Matharu NM, Butler LM, Rainger GE, Gosling P, Vohra RK, Nash GB: Mechanisms of the anti-inflammatory effects of hydroxyethyl starch demonstrated in a flow-based model of neutrophil recruitment by endothelial cells
To determine whether plasma volume expander hydroxyethyl starch (HES) may protect against reperfusion injury through an ability to reduce neutrophil recruitment.
An in vitro study using paired comparisons of adhesion of flowing neutrophils.
A collaboration between clinical and basic science departments in a university hospital.
Neutrophils and cultured human umbilical vein endothelial cells (HUVEC).
Treatment with HES (average molecular weight of 200 kd and substitution of 0.62) at clinically relevant concentrations or with gelatin solution (average molecular weight of 30 kDa) of comparable viscosity.
Glass capillaries were coated internally with either purified adhesion molecules or HUVEC, which were treated with tumor necrosis factor-alpha in the presence or absence of HES. Neutrophils were perfused over these surfaces (with or without HES) and their recruitment quantified by video microscopy. Expression of adhesion molecules and of the chemokine interleukin-8 by HUVEC were analyzed by enzyme-linked immunosorbent assay and quantitation of messenger RNA. HES over a wide range of concentrations had no effect on selectin- or integrin-mediated adhesion of neutrophils. However, when HUVEC were cultured with 1.5% wt/vol HES, neutrophil capture induced by low-dose (1 unit/mL) tumor necrosis factor-alpha and transendothelial migration induced by high-dose (100 units/mL) tumor necrosis factor-alpha were significantly inhibited (p < .05, in each case). The effects were linked with reductions in expression of E-selectin and interleukin-8 by HUVEC at these respective tumor necrosis factor-alpha concentrations (p < .05, in each case). Gelatin (2% wt/vol) had no significant effect in assays with HUVEC.
Application of HES to HUVEC exerts an inhibitory effect on different stages of neutrophil recruitment, depending on the level of the inflammatory stimulus. These effects are associated with reduced adhesion molecule expression and chemokine production. In vivo, comparable effects might protect against complications associated with reperfusion injury.
"In any case, the histology of several tissues suggested that overhydration and (pulmonary) edema had not increased in the 'liberal' compared to the 'restrictive' fluid loading groups, even in the presence of so-called colloid plaques observed in lungs, for instance, although the nature of these remains relatively unclear. Finally, starch preparations may have multiple anti-inflammatory effects, but we do not know whether this is good or bad during sepsis . Collectively, the experiments reported raise the interesting idea that too much of a good thing is detrimental, whether related to relative overtreatment or to toxicity of the hydroxyethyl starch colloid. "
[Show abstract][Hide abstract] ABSTRACT: In a recent issue of Critical Care, Brandt and colleagues report the effects of a 'liberal' fluid loading protocol compared to a more 'restrictive' protocol on hemodynamics and mortality in pigs in which septic shock had been induced. It appears that the former protocol was associated with higher mortality in spite of improved hemodynamics compared to the latter. The results of the paper are discussed here in view of the scope and mechanisms of these findings. With regard to fluid resuscitation, they indicate that too much of an otherwise good thing is harmful, even if overhydration and edema formation seem to have been prevented. They also do not exclude a specific toxic effect of the larger volumes of hydroxyethyl starch in the 'liberal' strategy. The precise nature of a toxic effect remains obscure, however, but may involve the kidneys.
"The most modern HES with a mean molecular weight of 130 kDa and a mean degree of substitution of 0.4 (HES 130/0.4) is therefore claimed to have fewer adverse effects on haemostasis and renal function than formerly used HES solutions [12,13]. Furthermore, HES 130/0.4 has been reported to have some anti-inflammatory effects that might provide benefit to patients with systemic inflammation and sepsis [14-16]. Recent ex vivo studies, however, have shown that HES 130/0.4 "
[Show abstract][Hide abstract] ABSTRACT: Hydroxyethyl starch (HES) solutions are widely used for volume replacement therapy but are also known to compromise coagulation, impair renal function and increase long-term mortality. To test the hypotheses that HES 130/0.4 has fewer adverse effects than HES 200/0.5 and exerts anti-inflammatory properties, we compared the effects of HES 130/0.4, HES 200/0.5 and saline on in vitro haemostasis and pro-inflammatory platelet function.
Whole blood samples from healthy volunteers were mixed with 6% HES 130/0.4, 10% HES 200/0.5, or normal saline to achieve a final haemodilution rate of 10% or 40%. Haemostatic capacity was characterised by thromboelastography (ROTEM) and measurement for FXIIIa activity. Platelet activation and pro-inflammatory platelet functions were characterised by flow cytometry measuring the platelet activation marker CD62P and binding of fibrinogen to platelets as well as the formation of heterotypic platelet-leukocyte conjugates.
Compared with saline, HES 130/0.4 dose-dependently impaired formation and firmness of the fibrin clot but did not affect the fibrin crosslinking activity of FXIIIa. At 40% but not at 10% haemodilution rate, HES 200/0.5 also increased platelet fibrinogen binding and both HES solutions increased expression of CD62P, the main receptor for platelet-leukocyte adhesion. HES 130/0.4 but not HES 200/0.5 increased formation of platelet-neutrophil conjugates and, to a lesser degree, platelet-monocyte conjugates.
Our data demonstrate that HES 130/0.4 has similar adverse effects as HES 200/0.5. In particular, both types of HES impair coagulation capacity and stimulate, rather than attenuate, pro-inflammatory platelet function.
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