María M Martín

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

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Publications (40)110.35 Total impact

  • PLoS ONE 05/2015; 10(5):e0125893. DOI:10.1371/journal.pone.0125893 · 3.53 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; DOI:10.1016/j.jcrc.2015.03.023 · 2.19 Impact Factor
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    ABSTRACT: 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.
    PLoS ONE 10/2014; 9(10):e109618. DOI:10.1371/journal.pone.0109618 · 3.53 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: ObjectiveHigher 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.MethodsWe 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.ResultsWe 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.ConclusionsThe 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 · 3.53 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 · 3.53 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 · 3.53 Impact Factor
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    ABSTRACT: Background 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. Methods 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. Results 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. Conclusions 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 01/2014; 134(1):182–186. · 2.43 Impact Factor
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    ABSTRACT: There is a hyperoxidative state in sepsis. The objective of this study was to determine serum malondialdehyde (MDA) levels during the first week of follow up, whether such levels are associated with severity during the first week and whether non-surviving patients showed higher MDA levels than survivors during the first week. We performed an observational, prospective, multicenter study in six Spanish Intensive Care Units. Serum levels of MDA were measured in 328 patients (215 survivors and 113 non-survivors) with severe sepsis at days one, four and eight of diagnosis, and in 100 healthy controls. The primary endpoint was 30-day mortality and the secondary endpoint was six-month mortality. The association between continuous variables was carried out using Spearman's rank correlation coefficient. Cox regression analysis was applied to determine the independent contribution of serum MDA levels on the prediction of 30-day and 6-month mortality. Hazard ratio (HR) and 95% confidence intervals (CI) were calculated as measures of the clinical impact of the predictor variables. We found higher serum MDA in septic patients at day one (p < 0.001), day four (p < 0.001) and day eight (p < 0.001) of diagnosis than in healthy controls. Serum MDA was higher in surviving than non-surviving septic patients at day one (p < 0.001), day four (p < 0.001) and day eight (p < 0.001). Serum MDA levels were positively correlated with lactic acid and SOFA during the first week. Finally, serum MDA levels were associated with 30-day mortality (HR = 1.05; 95% CI = 1.02-1.09; p = 0.005) and six-month mortality (hazard ratio (HR) = 1.05; 95% CI = 1.02-1.09; p = 0.003) after controlling for lactic acid levels, acute physiology and chronic health evaluation (APACHE)-II, diabetes mellitus, bloodstream infection and chronic renal failure. To our knowledge, this is the largest series providing data on the oxidative state in septic patients to date. The novel finding is that high serum MDA levels sustained throughout the first week of follow up were associated with severity and mortality in septic patients.
    Critical care (London, England) 12/2013; 17(6):R290. DOI:10.1186/cc13155
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    ABSTRACT: 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. 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. 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. 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.
    PLoS ONE 09/2013; 8(9):e73320. DOI:10.1371/journal.pone.0073320 · 3.53 Impact Factor
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    ABSTRACT: Introduction Previous studies have found higher circulating levels of tissue inhibitor of matrix metalloproteinase (TIMP)-1 in nonsurviving septic patients than in surviving septic patients, and an association between the 372 T/C genetic polymorphism of TIMP-1 and the risk of developing certain diseases. However, the relationship between genetic polymorphisms of TIMP-1, circulating TIMP-1 levels and survival in patients with severe sepsis has not been examined, and this was the objective of the study. Methods This multicentre, prospective, observational study was carried out in six Spanish ICUs. We determined the 372 T/C genetic polymorphism of TIMP-1 (rs4898), serum levels of TIMP-1, matrix metalloproteinase (MMP)-9, MMP-10, TNFα, IL-10 and plasma plasminogen activator inhibitor-1 (PAI-1). Survival at 30 days from ICU admission was the endpoint assessed. The association between continuous variables was carried out using Spearman's rank correlation coefficient or Spearman's rho coefficient. Multivariate logistic regression analysis was applied to determine the association between the 372 T/C genetic polymorphism and survival 30 days from ICU admission. Results Of 275 patients with severe sepsis, 80 had genotype CC, 55 had genotype CT and 140 had genotype TT of the 372 T/C genetic polymorphism of TIMP-1. Patients with the T allele showed higher serum levels of TIMP-1 than patients without the T allele (P = 0.004). Multiple logistic regression analysis showed that the T allele was associated with higher mortality at 30 days (odds ratio = 2.08; 95% confidence interval = 1.06 to 4.09; P = 0.03). Survival analysis showed that patients with the T allele presented lower 30-day survival than patients without the T allele (χ2 = 5.77; P = 0.016). We found an association between TIMP-1 levels and levels of MMP-9 (ρ = -0.19; P = 0.002), MMP-10 (ρ = 0.55; P <0.001), TNFα (ρ = 0.56; P <0.001), IL-10 (ρ = 0.48; P <0.001) and PAI-1 (ρ = 0.49; P <0.001). Conclusion The novel findings of our study are that septic patients with the T allele in the 372 T/C genetic polymorphism of TIMP-1 showed higher serum TIMP-1 levels and lower survival rate. The determination of the 372 T/C genetic polymorphism of TIMP-1 thus has prognostic implications and could help in the selection of patients who may benefit from modulation of the MMP/TIMP balance.
    Critical care (London, England) 05/2013; 17(3):R94. DOI:10.1186/cc12739
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    ABSTRACT: 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. 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. 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<0.001). The novel findings of our study on severe septic patients, to our knowledge the largest series providing data on the oxidative state, are that elevated MDA serum levels probably represent an unbalanced oxidant state and are related with poor prognosis in patients with severe sepsis.
    PLoS ONE 01/2013; 8(1):e53741. DOI:10.1371/journal.pone.0053741 · 3.53 Impact Factor
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    ABSTRACT: We recently found that platelet cytochrome c oxidase (COX) activities and quantities in 6-month-survival septic patients are significantly higher than those of patients who died before 6 months. Other studies suggested that the mitochondrial DNA (mtDNA) genotype could play a major role in sepsis survival. Given that COX catalytic subunits are encoded by mtDNA, the objective of the present study was to explore whether mtDNA population genetic variation could affect COX activity and quantity and favors sepsis survival. A prospective, multicenter, observational study was carried out in six Spanish ICUs. We included 96 patients with severe sepsis. We determined the mtDNA haplogroup, the COX specific activity/citrate synthase specific activity (COXa/CSa) ratio and the COX quantity/citrate synthase specific activity (COXq/CSa) ratio in circulating platelets at the time of diagnosis, day 4 and day 8. We used survival at 1 and 6 months as endpoints. Patients with the JT mtDNA haplogroup (n=15) showed higher COXq/CSa ratio at day 4 (P=0.04) and day 8 (P=0.02) than those with other haplogroups (n=81). Logistic regression analysis showed that the JT mtDNA haplogroup (odds ratio=0.18; 95% confidence interval=0.04 to 0.94; P=0.04) and COXq/CSa ratio (odds ratio=0.53; 95% confidence interval=0.30 to 0.93; P=0.03) were associated with 1-month survival after controlling for age and lactic acid levels. The novel findings of our study are that 1-month surviving septic patients showed higher COXq/CSa ratio than nonsurviving individuals, that patients from the JT mtDNA haplogroup showed a higher COXq/CSa ratio and that JT patients had a higher 1-month survival than patients from other mtDNA haplogroups.
    Critical care (London, England) 01/2012; 16(1):R10. DOI:10.1186/cc11150
  • Critical care medicine 01/2012; 40(1):357-9. DOI:10.1097/CCM.0b013e318236e341 · 6.15 Impact Factor