Platelet cytochrome c oxidase activity and quantity in septic patients.

OBJECTIVE: The cytopathic hypoxia theory proposes that there is an impaired cellular oxygen utilization during sepsis. Respiratory complex IV, or cytochrome c oxidase, was only previously studied in muscle biopsies of 16 surviving and 12 nonsurviving septic patients. We hypothesized that higher activities and quantities of this enzyme complex could be associated with septic patient survival. The objective was to evaluate the relationship between cytochrome c oxidase activities and quantities and 6-month survival in a larger series of septic patients using a less invasive method (circulating platelets). DESIGN: Prospective, multicenter, observational study. SETTING: The study was carried out in six Spanish intensive care units. PATIENTS: We included 96 septic patients. INTERVENTIONS: We determined the cytochrome c oxidase activity per citrate synthase activity ratio and cytochrome c oxidase quantity per citrate synthase activity ratio in circulating platelets at the time of diagnosis and related them to 6-month survival. The written informed consent from the family members was obtained. MEASUREMENTS AND MAIN RESULTS: Survivor patients (n = 54) showed higher cytochrome c oxidase activity per citrate synthase activity ratio (p = .04) and cytochrome c oxidase quantity per citrate synthase activity ratio (p = .006) than nonsurvivors (n = 42). Logistic regression analyses confirmed that the cytochrome c oxidase activity per citrate synthase activity ratio (p = .04) and cytochrome c oxidase quantity per citrate synthase activity ratio (p = .02) were independent predictors of 6-month survival. The area under the curve to predict 6-month survival was 0.62 (95% confidence interval 0.51-0.74; p = .04) for the cytochrome c oxidase activity per citrate synthase activity ratio and 0.67 (95% confidence interval 0.56-0.76; p = .003) for the cytochrome c oxidase quantity per citrate synthase activity ratio. A negative correlation was found between the cytochrome c oxidase quantity per citrate synthase activity ratio and Sepsis-Related Organ Failure Assessment score (p = .04). CONCLUSIONS: Platelet cytochrome c oxidase activity and quantity were independent predictors of 6-month survival and could be used as biomarkers of sepsis mortality. This is a rapid, easy, and less invasive protocol to assess mitochondrial function. Patients with lower cytochrome c oxidase activity and quantity could benefit from drugs that improve mitochondrial function.

Association between serum soluble CD40 ligand levels and mortality in patients with severe sepsis.

INTRODUCTION: CD40 Ligand (CD40L) and its soluble counterpart (sCD40L) are proteins that exhibit prothrombotic and proinflammatory properties on binding to their cell surface receptor CD40. The results of small clinical studies suggest that sCD40L levels could play a role in sepsis; however, there are no data on the association between sCD40L levels and mortality of septic patients. Thus, the aim of this study was to determine whether circulating sCD40L levels could be a marker of adverse outcome in a large cohort of patients with severe sepsis. METHODS: This was a multicenter, observational and prospective study carried out in six Spanish intensive care units. Serum levels of sCD40L, tumour necrosis factor-alpha and interleukin-10, and plasma levels of tissue factor were measured in 186 patients with severe sepsis at the time of diagnosis. Serum sCD40L was also measured in 50 age- and sex-matched controls. Survival at 30 days was used as the endpoint. RESULTS: Circulating sCD40L levels were significantly higher in septic patients than in controls (P = 0.01), and in non-survivors (n = 62) compared to survivors (n = 124) (P = 0.04). However, the levels of CD40L were not different regarding sepsis severity. Logistic regression analysis showed that sCD40L levels >3.5 ng/mL were associated with higher mortality at 30 days (odds ratio = 2.89; 95% confidence interval = 1.37 to 6.07; P = 0.005). The area under the curve of sCD40L levels >3.5 ng/mL as predictor of mortality at 30 days was 0.58 (95% CI = 0.51 to 0.65; P = 0.03). CONCLUSIONS: In conclusion, circulating sCD40L levels are increased in septic patients and are independently associated with mortality in these patients; thus, its modulation could represent an attractive therapeutic target.

Matrix metalloproteinase-9, -10, and tissue inhibitor of matrix metalloproteinases-1 blood levels as biomarkers of severity and mortality in sepsis.

INTRODUCTION: Matrix metalloproteinases (MMPs) play a role in infectious diseases through extracellular matrix (ECM) degradation, which favors the migration of immune cells from the bloodstream to sites of inflammation. Although higher levels of MMP-9 and tissue inhibitor of matrix metalloproteinases-1 (TIMP-1) have been found in small series of patients with sepsis, MMP-10 levels have not been studied in this setting. The objective of this study was to determine the predictive value of MMP-9, MMP-10, and TIMP-1 on clinical severity and mortality in a large series of patients with severe sepsis. METHODS: This was a multicenter, observational, and prospective study carried out in six Spanish Intensive Care Units. We included 192 (125 surviving and 67 nonsurviving) patients with severe sepsis and 50 age- and sex-matched healthy controls in the study. Serum levels of MMP-9, MMP-10, TIMP-1, tumor necrosis factor (TNF)-alpha, and interleukin (IL)-10 were measured in patients with severe sepsis at the time of diagnosis and in healthy controls. RESULTS: Sepsis patients had higher levels of MMP-10 and TIMP-1, higher MMP-10/TIMP-1 ratios, and lower MMP-9/TIMP-1 ratios than did healthy controls (P < 0.001). An association was found between MMP-9, MMP-10, TIMP-1, and MMP-9/TIMP-1 ratios and parameters of sepsis severity, assessed by the SOFA score, the APACHE-II score, lactic acid, platelet count, and markers of coagulopathy. Nonsurviving sepsis patients had lower levels of MMP-9 (P = 0.037), higher levels of TIMP-1 (P < 0.001), lower MMP-9/TIMP-1 ratio (P = 0.003), higher levels of IL-10 (P < 0.001), and lower TNF-alpha/IL-10 ratio than did surviving patients. An association was found between MMP-9, MMP-10, and TIMP-1 levels, and TNF-alpha and IL-10 levels. The risk of death in sepsis patients with TIMP-1 values greater than 531 ng/ml was 80% higher than that in patients with lower values (RR = 1.80; 95% CI = 1.13 to 2.87;P = 0.01; sensitivity = 0.73; specificity = 0.45). CONCLUSIONS: The novel findings of our study on patients with severe sepsis (to our knowledge, the largest series reporting data about MMP levels in sepsis) are that reduced MMP-9/TIMP-1 ratios and increased MMP-10 levels may be of great pathophysiologic significance in terms of severity and mortality, and that TIMP-1 levels may represent a biomarker to predict the clinical outcome of patients with sepsis.