Does intranasal dexmedetomidine provide adequate plasma concentrations for sedation in children: a pharmacokinetic study.

BACKGROUND: Atomised intranasal dexmedetomidine administration is an attractive option when sedation is required for paediatric diagnostic procedures, as vascular access is not required. The risk of haemodynamic instability caused by dexmedetomidine necessitates better understanding of its pharmacokinetics in young children. To date, intranasal dexmedetomidine pharmacokinetics has only been studied in adults. METHODS: Eighteen paediatric patients received dexmedetomidine 1 or 2 µg kg-1 intranasally or 1 µg kg-1 i.v. Plasma concentrations were determined by liquid chromatography/mass spectrometry. Non-compartmental analysis provided estimates of Cmax and Tmax. Volume of distribution, clearance, and bioavailability were estimated by simultaneous population PK analysis of data after intranasal and i.v. administration. Dexmedetomidine plasma concentration-time profiles were evaluated by simulation for intranasal and i.v. administration. RESULTS: An average peak plasma concentration of 199 pg ml-1 was achieved 46 min after 1 µg kg-1 dosing and 355 pg ml-1 was achieved 47 min after 2 µg kg-1 dosing. A two-compartment pharmacokinetic model, with allometrically scaled parameters, adequately described the data. Typical bioavailability was 83.8% (95% confidence interval 69.5-98.1%). CONCLUSION: Mean arterial plasma concentrations of dexmedetomidine in infants and toddlers approached 100 pg ml-1, the low end reported for sedative efficacy, within 20 min of an atomised intranasal administration of 1 µg kg-1. Doubling the dose to 2 µg kg-1 reached this plasma concentration within 10 min and achieved almost twice the peak concentration. Peak plasma concentrations with both doses were reached within 47 min of intranasal administration, with an overall bioavailability of 84%.

Anesthesia for the micropremie.

Providing anesthesia for the micropremie involves many considerations beyond what is needed for the full-term neonate. Immaturity of the airway, lungs, cardiovascular system, liver, kidneys, and central nervous system makes the micropremie susceptible to anesthestic complications. Immature respiratory mechanisms and respiratory control increase the risk of apnea, hypoxemia, and hypercapnia intraoperatively as well as postoperatively. Anesthetic drugs depress myocardial contractility and impair baroreflexes in the micropremie to increase the risk of hypotension during anesthesia. Drug metabolism in the micropremie is slow because of the immature liver and kidneys. The micropremie brain requires less drug to achieve the anesthetized state. As a result, administration of the dose and timing of anesthetic drugs differs in the micropremie compared with the full-term neonate. This article describes anesthetic considerations for a few surgical prodedures common in the micropremie.

Halothane and isoflurane inhibit endothelium-derived relaxing factor-dependent cyclic guanosine monophosphate accumulation in endothelial cell-vascular smooth muscle co-cultures independent of an effect on guanylyl cyclase activation.

BACKGROUND: Interaction of inhalational anesthetics with the nitric oxide signaling pathway and the mechanism of such effects are controversial. The aim of this study was to clarify the sites and mechanism of inhalational anesthetic interaction with the vascular nitric oxide and guanylyl cyclase signaling pathway. METHODS: To specifically study the mechanism of anesthetic interaction with the nitric oxide-guanylyl cyclase pathway, cultured vascular smooth muscle and endothelial cell-vascular smooth muscle (EC-VSM) co-culture models were chosen. Monolayer cultures of VSM with or without cultured endothelial cells grown on microcarrier beads were preequilibrated with anesthetic and stimulated with agonists. The effect of inhalational anesthetics on cyclic guanosine monophosphate (GMP) content of unstimulated VSM and of VSM in which soluble guanylyl cyclase had been activated by the endothelium-independent nitrovasodilators, sodium nitroprusside, nitroglycerin, or nitric oxide was determined. Experiments were also performed to assess the effect of inhalational anesthetics on unstimulated endothelial cell-vascular smooth muscle co-cultures and on co-cultures in which nitric oxide synthase and subsequent cyclic GMP production had been activated by the receptor-mediated agonists bradykinin and adenosine triphosphate and by the non-receptor-mediated calcium ionophore A23187. RESULTS: Increasing concentrations of halothane and isoflurane from 0.5 to 5% had no effect on basal cyclic GMP concentrations in cultured VSM alone or in endothelial cell-vascular smooth muscle co-cultures, and had no effect on sodium nitroprusside, nitroglycerin, or nitric oxide stimulated cyclic GMP accumulation in cultured VSM. In agonist-stimulated co-cultures, however, halothane and isoflurane significantly (P < 0.05) inhibited increases in cyclic GMP concentration in response to both receptor- and non-receptor-mediated nitric oxide synthase activating agents. CONCLUSIONS: Inhalational anesthetics do not stimulate or inhibit basal cyclic GMP production in co-cultures or VSM, suggesting that inhalational anesthetics do not activate soluble or particulate guanylyl cyclase and do not activate nitric oxide synthase. Inhalational anesthetics do not inhibit nitrovasodilator-induced cyclic GMP formation, suggesting a lack of interference with soluble guanylyl cyclase activation. Inhalational anesthetics inhibit both agonist and calcium ionophore-stimulated nitric oxide-dependent cyclic GMP accumulation in endothelial cell-vascular smooth muscle co-cultures. Consistent with previous vascular ring studies, anesthetics appear to inhibit nitric oxide-guanylyl cyclase signaling distal to receptor activation in the endothelial cell and proximal to nitric oxide activation of guanylyl cyclase.