Sepsis & critical care: 26 papers
Peer-reviewed work on the endothelial glycocalyx, microvascular health and the ingredients in our formulas, newest first. Abstracts are indexed here and every paper links to the journal.
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Published paper
Managing sepsis and septic shock in an endothelial glycocalyx-friendly way: from the viewpoint of surviving sepsis campaign guidelines
This narrative review examines how the endothelial glycocalyx — the gel-like carbohydrate layer lining blood vessels — is degraded in sepsis and how standard sepsis treatments may either protect or further injure it. The authors map recommendations in the Surviving Sepsis Campaign Guidelines 2021 (fluid strategy, albumin use, catecholamine limitation, corticosteroids, glycemic control, anticoagulants) onto the available evidence for glycocalyx preservation. They note that no current guideline recommendation is explicitly aimed at glycocalyx protection and call for this to be addressed in future sepsis research and guidelines.
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Published paper
Long-term efficacy of liposomal nanocarriers of preassembled glycocalyx in restoring cerebral endothelial glycocalyx in sepsis
Researchers used a chronic cranial window and sidestream dark-field imaging (GlycoCheck analysis) to track cerebral microvascular density and perfused boundary region (PBR, an inverse index of glycocalyx thickness) in mice given LPS to model sepsis. LPS reduced vascular density and increased PBR within 3 hours; intravenous liposomal nanocarriers carrying preassembled glycocalyx (glycosylated syndecan-1 inserted into liposomes) blunted the PBR rise, with two doses giving longer-lasting benefit than one. Untreated animals recovered PBR spontaneously by 48 hours and vascular density by 72 hours.
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Published paper
Doxycycline protects against sepsis-induced endothelial glycocalyx shedding
In a rat model of sepsis induced by intraperitoneal E. coli lipopolysaccharide, pretreatment with oral doxycycline (an inhibitor of matrix metalloproteinases) largely preserved the endothelial glycocalyx in heart and lung capillaries, as shown by electron microscopy, lower serum syndecan-1, and lower perfused boundary region on mesenteric video capillaroscopy. Doxycycline-pretreated animals also had less vascular leakage, less perivascular edema, fewer transmigrating neutrophils, and better microvascular health scores. The authors attribute the effect to MMP inhibition, although MMP activity was not measured directly.
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Published paper
Microcirculation, endothelium and glycocalyx changes associated with the use of milrinone in children with septic shock
This prospective single-center observational study used sublingual video microscopy (GlycoCheck) to compare microcirculation and glycocalyx measures in 140 children with septic shock, 81 of whom received milrinone infusions. Children given milrinone maintained functional capillary density and capillary blood volume recruitment capacity at 24 hours and showed less glycocalyx degradation (lower perfused boundary region) than those not given milrinone, with the effect most apparent in children under two years old. Higher PBR was associated with mortality in both groups.
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Published paper
Association between the lactate-albumin ratio and microcirculation changes in Pediatric Septic patients
This retrospective single-center study of 178 children with sepsis compared the lactate/albumin ratio (LAR) measured on PICU admission with sublingual video microscopy measures of the microcirculation taken at the same time. An elevated LAR (>0.5) was associated with reduced microvascular blood flow, lower small-capillary (4–6 µm) density, greater inflammation, more vasoactive support and higher mortality, but was not associated with glycocalyx thickness as measured by the perfused boundary region (PBR).
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Published paper
Biomarkers of endothelial glycocalyx damage are associated with microvascular dysfunction in resuscitated septic shock patients
This cross-sectional study compared 31 resuscitated septic shock patients with 20 healthy individuals, measuring circulating and urinary markers of endothelial glycocalyx shedding alongside sublingual microcirculation imaging with GlycoCheck. Higher levels of syndecan-1, soluble CD44, thrombomodulin, and urinary sulfated glycosaminoglycans corresponded to worse measured microvascular function in the septic patients.
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Published paper
The association between prolonged capillary refill time and microcirculation changes in children with sepsis
This prospective single-center cohort study measured sublingual microcirculation with GlycoCheck sidestream dark-field video microscopy and blood biomarkers in 132 children with sepsis, comparing those with normal versus prolonged (>2 s) capillary refill time. Children with prolonged capillary refill had thinner glycocalyx (higher perfused boundary region) and fewer small capillaries recruited. Persistence of these abnormalities, especially with normal blood pressure ('hemodynamic incoherence'), was linked to higher mortality and longer stay.
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Published paper
Capillary leak and endothelial permeability in critically ill patients: a current overview
This narrative review synthesizes current understanding of capillary leak syndrome (CLS) in critical illness, covering pathophysiology, diagnosis, and management. It describes how systemic inflammation disrupts endothelial cell junctions via the angiopoietin-2/Tie2 axis and drives enzymatic shedding of the endothelial glycocalyx, producing fluid extravasation, edema, and hypoperfusion. The authors note there are no accepted diagnostic criteria and no specific treatment, so care remains supportive with phased fluid resuscitation and de-resuscitation.
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Published paper
Endothelial Damage and the Microcirculation in Critical Illness
This narrative review examines how endothelial glycocalyx damage relates to bedside-observable microcirculatory changes in critically ill patients, including sepsis, trauma, cardiogenic shock, cardiopulmonary bypass, and COVID-19. It compares biochemical markers of glycocalyx shedding (syndecan-1, heparan sulfate, hyaluronan, angiopoietin-2) with sidestream dark-field imaging measures such as perfused boundary region (PBR) and capillary density. The authors conclude that the two classes of measurement correlate in some conditions but results are highly variable, and argue that combined bedside imaging plus biomarkers could support patient phenotyping and personalized ICU care.
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Published paper
Effect of high-dose intravenous ascorbic acid on microcirculation and endothelial glycocalyx during sepsis and septic shock: a double-blind, randomized, placebo-controlled study
This small double-blind randomized trial gave 23 ICU patients with sepsis or septic shock either high-dose intravenous ascorbic acid (50 mg/kg every 6 hours for 96 hours) or placebo, and measured sublingual microcirculation with handheld video microscopy plus glycocalyx thickness with GlycoCheck-based perfused boundary region (PBR). The ascorbic acid group showed a higher proportion of perfused small vessels at 6 hours and a lower PBR in the smallest capillaries right after the first infusion, but there were no differences in most other microcirculatory, hemodynamic, inflammatory, or mortality outcomes.
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Published paper
The association between hypoalbuminemia and microcirculation, endothelium, and glycocalyx disorders in children with sepsis
This prospective observational PICU study measured sublingual microcirculation and glycocalyx thickness (perfused boundary region, PBR, by GlycoCheck) plus plasma endothelial biomarkers in 125 children with sepsis, comparing those with low serum albumin (<3.0 g/dL, n=48) to those with normal albumin. Children with hypoalbuminemia had thinner glycocalyx (higher flow-corrected PBR), greater small-capillary recruitment, and higher angiopoietin-2 and annexin A5, and more often required mechanical ventilation. In an observational subgroup analysis, children whose hypoalbuminemia was corrected with 20% albumin infusion had less abnormal PBR at 24 hours, shorter PICU stay, and lower mortality.
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Published paper
Endothelial and Glycocalyx Biomarkers in Children With Sepsis After One Bolus of Unbalanced or Balanced Crystalloids
This single-center prospective cohort study followed 106 children with sepsis or septic shock who received a bolus of either balanced or unbalanced crystalloid fluid. Glycocalyx integrity was assessed by sublingual video microscopy (perfused boundary region) plus blood biomarkers. Children given unbalanced crystalloids showed more glycocalyx degradation at 6 hours, along with markers of vascular permeability and apoptosis, and higher odds of metabolic acidosis and acute kidney injury; the perfused boundary region normalized by 24 hours.
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Published paper
Microvascular and proteomic signatures overlap in COVID-19 and bacterial sepsis: the MICROCODE study
This multi-center observational study compared sublingual microcirculation, glycocalyx dimensions (PBR by GlycoCheck) and 184 plasma proteins in 22 COVID-19 patients, 43 bacterial sepsis patients and 10 healthy controls. Microvascular and proteomic abnormalities were largely similar in the two diseases and tracked with illness severity rather than diagnosis. Two mutually opposed coregulated protein clusters were identified, and their ratio ("Microcode") predicted 28-day mortality/intubation in an independent COVID-19 cohort.
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Published paper
The microvascular endothelial glycocalyx: An additional piece of the puzzle in veterinary medicine
This narrative review summarizes the structure, functions, and disease relevance of the endothelial glycocalyx (eGlx), with a focus on the near-absence of research in cats and dogs. It compares direct visualization methods (perfusion/immersion fixation electron microscopy, lectin staining) with clinically applicable indirect methods (ELISAs for shed hyaluronan, syndecan-1, heparan sulfate; sidestream dark-field imaging of the perfused boundary region). It also reviews evidence for glycocalyx damage in sepsis, kidney disease, hypervolemia and hypertension, and outlines candidate protective or restorative strategies.
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Published paper
Links between Endothelial Glycocalyx Changes and Microcirculatory Parameters in Septic Patients
In this single-center prospective observational study, sublingual microcirculation (Cytocam incident dark field imaging) and glycocalyx perfused boundary region (PBR, GlycoCheck) were compared between adults with sepsis or septic shock and healthy age-matched volunteers. Septic patients had significantly increased PBR (indicating thinner glycocalyx) across all vessel diameter classes, and PBR in the smallest capillaries correlated inversely with capillary density measures. The authors conclude there may be a functional link between glycocalyx damage in the smallest capillaries and sepsis-related microcirculatory alterations.
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Published paper
Identification of novel sublingual parameters to analyze and diagnose microvascular dysfunction in sepsis: the NOSTRADAMUS study (link to Critical Care)
This single-center observational study used sublingual sidestream dark-field videomicroscopy with a new GlycoCheck software version to analyze microvessels in 1-micrometer diameter classes (4-25 um) in 34 septic ICU patients and 17 healthy controls. Sepsis was associated with loss of the very smallest capillaries, impaired capillary recruitment, and increased perfused boundary region (indicating a thinner/more permeable glycocalyx). The authors combined capillary blood volume and PBR into a composite 'Microvascular Health Score' that separated patients from controls and correlated with sepsis severity.
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Published paper
Variability of Microcirculatory Measurements in Critically Ill Patients
This study tested how reproducible sublingual GlycoCheck microcirculation measurements are in 60 critically ill patients, using repeated measurements by one or two experienced observers. Single measurements of glycocalyx thickness (perfused boundary region) showed poor reliability, while red blood cell filling percentage and vessel density were more consistent. Averaging three consecutive measurements substantially improved reproducibility for all parameters.
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Published paper
Decreased endothelial glycocalyx thickness is an early predictor of mortality in sepsis
Researchers measured sublingual glycocalyx thickness (as the perfused boundary region, PBR) with sidestream dark-field imaging and GlycoCheck software within 24 hours of ICU admission in 21 septic patients, and compared results with plasma markers and survival. Patients who did not survive to hospital discharge had a thinner glycocalyx (higher PBR) than survivors, and admission PBR discriminated survivors from non-survivors moderately well. PBR correlated with angiopoietin-2 but not with syndecan-1 or severity scores.
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Published paper
Tie2 Activation Promotes Protection and Reconstitution of the Endothelial Glycocalyx in Human Sepsis
Researchers measured the perfused boundary region (PBR), an inverse marker of endothelial glycocalyx thickness, in sublingual microvessels of septic patients and nonseptic controls, and found thicker PBR (thinner glycocalyx) in sepsis that correlated with serum angiopoietin-2 levels. Serum from septic patients thinned the glycocalyx of cultured human endothelial cells, an effect abolished by blocking angiopoietin-2 or activating the Tie2 receptor. Mechanistically, damage required heparan sulfate loss via heparanase, which Tie2 activation suppressed; Tie2 activation after injury also accelerated glycocalyx recovery.
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Published paper
Association of sublingual microcirculation parameters and endothelial glycocalyx dimensions in resuscitated sepsis
In 30 ICU patients with resuscitated sepsis and 10 healthy controls, researchers simultaneously measured endothelial glycocalyx dimensions (sublingual perfused boundary region, PBR, via GlycoCheck) and conventional sublingual microcirculation parameters (incident dark field imaging). Septic patients had both thicker PBR (indicating glycocalyx damage) and impaired microvascular perfusion, and both correlated with markers of illness severity, but the two sets of measures did not correlate with each other. PBR values agreed well with circulating syndecan-1 and with glycocalyx thickness measured by atomic force microscopy in endothelial cells exposed to patient serum.
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Published paper
Derangement of the endothelial glycocalyx in sepsis
This narrative review describes the structure and functions of the endothelial glycocalyx and how it is degraded during sepsis. It covers glycocalyx roles in leukocyte adhesion, anticoagulation, vascular permeability and mechanosensing, methods of assessment (circulating syndecan-1, heparan sulfate, hyaluronan; electron and intravital microscopy; sidestream dark-field imaging with automated PBR analysis), and candidate protective strategies. The authors conclude that no treatment has yet been proven clinically effective and that links between glycocalyx damage, sepsis severity and DIC remain inadequately defined.
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Published paper
Impact of Intravenous Fluid Challenge Infusion Time on Macrocirculation and Endothelial Glycocalyx in Surgical and Critically Ill Patients.
This open randomized single-center trial compared fast (5-10 min) versus slow (20-30 min) infusion of a 5 ml/kg balanced crystalloid fluid challenge in 50 spinal surgery patients and 16 septic patients, measuring sublingual perfused boundary region (PBR, a marker inversely related to glycocalyx integrity) with GlycoCheck side-stream dark-field imaging plus standard hemodynamics. Fluid administration raised PBR regardless of infusion speed, with recovery by 60 minutes in surgical patients but persistent elevation in septic fluid responders. Infusion time did not change the rate of fluid responsiveness, though fast boluses produced a larger but transient blood pressure rise.
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Published paper
Bedside analysis of the sublingual microvascular glycocalyx in the emergency room and intensive care unit – the GlycoNurse study
This single-center observational study tested whether bedside sublingual glycocalyx measurement with sidestream dark-field imaging and GlycoCheck software is practical and reproducible in routine emergency and critical care settings. A physician's repeated measurements and measurements by eight trained nurses agreed closely, and the procedure was quick and well tolerated. Perfused boundary region (PBR) values were higher in ICU than ER patients and modestly correlated with markers of acute illness.
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Published paper
Plasma free hemoglobin and microcirculatory response to fresh or old blood transfusions in sepsis
This secondary analysis of a randomized pilot trial compared transfusion of fresh (<10 days) versus old (>15 days) non-leukodepleted red blood cells in 20 septic ICU patients, measuring plasma free hemoglobin, sublingual microcirculation by sidestream dark-field imaging (including perfused boundary region as a glycocalyx index), and near-infrared spectroscopy variables. Plasma free hemoglobin rose after old blood transfusion despite similar free hemoglobin in the blood units themselves, while sublingual microcirculatory parameters, including PBR, did not change significantly in either group. Larger increases in plasma free hemoglobin correlated with decreases in microvascular density and less increase in tissue hemoglobin index.
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Published paper
Microcirculatory effects of the transfusion of leukodepleted or non-leukodepleted red blood cells in patients with sepsis: a pilot study
This small randomized pilot trial compared sublingual microcirculatory and tissue oxygenation responses one hour after transfusion of leukodepleted versus non-leukodepleted red blood cells in 20 septic ICU patients. Most between-group differences were not significant, though microvascular flow index and blood flow velocity changed more favorably with leukodepleted units. Glycocalyx was assessed by sidestream dark-field perfused boundary region (GlycoCheck software) and by serum syndecan-1, hyaluronan, and heparan sulfate.
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Published paper
Alteration of the sublingual microvascular glycocalyx in critically ill patients
Using sidestream dark-field video microscopy of the sublingual microcirculation, researchers compared the Perfused Boundary Region (PBR), an index of glycocalyx damage, between 50 critically ill patients and 16 healthy volunteers. PBR was significantly higher in ICU patients, and tended to be highest in those with sepsis, indicating greater glycocalyx disruption. Higher PBR also correlated with more rolling leukocytes in post-capillary venules in a subgroup of septic patients.
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