Anesthesiology
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Several recent studies have suggested that the terminal half-lives of many drugs do not predict the rate of washout of drug after the relatively short durations of infusions used in anesthesia. Many anesthetic drugs fit a three-compartment mamillary model, with three volumes of distribution (central [V1] and peripheral [V2 and V3]) and three clearances (elimination or metabolic [Cl1] and distribution [Cl2 and Cl3]). It has been suggested that a large V3:Cl3 ratio contributes to rapid recovery after infusion. We investigated the role of each of these primary pharmacokinetic parameters to determine values of each that would contribute to rapid recovery after various dosing schemes. ⋯ This study proposes qualitative guidelines for pharmacokinetic properties desirable in anesthetic drugs. If a rapid decrease in plasma concentration is desired after an infusion, it is always beneficial to have a small V1 and a large Cl1. For infusions of short duration, after which only a small decrease in plasma concentration is required, it is beneficial to have a larger V2, V3, Cl2, and Cl3. For infusions of longer duration, after which a large decrease in plasma concentration is desired, it is beneficial to have a smaller V2, V3, Cl2, and Cl3. These proposals may be beneficial for planning clinical trials of new drugs.
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Comparative Study
Effect of interfacing between spontaneous breathing and mechanical cycles on the ventilation-perfusion distribution in canine lung injury.
Improved matching between ventilation and perfusion (VA/Q) has been proposed to be a major advantage of partial ventilatory support compared with controlled mechanical ventilation. This study was designed to determine whether a difference in gas exchange exists between partial ventilatory support techniques that allow unsupported spontaneous breathing to occur during any phase of the mechanical ventilatory cycle and those that provide mechanical support for each spontaneous inspiratory effort. ⋯ Spontaneous breathing superimposed on mechanical ventilation contributes to improved VA/Q matching and increased systemic blood flow. Apparently, the spontaneous contribution to a mechanically assisted breath during PSV is not sufficient to counteract the VA/Q maldistribution of positive pressure lung insufflation during acute lung injury.
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Levosimendan is a myofilament calcium sensitizer with phosphodiesterase III inhibiting properties which increases contractile state in vitro by stabilizing calcium-induced changes in troponin C. This latter effect may produce positive inotropic actions but may also cause deleterious negative lusitropic effects. This investigation examined the effects of levosimendan on systemic and coronary hemodynamics and left ventricular systolic and diastolic function in conscious and anesthetized dogs. ⋯ The results indicate that levosimendan causes systemic and coronary vasodilatation in conscious and anesthetized dogs during blockade of the autonomic nervous system. Levosimendan caused direct positive inotropic effects and improved rapid ventricular filling but did not alter indices of isovolumic relaxation, suggesting that levosimendan may selectively enhance systolic performance and diastolic filling without affecting left ventricular relaxation.
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Isoflurane-N2O anesthesia (as compared with halothane-N2O) reduces the cerebral blood flow (CBF) at which electroencephalographic changes occur in humans subjected to carotid occlusion. In contrast, no differences were seen in rats when cortical depolarization (instead of the electroencephalogram) was used as the ischemic marker during equi-MAC isoflurane-N2O and halothane-N2O anesthesia. To extend these findings, we used laser-Doppler flowmetry to continuously examine CBF (CBFLDF) and attempted to better define the relation between CBF and the time to depolarization (as a measure of the rate of energy depletion after ischemia). ⋯ The CBF threshold for cortical depolarization as measured by laser-Doppler flowmetry did not differ significantly between halothane-N2O- and isoflurane-N2O-anesthetized rats. There were also no important differences in the times until depolarization, other than a small difference when flow = 0. If the time to depolarization is reflects the potential ischemic injury, the it is unlikely that isoflurane-N2O conveys any protective advantage relative to halothane-N2O.
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Activation of the gamma-aminobutyric acidA (GABAA) receptor-ionophore complex has been reported as a possible molecular mechanism of the anesthetic action of propofol. Augmentation of GABA-induced inhibitory transmission has also been suggested as a mechanism. Because data describing this latter mechanism in mammalian neurons are few, we have examined the effects of propofol on the GABA response in central neurons of the rat. ⋯ Propofol at clinically relevant concentrations enhances the inhibitory GABAA receptor-mediated response in mammalian central neurons. The enhancement may result in reduced excitability of the neuronal network and may, consequently, contribute to the anesthetic action of the agent.