Background:Management of cognitive deficits in Major Depressive Disorder (MDD) remains an important unmet need. This meta-analysis evaluated the effects of vortioxetine on cognition in patients with MDD.Methods:Random effects meta-analysis was applied to three randomized, double-blind, placebo-controlled 8-week trials of vortioxetine (5–20mg/day) in MDD, and separately to two duloxetine-referenced trials. The primary outcome measure was change in Digit Symbol Substitution Test (DSST) score. Standardized effect sizes (SES) versus placebo (Cohen’s d) were used as input. Path analysis was employed to determine the extent to which changes in DSST were mediated independently of a change in Montgomery-Åsberg Depression Rating Scale (MADRS) score. Meta-analysis was applied to MADRS-adjusted and -unadjusted SES values. Changes on additional cognitive tests were evaluated (source studies only).Results:Before adjustment for MADRS, vortioxetine separated from placebo on DSST score (SES 0.25–0.48; nominal p < 0.05) in all individual trials, and statistically improved DSST performance versus placebo in meta-analyses of the three trials (SES = 0.35; p < 0.0001) and two duloxetine-referenced trials (SES = 0.26; p = 0.001). After adjustment for MADRS, vortioxetine maintained DSST improvement in one individual trial (p = 0.001) and separation from placebo was maintained in meta-analyses of all three trials (SES = 0.24; p < 0.0001) and both duloxetine-referenced trials (SES 0.19; p = 0.01). Change in DSST with duloxetine failed to separate from placebo in individual trials and both meta-analyses. Change in DSST statistically favored vortioxetine versus duloxetine after MADRS adjustment (SES = 0.16; p = 0.04).Conclusions:Vortioxetine, but not duloxetine, significantly improved cognition, independent of depressive symptoms. Vortioxetine represents an important treatment for MDD-related cognitive dysfunction.
While ICU health care workers consistently identify a number of patient factors as important in decisions to withdraw care, there is extreme variability, which may be explained in part by the values of individual health care providers.
IT IS "WELL KNOWN that the pattern of mechanical ventilation can affect the efficiency of pulmonary gas exchange. Despite this, the optimum ventilatory wave form has yet to be defined. In the past, most research has pertained to the pattern of inspiration TM and relatively little attention has been directed to the expiratory phase of ventilation. The concept of a maintained expiratory pressure as a means of improving gas exchange during mechanical ventilation is not new. Enthusiasm for the clinical use of maintained pressure during expiration has been tempered somewhat by Cournand's work, 5 which predicts a fall in cardiac output because of the inevitable associated rise in mean inflating pressure. There are relevant reports from animal studies ",7 and from studies using anaesthetized human subjects. 8-1~ In these studies, methodology varies and the results are conflicting. More recently, however, several workers have ventilated critically ill patients using a maintained expiratory pressure and have shown improved oxygenation, n-13 It was the object of the present study to examine the effects of a Positive Expiratory Pressure Plateau (PEEP) on gas exchange, cardiac output, and functional residual capacity, and to define its place in the clinical management of patients receiving artificial ventilation. Pm, P refers to a particular feature of the ventilator), wave form. Figure 1 is a tracing of airway pressure and shows the characteristic feature. A constant pressure is maintained throughout the expiratory phase, and airway pressure at no time returns to ambient pressure. This should be distinguished from an expiratory flow retard resulting from a restriction in the expiratory line. METHODOLOGY AND DESIGN OF STUDY The subjects for study were five patients in severe respiratory failure. The clinical details of these patients are recorded in Table I. All patients were on controlled ventilation with constant volume ventilators-the Ohio 560 or the Bennett MA1. Tidal volumes ranged from 8 to 14 ml/kg without intermittent sighs. All patients were ventilated with 100 per cent oxygen at the time the measurements were made. (Three patients required this level of inspired oxygen to maintain adequate oxygenation.) On the Ohio 560, provision is made for applying PEPP. When the Bennett MA1
Isoflurane is a potent systemic vasodilator. Because isoflurane vasodilation is clinically significant, we sought to explore whether decreases in systemic vascular resistance caused by isoflurane involve the alpha-adrenergic nervous system in humans. Specifically, we tested the hypothesis that isoflurane systemic vasodilation is mediated via inhibition of vascular alpha 1-adrenergic responsiveness. Phenylephrine pressor dose-response curves were established before anesthesia and during isoflurane/oxygen anesthesia in patients undergoing coronary artery bypass surgery; all patients included in the study (n = 11) demonstrated significant (P = 0.0001) decreases in systemic vascular resistance when isoflurane was given in concentrations adequate to produce a 20% decrease in mean arterial blood pressure. Polynomial regression of the phenylephrine dose-response curve was used to estimate the phenylephrine dose required to increase mean arterial blood pressure 15 mm Hg, designated PD15 mm Hg. Each patient served as his or her own control. Preanesthetic baseline PD15 mm Hg values (115 +/- 23 micrograms [1.4 +/- 0.3 micrograms/kg], mean +/- SEM) were not significantly different from isoflurane PD15 mm Hg values (124 +/- 20 micrograms [1.5 +/- 0.3 micrograms/kg]). End-tidal isoflurane concentration ranged from 0.6%-1.5%; isoflurane PD15 mm Hg was not correlated with end-tidal isoflurane concentration. Patient characteristics and hemodynamics did not affect PD15 mm Hg. These results suggest that isoflurane-induced systemic vasodilation is not mediated via inhibition of alpha 1-adrenergic responsiveness, disproving our hypothesis. This finding has clinical importance because it demonstrates that alpha 1-adrenergic stimulation with phenylephrine is effective in correcting hypotension in patients receiving isoflurane anesthesia.
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