Plasma Nucleosomes Are Associated With Mortality in Pediatric Acute Respiratory Distress Syndrome.

OBJECTIVES: Circulating nucleosomes and their component histones have been implicated as pathogenic in sepsis and acute respiratory distress syndrome in adults. However, their role in pediatric acute respiratory distress syndrome is unknown. DESIGN: We performed a prospective cohort study in children with acute respiratory distress syndrome, with plasma collection within 24 hours of acute respiratory distress syndrome onset. We associated nucleosome levels with severity of acute respiratory distress syndrome and with nonpulmonary organ failures and tested for association of nucleosomes with PICU mortality and ventilator-free days at 28 days in univariate and multivariable analyses. We also performed proteomics of DNA-bound plasma proteins in a matched case-control study of septic children with and without acute respiratory distress syndrome in order to identify specific histone proteins elevated in acute respiratory distress syndrome. SETTING: Large academic tertiary-care PICU. PATIENTS: Intubated children meeting Berlin criteria for acute respiratory distress syndrome. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We enrolled 333 children with acute respiratory distress syndrome, with 69 nonsurvivors (21%). Plasma nucleosomes were correlated with acute respiratory distress syndrome severity and with the number of nonpulmonary organ failures at acute respiratory distress syndrome onset. Nucleosomes were higher (p < 0.001) in nonsurvivors (0.40 [interquartile range, 0.20-0.71] arbitrary units) relative to survivors (0.10 [interquartile range, 0.04-0.25] arbitrary units). Nucleosomes were associated with PICU mortality in multivariable analysis (adjusted odds ratio 1.84 per 1 sd increase; 95% CI, 1.38-2.45; p < 0.001). Nucleosomes were also associated with a lower probability of being extubated alive by day 28 after multivariable adjustment (adjusted subdistribution hazard ratio, 0.74; 95% CI, 0.63-0.88; p = 0.001). Proteomic analysis demonstrated higher levels of the core nucleosome histones H2A, H2B, H3, and H4 in septic children with acute respiratory distress syndrome, relative to septic children without acute respiratory distress syndrome. CONCLUSIONS: Plasma nucleosomes are associated with acute respiratory distress syndrome severity, nonpulmonary organ failures, and worse outcomes in pediatric acute respiratory distress syndrome.

Systemic Endothelial Activation Is Associated With Early Acute Respiratory Distress Syndrome in Children With Extrapulmonary Sepsis.

OBJECTIVES: Systemic endothelial activation may contribute to sepsis-associated organ injury, including acute respiratory distress syndrome. We hypothesized that children with extrapulmonary sepsis with versus without acute respiratory distress syndrome would have plasma biomarkers indicative of increased endothelial activation and that persistent biomarker changes would be associated with poor outcome. DESIGN: Observational cohort. SETTING: Academic PICU. PATIENTS: Patients less than 18 years old with sepsis from extrapulmonary infection with (n = 46) or without (n = 54) acute respiratory distress syndrome and noninfected controls (n = 19). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Endothelial (angiopoietin-1, angiopoietin-2, tyrosine kinase with immunoglobulin-like loop epidermal growth factor homology domain 2, vascular endothelial growth factor, soluble fms-like tyrosine kinase, von Willebrand factor, E-selectin, intercellular adhesion molecule, vascular cell adhesion molecule, thrombomodulin) and inflammatory biomarkers (C-reactive protein, interleukin-6, and interleukin-8) were measured from peripheral plasma collected within 3 days (time 1) of sepsis recognition and at 3-6 days (time 2) and 7-14 days (time 3). Time 1 biomarkers and longitudinal measurements were compared for sepsis patients with versus without acute respiratory distress syndrome and in relation to complicated course, defined as greater than or equal to two organ dysfunctions at day 7 or death by day 28. Angiopoietin-2, angiopoietin-2/angiopoietin-1 ratio, tyrosine kinase with immunoglobulin-like loop epidermal growth factor homology domain 2, vascular endothelial growth factor, von Willebrand factor, E-selectin, intercellular adhesion molecule, vascular cell adhesion molecule, thrombomodulin, endocan, C-reactive protein, interleukin-6, and interleukin-8 were different between sepsis and noninfected control patients at time 1. Among patients with sepsis, those with acute respiratory distress syndrome had higher angiopoietin-2/angiopoietin-1 ratio, vascular endothelial growth factor, vascular cell adhesion molecule, thrombomodulin, endocan, interleukin-6, and interleukin-8 than those without acute respiratory distress syndrome (all p < 0.003). Angiopoietin-2 and angiopoietin-2/angiopoietin-1 ratio remained higher in sepsis with versus without acute respiratory distress syndrome after multivariable analyses. Time 1 measures of angiopoietin-2, angiopoietin-2/-1 ratio, von Willebrand factor, and endocan were indicative of complicated course in all sepsis patients (all area under the receiver operating curve ≥ 0.80). In sepsis without acute respiratory distress syndrome, soluble fms-like tyrosine kinase decreased more quickly and von Willebrand factor and thrombomodulin decreased more slowly in those with complicated course. CONCLUSIONS: Children with extrapulmonary sepsis with acute respiratory distress syndrome had plasma biomarkers indicative of greater systemic endothelial activation than those without acute respiratory distress syndrome. Several endothelial biomarkers measured near sepsis recognition were associated with complicated course, whereas longitudinal biomarker changes yielded prognostic information only in those without sepsis-associated acute respiratory distress syndrome.

Host-Response Subphenotypes Offer Prognostic Enrichment in Patients With or at Risk for Acute Respiratory Distress Syndrome.

OBJECTIVES: Classification of patients with acute respiratory distress syndrome into hyper- and hypoinflammatory subphenotypes using plasma biomarkers may facilitate more effective targeted therapy. We examined whether established subphenotypes are present not only in patients with acute respiratory distress syndrome but also in patients at risk for acute respiratory distress syndrome (ARFA) and then assessed the prognostic information of baseline subphenotyping on the evolution of host-response biomarkers and clinical outcomes. DESIGN: Prospective, observational cohort study. SETTING: Medical ICU at a tertiary academic medical center. PATIENTS: Mechanically ventilated patients with acute respiratory distress syndrome or ARFA. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We performed longitudinal measurements of 10 plasma biomarkers of host injury and inflammation. We applied unsupervised latent class analysis methods utilizing baseline clinical and biomarker variables and demonstrated that two-class models (hyper- vs hypoinflammatory subphenotypes) offered improved fit compared with one-class models in both patients with acute respiratory distress syndrome and ARFA. Baseline assignment to the hyperinflammatory subphenotype (39/104 [38%] acute respiratory distress syndrome and 30/108 [28%] ARFA patients) was associated with higher severity of illness by Sequential Organ Failure Assessment scores and incidence of acute kidney injury in patients with acute respiratory distress syndrome, as well as higher 30-day mortality and longer duration of mechanical ventilation in ARFA patients (p < 0.0001). Hyperinflammatory patients exhibited persistent elevation of biomarkers of innate immunity for up to 2 weeks postintubation. CONCLUSIONS: Our results suggest that two distinct subphenotypes are present not only in patients with established acute respiratory distress syndrome but also in patients at risk for its development. Hyperinflammatory classification at baseline is associated with higher severity of illness, worse clinical outcomes, and trajectories of persistently elevated biomarkers of host injury and inflammation during acute critical illness compared with hypoinflammatory patients. Our findings provide strong rationale for examining treatment effect modifications by subphenotypes in randomized clinical trials to inform precision therapeutic approaches in critical care.

Angiopoietin-2 as a predictor of acute kidney injury in critically ill patients and association with ARDS.

BACKGROUND AND OBJECTIVE: Angiopoietin-2 (AGPT2) has been proposed as a key mediator of organ dysfunction, mainly in acute respiratory distress syndrome (ARDS). It has also been associated with acute kidney injury (AKI). We aimed to investigate the role of AGPT2 in patients with and without ARDS. METHODS: In a cohort study with critically ill patients, AGPT1 and AGPT2 were assayed in plasma collected within the first 24 h after admission to intensive care unit (ICU). Severe AKI and the need for dialysis were outcome measures from comparative analysis with clinical characteristics useful for AKI risk stratification. RESULTS: Among 283 patients (50.2% males), 109 (38.5%) had ARDS. AGPT2 levels at admission were higher in patients with ARDS. Although overall AGPT2 and AGPT2/AGPT1 levels were associated with severe AKI, this association was not significant in patients without ARDS; however, it remained strongly significant in ARDS patients. In patients without ARDS, AGPT2 showed only a weak discriminatory capacity to predict severe AKI (area under the curve (AUC): 0.64 vs 0.81 in the ARDS group). The continuous net reclassification improvement (NRI) in the ARDS group resulting from AGPT2 inclusion was 64.1% (P < 0.001) and the integrated discrimination improvement (IDI) index was 0.057 (P = 0.003). There was no significant difference in NRI in the no-ARDS group. CONCLUSION: AGPT2 and AGPT2/AGPT1 ratio are associated with severe AKI and there was only a need of renal replacement therapy (RRT) in patients with or at risk of ARDS, not in other critically ill patients. Adding AGPT2 to a clinical model resulted in a significant improvement in the capacity to predict severe AKI specifically in ARDS patients.

Platelet-derived TLT-1 is a prognostic indicator in ALI/ARDS and prevents tissue damage in the lungs in a mouse model.

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) affect >200 000 individuals yearly with a 40% mortality rate. Although platelets are implicated in the progression of ALI/ARDS, their exact role remains undefined. Triggering receptor expressed in myeloid cells (TREM)-like transcript 1 (TLT-1) is found on platelets, binds fibrinogen, and mediates clot formation. We hypothesized that platelets use TLT-1 to manage the progression of ALI/ARDS. Here we retrospectively measure plasma levels of soluble TLT-1 (sTLT-1) from the ARDS Network clinical trial and show that patients whose sTLT-1 levels were >1200 pg/mL had nearly twice the mortality risk as those with <1200 pg/mL (P < .001). After correcting for confounding factors such as creatinine levels, Acute Physiology And Chronic Health Evaluation III scores, age, platelet counts, and ventilation volume, sTLT-1 remains significant, suggesting that sTLT-1 is an independent prognostic factor (P < .0001). These data point to a role for TLT-1 during the progression of ALI/ARDS. We use a murine lipopolysaccharide-induced ALI model and demonstrate increased alveolar bleeding, aberrant neutrophil transmigration and accumulation associated with decreased fibrinogen deposition, and increased pulmonary tissue damage in the absence of TLT-1. The loss of TLT-1 resulted in an increased proportion of platelet-neutrophil conjugates (43.73 ± 24.75% vs 8.92 ± 2.4% in wild-type mice), which correlated with increased neutrophil death. Infusion of sTLT-1 restores normal fibrinogen deposition and reduces pulmonary hemorrhage by 40% (P ≤ .001) and tissue damage by 25% (P ≤ .001) in vivo. Our findings suggest that TLT-1 uses fibrinogen to govern the transition between inflammation and hemostasis and facilitate controlled leukocyte transmigration during the progression of ARDS.

High Levels of Soluble Triggering Receptor Expressed on Myeloid Cells-Like Transcript (TLT)-1 Are Associated With Acute Respiratory Distress Syndrome.

We have previously demonstrated that elevated levels of soluble triggering receptor expressed on myeloid cells-like transcript 1 (sTLT-1) modulate sepsis-induced inflammation and positively correlate with disseminated intravascular coagulation (DIC). Here, we evaluate the clinical implications of plasma sTLT-1 in acute respiratory distress syndrome (ARDS), which is common in sepsis patients. Soluble TLT-1 levels in the plasma of ARDS patients (n = 20) were determined by slot blot analysis and were compared with clinical parameters to identify significant associations. For comparisons to ARDS, we also measured sTLT-1 levels in matched healthy controls (n = 20). Of the 20 plasma samples evaluated from patients with ARDS, 60% were diagnosed with sepsis and 40% were diagnosed with septic shock. The white blood cells (WBCs) of patients with ARDS were found to be significantly elevated over healthy controls with a mean of 13 k/µL over 6.2 k/µL, respectively. The mean plasma levels of sTLT-1 were 148.4 pg/mL ± 16.52 in the patient cohort and 92.45 pg/mL ± 17.12 in the control group ( P = .02). No statistically significant correlations were found between plasma levels of sTLT-1 and WBCs, sepsis, septic shock or acute physiologic, and chronic health evaluation II scores. A statistically significant inverse correlation (r2 = .25, P < .05) was found between plasma sTLT-1 and peripheral platelet counts in patients with ARDS. Increased levels of sTLT-1 in ARDS patients suggest that TLT-1 may mediate the pathobiology of ARDS. Moreover, our data are the first to demonstrate a specific platelet marker in the development of ARDS due to sepsis.

Adaptation of a Biomarker-Based Sepsis Mortality Risk Stratification Tool for Pediatric Acute Respiratory Distress Syndrome.

OBJECTIVES: The original Pediatric Sepsis Biomarker Risk Model and revised (Pediatric Sepsis Biomarker Risk Model-II) biomarker-based risk prediction models have demonstrated utility for estimating baseline 28-day mortality risk in pediatric sepsis. Given the paucity of prediction tools in pediatric acute respiratory distress syndrome, and given the overlapping pathophysiology between sepsis and acute respiratory distress syndrome, we tested the utility of Pediatric Sepsis Biomarker Risk Model and Pediatric Sepsis Biomarker Risk Model-II for mortality prediction in a cohort of pediatric acute respiratory distress syndrome, with an a priori plan to revise the model if these existing models performed poorly. DESIGN: Prospective observational cohort study. SETTING: University affiliated PICU. PATIENTS: Mechanically ventilated children with acute respiratory distress syndrome. INTERVENTIONS: Blood collection within 24 hours of acute respiratory distress syndrome onset and biomarker measurements. MEASUREMENTS AND MAIN RESULTS: In 152 children with acute respiratory distress syndrome, Pediatric Sepsis Biomarker Risk Model performed poorly and Pediatric Sepsis Biomarker Risk Model-II performed modestly (areas under receiver operating characteristic curve of 0.61 and 0.76, respectively). Therefore, we randomly selected 80% of the cohort (n = 122) to rederive a risk prediction model for pediatric acute respiratory distress syndrome. We used classification and regression tree methodology, considering the Pediatric Sepsis Biomarker Risk Model biomarkers in addition to variables relevant to acute respiratory distress syndrome. The final model was comprised of three biomarkers and age, and more accurately estimated baseline mortality risk (area under receiver operating characteristic curve 0.85, p < 0.001 and p = 0.053 compared with Pediatric Sepsis Biomarker Risk Model and Pediatric Sepsis Biomarker Risk Model-II, respectively). The model was tested in the remaining 20% of subjects (n = 30) and demonstrated similar test characteristics. CONCLUSIONS: A validated, biomarker-based risk stratification tool designed for pediatric sepsis was adapted for use in pediatric acute respiratory distress syndrome. The newly derived Pediatric Acute Respiratory Distress Syndrome Biomarker Risk Model demonstrates good test characteristics internally and requires external validation in a larger cohort. Tools such as Pediatric Acute Respiratory Distress Syndrome Biomarker Risk Model have the potential to provide improved risk stratification and prognostic enrichment for future trials in pediatric acute respiratory distress syndrome.

Hemodiafiltration Decreases Serum Levels of Inflammatory Mediators in Severe Leptospirosis: A Prospective Study.

BACKGROUND: Leptospirosis is a health problem worldwide. Its most severe form is a classic model of sepsis, provoking acute respiratory distress syndrome (ARDS) and acute kidney injury (AKI), with associated mortality that remains unacceptably high. We previously demonstrated that early initiation of sustained low-efficiency dialysis (SLED) followed by daily SLED significantly decreases mortality. However, the mode of clearance can also affect dialysis patient outcomes. Therefore, the objective of this study was to compare the effects of SLED with traditional (diffusive) clearance, via hemodialysis, and SLED with convective clearance, via hemodiafiltration (SLEDf), in patients with severe leptospirosis. METHODS: In this prospective study, conducted in the intensive care unit (ICU) from 2009 through 2012, we compared two groups-SLED (n = 19) and SLEDf (n = 20)-evaluating demographic, clinical, and biochemical parameters, as well as serum levels of interleukins, up to the third day after admission. All patients received dialysis early and daily thereafter. RESULTS: During the study period, 138 patients were admitted to our ICU with a diagnosis of leptospirosis; 39 (36 males/3 females) met the criteria for ARDS and AKI. All patients were on mechanical ventilation and were comparable in terms of respiratory parameters. Mortality did not differ between the SLEDf and SLED groups. However, post-admission decreases in the serum levels of interleukin (IL)-17, IL-7, and monocyte chemoattractant protein-1 were significantly greater in the SLEDf group. Direct bilirubin and the arterial oxygen tension/fraction of inspired oxygen ratio were significantly higher in the SLED group. We identified the following risk factors (sensitivities/specificities) for mortality in severe leptospirosis: age ≥ 55 years (67%/91%); serum urea ≥ 204 mg/dl (100%/70%); creatinine ≥ 5.2 mg/dl (100%/58%); Acute Physiology and Chronic Health Evaluation II score ≥ 39.5 (67%/88%); Sequential Organ Failure Assessment score ≥ 20.5 (67%/85%); and inspiratory pressure ≥ 31 mmHg (84%/85%). CONCLUSIONS: The mode of dialysis clearance might not affect outcomes in severe leptospirosis.

Effects of the open lung concept following ARDSnet ventilation in patients with early ARDS.

BACKGROUND: Ventilation with low tidal volume (VT) is well recognized as a protective approach to patients with acute respiratory distress syndrome (ARDS), but the optimal level of positive end-expiratory pressure (PEEP) remains uncertain. This study aims to evaluate two protective ventilatory strategies sequentially applied in patients with early ARDS. METHODS: In this prospective cohort study, fifteen patients were ventilated during 24 h with positive end-expiratory pressure (PEEP) adjusted according to the ARDSnet low-PEEP table (ARDSnet-24 h). During the next 24 h, nine patients with PaO2/FIO2 ratio below 350 mmHg were ventilated with PEEP titrated according to the Open Lung Concept protocol (ARDSnet + OLC). In the other six patients, regardless of their PaO2/FIO2 ratio, the ARDSnet remained for a further 24 h (ARDSnet-48 h). Ventilatory variables, arterial blood-gas and cytokine were obtained at baseline, 24 and 48 h. Additionally, whole-lung-computed tomography was acquired at 24 and 48 h. RESULTS: A sustained improvement in PaO2/FIO2 ratio (P = 0.008) with a decrease in collapsed regions (P = 0.008) was observed in the ARDSnet + OLC group compared with the ARDSnet-24 h group. A reduction in IL-6 in plasma (P < 0.02) was observed throughout the protocol in the ARDSnet + OLC group. Compared with the ARDSnet-48 h group, the ARDSnet + OLC presented smaller amounts of collapsed areas (P = 0.018) without significant differences in hyperinflated regions and in driving and plateau pressures. CONCLUSIONS: In this set of patients with early ARDS, mechanical ventilation with an individually tailored PEEP sustained improved pulmonary function with better aeration, without significant increase in hyperinflated areas". TRIAL REGISTRATION: Brazilian Clinical Trials Registry (ReBec). RBR-5zm9pr. 04th November 2015.

Cortisol Correlates with Severity of Illness and Poorly Reflects Adrenal Function in Pediatric Acute Respiratory Distress Syndrome.

OBJECTIVE: To test the association between random cortisol and severity of illness in a "real-world" application of current guidelines. STUDY DESIGN: We performed a secondary analysis of a prospective observational cohort of acute respiratory distress syndrome (ARDS). Children with ARDS and vasopressor-dependent shock were identified and random cortisol levels before potential hydrocortisone initiation recorded. The cohort was dichotomized to cortisol < 18 and ≥ 18 µg/dL, and hydrocortisone use and outcomes compared. RESULTS: Of 357 children with ARDS, 155 (15 nonsurvivors; 10%) had vasopressors initiated with cortisol drawn before possible hydrocortisone use. Patients with cortisol < 18 µg/dL had lower severity of illness scores, fewer organ failures, and lower vasopressor scores (all rank-sum P < .05). No benefit was seen with hydrocortisone in either the entire cohort, or when dichotomized by a cortisol cutoff of 18 µg/dL. In patients with cortisol ≥ 18 µg/dL, hydrocortisone was associated with increased mortality after adjustment for either organ dysfunction or vasopressor score. CONCLUSIONS: In children with ARDS with vasopressor-dependent shock, low cortisol correlated with lower severity of illness. Random cortisol was a poor method of diagnosing adrenal insufficiency, and a strategy of hydrocortisone replacement for cortisol < 18 µg/dL did not target a population likely to benefit from hydrocortisone. Future guidelines should reconsider using random cortisol levels alone for assessing adrenal function.

Glucose Metabolism Disorder Is Associated with Pulmonary Tuberculosis in Individuals with Respiratory Symptoms from Brazil.

BACKGROUND: Diabetes mellitus (DM) has been associated with increased risk for pulmonary tuberculosis (PTB) in endemic settings but it is unknown whether PTB risk is also increased by pre-DM. Here, we prospectively examined the association between glucose metabolism disorder (GMD) and PTB in patients with respiratory symptoms at a tuberculosis primary care reference center in Brazil. METHODS: Oral glucose tolerance test was performed and levels of fasting plasma glucose and glycohemoglobin (HbA1c) were measured in a cohort of 892 individuals presenting with respiratory symptoms of more than two weeks duration. Patients were also tested for PTB with sputum cultures. Prevalence of pre-DM and DM (based on HbA1c) was estimated and tested for association with incident PTB. Other TB risk factors including smoking history were analyzed. RESULTS: The majority of the study population (63.1%) exhibited GMD based on HbA1c ≥5.7%. Patients with GMD had higher prevalence of PTB compared to normoglycemic patients. Individuals with DM exhibited increased frequency of TB-related symptoms and detection of acid-fast bacilli in sputum smears. Among patients with previous DM diagnosis, sustained hyperglycemia (HbA1c ≥7.0%) was associated with increased TB prevalence. Smoking history alone was not significantly associated with TB in our study population but the combination of smoking and HbA1c ≥7.0% was associated with 6 times higher odds for PTB. CONCLUSIONS: Sustained hyperglycemia and pre-DM are independently associated with active PTB. This evidence raises the question whether improving glycemic control in diabetic TB patients would reduce the risk of TB transmission and simultaneously reduce the clinical burden of disease. A better understanding of mechanisms underlying these associations, especially those suggesting that pre-DM may be a factor driving susceptibility to TB is warranted.

The Association of Vitamin D Status with Acute Respiratory Morbidity in Preterm Infants.

OBJECTIVE: To assess the association between serum 25-hydroxyvitamin D (25OHD) levels and outcomes in preterm infants (<32 weeks gestation). STUDY DESIGN: Serum 25OHD was measured in mothers and their infants within 24 hours of birth, before the start of enteral vitamin D supplementation, and at discharge from the neonatal intensive care unit. We evaluated the associations between vitamin D status and various early preterm outcomes. RESULTS: Ninety-four preterm infants and their mothers were included; 92% of the infants had a 25OHD level≤50 nmol/L (20 ng/mL), and 64% had a 25OHD level<30 nmol/L (12 ng/mL). A low 25OHD level (<30 nmol/L) in preterm infants at birth was associated with increased oxygen requirement (P=.008), increased duration of intermittent positive-pressure ventilation during resuscitation at delivery (P=.032), and greater need for assisted ventilation (P=.013). CONCLUSION: We observed a high prevalence of low 25OHD (<30 nmol/L), and found an association between vitamin D status and acute respiratory morbidity in preterm infants after birth.

Serum surfactant protein D (SP-D) is a prognostic marker of poor outcome in patients with A/H1N1 virus infection.

INTRODUCTION: Surfactant protein D (SP-D) plays an important role in the innate responses against pathogens and its production is altered in lung disorders. METHODS: We studied the circulating levels of SP-D in 37 patients with acute respiratory distress syndrome due to the A/H1N1 virus infection and in 40 healthy controls. Cox logistic regression models were constructed to explore the association of SP-D levels and risk of death. RESULTS: Mortality rate after a 28-day was 32.42 %. Significant higher levels of SP-D were detected in A/H1N1 patients with fatal outcome (p < 0.05). After adjusting for confounding variables, levels of SP-D ≥250 ng/mL were associated with increased the risk of death (HR = 8.27, 95 % CI 1.1-64.1, p = 0.043). CONCLUSIONS: Our results revealed that higher circulating levels of SP-D are associated with higher mortality risk in critically ill A/H1N1 patients. SP-D might be a predictive factor of poor outcomes in viral pneumonia.

High lactate levels are predictors of major complications after cardiac surgery.

OBJECTIVE: Although hyperlactatemia after cardiac surgery is common, the implications of raised levels remain controversial. The aim of this study was to evaluate whether high lactate levels after cardiac surgery are predictors of major complications including mortality. PATIENTS AND METHODS: This was a substudy of TRACS (Transfusion Requirements After Cardiac Surgery), which was designed as a prospective, randomized, controlled trial evaluating the effects of a transfusion strategy on morbidity and mortality. RESULTS: Of the 502 patients enrolled, 52 (10%) had at least 1 major complication. Patients with complications were older, had a higher EuroSCORE, lower left ventricular ejection fraction, lower preoperative hemoglobin, a higher prevalence of renal disease, and received more blood transfusions than the group without complications. Lactate levels were higher in the group with complications at the end of surgery (3.6 mmol/L [2.8-5.1] vs 3.3 mmol/L [2.2-4.8]; P = .018), immediately after intensive care unit (ICU) admission (0 hour) (4.4 mmol/L [3.1-8.4] vs 4 mmol/L [2.6-6.4]; P = .048); 6 hours (4 mmol/L [2.7-5.8] vs 2.6 mmol/L [2-3.6], P < .001), and 12 hours after admission (2.3 mmol/L [1.8-3.2] vs 1.7 mmol/L [1.3-2]; P < .001). In a multivariate model, higher age (odds ratio [OR], 1.048, 95% confidence interval [CI], 1.011-1.086; P = .010), left ventricular ejection fraction (LVEF) lower than 40% (OR, 3.03; 95% CI, 1.200-7.510; P = .019 compared with LVEF of 40%-59%; OR, 3.571; 95% CI, 1.503-8.196; P = .004 compared with LVEF higher than 60%), higher EuroSCORE (OR, 1.138; 95% CI; 1.007-1.285; P = .038), red blood cell transfusion (OR, 1.230; 95% CI, 1.086-1.393; P = .001), and lactate levels 6 hours after ICU admission (OR, 3.28, 95% CI; 1.61-6.69; P = .001) are predictors of major complications. CONCLUSIONS: Hyperlactatemia 6 hours after ICU admission is an independent risk factor for worse outcomes in adult patients after cardiac surgery.

HMGB1 and LPS induce distinct patterns of gene expression and activation in neutrophils from patients with sepsis-induced acute lung injury.

OBJECTIVES: Circulating levels of the proinflammatory mediator High Mobility Group Box Protein 1 (HMGB1) are increased in septic patients and may contribute to sepsis-induced organ dysfunction. Although HMGB1 has been shown to activate neutrophils from healthy volunteers, the responses of neutrophils from septic patients to HMGB1 have not been reported. In the present study we evaluated gene expression and activation of major intracellular signaling pathways in peripheral blood neutrophils obtained from patients with sepsis-induced acute lung injury after culture with HMGB1 or LPS. DESIGN: Ex-vivo study performed in neutrophils from patients with sepsis-induced acute lung injury. SETTING: Immunology and genetics laboratory at an academic medical center. PATIENTS AND PARTICIPANTS: Twenty-two adult patients with sepsis-induced acute lung injury. MEASUREMENTS AND RESULTS: Using gene arrays, distinct patterns of gene expression were found in neutrophils from septic patients after stimulation with HMGB1 or LPS. While more than three-quarters of the genes upregulated by HMGB1 in neutrophils from septic patients also demonstrated increased expression after culture with LPS, the majority of genes affected by LPS did not show altered expression in neutrophils stimulated with HMGB1. Culture of neutrophils with HMGB1 induced downregulation of its own expression, a finding not present after exposure to LPS. Although HMGB1 and LPS both increased nuclear translocation of NF-kappaB, the magnitude of this effect was greater in LPS stimulated neutrophils from patients with sepsis-induced acute lung injury. CONCLUSION: These findings demonstrate that the patterns of gene expression differ between neutrophils from septic patients stimulated with HMGB1 or LPS, and also that neutrophils from septic patients are not anergic but instead demonstrate intact activation of NF-kappaB after exposure to LPS or HMGB1.

[Mechanical ventilatory parameters guided by the low flow pressure-volume curve in patients with acute lung injury/acute respiratory distress syndrome]. / Ajuste a la ventilación mecánica guiado por curvas presión-volumen de flujo lento en pacientes con síndrome de distress respiratorio agudo e injuria pulmonar aguda.

BACKGROUND: Mechanical ventilation may contribute to lung injury and then enhance systemic inflammation. Optimal ventilatory parameters such as tidal volume (VT) and positive end expiratory pressure (PEEP) can be determined using different methods. Low flow pressure volume (P/V-LF) curve is a useful tool to assess the respiratory system mechanics and set ventilatory parameters. AIM: To set VT and PEEP according P/V-LF curve analysis and evaluate its effects on gas exchange and hemodynamic parameters. MATERIALS AND METHODS: Twenty seven patients underwent P/V-LF within the first 72 hours of acute lung injury/acute respiratory distress syndrome (ALI/ARDS). P/V-LF curves were obtained from the ventilator and both lower and upper inflexion points determined. Gas exchange and hemodynamic parameters were measured before and after modifying ventilator settings guided by P/V-LF curves. RESULTS: Ventilatory parameters set according P/V-LF curve, led to a rise of PEEP and reduction of VT: 11.6+/-2.8 to 14.1+/-2.1 cm H2O, and 9.7+/-2.4 to 8.8+/-2.2 mL/kg (p<0.01). Arterial to inspired oxygen fraction ratio increased from 158.0+/-66 to 188.5+/-68.5 (p<0.01), and oxygenation index was reduced, 13.7+/-8.2 to 12.3+/-7.2 (p<0.05). Cardiac output and oxygen delivery index (IDO2) were not modified. Demographic data, gas exchange improvement and respiratory system mechanics showed no significant difference between patients with extra-pulmonary and pulmonary ALI/ARDS. There was no evidence of significant adverse events related with this technique. CONCLUSION: P/V-LF curves information allowed us to adjust ventilatory parameters and optimize gas exchange without detrimental effects on oxygen delivery in mechanically ventilated ALI/ARDS patients.

Ajuste a la ventilación mecánica guiado por curvas presión-volumen de flujo lento en pacientes con síndrome de distress respiratorio agudo e injuria pulmonar aguda / Mechanical ventilatory parameters guided by the low flow pressure-volume curve in patients with acute lung injury/acute respiratory distress syndrome

Background: Mechanical ventilation may contribute to lung injury and then enhance systemic inflammation. Optimal ventilatory parameters such as tidal volume (V T) and positive end expiratory pressure (PEEP) can be determined using different methods. Low flow pressure volume (P/V-LF) curve is a useful tool to assess the respiratory system mechanics and set ventilatory parameters. Aim: To set V T and PEEP according P/V-LF curve analysis and evaluate its effects on gas exchange and hemodynamic parameters. Materials and methods: Twenty seven patients underwent P/V-LF within the first 72 hours of acute lung injury/acute respiratory distress syndrome (ALI/ARDS). P/V-LF curves were obtained from the ventilator and both lower and upper inflexion points determined. Gas exchange and hemodynamic parameters were measured before and after modifying ventilator settings guided by P/V-LF curves. Results: Ventilatory parameters set according P/V-LF curve, led to a rise of PEEP and reduction of V T: 11.6±2.8 to 14.1±2.1 cm H2O, and 9.7±2.4 to 8.8±2.2 mL/kg (p <0.01). Arterial to inspired oxygen fraction ratio increased from 158.0±66 to 188.5±68.5 (p <0.01), and oxygenation index was reduced, 13.7±8.2 to 12.3±7.2 (p <0.05). Cardiac output and oxygen delivery index (IDO2) were not modified. Demographic data, gas exchange improvement and respiratory system mechanics showed no significant difference between patients with extra-pulmonary and pulmonary ALI/ARDS. There was no evidence of significant adverse events related with this technique. Conclusion: P/V-LF curves information allowed us to adjust ventilatory parameters and optimize gas exchange without detrimental effects on oxygen delivery in mechanically ventilated ALI/ARDS patients.

Neutrophil apoptosis: a marker of disease severity in sepsis and sepsis-induced acute respiratory distress syndrome.

INTRODUCTION: Apoptosis of neutrophils (polymorphonuclear neutrophils [PMNs]) may limit inflammatory injury in sepsis and acute respiratory distress syndrome (ARDS), but the relationship between the severity of sepsis and extent of PMN apoptosis and the effect of superimposed ARDS is unknown. The objective of this study was to correlate neutrophil apoptosis with the severity of sepsis and sepsis-induced ARDS. METHODS: A prospective cohort study was conducted in intensive care units of three tertiary hospitals in Porto Alegre, southern Brazil. Fifty-seven patients with sepsis (uncomplicated sepsis, septic shock, and sepsis-induced ARDS) and 64 controls were enrolled. Venous peripheral blood was collected from patients with sepsis within 24 hours of diagnosis. All surgical groups, including controls, had their blood drawn 24 hours after surgery. Control patients on mechanical ventilation had blood collected within 24 hours of initiation of mechanical ventilation. Healthy controls were blood donors. Neutrophils were isolated, and incubated ex vivo, and apoptosis was determined by light microscopy on cytospun preparations. The differences among groups were assessed by analysis of variance with Tukeys. RESULTS: In medical patients, the mean percentage of neutrophil apoptosis (+/- standard error of the mean [SEM]) was lower in sepsis-induced ARDS (28% +/- 3.3%; n = 9) when compared with uncomplicated sepsis (57% +/- 3.2%; n = 8; p < 0.001), mechanical ventilation without infection, sepsis, or ARDS (53% +/- 3.0%; n = 11; p < 0.001) and healthy controls (69% +/- 1.1%; n = 33; p < 0.001) but did not differ from septic shock (38% +/- 3.7%; n = 12; p = 0.13). In surgical patients with sepsis, the percentage of neutrophil apoptosis was lower for all groups when compared with surgical controls (52% +/- 3.6%; n = 11; p < 0.001). CONCLUSION: In medical patients with sepsis, neutrophil apoptosis is inversely proportional to the severity of sepsis and thus may be a marker of the severity of sepsis in this population.