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. 2019 Apr:176:39-45.
doi: 10.1016/j.thromres.2019.02.015. Epub 2019 Feb 12.

Fluid resuscitation with 0.9% saline alters haemostasis in an ovine model of endotoxemic shock

Margaret R Passmore  1 , Nchafatso G Obonyo  2 , Liam Byrne  3 , Ai-Ching Boon  4 , Sara D Diab  5 , Kimble R Dunster  6 , Yoke L Fung  7 , Michelle M Spanevello  8 , Mohd H Fauzi  9 , Sanne E Pedersen  10 , Gabriela Simonova  11 , Chris M Anstey  12 , Kiran Shekar  13 , John-Paul Tung  14 , Kathryn Maitland  15 , John F Fraser  16
Affiliations

Fluid resuscitation with 0.9% saline alters haemostasis in an ovine model of endotoxemic shock

Margaret R Passmore et al. Thromb Res. 2019 Apr.

Abstract

Introduction: Fluid resuscitation is a cornerstone of severe sepsis management, however there are many uncertainties surrounding the type and volume of fluid that is administered. The entire spectrum of coagulopathies can be seen in sepsis, from asymptomatic aberrations to fulminant disseminated intravascular coagulation (DIC). The aim of this study was to determine if fluid resuscitation with saline contributes to the haemostatic derangements in an ovine model of endotoxemic shock.

Materials and methods: Twenty-one adult female sheep were randomly divided into no endotoxemia (n = 5) or endotoxemia groups (n = 16) with an escalating dose of lipopolysaccharide (LPS) up to 4 μg/kg/h administered to achieve a mean arterial pressure below 60 mmHg. Endotoxemia sheep received either no bolus fluid resuscitation (n = 8) or a 0.9% saline bolus (40 mL/kg over 60 min) (n = 8). No endotoxemia, saline only animals (n = 5) underwent fluid resuscitation with a 0.9% bolus of saline as detailed above. Hemodynamic support with vasopressors was initiated if needed, to maintain a mean arterial pressure (MAP) of 60-65 mm Hg in all the groups.

Results: Rotational thromboelastometry (ROTEM®) and conventional coagulation biomarker tests demonstrated sepsis induced derangements to secondary haemostasis. This effect was exacerbated by saline fluid resuscitation, with low pH (p = 0.036), delayed clot initiation and formation together with deficiencies in naturally occurring anti-coagulants antithrombin (p = 0.027) and Protein C (p = 0.001).

Conclusions: Endotoxemia impairs secondary haemostasis and induces changes in the intrinsic, extrinsic and anti-coagulant pathways. These changes to haemostasis are exacerbated following resuscitation with 0.9% saline, a commonly used crystalloid in clinical settings.

Keywords: Coagulation; Coagulation factors; Fibrinogen; Sepsis; Thromboelastometry.

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Conflict of interest statement

Conflict of interest

JFF received funding from the Office of Health and Medical Research, Queensland Health. The remaining authors declare no competing financial interests

Figures

Fig. 1
Fig. 1. Schematic overview of the experimental plan.
Fig. 2
Fig. 2
The effect of saline resuscitation on physiological parameters. Endotoxemia + saline altered pH (A) compared to endotoxemia only while there was no change in ionized calcium (B) or body temperature (C). There was a significant increase in the volume of fluid administered during resuscitation for saline only and endotoxemia + saline animals (D). Data are presented as mean ± SEM. *p < 0.01 versus saline only; #p < 0.05 versus endotoxemia only; $p < 0.05 versus endotoxemia only. n = 5 saline only, n = 8 endotoxemia only, n = 8 endotoxemia + saline. LPS = lipopolysaccharide; B = baseline.
Fig. 3
Fig. 3
The effect of saline resuscitation on INTEM parameters. INTEM-CT (A) and –CFT (B) were prolonged in endotoxemia + saline compared to endotoxemia only. INTEM-MCF (C) was subsequently lower in endotoxemic animals compared to saline only and lower in the endotoxemia + saline group compared to endotoxemia only. Data are presented as mean ± SEM. *p < 0.01 versus saline only; #p < 0.01 versus endotoxemia only; $p = 0.05 versus endotoxemia only. n = 5 saline only, n = 8 endotoxemia only, n = 8 endotoxemia + saline. LPS = lipopolysaccharide; B = baseline.
Fig. 4
Fig. 4
The effect of saline resuscitation on EXTEM parameters. EXTEM-CT (A) and –CFT (B) were prolonged in endotoxemia + saline compared to endotoxemia only. EXTEM-MCF (C) decreased in endotoxemic animals compared to saline only. Data are presented as mean ± SEM. *p < 0.05 versus saline only; #p < 0.01 versus endotoxemia only. n = 5 saline only, n = 8 endotoxemia only, n = 8 endotoxemia + saline. LPS = lipopolysaccharide; B = baseline.
Fig. 5
Fig. 5
The effect of saline resuscitation on FIBTEM parameters. FIBTEM-CT (A) was prolonged in endotoxemia + saline animals compared to endotoxemia only while FIBTEM-CFT (B) was unchanged. FIBTEM-MCF (C) was decreased after LPS was established in both endotoxemic groups compared to saline only. Clauss fibrinogen (D) strongly correlated with FIBTEM-MCF. Data are presented as mean ± SEM. *p < 0.001 versus saline only; #p < 0.01 versus endotoxemia only. n = 5 saline only, n = 8 endotoxemia only, n = 8 endotoxemia + saline. LPS = lipopolysaccharide; B = baseline.
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