Dexmedetomidine Improves Cardiovascular and Ventilatory Outcomes in Critically Ill Patients: Basic and Clinical Approaches

Dexmedetomidine (DEX) is a highly selective α2-adrenergic agonist with sedative and analgesic properties, with minimal respiratory effects. It is used as a sedative in the intensive care unit and the operating room. The opioid-sparing effect and the absence of respiratory effects make dexmedetomidine an attractive adjuvant drug for anesthesia in obese patients who are at an increased risk for postoperative respiratory complications. The pharmacodynamic effects on the cardiovascular system are known; however the mechanisms that induce cardioprotection are still under study. Regarding the pharmacokinetics properties, this drug is extensively metabolized in the liver by the uridine diphosphate glucuronosyltransferases. It has a relatively high hepatic extraction ratio, and therefore, its metabolism is dependent on liver blood flow. This review shows, from a basic clinical approach, the evidence supporting the use of dexmedetomidine in different settings, from its use in animal models of ischemia-reperfusion, and cardioprotective signaling pathways. In addition, pharmacokinetics and pharmacodynamics studies in obese subjects and the management of patients subjected to mechanical ventilation are described. Moreover, the clinical efficacy of delirium incidence in patients with indication of non-invasive ventilation is shown. Finally, the available evidence from DEX is described by a group of Chilean pharmacologists and clinicians who have worked for more than 10 years on DEX.

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title: The role of alpha2-agonists in neurosurgery.
abstract: Alpha2-agonists have been extensively used and studied in anaesthesia and intensive care medicine. A list of benefits includes anxiolysis, blood pressure stabilization, analgesia, anaesthetic sparing effects and sedation without respiratory depression or significant cognitive impairment. Fear of inadvertent hypotension, bradycardia or post-operative sedation, and the variability of the haemodynamic response to different doses or rates of administration, have meant that universal acceptance in clinical practice has not yet been seen. Recently, the actions of these agents on the alpha2-adrenoreceptor and the imidazoline receptor have been more accurately identified, helping to explain the differences between the actions of various agents. The two readily available agents, clonidine and dexmedetomidine have already been used in many different anaesthetic situations, for a wide variety of surgical procedures. We believe that both of these alpha2-agonists are useful adjuncts for the management of the neurosurgical patient during surgery, and in the intensive care unit.

title: Dexmedetomidine protects the heart against ischemia-reperfusion injury by an endothelial eNOS/NO dependent mechanism.
abstract: The alpha2-adrenergic receptor agonist Dexmedetomidine (Dex) is a sedative medication used by anesthesiologists. Dex protects the heart against ischemia-reperfusion (IR) and can also act as a preconditioning mimetic. The mechanisms involved in Dex-dependent cardiac preconditioning, and whether this action occurs directly or indirectly on cardiomyocytes, still remain unclear. The endothelial nitric oxide synthase (eNOS)/nitric oxide (NO) signaling pathway and endothelial cells are known to play key roles in cardioprotection against IR injury. Therefore, the aims of this work were to evaluate whether the eNOS/NO pathway mediates the pharmacological cardiac effect of Dex, and whether endothelial cells are required in this cardioprotective action. Isolated adult rat hearts were treated with Dex (10nM) for 25min and the dimerization of eNOS and production of NO were measured. Hearts were then subjected to global IR (30/120min) and the role of the eNOS/NO pathway was evaluated. Dex promoted the activation of eNOS and production of NO. Dex reduced the infarct size and improved the left ventricle function recovery, but this effect was reversed when Dex was co-administered with inhibitors of the eNOS/NO/PKG pathway. In addition, Dex was unable to reduce cell death in isolated adult rat cardiomyocytes subjected to simulated IR. Cardiomyocyte death was attenuated by co-culturing them with endothelial cells pre-treated with Dex. In summary, our results show that Dex triggers cardiac protection by activating the eNOS/NO signaling pathway. This pharmacological effect of Dex requires its interaction with the endothelium.

title: The cardioprotective effect of dexmedetomidine on regional ischemia/reperfusion injury in type 2 diabetic rat hearts.
abstract: Dexmedetomidine (DEX) is an α2-adrenergic receptor agonist commonly used during perioperative periods due to its sedation and analgesia effect. It is confirmed that DEX has cardioprotective effects against ischemia/reperfusion (I/R) injury. We investigated whether DEX administration is beneficial to type 2 diabetic rats subjected to I/R injury.



The diabetes model was established by providing a high-fat diet for 2 weeks followed by injecting 35 mg/kg streptozotocin (STZ). The myocardial I/R model consisted of left anterior descending coronary artery occlusion for 30 min followed by reperfusion for two-hours. DEX was administered before ischemia; alternatively, yohimbine was administered with or without DEX before ischemia. At the end of reperfusion, the rats were sacrificed, and hearts were isolated for histology. The levels of glycogen synthase kinase-3β (GSK-3β) and phosphorylated GSK-3β (p-GSK-3β) were quantitatively analyzed. The infarct size was measured via Evans Blue and 2,3,5‑triphenyltetrazolium chloride (TTC) staining. Plasma samples were collected to measure the levels of cardiac Troponin T (cTnT). Arrhythmia scores were recorded during the first few minutes of reperfusion.



DEX preconditioning significantly reduced myocardial infarct size, arrhythmia scores and the plasma cTnT levels, and increased the p-GSK-3β levels. All of these protective effects of DEX were reversed by co-administration of yohimbine.



These results suggested that DEX preconditioning exerted a cardioprotective effect against regional I/R injury in diabetic rats.

title: Pharmacokinetics of prolonged infusion of high-dose dexmedetomidine in critically ill patients
abstract: IntroductionOnly limited information exists on the pharmacokinetics of prolonged (> 24 hours) and high-dose dexmedetomidine infusions in critically ill patients. The aim of this study was to characterize the pharmacokinetics of long dexmedetomidine infusions and to assess the dose linearity of high doses. Additionally, we wanted to quantify for the first time in humans the concentrations of H-3, a practically inactive metabolite of dexmedetomidine.MethodsThirteen intensive care patients with mean age of 57 years and Simplified Acute Physiology Score (SAPS) II score of 45 were included in the study. Dexmedetomidine infusion was commenced by using a constant infusion rate for the first 12 hours. After the first 12 hours, the infusion rate of dexmedetomidine was titrated between 0.1 and 2.5 μg/kg/h by using predefined dose levels to maintain sedation in the range of 0 to -3 on the Richmond Agitation-Sedation Scale. Dexmedetomidine was continued as long as required to a maximum of 14 days. Plasma dexmedetomidine and H-3 metabolite concentrations were measured, and pharmacokinetic variables were calculated with standard noncompartmental methods. Safety and tolerability were assessed by adverse events, cardiovascular signs, and laboratory tests.ResultsThe following geometric mean values (coefficient of variation) were calculated: length of infusion, 92 hours (117%); dexmedetomidine clearance, 39.7 L/h (41%); elimination half-life, 3.7 hours (38%); and volume of distribution during the elimination phase, 223 L (35%). Altogether, 116 steady-state concentrations were found in 12 subjects. The geometric mean value for clearance at steady state was 53.1 L/h (55%). A statistically significant linear relation (r2 = 0.95; P < 0.001) was found between the areas under the dexmedetomidine plasma concentration-time curves and cumulative doses of dexmedetomidine. The elimination half-life of H-3 was 9.1 hours (37%). The ratio of AUC0-∞ of H-3 metabolite to that of dexmedetomidine was 1.47 (105%), ranging from 0.29 to 4.4. The ratio was not statistically significantly related to the total dose of dexmedetomidine or the duration of the infusion.ConclusionsThe results suggest linear pharmacokinetics of dexmedetomidine up to the dose of 2.5 μg/kg/h. Despite the high dose and prolonged infusions, safety findings were as expected for dexmedetomidine and the patient population.

title: The pharmacokinetics of dexmedetomidine in patients with obstructive jaundice: A clinical trial
abstract: Dexmedetomidine, a highly selective central α2-agonist, undergoes mainly biotransformation in the liver. The pharmacokinetics of dexmedetomidine were significantly affected by hepatic insufficiency. The clearance of dexmedetomidine in patients with severe hepatic failure decreased by 50% compared with controls. We tested the hypothesis that the pharmacokinetics of dexmedetomidine would be affected by obstructive jaundice. The prospective registration number of clinical trial is ChiCTR-IPR-15007572. Methods 18 patients with obstructive jaundice and 12 non-jaundiced patient controls received dexmedetomidine, 1 μg/kg, over 10 min. Arterial blood samples were drawn before, during, and up to 5 h after the infusion. Plasma dexmedetomidine concentrations were determined by 1290 infinity high performance liquid chromatography coupled with 6470 tandem mass spectrometry. The relevant pharmacokinetic parameters were calculated by non-compartmental analysis using Phoenix WinNonlin 7.0.  Plasma clearance of dexmedetomidine was decreased by 33.3% in the obstructive jaundice group as compared with the control group (0.0068±0.0017 vs. 0.0102±0.0033 L/kg/min; P = 0.002). Volume of distribution was decreased by 29.2% in the obstructive jaundice group as compared with the control group (1.43±0.58 vs. 2.02±0.84 L/kg; P = 0.041).  This study demonstrates that the clearance and distribution volume of dexmedetomidine were decreased in patients with obstructive jaundice. It may be advisable to adjust the dose of dexmedetomidine in those patients.

title: Influence of cardiac output on dexmedetomidine pharmacokinetics.
abstract: Dexmedetomidine, a highly selective alpha(2)-adrenoceptor agonist, reduces the requirements for anesthetic, analgesic, sedative, and hypnotic drugs. Dexmedetomidine pharmacokinetics were characterized in healthy subjects after intravenous administration by means of a computer-controlled infusion pump. A series of seven stepwise increasing pseudo-steady-state plasma concentrations were targeted. The influence of cardiac output on the pharmacokinetics was investigated by use of a compartmental modeling approach in which the elimination clearance was characterized as being either cardiac output independent or dependent. At dexmedetomidine concentrations of 0, 0.6, and 1.2 ng/mL, mean (SD) estimated cardiac outputs were 5. 6 (0.85), 5.1 (0.67), and 4.5 (0.83) L/min, and mean (SD) clearances were 40 (10), 38 (9.0), and 35 (8.5) L/h, respectively. Dexmedetomidine V(SS) and elimination half-life were 72 (19) L and 1. 9 (0.62) h, respectively. The approximately 3 to 19% decrease in cardiac output observed within the anticipated therapeutic range of 0.3 to 1.2 ng/mL was similar to that observed for clonidine. The decrease in cardiac output with increasing plasma concentrations of dexmedetomidine resulted in a corresponding decrease in drug elimination clearance of < or =12% within the therapeutic range; however, this decrease in dexmedetomidine clearance is likely not clinically relevant.

title: Population pharmacokinetics of dexmedetomidine during long-term sedation in intensive care patients.
abstract: Dexmedetomidine is a highly selective and potent α(2)-adrenoceptor agonist registered for sedation of patients in intensive care units. There is little information on factors possibly affecting its pharmacokinetics during long drug infusions in critically ill patients. We characterized the pharmacokinetics of dexmedetomidine in critically ill patients during long-term sedation using a population pharmacokinetic approach.



Twenty-one intensive care patients requiring sedation and mechanical ventilation received dexmedetomidine with a loading dose of 3-6 µg kg(-1) h(-1) in 10 min and a maintenance dose of 0.1-2.5 µg kg(-1) h(-1) for a median duration of 96 h (range, 20-571 h). Cardiac output (CO), laboratory and respiratory parameters, and dexmedetomidine concentrations in arterial plasma were measured. The pharmacokinetics was determined by population analysis using linear multicompartment models.



The pharmacokinetics of dexmedetomidine was best described by a two-compartment model. The population values (95% confidence interval) for elimination clearance, inter-compartmental clearance, central volume of distribution, and volume of distribution at steady state were 57.0 (42.1, 65.6), 183 (157, 212) litre h(-1), 12.3 (7.6, 17.0), and 132 (96, 189) litre. Dexmedetomidine clearance decreased with decreasing CO and with increasing age, whereas its volume of distribution at steady state was increased in patients with low plasma albumin concentration.



The population pharmacokinetics of dexmedetomidine was generally in line with results from previous studies. In elderly patients and in patients with hypoalbuminaemia, the elimination half-life and the context-sensitive half-time of dexmedetomidine were prolonged.

title: Bioavailability of dexmedetomidine after extravascular doses in healthy subjects.
abstract: To determine the absolute bioavailability of extravascularly administered dexmedetomidine, a novel a2-adrenoceptor agonist, in healthy subjects.



Single 2 microg x kg-1 doses of dexmedetomidine were given intravenously, intramuscularly, perorally and buccally (where the solution is not swallowed) to 12 healthy male subjects. The drug concentration-time data were analysed using linear one-compartment (buccal and peroral data), or two-compartment modelling (intravenous data), or noncompartmental methods (intramuscular data).



Mean (95% CI) absolute bioavailability after peroral, buccal and intramuscular administration was 16% (12-20%), 82% (73-92%) and 104% (96-112%), respectively.



Dexmedetomidine is well absorbed systemically through the oral mucosa, and therefore buccal dosing may provide an effective, noninvasive route to administer the drug.

title: Bioavailability of dexmedetomidine after intranasal administration
abstract: PurposeThe aim of this proof-of-concept study was to characterize the pharmacokinetics and pharmacodynamics of intranasal dexmedetomidine compared with its intravenous administration in a small number of healthy volunteers.MethodsSingle doses of 84 μg of dexmedetomidine were given once intravenously and once intranasally to seven healthy men. Plasma dexmedetomidine concentrations were measured for 10 h, and pharmacokinetic variables were calculated with standard noncompartmental methods. Heart rate, blood pressure, concentrations of adrenaline and noradrenaline in plasma, and central nervous system drug effects (with the Maddox wing, Bispectral Index, and three visual analog scales) were monitored to assess the pharmacological effects of dexmedetomidine.ResultsSix individuals were included in the analyses. Following intranasal administration, peak plasma concentrations of dexmedetomidine were reached in 38 (15–60) min and its absolute bioavailability was 65% (35–93%) (medians and ranges). Pharmacological effects were similar with both routes of administration, but their onset was more rapid after intravenous administration.ConclusionsDexmedetomidine is rather rapidly and efficiently absorbed after intranasal administration. Compared with intravenous administration, intranasal administration may be a feasible alternative in patients requiring light sedation.

title: Mechanism-based population pharmacokinetic and pharmacodynamic modeling of intravenous and intranasal dexmedetomidine in healthy subjects
abstract: PurposeDexmedetomidine is an α2-adrenoceptor agonist used for perioperative and intensive care sedation. This study develops mechanism-based population pharmacokinetic-pharmacodynamic models for the cardiovascular and central nervous system (CNS) effects of intravenously (IV) and intranasally (IN) administered dexmedetomidine in healthy subjects.MethodSingle doses of 84 μg of dexmedetomidine were given once IV and once IN to six healthy men. Plasma dexmedetomidine concentrations were measured for 10 h along with plasma concentrations of norepinephrine (NE) and epinephrine (E). Blood pressure, heart rate, and CNS drug effects (three visual analog scales and bispectral index) were monitored to assess the pharmacological effects of dexmedetomidine. PK-PD modeling was performed for recently published data ( 825, 2011).ResultsPharmacokinetic profiles for both IV and IN doses of dexmedetomidine were well fitted using a two-compartment PK model. Intranasal bioavailability was 82 %. Dexmedetomidine inhibited the release of NE and E to induce their decline in blood. This decrease in NE was captured with an indirect response model. The concentrations of the mediator NE served via a biophase/transduction step and nonlinear pharmacologic functions to produce reductions in blood pressure and heart rate, while a direct effect model was used for the CNS effects.ConclusionThe comprehensive panel of two biomarkers and seven response measures were well captured by the population PK/PD models. The subjects were more sensitive to the CNS (lower EC50 values) than cardiovascular effects of dexmedetomidine.

title: The Pharmacokinetics and Hemodynamic Effects of Intravenous and Intramuscular Dexmedetomidine Hydrochloride in Adult Human Volunteers
abstract: Dexmedetomidine is an α2 agonist with potential utility in clinical anesthesia for both its sedative and sympatholytic properties. The pharmacokinetics and hemodynamic changes that occurred in ten healthy male volunteers were determined after administration of dexmedetomidine 2 µg/kg by intravenous or intramuscular route in separate study sessions. The intramuscular absorption profile of dexmedetomidine, as determined by deconvolution of the observed concentrations against the unit disposition function derived from the intravenous data, was biphasic. The percentage bioavailability of dexmedetomidine administered intramuscularly compared with the same dose administered intravenously was 73 ± 11% (mean ± SD). After Intramuscular administration, the mean time to peak concentration was 12 min (range 2-60 min) and the mean peak concentration was 0.81 ± 0.27 ng/ml. After intravenous administration of dexmedetomidine, there were biphasic changes in blood pressure. During the 5-min intravenous infusion of 2 μg/kg dexmedetomidine, the mean arterial pressure (MAP) increased by 22% and heart rate (HR) declined by 27% from baseline values. Over the 4 h after the infusion, MAP declined by 20% from baseline and HR rose to 5% below baseline values. The hemodynamic profile did not show acute alterations after intramuscular administration. During the 4 h after intramuscular administration, MAP declined by 20% and HR declined by 10% The intramuscular administration of dexmedetomidine avoids the acute hemodynamic changes seen with intravenous administration, but results in similar hemodynamic alterations within 4 h.

title: Effects of dexmedetomidine on isoflurane requirements in healthy volunteers. 1: Pharmacodynamic and pharmacokinetic interactions.
abstract: Dexmedetomidine is a highly selective alpha 2-adrenoceptor agonist with anaesthetic-sparing effects. We have determined the pharmacodynamic and pharmacokinetic interactions between dexmedetomidine and isoflurane in volunteers. Nine male subjects were allocated randomly to receive isoflurane anaesthesia preceded by infusion of dexmedetomidine on three separate occasions, 2 weeks apart. Dexmedetomidine target plasma concentrations were 0.0 (placebo), 0.3 ng ml-1 (low-dex) and 0.6 ng ml-1 (high-dex). End-tidal isoflurane concentrations at which gross purposeful movement and response to verbal commands occurred were identified. In the recovery period, sedation scores and digit symbol substitution tests were recorded. Venous blood samples were obtained before, during and after anaesthesia at predetermined intervals for measurement of plasma concentrations of dexmedetomidine and calculation of standard pharmacokinetic indices (AUC, Cl, Vss, T1/2 alpha, T1/2 beta). The end-tidal isoflurane concentration at which 50% of subjects first responded to the tetanic stimulus was 1.05% in the placebo group, 0.72% in the low-dex group and 0.52% in the high-dex group. We conclude that dexmedetomidine decreased isoflurane requirements in a dose-dependent manner and reduced heart rate, systolic and diastolic arterial pressures. Sedation and slight impairment of cognitive function persisted for several hours after anaesthesia and the end of infusion of dexmedetomidine. Isoflurane did not appear to influence the pharmacokinetics of dexmedetomidine.

title: Determinants of gentamicin concentrations in critically ill patients: a population pharmacokinetic analysis.
abstract: When treating critically ill patients with gentamicin for severe infection, peak concentrations (Cmax) determine clinical efficacy and trough concentrations (Cmin) determine toxicity. Despite administration of body weight-standardised starting doses, a wide range of Cmax is generally observed. Furthermore, in therapeutic drug monitoring, several measures of renal function are used to predict appropriate Cmin and gentamicin dosing intervals, but the most accurate predictor is not known. This study aimed to quantify the impact of several patient parameters on gentamicin Cmax values and to determine which measure of renal function best predicts gentamicin clearance (CL). Clinical data and serum gentamicin levels were retrospectively collected from all critically ill patients treated with gentamicin at our intensive care unit between 1 January and 30 June 2011. Data were analysed using non-linear mixed-effects modelling (NONMEM v.7.1.2). A two-compartmental model was developed based on 303 gentamicin concentration-time data from 44 critically ill patients. Serum albumin levels explained 25% of interindividual variability in the volume of distribution (Vd). Creatinine clearance calculated from the creatinine concentration in a 6-h urine portion (CalcCLCr) resulted in acceptable estimation of gentamicin CL, whilst serum creatinine (SCr) and creatinine clearance estimated by the Cockcroft-Gault formula (CGCLCr) overestimated gentamicin CL and therefore underestimated Cmin. In conclusion, low albumin concentrations resulted in a larger Vd and lower Cmax of gentamicin. These results suggest that use of a higher gentamicin starting dose in critically ill patients with hypoalbuminaemia may prevent underdosing. Urinary CalcCLCr is a better predictor of Cmin than SCr or CGCLCr.

title: Dexmedetomidine: Clinical update
abstract: Dex is a sedative agent that acts via a unique alpha-2 agonist mechanism. It produces sedation while frequently preserving the ability of the patient to interact with other individuals such as caregivers or family. Other properties of Dex including respiratory stability, sympatholysis, and analgesia make it an important new drug for patients requiring sedation in the critical care setting. Although only minimally explored at this time, additional areas of potential use may include amelioration of opioid, alcohol, and sedative withdrawal syndromes, use for sedation in settings outside the critical care unit, and use in pediatric intensive care 93–96 . The primary known risks of Dex are extensions of its alpha-2 agonist mechanism: hypotension and bradycardia. Both are readily manageable with fluid administration and atropine. At higher plasma concentrations that may occur during loading of the drug, hypertension may be briefly seen. Sympatholytic effects of Dex may be particularly useful for hypertensive or tachycardic patients who require sedation. In hemodynamically marginal or unstable patients, however, the potential for significant hypotension should be considered. A careful consideration of volume status and potential conduction abnormalities is necessary before starting the drug in any patient. Sedation in the ICU is often administered for days to weeks. Presently, the safety of Dex has only been documented for infusions up to 24 hours due to a lack of controlled studies extending beyond this time frame. As a result, the agent is approved only for 38,39 Unanswered questions include the potential for tolerance and withdrawal, accumulation of parent drug and/or metabolites, and potential changes in the pharmacokinetic profile of long term infusions of Dex. Although Dex already represents a significant addition to the arsenal of ICU sedatives, further work is necessary to identify patient groups most likely to benefit.

title: CYP2A6 genetic variation and dexmedetomidine disposition
abstract: PurposeThere is a large interindividual variability in dexmedetomidine dose requirements for sedation of patients in intensive care units (ICU). Cytochrome P450 2A6 (CYP2A6) mediates an important route of dexmedetomidine metabolism, and genetic variation in CYP2A6 affects the clearance of other substrate drugs. We examined whether CYP2A6 genotypes affect dexmedetomidine disposition.MethodsIn 43 critically ill ICU patients receiving dexmedetomidine infusions adjusted to achieve the desired level of sedation, we determined a median of five plasma dexmedetomidine concentrations each. Forty subjects were genotyped for five common CYP2A6 alleles and grouped into normal (n = 33), intermediate (n = 5), and slow metabolizers (n = 2).ResultsUsing a Bayesian hierarchical nonlinear mixture model, estimated dexmedetomidine clearance was 49.1 L/h (posterior mean; 95% credible interval 41.4–57.6 L/h). There were no significant differences in dexmedetomidine clearance among normal, intermediate, and slow CYP2A6 metabolizer groups.ConclusionGenetic variation in CYP2A6 does not appear to be an important determinant of dexmedetomidine clearance in ICU patients.

title: Pharmacokinetics of dexmedetomidine infusions for sedation of postoperative patients requiring intensive caret.
abstract: The pharmacokinetics of the alpha-2 adrenoceptor agonist dexmedetomidine were studied in 10 patients requiring postoperative sedation and mechanical ventilation in the intensive care unit (ICU), and compared with previous volunteer data.



On arrival in the ICU, sedation with dexmedetomidine was commenced with a loading dose of 2.5 microg kg(-1) h(-1) over 10 min followed by a maintenance infusion of 0.7 microg kg(-1) h(-1) into a central vein. Blood samples for measurement of plasma dexmedetomidine concentrations were taken during and after sedative infusions at predetermined intervals. Pharmacokinetic variables were estimated using non-compartmental methods. In addition, non-linear mixed effects modelling was used to obtain variable estimates not readily attainable from non-compartmental methods. Respiratory and haemodynamic data were recorded to enable correlation of any adverse events with the calculated pharmacokinetic profile.



The harmonic mean distribution half-life of dexmedetomidine was 8.6 min and the harmonic mean terminal half-life was 3.14 h. Steady-state volume of distribution averaged 173 litres, clearance averaged 48.3 litres h(-1), and the mean residence time averaged 3.86 h.



Mean dexmedetomidine pharmacokinetic variables seen in postoperative, intensive care patients were similar to those previously found in volunteers, with the exception of the steady-state volume of distribution. A small loading dose provided effective sedation with no adverse events.

title: Effects of mild hypoalbuminemia on the pharmacokinetics and pharmacodynamics of dexmedetomidine in patients after major abdominal or thoracic surgery.
abstract: To explore the effects of mild hypoalbuminemia on pharmacokinetics and pharmacodynamics of dexmedetomidine in patients after major abdominal or thoracic surgery.



A prospective cohort study.



University-affiliated teaching hospital.



The study was performed in 30 consecutive patients undergoing major abdominal or thoracic surgery. They were aged 18 to 65 years and graded as American Society of Anesthesiologists physical status I and II. All patients were scheduled to require more than 6 hours of postoperative sedation and mechanical ventilation. Nine of the patients had low plasma albumin levels (<35 g/L but >24 g/L; male/female, 6/3) after the operation, who were assigned to hypoalbuminemia group, and the remainder with normoalbuminemia (>35 g/L; male/female, 15/6) were assigned to normoalbuminemia group.



All patients were administered a loading dose of dexmedetomidine 1.0 μg/kg infused over 10 minutes after admitted into intensive care unit and a maintenance dose of 0.4 μg/kg per hour followed for 6 hours.



Plasma dexmedetomidine levels were determined by high performance liquid chromatography - mass spectrum. Sedation was evaluated using Ramsay sedation score. Heart rate and arterial pressures were monitored. Adverse events were recorded.



Compared with patients with normoalbuminemia, maximum plasma concentration of dexmedetomidine decreased by 21.2% in patients with hypoalbuminemia (P < .01). Its volume of distribution at steady state increased by 40.5%; elimination half-life decreased by 33.5% (P < .01). However, heart rates, arterial pressures, and Ramsay sedation scores did not differ significantly between the 2 groups. No serious adverse events occurred in either the patients with hypoalbuminemia or normoalbuminemia.



Sedation and adverse reactions of dexmedetomidine infusion did not differ significantly between patients with mild hypoalbuminemia and normoalbuminemia, although its volume of distribution at steady state increased and elimination half-life shortened in patients with hypoalbuminemia. This suggests that dexmedetomidine infusion can safely be used in mild hypoalbuminemia patients after major abdominal or thoracic surgery.

title: Pharmacokinetics and interaction pharmacodynamics of dexmedetomidine in humans
abstract: Dexmedetomidine is a potent and highly selective α 2 -adrenoceptor agonist with a selectivity ratio of 1600:1 (α 2 :α 1 ). Dexmedetomidine is a highly lipophylic agent that is rapidly distributed to tissues with a distribution half-life (t 1/2α ) of approximately 6 minutes. It is extensively distributed and rapidly eliminated, with a mean elimination half-life (t 1/2 ) of 2–2.5 hours. This rapid distribution and short elimination kinetics makes dexmedetomidine amenable to frequent titration allowing adjustability of dosage and effects. Generally, dexmedetomidine does not exhibit pharmacokinetic-based interactions; however, dosage modifications of some concomitant medications may be needed to be adjusted due primarily to common pharmacological actions of the two drugs. Dexmedetomidine is eliminated by metabolism to inactive metabolites, primarily glucuronides. Eighty to ninety percent of an administered dose is excreted in the urine and 5%–13% in the faeces.

title: Ethnic and Genetic Determinants of Cardiovascular Response to the Selective &agr;2-Adrenoceptor Agonist Dexmedetomidine
abstract: The &agr;2-adrenoceptor agonist clonidine reduces blood pressure more effectively in White than Black Americans despite similar degrees of sympatholysis. Functional genetic variation in receptor signaling mechanisms, for example in the &bgr;3 G-protein subunit (GNB3 C825T) and in the &agr;2C-adrenoceptor subtype (ADRA2C del322–325), may affect drug responses. We examined the hypothesis that there are ethnic differences in the responses to the highly selective &agr;2-agonist, dexmedetomidine, and that these genetic variants contribute to interindividual variability in drug responses. In a placebo-controlled, single-masked study, 73 healthy subjects (37 whites and 36 blacks) received 3 placebo infusions and then 3 incremental doses of dexmedetomidine (cumulative dose, 0.4 &mgr;g/kg), each separated by 30 minutes. Blood pressure, heart rate, and plasma catecholamine concentrations were determined after each infusion. We measured dexmedetomidine concentrations after the last infusion and determined ADRA2C del322–325 and GNB3 C825T genotypes. Dexmedetomidine lowered blood pressure and plasma catecholamine concentrations significantly (all P<0.001). There was substantial interindividual variability in the reduction of systolic blood pressure (range, 1 to 34 mm Hg) and plasma norepinephrine concentrations (range, 24 to 424 pg/mL). However, there were no differences between black and white subjects in dexmedetomidine responses (P>0.16 for all outcomes) before or after adjustment for covariates. Neither ADRA2C del322–325 nor GNB3 C825T genotypes affected the responses to dexmedetomidine (all P>0.66). There is large interindividual variability in response to the selective &agr;2-AR agonist dexmedetomidine, and neither ethnicity nor ADRA2C and GNB3 genotypes contribute to it. Further studies to identify determinants of &agr;2-AR–mediated responses will be of interest.

title: Dexmedetomidine pharmacokinetics in the obese
abstract: PurposeThis study aims to characterize the influence of body weight and composition on the pharmacokinetics of dexmedetomidine.MethodsTwenty obese patients and 20 non-obese patients scheduled for elective laparoscopic surgery were given dexmedetomidine infusion schemes. Venous blood samples were taken during and after dexmedetomidine administration. Population pharmacokinetic modeling was undertaken to investigate fat free mass (FFM) and normal fat mass (NFM) as size descriptors of volumes and clearances using non-linear mixed effects modeling. NFM partitions total body weight into FFM and fat mass calculated from total body weight (TBW) minus FFM. The relative influence of fat mass compared to FFM is described by the fraction of fat mass that makes fat equivalent to FFM (Ffat).ResultsTheory-based allometric scaling using FFM best described weight and body composition differences in clearances and volumes A negative effect of fat mass of with an exponential parameter of −0.00541/kg (95 % CI −0.0118 to −0.00246) was estimated for clearance which indicates increased fat mass is associated with impairment of clearance.ConclusionsThe use of theory-based allometry with predictions of fat free mass has been able to separate the influences of weight and body composition and indicates that size-normalized clearance of dexmedetomidine is impaired in patients who are obese.

title: Pharmacokinetics of dexmedetomidine in Chinese post‐surgical intensive care unit patients
abstract: Dexmedetomidine is a rather new drug in China. We sought to describe the pharmacokinetics of dexmedetomidine in patients requiring post‐operative sedation and ventilation in our surgical intensive care unit.

title: Development of an Optimized Pharmacokinetic Model of Dexmedetomidine Using Target-controlled Infusion in Healthy Volunteers
abstract: Several pharmacokinetic models are available for dexmedetomidine, but these have been shown to underestimate plasma concentrations. Most were developed with data from patients during the postoperative phase and/or in intensive care, making them susceptible to errors due to drug interactions. The aim of this study is to improve on existing models using data from healthy volunteers. After local ethics committee approval, the authors recruited 18 volunteers, who received a dexmedetomidine target-controlled infusion with increasing target concentrations: 1, 2, 3, 4, 6, and 8 ng/ml, repeated in two sessions, at least 1 week apart. Each level was maintained for 30 min. If one of the predefined safety criteria was breached, the infusion was terminated and the recovery period began. Arterial blood samples were collected at preset times, and NONMEM (Icon plc, Ireland) was used for model development. The age, weight, and body mass index ranges of the 18 volunteers (9 male and 9 female) were 20 to 70 yr, 51 to 110 kg, and 20.6 to 29.3 kg/m2, respectively. A three-compartment allometric model was developed, with the following estimated parameters for an individual of 70 kg: V1 = 1.78 l, V2 = 30.3 l, V3 = 52.0 l, CL = 0.686 l/min, Q2 = 2.98 l/min, and Q3 = 0.602 l/min. The predictive performance as calculated by the median absolute performance error and median performance error was better than that of existing models. Using target-controlled infusion in healthy volunteers, the pharmacokinetics of dexmedetomidine were best described by a three-compartment allometric model. Apart from weight, no other covariates were identified.

title: Clinical Pharmacokinetics and Pharmacodynamics of Dexmedetomidine
abstract: Dexmedetomidine is an α2-adrenoceptor agonist with sedative, anxiolytic, sympatholytic, and analgesic-sparing effects, and minimal depression of respiratory function. It is potent and highly selective for α2-receptors with an α2:α1 ratio of 1620:1. Hemodynamic effects, which include transient hypertension, bradycardia, and hypotension, result from the drug’s peripheral vasoconstrictive and sympatholytic properties. Dexmedetomidine exerts its hypnotic action through activation of central pre- and postsynaptic α2-receptors in the locus coeruleus, thereby inducting a state of unconsciousness similar to natural sleep, with the unique aspect that patients remain easily rousable and cooperative. Dexmedetomidine is rapidly distributed and is mainly hepatically metabolized into inactive metabolites by glucuronidation and hydroxylation. A high inter-individual variability in dexmedetomidine pharmacokinetics has been described, especially in the intensive care unit population. In recent years, multiple pharmacokinetic non-compartmental analyses as well as population pharmacokinetic studies have been performed. Body size, hepatic impairment, and presumably plasma albumin and cardiac output have a significant impact on dexmedetomidine pharmacokinetics. Results regarding other covariates remain inconclusive and warrant further research. Although initially approved for intravenous use for up to 24 h in the adult intensive care unit population only, applications of dexmedetomidine in clinical practice have been widened over the past few years. Procedural sedation with dexmedetomidine was additionally approved by the US Food and Drug Administration in 2003 and dexmedetomidine has appeared useful in multiple off-label applications such as pediatric sedation, intranasal or buccal administration, and use as an adjuvant to local analgesia techniques.

title: Pharmacokinetics and pharmacodynamics of intravenous dexmedetomidine in healthy Korean subjects
abstract: What is known and Dexmedetomidine is a selective alpha2‐adrenoreceptor agonist used for sedation in critically ill patients. The current study aimed to evaluate the pharmacokinetics (PKs), pharmacodynamics and tolerability of intravenous dexmedetomidine in healthy Korean subjects.

title: Population pharmacokinetics study of dexmedetomidine in Chinese adult patients during spinal anesthesia.
abstract: The objectives of this study were to construct a population pharmacokinetics model for dexmedetomidine used in Chinese adult patients with spinal anesthesia and to identify the key factors affecting the pharmacokinetics of dexmedetomidine.



A total of 34 subjects (elderly group: n = 15; young group: n = 19) undergoing spinal anesthesia received dexmedetomidine with a loading dose of 0.5 μg×kg(-1) for 10 minutes, followed by a maintenance dose of 0.5 μg×kg-1×h(-1) for 50 minutes. Blood samples were collected until 10 hours after dosing. Laboratory and respiratory parameters, and dexmedetomidine concentrations were measured. A population pharmacokinetic model for dexmedetomidine was constructed using a nonlinear mixed effects model (NONMEM).



Pharmacokinetics of dexmedetomidine can be described by a three-compartment model. The respective typical values for clearance (CL), V1, V2, Q2, Q3, and V3 were 0.883 L×min(-1), 17.6 L, 51.5 L, 2.37 L×min(-1), 0.517 L×min(-1), and 44.00 L. Alanine aminotransferase (ALT), age, and body weight were key factors affecting CL, V1, and V2, respectively.



A three-compartment model can be used to describe the pharmacokinetics processing of dexmedetomidine for Chinese adult patients during spinal anesthesia. The population pharmacokinetic of dexmedetomidine was generally in line with results from previous studies.

title: Dexmedetomidine metabolic clearance is not affected by fat mass in obese patients
abstract: Obesity has been associated with reduced dexmedetomidine clearance, suggesting impaired hepatic function or reduced hepatic blood flow. The aim of this study was to clarify the effect of obesity in dexmedetomidine metabolic clearance.  Forty patients, ASA I–III, 18–60 yr old, weighing 47–126 kg, scheduled for abdominal laparoscopic surgery, were enrolled. Anaesthetic agents (propofol, remifentanil, and dexmedetomidine) were dosed based on lean body weight measured by dual X‐ray absorptiometry. Serial venous samples were drawn during and after dexmedetomidine infusion. A pharmacokinetic analysis was undertaken using non‐linear mixed‐effect models. In the modelling approach, the total body weight, lean body weight, and adjusted body weight were first tested as size descriptors for volumes and clearances. Hepatic blood flow, liver histopathology, liver enzymes, and gene expression of metabolic enzymes (UGT2B10 and UGT1A4) were tested as covariates of dexmedetomidine metabolic clearance. A decrease in NONMEM objective function value (&Dgr;OFV) of 3.84 points, for an added parameter, was considered significant at the 0.05 level.  A total of 637 dexmedetomidine serum samples were obtained. A two‐compartmental model scaled to measured lean weight adequately described the dexmedetomidine pharmacokinetics. Liver blood flow was a covariate for dexmedetomidine clearance (&Dgr;OFV=–5.878). Other factors, including fat mass, histopathological damage, and differential expression of enzymes, did not affect the dexmedetomidine clearance in the population studied (&Dgr;OFV<3.84).  We did not find a negative influence of obesity in dexmedetomidine clearance when doses were adjusted to lean body weight. Liver blood flow showed a significant effect on dexmedetomidine clearance.

title: Dexmedetomidine: review, update, and future considerations of paediatric perioperative and periprocedural applications and limitations.
abstract: Despite lack of paediatric labelling, contributions to the literature on paediatric applications of dexmedetomidine have increased over recent years. Dexmedetomidine possesses many properties that are advantageous for a sedative and anaesthetic; it has been reported to provide sedation that parallels natural sleep, anxiolysis, analgesia, sympatholysis, and an anaesthetic-sparing effect with minimal respiratory depression. In addition, there is increasing evidence supporting its organ-protective effects against ischaemic and hypoxic injury. These favourable physiological effects combined with a limited adverse effect profile make dexmedetomidine an attractive adjunct to anaesthesia (general and regional) for a variety of procedures in paediatric operating rooms. A comprehensive understanding of the pharmacological, pharmacokinetic, and pharmacodynamic effects of dexmedetomidine is critical to maximize its safe, efficacious, and efficient paediatric perioperative applications. This review focuses on the current paediatric perioperative and periprocedural applications of dexmedetomidine and its limitations, with a consideration for the future.

title: Dexmedetomidine pharmacokinetics in pediatric intensive care – a pooled analysis
abstract: Published dexmedetomidine pharmacokinetic studies in children are limited by participant numbers and restricted pathology. Pooling the available studies allows investigation of covariate effects.

title: Population Pharmacokinetics of Dexmedetomidine in Infants After Open Heart Surgery
abstract: Dexmedetomidine is a highly selective &agr;2-agonist with hypnotic, analgesic, and anxiolytic properties. In adults, it provides sedation while preserving respiratory function facilitating extubation. Only limited pharmacokinetic data are available for pediatric patients. The primary aim of this study was to determine the pharmacokinetics of dexmedetomidine in infants after open heart surgery.  We evaluated 36 infants, aged 1 to 24 months, after open heart surgery. Cohorts of 12 infants requiring mechanical ventilation after open heart surgery were enrolled sequentially to 1 of the 3 initial loading dose—continuous IV infusion (CIVI) regimens: 0.35–0.25, 0.7–0.5, or 1–0.75 &mgr;g/kg-&mgr;g/kg/h. The initial loading dose was administered over 10 minutes immediately postoperatively followed by a CIVI of up to 24 hours. Plasma dexmedetomidine concentrations were determined using a validated high-performance liquid chromatography tandem mass spectrometry assay. A population nonlinear mixed effects modeling approach was used to characterize dexmedetomidine pharmacokinetics.  Pharmacokinetic parameters of dexmedetomidine were estimated using a 2-compartment disposition model with weight on drug clearance, intercompartmental clearance, central and peripheral volume of distributions, total bypass time as a covariate on clearance and central volume of distribution, and age and ventricular physiology as covariates on clearance. Infants demonstrated a clearance of 28.1 mL/min/kg0.75, intercompartmental clearance of 93.4 mL/min/kg0.75, central volume of distribution of 1.2 L/kg, and peripheral volume of distribution of 1.5 L/kg.  Dexmedetomidine clearance increased with weight, age, and single-ventricle physiology, whereas total bypass time was associated with a trend toward decreasing clearance, and central volume of distribution increased as a function of total bypass time. The dependence of clearance on body weight supports current practice of weight-based dexmedetomidine dosing, whereas the clinical impact of the remaining covariate effects requires further investigation. Initial loading doses in the range of 0.35 to 1 &mgr;g/kg over 10 minutes and CIVI of 0.25 to 0.75 &mgr;g/kg/h were well tolerated in this infant population.

title: The pharmacokinetics of dexmedetomidine during long-term infusion in critically ill pediatric patients. A Bayesian approach with informative priors
abstract: The purpose of this study was to assess the pharmacokinetics of dexmedetomidine in the ICU settings during the prolonged infusion and to compare it with the existing literature data using the Bayesian population modeling with literature-based informative priors. Thirty-eight patients were included in the analysis with concentration measurements obtained at two occasions: first from 0 to 24 h after infusion initiation and second from 0 to 8 h after infusion end. Data analysis was conducted using WinBUGS software. The prior information on dexmedetomidine pharmacokinetics was elicited from the literature study pooling results from a relatively large group of 95 children. A two compartment PK model, with allometrically scaled parameters, maturation of clearance and t-student residual distribution on a log-scale was used to describe the data. The incorporation of time-dependent (different between two occasions) PK parameters improved the model. It was observed that volume of distribution is 1.5-fold higher during the second occasion. There was also an evidence of increased (1.3-fold) clearance for the second occasion with posterior probability equal to 62 %. This work demonstrated the usefulness of Bayesian modeling with informative priors in analyzing pharmacokinetic data and comparing it with existing literature knowledge.

title: Population Pharmacokinetics of Dexmedetomidine After Short Intravenous Infusion in Chinese Children
abstract: Background and ObjectiveDexmedetomidine is a highly selective alpha2-adrenoceptor agonist with sedative and analgesic properties which is also used in pediatric anesthesia. Although the pharmacokinetics of dexmedetomidine have been studied in pediatric patients, there are no data for Chinese children available. As alterations in pharmacokinetics due to ethnicity cannot be ruled out, it was the aim of this study to characterize the pharmacokinetics of dexmedetomidine in Chinese pediatric patients.MethodsThirty-nine children aged 1–9 years undergoing surgery were enrolled in the study. Dexmedetomidine was administered as short intravenous infusion of 1–2 µg/kg in 10 min. Venous blood samples were drawn until 480 min after stopping of infusion. Dexmedetomidine plasma concentrations were measured with high-performance liquid chromatography and mass spectrometry. Pharmacokinetic modeling was performed by population analysis using linear compartment models.ResultsData of 36 patients (age 1–9 years, weight 10–27 kg) were analyzed. The pharmacokinetics of dexmedetomidine were best described by a two-compartment model with an allometric power model and estimates standardized to 70 kg body weight. The population estimates (95 % CI) per 70 kg bodyweight were: clearance 36.2 (33.3–41.1) l/h, central volume of distribution 84.3 (70.3–91.4) l, intercompartmental clearance 82.8 (63.6–136.6) l/h, peripheral volume of distribution 114 (95–149) l, and terminal half-life 4.4 (3.6–5.3) h. Age did not show any influence on weight-adjusted parameters.ConclusionsChinese children showed a similar clearance, but larger volumes of distribution and longer terminal half-life when compared to studies in Caucasians.

title: Clonidine‐induced nitric oxide‐dependent vasorelaxation mediated by endothelial α2‐adrenoceptor activation
abstract: To assess the involvement of endothelial α2‐adrenoceptors in the clonidine‐induced vasodilatation, the mesenteric artery of Sprague Dawley rats was cannulated and perfused with Tyrode solution (2 ml min−1). We measured perfusion pressure, nitric oxide (NO) in the perfusate using chemiluminescence, and tissue cyclic GMP by RIA. In phenylephrine‐precontracted mesenteries, clonidine elicited concentration‐dependent vasodilatations associated to a rise in luminal NO. One hundred nM rauwolscine or 100 μM Lω‐nitro‐L‐arginine antagonized the clonidine‐induced vasodilatation. Guanabenz, guanfacine, and oxymetazoline mimicked the clonidine‐induced vasorelaxation. In non‐contracted mesenteries, 100 nM clonidine elicited a maximal rise of NO (123±13 pmol); associated to a peak in tissue cyclic GMP. Endothelium removal, Lω‐nitro‐L‐arginine, or rauwolscine ablated the rise in NO. One hundred nM aminoclonidine, guanfacine, guanabenz, UK14,304 and oxymetazoline mimicked the clonidine‐induced surge of NO. Ten μM ODQ obliterated the clonidine‐induced vasorelaxation and the associated tissue cyclic GMP accumulation; 10 – 100 nM sildenafil increased tissue cyclic GMP accumulation without altering the clonidine‐induced NO release. α2‐Adrenergic blockers antagonized the clonidine‐induced rise in NO. Consistent with a preferential α2D‐adrenoceptor activation, the KBs for yohimbine, rauwolscine, phentolamine, WB‐4101, and prazosin were: 6.8, 24, 19, 165, and 1489 nM, respectively. Rat pretreatment with 100 mg kg−1 6‐hydroxydopamine reduced 95% tissue noradrenaline and 60% neuropeptide Y. In these preparations, 100 nM clonidine elicited a rise of 91.9±15.5 pmol NO. Perfusion with 1 μM guanethidine or 1 μM guanethidine plus 1 μM atropine did not modify the NO surge evoked by 100 nM clonidine. Clonidine and congeners activate endothelial α2D‐adrenoceptors coupled to the L‐arginine pathway, suggesting that the antihypertensive action of clonidine involves an endothelial vasorelaxation mediated by NO release, in addition to presynaptic mechanisms.

title: Effects of Low and High Plasma Concentrations of Dexmedetomidine on Myocardial Perfusion and Cardiac Function in Healthy Male Subjects
abstract: Dexmedetomidine, a selective &agr;2-adrenoceptor agonist, has counteracting effects on the cardiovascular system. It mediates sympatholysis by activating &agr;2 adrenoceptors in the central and peripheral nervous system, and vasoconstriction and vasorelaxation by activating postsynaptic &agr;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. 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.

title: The effects of intra‐operative dexmedetomidine on postoperative pain, side‐effects and recovery in colorectal surgery
abstract: In this double‐blind, randomised study, 100 patients undergoing open or conventional laparoscopic colorectal surgery received an intra‐operative loading dose of dexmedetomidine 1 μg.kg−1 followed by an infusion of 0.5 μg.kg−1.h−1, or a bolus and infusion of saline 0.9% of equivalent volume. Forty‐six patients in the dexmedetomidine group and 50 in the saline group completed the study. The area under the curve of numerical rating scores for pain at rest for 1–48 h postoperatively was significantly lower in the patients receiving dexmedetomidine (p = 0.041). There was no difference in morphine consumption, duration of recovery ward or hospital stay. From the data obtained in this study, we calculated a number needed to treat for effective pain relief of 4. Intra‐operative dexmedetomidine in colorectal surgery resulted in a reduction in resting pain scores, but there was no morphine‐sparing effect or improvement in patients' recovery outcome measures.

title: Rapid reversal of alpha 2-adrenoceptor agonist effects by atipamezole in human volunteers.
abstract: 1. The ability of atipamezole, a specific and selective alpha 2-adrenoceptor antagonist, to reverse the pharmacological effects induced by the alpha 2-adrenoceptor agonist dexmedetomidine was studied in six healthy male volunteers. Each volunteer received in four sessions in a randomized and single-blind manner three different doses (6.7 micrograms kg-1, 27 micrograms kg-1 and 67 micrograms kg-1) of atipamezole or saline placebo as 5 min i.v. infusions preceded by a fixed i.v. dose of dexmedetomidine (0.67 micrograms kg-1). 2. Dexmedetomidine caused profound sedation, with the subjects actually falling asleep. This was effectively reversed by the two highest doses of antipamezole. 3. Dexmedetomidine reduced salivary flow on average by 70%. A rapid and full reversal of this effect was seen after the highest dose of antipamezole. 4. Hypotension induced by dexmedetomidine was also effectively antagonized by atipamezole. Bradycardia was very modest after dexmedetomidine in this study, and thus no reversal of alpha 2-adrenoceptor agonist-induced bradycardia could be demonstrated. 5. Plasma noradrenaline concentrations were reduced by 80% by dexmedetomidine. This was effectively antagonized by atipamezole, and the highest dose caused a 50% overshoot in plasma noradrenaline concentrations over the basal levels. 6. It is concluded that the effects of dexmedetomidine are effectively reversible by atipamezole. A dose ratio of 10:1 for atipamezole:dexmedetomidine was clearly insufficient for this purpose, but ratios in the range of 40:1 to 100:1 were found to be effective in the current experimental situation.

title: Reversal of the Sedative and Sympatholytic Effects of Dexmedetomidine with a Specific α2-Adrenoceptor Antagonist Atipamezole: A Pharmacodynamic and Kinetic Study in Healthy Volunteers
abstract: 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.  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.  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.  The sedative and sympatholytic effects of intramuscular dexmedetomidine were dose dependently antagonized by intravenous atipamezole. The applied infusion rate (75 [micro sign]g/kg-1 [middle dot] min-1) for the highest atipamezole dose was, however, too fast, as evident by transient sympathoactivation. Similar elimination half-lives of these two drugs are a clear advantage considering the possible clinical applications.

title: Pharmacology of sedative-analgesic agents: dexmedetomidine, remifentanil, ketamine, volatile anesthetics, and the role of peripheral Mu antagonists.
abstract: In this article, the authors discuss the pharmacology of sedative-analgesic agents like dexmedetomidine, remifentanil, ketamine, and volatile anesthetics. Dexmedetomidine is a highly selective alpha-2 agonist that provides anxiolysis and cooperative sedation without respiratory depression. It has organ protective effects against ischemic and hypoxic injury, including cardioprotection, neuroprotection, and renoprotection. Remifentanil is an ultra-short-acting opioid that acts as a mu-receptor agonist. Ketamine is a nonbarbiturate phencyclidine derivative and provides analgesia and apparent anesthesia with relative hemodynamic stability. Volatile anesthetics such as isoflurane, sevoflurane, and desflurane are in daily use in the operating room in the delivery of general anesthesia. A major advantage of these halogenated ethers is their quick onset, quick offset, and ease of titration in rendering the patient unconscious, immobile, and amnestic.

title: Dexmedetomidine: a guide to its use for sedation in the US.
abstract: Intravenous dexmedetomidine (Precedex(®)) provides both effective sedation in mechanically ventilated patients in an intensive care setting and effective procedural sedation. In these patient populations, it reduces the need for rescue sedation with intravenous propofol or intravenous midazolam and reduces opioid requirements. In addition, patients receiving dexmedetomidine are calm and easy to arouse and manage. Intravenous dexmedetomidine is generally well tolerated and is not associated with respiratory depression. Although the utilization of dexmedetomidine is associated with hypotension and bradycardia, both usually resolve without intervention.

title: Hemodynamic and respiratory changes following dexmedetomidine administration during general anesthesia: sevoflurane vs desflurane
abstract: The current study evaluates the hemodynamic and respiratory effects of dexmedetomidine (DEX) when administered to children anesthetized with sevoflurane (SEVO) or desflurane (DES).

title: Dexmedetomidine and cardiac protection for non‐cardiac surgery: a meta‐analysis of randomised controlled trials
abstract: We conducted a systematic review of the effects of dexmedetomidine on cardiac outcomes following non‐cardiac surgery. We included prospective, randomised peri‐operative studies of dexmedetomidine that reported mortality, cardiac morbidity or adverse drug events. A PubMed Central and EMBASE search was conducted up to July 2007. The reference lists of identified papers were examined for further trials. Of 425 studies identified, 20 were included in the meta‐analysis (840 patients). Dexmedetomidine was associated with a trend towards improved cardiac outcomes; all‐cause mortality (OR 0.27, 95% CI 0.01–7.13, p = 0.44), non‐fatal myocardial infarction (OR 0.26, 95% CI 0.04–1.60, p = 0.14), and myocardial ischaemia (OR 0.65, 95% CI 0.26–1.63, p = 0.36). Peri‐operative hypotension (26%, OR 3.80, 95% CI 1.91–7.54, p = 0.0001) and bradycardia (17%, OR 5.45, 95% CI 2.98–9.95, p < 0.00001) were significantly increased. An anticholinergic did not reduce the incidence of bradycardia (p = 0.43). A randomised placebo‐controlled trial of dexmedetomidine is warranted.

title: Alpha-2 adrenergic agonists for the prevention of cardiac complications among patients undergoing surgery.
abstract: The surgical stress response plays an important role on the pathogenesis of perioperative cardiac complications. Alpha-2 adrenergic agonists attenuate this response and may thereby prevent cardiac complications.



This review assessed the efficacy and safety of preoperative (within 24 hours), intraoperative, and postoperative (first 48 hours) alpha-2 adrenergic agonists for preventing mortality and cardiac complications after surgery performed under either general or neuraxial anaesthesia, or both.


SEARCH STRATEGY
We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2008, Issue 3), MEDLINE (1950 to August week 4 2008), EMBASE (1980 to week 36 2008), the Science Citation Index, and reference lists of articles.



We included randomized controlled trials that compared alpha-2 adrenergic agonists (clonidine, dexmedetomidine, or mivazerol) against placebo or non-alpha-2 adrenergic agonists. Included studies had to report on mortality, myocardial infarction, myocardial ischaemia, or supraventricular tachyarrhythmia.



Three authors independently assessed trial quality and extracted data. Two authors independently performed computer entry of abstracted data. We contacted study authors for additional information. Adverse event data were gathered from the trials.



We included 31 studies (4578 participants). Study quality was generally inadequate, with only six studies clearly reporting methods for blinding and allocation concealment. Overall, alpha-2 adrenergic agonists reduced mortality (relative risk (RR) 0.66; 95% CI 0.44 to 0.98; P = 0.04) and myocardial ischaemia (RR 0.68; 95% CI 0.57 to 0.81; P < 0.0001). However, their effects appeared to vary with the surgical procedure. The most encouraging data pertained to vascular surgery, where they reduced mortality (RR 0.47; 95% CI 0.25 to 0.90; P = 0.02), cardiac mortality (RR 0.36; 95% CI 0.16 to 0.79; P = 0.01), and myocardial infarction (RR 0.66; 95% CI 0.46 to 0.94; P = 0.02). With regard to adverse effects, alpha-2 adrenergic agonists significantly increased perioperative hypotension (RR 1.32; 95% CI 1.07 to 1.62; P = 0.009) and bradycardia (RR 1.66; 95% CI 1.14 to 2.41; P = 0.008).



Our study provides encouraging evidence that alpha-2 adrenergic agonists may reduce cardiac risk, especially during vascular surgery. Nonetheless, these data remain insufficient to make firm conclusions about their efficacy and safety. A large randomized trial of alpha-2 adrenergic agonists is therefore warranted. Additionally, future research must determine which specific alpha-2 adrenergic agonist should be used, and whether it is safe to combine them with other perioperative interventions (for example beta-adrenergic blockade).

title: The Use of Dexmedetomidine in Pediatric Cardiac Surgery
abstract: We tested dexmedetomidine, an &agr;2 agonist, for its ability to decrease heart rate, arterial blood pressure, and neuroendocrinal responses during pediatric cardiac surgery. In a randomized, placebo-controlled study, 30 pediatric patients undergoing open heart surgery were randomly assigned to one of two equal groups. The control group received saline, whereas the treatment group (DEX group) received an initial bolus dose of dexmedetomidine (0.5 &mgr;g/kg) over 10 min, followed immediately by a continuous infusion of 0.5 &mgr;g · kg−1 · h−1. Arterial blood pressure, heart rate, and sequential concentrations of circulating cortisol, epinephrine, norepinephrine, and blood glucose were measured. Relative to baseline, arterial blood pressure and heart rate decreased significantly after the administration of dexmedetomidine through skin incision. In the control group, patients' heart rate and arterial blood pressure measures increased after skin incision until the end of bypass (P < 0.05). In both groups, plasma cortisol, epinephrine, norepinephrine, and blood glucose increased significantly relative to baseline, after sternotomy, and after bypass. However, the values were significantly higher in the control group compared with the DEX group (P < 0.05). In conclusion, intraoperative dexmedetomidine infusion attenuated the hemodynamic and neuroendocrinal response to surgical trauma and cardiopulmonary bypass in pediatric patients undergoing corrective surgery for congenital heart disease.

title: Eszopiclone and dexmedetomidine depress ventilation in obese rats with features of metabolic syndrome.
abstract: Obesity alters the therapeutic window of sedative/hypnotic drugs and increases the probability of respiratory complications. The current experiments used an established rodent model of obesity to test the hypothesis that the sedative/hypnotic drugs eszopiclone and dexmedetomidine alter ventilation differentially in obese rats compared with lean/fit rats.



This study used a within-groups/between-groups experimental design.



University of Michigan.



Experiments were conducted using lean/fit rats (n = 21) and obese rats (n = 21) that have features of metabolic syndrome.



Breathing was measured with whole-body plethysmography after systemic administration of vehicle (control), the nonbenzodiazepine, benzodiazepine site agonist eszopiclone, or the alpha-2 adrenergic receptor agonist dexmedetomidine.



Data were analyzed using two-way analysis of variance and appropriate post hoc comparisons. At baseline, the obese/metabolic syndrome rats had increased respiratory rates (21.6%), lower tidal volumes/body weight (-24.1%), and no differences in minute ventilation compared to lean/fit rats. In the obese rats, respiratory rate was decreased by dexmedetomidine (-29%), but not eszopiclone. In the lean and the obese rats, eszopiclone decreased tidal volume (-12%). Both sedative/hypnotic drugs caused a greater decrease in minute ventilation in the obese (-26.3%) than lean (-18%) rats. Inspiratory flow rate (VT / TI) of the obese rats was decreased by dexmedetomidine (-10.6%) and eszopiclone (-18%). Duty cycle (TI / TTOT) in both rat lines was decreased by dexmedetomidine (-16.5%) but not by eszopiclone.



Dexmedetomidine, in contrast to eszopiclone, decreased minute ventilation in the obese/metabolic syndrome rats by depressing both duty cycle and inspiratory flow rate. The results show for the first time that the obese phenotype differentially modulates the respiratory effects of eszopiclone and dexmedetomidine. These differences in breathing are consistent with previously documented differences in sleep between lean/fit and obese rats. These findings also encourage future studies of obese/metabolic syndrome rats that quantify the effect of sedative/hypnotic drugs on respiratory mechanics as well as hypoxic and hypercapnic ventilatory responses. Continued findings of favorable homology between obese humans and rodents will support the interpretation that these obese rats offer a unique animal model for mechanistic studies.

title: Dexmedetomidine Pharmacodynamics: Part I: Crossover Comparison of the Respiratory Effects of Dexmedetomidine and Remifentanil in Healthy Volunteers
abstract: Dexmedetomidine, a highly selective &agr;2-adrenoceptor agonist used for short-term sedation of mechanically ventilated patients, has minimal effect on ventilation. This study compared the respiratory effect of dexmedetomidine to that of remifentanil. The authors measured and compared respiratory responses of six healthy male volunteers during (1) a stepwise target-controlled infusion of remifentanil, (2) a stepwise target-controlled infusion of dexmedetomidine, and (3) a pseudonatural sleep session. Compared with baseline, remifentanil infusions resulted in respiratory depression as evidenced by a decrease in respiratory rate and minute ventilation, respiratory acidosis, and apnea episodes resulting in desaturations. Remifentanil disturbed the natural pattern of breathing and flattened the distribution of ventilatory timing (inspiratory time/ventilatory cycle time). The respiratory effects of dexmedetomidine markedly contrasted with those of remifentanil. When compared with baseline, during dexmedetomidine infusions, the respiratory rate significantly increased, and the overall apnea/hypopnea index significantly decreased. The distribution of inspiratory time/ventilatory cycle time showed an increased peak. In addition, dexmedetomidine seemed to mimic some aspect of natural sleep. While the subjects were breathing a 5% CO2 mixture, hypercapnic arousal phenomena (documented by the Bispectral Index, the electroencephalogram, and sudden increase in the minute ventilation) were observed during dexmedetomidine infusions. Similar phenomena during natural sleep have been reported in the literature. In comparison with remifentanil, dexmedetomidine infusions (1) did not result in clinically significant respiratory depression, (2) decreased rather than increased the apnea/hypopnea index, and (3) exhibited some similarity with natural sleep.

title: Dexmedetomidine and S(+)-ketamine in ischemia and reperfusion injury in the rat kidney.
abstract: To investigate blood creatinine and renal histology in rats anesthetized with S(+)-ketamine (keta) or dexmedetomidine (dex) and submitted to kidney ischemia/reperfusion injury (IRI).



Under intraperitoneal (ip) S(+)-ketamine, 20 male Wistar rats were divided into two groups (n=10): maintenance with iv S(+)-ketamine or dex (keta and dex groups), and submitted to right (R) nephrectomy and left (L) renal artery clamping for 45 min. Blood creatinine was measured before ischemia (T1) and 48h after reperfusion (T2), when L nephrectomy was performed. Histological analysis was performed in all kidneys.



Blood creatinine was significantly higher at T2 in both groups, but dex group results were lower than those of keta group. Histological changes: between groups, R kidneys did not differ; there were significant high scores for vascular dilation: keta L kidneys; for vascular congestion, tubular dilation, and necrosis: L kidneys from both groups; for tubular degeneration: keta R kidneys.



S(+)-ketamine plus IRI were aggressive to rat kidneys, according to histological changes, and dexmedetomidine may have not totally protected the kidneys from these injuries, despite the better results of blood creatinine.

title: α2 adrenoreceptor agonist regulates protein kinase C‐induced heat shock protein 27 phosphorylation in C6 glioma cells
abstract: Dexmedetomidine (Dexmd), a potent and highly specific α2 adrenoreceptor agonist, is an efficient therapeutic agent for sedation. Dexmd has been recently reported to have a neuroprotective effect. Heat shock protein (HSP) 27, a low‐molecular weight HSP has been shown to be expressed following cerebral ischemia in astrocytes but not in neurons. HSP27 expression is involved in ischemic tolerance of the brain. This study investigated the effect of Dexmd on HSP27 in rat C6 glioma cells. 12‐O‐tetradecanoylphorbol‐13‐actate (TPA), a direct activator of protein kinase C (PKC), stimulated the phosphorylation of HSP27 at Ser82, but not Ser15 in a time‐dependent manner. Prostaglandin (PG) E1 or PGE2 which activates the adenylyl cyclase‐cAMP system as well as forskolin and dibutyryl‐cAMP, suppressed the TPA‐induced phosphorylation of HSP27. Dexmd reversed the suppression of HSP27 phosphorylation by the adenylyl cyclase‐cAMP system. Therefore, these results strongly suggest that Dexmd reverses the suppression of HSP27 phosphorylation by the adenylyl cyclase‐cAMP system activation through the inhibition of its system in C6 cells.  Adrenoreceptor agonists may therefore show a neuroprotective effect through the modification of HSP27 phosphorylation induced by PKC activation.

title: Phosphorylation status of heat shock protein 27 regulates the interleukin-1β-induced interleukin-6 synthesis in C6 glioma cells
abstract: Heat shock protein 27 (HSP27), a low-molecular-weight HSP, is recognized as a molecular chaperone. In response to various stimuli, HSP27 expression is induced in the CNS. However, the exact roles of HSP27 in the CNS have not yet been clarified. It has been reported that interleukin (IL)-1β stimulates IL-6 synthesis in C6 glioma cells. In the present study, we investigated the role of HSP27 in the IL-1β-induced IL-6 synthesis in C6 cells. IL-1β alone did not affect the levels of HSP27. The IL-1β-induced IL-6 release in HSP27-downregulated C6 cells were enhanced compared with those in control siRNA-transfected cells. On the other hand, the IL-1β-induced IL-6 release was significantly enhanced in C6 cells transfected with HSP27 than those in control cells in time- and dose-dependent manner. The IL-1β-induced IL-6 release and the mRNA expression were markedly suppressed in C6 cells transfected with phosphorylated HSP27, while those in the cells transfected with unphosphorylated HSP27 were enhanced. In conclusion, these results strongly suggest that phosphorylated status of HSP27 has a switching role in the IL-1β-induced IL-6 synthesis in C6 glioma cells.

title: FAK and PYK2/CAKβ in the nervous system: a link between neuronal activity, plasticity and survival?
abstract: A major aim of neurobiology today is to improve understanding of the signaling pathways that couple rapid events, such as the action potential and neurotransmitter release, to long-lasting changes in synaptic strength and increased neuronal survival. These adaptations involve interactions of neurons with other cells and with the extracellular matrix. They use, in part, the same molecular machinery that controls adhesion, motility or survival in non-neuronal cells. This machinery includes two homologous non-receptor tyrosine kinases, FAK and PYK2/CAKbeta, and the associated SRC-family tyrosine kinases. Specific brain isoforms of FAK with distinct properties are regulated by neurotransmitters, whereas PYK2/CAKbeta is highly sensitive to depolarization. The multiplicity of the pathways that can be activated by these tyrosine kinases indicates their importance in signal transduction in the adult brain.

title: PKB and the mitochondria: AKTing on apoptosis.
abstract: Cellular homeostasis depends upon the strict regulation of responses to external stimuli, such as signalling cascades triggered by nutrients and growth factors, and upon cellular metabolism. One of the major molecules coordinating complex signalling pathways is protein kinase B (PKB), a serine/threonine kinase also known as Akt. The number of substrates known to be phosphorylated by PKB and its interacting partners, as well as our broad understanding of how PKB is implicated in responses to growth factors, metabolic pathways, proliferation, and cell death via apoptosis is constantly increasing. Activated by the insulin/growth factor-phosphatidylinositol 3-kinase (PI3K) cascade, PKB triggers events that promote cell survival and prevent apoptosis. It is also now widely accepted that mitochondria are not just suppliers of ATP, but that they participate in regulatory and signalling events, responding to multiple physiological inputs and genetic stresses, and regulate both cell proliferation and death. Thus, mitochondria are recognized as important players in apoptotic events and it is logical to predict some form of interplay with PKB. In this review, we will summarize mechanisms by which PKB mediates its anti-apoptotic activities in cells and survey recent developments in understanding mitochondrial dynamics and their role during apoptosis.

title: Dexmedetomidine Increases Hippocampal Phosphorylated Extracellular Signal–regulated Protein Kinase 1 and 2 Content by an α2-Adrenoceptor–independent Mechanism: Evidence for the Involvement of Imidazoline I1 Receptors
abstract: Dexmedetomidine is a potent and selective α2-adrenoceptor (α2AR) agonist that exhibits a broad pattern of actions, including sedation, analgesia, and neuroprotection. Recent studies have emphasized the role of phosphorylated extracellular signal–regulated protein kinases (pERK1 and 2) in coupling rapid events such as neurotransmitter release and receptor stimulation long-lasting changes in synaptic plasticity and cell survival. Here, the authors hypothesized that dexmedetomidine increases pERK1 and 2 content and examined the mechanisms involved in this effect. The effects of dexmedetomidine and their sensitivity to various pharmacologic agents on expression of pERK1 and 2 were studied by Western blots in hippocampal slices obtained from rats, wild-type mice, and mice carrying targeted deletions of the α2AR subtypes. Dexmedetomidine induced a concentration-related increase in the expression of pERK1 and 2 in rat hippocampal slices (EC50 [95% confidence interval] for pERK1, 0.97 [0.68–1.37] &mgr;m; for pERK2, 1.15 [0.62–2.14] &mgr;m). This effect was insensitive to the inhibitors of the α2AR-mediated signaling pathway, to prazosin, and to PP2, an inhibitor of the focal adhesion kinase–Src kinases. In contrast, it was still present in mice deleted for each of the α2AR subtypes and was markedly decreased by the antagonist of the I1-imidazoline receptors efaroxan, by phospholipase C and protein kinase C inhibitors, and by PD 098059, a direct inhibitor of ERK1 and 2 phosphorylation. Dexmedetomidine increases the expression of pERK1 and 2 via mechanisms independent of α2AR activation. The I1-imidazoline receptors likely contribute to these effects. The results may be relevant to some long-term effects (e.g., neuroprotective) of dexmedetomidine in the brain.

title: Characterization of the Postconditioning Effect of Dexmedetomidine in Mouse Organotypic Hippocampal Slice Cultures Exposed to Oxygen and Glucose Deprivation
abstract: There is an increasing interest in the use of dexmedetomidine for anesthesia and sedation. Here, we used the mouse organotypic hippocampal slice culture to investigate whether dexmedetomidine exhibits postconditioning properties against oxygen and glucose deprivation (OGD). The role of the focal adhesion and extracellular-regulated kinases pathways in these effects were examined in both postconditioning and preconditioning. Slices were obtained from P5 mouse. In postconditioning experiments, Dexmedetomidine (1 &mgr;m) was incubated 60 min after the end of OGD. In preconditioning experiments, dexmedetomidine was applied 3 h before OGD. Pharmacologic modulation of the studied pathways was achieved by using selective inhibitors of these cascades. Cell death was assessed 72 h after OGD using propidium iodide labeling and protein expression of activated caspase 3. Maximum cell death increased with the duration of OGD. Dexmedetomidine induced a postconditioning effect in the CA1 (but not dentate gyrus) subfield area, which was significantly reduced by modulators of the focal adhesion and the extracellular-regulated kinases pathways. The combination of the inhibitors of the two pathways completely abolished the postconditioning effect of dexmedetomidine. The preconditioning effect of dexmedetomidine against ischemia-induced injury was observed in all hippocampal subfield areas. Results obtained with the pharmacologic modulation used for postconditioning also applied to dexmedetomidine-induced preconditioning. Dexmedetomidine exhibits significant, but moderate, postconditioning properties against oxygen and glucose deprivation-induced injury. Activation of focal adhesion and the imidazoline 1 receptors-extracellular-regulated kinases pathways is involved in dexmedetomidine-induced postconditioning and preconditioning as well.

title: Both PI3K/Akt and ERK1/2 pathways participate in the protection by dexmedetomidine against transient focal cerebral ischemia/reperfusion injury in rats
abstract: Dexmedetomidine (Dex) has been demonstrated to provide neuroprotection against ischemia/reperfusion (I/R) injury. However, the exact mechanism of this protection remains unknown. Here, we explored the neuroprotective effect of Dex in rats exposed to cerebral I/R-induced by middle cerebral artery occlusion (MCAO) and the role of phosphatidylinositol 3-kinase (PI3K)/Akt, extracellular signal-regulated kinase 1/2 (ERK1/2), and glycogen synthase kinase-3β (GSK-3β) in this protective action. Adult male Sprague-Dawley rats were subjected to MCAO for 90 min followed by reperfusion for 24h and Dex (15 μg/kg, i.v.) was administered immediately after the onset of MCAO. The neurological deficit score, cerebral infarct volume, brain edema, and neuron survival were evaluated at 24h of reperfusion. The effect of Dex on p-Akt, p-ERK1/2 and p-GSK-3β expression in the ischemic hemisphere was assayed by Western blot. Treatment of rats exposed to I/R with Dex caused not only marked reduction in the neurological deficit score, cerebral infarct volume, and brain edema (P <0.01 vs. I/R alone), but also a decrease in neuron death in hippocampal CA1 and cortex (P<0.01 vs. I/R alone). The Dex-induced increment of neuron survival in the ischemic CA1 and cortex was diminished by the PI3K inhibitor LY294002 and the MEK inhibitor U0126. The increasing expressions of p-Akt and p-ERK1/2 induced by Dex in the ischemic hemisphere were markedly inhibited by LY294002 (or wortmannin) and U0126 (or PD98059), respectively. The up-regulation of p-GSK-3β by Dex in the ischemic hemisphere was significantly decreased by both LY294002 (or wortmannin) and U0126 (or PD98059). Our data demonstrated that treatment with Dex reduced cerebral injury in rats exposed to transient focal I/R, and this was mediated by the activation of the PI3K/Akt and ERK1/2 pathways as well the phosphorylation of downstream GSK-3β.

title: Dexmedetomidine Reduces Long-term Potentiation in Mouse Hippocampus
abstract: Dexmedetomidine (Precedex; Abbott Laboratories, Abbott Park, IL) is a selective &agr;2-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 &agr;2-adrenoceptor antagonist (yohimbine), an imidazoline type 1 receptor and &agr;2-adrenoceptor antagonist (efaroxan), an &agr;1-adrenoceptor antagonist (prazosin), or a &ggr;-aminobutyric acid type A receptor antagonist (picrotoxin). However, an imidazoline type 2 receptor and &agr;2-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 &agr;2-adrenoceptors.

title: ERK phosphorylation in intact, adult brain by α2-adrenergic transactivation of EGF receptors
abstract: Our previous work demonstrated dexmedetomidine-activated phosphorylation of extracellular regulated kinases 1 and 2 (ERK(1/2)) in primary cultures of mouse astrocytes and showed that it is evoked by alpha(2)-adrenoceptor-mediated transactivation of epidermal growth factor (EGF) receptors, a known response to activation of G(i/o)- or G(q)-coupled receptors [Li, B., Du, T., Li, H., Gu, L., Zhang, H., Huang, J., Hertz, L., Peng, L., 2008a. Signaling pathways for transactivation by dexmedetomidine of epidermal growth factor receptors in astrocytes and its paracrine effect on neurons. Br. . Like most studies of transactivation, that study used cultured cells, raising the question whether a similar effect can be demonstrated in intact brain tissue and the brain in vivo. In the present study we have shown that (i) dexmedetomidine-mediated ERK(1/2) phosphorylation occurs in mouse brain slices with a similar concentration dependence as in cultured astrocytes (near-maximum effect at 50nM); (ii) intraperitoneal injection of dexmedetomidine (3microg/kg) in adult mice causes rapid phosphorylation of the EGF receptor (at Y845 and Y992) and of ERK(1/2) in the brain; (iii) both EGF receptor and ERK(1/2) phosphorylation are inhibited by intraventricular administration of (a) AG 1478, a specific inhibitor of the receptor-tyrosine kinase of the EGF receptor; (b) GM 6001, an inhibitor of metalloproteinase(s) required for release of EGF receptor agonists from membrane-bound precursors; or (c) heparin, neutralizing heparin-binding EGF (HB-EGF). Thus, in intact brain HB-EGF, known to be expressed in brain, may be the major EGF agonist released in response to stimulation of alpha(2)-adrenoceptors, the released agonist(s) activate(s) EGF receptors, and ERK(1/2) is phosphorylated as a conventional response to EGF receptor activation. Our previous paper (see above) showed that dexmedetomidine evokes no ERK(1/2) phosphorylation in cultured neurons, but neurons respond to astrocyte-conditioned medium (and to EGF) with ERK(1/2) phosphorylation. The present findings therefore suggest that EGF receptor transactivation in astrocytes in the mature brain in vivo is an important process in response to alpha(2)-adrenoceptor stimulation and may lead to phosphorylation of ERK(1/2) both in astrocytes themselves and in adjacent neurons.

title: alpha(2)-Adrenergic receptors activate MAPK and Akt through a pathway involving arachidonic acid metabolism by cytochrome P450-dependent epoxygenase, matrix metalloproteinase activation and subtype-specific transactivation of EGFR.
abstract: Previous study carried out on PC12 cells expressing each alpha(2)-adrenergic receptor subtype individually (PC12/alpha(2A), /alpha(2B) or /alpha(2C)) have shown that epinephrine causes activation of PI3K and phosphorylation of Erk 1/2. The signal transduction mechanisms whereby each alpha(2)-AR subtype triggers these actions were investigated in the present study. In all three clones, epinephrine-induced phosphorylation of MAPK or Akt was abolished by prior treatment with ketoconazole, but not with indomethacin or nordihydroguaiaretic acid. On the other hand, treatment of the clones with epinephrine caused a rapid increase of AA release, which was fully abolished by the PLC inhibitor U73122, but was unaffected by the PLA(2) inhibitor quinacrine. The effects of epinephrine on MAPK and Akt were mimicked by cell exposure to exogenous AA. Furthermore, whereas U73122 abolished the effects of epinephrine, quinacrine only prevented the effects of epinephrine, suggesting that AA release through PLC and its metabolites are responsible for MAPK and Akt activation by alpha(2)-ARs. Treatment with 1,10-phenanthroline, CRM197, or tyrphostin AG1478 suppressed MAPK and Akt phosphorylation by epinephrine or AA, in a subtype-specific manner. Furthermore, conditioned culture medium from epinephrine-treated PC12/alpha(2) induced MAPK and Akt phosphorylation in wild-type PC12. Inhibition of NGFR tyrosine phosphorylation had no effect but the src inhibitor PP1 abolished MAPK and Akt phosphorylation in all three clones. Our results provide evidence for a putative pathway by which alpha(2)-ARs activate MAPK and Akt in PC12 cells, involving stimulation of PLC, AA release, AA metabolism by cytochrome P450-dependent epoxygenase, stimulation of matrix metalloproteinases and subtype-specific transactivation of EGFR through src activation and heparin-binding EGF-like growth factor release.

title: Dexmedetomidine Decreases Perioperative Myocardial Lactate Release in Dogs
abstract: The sympatholytic effect of the &agr;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).

title: The cardioprotective effect of dexmedetomidine on global ischaemia in isolated rat hearts.
abstract: Dexmedetomidine is a highly specific and selective alpha-2 adrenergic agonist that is now widely used in the intensive care setting. Many intensive care unit (ICU) patients are at risk of respiratory or cardiac arrest. This study was conducted to determine whether dexmedetomidine exhibits a cardioprotective effect on global ischaemia and subsequent myocardial infarction.



Isolated rat hearts were subjected to 30 min of global ischaemia followed by 120 min reperfusion, with administration of 0, 1 and 10nM dexmedetomidine during the pre-ischaemic period (n=7 each group). Secondly, 1 microM yohimbine, an alpha-2 antagonist, was given during the pre-ischaemic period, alone or in combination with 10 nM dexmedetomidine (n=7 each group).



Dexmedetomidine administration reduced coronary flow significantly (103.6+/-4.7%, 77.9+/-3.7, 63.7+/-6.1%, of the baseline values for 0, 1 and 10 nM dexmedetomidine, respectively), and yohimbine administration reversed this effect (88.0+/-2.2%). Dexmedetomidine improved the infarct size at each concentration (45.3+/-3.6, 30.2+/-3.3, and 21.2+/-2.3% of the total left ventricular mass for 0, 1, and 10nM dexmedetomidine, respectively), which was also reversed by yohimbine (43.6+/-1.4%).



Dexmedetomidine exhibited a cardioprotective effect on global ischaemia in the isolated rat heart model, which was mediated by alpha-2 adrenergic stimulation.

title: Dexmedetomidine preconditioning activates pro-survival kinases and attenuates regional ischemia/reperfusion injury in rat heart.
abstract: Pharmacological preconditioning limits myocardial infarct size after ischemia/reperfusion. Dexmedetomidine is an α(2)-adrenergic receptor agonist used in anesthesia that may have cardioprotective properties against ischemia/reperfusion injury. We investigate whether dexmedetomidine administration activates cardiac survival kinases and induces cardioprotection against regional ischemia/reperfusion injury. In in vivo and ex vivo models, rat hearts were subjected to 30 min of regional ischemia followed by 120 min of reperfusion with dexmedetomidine before ischemia. The α(2)-adrenergic receptor antagonist yohimbine was also given before ischemia, alone or with dexmedetomidine. Erk1/2, Akt and eNOS phosphorylations were determined before ischemia/reperfusion. Cardioprotection after regional ischemia/reperfusion was assessed from infarct size measurement and ventricular function recovery. Localization of α(2)-adrenergic receptors in cardiac tissue was also assessed. Dexmedetomidine preconditioning increased levels of phosphorylated Erk1/2, Akt and eNOS forms before ischemia/reperfusion; being significantly reversed by yohimbine in both models. Dexmedetomidine preconditioning (in vivo model) and peri-insult protection (ex vivo model) significantly reduced myocardial infarction size, improved functional recovery and yohimbine abolished dexmedetomidine-induced cardioprotection in both models. The phosphatidylinositol 3-kinase inhibitor LY-294002 reversed myocardial infarction size reduction induced by dexmedetomidine preconditioning. The three isotypes of α(2)-adrenergic receptors were detected in the whole cardiac tissue whereas only the subtypes 2A and 2C were observed in isolated rat adult cardiomyocytes. These results show that dexmedetomidine preconditioning and dexmedetomidine peri-insult administration produce cardioprotection against regional ischemia/reperfusion injury, which is mediated by the activation of pro-survival kinases after cardiac α(2)-adrenergic receptor stimulation.

title: DIRECT EFFECT OF DEXMEDETOMIDINE ON RAT ISOLATED AORTA INVOLVES ENDOTHELIAL NITRIC OXIDE SYNTHESIS AND ACTIVATION OF THE LIPOXYGENASE PATHWAY
abstract: 1 The aims of the present in vitro study were to examine the roles of pathways associated with arachidonic acid metabolism in dexmedetomidine‐induced contraction and to determine which endothelium‐derived vasodilators are involved in the endothelium‐dependent attenuation of vasoconstriction elicited by dexmedetomidine. 2 Dexmedetomidine (10−9–10−6 mol/L) concentration–response curves were constructed in: (i) aortic rings with no drug pretreatment; (ii) endothelium‐denuded aortic rings pretreated with either 2 × 10−5 mol/L quinacrine dihydrochloride, 10−5 mol/L nordihydroguaiaretic acid (NDGA), 3 × 10−5 mol/L indomethacin or 10−5 mol/L fluconazole; and (iii) endothelium‐intact aortic rings pretreated with either 5 × 10−5 mol/L NG‐nitro‐l‐arginine methyl ester (l‐NAME), 10−5 mol/L fluconazole, 10−5 mol/L indomethacin, 10−5 mol/L glibenclamide, 5 × 10−3 mol/L tetraethylammonium or 5 × 10−5 mol/L l‐NAME plus rauwolscine (10−5, 10−6 mol/L). The production of nitric oxide (NO) metabolites was determined in human umbilical vein endothelial cells treated with dexmedetomidine. 3 Quinacrine dihydrochloride, NDGA and indomethacin attenuated the dexmedetomidine‐induced contraction of endothelium‐denuded rings. Dexmedetomidine (10−7–10−6 mol/L)‐induced contractions of endothelium‐denuded rings were enhanced compared with those of endothelium‐intact rings, as were dexmedetomidine‐induced contractions of endothelium‐intact rings pretreated with l‐NAME or tetraethylammonium. Rauwolscine attenuated dexmedetomidine‐induced contractions in endothelium‐intact rings pretreated with l‐NAME. Dexmedetomidine (10−6 mol/L) was found to activate NO production. 4 Taken together, the results indicate that dexmedetomidine‐induced contraction of aortic rings involves activation of the lipoxygenase and cyclo‐oxygenase pathways and is attenuated by increased NO production following stimulation of endothelial α2‐adrenoceptors by dexmedetomidine.

title: Control of mitochondrial ATP synthesis in the heart.
abstract: over 90% of its ATP is made by mitochondrial oxidative phosphorylation. Thus, to a first approximation, we can consider the heart as a system in which ATP is made by the mitochondrial ATP synthase (F1Fo ATPase) and consumed by contraction. The validity of this model is attested by the correlation between heart work rate and the rate of oxidative phosphorylation (as measured by oxygen uptake) . A number of recent reviews have dealt with the control of oxidative phosphorylation in the heart [1,3-9]. In general, however, they have concentrated on the means employed by the cell to modulate the mitochondrial electron transfer chain; the ATP synthase was considered as essentially responding passively to changes in these other events. It is the aim of this Review to redress the balance and focus attention on the ATP synthase within heart mitochondria, and on its regulation.

title: Dexmedetomidine attenuates H2O2-induced neonatal rat cardiomyocytes apoptosis through mitochondria- and ER-medicated oxidative stress pathways
abstract: Dexmedetomidine (DEX), an α2 adrenoceptor agonist, has sedative and analgesic properties and myocardial protective effects. However, the mechanism underlying the protective effects of DEX on the myocardium remain unclear. The present study aimed to determine whether DEX serves an important role on cardioprotection through the endoplasmic reticulum (ER)- and mitochondria-mediated apoptosis signaling pathways. Neonatal rat cardiomyocytes (NRCMs) were cultured and divided four groups: i) Normal culture medium with 10% fetal bovine serum (control group); ii) H2O2 at 500 µM (H2O2 group); iii) DEX at 5 µM (DEX group); and iv) H2O2 plus DEX (H2O2 + DEX group). The levels of apoptosis and oxidative stress of NRCMs were investigated by ELISA, western blotting, flow cytometry and cell immunofluorescence. DEX significantly suppressed H2O2-induced apoptosis, and increased activity of caspases 3, 8 and 9 of NRCMs. DEX inhibited mitochondria-mediated oxidative stress and apoptosis, as evidenced by decreased levels of reactive oxygen species and lactic dehydrogenase, alleviated mitochondrial membrane potential depolarization, and increased Bcl-2-associated X protein/B-cell lymphoma 2 ratio. In addition, DEX decreased the activity of caspase 12, and the expression levels of glucose-regulated protein 78 kDa and serine/threonine-protein kinase/endoribonuclease IRE1, three major signaling molecules involved in the ER stress-mediated apoptosis pathway. Preventive treatment with DEX alleviates cardiomyocyte against H2O2-induced oxidative stress injury through attenuating the mitochondria- and ER-mediated apoptosis pathways.

title: Reduced mitochondrial response sensitivity is involved in the anti‑apoptotic effect of dexmedetomidine pretreatment in cardiomyocytes.
abstract: Dexmedetomidine is a commonly used α2-adreno-ceptor agonist, which affects various organs, including providing beneficial effects on the heart. However, the mechanism underlying the cardiac benefit remains to be fully elucidated. In the present study, it was demonstrated that dexmedetomidine pretreatment on primary cultured rat cardiomyocytes protected against reactive oxygen species (ROS)‑induced apoptosis. In terms of the potential mechanism, it was demonstrated that dexmedetomidine inhibited mitochondrial biogenesis and mitochondrial respiratory complexes, but with increased coupling efficiency. However, dexmedetomidine upregulated mitochondrial membrane potential (Δψm) and resisted against the loss of Δψm induced by carbonilcyanide p‑triflouromethoxyphenylhydrazone. Due to the importance of mitochondria affecting ROS, the present study investigated the dexmedetomidine‑suppressed mitochondrial response to H2O2 stimulation, which was explained by suppressed ROS levels and the suppression of the increased oxygen consumption rate. Results demonstrated for the first time, to the best of our knowledge, a novel protective mechanism for dexmedetomidine on cardiomyocytes through the attenuated response of mitochondria towards H2O2, which had a protective effect against ROS‑induced apoptosis.

title: [Dexmedetomidine preconditioning protects isolated rat hearts against ischemia/reperfusion injuries and its mechanism].
abstract: To investigate the protective effect of dexmedetomidine (Dex) preconditioning against ischemia/reperfusion (I/R) injuries in isolated rat hearts and its relation to mitochondrial permeability transition pore (mPTP) and mitochondrial ATP-sensitive K(+) channel (mitoKATP).



The hearts of male SD rats were isolated to mount on the Langendorff apparatus and subjected to 30 min global ischemia followed by 120 min reperfusion. The isolated hearts were treated with Dex (10 nmol/L) before ischemia for 15 min. The left ventricular hemodynamic parameters,coronary flow (CF) and the lactate dehydrogenase (LDH) release in the coronary effluent at 5 min reperfusion were measured. The formazan content was assayed to determine the myocardial viability at the end of reperfusion.



Compared with normal controls, I/R markedly decreased the left ventricular developed pressure and CF during the whole reperfusion period and the formazan content; while the left ventricular end diastolic pressure and LDH release were significantly increased. Dex preconditioning markedly improved the myocardial viability and cardiac function (P<0.01), which were reversed by the treatment with both atractyloside (20 μmol/L before ischemia), an opener of mPTP, and 5-hydroxydecanoate (100 μmol/L at the beginning of reperfusion), an inhibitor of mitoKATP, for 20 min.



Dex has protective effect against I/R injuries in isolated rat hearts, which may be related to inhibiting the opening of mPTP at the beginning of reperfusion and activating mitoKATP before ischemia.

title: The Ca2+-induced membrane transition in mitochondria. I. The protective mechanisms.
abstract: Some physiological factors which control the rate of induction of the Ca2+-induced membrane transition (the term “Ca2+-induced membrane transition” is defined in the introduction) have been systematically investigated. To exclude the complicating factors of electron flow and energization, the transition was studied in mitochondria depleted of endogenous substrate, in the presence of uncoupler. In these mitochondria the transition could be induced by Ca2+, whether entry was mediated by ruthenium red-sensitive permeation or by A23187 facilitated diffusion. The rate of the transition was reduced fivefold by any agent which caused complete reduction of endogenous NAD. The rate of the transition was increased threefold by the exchange of endogenous ADP for phosphoenolpyruvate. A further increase was found on the addition of atractyloside, but bongkrekic acid caused inhibition. Addition of uncoupler to energized mitochondria when the endogenous NAD was already fully oxidized caused a stimulation of the transition. From these observations we conclude that mitochondria have a set of protective mechanisms (the term “protective mechanism” refers to the means by which these agents inhibit the Ca2+-induced transition; such a mechanism could be through allosteric interactions between the sites of binding of inhibitor and Ca2+; it would, however, be premature to conclude this on the basis of this paper) involving endogenous NADH, ADP, and energization which regulate the rate of the Ca2+-induced transition. ADP appears to work at two sites: one site which is internal, and another at the ADP/ATP translocase. In addition, we conclude that the transition requires neither electron flow nor energy, but rather the mere accessibility of some internal site to Ca2+. Finally, the key roles played by the protective agents in metabolism give the cell great potential flexibility in regulating the Ca2+-induced transition. This degree of control suggests that the transition has substantial physiological significance.

title: What is the mitochondrial permeability transition pore?
abstract: Under conditions of mitochondrial calcium overload, especially when accompanied by oxidative stress, elevated phosphate concentrations and adenine nucleotide depletion, a non-specific pore, the mitochondrial permeability transition pore (MPTP), opens in the inner mitochondrial membrane. MPTP opening enables free passage into the mitochondria of molecules of <1.5 kDa including protons. The resulting uncoupling of oxidative phosphorylation leads to ATP depletion and necrotic cell death and it is now widely recognised that MPTP opening is a major cause of reperfusion injury and an effective target for cardioprotection. The properties of the MPTP are well defined, but despite extensive research in many laboratories, its exact molecular identity remains uncertain. Knockout studies have confirmed a role for cyclophilin-D (CyP-D), probably mediated by its peptidyl-prolyl cis-trans isomerase activity facilitating a conformational change of an inner membrane protein. However, the identity of the membrane component(s) remains controversial. Knockout studies have eliminated an essential role for either the voltage dependent anion channel (VDAC) or the adenine nucleotide translocase (ANT), although a regulatory role for the ANT was confirmed. Our own studies implicate the mitochondrial phosphate carrier (PiC) in MPTP formation and are consistent with a calcium-triggered conformational change of the PiC, facilitated by CyP-D, inducing pore opening. We propose that this is enhanced by an association of the PiC with the "c" conformation of the ANT. Agents that modulate pore opening may act on either or both the PiC and the ANT. However, knockdown and reconstitution studies are awaited to confirm or refute this model.

title: Genetic and pharmacologic inhibition of mitochondrial-dependent necrosis attenuates muscular dystrophy
abstract: Muscular dystrophies comprise a diverse group of genetic disorders that lead to muscle wasting and, in many instances, premature death. Many mutations that cause muscular dystrophy compromise the support network that connects myofilament proteins within the cell to the basal lamina outside the cell, rendering the sarcolemma more permeable or leaky. Here we show that deletion of the gene encoding cyclophilin D (Ppif) rendered mitochondria largely insensitive to the calcium overload–induced swelling associated with a defective sarcolemma, thus reducing myofiber necrosis in two distinct models of muscular dystrophy. Mice lacking δ-sarcoglycan (Scgd−/− mice) showed markedly less dystrophic disease in both skeletal muscle and heart in the absence of Ppif. Moreover, the premature lethality associated with deletion of Lama2, encoding the α-2 chain of laminin-2, was rescued, as were other indices of dystrophic disease. Treatment with the cyclophilin inhibitor Debio-025 similarly reduced mitochondrial swelling and necrotic disease manifestations in mdx mice, a model of Duchenne muscular dystrophy, and in Scgd−/− mice. Thus, mitochondrial-dependent necrosis represents a prominent disease mechanism in muscular dystrophy, suggesting that inhibition of cyclophilin D could provide a new pharmacologic treatment strategy for these diseases.

title: The mitochondrial permeability transition pore in motor neurons: Involvement in the pathobiology of ALS mice
abstract: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease of motor neurons (MNs) that causes paralysis. Some forms of ALS are inherited, caused by mutations in the superoxide dismutase-1 (SOD1) gene. The mechanisms of human mutant SOD1 (mSOD1) toxicity to MNs are unresolved. Mitochondria in MNs might be key sites for ALS pathogenesis, but cause-effect relationships between mSOD1 and mitochondriopathy need further study. We used transgenic mSOD1 mice to test the hypothesis that the mitochondrial permeability transition pore (mPTP) is involved in the MN degeneration of ALS. Components of the multi-protein mPTP are expressed highly in mouse MNs, including the voltage-dependent anion channel, adenine nucleotide translocator (ANT), and cyclophilin D (CyPD), and are present in mitochondria marked by manganese SOD. MNs in pre-symptomatic mSOD1-G93A mice form swollen megamitochondria with CyPD immunoreactivity. Early disease is associated with mitochondrial cristae remodeling and matrix vesiculation in ventral horn neuron dendrites. MN cell bodies accumulate mitochondria derived from the distal axons projecting to skeletal muscle. Incipient disease in spinal cord is associated with increased oxidative and nitrative stress, indicated by protein carbonyls and nitration of CyPD and ANT. Reducing the levels of CyPD by genetic ablation significantly delays disease onset and extends the lifespan of G93A-mSOD1 mice expressing high and low levels of mutant protein in a gender-dependent pattern. These results demonstrate that mitochondria have causal roles in the disease mechanisms in MNs in ALS mice. This work defines a new mitochondrial mechanism for MN degeneration in ALS.

title: Cyclophilin D deficiency protects against acetaminophen-induced oxidant stress and liver injury
abstract: Acetaminophen (APAP) hepatotoxicity is the main cause of acute liver failure in humans. Although mitochondrial oxidant stress and induction of the mitochondrial permeability transition (MPT) have been implicated in APAP-induced hepatotoxicity, the link between these events is unclear. To investigate this, this study evaluated APAP hepatotoxicity in mice deficient of cyclophilin D, a protein component of the MPT. Treatment of wild type mice with APAP resulted in focal centrilobular necrosis, nuclear DNA fragmentation and formation of reactive oxygen (elevated glutathione disulphide levels) and peroxynitrite (nitrotyrosine immunostaining) in the liver. CypD-deficient (Ppif−/−) mice were completely protected against APAP-induced liver injury and DNA fragmentation. Oxidant stress and peroxynitrite formation were blunted but not eliminated in CypD-deficient mice. Thus, mitochondrial oxidative stress and induction of the MPT are critical events in APAP hepatotoxicity in vivo and at least part of the APAP-induced oxidant stress and peroxynitrite formation occurs downstream of the MPT.

title: Does Dexmedetomidine Ameliorate Postoperative Cognitive Dysfunction? A Brief Review of the Recent Literature
abstract: Purpose of ReviewPostoperative cognitive dysfunction (POCD) occurs in 20–50% of postsurgical patients with a higher prevalence in elderly patients and patients with vascular disease and heart failure. In addition, POCD has been associated with many negative outcomes, such as increased hospital length of stay, increased rates of institutionalization, and higher patient mortality. This brief review discusses select evidence suggesting an association between neuroinflammation and POCD and whether the use of dexmedetomidine, a short-acting alpha 2 agonist, may ameliorate the incidence of POCD. We review the recent evidence for neuroinflammation in POCD, dexmedetomidine’s properties in reducing inflammatory-mediated brain injury, and clinical studies of dexmedetomidine and POCD.Recent FindingsThere is evidence to support the anti-inflammatory and immunomodulatory effects of dexmedetomidine in animal models. Several clinical investigations have demonstrated favorable outcomes using dexmedetomidine over placebo for the reduction of postoperative delirium. Few studies have used high-quality endpoints for the assessment of POCD and no demonstrable evidence supports the use of dexmedetomidine for the prevention of POCD.SummaryWhile evidence exists for the neural anti-inflammatory properties of dexmedetomidine, human trials have yielded incomplete results concerning its use for the management of POCD. Dexmedetomidine may reduce acute postoperative delirium, but further studies are needed prior to recommending the use of dexmedetomidine for the direct reduction of POCD.

title: Pre-microRNA and Mature microRNA in Human Mitochondria
abstract: Because of the central functions of the mitochondria in providing metabolic energy and initiating apoptosis on one hand and the role that microRNA (miRNA) play in gene expression, we hypothesized that some miRNA could be present in the mitochondria for post-transcriptomic regulation by RNA interference. We intend to identify miRNA localized in the mitochondria isolated from human skeletal primary muscular cells.  To investigate the potential origin of mitochondrial miRNA, we in-silico searched for microRNA candidates in the mtDNA. Twenty five human pre-miRNA and 33 miRNA aligments (E-value<0.1) were found in the reference mitochondrial sequence and some of the best candidates were chosen for a co-localization test. In situ hybridization of pre-mir-302a, pre-let-7b and mir-365, using specific labelled locked nucleic acids and confocal microscopy, demonstrated that these miRNA were localized in mitochondria of human myoblasts. Total RNA was extracted from enriched mitochondria isolated by an immunomagnetic method from a culture of human myotubes. The detection of 742 human miRNA (miRBase) were monitored by RT-qPCR at three increasing mtRNA inputs. Forty six miRNA were significantly expressed (2nd derivative method Cp>35) for the smallest RNA input concentration and 204 miRNA for the maximum RNA input concentration. In silico analysis predicted 80 putative miRNA target sites in the mitochondrial genome (E-value<0.05).  The present study experimentally demonstrated for the first time the presence of pre-miRNA and miRNA in the human mitochondria isolated from skeletal muscular cells. A set of miRNA were significantly detected in mitochondria fraction. The origin of these pre-miRNA and miRNA should be further investigate to determine if they are imported from the cytosol and/or if they are partially processed in the mitochondria.

title: Effect of dexmedetomidine on cerebral ischemia-reperfusion rats by activating mitochondrial ATP-sensitive potassium channel
abstract: The aim of the study reported here was to evaluate whether the mitochondrial ATP-sensitive potassium (mitoKATP) channel could participate in the effect of dexmedetomidine on cerebral ischemia-reperfusion (I/R) rats. Forty rats were randomly assigned into 5 groups: sham operation (S) group; cerebral I/R group; dexmedetomidine (D) group; 5-hydroxydecanoate (5-HD) group; 5-HD + D group. The cerebral I/R were produced by 2 h right middle cerebral artery occlusion followed by 24 h reperfusion. Dexmedetomidine (50μg/kg) was injected intraperitoneally before ischemia and after the onset of reperfusion. 5-HD (30 mg/kg) was injected intraperitoneally at 1 h before ischemia. The neurological deficit score (NDS) and the levels of super oxide dismutase (SOD), malondialdehyde (MDA), myeloperoxidase (MPO), Interleukin 6 (IL-6) and tumor necrosis factor-α (TNF-α) were evaluated. Compared to group S, NDS and the levels of MDA, MPO, IL-6 and TNF-α were significantly higher, and SOD levels were significantly lower in the other groups (P < 0.05). Compared to group I/R,NDS and the levels of MDA, MPO, IL-6 and TNF-α were significantly lower, and SOD level was significantly higher in group D (P < 0.05). Compared to group D, NDS and the levels of MDA, MPO, IL-6 and TNF-α were significantly higher, and SOD level was significantly lower in group5-HD + D (P < 0.05). The activation of the mitoKATP channel could contribute to the protective effect of dexmedetomidine on rats induced by focal cerebral ischemia-reperfusion injury.

title: Protective effect of adenosine receptors against lipopolysaccharide-induced acute lung injury.
abstract: Acute lung injury and acute respiratory distress syndrome (ALI/ARDS) affect 200,000 people a year in the USA. Pulmonary vascular and specifically endothelial cell (EC) barrier compromise is a hallmark of these diseases. We have recently shown that extracellular adenosine enhances human pulmonary (EC) barrier via activation of adenosine receptors (ARs) in cell cultures. On the basis of these data, we hypothesized that activation of ARs might exert barrier-protective effects in a model of ALI/ARDS in mice. To test this hypothesis, we examined the effects of pre- and posttreatment of adenosine and 5'-N-ethylcarboxamidoadenosine (NECA), a nonselective stable AR agonist, on LPS-induced lung injury. Mice were given vehicle or LPS intratracheally followed by adenosine, NECA, or vehicle instilled via the internal jugular vein. Postexperiment cell counts, Evans Blue Dye albumin (EBDA) extravasation, levels of proteins, and inflammatory cytokines were analyzed. Harvested lungs were used for histology and myeloperoxidase studies. Mice challenged with LPS alone demonstrated an inflammatory response typical of ALI. Cell counts, EBDA extravasation, as well as levels of proteins and inflammatory cytokines were decreased in adenosine-treated mice. Histology displayed reduced infiltration of neutrophils. NECA had a similar effect on LPS-induced vascular barrier compromise. Importantly, posttreatment with adenosine or NECA recovers lung vascular barrier and reduces inflammation induced by LPS challenge. Furthermore, adenosine significantly attenuated protein degradation of A2A and A3 receptors induced by LPS. Collectively, our results demonstrate that activation of ARs protects and restores vascular barrier functions and reduces inflammation in LPS-induced ALI.

title: Protective effect of dexmedetomidine in a rat model of α-naphthylthiourea-induced acute lung injury.
abstract: We assessed the effects of dexmedetomidine in a rat model of α-naphthylthiourea (ANTU)-induced acute lung injury.



Forty Wistar Albino male rats weighing 200-240 g were divided into 5 groups (n = 8 each), including a control group. Thus, there were one ANTU group and three dexmedetomidine groups (10-, 50-, and 100-μg/kg treatment groups), plus a control group. The control group provided the normal base values. The rats in the ANTU group were given 10 mg/kg of ANTU intraperitoneally and the three treatment groups received 10, 50, or 100 μg/kg of dexmedetomidine intraperitoneally 30 min before ANTU application. The rat body weight (BW), pleural effusion (PE), and lung weight (LW) of each group were measured 4 h after ANTU administration. The histopathologic changes were evaluated using hematoxylin-eosin staining.



The mean PE, LW, LW/BW, and PE/BW measurements in the ANTU group were significantly greater than in the control groups and all dexmedetomidine treatment groups (P < 0.05). There were also significant decreases in the mean PE, LW, LW/BW and PE/BW values in the dexmedetomidine 50-μg/kg group compared with those in the ANTU group (P < 0.01). The inflammation, hemorrhage, and edema scores in the ANTU group were significantly greater than those in the control or dexmedetomidine 50-μg/kg group (P < 0.01).



Dexmedetomidine treatment has demonstrated a potential benefit by preventing ANTU-induced acute lung injury in an experimental rat model. Dexmedetomidine could have a potential protective effect on acute lung injury in intensive care patients.

title: Dexmedetomidine attenuates lipopolysaccharide-induced acute lung injury by inhibiting oxidative stress, mitochondrial dysfunction and apoptosis in rats
abstract: Previous studies have identified that dexmedetomidine (DEX) treatment can ameliorate the acute lung injury (ALI) induced by lipopolysaccharide and ischemia-reperfusion. However, the molecular mechanisms by which DEX ameliorates lung injury remain unclear. The present study investigated whether DEX, which has been reported to exert effects on oxidative stress, mitochondrial permeability transition pores and apoptosis in other disease types, can exert protective effects in lipopolysaccharide (LPS)-induced ALI by inhibiting oxidative stress, mitochondrial dysfunction and mitochondrial-dependent apoptosis. It was revealed that LPS-challenged rats exhibited significant lung injury, characterized by the deterioration of histopathology, vascular hyperpermeability, wet-to-dry weight ratio and oxygenation index (PaO2/FIO2), which was attenuated by DEX treatment. DEX treatment inhibited LPS-induced mitochondrial dysfunction, as evidenced by alleviating the cellular ATP and mitochondrial membrane potential in vitro. In addition, DEX treatment markedly prevented the LPS-induced mitochondrial-dependent apoptotic pathway in vitro (increases of cell apoptotic rate, cytosolic cytochrome c, and caspase 3 activity) and in vivo (increases of |terminal deoxynucleotidyl transferase dUTP nick-end labeling positive cells, cleaved caspase 3, Bax upregulation and Bcl-2 downregulation). Furthermore, DEX treatment markedly attenuated LPS-induced oxidative stress, as evidenced by downregulation of cellular reactive oxygen species in vitro and lipid peroxides in serum. Collectively, the present results demonstrated that DEX ameliorates LPS-induced ALI by reducing oxidative stress, mitochondrial dysfunction and mitochondrial-dependent apoptosis.

title: The effects of dexmedetomidine on human neutrophil apoptosis.
abstract: 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.

title: Safety and efficacy of dexmedetomidine for long-term sedation in critically ill patients
abstract: PurposeWe evaluated the safety and efficacy of long-term administration of dexmedetomidine in patients in the intensive care unit (ICU). Primary endpoint was the incidence of hypotension, hypertension, and bradycardia. Secondary endpoints were withdrawal symptoms, rebound effects, the duration of sedation with Richmond Agitation-Sedation Scale (RASS) ≤ 0 relative to the total infusion time of dexmedetomidine, and the dose of additional sedatives or analgesics.MethodsDexmedetomidine 0.2–0.7 μg/kg/h was continuously infused for maintaining RASS ≤ 0 in patients requiring sedation in the ICU. Safety and efficacy of short-term (≤24 h) and long-term (>24 h) dexmedetomidine administration were compared.ResultsSeventy-five surgical and medical ICU patients were administered dexmedetomidine. The incidence of hypotension, hypertension, and bradycardia that occurred after 24 h (long-term) was not significantly different from that occurring within 24 h (short-term) (P = 0.546, 0.513, and 0.486, respectively). Regarding withdrawal symptoms, one event each of hypertension and headache occurred after the end of infusion, but both were mild in severity. Increases of mean arterial blood pressure and heart rate after terminating the infusion of dexmedetomidine were not associated with the increasing duration of its infusion. The ratio of duration with RASS ≤ 0 was ≥ 85 % until day 20, except day 9 (70 %) and day 10 (75 %). There was no increase in the dose of additional sedatives or analgesics after the first 24-h treatment period.ConclusionsLong-term safety of dexmedetomidine compared to its use for 24 h was confirmed. Dexmedetomidine was useful to maintain an adequate sedation level (RASS ≤ 0) during long-term infusion.

title: A new dosing protocol reduces dexmedetomidine-associated hypotension in critically ill surgical patients.
abstract: Although no ideal sedative exists, dexmedetomidine is unique because it produces sedation and analgesia without decreasing the respiratory drive. Hemodynamic responses to dexmedetomidine are variable and dependent on the patient population. Our initial experience was associated with an unacceptable incidence of hypotension and bradycardia. We evaluated occurrence of hypotension and bradycardia in critically ill surgical patients receiving dexmedetomidine before and after implementation of a dosing protocol.



This is a retrospective chart review of all admissions to a university medical center-based, 44-bed surgical intensive care unit pre and post protocol implementation.



Forty-four patients received dexmedetomidine including 19 historic controls and 25 dosed via protocol. Both groups had comparable demographics and initial and maximum dosages of dexmedetomidine. Use of the dosing protocol resulted in fewer dosage changes (mean +/- standard deviation, 4.8 +/- 3.8 compared to 7.8 +/- 3.9; P = .014) and fewer episodes of hypotension (16% vs 68.4%; P = .0006) but did not influence bradycardic episodes (20% vs 15.5%; P > .99).



We found that use of a protocol that increases the time interval between dosage adjustments may reduce dexmedetomidine-associated hypotension.

title: Dexmedetomidine use in general anaesthesia.
abstract: Dexmedetomidine is a potent and highly selective alpha(2)-adrenoreceptor agonist currently utilized for continuous infusion for sedation/analgesia in the intensive care unit (ICU). Dexmedetomidine offers remarkable pharmacological properties including sedation, anxiolysis, and analgesia with the unique characteristic to cause no respiratory depression. In addition it posses sympatholytic and antinociceptive effects that allow hemodynamic stability during surgical stimulation. Different from most of clinically used anesthetics, dexmedetomidine brings about not only a sedative-hypnotic effect via an action on a single type of receptors, but also an analgesic effect and an autonomic blockade that is beneficial in cardiac risk situations. Several studies have demonstrated its safety, although bradycardia and hypotension are the most predictable and frequent side effects. Dexmedetomidine has shown to consistently reduce opioids, propofol, and benzodiazepines requirements. In the last years it has emerged as an affective therapeutic drug in a wide range of anesthetic management, promising large benefits in the perioperative use. In particular this review focuses on dexmedetomidine utilization in premedication, general surgery, neurosurgery, cardiac surgery, bariatric surgery, and for procedural sedation and awake fiberoptic intubation. In all these fields dexmedetomidine has demonstrated to be an efficacious and safe adjuvant to other sedative and anesthetic medications.

title: Dexmedetomidine: its use in intensive care medicine and anaesthesia
abstract: Dexmedetomidine is a relatively new drug to the UK having been launched in October 2011 with marketing authorization for sedation of adult intensive care unit (ICU) patients only. Despite this, its unique pharmacological profile has led to its unlicensed use in a number of areas of anaesthetic and critical care practice where evidence for its efficacy is mounting.

Dexmedetomidine is the S -enantiomer of the veterinary sedative medetomidine. It is a highly selective α2-adrenoceptor agonist demonstrating an α2:α1 selectivity ratio of 1620:1. This makes it eight times more selective for the α2-adrenoceptor than clonidine. 



Fig 1 
Effects of dexmedetomidine on organ systems.



### Sedation and anxiolysis

These properties are mediated via agonism of α2-adrenoceptors primarily in the locus coeruleus of the pons where it results in dose-dependent inhibition of norepinephrine release. It is postulated that this results in disinhibition of the ventrolateral preoptic nucleus which then releases inhibitory neurotransmitters. This pathway is part of the complex circuitry governing natural sleep, resulting in a quality of sedation with dexmedetomidine which more closely resembles normal physiological sleep than the more familiar GABA-ergic sedatives (propofol and the benzodiazepines). This sedation is characterized by preserved muscle tone and ventilation, by spontaneous and evoked movements, and by awakening by external stimuli. Once roused, patients are cooperative and can typically obey simple instructions. Once the external stimulus is discontinued, patients resume the previous level of sedation. Electroencephalogram studies have further confirmed that the sedative effects of dexmedetomidine mimic …

title: Systematic assessment of dexmedetomidine as an anesthetic agent: a meta-analysis of randomized controlled trials
abstract: Here we aimed to study the effectiveness of dexmedetomidine as an anesthetic adjunct in surgery.  A systematic evaluation was performed on published clinical trials. Major databases such as Medline database were employed to search and identify relevant studies and then Rev.Man 5 was used for meta-analysis as well as forest plots. Mean difference (MD) was chosen as the effect size for measurement data, while odds ratio (OR) was calculated for enumeration data.  A total of 18 studies met the inclusion criteria. The postoperative heart rate and mean arterial pressure for the dexmedetomidine group were significantly lower than the control group (combined MDs were –14.12 and –9.96). The incidence rates of postoperative nausea and vomiting, chills, and shivering of the dexmedetomidine group were lower than the control group (pooled ORs were 0.41, 0.21 and 0.14, respectively). However, the occurrence rates of bradycardia and hypotension in the dexmedetomidine group were higher than the control group (pooled ORs were 5.14 and 3.00).  Dexmedetomidine can stabilize blood pressure and heart rate, and prevent postoperative adverse reactions. However, patients with original hypovolemia or heart block should be cautious. Besides, the quality of such studies should be improved in methodology to evaluate their efficacy and safety comprehensively.

title: Dexmedetomidine in the General Anesthesia:A Meta-analysis of Randomized Controlled Trials
abstract: To determine the efficiency and safety of dexmedetomidine in general anesthesia.  Trials were located through electronic searches of the PubMed, EBSCO, OVID, Springer, Foreign Journals Integration System, CNKI, CMBdisk (from the date of establishment of the databases to April 2008). Bibliographies of the retrieved articles were also checked.  A total of 25 trials involving 1 241 patients were included.The Meta-analysis showed: dexmedetomidine reduced peri-operative heart rate and blood pressure, reduced the occurrence of postoperative nausea and vomitting [RR=0.57, 95%CI (0.38, 0.84)], postoperative agitation [RR=0.29, 95%CI (0.17, 0.51)], shivering [RR=0.45, 95%CI (0.29, 0.68)], increase the occurrence of bradycardia [RR=2.16, 95%CI (1.58, 2.95)], hypotension [RR=2.97, 95%CI (1.42, 6.18)]. Dexmedetomidine reduced administration of thiopental, isoflurane and fentanyl, while there was no difference in muscle relaxant.Dexmedetomidine showed no difference in emergency time compared with the control group.As a result of low incidence of adverse reaction, dexmedetomidine showed superior in discharge time [WMD15.17, 95%CI (3.87, 26.46)].  The limited current evidence shows that dexmedetomidine is better in maintaining the hemodynamic balance; reducing occurrence of nausea, vomiting, agitation and shivering; and reducing doses of anesthetics. In emergency time, dexmedetomidine shows no difference except discharge time.

title: Is intraoperative dexmedetomidine a new option for postoperative pain treatment? A meta-analysis of randomized controlled trials
abstract: &NA; Adults treated with intraoperative dexmedetomidine infusion reported lower postoperative pain intensities and consumed less postoperative opioids compared with placebo. &NA; In the present meta‐analysis, we assessed the efficacy and safety of intravenous administration of dexmedetomidine (DEX) compared with placebo or opioids for acute postoperative pain treatment in adults undergoing surgery. The meta‐analysis was performed according to the preferred reporting items for systematic reviews and meta‐analyses (PRISMA) statement and the recommendations of the Cochrane Collaboration. Randomized controlled trials investigating perioperative administration of DEX were included. For dichotomous outcomes relative risks (RR; 95% confidence intervals [CI]) and for continuous outcomes mean differences (MD; 95% CI) were calculated. Twenty‐eight randomized controlled trials including 1420 patients were finally included. Patients treated with DEX reported lower postoperative pain intensity (MD1 h postoperatively: −1.59 U (numeric rating scale: 0 to 10) 95% CI: −2.37 to −0.82; P = .000001) and showed a lower postoperative opioid consumption (MD24 h postoperatively: −17.24 mg; 95% CI: −24.38 to −10.10; P = .00001) compared with placebo. Additionally, the DEX group showed a lower RR for opioid‐related adverse events (e.g. RRNausea (postanesthesia care unit): 0.66; 95% CI: 0.43 to 1.02; P = .06). The most common adverse event in patients treated with DEX was intraoperative bradycardia with a RR of 2.66 (RR: 2.66; 95% CI: 1.54 to 4.58; P = .0004) compared with placebo. There is evidence that DEX administration leads to lower postoperative pain, reduced opioid consumption, and a lower risk for opioid‐related adverse events. The comparison of DEX vs opioids for postoperative pain treatment is less clear due to limited data. The most common adverse event was intraoperative bradycardia after DEX administration. Therefore cautions in patients at risk are warranted, and large trials focusing on long‐ term outcomes after intraoperative DEX use are needed.

title: Efficacy and safety of intraoperative dexmedetomidine for acute postoperative pain in children: a meta‐analysis of randomized controlled trials
abstract: Aim of the current meta‐analysis was to assess the effects of intraoperative dexmedetomidine on postoperative pain, analgesic consumption, and adverse events in comparison with placebo or opioids in children undergoing surgery.

title: Effect of preemptive local injection of ropivocaine with dexmedetomidine on mirror pain in rats and its mechanism.
abstract: To observe the effect of preemptive local injection of ropivocaine with dexmedetomidine on activation of glial cells and on the mirror pain in rats and its mechanism.



A total of 48 adult male Sprague-Dawley rats (weighing 180 g-220 g) were included in the study and randomized into 3 groups, Group S, Group R, and Group RD1. A rat model of persistent postoperative pain evoked by skin/muscle incision and retraction was established in the three groups. Before procedures and nerve extraction, Group S (n = 16) was injected 0.9% saline locally; Group R (n = 16) was injected 0.5% ropivocaine locally, and Group RD1 (n = 16) was injected 0.5% ropivocaine in combined with 1 μg dexmedetomidine locally. After the model being established in the three groups, 8 rats were used for behavior test until 28 d, and dorsal root ganglions (DRGs) of the other 8 rats were harvested on the 3rd day after surgery. Immunofluorescent and transmission electron microscopy were used to observe the activation of glial cells in DRG, and the behavior test results in the three groups were compared.



The results showed that mechanical pain threshold in ipsilateral hind-paws of the Group S, Group R, Group RD1 animals dropped to (3.640 ± 1.963) g, (5.827 ± 1.204) g, (7.482) ± 1.412 g at 3 d respectively; while in contralateral paws dropped to (7.100 ± 1.789) g, (17.687 ± 1.112) g, (16.213 ± 1.345) g on the 3 d respectively. Immunofluorescent showed that the glial cells were activated in bilateral side DRG after surgery in 3 groups, but ipsilateral paws expressed more active glial cells than contralateral paws. Transmission electron microscopy showed that mitochondria swelling/vacuolization and lysosomes were more obvious in ipsilateral paws than contralateral paws, but Group RD1 formula could reduce glial cells activity, mitochondria swelling/vacuolization and the amount of lysosomes.



Local injection of ropivocaine and/or dexmedetomidine can effectively inhibit the activation of glial cells in DRG, mitigate the pathological changes of neuron in DRG and reduce mirror image pain.

title: Alpha-2 adrenergic agonists for the prevention of shivering following general anaesthesia.
abstract: Shivering after general anaesthesia is common. It is unpleasant but can also have adverse physiological effects. Alpha-2 (α-2) adrenergic agonist receptors, which can lead to reduced sympathetic activity and central regulation of vasoconstrictor tone, are a group of drugs that have been used to try to prevent postoperative shivering.



To assess the following: the effects of α-2 agonists on the prevention of shivering and subsequent complications after general anaesthesia in people undergoing surgery; the effects of α-2 agonists on the risk of inadvertent perioperative hypothermia; and whether any adverse effects are associated with these interventions.



We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, and EMBASE on 13 June 2014. Our search terms were relevant to the review question and limited to studies that assessed shivering or hypothermia. We also carried out searches of clinical trials registers, and forward and backward citation tracking.



We considered all randomized controlled trials, quasi-randomized studies, and cluster-randomized studies with adult participants undergoing surgery with general anaesthesia in which an α-2 agonist was compared with another α-2 agonist or a placebo for the prevention of shivering.



Two review authors independently assessed trial quality and extracted data, consulting a third review author in the case of disagreements. We used standard Cochrane methodological procedures, including an assessment of risk of bias and use of GRADEpro software to interpret findings.



We included 20 studies with 1401 surgical participants comparing an α-2 agonist against a control. Thirteen studies compared clonidine with a control, whilst seven compared dexmedetomidine with a control. The doses, methods, and time of administration varied between studies: three studies gave the drug orally or as an intravenous bolus preoperatively and nine intraoperatively; one study gave the drug as an infusion starting preoperatively and seven started at varying points from anaesthetic induction to the end of surgery. Whilst all the studies were described as randomized, many provided insufficient detail on methods used. We had anticipated that attempts would be made to reduce performance bias by blinding of personnel and participants, however this was detailed in only six of the papers. Similarly, in some studies detail was lacking on methods to reduce the risk of detection bias. We therefore downgraded the quality of evidence in our 'Summary of findings' table by one level for risk of bias using the Grades of Recommendation, Assessment, Development and Evaluation (GRADE) approach.All 20 included studies presented outcome data for postoperative shivering, and in meta-analysis α-2 agonists were shown to significantly reduce the risk of shivering (Mantel-Haenszel risk ratio 0.28, 95% confidence interval 0.18 to 0.43, P value < 0.0001). We found significant evidence of heterogeneity (I(2) = 80%) for this result that was not explained by sensitivity or subgroup analysis; we therefore downgraded the inconsistency of the evidence by one level. Although we did not feel that there were concerns with imprecision or indirectness of the data, we downgraded the quality of the evidence for the risk of publication bias following visual analysis of a funnel plot. Using GRADEpro, we rated the overall quality of the data for shivering as very low. Only one study reported the incidence of core hypothermia, whilst 12 studies measured core temperature. However, as the results for core temperature were reported in different styles, pooling the results was inappropriate. We found no studies with participant-reported outcomes such as experience of shivering or participant satisfaction. We found limited data for the outcomes of length of stay in the postanaesthetic care unit (three studies, 200 participants) and the following adverse effects: sedation (nine studies, 875 participants), bradycardia (eight studies, 716 participants), and hypotension (seven studies, 688 participants). Unpooled analysis suggested that sedation and bradycardia were significantly more common with dexmedetomidine than placebo, with all seven dexmedetomidine studies and none of the clonidine studies reporting statistically significantly higher levels of sedation as an adverse effect.



There is evidence that clonidine and dexmedetomidine can reduce postoperative shivering, but patients given dexmedetomidine may be more sedated. However, our assessment of the quality of this evidence is very low.

title: Effectiveness of dexmedetomidine use in general anesthesia to prevent postoperative shivering: a systematic review protocol
abstract: Review question/objective The following question guides the systematic review: In adult patients undergoing general anesthesia, what is the effectiveness of dexmedetomidine, compared to placebo, in preventing shivering in the first two hours after surgery? The objective of this systematic review is to synthesize the best available evidence on the efficacy of dexmedetomidine in preventing the occurrence of postanesthetic shivering (PAS).  Shivering is a common phenomenon noted after surgery and occurs in up to 66% of patients who received general anesthesia.1–6 Postanesthetic shivering can be uncomfortable to the patient leading to increased pain at the surgical site.6 Shivering can increase metabolic demand up to 600% leading to hypoxemia, elevated carbon dioxide production, lactic acidosis and increased circulating catecholamine levels.2,7,8,9 These side effects place patients with cardiac and pulmonary impairment at an increased risk of adverse outcomes.9 Other adverse effects of shivering include increased intracranial and intraocular pressures, tachycardia, and hypertension.2,8 Shivering can also interfere with the accuracy of postanesthesia monitoring of blood pressure, heart rate, pulse oximetry and electrocardiogram.8,10,11 The prevention and treatment of shivering can help decrease the postoperative complications as listed above and aid in a smoother recovery from general anesthesia.12 Perioperative hypothermia occurs in three phases during general anesthesia: first, a rapid redistribution of body heat to the periphery resulting in a 1‐2°C decrease in temperature due to anesthetic‐induced vasodilation; second, a slower, more gradual decrease in core temperature over the next two to four hours; finally, a lower steady‐state temperature is reached with a slowed rate of heat loss noted.9,13 Risk factors for perioperative hypothermia include extremes of age, type and length of surgical intervention, environmental factors (radiation, convection, conduction, and evaporation), anesthetic agents and other perioperative medications.12 Shivering, vasoconstriction and nonshivering thermogenesis are the body's way to compensate for heat loss and restore homeostasis.2,8,14 Shivering is characterized by involuntary muscle contractions and vasoconstriction in an attempt to increase metabolic activity and heat production. 4 General anesthetics inhibit the thermoregulation center of the hypothalamus by lowering the shivering threshold and preventing the compensatory mechanism of shivering. The use of muscle relaxants will also inhibit the body's ability to  Once anesthetic medications are discontinued, the compensatory mechanisms are restored, increasing the likelihood of the body to shiver. Postanesthetic shivering also occurs in the normothermic patient, which has led to researching pharmacologic prophylaxis and treatment options for shivering.3,7,12 As listed above, the consequences of shivering can be detrimental to patient outcomes, exemplifying the importance of preventive measures with forced air warmers, warmed fluids, humidified ventilators and medications.4,7 Numerous agents have been identified as having antishivering properties.11,15 Studies have found nefopam, tramadol, physostigmine, meperidine (pethidine), clonidine, morphine, fentanyl, doxapram, ketamine, nalbuphine, and ketanserin as effective agents for use in preventing PAS. 11,15,16 Although many medications have been examined in the literature, no single medication has been identified as the gold standard for pharmacologic prophylaxis or management of PAS.15,17 Despite its adverse side effects, meperidine is often considered the best agent for PAS and is the most common medication used in treating it.9,16,17,18 Recent practice guidelines for postanesthetic care by the American Society of Anesthesiologists states no other opioid agonist or agonist‐antagonist has been found to be more effective than meperidine at treating PAS.18 Reported adverse effects of meperidine include nausea and vomiting, significant drowsiness, dizziness and respiratory depression.16 Common side effects of other PAS prophylaxis medications also include nausea, vomiting and respiratory depression along with hypotension, drowsiness and pruritus. 16 These side effects increase the potential for patient discomfort and physiologic decompensation. Recent studies have examined the use of intraoperative dexmedetomidine as a method of decreasing PAS. Dexmedetomidine is a highly selective &agr; 2‐adrenoceptor agonist that causes sedation, analgesia, anxiolysis and attenuation of the neuroendocrine and hemodynamic responses to anesthesia and surgery.19 It has also been found to decrease the vasoconstriction and shivering thresholds; making dexmedetomidine a plausible modality in the prevention of PAS.20 The exact role of the &agr;2 receptor in PAS has yet to be completely identified. &agr;2 receptors are located on blood vessels and sympathetic terminals and within the central nervous system and spinal cord.21 Deexmedetomidine's effect on PAS is thought to be through centrally mediated actions.14 Dexmedetomidine's &agr;2‐/&agr;1‐adrenoreceptor selectivity is 1,620:1, compared to clonidine's 220:1.22 This degree of &agr;2 selectivity provides dexmedetomidine with a more desirable pharmacokinetic profile.22 Bolus dosing of 1 &mgr;g/kg dexmedetomidine, a common administration technique, has been associated with transient increases in blood pressure associated with a reflex decrease in heart rate.21 These negative effects can be attenuated by slowing infusion rates or decreasing bolus doses. Doses as low as 0.75 &mgr;g/kg, infused over 10 minutes, have been shown to be effective at preventing PAS when administered 30 minutes prior to the end of surgery.7 Intraoperative administration of dexmedetomidine, both single bolus doses of 0.75‐1 &mgr;g/kg infused over 10 minutes and bolus doses of 1 &mgr;g/kg followed by an infusion of 0.4 &mgr;g/kg/hr, administered at various times during the surgical procedure have been associated with an increased need for atropine, delayed extubation and increased sedation.7,12,23 However, no major impact on overall recovery from anesthesia has been noted and dexmedetomidine continues to be explored as a possible PAS prophylactic agent. 7,12,23 The Joanna Briggs Institute (JBI), Cochrane Library of Systematic Reviews, EMBASE, PubMed, and PROSPERO databases were searched prior to conducting this review. A similar review was initiated on September 25, 2014 in PROSPERO, but the protocol does not define the specific type of anesthesia as outlined in this review. A meta‐analysis was published in 2013 evaluating the efficacy of dexmedetomidine as an anesthetic adjunct in surgery. This analysis did not focus on the treatment or prevention of PAS but the results did support that perioperative dexmedetomidine reduced the incidence of PAS.24 This systematic review is needed to evaluate the effectiveness of dexmedetomidine for the prevention of PAS. Definition of terms used in this review: Postoperative shivering or post‐anesthetic shivering (PAS) is an involuntary, tremor‐like, defense mechanism to increase the body's heat production following general  PAS was monitored by direct observation and recorded by a yes/no response or variation of a 4 or 5 point Likert shivering scale. General anesthesia is the reversible drug induced depression of perception, consciousness and awareness of one's external environment.25 Normothermia (normothermic) is defined as a body temperature within the range of 36.5‐37.5°C and hypothermia is any temperature less than 36.5°C. 8 Thermoregulation (thermogenesis) is the body's compensatory mechanism to maintain a normothermic temperature based on physiological changes sensed by central and peripheral thermal receptors.8 Thermoregulatory effects that maintain a normal body temperature include vasoconstriction, vasodilation, shivering, and

title: Effect of clonidine and dexmedetomidine premedication on perioperative oxygen consumption and haemodynamic state.
abstract: Premedication has been shown to affect both oxygen consumption and metabolic rate. We have compared the perioperative metabolic and haemodynamic effects of two alpha 2-agonists, clonidine and the more selective dexmedetomidine, in 30 ASA I patients undergoing plastic surgical procedures under general anaesthesia. Patients were premedicated with clonidine 4 micrograms kg-1 (n = 10), dexmedetomidine 2.5 micrograms kg-1 (n = 10) or saline (n = 10) i.m. The doses of clonidine and dexmedetomidine were intended to be equipotent. The maximum decrease in preoperative oxygen consumption was 8% and decreases in systolic and diastolic arterial pressures were 11% from baseline after clonidine and dexmedetomidine. During operation, the maximum reduction in heart rate was 18% in the clonidine and dexmedetomidine groups compared with the placebo group. After operation, the maximum decrease in systolic arterial pressure was 11%, diastolic arterial pressure 15% and oxygen consumption 17% in the clonidine and dexmedetomidine groups compared with placebo. In summary, both clonidine 4 micrograms kg-1 and dexmedetomidine 2.5 micrograms kg-1 decreased perioperative oxygen consumption effectively, with a similar haemodynamic profile.

title: Safety and Acceptability of Patient‐Administered Sedatives During Mechanical Ventilation
abstract: Safety and acceptability of sedative selfadministration by patients receiving mechanical ventilation is unknown.  To determine if self‐administration of dexmedetomidine by patients is safe and acceptable for selfmanagement of anxiety during ventilatory support.  In a pilot trial in 3 intensive care units, 17 intubated patients were randomly assigned to dexmedetomidine and 20 to usual care. Dexmedetomidine was administered via standard pumps for patient‐controlled analgesia, with a basal infusion (0.1–0.7 &mgr;g/kg per hour) titrated by the number of patient‐triggered doses (0.25 &mgr;g/kg per dose). Safety goals were heart rate greater than 40/min, systolic blood pressure greater than 80 mm Hg, and diastolic blood pressure greater than 50 mm Hg. Acceptability was based on patients’ self‐reported satisfaction and ability to administer the sedative. A 100‐mm visual analog scale was used daily to assess patients’ anxiety.  The sample was 59% male and 89% white. Mean values were age, 50.6 years; score on the Acute Physiology and Chronic Health Evaluation, 60.1; and protocol duration, 3.4 days. Five dexmedetomidine patients had blood pressure and/or heart rate lower than safety parameters, necessitating short‐term treatment. Nurses’ adherence to reporting of safety parameters was 100%; adherence to the dexmedetomidine titration algorithm was 73%. Overall baseline anxiety score was 38.4 and did not change significantly (&bgr;day = 2.1; SE, 2.5; P = .40). Most dexmedetomidine patients (92%) were satisfied or very satisfied with their ability to self‐administer medication.  For select patients, self‐administration of dexmedetomidine is safe and acceptable.

title: Clinical Practice Guidelines for the Prevention and Management of Pain, Agitation/Sedation, Delirium, Immobility, and Sleep Disruption in Adult Patients in the ICU
abstract: To update and expand the 2013 Clinical Practice Guidelines for the Management of Pain, Agitation, and Delirium in Adult Patients in the ICU.  Thirty-two international experts, four methodologists, and four critical illness survivors met virtually at least monthly. All section groups gathered face-to-face at annual Society of Critical Care Medicine congresses; virtual connections included those unable to attend. A formal conflict of interest policy was developed a priori and enforced throughout the process. Teleconferences and electronic discussions among subgroups and whole panel were part of the guidelines’ development. A general content review was completed face-to-face by all panel members in January 2017.  Content experts, methodologists, and ICU survivors were represented in each of the five sections of the guidelines: Pain, Agitation/sedation, Delirium, Immobility (mobilization/rehabilitation), and Sleep (disruption). Each section created Population, Intervention, Comparison, and Outcome, and nonactionable, descriptive questions based on perceived clinical relevance. The guideline group then voted their ranking, and patients prioritized their importance. For each Population, Intervention, Comparison, and Outcome question, sections searched the best available evidence, determined its quality, and formulated recommendations as “strong,” “conditional,” or “good” practice statements based on Grading of Recommendations Assessment, Development and Evaluation principles. In addition, evidence gaps and clinical caveats were explicitly identified.  The Pain, Agitation/Sedation, Delirium, Immobility (mobilization/rehabilitation), and Sleep (disruption) panel issued 37 recommendations (three strong and 34 conditional), two good practice statements, and 32 ungraded, nonactionable statements. Three questions from the patient-centered prioritized question list remained without recommendation.  We found substantial agreement among a large, interdisciplinary cohort of international experts regarding evidence supporting recommendations, and the remaining literature gaps in the assessment, prevention, and treatment of Pain, Agitation/sedation, Delirium, Immobility (mobilization/rehabilitation), and Sleep (disruption) in critically ill adults. Highlighting this evidence and the research needs will improve Pain, Agitation/sedation, Delirium, Immobility (mobilization/rehabilitation), and Sleep (disruption) management and provide the foundation for improved outcomes and science in this vulnerable population.

title: Awake or Sedated: Trends in the Evaluation and Management of Agitation in the Intensive Care Unit.
abstract: Critically ill intensive care unit (ICU) patients often require sedation to tolerate life-saving interventions such as mechanical ventilation. Pain, anxiety, and delirium all contribute to patient distress and agitation which can interfere with ICU medical care if not addressed and treated appropriately. Sedation practices to treat pain, anxiety, and delirium that deviate from established practice guidelines affect mechanical ventilation duration, ICU and hospital length of stay, functional impairment, and mortality. Historically patients were kept deeply sedated in the ICU. However, considerable research has demonstrated that minimizing sedation with the goal to achieve comfortable wakefulness is preferred in most ICU patients and is associated with improved clinical outcomes. This review will focus on changes in sedation practice in the ICU over the past three decades. With the implementation of validated sedation assessment scales, a multidisciplinary treatment model, and development of daily awakening protocols, no or minimal sedation can be achieved in the majority of ICU patients. Frequent, careful consideration of the environmental stimuli that contribute to patient discomfort and agitation and judicious use of sedative medications individualized to each patient are important in achieving this goal.

title: Dexmedetomidine for prevention of delirium in elderly patients after non-cardiac surgery: a randomised, double-blind, placebo-controlled trial
abstract: Delirium is a postoperative complication that occurs frequently in patients older than 65 years, and presages adverse outcomes. We investigated whether prophylactic low-dose dexmedetomidine, a highly selective α2 adrenoceptor agonist, could safely decrease the incidence of delirium in elderly patients after non-cardiac surgery.



We did this randomised, double-blind, placebo-controlled trial in two tertiary-care hospitals in Beijing, China. We enrolled patients aged 65 years or older, who were admitted to intensive care units after non-cardiac surgery, with informed consent. We used a computer-generated randomisation sequence (in a 1:1 ratio) to randomly assign patients to receive either intravenous dexmedetomidine (0·1 μg/kg per h, from intensive care unit admission on the day of surgery until 0800 h on postoperative day 1), or placebo (intravenous normal saline). Participants, care providers, and investigators were all masked to group assignment. The primary endpoint was the incidence of delirium, assessed twice daily with the Confusion Assessment Method for intensive care units during the first 7 postoperative days. Analyses were done by intention-to-treat and safety populations. 
Between Aug 17, 2011, and Nov 20, 2013, of 2016 patients assessed, 700 were randomly assigned to receive either placebo (n=350) or dexmedetomidine (n=350). The incidence of postoperative delirium was significantly lower in the dexmedetomidine group (32 [9%] of 350 patients) than in the placebo group (79 [23%] of 350 patients; odds ratio [OR] 0·35, 95% CI 0·22-0·54; p<0·0001). Regarding safety, the incidence of hypertension was higher with placebo (62 [18%] of 350 patients) than with dexmedetomidine (34 [10%] of 350 patients; 0·50, 0·32-0·78; p=0·002). Tachycardia was also higher in patients given placebo (48 [14%] of 350 patients) than in patients given dexmedetomidine (23 [7%] of 350 patients; 0·44, 0·26-0·75; p=0·002). Occurrence of hypotension and bradycardia did not differ between groups.



For patients aged over 65 years who are admitted to the intensive care unit after non-cardiac surgery, prophylactic low-dose dexmedetomidine significantly decreases the occurrence of delirium during the first 7 days after surgery. The therapy is safe.


 Fund and Wu Jieping Medical Foundation, Beijing, China. Study drugs were manufactured and supplied by Jiangsu Hengrui Medicine Co, Ltd, Jiangsu, China.

title: Effect of Sedation Regimen on Weaning from Mechanical Ventilation in the Intensive Care Unit
abstract: BackgroundIntensive care unit patients undergoing mechanical ventilation have traditionally been sedated to make them comfortable and to avoid pain and anxiety. However, this may lead to prolonged mechanical ventilation and a longer length of stay.ObjectiveThe aim of this retrospective study was to explore whether different sedation regimens influence the course and duration of the weaning process.Patients and methodsIntubated adult patients (n = 152) from 15 general intensive care units in Sweden were mechanically ventilated for ≥ 24 h. Patients were divided into three groups according to the sedative(s) received during the weaning period (i.e. from being assessed as ‘fit for weaning’ until extubation): dexmedetomidine alone (DEX group, n = 32); standard of care with midazolam and/or propofol (SOC group, n = 67); or SOC plus dexmedetomidine (SOCDEX group, n = 53).ResultsPatients receiving dexmedetomidine alone were weaned more rapidly than those in the other groups despite spending longer time on mechanical ventilation prior to weaning. Anxiety during weaning was present in 0, 9 and 24% patients in the DEX, SOC and SOCDEX groups, respectively. Anxiety after extubation was present in 41, 20 and 34% in the DEX, SOC and SOCDEX groups, respectively. Delirium during weaning was present in 1, 2 and 1 patient in the DEX, SOC and SOCDEX groups, respectively. Delirium at ICU discharge was present in 1, 0 and 3 patients in the DEX, SOC and SOCDEX groups, respectively. Few patients fulfilled criteria for post-traumatic stress disorder.ConclusionDexmedetomidine, used as a single sedative, may have contributed to a shorter weaning period than SOC or SOCDEX. Patients who received dexmedetomidine-only sedation tended to report better health-related quality of life than those receiving other forms of sedation.

title: Efficacy and safety of sedation with dexmedetomidine in critical care patients: a meta-analysis of randomized controlled trials.
abstract: Dexmedetomidine may help physicians target a low level of sedation. Unfortunately, the impact of dexmedetomidine on major endpoints remains unclear in intensive care unit (ICU).



To evaluate the association between dexmedetomidine use with efficacy and safety outcomes, two reviewers independently identified randomized controlled trials comparing dexmedetomidine with other sedative agents in non-post-cardiac surgery critically ill patients in the PubMed and Cochrane databases. Random effects models were considered if heterogeneity was detected using the DerSimonian and Laird estimation method. Statistical heterogeneity between results was assessed by examining forest plots, confidence intervals (CI) and by using the I(2) statistic. The risk of bias was assessed using the risk of bias tool.



This meta-analysis included 1994 patients from 16 randomized controlled trials. Comparators were lorazepam, midazolam and propofol. Dexmedetomidine was associated with a reduction in ICU length of stays (WMD=-0.304; 95% CI [-0.477, -0.132]; P=0.001), mechanical ventilation duration (WMD=-0.313, 95% CI [-0.523, -0.104]; P=0.003) and delirium incidence (RR=0.812, 95% CI [0.680, 0.968]; P=0.020). Dexmedetomidine is also associated with an increase in the incidence of bradycardia (RR=1.947, 95% CI [1.387, 2.733]; P=0.001) and hypotension (RR=1.264; 95% CI [1.013, 1.576]; P=0.038).



In this first meta-analysis including only randomized controlled trials related to ICU patients, dexmedetomidine was associated with a 48h reduction in ICU length of stay, mechanical ventilation duration and delirium occurrence despite a significant heterogeneity among studies. Dexmedetomidine was also associated with an increase in bradycardia and hypotension.

title: Anxiety and Agitation in Mechanically Ventilated Patients
abstract: During an ethnography conducted in an intensive care unit (ICU), we found that anxiety and agitation occurred frequently and were important considerations in the care of 30 patients weaning from prolonged mechanical ventilation. We conducted a secondary analysis to (a) describe characteristics of anxiety and agitation experienced by mechanically ventilated patients, (b) explore how clinicians recognized and interpreted anxiety and agitation, and (c) describe strategies and interventions used to manage anxiety and agitation with mechanically ventilated patients. We constructed the Anxiety/Agitation in Mechanical Ventilation Model to illustrate the multidimensional features of symptom recognition and management. Patients’ ability to interact with the environment served as a basis for identification and management of anxiety or agitation. Clinicians’ attributions about anxiety or agitation, and “knowing the patient,” contributed to their assessment of patient responses. Clinicians chose strategies to overcome either the stimulus or the patient’s appraisal of risk of the stimulus. This article contributes to the body of knowledge about symptom recognition and management in the ICU by providing a comprehensive model to guide future research and practice.

title: Influence of sedation on morbidity and mortality in the intensive care unit.
abstract: Although 30 to 50% of hospitalized patients in a critical care unit are under sedation, there is sparse data on the impact of sedation on morbidity and case-fatality rates in Brazil. Sedation is associated with higher risks of infection and death rate among patients. However, it is difficult to assess the clinical impact of sedation.



To evaluate the impact of sedation on the incidence of nosocomial infection and all-cause deaths at a critical care unit.



Prospective study.



Tertiary-care teaching hospital.



After the exclusion of patients hospitalized for less than 24 hours, 307 patients were assigned to two groups, considering their states of sedation. After confirmation of heterogeneity in relation to the Acute Physiology and Chronic Health Evaluation (APACHE II) prognostic system, 97 sedated and 97 non-sedated patients were matched in relation to this severity index.



Impact of sedation on deep venous thrombosis, incidence of decubital eschars, presence of infection, mortality and length of hospital stay.



There was no difference in the incidence of deep venous thrombosis between the sedated and non-sedated groups, while the frequency of decubital eschars was significantly higher among sedated patients (p = 0.03). Infection was detected in 45.4% of patients under sedation and 21.6% of patients not under sedation (p = 0.006). Mortality for patients that did not receive any kind of sedative was 20.6% and, for those that were sedated during hospitalization, the role was 52.6% (p < 0.0001). The sedated patients had longer hospitalization (11 vs. 4 days) (p < 0.0001).



We concluded that sedation is associated with higher infection risk and case-fatality rate, and longer hospital stay.

title: Weighing the costs and benefits of a sedative.
abstract: RITICALLY ILL PATIENTS TRADITIONALLY WERE HEAVily sedated for safety and to mitigate pain, anxiety, and agitation in the intensive care unit (ICU). But the approach to sedation has shifted with the recognition that heavy sedation may impede care goals such as ventilator weaning and mobilization. 1,2 A related concern is that standard sedatives may contribute to delirium, which hinders patient care, increases length of stay, and is associated with increased mortality. 3 Many approaches are used to decrease the amount of sedation given, including daily interruptions of sedation to reassess a patient, protocols to target sedation to a prespecified level, emphasis on analgesia first, and a change from default sedation for mechanically ventilated patients to individual assessment of need for sedation.

title: ICU-acquired weakness and recovery from critical illness.
abstract: Stays in intensive care units are commonly accompanied by muscle weakness. This article reviews the basis for these changes and provides guidance on how to prevent, diagnose, and treat this condition.

title: Sedation and delirium in the intensive care unit.
abstract: Patients in ICUs often require pain relief and sedation to treat both the underlying medical condition and the unpleasantness associated with being in an ICU. This review provides guidance on the identification and treatment of delirium and sedation.

title: [Effect of sedation on respiratory function of patients undergoing mechanical ventilation].
abstract: Sedation and analgesia for ventilated patients is an important treatment in intensive care unit (ICU). Patients receiving mechanical ventilation therapy comfortably and safely can improve patient-ventilator synchrony, reduce ventilation-related lung injury (VILI), improve compliance, decrease oxygen consumption and stress, prevent accidents, and reduce the incidence of complications and mortality in critical patients. Although sedation may protect lung function, it also has a greater impact on respiratory function. Therefore, based on domestic and overseas related researches about sedation therapy in ventilated patients, we expounded on the effects of sedation therapy, different sedatives and different sedative methods on respiratory function of ventilated patients. The effects of sedation improving patient-ventilator synchrony or protecting pulmonary function as well as problems about inhibition of spontaneous respiration or delayed extubation were discussed to provide references for sedation treatment in patients with mechanical ventilation.

title: [Effects of sedative agents on metabolic demand].
abstract: Literature about the effects of sedative drugs on the metabolic demand of critically ill patients is relatively old and of relatively poor quality. Most are experimental or observational studies. Level of evidence is therefore relatively low corresponding to "expert opinion". The effects of analgesics and hypnotics on tissue metabolic demand associated remain difficult to be adequately quantified. They are essentially related to a decreased neuro-humoral response to stress. This response involves principally the sympathetic system, which could be effectively blocked by most of the anesthetic agents. Other factors could participate to the observed reduction in tissue metabolic demand, as a decrease in spontaneous muscular activity, a reduction in work of breathing and/or a decrease in body temperature. The relative contribution of these different factors will depend on the clinical situation of the patient. Proper effects of anesthetic agents on cellular metabolism are limited as they can only decrease the functional component of this metabolism especially at the level of the heart and to some extent, at the level of the brain. Although the control of the sympathetic activity may be beneficial in critically ill patient, complete sympathetic blockade could be detrimental. Indeed, when oxygen transport to the tissues is acutely reduced, the sympathetic system plays an important role in the redistribution of blood flow according of local metabolic demand. The complete blunting of the neuro-humoral response to stress and therefore of the sympathetic system alters this physiological mechanism and results in a decrease in tissue oxygen extraction capabilities. An imbalance between tissue oxygen demand and delivery could appear with the development of cellular hypoxia. The institution of sedation in a critically ill patient requires careful evaluation of the sedation level using an appropriate scale. In patients in whom a reduction in metabolic demand is specifically requested, but also in patients with limited oxygen transport, the effects of sedative agents on the oxygen consumption-oxygen delivery relationship must also be monitored. The choice of the different agents to be administered will depend on the predefined objectives. As far as intravenous agents are concerned, there is no evidence than one association is more efficient in reducing patient's metabolic demand.

title: Optimizing sedation in patients with acute brain injury
abstract: Daily interruption of sedative therapy and limitation of deep sedation have been shown in several randomized trials to reduce the duration of mechanical ventilation and hospital length of stay, and to improve the outcome of critically ill patients. However, patients with severe acute brain injury (ABI; including subjects with coma after traumatic brain injury, ischaemic/haemorrhagic stroke, cardiac arrest, status epilepticus) were excluded from these studies. Therefore, whether the new paradigm of minimal sedation can be translated to the neuro-ICU (NICU) is unclear. In patients with ABI, sedation has ‘general’ indications (control of anxiety, pain, discomfort, agitation, facilitation of mechanical ventilation) and ‘neuro-specific’ indications (reduction of cerebral metabolic demand, improved brain tolerance to ischaemia). Sedation also is an essential therapeutic component of intracranial pressure therapy, targeted temperature management and seizure control. Given the lack of large trials which have evaluated clinically relevant endpoints, sedative selection depends on the effect of each agent on cerebral and systemic haemodynamics. Titration and withdrawal of sedation in the NICU setting has to be balanced between the risk that interrupting sedation might exacerbate brain injury (e.g. intracranial pressure elevation) and the potential benefits of enhanced neurological function and reduced complications. In this review, we provide a concise summary of cerebral physiologic effects of sedatives and analgesics, the advantages/disadvantages of each agent, the comparative effects of standard sedatives (propofol and midazolam) and the emerging role of alternative drugs (ketamine). We suggest a pragmatic approach for the use of sedation-analgesia in the NICU, focusing on some practical aspects, including optimal titration and management of sedation withdrawal according to ABI severity.

title: Conservative fluid management or deresuscitation for patients with sepsis or acute respiratory distress syndrome following the resuscitation phase of critical illness: a systematic review and meta-analysis
abstract: BackgroundIt is unknown whether a conservative approach to fluid administration or deresuscitation (active removal of fluid using diuretics or renal replacement therapy) is beneficial following haemodynamic stabilisation of critically ill patients.PurposeTo evaluate the efficacy and safety of conservative or deresuscitative fluid strategies in adults and children with acute respiratory distress syndrome (ARDS), sepsis or systemic inflammatory response syndrome (SIRS) in the post-resuscitation phase of critical illness.MethodsWe searched Medline, EMBASE and the Cochrane central register of controlled trials from 1980 to June 2016, and manually reviewed relevant conference proceedings from 2009 to the present. Two reviewers independently assessed search results for inclusion and undertook data extraction and quality appraisal. We included randomised trials comparing fluid regimens with differing fluid balances between groups, and observational studies investigating the relationship between fluid balance and clinical outcomes.ResultsForty-nine studies met the inclusion criteria. Marked clinical heterogeneity was evident. In a meta-analysis of 11 randomised trials (2051 patients) using a random-effects model, we found no significant difference in mortality with conservative or deresuscitative strategies compared with a liberal strategy or usual care [pooled risk ratio (RR) 0.92, 95 % confidence interval (CI) 0.82–1.02, I2 = 0 %]. A conservative or deresuscitative strategy resulted in increased ventilator-free days (mean difference 1.82 days, 95 % CI 0.53–3.10, I2 = 9 %) and reduced length of ICU stay (mean difference −1.88 days, 95 % CI −0.12 to −3.64, I2 = 75 %) compared with a liberal strategy or standard care.ConclusionsIn adults and children with ARDS, sepsis or SIRS, a conservative or deresuscitative fluid strategy results in an increased number of ventilator-free days and a decreased length of ICU stay compared with a liberal strategy or standard care. The effect on mortality remains uncertain. Large randomised trials are needed to determine optimal fluid strategies in critical illness.

title: The relationship between sedative drug utilization and outcomes in critically ill patients undergoing mechanical ventilation
abstract: ObjectivesThe objectives of this study were to describe current sedative drug utilization patterns in critically ill patients undergoing mechanical ventilation (MV) in intensive care units (ICUs) in Japanese hospitals and to elucidate the relationship of these utilization patterns with patient clinical outcomes.MethodAnalysis of hospital claims data derived from the Quality Indicator/Improvement Project identified 12,395 critically ill adult patients who had undergone MV while hospitalized in the ICUs of 114 Japanese hospitals and had been discharged between April 2008 and March 2010. Descriptive statistics were calculated for the daily utilization of sedative drugs, opioids, and muscle relaxants in this patient sample, and the relationship between drug utilization and patient outcomes using Cox proportional hazards analysis were examined.ResultsOf the 12,395 patients included in the analysis, 7300 (58.9 %), 580 (4.7 %), and 671 (5.4 %) received sedative drugs, opioids, and muscle relaxants, respectively, for ≥2 days after intubation. Compared to the other patient groups, there was a higher proportion of males in the group given sedative drugs and the patients were significantly younger (P < 0.001). Propofol was the most frequently used sedative drug, followed by benzodiazepines, barbiturates, and dexmedetomidine. The mortality rate was lower and ventilator weaning was earlier among patients who received only propofol than among those who received only benzodiazepines. Muscle relaxants were associated with increased duration of MV.ConclusionsThis is the first study based on a large-scale analysis in Japan to elucidate sedative drug utilization patterns and their relationship with outcomes in critically ill patients. The most commonly used sedative was propofol, which was associated with favorable patient outcomes. Further prospective research must be conducted to discern effective sedative drug utilization.

title: Postoperative Noninvasive Ventilation
abstract: Thesemodificationsoftherespiratoryfunctionoccur early after surgery and are more often transient andcould lead to ARF. The clinical result (severity of theARF) is the product of perioperative-related ventilatoryimpairment and severity of the preoperative pulmonarycondition. Maintenance of adequate oxygenation in thepostoperative period is of major importance, especiallywhen pulmonary complications such as ARF occur. Al-though invasive endotracheal mechanical ventilation hasremained the cornerstone of ventilatory strategy for manyyearsforsevereARF,severalstudieshaveshownthatmor-tality associated with pulmonary disease is largely relatedto complications of postoperative reintubation and me-chanicalventilation.Therefore,majorobjectivesforanes-thesiologists are first to prevent the occurrence of postop-erative complications and second to ensure oxygenadministration and carbon dioxide removal while avoid-ing intubation if ARF occurs. Noninvasive ventilation(NIV) does not require an artificial airway (endotrachealtube or tracheotomy), and its use is well established toprevent ARF occurrence (prophylactic treatment) or totreat ARF to avoid reintubation (curative treatment) (fig.1). Studies show that patient-related risk factors, such aschronic obstructive pulmonary disease, age older than 60yr, American Society of Anesthesiologists class of II orhigher, obesity, functional dependence, and congestiveheart failure, increase the risk for postoperative pulmo-nary complications.

title: Non-invasive ventilation for the management of acute hypercapnic respiratory failure due to exacerbation of chronic obstructive pulmonary disease.
abstract: Non-invasive ventilation (NIV) with bi-level positive airway pressure (BiPAP) is commonly used to treat patients admitted to hospital with acute hypercapnic respiratory failure (AHRF) secondary to an acute exacerbation of chronic obstructive pulmonary disease (AECOPD).



To compare the efficacy of NIV applied in conjunction with usual care versus usual care involving no mechanical ventilation alone in adults with AHRF due to AECOPD. The aim of this review is to update the evidence base with the goals of supporting clinical practice and providing recommendations for future evaluation and research.



We identified trials from the Cochrane Airways Group Specialised Register of trials (CAGR), which is derived from systematic searches of bibliographic databases including the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, the Cumulative Index to Nursing and Allied Health Literature (CINAHL), the Allied and Complementary Medicine Database (AMED), and PsycINFO, and through handsearching of respiratory journals and meeting abstracts. This update to the original review incorporates the results of database searches up to January 2017.



All randomised controlled trials that compared usual care plus NIV (BiPAP) versus usual care alone in an acute hospital setting for patients with AECOPD due to AHRF were eligible for inclusion. AHRF was defined by a mean admission pH < 7.35 and mean partial pressure of carbon dioxide (PaCO2) > 45 mmHg (6 kPa). Primary review outcomes were mortality during hospital admission and need for endotracheal intubation. Secondary outcomes included hospital length of stay, treatment intolerance, complications, changes in symptoms, and changes in arterial blood gases.



Two review authors independently applied the selection criteria to determine study eligibility, performed data extraction, and determined risk of bias in accordance with Cochrane guidelines. Review authors undertook meta-analysis for data that were both clinically and statistically homogenous, and analysed data as both one overall pooled sample and according to two predefined subgroups related to exacerbation severity (admission pH between 7.35 and 7.30 vs below 7.30) and NIV treatment setting (intensive care unit-based vs ward-based). We reported results for mortality, need for endotracheal intubation, and hospital length of stay in a 'Summary of findings' table and rated their quality in accordance with GRADE criteria.



We included in the review 17 randomised controlled trials involving 1264 participants. Available data indicate that mean age at recruitment was 66.8 years (range 57.7 to 70.5 years) and that most participants (65%) were male. Most studies (12/17) were at risk of performance bias, and for most (14/17), the risk of detection bias was uncertain. These risks may have affected subjective patient-reported outcome measures (e.g. dyspnoea) and secondary review outcomes, respectively.Use of NIV decreased the risk of mortality by 46% (risk ratio (RR) 0.54, 95% confidence interval (CI) 0.38 to 0.76; N = 12 studies; number needed to treat for an additional beneficial outcome (NNTB) 12, 95% CI 9 to 23) and decreased the risk of needing endotracheal intubation by 65% (RR 0.36, 95% CI 0.28 to 0.46; N = 17 studies; NNTB 5, 95% CI 5 to 6). We graded both outcomes as 'moderate' quality owing to uncertainty regarding risk of bias for several studies. Inspection of the funnel plot related to need for endotracheal intubation raised the possibility of some publication bias pertaining to this outcome. NIV use was also associated with reduced length of hospital stay (mean difference (MD) -3.39 days, 95% CI -5.93 to -0.85; N = 10 studies), reduced incidence of complications (unrelated to NIV) (RR 0.26, 95% CI 0.13 to 0.53; N = 2 studies), and improvement in pH (MD 0.05, 95% CI 0.02 to 0.07; N = 8 studies) and in partial pressure of oxygen (PaO2) (MD 7.47 mmHg, 95% CI 0.78 to 14.16 mmHg; N = 8 studies) at one hour. A trend towards improvement in PaCO2 was observed, but this finding was not statistically significant (MD -4.62 mmHg, 95% CI -11.05 to 1.80 mmHg; N = 8 studies). Post hoc analysis revealed that this lack of benefit was due to the fact that data from two studies at high risk of bias showed baseline imbalance for this outcome (worse in the NIV group than in the usual care group). Sensitivity analysis revealed that exclusion of these two studies resulted in a statistically significant positive effect of NIV on PaCO2. Treatment intolerance was significantly greater in the NIV group than in the usual care group (risk difference (RD) 0.11, 95% CI 0.04 to 0.17; N = 6 studies). Results of analysis showed a non-significant trend towards reduction in dyspnoea with NIV compared with usual care (standardised mean difference (SMD) -0.16, 95% CI -0.34 to 0.02; N = 4 studies). Subgroup analyses revealed no significant between-group differences.



Data from good quality randomised controlled trials show that NIV is beneficial as a first-line intervention in conjunction with usual care for reducing the likelihood of mortality and endotracheal intubation in patients admitted with acute hypercapnic respiratory failure secondary to an acute exacerbation of chronic obstructive pulmonary disease (COPD). The magnitude of benefit for these outcomes appears similar for patients with acidosis of a mild (pH 7.30 to 7.35) versus a more severe nature (pH < 7.30), and when NIV is applied within the intensive care unit (ICU) or ward setting.

title: Non-invasive ventilation in cardiogenic pulmonary edema.
abstract: Cardiogenic pulmonary edema (CPE) is among the most common causes of acute respiratory failure (ARF) in the acute care setting and often requires ventilatory assistance. In patients with ARF due to CPE, use of non-invasive positive airway pressure can decrease the systemic venous return and the left ventricular (LV) afterload, thus reducing LV filling pressure and limiting pulmonary edema. In these patients, either non-invasive ventilation (NIV) or continuous positive airway pressure (CPAP) can improve vital signs and physiological parameters, decreasing the need for endotracheal intubation (ETI) and hospital mortality when compared to conventional oxygen therapy. Results on the use of NIV or CPAP in patients with CPE prior to hospitalization are not homogeneous among studies, hampering any conclusive recommendation regarding their role in the pre-hospital setting.

title: Noninvasive versus conventional mechanical ventilation. An epidemiologic survey.
abstract: A prospective survey was performed over a period of 3 wk among 42 intensive care units to assess the incidence of use and effectiveness of noninvasive mechanical ventilation (NIV) in clinical practice. All patients requiring ventilatory support for acute respiratory failure (ARF), either with endotracheal intubation (ETI) or NIV, were included. Ventilatory support was required in 689 patients, 581 with ETI and 108 (16%) with NIV (35% of patients not intubated on admission). Reasons for mechanical ventilation were coma (30%), cardiogenic pulmonary edema (7%), and hypoxemic (48%) and hypercapnic ARF (15%). NIV was never used for patients in coma (who were excluded from further analysis), but was used in 14% of patients with hypoxemic ARF, in 27% of those with pulmonary edema, and in 50% of those with hypercapnic ARF. NIV was followed by ETI in 40% of cases. The incidence of both nosocomial pneumonia (10% versus 19%, p = 0.03), and mortality (22% versus 41%, p < 0.001) was lower in NIV patients than in those with ETI. After adjusting for differences at baseline, Simplified Acute Physiology Score (SAPS) II (odds ratio [OR] = 1.05 per point; confidence interval [CI]: 1.04 to 1.06), McCabe/Jackson score (OR = 2.18; CI: 1.57 to 3.03), and hypoxemic ARF (OR = 2.30; CI: 1.33 to 4.01) were identified as risk factors explaining mortality; success of NIV was associated with a lower risk of pneumonia (OR = 0.06; CI: 0.01 to 0.45) and of death (OR = 0.16; CI: 0.05 to 0.54). In NIV patients, SAPS II and a poor clinical tolerance predicted secondary ETI. Failure of NIV was associated with a longer length of stay. In conclusion, NIV can be successful in selected patients, and is associated with a lower risk of pneumonia and death than is ETI.

title: Delirium in elderly people
abstract: Delirium is an acute disorder of attention and cognition in elderly people (ie, those aged 65 years or older) that is common, serious, costly, under-recognised, and often fatal. A formal cognitive assessment and history of acute onset of symptoms are necessary for diagnosis. In view of the complex multifactorial causes of delirium, multicomponent non-pharmacological risk factor approaches are the most effective strategy for prevention. No convincing evidence shows that pharmacological prevention or treatment is effective. Drug reduction for sedation and analgesia and non-pharmacological approaches are recommended. Delirium offers opportunities to elucidate brain pathophysiology--it serves both as a marker of brain vulnerability with decreased reserve and as a potential mechanism for permanent cognitive damage. As a potent indicator of patients' safety, delirium provides a target for system-wide process improvements. Public health priorities include improvements in coding, reimbursement from insurers, and research funding, and widespread education for clinicians and the public about the importance of delirium.

title: Addition of dexmedetomidine to bupivacaine for greater palatine nerve block prolongs postoperative analgesia after cleft palate repair
abstract: The effect of dexmedetomidine on the duration of sensory blockade has not been studied in humans. We evaluated the effect of adding dexmedetomidine to bupivacaine on the duration of postoperative analgesia in children who underwent repair of a cleft palate.  Thirty children who were scheduled for repair of a complete cleft palate using a combination of general anaesthesia and greater palatine nerve block were allocated randomly into one of two equal groups (n = 15). In both groups, the greater palatine nerve block was performed bilaterally using 0.5 ml of solution on each side. The B group received bupivacaine 0.25%, whereas the BD group received bupivacaine 0.25% with 1 μg kg−1 dexmedetomidine. Heart rate, systolic blood pressure, pain score, the time to the first request for analgesia, and the degree of sedation were recorded.  There was no difference in haemodynamic variables between the two groups. The pain score was significantly higher in the B group as compared with the BD group. The time to the first request for analgesia was significantly longer in children in the BD group (mean 22 h, range 20.6–23.7 h) as compared with those who received bupivacaine alone (14.2 h, 13–15 h). Sedation scores in the postoperative period did not differ between the study groups.  Greater palatine nerve block with a combination of dexmedetomidine and bupivacaine increased the duration of analgesia after repair of a cleft palate by 50% with no clinically relevant side effects.

title: Delirium as a predictor of mortality in mechanically ventilated patients in the intensive care unit.
abstract: In the intensive care unit (ICU), delirium is a common yet underdiagnosed form of organ dysfunction, and its contribution to patient outcomes is unclear.



To determine if delirium is an independent predictor of clinical outcomes, including 6-month mortality and length of stay among ICU patients receiving mechanical ventilation.



Prospective cohort study enrolling 275 consecutive mechanically ventilated patients admitted to adult medical and coronary ICUs of a US university-based medical center between February 2000 and May 2001. Patients were followed up for development of delirium over 2158 ICU days using the Confusion Assessment Method for the ICU and the Richmond Agitation-Sedation Scale.



Primary outcomes included 6-month mortality, overall hospital length of stay, and length of stay in the post-ICU period. Secondary outcomes were ventilator-free days and cognitive impairment at hospital discharge.



Of 275 patients, 51 (18.5%) had persistent coma and died in the hospital. Among the remaining 224 patients, 183 (81.7%) developed delirium at some point during the ICU stay. Baseline demographics including age, comorbidity scores, dementia scores, activities of daily living, severity of illness, and admission diagnoses were similar between those with and without delirium (P>.05 for all). Patients who developed delirium had higher 6-month mortality rates (34% vs 15%, P =.03) and spent 10 days longer in the hospital than those who never developed delirium (P<.001). After adjusting for covariates (including age, severity of illness, comorbid conditions, coma, and use of sedatives or analgesic medications), delirium was independently associated with higher 6-month mortality (adjusted hazard ratio [HR], 3.2; 95% confidence interval [CI], 1.4-7.7; P =.008), and longer hospital stay (adjusted HR, 2.0; 95% CI, 1.4-3.0; P<.001). Delirium in the ICU was also independently associated with a longer post-ICU stay (adjusted HR, 1.6; 95% CI, 1.2-2.3; P =.009), fewer median days alive and without mechanical ventilation (19 [interquartile range, 4-23] vs 24 [19-26]; adjusted P =.03), and a higher incidence of cognitive impairment at hospital discharge (adjusted HR, 9.1; 95% CI, 2.3-35.3; P =.002).



Delirium was an independent predictor of higher 6-month mortality and longer hospital stay even after adjusting for relevant covariates including coma, sedatives, and analgesics in patients receiving mechanical ventilation.

title: Role of Dexmedetomidine for the Prevention and Treatment of Delirium in Intensive Care Unit Patients
abstract: To review recent clinical studies regarding the role of dexmedetomidine for prevention and treatment of delirium in intensive care unit (ICU) patients.  MEDLINE and PubMed searches (1988-Feburary 2013) were conducted, using the key words delirium, dexmedetomidine, Precedex, agitation, α-2 agonists, critical care, and intensive care. References from relevant articles were reviewed for additional information.  Clinical trials comparing dexmedetomidine with other sedatives/analgesics or with antipsychotics for delirium were selected. Studies that evaluated the use of dexmedetomidine for sedation for more than 6 hours were included in this review.  Dexmedetomidine is a highly selective α-2 receptor agonist that provides sedation, anxiolysis, and modest analgesia with minimal respiratory depression. Its mechanism of action is unique compared with that of traditional sedatives because it does not act on γ-aminobutyric acid receptors. In addition, dexmedetomidine lacks anticholinergic activity and promotes a natural sleep pattern. These pharmacologic characteristics may explain the possible antidelirium effects of dexmedetomidine. Eight clinical trials, including 5 double-blind randomized trials, were reviewed to evaluate the impact of dexmedetomidine on ICU delirium.  Currently available evidence suggests that dexmedetomidine is a promising agent, not only for prevention but also for treatment of ICU-associated delirium. However, larger, well-designed trials are warranted to define the role of dexmedetomidine in preventing and treating delirium in the ICU.

title: Dexmedetomidine reduces the risk of delirium, agitation and confusion in critically Ill patients: a meta-analysis of randomized controlled trials.
abstract: Delirium frequently is observed in critically ill patients in the intensive care unit (ICU) and is associated strongly with a poor outcome. Dexmedetomidine seems to reduce time to extubation and ICU stay without detrimental effects on mortality. The objective of the authors' study was to evaluate the effect of this drug on delirium, agitation, and confusion in the ICU setting.



Meta-analysis of all the randomized clinical trials ever performed on dexmedetomidine versus any comparator in the ICU setting.



Intensive care units.



Critically ill patients.



None



Pertinent studies were independently searched in BioMedCentral, PubMed, Embase, and the Cochrane Central Register of clinical trials. Primary endpoint was the rate of delirium, including the adverse events, agitation and confusion. The 13 included manuscripts (14 trials) randomized 3,029 patients. Overall analysis showed that the use of dexmedetomidine was associated with significant reductions in the incidence of delirium, agitation and confusion (298/1,565 [19%] in the dexmedetomidine group v 337/1,464 [23%] in the control group, RR = 0.68 [0.49 to 0.96], p = 0.03). Results were confirmed in subanalyses performed on patients undergoing noninvasive ventilation (1/53 [2%] in the dexmedetomidine group v 7/49 [14%] in the control group, RR=0.18 [0.03 to 1.01], p = 0.05), receiving midazolam as a comparator (268/1,164 [23%] in the dexmedetomidine group v 277/1,025 [27%] in the control group, RR = 0.68 [0.47 to 1.00], p = 0.05) and in general ICU setting patients (204/688 [30%] in the dexmedetomidine group v 204/560 [36%] in the control group, RR = 0.68 [0.45 to 0.81], p < 0.01).



This meta-analysis of randomized controlled studies suggests that dexmedetomidine could help to reduce delirium in critically ill patients.

title: Efficacy of perioperative dexmedetomidine on postoperative delirium: systematic review and meta‐analysis with trial sequential analysis of randomised controlled trials
abstract: The influence of dexmedetomidine on postoperative delirium (POD) in adult surgical patients remains controversial. We aimed to analyse whether dexmedetomidine use could decrease POD incidence in this population and its relation to timing of dexmedetomidine administration and patient age.  We used random‐effects modelled meta‐analysis, trial sequential analysis, and followed Cochrane methodology with Grading of Recommendations Assessment, Development, and Evaluation (GRADE). PubMed and Cochrane library were searched up to July 2017 for randomised controlled trials that analysed POD incidence of adult surgical patients (age ≥18 yr) after dexmedetomidine administration.  Eighteen studies (comprising 3309 patients) were included. There was decreased risk of POD with dexmedetomidine use for the entire adult surgical population [odds ratio (OR) 0.35; 95% confidence interval (CI) 0.24–0.51)], with firm evidence from trial sequential analysis. Pre‐specified subgroup analyses confirmed this result with firm evidence for cardiac and non‐cardiac surgical patients, (OR 0.41; 95% CI 0.26–0.63) and (OR 0.33; 95% CI 0.18–0.59), respectively. We also found firm evidence for reduction of POD if dexmedetomidine is administered during the postoperative period (OR 0.30; 95% CI 0.21–0.44), in patients aged <65 yr (OR 0.19; 95% CI 0.10–0.36) or ≥65 yr (OR 0.44; 95% CI 0.30–0.65). Evidence for dexmedetomidine's influence on secondary outcomes (in‐hospital mortality, intensive care unit and hospital length of stay, bradycardia, and hypotension) is thus far insufficient to draw conclusions.  Dexmedetomidine can reduce POD incidence for adult cardiac and non‐cardiac surgical patients. The optimal dose and timing of dexmedetomidine and influence on other outcomes or particular patient populations with risk factors warrants further studies.

title: Dexmedetomidine in prevention and treatment of postoperative and intensive care unit delirium: a systematic review and meta-analysis
abstract: BackgroundTo determine the preventive and therapeutic effect of dexmedetomidine on intensive care unit (ICU) delirium.MethodsThe literature search using PubMed and the Cochrane Central Register of Controlled Trials was performed (August 1, 2018) to detect all randomized controlled trials (RCTs) of adult ICU patients receiving dexmedetomidine. Articles were included if they assessed the influence of dexmedetomidine compared to a sedative agent on incidence of ICU delirium or treatment of this syndrome. Accordingly, relevant articles were allocated to the following two groups: (1) articles that assessed the delirium incidence (incidence comparison) or articles that assessed the treatment of delirium (treatment comparison). Incidence of delirium and delirium resolution were the primary outcomes. We combined treatment effects comparing dexmedetomidine versus (1) placebo, (2) standard sedatives, and (3) opioids in random-effects meta-analyses. Risk of bias for each included RCT was assessed following Cochrane standards.ResultsThe literature search resulted in 28 articles (25  patients for the incidence comparison and three articles/166 patients for the treatment comparison). In the incidence comparison, heterogeneity was present in different subgroups. Administration of dexmedetomidine was associated with significantly lower overall incidence of delirium when compared to placebo (RR 0.52; 95% CI 0.39–0.70; I2 = 37%), standard sedatives (RR 0.63; 95% CI 0.46–0.86; I2 = 69%), as well as to opioids (RR 0.61; 95% CI 0.44–0.83; I2 = 0%). Use of dexmedetomidine significantly increased the risks of bradycardia and hypotension. Limited data were available on circulatory insufficiency and mortality. In the treatment comparison, the comparison drugs in the three RCTs were placebo, midazolam, and haloperidol. The resolution of delirium was measured differently in each study. Two out of the three studies indicated clear favorable effects for dexmedetomidine (i.e., compared to placebo and midazolam). The study comparing dexmedetomidine with haloperidol was a pilot study (n = 20) with high variability in the results.ConclusionFindings suggest that dexmedetomidine reduces incidence and duration of ICU delirium. Furthermore, our systematic searches show that there is limited evidence if a delirium shall be treated with dexmedetomidine.

title: Neuroprotection and neurotoxicity in the developing brain: an update on the effects of dexmedetomidine and xenon.
abstract: Growing and consistent preclinical evidence, combined with early clinical epidemiological observations, suggest potentially neurotoxic effects of commonly used anesthetic agents in the developing brain. This has prompted the FDA to issue a safety warning for all sedatives and anesthetics approved for use in children under three years of age. Recent studies have identified dexmedetomidine, the potent α2-adrenoceptor agonist, and xenon, the noble gas, as effective anesthetic adjuvants that are both less neurotoxic to the developing brain, and also possess neuroprotective properties in neonatal and other settings of acute ongoing neurologic injury. Dexmedetomidine and xenon are effective anesthetic adjuvants that appear to be less neurotoxic than other existing agents and have the potential to be neuroprotective in the neonatal and pediatric settings. Although results from recent clinical trials and case reports have indicated the neuroprotective potential of xenon and dexmedetomidine, additional randomized clinical trials corroborating these studies are necessary. By reviewing both the existing preclinical and clinical evidence on the neuroprotective effects of dexmedetomidine and xenon, we hope to provide insight into the potential clinical efficacy of these agents in the management of pediatric surgical patients.

title: The protective effects of dexmedetomidine on ischemic brain injury: A meta-analysis.
abstract: Intracranial lesions, trauma or surgery-related damage activate immune inflammation and neuroendocrine responses, causing ischemic brain injury. Studies have shown that inflammatory cascade mediated by neuroendocrine hormones and proinflammatory mediators is implicated in the pathophysiology of ischemic brain injury. Alpha2-adrenoceptor agonists, dexmedetomidine, is widely used as neuroprotectants in anesthesia practice. However, it is still lack of a comprehensive meta-analysis to evaluate the neuroprotection of dexmedetomidine against ischemic brain injury via suppressing these two physiological responses.



Searched the Cochrane Library, Pub-Med, EMBASE, EBSCO, Ovid, Chinese biological and medical database (CBM). Related literatures published in English or Chinese before January 2017 were enrolled. We assessed the quality of eligible studies and synthesized predefined outcomes with a random-effects model or fixed-effects model.



Nineteen Randomized Controlled Trials including 879 patients were included. Findings for meta-analysis of various outcomes were summarised. Primary results shown that compared with placebo, dexmedetomidine reduced a surge of TNF-α [SMD=-2.34, 95%CI (-3.25, -1.44)], IL-6 [SMD=-2.44, 95%CI (-3.40, -1.47)], S100-β [SMD=-2.73, 95%CI (-3.65, -1.82)], NSE [SMD=-1.69, 95%CI (-2.77, -0.61)], cortisol [SMD=-2.48, 95%CI (-3.38, -1.58)] and glucose [SMD=-1.44, 95%CI (-1.85, -1.04)]; maintained the level of SOD [SMD=1.36, 95%CI (0.62, 2.10)]; decreased the rise in CRP level at postoperative one day. In response to stress reaction, dexmedetomidine attenuated the stress-related increasing of MAP, HR and intracranial pressure without significant effects on cerebral oxygen metabolism.



Alpha2-adrenoceptor agonists, dexmedetomidine, could reduce the release of inflammatory mediators and neuroendocrine hormones as well as maintain intracranial homoeostasis, alleviating ischemic brain injury and exerting an effect on brain protection.

title: Late phase of long-term potentiation induced by co-application of N-methyl-d-aspartic acid and the antagonist of NR2B-containing N-methyl-d-aspartic acid receptors in rat hippocampus
abstract: Activation of N-methyl-d-aspartic acid (NMDA) glutamate receptors (NMDARs) is required for long-term potentiation (LTP) of excitatory synaptic transmission at hippocampal CA1 synapses, the proposed cellular mechanisms of learning and memory. We demonstrate here that a brief bath co-application of a low concentration of NMDA, an agonist of NMDARs, and the selective antagonist of NR2B-containing NMDARs, (alpha R, beta S)-alpha-(4-hydroxyphenyl)-beta-methyl-4-(phenylmethyl)-1-piperidinepropanol (Ro25-6981), to hippocampal slices from young adult rats produced a slowly developing LTP persisting at least for 6 h following a transient depression of synaptic transmission in CA1 synapses. The LTP was likely to occur at postsynaptic site and was initiated by activation of NMDARs, and its development was mediated by cAMP-dependent protein kinase (PKA) activation and protein synthesis. This chemically induced LTP and the tetanus-induced late phase of LTP (L-LTP) were mutually occluding, suggesting a common expression mechanism. Thus, we have demonstrated that a brief bath co-application of NMDA with Ro25-6981 to a slice offers an alternative to electrical stimulation as a stimulation method to induce L-LTP. The chemically induced LTP did not require the low-frequency test stimulation typically used to monitor the strength of synapses during and after drug application. Thus, the LTP may occur at a large fraction of synapses in the slice and not to be confined to a small fraction of the synapses where electrical stimulation can reach and induce LTP. Therefore, this chemically induced LTP may be useful for assessing the biochemical and morphological correlates and the molecular aspects of the expression mechanism for L-LTP that has been proven to correlate to hippocampal long-term memory.

title: Dexmedetomidine Postconditioning Reduces Brain Injury after Brain Hypoxia-Ischemia in Neonatal Rats
abstract: Perinatal asphyxia can lead to death and severe disability. Brain hypoxia-ischemia (HI) injury is the major pathophysiology contributing to death and severe disability after perinatal asphyxia. Here, seven-day old Sprague-Dawley rats were subjected to left brain HI. Dexmedetomidine was given intraperitoneally after the brain HI. Yohimbine or atipamezole, two α2 adrenergic receptor antagonists, were given 10 min before the dexmedetomidine injection. Neurological outcome was evaluated 7 or 28 days after the brain HI. Frontal cerebral cortex was harvested 6 h after the brain HI. Left brain HI reduced the left cerebral hemisphere weight assessed 7 days after the brain HI. This brain tissue loss was dose-dependently attenuated by dexmedetomidine. Dexmedetomidine applied within 1 h after the brain HI produced this effect. Dexmedetomidine attenuated the brain HI-induced brain tissue and cell loss as well as neurological and cognitive dysfunction assessed from 28 days after the brain HI. Dexmedetomidine postconditioning-induced neuroprotection was abolished by yohimbine or atipamezole. Brain HI increased tumor necrosis factor α and interleukin 1β in the brain tissues. This increase was attenuated by dexmedetomidine. Atipamezole inhibited this dexmedetomidine effect. Our results suggest that dexmedetomidine postconditioning reduces HI-induced brain injury in the neonatal rats. This effect may be mediated by α2 adrenergic receptor activation that inhibits inflammation in the ischemic brain tissues.

title: Dexmedetomidine for Refractory Intracranial Hypertension
abstract: Dexmedetomidine (DEX) is a selective α2 adrenergic agonist that is commonly used for sedation in the intensive care unit (ICU). The role of DEX for adjunctive treatment of refractory intracranial hypertension is poorly defined. The primary objective of this study was to determine the effect of DEX on the need for rescue therapy (ie, hyperosmolar boluses, extraventricular drain [EVD] drainages) for refractory intracranial hypertension. Secondary objectives included the number of intracranial pressure (ICP) excursions, bradycardic, hypotensive, and compromised cerebral perfusion pressure episodes. This retrospective cohort study evaluated patients admitted to the neurosurgical ICU from August 1, 2009, to July 29, 2015, and who received DEX for refractory intracranial hypertension. The objectives were compared between the 2 time periods—before (pre-DEX) and during therapy (DEX). Twenty-three patients with 26 episodes of refractory intracranial hypertension met the inclusion criteria. The number of hyperosmolar boluses was decreased after DEX therapy was initiated. Mannitol boluses required were statistically reduced (1 vs 0.5, P = .03); however, reduction in hypertonic boluses was not statistically significant (1.3 vs 0.9, P = .2). The mean number of EVD drainages per 24 hours was not significantly different between the time periods (15.7 vs 14.0, P = .35). The rate of ICP excursions did not differ between the 2 groups (24.3 vs 22.5, P = .62). When compared to pre-DEX data, there was no difference in the median number of hypotensive (0 vs 0), bradycardic (0 vs 0), or compromised cerebral perfusion pressure episodes (0.5 vs 1.0). Dexmedetomidine may avoid increases in the need for rescue therapy when used as an adjunctive treatment of refractory intracranial hypertension without compromising hemodynamics.

title: Dexmedetomidine suppresses proinflammatory mediator production in human whole blood in vitro
abstract: It has been demonstrated that proinflammatory mediators increase in patients with sepsis, trauma, and burns. These mediators are associated with the development of septic shock and organ dysfunction. Dexmedetomidine (DEX), a selective agonist of the [alpha]2‐adrenergic receptors, is used in intensive care units for sedation. However, it still remains unclear whether DEX administration has any effects on the production of proinflammatory mediators. In this study, we investigated the effects of DEX on lipopolysaccharide (LPS)–induced production of tumor necrosis factor [alpha], interleukin 6 (IL‐6), IL‐8, and high‐mobility group box 1 protein in human whole blood.  Human whole blood was cultured with LPS for up to 24 hours, and LPS‐induced proinflammatory mediator production was measured. Next, we tested the effect of DEX on whole blood proinflammatory mediator production. Human whole blood was cultured with LPS and various concentrations of DEX for 12 hours. Then, we investigated the influence of yohimbine, an antagonist of the [alpha]2‐adrenergic receptors, on the effects of DEX. The effect of DEX on necrosis factor [kappa]B (NF[kappa]B) activation was also investigated.  DEX suppressed tumor necrosis factor [alpha], IL‐6, IL‐8, and high‐mobility group box 1 protein production in human whole blood. The suppressing effects of DEX on proinflammatory mediator production were reversed by yohimbine. The results suggested that the mechanism for the suppressive effects of DEX on proinflammatory mediator production is meditated via [alpha]2‐adrenergic receptors. These effects of DEX also include an inhibitory effect on NF[kappa]B activation.  We demonstrate the suppressing effect of DEX on inflammatory mediator production in human whole blood after LPS stimulation. The mechanism for the suppressive effect of DEX on proinflammatory mediator production may be through the [alpha]2‐adrenergic receptors and NF[kappa]B inhibition.

title: Dexmedetomidine Controls Systemic Cytokine Levels through the Cholinergic Anti-inflammatory Pathway
abstract: Previous studies have shown that dexmedetomidine exerted anti-inflammatory effect on several animal models with inflammation, but the mechanism is not clear. This study intends to elucidate the anti-inflammatory mechanism of dexmedetomidine through the cholinergic anti-inflammatory pathway. To investigate this therapeutic potential of dexmedetomidine, a murine model of endotoxemia was established induced by lipopolysaccharide (LPS). Animals were assigned to one of four protocols.  The survival rate was assessed up to 120 h after endotoxin injection.  and sterile saline to observe the discharge activity of cervical vagus nerves by using BL-420F data acquisition and analysis system (n = 16 each). In the survival analysis groups, the survival rate of dexmedetomidine group was significantly higher than that of the endotoxemia group (65 versus 25 %, P < 0.01). Preemptive administration of dexmedetomidine significantly attenuated the cytokine response after lipopolysaccharide (LPS) induced endotoxemia (TNF-alpha, IL-1beta, IL-6, P < 0.01, respectively). However, preemptive administration of dexmedetomidine failed to suppress cytokine response in α-bungarotoxin group and vagotomy group (TNF-alpha, IL-1beta, IL-6, P > 0.05, respectively). Furthermore, preemptive administration of dexmedetomidine significantly increased the discharge frequency of cervical vagus nerves in comparison with sterile saline treatment (P < 0.01).Our results demonstrate that the preemptive administration of dexmedetomidine increases the activity of cervical vagus nerve and have the ability to successfully improve survival in experimental endotoxemia by inhibiting the inflammatory cytokines release. However, administration of dexmedetomidine to vagotomy or α7 nAChR antagonist pretreatment mice failed to suppress TNF levels, indicating that the vagus nerve and α7nAChR-mediated cholinergic anti-inflammatory pathway is required for the anti-inflammatory effect of dexmedetomidine. These findings show that central alpha-2 agonist dexmedetomidine suppresses systemic inflammation through vagal- and α7nAChR-dependent mechanism.

title: Sepsis pathophysiology and anesthetic consideration.
abstract: Sepsis remains to be a significant health care issue associated with high mortality and healthcare cost, despite the extensive effort to better understand the pathophysiology of the sepsis. Recently updated clinical guideline for severe sepsis and septic shock, "Surviving Sepsis Campaign 2012", emphasizes the importance of early goal-directed therapy, which can be implemented in intraoperative management of sepsis patients. Herein, we review the updates of current guideline and discuss its application to anesthesic management. Furthermore, we review the recent advance in knowledge of sepsis pathophysiology, focusing on immune modulation, which may lead to new clinical therapeutic approach to sepsis.

title: Impact of Anesthetics, Analgesics, and Perioperative Blood Transfusion in Pediatric Cancer Patients: A Comprehensive Review of the Literature.
abstract: Cancer is the leading cause of death by disease in developed countries. Children and adolescents with cancer need surgical interventions (ie, biopsy or major surgery) to diagnose, treat, or palliate their malignancies. Surgery is a period of high vulnerability because it stimulates the release of inflammatory mediators, catecholamines, and angiogenesis activators, which coincides with a period of immunosuppression. Thus, during and after surgery, dormant tumors or micrometastasis (ie, minimal residual disease) can grow and become clinically relevant metastasis. Anesthetics (ie, volatile agents, dexmedetomidine, and ketamine) and analgesics (ie, opioids) may also contribute to the growth of minimal residual disease or disease progression. For instance, volatile anesthetics have been implicated in immunosuppression and direct stimulation of cancer cell survival and proliferation. Contrarily, propofol has shown in vitro anticancer effects. In addition, perioperative blood transfusions are not uncommon in children undergoing cancer surgery. In adults, an association between perioperative blood transfusions and cancer progression has been described for some malignancies. Transfusion-related immunomodulation is one of the mechanisms by which blood transfusions can promote cancer progression. Other mechanisms include inflammation and the infusion of growth factors. In the present review, we discuss different aspects of tumorigenesis, metastasis, angiogenesis, the immune system, and the current studies about the impact of anesthetics, analgesics, and perioperative blood transfusions on pediatric cancer progression.

title: The Effect of Propofol and Dexmedetomidine Sedation on Norepinephrine Requirements in Septic Shock Patients: A Crossover Trial
abstract: Propofol-based sedation may increase hemodynamic instability by decreasing vascular tone and venous return. Incremental exogenous catecholamines doses may be required to counteract such effects, aggravating the deleterious effects of sympathetic overstimulation. & adrenergic agonists have been reported to decrease norepinephrine requirements in experimental septic shock. The aim of the present study is to test the hypothesis that switching from sedation with propofol to the &agr;-2 agonist dexmedetomidine may decrease norepinephrine doses in septic shock.  Prospective open-label crossover study.  University hospital, ICU.  Thirty-eight septic shock patients requiring norepinephrine to maintain adequate mean arterial pressure and needing deep sedation with propofol and remifentanil to maintain a Richmond Agitation-Sedation Scale score between –3 and –4.  An initial set of measurements including hemodynamics, norepinephrine doses, and depth of sedation were obtained during sedation with propofol. Propofol was then replaced by dexmedetomidine and a second set of data was obtained after 4 hours of dexmedetomidine infusion. Sedation was switched back to propofol, and a final set of measurements was obtained after 8 hours. A Richmond Agitation-Sedation Scale score between –3 and –4 was maintained during the study period.  Norepinephrine requirements decreased from 0.69 ± 0.72 &mgr;g/kg/min before dexmedetomidine to 0.30 ± 0.25 &mgr;g/kg/min 4 hours after dexmedetomidine infusion, increasing again to 0.42 ± 0.36 &mgr;g/kg/min while on propofol 8 hours after stopping dexmedetomidine (p < 0.005). Dexmedetomidine dosage was 0.7 ± 0.2 &mgr;g/kg/hr. Before and after dexmedetomidine infusion, sedative doses remained unchanged (propofol 2.6 ± 1.2 vs 2.6 ± 1.2 mg/kg/hr; p = 0.23 and remifentanil 1.27 ± 0.17 vs 1.27 ± 0.16 &mgr;g/kg/hr; p = 0.52, respectively). Richmond Agitation-Sedation Scale was –4 (–4 to –3) before, –4 (–4 to –3) during, and –4 (–4 to –4) after dexmedetomidine (p = 0.07).  For a comparable level of sedation, switching from propofol to dexmedetomidine resulted in a reduction of catecholamine requirements in septic shock patients.

title: Alpha-2 Agonists.
abstract: Alpha-2 adrenergic receptors are spread throughout the central and peripheral nervous system, specifically in the pontine locus coeruleus, medullospinal tracts, rostral ventrolateral medulla, and the dorsal horn of the spinal cord. Alpha-2 agonist agents cause neuromodulation in these centers, leading to sedation, analgesia, vasodilatation, and bradycardia with little effect on the respiratory drive, which accounts for their good safety profile. The 2 major drugs in this group are clonidine and dexmedetomidine. Their clinical applications in anesthesia practice include providing sedation in the intensive care unit or for minor procedures, adjuvant to general and regional anesthesia, analgesia, and as premedicating agents.

title: Effects of dexmedetomidine on mortality rate and inflammatory responses to endotoxin-induced shock in rats
abstract: The aim of this study was to document the effects of a new sedative agent, dexmedetomidine, on the mortality rate and inflammatory responses to endotoxin-induced shock in rats. Randomized laboratory study. University experimental laboratory. Fifty-seven male rats. The animals were randomly assigned to one of four groups. The endotoxemic group (n = 16) received intravenous Escherichia coli endotoxin (15 mg/kg over 2 mins). The saline control group (n = 10) was given saline alone. The dexmedetomidine alone group (n = 15) was treated identically to the control group but also received dexmedetomidine (infusion at 5 μg·kg−1·hr−1) immediately after the injection of 0.9% saline. The dexmedetomidine-endotoxin group (n = 16) was treated identically to the endotoxemic group with the additional administration of dexmedetomidine (infusion at 5 μg·kg−1·hr−1) immediately after endotoxin injection. Hemodynamics and arterial blood gases were recorded and plasma cytokine concentrations measured during the observation. The mortality rate was assessed up to 8 hrs after endotoxin or saline injection. In addition, microscopic findings of lung tissue for each group were obtained at necropsy. Mortality rates 8 hrs after endotoxin injection were 94%, 10%, 0%, and 44% for the endotoxemic, saline control, dexmedetomidine alone, and dexmedetomidine-endotoxin groups, respectively. Hypotension and increases in plasma cytokine (tumor necrosis factor-&agr; and interleukin-6) concentrations and infiltration of neutrophils in the airspace or vessel walls of the lungs were less in the dexme-detomidine-endotoxin group than in the endotoxemic group. Dexmedetomidine reduced mortality rate and had an inhibitory effect on inflammatory response during endotoxemia. These findings suggest that dexmedetomidine administration may inhibit the inflammatory response.

title: Dexmedetomidine protects against cisplatin-induced acute kidney injury in mice through regulating apoptosis and inflammation
abstract: Objective and designCisplatin-based chemotherapy has been widely used in the perioperative period of cancer surgery, which exacerbates the risk of renal injury. In this study, we examined whether dexmedetomidine (DEX), a commonly used anesthetic adjuvant, shows a protective effect against cisplatin-induced acute kidney injury.MaterialsAcute kidney injury in mice was induced by cisplatin.TreatmentsMice were administered with DEX 25 μg/kg or atipamezole 250 μg/kg (once a day, for 3 days) after cisplatin treatment.MethodsThe renal function and tubular damage score were evaluated at 72 h following cisplatin administration. Apoptotic tubular cells were detected by TUNEL assay. Caspase-3, p53, Bax, F4/80+ macrophages, CD3+ T cells, and NF-κB were examined by immunohistochemistry staining or Western blot. Tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, and monocyte chemoattractant protein (MCP)-1 in kidney were measured using real-time polymerase chain reaction.ResultsDEX treatment preserved renal function and reduced tubular damage score of mice after cisplatin administration. Mice treated with DEX exhibited less apoptotic tubular cells in response to cisplatin insult, which was associated with decreased Bax and reduced activation of p53 and caspase-3. DEX suppressed the infiltration of macrophages and T cells into the kidneys following cisplatin treatment, which was involved in the inhibition of NF-κB activation and decreased expression of TNF-α, IL-1β, IL-6, and MCP-1. Furthermore, we showed that the renoprotective effect conferred by DEX may be related to α2 adrenoceptor-dependent pathway.ConclusionWe demonstrate that DEX protects the kidney against cisplatin-induced AKI by the regulation of apoptosis and inflammatory response.

title: Incidence, risk factors, and outcomes for sepsis-associated delirium in patients with mechanical ventilation: A sub-analysis of a multicenter randomized controlled trial.
abstract: This study aimed to investigate incidence, risk factors, and outcomes for sepsis-associated delirium (SAD) in mechanically ventilated patients.



We performed a retrospective post-hoc analysis of the DExmedetomidine for Sepsis in Intensive care unit Randomized Evaluation (DESIRE) trial. Outcomes included 28-day mortality, ventilator-free days, length of ICU stay, self-extubation, and re-intubation. Multivariable analysis was performed to identify variables independently associated with SAD.



We retrospectively divided the patients into two groups: delirium group (n = 89) and non-delirium group (n = 98). There were no significant differences between the groups in 28-day mortality, self-extubation, and re-intubation. The number of ventilator-free days was significantly less in the delirium vs. non-delirium group (17 vs. 22 days, p = .006), and the length of ICU stay was significantly longer in the delirium group (10 vs. 5 days, p = .04). Multivariable analyses revealed that emergency surgery, more doses of midazolam, and fentanyl were independent predictors for SAD.



SAD was associated with a less number of ventilator-free days and longer length of ICU stay. Emergency surgery, more doses of midazolam, and fentanyl may be independent risk factors for SAD in mechanically ventilated patients with sepsis.

title: Effects of Dexmedetomidine Postconditioning on Myocardial Ischemia/Reperfusion Injury in Diabetic Rats: Role of the PI3K/Akt-Dependent Signaling Pathway
abstract: The present study was designed to determine whether dexmedetomidine (DEX) exerts cardioprotection against myocardial I/R injury in diabetic hearts and the mechanisms involved.  A total of 30 diabetic rats induced by high-glucose-fat diet and streptozotocin (STZ) were randomly assigned to five groups: diabetic sham-operated group (DM-S), diabetic I/R group (DM-I/R), diabetic DEX group (DM-D), diabetic DEX + Wort group (DM-DW), and diabetic Wort group (DM-W). Another 12 age-matched male normal SD rats were randomly divided into two groups: sham-operated group (S) and I/R group (I/R). All rats were subjected to 30 min myocardial ischemia followed by 120 min reperfusion except sham groups. Plasmas were collected to measure the malondialdehyde (MDA), creatine kinase isoenzymes (CK-MB), and lactate dehydrogenase (LDH) levels and superoxide dismutase (SOD) activity at the end of reperfusion. Pathologic changes in myocardial tissues were observed by H-E staining. The total and phosphorylated form of Akt and GSK-3β protein expressions were measured by western blot. The ratio of Bcl-2/Bax at mRNA level was detected by reverse transcription-polymerase chain reaction (RT-PCR).  DEX significantly reduced plasma CK-MB, MDA concentration, and LDH level and increased SOD activity caused by I/R. The phosphorylation of Akt and GSK-3β was increased, Bcl-2 mRNA and the Bcl-2/Bax ratio was increased, and Bax mRNA was decreased in the DEX group as compared to the I/R group, while posttreatment with Wort attenuated the effects induced by DEX.  The results of this study suggest that DEX postconditioning may increase the phosphorylation of GSK-3β by activating the PI3K/Akt signaling pathway and may inhibit apoptosis and oxidative stress of the myocardium, thus exerting protective effects in diabetic rat hearts suffering from I/R injury.

title: Dexmedetomidine Protects Against Neurological Dysfunction in a Mouse Intracerebral Hemorrhage Model by Inhibiting Mitochondrial Dysfunction-Derived Oxidative Stress.
abstract: Intracerebral hemorrhage (ICH) is a subtype of stroke with high disability and mortality. Dexmedetomidine (Dex) has been shown to provide neuroprotection in several neurological diseases. The aim of present study was to investigate the effects of Dex on ICH-induced neurological deficits and brain injury and the underlying mechanisms.



ICH mouse model was established by intracerebral injection of autologous blood, followed by Dex or vehicle treatment. Neurological function, brain water content, neuronal activity, and oxidative parameters were determined. The protein expressions of peroxisome proliferator-activated receptor gamma coactivator 1-α (PGC-1α), uncoupling protein 2, and manganese-dependent superoxide dismutase were examined by western blotting.



Dex administration significantly inhibited ICH-induced the memory impairment, dyskinesia, brain edema, and neuron loss. In addition, ICH-induced the increase in brain oxidative stress level was markedly attenuated after Dex treatment, as evidenced by increased glutathione peroxidase and superoxide dismutase levels and reduced malondialdehyde and nitric oxide levels. Compared with vehicle-treated ICH mice, Dex-treated ICH mice showed significantly decreased intracellular reactive oxygen species (ROS) and mitochondrial ROS (mROS) production in brain, but had no effects on the increased nicotinamide-adenine dinucleotide phosphate oxidase activity. However, stimulation of mROS abrogated the inhibitory effects of Dex on neurological deficits and oxidative stress. The decrease in production of adenosine triphosphate and the expressions of PGC-1α, uncoupling protein 2, and manganese-dependent superoxide dismutase induced by ICH was restored by Dex treatment.



Our results reveal that Dex improves ICH-induced neurological deficits and brain injury by inhibiting PGC-1α pathway inactivation and mitochondrial dysfunction-derived oxidative stress.

title: Low‐Dose Nocturnal Dexmedetomidine Prevents ICU Delirium. A Randomized, Placebo‐controlled Trial
abstract: Dexmedetomidine is associated with less delirium than benzodiazepines and better sleep architecture than either benzodiazepines or propofol; its effect on delirium and sleep when administered at night to patients requiring sedation remains unclear.  To determine if nocturnal dexmedetomidine prevents delirium and improves sleep in critically ill adults.  This two‐center, double‐blind, placebo‐controlled trial randomized 100 delirium‐free critically ill adults receiving sedatives to receive nocturnal (9:30 p.m. to 6:15 a.m.) intravenous dexmedetomidine (0.2 &mgr;g/kg/h, titrated by 0.1 &mgr;g /kg/h every 15 min until a goal Richmond Agitation and Sedation Scale score of −1 or maximum rate of 0.7 &mgr;g/kg/h was reached) or placebo until ICU discharge. During study infusions, all sedatives were halved; opioids were unchanged. Delirium was assessed using the Intensive Care Delirium Screening Checklist every 12 hours throughout the ICU admission. Sleep was evaluated each morning by the Leeds Sleep Evaluation Questionnaire.  Nocturnal dexmedetomidine (vs. placebo) was associated with a greater proportion of patients who remained delirium‐free during the ICU stay (dexmedetomidine [40 (80%) of 50 patients] vs. placebo [27 (54%) of 50 patients]; relative risk, 0.44; 95% confidence interval, 0.23‐0.82; P = 0.006). The average Leeds Sleep Evaluation Questionnaire score was similar (mean difference, 0.02; 95% confidence interval, 0.42‐1.92) between the 34 dexmedetomidine (average seven assessments per patient) and 30 placebo (six per patient) group patients able to provide one or more assessments. Incidence of hypotension, bradycardia, or both did not differ significantly between groups.  Nocturnal administration of low‐dose dexmedetomidine in critically ill adults reduces the incidence of delirium during the ICU stay; patient‐reported sleep quality appears unchanged.