Fluidoterapia reflexiva: desde la fisiología a la práctica clínica / Reflexive fluid therapy: From physiology to clinical practice

Introducción. La fluidoterapia es una intervención ampliamente usada en la práctica clínica. No obstante, su aplicación no está exenta de riesgos y demanda una evaluación cuidadosa de la tolerancia del paciente y su respuesta al volumen. La práctica empírica de la reanimación con líquidos puede ser potencialmente letal. El propósito de esta revisión fue proporcionar una visión general de los principios fisiológicos y terapéuticos para la administración de líquidos intravenosos en pacientes críticamente enfermos, abordando poblaciones especiales, como los pacientes quirúrgicos, sépticos y politraumatizados. Métodos. Se hizo una revisión narrativa a partir de artículos publicados en PUBMED, ScienceDirect y LILACS, entre 2001 y 2023. Para la búsqueda se emplearon los términos MESH fluid therapy, crystalloid solutions y colloids. Resultados. Se encontraron 371 artículos, de los cuales se seleccionaron los estudios clínicos aleatorizados, las revisiones narrativas, las revisiones sistemáticas y los metaanálisis que analizaron el rol de los cristaloides y coloides. Se incluyeron manuscritos publicados en fechas por fuera del rango de búsqueda, que se consideraron relevantes para la descripción de la fisiopatología y los fundamentos del uso de líquidos endovenosos. Conclusión. La reanimación reflexiva se fundamenta en un entendimiento holístico de la fisiología y la individualización de la fluidoterapia. El uso liberal de líquidos endovenosos tiene potenciales efectos nocivos y las estrategias de reanimación deben ser guiadas por medidas dinámicas y estáticas individuales, que proporcionan un panorama seguro para el manejo de los líquidos.

Introduction. Fluid therapy is an intervention widely used in clinical practice. However, its application is not without risks and requires a careful evaluation of patient's tolerance and response to volume. The empirical practice of fluid resuscitation can be potentially lethal. The purpose of this review was to provide an overview of the physiological and therapeutic principles for the administration of intravenous fluids in critically ill patients, addressing special populations, such as surgical, septic, and trauma patients. Methods. A narrative review was carried out based on articles published in PUBMED, ScienceDirect, and LILACS between 2001 and 2023. MESH terms fluid therapy, crystalloid solutions, and colloids were employed. Results. A total of 371 articles were found, of which randomized clinical trials studies, narrative reviews, systematic reviews, and meta-analyses that analyzed the role of crystalloids and colloids were selected. Manuscripts published on dates outside the search range, which were considered relevant for the description of the pathophysiology and the rationale for the use of intravenous fluids, were included. Conclusion. Reflective resuscitation is based on a holistic understanding of physiology and individualization of fluid therapy. The liberal use of intravenous fluids has potential harmful effects and resuscitation strategies should be guided by individual dynamic and static measures, which provide a safe framework for fluid management

Doxycycline protects against sepsis-induced endothelial glycocalyx shedding.

Endothelial glycocalyx (eGC) covers the inner surface of the vessels and plays a role in vascular homeostasis. Syndecan is considered the "backbone" of this structure. Several studies have shown eGC shedding in sepsis and its involvement in organ dysfunction. Matrix metalloproteinases (MMP) contribute to eGC shedding through their ability for syndecan-1 cleavage. This study aimed to investigate if doxycycline, a potent MMP inhibitor, could protect against eGC shedding in lipopolysaccharide (LPS)-induced sepsis and if it could interrupt the vascular hyperpermeability, neutrophil transmigration, and microvascular impairment. Rats that received pretreatment with doxycycline before LPS displayed ultrastructural preservation of the eGC observed using transmission electronic microscopy of the lung and heart. In addition, these animals exhibited lower serum syndecan-1 levels, a biomarker of eGC injury, and lower perfused boundary region (PBR) in the mesenteric video capillaroscopy, which is inversely related to the eGC thickness compared with rats that only received LPS. Furthermore, this study revealed that doxycycline decreased sepsis-related vascular hyperpermeability in the lung and heart, reduced neutrophil transmigration in the peritoneal lavage and inside the lungs, and improved some microvascular parameters. These findings suggest that doxycycline protects against LPS-induced eGC shedding, and it could reduce vascular hyperpermeability, neutrophils transmigration, and microvascular impairment.

Biomarkers of endothelial glycocalyx damage are associated with microvascular dysfunction in resuscitated septic shock patients.

BACKGROUND: Microvascular dysfunction plays a central role in organ dysfunction during septic shock. Endothelial glycocalyx (eGC) damage could contribute to impaired microcirculation. The aim was to assess whether several eGC-damaged biomarkers are associated with microvascular dysfunction in resuscitated septic shock patients. METHODS: This cross-sectional study included resuscitated septic shock patients (N = 31), and a group of healthy individuals (N = 20). The eGC damage biomarkers measured were syndecan-1 (SDC-1), soluble CD44 (CD44s), hyaluronic acid (HYAL) in blood sample; sulfated glycosaminoglycans (GAGs) in urine sample; and thrombomodulin (TBML) in blood sample as biomarker of endothelial cell damage. Microcirculation was assessed through sublingual videocapillaroscopy using the GlycoCheck™, which estimated the perfused vascular density (PVD); the perfused boundary region (PBR), an inverse parameter of the eGC thickness; and the microvascular health score (MVHS). We defined a low MVHS (<50th percentile in septic patients) as a surrogate for more impaired microvascular function. RESULTS: The SDC-1, CD44s, TBML and GAGs levels were correlated with impaired microvascular parameters (PVD of vessels with diameter < 10 µm, MVHS and flow-adjusted PBR); p < 0.05 for all comparisons, except for GAGs and flow-adjusted PBR. The SDC-1 [78 ng/mL (interquartile range (IQR) 45-336) vs. 48 ng/mL (IQR 9-85); p = 0.052], CD44s [796ρg/mL (IQR 512-1995) vs. 526ρg/mL (IQR 287-750); p = 0.036], TBML [734ρg/mL (IQR 237-2396) vs. 95ρg/mL (IQR 63-475); p = 0.012] and GAGs levels [0.42 ρg/mg (IQR 0.04-1.40) vs. 0.07 ρg/mg (IQR 0.02-0.20); p = 0.024]; were higher in septic patients with more impaired sublingual microvascular function (low MVHS vs. high MVHS). CONCLUSION: SDC-1, CD44s, TBML and GAGs levels were associated with impaired microvascular function in resuscitated septic shock patients.

Blood flow-bearing physical forces, endothelial glycocalyx, and liver enzyme mobilization: A hypothesis.

Numerous elements involved in shear stress-induced signaling have been identified, recognizing their functions as mechanotransducing ion channels situated at cellular membranes. This form of mechanical signaling relies on transmembrane proteins and cytoplasmic proteins that restructure the cytoskeleton, contributing to mechanotransduction cascades. Notably, blood flow generates mechanical forces that significantly impact the structure and remodeling of blood vessels. The primary regulation of blood vessel responses occurs through hemodynamic forces acting on the endothelium. These mechanical events intricately govern endothelial biophysical, biochemical, and genetic responses. Endothelial cells, positioned on the intimal surface of blood vessels, have the capability to express components of the glycocalyx. This endothelial structure emerges as a pivotal factor in mechanotransduction and the regulation of vascular tone. The endothelial glycocalyx assumes diverse roles in both health and disease. Our findings propose a connection between the release of specific enzymes from the rat liver and variations in the hepatic blood flow/mass ratio. Importantly, this phenomenon is not correlated with liver necrosis. Consequently, this review serves as an exploration of the potential involvement of membrane proteins in a hypothetical mechanotransducing phenomenon capable of controlling the release of liver enzymes.

The association between hypoalbuminemia and microcirculation, endothelium, and glycocalyx disorders in children with sepsis.

OBJECTIVE: The objective of this study was to evaluate the association between serum albumin levels and microcirculation changes, glycocalyx degradation, and the clinical outcomes of interest. METHODS: Observational, prospective study in children with sepsis. The primary outcome was the association between hypoalbuminemia and microcirculation disorders, endothelial activation and glycocalyx degradation using a perfused boundary region (PBR) (abnormal >2.0 µm on sublingual video microscopy) or plasma biomarkers (syndecan-1, angiopoietin-2). RESULTS: A total of 125 patients with sepsis were included. The median age was 2.0 years (IQR 0.5-12.5). Children with hypoalbuminemia had more abnormal microcirculation with a higher PBR (2.16 µm [IQR 2.03-2.47] vs. 1.92 [1.76-2.28]; p = .01) and more 4-6 µm capillaries recruited (60% vs. 40%; p = .04). The low albumin group that had the worst PBR had the most 4-6 µm capillaries recruited (rho 0.29; p < .01), 48% higher Ang-2 (p = .04), worse annexin A5 (p = 0.03) and no syndecan-1 abnormalities (p = .21). Children with hypoalbuminemia and a greater percentage of blood volume in their capillaries needed mechanical ventilation more often (56.3% vs. 43.7%; aOR 2.01 95% CI 1.38-3.10: p < .01). CONCLUSIONS: In children with sepsis, an association was found between hypoalbuminemia and microcirculation changes, vascular permeability, and greater endothelial glycocalyx degradation.

Endothelial and Glycocalyx Biomarkers in Children With Sepsis After One Bolus of Unbalanced or Balanced Crystalloids.

OBJECTIVES: To assess the disruption of endothelial glycocalyx integrity in children with sepsis receiving fluid resuscitation with either balanced or unbalanced crystalloids. The primary outcome was endothelial glycocalyx disruption (using perfused boundary region >2 µm on sublingual video microscopy and syndecan-1 greater than 80 mg/dL) according to the type of crystalloid. The secondary outcomes were increased vascular permeability (using angiopoietin-2 level), apoptosis (using annexin A5 level), and associated clinical changes. DESIGN: A single-center prospective cohort study from January to December 2021. SETTING: Twelve medical-surgical PICU beds at a university hospital. PATIENTS: Children with sepsis/septic shock before and after receiving fluid resuscitation with crystalloids for hemodynamic instability. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We included 106 patients (3.9 yr [interquartile range, 0.60-13.10 yr]); 58 of 106 (55%) received boluses of unbalanced crystalloid. This group had greater odds of endothelial glycocalyx degradation (84.5% vs 60.4%; adjusted odds ratio, 3.78; 95% CI, 1.49-9.58; p < 0.01) 6 hours after fluid administration, which correlated with increased angiopoietin-2 (rho = 0.4; p < 0.05) and elevated annexin A5 ( p = 0.04). This group also had greater odds of metabolic acidosis associated with elevated syndecan-1 (odds ratio [OR], 4.88; 95% CI, 1.23-28.08) and acute kidney injury (OR, 1.7; 95% CI, 1.12-3.18) associated with endothelial glycocalyx damage. The perfused boundary region returned to baseline 24 hours after receiving the crystalloid boluses. CONCLUSIONS: Children with sepsis, particularly those who receive unbalanced crystalloid solutions during resuscitation, show loss and worsening of endothelial glycocalyx. The abnormality peaks at around 6 hours after fluid administration and is associated with greater odds of metabolic acidosis and acute kidney injury.

Biomarkers of Glycocalyx Injury and Endothelial Activation are Associated with Clinical Outcomes in Patients with Sepsis: A Systematic Review and Meta-Analysis.

OBJECTIVE: Sepsis is one of the main causes of morbidity and mortality worldwide. Microcirculatory impairment, especially damage to the endothelium and glycocalyx, is often not assessed. The objective of this systematic review and meta-analysis was to summarize the available evidence of the risk of unsatisfactory outcomes in patients with sepsis and elevated glycocalyx injury and endothelial activation biomarkers. DESIGN: A systematic search was carried out on PubMed/MEDLINE, Embase, Cochrane and Google Scholar up to December 31, 2021, including studies in adults and children with sepsis which measured glycocalyx injury and endothelial activation biomarkers within 48 hours of hospital admission. The primary outcome was the risk of mortality from all causes and the secondary outcomes were the risk of developing respiratory failure (RF) and multiple organ dysfunction syndrome (MODS) in patients with elevations of these biomarkers. MEASUREMENTS AND MAIN RESULTS: A total of 17 studies (3,529 patients) were included: 11 evaluated syndecan-1 (n=2,397) and 6 endocan (n=1,132). Syndecan-1 was higher in the group of patients who died than in those who survived [255 ng/mL (IQR: 139-305) vs. 83 ng/mL (IQR:40-111); p=0.014]. Patients with elevated syndecan-1 had a greater risk of death (OR 2.32; 95% CI 1.89, 3.10: p<0.001), MODS (OR 3.3; 95% CI 1.51, 7.25: p=0.003;), or RF (OR 7.53; 95% CI 1.86-30.45: p=0.005). Endocan was higher in patients who died [3.1 ng/mL (IQR 2.3, 3.7) vs. 1.62 ng/mL (IQR 1.2, 5.7); OR 9.53; 95% CI 3.34, 27.3; p<0.001], who had MODS (OR 8.33; 95% CI 2.07, 33.58; p=0.003) and who had RF (OR 9.66; 95% CI 2.26, 43.95; p=0.002). CONCLUSION: Patients with sepsis and abnormal glycocalyx injury and endothelial activation biomarkers have a greater risk of developing respiratory failure, multiple organ failure, and death. Microcirculatory impairment should be routinely evaluated in patients with sepsis, using biomarkers to stratify risk groups.

Syndecan-1 Depletion Has a Differential Impact on Hyaluronic Acid Metabolism and Tumor Cell Behavior in Luminal and Triple-Negative Breast Cancer Cells.

Glycosaminoglycans (GAGs) and proteoglycans (PGs) are major components of the glycocalyx. The secreted GAG and CD44 ligand hyaluronic acid (HA), and the cell surface PG syndecan-1 (Sdc-1) modulate the expression and activity of cytokines, chemokines, growth factors, and adhesion molecules, acting as critical regulators of tumor cell behavior. Here, we studied the effect of Sdc-1 siRNA depletion and HA treatment on hallmark processes of cancer in breast cancer cell lines of different levels of aggressiveness. We analyzed HA synthesis, and parameters relevant to tumor progression, including the stem cell phenotype, Wnt signaling constituents, cell cycle progression and apoptosis, and angiogenic markers in luminal MCF-7 and triple-negative MDA-MB-231 cells. Sdc-1 knockdown enhanced HAS-2 synthesis and HA binding in MCF-7, but not in MDA-MB-231 cells. Sdc-1-depleted MDA-MB-231 cells showed a reduced CD24-/CD44+ population. Furthermore, Sdc-1 depletion was associated with survival signals in both cell lines, affecting cell cycle progression and apoptosis evasion. These changes were linked to the altered expression of KLF4, MSI2, and miR-10b and differential changes in Erk, Akt, and PTEN signaling. We conclude that Sdc-1 knockdown differentially affects HA metabolism in luminal and triple-negative breast cancer model cell lines and impacts the stem phenotype, cell survival, and angiogenic factors.

Heparin prevents in vitro glycocalyx shedding induced by plasma from COVID-19 patients.

The severe forms and worsened outcomes of COVID-19 (coronavirus disease 19) are closely associated with hypertension and cardiovascular disease. Endothelial cells express Angiotensin-Converting Enzyme 2 (ACE2), which is the entrance door for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The hallmarks of severe illness caused by SARS-CoV-2 infection are increased levels of IL-6, C-reactive protein, D-dimer, ferritin, neutrophilia and lymphopenia, pulmonary intravascular coagulopathy and microthrombi of alveolar capillaries. The endothelial glycocalyx, a proteoglycan- and glycoprotein-rich layer covering the luminal side of endothelial cells, contributes to vascular homeostasis. It regulates vascular tonus and permeability, prevents thrombosis, and modulates leukocyte adhesion and inflammatory response. We hypothesized that cytokine production and reactive oxygen species (ROS) generation associated with COVID-19 leads to glycocalyx degradation. A cohort of 20 hospitalized patients with a confirmed COVID-19 diagnosis and healthy subjects were enrolled in this study. Mechanisms associated with glycocalyx degradation in COVID-19 were investigated. Increased plasma concentrations of IL-6 and IL1-ß, as well as increased lipid peroxidation and glycocalyx components were detected in plasma from COVID-19 patients compared to plasma from healthy subjects. Plasma from COVID-19 patients induced glycocalyx shedding in cultured human umbilical vein endothelial cells (HUVECs) and disrupted redox balance. Treatment of HUVECs with low molecular weight heparin inhibited the glycocalyx perturbation. In conclusion, plasma from COVID-19 patients promotes glycocalyx shedding and redox imbalance in endothelial cells, and heparin treatment potentially inhibits glycocalyx disruption.

Reactive hyperemia correlates with the presence of sepsis and glycocalyx degradation in the intensive care unit: a prospective cohort study. / A hiperemia reativa correlaciona-se com presença de sepse e degradação de glicocálix na unidade de terapia intensiva: um estudo de coorte prospectiva.

OBJECTIVE: To investigate whether reactive hyperemia measured by peripheral arterial tonometry correlates with markers of endothelial dysfunction and may be used to identify sepsis in critical illness. METHODS: A prospective study was performed using a cohort of critically ill patients. Endothelial dysfunction was assessed on admission by quantifying reactive hyperemia-peripheral arterial tonometry and plasma levels of endothelin-1, soluble E-selectin, endocan and syndecan-1. Septic patients were compared to patients without evidence of infection. RESULTS: Fifty-eight septic patients were compared to 28 controls. The natural logarithm of reactive hyperemia-peripheral arterial tonometry was negatively correlated with cardiovascular comorbidities, disease severity and plasma levels of soluble E-selectin (p = 0.024) and syndecan-1 (p < 0.001). The natural logarithm of reactive hyperemia-peripheral arterial tonometry was lower in septic patients than in controls (0.53 ± 0.48 versus 0.69 ± 0.42, respectively). When adjusted for age, the multivariable model predicted that each 0.1-unit decrease in natural logarithm of reactive hyperemia-peripheral arterial tonometry increased the odds for infection by 14.6%. m. CONCLUSION: Reactive hyperemia-peripheral arterial tonometry is closely related to soluble E-selectin and syndecan-1, suggesting an association between endothelial activation, glycocalyx degradation and vascular reactivity. Reactive hyperemia-peripheral arterial tonometry appears to be compromised in critically ill patients, especially those with sepsis.

OBJETIVO: Investigar se a hiperemia reativa correlaciona-se com marcadores de disfunção endotelial e pode ser utilizada para identificar sepse na doença crítica. MÉTODOS: Trata-se de estudo prospectivo em uma coorte de pacientes críticos. A disfunção endotelial foi avaliada quando da admissão, por meio da quantificação de hiperemia por tonometria arterial periférica e níveis plasmáticos de endotelina 1, E-selectina solúvel, endocana e sindecano 1. Os pacientes sépticos foram comparados com pacientes sem evidência de infecção. RESULTADOS: Cinquenta e oito pacientes sépticos foram comparados com 28 controle. O logaritmo natural da tonometria arterial periférica teve correlação negativa com comorbidades cardiovasculares, severidade da doença e níveis plasmáticos de E-selectina solúvel (p = 0,024) e sindecano 1 (p < 0,001). O logaritmo natural da tonometria arterial periférica foi mais baixo nos pacientes sépticos quando comparado com os de pacientes controle (0,53 ± 0,48 versus 0,69 ± 0,42, respectivamente) e, quando ajustado à idade, o modelo multivariado predisse que cada 0,1 de diminuição em unidades de logaritmo natural da tonometria arterial periférica levou a aumento de 14,6% na probabilidade de infecção. CONCLUSÃO: A hiperemia reativa avaliada por tonometria arterial periférica tem estreita relação com E-selectina solúvel e sindecano 1, o que sugere associação entre ativação endotelial, degradação de glicocálix e reatividade vascular. A hiperemia reativa por tonometria arterial periférica parece estar comprometida em pacientes críticos, especialmente os com sepse.

A hiperemia reativa correlaciona-se com presença de sepse e degradação de glicocálix na unidade de terapia intensiva: um estudo de coorte prospectiva / Reactive hyperemia correlates with the presence of sepsis and glycocalyx degradation in the intensive care unit: a prospective cohort study

RESUMO Objetivo: Investigar se a hiperemia reativa correlaciona-se com marcadores de disfunção endotelial e pode ser utilizada para identificar sepse na doença crítica. Métodos: Trata-se de estudo prospectivo em uma coorte de pacientes críticos. A disfunção endotelial foi avaliada quando da admissão, por meio da quantificação de hiperemia por tonometria arterial periférica e níveis plasmáticos de endotelina 1, E-selectina solúvel, endocana e sindecano 1. Os pacientes sépticos foram comparados com pacientes sem evidência de infecção. Resultados: Cinquenta e oito pacientes sépticos foram comparados com 28 controle. O logaritmo natural da tonometria arterial periférica teve correlação negativa com comorbidades cardiovasculares, severidade da doença e níveis plasmáticos de E-selectina solúvel (p = 0,024) e sindecano 1 (p < 0,001). O logaritmo natural da tonometria arterial periférica foi mais baixo nos pacientes sépticos quando comparado com os de pacientes controle (0,53 ± 0,48 versus 0,69 ± 0,42, respectivamente) e, quando ajustado à idade, o modelo multivariado predisse que cada 0,1 de diminuição em unidades de logaritmo natural da tonometria arterial periférica levou a aumento de 14,6% na probabilidade de infecção. Conclusão: A hiperemia reativa avaliada por tonometria arterial periférica tem estreita relação com E-selectina solúvel e sindecano 1, o que sugere associação entre ativação endotelial, degradação de glicocálix e reatividade vascular. A hiperemia reativa por tonometria arterial periférica parece estar comprometida em pacientes críticos, especialmente os com sepse.

Abstract Objective: To investigate whether reactive hyperemia measured by peripheral arterial tonometry correlates with markers of endothelial dysfunction and may be used to identify sepsis in critical illness. Methods: A prospective study was performed using a cohort of critically ill patients. Endothelial dysfunction was assessed on admission by quantifying reactive hyperemia-peripheral arterial tonometry and plasma levels of endothelin-1, soluble E-selectin, endocan and syndecan-1. Septic patients were compared to patients without evidence of infection. Results: Fifty-eight septic patients were compared to 28 controls. The natural logarithm of reactive hyperemia-peripheral arterial tonometry was negatively correlated with cardiovascular comorbidities, disease severity and plasma levels of soluble E-selectin (p = 0.024) and syndecan-1 (p < 0.001). The natural logarithm of reactive hyperemia-peripheral arterial tonometry was lower in septic patients than in controls (0.53 ± 0.48 versus 0.69 ± 0.42, respectively). When adjusted for age, the multivariable model predicted that each 0.1-unit decrease in natural logarithm of reactive hyperemia-peripheral arterial tonometry increased the odds for infection by 14.6%. m. Conclusion: Reactive hyperemia-peripheral arterial tonometry is closely related to soluble E-selectin and syndecan-1, suggesting an association between endothelial activation, glycocalyx degradation and vascular reactivity. Reactive hyperemia-peripheral arterial tonometry appears to be compromised in critically ill patients, especially those with sepsis.

Effect of sevoflurane and propofol on tourniquet-induced endothelial damage: a pilot randomized controlled trial for knee-ligament surgery.

BACKGROUND: The glycocalyx layer is a key structure in the endothelium. Tourniquet-induced ischemic periods are used during orthopedic surgery, and the reactive oxygen species generated after ischemia-reperfusion may mediate the shedding of the glycocalyx. Here, we describe the effects of tourniquet-induced ischemia-reperfusion and compare the effects of sevoflurane and propofol on the release of endothelial biomarkers after ischemia-reperfusion in knee-ligament surgery. METHODS: This pilot, single-center, blinded, randomized, controlled trial included 16 healthy patients. After spinal anesthesia, hypnosis was achieved with sevoflurane or propofol according to randomization. During the perioperative period, five venous blood samples were collected for quantification of syndecan-1, heparan sulfate, and thrombomodulin from blood serum by using ELISA assays kits. Sample size calculation was performed to detect a 25% change in the mean concentration of syndecan-1 with an alpha of 0.05 and power of 80%. RESULTS: For our primary outcome, a two-way ANOVA with post-hoc Bonferroni correction analysis showed no differences in syndecan-1 concentrations between the sevoflurane and propofol groups at any time point. In the sevoflurane group, we noted an increase in syndecan-1 concentrations 90 min after tourniquet release in the sevoflurane group from 34.6 ± 24.4 ng/mL to 47.9 ± 29.8 ng/mL (Wilcoxon test, p < 0.01) that was not observed in patients randomized to the propofol group. The two-way ANOVA showed no intergroup differences in heparan sulfate and thrombomodulin levels. CONCLUSIONS: Superficial endothelial damage without alterations in the cell layer integrity was observed after tourniquet knee-ligament surgery. There was no elevation in serum endothelial biomarkers in the propofol group patients. Sevoflurane did not show the protective effect observed in in vitro and in vivo studies. TRIAL REGISTRATION: The trial was registered in www.clinicaltrials.gov (ref: NCT03772054, Registered 11 December 2018).

The Endothelial Glycocalyx: A Fundamental Determinant of Vascular Permeability in Sepsis.

OBJECTIVES: Sepsis is a significant cause of morbidity and mortality. Children with sepsis often have alterations in microcirculation and vascular permeability. Our objective is current evidence regarding the role of the endothelial glycocalyx as a determinant of capillary leakage in these patients. DATA SOURCES: We reviewed PubMed, EMBASE, and Google scholar using MeSH terms "glycocalyx", "fluids", "syndecan", "endothelium", "vascular permeability", "edema", "sepsis", "septic shock", "children". STUDY SELECTION: Articles in all languages were included. We include all studies in animals and humans related to glycocalyx and vascular permeability. DATA EXTRACTION: Studies in children and adults, as well as animal studies, were included. DATA SYNTHESIS: One of the fundamental components of the endothelial barrier structure is the glycocalyx. It is a variable thickness layer distributed throughout the whole body, which fulfills a very important function for life: the regulation of blood vessel permeability to water and solutes, favoring vascular protection, modulation, and hemostasis. In the last few years, there has been a special interest in glycocalyx disorders and their relationship to increased vascular permeability, especially in patients with sepsis in whom the alterations that occur in the glycocalyx are unknown when they are subjected to different water resuscitation strategies, vasopressors, etc. This review describes the structural and functional characteristics of the glycocalyx, alterations in patients with sepsis, with regard to its importance in vascular permeability conservation and the possible impact of strategies to prevent and/or treat the injury of this fundamental structure. CONCLUSIONS: The endothelial glycocalyx is a fundamental component of the endothelium and an important determinant of the mechanotransduction and vascular permeability in patients with sepsis. Studies are needed to evaluate the role of the different types of solutions used in fluid bolus, vasoactive support, and other interventions described in pediatric sepsis on microcirculation, particularly on endothelial integrity and the glycocalyx.

Don't sugarcoat it: How glycocalyx composition influences cancer progression.

Mechanical interactions between tumors and the extracellular matrix (ECM) of the surrounding tissues have profound effects on a wide variety of cellular functions. An underappreciated mediator of tumor-ECM interactions is the glycocalyx, the sugar-decorated proteins and lipids that act as a buffer between the tumor and the ECM, which in turn mediates all cell-tissue mechanics. Importantly, tumors have an increase in the density of the glycocalyx, which in turn increases the tension of the cell membrane, alters tissue mechanics, and drives a more cancerous phenotype. In this review, we describe the basic components of the glycocalyx and the glycan moieties implicated in cancer. Next, we examine the important role the glycocalyx plays in driving tension-mediated cancer cell signaling through a self-enforcing feedback loop that expands the glycocalyx and furthers cancer progression. Finally, we discuss current tools used to edit the composition of the glycocalyx and the future challenges in leveraging these tools into a novel tractable approach to treat cancer.

Glicocálix endotelial: relevancia clínica y enfoque traslacional / Endothelial glycocalyx: clinical relevance and translational approach

El glicocálix endotelial es una estructura sin forma definida que recubre la capa luminal del endotelio vascular y que está constituido, principalmente, por tres elementos: proteoglicanos, glucosaminoglicanos y glicoproteínas. Cumple distintas funciones, como regular la permeabilidad vascular a las moléculas y líquidos, la transducción de las fuerzas mecánicas de tensión y las cascadas de fibrinólisis y coagulación vascular; además, protege de la adhesión leucocitaria, plaquetaria y de patógenos. Los determinantes de lesión del glicocálix pueden ser de varios tipos, por ejemplo, incremento las fuerzas de tensión, especies reactivas de oxígeno (O2), aumento, a nivel plasmático, de sustancias como el sodio (hipernatremia), glucosa (hiperglicemia) y colesterol (hipercolesterolemia), y las moléculas proinflamatorias. Cualquiera de las noxas citadas, individualmente o combinadas, lesionan el glicocálix y la disfunción resultante se expresará clínicamente como disfunción endotelial, aumento de la permeabilidad vascular, paso de lipoproteínas al subendotelio, activación de la coagulación o aumento de la adhesión de plaquetas y leucocitos al endotelio.

Endothelial glycocalyx is an undefined structure covering the luminal layer of the vascular endothelium and consisting mainly of three elements: proteoglycans, glycosaminoglycans and glycoproteins. It has different functions, such as the regulation of vascular permeability to liquids and molecules; transduction of the mechanical forces of vascular tension; regulation of coagulation and fibrinolysis cascades; and protection of leukocyte, platelet and pathogen adhesion. The determinants of a glycocalyx lesion can be of several types­e.g., increased tensile forces; reactive oxygen (O2) species; increased plasma level of substances such as sodium (hypernatremia), glucose (hyperglycemia) and cholesterol (hypercholesterolemia); and pro-inflammatory molecules. Any of the above-mentioned noxas, alone or combined, injure the glycocalyx. Its dysfunction will be clinically expressed as endothelial dysfunction, increased vascular permeability, filtration of lipoproteins to the subendothelium, activation of coagulation, or increased adhesion of leukocytes and platelets to the endothelium.

Revisión Bibliográfica: Glicocálix Endotelial como Blanco de Agresión del Fenómeno Isquemia Reperfusión / Bibliographic Review: Endothelial Glycocalyx as Target of Aggression of the Ischemia-Reperfusion Injury

El glicocálix endotelial es una estructura rica en glucosaminoglicanos, proteoglicanos y glucoproteínas que recubre el endotelio vascular; además de ser una estructura de protección, al estar en contacto directo con la sangre se convierte en el blanco de agresión de diversos mecanismos fisiopatológicos. El fenómeno isquemia-reperfusión se presenta comúnmente en varias entidades del paciente crítico, incluyendo: eventos cerebro vasculares isquémicos, síndrome coronario agudo, sepsis y choque en sus distintos tipos, traumatismos mayores, cirugía y trasplante. Las complicaciones derivadas de este fenómeno son múltiples y dependientes del sitio de presentación; el común denominador es la disfunción microvascular que potencialmente podría desencadenar un fallo multisistémico. El objetivo de esta revisión bibliográfica fue realizar una actualización de los conocimientos en relación a la injuria del glicocálix endotelial durante el fenómeno isquemia-reperfusión.(au)

The endothelial glycocalyx is a structure rich in glycosaminoglycans, proteoglycans and glycoproteins that cover vascular endothelium; in addition of being a protective structure, the direct contact with blood turns it the target of aggression of multiple physiopathological mechanisms. The ischemia-reperfusion injury commonly presents in several critical care entities, including: ischemic stroke, acute coronary syndrome, sepsis and shock, major trauma, surgery and transplantation. Complications are multiple and dependent of the site of presentation; the common denominator is microvascular dysfunction that could potentially trigger multiple organ dysfunction syndrome. The aim of this bibliographic review was to update the knowledge regarding endothelial glycocalyx damage and ischemia-reperfusion injury.(au)

Effects of respiratory muscle training on endothelium and oxidative stress biomarkers in hemodialysis patients: A randomized clinical trial.

INTRODUCTION: Hemodialysis (HD) patients have altered pulmonary function and this is associated with impaired endothelial function and cardiovascular events. Respiratory muscle training (RMT) has the potential to improve cardiovascular outcomes in patients undergoing maintenance HD. Here, we evaluated the effects of RMT on endothelium/glycocalyx, oxidative stress biomarkers and pulmonary function test in HD patients. METHODS: This is a randomized controlled clinical trial including 41 patients undergoing thrice-weekly maintenance HD. Patients were randomly assigned at a 2:1 ratio to receive or not RMT during HD sessions for 8 weeks. Main outcomes were changes in levels of the biomarkers related to endothelium activation (vascular cell adhesion molecule 1, VCAM-1, and intercellular adhesion molecule 1, ICAM-1), glycocalyx derangement (syndecan-1), aberrant angiogenesis (angiopoietin-2) and oxidative stress (malondialdehyde) compared to baseline. Also, maximal inspiratory/expiratory pressure (MIP, MEP), Forced vital capacity (FVC) and forced expiratory volume in the first second (FEV1) were evaluated. Other outcomes included changes in functional capacity and pulmonary function test. We also performed a post-hoc analysis of plasma endothelin-1 levels. RESULTS: Of 56 randomly assigned patients, 41 were included in the primary final analyses. RMT increased all pulmonary function parameters evaluated and significantly reduced plasma syndecan-1 levels at 8 weeks compared to placebo (between-group difference: -84.5; 95% CI, -148.1 to -20.9). Also, there was a reduction in plasma levels of angiopoietin-2 (between-group difference: -0.48; 95% CI, -1.03 to -0.097). Moreover, there was a significant reduction in mean blood pressure at rest (between-group difference: -12.2; 95%CI, -17.8 to -6.6) associated with a reduction in endothelin-1 levels (between-group difference: -0.164; 95% CI, -0.293 to -0.034). There was no difference regarding biomarkers of endothelial activation or oxidative stress. CONCLUSION: A short-term RMT program ameliorate FVC, FEV1 and reduces syndecan-1 and angiopoietin-2 biomarker levels. Finally, better blood pressure control was attained during training and it was associated with a reduction in endothelin-1 levels.

Male reproductive tract and spermatozoa ultrastructure in the grasshopper Orphulella punctata (De Geer, 1773) (Insecta, Orthoptera, Caelifera).

Identification Orphulellini grasshoppers (Acrididae: Gomphocerinae) species has been difficult due to high polymorphism rate. Orphulella Giglio-Tos, 1894 is a genus with widespread geographical distribution and poor descriptions. Orphulella punctata (De Geer, 1773) has an extensive record of occurrence and available information about the phallic complex, however, there is poor data describing other parts of the male reproductive tract. The objective of this study was characterizes the internal organs of the male reproductive system and spermatozoa of O. punctata. Orphulella punctata testes are of Fountain type, each having only four follicles. Spermatozoa into the seminal vesicle are arranged in bundles with c.a. 2320 µm length, with a nucleus 110 µm long. The spermatozoa are covered by a glycocalyx, the nucleus is cylindrical with condensed chromatin and connected to the flagellum by a dense and lamellar centriole adjunct. The axoneme have 9 + 9 + 2 pattern and present two symmetrical mitochondrial derivatives. A fibrous net and two flat membranous cisternae fill the space between the axoneme and mitochondrial derivatives. This is the first description of the reproductive system of a Gomphocerinae representative.

Endothelial Glycocalyx Damage and Renal Dysfunction in HIV Patients Receiving Combined Antiretroviral Therapy.

Widespread use of combined antiretroviral therapy (cART) increased HIV patients' life expectancy, however, favored the development of kidney and cardiovascular diseases. The aim of this study was to investigate endothelial glycocalyx (eGC) damage and its association with renal function in HIV patients receiving cART. This is a cross-sectional study with HIV-infected patients with no renal and cardiovascular disease, recruited in public health centers in Brazil. Clinical and laboratory parameters of HIV patients were compared according to cART use and with a healthy control group. Blood ICAM-1 and syndecan-1 levels were quantified by ELISA kit. Estimated glomerular filtration rate (eGFR) was evaluated. A total of 69 HIV patients were included, with mean age of 33.4 ± 8.9 years, and 77.3% were male. Serum urea, creatinine, and eGFR were similar in all groups. No HIV patient had decreased GFR <60 ml/min. All HIV patients had higher systemic syndecan-1 compared with healthy controls (71.8 ± 25.4 ng/ml vs. 36.5 ± 14.3 ng/ml, p < .001). Syndecan-1 showed a significant positive correlation with serum creatinine (r = 0.437, p = .001), serum urea levels (r = 0.352, p = .006), and a negative correlation with eGFR (r = -0.315, p = .015) in HIV patients. Syndecan-1 remained independently associated with serum creatinine and reduced GFR even after we forced variables related with HIV infection status, tenofovir use, treatment time, dyslipidemia, and others in a multivariate analysis. HIV patients using cART with no clinical renal and cardiovascular disease presented eGC damage and it is associated with clinical markers of kidney dysfunction. Syndecan-1 may be a useful early biomarker to monitoring renal dysfunction in HIV patients in chronic use of cART. Further research is needed to evaluate this applicability.

Rat Liver Enzyme Release Depends on Blood Flow-Bearing Physical Forces Acting in Endothelium Glycocalyx rather than on Liver Damage.

We have found selective elevation of serum enzyme activities in rats subjected to partial hepatectomy (PH), apparently controlled by hemodynamic flow-bearing physical forces. Here, we assess the involvement of stretch-sensitive calcium channels and calcium mobilization in isolated livers, after chemical modifications of the endothelial glycocalyx and changing perfusion directionality. Inhibiting in vivo protein synthesis, we found that liver enzyme release is influenced by de novo synthesis of endothelial glycocalyx components, and released enzymes are confined into a liver "pool." Moreover, liver enzyme release depended on extracellular calcium entry possibly mediated by stretch-sensitive calcium channels, and this endothelial-mediated mechanotransduction in liver enzyme release was also evidenced by modifying the glycocalyx carbohydrate components, directionality of perfusing flow rate, and the participation of nitric oxide (NO) and malondialdehyde (MDA), leading to modifications in the intracellular distribution of these enzymes mainly as nuclear enrichment of "mitochondrial" enzymes. In conclusion, the flow-induced shear stress may provide fine-tuned control of released hepatic enzymes through mediation by the endothelium glycocalyx, which provides evidence of a biological role of the enzyme release rather to be merely a biomarker for evaluating hepatotoxicity and liver damage, actually positively influencing progression of liver regeneration in mammals.