Higher serum caspase-cleaved cytokeratin-18 levels during the first week of sepsis diagnosis in non-survivor patients.

BACKGROUND: Caspase-cleaved cytokeratin (CCCK)-18 is a protein released into the blood during apoptosis. Higher circulating CCCK-18 concentrations have been found in non-survivor than in survivor septic patients at moment of sepsis diagnosis. The following questions arise now: (1) How are serum CCCK-18 levels during the first week of sepsis? (2) Is there an association between sepsis severity and mortality and serum CCCK-18 levels during the first week? The aims of this study were to answer these questions. METHODS: Multicenter study with 321 severe septic patients from eight Spanish intensive care units. We determined serum concentration of CCCK-18, tumor necrosis factor (TNF)-α, and interleukin (IL)-10 during the first week. Our end-point study was 30-day mortality. RESULTS: Non-survivor (n=108) compared to survivor patients (n=213) showed higher serum CCCK-18 levels at days 1, 4 and 8 (p<0.001). ROC curve analyses showed that serum CCCK-18 levels at days 1 (AUC=0.77; 95% CI=0.72-0.82), 4 (AUC=0.81; 95% CI=0.76-0.85) and 8 (AUC=0.83; 95% CI=0.78-0.88) could predict mortality at 30 days (p<0.001). Logistic regression analyses showed that serum CCCK-18 levels at days 1 (OR=4.367; 95% CI=2.491-7.659), 4 (OR=10.137; 95% CI=4.741-21.678) and 8 (OR=8.781; 95% CI=3.626-21.268) were associated with 30-day mortality (p<0.001). We found a positive correlation between CCCK-18, SOFA, and lactic acid at days 1, 4 and 8. CONCLUSIONS: Non-survivor septic patients showed persistently during the first week higher serum CCCK-18 levels than survivor patients, and there is an association between sepsis severity and mortality and serum CCCK-18 levels during the first week.

Sustained Low Serum Substance P Levels in Non-Surviving Septic Patients.

Previously, researchers found higher serum substance P (SP) concentrations in survivors of severe sepsis than in non-survivors at the time of severe sepsis diagnosis. The objectives of our current study were to determine whether there is an association between serum SP levels during the first week and sepsis mortality, sepsis severity, serum levels of tumor necrosis factor (TNF)-α and interleukin (IL)-10, and whether serum SP levels during the first week could be used as a biomarker of sepsis mortality. We determined serum concentration of SP, TNF-α, and IL-10 at days 1, 4, and 8. The end-point of the study was mortality at 30 days. We found that non-survivor (n = 104) compared to survivor patients (n = 206) showed lower serum SP levels at days 1, 4, and 8 (p < 0.001). Multiple logistic regression analyses showed an association between 30-day mortality and serum SP levels at days 1, 4, and 8 (p < 0.001) controlling for SOFA score, diabetes mellitus, age, and lactic acid levels. The most interesting findings of our study were that there is an association between serum SP levels during the first week and sepsis mortality, and that serum SP levels during the first week could be used as a biomarker of sepsis mortality.

Association between Interleukin-6 Promoter Polymorphism (-174 G/C), Serum Interleukin-6 Levels and Mortality in Severe Septic Patients.

The association between interleukin (IL)-6 promoter polymorphism (-174 G/C), circulating IL-6 levels and mortality in septic patients has scarcely been addressed, and then only in studies of small sample size, and a direct association among them has not been previously reported. Therefore, the purpose of our study was to determine whether this association exists. An observational, prospective and multicenter study including severe septic patients was undertaken and serum IL-6 levels at severe sepsis diagnosis and IL-6 promoter polymorphism (-174 G/C) were determined. The end-point of the study was 30-day mortality. The study included 263 patients with the following genotypes of IL-6 promoter polymorphism (-174 G/C): 123 (46.8%) GG, 110 (41.8%) GC and 30 (11.4%) CC. CC homozygous patients showed lower sepsis-related organ failure assessment (SOFA) score, serum IL-6 levels and mortality at 30 days compared to those with other genotypes (GC or GG). On regression analysis, CC homozygous patients showed lower 30-day mortality than those with genotype GG (odds ratio = 0.21; 95% CI = 0.053-0.838; p = 0.03) or GC (hazard ratio = 0.28; 95% CI = 0.074-1.037; p = 0.06). The most important results of our study were that CC might be a favorable genotype in septic patients showing lower serum IL-6 levels and lower risk of death within 30 days.

Higher platelet cytochrome oxidase specific activity in surviving than in non-surviving septic patients.

INTRODUCTION: In a previous study with 96 septic patients, we found that circulating platelets in 6-months surviving septic patients showed higher activity and quantity of cytochrome c oxidase (COX) normalized by citrate synthase (CS) activity at moment of severe sepsis diagnosis than non-surviving septic patients. The objective of this study was to estimate whether COX specific activity during the first week predicts 1-month sepsis survival in a larger cohort of patients. METHODS: Using a prospective, multicenter, observational study carried out in six Spanish intensive care units with 198 severe septic patients, we determined COX activity per proteins (COXact/Prot) in circulating platelets at day 1, 4 and 8 of the severe sepsis diagnosis. Endpoints were 1-month and 6-months mortality. RESULTS: Survivor patients (n = 130) showed higher COXact/Prot (P < 0.001) than non-survivors (n = 68) at day 1, 4 and 8 of severe sepsis diagnosis. More than a half of the 6-months survivor patients showed an increase in their COXact/Prot from day 1 to 8. However, most of the 1-month non-survivors exhibited a decrease in their COXact/Prot from day 1 to 8. Multiple logistic regression analyses showed that of platelet COXact/Prot > 0.30 mOD/min/mg at day 1 (P = 0.002), 4 (P = 0.006) and 8 (P = 0.02) was associated independently with 1-month mortality. Area under the curve of COXact/Prot at day 1, 4 and 8 to predict 30-day survival were 0.70 (95% CI = 0.63-0.76; P < 0.001), 0.71 (95% CI = 0.64-0.77; P < 0.001) and 0.71 (95% CI = 0.64-0.78; P < 0.001), respectively. CONCLUSIONS: The new findings of our study, to our knowledge the largest series reporting data about mitochondrial function during follow-up in septic patients, were that septic patients that survive 1-month have a higher platelet cytochrome oxidase activity at moment of sepsis diagnosis and during the first week than non-survivors, and that platelet cytochrome oxidase activity at moment of sepsis diagnosis and during the first week could be used as biomarker to predict the clinical outcome in septic patients.

Sustained high serum malondialdehyde levels are associated with severity and mortality in septic patients.

INTRODUCTION: There is a hyperoxidative state in sepsis. The objective of this study was to determine serum malondialdehyde (MDA) levels during the first week of follow up, whether such levels are associated with severity during the first week and whether non-surviving patients showed higher MDA levels than survivors during the first week. METHODS: We performed an observational, prospective, multicenter study in six Spanish Intensive Care Units. Serum levels of MDA were measured in 328 patients (215 survivors and 113 non-survivors) with severe sepsis at days one, four and eight of diagnosis, and in 100 healthy controls. The primary endpoint was 30-day mortality and the secondary endpoint was six -month mortality. The association between continuous variables was carried out using Spearman's rank correlation coefficient. Cox regression analysis was applied to determine the independent contribution of serum MDA levels on the prediction of 30-day and 6-month mortality. Hazard ratio (HR) and 95% confidence intervals (CI) were calculated as measures of the clinical impact of the predictor variables. RESULTS: We found higher serum MDA in septic patients at day one (p < 0.001), day four (p < 0.001) and day eight (p < 0.001) of diagnosis than in healthy controls. Serum MDA was lower in surviving than non-surviving septic patients at day one (p < 0.001), day four (p < 0.001) and day eight (p < 0.001). Serum MDA levels were positively correlated with lactic acid and SOFA during the first week. Finally, serum MDA levels were associated with 30-day mortality (HR = 1.05; 95% CI = 1.02-1.09; p = 0.005) and six-month mortality (hazard ratio (HR) = 1.05; 95% CI = 1.02-1.09; p = 0.003) after controlling for lactic acid levels, acute physiology and chronic health evaluation (APACHE)-II, diabetes mellitus, bloodstream infection and chronic renal failure. CONCLUSIONS: To our knowledge, this is the largest series providing data on the oxidative state in septic patients to date. The novel finding is that high serum MDA levels sustained throughout the first week of follow up were associated with severity and mortality in septic patients.

The 372 T/C genetic polymorphism of TIMP-1 is associated with serum levels of TIMP-1 and survival in patients with severe sepsis.

INTRODUCTION: Previous studies have found higher circulating levels of tissue inhibitor of matrix metalloproteinase (TIMP)-1 in nonsurviving septic patients than in surviving septic patients, and an association between the 372 T/C genetic polymorphism of TIMP-1 and the risk of developing certain diseases. However, the relationship between genetic polymorphisms of TIMP-1, circulating TIMP-1 levels and survival in patients with severe sepsis has not been examined, and this was the objective of the study. METHODS: This multicentre, prospective, observational study was carried out in six Spanish ICUs. We determined the 372 T/C genetic polymorphism of TIMP-1 (rs4898), serum levels of TIMP-1, matrix metalloproteinase (MMP)-9, MMP-10, TNFα, IL-10 and plasma plasminogen activator inhibitor-1 (PAI-1). Survival at 30 days from ICU admission was the endpoint assessed. The association between continuous variables was carried out using Spearman's rank correlation coefficient or Spearman's rho coefficient. Multivariate logistic regression analysis was applied to determine the association between the 372 T/C genetic polymorphism and survival 30 days from ICU admission. RESULTS: Of 275 patients with severe sepsis, 80 had genotype CC, 55 had genotype CT and 140 had genotype TT of the 372 T/C genetic polymorphism of TIMP-1. Patients with the T allele showed higher serum levels of TIMP-1 than patients without the T allele (P=0.004). Multiple logistic regression analysis showed that the T allele was associated with higher mortality at 30 days (odds ratio=2.08; 95% confidence interval=1.06 to 4.09; P=0.03). Survival analysis showed that patients with the T allele presented lower 30-day survival than patients without the T allele (χ2=5.77; P=0.016). We found an association between TIMP-1 levels and levels of MMP-9 (ρ=-0.19; P=0.002), MMP-10 (ρ=0.55; P<0.001), TNFα (ρ=0.56; P<0.001), IL-10 (ρ=0.48; P<0.001) and PAI-1 (ρ=0.49; P<0.001). CONCLUSION: The novel findings of our study are that septic patients with the T allele in the 372 T/C genetic polymorphism of TIMP-1 showed higher serum TIMP-1 levels and lower survival rate. The determination of the 372 T/C genetic polymorphism of TIMP-1 thus has prognostic implications and could help in the selection of patients who may benefit from modulation of the MMP/TIMP balance.

Survival and mitochondrial function in septic patients according to mitochondrial DNA haplogroup.

INTRODUCTION: We recently found that platelet cytochrome c oxidase (COX) activities and quantities in 6-month-survival septic patients are significantly higher than those of patients who died before 6 months. Other studies suggested that the mitochondrial DNA (mtDNA) genotype could play a major role in sepsis survival. Given that COX catalytic subunits are encoded by mtDNA, the objective of the present study was to explore whether mtDNA population genetic variation could affect COX activity and quantity and favors sepsis survival. METHODS: A prospective, multicenter, observational study was carried out in six Spanish ICUs. We included 96 patients with severe sepsis. We determined the mtDNA haplogroup, the COX specific activity/citrate synthase specific activity (COXa/CSa) ratio and the COX quantity/citrate synthase specific activity (COXq/CSa) ratio in circulating platelets at the time of diagnosis, day 4 and day 8. We used survival at 1 and 6 months as endpoints. RESULTS: Patients with the JT mtDNA haplogroup (n=15) showed higher COXq/CSa ratio at day 4 (P=0.04) and day 8 (P=0.02) than those with other haplogroups (n=81). Logistic regression analysis showed that the JT mtDNA haplogroup (odds ratio=0.18; 95% confidence interval=0.04 to 0.94; P=0.04) and COXq/CSa ratio (odds ratio=0.53; 95% confidence interval=0.30 to 0.93; P=0.03) were associated with 1-month survival after controlling for age and lactic acid levels. CONCLUSIONS: The novel findings of our study are that 1-month surviving septic patients showed higher COXq/CSa ratio than nonsurviving individuals, that patients from the JT mtDNA haplogroup showed a higher COXq/CSa ratio and that JT patients had a higher 1-month survival than patients from other mtDNA haplogroups.

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.

Genetic aspects of the oxidative phosphorylation dysfunction in dilated cardiomyopathy.

Dilated cardiomyopathy is a frequent and extremely heterogeneous medical condition. Deficits in the oxidative phosphorylation system have been described in patients suffering from dilated cardiomyopathy. Hence, mutations in proteins related to this biochemical pathway could be etiological factors for some of these patients. Here, we review the clinical phenotypes of patients harboring pathological mutations in genes related to the oxidative phosphorylation system, either encoded in the mitochondrial or in the nuclear genome, presenting with dilated cardiomyopathy. In addition to the clinical heterogeneity of these patients, the large genetic heterogeneity has contributed to an improper allocation of pathogenicity for many candidate mutations. We suggest criteria to avoid incorrect assignment of pathogenicity to newly found mutations and discuss possible therapies targeting the oxidative phosphorylation function.

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.

Association between DNA and RNA oxidative damage and mortality in septic patients.

PURPOSE: DNA and RNA oxidative damage occurs during sepsis. Higher urinary 8-hydroxy-2'-deoxyguanosine (8-OHdG) levels (from oxidation of guanosine from DNA) have been found in non-surviving patients than in surviving septic patients. However, the relation between DNA and RNA oxidative damage and mortality in septic patients has never been published; thus, the objective of this study was to determine the existence of this association. METHODS: This prospective and observational study including septic patients was conducted in 8 Spanish Intensive Care Units. Serum concentrations of the three oxidizied guanine species (OGS) (8-OHdG from DNA, 8-hydroxyguanosine from RNA, and 8-hydroxyguanine from DNA or RNA) were determined, and malondialdehyde (to estimate lipid peroxidation) in the diagnosis of sepsis. Mortality at 30 days was the end-point study. RESULTS: Non-surviving patients (n = 78) compared to surviving patients (n = 139) showed higher serum concentrations of OGS (p = .004) and malondialdehyde (p < .001). Simultaneously, an association between serum OGS concentrations and mortality in logistic regression analysis was found (OR = 1.105; 95% CI = 1.024-1.193; p = .01), and a positive correlation between serum levels of OGS and malondialdehyde (rho = 0.21; p = .002). CONCLUSIONS: The new findings from our study were that oxidative DNA and RNA damage in septic patients was associated with mortality and lipid peroxidation.

Serum total antioxidant capacity during the first week of sepsis and mortality.

PURPOSE: Higher circulating total antioxidant capacity (TAC) concentrations have been found in non-survivor than in survivor septic patients at moment of sepsis diagnosis. The objectives of this study were to determine whether serum TAC levels during the first week of sepsis are associated with lipid peroxidation, sepsis severity, and sepsis mortality, and whether could be used as a prognostic biomarker. METHODS: This prospective and observational study with 319 septic patients admitted to Intensive Care Units was carried out in 8 Spanish hospitals. We determined serum concentrations of malondialdehyde (to estimate lipid peroxidation) and TAC at days 1, 4 and 8 of sepsis. Mortality at 30 days was the end-point study. RESULTS: We found that serum TAC concentrations at days 1, 4 and 8 could predict 30-day mortality according to ROC curve analyses (p < 0.001), that were associated with 30-day mortality according to regression analyses (p < 0.001), and that were associated with serum levels of malondialdehyde and SOFA score. CONCLUSIONS: The new findings of our study were that serum TAC levels during the first week of sepsis are associated with lipid peroxidation, sepsis severity, and sepsis mortality, and that could be used as a prognostic biomarker.

Lower mitochondrial dysfunction in survivor septic patients with mitochondrial DNA haplogroup JT.

OBJECTIVE: The comparison on mitochondrial function between severe septic patients and healthy control subjects according to mitochondrial deoxyribonucleic acid (mtDNA) haplogroup has not been previously reported; and this was the objective of the current study. METHODS: Prospective, multicenter, observational study. We obtained blood samples from 198 severe septic patients at days 1, 4 and 8 of severe sepsis diagnosis and from 96 sex- and age-matched healthy controls to determine mtDNA haplogroup and platelet respiratory complex IV (CIV) specific activity. The endpoint of the study was 30-day mortality. RESULTS: We included 198 severe septic patients (38 with mtDNA haplogroup JT and 160 with mtDNA haplogroup non-JT) and 96 healthy control subjects (16 with mtDNA haplogroup JT and 80 with mtDNA haplogroup non-JT). We have no found statistically significant differences in platelet CIV specific activity between healthy controls and survivor severe septic patients with mtDNA haplogroup JT at days 1, 4 and 8 of severe sepsis diagnosis; and the remaining severe septic patients showed lower platelet CIV specific activity than healthy controls with the same mtDNA haplogroup. CONCLUSIONS: The new finding of our study was that survivor severe septic patients and healthy controls with mtDNA haplogroup JT showed no different platelet Civ specific activity.

Serum melatonin levels during the first seven days of severe sepsis diagnosis are associated with sepsis severity and mortality.

OBJECTIVE: Higher serum melatonin levels have previously been found in patients with severe sepsis who died within 30 days of diagnosis than in survivors. The objective of our study were to determine whether serum melatonin levels during the first seven days of severe sepsis diagnosis could be associated with sepsis severity and mortality. METHODS: Multicentre study in eight Spanish Intensive Care Units which enrolled 308 patients with severe sepsis. We determined serum levels of melatonin, malondialdehyde (as biomarker of lipid peroxidation) and tumor necrosis factor-alpha at days 1, 4 and 8 of severe sepsis diagnosis. The study's primary endpoint was 30-day mortality. RESULTS: A total of 103 patients had died and 205 survived at 30 days of severe sepsis diagnosis, with the non-survivors presenting higher serum melatonin levels at days 1 (p<0.001), 4 (p<0.001) and 8 (p<0.001) of severe sepsis diagnosis than the survivor patient group. The multiple logistic regression analysis found that serum melatonin levels at days 1, 4 and 8 of severe sepsis diagnosis (p<0.001, p=0.01 and p=0.001, respectively) were associated with mortality adjusted for age, serum lactic acid, SOFA score and diabetes mellitus. CONCLUSIONS: The novel and more interesting findings of our study were that serum melatonin levels during the first seven days of severe sepsis diagnosis are associated with sepsis severity and mortality.

Non-survivor septic patients have persistently higher serum sCD40L levels than survivors.

INTRODUCTION: Soluble CD40 ligand (sCD40L) is a protein with proinflammatory and prothrombotic effects. Previously we found higher circulating sCD40L levels in non-survivor than in survivor patients at sepsis diagnosis. Now some questions arise such as how are serum sCD40L levels during the first week of severe sepsis?, is there an association between serum sCD40L levels during the first week and mortality?, and serum sCD40L levels during the first week could be used as sepsis mortality biomarker?. This study was developed to answer these asks. METHODS: Study from 6 Spanish Intensive Care Units with 291 severe septic patients. There were determined serum levels of sCD40L and tumor necrosis factor (TNF)-alpha during the first week. The end-point study was 30-day mortality. RESULTS: We found that serum sCD40L at days 1, 4, and 8 could predict mortality at 30days, and are associated with mortality. CONCLUSIONS: The novel findings of our study were that there were higher serum sCD40L levels persistently during the first week in non-survivor than in survivor patients, that there is an association between serum sCD40L levels during the first week and sepsis mortality, and that serum sCD40L levels during the first week could be used as sepsis mortality biomarker.

Septic patients with mitochondrial DNA haplogroup JT have higher respiratory complex IV activity and survival rate.

OBJECTIVE: The influence of mitochondrial deoxyribonucleic acid (mtDNA) haplogroup or oxidative phosphorylation system (OXPHOS) function on survival of septic patients has been scarcely studied. However, the association between mtDNA haplogroup, OXPHOS capacity at diagnosis of severe sepsis, and survival has been not previously reported, and that was the objective of the present study. METHODS: This was a prospective, multicenter, observational study. Blood samples from 198 patients at diagnosis of severe sepsis were analyzed to determine mtDNA haplogroup and platelet respiratory complex IV (CIV) specific activity. The end point of the study was 30-day survival. RESULTS: Septic patients with mtDNA haplogroup JT showed higher 30-day survival than those with mtDNA haplogroup non-JT (31/38 [81.6%] vs 99/160 [61.9%]; P= .02). Septic patients with mtDNA haplogroup JT showed higher platelet CIV specific activity than those with mtDNA haplogroup non-JT (P= .002). CONCLUSIONS: The main novel finding of our study, including the largest series providing data on platelet CIV specific activity according to mtDNA haplogroup in severe septic patients, was that those with mtDNA haplogroup JT showed higher survival and higher platelet CIV specific activity at diagnosis of severe sepsis than patients with mtDNA haplogroup non-JT.

Serum caspase 3 levels are associated with early mortality in severe septic patients.

OBJECTIVE: Higher caspase 3 activity has been found in lymphocytes of septic patients than of healthy controls. However, an association between serum caspase 3 levels at moment of severe sepsis diagnosis and mortality in septic patients has not been previously demonstrated, and this was the main objective of the present study. METHODS: This is an observational study of 216 patients with severe sepsis in 6 Spanish intensive care units. We collected serum samples at moment of severe sepsis diagnosis to determine levels of caspase 3 and caspase-cleaved cytokeratin (CCCK) 18. End point was 30-day mortality. RESULTS: We found higher serum caspase 3 levels (P<.001) and caspase-cleaved cytokeratin 18 (P=.001) in nonsurvivors (n=76) than in survivors (n=140). Multiple binary logistic regression analysis showed that serum caspase 3 levels greater than 0.25 ng/mL were associated with 30-day mortality (odds ratio, 6.51; 95% confidence interval, 3.32-12.77; P<.001). Receiver operating characteristic analysis showed that the area under the curve to predict 30-day mortality for serum caspase 3 levels was 0.73 (95% confidence interval, 0.67-0.79; P<.001). CONCLUSIONS: The major novel findings of our study were that there is an association between serum caspase 3 levels at moment of severe sepsis diagnosis and mortality in septic patients and that serum caspase 3 levels could be used as prognostic biomarker, and further studies are needed to corroborate these findings.

The 4G/4G Genotype of PAI-1 Polymorphism Is Associated with Higher Plasma PAI-1 Concentrations and Mortality in Patients with Severe Sepsis.

OBJECTIVE: Two studies have reported that patients with the 4G/4G genotype of the plasminogen activator inhibitor-1 (PAI-1) genetic polymorphism had higher plasma PAI-1 concentrations and higher risk of death than those with the 4G/5G or 5G/5G genotypes; one study involved 175 children with meningococcal disease, and the other included 88 adult patients with septic shock. Thus, the objective of this study was to determine whether there is an association between carriage of the 4G/4G genotype, plasma PAI-1 concentrations and mortality in a large series of adult septic patients. METHODS: An observational, prospective, multicenter study was carried out in six Spanish Intensive Care Units including severe septic patients. We determined the PAI-1 4G/5G polymorphism and plasma PAI-1 concentrations in all patients. The end-points of the study were 30-day and 6-month mortality. RESULTS: We included a total of 260 patients, 82 (31.5%) with 4G/4G, 126 (48.5%) with 4G/5G and 52 (20.0%) with 5G/5G genotype. Multivariate logistic regression analysis showed that the 4G/4G genotype was associated with higher mortality at 30 days (Odds Ratio = 1.95; 95% CI = 1.063-3.561; p = 0.03) and at 6 months (Odds Ratio = 2.19; 95% CI = 1.221-3.934; p = 0.01), and that higher plasma PAI-1 concentrations were associated with higher mortality at 30 days (Odds Ratio = 1.01; 95% CI = 1.002-1.022; p = 0.02) at 6 months (Odds Ratio = 1.01; 95% CI = 1.003-1.023; p = 0.01). Multivariate linear regression analysis showed that increased plasma PAI-1 concentrations were associated with the PAI-1 4G/4G genotype (regression coefficient = 4.82; 95% CI = 3.227 to 6.406; p<0.001). CONCLUSIONS: The major findings of our study, to our knowledge the largest series reporting data about 4G/5G polymorphism of the PAI-1 gene, plasma PAI-1 concentrations and mortality in septic patients, were that septic patients with the 4G/4G genotype had higher plasma PAI-1 concentrations and higher risk of death than those with 4G/5G or 5G/5G genotypes.

Association between serum substance P levels and mortality in patients with severe sepsis.

BACKGROUND: Substance P (SP) is a peptide of the tachykinins family involved in the inflammatory response. Circulating SP levels have been assessed in septic patients in 2 previous studies with a small number of subjects (61 and 42 patients, respectively), and there were no significant differences in SP levels at the moment of sepsis diagnosis between surviving and nonsurviving patients. The main goal of this study was to determine a possible relationship between serum SP levels and patient outcome in the largest cohort of severe septic patients analyzed so far. METHODS: We performed an observational, prospective, multicenter study in 6 Spanish intensive care units. Serum SP levels were measured at the moment of severe sepsis diagnosis in 238 patients. The end point of the study was 30-day mortality. RESULTS: We found that surviving septic patients (n = 153) showed higher serum SP levels than did nonsurvivors (n = 85). Multiple logistic regression analysis showed that serum SP levels higher than 350 pg/mL were associated with survival at 30 days (odds ratio, 0.43; 95% confidence interval, 0.24-0.77; P = .005) after controlling for serum lactic acid levels and Sepsis-related Organ Failure Assessment score. CONCLUSIONS: The major new finding of our study was that serum SP levels were associated with mortality in severe septic patients.