Discussion
sepsis, sepsis-induced microcirculatory alterations, scurvy, microvascular alterations
VASODILATION, ABDOMINAL SEPSIS, SCURVY, DEFICIENCY OF ASCORBIC ACID, SEPSIS, ENDOTHELIAL DYSFUNCTION
This study, to our knowledge, is the first to investigate the effects of ascorbic acid on microcirculation during sepsis in humans using in vivo video microscopy.We found a statistically significantly higher proportion of perfused small blood vessels in the experimental group 6 h after the beginning of the study. No other significant differences were found between microcirculation flow and density parameters. Physiologically, there is reason to believe that ascorbic acid at sufficiently high doses should act as a vasodilator in microvessels both directly and through endothelial nitric oxide synthase (eNOS). Increased NADPH oxidase and iNOS activity, impaired mitochondrial oxidative phosphorylation, and altered eNOS expression play a vital role in the evolution of sepsis-induced endothelial dysfunction [The role of AA in these reactions has been demonstrated in in vitro studies. AA reduces NADPH oxidase activity [The importance of AA in endothelium-dependent vasodilation has also been demonstrated in preclinical animal studies. Parenteral administration of various doses (10–200 mg/kg) of vitamin C during experimental sepsis in the very early period prevents sepsis-induced microcirculatory alterations and facilitates subsequent restoration of impaired microcirculation 6 h from the onset of sepsis [There are a couple of published studies on high-dose AA treatment involving humans. Friedrich Mittermayer and colleagues investigated eight healthy volunteers infused with A study by Jean-Remi Lavillegrand and colleagues showed that a relatively low dose (40 mg/kg) of intravenous ascorbic acid helps to maintain vascular reactivity during sepsis, which was measured in the forearm area by transdermal iontophoresis of acetylcholine [It is important to mention that deficiency of ascorbic acid during sepsis is detected not only in serum but also intracellularly (24). Data on how intracellular level of AA changes during the administration of high dose of AA intravenously is lacking. It might be important for microvascular blood flow changes considering the fact that intracellular AA helps to restore endothelial function by inhibiting NADPH oxidase dependent processes. (330)We did not find significant differences in PBRs, as a marker of glycocalyx thickness between the groups except forin the smallest diameter capillaries immediately after the first ascorbic acid infusion. Data show that recovery of the hemodynamically significant glycocalyx layer may take up to several days after various lesions [Surprisingly, we did not observe any statistically significant differences in the dose of vasopressors between groups during the study. Bearing in mind that AA is an important cofactor in noradrenaline synthesis and its deficiency is associated with decreased noradrenaline levels [Potentially beneficial ascorbic acid’s role was challenged by a recently published LOVIT trial [This hypothesis is supported by Sun-Young Jung and collegues [On the other hand in the context of microcirculation there are plenty of animal data indicating that even a single dose of intravenous AA might help to prevent sepsis induced microvascular alterations and restore microvascular properties [The main limitation of this study is the small sample size, but patients were recruited in the study following strict inclusion criteria within the first 24 h after ICU admission.Abdominal sepsis was predominant in the experimental group. We did not determine the serum AA levels of our patients and, therefore, do not know if they were initially deficient, but many other studies have shown that AA levels are already deficient in patients in the first hours of sepsis, comparable to the levels observed in scurvy [Syndecan-1 levels were not reported. Syndecan-1 would allow to evaluate degree of the glycocalyx damage systemically throughout the body. Imaging device we have used allows investigating the area of interest in real-time to evaluate the dynamics and the thickness of the glycocalyx in microvessels of different diameters, which is very important in the context of microcirculation.