Explore the vast range of titles available.

Cell-free hemoglobin (CFH) is a potent oxidant associated with poor clinical outcomes in a variety of clinical settings. Recent studies suggest that acetaminophen (APAP), a specific hemoprotein reductant, can abrogate CFH-mediated oxidative injury and organ dysfunction. Preoperative plasma CFH levels are independently associated with primary graft dysfunction (PGD) after lung transplant ( 1 ). Our objectives were to determine whether CFH would increase lung vascular permeability in the isolated perfused human lung and whether APAP would limit these effects. Human lungs declined for transplant were inflated and perfused with Dulbecco's modified Eagle medium/5% albumin at a pulmonary artery pressure of 8-12 mm Hg. After steady state was achieved, CFH (100 mg/dl) was added to the perfusate ± APAP (15 μg/ml). Lung permeability was measured by continuous monitoring of lung weight gain and by extravasation of Evans blue dye-labeled albumin from the vasculature into bronchoalveolar lavage. To test the mechanism of increased permeability, human pulmonary microvascular endothelial cells were exposed to CFH (0.5 mg/ml) ± APAP (160 μM) for 24 hours and permeability was assessed by electrical cell-substrate impedance sensing. In the isolated perfused human lung, CFH increased lung permeability over 2 hours compared with control lungs (12% vs. 2% weight gain from baseline, P = 0.03). Increased vascular permeability was confirmed by a 4.8-fold increase in Evans blue dye-labeled albumin in the airspace compared with control lungs. Pretreatment with APAP prevented lung weight gain (P = 0.06 vs. CFH). In human pulmonary microvascular endothelial cells, CFH increased monolayer permeability (P = 0.03 vs. control), and this was attenuated by APAP (P = 0.045 vs. CFH). Circulating CFH increases vascular permeability in the isolated perfused human lung and paracellular permeability in lung microvascular endothelial cells. These effects may explain the association of plasma CFH levels with PGD. The hemoprotein reductant APAP attenuates the effects of CFH and merits further exploration as a potential therapy for PGD prevention.

Hypoxemia during tracheal intubation may increase the risk of cardiac arrest and death. In this multicenter trial, adults undergoing tracheal intubation were randomly assigned to receive bag-mask ventilation during the interval between induction and laryngoscopy or no ventilation. Bag-mask ventilation increased oxygen saturation as compared with no ventilation.

Hypoxemia is common during endotracheal intubation of critically ill patients and may predispose to cardiac arrest and death. Administration of supplemental oxygen during laryngoscopy (apneic oxygenation) may prevent hypoxemia. To determine if apneic oxygenation increases the lowest arterial oxygen saturation experienced by patients undergoing endotracheal intubation in the intensive care unit. This was a randomized, open-label, pragmatic trial in which 150 adults undergoing endotracheal intubation in a medical intensive care unit were randomized to receive 15 L/min of 100% oxygen via high-flow nasal cannula during laryngoscopy (apneic oxygenation) or no supplemental oxygen during laryngoscopy (usual care). The primary outcome was lowest arterial oxygen saturation between induction and 2 minutes after completion of endotracheal intubation. Median lowest arterial oxygen saturation was 92% with apneic oxygenation versus 90% with usual care (95% confidence interval for the difference, -1.6 to 7.4%; P = 0.16). There was no difference between apneic oxygenation and usual care in incidence of oxygen saturation less than 90% (44.7 vs. 47.2%; P = 0.87), oxygen saturation less than 80% (15.8 vs. 25.0%; P = 0.22), or decrease in oxygen saturation greater than 3% (53.9 vs. 55.6%; P = 0.87). Duration of mechanical ventilation, intensive care unit length of stay, and in-hospital mortality were similar between study groups. Apneic oxygenation does not seem to increase lowest arterial oxygen saturation during endotracheal intubation of critically ill patients compared with usual care. These findings do not support routine use of apneic oxygenation during endotracheal intubation of critically ill adults. Clinical trial registered with www.clinicaltrials.gov (NCT 02051816).

Delirium affects 50% to 80% of intensive care unit (ICU) patients and is associated with increased risk of mortality. Given the paucity of data reporting the neuropathologic findings in ICU patients experiencing delirium, the purpose of this pilot, hypothesis-generating study was to evaluate brain autopsies in ICU patients who suffered from delirium to explore possible neuroanatomical correlates. Using delirium databases at Vanderbilt University, we identified patients who had delirium in the ICU and subsequently died and received a brain autopsy during the same hospitalization. Brain autopsy reports were collected retrospectively on all 7 patients who met these criteria. Patients' mean age was 55 (SD ± 8.4) years, and median number of days spent with delirium was 7 (±5 interquartile range). In 6 (86%) of 7 patients, pathologic lesions normally attributed to hypoxia or ischemia were noted in the hippocampus, pons, and striatum. Hippocampal lesions represented the most common neuropathologic site of injury, present in 5 (71%) of 7 patients. Hypoxic ischemic injury in multiple locations of the brain was a common finding. The biological plausibility of hippocampal lesions as a contributor to long-term cognitive impairment warrants postmortem investigation on a larger scale with comparison to patients not experiencing ICU delirium.

Purpose Advances in supportive care and ventilator management for acute respiratory distress syndrome (ARDS) have resulted in declines in short-term mortality, but risks of death after survival to hospital discharge have not been well described. Our objective was to quantify the difference between short-term and long-term mortality in ARDS and to identify risk factors for death and causes of death at 1 year among hospital survivors. Methods This multi-intensive care unit, prospective cohort included patients with ARDS enrolled between January 2006 and February 2010. We determined the clinical characteristics associated with in-hospital and 1-year mortality among hospital survivors and utilized death certificate data to identify causes of death. Results Of 646 patients hospitalized with ARDS, mortality at 1 year was substantially higher (41 %, 95 % CI 37–45 %) than in-hospital mortality (24 %, 95 % CI 21–27 %), P  < 0.0001. Among 493 patients who survived to hospital discharge, the 110 (22 %) who died in the subsequent year were older ( P  < 0.001) and more likely to have been discharged to a nursing home, other hospital, or hospice compared to patients alive at 1 year ( P  < 0.001). Important predictors of death among hospital survivors were comorbidities present at the time of ARDS, and not living at home prior to admission. ARDS-related measures of severity of illness did not emerge as independent predictors of mortality in hospital survivors. Conclusions Despite improvements in short-term ARDS outcomes, 1-year mortality is high, mostly because of the large burden of comorbidities, which are prevalent in patients with ARDS.

BackgroundAcute respiratory distress syndrome (ARDS) is common after severe traumatic injuries but is underdiagnosed and undertreated. We hypothesized that a panel of plasma biomarkers could be used to diagnose ARDS in severe trauma. To test this hypothesis, we derived and validated a biomarker panel in three independent cohorts and compared the diagnostic performance to clinician recognition of ARDS.MethodsEleven plasma biomarkers of inflammation, lung epithelial and endothelial injury were measured in a derivation cohort of 439 severe trauma patients. ARDS status was analyzed by two-investigator consensus, and cases were required to meet Berlin criteria on intensive care unit (ICU) day 1. Controls were subjects without ARDS during the first 4 days of study enrollment. A multivariable logistic regression model was used to generate probabilities for ARDS. A reduced model with the top two performing markers was then tested in two independent validation cohorts. To assess clinical diagnosis of ARDS, medical records in the derivation cohort were systematically searched for documentation of ARDS diagnosis made by a clinical provider.ResultsAmong 11 biomarkers, the combination of the endothelial injury marker angiopoietin-2 (Ang-2) and the lung epithelial injury marker receptor for advanced glycation endproducts (RAGE) provided good discrimination for ARDS in the derivation cohort (area under the curve (AUC)=0.74 (95% CI 0.67 to 0.80). In the validation cohorts, the AUCs for this model were 0.70 (0.61 to 0.77) and 0.78 (0.71 to 0.84). In contrast, provider assessment demonstrated poor diagnostic accuracy for ARDS, with AUC of 0.55 (0.51 to 0.60).DiscussionA two-biomarker panel consisting of Ang-2 and RAGE performed well across multiple patient cohorts and outperformed clinical providers for diagnosing ARDS in severe trauma. Clinical application of this model could improve both diagnosis and treatment of ARDS in patients with severe trauma.Level of evidenceDiagnostic study, level II.

Abstract Rationale “Target trial emulation” has been proposed as an observational method to answer comparative effectiveness questions, but it has rarely been attempted concurrently with a randomized clinical trial (RCT). Objectives We tested the hypothesis that blinded analysts applying target trial emulation to existing observational data could predict the results of an RCT. Methods PreVent (Preventing Hypoxemia with Manual Ventilation during Endotracheal Intubation) was a multicenter RCT examining the effects of positive-pressure ventilation during tracheal intubation on oxygen saturation and severe hypoxemia. Analysts unaware of PreVent’s results used patient-level data from three previous trials evaluating airway management interventions to emulate PreVent’s eligibility criteria, randomization procedure, and statistical analysis. After PreVent’s release, results of this blinded observational analysis were compared with those of the RCT. Difference-in-differences estimates for comparison of treatment effects between the observational analysis and the PreVent trial are reported on the absolute scale. Results Using observational data, we were able to emulate PreVent’s randomization procedure to produce balanced groups for comparison. The lowest oxygen saturation during intubation was higher in the positive-pressure ventilation group than the no positive-pressure ventilation group in the observational analysis (n = 360; mean difference = 1.8%; 95% confidence interval [CI] = −1.0 to 4.6) and in the PreVent trial (n = 401; mean difference = 3.9%; 95% CI = 1.4 to 6.4), though the observational analysis could not exclude no difference. Difference-in-differences estimates comparing treatment effects showed reasonable agreement for lowest oxygen saturation between the observational analysis and the PreVent trial (mean difference = −2.1%; 95% CI = −5.9 to 1.7). Positive-pressure ventilation resulted in lower rates of severe hypoxemia in both the observational analysis (risk ratio = 0.60; 95% CI = 0.38 to 0.93) and in the PreVent trial (risk ratio = 0.48; 95% CI = 0.30 to 0.77). The absolute reduction in the incidence of severe hypoxemia with positive-pressure ventilation was similar in the observational analysis (9.4%) and the PreVent trial (12.0%), though the difference between these estimates had wide CIs (mean difference = 2.5%; 95% CI = −8.0 to 13.6%). Conclusions Applying target trial emulation methods to existing observational data for the evaluation of a novel intervention produced results similar to those of a randomized trial. These findings support the use of target trial emulation for comparative effectiveness research.

Hypoxemia is a common complication during tracheal intubation of critically ill adults and is a frequently used endpoint in airway management research. Identifying patients likely to experience low oxygen saturations during tracheal intubation may be useful for clinical practice and clinical trials. To identify risk factors for lower oxygen saturations and severe hypoxemia during tracheal intubation of critically ill adults and develop prediction models for lowest oxygen saturation and hypoxemia. Using data on 433 intubations from two randomized trials, we developed linear and logistic regression models to identify preprocedural risk factors for lower arterial oxygen saturations and severe hypoxemia between induction and 2 minutes after intubation. Penalized regression was used to develop prediction models for lowest oxygen saturation after induction and severe hypoxemia. A simplified six-point score was derived to predict severe hypoxemia. Among the 433 intubations, 426 had complete data and were included in the model. The mean (standard deviation) lowest oxygen saturation was 88% (14%); median (interquartile range) was 93% (83-98%). Independent predictors of severe hypoxemia included hypoxemic respiratory failure as the indication for intubation (odds ratio [OR], 2.70; 95% confidence interval [CI], 1.58-4.60), lower oxygen saturation at induction (OR, 0.92 per 1% increase; 95% CI, 0.89-0.96 per 1% increase), younger age (OR, 0.97 per 1-year increase; 95% CI, 0.95-0.99 per 1-year increase), higher body mass index (OR, 1.03 per 1 kg/m ; 95% CI, 1.00-1.06 per 1 kg/m ), race (OR, 4.58 for white vs. black; 95% CI, 1.97-10.67; OR, 4.47 for other vs. black; 95% CI, 1.19-16.84), and operator with fewer than 100 prior intubations (OR, 2.83; 95% CI, 1.37-5.85). A six-point score using the identified risk factors predicted severe hypoxemia with an area under the receiver operating curve of 0.714 (95% CI, 0.653 to 0.778). Lowest oxygen saturation and severe hypoxemia during tracheal intubation in the intensive care unit can be accurately predicted using routinely available preprocedure clinical data, with saturation at induction and hypoxemic respiratory failure being the strongest predictors. A simple bedside score may identify patients at risk for hypoxemia during intubation to help target preventative interventions and facilitate enrichment in clinical trials.

The primary focus of research into the pathophysiology of the acute respiratory distress syndrome (ARDS) has been on the interaction between the lung, underlying causes of ARDS, and the role of white blood cells and platelets in contributing to lung injury. Given a lack of specific therapies for this common complication of critical illness, further insight into the pathophysiology of this syndrome is greatly needed to develop targeted interventions. The red blood cell (RBC) has been reported to undergo deleterious changes in critical illness and be present in the alveoli of patients with ARDS. Release of RBC contents is known to be injurious in other conditions but has only recently been studied in critical illness and ARDS. The contribution of the RBC to ARDS represents a new avenue of research that may produce new, targeted therapies for this deadly syndrome.