Metabolic, cardiac and renal effects of the slow hydrogen sulfide-releasing molecule GYY4137 during resuscitated septic shock in swine with pre-existing coronary artery disease

This is the author accepted manuscript. The final version is available from the publisher via the DOI in this record.Published Ahead of Print, 19 January 2017Decreased levels of endogenous hydrogen sulfide (H2S) contribute to atherosclerosis, whereas equivocal data are available on H2S effects during sepsis. Moreover, H2S improved glucose utilization in anaesthetized, ventilated, hypothermic mice, but normothermia and/or sepsis blunted this effect. The metabolic effects of H2S in large animals are controversial. Therefore, we investigated the effects of the H2S donor GYY4137 during resuscitated, fecal peritonitis-induced septic shock in swine with genetically and diet-induced coronary artery disease (CAD). 12 and 18 hours after peritonitis induction, pigs received either GYY4137 (10 mg kg, n = 9) or vehicle (n = 8). Before, at 12 and 24 hours of sepsis, we assessed left ventricular (pressure-conductance catheters) and renal (creatinine clearance, blood NGAL levels) function. Endogenous glucose production and glucose oxidation were derived from the plasma glucose isotope and the expiratory CO2/CO2 enrichment during continuous i.v. 1,2,3,4,5,6-C6-glucose infusion. GYY4137 significantly increased aerobic glucose oxidation, which coincided with higher requirements of exogenous glucose to maintain normoglycemia, as well as significantly lower arterial pH and decreased base excess. Apart from significantly lower cardiac eNOS expression and higher troponin levels, GYY4137 did not significantly influence cardiac and kidney function or the systemic inflammatory response. During resuscitated septic shock in swine with CAD, GYY4137 shifted metabolism to preferential carbohydrate utilization. Increased troponin levels are possibly due to reduced local NO availability. Cautious dosing, the timing of GYY4137 administration and interspecies differences most likely account for the absence of any previously described anti-inflammatory or organ-protective effects of GYY4137 in this model

Effects of the PPAR-β/δ agonist GW0742 during resuscitated porcine septic shock.

BACKGROUND: In un-resuscitated rodent models of septic shock, the peroxisome proliferator-activated receptor-β/δ (PPAR-β/δ) agonist GW0742 improved visceral organ function. Therefore, we tested the hypothesis whether GW0742 would attenuate kidney injury during long-term, resuscitated, porcine polymicrobial septic shock. METHODS: Six, 12, and 18 h after the induction of fecal peritonitis by inoculation of autologous feces, anesthetized, mechanically ventilated, and instrumented male pigs with pre-existing atherosclerosis resulting from familial hypercholesteremia and atherogenic diet randomly received either vehicle (dimethyl sulfoxide, n = 12) or GW0742 (n = 10). Resuscitation comprised hydroxyethyl starch and norepinephrine infusion titrated to maintain mean arterial pressure at baseline values. RESULTS: Despite aggressive fluid resuscitation, fecal peritonitis was associated with arterial hypotension requiring norepinephrine infusion, ultimately resulting in progressive lactic acidosis and acute kidney injury. GW0742 did not beneficially affect any parameter of systemic and regional hemodynamics, gas exchange, metabolism, or organ function. The parameters of inflammation, oxidative and nitrosative stress, and organ injury (post-mortem analysis for histomorphology and markers of apoptosis) were not influenced either. Immunohistochemistry of pre-shock kidney biopsies from a previous study in this swine strain showed markedly lower PPAR-β/δ receptor expression than in healthy animals. CONCLUSIONS: In swine with pre-existing atherosclerosis, the PPAR-β/δ agonist GW0742 failed to attenuate septic shock-induced circulatory failure and kidney dysfunction, most likely due to reduced receptor expression coinciding with cardiovascular and metabolic co-morbidity

Cardiac Effects of Hyperoxia During Resuscitation from Hemorrhagic Shock in Swine

Hyperoxia (ventilation with FIO2 = 1.0) has vasoconstrictor properties, in particular in the coronary vascular bed, and, hence, may promote cardiac dysfunction. However, we previously showed that hyperoxia attenuated myocardial injury during resuscitation from hemorrhage in swine with coronary artery disease. Therefore, we tested the hypothesis whether hyperoxia would also mitigate myocardial injury and improve heart function in the absence of chronic cardiovascular co-morbidity.After 3 hours of hemorrhage (removal of 30% of the calculated blood volume and subsequent titration of mean arterial pressure to 40mmHg) 19 anesthetized, mechanically ventilated and instrumented pigs received FIO2 = 0.3(control) or hyperoxia(FIO2 = 1.0) during the first 24 hours. Before, at the end of and every 12 hours after shock, hemodynamics, blood gases, metabolism, cytokines and cardiac function (pulmonary artery thermodilution, left ventricular pressure-conductance catheterization) were recorded. At 48 hours, cardiac tissue was harvested for western blotting, immunohistochemistry and mitochondrial respiration.Except for higher left ventricular end-diastolic pressures at 24 hours (hyperoxia 21(17;24),control 17(15;18)mmHg;p = 0.046), hyperoxia affected neither left ventricular function cardiac injury (max. Troponin I at 12 hours: hyperoxia:9(6;23),control:17(11;24)ng mL;p = 0.395), nor plasma cytokines (except for interleukin-1β: hyperoxia 10(10;10) and 10(10;10)/control 14(10;22), 12(10;15)pg mL, p = 0.023 and 0.021 at 12 and 24 hours, respectively), oxidation and nitrosative stress, and mitochondrial respiration. However, hyperoxia decreased cardiac tissue 3-nitrotyrosine formation (p < 0.001) and inducible nitric oxide synthase expression (p = 0.016). Ultimately, survival did not differ significantly either.In conclusion, in contrast to our previous study in swine with coronary artery disease, hyperoxia did not beneficially affect cardiac function or tissue injury in healthy swine, but was devoid of deleterious side effects

Numerical Investigation of Turbulent Reacting Flows in a Scramjet Combustor Model

For the design of airbreathing hypersonic vehicles the simulation of the flow inside the propulsion system is of essential interest. Due to the importance of supersonic combustion in airbreathing hypersonic propulsion the flowfield within a scramjet combustor model has been investigated numerically. In the model hydrogen was injected through a symmetric wedge parallel into a heated Mach 2.0 air stream. The simulated test conditions correspond to a free flight Mach number up to Ma=5.5

Reduction of shock-induced boundary layer separation in hypersonic inlets using bleed

The proper design of the inlet system is of great importance for the performance of air-breathing hypersonic space planes. One of the dominating flow phenomena inside such a hypersonic inlet is the mutual interaction of oblique shocks with boundary layers, forcing the boundary layer to separate from the inlet wall. As a method to improve the inlet efficiency, the application of bleed is examined using a generic flat plate model and a single shock/laminar boundary layer interaction. By means of computational fluid dynamics as well as experiments in the hypersonic wind tunnel facility H2K of the DLR, favourable design parameters for the bleed set-up are presented and the efficiency of bleed for the reduction of the boundary layer separation and the thermal loads on the surface is demonstrate

Numerical Simulation of Shock Wave Interaction Effects on Supersonic Mixing Layer Growth

This work is motivated by the need of the development of improved numerical tools to investigate the flow field in a supersonic combustion ramjet engine. For the application of supersonics combustion in air breathing propulsion systems the mixing process is a major problem. The injected fuel has to be mixed with air before reaction takes place. Several experiments show a decrease of the spreading rate of a supersonic mixing layer with increasing convective Mach numer. Aim of this work is to investigate the influence of shock/mixing layer interactions on the mixing process by means of computational fluid dynamics. Experiments carried out at the DLR Space Propulsion Institute predict an enhancement of the mixing layer growth due to shock waves