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Purpose: To assess the effect of antisense therapy to block kallikrein-kinin pathway in COVID-19 patients., Material and Methods: Randomized, placebo-controlled, double blind, controlled trial enrolling hospitalized COVID-19 patients that required supplementary oxygen to sustain peripheral oxygen saturation. Key exclusion criteria included use of mechanical ventilation or vasopressors, and patients with more than 10 days since symptom onset or more than 48 h of oxygen use. Patients were randomized to either one subcutaneous dose of ISIS721744, an antisense that blocks prekallikrein, or placebo. The primary outcome was the number of days alive and free of oxygen support up to 15 days (DAFOR15). Secondary endpoints included organ failure score, need and duration of mechanical ventilation up to 15 days, and all-cause mortality at 30 days. Exploratory endpoints included physiological parameters, biomarkers, and quality of life., Results: From October 10, 2020, to December 09, 2020, 111 patients were randomized at thirteen sites in Brazil (56 to treatment and 55 to control group). Average age was 57.5 years, and most patients were male (68.5%). There were no significant differences in DAFOR15 between groups (5.9 ± 5.2 days for the intervention arm and 7.7 ± 5.1 for the control group; mean difference - 0.65, 95% confidence intervals from -2.95 to 1.36, p = 0.520)., Conclusion: Antisense therapy designed to block the kallikrein-kinin pathway did not demonstrate clinical benefits in increasing days-alive without respiratory support at 15 days in patients with COVID-19 during the first wave in 2020., Gov Identifier: NCT04549922., Competing Interests: Declaration of competing interest None. This study was funded by Ionis Pharmaceutical, US, through a grant provided to HCor. The sponsor reviewed and agreed with the protocol, but had no role in any other aspect of the trial execution. MJ and GB were Ionis employees at the time this study was designed and provided relevant feedback on design of the trial and reviewed the final manuscript for intellectually relevant content. FGZ has received consulting fees from Baxter, unrelated to the scope of this manuscript., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

The growing population of solid organ transplant (SOT) recipients is at a significantly increased risk for developing infections. In some patients, the infection can lead to a dysregulated systemic inflammatory response with acute organ dysfunction. SOT recipients with sepsis tend to have less fever and leukocytosis instances. Moreover, they have diminished symptoms and attenuated clinical and radiologic findings. The current management of sepsis is similar to general patients. It relies mainly on early recognition and treatment, including appropriate administration of antibiotics and resuscitation with intravenous fluids and vasoactive drugs when needed. The infusion of fluids should be closely monitored because elevated central venous pressure levels and fluid overload can be particularly harmful. There is no consensus on how to manage immunosuppressive therapies during sepsis, although dose reduction or withdrawal is suggested to improve the host immunological response. There is compelling evidence suggesting that infections are associated with reduced allograft and patient survival. However, the traditional belief that SOT patients who develop sepsis have worse outcomes than non-transplanted patients has been challenged.

Background: The purpose of this study was to assess the efficacy of open lung biopsy (OLB) in determining the specific diagnosis and the related complications in patients with undiagnosed diffuse pulmonary infiltrates., Methods: This single center, retrospective study included adult kidney transplant patients who underwent OLB. The patients had diffuse pulmonary infiltrates without definitive diagnoses and failed to respond to empiric antibiotic treatment. We analyzed the number of specific diagnoses, changes in treatment and the occurrence of complications in these patients. A logistic regression was used to determine which variables were predictors of hospital mortality., Results: From April 2010 to April 2014, 87 patients consecutively underwent OLB. A specific diagnosis was reached in 74 (85.1%) patients. In 46 patients (53%), their therapeutic management was changed after the OLB results. Twenty-five (28.7%) patients had complications related to the OLB. The hospital mortality rate was 25.2%. Age, SAPS3 score and complications related to the procedure were independent predictors of all-cause mortality., Conclusions: OLB is a high-risk procedure with a high diagnostic yield in kidney transplant patients with diffuse pulmonary infiltrates who did not have a definitive diagnosis and who failed to respond to empiric antibiotic treatment. Complications related to OLB were common and were independently associated with intra-hospital mortality., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare.

Objective:: To evaluate the incidence of agitation in the first 7 days after intensive care unit admission, its risk factors and its associations with clinical outcomes., Methods:: This single-center prospective cohort study included all patients older than 18 years with a predicted stay > 48 hours within the first 24 hours of intensive care unit admission. Agitation was defined as a Richmond Agitation Sedation Scale score ≥ +2, an episode of agitation or the use of a specific medication recorded in patient charts., Results:: Agitation occurred in 31.8% of the 113 patients. Multivariate analysis showed that delirium [OR = 24.14; CI95% 5.15 - 113.14; p < 0.001], moderate or severe pain [OR = 5.74; CI95% 1.73 - 19.10; p = 0.004], mechanical ventilation [OR = 10.14; CI95% 2.93 - 35.10; p < 0.001], and smoking habits [OR = 4.49; CI95% 1.33 - 15.17; p = 0.015] were independent factors for agitation, while hyperlactatemia was associated with a lower risk [OR = 0.169; CI95% 0.04 - 0.77; p = 0.021]. Agitated patients had fewer mechanical ventilation-free days at day 7 (p = 0.003)., Conclusion:: The incidence of agitation in the first 7 days after admission to the intensive care unit was high. Delirium, moderate/severe pain, mechanical ventilation, and smoking habits were independent risk factors. Agitated patients had fewer ventilator-free days in the first 7 days., Competing Interests: None.

Purpose: The objective of our study was to assess the reliability of the distensibility index of the inferior vena cava (dIVC) as a predictor of fluid responsiveness in postoperative, mechanically ventilated patients and compare its accuracy with that of the pulse pressure variation (PPV) measurement., Materials and Methods: We included postoperative mechanically ventilated and sedated patients who underwent volume expansion with 500mL of crystalloids over 15minutes. A response to fluid infusion was defined as a 15% increase in the left ventricular outflow tract velocity time integral according to transthoracic echocardiography. The inferior vena cava diameters were recorded by a subcostal view using the M-mode and the PPV by automatic calculation. The receiver operating characteristic (ROC) curves were generated for the baseline dIVC and PPV., Results: Twenty patients were included. The area under the ROC curve for dIVC was 0.84 (95% confidence interval, 0.63-1.0), and the best cutoff value was 16% (sensitivity, 67%; specificity, 100%). The area under the ROC curve for PPV was 0.92 (95% confidence interval, 0.76-1.0), and the best cutoff was 12.4% (sensitivity, 89%; specificity, 100%). A noninferiority test showed that dIVC cannot replace PPV to predict fluid responsiveness (P=.28)., Conclusion: The individual PPV discriminative properties for predicting fluid responsiveness in postoperative patients seemed superior to those of dIVC., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objectives: To evaluate the serum concentrations of vitamin D and their variations in patients with severe sepsis or septic shock and in control subjects upon admission and after 7 days of hospitalization in the intensive care unit and to correlate these concentrations with the severity of organ dysfunction., Methods: This case-control, prospective, observational study involved patients aged > 18 years with severe sepsis or septic shock paired with a control group. Serum vitamin D concentrations were measured at inclusion (D0) and on the seventh day after inclusion (D7). Severe deficiency was defined as vitamin D levels < 10ng/ml, deficiency as levels between 10 and 20ng/ml, insufficiency as levels between 20 and 30ng/ml, and sufficiency as levels ≥ 30ng/mL. We considered a change to a higher ranking, together with a 50% increase in the absolute concentration, to represent an improvement., Results: We included 51 patients (26 with septic shock and 25 controls). The prevalence of vitamin D concentration ≤ 30ng/ml was 98%. There was no correlation between the serum concentration of vitamin D at D0 and the SOFA score at D0 or D7 either in the general population or in the group with septic shock. Patients with improvement in vitamin D deficiency had an improved SOFA score at D7 (p = 0.013)., Conclusion: In the population studied, patients with septic shock showed improvement in the serum concentrations of vitamin D on the seventh day compared with the controls. We also found a correlation between higher vitamin D concentrations and a greater decrease in the severity of organ dysfunction.

Objectives: The purpose of this study was to test if venous blood drawn from femoral access can be used to estimate the central venous oxygen saturation and arterial lactate levels in critically ill patients., Methods: Bland-Altman analysis and Spearman correlations were used to compare the femoral venous oxygen saturation and central venous oxygen saturation as well as arterial lactate levels and femoral lactate. A pre-specified subgroup analysis was conducted in patients with signs of hypoperfusion. In addition, the clinical agreement was also investigated., Results: Blood samples were obtained in 26 patients. In 107 paired samples, there was a moderate correlation (r = 0.686, p < 0.0001) between the central venous oxygen saturation and femoral venous oxygen saturation with a bias of 8.24 ± 10.44 (95% limits of agreement: -12.23 to 28.70). In 102 paired samples, there was a strong correlation between the arterial lactate levels and femoral lactate levels (r = 0.972, p < 0.001) with a bias of -2.71 ± 9.86 (95% limits of agreement: -22.03 to 16.61). The presence of hypoperfusion did not significantly change these results. The clinical agreement for venous saturation was inadequate, with different therapeutic decisions in 22.4% of the situation; for lactate, this was the case only in 5.2% of the situations., Conclusion: Femoral venous oxygen saturation should not be used as a surrogate of central venous oxygen saturation. However, femoral lactate levels can be used in clinical practice, albeit with caution.

Introduction: Constipation is a common problem in intensive care units. We assessed the efficacy and safety of laxative therapy aiming to promote daily defecation in reducing organ dysfunction in mechanically ventilated patients., Methods: We conducted a prospective, randomized, controlled, nonblinded phase II clinical trial at two general intensive care units. Patients expected to remain ventilated for over 3 days were randomly assigned to daily defecation or control groups. The intervention group received lactulose and enemas to produce 1-2 defecations per day. In the control group, absence of defecation was tolerated up to 5 days. Primary outcome was the change in Sequential Organ Failure Assessment (SOFA) score between the date of enrollment and intensive care unit discharge, death or day 14., Results: We included 88 patients. Patients in the treatment group had a higher number of defecations per day (1.3 ± 0.42 versus 0.7 ± 0.56, p < 0.0001) and lower percentage of days without defecation (33.1 ± 15.7% versus 62.3 ± 24.5%, p < 0.0001). Patients in the intervention group had a greater reduction in SOFA score (-4.0 (-6.0 to 0) versus -1.0 (-4.0 to 1.0), p = 0.036) with no difference in mortality rates or in survival time. Adverse events were more frequent in the treatment group (4.5 (3.0-8.0) versus 3.0 (1.0-5.7), p = 0.016), including more days with diarrhea (2.0 (1.0-4.0) versus 1.0 (0-2.0) days, p < 0.0001). Serious adverse events were rare and did not significantly differ between groups., Conclusions: Laxative therapy improved daily defecation in ventilated patients and was associated with a greater reduction in SOFA score., Trial Registration: Clinical Trials.gov NCT01607060, registered 24 May 2012.

Purpose: The purpose of this study is to assess whether late positive fluid balances are associated with acute kidney injury and mortality in severe sepsis and septic shock., Methods: In this retrospective study, fluid balances were calculated at 3 different time points: the onset of organ dysfunction attributed to sepsis, sepsis diagnosis, and vasopressors initiation. Data were analyzed in logistic regression models for mortality and acute kidney injury as outcomes., Results: We included 116 patients. A RIFLE score F, diuresis less than 0.9 L from the second day after the first organ dysfunction, and fluid balance more than 3 L between the 24th and the 48th hour after diagnosis were independently associated with higher mortality, whereas in the subgroup with shock, only the latter parameter and diuresis less than 0.85 L on the first day of shock were independent risk factors. After adjusting for age, creatinine more than 1.2 mg/dL, a nonrenal Sequential Organ Failure Assessment greater than or equal to 7.5 on the first day and urine output less than 1.3 L on the first day after organ dysfunction were independent risk factors for RIFLE F. No relationship was found between fluid balance and acute kidney injury., Conclusion: Late positive fluid balance is an independent risk factor for mortality in severe sepsis. Positive fluid balances are not associated with either protection against or risk for acute kidney injury., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Objective: To evaluate the immediate effects of red blood cell transfusion on central venous oxygen saturation and lactate levels in septic shock patients with different transfusion triggers., Methods: We included patients with a diagnosis of septic shock within the last 48 hours and hemoglobin levels below 9.0 g/dL Patients were randomized for immediate transfusion with hemoglobin concentrations maintained above 9.0 g/dL (Group Hb9) or to withhold transfusion unless hemoglobin felt bellow 7.0 g/dL (Group Hb7). Hemoglobin, lactate, central venous oxygen saturation levels were determined before and one hour after each transfusion., Results: We included 46 patients and 74 transfusions. Patients in Group Hb7 had a significant reduction in median lactate from 2.44 (2.00 - 3.22) mMol/L to 2.21 (1.80 - 2.79) mMol/L, p = 0.005, which was not observed in Group Hb9 [1.90 (1.80 - 2.65) mMol/L to 2.00 (1.70 - 2.41) mMol/L, p = 0.23]. Central venous oxygen saturation levels increased in Group Hb7 [68.0 (64.0 - 72.0)% to 72.0 (69.0 - 75.0)%, p < 0.0001] but not in Group Hb9 [72.0 (69.0 - 74.0)% to 72.0 (71.0 - 73.0)%, p = 0.98]. Patients with elevated lactate or central venous oxygen saturation < 70% at baseline had a significant increase in these variables, regardless of baseline hemoglobin levels. Patients with normal values did not show a decrease in either group., Conclusion: Red blood cell transfusion increased central venous oxygen saturation and decreased lactate levels in patients with hypoperfusion regardless of their baseline hemoglobin levels. Transfusion did not appear to impair these variables in patients without hypoperfusion. ClinicalTrials.gov NCT01611753.

Introduction: The growing number of renal transplant recipients in a sustained immunosuppressive state is a factor that can contribute to increased incidence of sepsis. However, relatively little is known about sepsis in this population. The aim of this single-center study was to evaluate the factors associated with hospital mortality in renal transplant patients admitted to the intensive care unit (ICU) with severe sepsis and septic shock., Methods: Patient demographics and transplant-related and ICU stay data were retrospectively collected. Multiple logistic regression was conducted to identify the independent risk factors associated with hospital mortality., Results: A total of 190 patients were enrolled, 64.2% of whom received kidneys from deceased donors. The mean patient age was 51 ± 13 years (males, 115 [60.5%]), and the median APACHE II was 20 (16-23). The majority of patients developed sepsis late after the renal transplantation (2.1 [0.6-2.3] years). The lung was the most common infection site (59.5%). Upon ICU admission, 16.4% of the patients had ≤ 1 systemic inflammatory response syndrome criteria. Among the patients, 61.5% presented with ≥ 2 organ failures at admission, and 27.9% experienced septic shock within the first 24 hours of ICU admission. The overall hospital mortality rate was 38.4%. In the multivariate analysis, the independent determinants of hospital mortality were male gender (OR = 5.9; 95% CI, 1.7-19.6; p = 0.004), delta SOFA 24 h (OR = 1.7; 95% CI, 1.2-2.3; p = 0.001), mechanical ventilation (OR = 30; 95% CI, 8.8-102.2; p<0.0001), hematologic dysfunction (OR = 6.8; 95% CI, 2.0-22.6; p = 0.002), admission from the ward (OR = 3.4; 95% CI, 1.2-9.7; p = 0.02) and acute kidney injury stage 3 (OR = 5.7; 95% CI,1.9-16.6; p = 0.002)., Conclusions: Hospital mortality in renal transplant patients with severe sepsis and septic shock was associated with male gender, admission from the wards, worse SOFA scores on the first day and the presence of hematologic dysfunction, mechanical ventilation or advanced graft dysfunction.

Background: In the later stages of circulatory shock, monitoring should help to avoid fluid overload. In this setting, volume expansion is ideally indicated only for patients in whom the cardiac index (CI) is expected to increase. Crystalloids are usually the choice for fluid replacement. As previous studies evaluating the hemodynamic effect of crystalloids have not distinguished responders from non-responders, the present study was designed to evaluate the duration of the hemodynamic effects of crystalloids according to the fluid responsiveness status., Methods: This is a prospective observational study conducted after the initial resuscitation phase of circulatory shock (>6 h vasopressor use). Critically ill, sedated adult patients monitored with a pulmonary artery catheter who received a fluid challenge with crystalloids (500 mL infused over 30 min) were included. Hemodynamic variables were measured at baseline (T0) and at 30 min (T1), 60 min (T2), and 90 min (T3) after a fluid bolus, totaling 90 min of observation. The patients were analyzed according to their fluid responsiveness status (responders with CI increase >15% and non-responders ≤15% at T1). The data were analyzed by repeated measures of analysis of variance., Results: Twenty patients were included, 14 of whom had septic shock. Overall, volume expansion significantly increased the CI: 3.03 ± 0.64 L/min/m(2) to 3.58 ± 0.66 L/min/m(2) (p < 0.05). From this period, there was a progressive decrease: 3.23 ± 0.65 L/min/m(2) (p < 0.05, T2 versus T1) and 3.12 ± 0.64 L/min/m(2) (p < 0.05, period T3 versus T1). Similar behavior was observed in responders (13 patients), 2.84 ± 0.61 L/min/m(2) to 3.57 ± 0.65 L/min/m(2) (p < 0.05) with volume expansion, followed by a decrease, 3.19 ± 0.69 L/min/m(2) (p < 0.05, T2 versus T1) and 3.06 ± 0.70 L/min/m(2) (p < 0.05, T3 versus T1). Blood pressure and cardiac filling pressures also decreased significantly after T1 with similar findings in both responders and non-responders., Conclusions: The results suggest that volume expansion with crystalloids in patients with circulatory shock after the initial resuscitation has limited success, even in responders.

Background and Objectives: anemia is a common clinical finding in intensive care units. The red blood cell transfusion is the main form of treatment, despite the associated risks. Thus, we proposed to evaluate the profile of transfusional patients in different intensive care units., Methods: prospective analysis of patients admitted in the intensive care units of a tertiary university hospital with an indication for transfusion of packed red blood cells. Demographic profile and transfusional profile were collected, a univariate analysis was done, and the results were considered significant at p ≤ 0.05., Results: 408 transfusions were analyzed in 71 patients. The mean hemoglobin concentration on admission was 9.7 ± 2.3g/dL and the pre-transfusional concentration was 6.9 ± 1.1g/dL. The main indications for transfusion were hemoglobin concentration (49%) and active bleeding (32%). The median number of units transfused per episode was 2 (1-2) and the median storage time was 14 (7-21) days. The number of patients transfused with hemoglobin levels greater than 7 g/dL and the number of bags transfused per episode were significantly different among intensive care units. Patients who received three or more transfusions had longer mechanical ventilation time and intensive care unit stay and higher mortality after 60 days. There was an association of mortality with disease severity but not with transfusional characteristics., Conclusions: the practice of blood products transfusion was partially in agreement with the guidelines recommended, although there are differences in behavior between the different profiles of intensive care units. Transfused patients evolved with unfavorable outcomes. Despite the scarcity of blood in blood banks, the mean storage time of the bags was high., (Copyright © 2013 Sociedade Brasileira de Anestesiologia. Published by Elsevier Editora Ltda. All rights reserved.)

Background: Inadequate nutrition support is common among critically ill patients, and identification of risk factors for such inadequacy might help in improving nutrition support., Objective: To determine how often daily calorie goals are met and the factors responsible for inadequate nutrition support. Methods A single-center prospective cohort study. Each patient's demographic and clinical characteristics, the need for ventilatory support, the use and dosage of medications, the number of nursing staff per bed, the time elapsed from admission to the intensive care unit until the effective start of enteral feeding, and the causes for nonadministration were recorded. Achievement of daily calorie goals was determined and correlated with risk factors., Results: A total of 262 daily evaluations were done in 40 patients. Daily calorie goal was achieved in only 46.2% of the evaluations (n = 121), with a mean of 74.8% of the prescribed volume of enteral nutrition infused daily. Risk factors for inadequate nutrition support were the use of midazolam (odds ratio, 1.58; 95% CI, 1.18-2.11) and fewer nursing professionals per bed (odds ratio, 2.56; 95% CI, 1.43-4.57). Conclusion Achievement of daily calorie goals was inadequate, and the main factors associated with this failure were the use and dosage of midazolam and the number of nurses available.

Background: Previous studies showed higher sepsis mortality rates in Brazil compared to other developed or developing countries. Moreover, another trial demonstrated an increased mortality rate in public hospitals compared to private hospitals in Brazil. The reasons for these findings may include delayed recognition and inadequate treatment of sepsis in public facilities. We designed this study to evaluate the factors associated with mortality in septic patients admitted to intensive care units in a network of public and private institutions., Materials and Methods: This study is a retrospective analysis of a prospective cohort of sepsis patients in 19 private and public institutions in Brazil. We analyzed data from the original database and collected additional data to assess compliance to the treatment guidelines and to determine the time from the onset of organ dysfunction and the sepsis diagnosis by the healthcare team., Results: A total of 396 patients were analyzed. Patients in public hospitals were younger, had a greater number of dysfunctional organs at baseline and a lower chance to have sepsis diagnosed within two hours of the onset of organ dysfunction. Private hospitals had a better compliance to lactate and blood culture sampling and maintenance of glycemic control. The multivariate analysis showed that age, disease severity at baseline and being treated at a public hospital were independent risk factors for mortality. A delay in the sepsis diagnosis of longer than two hours was associated with mortality only in the public setting., Conclusions: We confirmed a lower sepsis mortality rate in the private hospitals of this network. Being treated in a public hospital was an independent factor for mortality. Delayed recognition of sepsis was more frequent in public institutions and this might have been associated with a higher mortality. Improving sepsis recognition and early diagnosis may be important targets in public institutions.

Background: The applicability of pulse pressure variation (ΔPP) to predict fluid responsiveness using lung-protective ventilation strategies is uncertain in clinical practice. We designed this study to evaluate the accuracy of this parameter in predicting the fluid responsiveness of septic patients ventilated with low tidal volumes (TV) (6 ml kg(-1))., Methods: Forty patients after the resuscitation phase of severe sepsis and septic shock who were mechanically ventilated with 6 ml kg(-1) were included. The ΔPP was obtained automatically at baseline and after a standardized fluid challenge (7 ml kg(-1)). Patients whose cardiac output increased by more than 15% were considered fluid responders. The predictive values of ΔPP and static variables [right atrial pressure (RAP) and pulmonary artery occlusion pressure (PAOP)] were evaluated through a receiver operating characteristic (ROC) curve analysis., Results: Thirty-four patients had characteristics consistent with acute lung injury or acute respiratory distress syndrome and were ventilated with high levels of PEEP [median (inter-quartile range) 10.0 (10.0-13.5)]. Nineteen patients were considered fluid responders. The RAP and PAOP significantly increased, and ΔPP significantly decreased after volume expansion. The ΔPP performance [ROC curve area: 0.91 (0.82-1.0)] was better than that of the RAP [ROC curve area: 0.73 (0.59-0.90)] and pulmonary artery occlusion pressure [ROC curve area: 0.58 (0.40-0.76)]. The ROC curve analysis revealed that the best cut-off for ΔPP was 6.5%, with a sensitivity of 0.89, specificity of 0.90, positive predictive value of 0.89, and negative predictive value of 0.90., Conclusions: Automatized ΔPP accurately predicted fluid responsiveness in septic patients ventilated with low TV.

Objective: To evaluate the presence of diabetes mellitus and impaired glucose tolerance in intensive care unit inpatients., Methods: The study included patients in post-surgical care for elective and emergency surgery and excluded those patients with known diabetes mellitus. To diagnose prior serum glucose level disorders, we considered the value of glycated hemoglobin (HbA1c) at the time of admission, classifying the patients as normal (<5.7%), glucose intolerant (5.7-6.4%) or diabetic (>6.4%). During the first 3 days of the patient's hospital stay, glycemic control and clinical complications were assessed. Mortality was monitored for 28 days. For the statistical analyses, chi-square, ANOVA, student's t, Kruskal-Wallis or Mann Whitney tests were used., Results: Thirty patients were included in the present study, 53% of whom were women; the patients had a mean age of 53.4±19.7 years and an APACHE II score of 13.6±6.6. The majority of patients were admitted for severe sepsis or septic shock followed by post-operative care for elective surgery, oncological surgery, multiple traumas and emergency surgery. When classifying these patients according to HbA1c, despite the absence of a prior history of diabetes mellitus, only 13.3% had a normal HbA1c level, 23.3% had levels compatible with the diagnosis of diabetes mellitus and 63.3% had levels compatible with impaired glucose tolerance. We found a significant association between the diagnosis of diabetes mellitus or impaired glucose tolerance and the use of vasoactive drugs (p=0.04)., Conclusion: A high prevalence of undiagnosed diabetes mellitus and impaired glucose tolerance was observed in inpatients at a general intensive care unit.

Context and Objective: The ideal site for lactate collection has not been clearly established. This study aimed to evaluate associations between lactate levels in arterial blood (Lart), peripheral venous blood (Lper) and central venous blood (Lcen) in patients with severe sepsis or septic shock., Design and Setting: Cross-sectional analytical study in an tertiary university hospital., Method: Samples from patients with a central venous catheter and from healthy volunteers (control group) were collected. Blood was drawn simultaneously for measurements of Lart, Lper and Lcen, and the first sample was collected less than 24 hours after the onset of organ dysfunction. The results were analyzed using Pearson correlation, Bland-Altman and McNemar tests., Results: A total of 238 samples were collected from 32 patients. The correlation results were r = 0.79 (P < 0.0001) for Lart/Lper and r = 0.84 (P < 0.0001) for Lart/Lcen. Bland-Altman showed large limits of agreement: -3.2 ± 4.9 (-12.8 to 6.4) and -0.8 ± 5.9 (-12.5 to 10.8), for Lper and Lcen respectively. In the control group, there was greater correlation (r = 0.9009, P = 0.0004) and agreement: -0.7 ± 1.2 (-3.1 to 1.7). Regarding clinical intervention, there was good agreement between Lart/Lcen (96.3%; three disagreements), with worst results for Lart/Lper (87.0%) with 10 cases of disagreement (P = 0.04). In eight patients (80.0%) Lper was higher than Lart., Conclusion: Lcen, and not Lper, can replace Lart with good correlation and clinical agreement. Lper tends to overestimate Lart, thus leading to unnecessary therapeutic interventions.

Objective: Homocysteine and sepsis are both associated with inflammation and endothelial activation. Therefore this study was aimed to evaluate if the plasma homocystein level is related with the septic patient clinical severity., Methods: Severe sepsis or septic shock patients, with less than 48 hours from organ dysfunction start, were admitted to this prospective observational study. Homocysteine levels were determined by the time of study admission and then on the Days 3, 7 and 14. The homocysteine association with the Sequential Organ Failure Assessment (SOFA) score was evaluated using the Sperman test, and its association with mortality using the Mann-Whitney test. A p<0.05 value was considered statistically significant., Results: Twenty one patients were enrolled, and 60 blood samples were collected to measure total homocysteine [median 6.92 (5.27 - 9.74 μmol/L)]. The Sperman correlation test showed no association between homocysteine and SOFA ( r=0.15 and p=0.26). Also no correlation was found for the homocysteine level by the study admission time and the difference between the Day 3 SOFA score versus by study admission (deltaSOFA) (r=0.04 and p=0.87). Homocysteine variation between the Day 3 and the study admission (deltaHmc) and SOFA score variation in the same period were not correlated (r=-0.11 and p=0.66). Homocysteine by the study admission was not correlated with death in intensive care unit rate (p= 0.46) or in-hospital death rate (p = 0.13). This was also true for deltaHmc (p=0.12 and p=0.99, respectively)., Conclusion: Baseline homocysteine levels and its variations within the first dysfunction days were not related with septic patients' worsened organ function parameters or mortality.

Context and Objective: Although glucometers have not been validated for intensive care units, they are regularly used. The aim of this study was to compare and assess the accuracy and clinical agreement of arterial glucose concentration obtained using colorimetry (Agluc-lab), capillary (Cgluc-strip) and arterial (Agluc-strip) glucose concentration obtained using glucometry and central venous glucose concentration obtained using colorimetry (Vgluc-lab)., Design and Setting: Cross-sectional study in a university hospital., Method: Forty patients with septic shock and stable individuals without infection were included. The correlations between measurements were assessed both in the full sample and in subgroups using noradrenalin and presenting signs of tissue hypoperfusion., Results: Cgluc-strip showed the poorest correlation (r = 0.8289) and agreement (-9.87 +/- 31.76). It exceeded the limits of acceptable variation of the Clinical and Laboratory Standards Institute in 23.7% of the cases, and was higher than Agluc-lab in 90% of the measurements. Agluc-strip showed the best correlation (r = 0.9406), with agreement of -6.75 +/- 19.07 and significant variation in 7.9%. For Vgluc-lab, r = 0.8549, with agreement of -4.20 +/- 28.37 and significant variation in 15.7%. Significant variation was more frequent in patients on noradrenalin (36.4% versus 6.3%; P = 0.03) but not in the subgroup with hypoperfusion. There was discordance regarding clinical management in 25%, 22% and 15% of the cases for Cgluc-strip, Vgluc-lab and Agluc-strip, respectively., Conclusion: Cgluc-strip should be avoided, particularly if noradrenalin is being used. This method usually overestimates the true glucose levels and gives rise to management errors., Clinical Trial Registration: ACTRN12608000513314 (registered as an observational, cross-sectional study).

Constipation is a common complication identified among critically ill patients. Its incidence is highly variable due to lack of definition of such patients. Besides the already known consequences of constipation, in recent years it was observed that this complication may also be related to worse prognosis of critically ill patients. This review endeavors to describe the main available scientific evidence showing that constipation is a prognostic marker and a clinical representation of intestinal dysfunction, in addition to eventually interfering in the prognosis with treatment. Ogilvie syndrome, a major cause of morbidity and mortality in intensive care units was also reviewed. Considering the above cases it was concluded that more attention to this disorder is required in intensive care units as well as development of protocols for diagnosis and management of critically ill patients.

Introduction: Central venous oxygen saturation (SvcO2) has been proposed as an alternative for mixed venous oxygen saturation (SvO2), with a variable level of acceptance according to available data. This study aimed to evaluate possible differences between SvO2 and SvcO2 or atrial venous saturation (SvaO2), with emphasis on the role of cardiac output and their impact on clinical management of the septic patient., Methods: This is an observational, prospective study of patients with septic shock monitored by pulmonary artery catheter. Blood was obtained simultaneously for SvcO2, SvO2 and SvaO2 determination. Linear correlation (significant if p<0.05) and agreement analysis (Bland-Altman) were performed with samples and subgroups according to cardiac output. Moreover, agreement about clinical management based on these samples was evaluated., Results: Sixty one measurements from 23 patients were obtained, median age of 65.0 (49.0-75.0) years and mean APACHE II of 27.7±6.3. Mean values of SvO2, SvcO2 and SvaO2 were 72.20±8.26%, 74.61±7.60% and 74.64±8.47%. Linear correlation test showed a weak correlation between SvO2 and SvcO2 (r=0.61, p<0.0001) and also between SvO2 and SvaO2 (r=0.70, p<0.0001). Agreements between SvcO2/SvO2 and SvaO2/SvO2 were -2.40±1.96 (-16.20 and 11.40) and -2.40±1.96 (-15.10 and 10.20), respectively, with no difference in the cardiac output subgroups. No agreement was found in clinical management for 27.8% of the cases, both for SvcO2/SvO2 and for SvaO2/SvO2., Conclusion: This study showed that the correlation and agreement between SvO2 and SvcO2 is weak and may lead to different clinical management.

Objectives: This study aimed to assess the impact of the duration of organ dysfunction on the outcome of patients with severe sepsis or septic shock., Methods: Clinical data were collected from hospital charts of patients with severe sepsis and septic shock admitted to a mixed intensive care unit from November 2003 to February 2004. The duration of organ dysfunction prior to diagnosis was correlated with mortality. Results were considered significant if p<0.05., Results: Fifty-six patients were enrolled. Mean age was 55.6+/-20.7 years, mean APACHE II score was 20.6+/-6.9, and mean SOFA score was 7.9+/-3.7. Thirty-six patients (64.3%) had septic shock. The mean duration of organ dysfunction was 1.9+/-1.9 days. Within the univariate analysis, the variables correlated with hospital mortality were: age (p=0.015), APACHE II (p=0.008), onset outside the intensive care unit (p=0.05), blood glucose control (p=0.05) and duration of organ dysfunction (p=0.0004). In the multivariate analysis, only a duration of organ dysfunction persisting longer than 48 hours correlated with mortality (p=0.004, OR: 8.73 (2.37-32.14)), whereas the APACHE II score remained only a slightly significant factor (p=0.049, OR: 1.11 (1.00-1.23)). Patients who received therapeutic interventions within the first 48 hours after the onset of organ dysfunction exhibited lower mortality (32.1% vs. 82.1%, p=0.0001)., Conclusions: These findings suggest that the diagnosis of organ dysfunction is not being made in a timely manner. The time elapsed between the onset of organ dysfunction and initiation of therapeutic intervention can be quite long, and this represents an important determinant of survival in cases of severe sepsis and septic shock.

We examined the behavior of the transcription factor Max during retrograde neuronal degeneration of retinal ganglion cells. Using immunohistochemistry, we found a progressive redistribution of full-length Max from the nucleus to the cytoplasm and dendrites of the ganglion cells following axon damage. Then, the axotomized cells lose all their content of Max, while undergoing nuclear pyknosis and apoptotic cell death. After treatment of retinal explants with either anisomycin or thapsigargin, the rate of nuclear exclusion of Max accompanied the rate of cell death as modulated by either drug. Treatment with a pan-caspase inhibitor abolished both TUNEL staining and immunoreactivity for activated caspase-3, but did not affect the subcellular redistribution of Max immunoreactivity after axotomy. The data show that nuclear exclusion of the transcription factor Max is an early event, which precedes and is independent of the activation of caspases, during apoptotic cell death in the central nervous system., (Copyright 2003 Wiley-Liss, Inc.)

Photoreceptor cell death occurs during both normal and pathological retinal development. We tested for selective induction and blockade of cell death in either retinal photoreceptors or their precursors. Organotypical retinal explants from rats at postnatal days 3-11 were treated in vitro for 24 hr with thapsigargin, okadaic acid, etoposide, anisomycin, or forskolin. Explant sections were examined for cell death, and identification of either photoreceptors or proliferating/immediate postmitotic cells followed imunohistochemistry for either rhodopsin or bromodeoxyuridine and proliferating cell nuclear antigen, respectively. Photoreceptor cell death was selectively induced by either thapsigargin or okadaic acid, whereas death of proliferating/immediate postmitotic cells was induced by etoposide. Prelabeling of proliferating precursors allowed direct demonstration of changing sensitivity of photoreceptors to various chemicals. Degeneration of both photoreceptors and proliferating/immediate postmitotic cells depended on protein synthesis. Increase of intracellular cyclic AMP blocked degeneration of postmitotic, but not of proliferating, photoreceptor precursors. The selective induction and blockade of cell death show that developing photoreceptors undergo progressive changes in mechanisms of programmed cell death associated with phenotypic differentiation., (Copyright 2003 Wiley-Liss, Inc.)

1. We investigated the association of c-Jun with apoptosis within retinal tissue. Explants of the retina of neonatal rats were subject to a variety of procedures that cause apoptosis of specific classes of retinal cells at distinct stages of differentiation. The expression of c-Jun was detected by Western Blot, and immunohistochemistry was done with antibodies made for either N-terminal or C-terminal domains of c-Jun, and correlated with apoptosis detected either by chromatin condensation or by in situ nick end labeling of fragmented DNA. 2. c-Jun protein content was increased in retinal tissue subject to induction of both photoreceptor and ganglion cell death. 3. c-Jun N-terminal immunoreactivity was found mainly in the cytoplasm of apoptotic cells regardless of cell type, of the stage of differentiation, including proliferating cells, or of the means of induction of apoptosis. 4. The data are consistent with the hypothesis that c-Jun is involved in the control of cell death in retinal tissue, but other proteins that cross-react with c-Jun N-terminal antibodies may also be major markers of retinal apoptosis. 5. Antibodies directed to c-Jun N-terminal (aa 91-105) are useful tools to follow apoptotic changes in retinal tissue.

An ATP diphosphohydrolase was identified in the plasma membranes isolated from promastigote forms of Leishmania amazonensis. Both ATP and ADP were hydrolysed at similar rates by the enzyme. Other nucleotides such as UTP, GTP and CTP were also degraded, revealing a broad substrate specificity. Adding ATP and ADP simultaneously, the amount of hydrolysis achieved was compatible with the presence of a single enzyme. ATPase activity was not affected by addition of vanadate, ouabain, thapsigargin, dicyclohexylcarbodiimide, oligomycin and bafilomycin A, thus excluding involvement of P-, F- and V-type ATPases. The effects of pH in the range 6.5-8.5 were examined using ATP or p-NPP as substrate. At pH 7.4, the phosphatase activity decreased, and did not show a significant contribution to ATP hydrolysis. In addition, the enzyme was not inhibited by levamisole and ammonium molybdate, excluding alkaline phosphatase and nucleotidase activities, respectively. Sodium azide (5-10 mM) caused inhibition of the ATP and ADP hydrolysis in a dose-dependent manner. Calcium was the best activating metal ion for both ATPase and ADPase activities. Ultrastructural cytochemical microscopy showed ATP diphosphohydrolase on the surface and flagellar pocket of the parasite. We have proposed that L. amazonensis ATP diphosphohydrolase may participate in the salvage pathway of nucleosides.

Retinal cell differentiation leads to resistance to apoptosis induced by inhibition of protein synthesis, suggesting the accumulation of anti-apoptotic proteins. The redox factor/AP endonuclease Ref-1 (APE, APEX, HAP1) affects both DNA repair and the activity of various transcription factors, and controls sensitivity to genotoxic insults. We studied the expression of Ref-1 in the retina and brain of developing rats. Ref-1 immunoreactivity increased progressively within the nucleus of differentiating retinal cells, whereas it decreased in the developing hippocampal formation. During both natural and experimentally-induced cell death, Ref-1 disappeared from the nucleus of apoptotic cells. Degradation of Ref-1 in axotomized ganglion cells preceded the morphological characteristics of apoptosis. The sensitivity to apoptosis triggered by either thapsigargin or okadaic acid was the highest in photoreceptors, that contain the least Ref-1 among differentiated retinal cells. In both these differentiated cell types, inhibition of protein synthesis prevented the loss of Ref-1 and rescued the neurons. The data suggest that Ref-1 is an anti-apoptotic protein associated with cell differentiation in the retina.

Studies of programmed cell death in the developing retina in vitro are currently reviewed. The results of inhibiting protein synthesis in retinal explants indicate two mechanisms of apoptosis. One mechanism depends on the synthesis of positive modulators ('killer proteins'), while a distinct, latent mechanism appears to be continuously blocked by negative modulators. Extracellular modulators of apoptosis include the neurotrophic factors NT-4 and BDNF, while glutamate may have either a positive or a negative modulatory action on apoptosis. Several protein kinases selectively modulate apoptosis in distinct retinal layers. Calcium and nitric oxide were also shown to affect apoptosis in the developing retinal tissue. The protein c-Jun was found associated with apoptosis in various circumstances, while p53 seems to be selectively expressed in some instances of apoptosis. The results indicate that the sensitivity of each retinal cell to apoptosis is controlled by multiple, interactive, cell type- and context-specific mechanisms. Apoptosis in the retina depends on a critical interplay of extracellular signals delivered through neurotrophic factors, neurotransmitters and neuromodulators, several signal transduction pathways, and the expression of a variety of genes.

The role of protein synthesis in apoptosis was investigated in the retina of developing rats. In the neonatal retina, a ganglion cell layer, containing neurons with long, centrally projecting axons, is separated from an immature neuroblastic layer by a plexiform layer. This trilaminar pattern subsequently evolves to five alternating cell and plexiform layers that constitute the mature retina and a wave of programmed neuron death sweeps through the layers. Apoptosis due to axon damage was found in ganglion cells of retinal explants within 2 days in vitro and was prevented by inhibition of protein synthesis. Simultaneously, protein synthesis blockade induced apoptosis among the undamaged cells of the neuroblastic layer, which could be selectively prevented by an increase in intracellular cyclic AMP. Both the prevention and the induction of apoptosis among ganglion cells or neuroblastic cells, respectively, occurred after inhibition of protein synthesis in vivo. The results show the coexistence of two mechanisms of apoptosis within the organized retinal tissue. One mechanism is triggered in ganglion cells by direct damage and depends on the synthesis of proteins acting as positive modulators of apoptosis. A distinct, latent mechanism is found among immature neuroblasts and may be repressed by continuously synthesized negative modulators, or by an increase in intracellular cyclic AMP.