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Objective: To investigate the effects of fenofibrate, an activator of peroxysome proliferator activated receptor (PPAR) alpha, on vascular endothelium and on hemostasis in a rabbit endotoxic shock model., Design and Setting: Prospective laboratory study in a university laboratory., Subjects: 36 male New Zealand rabbits weighing 2.5-3 kg., Interventions: We determined in vitro vascular reactivity, endothelium CD31-platelet/endothelial cell adhesion molecule (PECAM) 1 immunohistochemistry, plasma coagulation factors, and monocyte tissue factor expression 5 days after onset of endotoxic shock (0.5 mg/kg intravenous bolus, Escherichia coli lipopolysaccharide) with or without treatment by fenofibrate (mixed in the chow at a concentration of 0.5%) for 15 days before lipopolysaccharide injection and 5 days afterward., Measurements and Results: Metabolic acidosis and coagulation activation confirmed presence of shock. Fenofibrate decreased monocyte tissue factor expression. It improved endothelial-dependent relaxation at 5 days (Emax=68.2+/-3.3%, vs. 44.2+/-2.5% in the non-treated group). Endotoxin-induced deendothelialization was significantly decreased by fenofibrate at 5 days (8.5+/-1.3% vs. 19.2+/-3.1% in the nontreated group) ., Conclusions: These data indicate for the first time that fenofibrate, an activator of PPAR-alpha, inhibits monocyte tissue factor expression and protects against endothelial dysfunction and histological injury in endotoxin-induced shock.

Objective: Unmethylated cytosine-phosphate-guanine (CpG) oligodeoxynucleotides are highly frequent motifs in bacterial DNA and rare in the mammalian genome. They are potent inducers of inflammatory cytokines and act synergistically with lipopolysaccharide (LPS) for the induction of tumor necrosis factor alpha (TNF-alpha) production in vivo. It has therefore been suggested that innate immune reaction to bacterial unmethylated CpG motifs might contribute to the development of septic shock. We designed this study to assess the sensitization role of CpG motifs in LPS-induced shock using the D-galactosamine (D-GalN)-sensitized mouse model., Design: A prospective, randomized in vivo animal laboratory study., Setting: Experimental research laboratory., Intervention: We performed experiments in which CpG, LPS and D-GalN were administrated sequentially in various orders or simultaneously in 8 week-old BALB/c mice., Measurements and Results: Cytosine-phosphate-guanine treatment potentiated LPS action only if injected prior to LPS. A combination of predefined sublethal doses of CpG (1 nmol/mouse) and LPS (1 ng/mouse) not only had a synergetic effect on TNF-alpha production (20.3+/-9.2 IU/ml versus 2.5+/-1.4 IU/ml and 5.6+/-3.4 IU/ml for CpG and LPS groups, respectively, p<0.05), but also led to animal death (5/5). An CpG effect requires de novo mRNA synthesis, since the sensitizing effect was inhibited by co-administration of mRNA transcription inhibitors such as D-GalN and pentoxifylline, which is a specific TNF-alpha transcription inhibitor. Furthermore, CpG treatment provoked a strong TNF-alpha mRNA production in the liver that was dramatically reduced by pre-treatment with D-GalN., Conclusion: Our findings indicate that CpG motifs act synergistically with LPS by initializing the synthesis of TNF-alpha and/or TNF-alpha regulating factors, thereby acting as a sensitizing agent.

Objectives: To evaluate the effect of an early dobutamine infusion on gastrointestinal perfusion in patients with severe sepsis., Design: Prospective, randomized, controlled, multicenter clinical study., Setting: Six medical and/or surgical intensive care units (ICU) of teaching hospitals., Patients: Forty-two patients with severe sepsis., Interventions: Patients were divided into two groups according to gastric-to-arterial CO2 gap (DeltaCO2) [normal DeltaCO2 group ( n=17): DeltaCO2 < or = 8 mmHg; increased DeltaCO2 group ( n=25): DeltaCO2 > 8 mmHg]. Patients within each group were then randomized to receive either dobutamine (5 microg/kg per min) or saline for 72 h., Measurements and Main Results: SAPS II was similar in both groups [group 1: 44.0 (33.0-56.5); group 2: 48.5 (40.5-59.0), p=0.27]. At ICU admission, mean arterial pressure was lower in the high DeltaCO2 group [73.0 (67.0-79.5) mmHg, p=0.03] than in the normal DeltaCO2 group [84.0 (73.7-104.0) mmHg] while blood lactate [normal DeltaCO2 group: 1.6 (0.8-2.3); high DeltaCO2 group: 1.6 (1.1-1.9) mmol/l] was similar for the two groups. DeltaCO2 was significantly lower in the normal DeltaCO2 group [5.0 (2.0-6.0) mmHg)] than in the high DeltaCO2 group [11.0 (10.0-19.0) mmHg]. Dobutamine infusion did not significantly change hemodynamics, blood lactate concentration or tonometric parameters in any group within the first 72 h and had no particular beneficial effect in this population., Conclusions: An early infusion of dobutamine at a fixed dose of 5 microg/kg per min during the first 72 h of severe sepsis does not influence gastric DeltaCO2.