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Objectives: We sought to evaluate the association between the carbon dioxide ( co2 ) ventilatory equivalent (VEq co2 = minute ventilation/volume of co2 produced per min), a marker of dead space that does not require a blood gas measurement, and mortality risk. We compared the strength of this association to that of physiologic dead space fraction (V D /V t = [Pa co2 -mixed-expired P co2 ]/Pa co2 ) as well as to other commonly used markers of dead space (i.e., the end-tidal alveolar dead space fraction [AVDSf = (Pa co2 -end-tidal P co2 )/Pa co2 ], and ventilatory ratio [VR = (minute ventilation × Pa co2 )/(age-adjusted predicted minute ventilation × 37.5)])., Design: Retrospective cohort data, 2017-2023., Setting: Quaternary PICU., Patients: One hundred thirty-one children with acute respiratory distress syndrome., Interventions: None., Measurements and Main Results: All dead space markers were calculated at the same 1-minute timepoint for each patient within the first 72 hours of using invasive mechanical ventilation. The 131 children had a median (interquartile range, IQR) age of 5.8 (IQR 1.4, 12.6) years, oxygenation index (OI) of 7.5 (IQR 4.6, 14.3), V D /V t of 0.47 (IQR 0.38, 0.61), and mortality was 17.6% (23/131). Higher VEq co2 ( p = 0.003), V D /V t ( p = 0.002), and VR ( p = 0.013) were all associated with greater odds of mortality in multivariable models adjusting for OI, immunosuppressive comorbidity, and overall severity of illness. We failed to identify an association between AVDSf and mortality in the multivariable modeling. Similarly, we also failed to identify an association between OI and mortality after controlling for any dead space marker in the modeling. For the 28-day ventilator-free days outcome, we failed to identify an association between V D /V t and the dead space markers in multivariable modeling, although OI was significant., Conclusions: VEq co2 performs similarly to V D /V t and other surrogate dead space markers, is independently associated with mortality risk, and may be a reasonable noninvasive surrogate for V D /V t ., Competing Interests: Dr. Khemani is supported by the National Institutes of Health (NIH)/the National Heart, Lung, and Blood Institute (NHLBI) R01 HL134666. Dr. Khemani is a consultant for Nihon-Kohden OrangeMed and Bayer. Nihon-Kohdon was not involved in this study and their module for volumetric capnography was not used in this study. Dr. Bhalla is supported by the NIH/NHLBI K23 HL153756. This work was also supported by grant UL1TR001855 from the NIH/National Center for Advancing Translational Science and support from the Department of Anesthesiology and Critical Care at Children’s Hospital Los Angeles. Drs. Bhalla and Khemani’s institutions received funding from the NHLBI. Dr. Bhalla disclosed personal stock ownership. Drs. Bhalla and, Khemani received support for article research from the NIH. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2024 by the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies.)

Objectives: High driving pressure (DP, ratio of tidal volume (V t ) over respiratory system compliance) is a risk for poor outcomes in patients with pediatric acute respiratory distress syndrome (PARDS). We therefore assessed the time course in level of DP (i.e., 24, 48, and 72 hr) after starting mechanical ventilation (MV), and its association with 28-day mortality., Design: Multicenter, prospective study conducted between February 2018 and December 2022., Setting: Twelve tertiary care PICUs in Colombia., Patients: One hundred eighty-four intubated children with moderate to severe PARDS., Interventions: None., Measurements and Main Results: The median (interquartile range [IQR]) age of the PARDS cohort was 11 (IQR 3-24) months. A total of 129 of 184 patients (70.2%) had a pulmonary etiology leading to PARDS, and 31 of 184 patients (16.8%) died. In the first 24 hours after admission, the plateau pressure in the nonsurvivor group, compared with the survivor group, differed (28.24 [IQR 24.14-32.11] vs. 23.18 [IQR 20.72-27.13] cm H 2 O, p < 0.01). Of note, children with a V t less than 8 mL/kg of ideal body weight had lower adjusted odds ratio (aOR [95% CI]) of 28-day mortality (aOR 0.69, [95% CI, 0.55-0.87]; p = 0.02). However, we failed to identify an association between DP level and the oxygenation index (aOR 0.58; 95% CI, 0.21-1.58) at each of time point. In a diagnostic exploratory analysis, we found that DP greater than 15 cm H 2 O at 72 hours was an explanatory variable for mortality, with area under the receiver operating characteristic curve of 0.83 (95% CI, 0.74-0.89); there was also increased hazard for death with hazard ratio 2.5 (95% CI, 1.07-5.92). DP greater than 15 cm H 2 O at 72 hours was also associated with longer duration of MV (10 [IQR 7-14] vs. 7 [IQR 5-10] d; p = 0.02)., Conclusions: In children with moderate to severe PARDS, a DP greater than 15 cm H 2 O at 72 hours after the initiation of MV is associated with greater odds of 28-day mortality and a longer duration of MV. DP should be considered a variable worth monitoring during protective ventilation for PARDS., Competing Interests: The authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2024 by the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies.)

Objectives: Prone position is used in acute respiratory distress syndrome and in coronavirus disease 2019 acute respiratory distress syndrome. However, it is unclear how responders may be identified and whether an oxygenation response improves outcome. The objective of this study was to quantify the response to prone position, describe the differences between coronavirus disease 2019 acute respiratory distress syndrome and acute respiratory distress syndrome, and explore variables associated with survival., Design: Retrospective, observational, multicenter, international cohort study., Setting: Seven ICUs in Italy, United Kingdom, and France., Patients: Three hundred seventy-six adults (220 coronavirus disease 2019 acute respiratory distress syndrome and 156 acute respiratory distress syndrome)., Intervention: None., Measurements and Main Results: Preproning, a greater proportion of coronavirus disease 2019 acute respiratory distress syndrome patients had severe disease (53% vs 40%), worse Pao2/Fio2 (13.0 kPa [interquartile range, 10.5-15.5 kPa] vs 14.1 kPa [interquartile range, 10.5-18.6 kPa]; p = 0.017) but greater compliance (38 mL/cm H2O [interquartile range, 27-53 mL/cm H2O] vs 31 mL/cm H2O [interquartile range, 21-37 mL/cm H2O]; p < 0.001). Patients with coronavirus disease 2019 acute respiratory distress syndrome had a longer median time from intubation to prone position (2.0 d [interquartile range, 0.7-5.0 d] vs 1.0 d [interquartile range, 0.5-2.9 d]; p = 0.03). The proportion of responders, defined by an increase in Pao2/Fio2 greater than or equal to 2.67 kPa (20 mm Hg), upon proning, was similar between acute respiratory distress syndrome and coronavirus disease 2019 acute respiratory distress syndrome (79% vs 76%; p = 0.5). Responders had earlier prone position (1.4 d [interquartile range, 0.7-4.2 d] vs 2.5 d [interquartile range, 0.8-6.2 d]; p = 0.06)]. Prone position less than 24 hours from intubation achieved greater improvement in oxygenation (11 kPa [interquartile range, 4-21 kPa] vs 7 kPa [interquartile range, 2-13 kPa]; p = 0.002). The variables independently associated with the "responder" category were Pao2/Fio2 preproning (odds ratio, 0.89 kPa-1 [95% CI, 0.85-0.93 kPa-1]; p < 0.001) and interval between intubation and proning (odds ratio, 0.94 d-1 [95% CI, 0.89-0.99 d-1]; p = 0.019). The overall mortality was 45%, with no significant difference observed between acute respiratory distress syndrome and coronavirus disease 2019 acute respiratory distress syndrome. Variables independently associated with mortality included age (odds ratio, 1.03 yr-1 [95% CI, 1.01-1.05 yr-1]; p < 0.001); interval between hospital admission and proning (odds ratio, 1.04 d-1 [95% CI, 1.002-1.084 d-1]; p = 0.047); and change in Pao2/Fio2 on proning (odds ratio, 0.97 kPa-1 [95% CI, 0.95-0.99 kPa-1]; p = 0.002)., Conclusions: Prone position, particularly when delivered early, achieved a significant oxygenation response in ~80% of coronavirus disease 2019 acute respiratory distress syndrome, similar to acute respiratory distress syndrome. This response was independently associated with improved survival., Competing Interests: Dr. Terzi received funding from Pfizer. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2022 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.)

Background: The pathomechanisms of hypoxemia and treatment strategies for type H and type L acute respiratory distress syndrome (ARDS) in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-induced coronavirus disease 2019 (COVID-19) have not been elucidated., Main Text: SARS-CoV-2 mainly targets the lungs and blood, leading to ARDS, and systemic thrombosis or bleeding. Angiotensin II-induced coagulopathy, SARS-CoV-2-induced hyperfibrin(ogen)olysis, and pulmonary and/or disseminated intravascular coagulation due to immunothrombosis contribute to COVID-19-associated coagulopathy. Type H ARDS is associated with hypoxemia due to diffuse alveolar damage-induced high right-to-left shunts. Immunothrombosis occurs at the site of infection due to innate immune inflammatory and coagulofibrinolytic responses to SARS-CoV-2, resulting in microvascular occlusion with hypoperfusion of the lungs. Lung immunothrombosis in type L ARDS results from neutrophil extracellular traps containing platelets and fibrin in the lung microvasculature, leading to hypoxemia due to impaired blood flow and a high ventilation/perfusion (VA/Q) ratio. COVID-19-associated ARDS is more vascular centric than the other types of ARDS. D-dimer levels have been monitored for the progression of microvascular thrombosis in COVID-19 patients. Early anticoagulation therapy in critical patients with high D-dimer levels may improve prognosis, including the prevention and/or alleviation of ARDS., Conclusions: Right-to-left shunts and high VA/Q ratios caused by lung microvascular thrombosis contribute to hypoxemia in type H and L ARDS, respectively. D-dimer monitoring-based anticoagulation therapy may prevent the progression to and/or worsening of ARDS in COVID-19 patients., Competing Interests: The authors report no conflicts of interest., (Copyright © 2021 by the Shock Society.)

The coronavirus 2019 (COVID-19) pandemic has presented many new challenges to the healthcare community with the sheer number of individuals affected and the range of symptoms at presentation. Early findings have shown that increased age is an independent risk factor for COVID-19 severity. Diabetes and hypertension were also found to be strong independent risk factors for severe COVID-19. It was later discovered that obesity is a strong risk factor for severe disease as well. Possible mechanisms for the increased risk associated with metabolic disease include the increased prevalence of acute respiratory syndrome, immune cell dysfunction, and chronic inflammatory states associated with obesity and diabetes. Acknowledging these risk factors has consequences for addressing vaccination strategies as well as healthcare disparities., Competing Interests: Disclosure: The authors have no conflicts of interest to report., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background and Purpose: Stroke may complicate coronavirus disease 2019 (COVID-19) infection based on clinical hypercoagulability. We investigated whether transcranial Doppler ultrasound has utility for identifying microemboli and clinically relevant cerebral blood flow velocities (CBFVs) in COVID-19., Methods: We performed transcranial Doppler for a consecutive series of patients with confirmed or suspected COVID-19 infection admitted to 2 intensive care units at a large academic center including evaluation for microembolic signals. Variables specific to hypercoagulability and blood flow including transthoracic echocardiography were analyzed as a part of routine care., Results: Twenty-six patients were included in this analysis, 16 with confirmed COVID-19 infection. Of those, 2 had acute ischemic stroke secondary to large vessel occlusion. Ten non-COVID stroke patients were included for comparison. Two COVID-negative patients had severe acute respiratory distress syndrome and stroke due to large vessel occlusion. In patients with COVID-19, relatively low CBFVs were observed diffusely at median hospital day 4 (interquartile range, 3-9) despite low hematocrit (29.5% [25.7%-31.6%]); CBFVs in comparable COVID-negative stroke patients were significantly higher compared with COVID-positive stroke patients. Microembolic signals were not detected in any patient. Median left ventricular ejection fraction was 60% (interquartile range, 60%-65%). CBFVs were correlated with arterial oxygen content, and C-reactive protein (Spearman ρ=0.28 [ P =0.04]; 0.58 [ P <0.001], respectively) but not with left ventricular ejection fraction (ρ=-0.18; P =0.42)., Conclusions: In this cohort of critically ill patients with COVID-19 infection, we observed lower than expected CBFVs in setting of low arterial oxygen content and low hematocrit but not associated with suppression of cardiac output.

Abstract: Extracorporeal life support (ECLS) is a support modality for patients with severe acute respiratory distress syndrome (ARDS) who have failed conventional treatments including low tidal volume ventilation, prone positioning, and neuromuscular blockade. In addition, ECLS can be used for hemodynamic support for patients with cardiogenic shock or following cardiac arrest. Injured patients may also require ECLS support for ARDS and other indications. We review the use of ECLS for ARDS patients, trauma patients, cardiogenic shock patients, and post-cardiac arrest patients. We then describe how these principles are applied in the management of the novel coronavirus disease 2019 pandemic. Indications, predictors, procedural considerations, and post-cannulation management strategies are discussed., Competing Interests: The authors report no conflicts of interest., (Copyright © 2020 by the Shock Society.)

Background: Whether train-of-four (TOF) monitoring is more effective than clinical monitoring to guide neuromuscular blockade (NMB) in patients with acute respiratory distress syndrome (ARDS) is unclear. We compared clinical monitoring alone or with TOF monitoring to guide atracurium dosage adjustment with respect to drug dose and respiratory parameters., Methods: From 2015 to 2016, we conducted a randomized controlled trial comparing clinical assessments every 2 hours with or without corrugator supercilii TOF monitoring every 4 hours in patients who developed ARDS (Pao2/Fio2 <150 mm Hg) in a cardiothoracic intensive care unit. The primary outcome was the cumulative atracurium dose (mg/kg/h). Secondary outcomes included respiratory parameters during the neuromuscular blockade., Results: A total of 38 patients in the clinical + TOF (C + TOF) group and 39 patients in the clinical (C) group were included in an intention-to-treat (ITT) analysis. The cumulative atracurium dose was higher in the C + TOF group (1.06 [0.75-1.30] vs 0.65 [0.60-0.89] mg/kg/h in the C group; P < .001) compared to C group, as well as the atracurium daily dose (C + TOF - C group mean difference = 0.256 mg/kg/h [95% confidence interval {CI}, 0.099-0.416], P = .026). Driving pressures during neuromuscular blocking agent (NMBA) administration did not differ between groups (P = .653). Intensive care unit (ICU) mortality was 22% in the C group and 27% in the C + TOF group (P = .786). Days on ventilation were 17 (8-26) in the C group and 16 (10-35) in the C + TOF group., Conclusions: In patients with ARDS, adding TOF to clinical monitoring of neuromuscular blockade did not change ICU mortality or days on mechanical ventilation (MV) but did increase atracurium consumption when compared to clinical assessment alone. TOF monitoring may not be needed in all patients who receive neuromuscular blockade for ARDS., Competing Interests: Conflicts of Interest: See Disclosures at the end of the article., (Copyright © 2020 International Anesthesia Research Society.)

Background: Acute respiratory distress syndrome (ARDS) was first described in 1967, but its definition has evolved considerably since then. ARDS is defined as the onset of hypoxemia, tachypnea, and loss of lung compliance due to some stimulus. In the United States, the incidence of ARDS has been growing because it is being increasingly recognized. The incidence of ARDS has also gone up recently due to the COVID-19 pandemic., Areas of Uncertainty: To date, there is no known one treatment for ARDS. Multiple studies have looked into various causes of ARDS, pathophysiology, and ventilation and management strategies. However, there is still considerable variability in the treatment and management of these patients from institution to institution., Data Sources: A literature search was conducted through PubMed and Google Scholar. Publications describing the epidemiology, diagnostic criteria, pathophysiology, and treatment were included in this review., Results: The definition of ARDS has evolved over the years. The most recent and agreed upon diagnostic criteria are based on the Berlin criteria for ARDS. Management of patients with ARDS includes low tidal volume ventilation, prone ventilation, paralysis in certain patient populations, and perhaps extracorporeal membrane oxygenation (ECMO). This also applies to patients with ARDS due to COVID-19., Conclusions: Patients with ARDS have a high mortality due to the incredibly complex disease process. Because of the complexity of ARDS, the management and treatment is equally as difficult. This article reviews some of the strategies used to date, including the role of ECMO, and includes some society recommendations. Further research must be done into which methods best guide lung ventilation in severe ARDS and patients on ECMO., Competing Interests: The author has no conflicts of interest to declare., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Abstract: Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are caused by an exaggerated inflammatory response arising from a wide variety of pulmonary and systemic insults. Lung tissue is composed of a variety of cell populations, including parenchymal and immune cells. Emerging evidence has revealed that multiple cell populations in the lung work in concert to regulate lung inflammation in response to both direct and indirect stimulations. To date, the question of how different types of pulmonary cells communicate with each other and subsequently regulate or modulate inflammatory cascades remains to be fully addressed. In this review, we provide an overview of current advancements in understanding the role of cell-cell interaction in the development of ALI and depict molecular mechanisms by which cell-cell interactions regulate lung inflammation, focusing on inter-cellular activities and signaling pathways that point to possible therapeutic opportunities for ALI/ARDS., Competing Interests: The authors report no conflicts of interest., (Copyright © 2020 by the Shock Society.)

Objectives: Prone position ventilation improves oxygenation and reduces the mortality of patients with severe acute respiratory distress syndrome. However, there is limited evidence about which patients would gain most survival benefit from prone positioning. Herein, we investigated whether the improvement in oxygenation after prone positioning is associated with survival and aimed to identify patients who will gain most survival benefit from prone positioning in patients with acute respiratory distress syndrome., Design: A retrospective cohort study., Setting: Medical ICU at a tertiary academic hospital between 2014 and 2020., Patients: Adult patients receiving prone positioning for moderate-to-severe acute respiratory distress syndrome., Interventions: None., Measurements and Main Results: The main outcomes were ICU and 28-day mortality. A total of 116 patients receiving prone positioning were included, of whom 45 (38.8%) were ICU survivors. Although there was no difference in PaO2:FIO2 ratio before the first prone session between ICU survivors and nonsurvivors, ICU survivors had a higher PaO2:FIO2 ratio after prone positioning than nonsurvivors, with significant between-group difference (p < 0.001). The area under the receiver operating characteristic curve of the percentage change in the PaO2:FIO2 ratio between the baseline and 8-12 hours after the first prone positioning to predict ICU mortality was 0.87 (95% CI, 0.80-0.94), with an optimal cutoff value of 53.5% (sensitivity, 91.5%; specificity, 73.3%). Prone responders were defined as an increase in PaO2:FIO2 ratio of greater than or equal to 53.5%. In the multivariate Cox regression analysis, prone responders (hazard ratio, 0.11; 95% CI, 0.05-0.25), immunocompromised condition (hazard ratio, 2.15; 95% CI, 1.15-4.03), and Sequential Organ Failure Assessment score (hazard ratio, 1.16; 95% CI, 1.06-1.27) were significantly associated with 28-day mortality., Conclusions: The PaO2:FIO2 ratio after the first prone positioning differed significantly between ICU survivors and nonsurvivors. The improvement in oxygenation after the first prone positioning was a significant predictor of survival in patients with moderate-to-severe acute respiratory distress syndrome.

Objectives: Venovenous extracorporeal membrane oxygenation is an effective intervention to improve gas exchange in patients with severe acute respiratory distress syndrome. However, the mortality of patients with severe acute respiratory distress syndrome supported with venovenous extracorporeal membrane oxygenation remains high, and this may be due in part to a lack of standardized mechanical ventilation strategies aimed at further minimizing ventilator-induced lung injury. We tested whether a continuous positive airway pressure ventilation strategy mitigates ventilator-induced lung injury in patients with severe acute respiratory distress syndrome on venovenous extracorporeal membrane oxygenation, compared with current ventilation practice that employs tidal ventilation with limited driving pressure. We used plasma biomarkers as a surrogate outcome for ventilator-induced lung injury., Design: Randomized crossover physiologic study., Setting: Single-center ICU., Patients: Ten patients with severe acute respiratory distress syndrome supported on venovenous extracorporeal membrane oxygenation., Interventions: The study included four phases. After receiving pressure-controlled ventilation with driving pressure of 10 cm H2O for 1 hour (phase 1), patients were randomly assigned to receive first either pressure-controlled ventilation 20 cm H2O for 2 hours (phase 2) or continuous positive airway pressure for 2 hours (phase 3), and then crossover to the other phase for 2 hours; during phase 4 ventilation settings returned to baseline (pressure-controlled ventilation 10 cm H2O) for 4 hours., Measurements and Main Results: There was a linear relationship between the change in driving pressure and the plasma concentration of interleukin-6, soluble receptor for advanced glycation end products, interleukin-1ra, tumor necrosis factor alpha, surfactant protein D, and interleukin-10., Conclusions: Ventilator-induced lung injury may occur in acute respiratory distress syndrome patients on venovenous extracorporeal membrane oxygenation despite the delivery of volume- and pressure-limited mechanical ventilation. Reducing driving pressure to zero may provide more protective mechanical ventilation in acute respiratory distress syndrome patients supported with venovenous extracorporeal membrane oxygenation. However, the risks versus benefits of such an approach need to be confirmed in studies that are designed to test patient centered outcomes.

Rationale: Steroid is known to cause generalized immunosuppression, thereby increasing the risk of new infection or recurrence of tuberculosis. However, corticosteroid as a culprit for exacerbation of miliary tuberculosis-from a cryptic to an overt form-has rarely been described in the literature. Moreover, miliary tuberculosis is hardly diagnosed in a living patient as a primary cause of ARDS even in TB-endemic regions. To the best of our knowledge, this is the first case of a steroid-induced progression of cryptic miliary tuberculosis to ARDS, provided with clear depiction of its radiologic evolution., Patient Concerns: A 36-year-old male was treated with corticosteroid under suspicion of adult onset still's disease for six-week history of fever. Within 2 weeks since the initiation of corticosteroid therapy, the patient experienced acute exacerbation of cryptic miliary tuberculosis, which evolved to an overt form, appearing as miliary nodules on both chest radiograph and HRCT. Then, his condition suddenly deteriorated to severe acute respiratory distress syndrome in less than a day., Diagnosis: The final diagnosis was miliary tuberculosis complicated by severe acute respiratory distress syndrome., Interventions: The patient was placed on classic quadruple anti-TB treatment (isoniazide, ethambutol, rifampin, and pyrazinamide)., Outcomes: His fever subsided in about 6 weeks and 3 consecutive sputum AFB smears collected on different days were confirmed negative. Diffuse infiltrates on his chest x-ray were completely resolved., Lessons: The case described here draws a clinical and radiological picture of how an occult form of miliary TB evolved to an overt form with use of steroid, and then suddenly progressed to acute respiratory distress syndrome in an immunocompetent young male. This raises awareness on the potential risk of using corticosteroid in patients with cryptic miliary TB. There is formidable challenge in the diagnosis of miliary TB, especially in the early stages. Atypical or even normal outcomes of clinical, microbiochemical, and radiologic evaluation should not be overlooked and dedicated diagnostic work-up should be performed. For equivocal cases, active surveillance with serial radiographs can be helpful.

The severe acute respiratory syndrome coronavirus-2 emerged as a serious human pathogen in late 2019, causing the disease coronavirus disease 2019 (COVID-19). The most common clinical presentation of severe COVID-19 is acute respiratory failure consistent with the acute respiratory distress syndrome. Airway, lung parenchymal, pulmonary vascular, and respiratory neuromuscular disorders all feature in COVID-19. This article reviews what is known about the effects of severe acute respiratory syndrome coronavirus-2 infection on different parts of the respiratory system, clues to understanding the underlying biology of respiratory disease, and highlights current and future translation and clinical research questions.

Background: A lung rest strategy is recommended during extracorporeal membrane oxygenation in severe acute respiratory distress syndrome (ARDS). However, spontaneous breathing modes are frequently used in this context. The impact of this approach may depend on the intensity of breathing efforts. The authors aimed to determine whether a low spontaneous breathing effort strategy increases lung injury, compared to a controlled near-apneic ventilation, in a porcine severe ARDS model assisted by extracorporeal membrane oxygenation., Methods: Twelve female pigs were subjected to lung injury by repeated lavages, followed by 2-h injurious ventilation. Thereafter, animals were connected to venovenous extracorporeal membrane oxygenation and during the first 3 h, ventilated with near-apneic ventilation (positive end-expiratory pressure, 10 cm H2O; driving pressure, 10 cm H2O; respiratory rate, 5/min). Then, animals were allocated into (1) near-apneic ventilation, which continued with the previous ventilatory settings; and (2) spontaneous breathing: neuromuscular blockers were stopped, sweep gas flow was decreased until regaining spontaneous efforts, and ventilation was switched to pressure support mode (pressure support, 10 cm H2O; positive end-expiratory pressure, 10 cm H2O). In both groups, sweep gas flow was adjusted to keep Paco2 between 30 and 50 mmHg. Respiratory and hemodynamic as well as electric impedance tomography data were collected. After 24 h, animals were euthanized and lungs extracted for histologic tissue analysis., Results: Compared to near-apneic group, the spontaneous breathing group exhibited a higher respiratory rate (52 ± 17 vs. 5 ± 0 breaths/min; mean difference, 47; 95% CI, 34 to 59; P < 0.001), but similar tidal volume (2.3 ± 0.8 vs. 2.8 ± 0.4 ml/kg; mean difference, 0.6; 95% CI, -0.4 to 1.4; P = 0.983). Extracorporeal membrane oxygenation settings and gas exchange were similar between groups. Dorsal ventilation was higher in the spontaneous breathing group. No differences were observed regarding histologic lung injury., Conclusions: In an animal model of severe ARDS supported with extracorporeal membrane oxygenation, spontaneous breathing characterized by low-intensity efforts, high respiratory rates, and very low tidal volumes did not result in increased lung injury compared to controlled near-apneic ventilation., (Copyright © 2020, the American Society of Anesthesiologists, Inc. All Rights Reserved.)

Acute respiratory distress syndrome (ARDS) is a significant cause of morbidity and mortality in the intensive care unit (ICU) and is characterized by lung epithelial and endothelial cell injury, with increased permeability of the alveolar-capillary membrane, leading to pulmonary edema, severe hypoxia, and difficulty with ventilation. The most common cause of ARDS is sepsis, and currently, treatment of ARDS and sepsis has consisted mostly of supportive care because targeted therapies have largely been unsuccessful. The molecular mechanisms behind ARDS remain elusive. Recently, a number of microRNAs (miRNAs) identified through high-throughput screening studies in ARDS patients and preclinical animal models have suggested a role for miRNA in the pathophysiology of ARDS. miRNAs are small noncoding RNAs ranging from 18 to 24 nucleotides that regulate gene expression via inhibition of the target mRNA translation or by targeting complementary mRNA for early degradation. Unsurprisingly, some miRNAs that are differentially expressed in ARDS overlap with those important in sepsis. In addition, circulatory miRNA may be useful as biomarkers or as targets for pharmacologic therapy. This can be revolutionary in a syndrome that has neither a measurable indicator of the disease nor a targeted therapy. While there are currently no miRNA-based therapies targeted for ARDS, therapies targeting miRNA have reached phase II clinical trials for the treatment of a wide range of diseases. Further studies may yield a unique miRNA profile pattern that serves as a biomarker or as targets for miRNA-based pharmacologic therapy. In this review, we discuss miRNAs that have been found to play a role in ARDS and sepsis, the potential mechanism of how particular miRNAs may contribute to the pathophysiology of ARDS, and strategies for pharmacologically targeting miRNA as therapy.

Background: Complete airway closure during expiration may underestimate alveolar pressure. It has been reported in cases of acute respiratory distress syndrome (ARDS), as well as in morbidly obese patients with healthy lungs. The authors hypothesized that complete airway closure was highly prevalent in obese ARDS and influenced the calculation of respiratory mechanics., Methods: In a post hoc pooled analysis of two cohorts, ARDS patients were classified according to body mass index (BMI) terciles. Low-flow inflation pressure-volume curve and partitioned respiratory mechanics using esophageal manometry were recorded. The authors' primary aim was to compare the prevalence of complete airway closure according to BMI terciles. Secondary aims were to compare (1) respiratory system mechanics considering or not considering complete airway closure in their calculation, and (2) and partitioned respiratory mechanics according to BMI., Results: Among the 51 patients analyzed, BMI was less than 30 kg/m2 in 18, from 30 to less than 40 in 16, and greater than or equal to 40 in 17. Prevalence of complete airway closure was 41% overall (95% CI, 28 to 55; 21 of 51 patients), and was lower in the lowest (22% [3 to 41]; 4 of 18 patients) than in the highest BMI tercile (65% [42 to 87]; 11 of 17 patients). Driving pressure and elastances of the respiratory system and of the lung were higher when complete airway closure was not taken into account in their calculation. End-expiratory esophageal pressure (ρ = 0.69 [95% CI, 0.48 to 0.82]; P < 0.001), but not chest wall elastance, was associated with BMI, whereas elastance of the lung was negatively correlated with BMI (ρ = -0.27 [95% CI, -0.56 to -0.10]; P = 0.014)., Conclusions: Prevalence of complete airway closure was high in ARDS and should be taken into account when calculating respiratory mechanics, especially in the most morbidly obese patients., (Copyright © 2020, the American Society of Anesthesiologists, Inc. All Rights Reserved.)

Objectives: Hysteresis of the respiratory system pressure-volume curve is related to alveolar surface forces, lung stress relaxation, and tidal reexpansion/collapse. Hysteresis has been suggested as a means of assessing lung recruitment. The objective of this study was to determine the relationship between hysteresis, mechanical characteristics of the respiratory system, and lung recruitment assessed by a CT scan in mechanically ventilated acute respiratory distress syndrome patients., Design: Prospective observational study., Setting: General ICU of a university hospital., Patients: Twenty-five consecutive sedated and paralyzed patients with acute respiratory distress syndrome (age 64 ± 15 yr, body mass index 26 ± 6 kg/m, PaO2/FIO2 147 ± 42, and positive end-expiratory pressure 9.3 ± 1.4 cm H2O) were enrolled., Interventions: A low-flow inflation and deflation pressure-volume curve (5-45 cm H2O) and a sustained inflation recruitment maneuver (45 cm H2O for 30 s) were performed. A lung CT scan was performed during breath-holding pressure at 5 cm H2O and during the recruitment maneuver at 45 cm H2O., Measurements and Main Results: Lung recruitment was computed as the difference in noninflated tissue and in gas volume measured at 5 and at 45 cm H2O. Hysteresis was calculated as the ratio of the area enclosed by the pressure-volume curve and expressed as the hysteresis ratio. Hysteresis was correlated with respiratory system compliance computed at 5 cm H2O and the lung gas volume entering the lung during inflation of the pressure-volume curve (R = 0.749, p < 0.001 and R = 0.851, p < 0.001). The hysteresis ratio was related to both lung tissue and gas recruitment (R = 0.266, p = 0.008, R = 0.357, p = 0.002, respectively). Receiver operating characteristic analysis showed that the optimal cutoff value to predict lung tissue recruitment for the hysteresis ratio was 28% (area under the receiver operating characteristic curve, 0.80; 95% CI, 0.62-0.98), with sensitivity and specificity of 0.75 and 0.77, respectively., Conclusions: Hysteresis of the respiratory system computed by low-flow pressure-volume curve is related to the anatomical lung characteristics and has an acceptable accuracy to predict lung recruitment.

Objective: To describe neuroimaging findings and to report the epidemiologic and clinical characteristics of patients with coronavirus disease 2019 (COVID-19) with neurologic manifestations., Methods: In this retrospective multicenter study (11 hospitals), we included 64 patients with confirmed COVID-19 with neurologic manifestations who underwent a brain MRI., Results: The cohort included 43 men (67%) and 21 women (33%); their median age was 66 (range 20-92) years. Thirty-six (56%) brain MRIs were considered abnormal, possibly related to severe acute respiratory syndrome coronavirus. Ischemic strokes (27%), leptomeningeal enhancement (17%), and encephalitis (13%) were the most frequent neuroimaging findings. Confusion (53%) was the most common neurologic manifestation, followed by impaired consciousness (39%), presence of clinical signs of corticospinal tract involvement (31%), agitation (31%), and headache (16%). The profile of patients experiencing ischemic stroke was different from that of other patients with abnormal brain imaging: the former less frequently had acute respiratory distress syndrome ( p = 0.006) and more frequently had corticospinal tract signs ( p = 0.02). Patients with encephalitis were younger ( p = 0.007), whereas agitation was more frequent for patients with leptomeningeal enhancement ( p = 0.009)., Conclusions: Patients with COVID-19 may develop a wide range of neurologic symptoms, which can be associated with severe and fatal complications such as ischemic stroke or encephalitis. In terms of meningoencephalitis involvement, even if a direct effect of the virus cannot be excluded, the pathophysiology seems to involve an immune or inflammatory process given the presence of signs of inflammation in both CSF and neuroimaging but the lack of virus in CSF., Clinicaltrialsgov Identifier: NCT04368390., (© 2020 American Academy of Neurology.)

Objectives: Severe cases of coronavirus disease 2019 develop the acute respiratory distress syndrome, requiring admission to the ICU. This study aimed to describe specific pathophysiological characteristics of acute respiratory distress syndrome from coronavirus disease 2019., Design: Prospective crossover physiologic study., Setting: ICU of a university-affiliated hospital from northern Italy dedicated to care of patients with confirmed diagnosis of coronavirus disease 2019., Patients: Ten intubated patients with acute respiratory distress syndrome and confirmed diagnosis of coronavirus disease 2019., Interventions: We performed a two-step positive end-expiratory pressure trial with change of 10 cm H2O in random order., Measurements and Main Results: At each positive end-expiratory pressure level, we assessed arterial blood gases, respiratory mechanics, ventilation inhomogeneity, and potential for lung recruitment by electrical impedance tomography. Potential for lung recruitment was assessed by the recently described recruitment to inflation ratio. In a subgroup of seven paralyzed patients, we also measured ventilation-perfusion mismatch at lower positive end-expiratory pressure by electrical impedance tomography. At higher positive end-expiratory pressure, respiratory mechanics did not change significantly: compliance remained relatively high with low driving pressure. Oxygenation and ventilation inhomogeneity improved but arterial CO2 increased despite unchanged respiratory rate and tidal volume. The recruitment to inflation ratio presented median value higher than previously reported in acute respiratory distress syndrome patients but with large variability (median, 0.79 [0.53-1.08]; range, 0.16-1.40). The FIO2 needed to obtain viable oxygenation at lower positive end-expiratory pressure was significantly correlated with the recruitment to inflation ratio (r = 0.603; p = 0.05). The ventilation-perfusion mismatch was elevated (median, 34% [32-45%] of lung units) and, in six out of seven patients, ventilated nonperfused units represented a much larger proportion than perfused nonventilated ones., Conclusions: In patients with acute respiratory distress syndrome from coronavirus disease 2019, potential for lung recruitment presents large variability, while elevated dead space fraction may be a specific pathophysiological trait. These findings may guide selection of personalized mechanical ventilation settings.

Introduction: Sepsis is the most common etiology of acute lung injury (ALI) or acute respiratory distress syndrome (ARDS). Capillary leakage caused by lung endothelial injury is the central cause of ARDS. The results of research in modern medicine in reducing endothelial damage and restoring endothelial functions are limited. In the previous clinical observations, we found that the Fusu mixture not only improves the clinical symptoms but also reduces the leakage of pulmonary capillaries. Therefore, the purpose of this study is to determine the clinical efficacy of the Fusu mixture combined with Western medicine in the treatment of ARDS caused by sepsis and to explore the mechanism of traditional Chinese medicine., Methods: This is a prospective, single-center, randomized, single-blind, and controlled clinical study involving 620 eligible patients. The patients will be randomly divided into 2 groups: the Western medicine treatment group and the combination of Chinese and Western medicine treatment group. After 14 days of intervention, the clinical efficacy and safety of the Fusu mixture on sepsis-induced ARDS patients will be observed. The primary outcome will be measured as 28-day mortality. The secondary outcome indices include inflammatory markers (CRP, PCT, IL-6, TNF - α), APACHE II score, SOFA score, days without a ventilator, blood gas analysis (Lac, PaO2 / FiO2), intensive care unit hospital stay time, intensive care unit mortality. Simultaneously, the analysis of the exploratory results will be carried out to analyze the possible mechanism of Fusu mixture in the treatment of sepsis-induced ARDS by the high-throughput sequencing and bioinformatics., Discussion: The purpose of this study is to evaluate the clinical efficacy of Fusu mixture in the treatment of sepsis-induced ARDS and explore its possible mechanism of action. If successful, it will provide evidence-based adjuvant therapy for the clinical treatment of ARDS.

In patients undergoing extracorporeal membrane oxygenation (ECMO) for acute respiratory distress syndrome (ARDS), it is unknown which clinical physiologic variables should be monitored to follow the evolution of lung injury and extrapulmonary organ dysfunction and to differentiate patients according to their course. We analyzed the time-course of prospectively collected clinical physiologic variables in 83 consecutive ARDS patients undergoing ECMO at a single referral center. Selected variables-including ventilator settings, respiratory system compliance, intrapulmonary shunt, arterial blood gases, central hemodynamics, and sequential organ failure assessment (SOFA) score-were compared according to outcome at time-points corresponding to 0%, 25%, 50%, 75%, and 100% of the entire ECMO duration and daily during the first 7 days. A logistic regression analysis was performed to identify changes between ECMO start and end that independently predicted hospital mortality. Tidal volume, intrapulmonary shunt, arterial lactate, and SOFA score differentiated survivors and nonsurvivors early during the first 7 days and over the entire ECMO duration. Respiratory system compliance, PaO2/FiO2 ratio, arterial pH, and mean pulmonary arterial pressure showed distinct temporal course according to outcome over the entire ECMO duration. Lack of improvement of SOFA score independently predicted hospital mortality. In ARDS patients on ECMO, temporal trends of specific physiologic parameters differentiate survivors from non-survivors and could be used to monitor the evolution of lung injury. Progressive worsening of extrapulmonary organ dysfunction is associated with worse outcome.

Objectives: Recent evidence from the fields of microbiology and immunology, as well as a small number of human sepsis studies, suggest that epigenetic regulation may play a central role in the pathogenesis of sepsis. The term "epigenetics" refers to regulatory mechanisms that control gene expression but are not related to changes in DNA sequence. These include DNA methylation, histone modifications, and regulation of transcription via non-coding RNAs. Epigenetic modifications, occurring in response to external stressors, lead to changes in gene expression, and thus lie at the intersection between genetics and the environment. In this review, we examine data from in vitro studies, animal studies, and the existing human sepsis studies in epigenetics to demonstrate that epigenetic mechanisms are likely central to the pathogenesis of sepsis and that epigenetic therapies may have potential in the treatment of sepsis and its associated organ failures., Data Sources: Online search of published scientific literature via Pubmed using the term "epigenetics" in combination with the terms "sepsis", "infection", "bacterial infection", "viral infection", "critical illness", "acute respiratory distress syndrome", and "acute lung injury"., Study Selection: Articles were chosen for inclusion based on their relevance to sepsis, acute inflammation, sepsis-related immune suppression, and sepsis-related organ failure. Reference lists were reviewed to identify additional relevant articles., Data Extraction: Relevant data was extracted and synthesized for narrative review., Data Synthesis: Epigenetic regulation is a key determinant of gene expression in sepsis. At the onset of infection, host-pathogen interactions often result in epigenetic alterations to host cells that favor pathogen survival. In parallel, the host inflammatory response is characterized by epigenetic modifications in key regulatory genes, including tumor necrosis factor and interleukin-1β. In human sepsis patients, multiple epigenetic modifying enzymes show differential expression in early sepsis, suggesting a role for epigenetics in coordinating the response to infection. In the later stages of sepsis, epigenetic modifications accompany endotoxin tolerance and the immune-suppressed state. In animal models, treatment with epigenetic modifiers can mitigate the effects of sepsis and improve survival as well as reverse sepsis-associated organ injury., Conclusions: Epigenetic modifications are associated with key phases of sepsis, from the host-pathogen interaction, to acute inflammation, to immune suppression. Epigenetic markers show promise in the diagnosis and prognosis of sepsis and epigenetic modifying agents show promise as therapeutic tools in animal models of sepsis. Human studies in the area of epigenetics are sorely lacking and should be a priority for sepsis researchers.

Objectives: Survival from acute respiratory distress syndrome is improving, and outcomes beyond mortality may be important for testing new treatments. The "ventilator-free days" score, is an established composite that equates ventilation on day 28 to death. A hierarchical outcome treating death as a worse than prolonged ventilation would enhance face validity, but performance characteristics and reporting of such an outcome are unknown. We therefore evaluated the performance of a novel hierarchical composite endpoint, the Alive and Ventilator Free score., Design: Using data from four Acute Respiratory Distress Syndrome Network clinical trials, we compared Alive and Ventilator Free to the ventilator-free days score. Alive and Ventilator Free compares each patient with every other patient in a win-lose-tie for each comparison. Duration of mechanical ventilation is only compared if both patients survived. We evaluated power of Alive and Ventilator Free versus ventilator-free days score under various circumstances., Setting: ICUs within the Acute Respiratory Distress Syndrome Network., Patients: Individuals enrolled in four Acute Respiratory Distress Syndrome Network trials., Interventions: None for this analysis., Measurements and Main Results: Within the four trials (n = 2,410 patients), Alive and Ventilator Free and ventilator-free days score had similar power, with Alive and Ventilator Free slightly more powerful when a mortality difference was present, and ventilator-free days score slightly more powerful with a difference in duration of mechanical ventilation. Alive and Ventilator Free less often found in favor of treatments that increased mortality and increased days free of ventilation among survivors., Conclusions: A hierarchical composite endpoint, Alive and Ventilator Free, preserves statistical power while improving face validity. Alive and Ventilator Free is less prone to favor a treatment with discordant effects on survival and days free of ventilation. This general approach can support complex outcome hierarchies with multiple constituent outcomes. Approaches to interpretation of differences in Alive and Ventilator Free are also presented.

First successfully described in 1967, acute respiratory distress syndrome has since garnered much interest and debate. Extensive studies and clinical trials have been carried out in efforts to address the associated high mortality; however, it remains a significant burden on health care. Despite the heterogeneous etiologies that lead to the development of acute respiratory distress syndrome, this rapidly progressing form of respiratory failure, characterized by severe hypoxemia and nonhydrostatic pulmonary edema, has a recognizable pattern of lung injury. In this chapter, we will review the clinical manifestations, definitions, causes, and a brief overview of the pathophysiology of this complex syndrome.

Background: Effect of prone positioning on acute hemodynamic changes (within 10 min) in acute respiratory distress syndrome (ARDS) has not been studied., Methods: In this prospective observational study, hemodynamic assessment by trans-esophageal Doppler (TED) was done with the primary aim of measuring early changes in cardiac index (CI), if any, after prone positioning in moderate to severe ARDS patients. A subgroup analysis was also done based on the response to passive leg raise (PLR)., Results: The baseline hemodynamic variables of 26 included patients were: CI 3.5 (3.1-4.3) L/min/m, peak velocity (PV) 83.2 (60.9-99.3) cm/s, flow time corrected (FTc) 341 (283-377) ms, mean acceleration (MA) 9.0 (7.04-11.7) m/s. After prone position, there were no statistically significant changes in CI, 3.5 (P=0.83), 3.75 (P = 0.96), 3.7 (P = 0.34), and 3.9 (P = 0.95) at 5, 10, 20, and 30 min respectively. FTc, mainly indicator of preload, showed decreasing trend to 315 (275-367) ms at 30 min post prone (P = 0.06). On the basis of PLR test also, CI did not change significantly in both PLR+ and PLR- groups. In PLR+ group, PV increased from 72.4 to 83 (P = 0.01), 74.9 (P = 0.03), 82 (P = 0.02), and 82 (P = 0.03) cm/s; while in PLR- group, MA increased from 8.8 to 9.7 (P = 0.03), 10.1 (P = 0.03), 9.3 (P = 0.04), and 10.6 (P = 0.01) m/s at 5, 10, 20, and 30 min respectively., Conclusions: In moderate to severe ARDS patients, there were no significant changes in CI during first 30 min after prone positioning, even in the subgroups on the basis of PLR response.

Adult respiratory distress syndrome (ARDS) is a clinical entity characterized by hypoxemic respiratory failure in the setting of noncardiogenic pulmonary edema. It is associated with significant morbidity and mortality. Prone positioning is a beneficial strategy in patients with severe ARDS because it improves alveolar recruitment, ventilation/perfusion (V/Q) ratio, and decreases lung strain. The outcome is improved oxygenation, decreased severity of lung injury, and, subsequently, mortality benefit. In this article, we discuss the physiology of prone positioning on chest mechanics and V/Q ratio, the placement and maintenance of patients in the prone position with use of a prone bed and the current literature regarding benefits of prone positioning in patients with ARDS.

Acute respiratory distress syndrome (ARDS) was first described in 1967. Since then, several landmark studies have been published that have greatly influenced the way we diagnose and treat patients with ARDS. Despite extensive research and advancements in ventilator strategies, moderate-severe ARDS has been associated with high mortality rates. Current treatment remains primarily supportive with lung-protective ventilation strategies. Pharmacological therapies that reduce the severity of lung injury in vivo and in vitro have not yet translated into effective clinical treatment options. Currently, the mortality rate of severe ARDS remains in the range of 30% to 40%. To review, the mainstay of ARDS management includes mechanical ventilation with low tidal volumes to decrease barotrauma, prone ventilation, conservative fluid management, and neuromuscular blockade. ARDS survivors tend to have long-term and potentially permanent neuromuscular, cognitive, and psychological symptoms, affecting patient's quality of life posthospitalization. These long-term effects are likely secondary to prolonged hospitalizations, prolonged mechanical ventilation, utilization of prone strategies, utilization of paralytic drugs, and occasionally steroids. Therefore, several novel therapies outside the realm of advanced ventilation and prone positioning methods are being studied. In this article, we discuss a few of these novel therapies including prophylactic aspirin, inhaled nitric oxide, mesenchymal stem cells, and intravenous β-agonists. Steroids and extracorporeal membrane oxygenation have been discussed in a previous article.

Objectives: Quantification of potential for lung recruitment may guide the ventilatory strategy in acute respiratory distress syndrome. However, there are no quantitative data on recruitability in patients with severe acute respiratory distress syndrome who require extracorporeal membrane oxygenation. We sought to quantify potential for lung recruitment and its relationship with outcomes in this cohort of patients., Design: A single-center, retrospective, observational cohort study., Setting: Tertiary referral severe respiratory failure center in a university hospital in the United Kingdom., Patients: Forty-seven adults with severe acute respiratory distress syndrome requiring extracorporeal membrane oxygenation., Intervention: None., Measurements and Main Results: In patients with severe acute respiratory distress syndrome-mainly of pulmonary origin (86%)-the potential for lung recruitment and the weight of nonaerated, poorly aerated, normally aerated, and hyperaerated lung tissue were assessed at low (5 cmH2O) and high (45 cmH2O) airway pressures. Patients were categorized as high or low potential for lung recruitment based on the median potential for lung recruitment value of the study population. The median potential for lung recruitment was 24.3% (interquartile range = 11.4-37%) ranging from -2% to 76.3% of the total lung weight. Patients with potential for lung recruitment above the median had significantly shorter extracorporeal membrane oxygenation duration (8 vs 13 d; p = 0.013) and shorter ICU stay (15 vs 22 d; p = 0.028), but mortality was not statistically different (24% vs 46%; p = 0.159)., Conclusions: We observed significant variability in potential for lung recruitment in patients with severe acute respiratory distress syndrome requiring extracorporeal membrane oxygenation. Patients with high potential for lung recruitment had a shorter ICU stay and shorter extracorporeal membrane oxygenation duration.

Acute respiratory distress syndrome (ARDS) consists of acute hypoxemic respiratory failure characterized by massive and heterogeneously distributed loss of lung aeration caused by diffuse inflammation and edema present in interstitial and alveolar spaces. It is defined by consensus criteria, which include diffuse infiltrates on chest imaging-either plain radiography or computed tomography. This review will summarize how imaging sciences can inform modern respiratory management of ARDS and continue to increase the understanding of the acutely injured lung. This review also describes newer imaging methodologies that are likely to inform future clinical decision-making and potentially improve outcome. For each imaging modality, this review systematically describes the underlying principles, technology involved, measurements obtained, insights gained by the technique, emerging approaches, limitations, and future developments. Finally, integrated approaches are considered whereby multimodal imaging may impact management of ARDS.

Mechanical ventilation (MV) is frequently employed to manage respiratory failure in sepsis patients and is required for the surgical management of intra-abdominal sepsis. The impact of MV varies dramatically depending on tidal volume, with even moderate tidal volume (MTV) ventilation leading to ventilator-induced lung injury, whereas low tidal volume (LTV) ventilation protects against sepsis-induced acute respiratory distress syndrome. Interleukin (IL)-33 is known to contribute to lung injury in sepsis and its release can be induced by mechanical stress. To determine the relationship between the IL-33-suppression of tumorigenicity 2 (ST2) pathway and patterns of lung injury associated with MV in sepsis, mice were subjected to cecal ligation and puncture (CLP) followed 6 h later by either MTV (10 mL/kg) or LTV (6 mL/kg) ventilation for 4 h. MTV and LTV ventilation alone for 4 h had no impact on lung injury. MTV markedly exacerbated lung injury and inflammation, while LTV significantly suppressed these parameters in septic mice. Lung and plasma levels of IL-33 ST2 were significantly elevated by CLP alone at 10 h. MTV caused further and significant increases in IL-33 and sST2 levels, while LTV significantly suppressed levels induced by CLP. Deletion of IL-33 or ST2 prevented the increase in lung injury and inflammation induced by MTV in septic mice, while administration of recombinant IL-33 in the airway reversed the protection seen with LTV. Taken together, these findings implicate the IL-33-ST2 pathway in the pro-inflammatory changes induced by the mechanical ventilation that leads to lung injury in the setting of intra-abdominal sepsis in a tidal volume-dependent manner.

Objectives: To evaluate the effect of prolonged duration of prone position (with head laterally rotated) on intraocular pressure in acute respiratory distress syndrome patients., Design: Prospective observational study., Setting: University hospital ICU., Patients: Twenty-five acute respiratory distress syndrome patients, age 60 years (51-67 yr), Sequential Organ Failure Assessment score 10 (10-12), PaO2/FIO2 ratio of 90 (65-120), and all in septic shock., Interventions: None., Measurements and Main Results: Intraocular pressure (in mm Hg) measured by hand-held applanation tonometer, at different time points. Before prone (in both eyes): at 30-45° head-end elevation position (THE pre-prone), in supine position just before turning prone (Tsupine pre-prone); during prone (in nondependent eye): at 10 minutes (T10 prone), 30 minutes (T30 prone), and at just before end of prone session (Tend-prone). After end of prone session (both eyes): at 5 minutes (T5 supine post-prone), 10 minutes (T10 HE post-prone), 15 minutes (T15 HE post-prone), and 30 minutes (T30 HE post-prone). Median duration of prone position was 14 hours (12-18 hr). Median intraocular pressure increased significantly (p ≤ 0.001) in both eyes. In dependent eye, from 15 (12-19) at THE pre-prone to 24, 21, 19, and 16 at T5 supine post-prone, T10 HE post-prone, T15 HE post-prone, and T30 HE post-prone respectively, whereas in nondependent eye from 14 (12-18.5) at THE pre-prone to 23, 25, 32, 25, 22, 20, and 17 at T10 prone, T30 prone, Tend-prone, T5 supine post-prone, T10 HE post-prone, T15 HE post-prone, and T30 HE post-prone respectively. Bland-Altman plot analysis showed significant linear relationship (r = 0.789; p ≤ 0.001) with good agreement between rise in mean intraocular pressure of the both eyes (dependent eye and nondependent eye) with their paired differences after the end of different duration of prone session (T5 supine post-prone)., Conclusions: There is significant increase in intraocular pressure due to prone positioning among acute respiratory distress syndrome patients. Intraocular pressure increases as early as 10 minutes after proning, with increasing trend during prone position, which persisted even at 30 minutes after the end of post prone session although with decreasing trend.

This single-center case series investigated the effect of almitrine infusion on PaO2/fraction of inspired oxygen (FIO2) in 25 patients on veno-venous extracorporeal membrane oxygenation for severe acute respiratory distress syndrome. A positive trial was defined as an increase of PaO2/FIO2 ratio ≥20%. Thirty-two trials were performed. Twenty (62.5%, 95% confidence interval, 37.5%-75%) trials in 18 patients were positive, with a median PaO2/FIO2 ratio increase of 35% (25%-43%). A focal acute respiratory distress syndrome and inhaled nitric oxide therapy were more frequent in patients with a positive response to almitrine. We observed no complications of almitrine use.

In patients with uninjured lungs, increasing evidence indicates that tidal volume (VT) reduction improves outcomes in the intensive care unit (ICU) and in the operating room (OR). However, the degree to which this evidence has translated to clinical changes in ventilator settings for patients with uninjured lungs is unknown. To clarify whether ventilator settings have changed, we searched MEDLINE, Cochrane Central Register of Controlled Trials, and Web of Science for publications on invasive ventilation in ICUs or ORs, excluding those on patients <18 years of age or those with >25% of patients with acute respiratory distress syndrome (ARDS). Our primary end point was temporal change in VT over time. Secondary end points were changes in maximum airway pressure, mean airway pressure, positive end-expiratory pressure, inspiratory oxygen fraction, development of ARDS (ICU studies only), and postoperative pulmonary complications (OR studies only) determined using correlation analysis and linear regression. We identified 96 ICU and 96 OR studies comprising 130,316 patients from 1975 to 2014 and observed that in the ICU, VT size decreased annually by 0.16 mL/kg (-0.19 to -0.12 mL/kg) (P < .001), while positive end-expiratory pressure increased by an average of 0.1 mbar/y (0.02-0.17 mbar/y) (P = .017). In the OR, VT size decreased by 0.09 mL/kg per year (-0.14 to -0.04 mL/kg per year) (P < .001). The change in VTs leveled off in 1995. Other intraoperative ventilator settings did not change in the study period. Incidences of ARDS (ICU studies) and postoperative pulmonary complications (OR studies) also did not change over time. We found that, during a 39-year period, from 1975 to 2014, VTs in clinical studies on mechanical ventilation have decreased significantly in the ICU and in the OR.

Objectives: To study the clinical profile, predictors of mortality, and outcomes of pediatric acute respiratory distress syndrome., Design: A prospective observational study., Setting: PICU, Advanced Pediatric Centre, Postgraduate Institute of Medical Education and Research, Chandigarh, India., Patients: All children (age > 1 mo to < 14 yr) admitted in PICU with a diagnosis of pediatric acute respiratory distress syndrome (as per Pediatric Acute Lung Injury Consensus Conference definition) from August 1, 2015, to November 2016., Interventions: None., Measurements and Main Results: Out of 1,215 children admitted to PICU, 124 (11.4%) had pediatric acute respiratory distress syndrome. Fifty-six children (45.2%) died. Median age was 2.75 years (1.0-6.0 yr) and 66.9% were male. Most common primary etiologies were pneumonia, severe sepsis, and scrub typhus. Ninety-seven children (78.2%) were invasively ventilated. On multiple logistic regressions, Lung Injury Score (p = 0.004), pneumothorax (p = 0.012), acute kidney injury at enrollment (p = 0.033), FIO2-D1 (p = 0.018), and PaO2/FIO2 ratio-D7 (p = 0.020) were independent predictors of mortality. Positive fluid balance (a cut-off value > 102.5 mL/kg; p = 0.016) was associated with higher mortality at 48 hours. Noninvasive oxygenation variables like oxygenation saturation index and saturation-FIO2 ratio were comparable to previously used invasive variables (oxygenation index and PaO2/FIO2 ratio) in monitoring the course of pediatric acute respiratory distress syndrome., Conclusions: Pediatric acute respiratory distress syndrome contributes to a significant burden in the PICU of a developing country and is associated with significantly higher mortality. Infection remains the most common etiology. Higher severity of illness scores at admission, development of pneumothorax, and a positive fluid balance at 48 hours predicted poor outcome.

Objectives: Acute respiratory distress syndrome is a clinical syndrome characterized by a refractory hypoxemia due to an inflammatory and high permeability pulmonary edema secondary to direct or indirect lung insult (pulmonary and extrapulmonary form). Aim of this study was to evaluate in a large database of acute respiratory distress syndrome patients, the pulmonary versus extrapulmonary form in terms of respiratory mechanics, lung recruitment, gas exchange, and positive end-expiratory pressure response., Design: A secondary analysis of previously published data., Patients: One-hundred eighty-one sedated and paralyzed acute respiratory distress syndrome patients (age 60 yr [46-72 yr], body mass index 25 kg/m [22-28 kg/m], and PaO2/FIO2 184 ± 66)., Interventions: Lung CT scan performed at 5 and 45 cm H2O. Two levels of positive end-expiratory pressure (5 and 15 cm H2O) were randomly applied., Measurements and Main Results: Ninety-seven and 84 patients had a pulmonary and extrapulmonary acute respiratory distress syndrome. The median time from intensive care admission to the CT scan and respiratory mechanics analysis was 4 days (interquartile range, 2-6). At both positive end-expiratory pressure levels, pulmonary acute respiratory distress syndrome presented a significantly lower PaO2/FIO2 and higher physiologic dead space compared with extrapulmonary acute respiratory distress syndrome. The lung and chest wall elastance were similar between groups. The intra-abdominal pressure was significantly higher in extrapulmonary compared with pulmonary acute respiratory distress syndrome (10 mm Hg [7-12 mm Hg] vs 7 mm Hg [5-8 mm Hg]). The lung weight and lung recruitability were significantly higher in pulmonary acute respiratory distress syndrome (1,534 g [1,286-1,835 g] vs 1,342 g [1,090-1,507 g] and 16% [9-25%] vs 9% [5-14%])., Conclusions: In the early stage, pulmonary acute respiratory distress syndrome is characterized by a greater impairment of gas exchange and higher lung recruitability. The recognition of the origin of acute respiratory distress syndrome is important for a more customized ventilatory management.

Objectives: To investigate the impact of body temperature on disease severity, implementation of sepsis bundles, and outcomes in severe sepsis patients., Design: Retrospective sub-analysis., Setting: Fifty-nine ICUs in Japan, from January 2016 to March 2017., Patients: Adult patients with severe sepsis based on Sepsis-2 were enrolled and divided into three categories (body temperature < 36°C, 36-38°C, > 38°C), using the core body temperature at ICU admission., Interventions: None., Measurements and Main Results: Compliance with the bundles proposed in the Surviving Sepsis Campaign Guidelines 2012, in-hospital mortality, disposition after discharge, and the number of ICU and ventilator-free days were evaluated. Of 1,143 enrolled patients, 127, 565, and 451 were categorized as having body temperature less than 36°C, 36-38°C, and greater than 38°C, respectively. Hypothermia-body temperature less than 36°C-was observed in 11.1% of patients. Patients with hypothermia were significantly older than those with a body temperature of 36-38°C or greater than 38°C and had a lower body mass index and higher prevalence of septic shock than those with body temperature greater than 38°C. Acute Physiology and Chronic Health Evaluation II and Sequential Organ Failure Assessment scores on the day of enrollment were also significantly higher in hypothermia patients. Implementation rates of the entire 3-hour bundle and administration of broad-spectrum antibiotics significantly differed across categories; implementation rates were significantly lower in patients with body temperature less than 36°C than in those with body temperature greater than 38°C. Implementation rate of the entire 3-hour resuscitation bundle + vasopressor use + remeasured lactate significantly differed across categories, as did the in-hospital and 28-day mortality. The odds ratio for in-hospital mortality relative to the reference range of body temperature greater than 38°C was 1.760 (95% CI, 1.134-2.732) in the group with hypothermia. The proportions of ICU-free and ventilator-free days also significantly differed between categories and were significantly smaller in patients with hypothermia., Conclusions: Hypothermia was associated with a significantly higher disease severity, mortality risk, and lower implementation of sepsis bundles.

Objectives: To develop a pharmacokinetic-pharmacogenomic population model of midazolam in critically ill children with primary respiratory failure., Design: Prospective pharmacokinetic-pharmacogenomic observational study., Setting: Thirteen PICUs across the United States., Patients: Pediatric subjects mechanically ventilated for acute respiratory failure, weight greater than or equal to 7 kg, receiving morphine and/or midazolam continuous infusions., Interventions: Serial blood sampling for drug quantification and a single blood collection for genomic evaluation., Measurements and Main Results: Concentrations of midazolam, the 1' (1`-hydroxymidazolam metabolite) and 4' (4`-hydroxymidazolam metabolite) hydroxyl, and the 1' and 4' glucuronide metabolites were measured. Subjects were genotyped using the Illumina HumanOmniExpress genome-wide single nucleotide polymorphism chip. Nonlinear mixed effects modeling was performed to develop the pharmacokinetic-pharmacogenomic model. Body weight, age, hepatic and renal functions, and the UGT2B7 rs62298861 polymorphism are relevant predictors of midazolam pharmacokinetic variables. The estimated midazolam clearance was 0.61 L/min/70kg. Time to reach 50% complete mature midazolam and 1`-hydroxymidazolam metabolite/4`-hydroxymidazolam metabolite clearances was 1.0 and 0.97 years postmenstrual age. The final model suggested a decrease in midazolam clearance with increase in alanine transaminase and a lower clearance of the glucuronide metabolites with a renal dysfunction. In the pharmacogenomic analysis, rs62298861 and rs28365062 in the UGT2B7 gene were in high linkage disequilibrium. Minor alleles were associated with a higher 1`-hydroxymidazolam metabolite clearance in Caucasians. In the pharmacokinetic-pharmacogenomic model, clearance was expected to increase by 10% in heterozygous and 20% in homozygous for the minor allele with respect to homozygous for the major allele., Conclusions: This work leveraged available knowledge on nonheritable and heritable factors affecting midazolam pharmacokinetic in pediatric subjects with primary respiratory failure requiring mechanical ventilation, providing the basis for a future implementation of an individual-based approach to sedation.

Purpose of Review: High-flow nasal cannula oxygen therapy (HFOT) is becoming an alternative to noninvasive ventilation (NIV) and standard oxygen in management of patients with acute respiratory failure., Recent Findings: Patients with de novo acute respiratory failure should be managed with HFOT rather than NIV. Indeed, the vast majority of patients with de novo respiratory failure meet the criteria for ARDS, and NIV does not seem protective, as patients generate overly high tidal volume that may worsen underlying lung injury. However, NIV remains the first-line oxygenation strategy in postoperative patients and those with acute hypercapnic respiratory failure when pH is equal to or below 7.35. During preoxygenation, NIV also seems to be more efficient than standard oxygen using valve-bag mask to prevent profound oxygen desaturation. In postoperative cardiothoracic patients, HFOT could be an alternative to NIV in the management of acute respiratory failure., Summary: Recent recommendations for managing patients with acute respiratory failure have been established on the basis of studies comparing NIV with standard oxygen. Growing use of HFOT will lead to new studies comparing NIV versus HFOT in view of more precisely defining the appropriate indications for each treatment.

Objectives: Incomplete or ambiguous evidence for identifying high-risk patients with acute respiratory distress syndrome for enrollment into randomized controlled trials has come at the cost of an unreasonable number of negative trials. We examined a set of selected variables early in acute respiratory distress syndrome to determine accurate prognostic predictors for selecting high-risk patients for randomized controlled trials., Design: A training and testing study using a secondary analysis of data from four prospective, multicenter, observational studies., Setting: A network of multidisciplinary ICUs., Patients: We studied 1,200 patients with moderate-to-severe acute respiratory distress syndrome managed with lung-protective ventilation., Interventions: None., Measurements and Main Results: We evaluated different thresholds for patient's age, PaO2/FIO2, plateau pressure, and number of extrapulmonary organ failures to predict ICU outcome at 24 hours of acute respiratory distress syndrome diagnosis. We generated 1,000 random scenarios as training (n = 900, 75% of population) and testing (n = 300, 25% of population) datasets and averaged the logistic coefficients for each scenario. Thresholds for age (< 50, 50-70, > 70 yr), PaO2/FIO2 (≤ 100, 101-150, > 150 mm Hg), plateau pressure (< 29, 29-30, > 30 cm H2O), and number of extrapulmonary organ failure (< 2, 2, > 2) stratified accurately acute respiratory distress syndrome patients into categories of risk. The model that included all four variables proved best to identify patients with the highest or lowest risk of death (area under the receiver operating characteristic curve, 0.86; 95% CI, 0.84-0.88). Decision tree analyses confirmed the accuracy and robustness of this enrichment model., Conclusions: Combined thresholds for patient's age, PaO2/FIO2, plateau pressure, and extrapulmonary organ failure provides prognostic enrichment accuracy for stratifying and selecting acute respiratory distress syndrome patients for randomized controlled trials.

Objectives: To describe the characteristics and outcomes of patients with acute respiratory distress syndrome with or without spontaneous breathing and to investigate whether the effects of spontaneous breathing on outcome depend on acute respiratory distress syndrome severity., Design: Planned secondary analysis of a prospective, observational, multicentre cohort study., Setting: International sample of 459 ICUs from 50 countries., Patients: Patients with acute respiratory distress syndrome and at least 2 days of invasive mechanical ventilation and available data for the mode of mechanical ventilation and respiratory rate for the 2 first days., Interventions: Analysis of patients with and without spontaneous breathing, defined by the mode of mechanical ventilation and by actual respiratory rate compared with set respiratory rate during the first 48 hours of mechanical ventilation., Measurements and Main Results: Spontaneous breathing was present in 67% of patients with mild acute respiratory distress syndrome, 58% of patients with moderate acute respiratory distress syndrome, and 46% of patients with severe acute respiratory distress syndrome. Patients with spontaneous breathing were older and had lower acute respiratory distress syndrome severity, Sequential Organ Failure Assessment scores, ICU and hospital mortality, and were less likely to be diagnosed with acute respiratory distress syndrome by clinicians. In adjusted analysis, spontaneous breathing during the first 2 days was not associated with an effect on ICU or hospital mortality (33% vs 37%; odds ratio, 1.18 [0.92-1.51]; p = 0.19 and 37% vs 41%; odds ratio, 1.18 [0.93-1.50]; p = 0.196, respectively ). Spontaneous breathing was associated with increased ventilator-free days (13 [0-22] vs 8 [0-20]; p = 0.014) and shorter duration of ICU stay (11 [6-20] vs 12 [7-22]; p = 0.04)., Conclusions: Spontaneous breathing is common in patients with acute respiratory distress syndrome during the first 48 hours of mechanical ventilation. Spontaneous breathing is not associated with worse outcomes and may hasten liberation from the ventilator and from ICU. Although these results support the use of spontaneous breathing in patients with acute respiratory distress syndrome independent of acute respiratory distress syndrome severity, the use of controlled ventilation indicates a bias toward use in patients with higher disease severity. In addition, because the lack of reliable data on inspiratory effort in our study, prospective studies incorporating the magnitude of inspiratory effort and adjusting for all potential severity confounders are required.

Purpose of Review: Noninvasive ventilation (NIV) is widely used in ICU patients to treat or to prevent acute respiratory failure. Whereas its physiological effects are clearly beneficial in hypercapnic patients, it could be deleterious in hypoxemic patients without hypercapnia., Recent Findings: NIV should be cautiously used in patients with de-novo respiratory failure, the vast majority of whom meet the criteria for acute respiratory distress syndrome. Spontaneous breathing with high tidal volumes may worsen lung injury in these patients, and recent findings suggest that NIV may increase the risk of mortality. Even though high-flow oxygen therapy is increasingly applied in this context, NIV remains recommended for management of immunocompromised patients with acute respiratory failure. NIV should be the first-line oxygenation strategy in patients with acute hypercapnic respiratory failure when pH is equal to or below 7.35. Prophylactic NIV prevents respiratory failure after extubation of patients at high risk of reintubation., Summary: Most previous studies have compared NIV with standard oxygen, and recent recommendations have been established from these findings. Given the growing use of high-flow oxygen therapy, new studies are needed to compare NIV versus high-flow oxygen therapy so as to better define the appropriate indications for each treatment.

Objectives: Lung ultrasound is commonly used to evaluate lung morphology in patients with acute respiratory distress syndrome. Aim of this study was to determine lung ultrasound reliability in assessing lung aeration and positive end-expiratory pressure-induced recruitment compared with CT., Design: Randomized crossover study., Setting: University hospital ICU., Patients: Twenty sedated paralyzed acute respiratory distress syndrome patients: age 56 years (43-72 yr), body mass index 25 kg/m (22-27 kg/m), and PaO2/FIO2 160 (113-218)., Interventions: Lung CT and lung ultrasound examination were performed at positive end-expiratory pressure 5 and 15 cm H2O., Measurements and Main Results: Global and regional Lung Ultrasound scores were compared with CT quantitative analysis. Lung recruitment (i.e., decrease in not aerated tissue as assessed with CT) was compared with global Lung Ultrasound score variations. Global Lung Ultrasound score was strongly associated with average lung tissue density at positive end-expiratory pressure 5 (R = 0.78; p < 0.0001) and positive end-expiratory pressure 15 (R = 0.62; p < 0.0001). Regional Lung Ultrasound score strongly correlated with tissue density at positive end-expiratory pressure 5 (rs = 0.79; p < 0.0001) and positive end-expiratory pressure 15 (rs = 0.79; p < 0.0001). Each step increase of regional Lung Ultrasound score was associated with significant increase of tissue density (p < 0.005). A substantial agreement was found between regional Lung Ultrasound score and CT classification at positive end-expiratory pressure 5 (k = 0.69 [0.63-0.75]) and at positive end-expiratory pressure 15 (k = 0.70 [0.64-0.75]). At positive end-expiratory pressure 15, both global Lung Ultrasound score (22 [16-27] vs 26 [21-29]; p < 0.0001) and not aerated tissue (42% [25-57%] vs 52% [39-67%]; p < 0.0001) decreased. However, Lung Ultrasound score variations were not associated with lung recruitment (R = 0.01; p = 0.67)., Conclusions: Lung Ultrasound score is a valid tool to assess regional and global lung aeration. Global Lung Ultrasound score variations should not be used for bedside assessment of positive end-expiratory pressure-induced recruitment.

Objectives: The prevalence and importance of early right ventricular dysfunction and pulmonary hypertension in pediatric acute respiratory distress syndrome are unknown. We aimed to describe the prevalence of right ventricular dysfunction and pulmonary hypertension within 24 hours of pediatric acute respiratory distress syndrome diagnosis and their associations with outcomes., Design: Retrospective, single-center cohort study., Setting: Tertiary care, university-affiliated PICU., Patients: Children who had echocardiograms performed within 24 hours of pediatric acute respiratory distress syndrome diagnosis., Interventions: None., Measurements and Main Results: Between July 1, 2012, and June 30, 2016, 103 children met inclusion criteria. Echocardiograms were analyzed using established indices of right ventricular and left ventricular systolic function and for evidence of pulmonary hypertension. Echocardiographic abnormalities were common: 26% had low right ventricular fractional area change, 65% had low tricuspid annular plane systolic excursion, 30% had low left ventricular fractional shortening, and 21% had evidence of pulmonary hypertension. Abnormal right ventricular global longitudinal strain and abnormal right ventricular free wall strain were present in 35% and 40% of patients, respectively. No echocardiographic variables differed between or across pediatric acute respiratory distress syndrome severity. In multivariable analyses, right ventricular global longitudinal strain was independently associated with PICU mortality (odds ratio, 3.57 [1.33-9.60]; p = 0.01), whereas right ventricular global longitudinal strain, right ventricular free wall strain, and the presence of pulmonary hypertension were independently associated with lower probability of extubation (subdistribution hazard ratio, 0.46 [0.26-0.83], p = 0.01; subdistribution hazard ratio, 0.58 [0.35-0.98], p = 0.04; and subdistribution hazard ratio, 0.49 [0.26-0.92], p = 0.03, respectively)., Conclusions: Early ventricular dysfunction and pulmonary hypertension were detectable, prevalent, and independent of lung injury severity in children with pediatric acute respiratory distress syndrome. Right ventricular dysfunction was associated with PICU mortality, whereas right ventricular dysfunction and pulmonary hypertension were associated with lower probability of extubation.