedetomidine (Yoh group) and at 1 μM with 10 nM dexmedetomidine (Yoh + Dex 10 group). The area of infarction was measured using 2,3,5-triphenyltetrazolium staining. Results Dexmedetomidine administration did not influence haemodynamics or the coronary flow (CF), but did increase the myocardial infarct size. Neither concentration of dexmedetomidine affected the infarct size as the Dex 1 and Dex 10 groups had almost the same infarct size. The infarct size was 40.5 ± 2.9% in the control group, 60.9 ± 5.3% in the Dex 1 group, and 60.9 ± 2.8% in the Dex 10 group. The infarct size was reduced in the yohimbine groups. The infarct size was 39.2 ± 3.3% in the Yoh + Dex 10 group and 45.0 ± 3.2% in the Yoh group. Conclusion Dexmedetomidine administration does not influence haemodynamics or CF, but does increase the cardiac infarct size. α-2 Adrenergic stimulation may induce this mechanism.

Dexmedetomidine hemodynamics in children after cardiac surgery

Dexmedetomidine has opposing effects on the cardiovascular system. Action in the central nervous system produces sympatholysis and a reduction in blood pressure, while peripherally it causes vasoconstriction leading to an increase in blood pressure. The purpose of our study is to define the concentration-response profile for these hemodynamic effects in children after cardiac surgery. A simultaneous pharmacokinetic-pharmacodynamic analysis of data from 29 children given a single bolus of dexmedetomidine 1-4 mcg.kg(-1) following cardiac surgery was undertaken using mixed effects modeling. There were four dexmedetomidine concentrations available from each patient, and mean arterial blood pressure (MAP) was recorded electronically every 5 min for 5 h after drug administration. A composite Emax model was used to relate mean arterial pressure changes to plasma dexmedetomidine concentration. Children had a mean age of 2.67 years (range 4 days-14 years) and a mean weight of 12.34 (range 3.4-48.4) kg. The peripheral vasopressor effect was directly related to plasma concentration with an Emax(pos) of 50.3 (CV 44.50%) mmHg, EC(50pos) 1.1 (48.27%) microg.l(-1) and a Hill(pos) coefficient of 1.65. The delayed central sympatholytic response was described with an Emax(neg) of -12.30 (CV 37.01%) mmHg, EC(50neg) 0.10 (104.40%) microg.l(-1) and a Hill(neg) coefficient of 2.35. The equilibration half-time (T(1/2)keo) was 9.66 (165.23%) min. Dexmedetomidine administered as a single bolus dose following cardiac surgery produces a biphasic effect on MAP. A plasma dexmedetomidine concentration of above 1.0 microg.l(-1) was associated with a 20% increase in MAP in this specific cohort. A dosage regimen involving a small bolus dose (0.5 microg.kg(-1)) followed by a continuous infusion should be used to avoid initial increases in MAP.

Highly variable pharmacokinetics of dexmedetomidine during intensive care: a case report

IntroductionDexmedetomidine is a selective and potent alpha2-adrenoceptor agonist licensed for use in the sedation of patients initially ventilated in intensive care units at a maximum dose rate of 0.7 μg/kg/h administered for up to 24 hours. Higher dose rates and longer infusion periods are sometimes required to achieve sufficient sedation. There are some previous reports on the use of long-term moderate to high-dose infusions of dexmedetomidine in patients in intensive care units, but none of these accounts have cited dexmedetomidine plasma concentrations.Case presentationWe describe the case of a 42-year-old Caucasian woman with severe hemorrhagic pancreatitis following laparoscopic cholecystectomy who received dexmedetomidine for 24 consecutive days at a maximum dose rate of 1.9 μg/kg/h. Samples for the measurement of dexmedetomidine concentrations in her plasma were drawn at intervals of eight hours. On average, the observed plasma concentrations were well in accordance with previous knowledge on the pharmacokinetics of dexmedetomidine. There was, however, marked variability in the concentration of dexmedetomidine in her plasma despite a stable infusion rate.ConclusionThe pharmacokinetics of dexmedetomidine appears to be highly variable during intensive care.

Buccal administration of dexmedetomidine as a preanesthetic in children

The objective of this study was to evaluate the efficacy and safety of buccal dexmedetomidine as a preanesthetic in children, to compare it with diazepam, and to investigate the optimal dosage for buccal dexmedetomidine administration by measuring its serum concentration. We performed a prospective study with 40 children who were assigned to two groups. The patients underwent an operation for inguinal or umbilical hernia. Twenty children received dexmedetomidine buccally at 3-4 microg/kg (Dex Group) and 20 received a diazepam suppository at 0.7 mg/kg (Diazepam Group) as preanesthetics 1 h before the operation. Heart rate, systolic blood pressure, SpO2, and respiratory rate were measured 1 h after premedication in all children. Sedation level was preoperatively evaluated, and compared with the Ramsay score, in the ward, at the entrance to the main operating rooms, and at anesthesia induction between the two groups. To investigate the optimal dosage of buccal dexmedetomidine, we compared the mean serum concentration of dexmedetomidine at induction between patients with a Ramsay score of 5 or greater and those with a Ramsay score less than 5. The Mann-Whitney U test was used for statistical analysis. There was no significant difference between the two groups in age or body weight. Furthermore, there was no significant difference between the two groups in heart rate, systolic blood pressure, SpO2, or respiratory rate after administration of either medication. The Ramsay score of the Dex Group was significantly higher than that of the Diazepam Group at all times. The mean serum dexmedetomidine concentration at induction in patients with a Ramsay score of 5 or greater (75 +/- 50 pg/ml) was significantly higher than in those with a Ramsay score less than 5 (34 +/- 36 pg/ml, P < 0.05). These results suggest that the buccal administration of dexmedetomidine (3-4 microg/kg) 1 h before the operation can be safely and effectively applied as a preanesthetic in children.

Dexmedetomidine for awake fiberoptic intubation in a parturient with spinal muscular atrophy type III for cesarean delivery

Spinal muscular atrophy in pregnancy is rare and poses multiple problems for the anesthesiologist. The effects of dexmedetomidine on a parturient with spinal muscular atrophy have not previously been reported. There are also no in vivo data on placental transfer of dexmedetomidine and its effects on a human neonate. We report the hemodynamic, respiratory and sedative effects of dexmedetomidine on a parturient and neonate when used for awake fiberoptic intubation before cesarean section. A 35-year-old, gravida 4 para 0 aborta 3, 41-kg parturient at 35 weeks of gestation with spinal muscular atrophy presented for cesarean section. Dexmedetomidine was administered intravenously, total dose 1.84 μg/kg over 38 minutes, followed by fiberoptic endotracheal intubation. Dexmedetomidine was then discontinued and general anesthesia was induced. The baby was delivered 68 minutes after the dexmedetomidine infusion was discontinued at which time blood samples were obtained for measurement of dexmedetomidine. During administration of dexmedetomidine, maternal heart rate, blood pressure and oxygen saturation remained stable. Apgar scores at 1 and 5 min were 6 and 8. The fetal concentration of dexmedetomidine (540 pg/mL) indicates significant placental transfer, but significant adverse neonatal effects were not observed. Dexmedetomidine alone provided adequate sedation for awake intubation without respiratory compromise in this patient.

Effects of variation in the human α 2A- and α 2C-adrenoceptor genes on cognitive tasks and pain perception

Background The mechanisms underlying interindividual variability in pain perception and cognitive responses are undefined but highly heritable. α 2C- and α 2A-adrenergic receptors regulate noradrenergic activity and are important mediators of pain perception and analgesia. We hypothesized that common genetic variants in these genes, particularly the ADRA2C 322–325 deletion variant, affect pain perception or cognitive responses. Methods We studied 73 healthy subjects (37 Caucasians and 36 African–Americans) aged 25.4 ± 4.6 years. Pain response to a cold pressor test was measured using a 10 cm visual analog scale and again on the next day, after three infusions of the selective α 2-agonist dexmedetomidine. Standardized cognitive tests were administered at baseline and after each infusion. The contribution of ADRA2C deletion genotype, dexmedetomidine concentration, and other covariates to pain perception and cognitive responses was determined using multiple linear regression models. Secondary analysis examined the effects of ADRA2A and other ADRA2C variants on pain perception. Results ADRA2C Del homozygotes had higher pain scores in response to cold at baseline (6.3 ± 1.8 cm) and after dexmedetomidine (5.6 ± 2.2 cm) than insertion allele carriers (4.6 ± 2.1 cm [baseline] and 3.8 ± 1.9 cm [after dexmedetomidine]; adjusted P-values = 0.019 and 0.004, respectively). Cognitive responses were unrelated to ADRA2C Ins/Del genotype. None of the other ADRA2A and ADRA2C variants was significantly related to cold pain sensitivity before dexmedetomidine; after dexmedetomidine, ADRA2A rs1800038 was marginally associated ( P = 0.03). Conclusion The common ADRA2C del322–325 variant affected pain perception before and after dexmedetomidine but did not affect other cognitive responses, suggesting that it contributes to interindividual variability in pain perception.

Pharmacokinetics of intravenous dexmedetomidine in children under 11 yr of age

BackgroundInformation has been very limited on the pharmacokinetics of the selective α2-adrenoceptor agonist dexmedetomidine in children, particularly in children <2 yr of age. MethodsEight children aged between 28 days and 23 months and eight children aged between 2 and 11 yr undergoing either elective bronchoscopy or nuclear magnetic resonance imaging were included in the study. Dexmedetomidine 1 μg kg−1 was infused i.v. over 5 min. Blood samples for the measurement of plasma concentrations of dexmedetomidine were collected for 5 h after starting the infusion. Pharmacokinetic calculations were based on non-compartmental methods. ResultsIn the two groups of paediatric patients, the median (range) values for total plasma clearance of dexmedetomidine were 17.4 (14.1–27.6) and 17.3 (9.3–22.5) ml kg−1 min−1, for volume of distribution at steady state 3.8 (1.9–4.6) and 2.2 (1.3–2.8) litre kg−1 (P<0.05), and for elimination half-life 139 (90–198) and 96 (69–140) min (P<0.05), respectively. The volume of distribution at steady state was negatively associated with subject age (r=−0.69, P<0.05). ConclusionsTo reach a certain plasma concentration, children younger than 2 yr of age evidently need larger initial doses of dexmedetomidine than the older children, as young children have a larger volume of distribution of the drug than older children and adults. Since the total plasma clearance of dexmedetomidine is independent of age, similar rates of infusion can be used in younger and older children to maintain a steady-state concentration of dexmedetomidine in plasma.

The effects of dexmedetomidine on human neutrophil apoptosis

The purpose of the present study was to evaluate the effect of dexmedetomidine, used as a sedative in the intensive care unit, on human neutrophil apoptosis and superoxide production in vitro. Neutrophils from healthy volunteers were incubated in different concentrations of dexmedetomidine (1, 10 and 100 ng/mL). Apoptosis was assessed by Hoechst 33342 staining, caspase activities and loss of mitochondrial transmembrane potential (MTP). Superoxide production was determined by the WST-1 assay. After 24 h of incubation, dexmedetomidine accelerated neutrophil apoptosis in a dose-dependent manner and 100 microM yohimbine did not inhibit the apoptosis. Treatment with 100 ng/mL of dexmedetomidine significantly enhanced the activation of caspases-3/7, -8 and -9, and also markedly increased the number of neutrophils with decreased MTP. At 24 h, the suppression of superoxide production was dependent on dexmedetomidine concentrations. However, a clinically relevant concentration (1 ng/mL) of dexmedetomidine did not affect neutrophil apoptosis and superoxide production. These results suggest that high doses of dexmedetomidine induce apoptosis without alpha(2)-adrenoceptors stimulus and inhibit superoxide production after long-term incubation. The mechanisms of dexmedetomidine-induced apoptosis are associated with the caspase cascade and loss of MTP.

Dexmedetomidine Reduces Long-term Potentiation in Mouse Hippocampus

Dexmedetomidine (Precedex; Abbott Laboratories, Abbott Park, IL) is a selective alpha2-adrenergic agonist that also has affinity for imidazoline receptors. In clinical studies, dexmedetomidine has sedative effects and impairs memory, but the action of dexmedetomidine on synaptic plasticity in the brain has yet to be established. In the present study, the authors investigated the effects of dexmedetomidine on two forms of synaptic plasticity-long-term potentiation (LTP) and paired-pulse facilitation-in the CA1 region of mouse hippocampal slices. The authors recorded Schaffer collateral-evoked field excitatory postsynaptic potentials from mouse hippocampal slices in CA1 stratum radiatum. The slope of the rising phase of the field excitatory postsynaptic potential was used to estimate the strength of synaptic transmission. Application of dexmedetomidine for 20 min before "theta burst" stimulation dose-dependently attenuated LTP, and half-inhibitory concentration of dexmedetomidine was 28.6 +/- 5.7 nm. The inhibitory effect of dexmedetomidine on LTP was not abolished by an alpha2-adrenoceptor antagonist (yohimbine), an imidazoline type 1 receptor and alpha2-adrenoceptor antagonist (efaroxan), an alpha1-adrenoceptor antagonist (prazosin), or a gamma-aminobutyric acid type A receptor antagonist (picrotoxin). However, an imidazoline type 2 receptor and alpha2-adrenoceptor antagonist (idazoxan) completely blocked the dexmedetomidine-induced attenuation. Furthermore, 2-benzofuranyl-2-imidaloline, a selective imidazoline type 2 receptor ligand, reduced LTP. 2-(4,5-dihydroimidaz-2-yl)-quinoline, another imidazoline type 2 receptor ligand, abolished the 2-benzofuranyl-2-imidaloline-induced attenuation, but the inhibitory effect of dexmedetomidine on LTP was not abolished by 2-(4,5-dihydroimidaz-2-yl)-quinoline. Dexmedetomidine did not affect paired-pulse facilitation. Dexmedetomidine impairs LTP in area CA1 of the mouse hippocampus via imidazoline type 2 receptors and alpha2-adrenoceptors.

The Effect of Dexmedetomidine on Electrocorticography in Patients with Temporal Lobe Epilepsy Under Sevoflurane Anesthesia

Although dexmedetomidine is often used in neuroanesthesia and neuronal critical care practice, its effect on cerebral electrical activity in those with an abnormal electroencephalogram is not known. The electrocorticogram (ECoG), a sensitive method for examining the effect of drugs on cerebral electrical activity and surgical treatment for epilepsy, is usually guided by monitoring of the ECoG. We investigated the effect of dexmedetomidine on ECoG in patients with epilepsy undergoing surgery with sevoflurane. Patients with medically intractable temporal lobe epilepsy undergoing resection of the epileptic foci (n = 11) were enrolled. Under general anesthesia with 2.5% sevoflurane and end-tidal carbon dioxide tension at 30 mm Hg, ECoG was recorded by strip electrodes with eight contacts placed on the mesial temporal lobe ipsilateral to the epilepsy foci. Dexmedetomidine was given as a computer-controlled infusion to achieve target plasma concentrations of 0.5 and 1.5 ng/mL. Each concentration was maintained for 20 min and ECoG was recorded before infusion of dexmedetomidine and between the 10th and 20th min after starting infusion. The median frequency of ECoG, spectral power density of each spectral band, and number of spikes at each concentration of dexmedetomidine were compared by Kruskal-Wallis test, followed by Student-Newman-Keuls test. The median frequency of ECoG in 88 leads from all leads from all patients was significantly decreased by 1.5 ng/mL of dexmedetomidine compared with those at baseline and 0.5 ng/mL (P = 0.003 and 0.03, respectively); however, spectral power densities in the frequency bands: delta (<4 Hz), theta (> or =4 and <8 Hz), alpha (> or =8 and <13 Hz), and beta (> or =13 Hz), were not changed. Neither the number of leads with spikes nor the number of spikes in all leads and in the lead with highest number of spikes at baseline was affected by dexmedetomidine. Dexmedetomidine at plasma concentrations of 0.48 and 1.60 ng/mL decreased the median frequency of ECoG, but did not affect spike activity in patients with temporal lobe epilepsy anesthetized with 2.5% sevoflurane.

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

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. 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. 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. 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.

Comparison of cardiopulmonary effects of dexmedetomidine administered as a constant rate infusion without loading dose in sheep and goats anaesthetised with sevoflurane

The purpose of this study was to compare the cardiopulmonary effects of dexmedetomidine in anaesthetised sheep and goats. The initial vasopressor effects were prevented by using a constant rate infusion (CRI), without a loading dose. In six sevoflurane anaesthetised goats and sheep dexmedetomidine was infused as CRI (2 μg/kg/h). Before, during and for 30 min after the infusion, cardiac output (CO), systemic and pulmonary arterial pressures, heart rate (HR), respiratory mechanics, inspired and expired gas concentrations, arterial and mixed venous blood gases and the plasma concentration of dexmedetomidine were measured. In goats, CO, HR and mean arterial pressure decreased below baseline values by 20, 40 and 20%, respectively. Systemic vascular resistance (SVR) only decreased after the infusion. Gas exchange and respiratory mechanics remained unchanged. In sheep, CO did not change and SVR decreased progressively up to 45% below baseline. Changes in gas exchange and respiratory mechanics were mild but highly variable. The plasma concentrations of dexmedetomidine were similar in sheep and goats. In conclusion, goats seem to be more sensitive to centrally mediated cardiovascular effects of dexmedetomidine than sheep, which is not related to dexmedetomidine disposition. Adverse pulmonary effects were completely prevented by CRI without loading dose in goats but not in sheep.

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

Alpha-2B adrenoceptor is the vasoconstrictive subtype in the mouse. Human alpha2B-AR deletion (D) allele has been associated with loss of short-term agonist-promoted receptor desensitization, which may lead to increased vasoconstriction on alpha2 activation. The goal of this study was to test the hypothesis that alpha2B-adrenoceptor activation induces enhanced vasoconstriction in carriers of the DD genotype, compared with carriers of the insertion/insertion (II) genotype. 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 alpha2B 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. 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. The results of this study confirm the alpha2 agonist induced vasomotor and hemodynamic effects in peripheral vasculature. However, the results do not support the hypothesis that alpha2B-adrenoceptor polymorphism has an effect on peripheral vasoconstriction in humans.

Dexmedetomidine-Induced Sedation in Volunteers Decreases Regional and Global Cerebral Blood Flow

Dexmedetomidine is a selective α2-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 μg/kg IV loading dose of dexmedetomidine, followed by an infusion of 0.2 μg · kg−1 · h−1 (LOW DEX) and 0.6 μg · 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]).