BACKGROUND:In patients with sepsis, an inflammatory response can lead to destruction of the glycocalyx. These alterations cause the progression of organ dysfunction. Destruction of the glycocalyx can also occur in chronic hyperglycemia. Glycated hemoglobin (HbA1c) is a reliable marker of premorbid hyperglycemia. We investigated the association between HbA1c level at admission and the degree of organ dysfunction progression 72 hours after admission and ICU mortality. METHODS AND FINDINGS:This study was a retrospective observational study. Logistic regression and correlation analyses were performed to evaluate the association between the HbA1c level and the degree of organ dysfunction progression 72 hours after ICU admission. We applied survival analysis to examine the association between HbA1c level and ICU mortality. A total of 90 patients were included in this study. The association between HbA1c level and degree of organ dysfunction progression was significant (r = 0.320; P = 0.002). Multivariable logistic regression analysis showed that high HbA1c level (≥6.5%) (OR, 2.98; 95% CI, 1.033-8.567; P = 0.043) were significant, independent predictors of severe organ dysfunction progression. Patients with an HbA1c level ≥6.5% exhibited significantly greater liver and kidney dysfunction progression 72 hours after ICU admission compared with those with an HbA1c level <6.5%. Kaplan-Meier analysis showed that the survival period was significantly shorter in patients with an HbA1c level ≥6.5% than in those with an HbA1c level <6.5% (P < 0.001). Multivariable Cox proportional hazard analysis showed that HbA1c level ≥6.5% (HR, 3.49; 95% CI, 1.802-6.760; P <0.001) were significant, independent predictors of ICU mortality. CONCLUSIONS:In patients with sepsis, the HbA1c level at ICU admission is associated with progression of organ dysfunction 72 hours later and with ICU mortality. It may be important to assess HbA1c level at ICU admission because it may be a predictor of ICU outcome. For patients with a high HbA1c level (≥6.5%), greater attention should be paid to the possibility of organ dysfunction progression.

Objective:To date, there are no studies regarding the lactylation profile and its role in critically ill patients. Thus, we aimed to examine expression of histone H3 lysine 18 (H3K18) lactylation and its role in patients with septic shock. Methods:Thirteen healthy volunteers and 35 critically ill patients from the Department of Surgical Intensive Care Medicine, Beijing Hospital were enrolled in our study. Baseline information and clinical outcomes were obtained prospectively. Lactylation levels of all proteins and H3K18 from peripheral blood mononuclear (PBMC) were determined by western blotting and serum levels of inflammatory cytokines by flow cytometry. Arginase-1 () and Krüppel-like factor-4 () mRNA expression was evaluated by quantitative real-time PCR (qRT-PCR). Results:Lactylation was found to be an all-protein post-translational modification and was detected in PBMCs from both healthy volunteers and critically ill patients, with a significantly higher relative density in shock patients (=2.172, =0.045). H3K18la was expressed in all subjects, including healthy volunteers, with the highest level in septic shock patients (compared with non-septic shock patients, critically ill without shock patients and healthy volunteers =0.033, 0.000 and 0.000, respectively). Furthermore, H3K18la protein expression correlated positively with APACHE II scores, SOFA scores on day 1, ICU stay, mechanical ventilation time and serum lactate (=0.42, 0.63, 0.39, 0.51 and 0.48, respectively, =0.012, 0.000, 0.019, 0.003 and 0.003, respectively). When we matched patients with septic shock and with non-septic shock according to severity, we found higher H3K18la levels in the former group (=-2.208, =0.040). Moreover, H3K18la exhibited a close correlation with procalcitonin levels (=0.71, =0.010). Patients with high H3K18la expression showed higher IL-2, IL-5, IL-6, IL-8, IL-10, IL-17, IFN-α levels (=0.33, 0.37, 0.62, 0.55, 0.65, 0.49 and 0.374 respectively, =0.024, 0.011, 0.000, 0.000, 0.000 and 0.000 respectively). H3K18la expression also displayed a positive correlation with the level of mRNA (=0.561, =0.005). Conclusions:Lactylation is an all-protein post-translational modification occurring in both healthy subjects and critically ill patients. H3K18la may reflect the severity of critical illness and the presence of infection. H3K18la might mediate inflammatory cytokine expression and overexpression and stimulate the anti-inflammatory function of macrophages in sepsis.

PURPOSE:Endocan is a circulating proteoglycan measured at high blood levels during severe sepsis, with a likely lung anti-inflammatory function. The aim of this study was to assess whether paradoxically low endocan levels at Intensive Care Unit (ICU) admission could predict Acute Respiratory Distress Syndrome (ARDS) within 72 h in severe septic patients. MATERIALS AND METHODS:Patients admitted for severe sepsis in the ICU of a French University Hospital were included in a prospective single-center observational study between October 2014 and March 2016. RESULTS:72 patients admitted in ICU for severe sepsis were included. Endocan blood values at inclusion were significantly lower in patients who developed an ARDS at 72 h (p < 0.001). For endocan blood values > 5.36 ng/mL, the adjusted OR for development of ARDS at 72 h was of 0.001 (95% CI 0-0.215; p = 0.011). In our cohort, an endocan value < 2.54 ng/mL predicted ARDS at 72 h with a positive predictive value of 1 (Sp = 1 (95% CI 0.94-1)). CONCLUSIONS:In a cohort of severe septic patients, we observed that low blood levels of endocan at ICU admission were predictive of ARDS at 72 h.

BACKGROUND:Deterioration of the endothelial glycocalyx (eGC), a protective carbohydrate-rich layer lining the luminal surface of the endothelium, plays a key role in vascular barrier dysfunction and eventually organ-failure in systemic inflammatory response syndrome and sepsis. Early detection of glycocalyx damage could thus become an important goal in critical care. This study was designed to determine the feasibility and reproducibility of quantitative, real-time glycocalyx measurements performed at bedside in the emergency room (ER) and intensive care unit (ICU). METHODS:The observational study included 70 patients admitted to the ER or ICU of a university hospital. A physician and the nurse in charge of the patient performed sublingual microcirculatory measurements using sidestream dark field (SDF) imaging. A novel data acquisition and analysis software (GlycoCheck™) was used to analyze the perfused boundary region (PBR), an inverse parameter of endothelial glycocalyx dimensions in vessels with diameters of between 5 and 25 μm. RESULTS:The method showed a good intra-observer reproducibility. Specifically, intraclass correlation coefficient analysis showed an excellent reproducibility between the physician's measurements (0.77 [CI 95%: 0.52-0.89]). The bias between the two PBRs was - 0.077 ± 0.24 μm. Moreover, there were no significant differences in the PBR values obtained by the nurses when compared to those reported by the physician (regarded as the "gold standard" measurement). Intraclass correlation coefficient analysis showed excellent reproducibility between the nurses' and physician's PBRs (0.75 [95% CI: 0.52-0.87]). The mean difference between the two PBRs (i.e., the bias) was 0.007 ± 0.25 μm. The nurses' PBR assessment had a 90% sensitivity (95% CI: 60-99%) and 90% specificity (95% CI: 80-93%) to identify a severely impaired glycocalyx. CONCLUSION:Glycocalyx dimensions can be measured at patients' bedside precisely by non-invasive assessment of the PBR. This assessment could become part of standard monitoring and contribute to clinical decision-making and resuscitation protocols in clinical trials and daily practice.

PURPOSE:One of the pathophysiological processes in sepsis is endothelial dysfunction, which leads to disseminated intravascular coagulation (DIC). Syndecan-1 is a major structural component of the endothelium and plays a key role in endothelial function. The purpose of this study was to assess the value of syndecan-1 as a predictive marker for DIC in sepsis. METHODS:We performed a prospective observational study of patients with sepsis from February 2014 to July 2015. Serial change of hemostatic markers, anticoagulant and fibrinolytic markers (antithrombin, PAI-1), endothelial markers (syndecan-1, VCAM-1, E-selectin), and inflammatory markers (IL-1β, IL-6, IL-8, HMGB-1, histone-H3) were analyzed. Clinical data including APACHE II, SOFA, and DIC scores and 28-day mortality were also evaluated. RESULTS:During the study, 39 septic patients and 15 healthy controls were included. Syndecan-1 levels were significantly increased in the septic patients compared with the healthy controls. Of the septic patients, non-survivors had higher syndecan-1 levels than did the survivors on days 1, 2, and 4. Significant correlations on day 1 were found between syndecan-1 levels and APACHE II, SOFA, and DIC scores, hemostatic markers, IL-1β, IL-8, and PAI-1. Syndecan-1 levels on day 1 were also significantly higher in patients with than without DIC and had strong discriminative power for the prediction of both DIC development and subsequent mortality, with AUCs of 0.79 and 0.85, respectively. CONCLUSION:Syndecan-1 levels were associated with not only the severity of illness and mortality but also DIC development in sepsis, suggesting that syndecan-1 could be a predictive marker of DIC.

It has been well established that angiopoietin 2 (Ang-2), a glycoprotein involved in activation of the endothelium, plays an integral role in the pathophysiology of sepsis and many other inflammatory conditions. However, the role of Ang-2 in sepsis-associated coagulopathy (SAC) specifically has not been defined. The aim of this study was to measure Ang-2 plasma levels in patients with sepsis and suspected disseminated intravascular coagulation (DIC) in order to demonstrate its predictive value in SAC severity determination and 28-day mortality outcome. Plasma samples were collected from 102 patients with sepsis and suspected DIC at intensive care unit (ICU) admission. The Ang-2 plasma levels were quantified using a sandwich enzyme-linked immunosorbent assay method. The International Society on Thrombosis and Haemostasis DIC scoring system was used to compare the accuracy of Ang-2 levels versus clinical illness severity scores in predicting SAC severity. Mean Ang-2 levels in patients with sepsis and DIC were significantly higher in comparison to healthy controls ( P < 0.0001), and median Ang-2 levels showed a downward trend over time ( P = 0.0008). Baseline Ang-2 levels and clinical illness severity scores were higher with increasing severity of disease, and Ang-2 was a better predictor of DIC severity than clinical illness scores. This study demonstrates that Ang-2 levels are significantly upregulated in SAC, and this biomarker can be used to risk stratify patients with sepsis into non-overt DIC and overt DIC. Furthermore, the Ang-2 level at ICU admission in a patient with sepsis and suspected DIC may provide a predictive biomarker for mortality outcome.

BACKGROUND:Endothelial dysfunction and injury is a major pathophysiologic feature of sepsis. Sepsis is also the most frequent cause of acute kidney injury (AKI) in critically ill patients. Though most studies of AKI in sepsis have focused on tubular epithelial injury, the role of endothelial dysfunction and injury is less well studied. The goal of this study was first to investigate whether endothelial dysfunction and injury biomarkers were associated with severe AKI in sepsis patients. The second goal was to determine the best performing biomarker for severe AKI and whether this biomarker was associated with severe AKI across different etiologies of sepsis and clinical outcomes. METHODS:We studied adults with severe sepsis and acute respiratory failure (ARF) enrolled in the prospective observational Validating Acute Lung Injury markers for Diagnosis (VALID) study. Plasma endothelial dysfunction and injury biomarkers, including angiopoietin-2, soluble vascular endothelial cadherin (sVE-cadherin), endocan and syndecan-1, were measured at study enrollment. Primary analysis focused on the association between endothelial biomarker levels with severe AKI (defined as Kidney Disease: Improving Global Outcomes [KDIGO] AKI stage 2 or 3), other organ dysfunctions (defined by Brussels organ failure scores), and comparison of pulmonary versus non-pulmonary sepsis. RESULTS:Among 228 sepsis patients enrolled, 141 developed severe AKI. Plasma levels of angiopoietin-2, endocan, sVE-cadherin, and syndecan-1 were significantly higher in sepsis patients with severe AKI compared to those without severe AKI. Among four endothelial biomarkers, only angiopoietin-2 was independently associated with severe AKI (odds ratio 6.07 per log increase, 95% CI 2.34-15.78, p < 0.001). Plasma angiopoietin-2 levels by quartile were significantly higher in sepsis patients with hepatic, coagulation, and circulatory failure. Plasma angiopoietin-2 levels were also significantly higher in patients with non-pulmonary sepsis compared to subjects with pulmonary sepsis. CONCLUSION:Among four biomarkers of endothelial dysfunction and injury, angiopoietin-2 had the most robust independent association with development of severe AKI in patients with severe sepsis and ARF. Plasma angiopoietin-2 levels were also associated with other organ dysfunctions, non-pulmonary sepsis, and death. These findings highlight the importance of early endothelial dysfunction and injury in the pathogenesis of sepsis-induced AKI.

The endothelial glycocalyx (eGC), a carbohydrate-rich layer lining the luminal surface of the endothelium, provides a first vasoprotective barrier against vascular leakage in sepsis. We hypothesized that angiopoietin-2 (Angpt-2), antagonist of the endothelium-stabilizing receptor Tie2, induces a rapid loss of the eGC in human sepsis. Using intravital microscopy, we measured the perfused boundary region (PBR), an inverse parameter of eGC dimensions in sublingual microvessels, in patients with sepsis and age-matched nonseptic subjects. Median PBR values were significantly higher in patients compared with controls and correlated with serum Angpt-2 levels. To transfer and further explore these findings in a cell culture system, we exposed endothelial cells (ECs) to serum (5%) from a subgroup of septic patients and nonseptic controls. Confocal and atomic force microscopy revealed that sepsis serum, but not control serum, induced thinning of the eGC on human ECs in vitro, which correlated with paired PBR values obtained in vivo ( = 0.96,  < 0.01). Inhibition of Angpt-2 or Tie2 activation completely abolished eGC damage. Mechanistically, sepsis-induced eGC breakdown required the loss of its main constituent heparan sulfate; a result of heparan sulfate-specific enzyme heparanase, which was suppressed by Tie2 activation. Finally, Tie2 activation, but not Angpt-2 inhibition, initiated after septic or enzymatic damage provoked rapid refurbishment of the eGC. Our data indicate that eGC breakdown in human sepsis is mediated via Tie2 deactivation by Angpt-2. Activation of Tie2 seems to accelerate recovery of the eGC and might hold promise as a therapeutic target in human sepsis.

PURPOSE:Endothelial glycocalyx (EG) shedding may promote organ failure in sepsis. This study describes temporal changes in EG biomarkers from Emergency Department (ED) arrival, and associations with clinical characteristics. MATERIALS AND METHODS:This prospective observational study included 23 patients with simple infection, 86 with sepsis and 29 healthy controls. Serum EG biomarkers included syndecan-1, syndecan-4 and hyaluronan. Samples were taken on enrolment in the ED (T0), 1 hour (T1), 3 hours (T3) and 12 to 24 hours (T24) later. RESULTS:Syndecan-1 concentration increased incrementally over time (T0-T24, both patient groups, P < .001) whereas hyaluronan concentration peaked at T3 (T0-T3, sepsis group, P < .001). Hyaluronan was positively associated with cumulative fluid volumes (P < .001) at T0, T1, and T3, independent of illness severity. Both syndecan-1 (OR 1.04, 95% CI 1.01-1.07, P = .017) and hyaluronan (OR 1.83, 95% CI 1.46-2.30, P < .001) were associated with organ failure, independent of age and comorbidity. Syndecan-4 concentration was not different between groups or over time. CONCLUSIONS:In contrast to previous ICU studies, EG biomarkers increased during the first 24 hours of sepsis treatment and were associated with fluid volumes and organ failure. Further investigation is required to determine if interventions delivered in the ED contribute to EG shedding.

BACKGROUND:Degradation of the endothelial glycocalyx is recognized as a major part of the pathophysiology of sepsis. Previous clinical studies, mostly conducted in intensive care settings, showed associations between glycocalyx shedding and clinical outcomes. We aimed to explore the association of plasma syndecan-1, a marker of glycocalyx degradation, with the subsequent fluid requirements and clinical outcomes of emergency department patients with sepsis. METHODS:This was a post hoc analysis of a randomized trial of fluid resuscitation in the emergency department. The study was conducted in the emergency department of an urban 1500-bed tertiary care center. The data of 95 adults who were diagnosed with sepsis-induced hypoperfusion and had undergone baseline syndecan-1 measurement were included. The syndecan-1 levels at baseline (T0) and hour 6 (T6) were studied to characterize their association with clinical outcomes, including subsequent fluid administration, organ failure outcomes and mortality. RESULTS:The median syndecan-1 levels at T0 and T6 were 207 (IQR 135-438) and 207 (IQR 128-490) ng/ml, respectively. Syndecan-1 levels at T0 were correlated with baseline sequential organ failure assessment (SOFA) score (ρ = 0.35, p < 0.001). Syndecan-1 levels at both T0 and T6 were correlated with subsequent fluid administration over 24 and 72 h and associated with the diagnosis of septic shock, the maximum dose of vasopressors and the need for renal replacement therapy (p < 0.05). Higher syndecan-1 levels at T6 were associated with higher 90-day mortality (p = 0.03). CONCLUSIONS:In the emergency department, syndecan-1 levels were associated with fluid requirements, sepsis severity, organ dysfunction, and mortality.

Capillary leakage frequently occurs during sepsis and after major surgery and is associated with microvascular dysfunction and adverse outcome. Procalcitonin is a well-established biomarker in inflammation without known impact on vascular integrity. We determined how procalcitonin induces endothelial hyperpermeability and how targeting procalcitonin protects vascular barrier integrity. In a prospective observational clinical study, procalcitonin levels were assessed in 50 patients who underwent cardiac surgery and correlated to postoperative fluid and vasopressor requirements along with sublingual microvascular functionality. Effects of the procalcitonin signaling pathway on endothelial barrier and adherens junctional integrity were characterized and verified in mice. Inhibition of procalcitonin activation by dipeptidyl-peptidase 4 (DPP4) was evaluated in murine polymicrobial sepsis and clinically verified in cardiac surgery patients chronically taking the DPP4 inhibitor sitagliptin. Elevated postoperative procalcitonin levels identified patients with 2-fold increased fluid requirements ( < 0.01), 1.8-fold higher vasopressor demand ( < 0.05), and compromised microcirculation (reduction to 63.5 ± 2.8% of perfused vessels,  < 0.05). Procalcitonin induced 1.4-fold endothelial and 2.3-fold pulmonary capillary permeability (both s < 0.001) by destabilizing VE-cadherin. Procalcitonin effects were dependent on activation by DPP4, and targeting the procalcitonin receptor or DPP4 during sepsis-induced hyperprocalcitonemia reduced capillary leakage by 54 ± 10.1% and 60.4 ± 6.9% (both s < 0.01), respectively. Sitagliptin before cardiac surgery was associated with augmented microcirculation (74.1 ± 1.7% vs. 68.6 ± 1.9% perfused vessels in non-sitagliptin-medicated patients,  < 0.05) and with 2.3-fold decreased fluid ( < 0.05) and 1.8-fold reduced vasopressor demand postoperatively ( < 0.05). Targeting procalcitonin's action on the endothelium is a feasible means to preserve vascular integrity during systemic inflammation associated with hyperprocalcitonemia.

BACKGROUND:Acute respiratory failure (ARF) can progress to acute respiratory distress syndrome and death. Biomarkers may allow for risk stratification and prognostic enrichment in ARF. Thrombomodulin (TM) is a transmembrane antithrombotic mediator expressed in endothelial cells. It is cleaved into its soluble form (sTM) during inflammation and vascular injury. Levels of sTM correlate with inflammation and end organ dysfunction. METHODS:This was a prospective observational study of 432 patients aged 2 weeks-17 years requiring invasive mechanical ventilation. It was ancillary to the multicenter clinical trial, Randomized Evaluation of Sedation Titration for Respiratory Failure (RESTORE). After consent, patients had up to 3 plasma samples collected at 24-h intervals within 5 days after intubation. sTM was assayed by ELISA. The Hazard ratio (HR) for 90-day mortality was determined by Cox regression. Mixed effect models (MEM) were used to test for association with extrapulmonary multiorgan failure (MOF) and oxygenation index (OI). Age, race, sex and PRISM-III scores were used as confounding variables for multivariable analyses. RESULTS:sTM values ranged from 16.6 to 670.9 ng/ml within 5 days after intubation. Higher sTM was associated with increased 90-day mortality (n = 432, adjusted HR = 1.003, p = 0.02) and worse OI in the first 5 days after intubation (n = 252, Estimate = 0.02, p < 0.01). Both initial and slope of sTM were associated with increased extrapulmonary MOF in unadjusted and adjusted analyses (Intercept, Estimate = 0.003, p < 0.0001; and slope, Estimate = 0.01, p = 0.0009, n = 386). CONCLUSIONS:Plasma sTM is associated with mortality, severity of hypoxic respiratory failure and worsening extrapulmonary MOF in children with ARF. This suggests a role of vascular injury in the pathogenesis of ARF and provides potential applicability towards targeted therapies. TRIAL REGISTRATION:https://clinicaltrials.gov/ct2/show/NCT00814099 . In healthy lung endothelium, thrombomodulin (TM) recruits thrombin to activate Protein-C (PC/APC), that inhibits plasminogen activator-1 (PAI-1) and thrombosis. In inflamed and damaged endothelium, TM is cleaved into its soluble form (sTM), precluding its usual regulation of thrombosis. In this study, we measured plasma sTM levels in pediatric patients with respiratory failure and found that sTM correlated with mortality and other clinical markers of poor outcomes.

BACKGROUND:Sepsis coagulopathy or disseminated intravascular coagulation (DIC) mainly due to progressive endothelial disruption and damage. The glycocalyx is expressed on the endothelial cell surface and contributes to anti-thrombogenicity, anti-inflammatory, and regulates vascular permeability. We aimed to evaluate the clinical utility of plasma glycocalyx components as biomarkers in predicting the onset of DIC in sepsis. MATERIALS AND METHODS:This was a prospective observational study of 45 patients with sepsis (June to December 2018). Demographic, clinical (Acute Physiology, Age, Chronic Health Evaluation II [APACHE II], Sequential Organ Failure Assessment [SOFA]), and laboratory data from medical records were analyzed. Endothelial glycocalyx components (syndecan-1, heparan sulfate, hyaluronan) were measured using an ELISA kit. RESULTS:Among the 45 patients (23, sepsis; 22, septic shock), plasma syndecan-1, heparan sulfate, and hyaluronan levels were higher in those with septic shock and were positively correlated with disease severity as determined by the APACHE II and SOFA scores and lactate levels. Receiver operating characteristic curve analysis revealed high sensitivity and specificity of syndecan-1 for predicting septic shock. Further, these levels were compared between patients with or without the development of DIC. Plasma syndecan-1 and hyaluronan levels were significantly elevated in patients with DIC compared to those in patients without DIC and were strongly associated with activated partial thromboplastin time, prothrombin time, and platelet counts. Area under the curve values for predicting DIC based on syndecan-1 and hyaluronan levels measurements were 0.774 and 0.740, respectively. CONCLUSIONS:Increased plasma syndecan-1 and hyaluronan levels may be indicators of disease severity and useful predictors for DIC development in sepsis.

BACKGROUND:In patients with septic shock, the skin is often chosen for the evaluation of peripheral perfusion and oxygenation. Changes in skin microcirculatory vessel oxygen saturation and relative hemoglobin concentration can be described using a mottling score or captured with hyperspectral imaging. However, the effectiveness of the mottling score in assessing microcirculation remains to be shown. We hypothesize that the mottling score in patients with septic shock is related to skin microcirculatory perfusion indices quantified by hyperspectral imaging, biomarkers that reflect endothelium activation and damage, and clinical outcome. METHODS:Hyperspectral imaging of the knee area was performed in 95 intensive care patients with septic shock enrolled in a single-center observational study to obtain relative oxy/deoxyhemoglobin concentration values and construct anatomical maps of skin microcirculatory saturation. The blood was sampled to obtain concentrations of thrombomodulin, plasminogen activator inhibitor-1 (PAI-1), soluble intercellular adhesion molecule-1 (ICAM-1), soluble vascular cell adhesion molecule-1 (VCAM-1), angiopoietin-2, and syndecan-1. The spectrophotometrically obtained skin microvascular perfusion indices were compared to the mottling score and biomarker concentration. The association between mottling score, skin microcirculatory perfusion indices, and 28-day mortality was also analyzed. RESULTS:Microcirculatory oxygen saturation was significantly lower and total hemoglobin concentration was significantly higher in patients with a mottling score of 2 compared to those with a score of 0 (p = 0.02), with no difference between other scores. We found an association between microcirculatory oxygen saturation and PAI-1 levels (rho = - 0.3; p = 0.007). Increased mottling score and decreased microcirculatory oxygen saturation were predictive of 28-day mortality (mottling score 2 vs 0: OR 15.31, 95% CI 4.12-68.11; microcirculatory oxygen saturation: OR 0.90, 95% CI 0.85-0.95). Endothelial biomarkers did not increase the predictive value of skin microcirculatory perfusion indices. CONCLUSIONS:Higher mottling scores are associated with lower microcirculatory oxygen saturation but with significant overlap between scores. Microcirculatory oxygen saturation is a quantitative measure of peripheral oxygenation and is more specific than the mottling score in predicting 28-day mortality.

BACKGROUND:The EMiC2 membrane is a medium cut-off haemofilter (45 kiloDalton). Little is known regarding its efficacy in eliminating medium-sized cytokines in sepsis. This study aimed to explore the effects of continuous veno-venous haemodialysis (CVVHD) using the EMiC2 filter on cytokine clearance. METHODS:This was a prospective observational study conducted in critically ill patients with sepsis and acute kidney injury requiring kidney replacement therapy. We measured concentrations of 12 cytokines [Interleukin (IL) IL-1β, IL-1α, IL-2, IL-4, IL-6, IL-8, IL-10, interferon (IFN)-γ, tumour necrosis factor (TNF)-α, vascular endothelial growth factor, monocyte chemoattractant protein (MCP)-1, epidermal growth factor (EGF)] in plasma at baseline (T0) and pre- and post-dialyzer at 1, 6, 24, and 48 h after CVVHD initiation and in the effluent fluid at corresponding time points. Outcomes were the effluent and adsorptive clearance rates, mass balances, and changes in serial serum concentrations. RESULTS:Twelve patients were included in the final analysis. All cytokines except EGF concentrations declined over 48 h (p < 0.001). The effluent clearance rates were variable and ranged from negligible values for IL-2, IFN-γ, IL-1α, IL-1β, and EGF, to 19.0 ml/min for TNF-α. Negative or minimal adsorption was observed. The effluent and adsorptive clearance rates remained steady over time. The percentage of cytokine removal was low for most cytokines throughout the 48-h period. CONCLUSION:EMiC2-CVVHD achieved modest removal of most cytokines and demonstrated small to no adsorptive capacity despite a decline in plasma cytokine concentrations. This suggests that changes in plasma cytokine concentrations may not be solely influenced by extracorporeal removal. TRIAL REGISTRATION:NCT03231748, registered on 27th July 2017.

OBJECTIVES:Systemic endothelial activation may contribute to sepsis-associated organ injury, including acute respiratory distress syndrome. We hypothesized that children with extrapulmonary sepsis with versus without acute respiratory distress syndrome would have plasma biomarkers indicative of increased endothelial activation and that persistent biomarker changes would be associated with poor outcome. DESIGN:Observational cohort. SETTING:Academic PICU. PATIENTS:Patients less than 18 years old with sepsis from extrapulmonary infection with (n = 46) or without (n = 54) acute respiratory distress syndrome and noninfected controls (n = 19). INTERVENTIONS:None. MEASUREMENTS AND MAIN RESULTS:Endothelial (angiopoietin-1, angiopoietin-2, tyrosine kinase with immunoglobulin-like loop epidermal growth factor homology domain 2, vascular endothelial growth factor, soluble fms-like tyrosine kinase, von Willebrand factor, E-selectin, intercellular adhesion molecule, vascular cell adhesion molecule, thrombomodulin) and inflammatory biomarkers (C-reactive protein, interleukin-6, and interleukin-8) were measured from peripheral plasma collected within 3 days (time 1) of sepsis recognition and at 3-6 days (time 2) and 7-14 days (time 3). Time 1 biomarkers and longitudinal measurements were compared for sepsis patients with versus without acute respiratory distress syndrome and in relation to complicated course, defined as greater than or equal to two organ dysfunctions at day 7 or death by day 28. Angiopoietin-2, angiopoietin-2/angiopoietin-1 ratio, tyrosine kinase with immunoglobulin-like loop epidermal growth factor homology domain 2, vascular endothelial growth factor, von Willebrand factor, E-selectin, intercellular adhesion molecule, vascular cell adhesion molecule, thrombomodulin, endocan, C-reactive protein, interleukin-6, and interleukin-8 were different between sepsis and noninfected control patients at time 1. Among patients with sepsis, those with acute respiratory distress syndrome had higher angiopoietin-2/angiopoietin-1 ratio, vascular endothelial growth factor, vascular cell adhesion molecule, thrombomodulin, endocan, interleukin-6, and interleukin-8 than those without acute respiratory distress syndrome (all p < 0.003). Angiopoietin-2 and angiopoietin-2/angiopoietin-1 ratio remained higher in sepsis with versus without acute respiratory distress syndrome after multivariable analyses. Time 1 measures of angiopoietin-2, angiopoietin-2/-1 ratio, von Willebrand factor, and endocan were indicative of complicated course in all sepsis patients (all area under the receiver operating curve ≥ 0.80). In sepsis without acute respiratory distress syndrome, soluble fms-like tyrosine kinase decreased more quickly and von Willebrand factor and thrombomodulin decreased more slowly in those with complicated course. CONCLUSIONS:Children with extrapulmonary sepsis with acute respiratory distress syndrome had plasma biomarkers indicative of greater systemic endothelial activation than those without acute respiratory distress syndrome. Several endothelial biomarkers measured near sepsis recognition were associated with complicated course, whereas longitudinal biomarker changes yielded prognostic information only in those without sepsis-associated acute respiratory distress syndrome.

Background:Thrombomodulin (TM) is a type-1 trans-membrane glycoprotein on endothelial cells which is known to be involved in various biochemical pathways. TM can be detected in biological fluids such as blood and urine under many forms. Soluble thrombomodulin (sTM), consist of various particles of TM, is the predominant agent which is created by enzymatic or chemical catalysis of the whole protein under divergent conditions. TM plays a vital role in protein C system and is crucial in the pathogenesis of Sepsis. Objective:To identify the serum level of soluble thrombomodulin (sTM) in groups of patients: sepsis and septic shock including their survival and fatal in-hospital outcome; and validate the death prediction of serum sTM in patients with sepsis. Methods:This prospective observational study was conducted in 63 patients who were diagnosed with sepsis, septic shock according to Sepsis 3 criteria at the ICU Department of Hue Central Hospital, Vietnam, from 3/2022 to 3/2023. Results:Twenty participants developed septic shock (31.7%), morality within 28-days was 19 patients (30.2%), 22 patients complicated with acute kidney injury that necessitated renal replacement therapy (34.9%), 30 patients required mechanical ventilation (47.6%), the median length of ICU stay was 8 (3-28) days. Serum level of lactate and creatinine were significantly higher in septic shock group compared with sepsis and survival group (p<0.05). The median sTM level in septic shock group and fatal group were 4.68(3.38-6.46) ng/mL and 4.68 (1.69-6.46) ng/mL, respectively. These results were significantly higher than sepsis group [3.62 (1.51-1.94) ng/mL] and survival group [3.73 (1.51-5.9) ng/mL] (p<0.05). The death predictive power of DIC score, APACHE II score, creatinine, sTM and SOFA presented with AUC values of 0.723, 0.726, 0.777, 0.803 and 0.807, respectively. There were no significant difference of serum level IL-6 and PCT between survival and fatal group. The median DIC score in fatal group was 7 (3-7), which was significantly higher than survival group 4 (2-7) (p= 0.001). Conclusion:Sepsis is a common diagnosis among ICU settings which links the critically ill patients to higher complications and mortalities. Serum level of sTM in septic shock and fatal groups were significantly higher than sepsis and survival groups. sTM is a reliable marker and should be used in predict severity and mortality in sepsis patients.

PURPOSE:It has been reported that hyperuricemia causes vascular endothelial injury. Most hemodialysis patients present with hyperuricemia and also with vascular injury, resulting in cardiovascular diseases (CVD). However, the association of serum uric acid (sUA) with vascular injury markers in hemodialysis patients remains unclear. This study aimed to investigate this and discuss the mechanism by which uric acid causes vascular injury. METHODS:We enrolled 48 Japanese maintenance hemodialysis patients without any history of CVD. The association between sUA level and three vascular injury markers (reactive hyperemia index [RHI], ankle-brachial index [ABI], and cardio ankle vascular index [CAVI]) was investigated by linear- and logistic regression analyses. RESULTS:The median natural logarithm RHI (LnRHI) was 0.36. Linear regression analysis revealed a significant positive correlation between sUA level and LnRHI (β = 0.42, p = 0.001) in all patients. Moreover, a significant, strongly positive correlation was observed between sUA and LnRHI in patients who were treated with xanthine oxidase inhibitors (XOIs) (β = 0.75, p = 0.001). Further, the linear analysis showed a significant negative correlation between sUA level and CAVI in patients who were treated with XOIs (β = - 0.52, p = 0.049). sUA level was not significantly associated with ABI abnormality. CONCLUSIONS:It is possible that a high level of sUA is significantly associated with better vascular endothelial function and condition of vascular tone in hemodialysis patients who were treated with XOIs. The findings suggest a significant paradox between sUA level and vascular endothelial function in hemodialysis patients; however, the opposite has been reported in patients without hemodialysis.