Effects of supplementing resuscitation fluids with N-acetylcysteine on renal hemodynamics, oxygenation and inflammation in a rat model of septic shock

Background: Fluid resuscitation is considered crucial for the preservation of adequate intravascular volume and blood pressure and, therefore, the promotion of microvascular perfusion and tissue oxygenation during sepsis. However, there is increasing evidence that inappropriate use of fluid resuscitation can also activate oxidative pathways and inflammation, resulting in a heterogeneous distribution of blood flow and tissue oxygenation, especially in the renal cortex, contributing to acute kidney injury (AKI). N-acetylcystein (NAC) is regarded as an important antioxidant as it is a source of sulfhydryl and glutathione groups in cells and is a scavenger of free radicals. The aim of this study was to investigate the acute effects of Hydroxyethyl starch- ringer acetate (HES-RA) as a resuscitation fluid supplemented with NAC on physiological factors and renal function during lipopolysaccharide (LPS)-induced endotoxemic shock in rats. Methods: Rats were first randomized at the baseline (BL) time point to receive intravenous administration of 10 mg kg-1 LPS or vehicle in 30 min. After 120 min of evolution without fluid resuscitation, LPS groups were subsequently randomized to receive either a volume replacement regimen (n = 8) consisting of a balanced 6% HES-RA 130/0.4 dissolved in a balanced preparation (Volulyte; 30 mL kg-1 h-1), (LPS + HES-RA)) or this volume plus NAC (150 mg kg-1 h-1) (LPS+HES-RA+NAC). The effects of NAC was also determined in the absence of LPS (Control+NAC) as well as a Control group and LPS group without resuscitation. The resuscitation period at 180 min was defined as a steady plateau in mean arterial pressure. Results: Fluid resuscitation significantly improved systemic and renal hemodynamic parameters. However, addition of NAC to the fluid did only improve renal parameter compared to LPS group. Compared to controls, LPS infusion induced a significant decrease of cortical renal oxygenation. Fluid resuscitation with HES-RA alone did not improve cortical renal oxygenation. Administration of HES-RA combined with NAC improved significantly cortical renal oxygenation, renal oxygen consumption and renal oxygen delivery during sepsis. Moreover, fluid supplemented with NAC improved early markers of acute kidney injury, such as NGAL or L-FABP. Fluid supplemented with NAC decreased significantly renal nitric oxide levels and hyaluronic acid levels after sepsis. Conclusion: In conclusion, addition of NAC to fluid resuscitation may improve renal oxygenation, microvascular dysfunction and AKI. Decrease of renal nitric oxide levels and acid hyaluronic levels may be involved in this beneficial effect.