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Abstract Background Community-acquired pneumonia (CAP) is associated with high morbidity and hospitalization rate. In infectious diseases, host genetics plays a critical role in susceptibility and immune response, and the immune pathways involved are highly dependent on the microorganism and its route of infection. Here we aimed to identify genetic risk loci for CAP using a case-control genome-wide association study (GWAS). Methods We performed a GWAS on 3,765 Spanish individuals, including 257 adult patients hospitalized with CAP and 3,508 population controls. Pneumococcal CAP was documented in 30% of patients; the remaining 70% were selected among patients with unidentified microbiological etiology. We tested 7,6 million imputed genotypes using logistic regressions. UK Biobank GWAS of bacterial pneumonia were used for results validation. Subsequently, we prioritized genes and likely causal variants based on Bayesian fine mapping and functional evidence. Imputation and association of classical HLA alleles and amino acids were also conducted. Results Six independent sentinel variants reached the genome-wide significance (p

Abstract Background Some unanswered questions persist regarding the effectiveness of corticosteroids for severe coronavirus disease 2019 (COVID-19) patients. We aimed to assess the clinical effect of corticosteroids on intensive care unit (ICU) mortality among mechanically ventilated COVID-19-associated acute respiratory distress syndrome (ARDS) patients. Methods This was a retrospective study of prospectively collected data conducted in 70 ICUs (68 Spanish, one Andorran, one Irish), including mechanically ventilated COVID-19-associated ARDS patients admitted between February 6 and September 20, 2020. Individuals who received corticosteroids for refractory shock were excluded. Patients exposed to corticosteroids at admission were matched with patients without corticosteroids through propensity score matching. Primary outcome was all-cause ICU mortality. Secondary outcomes were to compare in-hospital mortality, ventilator-free days at 28 days, respiratory superinfection and length of stay between patients with corticosteroids and those without corticosteroids. We performed survival analysis accounting for competing risks and subgroup sensitivity analysis. Results We included 1835 mechanically ventilated COVID-19-associated ARDS, of whom 1117 (60.9%) received corticosteroids. After propensity score matching, ICU mortality did not differ between patients treated with corticosteroids and untreated patients (33.8% vs. 30.9%; p = 0.28). In survival analysis, corticosteroid treatment at ICU admission was associated with short-term survival benefit (HR 0.53; 95% CI 0.39–0.72), although beyond the 17th day of admission, this effect switched and there was an increased ICU mortality (long-term HR 1.68; 95% CI 1.16–2.45). The sensitivity analysis reinforced the results. Subgroups of age

It has been previously established that total antioxidant capacity concentrations of blood on the first day of ischemic stroke could predict mortality. Therefore, our study objective was to determine whether total antioxidant capacity concentrations in the blood during the first week of a cerebral infarction could help predict mortality. We included severe and malignant middle cerebral artery infarction patients (affecting 50% or more of the territory in computed tomography and a score of nine or fewer points in the Glasgow Coma Scale). Serum total antioxidant capacity concentrations were determined on days first, fourth, and eighth of the diagnosis of a malignant middle cerebral artery infarction. Higher serum total antioxidant capacity concentrations at first (P< 0.001), fourth (P< 0.001), and eighth (P = 0.003) day were found in non-surviving patients than in surviving ones. Serum total antioxidant capacity concentrations on first, fourth and eighth day of malignant middle cerebral artery infarction had an area under curve (95% Confidence Intervals) for 30-day mortality prediction of 0.86 (0.75-0.93; P

CD39/NTPDase1 has emerged as an important molecule that contributes to maintain inflammatory and coagulatory homeostasis. Various studies have hypothesized the possible role of CD39 in COVID-19 pathophysiology since no confirmatory data shed light in this regard. Therefore, we aimed to quantify CD39 expression on COVID-19 patients exploring its association with severity clinical parameters and ICU admission, while unraveling the role of purinergic signaling on thromboinflammation in COVID-19 patients. We selected a prospective cohort of patients hospitalized due to severe COVID-19 pneumonia (n=75), a historical cohort of Influenza A pneumonia patients (n=18) and sex/age-matched healthy controls (n=30). CD39 was overexpressed in COVID-19 patients’ plasma and immune cell subsets and related to hypoxemia. Plasma soluble form of CD39 (sCD39) was related to length of hospital stay and independently associated with intensive care unit admission (adjusted odds ratio 1.04, 95%CI 1.0-1.08, p=0.038), with a net reclassification index of 0.229 (0.118-0.287; p=0.036). COVID-19 patients showed extracellular accumulation of adenosine nucleotides (ATP and ADP), resulting in systemic inflammation and pro-coagulant state, as a consequence of purinergic pathway dysregulation. Interestingly, we found that COVID-19 plasma caused platelet activation, which was successfully blocked by the P2Y12 receptor inhibitor, ticagrelor. Therefore, sCD39 is suggested as a promising biomarker for COVID-19 severity. As a conclusion, our study indicates that CD39 overexpression in COVID-19 patients could be indicating purinergic signaling dysregulation, which might be at the basis of COVID-19 thromboinflammation disorder.

Abstract Objective Higher blood malondialdehyde (biomarker of lipid peroxidation) levels in the first hours of traumatic brain injury (TBI) have been found in patients with a worst prognosis. The objective of this study was to determine whether serum malondialdehyde levels during the first week of severe TBI could be used as mortality biomarkers. This was a multicenter, prospective and observational study performed in six Spanish Intensive Care Units. We included patients with severe TBI (defined as Glasgow Coma Scale

ABSTRACT: Background: It is unclear whether the changes in critical care throughout the pandemic have improved the outcomes in coronavirus disease 2019 (COVID-19) patients admitted to the intensive care units (ICUs). Methods: We conducted a retrospective cohort study in adults with COVID-19 pneumonia admitted to 73 ICUs from Spain, Andorra and Ireland between February 2020 and March 2021. The first wave corresponded with the period from February 2020 to June 2020, whereas the second/third waves occurred from July 2020 to March 2021. The primary outcome was ICU mortality between study periods. Mortality predictors and differences in mortality between COVID-19 waves were identified using logistic regression. Findings: As of March 2021, the participating ICUs had included 3795 COVID-19 pneumonia patients, 2479 (65·3%) and 1316 (34·7%) belonging to the first and second/third waves, respectively. Illness severity scores predicting mortality were lower in the second/third waves compared with the first wave according with the Acute Physiology and Chronic Health Evaluation system (median APACHE II score 12 [IQR 9–16] vs 14 [IQR 10–19]) and the organ failure assessment score (median SOFA 4 [3–6] vs 5 [3–7], p

Abstract Objective Previously there have been found higher circulating malondialdehyde levels during the first week of ischemic stroke in patients with worst neurological functional outcome, and at moment of ischemic stroke in non-survivor patients. Thus, the aim of our study was to determine the potential role of serum malondialdehyde levels during the first week of a severe cerebral infarction to mortality prediction. Methods This study was observational, prospective, and multicenter. We included patients with a severe malignant middle cerebral artery infarction (MMCAI) defined as patients with computed tomography showing acute infarction in more than of 50% of the territory and Glasgow Coma Scale (GCS) lower than 9. We determined serum concentrations of malondialdehyde on days 1, 4 and 8 of MMCAI. Results Serum malondialdehyde concentrations at days 1 (p

Abstract Background Higher circulating levels of tissue inhibitor of matrix metalloproteinases (TIMP)-1 early after ischemic stroke have been associated with lower survival. The objectives of this study were to determine serum TIMP-1 levels during the first week of a severe cerebral infarction in surviving and non-surviving patients, and whether those levels during the first week could be used as a mortality biomarker for these patients. Methods We included patients with severe malignant middle cerebral artery infarction (MMCAI) defined as computer tomography showing ischaemic changes in more than 50% of the middle cerebral artery territory and Glasgow Coma Scale (GCS) ≤ 8. We measured serum levels of matrix metalloproteinases (MMP)-9 and TIMP-1. End-point study was 30-day mortality. Results We found higher TIMP-1 concentrations at days 1 (p

Abstract Background Apoptotic changes after cerebral hemorrhage in brain samples of humans have been found. Caspase-cleaved cytokeratin (CCCK)-18 could be detected in the bloodstream during apoptosis. Higher circulating CCCK-18 levels have been associated with 6-month mortality in patients with basal ganglia hemorrhage. The aim of our study was to determine whether there is an association between serum CCCK-18 levels and early mortality of spontaneous intracerebral hemorrhage (SIH) patients. We performed an observational, prospective and multicentre study. There were included patients with severe SIH defined as Glasgow Coma Scale (GCS) lower than 9. We determined serum CCCK-18 levels at the severe SIH diagnosis moment. Results We found that non-surviving SIH patients (n = 46) showed lower GCS, and higher serum CCCK-18 levels and APACHE-II score than survivor ones (n = 54). In ROC analysis was found that the area under the curve of serum CCCK-18 levels for 30-day mortality prediction was 90% (95% CI 82–95%; p

Abstract Background There have been found apoptotic changes in brain tissue samples from humans after cerebral ischemia. Caspase-cleaved cytokeratin (CCCK)-18 could appears in blood during apoptosis. High circulating levels of CCCK-18 have been associated with a poor prognosis in patients with cerebral process, such as traumatic brain injury and spontaneous cerebral hemorrhage. However, they have not been explored in patients with ischemic stroke. Thus, the aim of this study was to determine whether there is an association between serum CCCK-18 levels and mortality in patients with severe malignant middle cerebral artery infarction (MMCAI). Methods This was an observational, prospective and multicentre study. We included patients with severe MMCAI. We considered MMCAI as severe when Glasgow Coma Scale (GCS) was lower than 9. We measured serum CCCK-18 levels at the diagnosis moment of the severe MMCAI. Results We found that non-surviving severe MMCAI patients (n = 33) showed lower GCS and platelet count, and higher serum CCCK-18 levels than survivor ones (n = 33). We found an area under the curve (AUC) of serum CCCK-18 levels to predict 30-day mortality of 82% (95% CI = 71%–91%; p

Abstract Background Circulating levels of melatonin in patients with traumatic brain injury (TBI) have been determined in a little number of studies with small sample size (highest sample size of 37 patients) and only were reported the comparison of serum melatonin levels between TBI patients and healthy controls. As to we know, the possible association between circulating levels of melatonin levels and mortality of patients with TBI have not been explored; thus, the objective of our current study was to determine whether this association actually exists. Methods This multicenter study included 118 severe TBI (Glasgow Coma Scale

Brain dysfunction is associated with poor outcome in critically ill patients. In a post hoc analysis of the Intensive Care over Nations (ICON) database, we investigated the effect of brain dysfunction on hospital mortality in critically ill patients. Brain failure was defined as a neurological sequential organ failure assessment (nSOFA) score of 3–4, based on the assumed Glasgow Coma Scale (GCS) score. Multivariable analyses were performed to assess the independent roles of nSOFA and change in nSOFA from admission to day 3 (ΔnSOFA) for predicting hospital mortality. Data from 7192 (2096 septic and 5096 non-septic) patients were analyzed. Septic patients were more likely than non-septic patients to have brain failure on admission (434/2095 (21%) vs. 617/4665 (13%), p < 0.001) and during the ICU stay (625/2063 (30%) vs. 736/4665 (16%), p < 0.001). The presence of sepsis (RR 1.66 (1.31–2.09)), brain failure (RR 4.85 (3.33–7.07)), and both together (RR 5.61 (3.93–8.00)) were associated with an increased risk of in-hospital death, but nSOFA was not. In the 3280 (46%) patients in whom ΔnSOFA was available, sepsis (RR 2.42 (1.62–3.60)), brain function deterioration (RR 6.97 (3.71–13.08)), and the two together (RR 10.24 (5.93–17.67)) were associated with an increased risk of in-hospital death, whereas improvement in brain function was not.

Background: Procalcitonin (PCT) and C-Reactive protein (CRP) are well-established sepsis biomarkers. The association of baseline PCT levels and mortality in pneumonia remains unclear, and we still do not know whether biomarkers levels could be related to the causative microorganism (GPC, GNB). The objective of this study is to address these issues. Methods: a retrospective observational cohort study was conducted in 184 Spanish ICUs (2009–2018). Results: 1608 patients with severe influenza pneumonia with PCT and CRP available levels on admission were included, 1186 with primary viral pneumonia (PVP) and 422 with bacterial Co-infection (BC). Those with BC presented higher PCT levels (4.25 [0.6–19.5] versus 0.6 [0.2–2.3]ng/mL) and CRP (36.7 [20.23–118] versus 28.05 [13.3–109]mg/dL) as compared to PVP (p < 0.001). Deceased patients had higher PCT (ng/mL) when compared with survivors, in PVP (0.82 [0.3–2.8]) versus 0.53 [0.19–2.1], p = 0.001) and BC (6.9 [0.93–28.5] versus 3.8 [0.5–17.37], p = 0.039). However, no significant association with mortality was observed in the multivariate analysis. The PCT levels (ng/mL) were significantly higher in polymicrobial infection (8.4) and GPC (6.9) when compared with GNB (1.2) and Aspergillus (1.7). The AUC-ROC of PCT for GPC was 0.67 and 0.32 for GNB. The AUROC of CRP was 0.56 for GPC and 0.39 for GNB. Conclusions: a single PCT/CRP value at ICU admission was not associated with mortality in severe influenza pneumonia. None of the biomarkers have enough discriminatory power to be used for predicting the causative microorganism of the co-infection.

Background: Meta-analysis has found that high baseline red blood cell distribution width (RDW) is associated with increased long-term mortality (mortality at one year or more) in ischemic stroke. The objectives of this study were to determine whether there is an association between RDW and 30-day mortality, and to explore whether RDW during the first week of ischemic stroke could be a 30-day mortality biomarker. Methods: We included patients with malignant middle cerebral artery infarction (MMCAI). RDW at days 1, 4, and 8 of MMCAI were determined. The end-point study was 30-day mortality. Results: We found that survivor (n = 37) in respect to non-survivor patients (n = 37) had lower RDW at days 1 (p < 0.001), 4 (p < 0.001), and 8 (p = 0.02). The area under curve (95% CI) for prediction of 30-day mortality by RDW at days 1, 4, and 8 of MMCAI were 0.80 (0.69−0.89; p < 0.001), 0.79 (0.66−0.89; p < 0.001), and 0.73 (0.58−0.84; p = 0.02). Regression analysis showed an association between RDW (odds ratio = 1.695; 95% CI = 1.230−2.335; p < 0.001) and 30-day mortality. Conclusions: The association between RDW and early mortality, and the potential role of RDW during the first week of MMCAI as a prognostic biomarker of early mortality were the main novelties of our study.

Objective: Oxidation is involved in secondary brain injury after traumatic brain injury (TBI). Increased concentrations of total antioxidant capacity (TAC) in blood at the time of admission for TBI have been found in non-surviving patients. The main objective of this study was to determine the role of serum TAC levels at any time during the first week of TBI for the prediction of early mortality. Methods: Isolated (p < 0.001), 4 (p < 0.001), and 8 (p = 0.002) of TBI were found in non-surviving (n = 34) than in surviving patients (n = 90). The area under curve (95% Confidence Interval) for prediction of 30-day mortality by serum TAC concentrations at days 1, 4, and 8 of TBI were 0.79 (0.71−0.86; p < 0.001), 0.87 (0.79−0.93; p < 0.001), and 0.76 (0.67−0.84; p = 0.006) respectively. Conclusions: The novelty of our study was the ability to predict 30-day mortality by serum TAC concentrations at any time during the first week of TBI.

Objective: Caspase-cleaved cytokeratin (CCCK)-18 could appear in blood during apoptosis. In two different studies, on day 1 of cerebral infarction and at 72 hours of cerebral infarction, respectively, higher circulating CCCK-18 levels were found in non-surviving than in surviving patients. The objective of this study was to analyze the ability of these levels to predict mortality at any time during the first week of cerebral infarction. Methods: Patients with malignant middle cerebral artery infarction (MMCAI) were included and the diagnosis criteria were the presence, observed in a computed tomography, of an acute cerebral infarction in at least 50% of this territory and midline shift, and an acute neurological deterioration with a Glasgow Coma Scale ≤ 8. Serum CCCK-18 levels at days 1, 4 and 8 of MMCAI were determined. Results: Serum concentrations of CCCK-18 at days 1, 4 and 8 of MMCAI were higher in non-surviving (n = 34) than in surviving patients (n = 34). Serum CCCK-18 concentrations at days 1, 4 and 8 of MMCAI had an area under curve (95% CI) used to predict a 30-day mortality of 0.83 (0.72­−0.91; p < 0.001), 0.78 (0.65−0.89; p < 0.001) and 0.82 (0.68−0.92; p < 0.001). Conclusions: The novel finding is that serum levels of CCCK-18 levels at any time after the first week of MMCAI could help predict 30-day mortality.

This study aimed to describe real-life microbiological testing of adults hospitalised with community-acquired pneumonia (CAP) and to assess concordance with the 2007 Infectious Diseases Society of America (IDSA)/American Thoracic Society (ATS) and 2011 European Respiratory Society (ERS) CAP guidelines. This was a cohort study based on the Global Initiative for Methicillin-resistant Staphylococcus aureus Pneumonia (GLIMP) database, which contains point-prevalence data on adults hospitalised with CAP across 54 countries during 2015. In total, 3702 patients were included. Testing was performed in 3217 patients, and included blood culture (71.1%), sputum culture (61.8%), Legionella urinary antigen test (30.1%), pneumococcal urinary antigen test (30.0%), viral testing (14.9%), acute-phase serology (8.8%), bronchoalveolar lavage culture (8.4%) and pleural fluid culture (3.2%). A pathogen was detected in 1173 (36.5%) patients. Testing attitudes varied significantly according to geography and disease severity. Testing was concordant with IDSA/ATS and ERS guidelines in 16.7% and 23.9% of patients, respectively. IDSA/ATS concordance was higher in Europe than in North America (21.5% versus 9.8%; p

Objectives Lower serum melatonin levels are found in patients with ischaemic stroke compared with healthy controls. This study aimed to determine whether serum melatonin levels are associated with peroxidation status, antioxidant status, and mortality in patients with ischaemic stroke. Methods Patients with severe malignant middle cerebral artery infarction (MMCAI), defined as a Glasgow coma scale (GCS) score lower than 9, were included. Serum levels of melatonin, malondialdehyde (to assess lipid peroxidation), and total antioxidant capacity at the time of diagnosing MMCAI were determined. We chose 30-day mortality as the endpoint of the study. Results We found significantly higher serum levels of melatonin, total antioxidant capacity, and malondialdehyde in non-survivors (n = 32) than in survivors (n = 32) with MMCAI. Serum melatonin levels were associated with 30-day mortality (odds ratio = 2.205; 95% confidence interval = 1.294–3.759) after controlling for GCS score and age. We found a positive association between serum melatonin levels and total antioxidant capacity (rho = 0.36), and between serum melatonin and malondialdehyde levels (rho = 0.35). Conclusions Our study shows that serum melatonin levels are associated with peroxidation status, antioxidant status, and mortality in patients with MMCAI.

Objective: Providing melatonin in animal models with spontaneous intracerebral hemorrhage (SIH) has been associated with beneficial effects. However, to our knowledge, there are no published data on circulating melatonin levels regarding the prognosis of SIH patients. Therefore, the objectives of this study were to determine whether serum melatonin levels in SIH patients were associated with early mortality and whether they could be used as prognostic biomarkers. Methods: This observational and prospective study included patients with supratentorial and clinically severe SIH (defined as Glasgow Coma Scale GCS Results: Non-surviving patients (n = 46) showed higher serum melatonin levels (p < 0.001) than surviving (n = 54) patients. An area under the curve was found for the prediction of 30-day mortality by serum melatonin levels of 0.89 (95% CI = 0.81−0.94; p < 0.001). Multiple logistic regression analysis showed an association of serum melatonin levels with 30-day mortality (Odds Ratio = 8.16; 95% CI = 2.30−28.95; p = 0.001) after controlling for midline shift, glycemia, early evacuation of SIH, and Intracerebral hemorrhage (ICH) score. Conclusions: The novel findings by our study were the presence of higher serum melatonin levels in non-surviving patients than in surviving patients and the association of these levels with mortality.

Objective: Apoptosis increases in traumatic brain injury (TBI). Caspase-cleaved cytokeratin (CCCK)-18 in blood during apoptosis could appear. At the time of admission due to TBI, higher blood CCCK-18 levels were found in non-surviving than in surviving patients. Therefore, the objective of our study was to analyze whether serum CCCK-18 levels determined during the first week after TBI could predict early mortality (at 30 days). Methods: Severe TBI patients were included (considering severe when Glasgow Coma Scale < 9) in this observational and multicentre study. Serum CCCK-18 levels were determined at day 1 of TBI, and at days 4 and 8 after TBI. Results: Serum CCCK-18 levels at day 1 of TBI, and in the days 4 and 8 after TBI were higher (p < 0.001) in non-surviving than in surviving patients (34 and 90 patients, respectively) and could predict early mortality (p < 0.001 in the area under the curve). Conclusions: The new findings from our study were that serum CCCK-18 levels at any moment of the first week of TBI were higher in non-surviving patients and were able to predict early mortality.

ObjectiveTwo 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.MethodsAn 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.ResultsWe 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; pConclusionsThe 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.

ObjectiveMalondialdehyde (MDA) is an end-product formed during lipid peroxidation, due to degradation of cellular membrane phospholipids. MDA is released into extracellular space and finally into the blood; it has been used as an effective biomarker of lipid oxidation. High circulating levels of MDA have been previously described in patients with ischemic stoke than in controls, and an association between circulating MDA levels and neurological functional outcome in patients with ischemic stoke. However, an association between serum MDA levels and mortality in patients with ischemic stroke has not been previously reported, and that was the objective of this study.MethodsObservational, prospective and multicenter study performed in six Intensive Care Units. We included patients with severe malignant middle cerebral artery infarction (MMCAI) defined as Glasgow Coma Scale (GCS) lower than 9. We measured serum MDA levels in 50 patients with severe MMCAI at the time of diagnosis and in 100 healthy subjects. Mortality at 30 days was the end point of the study.ResultsWe found that patients with severe MMCAI showed higher serum MDA levels than healthy subjects (p2.27 nmol/mL were associated with 30-day mortality (OR=7.23; 95% CI=1.84-28.73; p=0.005) controlling for GCS and age on multiple binomial logistic regression analysis.ConclusionsTo our knowledge, this is the first study showing that serum malondialdehyde levels in patients with MMCAI are associated with early mortality.

There have been found apoptotic changes in brain tissue samples from animals and humans after a traumatic brain injury (TBI). The protein cytokeratin 18 (CK-18), present in epithelial cells, is cleaved by the action of caspases during apoptosis, and the resulting fragments are released into the blood as caspase-cleaved CK (CCCK)-18. Circulating levels of CCCK-18, as biomarker of apoptosis, have been determined in patients with different processes; however, it has not been explored in TBI patients. Thus, the objective of this study was to determine whether there is an association between serum CCCK-18 levels and mortality and whether such levels could be used as a biomarker to predict outcomes in TBI patients.A prospective, observational, multicenter study carried out in six Spanish Intensive Care Units. We included patients with severe TBI defined as Glasgow Coma Scale (GCS) lower than 9; and were excluded those patients with Injury Severity Score (ISS) in non-cranial aspects higher than 9. We measured serum CCCK-18 levels at admission. The end-point of the study was 30-day mortality.Surviving patients (n = 73) showed lower serum CCCK-18 levels (P = 0.003) than non-survivors (n = 27). On ROC analysis, the area under the curve (AUC) for serum CCCK-18 levels as predictor of 30-day mortality was 0.69 (95% CI = 0.59-0.78; P = 0.006). We found in survival analysis that patients with serum CCCK-18 higher than 201 u/L had higher 30-day mortality than patients with lower levels (Hazard ratio = 3.9; 95% CI = 1.81-8.34; P

ObjectiveMatrix metalloproteinases (MMPs) and tissue inhibitors of matrix metalloproteinases (TIMPs) play a role in neuroinflammation after brain trauma injury (TBI). Previous studies with small sample size have reported higher circulating MMP-2 and MMP-9 levels in patients with TBI, but no association between those levels and mortality. Thus, the aim of this study was to determine whether serum TIMP-1 and MMP-9 levels are associated with mortality in patients with severe TBI.MethodsThis was a multicenter, observational and prospective study carried out in six Spanish Intensive Care Units. Patients with severe TBI defined as Glasgow Coma Scale (GCS) lower than 9 were included, while those with Injury Severity Score (ISS) in non-cranial aspects higher than 9 were excluded. Serum levels of TIMP-1, MMP-9 and tumor necrosis factor (TNF)-alpha, and plasma levels of tissue factor (TF) and plasminogen activator inhibitor (PAI)-1 plasma were measured in 100 patients with severe TBI at admission. Endpoint was 30-day mortality.ResultsNon-surviving TBI patients (n = 27) showed higher serum TIMP-1 levels than survivor ones (n = 73). We did not find differences in MMP-9 serum levels. Logistic regression analysis showed that serum TIMP-1 levels were associated 30-day mortality (OR = 1.01; 95% CI = 1.001-1.013; P = 0.03). Survival analysis showed that patients with serum TIMP-1 higher than 220 ng/mL presented increased 30-day mortality than patients with lower levels (Chi-square = 5.50; P = 0.02). The area under the curve (AUC) for TIMP-1 as predictor of 30-day mortality was 0.73 (95% CI = 0.624-0.844; PConclusionsThe most relevant and new findings of our study, the largest series reporting data on TIMP-1 and MMP-9 levels in patients with severe TBI, were that serum TIMP-1 levels were associated with TBI mortality and could be used as a prognostic biomarker of mortality in TBI patients.

ObjectiveHigher circulating levels of tissue inhibitor of matrix metalloproteinases (TIMP)-1 at the time of severe sepsis diagnosis have been reported in nonsurviving than in surviving patients. However, the following questions remain unanswered: 1) Does TIMP-1/MMP-9 ratio differ throughout the first week of intensive care between surviving and non-surviving patients? 2) Is there an association between TIMP-1/MMP-9 ratio and sepsis severity and mortality during such period? 3) Could TIMP-1/MMP-9 ratio during the first week be used as an early biomarker of sepsis outcome? 4) Is there an association between TIMP-1/MMP-9 ratio and coagulation state and circulating cytokine levels during the first week of intensive care in these patients? The present study sought to answer these questions.MethodsMulticenter, observational and prospective study carried out in six Spanish Intensive Care Units (ICUs) of 295 patients with severe sepsis. Were measured circulating levels of TIMP-1, MMP-9, tumour necrosis factor (TNF)-alpha, interleukin (IL)-10 and plasminogen activator inhibitor (PAI)-1 at day 1, 4 and 8. End-point was 30-day mortality.ResultsWe found higher TIMP-1/MMP-9 ratio during the first week in non-surviving (n = 98) than in surviving patients (n = 197) (pConclusionsThe novel findings of our study were that non-surviving septic patients showed persistently higher TIMP-1/MMP-9 ratio than survivors ones during the first week, which was associated with severity, coagulation state, circulating cytokine levels and mortality; thus representing a new biomarker of sepsis outcome.

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.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.Non-surviving patients (n = 80) showed higher serum CCCK-18 levels (P391 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

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

OBJECTIVE: The oxidant/antioxidant state in septic patients has only been studied in small series. We wished to determine whether malondialdehyde (MDA) serum levels were associated with severity and 30-day mortality in a large series of patients with sepsis. METHODS: We performed an observational, prospective, multicenter study in six Spanish Intensive Care Units. Serum levels of MDA were measured in a total of 228 patients (145 survivors and 83 non-survivors) with severe sepsis and 100 healthy controls. RESULTS: Serum levels of MDA were higher in severe septic patients than in healthy controls. Non-surviving septic patients had higher MDA values than survivors. MDA serum levels were associated with severity markers (lactic acid, SOFA, APACHE-II) and coagulation indices. Regression analysis showed that MDA serum levels were associated with 30-day survival (Hazard ratio = 1.05; 95% confidence interval = 1.009-1.091; p = 0.016). Receiver operating characteristic analysis showed that the area under curve of MDA serum levels to predict 30-day survival was 0.62 (95% CI = 0.56-0.69; P = 0.002). The risk of death in septic patients with MDA serum levels above 4.11 nmol/mL was higher than in patients with lower values (Hazard Ratio = 2.43; 95% CI = 1.49-3.94; p

OBJECTIVE: In a previous cohort study (n=96), we found an association between mitochondrial (mt) DNA haplogroup JT and increased survival of severe septic patients, after controlling for age and serum lactic acid levels. The aim of this research was to increase the predictive accuracy and to control for more confounder variables in a larger cohort (n=196) of severe septic patients, to confirm whether mtDNA haplogroup JT influences short and medium-term survival in these patients. METHODS: We conducted a prospective, multicenter, observational study in six Spanish Intensive Care Units. We determined 30-day and 6-month survival and mtDNA haplogroup in this second cohort of 196 patients and in the global cohort (first and second cohorts combined) with 292 severe septic patients. Multiple logistic regression and Cox regression analyses were used to test for the association of mtDNA haplogroups JT with survival at 30-days and 6-months, controlling for age, sex, serum interleukin-6 levels and SOFA score. RESULTS: Logistic and Cox regression analyses showed no differences in 30-day and 6-month survival between patients with mtDNA haplogroup JT and other haplogroups in the first cohort (n=96). In the second cohort (n=196), these analyses showed a trend to higher 30-day and 6-month survival in those with haplogroup JT. In the global cohort (n=292), logistic and Cox regression analyses showed higher 30-day and 6-month survival for haplogroup JT. There were no significant differences between J and T sub-haplogroups in 30-day and 6-month survival. CONCLUSIONS: The global cohort study (first and second cohorts combined), the largest to date reporting on mtDNA haplogroups in septic patients, confirmed that haplogroup JT patients showed increased 30-day and 6-month survival. This finding may be due to single nucleotide polymorphism defining the whole haplogroup JT and not separately for J or T sub-haplogroups.