Showing papers by "Michael A. Matthay published in 2016"
TL;DR: Outcomes in sepsis have greatly improved overall, probably because of an enhanced focus on early diagnosis and fluid resuscitation, the rapid delivery of effective antibiotics, and other improvements in supportive care for critically ill patients.
Abstract: Sepsis, severe sepsis, and septic shock represent increasingly severe systemic inflammatory responses to infection. Sepsis is common in the aging population, and it disproportionately affects patients with cancer and underlying immunosuppression. In its most severe form, sepsis causes multiple organ dysfunction that can produce a state of chronic critical illness characterized by severe immune dysfunction and catabolism. Much has been learnt about the pathogenesis of sepsis at the molecular, cell, and intact organ level. Despite uncertainties in hemodynamic management and several treatments that have failed in clinical trials, investigational therapies increasingly target sepsis induced organ and immune dysfunction. Outcomes in sepsis have greatly improved overall, probably because of an enhanced focus on early diagnosis and fluid resuscitation, the rapid delivery of effective antibiotics, and other improvements in supportive care for critically ill patients. These improvements include lung protective ventilation, more judicious use of blood products, and strategies to reduce nosocomial infections.
663 citations
TL;DR: It is demonstrated for the first time that mitochondrial transfer from MSC to innate immune cells leads to enhancement in phagocytic activity and reveals an important novel mechanism for the antimicrobial effect of MSC in ARDS.
Abstract: Mesenchymal stromal cells (MSC) have been reported to improve bacterial clearance in preclinical models of Acute Respiratory Distress Syndrome (ARDS) and sepsis. The mechanism of this effect is not fully elucidated yet. The primary objective of this study was to investigate the hypothesis that the antimicrobial effect of MSC in vivo depends on their modulation of macrophage phagocytic activity which occurs through mitochondrial transfer. We established that selective depletion of alveolar macrophages (AM) with intranasal (IN) administration of liposomal clodronate resulted in complete abrogation of MSC antimicrobial effect in the in vivo model of Escherichia coli pneumonia. Furthermore, we showed that MSC administration was associated with enhanced AM phagocytosis in vivo. We showed that direct coculture of MSC with monocyte-derived macrophages enhanced their phagocytic capacity. By fluorescent imaging and flow cytometry we demonstrated extensive mitochondrial transfer from MSC to macrophages which occurred at least partially through tunneling nanotubes (TNT)-like structures. We also detected that lung macrophages readily acquire MSC mitochondria in vivo, and macrophages which are positive for MSC mitochondria display more pronounced phagocytic activity. Finally, partial inhibition of mitochondrial transfer through blockage of TNT formation by MSC resulted in failure to improve macrophage bioenergetics and complete abrogation of the MSC effect on macrophage phagocytosis in vitro and the antimicrobial effect of MSC in vivo. Collectively, this work for the first time demonstrates that mitochondrial transfer from MSC to innate immune cells leads to enhancement in phagocytic activity and reveals an important novel mechanism for the antimicrobial effect of MSC in ARDS. Stem Cells 2016;34:2210-2223.
359 citations
TL;DR: Hemodynamic instability is frequently associated with hemodynamic instability which appears as the main factor associated with mortality and can be prevented or treated by applying RV protective MV (low driving pressure, limited hypercapnia, PEEP adapted to lung recruitability) and by prone positioning.
Abstract: Acute respiratory distress syndrome (ARDS) is frequently associated with hemodynamic instability which appears as the main factor associated with mortality. Shock is driven by pulmonary hypertension, deleterious effects of mechanical ventilation (MV) on right ventricular (RV) function, and associated-sepsis. Hemodynamic effects of ventilation are due to changes in pleural pressure (Ppl) and changes in transpulmonary pressure (TP). TP affects RV afterload, whereas changes in Ppl affect venous return. Tidal forces and positive end-expiratory pressure (PEEP) increase pulmonary vascular resistance (PVR) in direct proportion to their effects on mean airway pressure (mPaw). The acutely injured lung has a reduced capacity to accommodate flowing blood and increases of blood flow accentuate fluid filtration. The dynamics of vascular pressure may contribute to ventilator-induced injury (VILI). In order to optimize perfusion, improve gas exchange, and minimize VILI risk, monitoring hemodynamics is important. During passive ventilation pulse pressure variations are a predictor of fluid responsiveness when conditions to ensure its validity are observed, but may also reflect afterload effects of MV. Central venous pressure can be helpful to monitor the response of RV function to treatment. Echocardiography is suitable to visualize the RV and to detect acute cor pulmonale (ACP), which occurs in 20–25 % of cases. Inserting a pulmonary artery catheter may be useful to measure/calculate pulmonary artery pressure, pulmonary and systemic vascular resistance, and cardiac output. These last two indexes may be misleading, however, in cases of West zones 2 or 1 and tricuspid regurgitation associated with RV dilatation. Transpulmonary thermodilution may be useful to evaluate extravascular lung water and the pulmonary vascular permeability index. To ensure adequate intravascular volume is the first goal of hemodynamic support in patients with shock. The benefit and risk balance of fluid expansion has to be carefully evaluated since it may improve systemic perfusion but also may decrease ventilator-free days, increase pulmonary edema, and promote RV failure. ACP can be prevented or treated by applying RV protective MV (low driving pressure, limited hypercapnia, PEEP adapted to lung recruitability) and by prone positioning. In cases of shock that do not respond to intravascular fluid administration, norepinephrine infusion and vasodilators inhalation may improve RV function. Extracorporeal membrane oxygenation (ECMO) has the potential to be the cause of, as well as a remedy for, hemodynamic problems. Continuous thermodilution-based and pulse contour analysis-based cardiac output monitoring are not recommended in patients treated with ECMO, since the results are frequently inaccurate. Extracorporeal CO2 removal, which could have the capability to reduce hypercapnia/acidosis-induced ACP, cannot currently be recommended because of the lack of sufficient data.
201 citations
TL;DR: It is found that, in vitro, influenza A/H5N1 infection impaired alveolar fluid clearance more than did seasonal virus, mimicking its greater severity in patients, and it is demonstrated that this impairment is mediated by the release of soluble factors from infected cells, leading to down-regulation ofAlveolar sodium and chloride transporters.
Abstract: Influenza can cause acute lung injury. Because immune responses often play a role, antivirals may not ensure a successful outcome. To identify pathogenic mechanisms and potential adjunctive therapeutic options, we compared the extent to which avian influenza A/H5N1 virus and seasonal influenza A/H1N1 virus impair alveolar fluid clearance and protein permeability in an in vitro model of acute lung injury, defined the role of virus-induced soluble mediators in these injury effects, and demonstrated that the effects are prevented or reduced by bone marrow-derived multipotent mesenchymal stromal cells. We verified the in vivo relevance of these findings in mice experimentally infected with influenza A/H5N1. We found that, in vitro, the alveolar epithelium's protein permeability and fluid clearance were dysregulated by soluble immune mediators released upon infection with avian (A/Hong Kong/483/97, H5N1) but not seasonal (A/Hong Kong/54/98, H1N1) influenza virus. The reduced alveolar fluid transport associated with down-regulation of sodium and chloride transporters was prevented or reduced by coculture with mesenchymal stromal cells. In vivo, treatment of aged H5N1-infected mice with mesenchymal stromal cells increased their likelihood of survival. We conclude that mesenchymal stromal cells significantly reduce the impairment of alveolar fluid clearance induced by A/H5N1 infection in vitro and prevent or reduce A/H5N1-associated acute lung injury in vivo. This potential adjunctive therapy for severe influenza-induced lung disease warrants rapid clinical investigation.
169 citations
TL;DR: Criteria defining the acute respiratory distress syndrome prior to need for positive pressure ventilation are required so that these patients can be enrolled in clinical studies and to facilitate early recognition and treatment of acute ventilation distress syndrome.
Abstract: OBJECTIVE The prevalence, clinical characteristics, and outcomes of critically ill, nonintubated patients with evidence of the acute respiratory distress syndrome remain inadequately characterized. DESIGN Secondary analysis of a prospective observational cohort study. SETTING Vanderbilt University Medical Center. PATIENTS Among adult patients enrolled in a large, multi-ICU prospective cohort study between the years of 2006 and 2011, we studied intubated and nonintubated patients with acute respiratory distress syndrome as defined by acute hypoxemia (PaO2/FIO2 ≤ 300 or SpO2/FIO2 ≤ 315) and bilateral radiographic opacities not explained by cardiac failure. We excluded patients not committed to full respiratory support. INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS Of 457 patients with acute respiratory distress syndrome, 106 (23%) were not intubated at the time of meeting all other acute respiratory distress syndrome criteria. Nonintubated patients had lower morbidity and severity of illness than intubated patients; however, mortality at 60 days was the same (36%) in both groups (p = 0.91). Of the 106 nonintubated patients, 36 (34%) required intubation within the subsequent 3 days of follow-up; this late-intubation subgroup had significantly higher 60-day mortality (56%) when compared with the both early intubation group (36%, P<0.03) and patients never requiring intubation (26%; p = 0.002). Increased mortality in the late intubation group persisted at 2-year follow-up. Adjustment for baseline clinical and demographic differences did not change the results. CONCLUSIONS A substantial proportion of critically ill adults with acute respiratory distress syndrome were not intubated in their initial days of intensive care, and many were never intubated. Late intubation was associated with increased mortality. Criteria defining the acute respiratory distress syndrome prior to need for positive pressure ventilation are required so that these patients can be enrolled in clinical studies and to facilitate early recognition and treatment of acute respiratory distress syndrome.
160 citations
TL;DR: Patients with NPPE generate very negative airway pressures, which augment transvascular fluid filtration and precipitate interstitial and alveolar edema.
128 citations
TL;DR: The BREATHE criteria provide an objective definition of breath stacking dyssynchrony emphasizing occult exposure to high tidal volumes, assuring provision of the intended lung-protective strategy.
Abstract: Breath stacking dyssynchrony generates higher tidal volumes than intended, potentially increasing lung injury risk in acute respiratory distress syndrome (ARDS). Lack of validated criteria to quantify breath stacking dyssynchrony contributes to its under-recognition. This study evaluates performance of novel, objective criteria for quantifying breath stacking dyssynchrony (BREATHE criteria) compared to existing definitions and tests if neuromuscular blockade eliminates high-volume breath stacking dyssynchrony in ARDS. Airway flow and pressure were recorded continuously for up to 72 h in 33 patients with ARDS receiving volume-preset assist-control ventilation. The flow–time waveform was integrated to calculate tidal volume breath-by-breath. The BREATHE criteria considered five domains in evaluating for breath stacking dyssynchrony: ventilator cycling, interval expiratory volume, cumulative inspiratory volume, expiratory time, and inspiratory time. The observed tidal volume of BREATHE stacked breaths was 11.3 (9.7–13.3) mL/kg predicted body weight, significantly higher than the preset volume [6.3 (6.0–6.8) mL/kg; p < 0.001]. BREATHE identified more high-volume breaths (≥2 mL/kg above intended volume) than the other existing objective criteria for breath stacking [27 (7–59) vs 19 (5–46) breaths/h; p < 0.001]. Agreement between BREATHE and visual waveform inspection was high (raw agreement 96.4–98.1 %; phi 0.80–0.92). Breath stacking dyssynchrony was near-completely eliminated during neuromuscular blockade [0 (0–1) breaths/h; p < 0.001]. The BREATHE criteria provide an objective definition of breath stacking dyssynchrony emphasizing occult exposure to high tidal volumes. BREATHE identified high-volume breaths missed by other methods for quantifying this dyssynchrony. Neuromuscular blockade prevented breath stacking dyssynchrony, assuring provision of the intended lung-protective strategy.
121 citations
TL;DR: It is suggested that the miR-34 family of miRNAs regulate senescence in IPF type II AECs.
Abstract: Pathologic features of idiopathic pulmonary fibrosis (IPF) include genetic predisposition, activation of the unfolded protein response, telomere attrition, and cellular senescence. The mechanisms leading to alveolar epithelial cell (AEC) senescence are poorly understood. MicroRNAs (miRNAs) have been reported as regulators of cellular senescence. Senescence markers including p16, p21, p53, and senescence-associated β-galactosidase (SA-βgal) activity were measured in type II AECs from IPF lungs and unused donor lungs. miRNAs were quantified in type II AECs using gene expression arrays and quantitative RT-PCR. Molecular markers of senescence (p16, p21, and p53) were elevated in IPF type II AECs. SA-βgal activity was detected in a greater percentage in type II AECs isolated from IPF patients (23.1%) compared to patients with other interstitial lung diseases (1.2%) or normal controls (0.8%). The relative levels of senescence-associated miRNAs miR-34a, miR-34b, and miR-34c, but not miR-20a, miR-29c, or miR-let-7f were significantly higher in type II AECs from IPF patients. Overexpression of miR-34a, miR-34b, or miR-34c in lung epithelial cells was associated with higher SA-βgal activity (27.8%, 35.1%, and 38.2%, respectively) relative to control treated cells (8.8%). Targets of miR-34 miRNAs, including E2F1, c-Myc, and cyclin E2, were lower in IPF type II AECs. These results show that markers of senescence are uniquely elevated in IPF type II AECs and suggest that the miR-34 family of miRNAs regulate senescence in IPF type II AECs.
103 citations
TL;DR: The definition of ARDS remains clinical and the main objective of the diagnostic workup should be to be focused on identification of its aetiology, especially a treatable infection.
Abstract: Acute respiratory distress syndrome (ARDS) is defined by the association of bilateral infiltrates and hypoxaemia following an initial insult. Although a new definition has been recently proposed (Berlin definition), there are various forms of ARDS with potential differences regarding their management (ventilator settings, prone positioning use, corticosteroids). ARDS can be caused by various aetiologies, and the adequate treatment of the responsible cause is crucial to improve the outcome. It is of paramount importance to characterize the mechanisms causing lung injury to optimize both the aetiological treatment and the symptomatic treatment. If there is no obvious cause of ARDS or if a direct lung injury is suspected, bronchoalveolar lavage (BAL) should be strongly considered to identify microorganisms responsible for pneumonia. Blood samples can also help to identify microorganisms and to evaluate biomarkers of infection. If there is no infectious cause of ARDS or no other apparent aetiology is found, second-line examinations should include markers of immunologic diseases. In selected cases, open lung biopsy remains useful to identify the cause of ARDS when all other examinations remain inconclusive. CT scan is fundamental when there is a suspicion of intra-abdominal sepsis and in some cases of pneumonia. Ultrasonography is important not only in evaluating biventricular function but also in identifying pleural effusions and pneumothorax. The definition of ARDS remains clinical and the main objective of the diagnostic workup should be to be focused on identification of its aetiology, especially a treatable infection.
81 citations
TL;DR: A rising Ang-2 between days 1 and 3 was strongly associated with mortality, particularly in pediatric HCT patients, suggesting vulnerability to ongoing endothelial damage.
Abstract: Angiopoietin-2 (Ang-2) is a key mediator of pulmonary vascular permeability. This study tested the association between plasma Ang-2 and mortality in pediatric acute respiratory distress syndrome (A...
71 citations
TL;DR: Long-term ozone exposure is associated with development of ARDS in at-risk critically ill patients, particularly in trauma patients and current smokers, and may represent a previously unrecognized environmental risk factor for ARDS.
Abstract: Rationale: The contribution of air pollution to the risk of acute respiratory distress syndrome (ARDS) is unknown.Methods: We studied 1,558 critically ill patients enrolled in a prospective observational study at a tertiary medical center who lived less than 50 km from an air quality monitor and had an ARDS risk factor. Pollutant exposures (ozone, NO2, SO2, particulate matter < 2.5 μm, particulate matter < 10 μm) were assessed by weighted average of daily levels from the closest monitors for the prior 3 years. Associations between pollutant exposure and ARDS risk were evaluated by logistic regression controlling for age, race, sex, smoking, alcohol, insurance status, rural versus urban residence, distance to study hospital, and Acute Physiology and Chronic Health Evaluation II.Measurements and Main Results: The incidence of ARDS increased with increasing ozone exposure: 28% in the lowest exposure quartile versus 32, 40, and 42% in the second, third, and fourth quartiles (P < 0.001). In a logistic regressi...
TL;DR: The trajectory of SCr levels identifies AKI subphenotypes with different risks for death, even among AKI cases of similar severity, which might better define the patients at risk for poor outcomes who might benefit from novel interventions.
Abstract: Acute kidney injury (AKI) is common among intensive care unit (ICU) patients. AKI is highly heterogeneous, with variable links to poor outcomes. Current approaches to classify AKI severity and identify patients at highest risk for poor outcomes focus on the maximum change in serum creatinine (SCr) values. However, these scores are hampered by the need for a reliable baseline SCr value and the absence of a component differentiating transient from persistent rises in SCr. We hypothesized that identification of resolving or nonresolving AKI subphenotypes based on the early trajectory of SCr values in the ICU would better differentiate patients at risk of hospital mortality. We performed a secondary analysis of two prospective studies of ICU patients admitted to a trauma ICU (group 1; n = 1914) or general medical-surgical ICUs (group 2; n = 1867). In group 1, we tested definitions for resolving and nonresolving AKI subphenotypes and selected the definitions resulting in subphenotypes with the greatest separation in risk of death relative to non-AKI controls. We applied this definition to group 2 and tested whether the subphenotypes were independently associated with hospital mortality after adjustment for AKI severity. AKI occurred in 46% and 69% of patients in groups 1 and 2, respectively. In group 1, a resolving AKI subphenotype (defined as a decrease in SCr of 0.3 mg/dl or 25% from maximum in the first 72 h of study enrollment) was associated with a low risk of death. A nonresolving AKI subphenotype (defined as all AKI cases not meeting the “resolving” definition) was associated with a high risk of death. In group 2, the resolving AKI subphenotype was not associated with increased mortality (relative risk [RR] 0.86, 95% CI 0.63–1.17), whereas the nonresolving AKI subphenotype was associated with higher mortality (RR 1.68, 95% CI 1.15–2.44) even after adjustment for AKI severity stage. The trajectory of SCr levels identifies AKI subphenotypes with different risks for death, even among AKI cases of similar severity. These AKI subphenotypes might better define the patients at risk for poor outcomes who might benefit from novel interventions.
TL;DR: Cigarette smoke exposure may predispose to ARDS through an abnormal response to a ‘second hit,’ with increased alveolar-capillary membrane permeability, exaggerated inflammation, increased epithelial injury and endothelial dysfunction.
Abstract: Rationale Cigarette smoke exposure is associated with an increased risk of the acute respiratory distress syndrome (ARDS); however, the mechanisms underlying this relationship remain largely unknown. Objective To assess pathways of lung injury and inflammation in smokers and non-smokers with and without lipopolysaccharide (LPS) inhalation using established biomarkers. Methods We measured plasma and bronchoalveolar lavage (BAL) biomarkers of inflammation and lung injury in smokers and non-smokers in two distinct cohorts of healthy volunteers, one unstimulated (n=20) and one undergoing 50 μg LPS inhalation (n=30). Measurements and main results After LPS inhalation, cigarette smokers had increased alveolar-capillary membrane permeability as measured by BAL total protein, compared with non-smokers (median 274 vs 208 μg/mL, p=0.04). Smokers had exaggerated inflammation compared with non-smokers, with increased BAL interleukin-1β (p=0.002), neutrophils (p=0.02), plasma interleukin-8 (p=0.003), and plasma matrix metalloproteinase-8 (p=0.006). Alveolar epithelial injury after LPS was more severe in smokers than non-smokers, with increased plasma (p=0.04) and decreased BAL (p=0.02) surfactant protein D. Finally, smokers had decreased BAL vascular endothelial growth factor (VEGF) (p Conclusions Cigarette smoke exposure may predispose to ARDS through an abnormal response to a ‘second hit,’ with increased alveolar-capillary membrane permeability, exaggerated inflammation, increased epithelial injury and endothelial dysfunction. LPS inhalation may serve as a useful experimental model for evaluation of the acute pulmonary effects of existing and new tobacco products.
TL;DR: In the era of balanced hemostatic resuscitation practices, severity of head injury, male sex, early crystalloids, and early transfusion of platelets are associated with a higher risk of ARDS after severe isolated TBI.
Abstract: BACKGROUND Acute respiratory distress syndrome (ARDS) is common after traumatic brain injury (TBI) and is associated with worse neurologic outcomes and longer hospitalization. However, the incidence and associated causes of ARDS in isolated TBI have not been well studied. METHODS We performed a subgroup analysis of 210 consecutive patients with isolated severe TBI enrolled in a prospective observational cohort at a Level 1 trauma center between 2005 and 2014. Subjects required endotracheal intubation and had isolated severe TBI defined by a head Abbreviated Injury Scale (AIS) score of 3 or greater and AIS score lower than 3 in all other categories. ARDS within the first 8 days of admission was rigorously adjudicated using Berlin criteria. Regression analyses were used to test the association between predictors of interest and ARDS. RESULTS The incidence of ARDS in the first 8 days after severe isolated TBI was 30%. Patients who developed ARDS were administered more crystalloids (4.3 L vs. 3.5 L, p = 0.005) and blood products in the first 12 hours of admission. Patients with ARDS had significantly worse clinical outcomes measured at 28 days, including longer median intensive care unit and hospital stays (4 days vs. 13 days, p < 0.001, and 7.5 days vs. 14.5 days, p < 0.001, respectively). In unadjusted logistic regression analyses, the odds of developing ARDS were significantly associated with head AIS score (odds ratio [OR], 1.8; p = 0.018), male sex (OR, 2.9; p = 0.012), and early transfusion of platelets (OR, 2.8; p = 0.003). These associations were similar in a multivariate logistic regression model. CONCLUSION In the era of balanced hemostatic resuscitation practices, severity of head injury, male sex, early crystalloids, and early transfusion of platelets are associated with a higher risk of ARDS after severe isolated TBI. Early transfusion of platelets after severe TBI may be a modifiable risk factor for ARDS, and these findings invite further investigation into causal mechanisms driving this observed association. LEVEL OF EVIDENCE Prognostic/epidemiologic study, level III.
TL;DR: It is found that the genetically determined plasma sST2 reservoir, derived from the lung, neutralizes IL-33 activity, and two single nucleotide polymorphisms in IL1RL1 additively increase the risk of airway type 2 inflammation among asthmatics.
Abstract: Genome-wide association studies of asthma have identified genetic variants in the IL1RL1 gene, but the molecular mechanisms conferring risk are unknown. IL1RL1 encodes the ST2 receptor (ST2L) for IL-33 and an inhibitory decoy receptor (sST2). IL-33 promotes type 2 inflammation, which is present in some but not all asthmatics. We find that two single nucleotide polymorphisms (SNPs) in IL1RL1 - rs1420101 and rs11685480 - are strongly associated with plasma sST2 levels, though neither is an expression quantitative trait locus (eQTL) in whole blood. Rather, rs1420101 and rs11685480 mark eQTLs in airway epithelial cells and distal lung parenchyma, respectively. We find that the genetically determined plasma sST2 reservoir, derived from the lung, neutralizes IL-33 activity, and these eQTL SNPs additively increase the risk of airway type 2 inflammation among asthmatics. These risk variants define a population of asthmatics at risk of IL-33-driven type 2 inflammation.
TL;DR: In the PICU, oxygenation index and cancer/hematopoietic stem cell transplant history can be used on acute respiratory distress syndrome day 1 or day 3 to predict hospital mortality without the need for more complex models, which may simplify risk assessment for clinical trials, counseling families, and high-risk interventions such as extracorporeal life support.
Abstract: Objectives:Despite declining mortality, acute respiratory distress syndrome is still involved in up to one third of pediatric intensive care deaths. The recently convened Pediatric Acute Lung Injury Consensus Conference has outlined research priorities for the field, which include the need for accur
TL;DR: Genetic variants in thrombomodulin and endothelial protein C receptor genes are additively associated with mortality in ARDS, suggesting that genetic differences may be at least partially responsible for the observed associations between dysregulated coagulation and poor outcomes in AR DS.
Abstract: Altered plasma levels of protein C, thrombomodulin, and the endothelial protein C receptor are associated with poor clinical outcomes in patients with acute respiratory distress syndrome (ARDS). We hypothesized that common variants in these genes would be associated with mortality as well as ventilator-free and organ failure-free days in patients with ARDS. We genotyped linkage disequilibrium-based tag single-nucleotide polymorphisms in the ProteinC, Thrombomodulin and Endothelial Protein C Reptor Genes among 320 self-identified white patients of European ancestry from the ARDS Network Fluid and Catheter Treatment Trial. We then tested their association with mortality as well as ventilator-free and organ-failure free days. The GG genotype of rs1042580 (p = 0.02) and CC genotype of rs3716123 (p = 0.002), both in the thrombomodulin gene, and GC/CC genotypes of rs9574 (p = 0.04) in the endothelial protein C receptor gene were independently associated with increased mortality. An additive effect on mortality (p < 0.001), ventilator-free days (p = 0.01), and organ failure-free days was observed with combinations of these high-risk genotypes. This association was independent of age, severity of illness, presence or absence of sepsis, and treatment allocation. Genetic variants in thrombomodulin and endothelial protein C receptor genes are additively associated with mortality in ARDS. These findings suggest that genetic differences may be at least partially responsible for the observed associations between dysregulated coagulation and poor outcomes in ARDS.
TL;DR: Higher soluble suppression of tumorigenicity-2 and interleukin-6 concentrations are each associated with worse outcomes during weaning of mechanical ventilation and increased need for reintubation in patients with acute respiratory distress syndrome.
Abstract: OBJECTIVES Soluble suppression of tumorigenicity-2 and interleukin-6 concentrations have been associated with the inflammatory cascade of acute respiratory distress syndrome. We determined whether soluble suppression of tumorigenicity-2 and interleukin-6 levels can be used as prognostic biomarkers to guide weaning from mechanical ventilation and predict the need for reintubation. DESIGN, SETTING, AND PATIENTS We assayed plasma soluble suppression of tumorigenicity-2 (n = 826) concentrations and interleukin-6 (n = 755) concentrations in the Fluid and Catheter Treatment Trial, a multicenter randomized controlled trial of conservative fluid management in acute respiratory distress syndrome. We tested whether soluble suppression of tumorigenicity-2 and interleukin-6 levels were associated with duration of mechanical ventilation, the probability of passing a weaning assessment, and the need for reintubation. MEASUREMENTS AND MAIN RESULTS In models adjusted for Acute Physiology and Chronic Health Evaluation score and other relevant variables, patients with higher day 0 and day 3 median soluble suppression of tumorigenicity-2 and interleukin-6 concentrations had decreased probability of extubation over time (day 0 soluble suppression of tumorigenicity-2: hazard ratio, 0.85; 95% CI, 0.72-1.00; p = 0.05; day 0 interleukin-6: hazard ratio, 0.64; 95% CI, 0.54-0.75; p < 0.0001; day 3 soluble suppression of tumorigenicity-2: hazard ratio, 0.64; 95% CI, 0.54-0.75; p < 0.0001; and day 3 interleukin-6: hazard ratio, 0.73; 95% CI, 0.62-0.85; p = 0.0001). Higher biomarker concentrations were also predictive of decreased odds of passing day 3 weaning assessments (soluble suppression of tumorigenicity-2: odds ratio, 0.62: 95% CI, 0.44-0.87; p = 0.006 and interleukin-6: odds ratio, 0.61; 95% CI, 0.43-0.85; p = 0.004) and decreased odds of passing a spontaneous breathing trial (soluble suppression of tumorigenicity-2: odds ratio, 0.45; 95% CI, 0.28-0.71; p = 0.0007 and interleukin-6 univariate analysis only: odds ratio, 0.55; 95% CI, 0.36-0.83; p = 0.005). Finally, higher biomarker levels were significant predictors of the need for reintubation for soluble suppression of tumorigenicity-2 (odds ratio, 3.23; 95% CI, 1.04-10.07; p = 0.04) and for interleukin-6 (odds ratio, 2.58; 95% CI, 1.14-5.84; p = 0.02). CONCLUSIONS Higher soluble suppression of tumorigenicity-2 and interleukin-6 concentrations are each associated with worse outcomes during weaning of mechanical ventilation and increased need for reintubation in patients with acute respiratory distress syndrome. Biomarker-directed ventilator management may lead to improved outcomes in weaning of mechanical ventilation in patients with acute respiratory distress syndrome.
TL;DR: Low-tidal volume ventilation is underused in the first 24 hours of pediatric acute respiratory distress syndrome and using admission weight instead of ideal body weight resulted in misclassification of up to 14% of patients as receiving low-t tidal volume ventilation when they actually were not.
Abstract: Objectives: To determine the frequency of low-tidal volume ventilation in pediatric acute respiratory distress syndrome and assess if any demographic or clinical factors improve low-tidal volume ventilation adherence. Design: Descriptive post hoc analysis of four multicenter pediatric acute respiratory distress syndrome studies. Setting: Twenty-six academic PICU. Patients: Three hundred fifteen pediatric acute respiratory distress syndrome patients. Measurements and Main Results: All patients who received conventional mechanical ventilation at hours 0 and 24 of pediatric acute respiratory distress syndrome who had data to calculate ideal body weight were included. Two cutoff points for low-tidal volume ventilation were assessed: less than or equal to 6.5 mL/kg of ideal body weight and less than or equal to 8 mL/kg of ideal body weight. Of 555 patients, we excluded 240 for other respiratory support modes or missing data. The remaining 315 patients had a median PaO2-to-FIO2 ratio of 140 (interquartile range, 90–201), and there were no differences in demographics between those who did and did not receive low-tidal volume ventilation. With tidal volume cutoff of less than or equal to 6.5 mL/kg of ideal body weight, the adherence rate was 32% at hour 0 and 33% at hour 24. A low-tidal volume ventilation cutoff of tidal volume less than or equal to 8 mL/kg of ideal body weight resulted in an adherence rate of 58% at hour 0 and 60% at hour 24. Low-tidal volume ventilation use was no different by severity of pediatric acute respiratory distress syndrome nor did adherence improve over time. At hour 0, overweight children were less likely to receive low-tidal volume ventilation less than or equal to 6.5 mL/kg ideal body weight (11% overweight vs 38% nonoverweight; p = 0.02); no difference was noted by hour 24. Furthermore, in the overweight group, using admission weight instead of ideal body weight resulted in misclassification of up to 14% of patients as receiving low-tidal volume ventilation when they actually were not. Conclusions: Low-tidal volume ventilation is underused in the first 24 hours of pediatric acute respiratory distress syndrome. Age, Pediatric Risk of Mortality-III, and pediatric acute respiratory distress syndrome severity were not associated with improved low-tidal volume ventilation adherence nor did adherence improve over time. Overweight children were less likely to receive low-tidal volume ventilation strategies in the first day of illness.
TL;DR: This rat model of aspiration pneumonia-induced ALI will be useful for testing long-term effects of new therapeutic strategies in ALI, and caused activation of inflammatory responses, increased protein permeability and apoptosis, and induced mild hypoxemia in rat lungs at 24 h postinstillation.
Abstract: The majority of the animal models of acute lung injury (ALI) are focused on the acute phase. This limits the studies of the mechanisms involved in later phases and the effects of long-term treatments. Thus the goal of this study was to develop an experimental ALI model of aspiration pneumonia, in which diffuse alveolar damage continues for 72 h. Rats were intratracheally instilled with one dose of HCl (0.1 mol/l) followed by another instillation of one dose of LPS (0, 10, 20, 30, or 40 μg/g body weight) 2 h later, which models aspiration of gastric contents that progresses to secondary lung injury from bacteria or bacterial products. The rats were euthanized at 24, 48, and 72 h after the last instillation. The results showed that HCl and LPS at all doses caused activation of inflammatory responses, increased protein permeability and apoptosis, and induced mild hypoxemia in rat lungs at 24 h postinstillation. However, this lung damage was present at 72 h only in rats receiving HCl and LPS at the doses of 30 and 40 μg/g body wt. Mortality (∼50%) occurred in the first 48 h and only in the rats treated with HCl and LPS at the highest dose (40 μg/g body wt). In conclusion, intratracheal instillation of HCl followed by LPS at the dose of 30 μg/g body wt results in severe diffuse alveolar damage that continues at least 72 h. This rat model of aspiration pneumonia-induced ALI will be useful for testing long-term effects of new therapeutic strategies in ALI.
TL;DR: Eliciting the perspectives of key stakeholders early in the design process yielded important insights to create a tool tailored to the needs of surrogates and care providers in ICUs.
TL;DR: There has been substantial progress in reducing mortality in the intensive care unit, primarily because of improvements in supportive care, and a pivotal clinical trial demonstrated that lung protective ventilation reduced mortality from 40% to 31% in patients with acute illness.
Abstract: Over the past 25 years, considerable therapeutic success has been achieved in several areas of clinical medicine, including childhood cancer, some adult cancers, human immunodeficiency virus, and chronic liver disease. However, with the notable exception of surfactant therapy for infant respiratory distress syndrome, there has been limited success in the application of novel therapeutics to improve clinical outcomes in critically ill patients. This leads to the following questions: Why have so many pharmacological and other therapeutics failed in critically ill patients? What are the prospects for effective new therapies? and What can be done to increase the chance of success in the future? At the outset, it is important to recognize that despite the lack of novel pharmacotherapies, there has been substantial progress in reducing mortality in the intensive care unit, primarily because of improvements in supportive care. For example, a pivotal clinical trial demonstrated that lung protective ventilation reduced mortality from 40% to 31% in patients with acute
TL;DR: CTSL appears to support innate as well as adaptive responses, which confer a survival advantage on mice infected with the orthomyxovirus influenza A.
Abstract: Host-derived proteases can augment or help to clear infections. This dichotomy is exemplified by cathepsin L (CTSL), which helps Hendra virus and SARS coronavirus to invade cells, but is essential for survival in mice with mycoplasma pneumonia. The present study tested the hypothesis that CTSL protects mice from serious consequences of infection by the orthomyxovirus influenza A, which is thought to be activated by host-supplied proteases other than CTSL. Ctsl-/- mice infected with influenza A/Puerto Rico/8/34(H1N1) had larger lung viral loads and higher mortality than infected Ctsl+/+ mice. Lung inflammation in surviving infected mice peaked 14 days after initial infection, accompanied marked focal distal airway bronchiolization and epithelial metaplasia followed by desquamation and fibrotic interstitial remodeling, and persisted for at least 6 weeks. Most deaths occurred during the second week of infection in both groups of mice. In contrast to mycoplasma pneumonia, infiltrating cells were predominantly mononuclear rather than polymorphonuclear. The histopathology of lung inflammation and remodeling in survivors was similar in Ctsl-/- and Ctsl+/+ mice, although Ctsl+/+ mice cleared immunoreactive virus sooner. Furthermore, Ctsl-/- mice had profound deficits in CD4+ lymphocytes before and after infection and weaker production of pathogen-specific IgG. Thus, CTSL appears to support innate as well as adaptive responses, which confer a survival advantage on mice infected with the orthomyxovirus influenza A.
TL;DR: Results of the PRoVENT study report that the prevalence in the ICU of ventilated patients at risk of developing ARDS, as defined by the Berlin criteria, is low and the LIPS system is not optimum for predicting ARDS in at-risk patients.
TL;DR: In this article, the authors evaluated the effect of a nurse-implemented goal-directed sedation protocol on the duration of mechanical ventilation in critically ill children undergoing acute respiratory failure.
Abstract: Importance Protocolized sedation improves clinical outcomes in critically ill adults, but its effect in children is unknown. Objective To determine whether critically ill children managed with a nurse-implemented, goal-directed sedation protocol experience fewer days of mechanical ventilation than patients receiving usual care. Design, Setting, and Participants Cluster randomized trial conducted in 31 US pediatric intensive care units (PICUs). A total of 2449 children (mean age, 4.7 years; range, 2 weeks to 17 years) mechanically ventilated for acute respiratory failure were enrolled in 2009-2013 and followed up until 72 hours after opioids were discontinued, 28 days, or hospital discharge. Intervention Intervention PICUs (17 sites; n = 1225 patients) used a protocol that included targeted sedation, arousal assessments, extubation readiness testing, sedation adjustment every 8 hours, and sedation weaning. Control PICUs (14 sites; n = 1224 patients) managed sedation per usual care. Main Outcomes and Measures The primary outcome was duration of mechanical ventilation. Secondary outcomes included time to recovery from acute respiratory failure, duration of weaning from mechanical ventilation, neurological testing, PICU and hospital lengths of stay, in-hospital mortality, sedation-related adverse events, measures of sedative exposure (wakefulness, pain, and agitation), and occurrence of iatrogenic withdrawal. Results Duration of mechanical ventilation was not different between the 2 groups (intervention: median, 6.5 [IQR, 4.1-11.2] days; control: median, 6.5 [IQR, 3.7-12.1] days). Sedation-related adverse events including inadequate pain and sedation management, clinically significant iatrogenic withdrawal, and unplanned endotracheal tube/invasive line removal were not significantly different between the 2 groups. Intervention patients experienced more postextubation stridor (7% vs 4%; P = .03) and fewer stage 2 or worse immobility-related pressure ulcers ( P = .001). In exploratory analyses, intervention patients had fewer days of opioid administration (median, 9 [IQR, 5-15] days vs 10 [IQR, 4-21] days; P = .01), were exposed to fewer sedative classes (median, 2 [IQR, 2-3] classes vs 3 [IQR, 2-4] classes; P P = .004) than control patients, respectively; however, intervention patients had more days with any report of a pain score ≥4 (median, 50% [IQR, 27%-67%] of days vs 23% [IQR, 0%-46%] of days; P P = .003), respectively. Conclusions and Relevance Among children undergoing mechanical ventilation for acute respiratory failure, the use of a sedation protocol compared with usual care did not reduce the duration of mechanical ventilation. Exploratory analyses of secondary outcomes suggest a complex relationship among wakefulness, pain, and agitation. Trial Registration clinicaltrials.gov Identifier:NCT00814099
TL;DR: In this paper, the authors studied intubated and non-intubated patients with acute respiratory distress syndrome as defined by acute hypoxemia and bilateral radiographic opacities not explained by cardiac failure.
Abstract: OBJECTIVE The prevalence, clinical characteristics, and outcomes of critically ill, nonintubated patients with evidence of the acute respiratory distress syndrome remain inadequately characterized. DESIGN Secondary analysis of a prospective observational cohort study. SETTING Vanderbilt University Medical Center. PATIENTS Among adult patients enrolled in a large, multi-ICU prospective cohort study between the years of 2006 and 2011, we studied intubated and nonintubated patients with acute respiratory distress syndrome as defined by acute hypoxemia (PaO2/FIO2 ≤ 300 or SpO2/FIO2 ≤ 315) and bilateral radiographic opacities not explained by cardiac failure. We excluded patients not committed to full respiratory support. INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS Of 457 patients with acute respiratory distress syndrome, 106 (23%) were not intubated at the time of meeting all other acute respiratory distress syndrome criteria. Nonintubated patients had lower morbidity and severity of illness than intubated patients; however, mortality at 60 days was the same (36%) in both groups (p = 0.91). Of the 106 nonintubated patients, 36 (34%) required intubation within the subsequent 3 days of follow-up; this late-intubation subgroup had significantly higher 60-day mortality (56%) when compared with the both early intubation group (36%, P<0.03) and patients never requiring intubation (26%; p = 0.002). Increased mortality in the late intubation group persisted at 2-year follow-up. Adjustment for baseline clinical and demographic differences did not change the results. CONCLUSIONS A substantial proportion of critically ill adults with acute respiratory distress syndrome were not intubated in their initial days of intensive care, and many were never intubated. Late intubation was associated with increased mortality. Criteria defining the acute respiratory distress syndrome prior to need for positive pressure ventilation are required so that these patients can be enrolled in clinical studies and to facilitate early recognition and treatment of acute respiratory distress syndrome.