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Background  Relative hypovolemia is frequently found in early stages of severe sepsis and septic shock and prompt and aggressive fluid therapy has become standard of care improving tissue perfusion and patient outcome. This paper investigates the role of the nitric oxide pathway on beneficial microcirculatory effects of fluid resuscitation.    Methods  After skinfold chamber implantation procedures and endotoxemia induction by intravenous  Escherichia coli  lipopolysaccharide administration (2 mg.kg −1 ), male golden Syrian hamsters were fluid resuscitated and then sequentially treated with L-N  ω  -Nitroarginine and L-Arginine hydrochloride (LPS/FR/LNNA group). Intravital microscopy of skinfold chamber preparations allowed quantitative analysis of microvascular variables including venular leukocyte rolling and adhesion. Macro-hemodynamic, biochemical and hematological parameters as well as survival rate were also evaluated. Endotoxemic hamsters treated with fluid therapy alone (LPS/FR group) and non-treated animals (LPS group) served as controls.    Results  Fluid resuscitation was effective in reducing lipopolysaccharide-induced microcirculatory changes. After 3 hours of lipopolysaccharide administration, non-fluid resuscitated animals (LPS group) had the lowest functional capillary density (1% from baseline for LPS group  vs.  19% for LPS/FR one;  p  <0.05). At the same time point, arteriolar mean internal diameter was significantly wider in LPS/FR group than in LPS one (100%  vs.  50% from baseline). Fluid resuscitation also reduced leukocyte-endothelium interactions and sequestration ( p  <0.05 for LPS  vs.  LPS/FR group) and increased survival (median survival time: 2 and 5.5 days for LPS and LPS/FR groups, respectively;  p  <0.05). Nitric oxide synthase inhibition prevented these protective effects, while L-Arginine administration markedly restored many of them.    Conclusion  Our results suggest that the underlying mechanism of fluid therapy is the restoration of nitric oxide bioavailability, because inhibition of NOS prevented many of its beneficial effects. Nevertheless, further investigations are required in experimental models closer to conditions of human sepsis to confirm these results.

journal of translational medicine

Fluid resuscitation therapy in endotoxemic hamsters improves survival and attenuates capillary perfusion deficits and inflammatory responses by a mechanism related to nitric oxide