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Urinary Glycosaminoglycans Predict Outcomes in Septic Shock and Acute Respiratory Distress Syndrome.

ABSTRACT: Degradation of the endothelial glycocalyx, a glycosaminoglycan (GAG)-rich layer lining the vascular lumen, is associated with the onset of kidney injury in animal models of critical illness. It is unclear if similar pathogenic degradation occurs in critically ill patients.To determine if urinary indices of GAG fragmentation are associated with outcomes in patients with critical illnesses such as septic shock or acute respiratory distress syndrome (ARDS).We prospectively collected urine from 30 patients within 24 hours of admission to the Denver Health Medical Intensive Care Unit (ICU) for septic shock. As a nonseptic ICU control, we collected urine from 25 surgical ICU patients admitted for trauma. As a medical ICU validation cohort, we obtained serially collected urine samples from 70 patients with ARDS. We performed mass spectrometry on urine samples to determine GAG (heparan sulfate, chondroitin sulfate, and hyaluronic acid) concentrations as well as patterns of heparan sulfate/chondroitin sulfate disaccharide sulfation. We compared these indices to measurements obtained using dimethylmethylene blue, an inexpensive, colorimetric urinary assay of sulfated GAGs.In septic shock, indices of GAG fragmentation correlated with both the development of renal dysfunction over the 72 hours after urine collection and with hospital mortality. This association remained after controlling for severity of illness and was similarly observed using the inexpensive dimethylmethylene blue assay. These predictive findings were corroborated using urine samples previously collected at three consecutive time points from patients with ARDS.Early indices of urinary GAG fragmentation predict acute kidney injury and in-hospital mortality in patients with septic shock or ARDS. Clinical trial registered with www.clinicaltrials.gov (NCT01900275).

SUBMITTER: Schmidt EP

PROVIDER: S-EPMC5003330 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

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Urinary Glycosaminoglycans Predict Outcomes in Septic Shock and Acute Respiratory Distress Syndrome.

Schmidt Eric P EP Overdier Katherine H KH Sun Xiaojun X Lin Lei L Liu Xinyue X Yang Yimu Y Ammons Lee Anne LA Hiller Terra D TD Suflita Matt A MA Yu Yanlei Y Chen Yin Y Zhang Fuming F Cothren Burlew Clay C Edelstein Charles L CL Douglas Ivor S IS Linhardt Robert J RJ

American journal of respiratory and critical care medicine 20160801 4

<h4>Rationale</h4>Degradation of the endothelial glycocalyx, a glycosaminoglycan (GAG)-rich layer lining the vascular lumen, is associated with the onset of kidney injury in animal models of critical illness. It is unclear if similar pathogenic degradation occurs in critically ill patients.<h4>Objectives</h4>To determine if urinary indices of GAG fragmentation are associated with outcomes in patients with critical illnesses such as septic shock or acute respiratory distress syndrome (ARDS).<h4>M ...[more]

PMID: 26926297

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Project description:BackgroundNo direct approach assessing pulmonary vascular permeability exists in the current therapeutic strategy for patients with acute respiratory distress syndrome (ARDS). Transpulmonary thermodilution measures hemodynamic parameters such as pulmonary vascular permeability index and extravascular lung water, enabling clinicians to assess ARDS severity. The aim of this study is to explore a precise transpulmonary thermodilution-based criteria for quantifying the severity of lung injury using a clinically relevant septic-ARDS pig model.MethodsThirteen female pigs (weight: 31 ± 2 kg) were intubated, mechanically ventilated under anesthesia, and either assigned to septic shock-induced ARDS or control group. To confirm the development of ARDS, we performed computed tomography (CT) imaging in randomly selected animals. The pulmonary vascular permeability index, extravascular lung water, and other hemodynamic parameters were consecutively measured during the development of septic lung injury. Lung status was categorized as normal (partial pressure of oxygen/fraction of inspired oxygen ≥ 400), or injured at different degrees: pre-ARDS (300-400), mild-to-moderate ARDS (100-300), or severe ARDS (< 100). We also measured serum inflammatory cytokines and high mobility group box 1 levels during the experiment to explore the relationship of the pulmonary vascular permeability index with these inflammatory markers.ResultsUsing CT image, we verified that animals subjected to ARDS presented an extent of consolidation in bilateral gravitationally dependent gradient that expands over time, with diffuse ground-glass opacification. Further, the post-mortem histopathological analysis for lung tissue identified the key features of diffuse alveolar damage in all animals subjected to ARDS. Both pulmonary vascular permeability index and extravascular lung water increased significantly, according to disease severity. Receiver operating characteristic analysis demonstrated that a cut-off value of 3.9 for the permeability index provided optimal sensitivity and specificity for predicting severe ARDS (area under the curve: 0.99, 95% confidence interval, 0.98-1.00; sensitivity = 100%, and specificity = 92.5%). The pulmonary vascular permeability index was superior in its diagnostic value than extravascular lung water. Furthermore, the pulmonary vascular permeability index was significantly associated with multiple parameters reflecting clinicopathological changes in animals with ARDS.ConclusionThe pulmonary vascular permeability index is an effective indicator to measure septic ARDS severity.

Project description:Endothelial cell (EC) activation may increase systemic vascular permeability, causing extravascular lung water (EVLW) in sepsis with acute respiratory distress syndrome (ARDS). However, the correlation between thrombin and EVLW in sepsis and ARDS has not yet been addressed. Patients with sepsis and ARDS were prospectively enrolled between 2014 and 2016, and EVLW and serum thrombin levels on days 1 and 3 were measured and compared between surviving and non-surviving patients. Additionally, morphological changes in human umbilical vein endothelial cells (HUVECs) in the serum of patients with high and low EVLW were evaluated. The levels of EVLW, endothelial cells, and thrombin may positively correlate with the survival of patients with severe sepsis and ARDS. Twenty-seven patients were enrolled, and baseline characteristics, including age, sex, Acute Physiology and Chronic Health Evaluation (APACHE) II, prior 24-h fluid balance, body mass index, and shock status, were similar between survivors and non-survivors; however, day 1 EVLW was higher in non-survivors (27.5 ± 8.4 vs 22 ± 6.5 mL/kg, P = .047). EVLW of survivors improved from day 1 to day 3 (22 ± 6.5 vs 11 ± 3.8 mL/kg, P < .001), but did not improve in non-survivors (27.5 ± 8.4 vs 28 ± 6.7 mL/kg, P = .086), which means that patients had significantly lower EVLW on day 3 than on day 1. Thrombin levels of survivors significantly improved (1.03 ± 0.55 vs 0.87 ± 0.25 U/mL, P = .04) but did not improve in non-survivors (1.97 ± 0.75 vs 2.2 ± 0.75 U/mL, P = .08) from day 1 to day 3. EVLW and thrombin levels were positively correlated (r2 = 0.71, P < .0001). In vitro, the morphology and junctions of HUVECs changed when the serum from patients with high EVLW was added. The intercellular distances among the control, high EVLW, and low EVLW groups were 5.25 ± 1.22, 21.33 ± 2.15, and 11.17 ± 1.64 µm, respectively (P < .05).

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Urinary Glycosaminoglycans Predict Outcomes in Septic Shock and Acute Respiratory Distress Syndrome.

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Urinary Glycosaminoglycans Predict Outcomes in Septic Shock and Acute Respiratory Distress Syndrome.

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