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.

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.

Lower mitochondrial dysfunction in survivor septic patients with mitochondrial DNA haplogroup JT / Menor disfunción mitocondrial en pacientes septicos supervivientes con haplogrupo JT del ADN mitocondrial

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

OBJETIVO: La comparación en la función mitocondrial entre pacientes con sepsis grave y sujetos sanos según el haplogrupo del ácido desoxirribonucleico mitocondrial (ADNmt) no se ha reportado previamente; y este fue el objetivo del estudio. MÉTODOS: Estudio prospectivo, multicéntrico y observacional. Obtuvimos muestras sanguíneas de 198 pacientes con sepsis grave en los días 1, 4 y 8 del diagnóstico de la sepsis grave y de 96 sujetos sanos para determinar el haplogrupo del ADNmt y la actividad del complejo respiratorio mitocondrial IV (CIV) en plaquetas circulantes. La variable resultado principal del estudio fue la mortalidad a los 30 días. RESULTADOS: Se incluyeron 198 pacientes con sepsis grave (38 con haplogrupo JT del ADNmt y 160 con otro haplogrupo del ADNmt) y 96 sujetos sanos (16 con haplogrupo JT del ADNmt y 80 con otro haplogrupo del ADNmt). No encontramos diferencias estadísticamente significativas en la actividad de CIV plaquetaria entre los sujetos sanos y los pacientes sépticos supervivientes con haplogrupo JT del ADNmt en los días 1, 4 y 8 del diagnóstico de la sepsis grave; y el resto de los pacientes sépticos presentaron menor actividad de CIV plaquetaria que los sujetos sanos con su mismo haplogrupo del ADNmt. CONCLUSIONES: El nuevo hallazgo de nuestro estudio fue que los pacientes sépticos y sujetos sanos con haplogrupo JT del ADNmt no tenían diferencias en la actividad de CIV plaquetaria

Serum melatonin levels during the first seven days of severe sepsis diagnosis are associated with sepsis severity and mortality / Los niveles séricos de melatonina durante los primeros 7 días del diagnóstico de la sepsis grave están asociados con la gravedad y mortalidad

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

OBJETIVO: Previamente se han encontrado mayores niveles séricos de melatonina en pacientes con sepsis grave que fallecían en los primeros 30 días del diagnóstico de la sepsis grave en comparación con los supervivientes. Los objetivos de nuestro estudio fueron determinar si los niveles séricos de melatonina durante la primera semana del diagnóstico de la sepsis grave están asociados con la gravedad y mortalidad de la sepsis. MÉTODOS: Estudio multicéntrico en 8 Unidades de Cuidados Intensivos españolas con 308 pacientes con sepsis grave. Se determinaron niveles séricos de melatonina, malondialdehído (como biomarcador de peroxidación lipídica) y factor de necrosis tumoral-alfa en los días 1, 4 y 8 del diagnóstico de la sepsis grave. Consideramos la mortalidad a 30 días como la variable resultado principal del estudio. RESULTADOS: Un total de 103 pacientes estaban fallecidos y 205 vivos a los 30 días del diagnóstico de la sepsis grave, y los fallecidos presentaron superiores niveles séricos de melatonina en los días 1 (p < 0.001), 4 (p < 0.001), y 8 (p < 0.001) del diagnóstico de la sepsis grave que los supervivientes. En el análisis de regresión logística múltiple encontramos que los niveles séricos de melatonina en los días 1, 4 y 8 del diagnóstico de la sepsis grave (p < 0.001, p = 0.01 and p = 0.001, respectively) estaban asociados con la mortalidad controlando por la edad, niveles séricos de ácido lactico, SOFA score y diabetes mellitus. CONCLUSIONES: Los nuevos y más interesantes hallazgos de nuestro estudio son que los niveles séricos de melatonina durante la primera semana del diagnóstico de la sepsis grave están asociados con la gravedad y la mortalidad de la sepsis

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.

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.

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.

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.

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.

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.

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.

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.

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.

Decrease of oxidative phosphorylation system function in severe septic patients.

OBJECTIVE: The comparison of oxidative phosphorylation system capacities between septic patients and control subjects has been scarcely analyzed and only in studies with small sample size (fewer than 40 septic patients and 40 controls). Thus, the objective of this study was to compare platelet respiratory complex IV (CIV) activity between severe septic patients and healthy individuals in a larger series (including 198 severe septic patients and 96 healthy controls). METHODS: A prospective, multicenter, observational study was carried out in 6 Spanish intensive care units. We obtained blood samples from 198 severe septic patients at day 1, 4, and 8 of the severe sepsis diagnosis and 96 sex- and age-matched healthy control individuals and determined platelet CIV-specific activity. The end point of the study was 30-day mortality. RESULTS: Control individuals showed higher platelet CIV-specific activity (P < .001) than surviving (n = 130) or nonsurviving (n = 68) severe septic patients at day 1, 4, and 8 of severe sepsis diagnosis. CONCLUSIONS: The major finding of our work, involving the largest series to date of severe septic patients with data on oxidative phosphorylation system capacity, was that surviving and nonsurviving septic patients showed lower platelet CIV-specific activity during the first week of sepsis than healthy controls.

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.

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.

Serum melatonin levels are associated with mortality in severe septic patients.

OBJECTIVE: Melatonin in septic patients has been scarcely explored and only in studies of small sample size (maximum 20 patients). Thus, the objective of this study was to determine whether serum melatonin levels are associated with severity, oxidant and inflammatory state, and mortality in a large series of septic patients. METHODS: A prospective, observational, multicenter study was performed in 6 Spanish intensive care units with 201 severe septic patients. Serum levels of melatonin were measured at moment of severe sepsis diagnosis. The end point was 30-day mortality. RESULTS: Non-surviving patients (n = 71) showed higher serum melatonin levels (P < .001) than survivors (n = 130). Multiple logistic regression analysis showed that serum melatonin levels were associated with 30-day mortality (odds ratio, 1.022; 95% confidence interval, 1.001-1.043; P = .04), controlling for serum tumor necrosis factor-α levels, serum interleukin 6 levels and age. Serum melatonin levels were positively associated with serum levels of malondialdehyde as biomarker of oxidative stress, interleukin-6 and lactate, and with SOFA score. CONCLUSIONS: The novel finding of our study was that serum melatonin levels are associated with mortality in septic patients.

Association between serum total antioxidant capacity and mortality in severe septic patients.

PURPOSE: Total antioxidant capacity (TAC) in severe septic patients has been analyzed in few studies with limited number of subjects. In addition, no association between TAC serum levels and mortality in patients with sepsis has been investigated. We aimed at assessing a possible relationship between TAC serum levels and mortality using a large cohort of patients with severe sepsis. METHODS: We performed an observational, prospective, multicenter study in 6 Spanish intensive care units. Serum levels of TAC were measured in a total of 213 patients with severe sepsis. End point was 30-day mortality. RESULTS: Nonsurviving septic patients (n = 75) showed higher serum TAC levels (P = .006) than survivors (n = 138). Cox regression analysis showed that TAC serum levels were associated with 30-day survival (hazard ratio = 1.50, 95% confidence interval = 1.16-1.94, P = .002). Receiver operating characteristic analysis showed that the area under curve of TAC serum levels to predict 30-day survival was 0.61 (95% confidence interval = 0.545-0.680, P = .04). CONCLUSIONS: The most relevant and new findings of our study, the largest cohort of septic patients providing data on circulating TAC levels so far, were that serum TAC levels are associated with mortality and could be used as biomarker to outcome prediction in severe septic patients.

Serum levels of caspase-cleaved cytokeratin-18 and mortality are associated in severe septic patients: pilot study.

OBJECTIVE: Apoptosis is increased in sepsis. Cytokeratin 18 (CK-18), a protein of the intermediate filament group present in most epithelial and parenchymal cells, is cleaved by the action of caspases and released into the blood as caspase-cleaved CK (CCCK)-18 during apoptosis. Circulating levels of CCCK-18 have scarcely been explored in septic patients. In one study with 101 severe septic patients, the authors reported higher serum CCCK-18 levels in non-survivors than in survivors; however, the sample size was too small to demonstrate an association between serum CCCK-18 levels and early mortality and whether they could be used as a biomarker to predict outcomes in septic patients. Thus, these were the objectives of this study with a large series of patients. METHODS: We performed a prospective, multicenter, observational study in six Spanish Intensive Care Units with 224 severe septic patients. Blood samples were collected at the time that severe sepsis was diagnosed to determine serum levels of CCCK-18, tumor necrosis factor (TNF)-alpha, interleukin (IL)-6 and IL-10. The end point was 30-day mortality. RESULTS: Non-surviving patients (n = 80) showed higher serum CCCK-18 levels (P<0.001) than survivors (n = 144). Multiple logistic regression analysis showed that serum CCCK-18 levels>391 u/L were associated with 30-day survival (Odds ratio = 2.687; 95% confidence interval = 1.449-4.983; P = 0.002), controlling for SOFA score, serum lactic acid levels and age. Kaplan-Meier survival analysis showed that the risk of death in septic patients with serum CCCK-18 levels >391 u/L was higher than in patients with lower values (Hazard Ratio = 3.1; 95% CI = 1.96-4.84; P<0.001). Serum CCCK-18 levels were positively associated with serum levels of IL-6 and lactic acid, and with SOFA and APACHE scores. CONCLUSIONS: The major novel finding of our study, the largest cohort of septic patients providing data on circulating CCCK-18 levels, was that serum CCCK-18 levels are associated with mortality in severe septic patients.

Red blood cell distribution width during the first week is associated with severity and mortality in septic patients.

OBJECTIVE: Higher values of red blood cell distribution width (RDW) have been found in non-surviving than in surviving septic patients. However, it is unknown whether RDW during the first week of sepsis evolution is associated with sepsis severity and early mortality, oxidative stress and inflammation states, and these were the aims of the study. METHODS: We performed a prospective, observational, multicenter study in six Spanish Intensive Care Units with 297 severe septic patients. We measured RDW, serum levels of malondialdehyde (MDA) to assess oxidative stress, and tumour necrosis factor (TNF)-α to assess inflammation at days 1, 4, and 8. The end-point was 30-day mortality. RESULTS: We found higher RDW in non-surviving (n = 104) than in surviving (n = 193) septic patients at day 1 (p = 0.001), day 4 (p = 0.001), and day 8 (p = 0.002) of ICU admission. Cox regression analyses showed that RDW at day 1 (p<0.001), 4 (p = 0.005) and 8 (p = 0.03) were associated with 30-day mortality. Receiver operating characteristic curves showed that RDW at day 1 (p<0.001), 4 (p<0.001), and 8 (p<0.001) could be used to predict 30-day mortality. RDW showed a positive correlation with serum MDA levels at day 1 and day 4, with serum TNF-α levels at days 4 and 8, and with SOFA score at days 1, 4 and 8. CONCLUSIONS: The major findings of our study were that non-surviving septic patients showed persistently higher RDW during the first week of ICU stay than survivors, that RDW during the first week was associated with sepsis severity and mortality, that RDW during the first week could be used as biomarker of outcome in septic patients, and that there was an association between RDW, serum MDA levels, and serum TNF-α levels during the first week.