Trends in Perinatal Practices and Neonatal Outcomes of Very Low Birth Weight Infants during a 16-year Period at NEOCOSUR Centers.

OBJECTIVE: To describe trends in mortality, major morbidity, and perinatal care practices of very low birth weight infants born at NEOCOSUR Neonatal Network centers from January 1, 2001, through December 31, 2016. STUDY DESIGN: A retrospective analysis of prospectively collected data from all inborn infants with a birthweight of 500-1500 g and 23-35 weeks of gestation. RESULTS: We examined data for 13 987 very low birth weight infants with a mean birth weight of 1081 ± 281 g and a gestational age of 28.8 ± 2.9 weeks. Overall mortality was 26.8% without significant changes throughout the study period. Decreases in early onset sepsis from 6.3% to 2.8% (P <.001), late onset sepsis from 21.1% to 19.5% (P = .002), retinopathy of prematurity from 21.3% to 13.8% (P <.001), and hydrocephalus from 3.8% to 2.4% (P <.001), were observed. The incidence for bronchopulmonary dysplasia decreased from 17.3% to 16% (P = .043), incidence of severe intraventricular hemorrhage was 10.4%, necrotizing enterocolitis 11.1%, and periventricular leukomalacia 3.8%, and did not change over the study period. Administration of antenatal corticosteroids increased from 70.2% to 82.3% and cesarean delivery from 65.9% to 75.4% (P <.001). The use of conventional mechanical ventilation decreased from 67.7% to 63.9% (P <.001) and continuous positive airway pressure use increased from 41.3% to 64.3% (P <.001). Survival without major morbidity increased from 37.4% to 44.5% over the study period (P <.001). CONCLUSIONS: Progress in perinatal and neonatal care at network centers was associated with an improvement in survival without major morbidity of very low birth weight infants during a 16-year period. However, overall mortality remained unchanged.

Electroporation optimizes the uptake of boron-10 by tumor for boron neutron capture therapy (BNCT) mediated by GB-10: a boron biodistribution study in the hamster cheek pouch oral cancer model.

Boron neutron capture therapy (BNCT) is a promising cancer binary therapy modality that utilizes the nuclear capture reaction of thermal neutrons by boron-10 resulting in a localized release of high- and low-linear energy transfer (LET) radiation. Electrochemotherapy (ECT) is based on electroporation (EP) that induces opening of pores in cell membranes, allowing the entry of compounds. Because EP is applied locally to a tumor, the compound is incorporated preferentially by tumor cells. Based on the knowledge that the therapeutic success of BNCT depends centrally on the boron content in tumor and normal tissues and that EP has proven to be an excellent facilitator of tumor biodistribution of an anti-tumor agent, the aim of this study was to evaluate if EP can optimize the delivery of boronated compounds. We performed biodistribution studies and qualitative microdistribution analyses of boron employing the boron compound sodium decahydrodecaborate (GB-10) + EP in the hamster cheek pouch oral cancer model. Syrian hamsters with chemically induced exophytic squamous cell carcinomas were used. A typical EP treatment was applied to each tumor, varying the moment of application with respect to the administration of GB-10 (early or late). The results of this study showed a significant increase in the absolute and relative tumor boron concentration and optimization of the qualitative microdistribution of boron by the use of early EP + GB-10 versus GB-10 without EP. This strategy could be a tool to improve the therapeutic efficacy of BNCT/GB-10 in vivo.

Age at Exposure to Arsenic in Water and Mortality 30-40 Years After Exposure Cessation.

Arsenic in drinking water is known to cause cancer and noncancer diseases, but little is known about its association with age at exposure. Here, we investigated age at arsenic exposure and mortality in Antofagasta, Chile, 30-40 years after a distinct period of very high water arsenic concentrations (1958-1970). We calculated standardized mortality ratios (SMRs) comparing Antofagasta with the rest of Chile for 2001-2010 by sex and age at potential first exposure. A remarkable relationship with age at first exposure was found for bronchiectasis, with increased risk in adults 30-40 years after exposure being confined to those who were in utero (SMR = 11.7, 95% confidence interval (CI): 4.3, 25.4) or aged 1-10 years (SMR = 5.4, 95% CI: 1.1, 15.8) during the high-exposure period. Increased SMRs for lung, bladder, and laryngeal cancer were evident for exposures starting at all ages, but the highest SMRs were for exposures beginning at birth (for bladder cancer, SMR = 16.0 (95% CI: 10.3, 23.8); for laryngeal cancer, SMR = 6.8 (95% CI: 2.2, 15.8); for lung cancer, SMR = 3.8 (95% CI: 2.9, 4.9)). These findings suggest that interventions targeting early-life arsenic exposure could have major impacts in reducing long-term mortality due to arsenic 30-40 years after exposure ends.

Minimally Invasive Electrochemotherapy Procedure for Treating Nasal Duct Tumors in Dogs using a Single Needle Electrode.

BACKGROUND: Nasal cavity tumors are usually diagnosed late, when they already have infiltrated adjacent tissues thus requiring very aggressive treatments with serious side effects. Here we use electrochemotherapy (ECT), a well demonstrated treatment modality for superficial tumors. MATERIALS AND METHODS: In the case of deep-seated tumors, the main limitation of ECT is reaching the tumor with an appropriate electric field. To overcome this limitation we introduce the single needle electrode (SiNE), a minimally invasive device that can deliver an appropriate electric field with a simple procedure. Twenty-one canine patients with spontaneous tumors were selected, eleven were treated using the SiNE with ECT, and ten with surgery plus adjuvant chemotherapy as a control group. RESULTS: In the SiNE group, 27% achieved a complete response, 64% had a partial response, and 9% had a stable disease. This means that 91% of objective responses were obtained. The mean overall survival was 16.86 months (4-32 months, median 16.5 months), with a survival rate significantly higher (p = 0.0008) when compared with control group. The only side effect observed was the inflammation of the treated nasal passage, which was controlled with corticosteroid therapy for one week. One year after the treatment, 60% of the canine of the SiNE group vs. 10% of the control group remained alive, and after the 32 months follow-up, the survival rate were 30% and 0%, respectively. CONCLUSIONS: ECT with the SiNE can be safely used in canine to treat nasal tumors with encouraging results.

Combined local and systemic bleomycin administration in electrochemotherapy to reduce the number of treatment sessions.

BACKGROUND: Electrochemotherapy (ECT), a medical treatment widely used in human patients for tumor treatment, increases bleomycin toxicity by 1000 fold in the treated area with an objective response rate of around 80%. Despite its high response rate, there are still 20% of cases in which the patients are not responding. This could be ascribed to the fact that bleomycin, when administered systemically, is not reaching the whole tumor mass properly because of the characteristics of tumor vascularization, in which case local administration could cover areas that are unreachable by systemic administration. PATIENTS AND METHODS: We propose combined bleomycin administration, both systemic and local, using companion animals as models. We selected 22 canine patients which failed to achieve a complete response after an ECT treatment session. Eleven underwent another standard ECT session (control group), while 11 received a combined local and systemic administration of bleomycin in the second treatment session. RESULTS: According to the WHO criteria, the response rates in the combined administration group were: complete response (CR) 54% (6), partial response (PR) 36% (4), stable disease (SD) 10% (1). In the control group, these were: CR 0% (0), PR 19% (2), SD 63% (7), progressive disease (PD) 18% (2). In the combined group 91% objective responses (CR+PR) were obtained. In the control group 19% objective responses were obtained. The difference in the response rate between the treatment groups was significant (p < 0.01). CONCLUSIONS: Combined local and systemic bleomycin administration was effective in previously to ECT non responding canine patients. The results indicate that this approach could be useful and effective in specific population of patients and reduce the number of treatment sessions needed to obtain an objective response.

Electrochemotherapy of tumors as in situ vaccination boosted by immunogene electrotransfer.

Electroporation is a platform technology for drug and gene delivery. When applied to cell in vitro or tissues in vivo, it leads to an increase in membrane permeability for molecules which otherwise cannot enter the cell (e.g., siRNA, plasmid DNA, and some chemotherapeutic drugs). The therapeutic effectiveness of delivered chemotherapeutics or nucleic acids depends greatly on their successful and efficient delivery to the target tissue. Therefore, the understanding of different principles of drug and gene delivery is necessary and needs to be taken into account according to the specificity of their delivery to tumors and/or normal tissues. Based on the current knowledge, electrochemotherapy (a combination of drug and electric pulses) is used for tumor treatment and has shown great potential. Its local effectiveness is up to 80 % of local tumor control, however, without noticeable effect on metastases. In an attempt to increase systemic antitumor effectiveness of electrochemotherapy, electrotransfer of genes with immunomodulatory effect (immunogene electrotransfer) could be used as adjuvant treatment. Since electrochemotherapy can induce immunogenic cell death, adjuvant immunogene electrotransfer to peritumoral tissue could lead to locoregional effect as well as the abscopal effect on distant untreated metastases. Therefore, we propose a combination of electrochemotherapy with peritumoral IL-12 electrotransfer, as a proof of principle, using electrochemotherapy boosted with immunogene electrotransfer as in situ vaccination for successful tumor treatment.

Enhancement in the Therapeutic Efficacy of In Vivo BNCT Mediated by GB-10 with Electroporation in a Model of Oral Cancer.

Boron neutron capture therapy (BNCT) combines preferential tumor uptake of 10B compounds and neutron irradiation. Electroporation induces an increase in the permeability of the cell membrane. We previously demonstrated the optimization of boron biodistribution and microdistribution employing electroporation (EP) and decahydrodecaborate (GB-10) as the boron carrier in a hamster cheek pouch oral cancer model. The aim of the present study was to evaluate if EP could improve tumor control without enhancing the radiotoxicity of BNCT in vivo mediated by GB-10 with EP 10 min after GB-10 administration. Following cancerization, tumor-bearing hamster cheek pouches were treated with GB-10/BNCT or GB-10/BNCT + EP. Irradiations were carried out at the RA-3 Reactor. The tumor response and degree of mucositis in precancerous tissue surrounding tumors were evaluated for one month post-BNCT. The overall tumor response (partial remission (PR) + complete remission (CR)) increased significantly for protocol GB-10/BNCT + EP (92%) vs. GB-10/BNCT (48%). A statistically significant increase in the CR was observed for protocol GB-10/BNCT + EP (46%) vs. GB-10/BNCT (6%). For both protocols, the radiotoxicity (mucositis) was reversible and slight/moderate. Based on these results, we concluded that electroporation improved the therapeutic efficacy of GB-10/BNCT in vivo in the hamster cheek pouch oral cancer model without increasing the radiotoxicity.

Electrochemotherapy using thin-needle electrode improves recovery in feline nasal planum squamous cell carcinoma - a translational model.

Aim: Cutaneous squamous cell carcinoma (cSCC) is a common disease in patients exposed to UV-light and human papillomavirus. Electrochemotherapy, a well-established treatment modality with minimum side effects in human and veterinary medicine, circumvents chemoresistance to bleomycin by the use of electric fields. However, patients are sensitive to the trauma produced by the insertion of the needles that lengthen recovery times, particularly cats with nasal planum cSCC. To address this matter, we developed thin-needles electrodes. Methods: Thin-needles electrodes developed using computer simulations and plant tissue models were compared to standard electrodes. A prospective non-randomized study recruiting 52 feline patients with nasal planum cSCC was performed. Local response, anorexia, and overall survival were evaluated. Results: Computer simulations and plant model experiments showed satisfactory results with both electrodes. The patients treated with the thin-needle electrode obtained similar local response rates compared to the standard group, OR 97.3% vs. 80%, respectively (P < 0.067). Most patients in the thin-needle group resumed eating in less than 48 h, as the anorexia was significantly lower (P < 0.0001). Using the standard electrode, most patients took 3 to 5 days to resume normal feeding. The electric current circulating in the standard electrode was 44% higher, contributing to a longer duration of anorexia due to tissue damage. The overall survival in both groups was similar. Conclusion: Electrochemotherapy using thin-needle electrodes provides equivalent local response rates and overall survival compared with standard electrodes but significantly reduced return to appetite after the treatment. These results may be useful in the development of new electrodes for human patients.

Evidence from Chile that arsenic in drinking water may increase mortality from pulmonary tuberculosis.

Arsenic in drinking water causes increased mortality from several cancers, ischemic heart disease, bronchiectasis, and other diseases. This paper presents the first evidence relating arsenic exposure to pulmonary tuberculosis, by estimating mortality rate ratios for Region II of Chile compared with Region V for the years 1958-2000. The authors compared mortality rate ratios with time patterns of arsenic exposure, which increased abruptly in 1958 in Region II and then declined starting in 1971. Tuberculosis mortality rate ratios in men started increasing in 1968, 10 years after high arsenic exposure commenced. The peak male 5-year mortality rate ratio occurred during 1982-1986 (rate ratio = 2.1, 95% confidence interval: 1.7, 2.6; P < 0.001) and subsequently declined. Mortality rates in women were also elevated but with fewer excess pulmonary tuberculosis deaths (359 among men and 95 among women). The clear rise and fall of tuberculosis mortality rate ratios in men following high arsenic exposure are consistent with a causal relation. The findings are biologically plausible in view of evidence that arsenic is an immunosuppressant and also a cause of chronic lung disease. Finding weaker associations in women is unsurprising, because this is true of most arsenic-caused health effects. Confirmatory evidence is needed from other arsenic-exposed populations.

Logistic regression when covariates are random effects from a non-linear mixed model.

In many studies, the association of longitudinal measurements of a continuous response and a binary outcome are often of interest. A convenient framework for this type of problems is the joint model, which is formulated to investigate the association between a binary outcome and features of longitudinal measurements through a common set of latent random effects. The joint model, which is the focus of this article, is a logistic regression model with covariates defined as the individual-specific random effects in a non-linear mixed-effects model (NLMEM) for the longitudinal measurements. We discuss different estimation procedures, which include two-stage, best linear unbiased predictors, and various numerical integration techniques. The proposed methods are illustrated using a real data set where the objective is to study the association between longitudinal hormone levels and the pregnancy outcome in a group of young women. The numerical performance of the estimating methods is also evaluated by means of simulation.

OpenEP: an open-source simulator for electroporation-based tumor treatments.

Electroporation (EP), the increase of cell membrane permeability due to the application of electric pulses, is a universal phenomenon with a broad range of applications. In medicine, some of the foremost EP-based tumor treatments are electrochemotherapy (ECT), irreversible electroporation, and gene electrotransfer (GET). The electroporation phenomenon is explained as the formation of cell membrane pores when a transmembrane cell voltage reaches a threshold value. Predicting the outcome of an EP-based tumor treatment consists of finding the electric field distribution with an electric threshold value covering the tumor (electroporated tissue). Threshold and electroporated tissue are also a function of the number of pulses, constituting a complex phenomenon requiring mathematical modeling. We present OpenEP, an open-source specific purpose simulator for EP-based tumor treatments, modeling among other variables, threshold, and electroporated tissue variations in time. Distributed under a free/libre user license, OpenEP allows the customization of tissue type; electrode geometry and material; pulse type, intensity, length, and frequency. OpenEP facilitates the prediction of an optimal EP-based protocol, such as ECT or GET, defined as the critical pulse dosage yielding maximum electroporated tissue with minimal damage. OpenEP displays a highly efficient shared memory implementation by taking advantage of parallel resources; this permits a rapid prediction of optimal EP-based treatment efficiency by pulse number tuning.

Kidney cancer mortality: fifty-year latency patterns related to arsenic exposure.

BACKGROUND: Arsenic in drinking water is associated with kidney cancer. Beginning in 1958, a region of Chile experienced a rapid onset of high arsenic exposure in drinking water, followed by sharp declines when water treatment plants were installed in 1971. METHODS: For the years 1950-1970, we obtained mortality data from death certificates for an exposed region and an unexposed region in Chile. We obtained computerized mortality data for all of Chile for 1971-2000. RESULTS: Kidney cancer risks for the exposed region compared with the unexposed started to increase about 10 years after high arsenic exposures began in 1958. The peak kidney cancer mortality rate ratio (RR) was 3.4 (95% confidence interval = 2.2-5.1) for men in 1981-1985, with subsequent declines to 1.6 (1.2-2.1) by 1996-2000. Mortality RRs among women were 2.9 (1.8-4.7) in 1981-1985 but remained high longer than for men, increasing further to a RR of 4.4 (3.0-6.4) in 1991-1995. Early-life exposure resulted in an increased RR of 7.1 (3.1-14) for young adults aged 30-39 years, born just before or during the high exposure period. CONCLUSIONS: This study shows a latency pattern of increased mortality from kidney cancer, continuing for at least 25 years after the high exposures began to decline. Early life exposure resulted in markedly higher kidney cancer mortality in young adults.

Electrochemotherapy in treatment of canine oral malignant melanoma and factors influencing treatment outcome.

Background Oral malignant melanoma is the most common, but aggressive oral cancer in dogs with poor prognosis. Electrochemotherapy (ECT) has therapeutic potential in such tumors as effective local treatment. Therefore, the aim of this prospective clinical study was to evaluate treatment effectiveness of ECT in as first line treatment for canine oral malignant melanoma, and search for factors influencing treatment outcome. Methods Sixty-seven canines with primary oral malignant melanoma, non-candidates for first-line therapy, were enrolled. All dogs received ECT and follow-up exams for the span of two years. Results Based on RECIST criteria, the objective response rate was 100%, 89.5%, 57.7%, and 36.4%, in stage I, II, III and IV, respectively. Only patients in stage I, II and III with partial or complete response improved their quality of life. The median time to progression was 11, 7, 4 and 4 months, and median survival time after the treatment was 16.5, 9.0, 7.5 and 4.5 months, for patients in stage I, II, III and IV, respectively. Significantly better was local response in stage I and II disease (p = 0.0013), without the bone involvement (p = 0.043) Conclusions Electrochemotherapy is effective local treatment of oral canine malignant melanoma when no alternative treatment is available. Better response is expected in stage I and II patients with tumors without bone involvement.

Electroporation as the Immunotherapy Strategy for Cancer in Veterinary Medicine: State of the Art in Latin America.

Electroporation is a technology that increases cell membrane permeability by the application of electric pulses. Electrochemotherapy (ECT), the best-known application of electroporation, is a very effective local treatment for tumors of any histology in human and veterinary medicine. It induces a local yet robust immune response that is responsible for its high effectiveness. Gene electrotransfer (GET), used in research to produce a systemic immune response against cancer, is another electroporation-based treatment that is very appealing for its effectiveness, low cost, and simplicity. In this review, we present the immune effect of electroporation-based treatments and analyze the results of the vast majority of the published papers related to immune response enhancement by gene electrotransfer in companion animals with spontaneous tumors. In addition, we present a brief history of the initial steps and the state of the art of the electroporation-based treatments in Latin America. They have the potential to become an essential form of immunotherapy in the region. This review gives insight into the subject and helps to choose promising research lines for future work; it also helps to select the adequate treatment parameters for performing a successful application of this technology.

Non-alcoholic fatty liver disease and its association with obesity, insulin resistance and increased serum levels of C-reactive protein in Hispanics.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is a metabolic disorder of the liver, which may progress to fibrosis or cirrhosis. Recent studies have shown a significant impact of ethnicity on susceptibility to steatosis-related liver disease. AIMS: To estimate the prevalence of NAFLD among Chilean Hispanics as well as the clinical and biochemical variables associated with the disease. METHODS: Population-based study among Chilean Hispanics. The diagnosis of NAFLD was made on the basis of ultrasound evidence of fatty liver and absence of significant alcohol consumption and hepatitis C virus infection. RESULTS: A total of 832 Hispanic subjects were included. Ultrasound findings revealed diffuse fatty liver in 23% of the subjects. Variables associated with fatty liver in multivariate analysis were body mass index >26.9 [odds ratio (OR) 6.2; 95% confidence interval (CI) 3.3-11.5], abnormal aspartate aminotransferase levels (OR 14; 95% CI 8.2-23.7), presence of insulin resistance as measured by homoeostasis model assessment-insulin resistance (OR 3; 95% CI 1.8-4.8) and serum levels of high-sensitivity C-reactive protein (hs-CRP) greater than 0.86 mg/L (OR 2.9; 95% CI 1.6-5.2). Among subjects with NAFLD, levels of hs-CRP were similar regardless of the alanine aminotransferase (ALT) level. CONCLUSIONS: Chilean Hispanics exhibit a high prevalence of NAFLD. Obesity, insulin resistance, abnormal aminotransferase levels and elevated hs-CRP were independently associated with the presence of NAFLD. ALT elevation underestimates the presence of ultrasonographical fatty liver, whereas hs-CRP is a sensitive independent marker of NAFLD, which may be useful for detecting fatty liver in the general population.

Discriminant analysis for longitudinal data with multiple continuous responses and possibly missing data.

Multiple outcomes are often used to properly characterize an effect of interest. This article discusses model-based statistical methods for the classification of units into one of two or more groups where, for each unit, repeated measurements over time are obtained on each outcome. We relate the observed outcomes using multivariate nonlinear mixed-effects models to describe evolutions in different groups. Due to its flexibility, the random-effects approach for the joint modeling of multiple outcomes can be used to estimate population parameters for a discriminant model that classifies units into distinct predefined groups or populations. Parameter estimation is done via the expectation-maximization algorithm with a linear approximation step. We conduct a simulation study that sheds light on the effect that the linear approximation has on classification results. We present an example using data from a study in 161 pregnant women in Santiago, Chile, where the main interest is to predict normal versus abnormal pregnancy outcomes.

Cluster analysis using multivariate mixed effects models.

A common situation in the biological and social sciences is to have data on one or more variables measured longitudinally on a sample of individuals. A problem of growing interest in these areas is the grouping of individuals into one of two or more clusters according to their longitudinal behavior. Recently, methods have been proposed to deal with cases where individuals are classified into clusters through a linear model of mixed univariate effects deriving from a longitudinally measured variable. The method proposed in the current work deals with the case of clustering and then classification based on two or more variables measured longitudinally, through the fitting of non-linear multivariate mixed effect models, and with consideration given to parameter estimation for balanced and unbalanced data using an EM algorithm. The application of the method is illustrated with an example in which the clusters are identified and the classification into clusters is compared with the true membership of individuals in one of two groups, which is known at the end of the follow-up period.

Bronchopulmonary dysplasia: risk prediction models for very-low- birth-weight infants.

OBJECTIVE: Our objective is to develop risk prediction models for moderate/severe bronchopulmonary dysplasia (BPD) and BPD and/or death in very-low-birth-weight infants (VLBWI) at birth, 3, 7, and 14 postnatal days. STUDY DESIGN: It is a multicenter study including 16,407 infants weighing 500-1500 g (2001-2015) from the Neocosur Network. BPD was defined as oxygen dependency at 36 weeks. Variables were selected using forward logistic regression models. Predictive values were evaluated using the ROC curve. RESULTS: In total, 2580 (15.7%) presented BPD and 6121 (37.3%) BPD/death. The AUC values for the BPD models were 0.788, 0.818, 0.827, and 0.894 respectively. For BPD/death, the AUC values were 0.860, 0.869, 0.867, and 0.906. BW and gestational age had higher contribution at birth; at later ages, the length of oxygen therapy and ventilation had the highest contribution. All AUC values were statistically significant when compared with a neutral value of 0.5 (p-value < 0.001). CONCLUSIONS: We developed high predictive power models for moderate/severe BPD and BPD/death at four postnatal ages.

Increased childhood liver cancer mortality and arsenic in drinking water in northern Chile.

Arsenic in drinking water is an established cause of lung, bladder, and skin cancers in adults and may also cause adult kidney and liver cancers. Some evidence for these effects originated from region II of Chile, which had a period of elevated arsenic levels in drinking water, in particular from 1958 to 1970. This unique exposure scenario provides a rare opportunity to investigate the effects of early-life arsenic exposure on childhood mortality; to our knowledge, this is the first study of childhood cancer mortality and high concentrations of arsenic in drinking water. In this article, we compare cancer mortality rates under the age of 20 in region II during 1950 to 2000 with those of unexposed region V, dividing subjects into those born before, during, or after the peak exposure period. Mortality from the most common childhood cancers, leukemia and brain cancer, was not increased in the exposed population. However, we found that childhood liver cancer mortality occurred at higher rates than expected. For those exposed as young children, liver cancer mortality between ages 0 and 19 was especially high: the relative risk (RR) for males born during this period was 8.9 [95% confidence interval (95% CI), 1.7-45.8; P = 0.009]; for females, the corresponding RR was 14.1 (95% CI, 1.6-126; P = 0.018); and for males and females pooled, the RR was 10.6 (95% CI, 2.9-39.2; P < 0.001). These findings suggest that exposure to arsenic in drinking water during early childhood may result in an increase in childhood liver cancer mortality.

Lipoperoxidation and protein oxidative damage exhibit different kinetics during septic shock.

Septic shock (SS)-related multiorgan dysfunction has been associated with oxidative damage, but little is known about the temporal damage profile and its relationship to severity. The present work investigated prospectively 21 SS patients. Blood samples were obtained at diagnosis, 24, 72 hours, day 7, and at 3 months. At admission, thiobarbituric acid reactive substances (TBARSs), plasma protein carbonyls, plasma protein methionine sulfoxide (MS), ferric/reducing antioxidant power (FRAP), total red blood cell glutathione (RBCG), uric acid (UA), and bilirrubin levels were increased (P < .05). Total radical-trapping antioxidant potential (TRAP) and vitamin-E were similar to controls, and vitamin-C was decreased (P < .05). During evolution, TBARS and RBCG increased (P < .001), vitamin-E levels remained stable, whereas plasma protein carbonyls and MS, TRAP, vitamin-C, reduced glutathione, and UA levels decreased (P < .006). After 3 months, plasma protein carbonyls and MS persisted elevated. More severe patients exhibited higher TBARS, TRAP, FRAP, vitamin-C, UA, and bilirrubin levels. Our results suggest early and persistent oxidative stress during septic shock and a correlation between increasing levels of lipoperoxidation and sepsis severity.