[Coagulation inhibitors in severe sepsis: state of the art]. / Inhibiteurs de la coagulation et états septiques graves.

OBJECTIVE: To present and discuss the rationale and the results of clinical trials using supplementation with physiologic anticoagulants (Tissue Factor Pathway Inhibitor (TFPI), AntiThrombin (AT), and Protein C (PC) in patients with severe sepsis. RATIONALE: An early activation of the coagulation cascade occurs in severe sepsis. TFPI, AT, and PC are major inhibitors of the coagulation cascade, and additionally modulate inflammatory and vascular reactions. They are consumed or inhibited in the sepsis pathologic process. Therapeutic supplementation with these inhibitors could improve the sepsis-induced organ failures and mortality. CLINICAL RESULTS: Randomized controlled studies were recently completed. No effect on the mortality rate could be documented after treatment with recombinant TFPI. AT concentrates neither improve mortality, but a biological interaction with heparin therapy could have biased the study results. Treatment with recombinant activated PC (alpha-drotrecogin) was associated with a significant reduction in the mortality rate of severely ill patients and received recently the approval from FDA and EC authorities in this indication. An increase in the rate of hemorrhagic adverse effects has been observed with these compounds, justifying a strict observance of contraindications and of patients selection. PROSPECTIVE: Additional studies are needed to give confirmation of the positive effects of activated PC supplementation in less severely ill patients, children and specific clinical situations. The effects of new anticoagulant compounds are currently evaluated in preclinical studies.

Therapeutic use of antithrombin concentrate in sepsis.

Sepsis and its associated complications of disseminated intravascular coagulation (DIC) and multiple organ dysfunction syndrome (MODS) continue to be a major cause of morbidity and mortality. Improved detection of all forms of DIC is essential to assure earlier diagnosis. Studies already indicate that the therapeutic use of antithrombin (AT) concentrate may produce a more positive outcome for sepsis-associated DIC. If DIC could be identified earlier and AT concentrate could then be given earlier in the sepsis continuum, study results for the use of AT concentrate in humans might reveal a statistically significant difference versus placebo, and the efficacy of AT concentrate for this syndrome is more likely to be proved. Fixed-bolus doses of AT concentrate based on body weight are currently preferred, but improved, user-friendly assays for plasma AT levels would permit more rapid turnaround time for AT results and could help fine-tune the use of AT concentrate to the specific needs of each patient. Clinical trials involving the therapeutic use of AT concentrate in sepsis should continue, and it can be hoped that their design will reflect the concepts and conclusions offered by this panel of investigators.

Effects of N omega-nitro-L-arginine methyl ester on the endotoxin-induced disseminated intravascular coagulation in porcine septic shock.

OBJECTIVES: Nitric oxide is known to prevent platelet aggregation and clot formation. Inhibitors of nitric oxide synthase might promote or enhance endotoxin disseminated intravascular coagulation. The present study was designed to evaluate the effects of the arginine analog, N omega-nitro-L-arginine methyl ester (L-NAME), on the endotoxin-induced disseminated intravascular coagulation in a porcine model of septic shock. DESIGN: Prospective, comparative, experimental study. SETTING: Laboratory at a large university hospital. SUBJECTS: Sixteen female piglets, weighing 20 to 28 kg. INTERVENTIONS: Three groups of animals were studied: a control group (n = 6); a lipopolysaccharide (LPS)-treated group (n = 5) receiving Escherichia coli endotoxin (5 micrograms/kg/min over 30 mins); and an LPS + L-NAME group (n = 5) receiving endotoxin and, 1 hr after, a bolus of L-NAME (25 mg/kg). MEASUREMENTS AND MAIN RESULTS: Hemodynamic changes, usual coagulation parameters, and plasma concentrations of thrombin-antithrombin complexes, antithrombin III activity (At III), tissue plasminogen activator, plasminogen activator inhibitor type 1, and von Willebrand factor were measured at baseline, and at 30, 60, 90, 120, 180, 240, and 300 mins. After euthanasia or death, lungs and kidneys were withdrawn for histologic study. The extent of microvascular thrombosis was assessed by a semiquantitative disseminated intravascular coagulation score. In both septic endotoxin group, administration of LPS resulted in hemodynamic changes typical of severe septic shock, with disseminated intravascular coagulation and histologic changes characterized by adult respiratory distress syndrome and kidney microthrombosis. L-NAME administration normalized mean arterial pressure with a dramatic increase in systemic vascular resistances and a marked decrease in cardiac index. The changes in usual coagulation parameters, AT III, tissue plasminogen activator, and plasminogen-activator inhibitor type 1 concentrations were not different between both septic groups. However, in the LPS + L-NAME group, thrombin-antithrombin complexes and von Willebrand factor were higher and associated with a higher histologic disseminated intravascular coagulation score. CONCLUSION: In this model of endotoxin septic shock, L-NAME administration resulted in histologic and coagulation changes consistent with an increased activation of intravascular coagulation.

[Value of determining trace elements in septicemia. Clinical correlations, prognostic value]. / Intérêt du dosage des oligo-éléments au cours des septicémies. Corrélations cliniques, valeur pronostique.

Among 17 septicemic patients, a statistically decrease of seric oligo-elements is demonstrated. The longitudinal study shows the rapid correction of these perturbations in the surviving group and the lack of correction among the non survivors. The level of phosphorus is the most interesting one. The importance of S.R.E. activity is probably the physiopathologic support of seric oligo-element modifications in sepsis.