Background and Aims: The systemic host response in sepsis is frequently accompanied by central nervous system (CNS) dysfunction. Evidence suggests that excessive formation of neutrophil extracellular traps (NETs) can increase the permeability of the blood–brain barrier (BBB) and that the evolving mitochondrial damage may contribute to the pathogenesis of sepsis-associated encephalopathy. Kynurenic acid (KYNA), a metabolite of tryptophan catabolism, exerts pleiotropic cell-protective effects under pro-inflammatory conditions. Our aim was to investigate whether exogenous KYNA or its synthetic analogues SZR-72 and SZR-104 affect BBB permeability secondary to NET formation and influence cerebral mitochondrial disturbances in a clinically relevant rodent model of intraabdominal sepsis.Methods: Sprague–Dawley rats were subjected to fecal peritonitis (0.6 g kg^-1 ip) or a sham operation. Septic animals were treated with saline or KYNA, SZR-72 or SZR-104 (160 µmol kg^-1 each ip) 16h and 22h after induction. Invasive monitoring was performed on anesthetized animals to evaluate respiratory, cardiovascular, renal, hepatic and metabolic parameters to calculate rat organ failure assessment (ROFA) scores. NET components (citrullinated histone H3 (CitH3); myeloperoxidase (MPO)) and the NET inducer IL-1β, as well as IL-6 and a brain injury marker (S100B) were detected from plasma samples. After 24h, leukocyte infiltration (tissue MPO) and mitochondrial complex I- and II-linked (CI–CII) oxidative phosphorylation (OXPHOS) were evaluated. In a separate series, Evans Blue extravasation and the edema index were used to assess BBB permeability in the same regions.Results: Sepsis was characterized by significantly elevated ROFA scores, while the increased BBB permeability and plasma S100B levels demonstrated brain damage. Plasma levels of CitH3, MPO and IL-1β were elevated in sepsis but were ameliorated by KYNA and its synthetic analogues. The sepsis-induced deterioration in tissue CI–CII-linked OXPHOS and BBB parameters as well as the increase in tissue MPO content were positively affected by KYNA/KYNA analogues.Conclusion: This study is the first to report that KYNA and KYNA analogues are potential neuroprotective agents in experimental sepsis. The proposed mechanistic steps involve reduced peripheral NET formation, lowered BBB permeability changes and alleviation of mitochondrial dysfunction in the CNS.

Mitochondrial‐derived reactive oxygen species have been deemed an important contributor in sepsis pathogenesis. We investigated whether two mitochondria‐targeted antioxidants (mtAOX; SkQ1 and MitoTEMPO) improved long‐term outcome, lessened inflammation, and improved organ homeostasis in polymicrobial murine sepsis. 3‐month‐old female CD‐1 mice (n = 90) underwent cecal ligation and puncture (CLP) and received SkQ1 (5 nmol/kg), MitoTEMPO (50 nmol/kg), or vehicle 5 times post‐CLP. Separately, 52 SkQ1‐treated CLP mice were sacrificed at 24 h and 48 h for additional endpoints. Neither MitoTEMPO nor SkQ1 exerted any protracted survival benefit. Conversely, SkQ1 exacerbated 28‐day mortality by 29%. CLP induced release of 10 circulating cytokines, increased urea, ALT, and LDH, and decreased glucose but irrespectively of treatment. Similar occurred for CLP‐induced lymphopenia/neutrophilia and the NO blood release. At 48 h post‐CLP, dying mice had approximately 100‐fold more CFUs in the spleen than survivors, but this was not SkQ1 related. At 48 h, macrophage and granulocyte counts increased in the peritoneal lavage but irrespectively of SkQ1. Similarly, hepatic mitophagy was not altered by SkQ1 at 24 h. The absence of survival benefit of mtAOX may be due to the extended treatment and/or a relatively moderate‐risk‐of‐death CLP cohort. Long‐term effect of mtAOX in abdominal sepsis appears different to sepsis/inflammation models arising from other body compartments.

In the assessment of hypovolemia the value of functional hemodynamic monitoring during spontaneous breathing is debated. The aim of our study was to investigate in spontaneously breathing subjects the changes in hemodynamic parameters during graded central hypovolemia and to test whether slow patterned breathing improved the discriminative value of stroke volume (SV), pulse pressure (PP), and their variations (SVV, PPV). In addition, we tested the alterations in labial microcirculation.

Introduction: Sepsis is a dysregulated host response to infection with macro- and microhemodynamic deterioration. Kynurenic acid (KYNA) is a metabolite of the kynurenine pathway of tryptophan catabolism with pleiotropic cell-protective effects under pro-inflammatory conditions. Our aim was to investigate whether exogenously administered KYNA or the synthetic analog SZR-72 affects the microcirculation and mitochondrial function in a clinically relevant rodent model of intraabdominal sepsis.Methods: Male Sprague–Dawley rats (n = 8/group) were subjected to fecal peritonitis (0.6 g kg⁻¹ feces ip) or a sham operation. Septic animals were treated with sterile saline or received ip KYNA or SZR-72 (160 μmol kg⁻¹ each) 16 and 22 h after induction. Invasive monitoring was performed on anesthetized animals to evaluate respiratory, cardiovascular, renal, hepatic and metabolic dysfunctions (PaO₂/FiO₂ ratio, mean arterial pressure, urea, AST/ALT ratio and lactate levels, respectively) based on the Rat Organ Failure Assessment (ROFA) score. The ratio of perfused vessels (PPV) of the ileal serosa was quantified with the intravital imaging technique. Complex I- and II-linked (CI; CII) oxidative phosphorylation capacities (OXPHOS) and mitochondrial membrane potential (ΔΨmt) were evaluated by High-Resolution FluoRespirometry (O2k, Oroboros, Austria) in liver biopsies. Plasma endothelin-1 (ET-1), IL-6, intestinal nitrotyrosine (NT) and xanthine oxidoreductase (XOR) activities were measured as inflammatory markers.Results: Sepsis was characterized by an increased ROFA score (5.3 ± 1.3 vs. 1.3 ± 0.7), increased ET-1, IL-6, NT and XOR levels, and decreased serosal PPV (65 ± 12% vs. 87 ± 7%), ΔΨmt and CI–CII-linked OXPHOS (73 ± 16 vs. 158 ± 14, and 189 ± 67 vs. 328 ± 81, respectively) as compared to controls. Both KYNA and SZR-72 reduced systemic inflammatory activation; KYNA treatment decreased serosal perfusion heterogeneity, restored PPV (85 ± 11%) and complex II-linked OXPHOS (307 ± 38), whereas SZR-72 improved both CI- and CII-linked OXPHOS (CI: 117 ± 18; CII: 445 ± 107) without effects on PPV 24 h after sepsis induction.Conclusion: Treatment with SZR-72 directly modulates mitochondrial respiration, leading to improved conversion of ADP to ATP, while administration of KYNA restores microcirculatory dysfunction. The results suggest that microcirculatory and mitochondrial resuscitation with KYNA or the synthetic analog SZR-72 might be an appropriate supportive tool in sepsis therapy.

Fluid resuscitation remains a cornerstone in the management of acute bleeding. According to Starling's “Three-compartment model”, four-times more crystalloids have the same volume effect as colloids. However, this volume-replacement ratio remains a controversial issue as it may be affected by the degradation of the endothelial glycocalyx layer, a situation often found in the critically ill. Our aim was to compare colloid and crystalloid based fluid resuscitation during an experimental stroke volume index (SVI) guided hemorrhage and resuscitation animal model. Anesthetized and mechanically ventilated pigs were randomized to receive a colloid (Voluven®,HES, n=15) or crystalloid (Ringerfundin®,RF, n=15) infusion. Animals were bled till baseline SVI (Tbsl) dropped by 50% (T0), followed by resuscitation until initial SVI was reached (T4) in four steps. Invasive hemodynamic measurements, blood gas analyses and laboratory tests were performed at each assessment points. Glycocalyx degradation markers (Syndecan-1/hematocrit ratio, Glypican/hematocrit ratio) were determined at Tbsl, T0 and T4. Similar amounts of blood were shed in both groups (HES group: 506±159 mls blood, RF group: 470±127 mls blood). Hemodynamic changes followed the same pattern without significant difference between the groups. Animals received significantly less resuscitation fluid in the HES compared to the RF-group: 425 [320-665], vs 1390 [884-1585] mls, p <0.001. The volume replacement ratio was 0.92 [0.79-1.54] for HES; and 3.03 [2.00-4.23] for the RF-group (p <0.001). There was no significant difference between the groups in the glycocalyx degradation markers. In this moderate bleeding-resuscitation animal model the volume-replacement ratio for crystalloids and colloids followed similar patterns as predicted by Starling's principle, and the glycocalyx remained intact. This indicates that in acute bleeding events, such as trauma or during surgery, colloids may be beneficial as hemodynamic stability may be achieved more rapidly than with crystalloids.