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.

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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

Aerosolized β-Adrenergic Agonist Therapy Reduces Pulmonary Edema Following Lung Surgery

Surviving paediatric sepsis in Tanzania: a prospective cohort study to identify risk factors

Clinical, Radiographic, Physiologic, and Biologic Measurements to Facilitate Personalized Medicine for ARDS.

I this issue of Transplantation, Dhar et al describe the results of a study that compared naloxone to placebo in deceased organ donors with the goal to improve oxygenation. The rationale for this study was based in part on the observation that naloxone reduced neurogenic pulmonary edema in the sheep when administered during experimental elevation of intracranial pressure to 100 mm Hg by mitigating the increase in cardiac output triggered by herniation. The sheep study generated the hypothesis that a decrease in cardiac output might decrease lung vascular pressures and thus reduce the hydrostatic forces contributing to pulmonary edema. In addition to the sheep study, a single uncontrolled human donor study also suggested that naloxone might improve oxygenation in deceased donors. Based on this uncontrolled study, naloxone has been widely incorporated into donor management protocols. However, the results of the current randomized trial showed no beneficial effect of naloxone treatment on oxygenation in deceased organ donors. The negative findings of the current trial should make it clear that naloxone is not an effective therapy to improve oxygenation during donor management. One limitation in this trial is that deceased donors were enrolled a median of 9 hours after declaration of brain death, suggesting that naloxone was administered several hours after the catecholamine surge triggered by herniation and perhaps outside the window for any potential benefit. Although it would be of interest to test the effect of naloxone on lung edema and oxygenation when administered before and during herniation in patients with severe brain injury, such a clinical trial would be outside the purview of deceased donor intervention research. As noted in the summary of the ventilator protocols, 3 of the 4 OPOs in the current trial routinely use albuterol or levalbuterol every 4 hours in donor management. In a large randomized clinical trial of inhaled albuterol versus placebo in 506 deceased organ donors, albuterol had no beneficial effect on oxygenation, severity of pulmonary edema, or lung utilization, indicating that there is no role for aerosolized beta-2 agonists in routine donor management. It is critical that both positive and negative findings from clinical trials inform medical practice, and more work is needed in the field of donor management to ensure that the best evidence is incorporated into clinical practice. Another major challenge in donor management research is the heterogeneity in donor management practices across the 58 organ procurement organizations (OPOs) in the United States. This heterogeneity is highlighted by marked differences in ventilator protocols used by the 4 OPOs that participated in the naloxone trial. Like most aspects of donor management, there is a paucity of clinical trials to guide ventilator management in deceased organ donors. Although a European trial suggested that an open lung protective ventilatory strategy improved oxygenation and lung utilization in deceased donors, the study intervention was short (6 h) and does not readily translate to the US donor management environment. A randomized trial of an open lung protective ventilatory strategy versus conventional ventilation for the duration of donor management in 400 deceased organ donors in Northern California (NCT#03439995) is currently enrolling and should provide evidence that is more applicable to donor management in the United States. We commend the investigators for completing the naloxone trial in a very challenging research environment. The difficulty of conducting rigorous research in this area has been discussed in more depth in several recent publications. As pointed out by the authors, the trial is one of the few prospective trials ever conducted in deceased organ donors. Some of the challenges of donor intervention research are well illustrated in the current trial. A major difficulty in conducting this type of research is related to appropriate communication with transplant centers receiving organs from deceased donors that were involved in interventional trials. This applies not only to the target organ of the intervention (here the lung) but also the nontargeted organs (heart, liver, kidneys, and pancreas). The struggle for appropriate communication is evident in the current trial. Similarly, when do intended recipients of all affected organs need to be notified of ongoing research Commentary Transplantation

The Continued Need for Clinical Trials in Deceased Organ Donor Management.

Background:Acute kidney injury (AKI) commonly occurs in patients with sepsis and acute respiratory distress syndrome (ARDS).Objective:To investigate whether statin treatment is protective against A...

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Michael A. Matthay

Papers

Aerosolized β-Adrenergic Agonist Therapy Reduces Pulmonary Edema Following Lung Surgery

Surviving paediatric sepsis in Tanzania: a prospective cohort study to identify risk factors

Clinical, Radiographic, Physiologic, and Biologic Measurements to Facilitate Personalized Medicine for ARDS.

The Continued Need for Clinical Trials in Deceased Organ Donor Management.

Effect of Rosuvastatin on Acute Kidney Injury in Sepsis-Associated Acute Respiratory Distress Syndrome