The protective effect of hydroxyethyl starch solution on the glycocalyx layer in an acute hemorrhage mouse model

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Abstract

Purpose

Fluid therapy focused on glycocalyx (GCX) protection in hemorrhagic shock is a current focus of research. Hydroxyethyl starch (HES) solution is commonly used for fluid resuscitation; however, its effects on the GCX remain unclear. The primary aim of this study was to explore the protective effect of HES130 in maintaining GCX thickness and reducing plasma syndecan-1 expression.

Methods

An acute hemorrhage murine model with the dorsal skin chambers was used to measure GCX thickness and to evaluate vascular permeability. Groups of mice were treated with normal saline (NS), albumin (NS-A), HES130 (NS-V), or no exsanguination or infusion (C). We measured syndecan-1 plasma concentrations, performed blood gas analysis, and analyzed the 7-day cumulative mortality.

Results

GCX thickness in NS mice was significantly reduced compared to that in group C, but no other groups showed a difference compared to group C. The plasma concentration of syndecan-1 was significantly higher in NS mice than in group C. There were no significant differences in the fluorescence intensity of dextran in the interstitial space. HES70 leakage was suppressed in NS-V mice compared to those in other groups. HES70 was localized to the inner vessel wall in C, NS, and NS-A mice, but not in group NS-V. Blood gas analysis indicated that pH and lactate showed the greatest improvements in NS-V mice. The 7-day cumulative mortality rate was the highest in group NS.

Conclusion

Resuscitation with HES130 protected the GCX and suppressed vascular permeability of HES70 during early stages of acute massive hemorrhage.

Electronic supplementary material

The online version of this article (10.1007/s00540-019-02692-8) contains supplementary material, which is available to authorized users.

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Most cited references 35

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A high admission syndecan-1 level, a marker of endothelial glycocalyx degradation, is associated with inflammation, protein C depletion, fibrinolysis, and increased mortality in trauma patients.

Pär Johansson, Jakob Stensballe, Lars S Rasmussen … (2011)

To investigate the association between markers of acute endothelial glycocalyx degradation, inflammation, coagulopathy, and mortality after trauma. Hyperinflammation and acute coagulopathy of trauma predict increased mortality. High catecholamine levels can directly damage the endothelium and may be associated with enhanced endothelial glycocalyx degradation, evidenced by high circulating syndecan-1. Prospective cohort study of trauma patients admitted to a Level 1 Trauma Centre in 2003 to 2005. Seventy-five patients were selected blindly post hoc from 3 predefined injury severity score (ISS) groups ( 27). In all patients, we measured 17 markers of glycocalyx degradation, inflammation, tissue and endothelial damage, natural anticoagulation, and fibrinolysis (syndecan-1, IL-6, IL-10, histone-complexed DNA fragments, high-mobility group box 1 (HMGB1), thrombomodulin, von Willebrand factor, intercellular adhesion molecule-1, E-selectin, protein C, tissue factor pathway inhibitor (TFPI), antithrombin, D-dimer, tissue-type plasminogen activator (tPA), urokinase-type plasminogen activator (uPA), soluble uPA receptor, and plasminogen activator inhibitor-1), hematology, coagulation, catecholamines, and assessed 30-day mortality. Variables were compared in patients stratified according to syndecan-1 median. Patients with high circulating syndecan-1 had higher catecholamines, IL-6, IL-10, histone-complexed DNA fragments, HMGB1, thrombomodulin, D-dimer, tPA, uPA (all P < 0.05), and 3-fold increased mortality (42% vs. 14%, P = 0.006) despite comparable ISS (P = 0.351). Only in patients with high glycocalyx degradation was higher ISS correlated with higher adrenaline, IL-6, histone-complexed DNA fragments, HMGB1, thrombomodulin, and APTT, lower protein C (all P < 0.05), unchanged TFPI and blunted D-dimer response (P < 0.001) because D-dimer was profoundly increased even at low ISS. After adjusting for age and ISS, syndecan-1 was an independent predictor of mortality (OR: 1.01 [95%CI, 1.00-1.02]; P = 0.043). In trauma patients, high circulating syndecan-1, a marker of endothelial glycocalyx degradation, is associated with inflammation, coagulopathy and increased mortality.

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Plasma restoration of endothelial glycocalyx in a rodent model of hemorrhagic shock.

Rosemary Kozar, Rongzhen Zhang, John Holcomb … (2011)

The use of plasma-based resuscitation for trauma patients in hemorrhagic shock has been associated with a decrease in mortality. Although some have proposed a beneficial effect through replacement of coagulation proteins, the putative mechanisms of protection afforded by plasma are unknown. We have previously shown in a cell culture model that plasma decreases endothelial cell permeability in comparison with crystalloid. The endothelial glycocalyx consists of proteoglycans and glycoproteins attached to a syndecan backbone, which together protect the underlying endothelium. We hypothesize that endothelial cell protection by plasma is due, in part, to its restoration of the endothelial glycocalyx and preservation of syndecan-1 after hemorrhagic shock. Rats were subjected to hemorrhagic shock to a mean arterial blood pressure of 30 mm Hg for 90 minutes followed by resuscitation with either lactated Ringer's (LR) solution or fresh plasma to a mean arterial blood pressure of 80 mm Hg and compared with shams or shock alone. After 2 hours, lungs were harvested for syndecan mRNA, immunostained with antisyndecan-1, or stained with hematoxylin and eosin. To specifically examine the effect of plasma on the endothelium, we infused small bowel mesentery with a lanthanum-based solution, identified venules, and visualized the glycocalyx by electron microscopy. All data are presented as mean ± SEM. Results were analyzed by 1-way analysis of variance with Tukey post hoc tests. Electron microscopy revealed degradation of the glycocalyx after hemorrhagic shock, which was partially restored by plasma but not LR. Pulmonary syndecan-1 mRNA expression was higher in animals resuscitated with plasma (2.76 ± 0.03) in comparison with shock alone (1.39 ± 0.22) or LR (0.82 ± 0.03) and correlated with cell surface syndecan-1 immunostaining. Shock also resulted in significant lung injury by histopathology scoring (1.63 ± 0.26), which was mitigated by resuscitation with plasma (0.67 ± 0.17) but not LR (2.0 ± 0.25). The protective effects of plasma may be due in part to its ability to restore the endothelial glycocalyx and preserve syndecan-1 after hemorrhagic shock.

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Hypotensive resuscitation strategy reduces transfusion requirements and severe postoperative coagulopathy in trauma patients with hemorrhagic shock: preliminary results of a randomized controlled trial.

Kenneth Mattox, Glynis Scott, K Liscum … (2011)

Trauma is a leading cause of death worldwide and is thus a major public health concern. Previous studies have shown that limiting the amount of fluids given by following a strategy of permissive hypotension during the initial resuscitation period may improve trauma outcomes. This study examines the clinical outcomes from the first 90 patients enrolled in a prospective, randomized controlled trial of hypotensive resuscitation, with the primary aim of assessing the effects of a limited transfusion and intravenous (IV) fluid strategy on 30-day morbidity and mortality. Patients in hemorrhagic shock who required emergent surgery were randomized to one of the two arms of the study for intraoperative resuscitation. Those in the experimental (low mean arterial pressure [LMAP]) arm were managed with a hypotensive resuscitation strategy in which the target mean arterial pressure (MAP) was 50 mm Hg. Those in the control (high MAP [HMAP]) arm were managed with standard fluid resuscitation to a target MAP of 65 mm Hg. Patients were followed up for 30 days. Intraoperative fluid requirements, mortality, postoperative complications, and other clinical data were prospectively gathered and analyzed. Patients in the LMAP group received a significantly less blood products and total i.v. fluids during intraoperative resuscitation than those in the HMAP group. They had significantly lower mortality in the early postoperative period and a nonsignificant trend for lower mortality at 30 days. Patients in the LMAP group were significantly less likely to develop immediate postoperative coagulopathy and less likely to die from postoperatively bleeding associated with coagulopathy. Among those who developed coagulopathy in both groups, patients in the LMAP group had significantly lower international normalized ratio than those in the HMAP group, indicating a less severe coagulopathy. Hypotensive resuscitation is a safe strategy for use in the trauma population and results in a significant reduction in blood product transfusions and overall IV fluid administration. Specifically, resuscitating patients with the intent of maintaining a target minimum MAP of 50 mm Hg, rather than 65 mm Hg, significantly decreases postoperative coagulopathy and lowers the risk of early postoperative death and coagulopathy. These preliminary results provide convincing evidence that support the continued investigation and use of hypotensive resuscitation in the trauma setting. Copyright © 2011 by Lippincott Williams & Wilkins

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Author and article information

Contributors

Tomoko Yorozu: tyorozu@ks.kyorin-u.ac.jp

Journal

Journal ID (nlm-ta): J Anesth

Journal ID (iso-abbrev): J Anesth

Title: Journal of Anesthesia

Publisher: Springer Singapore (Singapore )

ISSN (Print): 0913-8668

ISSN (Electronic): 1438-8359

Publication date (Electronic): 15 October 2019

Publication date PMC-release: 15 October 2019

Publication date (Print): 2020

Volume: 34

Issue: 1

Pages: 36-46

Affiliations

[1 ]GRID grid.411205.3, ISNI 0000 0000 9340 2869, Department of Anesthesiology, , Kyorin University School of Medicine, ; 6-20-2 Shinkawa, Mitaka-shi, Tokyo, 181-8611 Japan

[2 ]GRID grid.415776.6, ISNI 0000 0001 2037 6433, Department of Environmental Health, , National Institute of Public Health, ; 2-3-6 Minami, Wako, Saitama 351-0197 Japan

[3 ]GRID grid.411763.6, ISNI 0000 0001 0508 5056, Meiji Pharmaceutical University Graduate School of Pharmaceutical Sciences, ; 2-522-1, Noshio, Kiyose-shi, Tokyo, 204-8588 Japan

[4 ]GRID grid.410802.f, ISNI 0000 0001 2216 2631, Department of Anesthesiology, Saitama Medical Center, , Saitama Medical University, ; 1981, Kamoda, Kwagoe, Saitama 350-8550 Japan

Article

Publisher ID: 2692

DOI: 10.1007/s00540-019-02692-8

PMC ID: 6992552

PubMed ID: 31617003

SO-VID: 9b112da3-86f3-4c99-b5fd-cdbf499c1d9e

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

History

Date received : 27 May 2019

Date accepted : 26 September 2019

Custom metadata

ScienceOpen disciplines: Anesthesiology & Pain management

Keywords: glycocalyx layer,hydroxyethyl starch solution,dorsal skin chamber,microvascular circulation,fluid resuscitation

Data availability:

ScienceOpen disciplines: Anesthesiology & Pain management

Keywords: glycocalyx layer, hydroxyethyl starch solution, dorsal skin chamber, microvascular circulation, fluid resuscitation

The protective effect of hydroxyethyl starch solution on the glycocalyx layer in an acute hemorrhage mouse model

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Abstract

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Cardiovascular Innovations and Applications

Most cited references 35

A high admission syndecan-1 level, a marker of endothelial glycocalyx degradation, is associated with inflammation, protein C depletion, fibrinolysis, and increased mortality in trauma patients.

Plasma restoration of endothelial glycocalyx in a rodent model of hemorrhagic shock.

Hypotensive resuscitation strategy reduces transfusion requirements and severe postoperative coagulopathy in trauma patients with hemorrhagic shock: preliminary results of a randomized controlled trial.

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