Acute respiratory distress syndrome (ARDS) survivors experience a high prevalence of cognitive impairment with concomitantly impaired functional status and quality of life, often persisting months ...after hospital discharge. In this review, we explore the pathophysiological mechanisms underlying cognitive impairment following ARDS, the interrelations between mechanisms and risk factors, and interventions that may mitigate the risk of cognitive impairment. Risk factors for cognitive decline following ARDS include pre-existing cognitive impairment, neurological injury, delirium, mechanical ventilation, prolonged exposure to sedating medications, sepsis, systemic inflammation, and environmental factors in the intensive care unit, which can co-occur synergistically in various combinations. Detection and characterization of pre-existing cognitive impairment imparts challenges in clinical management and longitudinal outcome study enrollment. Patients with brain injury who experience ARDS constitute a distinct population with a particular combination of risk factors and pathophysiological mechanisms: considerations raised by brain injury include neurogenic pulmonary edema, differences in sympathetic activation and cholinergic transmission, effects of positive end-expiratory pressure on cerebral microcirculation and intracranial pressure, and sensitivity to vasopressor use and volume status. The blood-brain barrier represents a physiological interface at which multiple mechanisms of cognitive impairment interact, as acute blood-brain barrier weakening from mechanical ventilation and systemic inflammation can compound existing chronic blood-brain barrier dysfunction from Alzheimer's-type pathophysiology, rendering the brain vulnerable to both amyloid-beta accumulation and cytokine-mediated hippocampal damage. Although some contributory elements, such as the presenting brain injury or pre-existing cognitive impairment, may be irreversible, interventions such as minimizing mechanical ventilation tidal volume, minimizing duration of exposure to sedating medications, maintaining hemodynamic stability, optimizing fluid balance, and implementing bundles to enhance patient care help dramatically to reduce duration of delirium and may help prevent acquisition of long-term cognitive impairment.
Bilirubin is well-recognized marker of hepatic dysfunction in intensive care unit (ICU) patients. Multiple organ failure often complicates acute respiratory distress syndrome (ARDS) evolution and is ...associated with high mortality. The effect of early hepatic dysfunction on ARDS mortality has been poorly investigated. We evaluated the incidence and the prognostic significance of increased serum bilirubin levels in the initial phase of ARDS.
The data of 805 patients with ARDS were retrospectively analysed. This population was extracted from two recent multicenter, prospective and randomised trials. Patients presenting with ARDS with a ratio of the partial pressure of arterial oxygen to the fraction of inspired oxygen < 150 mmHg measured with a PEEP ≥ 5 cm of water were included. The total serum bilirubin was measured at inclusion and at days 2, 4, 7 and 14. The primary objective was to analyse the bilirubin at inclusion according to the 90-day mortality rate.
The 90-day mortality rate was 33.8% (n = 272). The non-survivors were older, had higher Sepsis-related Organ Failure Assessment (SOFA) score and were more likely to have a medical diagnosis on admission than the survivors. At inclusion, the SOFA score without the liver score (10.3±2.9 vs. 9.0±3.0, p<0.0001) and the serum bilirubin levels (36.1±57.0 vs. 20.5±31.5 μmol/L, p<0.0001) were significantly higher in the non-survivors than in the survivors. Age, the hepatic SOFA score, the coagulation SOFA score, the arterial pH level, and the plateau pressure were independently associated with 90-day mortality in patients with ARDS.
Bilirubin used as a surrogate marker of hepatic dysfunction and measured early in the course of ARDS was associated with the 90-day mortality rate.
There is no accurate, non-invasive measurement to estimate the degree of pulmonary oedema in acute respiratory distress syndrome (ARDS). We developed the Radiographic Assessment of Lung Oedema (RALE) ...score to evaluate the extent and density of alveolar opacities on chest radiographs. After first comparing the RALE score to gravimetric assessment of pulmonary oedema in organ donors, we then evaluated the RALE score in patients with ARDS for its relationship to oxygenation and clinical outcomes.
We compared radiographs with excised lung weights from 72 organ donors (derivation cohort) and radiographs with clinical data from 174 patients with ARDS in the ARDSNet Fluid and Catheter Treatment Trial (validation cohort). To calculate RALE, each radiographic quadrant was scored for extent of consolidation (0-4) and density of opacification (1-3). The product of the consolidation and density scores for each of the four quadrants was summed (maximum score=48).
Agreement between two independent reviewers for RALE score was excellent (intraclass correlation coefficient=0.93, 95% CI 0.91 to 0.95). In donors, pre-procurement RALE score correlated with height-adjusted total lung weight (ρ=0.59, p<0.001). In patients with ARDS, higher RALE scores were independently associated with lower PaO
/fractional inspired oxygen and worse survival. Conservative fluid management significantly decreased RALE score over 3 days compared with liberal fluid management.
The RALE score can be used to assess both the extent of pulmonary oedema and the severity of ARDS, by utilising information that is already obtained routinely, safely and inexpensively in every patient with ARDS. This novel non-invasive measure should be useful for assessing ARDS severity and monitoring response to therapy.
Two distinct subphenotypes have been identified in acute respiratory distress syndrome (ARDS), but the presence of subgroups in ARDS associated with coronavirus disease (COVID-19) is unknown.
To ...identify clinically relevant, novel subgroups in COVID-19-related ARDS and compare them with previously described ARDS subphenotypes.
Eligible participants were adults with COVID-19 and ARDS at Columbia University Irving Medical Center. Latent class analysis was used to identify subgroups with baseline clinical, respiratory, and laboratory data serving as partitioning variables. A previously developed machine learning model was used to classify patients as the hypoinflammatory and hyperinflammatory subphenotypes. Baseline characteristics and clinical outcomes were compared between subgroups. Heterogeneity of treatment effect for corticosteroid use in subgroups was tested.
From March 2, 2020, to April 30, 2020, 483 patients with COVID-19-related ARDS met study criteria. A two-class latent class analysis model best fit the population (
= 0.0075). Class 2 (23%) had higher proinflammatory markers, troponin, creatinine, and lactate, lower bicarbonate, and lower blood pressure than class 1 (77%). Ninety-day mortality was higher in class 2 versus class 1 (75% vs. 48%;
< 0.0001). Considerable overlap was observed between these subgroups and ARDS subphenotypes. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RT-PCR cycle threshold was associated with mortality in the hypoinflammatory but not the hyperinflammatory phenotype. Heterogeneity of treatment effect to corticosteroids was observed (
= 0.0295), with improved mortality in the hyperinflammatory phenotype and worse mortality in the hypoinflammatory phenotype, with the caveat that corticosteroid treatment was not randomized.
We identified two COVID-19-related ARDS subgroups with differential outcomes, similar to previously described ARDS subphenotypes. SARS-CoV-2 PCR cycle threshold had differential value for predicting mortality in the subphenotypes. The subphenotypes had differential treatment responses to corticosteroids.
Pathogenesis of Acute Respiratory Distress Syndrome Huppert, Laura A; Matthay, Michael A; Ware, Lorraine B
Seminars in respiratory and critical care medicine,
02/2019, Volume:
40, Issue:
1
Journal Article
Peer reviewed
Open access
Acute respiratory distress syndrome (ARDS) is a syndrome of acute respiratory failure caused by noncardiogenic pulmonary edema. Despite five decades of basic and clinical research, there is still no ...effective pharmacotherapy for this condition and the treatment remains primarily supportive. It is critical to study the molecular and physiologic mechanisms that cause ARDS to improve our understanding of this syndrome and reduce mortality. The goal of this review is to describe our current understanding of the pathogenesis and pathophysiology of ARDS. First, we will describe how pulmonary edema fluid accumulates in ARDS due to lung inflammation and increased alveolar endothelial and epithelial permeabilities. Next, we will review how pulmonary edema fluid is normally cleared in the uninjured lung, and describe how these pathways are disrupted in ARDS. Finally, we will explain how clinical trials and preclinical studies of novel therapeutic agents have further refined our understanding of this condition, highlighting, in particular, the study of mesenchymal stromal cells in the treatment of ARDS.
Uncontrolled inflammatory innate response and impaired adaptive immune response are associated with clinical severity in patients with coronavirus disease (COVID-19).
To compare the immunopathology ...of COVID-19 acute respiratory distress syndrome (ARDS) with that of non-COVID-19 ARDS, and to identify biomarkers associated with mortality in patients with COVID-19 ARDS.
Prospective observational monocenter study. Immunocompetent patients diagnosed with RT-PCR-confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and ARDS admitted between March 8 and March 30, 2020, were included and compared with patients with non-COVID-19 ARDS. The primary clinical endpoint of the study was mortality at Day 28. Flow cytometry analyses and serum cytokine measurements were performed at Days 1-2 and 4-6 of ICU admission.
As compared with patients with non-COVID-19 ARDS (
= 36), those with COVID-19 (
= 38) were not significantly different regarding age, sex, and Sequential Organ Failure Assessment and Simplified Acute Physiology Score II scores but exhibited a higher Day-28 mortality (34% vs. 11%,
= 0.030). Patients with COVID-19 showed profound and sustained T CD4
(
= 0.002), CD8
(
< 0.0001), and B (
< 0.0001) lymphopenia, higher HLA-DR expression on monocytes (
< 0.001) and higher serum concentrations of EGF (epithelial growth factor), GM-CSF, IL-10, CCL2/MCP-1, CCL3/MIP-1a, CXCL10/IP-10, CCL5/RANTES, and CCL20/MIP-3a. After adjusting on age and Sequential Organ Failure Assessment, serum CXCL10/IP-10 (
= 0.047) and GM-CSF (
= 0.050) were higher and nasopharyngeal RT-PCR cycle threshold values lower (
= 0.010) in patients with COVID-19 who were dead at Day 28.
Profound global lymphopenia and a "chemokine signature" were observed in COVID-19 ARDS. Increased serum concentrations of CXCL10/IP-10 and GM-CSF, together with higher nasopharyngeal SARS-CoV-2 viral load, were associated with Day-28 mortality.
There is no therapeutic intervention proven to prevent acute respiratory distress syndrome (ARDS). Novel mechanistic insights into the pathophysiology of ARDS are therefore required. Platelets are ...implicated in regulating many of the pathogenic processes that occur during ARDS; however, the mechanisms remain elusive. The platelet receptor CLEC-2 has been shown to regulate vascular integrity at sites of acute inflammation. Therefore the purpose of this study was to establish the role of CLEC-2 and its ligand podoplanin in a mouse model of ARDS. Platelet-specific CLEC-2-deficient, as well as alveolar epithelial type I cell (AECI)-specific or hematopoietic-specific podoplanin deficient, mice were established using
strategies. Combining these with intratracheal (IT) instillations of lipopolysaccharide (LPS), we demonstrate that arterial oxygen saturation decline in response to IT-LPS in platelet-specific CLEC-2-deficient mice is significantly augmented. An increase in bronchoalveolar lavage (BAL) neutrophils and protein was also observed 48 h post-IT-LPS, with significant increases in pro-inflammatory chemokines detected in BAL of platelet-specific CLEC-2-deficient animals. Deletion of podoplanin from hematopoietic cells but not AECIs also reduces lung function and increases pro-inflammatory chemokine expression following IT-LPS. Furthermore, we demonstrate that following IT-LPS, platelets are present in BAL in aggregates with neutrophils, which allows for CLEC-2 interaction with podoplanin expressed on BAL inflammatory alveolar macrophages. Taken together, these data suggest that the platelet CLEC-2-podoplanin signaling axis regulates the severity of lung inflammation in mice and is a possible novel target for therapeutic intervention in patients at risk of developing ARDS.
The application of prone positioning for acute respiratory distress syndrome (ARDS) has evolved, with recent trials focusing on patients with more severe ARDS, and applying prone ventilation for more ...prolonged periods.
This review evaluates the effect of prone positioning on 28-day mortality (primary outcome) compared with conventional mechanical ventilation in the supine position for adults with ARDS.
We updated the literature search from a systematic review published in 2010, searching MEDLINE, EMBASE, and CENTRAL (through to August 2016). We included randomized, controlled trials (RCTs) comparing prone to supine positioning in mechanically ventilated adults with ARDS, and conducted sensitivity analyses to explore the effects of duration of prone ventilation, concurrent lung-protective ventilation and ARDS severity. Secondary outcomes included Pa
/Fi
ratio on Day 4 and an evaluation of adverse events. Meta-analyses used random effects models. Methodologic quality of the RCTs was evaluated using the Cochrane risk of bias instrument, and methodologic quality of the overall body of evidence was evaluated using the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) guidelines.
Eight RCTs fulfilled entry criteria, and included 2,129 patients (1,093 51% proned). Meta-analysis revealed no difference in mortality (risk ratio RR, 0.84; 95% confidence interval CI, 0.68-1.04), but subgroup analyses found lower mortality with 12 hours or greater duration prone (five trials; RR, 0.74; 95% CI, 0.56-0.99) and for patients with moderate to severe ARDS (five trials; RR, 0.74; 95% CI, 0.56-0.99). Pa
/Fi
ratio on Day 4 for all patients was significantly higher in the prone positioning group (mean difference, 23.5; 95% CI, 12.4-34.5). Prone positioning was associated with higher rates of endotracheal tube obstruction and pressure sores. Risk of bias was low across the trials.
Prone positioning is likely to reduce mortality among patients with severe ARDS when applied for at least 12 hours daily.
Acute Respiratory Distress Syndrome (ARDS) is a clinical syndrome characterized by diffuse alveolar damage usually secondary to an intense host inflammatory response of the lung to a pulmonary or ...extrapulmonary infectious or non-infectious insult often leading to the development of intra-alveolar and interstitial fibrosis. Curcumin, the principal curcumoid of the popular Indian spice turmeric, has been demonstrated as an anti-oxidant and anti-inflammatory agent in a broad spectrum of diseases. Using our well-established model of reovirus 1/L-induced acute viral pneumonia, which displays many of the characteristics of the human ALI/ARDS, we evaluated the anti-inflammatory and anti-fibrotic effects of curcumin. Female CBA/J mice were treated with curcumin (50 mg/kg) 5 days prior to intranasal inoculation with 10(7)pfu reovirus 1/L and daily, thereafter. Mice were evaluated for key features associated with ALI/ARDS. Administration of curcumin significantly modulated inflammation and fibrosis, as revealed by histological and biochemical analysis. The expression of IL-6, IL-10, IFNγ, and MCP-1, key chemokines/cytokines implicated in the development of ALI/ARDS, from both the inflammatory infiltrate and whole lung tissue were modulated by curcumin potentially through a reduction in the phosphorylated form of NFκB p65. While the expression of TGFß1 was not modulated by curcumin, TGFß Receptor II, which is required for TGFß signaling, was significantly reduced. In addition, curcumin also significantly inhibited the expression of α-smooth muscle actin and Tenascin-C, key markers of myofibroblast activation. This data strongly supports a role for curcumin in modulating the pathogenesis of viral-induced ALI/ARDS in a pre-clinical model potentially manifested through the alteration of inflammation and myofibroblast differentiation.
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