Cardiopulmonary and isoflurane-sparing effects of epidural or intravenous infusion of dexmedetomidine in cats undergoing surgery with epidural lidocaine

Objective To compare the cardiorespiratory, anesthetic-sparing effects and quality of anesthetic recovery after epidural and constant rate intravenous (IV) infusion of dexmedetomidine (DEX) in cats given a low dose of epidural lidocaine under propofol-isoflurane anesthesia and submitted to elective ovariohysterectomy. Study design Randomized, blinded clinical trial. Animals Twenty-one adult female cats ( mean body weight: 3.1 +/- 0.4 kg). Methods Cats received DEX (4 mu g kg(-1), IM). Fifteen minutes later, anesthesia was induced with propofol and maintained with isoflurane. Cats were divided into three groups. In GI cats received epidural lidocaine (1 mg kg(-1), n = 7), in GII cats were given epidural lidocaine (1 mg kg(-1)) + DEX (4 mu g kg(-1), n = 7), and in GIII cats were given epidural lidocaine (1 mg kg(-1)) + IV constant rate infusion (CRI) of DEX (0.25 mu g kg(-1) minute(-1), n = 7). Variables evaluated included heart rate (HR), respiratory rate (f(R)), systemic arterial pressures, rectal temperature (RT), end-tidal CO(2), end-tidal isoflurane concentration (E`ISO), arterial blood gases, and muscle tone. Anesthetic recovery was compared among groups by evaluation of times to recovery, HR, f(R), RT, and degree of analgesia. A paired t-test was used to evaluate pre-medication variables and blood gases within groups. ANOVA was used to compare parametric data, whereas Friedman test was used to compare muscle relaxation. Results Epidural and CRI of DEX reduced HR during anesthesia maintenance. Mean +/- SD E/ISO ranged from 0.86 +/- 0.28% to 1.91 +/- 0.63% in GI, from 0.70 +/- 0.12% to 0.97 +/- 0.20% in GII, and from 0.69 +/- 0.12% to 1.17 +/- 0.25% in GIII. Cats in GII and GIII had longer recovery periods than in GI. Conclusions and clinical relevance Epidural and CRI of DEX significantly decreased isoflurane consumption and resulted in recovery of better quality and longer duration, despite bradycardia, without changes in systemic blood pressure.

Observations on the Pharmacokinetics and Pharmacodynamics of Dexmedetomidine. Clinical Studies on Healthy Volunteers and Intensive Care Patients

Patients treated in intensive care units require sedation and analgesia. However, sedative drugs also have potential adverse effects, and there is no single ideal sedativeanalgesic drug for these patients. Dexmedetomidine is an apha2-adrenoceptor agonist licenced for sedation of intensive care patients and patients undergoing surgery and other invasive procedures. Several routes of parenteral administration (intravenous, intramuscular, subcutaneous and intranasal) have been utilized. In the present series of studies, the pharmacokinetics and pharmacodynamics of intranasally administered dexmedetomidine as well as the gastrointestinal effects of intravenous dexmedetomidine were determined in healthy volunteers. Pharmacokinetics of dexmedetomidine during long lasting, high-dose infusions were characterized in intensive care patients. The bioavailability of intranasal dexmedetomidine was relatively good (65%), but interindividual variation was large. Dexmedetomidine significantly inhibited gastric emptying and gastrointestinal transit. In intensive care patients, the elimination half-life of dexmedetomidine was somewhat longer than reported for infusions of shorter duration and in less ill patients or healthy volunteers. Dexmedetomidine appeared to have linear pharmacokinetics up to the studied dose rate of 2.5 μg/kg/h. Dexmedetomidine clearance was decreasing with age and its volume of distribution was increased in hypoalbuminaemic patients, resulting in a longer elimination half-life and context-sensitive half-time. Intranasally administered dexmedetomidine was efficacious and well tolerated, making it appropriate for clinical situations requiring light sedation. The clinical significance of the gastrointestinal inhibitory effects of dexmedetomidine should be further evaluated in intensive care patients. The possibility of potentially altered potency and effect duration should be taken into account when administering dexmedetomidine to elderly or hypoalbuminaemic patients.

Alpha2-Adrenoceptor-mediated vascular responses induced by dexmedetomidine

Alpha2-Adrenoceptors are cell-surface G protein coupled receptors that mediate many of the effects of the catecholamines noradrenaline and adrenaline. The three human α2-adrenoceptor subtypes are widely expressed in different tissues and organs, and they mediate many different physiological and pharmacological effects in the central and peripheral nervous system and as postsynaptic receptors in target organs. Previous studies have demonstrated that α2-adrenoceptors mediate both vascular constriction and dilatation in humans. Large inter-individual variation has been observed in the vascular responses to α2-adrenoceptor activation in clinical studies. All three receptor subtypes are potential drug targets. It was therefore considered important to further elucidate the details of adrenergic vascular regulation and its genetic variation, since such knowledge may help to improve the development of future cardiovascular drugs and intensive care therapies. Dexmedetomidine is the most selective and potent α2-adrenoceptor agonist currently available for clinical use. When given systemically, dexmedetomidine induces nearly complete sympatholysis already at low concentrations, and postsynaptic effects, such vasoconstriction, can be observed with increasing concentrations. Thus, local infusions of small doses of dexmedetomidine into dorsal hand veins and the application of pharmacological sympathectomy with brachial plexus block provide a means to assess drug-induced peripheral vascular responses without interference from systemic pharmacological effects and autonomic nervous system regulation. Dexmedetomidine was observed to have biphasic effects on haemodynamics, with an initial decrease in blood pressure at low concentrations followed by substantial increases in blood pressure and coronary vascular resistance at high concentrations. Plasma concentrations of dexmedetomidine that significantly exceeded the recommended therapeutic level did not reduce myocardial blood flow below the level that is observed with the usual therapeutic concentrations and did not induce any evident myocardial ischaemia in healthy subjects. Further, it was demonstrated that dexmedetomidine also had significant vasodilatory effects through activation of endothelial nitric oxide synthesis, and thus when the endothelial component of the blood vessel response to dexmedetomidine was inhibited, peripheral vasoconstriction was augmented. Hand vein constriction responses to α2-adrenoceptor activation by dexmedetomidine were only weakly associated with the constriction responses to α1-adrenoceptor activation, pointing to independent cellular regulation by these two adrenoceptor classes. Substantial inter-individual variation was noted in the venous constriction elicited by activation of α2-adrenoceptors by dexmedetomidine. In two study populations from two different continents, a single nucleotide polymorphism in the PRKCB gene was found to be associated with the dorsal hand vein constriction response to dexmedetomidine, suggesting that protein kinase C beta may have an important role in the vascular α2-adrenoceptor signalling pathways activated by dexmedetomidine.

Prevention of etomidate-induced myoclonus during anesthetic induction by pretreatment with dexmedetomidine

Myoclonus induced by etomidate during induction of general anesthesia is undesirable. This study evaluated the effect of dexmedetomidine (DEX) pretreatment on the incidence and severity of etomidate-induced myoclonus. Ninety patients undergoing elective surgical procedures were randomly allocated to three groups (n=30 each) for intravenous administration of 10 mL isotonic saline (group I), 0.5 µg/kg DEX in 10 mL isotonic saline (group II), or 1.0 µg/kg DEX in 10 mL isotonic saline (group III) over 10 min. All groups subsequently received 0.3 mg/kg etomidate by intravenous push injection. The incidence and severity of myoclonus were recorded for 1 min after etomidate administration and the incidence of cardiovascular adverse events that occurred between the administration of the DEX infusion and 1 min after tracheal intubation was recorded. The incidence of myoclonus was significantly reduced in groups II and III (30.0 and 36.7%), compared with group I (63.3%). The incidence of severe sinus bradycardia was significantly increased in group III compared with group I (P<0.05), but there was no significant difference in heart rate in groups I and II. There were no significant differences in the incidence of low blood pressure among the 3 groups. Pretreatment with 0.5 and 1.0 µg/kg DEX significantly reduced the incidence of etomidate-induced myoclonus during anesthetic induction; however, 0.5 µg/kg DEX is recommended because it had fewer side effects.

Dexmedetomidine decreases the inflammatory response to myocardial surgery under mini-cardiopulmonary bypass

Cardiopulmonary bypass (CPB) with extracorporeal circulation produces changes in the immune system accompanied by an increase in proinflammatory cytokines and a decrease in anti-inflammatory cytokines. We hypothesize that dexmedetomidine (DEX) as an anesthetic adjuvant modulates the inflammatory response after coronary artery bypass graft surgery with mini-CPB. In a prospective, randomized, blind study, 12 patients (4 females and 8 males, age range 42-72) were assigned to DEX group and compared with a conventional total intravenous anesthesia (TIVA) group of 11 patients (4 females and 7 males). The endpoints used to assess inflammatory and biochemical responses to mini-CPB were plasma interleukin (IL)-1, IL-6, IL-10, interferon (INF)-γ, tumor necrosis factor (TNF)-α, C-reactive protein, creatine phosphokinase, creatine phosphokinase-MB, cardiac troponin I, cortisol, and glucose levels. These variables were determined before anesthesia, 90 min after beginning CPB, 5 h after beginning CPB, and 24 h after the end of surgery. Endpoints of oxidative stress, including thiobarbituric acid reactive species and delta-aminolevulinate dehydratase activity in erythrocytes were also determined. DEX+TIVA use was associated with a significant reduction in IL-1, IL-6, TNF-α, and INF-γ (P<0.0001) levels compared with TIVA (two-way ANOVA). In contrast, the surgery-induced increase in thiobarbituric acid reactive species was higher in the DEX+TIVA group than in the TIVA group (P<0.01; two-way ANOVA). Delta-aminolevulinate dehydratase activity was decreased after CPB (P<0.001), but there was no difference between the two groups. DEX as an adjuvant in anesthesia reduced circulating IL-1, IL-6, TNF-α, and INF-γ levels after mini-CPB. These findings indicate an interesting anti-inflammatory effect of DEX, which should be studied in different types of surgical interventions.

Effects of epidural administration of dexmedetomidine on the minimum alveolar concentration of isoflurane in dogs

Objective-To evaluate the effects of epidural administration of 3 doses of dexmedetomidine on isoflurane minimum alveolar concentration (MAC) and characterize changes in bispectral index (BIS) induced by nociceptive stimulation used for MAC determination in dogs.Animals-6 adult dogs.Procedures-Isoflurane-anesthetized dogs received physiologic saline (0.9% NaCl) solution (control treatment) or dexmedetomidine (1.5 [DEX1.5], 3.0 [DEX3], or 6.0 [DEX6] mu g/kg) epidurally in a crossover study. Isoflurane MAC (determined by use of electrical nociceptive stimulation of the hind limb) was targeted to be accomplished at 2 and 4.5 hours. Changes in BIS attributable to nociceptive stimulation and cardiopulmonary data were recorded at each MAC determination.Results-With the control treatment, mean +/- SD MAC values did not change over time (1.57 +/- 0.23% and 1.55 +/- 0.25% at 2 and 4.5 hours, respectively). Compared with the control treatment, MAC was significantly lower at 2 hours (13% reduction) but not at 4.5 hours (7% reduction) in DEX1.5-treated dogs and significantly lower at 2 hours (29% reduction) and 4.5 hours (13% reduction) in DEX3-treated dogs. The DEX6 treatment yielded the greatest MAC reduction (31 % and 22% at 2 and 4.5 hours, respectively). During all treatments, noxious stimulation increased BIS; but changes in BIS were correlated with increases in electromyographic activity.Conclusions and Clinical Relevance-In dogs, epidural administration of dexmedetomidine resulted in dose-dependent decreases in isoflurane MAC and that effect decreased over time, Changes in BIS during MAC determinations may not represent increased awareness because of the possible interference of electromyographic activity.

Dexmedetomidine Alters the Cardiovascular Response During Infra-Renal Aortic Cross-Clamping in Sevoflurane-Anesthetized Dogs

Some properties of the volatile anesthetics, such as vasodilatation and myocardial depression, combined with the sympathetic inhibition that alpha 2-agonists can produce may determine hemodynamic alterations during aortic, surgery. The interaction between dexmedetomidine (DEX), an alpha 2-agonist, and sevoflurane during aortic surgery is unknown. We studied the effects of DEX on hemodynamics and systemic oxygenation during aortic cross-clamping (Aox) and unclamping (UAox) in sevoflurane-anesthetized dogs Twenty dogs were. anesthetized with sevoflurane and were randomly assigned to two groups prior to Aox and UAox: control, n = 10, received saline infusion only, and DEX (1 mu g.kg(-1) load followed by 1 mu g.kg(-1).h(-1) infusion), n = 10. Hemodynamic and oxygenation variables were measured at baseline, after saline or DEX loading dose, 20 and 40 min after Aox, and 20 and 40 min after UAox. After DEX administration, heart rate, cardiac index l and systemic oxygen transport index (131021) were lower than in control group. Aox increased mean arterial pressure (MAP) and systemic vascular resistance index (SVRI) in both groups, but the effects were greater with DEX. Cl, heart rate, and DO(2)I were lower, while central venous pressure (CVP) and pulmonary artery occlusion pressure were higher in DEX compared to control. After UAox, MAP, CVP and SVRI were maintained higher in DEX in relation to control. We conclude that in sevoflurane-anesthetized dogs DEX alters the cardiovascular response during aortic surgery.

Hemodynamics and bispectral index (BIS) of dogs anesthetized with midazolam and ketamine associated with medetomidine or dexmedetomidine and submitted to ovariohysterectomy

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

Renal function and histology after acute hemorrhage in rats under dexmedetomidine action

OBJETIVO: Cerca de 50% de indicações de diálise em insuficiência renal aguda vêm de problemas do perioperatório. Alterações na hemodinâmica intra-operatória levam a vasoconstrição renal e hipoperfusão. Estudos prévios não definiram o papel renal da dexmedetomidina em hemorragia. Foram estudados os efeitos da dexmedetomidina na função e histologia renais, em ratos, após hemorragia aguda. MÉTODOS: Estudo encoberto com 20 ratos Wistar, anestesiados com pentobarbital sódico intraperitoneal, 50 mg. kg-1, divididos aleatoriamente em 2 grupos sob sangramento de 30% da volemia: GD - dexmedetomidina iv, 3 µg. kg-1 (10 min), e infusão contínua, 3 µg. kg-1. h-1; GC - pentobarbital. Para estimar depuração renal, administraram-se para-aminohipurato e iotalamato de sódio. Atributos estudados: freqüência cardíaca, pressão arterial média, temperatura retal, hematócrito, depuração de para-aminohipurato e iotalamato, fração de filtração, fluxo sangüíneo renal, resistência vascular renal, análise histológica dos rins. RESULTADOS: em GD, houve valores menores de freqüência cardíaca, pressão arterial média e resistência vascular, mas valores maiores de depuração de iotalamato e fração de filtração. A depuração de para-aminohipurato e o fluxo sangüíneo foram similares nos grupos. As alterações histológicas foram compatíveis com isquemia e houve maior dilatação tubular em GD. CONCLUSÃO: em ratos, após hemorragia aguda, a dexmedetomidina determinou melhor função renal, porém maior dilatação tubular.

Dexmedetomidine and S(+)-ketamine in ischemia and reperfusion injury in the rat kidney

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)

Sedative and cardiorespiratory effects of acepromazine or atropine given before dexmedetomidine in dogs

To test the hypothesis that acepromazine could potentiate the sedative actions and attenuate the pressor response induced by dexmedetomidine, the effects of acepromazine or atropine were compared in six healthy adult dogs treated with this alpha(2)-agonist. In a randomised block design, the dogs received intravenous doses of either physiological saline, 0.05 mg/kg acepromazine or 0.04 mg/kg atropine, 15 minutes before an intravenous dose of 5 mu g/kg dexmedetomidine. The dogs' heart rate was reduced by 50 to 63 per cent from baseline and their mean arterial blood pressure was increased transiently from baseline for 20 minutes after the dexmedetomidine. Atropine prevented the alpha(2)-agonist-induced bradycardia and increased the severity and duration of the hypertension, but acepromazine did not substantially modify the cardiovascular effects of the a2-agonist, except for a slight reduction in the magnitude and duration of its pressor effects. The dexmedetomidine induced moderate to intense sedation in all the treatments, but the dogs' sedation scores did not differ among treatments. The combination of acepromazine with dexmedetomidine had no obvious advantages in comparison with dexmedetomidine alone, but the administration of atropine before dexmedetomidine is contraindicated because of a severe hypertensive response.

Evaluation of cardiorespiratory effects of combinations of dexmedetomidine and atropine in cats

The cardiovascular effects of dexmedetomidine alone or in combination with atropine were studied in six cats. Cats underwent four treatments in a randomized crossover design as follows: DEX15, saline + dexmedetomidine 15 mu g/kg; DEX30, saline + dexmedetomidine 30 mu g/kg; ADEX15, atropine + dexmedetomidine 15 mu g/kg; ADEX30, atropine + dexmedetomidine 30 mu g/kg. Pulse rate (PR) and systolic arterial pressure (SAP) decreased in DEX15 and DEX30. Premedication with atropine was effective in preventing bradycardia (PR < 100 beats/min) and resulted in a biphasic effect in blood pressure. Hypertension was followed by a gradual decrease in SAP. Rate pressure product decreased in DEX15 and DEX30 whereas in ADEX15 and ADEX30 it remained within baseline values for at least 60 min. Although premedication with atropine in cats sedated with dexmedetomidine prevents bradycardia, it induces hypertension and increases myocardial oxygen consumption. The magnitude of cardiovascular effects produced by dexmedetomidine in cats does not seem to be dose-related. (C) 2009 ESFM and AAFP. Published by Elsevier Ltd. All rights reserved.

Comparison of medetomidine-ketamine and dexmedetomidine-ketamine anesthesia in golden-headed lion tamarins

The cardiovascular, respiratory, and anesthetic effects of medetomidine-ketamine (20 μg/kg bodyweight [BW] and 10 mg/kg BW) (MK group) or dexmedetomidine-ketamine (10 μg/kg BW and 10 mg/kg BW) (DK group) were studied in golden-headed lion tamarins. Heart rate decreased after administration of both combinations; this reduction was statistically greater in the DK group than in the MK group after 15 and 45 minutes. Systolic arterial pressure decreased in a similar way in both groups, except at 15 minutes, when systolic arterial pressure was significantly lower in the DK group. Diastolic arterial pressure, mean arterial pressure, respiratory rate, and rectal temperature were progressively reduced in all groups. Sedation time was significantly shorter and anesthesia time was significantly longer in the DK group compared with MK group. Anesthetic quality and analgesia scores were significantly greater at 5 and 15 minutes in the DK group compared with the MK group. The administration of dexmedetomidine-ketamine is as safe and effective as the administration of medetomidine-ketamine in tamarins.

Pharmacokinetics of dexmedetomidine administered intravenously in isofluraneanesthetized cats

Objective-To determine the pharmacokinetics of dexmedetomidine administered as a short-duration IV infusion in isoflurane-anesthetized cats. Animals-6 healthy adult domestic female cats. Procedures-Dexmedetomidine hydrochloride was injected IV (10 μg/kg over 5 minutes [rate, 2 μg/kg/min]) in isoflurane-anesthetized cats. Blood samples were obtained immediately prior to and at 1, 2, 5, 6, 7, 10, 15, 30, 60, 90, 120, 240, and 480 minutes following the start of the IV infusion. Collected blood samples were transferred to tubes containing EDTA, immediately placed on ice, and then centrifuged at 3,901 X g for 10 minutes at 4°C. The plasma was harvested and stored at -20°C until analyzed. Plasma dexmedetomidine concentrations were determined by means of liquid chromatography-mass spectrometry. Dexmedetomidine plasma concentration-time data were fitted to compartmental models. Results-A 2-compartment model with input in and elimination from the central compartment best described the disposition of dexmedetomidine administered via short-duration IV infusion in isoflurane-anesthetized cats. Weighted mean ± SEM apparent volume of distribution of the central compartment and apparent volume of distribution at steady-state were 402 ± 47 mL/kg and 1,701 ± 200 mL/kg, respectively; clearance and terminal half-life (harmonic mean ± jackknife pseudo-SD) were 6.3 ± 2.8 mL/min/kg and 198 ± 75 minutes, respectively. The area under the plasma concentration curve and maximal plasma concentration were 1,061 ± 292 min·ng/mL and 17.6 ± 1.8 ng/mL, respectively. Conclusions and Clinical Relevance-Disposition of dexmedetomidine administered via short-duration IV infusion in isoflurane-anesthetized cats was characterized by a moderate clearance and a long terminal half-life.

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

This study reports the effects of dexmedetomidine on the minimum alveolar concentration of isoflurane (MAC iso) in cats. Six healthy adult female cats were used. MAC iso and dexmedetomidine pharmacokinetics had previously been determined in each individual. Cats were anesthetized with isoflurane in oxygen. Dexmedetomidine was administered intravenously using target-controlled infusions to maintain plasma concentrations of 0.16, 0.31, 0.63, 1.25, 2.5, 5, 10, and 20ng/mL. MAC iso was determined in triplicate at each target plasma dexmedetomidine concentration. Blood samples were collected and analyzed for dexmedetomidine concentration. The following model was fitted to the concentration-effect data: where MAC iso.c is MAC iso at plasma dexmedetomidine concentration C, MAC iso.0 is MAC iso in the absence of dexmedetomidine, I max is the maximum possible reduction in MAC iso, and IC 50 is the plasma dexmedetomidine concentration producing 50% of I max. Mean±SE MAC iso.0, determined in a previous study conducted under conditions identical to those in this study, was 2.07±0.04. Weighted mean±SE I max, and IC 50 estimated by the model were 1.76±0.07%, and 1.05±0.08ng/mL, respectively. Dexmedetomidine decreased MAC iso in a concentration-dependent manner. The lowest MAC iso predicted by the model was 0.38±0.08%, illustrating that dexmedetomidine alone is not expected to result in immobility in response to noxious stimulation in cats at any plasma concentration. © 2011 Blackwell Publishing Ltd.