Effects of the alpha2-adrenoceptor agonist dexmedetomidine on bronchoconstriction in dogs

BACKGROUND: Tracheal intubation can elicit reflex bronchoconstriction in patients with asthma or chronic obstructive pulmonary disease, complicating mechanical ventilation and weaning from mechanical support. In vitro studies of human and animal bronchial tissue indicate that alpha2-adrenoceptor stimulation can lead to smooth muscle relaxation and prevention of bronchoconstriction. Dexmedetomidine is a selective alpha2-adrenoceptor agonist approved for sedation in the intensive care unit. Whether dexmedetomidine can affect reflex bronchoconstriction is unknown. METHODS: After the approval of the institutional animal care and use committee, five mongrel dogs were anesthetized with thiopental, endotracheally intubated, and ventilated, and their airways were challenged with histamine. High-resolution computed tomography was used to measure airway luminal areas at baseline and after nebulized histamine. After recovery to baseline, on separate days, dexmedetomidine (0.5 microg/kg) was administered either intravenously or as an aerosol, and the histamine challenge was repeated. RESULTS: At baseline, histamine constricted the airways to 66 +/- 27% (mean +/- SD) (P < 0.0001) and 59 +/- 30% (P < 0.0001) of maximum on the days dexmedetomidine was administered by intravenous and inhalational means, respectively. After recovery, intravenous administration of dexmedetomidine blocked the histamine-induced bronchoconstriction (87 +/- 30.4% of maximum, compared with histamine alone (P < 0.0001), whereas dexmedetomidine administered by inhalation showed no protective effect (45 +/- 30% of maximum; P < 0.0001 compared with histamine alone). CONCLUSION: alpha2-Adrenoceptor stimulation with intravenous dexmedetomidine completely blocked histamine-induced bronchoconstriction in dogs. Therefore, dexmedetomidine might be beneficial to decrease airway reactivity in patients with chronic obstructive pulmonary disease or asthma, particularly during weaning from mechanical ventilation, when neurally mediated airway reflexes may be elicited.     

Prevention of Lidocaine Aerosol-induced Bronchoconstriction with Intravenous Lidocaine

Background: Lidocaine applied topically provokes bronchoconstriction in persons with hyperreactive airway disease. The authors questioned whether intravenous lidocaine would prevent lidocaine-aerosol induced bronchoconstriction. They compared the effects of lidocaine administered intravenously and by the aerosol route on baseline airway tone, and on the prevention of histamine-induced bronchoconstriction in five Basenji-Greyhound dogs.

Methods: Dogs were pretreated with either intravenous or aerosol lidocaine followed by histamine aerosol challenge. On separate days, dogs were pretreated with intravenous lidocaine, followed by aerosol lidocaine administration at similar doses. Airway caliber was assessed using high-resolution computed tomography. Data were analyzed by two-way analysis of variance. Serum lidocaine concentrations were obtained.

Results: Histamine alone decreased the airway area by 32 +/- 3%. Lidocaine administered intravenously or by the aerosol route significantly inhibited histamine-induced bronchoconstriction. There was no significant difference between the two routes in preventing histamine-induced bronchoconstriction. At the dose that inhibited histamine-induced bronchoconstriction, lidocaine administered by the aerosol route decreased baseline airway area by 27 +/- 3% (P <0.01), whereas intravenous lidocaine had no effect. Intravenous lidocaine prevented lidocaine aerosol-induced bronchoconstriction, and the combination of intravenous and aerosol lidocaine significantly dilated the airways by 20 +/- 5% (P < 0.01 compared with control).     

Both Local Anesthetics and Salbutamol Pretreatment Affect Reflex Bronchoconstriction in Volunteers with Asthma undergoing Awake Fiberoptic Intubation

Background: Awake tracheal intubation may evoke reflex bronchoconstriction in asthmatics. Whether this effect is altered by the choice of the local anesthetic used or by pretreatment with a [beta]2-adrenoceptor agonist is unknown. Therefore, we assessed the effect of awake fiberoptic intubation after lidocaine or dyclonine inhalation with or without pretreatment with salbutamol on lung function in asthmatic volunteers.

Methods: Bronchial hyperreactivity was verified by an inhalational histamine challenge. On four different days in a randomized, double blind fashion the volunteers (n = 10) inhaled either dyclonine or lidocaine with or without salbutamol pretreatment. FEV1 was measured at baseline, following salbutamol or saline inhalation, after lidocaine or dyclonine inhalation, while intubated, and after extubation. Lidocaine and dyclonine plasma concentrations were also measured. Statistics: Two-way ANOVA, post hoc tests with Bonferroni correction, results are presented as mean +/- SD.

Results: Neither lidocaine nor dyclonine inhalation changed FEV1 significantly from baseline compared with placebo in-halation (4.43 +/- 0.67 l vs. 4.29 +/- 0.72 l, and 4.53 +/- 0.63 l vs. 4.24 +/- 0.80 l, respectively). Salbutamol slightly but significantly increased FEV1 (4.45 +/- 0.76 l vs. 4.71 +/- 0.61 l, P = 0.0034, and 4.48 +/- 0.62 l vs. 4.71 +/- 0.61 l, P = 0.0121, respectively). Following awake intubation FEV1 significantly decreased under lidocaine topical anesthesia (4.29 +/- 0.72 l to 2.86 +/- 0.87 l) but decreased even more under dyclonine anesthesia (4.24 +/- 0.80 l to 2.20 +/- 0.67 l;P < 0.0001). While salbutamol pretreatment significantly attenuated the response to intubation, it did not eliminate the difference between the effects of lidocaine and dyclonine. Only minutes after extubation FEV1 was similar compared with baseline.     

Efficacy of Propofol to Prevent Bronchoconstriction: Effects of Preservative

Background: The authors previously showed that propofol attenuates bronchoconstriction. Recently, a newer formulation of propofol with metabisulfite preservative has been introduced. metabisulfite causes airway narrowing in asthmatics. Therefore, we tested whether the preservative metabisulfite abolishes the ability of propofol to attenuate bronchoconstriction. The authors used a sheep model in which anesthetic agents could be directly administered to the airways via the bronchial artery.

Methods: After Internal Review Board approval, seven sheep were anesthetized (pentobarbital 20 mg [middle dot] kg-1 [middle dot] h-1) and paralyzed (pancuronium 2 mg), and the lungs were ventilated. After left thoracotomy, the bronchial artery was cannulated and perfused. In random order, propofol with and without metabisulfite, lidocaine (5 mg/ml), or metabisulfite alone (0.125 mg/ml) was infused into the bronchial artery at a rate of 0.06, 0.2, or 0.6 ml/min. After 10 min, airway resistance (Raw) was measured before and after vagal nerve stimulation (30 Hz, 30-ms duration at 30 V for 9 s.) and methacholine challenge (2 [mu]g/ml at 2 ml/min in the bronchial artery). Data were expressed as a percent of maximal response and analyzed by analysis of variance with correction and with significance accepted at P <= 0.05.

Results: Raw at baseline was not significantly different among the four drugs (P = 0.87). Infusion of lidocaine and propofol without metabisulfite into the bronchial artery caused a dose-dependent attenuation of the vagal nerve stimulation-induced bronchoconstriction (P = 0.001). Propofol with metabisulfite had no effect on vagal nerve stimulation-induced bronchoconstriction (P = 0.40). There was a significant difference in the ability of propofol without metabisulfite compared with propofol with metabisulfite to attenuate vagal nerve stimulation-induced (P = 0.0001) and methacholine-induced bronchoconstriction (P = 0.0001).     

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

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

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

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

Mechanisms of Desflurane-induced Preconditioning in Isolated Human Right Atria In Vitro

Background: The authors examined the role of adenosine triphosphate-sensitive potassium (KATP) channels, adenosine A1 receptor, and [alpha] and [beta] adrenoceptors in desflurane-induced preconditioning in human myocardium, in vitro.

Methods: The authors recorded isometric contraction of human right atrial trabeculae suspended in oxygenated Tyrode's solution (34[degrees]C; stimulation frequency, 1 Hz). Before a 30-min anoxic period, 3, 6, and 9% desflurane was administered during 15 min. Desflurane, 6%, was also administered in the presence of 10 [mu]m glibenclamide, a KATP channels antagonist; 10 [mu]m HMR 1098, a sarcolemmal KATP channel antagonist; 800 [mu]m 5-hydroxy-decanoate (5-HD), a mitochondrial KATP channel antagonist; 1 [mu]m phentolamine, an [alpha]-adrenoceptor antagonist; 1 [mu]m propranolol, a [beta]-adrenoceptor antagonist; and 100 nm 8-cyclopentyl-1,3-dipropylxanthine (DPX), the adenosine A1 receptor antagonist. Developed force at the end of a 60-min reoxygenation period was compared (mean +/- SD).

Results: Desflurane at 3% (95 +/- 13% of baseline), 6% (86 +/- 6% of baseline), and 9% (82 +/- 6% of baseline) enhanced the recovery of force after 60 min of reoxygenation as compared with the control group (50 +/- 11% of baseline). Glibenclamide (60 +/- 12% of baseline), 5-HD (57 +/- 21% of baseline), DPX (63 +/- 19% of baseline), phentolamine (56 +/- 20% of baseline), and propranolol (63 +/- 13% of baseline) abolished desflurane-induced preconditioning. In contrast, HMR 1098 (85 +/- 12% of baseline) did not modify desflurane-induced preconditioning.     

Altered Contractile Response due to Increased β3-Adrenoceptor Stimulation in Diabetic Cardiomyopathy: The Role of Nitric Oxide Synthase 1-derived Nitric Oxide

Background: In the diabetic heart, the positive inotropic response to [beta]-adrenoceptor stimulation is altered and [beta]1 and [beta]2 adrenoceptors are down-regulated, whereas [beta]3 adrenoceptor is up-regulated. In heart failure, [beta]3-adrenoceptor stimulation induces a negative inotropic effect that results from endothelial nitric oxide synthase (NOS3)-derived nitric oxide production. The objective of our study was to investigate the role of [beta]3-adrenoceptor in diabetic cardiomyopathy.

Methods: [beta]-Adrenergic responses were investigated in vivo (dobutamine echocardiography) and in vitro (left ventricular papillary muscle) in healthy and streptozotocin-induced diabetic rats. The effect of [beta]3-adrenoceptor inhibition on the inotropic response was studied in vitro. Immunoblots and NOS activities were performed in heart homogenates (electron paramagnetic resonance) and isolated cardiomyocytes. Data are mean percentage of baseline +/- SD.

Results: The impaired positive inotropic effect was confirmed in diabetes both in vivo (121 +/- 15% vs. 160 +/- 16%; P < 0.05) and in vitro (112 +/- 5% vs. 179 +/- 15%; P < 0.05). In healthy rat, the positive inotropic effect was not significantly modified in presence of [beta]3-adrenoceptor antagonist (174 +/- 20%), nonselective NOS inhibitor (N G-nitro-l-arginine methylester [l-NAME]; 183 +/- 19%), or selective NOS1 inhibitor (vinyl-l-N-5-(1-imino-3-butenyl)-l-ornithine [l-VNIO]; 172 +/- 13%). In diabetes, in parallel with the increase in [beta]3-adrenoceptor protein expression, the positive inotropic effect was partially restored by [beta]3-adrenoceptor antagonist (137 +/- 8%; P < 0.05), l-NAME (133 +/- 11%; P < 0.05), or l-VNIO (130 +/- 13%; P < 0.05). Nitric oxide was exclusively produced by NOS1 within diabetic cardiomyocytes. NOS2 and NOS3 proteins were undetectable.     

Treatment of Iron Deficiency Anemia in Orthopedic Surgery with Intravenous Iron: Efficacy and Limits: A Prospective Study

Background: Preoperative anemia is frequent in patients undergoing orthopedic surgery. The purpose of this study was to assess the preoperative increase of hemoglobin in iron deficiency anemia patients treated with intravenous iron.

Methods: After obtaining written informed consent, 20 patients with iron deficiency anemia received 900 mg intravenous iron sucrose over 10 days starting 4 weeks before surgery. Changes of hemoglobin and iron status were measured over 4 weeks and at discharge. In the last 11 patients, endogenous erythropoietin was also measured. Data were analyzed using the Friedman test followed by pairwise Wilcoxon signed rank tests with Bonferroni correction.

Results: Hemoglobin increased significantly (P < 0.0001) after intravenous iron treatment. Overall, the mean maximum increase was 1.0 +/- 0.6 g/dl (range, 0.2-2.2 g/dl). Ferritin increased from 78 +/- 70 to 428 +/- 191 [mu]g/l (P = 0.0001), ferritin index decreased from 2.7 +/- 2.4 to 1.5 +/- 1.0 (P = 0.0001), and soluble transferrin receptor decreased from 4.1 +/- 2.3 mg/l to 3.7 +/- 2.3 mg/l (P = 0.049), whereas transferrin saturation (20.5 +/- 9.0 to 22.9 +/- 9.0%) and serum iron (13.3 +/- 4.6 to 13.1 +/- 4.5 [mu]m) did not change significantly after intravenous iron treatment. Endogenous erythropoietin decreased from 261 +/- 130 pg/ml to 190 +/- 49 pg/ml 2 weeks after intravenous iron treatment (P = 0.050, not significant after Bonferroni correction). No adverse events related to intravenous iron were observed. The maximum increase of hemoglobin was observed 2 weeks after the start of intravenous iron treatment, indicating that administration of intravenous iron 2-3 weeks before surgery may be optimal.     

Mechanisms of bronchoprotection by anesthetic induction agents: propofol versus ketamine

BACKGROUND: Propofol and ketamine have been purported to decrease bronchoconstriction during induction of anesthesia and intubation. Whether they act on airway smooth muscle or through neural reflexes has not been determined. We compared propofol and ketamine to attenuate the direct activation of airway smooth muscle by methacholine and limit neurally mediated bronchoconstriction (vagal nerve stimulation). METHODS: After approval from the institutional review board, eight sheep were anesthetized with pentobarbital, paralyzed, and ventilated. After left thoracotomy, the bronchial artery was cannulated and perfused. In random order, 5 mg/ml concentrations of propofol, ketamine, and thiopental were infused into the bronchial artery at rates of 0.06, 0.20, and 0.60 ml/min. After 10 min, airway resistance was measured before and after vagal nerve stimulation and methacholine given via the bronchial artery. Data were expressed as a percent of baseline response before infusion of drug and analyzed by analysis of variance with significance set at P< or =0.05. RESULTS: Systemic blood pressure was not affected by any of the drugs (P>0.46). Baseline airway resistance was not different among the three agents (P = 0.56) or by dose (P = 0.96). Infusion of propofol and ketamine into the bronchial artery caused a dose-dependent attenuation of the vagal nerve stimulation-induced bronchoconstriction to 26+/-11% and 8+/-2% of maximum, respectively (P<0.0001). In addition, propofol caused a significant decrease in the methacholine-induced bronchoconstriction to 43+/-27% of maximum at the highest concentration (P = 0.05) CONCLUSIONS: The local bronchoprotective effects of ketamine and propofol on airways is through neurally mediated mechanisms. Although the direct effects on airway smooth muscle occur at high concentrations, these are unlikely to be of primary clinical relevance.     

Interaction of Protamine with α- and β-Adrenoceptor Stimulations in Rat Myocardium

Background : Protamine alters the inotropic responses to [beta]-adrenoceptor stimulation, but its mechanism of action is not well-understood. Moreover, its interaction with [alpha]-adrenoceptor stimulation and the lusitropic (relaxation) response to [beta]-adrenoceptor stimulation remain unknown.

Methods : The effects of protamine (10 or 100 [mu]g/ml) on the responses induced by phenylephrine and isoproterenol were studied in rat left ventricular papillary muscles. Inotropic and lusitropic effects were studied under low and high loads. The authors also studied the interaction of protamine with forskolin (50 [mu]m) and dibutyryl 3',5'-cAMP (0.5 mm). Data are mean percentage of baseline active force +/- SD.

Results : In control groups, phenylephrine (135 +/- 17%, P < 0.05) and isoproterenol (185 +/- 44%, P < 0.05) induced a positive inotropic effect. Isoproterenol induced positive lusitropic effects under low and high loads. Protamine abolished the inotropic responses to [alpha]- (102 +/- 23%, not significant) and [beta]-adrenoceptor stimulations (99 +/- 17%, not significant) but did not modify the lusitropic responses to isoproterenol. Protamine abolished the inotropic responses to forskolin (89 +/- 6 vs. 154 +/- 20%, P < 0.05) and markedly decreased that of dibutyryl 3',5'-cAMP (132 +/- 31 vs. 167 +/- 30%, P < 0.05) but did not modify their lusitropic responses.     

Mechanisms of Bronchoprotection by Anesthetic Induction Agents: Propofol versus Ketamine

Background: Propofol and ketamine have been purported to decrease bronchoconstriction during induction of anesthesia and intubation. Whether they act on airway smooth muscle or through neural reflexes has not been determined. We compared propofol and ketamine to attenuate the direct activation of airway smooth muscle by methacholine and limit neurally mediated bronchoconstriction (vagal nerve stimulation).

Methods: After approval from the institutional review board, eight sleep were anesthetized with pentobarbital, paralyzed, and ventilated. After left thoracotomy, the bronchial artery was cannulated and perfused. In random order, 5 mg/ml concentrations of propofol, ketamine, and thiopental were infused into the bronchial artery at rates of 0.06, 0.20, and 0.60 ml/min. After 10 min, airway resistance was measured before and after vagal nerve stimulation and methacholine given via the bronchial artery. Data were expressed as a percent of baseline response before infusion of drug and analyzed by analysis of variance with significance set at P Results: Systemic blood pressure was not affected by any of the drugs (P > 0.46). Baseline airway resistance was not different among the three agents (P = 0.56) or by dose (P = 0.96). Infusion of propofol and ketamine into the bronchial artery caused a dose-dependent attenuation of the vagal nerve stimulation-induced bronchoconstriction to 26 +/- 11% and 8 +/- 2% of maximum, respectively (P < 0.0001). In addition, propofol caused a significant decrease in the methacholine-induced bronchoconstriction to 43 +/- 27% of maximum at the highest concentration (P = 0.05).     

Effects of α2-Adrenoceptor Agonists on Perinatal Excitotoxic Brain Injury: Comparison of Clonidine and Dexmedetomidine

Background: A growing number of children have severe neurologic impairment related to very premature birth. Experimental data suggest that overstimulation of cerebral N-methyl-d-aspartate (NMDA) receptors caused by excessive glutamate release may be involved in the genesis of perinatal hypoxic-ischemic brain injury. [alpha]2-Adrenoceptor agonists are protective in models of brain ischemia in adults. The authors sought to determine whether they prevent perinatal excitotoxic neuronal damage.

Methods: Five-day-old mice were allocated at random to clonidine (4-400 [mu]g/kg), dexmedetomidine (1-30 [mu]g/kg), or saline injected intraperitoneally before an intracerebral stereotactic injection of the NMDA receptor agonist ibotenate; cortical and white matter lesions were quantified 5 days later by histopathologic examination. Cortical neuron cultures exposed to 300 [mu]m NMDA were used to evaluate the effects of clonidine or dexmedetomidine on neuronal death assessed by counting the number of pycnotic nuclei after fluorescent chromatin staining.

Results: In vivo, both clonidine and dexmedetomidine induced significant concentration-dependent reductions in the size of ibotenate-induced lesions in the cortex and white matter. In vitro, the number of neurons damaged by NMDA exposure was significantly decreased by both dexmedetomidine (-28 +/- 12% at 10 [mu]m;P < 0.01) and clonidine (-37 +/- 19% at 100 [mu]m;P < 0.01) as compared with controls. In both models, the selective [alpha]2-adrenoceptor antagonist yohimbine abolished the neuroprotective effect of clonidine and dexmedetomidine.     

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

BACKGROUND: Dexmedetomidine, a selective alpha2-adrenoceptor agonist, has counteracting effects on the cardiovascular system. It mediates sympatholysis by activating alpha2 adrenoceptors in the central and peripheral nervous system, and vasoconstriction and vasorelaxation by activating postsynaptic alpha2 adrenoceptors in blood vessels. The goal of this study was to determine the effects of therapeutic and high concentrations of dexmedetomidine on myocardial perfusion and cardiac function in healthy subjects. METHODS: The authors studied 12 healthy young men. Myocardial blood flow (assessed with positron emission tomography), myocardial function (by echocardiography), and hemodynamic data were collected before and during low (measured mean plasma concentration, 0.5 ng/ml) and high (5 ng/ml) plasma concentrations of dexmedetomidine. RESULTS: The low concentration of dexmedetomidine reduced myocardial perfusion (mean difference, -27% from baseline [95% confidence interval, -31 to -23%], P < 0.001) in parallel with a reduction in myocardial oxygen demand (estimated by the rate-pressure product (-23% [-28 to -18%], P < 0.001). The high dexmedetomidine plasma concentration did not further attenuate myocardial perfusion (-3% [-12 to +6%] from low dexmedetomidine, P > 0.05; -29% [-39 to -18%] from baseline, P < 0.001) or statistically significantly affect the rate-pressure product (+5% [0 to +10%], P > 0.05). Systolic myocardial function was attenuated by sympatholysis during the low infusion rate and was further attenuated by a combination of the sustained sympatholysis and increased afterload during the high infusion rate. CONCLUSIONS: In healthy subjects, plasma concentrations of dexmedetomidine that significantly exceed the recommended therapeutic level do not seriously attenuate myocardial perfusion below the level that is observed with usual therapeutic concentrations and do not induce evident myocardial ischemia.     

Effects of Radolmidine, A Novel α2-Adrenergic Agonist Compared with Dexmedetomidine in Different Pain Models in the Rat

Background: Intrathecally administered [alpha]2-adrenoceptor agonists produce effective antinociception, but sedation is an important adverse effect. Radolmidine is a novel [alpha]2-adrenoceptor agonist with a different pharmacokinetic profile compared with the well-researched dexmedetomidine. This study determined the antinociceptive and sedative effects of radolmidine in different models of acute and chronic pain. Dexmedetomidine and saline served as controls.

Methods: Male Sprague-Dawley rats were studied in acute pain (tail flick), carrageenan inflammation, and the spinal nerve ligation model of neuropathic pain. Mechanical allodynia was assessed with von Frey filaments, cold allodynia with the acetone test, and thermal hyperalgesia with the paw flick test. Locomotor activity-vigilance was assessed in a dark field. Dexmedetomidine and radolmidine were administered intrathecally in doses of 0.25 [mu]g, 2.5 [mu]g, 5 [mu]g, and 10 [mu]g.

Results: In the tail flick test, radolmidine showed a dose-dependent antinociceptive effect, being equipotent compared with dexmedetomidine. In carrageenan inflammation, intrathecal doses of 2.5 [mu]g or 5 [mu]g of dexmedetomidine/radolmidine produced significant antinociception compared with saline (P < 0.01). The two drugs were equianalgesic. In the neuropathic pain model, an intrathecal dose of 5 [mu]g dexmedetomidine-radolmidine had a significant antiallodynic effect compared with saline (P < 0.01). The two drugs were equipotent. Intrathecal administration of both dexmedetomidine and radolmidine dose dependently decreased spontaneous locomotor acitivity-vigilance, but this effect was significantly smaller after intrathecal administration of radolmidine than after intrathecal dexmedetomidine.     

Both local anesthetics and salbutamol pretreatment affect reflex bronchoconstriction in volunteers with asthma undergoing awake fiberoptic intubation

BACKGROUND: Awake tracheal intubation may evoke reflex bronchoconstriction in asthmatics. Whether this effect is altered by the choice of the local anesthetic used or by pretreatment with a beta2-adrenoceptor agonist is unknown. Therefore, we assessed the effect of awake fiberoptic intubation after lidocaine or dyclonine inhalation with or without pretreatment with salbutamol on lung function in asthmatic volunteers. METHODS: Bronchial hyperreactivity was verified by an inhalational histamine challenge. On four different days in a randomized, double blind fashion the volunteers (n = 10) inhaled either dyclonine or lidocaine with or without salbutamol pretreatment. FEV1 was measured at baseline, following salbutamol or saline inhalation, after lidocaine or dyclonine inhalation, while intubated, and after extubation. Lidocaine and dyclonine plasma concentrations were also measured. Statistics: Two-way ANOVA, post hoc tests with Bonferroni correction, results are presented as mean +/- SD. RESULTS: Neither lidocaine nor dyclonine inhalation changed FEV1 significantly from baseline compared with placebo inhalation (4.43 +/- 0.67 l vs. 4.29 +/- 0.72 l, and 4.53 +/- 0.63 l vs. 4.24 +/- 0.80 l, respectively). Salbutamol slightly but significantly increased FEV1 (4.45 +/- 0.76 l vs. 4.71 +/- 0.61 l, P = 0.0034, and 4.48 +/- 0.62 l vs. 4.71 +/- 0.61 l, P = 0.0121, respectively). Following awake intubation FEV1 significantly decreased under lidocaine topical anesthesia (4.29 +/- 0.72 l to 2.86 +/- 0.87 l) but decreased even more under dyclonine anesthesia (4.24 +/- 0.80 l to 2.20 +/- 0.67 l; P < 0.0001). While salbutamol pretreatment significantly attenuated the response to intubation, it did not eliminate the difference between the effects of lidocaine and dyclonine. Only minutes after extubation FEV1 was similar compared with baseline. CONCLUSION: In asthmatics, awake fiberoptic intubation evokes a more than 50% decrease in FEV1 following dyclonine inhalation. Using lidocaine for topical anesthesia the decrease in FEV1 is significantly mitigated (35%) and can be even further attenuated by salbutamol pretreatment. Therefore, combined treatment with lidocaine and salbutamol can be recommended for awake intubation while the use of dyclonine, despite its excellent and longer lasting topical anesthesia, may be contraindicated in patients with bronchial hyperreactivity.     

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

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

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

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

Ipratropium Decreases Airway Size in Dogs by Preferential M sub 2 Muscarinic Receptor Blockade In Vivo

Background: Two major groups of drugs are available to prevent bronchoconstriction: beta-agonists and muscarinic blocking agents. Ipratropium is the most commonly used anti-cholinergic agent to treat chronic obstructive pulmonary disease. The authors studied anti-muscarinic agents to determine if they are as effective bronchodilators as beta-adrenergic agents and if not to identify the mechanism of their reduced effectiveness.

Methods: Six anesthetized dogs were studied using high-resolution computed tomography to measure changes in the cross-sectional area of conducting airways induced by cumulative doses of ipratropium with and without gallamine, a selective M2 muscarinic receptor blocker, and after metaproterenol.

Results: Metaproterenol dilated the airways and ipratropium constricted the airways. Ipratropium in concentrations of 0.01 and 0.1 mg/ml constricted the airways to 22 +/- 2% and 20 +/- 3% of control, respectively (P < 0.01), whereas larger concentrations caused bronchodilation. After complete blockade of the M2 receptors by pretreatment with intravenous gallamine, the bronchoconstrictor effect of ipratropium was abolished, and ipratropium dilated the airways by 16 +/- 8% and 27 +/- 10% of pre-gallamine baseline after doses of 0.01 and 0.1 mg/ml, respectively (P < 0.01).     

Lidocaine inhalation for local anaesthesia and attenuation of bronchial hyper-reactivity with least airway irritation. Effect of three different dose regimens

The inhalation of lidocaine attenuates bronchial hyper-reactivity but also causes airway irritation. However, how lidocaine dose and plasma concentration influence relationships are unknown. Accordingly, we evaluated the effects of three concentrations of lidocaine (1, 4, and 10%, total dose of 0.5, 2.0, and 5.0 mg kg-1, respectively) vs. placebo in 15 mild asthmatic patients, selected by their response to a histamine challenge (decrease in FEV1 > 20% to less than 18 mg mL-1 of histamine [PC20]). Baseline lung function, histamine-induced bronchoconstriction, topical anaesthesia, and lidocaine plasma concentrations were obtained. FEV1 following lidocaine inhalation showed the greatest decrease for the highest dose (from 3.79 +/- 0.15-3.60 +/- 0.15; P = 0.0012). Lidocaine inhalation increased baseline PC20 (6.1 +/- 1.3 mg mL-1) significantly (to 11.8 +/- 3.1, 16.1 +/- 3.3, and 18.3 +/- 4.5 mg mL-1, respectively) with no difference between the two highest doses. The duration of local anaesthesia was not significantly different between lidocaine concentrations of 4% and 10%. Thus, lidocaine inhalation, with increasing concentrations of the aerosolized solution, increases initial bronchoconstriction while significant attenuation of bronchial hyper-reactivity is not further enhanced with increasing concentrations from 4 to 10%. Plasma concentrations of lidocaine were always far below the toxic threshold. In conclusion, when local anaesthesia of the airways is required a lidocaine dose of 2.0 mg kg-1 as a 4% solution can be recommended for local anaesthesia and attenuation of bronchial hyper-reactivity with the least airway irritation.     

Dexmedetomidine Reduces Long-term Potentiation in Mouse Hippocampus

Background: Dexmedetomidine (Precedex; Abbott Laboratories, Abbott Park, IL) is a selective [alpha]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.

Methods: 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.

Results: 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 [alpha]2-adrenoceptor antagonist (yohimbine), an imidazoline type 1 receptor and [alpha]2-adrenoceptor antagonist (efaroxan), an [alpha]1-adrenoceptor antagonist (prazosin), or a [gamma]-aminobutyric acid type A receptor antagonist (picrotoxin). However, an imidazoline type 2 receptor and [alpha]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.     

Rescue sedation with dexmedetomidine for diagnostic imaging: a preliminary report

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