Background Traditional approaches to mechanical ventilation use tidal volumes of 10 to 15 ml per kilogram of body weight and may cause stretch-induced lung injury in patients with acute lung injury and the acute respiratory distress syndrome. We therefore conducted a trial to determine whether ventilation with lower tidal volumes would improve the clinical outcomes in these patients. Methods Patients with acute lung injury and the acute respiratory distress syndrome were enrolled in a multicenter, randomized trial. The trial compared traditional ventilation treatment, which involved an initial tidal volume of 12 ml per kilogram of predicted body weight and an airway pressure measured after a 0.5-second pause at the end of inspiration (plateau pressure) of 50 cm of water or less, with ventilation with a lower tidal volume, which involved an initial tidal volume of 6 ml per kilogram of predicted body weight and a plateau pressure of 30 cm of water or less. The primary outcomes were death before a patient was discharged home and was breathing without assistance and the number of days without ventilator use from day 1 to day 28. Results The trial was stopped after the enrollment of 861 patients because mortality was lower in the group treated with lower tidal volumes than in the group treated with traditional tidal volumes (31.0 percent vs. 39.8 percent, P=0.007), and the number of days without ventilator use during the first 28 days after randomization was greater in this group (mean [+/-SD], 12+/-11 vs. 10+/-11; P=0.007). The mean tidal volumes on days 1 to 3 were 6.2+/-0.8 and 11.8+/-0.8 ml per kilogram of predicted body weight (P Conclusions In patients with acute lung injury and the acute respiratory distress syndrome, mechanical ventilation with a lower tidal volume than is traditionally used results in decreased mortality and increases the number of days without ventilator use.

Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome.

Objective:To provide an update to the “Surviving Sepsis Campaign Guidelines for Management of Severe Sepsis and Septic Shock,” last published in 2008.Design:A consensus committee of 68 international experts representing 30 international organizations was convened. Nominal groups were assembled at ke

Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2012.

The acute respiratory distress syndrome (ARDS) was defined in 1994 by the American-European Consensus Conference (AECC); since then, issues regarding the reliability and validity of this definition have emerged. Using a consensus process, a panel of experts convened in 2011 (an initiative of the European Society of Intensive Care Medicine endorsed by the American Thoracic Society and the Society of Critical Care Medicine) developed the Berlin Definition, focusing on feasibility, reliability, validity, and objective evaluation of its performance. A draft definition proposed 3 mutually exclusive categories of ARDS based on degree of hypoxemia: mild (200 mm Hg < PaO2/FIO2 ≤ 300 mm Hg), moderate (100 mm Hg < PaO2/FIO2 ≤ 200 mm Hg), and severe (PaO2/FIO2 ≤ 100 mm Hg) and 4 ancillary variables for severe ARDS: radiographic severity, respiratory system compliance (≤40 mL/cm H2O), positive end-expiratory pressure (≥10 cm H2O), and corrected expired volume per minute (≥10 L/min). The draft Berlin Definition was empirically evaluated using patient-level meta-analysis of 4188 patients with ARDS from 4 multicenter clinical data sets and 269 patients with ARDS from 3 single-center data sets containing physiologic information. The 4 ancillary variables did not contribute to the predictive validity of severe ARDS for mortality and were removed from the definition. Using the Berlin Definition, stages of mild, moderate, and severe ARDS were associated with increased mortality (27%; 95% CI, 24%-30%; 32%; 95% CI, 29%-34%; and 45%; 95% CI, 42%-48%, respectively; P < .001) and increased median duration of mechanical ventilation in survivors (5 days; interquartile [IQR], 2-11; 7 days; IQR, 4-14; and 9 days; IQR, 5-17, respectively; P < .001). Compared with the AECC definition, the final Berlin Definition had better predictive validity for mortality, with an area under the receiver operating curve of 0.577 (95% CI, 0.561-0.593) vs 0.536 (95% CI, 0.520-0.553; P < .001). This updated and revised Berlin Definition for ARDS addresses a number of the limitations of the AECC definition. The approach of combining consensus discussions with empirical evaluation may serve as a model to create more accurate, evidence-based, critical illness syndrome definitions and to better inform clinical care, research, and health services planning.

Acute respiratory distress syndrome: the Berlin Definition.

Although humans have been exposed to airborne nanosized particles (NSPs; < 100 nm) throughout their evolutionary stages, such exposure has increased dramatically over the last century due to anthropogenic sources. The rapidly developing field of nanotechnology is likely to become yet another source through inhalation, ingestion, skin uptake, and injection of engineered nanomaterials. Information about safety and potential hazards is urgently needed. Results of older bio-kinetic studies with NSPs and newer epidemiologic and toxicologic studies with airborne ultrafine particles can be viewed as the basis for the expanding field of nanotoxicology, which can be defined as safety evaluation of engineered nanostructures and nanodevices. Collectively, some emerging concepts of nanotoxicology can be identified from the results of these studies. When inhaled, specific sizes of NSPs are efficiently deposited by diffusional mechanisms in all regions of the respiratory tract. The small size facilitates uptake into cells and transcytosis across epithelial and endothelial cells into the blood and lymph circulation to reach potentially sensitive target sites such as bone marrow, lymph nodes, spleen, and heart. Access to the central nervous system and ganglia via translocation along axons and dendrites of neurons has also been observed. NSPs penetrating the skin distribute via uptake into lymphatic channels. Endocytosis and biokinetics are largely dependent on NSP surface chemistry (coating) and in vivo surface modifications. The greater surface area per mass compared with larger-sized particles of the same chemistry renders NSPs more active biologically. This activity includes a potential for inflammatory and pro-oxidant, but also antioxidant, activity, which can explain early findings showing mixed results in terms of toxicity of NSPs to environmentally relevant species. Evidence of mitochondrial distribution and oxidative stress response after NSP endocytosis points to a need for basic research on their interactions with subcellular structures. Additional considerations for assessing safety of engineered NSPs include careful selections of appropriate and relevant doses/concentrations, the likelihood of increased effects in a compromised organism, and also the benefits of possible desirable effects. An interdisciplinary team approach (e.g., toxicology, materials science, medicine, molecular biology, and bioinformatics, to name a few) is mandatory for nanotoxicology research to arrive at an appropriate risk assessment.

/pdf/nanotoxicology-an-emerging-discipline-evolving-from-studies-pb7art8sfp.pdf

Nanotoxicology: An Emerging Discipline Evolving from Studies of Ultrafine Particles

Importance Coronavirus disease 2019 (COVID-19) is an emerging infectious disease that was first reported in Wuhan, China, and has subsequently spread worldwide. Risk factors for the clinical outcomes of COVID-19 pneumonia have not yet been well delineated. Objective To describe the clinical characteristics and outcomes in patients with COVID-19 pneumonia who developed acute respiratory distress syndrome (ARDS) or died. Design, Setting, and Participants Retrospective cohort study of 201 patients with confirmed COVID-19 pneumonia admitted to Wuhan Jinyintan Hospital in China between December 25, 2019, and January 26, 2020. The final date of follow-up was February 13, 2020. Exposures Confirmed COVID-19 pneumonia. Main Outcomes and Measures The development of ARDS and death. Epidemiological, demographic, clinical, laboratory, management, treatment, and outcome data were also collected and analyzed. Results Of 201 patients, the median age was 51 years (interquartile range, 43-60 years), and 128 (63.7%) patients were men. Eighty-four patients (41.8%) developed ARDS, and of those 84 patients, 44 (52.4%) died. In those who developed ARDS, compared with those who did not, more patients presented with dyspnea (50 of 84 [59.5%] patients and 30 of 117 [25.6%] patients, respectively [difference, 33.9%; 95% CI, 19.7%-48.1%]) and had comorbidities such as hypertension (23 of 84 [27.4%] patients and 16 of 117 [13.7%] patients, respectively [difference, 13.7%; 95% CI, 1.3%-26.1%]) and diabetes (16 of 84 [19.0%] patients and 6 of 117 [5.1%] patients, respectively [difference, 13.9%; 95% CI, 3.6%-24.2%]). In bivariate Cox regression analysis, risk factors associated with the development of ARDS and progression from ARDS to death included older age (hazard ratio [HR], 3.26; 95% CI 2.08-5.11; and HR, 6.17; 95% CI, 3.26-11.67, respectively), neutrophilia (HR, 1.14; 95% CI, 1.09-1.19; and HR, 1.08; 95% CI, 1.01-1.17, respectively), and organ and coagulation dysfunction (eg, higher lactate dehydrogenase [HR, 1.61; 95% CI, 1.44-1.79; and HR, 1.30; 95% CI, 1.11-1.52, respectively] and D-dimer [HR, 1.03; 95% CI, 1.01-1.04; and HR, 1.02; 95% CI, 1.01-1.04, respectively]). High fever (≥39 °C) was associated with higher likelihood of ARDS development (HR, 1.77; 95% CI, 1.11-2.84) and lower likelihood of death (HR, 0.41; 95% CI, 0.21-0.82). Among patients with ARDS, treatment with methylprednisolone decreased the risk of death (HR, 0.38; 95% CI, 0.20-0.72). Conclusions and Relevance Older age was associated with greater risk of development of ARDS and death likely owing to less rigorous immune response. Although high fever was associated with the development of ARDS, it was also associated with better outcomes among patients with ARDS. Moreover, treatment with methylprednisolone may be beneficial for patients who develop ARDS.

https://jamanetwork.com/journals/jamainternalmedicine/articlepdf/2763184/jamainternal_wu_2020_oi_200022.pdf

Risk Factors Associated With Acute Respiratory Distress Syndrome and Death in Patients With Coronavirus Disease 2019 Pneumonia in Wuhan, China

Precision medicine for cell therapy in acute respiratory distress syndrome - Authors' reply.

Cells for Severe Acute Lung Injury Therapeutic Potential of Mesenchymal Stem

Purpose Although smoking is common in organ donors and recipients of donor lungs from smokers have worse clinical outcomes, the mechanisms are unknown. We tested the association between donor smoking and the degree of pulmonary edema, the rate of alveolar fluid clearance (AFC) and biomarkers of lung epithelial injury and inflammation in the ex vivo donor lung. Methods and Materials Among 661 donors evaluated for the Beta-agonists for Oxygenation in Lung Donors (BOLD) study (albuterol vs. placebo), 301 had lungs resected without perfusion for physiologic studies, and were included. After transport at 4C, lungs were weighed for quantification of pulmonary edema and a BAL was done. Lungs were rewarmed to 37°C for measurement of AFC by airspace instillation of a 5% albumin solution. IL-8 and surfactant protein D (SP-D) were measured in BAL by ELISA. Results 130 (43%) donors were current smokers. Pulmonary edema assessed by lung weight was 7% higher in current smokers compared to non-smokers (441 ± 113g vs. 411 ± 115g, p = 0.03), and current smokers had poorer oxygenation at study enrollment compared to non-smokers (PaO2/FiO2 239 ± 133 vs. 279 ± 143, p = 0.016). AFC did not differ based on smoking status. BAL IL-8 was significantly higher in smokers while SP-D was lower ( Figure ). Conclusions Donor smoking is associated with more pulmonary edema in the resected lung, higher levels of the chemokine IL-8 and lower levels of surfactant protein D. Chronic exposure to cigarette smoke has important effects on inflammation, permeability and lung fluid balance in the organ donor that could potentially influence lung function in the lung transplant recipient.

Pulmonary Edema and Biomarkers of Inflammation and Lung Epithelial Dysfunction Are Associated with Donor Smoking in the Ex Vivo Donor Lung

We read Dr. Prescott and colleagues’ study describing pathways to sepsis (1) with great interest. Their identification of three distinct presepsis trajectories using latent profile analysis is robust and intuitively appealing.Moreover, the patients they describe belonging to “low,” “rising,” and “high use” classes are immediately recognizable to clinicians. But what are we to make of their finding that rising users have increased 90-day mortality (adjusted odds ratio, 1.2–2.2) compared with low users? Moreover, how to interpret the fact that high users, with more comorbidities and functional limitations, have similar survival to low users in their validation cohorts? The authors speculate about reasons that rising use would uniquely predispose to vulnerability, and hence predict mortality, from impaired immunity to disruptions in the microbiome. These hypotheses involve two assumptions: First, that rising use is associated with excess mortality, and second, that this excess mortality is related to pathobiology. Although it seems plausible that rising use would confer additional mortality risk compared with “low use,” it is harder to understand why rising use should predict higher mortality than high use.What if the issue is not that rising users aremore likely to die but, instead, that high users are less likely to die? In addition, what if the survival advantage for high-use subjects is unrelated to pathobiology? Mortality is determined by factors beyond an illness’ intrinsic survivability, including patients’ goals and treatment preferences. Indeed, most deaths among the critically ill, such as those who die of sepsis, occur after decisions to limit treatment (2). Therefore, when comparing 90-day mortality among groups of patients with different presepsis trajectories, it is important to consider whether varying tendencies to limit treatment contribute to survival differences. Reconsidering the data through this lens, it may be that subjects in the high-use group died at a lower than expected rate because they were willing to undergo more aggressive interventions with the goal of prolonging life (e.g., intubation, tracheostomy, hemodialysis, etc.) These interventions could reduce mortality for high-use subjects while lengthening hospitalizations and yielding survivors with many comorbidities, functional limitations, and frequent use of skilled nursing facilities; in other words, survivors who look like the high users the authors describe. In contrast, rising users may not opt for such aggressive care, instead placing limits on life-sustaining treatment. This explanation would seem to fit with prototypical patients: the patient with a new terminal malignancy who values independence and foregoes aggressive treatment for sepsis, versus the nursing home resident with a tracheostomy and feeding tube who keeps coming in with aspiration pneumonia and surviving. It is also supported by studies of how people accommodate increasing debility and factor present function into decisions about their goals and future quality of life (3). We do not mean to suggest that goals of care mediate the entire relationship between presepsis trajectory and mortality. Clearly, decisions to limit treatment are typically made when the prognosis is grim. Still, goals and preferences could explain some of the observed survival differences, and thus warrant inclusion in multivariate models. The authors could use information they already have to evaluate whether patient’s goals varied with presepsis trajectory. Among Health and Retirement Study decedents, there are data on whether treatment was limited at the end of life. Similarly, Health and Retirement Study surveys and Medicare claims could be used to ascertain whether rising use and high use patients used hospice at different rates. Given that many of the excess deaths in the rising use group occurred after hospital discharge, it may be that more rising users pursued hospice care. These data would strengthen the investigators’ ability to ascribe observed survival differences to underlying pathobiology.

https://www.atsjournals.org/doi/pdf/10.1513/AnnalsATS.201810-680LE

Could Decisions to Limit Treatment Contribute to Mortality Differences between Patients with Different Presepsis Trajectories

Publisher Summary This chapter discusses the cellular and molecular foundations of pulmonary edema. The study of lung endothelium evolved from an early focus on barrier function to an intensive interest in the many interactive and regulatory functions of endothelium. However, the significance of the relationship between endothelial integrity and the clinically important problem of pulmonary edema is undiminished. To advance the treatment and prevention of alveolar flooding and inflammation, an improved and up-to-date mastery of the construction and maintenance of the dam is needed. The chapter presents the fundamentals of the structural elements of the endothelium and highlights the forces that challenge barrier integrity and the mechanisms of response. Detailed descriptions of the individual structural elements, their regulation, their contribution to barrier integrity or dysfunction, and the heterogeneity of endothelium are presented in the chapter. The interactions of endothelium with blood-borne cells, factors, infectious agents, and the injurious consequences are defined. Finally, the internal defenses and repair of the barrier by endothelium and the advances in the treatment to aid in resistance to activation, injury, and repair are reviewed.

Michael A. Matthay

Papers

Precision medicine for cell therapy in acute respiratory distress syndrome - Authors' reply.

Cells for Severe Acute Lung Injury Therapeutic Potential of Mesenchymal Stem

Pulmonary Edema and Biomarkers of Inflammation and Lung Epithelial Dysfunction Are Associated with Donor Smoking in the Ex Vivo Donor Lung

Could Decisions to Limit Treatment Contribute to Mortality Differences between Patients with Different Presepsis Trajectories

Chapter 1 The cellular and molecular foundations of pulmonary edema