Luciano C. P. Azevedo

Oxidative stress as a signaling mechanism of the vascular response to injury: the redox hypothesis of restenosis.

The prominent role of redox processes in tissue injury and in vascular cell signaling suggest their involvement in the repair reaction to vessel injury, which is a key determinant of restenosis post-angioplasty. Experimental studies showed a protective effect of superoxide dismutase or antioxidants on vasospasm, neointimal thickening or remodeling after balloon injury. It was also shown that oxidized thiols induce chelatable metal-dependent amplification of the vascular repair reaction. Ongoing or completed clinical trials show a promising effect of the antioxidant probucol against restenosis. However, few studies addressed the molecular physiological mechanisms underlying the redox hypothesis of restenosis. We recently showed evidence for marked oxidative stress early after balloon injury, with superoxide production mediated primarily by non-endothelial NAD(P)H oxidase-type flavoenzyme(s). This effect was closely related to the degree of injury. There is evidence supporting a role for such early redox processes in apoptotic cell loss and NF-kappa B activation. We present new data on the time course of oxidative stress after balloon injury of intact rabbit iliac arteries. Our data show that despite substantial neointimal growth and lumen narrowing, superoxide production and glutathione levels are unaltered at day 14 and 28 after balloon injury. At day 7 after injury, the peak neointimal proliferation in this model, there was significant decrease of vascular superoxide dismutase activity, without clear evidence of spontaneous superoxide production. Thus, oxidative stress after injury is likely to be an early transient event, which parallels the inflammatory and proliferative phases of the vascular response. We propose that such early redox processes act as dose-dependent signal transducers of gene programs that affect the final repair.

Outcomes for Patients With Cancer Admitted to the ICU Requiring Ventilatory Support: Results From a Prospective Multicenter Study

BACKGROUND This study was undertaken to evaluate the clinical characteristics and outcomes of patients with cancer requiring nonpalliative ventilatory support. METHODS This was a secondary analysis of a prospective cohort study conducted in 28 Brazilian ICUs evaluating adult patients with cancer requiring invasive mechanical ventilation (MV) or noninvasive ventilation (NIV) during the first 48 h of their ICU stay. We used logistic regression to identify the variables associated with hospital mortality. RESULTS Of 717 patients, 263 (37%) (solid tumors = 227; hematologic malignancies = 36) received ventilatory support. NIV was initially used in 85 patients (32%), and 178 (68%) received MV. Additionally, NIV followed by MV occurred in 45 patients (53%). Hospital mortality rates were 67% in all patients, 40% in patients receiving NIV only, 69% when NIV was followed by MV, and 73% in patients receiving MV only (P < .001). Adjusting for the type of admission, newly diagnosed malignancy (OR, 3.59; 95% CI, 1.28-10.10), recurrent or progressive malignancy (OR, 3.67; 95% CI, 1.25-10.81), tumoral airway involvement (OR, 4.04; 95% CI, 1.30-12.56), performance status (PS) 2 to 4 (OR, 2.39; 95% CI, 1.24-4.59), NIV followed by MV (OR, 3.00; 95% CI, 1.09-8.18), MV as initial ventilatory strategy (OR, 3.53; 95% CI, 1.45-8.60), and Sequential Organ Failure Assessment score (each point except the respiratory domain) (OR, 1.15; 95% CI, 1.03-1.29) were associated with hospital mortality. Hospital survival in patients with good PS and nonprogressive malignancy and without tumoral airway involvement was 53%. Conversely, patients with poor functional capacity and cancer progression had unfavorable outcomes. CONCLUSIONS Patients with cancer with good PS and nonprogressive disease requiring ventilatory support should receive full intensive care, because one-half of these patients survive. On the other hand, provision of palliative care should be considered the main goal for patients with poor PS and progressive underlying malignancy.

ABANDON THE MOUSE RESEARCH SHIP? NOT JUST YET!

ABSTRACT Many preclinical studies in critical care medicine and related disciplines rely on hypothesis-driven research in mice. The underlying premise posits that mice sufficiently emulate numerous pathophysiologic alterations produced by trauma/sepsis and can serve as an experimental platform for answering clinically relevant questions. Recently, the lay press severely criticized the translational relevance of mouse models in critical care medicine. A series of provocative editorials were elicited by a highly publicized research report in the Proceedings of the National Academy of Sciences (PNAS; February 2013), which identified an unrecognized gene expression profile mismatch between human and murine leukocytes following burn/trauma/endotoxemia. Based on their data, the authors concluded that mouse models of trauma/inflammation are unsuitable for studying corresponding human conditions. We believe this conclusion was not justified. In conjunction with resulting negative commentary in the popular press, it can seriously jeopardize future basic research in critical care medicine. We will address some limitations of that PNAS report to provide a framework for discussing its conclusions and attempt to present a balanced summary of strengths/weaknesses of use of mouse models. While many investigators agree that animal research is a central component for improved patient outcomes, it is important to acknowledge known limitations in clinical translation from mouse to man. The scientific community is responsible to discuss valid limitations without overinterpretation. Hopefully, a balanced view of the strengths/weaknesses of using animals for trauma/endotoxemia/critical care research will not result in hasty discount of the clear need for using animals to advance treatment of critically ill patients.

Original ResearchCritical CareFeaturedOutcomes for Patients With Cancer Admitted to the ICU Requiring Ventilatory Support: Results From a Prospective Multicenter Study

BACKGROUND This study was undertaken to evaluate the clinical characteristics and outcomes of patients with cancer requiring nonpalliative ventilatory support. METHODS This was a secondary analysis of a prospective cohort study conducted in 28 Brazilian ICUs evaluating adult patients with cancer requiring invasive mechanical ventilation (MV) or noninvasive ventilation (NIV) during the first 48 h of their ICU stay. We used logistic regression to identify the variables associated with hospital mortality. RESULTS Of 717 patients, 263 (37%) (solid tumors = 227; hematologic malignancies = 36) received ventilatory support. NIV was initially used in 85 patients (32%), and 178 (68%) received MV. Additionally, NIV followed by MV occurred in 45 patients (53%). Hospital mortality rates were 67% in all patients, 40% in patients receiving NIV only, 69% when NIV was followed by MV, and 73% in patients receiving MV only (P < .001). Adjusting for the type of admission, newly diagnosed malignancy (OR, 3.59; 95% CI, 1.28-10.10), recurrent or progressive malignancy (OR, 3.67; 95% CI, 1.25-10.81), tumoral airway involvement (OR, 4.04; 95% CI, 1.30-12.56), performance status (PS) 2 to 4 (OR, 2.39; 95% CI, 1.24-4.59), NIV followed by MV (OR, 3.00; 95% CI, 1.09-8.18), MV as initial ventilatory strategy (OR, 3.53; 95% CI, 1.45-8.60), and Sequential Organ Failure Assessment score (each point except the respiratory domain) (OR, 1.15; 95% CI, 1.03-1.29) were associated with hospital mortality. Hospital survival in patients with good PS and nonprogressive malignancy and without tumoral airway involvement was 53%. Conversely, patients with poor functional capacity and cancer progression had unfavorable outcomes. CONCLUSIONS Patients with cancer with good PS and nonprogressive disease requiring ventilatory support should receive full intensive care, because one-half of these patients survive. On the other hand, provision of palliative care should be considered the main goal for patients with poor PS and progressive underlying malignancy.

Clinical outcomes of patients requiring ventilatory support in Brazilian intensive care units: a multicenter, prospective, cohort study

IntroductionContemporary information on mechanical ventilation (MV) use in emerging countries is limited. Moreover, most epidemiological studies on ventilatory support were carried out before significant developments, such as lung protective ventilation or broader application of non-invasive ventilation (NIV). We aimed to evaluate the clinical characteristics, outcomes and risk factors for hospital mortality and failure of NIV in patients requiring ventilatory support in Brazilian intensive care units (ICU).MethodsIn a multicenter, prospective, cohort study, a total of 773 adult patients admitted to 45 ICUs over a two-month period requiring invasive ventilation or NIV for more than 24 hours were evaluated. Causes of ventilatory support, prior chronic health status and physiological data were assessed. Multivariate analysis was used to identifiy variables associated with hospital mortality and NIV failure.ResultsInvasive MV and NIV were used as initial ventilatory support in 622 (80%) and 151 (20%) patients. Failure with subsequent intubation occurred in 54% of NIV patients. The main reasons for ventilatory support were pneumonia (27%), neurologic disorders (19%) and non-pulmonary sepsis (12%). ICU and hospital mortality rates were 34% and 42%. Using the Berlin definition, acute respiratory distress syndrome (ARDS) was diagnosed in 31% of the patients with a hospital mortality of 52%. In the multivariate analysis, age (odds ratio (OR), 1.03; 95% confidence interval (CI), 1.01 to 1.03), comorbidities (OR, 2.30; 95% CI, 1.28 to 3.17), associated organ failures (OR, 1.12; 95% CI, 1.05 to 1.20), moderate (OR, 1.92; 95% CI, 1.10 to 3.35) to severe ARDS (OR, 2.12; 95% CI, 1.01 to 4.41), cumulative fluid balance over the first 72 h of ICU (OR, 2.44; 95% CI, 1.39 to 4.28), higher lactate (OR, 1.78; 95% CI, 1.27 to 2.50), invasive MV (OR, 2.67; 95% CI, 1.32 to 5.39) and NIV failure (OR, 3.95; 95% CI, 1.74 to 8.99) were independently associated with hospital mortality. The predictors of NIV failure were the severity of associated organ dysfunctions (OR, 1.20; 95% CI, 1.05 to 1.34), ARDS (OR, 2.31; 95% CI, 1.10 to 4.82) and positive fluid balance (OR, 2.09; 95% CI, 1.02 to 4.30).ConclusionsCurrent mortality of ventilated patients in Brazil is elevated. Implementation of judicious fluid therapy and a watchful use and monitoring of NIV patients are potential targets to improve outcomes in this setting.Trial registrationClinicalTrials.gov NCT01268410.

Circulating Microparticles as Therapeutic Targets in Cardiovascular Diseases

Microparticles are a heterogeneous population of small membrane-coated vesicles released by several cell lines upon activation or apoptosis. Microparticle generation seems to be a well regulated process, although these vesicles are highly variable in size, composition and function. Despite being previously considered inert debris without specific function, recent data demonstrated important pathophysiologic mechanisms orchestrated by microparticles in vascular diseases associated with endothelial dysfunction. These vesicles have been implicated, among others, in the pathogenesis of thrombosis, diabetes, inflammation, atherosclerosis and vascular cell proliferation. In addition to microparticles, circulating activated cells release smaller vesicles denominated exosomes that can also participate in vascular derangement. This mechanistic role of microparticles and exosomes in mediating vascular dysfunction indicates that they may represent novel pathways in short or long-distance paracrine transcellular signaling in vascular environment. The most recent patents regarding microparticles and exosomes are related to their procoagulant potential (U.S. Pat. No. 7005271), role in immune activation of T or B cells (Eurasian Pat. No. 0002827B1) and role in peptide vaccination (World Pat. No. 9705900A1). These commercial applications of microvesicles will be discussed in this review, as well as mechanisms involved in their origin, composition and participation in the pathogenesis of cardiovascular diseases.

Failure to reduce C-reactive protein levels more than 25% in the last 24 hours before intensive care unit discharge predicts higher in-hospital mortality: A cohort study ☆,☆☆

PURPOSE To discharge a patient from the intensive care unit (ICU) is a complex decision-making process because in-hospital mortality after critical illness may be as high as up to 27%. Static C-reactive protein (CRP) values have been previously evaluated as a predictor of post-ICU mortality with conflicting results. Therefore, we evaluated the CRP ratio in the last 24 hours before ICU discharge as a predictor of in-hospital outcomes. METHODS A retrospective cohort study was performed in 409 patients from a 6-bed ICU of a university hospital. Data were prospectively collected during a 4-year period. Only patients discharged alive from the ICU with at least 72 hours of ICU length of stay were evaluated. RESULTS In-hospital mortality was 18.3% (75/409). Patients with reduction less than 25% in CRP concentrations at 24 hours as compared with 48 hours before ICU discharge had a worse prognosis, with increased mortality (23% vs 11%, P = .002) and post-ICU length of stay (26 [7-43] vs 11 [5-27] days, P = .036). Moreover, among hospital survivors (n = 334), patients with CRP reduction less than 25% were discharged later (hazard ratio, 0.750; 95% confidence interval, 0.602-0.935; P = .011). CONCLUSIONS In this large cohort of critically ill patients, failure to reduce CRP values more than 25% in the last 24 hours of ICU stay is a strong predictor of worse in-hospital outcomes.

Sepsis-related deaths in Brazil: an analysis of the national mortality registry from 2002 to 2010

IntroductionLimited population-based epidemiologic information about sepsis’ demography, including its mortality and temporal changes is available from developing countries. We investigated the epidemiology of sepsis deaths in Brazil using secondary data from the Brazilian Mortality Information System.MethodsRetrospective descriptive analysis of Brazilian multiple-cause-of-death data between 2002 and 2010, with sepsis-associated International Classification of Diseases, 10th Revision (ICD-10) code indicated as the cause of death. Population-based sepsis associated mortality rates and trends were estimated. Annual population-based mortality rates were calculated using age-stratified population estimates from the 2010 census provided by the Brazilian Institute of Geography and Statistics as denominators.ResultsThe total number of annual deaths recorded in Brazil increased over the decade, from 982,294 deaths reported in 2002 to 1,133,761 deaths reported in 2010. The number of sepsis associated deaths also increased both in absolute numbers and proportions from 95,972 (9.77% of total deaths) in 2002 to 186,712 deaths (16.46%) in 2010. The age-adjusted rate of sepsis-associated mortality increased from 69.5 deaths per 100,000 to 97.8 deaths per 100,000 population from 2002 to 2010 (P <0.001). Sepsis-associated mortality was higher in individuals older than 60 years of age as compared to subjects aged 0 to 20 years (adjusted rate ratio 15.7 (95% confidence interval (CI) 15.6 to 15.8)) and in male subjects (1.15 (95% CI 1.15 to 1.16)).ConclusionsBetween 2002 and 2010 the contribution of sepsis to all cause mortality as reported in multiple-cause-of-death forms increased significantly in Brazil. Age-adjusted mortality rates by sepsis also increased in the last decade. Our results confirm the importance of sepsis as a significant healthcare issue in Brazil.

Sepsis-Associated Outcomes in Critically Ill Patients with Malignancies

RATIONALE Sepsis is a major cause of mortality among critically ill patients with cancer. Information about clinical outcomes and factors associated with increased risk of death in these patients is necessary to help physicians recognize those patients who are most likely to benefit from ICU therapy and identify possible targets for intervention. OBJECTIVES In this study, we evaluated cancer patients with sepsis chosen from a multicenter prospective study to characterize their clinical characteristics and to identify independent risk factors associated with hospital mortality. METHODS Subgroup analysis of a multicenter prospective cohort study conducted in 28 Brazilian intensive care units (ICUs) to evaluate adult cancer patients with severe sepsis and septic shock. We used logistic regression to identify variables associated with hospital mortality. MEASUREMENTS AND MAIN RESULTS Of the 717 patients admitted to the participating ICUs, 268 (37%) had severe sepsis (n = 142, 53%) or septic shock (n = 126, 47%). These patients comprised the population of the present study. The mean score on the third version of the Simplified Acute Physiology Score was 62.9 ± 17.7 points, and the median Sequential Organ Failure Assessment score was 9 (7-12) points. The most frequent sites of infection were the lungs (48%), intraabdominal region (25%), bloodstream as primary infection (19%), and urinary tract (17%). Half of the patients had microbiologically proven infections, and Gram-negative bacteria were the most common pathogens causing sepsis (31%). ICU and hospital mortality rates were 42% and 56%, respectively. In multivariable analysis, the number of acute organ dysfunctions (odds ratio [OR], 1.48; 95% confidence interval [CI], 1.16-1.87), hematological malignancies (OR, 2.57; 95% CI, 1.05-6.27), performance status 2-4 (OR, 2.53; 95% CI, 1.44-4.43), and polymicrobial infections (OR, 3.74; 95% CI, 1.52-9.21) were associated with hospital mortality. CONCLUSIONS Sepsis is a common cause of critical illness in patients with cancer and remains associated with high mortality. Variables related to underlying malignancy, sepsis severity, and characteristics of infection are associated with a grim prognosis.

One-year survival and resource use after critical illness: impact of organ failure and residual organ dysfunction in a cohort study in Brazil

IntroductionIn this study, we evaluated the impacts of organ failure and residual dysfunction on 1-year survival and health care resource use using Intensive Care Unit (ICU) discharge as the starting point.MethodsWe conducted a historical cohort study, including all adult patients discharged alive after at least 72 h of ICU stay in a tertiary teaching hospital in Brazil. The starting point of follow-up was ICU discharge. Organ failure was defined as a value of 3 or 4 in its corresponding component of the Sequential Organ Failure Assessment score, and residual organ dysfunction was defined as a score of 1 or 2. We fit a multivariate flexible Cox model to predict 1-year survival.ResultsWe analyzed 690 patients. Mortality at 1 year after discharge was 27 %. Using multivariate modeling, age, chronic obstructive pulmonary disease, cancer, organ dysfunctions and albumin at ICU discharge were the main determinants of 1-year survival. Age and organ failure were non-linearly associated with survival, and the impact of organ failure diminished over time. We conducted a subset analysis with 561 patients (81 %) discharged without organ failure within the previous 24 h of discharge, and the number of residual organs in dysfunction remained strongly associated with reduced 1-year survival. The use of health care resources among hospital survivors was substantial within 1 year: 40 % of the patients were rehospitalized, 52 % visited the emergency department, 90 % were seen at the outpatient clinic, 14 % attended rehabilitation outpatient services, 11 % were followed by the psychological or psychiatric service and 7 % used the day hospital facility. Use of health care resources up to 30 days after hospital discharge was associated with the number of organs in dysfunction at ICU discharge.ConclusionsOrgan failure was an important determinant of 1-year outcome of critically ill survivors. Nevertheless, the impact of organ failure tended to diminish over time. Resource use after critical illness was elevated among ICU survivors, and a targeted action is needed to deliver appropriate care and to reduce the late critical illness burden.