María M Martín

Hospital Universitario Nuestra Señora de Candelaria, Cancelaria, Canary Islands, Spain

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Publications (47)126.64 Total impact

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    ABSTRACT: In the last years, circulating matrix metalloproteinases (MMP)-9 levels have been associated with functional outcome in ischemic stroke patients. However the prognostic value of circulating levels of tissue inhibitor of matrix metalloproteinases (TIMP)-1 and MMP-10 in functional outcome of ischemic stroke patients has been scarcely studied. In addition, to our knowledge, serum MMP-9, MMP-10 and TIMP-1 levels in patients with malignant middle cerebral artery infarction (MMCAI) for mortality prediction have not been studied, and these were the objectives of this study. This was a multicenter, observational and prospective study carried out in six Spanish Intensive Care Units. We included patients with severe MMCAI defined as Glasgow Coma Scale (GCS) lower than 9. We measured circulating levels of MMP-9, MMP-10, TIMP-1, in 50 patients with severe MMCAI at diagnosis and in 50 healthy subjects. Endpoint was 30-day mortality. Patients with severe MMCAI showed higher serum levels of MMP-9 (p = 0.001), MMP-10 (p < 0.001), and TIMP-1 (p = 0.02) than healthy subjects. Non-surviving MMCAI patients (n = 26) compared to survivor ones (n = 24) showed higher circulating levels of TIMP-1 (p < 0.001), MMP-10 (p = 0.02) and PAI-1(p = 0.02), and lower MMP-9 levels (p = 0.04). Multiple binomial logistic regression analysis showed that serum TIMP-1 levels > 239 ng/mL are associated with 30-day mortality (OR = 5.82; 95 % CI = 1.37-24.73; P = 0.02) controlling for GCS and age. The area under the curve for TIMP-1 as predictor of 30-day mortality was 0.81 (95 % CI = 0.67-0.91; P < 0.001). We found an association between circulating levels of TIMP-1 and MMP-10 (rho = 0.45; P = 0.001), plasminogen activator inhibitor (PAI)-1 (rho = 0.53; P < 0.001), and tumor necrosis factor (TNF)-alpha (rho = 0.70; P < 0.001). The most relevant and new findings of our study, were that serum TIMP-1 levels in MMCAI patients were associated with mortality, and could be used as a prognostic biomarker of mortality in MMCAI patients.
    BMC Neurology 07/2015; 15(1):111. DOI:10.1186/s12883-015-0364-7 · 2.49 Impact Factor
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    ABSTRACT: 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. 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. 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). 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.
    PLoS ONE 06/2015; 10(6):e0129565. DOI:10.1371/journal.pone.0129565 · 3.23 Impact Factor
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    ABSTRACT: The comparison of oxidative phosphorylation system (OXPHOS) 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).
    Journal of Critical Care 06/2015; DOI:10.1016/j.jcrc.2015.05.031 · 2.19 Impact Factor
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    ABSTRACT: CD154 and its soluble counterpart (sCD154) are proteins of the tumor necrosis factor (TNF) family and exhibit proinflamatory and procoagulant properties. Higher circulating sCD154 levels have been found in ischemic stroke patients than in controls. However, the association between circulating sCD154 levels and mortality in ischemic stroke patients has not been reported, and was the focus of this study. This was a multicenter, observational and prospective study carried out in six Spanish Intensive Care Units. We measured serum sCD154 from 50 patients with severe malignant middle cerebral artery infarction (MMCAI), defined as Glasgow Coma Scale (GCS) lower than 9, at the moment of the severe MMCAI diagnosis and from 50 healthy controls. The end-point of the study was 30-day mortality. We found higher serum sCD154 levels in patients with severe MMCAI than in healthy controls (p < 0.001). We found higher serum sCD154 levels (p < 0.001) in non-surviving (n = 26) than in surviving MMCAI patients (n = 24). Multiple binomial logistic regression analysis showed that serum sCD154 levels >1.41 ng/mmL were associated with 30-day mortality (OR = 10.25; 95% CI = 2.34-44.95; p = 0.002). The new more important finding of our study was that serum sCD154 levels in MMCAI patients were associated with mortality.
    International Journal of Molecular Sciences 06/2015; 16(6):12147-12158. DOI:10.3390/ijms160612147 · 2.86 Impact Factor
  • Leonardo Lorente · María M Martín · Pedro Abreu-González
    Journal of critical care 05/2015; DOI:10.1016/j.jcrc.2015.05.008 · 2.19 Impact Factor
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    PLoS ONE 05/2015; 10(5):e0125893. DOI:10.1371/journal.pone.0125893 · 3.23 Impact Factor
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    ABSTRACT: 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. 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. 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. The major new finding of our study was that serum SP levels were associated with mortality in severe septic patients. Copyright © 2015. Published by Elsevier Inc.
    Journal of Critical Care 05/2015; DOI:10.1016/j.jcrc.2015.05.012 · 2.19 Impact Factor
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    ABSTRACT: Substance P (SP) is a member of the tachykinin family of neuropeptides widely distributed throughout central nervous system (CNS) and actively involved in inflammatory processes. SP is released early following acute injury to the CNS promoting a neurogenic inflammatory response characterized by an increase in the permeability of the blood-brain barrier and the development of vasogenic edema. High levels of SP could lead to an exacerbated inflammatory response that could be fatal for patients with traumatic brain injury (TBI). Thus, the main goal of the present study was to determine whether serum SP levels are associated with severity and mortality in severe TBI patients. This multicenter, observational, prospective study was carried out in six Spanish Hospital Intensive Care Units and included patients with Glasgow Coma Scale (GCS) scores ≤ 8. Patients with an Injury Severity Score (ISS) in non-cranial aspects ≥ 10 were excluded. Blood samples were collected on day 1 of TBI to measure serum SP levels. The endpoint was 30-day mortality. We found higher serum SP levels (p = 0.002) in non-surviving (N = 27) than in surviving patients (N = 73). The area under the curve (AUC) for serum SP levels to predict 30-day mortality was 0.70 (95% CI = 0.60-0.79; p < 0.001). Survival analysis showed that patients with serum SP levels higher than 299 pg/mL presented higher 30-day mortality than patients with lower levels (Hazard ratio = 3.7; 95% CI = 1.75-7.94; p < 0.001). Multiple binomial logistic regression analysis showed that serum SP levels higher than 299 pg/mL were associated with 30-day mortality controlling for APACHE-II and CT classification (OR = 5.97; 95% CI = 1.432-24.851; p = 0.01) and controlling for GCS and age (OR = 5.71; 95% CI = 1.461-22.280; p = 0.01). We found a negative association between serum SP levels and GCS (rho = -0.22; p = 0.03). We report for the first time that serum SP levels were associated with severity and mortality in severe TBI patients. These results open the possibility that SP antagonists may be useful for the treatment of severe TBI patients.
    Critical care (London, England) 04/2015; 19(1):192. DOI:10.1186/s13054-015-0911-z
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    ABSTRACT: 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. 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. 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. The novel finding of our study was that serum melatonin levels are associated with mortality in septic patients. Copyright © 2015. Published by Elsevier Inc.
    Journal of critical care 04/2015; 30(4). DOI:10.1016/j.jcrc.2015.03.023 · 2.19 Impact Factor
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    PLoS ONE 03/2015; 10(3):e0121739. DOI:10.1371/journal.pone.0121739 · 3.23 Impact Factor
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    ABSTRACT: 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.
    PLoS ONE 10/2014; 9(10):e109618. DOI:10.1371/journal.pone.0109618 · 3.23 Impact Factor
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    ABSTRACT: Best clinical practice for patients with suspected catheter-related infection (CRI) remains unclear according to the latest Infectious Diseases Society of America (IDSA) guidelines. Thus, the objective of this study was to analyze clinical practice concerning the central venous catheter (CVC) and its impact on prognosis in patients with suspected CRI. We performed a prospective, multicenter, observational study in 18 Spanish Intensive Care Units (ICUs). Inclusion criteria were patients with CVC and suspected CRI. The following exclusion criteria were used: age less than 18 years; pregnancy; lactation; human immunodeficiency virus; neutropenia; solid or haematological tumor; immunosuppressive or radiation therapy; transplanted organ; intravascular foreign body; haemodynamic instability; suppuration or frank erythema/induration at the insertion site of the CVC, and patients with bacteremia or fungemia. The end-point of the study was mortality at 30 days of CRI suspicion. The study included 384 patients. In 214 (55.8%) patients, CVC was removed at the moment of CRI suspicion, in 114 (29.7%) CVC was removed later and in 56 (14.6%) CVC was not removed. We did not find significant differences between survivors (n =311) and non-survivors (n =73) at 30 days according to CVC decision (P =0.26). The rate of confirmed catheter-related bloodstream infection (CRBSI) was higher in survivors than in non-survivors (14.5% versus 4.1%; P =0.02). Mortality rate was lower in patients with CRBSI than in the group of patients whose clinical symptoms were due to other causes (3/48 (6.25%) versus 70/336 (20.8%); P =0.02). We did not find significant differences in mortality in patients with confirmed CRBSI according to CVC removal at the moment of CRI suspicion (n =38) or later (n =10) (7.9% versus 0; P =0.99). In patients with suspected CRI, immediate CVC removal may be not necessary in all patients. Other aspects should be taken into account in the decision-making, such as vascular accessibility, the risk of mechanical complications during new cannulation that may be life-threatening, and the possibility that the CVC may not be the origin of the suspected CRI.
    Critical care (London, England) 10/2014; 18(5):564. DOI:10.1186/s13054-014-0564-3
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    ABSTRACT: 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.
    Journal of Critical Care 09/2014; 30(1). DOI:10.1016/j.jcrc.2014.09.012 · 2.19 Impact Factor
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    ABSTRACT: 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.
    PLoS ONE 08/2014; 9(8):e105436. DOI:10.1371/journal.pone.0105436 · 3.23 Impact Factor
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    ABSTRACT: Background: Serum soluble CD40 Ligand (sCD40L) levels, which exhibit prothrombotic and proinflammatory properties, have not been studied in patients with traumatic brain injury (TBI). Thus, the objective of this study was to determine whether serum sCD40L levels are associated with severity and mortality in patients with severe TBI. Methods: This was a prospective, observational and multicenter 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 sCD40L were measured on the day of TBI. Endpoint was established in 30-day mortality. Results: We found higher serum sCD40L levels (P < 0.001) in non-surviving TBI patients (N = 27) than in survivor ones (N = 73). Logistic regression analysis showed that serum sCD40L levels were associated with 30-day mortality (OR = 1.58; 95% CI = 1.12-2.21; P = 0.008) controlling for APACHE-II score and computer tomography findings. The area under the curve (AUC) for serum sCD40L levels as predictor of 30-day mortality was 0.79 (95% CI = 0.70-0.86; P < 0.001). Survival analysis showed that patients with serum sCD40L levels higher than 2.11 ng/mL presented increased 30-day mortality than patients with lower levels (Hazard ratio = 9.0; 95% CI = 4.25-19.27; P < 0.001). We found an association between serum sCD40L levels and APACHE-II (rho = 0.33; P = 0.001), and GCS score (rho = -0.21; P = 0.04). Conclusions: To our knowledge, this is the first study reporting data on serum sCD40L levels in patients with severe TBI. The most relevant and newer findings of our study are that serum sCD40L levels in non-surviving patients with severe TBI are higher than in surviving ones, and that there are an association between serum sCD40L levels and TBI severity and mortality.
    Thrombosis Research 08/2014; 134(4). DOI:10.1016/j.thromres.2014.07.034 · 2.43 Impact Factor
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    ABSTRACT: There is a hyperoxidative state in patients with trauma brain injury (TBI). Malondialdehyde (MDA) is an end-product formed during oxidative stress, concretely lipid peroxidation. In small studies (highest sample size 50 patients), higher levels of MDA have been found in non-surviving than surviving TBI patients. However, an association between serum MDA levels and mortality in patients with TBI has not been reported. Thus, the objective of this prospective, observational, multicenter study, carried out in six Spanish Intensive Care Units, was to determine whether MDA serum levels are associated with early mortality in a large series of patients with severe TBI. Serum MDA levels were measured in 100 patients with severe TBI on day 1 and in 75 healthy controls. The end-point of the study was 30-day mortality. We found higher serum MDA levels in patients with severe TBI than in healthy controls (P<0.001). Non-surviving TBI patients (N=27) showed higher serum MDA levels (P<0.001) than survivors (N=73). Logistic regression analysis showed that serum MDA levels were associated with 30-day mortality (OR=4.662; 95% CI=1.466-14.824; P=0.01), controlling for Glasgow coma score, age and computed tomography findings. Survival analysis showed that patients with serum MDA levels higher than 1.96 nmol/mL presented increased 30-day mortality than patients with lower levels (Hazard ratio=3.5; 95% CI=1.43-8.47; P<0.001). Thus, the most relevant new finding of our study, the largest to date on serum MDA levels in patients with severe TBI, was an association between serum MDA levels and early mortality.
    Journal of Neurotrauma 07/2014; 32(1). DOI:10.1089/neu.2014.3456 · 3.97 Impact Factor
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    ABSTRACT: 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.
    Critical care (London, England) 06/2014; 18(3):R136. DOI:10.1186/cc13956
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    ABSTRACT: Higher plasma plasminogen activator inhibitor-1 (PAI-1) levels have been reported in septic patients. However, some questions remain unanswered, such as whether there is an association between plasma PAI-1 levels and sepsis severity and mortality, and inflammation state during the first week. Multicenter, observational and prospective study carried out in six Spanish Intensive Care Units of 260 patients with severe sepsis. Circulating levels of PAI-1 and tumour necrosis factor (TNF)-α were measured at day 1, 4 and 8. End-point was 30-day mortality. Nonsurviving septic patients (n=89) presented higher PAI-1 levels than surviving (n=171) at day 1 (58.4 (33.3-83.8) vs 36.5 (21.1-62.5) ng/mL; p<0.001), 4 (34.0 (14.7-53.3) vs 16.2 (10.2-27.4) ng/mL; p<0.001) and 8 (30.6 (16.2-47.8) vs 18.9 (10.4-29.5) ng/mL; p=0.004). We found a positive correlation of PAI-1 levels with SOFA, lactic acid, aPTT, INR and TNF-α, and negative with platelet count at day 1, 4 and 8. Logistic regression analyses showed that PAI-1 levels at day 1 (p<0.001), 4 (p<0.001) and 8 (p=0.001) were associated with 30-day mortality. On ROC curve analysis to predict 30- day survival, the area under the curve of PAI-1 levels at day 1, 4 and 8 were 0.65 (95% CI=0.58-0.72; p<0.001), 0.69 (95% CI=0.60-0.78; p<0.001) and 0.65 (95% CI=0.54-0.75; p=0.005) respectively. The most interesting findings of our study, to our knowledge the largest series reporting PAI-1 levels during follow-up in septic patients, were that plasma PAI-1 levels during the first week were associated with inflammation, severity and mortality.
    Thrombosis Research 04/2014; 134(1). DOI:10.1016/j.thromres.2014.04.013 · 2.43 Impact Factor
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    ABSTRACT: Matrix 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. This 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. Non-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; P<0.001). An association between TIMP-1 levels and APACHE-II score, TNF- alpha and TF was found. The 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.
    PLoS ONE 04/2014; 9(4):e94370. DOI:10.1371/journal.pone.0094370 · 3.23 Impact Factor
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    ABSTRACT: Higher 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. Multicenter, 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. We found higher TIMP-1/MMP-9 ratio during the first week in non-surviving (n = 98) than in surviving patients (n = 197) (p<0.01). Logistic regression analyses showed that TIMP-1/MMP-9 ratio at days 1, 4 and 8 was associated with mortality. Receiver operating characteristic (ROC) curves showed that TIMP-1/MMP-9 ratio at days 1, 4 and 8 could predict mortality. There was an association between TIMP-1/MMP-9 ratio and TNF-alpha, IL-10, PAI-1 and lactic acid levels, SOFA score and platelet count at days 1, 4 and 8. The 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.
    PLoS ONE 04/2014; 9(4):e94318. DOI:10.1371/journal.pone.0094318 · 3.23 Impact Factor