Treatment with the sphingosine-1-phosphate analogue FTY 720 reduces loss of plasma volume during experimental sepsis in the rat.

BACKGROUND: Increased vascular leakage leading to hypovolaemia and tissue oedema is common in severe sepsis. Hypovolaemia together with oedema formation may contribute to hypoxia and result in multiorgan failure and death. To improve treatment during sepsis, a potential therapeutic target may be to reduce the vascular leakage. Substances affecting the endothelial barrier are interesting in this respect, as it is suggested that increase in vascular leakage depends on reorganisation of the endothelial cells and breakdown of the endothelial barrier. The agonist of the bioactive lipid sphingosine-1-phosphate, FTY720, has been shown to modulate the integrity of the endothelium and reduce permeability both in vitro and in vivo. The aim of the present study was to determine if FTY720 could reduce the loss of plasma volume during experimental sepsis in rats. METHODS: Sepsis was induced by ligation and incision of the caecum in the rat. Plasma volume was determined before and 4.5 h after induction of sepsis by a dilution technique using (125) I-labelled albumin. RESULTS: FTY720 in a dose of 0.2 mg/kg reduced the loss of plasma during sepsis by approximately 30% compared with vehicle, without any adverse effects on haemodynamic and physiological parameters. The increase in hematocrit and haemoglobin concentration was also found to be higher in the vehicle group. CONCLUSION: FTY720 in a dose without haemodynamic side effects reduces loss of plasma volume during experimental sepsis most likely because of reduction in permeability and may therefore be beneficial in sepsis.

[Microvascular effects of burn plasma transfer and therapeutic options in a rat model]. / Mikrovaskuläre Effekte des Verbrennungsplasma-transfers und therapeutische Optionen im Tiermodell.

INTRODUCTION: Thermal injuries with more than 20% of burned body surface area (BSA) lead to systemic shock with generalised oedema in addition to local tissue destruction. This condition, known as burn injury, is caused by immunmodulative mediators whose individual significance is not known in detail. We present an experimental model where plasma of burned animals (burn plasma) is transmitted to healthy animals, to trigger burn iniury without performing direct burn trauma. MATERIAL AND METHODS: The systemic oedema is measured by extravasation of fluorescent albumin in mesenterial venules of Wistar rats. In addition, leukocyte-endothelial interactions ("leukocyte rolling and sticking") is examined. RESULTS: The systemic capillary leak is induced by both direct thermal trauma as well as by infusion of burn plasma. This is evident even after plasma dilution (1% in Ringer's lactate) of the burn plasma. In addition, topical therapy for burned animals (donors) with cerium nitrate led to a significant reduction of plasma extravasation in receiver animals. In addition, systemic antioxidant therapy with high-dose vitamin C of receiver animals, led to a significant reduction of the capillary leak. Leukocyte-endothelial interactions are not significantly affected in either case. CONCLUSION: In summary, for the first time a reliable model of burn injury has been established, which eliminates mediator-independent effects. In addition, our studies show that antioxidant therapy with high doses of vitamin C and topical treatment with cerium nitrate both reduce the systemic capillary leak in receiver animals. Their positive influence could therefore soon be integrated in clinical treatment algorithms.

High-dose vitamin C treatment reduces capillary leakage after burn plasma transfer in rats.

Oxidative stress after burn injuries leads to systemic capillary leakage and leukocyte activation. This study evaluates whether antioxidative treatment with high-dose vitamin C leads to burn edema reduction and prevention of leukocyte activation after burn plasma transfer. Donor rats underwent a burn (n = 7; 100 degrees C water, 12 seconds, 30% body surface area) or sham burn (37 degrees C water; n = 2) procedure and were killed after 4 hours for plasma harvest. This plasma was administered to study rats (continuous infusion). Rats were randomized to four groups (n = 8 each; burn plasma alone [BP]; burn plasma/vitamin C-bolus 66 mg/kg and maintenance dose 33 mg/kg/hr [VC66]; burn plasma/vitamin C-bolus 33 mg/kg and maintenance dose 17.5 mg/kg/hr [VC33]; and sham burn plasma [SB]). Intravital fluorescence microscopy in the mesentery was performed at 0, 60, and 120 minutes for microhemodynamic parameters, leukocyte adherence, and fluorescein isothiocyanate-albumin extravasation. No differences were observed in microhemodynamics at any time. Burn plasma induced capillary leakage, which was significantly higher compared with sham burn controls (P < .001). VC66 treatment reduced microvascular barrier dysfunction to sham burn levels, whereas VC33 had no significant effect. Leukocyte sticking increased after burn plasma infusion, which was not found for sham burn. Vitamin C treatment did not influence leukocyte activation (P > .05). Burn plasma transfer leads to systemic capillary leakage. High-dose vitamin C treatment (bolus 66 mg/kg and maintenance dose 33 mg/kg/hr) reduces endothelial damage to sham burn levels, whereas half the dose is inefficient. Leukocyte activation is not influenced by antioxidative treatment. Therefore, capillary leakage seems to be independent from leukocyte-endothelial interactions after burn plasma transfer. High-dose vitamin C should be considered for parenteral treatment in every burn patient.