Neuroprotective properties of levosimendan in an in vitro model of traumatic brain injury

<p>Abstract</p> <p>Background</p> <p>We investigated the neuroprotective properties of levosimendan, a novel inodilator, in an in vitro model of traumatic brain injury.</p> <p>Methods</p> <p>Organotypic hippocampal brain slices from mouse pups were subjected to a focal mechanical trauma. Slices were treated after the injury with three different concentrations of levosimendan (0.001, 0.01 and 0.1 μM) and compared to vehicle-treated slices. After 72 hrs, the trauma was quantified using propidium iodide to mark the injured cells.</p> <p>Results</p> <p>A significant dose-dependent reduction of both total and secondary tissue injury was observed in cells treated with either 0.01 or 0.1 μM levosimendan compared to vehicle-treated slices.</p> <p><b>Conclusion</b></p> <p>Levosimendan represents a promising new pharmacological tool for neuroprotection after brain injury and warrants further investigation in an in vivo model.</p

Xenon protects left ventricular diastolic function during acute ischemia, less than ischemic preconditioning

Anesthetics modify regional left ventricular (LV) dysfunction following ischemia/reperfusion but their effects on global function in this setting are less clear. Aim of this study was to test the hypothesis that xenon would limit global LV dysfunction as caused by acute anterior wall ischemia, comparable to ischemic preconditioning. In an open-chest model under thiopental anesthesia, 30 pigs underwent 60-minute left anterior descending coronary artery occlusion, followed by 120 minutes of reperfusion. A xenon group (constant inhalation from previous to ischemia through end of reperfusion) was compared to control and ischemic preconditioning. Load-independent measures of diastolic function (end-diastolic pressure-volume relation, time constant of relaxation) and systolic function (end-systolic pressure-volume relation, preload-recruitable stroke work) were determined. Heart rate, arterial pressure, cardiac output, and arterial elastance were recorded. Data were compared in 26 pigs. Ischemia impaired global diastolic but not systolic function in control, which recovered during reperfusion. Xenon limited and preconditioning abolished diastolic dysfunction during ischemia. Arterial pressure decreased during reperfusion while arterial elastance increased. Tachycardia and antero-septal wall edema during reperfusion were observed in all groups. In spite of ischemia of 40% of LV mass, global systolic function was preserved. Deterioration in global diastolic function was limited by xenon and prevented by preconditioning

Effect of Aprotinin on Liver Injury after Transplantation of Extended Criteria Donor Grafts in Humans: A Retrospective Propensity Score Matched Cohort Analysis

The number of patients awaiting liver transplantation still widely exceeds the number of donated organs available. Patients receiving extended criteria donor (ECD) organs are especially prone to an aggravated ischemia reperfusion syndrome during liver transplantation leading to massive hemodynamic stress and possible impairment in organ function. Previous studies have demonstrated aprotinin to ameliorate reperfusion injury and early graft survival. In this single center retrospective analysis of 84 propensity score matched patients out of 274 liver transplantation patients between 2010 and 2014 (OLT), we describe the association of aprotinin with postreperfusion syndrome (PRS), early allograft dysfunction (EAD: INR 1,6, AST/ALT &gt; 2000 within 7–10 days) and recipient survival. The incidence of PRS (52.4% vs. 47.6%) and 30-day mortality did not differ (4.8 vs. 0%; p = 0.152) but patients treated with aprotinin suffered more often from EAD (64.3% vs. 40.5%, p = 0.029) compared to controls. Acceptable or poor (OR = 3.3, p = 0.035; OR = 9.5, p = 0.003) organ quality were independent predictors of EAD. Our data do not support the notion that aprotinin prevents nor attenuates PRS, EAD or mortality

Comparative assessment of coronary physiology using transthoracic pulsed-wave Doppler and myocardial contrast echocardiography in rats

Background: Coronary physiology assessment in rodents by ultrasound is an excellent noninvasive and easy to perform technique, including pulsed-wave Doppler (PWD) and myocardial contrast echocardiography (MCE). Both techniques and the corresponding calculated parameters were investigated in this study at rest as well as their response to pharmacologically induced stress. Methods: Left ventricular myocardial function was assessed in eight anaesthetised rats using transthoracic echocardiography. Coronary physiology was assessed by both PWD of the left coronary artery and MCE using a bolus method. Measurements were performed at rest and under stimulation with adenosine and dobutamine. Effects of stimulation on the calculated parameters were evaluated and rated by effect size (η2). Results: Changes could be demonstrated by selected parameters of PWD and MCE. The clearest effect in PWD was found for diastolic peak velocity (η2 = 0.58). It increased from 528 ± 110 mm/s (mean ± standard deviation) at rest to 839 ± 342 mm/s (p = 0.001) with adenosine and 1093 ± 302 mm/s with dobutamine (p = 0.001). The most distinct effect from MCE was found for the normalised wash-in rate (η2 = 0.58). It increased from 1.95 ± 0.35% at rest to 3.87 ± 0.85% with adenosine (p = 0.001) and 3.72 ± 1.03% with dobutamine (p = 0.001). Conclusion: Induced changes in coronary physiology by adenosine and dobutamine could successfully be monitored using MCE and PWD in anaesthetised rats. Due to the low invasiveness of the measurements, this protocol could be used for longitudinal animal studies

Visual quality assessment of the liver graft by the transplanting surgeon predicts postreperfusion syndrome after liver transplantation: a retrospective cohort study

Abstract Background The discrepancy between demand and supply for liver transplants (LT) has led to an increased transplantation of organs from extended criteria donors (ECD). Methods In this single center retrospective analysis of 122 cadaveric LT recipients, we investigated predictors of postreperfusion syndrome (PRS) including transplant liver quality categorized by both histological assessment of steatosis and subjective visual assessment by the transplanting surgeon using multivariable regression analysis. Furthermore, we describe the relevance of PRS during the intraoperative and postoperative course of LT recipients. Results 53.3% (n = 65) of the patients suffered from PRS. Risk factors for PRS were visually assessed organ quality of the liver grafts (acceptable: OR 12.2 [95% CI 2.43–61.59], P = 0.002; poor: OR 13.4 [95% CI 1.48–121.1], P = 0.02) as well as intraoperative norepinephrine dosage before reperfusion (OR 2.2 [95% CI 1.26–3.86] per 0.1 μg kg− 1 min− 1, P = 0.01). In contrast, histological assessment of the graft was not associated with PRS. LT recipients suffering from PRS were hemodynamically more instable after reperfusion compared to recipients not suffering from PRS. They had lower mean arterial pressures until the end of surgery (P < 0.001), received more epinephrine and norepinephrine before reperfusion (P = 0.02 and P < 0.001, respectively) as well as higher rates of continuous infusion of norepinephrine (P < 0.001) and vasopressin (P = 0.02) after reperfusion. Postoperative peak AST was significantly higher (P = 0.001) in LT recipients with PRS. LT recipients with intraoperative PRS had more postoperative adverse cardiac events (P = 0.05) and suffered more often from postoperative delirium (P = 0.04). Conclusions Patients receiving ECD liver grafts are especially prone to PRS. Anesthesiologists should keep these newly described risk factors in mind when preparing for reperfusion in patients receiving high-risk organs

The effects of levosimendan on brain metabolism during initial recovery from global transient ischaemia/hypoxia

<p>Abstract</p> <p>Backround</p> <p>Neuroprotective strategies after cardiopulmonary resuscitation are currently the focus of experimental and clinical research. Levosimendan has been proposed as a promising drug candidate because of its cardioprotective properties, improved haemodynamic effects <it>in vivo</it> and reduced traumatic brain injury <it>in vitro</it>. The effects of levosimendan on brain metabolism during and after ischaemia/hypoxia are unknown.</p> <p>Methods</p> <p>Transient cerebral ischaemia/hypoxia was induced in 30 male Wistar rats by bilateral common carotid artery clamping for 15 min and concomitant ventilation with 6% O₂ during general anaesthesia with urethane. After 10 min of global ischaemia/hypoxia, the rats were treated with an i.v. bolus of 24 μg kg^-1 levosimendan followed by a continuous infusion of 0.2 μg kg^-1 min^-1. The changes in the energy-related metabolites lactate, the lactate/pyruvate ratio, glucose and glutamate were monitored by microdialysis. In addition, the effects on global haemodynamics, cerebral perfusion and autoregulation, oedema and expression of proinflammatory genes in the neocortex were assessed.</p> <p>Results</p> <p>Levosimendan reduced blood pressure during initial reperfusion (72 ± 14 vs. 109 ± 2 mmHg, p = 0.03) and delayed flow maximum by 5 minutes (p = 0.002). Whereas no effects on time course of lactate, glucose, pyruvate and glutamate concentrations in the dialysate could be observed, the lactate/pyruvate ratio during initial reperfusion (144 ± 31 vs. 77 ± 8, p = 0.017) and the glutamate release during 90 minutes of reperfusion (75 ± 19 vs. 24 ± 28 μmol·L^-1) were higher in the levosimendan group. The increased expression of <it>IL-6, IL-1ß TNFα and ICAM-1</it>, extend of cerebral edema and cerebral autoregulation was not influenced by levosimendan.</p> <p>Conclusion</p> <p>Although levosimendan has neuroprotective actions <it>in vitro</it> and on the spinal cord <it>in vivo</it> and has been shown to cross the blood–brain barrier, the present results showed that levosimendan did not reduce the initial neuronal injury after transient ischaemia/hypoxia.</p