Microparticles are new biomarkers of septic shock-induced disseminated intravascular coagulopathy

PURPOSE: Septic shock-induced disseminated intravascular coagulopathy (DIC) contributes to multiple organ failure. Mechanisms governing vascular responses to open occurrence of DIC have not yet been established. Circulating plasma microparticles (MPs), released upon cell stress, constitute a catalytic procoagulant surface and are surrogates of vascular cell activation/injury. Herein, MPs were assessed as possible markers of haemostatic and vascular dysfunction in the DIC time course. METHODS: One hundred patients with septic shock from three ICUs were enrolled and their haemostatic status evaluated at admission (D1), D2, D3 and D7. Circulating procoagulant MPs were isolated, quantified by prothrombinase assay and their cellular origin determined. DIC diagnosis was made according to the JAAM 2006 score. RESULTS: Ninety-two patients were analysed and 40 had DIC during the first 24 h. Routine clotting times and factor/inhibitor activity did not allow assessing vascular cell involvement. At admission, thrombin generation and fibrinolysis were observed in both groups while impaired fibrin polymerisation was evidenced only in DIC patients. Sustained thrombin generation persisted over time in both groups at D7. While total microparticle concentrations were in the same range regardless of DIC diagnosis, specific phenotypes were already detected at admission in DIC patients. Endothelial- and leucocyte-derived MPs were higher in DIC while an increased soluble glycoprotein V/platelet ratio was delayed, underscoring the first involvement of endothelial cells and leucocytes whereas platelet activation was delayed. Endothelium-derived CD105-MPs (OR 6.55) and CD31-MPs (OR 0.49) were strongly associated with early DIC in multivariate analysis. CONCLUSION: Endothelial-derived microparticles are relevant biomarkers of septic shock-induced DIC and could be used to evaluate early vascular injury

Enteral versus parenteral early nutrition in ventilated adults with shock: a randomised, controlled, multicentre, open-label, parallel-group study (NUTRIREA-2)

BACKGROUND: Whether the route of early feeding affects outcomes of patients with severe critical illnesses is controversial. We hypothesised that outcomes were better with early first-line enteral nutrition than with early first-line parenteral nutrition. METHODS: In this randomised, controlled, multicentre, open-label, parallel-group study (NUTRIREA-2 trial) done at 44 French intensive-care units (ICUs), adults (18 years or older) receiving invasive mechanical ventilation and vasopressor support for shock were randomly assigned (1:1) to either parenteral nutrition or enteral nutrition, both targeting normocaloric goals (20-25 kcal/kg per day), within 24 h after intubation. Randomisation was stratified by centre using permutation blocks of variable sizes. Given that route of nutrition cannot be masked, blinding of the physicians and nurses was not feasible. Patients receiving parenteral nutrition could be switched to enteral nutrition after at least 72 h in the event of shock resolution (no vasopressor support for 24 consecutive hours and arterial lactate <2 mmol/L). The primary endpoint was mortality on day 28 after randomisation in the intention-to-treat-population. This study is registered with ClinicalTrials.gov, number NCT01802099. FINDINGS: After the second interim analysis, the independent Data Safety and Monitoring Board deemed that completing patient enrolment was unlikely to significantly change the results of the trial and recommended stopping patient recruitment. Between March 22, 2013, and June 30, 2015, 2410 patients were enrolled and randomly assigned; 1202 to the enteral group and 1208 to the parenteral group. By day 28, 443 (37%) of 1202 patients in the enteral group and 422 (35%) of 1208 patients in the parenteral group had died (absolute difference estimate 2·0%; [95% CI -1·9 to 5·8]; p=0·33). Cumulative incidence of patients with ICU-acquired infections did not differ between the enteral group (173 [14%]) and the parenteral group (194 [16%]; hazard ratio [HR] 0·89 [95% CI 0·72-1·09]; p=0·25). Compared with the parenteral group, the enteral group had higher cumulative incidences of patients with vomiting (406 [34%] vs 246 [20%]; HR 1·89 [1·62-2·20]; p<0·0001), diarrhoea (432 [36%] vs 393 [33%]; 1·20 [1·05-1·37]; p=0·009), bowel ischaemia (19 [2%] vs five [<1%]; 3·84 [1·43-10·3]; p=0·007), and acute colonic pseudo-obstruction (11 [1%] vs three [<1%]; 3·7 [1·03-13·2; p=0·04). INTERPRETATION: In critically ill adults with shock, early isocaloric enteral nutrition did not reduce mortality or the risk of secondary infections but was associated with a greater risk of digestive complications compared with early isocaloric parenteral nutrition. FUNDING: La Roche-sur-Yon Departmental Hospital and French Ministry of Health

Detrimental arterial inflammatory effect of microparticles circulating in preeclamptic women: ex vivo evaluation in human arteries

International audienceElevated plasmatic levels of lympho-monocyte and platelet microparticles (MPs) have been reported in preeclampsia. Previous studies suggest that MPs could participate in preeclampsia vascular impairment. In this study, we investigated the ex vivo vascular effects of MPs from preeclamptic women on arteries from normotensive pregnant women. Omental arteries were collected from normal pregnant women undergoing cesarean section and incubated during 24 h with MPs from normal pregnant or preeclamptic women. Vascular contraction to serotonin and phenylephrine was studied on a wire myograph with or without pharmacological selective inhibitors of inducible nitric oxide synthase (iNOS) and/or cyclo-oxygenase-2 (COX-2). Expression of iNOS, COX-2, and NF-κB and production of superoxide anion and 8-isoprostane were also assessed by immunohistological or biochemical staining and/or Western blot or ELISA assay, respectively. Microparticles from preeclamptic women, but not those from normal pregnant women, induced hyporeactivity to vasocontracturant agonists in omental arteries. Selective inhibitor of iNOS partially restored this arterial contraction, suggesting that nitric oxide (NO) is involved in vascular contractility alteration. Conversely, COX-2 induced 8-isoprostane release, a vasoconstricting metabolite modulating the agonist-induced contraction. COX-2 selective inhibitor almost abolished the arterial contraction in the same vessels. Interestingly, the association of iNOS and COX-2 selective inhibitors restored the contraction to control levels. Moreover, iNOS, COX-2, and NF-κB expressions are upregulated and superoxide anion levels increased in vessels incubated with MPs from preeclamptic women. In conclusion, circulating MPs from preeclamptic women induce vascular inflammation and enhance oxidative stress. These results suggest a possible role of MPs during preeclampsia-induced arterial dysfunction

Dexamethasone and Recombinant Human Activated Protein C Improve Myocardial Function and Efficiency During Experimental Septic Shock

International audienceCorticosteroids have been shown to reduce short-term mortality during septic shock and therefore recommended in the most severe patients as adjuvant therapy. Until recently, recombinant human activated protein C (APC) was also considered in the management of more severe cases. As myocardial depression has long been recognized as a manifestation of organ dysfunction during septic shock, we examined whether corticosteroids (dexamethasone, 150 µg/kg per hour) and/or APC (33 µg/kg per hour) treatments improve sepsis-induced cardiac dysfunction during cecal ligature and puncture-induced septic shock in Wistar rats. All rats received intravenous saline resuscitation (10 mL/kg per hour) and antibiotics. Eighteen hours after surgery, anesthesia was performed (isoflurane), and myocardial function was assessed using a conductance catheter introduced into the left ventricle. Rats were then killed; blood and heart were harvested for biological analysis, including radical oxygen species determination. Cecal ligature and puncture induced hypotension, depression of myocardial systolic performance (demonstrated by significant decreases in dP/dtmax [first derivative of maximal developed pressure during isovolumetric contraction], end-systolic pressure-volume relationship, and preload recruitable stroke work) and alteration of diastolic function (dP/dtmin [first derivative of minimal developed pressure during isovolumetric relaxation]), whereas dexamethasone, APC, and their combination thereof allowed correction of hemodynamic disorders and improved myocardial mechanical efficiency. Cecal ligature and puncture was associated with higher levels of nitric oxide and superoxide anion (O2) in heart (electron paramagnetic resonance studies) and consequently peroxynitrite. Dexamethasone and APC also improved cardiac dysfunction by downregulating the inducible nitric oxide synthase pathway and reducing myocardial oxidative stress

Is Thrombocytopenia an Early Prognostic Marker in Septic Shock?

IF 7.442International audienceObjectives: To assess whether early thrombocytopenia during septic shock is associated with an increased risk of death at day 28 and to identify risk factors associated with a low platelet count.Design: Prospective, multicenter, observational cohort study.Setting: Fourteen ICUs from 10 French university teaching and nonacademic hospitals.Patients: Consecutive adult patients with septic shock admitted between November 2009 and September 2011 were eligible.Intervention: None.Measurements and Main Results: Of the 1,495 eligible patients, 1,486 (99.4%) were included. Simplified Acute Physiology Score II score of greater than or equal to 56, immunosuppression, age of more than 65 years, cirrhosis, bacteremia (p 0.001 for each), and urinary sepsis (p = 0.005) were globally associated with an increased risk of thrombocytopenia within the first 24 hours following the onset of septic shock. Survival at day 28 estimated by the Kaplan-Meier method was lower in patients with thrombocytopenia and decreased with thrombocytopenia severity. By multivariate Cox regression, a platelet count of less than or equal to 100,000/mm(3) was independently associated with a significantly increased risk of death within the 28 days following septic shock onset. The risk of death increased with the severity of thrombocytopenia (hazard ratio, 1.65; 95% CI, 1.31-2.08 for a platelet count below 50,000/mm(3) vs > 150,000/mm(3); p < 0.0001).Conclusions: This is the first study to investigate thrombocytopenia within the first 24 hours of septic shock onset as a prognostic marker of survival at day 28 in a large cohort of ICU patients. Measuring platelet count is inexpensive and easily feasible for the physician in routine practice, and thus, it could represent an easy alert system among patients in septic shock

Lipid emulsions differentially affect LPS-induced acute monocytes inflammation: in vitro effects on membrane remodeling and cell viability

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