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Background: Preload responsive postoperative patients with signs of inadequate organ perfusion are commonly assumed to be hypovolemic and therefore treated with fluids to increase preload. However, preload is influenced not only by blood volume, but also by venous vascular tone and the contribution of these factors to preload responsiveness in this setting is unknown. Based on this, the objective of this study was to investigate blood volume status in preload-responsive postoperative patients., Methods: Data from a clinical trial including postoperative patients after major abdominal surgery were analyzed. Patients with signs of inadequate organ perfusion and with data from a passive leg raising test (PLR) were included. An increase in pulse pressure by ≥ 9% was used to identify patients likely to be preload responsive. Blood volume was calculated from plasma volume measured using radiolabelled albumin and hematocrit. Patients with a blood volume of at least 10% above or below estimated normal volume were considered hyper- and hypovolemic, respectively., Results: A total of 63 patients were included in the study. Median (IQR) blood volume in the total was 57 (50-65) ml/kg, and change in pulse pressure after PLR was 14 (7-24)%. A total of 43 patients were preload responsive. Of these patients, 44% were hypovolemic, 28% euvolemic and 28% hypervolemic., Conclusions: A large fraction of postoperative patients with signs of hypoperfusion that are likely to be preload responsive, are hypervolemic. In these patients, treatments other than fluid administration may be a more rational approach to increase cardiac output. Trial registration EudraCT 2013-004446-42., (© 2023. The Author(s).)

Background: Acute bacterial meningitis is a disease with a high mortality and a high incidence of neurological sequelae in survivors. There is an acute need to develop new adjuvant therapies. To ensure that new therapies evaluated in animal models are translatable to humans, studies must evaluate clinically relevant and patient-important outcomes, including neurological symptoms and sequelae., Methods: We developed and tested a functional observational battery to quantify the severity of a variety of relevant neurological and clinical symptoms in a rat model of bacterial meningitis. The functional observational battery included symptoms relating to general clinical signs, gait and posture abnormalities, involuntary motor movements, focal neurological signs, and neuromotor abnormalities which were scored according to severity and summed to obtain a combined clinical and neurological score. To test the functional observational battery, adult Sprague-Dawley rats were infected by intracisternal injection of a clinical isolate of Streptococcus pneumoniae. Rats were evaluated for 6 days following the infection., Results: Pneumococcal meningitis was not lethal in this model; however, it induced severe neurological symptoms. Most common symptoms were hearing loss (75% of infected vs 0% of control rats; p = 0.0003), involuntary motor movements (75% of infected vs 0% of control rats; p = 0.0003), and gait and posture abnormality (67% of infected vs 0% of control rats; p = 0.0013). Infected rats had a higher combined score when determined by the functional observational battery than control rats at all time points (24 h 12.7 ± 4.0 vs 4.0 ± 2.0; 48 h 17.3 ± 7.1 vs 3.4 ± 1.8; 6 days 17.8 ± 7.4 vs 1.7 ± 2.4; p < 0.0001 for all)., Conclusions: The functional observational battery described here detects clinically relevant neurological sequelae of bacterial meningitis and could be a useful tool when testing new therapeutics in rat models of meningitis.

Background: Increased vascular permeability is a key feature in the pathophysiology of sepsis and the development of organ failure. Shedding of the endothelial glycocalyx is increasingly being recognized as an important pathophysiological mechanism but at present it is unclear if glypicans contribute to this response. We hypothesized that plasma levels of glypicans (GPC) are elevated in patients with sepsis., Methods: Plasma GPC 1-6 levels were measured by ELISA in 10 patients with sepsis and 10 healthy controls as an initial screening. Plasma GPC 1, 3, and 4 were further measured in a cohort of 184 patients with a clinically confirmed infection. Patients were divided into groups of those who had sepsis and those who had an infection without organ failure. To determine whether plasma glypicans could predict the development of organ failure, patients were further subdivided to those who had organ failure at enrolment and those who developed it after enrollment. The association of plasma GPC 1, 3, and 4 with organ failure and with various markers of inflammation, disease severity, and glycocalyx shedding was investigated., Results: In the pilot study, only GPC 1, 3, and 4 were detectable in the plasma of sepsis patients. In the larger cohort, GPC 1, 3, and 4 levels were significantly higher (p < 0.001) in patients with sepsis than in those with infection without organ failure. GPC 1, 3, and 4 were significantly positively correlated with plasma levels of the disease severity markers C-reactive protein, lactate, procalcitonin, and heparin binding protein, and with the marker of glycocalyx degradation syndecan 1. They were significantly negatively correlated with plasma levels of the glycocalyx-protective factors apolipoprotein M and sphingosine-1-phosphate., Conclusions: We show that GPC 1, 3, and 4 are elevated in plasma of patients with sepsis and correlate with markers of disease severity, systemic inflammation, and glycocalyx damage.

Background: Even though crystalloids are the first choice for fluid resuscitation in hemodynamically unstable patients, their potency as plasma volume expanders in hypovolemia of different etiologies is largely unknown. The objective of the study was to investigate dose-response curves of a crystalloid in hypovolemia induced by either sepsis or hemorrhagic shock., Results: Rats were randomized to resuscitation with Ringers acetate at a dose 10, 30, 50, 75, or 100 ml/kg at 4 h after induction of sepsis by cecal ligation and puncture (CLP) or 2.5 h after a 30 ml/kg hemorrhage. Plasma volume ( 125 I-albumin) was the primary outcome. Plasma volume decreased by about 11.8 (IQR 9.9-14.5) ml/kg relative baseline after CLP and increased dose-dependently by at most 5.8 (IQR 3.3-7.0) ml/kg in the 100 ml/kg group at 15 min after resuscitation. In the hemorrhage group, the plasma volume increased by at most 13.8 (IQR 7.1-15.0) ml/kg in 100 ml/kg group. Blood volumes at baseline, calculated using hematocrit and plasma volumes, were 72.4 (IQR 68.2-79.5) ml/kg in sepsis group and 71.1 (IQR 69.1-74.7) ml/kg in hemorrhage group. At 15 min after resuscitation with a dose of 100 ml/kg blood volumes increased to 54.8 (IQR 52.5-57.7) ml/kg and ; 49.6 (IQR 45.3-56.4) ml/kg, in the sepsis and hemorrhage groups, respectively. Plasma volume expansion as the percentage of dose at 15 min was 5.9 (IQR 2.5-8.8)% and 14.5 (IQR 12.1-20.0)% in the sepsis and hemorrhage groups, respectively. At 60 min, average plasma volume as the percentage of dose had decreased to 2.9 (IQR ([-2.9] - 8.3)% (P = 0.006) in the sepsis group whereas no change was detected in the hemorrhage group. A dose-dependent decrease in the plasma oncotic pressure, which was more marked in sepsis, was detected at 60 min after resuscitation., Conclusions: We conclude that the efficacy of Ringers acetate as a plasma volume expander is context dependent and that plasma volume expansion is lower than previously realized across a wide range of doses. Ringers acetate decreases plasma oncotic pressure in sepsis, in part, by mechanisms other than dilution.

Background: Elevated plasma levels of heparin-binding protein (HBP) are associated with risk of organ dysfunction and mortality in sepsis, but little is known about causality and mechanisms of action of HBP. The objective of the present study was to test the hypothesis that HBP is a key mediator of the increased endothelial permeability observed in sepsis and to test potential treatments that inhibit HBP-induced increases in permeability., Methods: Association between HBP at admission with clinical signs of increased permeability was investigated in 341 patients with septic shock. Mechanisms of action and potential treatment strategies were investigated in cultured human endothelial cells and in mice., Results: Following adjustment for comorbidities and Acute Physiology and Chronic Health Evaluation (APACHE) II, plasma HBP concentrations were weakly associated with fluid overload during the first 4 days of septic shock and the degree of hypoxemia (PaO 2 /FiO 2 ) as measures of increased systemic and lung permeability, respectively. In mice, intravenous injection of recombinant human HBP induced a lung injury similar to that observed after lipopolysaccharide injection. HBP increased permeability of vascular endothelial cell monolayers in vitro, and enzymatic removal of luminal cell surface glycosaminoglycans (GAGs) using heparinase III and chondroitinase ABC abolished this effect. Similarly, unfractionated heparins and low molecular weight heparins counteracted permeability increased by HBP in vitro. Intracellular, selective inhibition of protein kinase C (PKC) and Rho-kinase pathways reversed HBP-mediated permeability effects., Conclusions: HBP is a potential mediator of sepsis-induced acute lung injury through enhanced endothelial permeability. HBP increases permeability through an interaction with luminal GAGs and activation of the PKC and Rho-kinase pathways. Heparins are potential inhibitors of HBP-induced increases in permeability.

Background: Early use of fresh frozen plasma (FFP) in haemorrhagic shock is associated with improved outcome. This effect may partly be due to protection of the endothelial glycocalyx and/or secondary to a superior efficacy of FFP as a plasma volume expander compared to crystalloids. The objective of the present study was to investigate if protection of the glycocalyx by FFP can be demonstrated when potential differences in plasma volume (PV) following resuscitation are accounted for., Methods: Rats were subjected to a volume-controlled haemorrhage (30 ml/kg). At 2.5 h after haemorrhage, animals were randomized to resuscitation with FFP (37.5 ml/kg), albumin (30 ml/kg) or Ringer's acetate (RA) (135 ml/kg, 4.5 times the bleed volume). PV was measured 2 h after completion of resuscitation using (125)I-albumin and effects on endothelial glycocalyx were evaluated by measuring circulating heparan sulphate and syndecan-1. Hemodynamic effects of resuscitation were evaluated by measuring lactate and mean arterial pressure (MAP)., Results: Resuscitation with FFP or albumin resulted in plasma volume expansion equalling the blood loss (to 55 ± 5 ml/kg and 54 ± 4 ml/kg (mean ± S.D.), respectively), whereas plasma volume expansion in RA group was lower (to 42 ± 7 ml/kg). Plasma concentration of heparan sulphate was lower in the FFP and albumin groups than in the RA group at 2 h after resuscitation. After correcting for differences in plasma volume, no significant difference in circulating amount of heparan sulphate was detected between the FFP and albumin groups (2879 ± 1075 μg/kg and 3318 ± 1814 μg/kg, respectively, P = 0.4) and the RA group (3731 ± 777 μg/kg). No differences between the groups in plasma concentration or amount of circulating syndecan-1 were detected after resuscitation. After resuscitation, MAP was higher in the FFP and albumin groups than in the RA group. Lactate did not differ between the FFP and RA groups after resuscitation., Conclusions: Improved outcome in trauma by FFP could in part be explained by better plasma volume expansion compared to crystalloids. The decrease in plasma concentration of markers of glycocalyx degradation after resuscitation with FFP are largely secondary to differences in plasma volume and may not accurately reflect effects of FFP on the glycocalyx.