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Rationale: Early post injury mitigation strategies in ARDS are in short supply. Treatments with allogeneic stromal cells are administered after ARDS develops, require specialized expertise and equipment, and to date have shown limited benefit. Objectives: Assess the efficacy of immediate post injury intravenous administration of autologous or allogeneic bone marrow-derived mesenchymal stromal cells (MSCs) for the treatment of acute respiratory distress syndrome (ARDS) due to smoke inhalation and burns. Methods: Yorkshire swine ( n  = 32, 44.3 ± 0.5 kg) underwent intravenous anesthesia, placement of lines, severe smoke inhalation, and 40% total body surface area flame burns, followed by 72 hours of around-the-clock ICU care. Mechanical ventilation, fluids, pressors, bronchoscopic cast removal, daily lung computed tomography scans, and arterial blood assays were performed. After injury and 24 and 48 hours later, animals were randomized to receive autologous concentrated bone marrow aspirate ( n  = 10; 3 × 10 6 white blood cells and a mean of 56.6 × 10 6 platelets per dose), allogeneic MSCs ( n  = 10; 6.1 × 10 6 MSCs per dose) harvested from healthy donor swine, or no treatment in injured control animals ( n  = 12). Measurements and Main Results: The intravenous administration of MSCs after injury and at 24 and 48 hours delayed the onset of ARDS in swine treated with autologous MSCs (48 ± 10 h) versus control animals (14 ± 2 h) ( P  = 0.004), reduced ARDS severity at 24 ( P  < 0.001) and 48 ( P  = 0.003) hours, and demonstrated visibly diminished consolidation on computed tomography (not significant). Mortality at 72 hours was 1 in 10 (10%) in the autologous group, 5 in 10 (50%) in the allogeneic group, and 6 in 12 (50%) in injured control animals (not significant). Both autologous and allogeneic MSCs suppressed systemic concentrations of TNF-α (tumor necrosis factor-α). Conclusions: The intravenous administration of three doses of freshly processed autologous bone marrow-derived MSCs delays ARDS development and reduces its severity in swine. Bedside retrieval and administration of autologous MSCs in swine is feasible and may be a viable injury mitigation strategy for ARDS.

The hallmark of acute respiratory distress syndrome (ARDS) pathobiology is unchecked inflammation-driven diffuse alveolar damage and alveolar-capillary barrier dysfunction. Currently, therapeutic interventions for ARDS remain largely limited to pulmonary-supportive strategies, and there is an unmet demand for pharmacologic therapies targeting the underlying pathology of ARDS in patients suffering from the illness. The complement cascade (ComC) plays an integral role in the regulation of both innate and adaptive immune responses. ComC activation can prime an overzealous cytokine storm and tissue/organ damage. The ARDS and acute lung injury (ALI) have an established relationship with early maladaptive ComC activation. In this review, we have collected evidence from the current studies linking ALI/ARDS with ComC dysregulation, focusing on elucidating the new emerging roles of the extracellular (canonical) and intracellular (non-canonical or complosome), ComC (complementome) in ALI/ARDS pathobiology, and highlighting complementome as a vital nexus of the pathobiological connectome for ALI/ARDS via its crosstalking with other systems of the immunome, DAMPome, PAMPome, coagulome, metabolome, and microbiome. We have also discussed the diagnostic/therapeutic potential and future direction of ALI/ARDS care with the ultimate goal of better defining mechanistic subtypes (endotypes and theratypes) through new methodologies in order to facilitate a more precise and effective complement-targeted therapy for treating these comorbidities. This information leads to support for a therapeutic anti-inflammatory strategy by targeting the ComC, where the arsenal of clinical-stage complement-specific drugs is available, especially for patients with ALI/ARDS due to COVID-19., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Yang, Nicholson, Cancio, Cancio and Li.)

Background: We investigated the expression of high mobility group box 1 (HMGB1) protein in a combat-relevant polytrauma/ acute respiratory distress syndrome (ARDS) model. We hypothesized that systemic HMGB1 expression is increased after injury and during aeromedical evacuation (AE) at altitude., Methods: Female Yorkshire swine (n =15) were anesthetized and cannulated with a 23Fr dual-lumen catheter. Venovenous extracorporeal life support (VV ECLS) was initiated via the right jugular vein and carried out with animals uninjured on day 1 and injured by bilateral pulmonary contusion on day 2. On both days, animals underwent transport and simulated AE. Systemic HMGB1 expression was measured in plasma by ELISA. Plasma-free Hb (pfHb) was measured with the use of spectrophotometric methods., Results: Plasma HMGB1 on day 1 was transiently higher at arrival to the AE chambers, increased significantly after injury, reaching highest values at 8,000 ft on day 2, after which levels decreased but remained elevated versus baseline at each time point. pfHb decreased on day 1 at 30,000 ft and significantly increased on day 2 at 8,000 ft and postflight., Conclusions: Systemic HMGB1 demonstrated sustained elevation after trauma and altitude transport and may provide a useful monitoring capability during en route care., (2020.)

Background: We investigated effects of mesenchymal stem cells (MSC) or low-flow extracorporeal life support (ECLS) as adjunctive treatments for acute respiratory distress syndrome (ARDS) due to inhalation injury and burns. We hypothesized that these interventions decrease histological end-organ damage., Methods: Anesthetized female swine underwent smoke inhalation injury and 40% TBSA burns, then critical care for 72h. The following groups were studied: CTR (no injury, n = 4), ICTR (injured untreated, n = 10), Allo (injured treated with allogenic MSC, n = 10), Auto (injured treated with autologous MSC, n = 10), Hemo (injured and treated with the Hemolung low flow ECLS system, n = 9), and Nova (injured and treated with the NovaLung low flow ECLS system, n = 8). Histology scores from lung, kidneys, liver, and jejunum were calculated. Data are presented as means±SEM., Results: Survival at 72h was 100% in CTR; 40% in ICTR; 50% in Allo; 90% in Auto; 33% in Hemo; 63% in Nova. ARDS developed in 0/10 CTR; 10/10 ICTR; 8/9 Hemo; 5/8 Nova; 9/10 Allo; 6/10 Auto. Diffuse alveolar damage (DAD) was present in all injured groups. MSC groups had significantly lower DAD scores than ICTR animals (Allo 26.6 ± 3.4 and Auto 18.9 ± 1.5 vs. ICTR 46.8 ± 2.1, p < 0.001). MSC groups also had lower DAD scores than ECLS animals (Allo vs. Nova, p < 0.05, Allo vs. Hemo p < 0.001, Auto vs. Nova p < 0.001, Auto vs. Hemo, p < 0.001). Kidney injury ICTR (p < 0.05) and Hemo (p < 0.01) were higher than in CTR. By logistic regression, a PaO 2 -to-FiO 2 ratio (PFR) < 300 was a function of the DAD score: logit (PFR < 300) = 0.84 + 0.072*DAD Score, odds ratio 1.074 (1.007, 1.147, p < 0.05) with a ROC AUC of 0.76, p < 0.001., Conclusion: Treatment with Auto MSC followed by Allo and then Nova were most effective in mitigating ARDS and MOF severity in this model. Further studies will elucidate the role of combination therapies of MSC and ECLS as comprehensive treatments for ARDS and MOF., (Copyright © 2019 Elsevier Ltd and ISBI. All rights reserved.)

Mesenchymal stem cells (MSCs) are a promising form of therapy for acute respiratory distress syndrome (ARDS). The objective of this study was twofold: (a) to characterize cytokine expression in serum from ARDS subjects receiving MSCs and (b) to determine MSC function following "preconditioning" with ARDS serum. In phase I, serum from three cohorts of animals (uninjured [no ARDS, n = 4], injured untreated [n = 5], and injured treated with approximately 6 million per kilogram MSCs [n = 7]) was analyzed for expression of inflammatory mediators. In phase II, the functional properties of bone marrow porcine MSCs were assessed following "preconditioning" with serum from the three cohorts. In phase III, the findings from the previous phases were validated using human bone marrow MSCs (hBM-MSCs) and lipopolysaccharide (LPS). Serum from injured treated animals had significantly lower levels of interferon-γ and significantly higher levels of interleukin (IL)-1 receptor antagonist (IL-1RA) and IL-6. Similarly, upon exposure to the injured treated serum ex vivo, the MSCs secreted higher levels of IL-1RA and IL-10, dampened the secretion of proinflammatory cytokines, exhibited upregulation of toll-like receptor 4 (TLR-4) and vascular endothelial growth factor (VEGF) genes, and triggered a strong immunomodulatory response via prostaglandin E2 (PGE 2 ). hBM-MSCs demonstrated a similar augmented therapeutic function following reconditioning in a LPS milieu. Administration of MSCs modulated the inflammatory milieu following ARDS. Exposure to ARDS serum ex vivo paralleled the trends seen in vivo, which appear to be mediated, in part, through TLR-4 and VEGF and PGE 2 . Reconditioning MSCs in their own serum potentiates their immunotherapeutic function, a technique that can be used in clinical applications. Stem Cells Translational Medicine 2019;8:1092-1106., (© 2019 The Authors. Stem Cells Translational Medicine published by Wiley Periodicals, Inc. on behalf of AlphaMed Press.)

Background: Smoke inhalation injury (SII) causes 30% to 40% mortality and will increase as a cause of death during prolonged field care. We used a combat relevant model of acute respiratory distress syndrome due to SII to study temporal changes in ventilation-perfusion (V/Q) matching, computed tomography (CT) scan data, and histopathology and hypothesized that SII leads to increase in shunt (Qshunt), V/Q mismatch, lung consolidation, and diffuse alveolar damage., Methods: Swine received severe SII and airway pressure release ventilation (APRV, n = 6), or conventional ARDSNet mechanical ventilation (MV) (CMV, n = 8). A control group without injury received volume controlled MV (CTRL, n = 6), The multiple inert gas elimination technique and CT were performed at baseline (BL), 0.5 hours, 1 hours, 2 hours, 24 hours, and 48 hours after injury. Diffuse alveolar damage scoring was performed post mortem. Significance at p less than 0.05: APRV versus CTRL; CMV versus CTRL; APRV versus CMV*; denotes changes versus BL., Results: (1) SII caused increases in Qshunt more so in APRV than CMV group. Qshunt did not change in CTRL. (2) PaO2-to-FIO2 ratio (PFR) was lower in APRV versus CTRL at 2 hours (375 ± 62‡ vs. 549 ± 40) and 24 hours (126 ± 34‡* vs. 445 ± 5) and 48 hours (120 ± 41‡& vs. 430 ± 13). In CMV animals, PFR was lower versus CTRL and BL at 24 hours (238 ± 33) and 48 hours (98 ± 27). Qshunt correlated with PFR (r = 0.75, p < 0.0001, APRV and (r = 0.65, p < 0.0001, CMV). CT showed decrease in normally aerated lung, while poorly and nonaerated lung increased., Conclusion: Smoke inhalation injury leads to early development of shunt, V/Q mismatch, lung consolidation, and diffuse alveolar damage. These data substantiate the need for new point of injury interventions in the prolonged field care setting., Level of Evidence: Animal research.

Background: Acute respiratory distress syndrome (ARDS) is a severe form of acute lung injury with a mortality rate of up to 40%. Early management of ARDS has been difficult due to the lack of sensitive imaging tools and robust analysis software. We previously designed an optical coherence tomography (OCT) system to evaluate mucosa thickness (MT) after smoke inhalation, but the analysis relied on manual segmentation. The aim of this study is to assess in vivo proximal airway volume (PAV) after inhalation injury using automated OCT segmentation and correlate the PAV to lung function for rapid indication of ARDS., Methods: Anesthetized female Yorkshire pigs (n = 14) received smoke inhalation injury (SII) and 40% total body surface area thermal burns. Measurements of PaO2-to-FiO2 ratio (PFR), peak inspiratory pressure (PIP), dynamic compliance, airway resistance, and OCT bronchoscopy were performed at baseline, postinjury, 24 hours, 48 hours, 72 hours after injury. A tissue segmentation algorithm based on graph theory was used to reconstruct a three-dimensional (3D) model of lower respiratory tract and estimate PAV. Proximal airway volume was correlated with PFR, PIP, compliance, resistance, and MT measurement using a linear regression model., Results: Proximal airway volume decreased after the SII: the group mean of proximal airway volume at baseline, postinjury, 24 hours, 48 hours, 72 hours were 20.86 cm (±1.39 cm), 17.61 cm (±0.99 cm), 14.83 cm (±1.20 cm), 14.88 cm (±1.21 cm), and 13.11 cm (±1.59 cm), respectively. The decrease in the PAV was more prominent in the animals that developed ARDS after 24 hours after the injury. PAV was significantly correlated with PIP (r = 0.48, p < 0.001), compliance (r = 0.55, p < 0.001), resistance (r = 0.35, p < 0.01), MT (r = 0.60, p < 0.001), and PFR (r = 0.34, p < 0.01)., Conclusion: Optical coherence tomography is a useful tool to quantify changes in MT and PAV after SII and burns, which can be used as predictors of developing ARDS at an early stage., Level of Evidence: Prognostic, level III.

Background: The prevalence of acute respiratory distress syndrome (ARDS) in mechanically ventilated burn patients is 33%, with mortality varying from 11-46% depending on ARDS severity. Despite the new Berlin definition for ARDS, prompt bedside diagnosis is lacking. We developed and tested a bedside technique of fiberoptic-bronchoscopy-based optical coherence tomography (OCT) measurement of airway mucosal thickness (MT) for diagnosis of ARDS following smoke inhalation injury (SII) and burns., Methods: 16 female Yorkshire pigs received SII and 40% thermal burns. OCT MT and PaO 2 -to-FiO 2 ratio (PFR) measurements were taken at baseline, after injury, and at 24, 48, and 72h after injury., Results: Injury led to thickening of MT which was sustained in animals that developed ARDS. Significant correlations were found between MT, PFR, peak inspiratory pressure (PIP), and total infused fluid volume., Conclusions: OCT is a useful tool to quantify MT changes in the airway following SII and burns. OCT may be effective as a diagnostic tool in the early stages of SII-induced ARDS and should be tested in humans., (Copyright © 2018 Elsevier Ltd and ISBI. All rights reserved.)

Background: It is known that, following a physiological insult, bone marrow-derived mesenchymal stem cells (MSCs) mobilize and home to the site of injury. However, the effect of injury on the function of endogenous MSCs is unknown. In this study, MSCs harvested from the bone marrow of swine with or without acute respiratory distress syndrome (ARDS) were assessed for their characteristics and therapeutic function., Methods: MSCs were harvested from three groups of anesthetized and mechanically ventilated swine (n = 3 in each group): 1) no ARDS ('Uninjured' group); 2) ARDS induced via smoke inhalation and 40% burn and treated with inhaled epinephrine ('Injured Treated' group); and 3) ARDS without treatment ('Injured Untreated' group). Cellular evaluation of the three groups included: flow cytometry for MSC markers; colony forming unit-fibroblast (CFU-F) assay; proliferative and metabolic capacity; gene expression using quantitative real-time polymerase chain reaction (qRT-PCR); and a lipopolysaccharide (LPS) challenge, with or without coculture with mononuclear cells (MNCs), for evaluation of their protein secretion profile using Multiplex. Statistical analysis was performed using one- or two-way analysis of variance (ANOVA) with a Tukey's post-test; a p-value less than 0.05 was considered statistically significant., Results: Cells from all groups exhibited nearly 100% expression of MSC surface markers and retained their multidifferentiation capacity. However, the MSCs from the 'Injured Untreated' group generated a significantly higher number of colonies compared with the other two groups (p < 0.0001), indicative of increased clonogenic capacity following ARDS. Following an LPS challenge, the MSCs from the 'Injured Untreated' group exhibited a significant reduction in their proliferative capacity (p = 0.0002), significant downregulation in the expression of high-mobility group box 1 (HMGB1; p < 0.001), Toll-like receptor (TLR)-4 (p < 0.01), and vascular endothelial growth factor (VEGF; p < 0.05) genes, and significantly diminished secretory capacity for the inflammatory mediators interleukin (IL)-6 (p < 0.0001), IL-8 (p < 0.05), and tumor necrosis factor (TNF)-α (p < 0.05) compared with the 'Uninjured' group., Conclusions: The results suggest that, following ARDS, there is an increase in the clonogenic capacity of MSCs to increase the available stem cell pool in vivo. However, MSCs harvested from subjects with ARDS seem to exhibit a diminished capacity to proliferate, express regenerative signals, and secrete pro/anti-inflammatory mediators.

Introduction: Recent reports on the use of extracorporeal membrane oxygenation (ECMO) in critically ill burn patients with Acute Respiratory Distress Syndrome (ARDS) recommended against the use of ECMO. The authors cited the high mortality rates associated with the use of ECMO in these patients with no appreciable benefit. Accumulating evidence from referral centers suggests improved survival in patients with ARDS receiving ECMO. We report our recent experience treating patients with severe ARDS with ECMO in a burn intensive care unit., Methods: This is a case series of consecutive patients placed on ECMO at our burn center from the initiation of our program in September 2012 to September 2017. We included only adult patients who had been placed on ECMO with burn injury, TEN, or inhalation injury and severe ARDS., Results: Fourteen patients with burn injury, inhalation injury or TEN were placed on ECMO from the initiation of the ECMO program to September 1st 2017. The average total body surface area burned in the 11 patients with burn injury was 27% (range 0.25-76%). The cause of ARDS in these patients included inhalation injury, airway trauma and bacterial pneumonia. Four patients had an inhalation injury and 1 patient had a grade 3 inhalation injury but no burn injury. In the majority of cases, prone positioning and use of neuromuscular blockade was also used in an attempt to improve oxygenation and patient synchrony with mechanical ventilation. The average time on ECMO was 276h (range 63-539h). Ten of the 14 patients survived to decanulation from ECMO (71%) and eight of 14 patients (57%) survived to hospital discharge., Conclusions: To our knowledge, this is the lowest mortality rate reported to date in burn patients with ARDS place on ECMO. ECMO is a viable therapy that can be utilized successfully as a rescue modality when conventional interventions are unsuccessful., (Copyright © 2018 Elsevier Ltd and ISBI. All rights reserved.)

This review describes the current state of the science on mesenchymal stem cell (MSC) treatment for acute lung injury (ALI). The general characteristics, regenerative potential, and mechanism of action of MSCs are first presented. Next, particular emphasis is placed on the application of MSCs for the treatment of acute respiratory distress syndrome (ARDS) in preclinical and clinical studies. Finally, we discuss current challenges and future directions in the field presented from a clinician-researcher perspective. The objective of this work is to provide the readership with a current review of the literature discussing the hurdles and overall promise of MSCs as therapeutic interventions for the treatment of ARDS.

Objective: To evaluate the association between acute respiratory distress syndrome and acute kidney injury with respect to their contributions to mortality in critically ill patients., Design: Retrospective analysis of consecutive adult burn patients requiring mechanical ventilation., Setting: A 16-bed burn ICU at tertiary military teaching hospital., Patients: Adult patients more than 18 years old requiring mechanical ventilation during their initial admission to our burn ICU from January 1, 2003, to December 31, 2011., Interventions: None., Measurements and Main Results: A total 830 patients were included, of whom 48.2% had acute kidney injury (n = 400). These patients had a 73% increased risk of developing acute respiratory distress syndrome after controlling for age, gender, total body surface area burned, and inhalation injury (hazard ratio, 1.73; 95% CI, 1.18-2.54; p = 0.005). In a reciprocal multivariate analysis, acute respiratory distress syndrome (n = 299; 36%) demonstrated a strong trend toward developing acute kidney injury (hazard ratio, 1.39; 95% CI, 0.99-1.95; p = 0.05). There was a 24% overall in-hospital mortality (n = 198). After adjusting for the aforementioned confounders, both acute kidney injury (hazard ratio, 3.73; 95% CI, 2.39-5.82; p < 0.001) and acute respiratory distress syndrome (hazard ratio, 2.16; 95% CI, 1.58-2.94; p < 0.001) significantly contributed to mortality. Age, total body surface area burned, and inhalation injury were also significantly associated with increased mortality., Conclusions: Acute kidney injury increases the risk of acute respiratory distress syndrome in mechanically ventilated burn patients, whereas acute respiratory distress syndrome similarly demonstrates a strong trend toward the development of acute kidney injury. Acute kidney injury and acute respiratory distress syndrome are both independent risks for subsequent death. Future research should look at this interplay for possible early interventions.

The purpose of this study was to compare the Berlin definition to the American-European Consensus Conference (AECC) definition in determining the prevalence of acute respiratory distress syndrome (ARDS) and associated mortality in the critically ill burn population. Consecutive patients admitted to our institution with burn injury that required mechanical ventilation for more than 24 hours were included for analysis. Included patients (N = 891) were classified by both definitions. The median age, % TBSA burn, and injury severity score (interquartile ranges) were 35 (24-51), 25 (11-45), and 18 (9-26), respectively. Inhalation injury was present in 35.5%. The prevalence of ARDS was 34% using the Berlin definition and 30.5% using the AECC definition (combined acute lung injury and ARDS), with associated mortality rates of 40.9 and 42.9%, respectively. Under the Berlin definition, mortality rose with increased ARDS severity (14.6% no ARDS; 16.7% mild; 44% moderate; and 59.7% severe, P < 0.001). By contrast, under the AECC definition increased mortality was seen only for ARDS category (14.7% no ARDS; 15.1% acute lung injury; and 46.0% ARDS, P < 0.001). The mortality of the 22 subjects meeting the AECC, but not the Berlin definition was not different from patients without ARDS (P = .91). The Berlin definition better stratifies ARDS in terms of severity and correctly excludes those with minimal disease previously captured by the AECC.

Introduction: In thermally injured patients, inhalation injury is often associated with acute respiratory distress syndrome (ARDS), and is an independent predictor of increased morbidity and mortality. Extracorporeal CO2 removal (ECCO2R) therapy offers new possibilities in protective mechanical ventilation in ARDS patients. We performed an early application of ECCO2R in mild-to-moderate ARDS in sheep ventilated in BiPAP mode. Our aim was to investigate its effect on severity of the lung injury., Material and Methods: Non-pregnant farm-bred ewes (n = 15) were anesthetized and injured by a combination of wood-bark smoke inhalation and a 40% total body surface area full-thickness burn, and were observed for 72 h or death. The animals were randomized to a Hemolung group (n = 7) or a Control group (n = 8) at time of ARDS onset. ECCO2R was performed in the Hemolung group after onset of ARDS.Histopathology, CT scans, systemic and pulmonary variables, and CO2 removal were examined., Results: Early application of ECCO2R therapy with Hemolung in spontaneously breathing sheep decreased PaCO2 significantly, while the device removed about 70  mL of CO2 per minute. This did not result in lower minute ventilation in the Hemolung group. Lungpathology and CT scans did not show a difference between groups., Conclusion: In an ovine model of ARDS due to smoke inhalation and burn injury, early institution of ECCO2R in spontaneously breathing animals was effective in removing CO2 and in reducing PaCO2. However, it had no effect on reducing the severity of lung injury or mortality. Further studies are necessary to detail the interaction between extracorporeal CO2 removal and pulmonary physiology.

Background: The objective of this report was to compare the prevalence of acute respiratory distress syndrome (ARDS) and associated mortality between military service members with burns sustained during or in support of combat operations and civilian burn patients treated at a single burn center., Methods: Demographic and physiologic data were collected retrospectively on mechanically ventilated military and civilian patients admitted to our burn intensive care unit between January 2003 and December 2011. Patients with ARDS were identified and categorized as mild, moderate, or severe using the Berlin criteria. Demographics and clinical outcomes were compared. After initial comparison, propensity matching was performed and mortality compared., Results: A total of 891 burn patients required mechanical ventilation during the study period; 291 military and 600 civilian. The prevalence of ARDS was 34% (n=304) for the entire cohort, 33% (n=96) for military, and 35% (n=208) for civilians (p=0.55). For the entire cohort, despite more severe injury burden, military patients had a significantly lower overall mortality (17% vs. 28%; p=0.0002) as well as ARDS mortality (33 vs. 48%, p=0.02) when compared to civilians. This difference was not significant after propensity matching based on age., Conclusion: In a retrospective cohort study, burned military patients on mechanical ventilation had a significantly lower overall and ARDS mortality despite larger burns and more severe injury when compared to civilian burn patients. This difference appears to be largely because of age., (Reprint & Copyright © 2015 Association of Military Surgeons of the U.S.)

Background: Recently, automated alerts have been used to identify patients with respiratory failure based on set criteria, which can be gleaned from the electronic medical record (EMR). Such an approach may also be useful for identifying patients with severe adult respiratory distress syndrome (ARDS) who may benefit from extracorporeal membrane oxygenation (ECMO). Inhaled nitric oxide (iNO) is a common rescue therapy for severe ARDS which can be easily tracked in the EMR, and some patients started on iNO may have indications for initiating ECMO. This case series summarizes our experience with using automated electronic alerts for ECMO team activation focused particularly on an alert triggered by the initiation of iNO., Methods: After a brief trial evaluation, our Smart Alert system generated an automated page and e-mail alert to ECMO team members whenever a nonzero value for iNO appeared in the respiratory care section of our EMR. If iNO was initiated for severe respiratory failure, a detailed evaluation by the ECMO team determined if ECMO was indicated. For those patients managed with ECMO, we tabulated baseline characteristics, indication for ECMO, and outcomes., Results: From September 2012 to July 2013, 45 iNO alerts were generated on 42 unique patients. Six patients (14%) met criteria for ECMO. Of these, four were identified exclusively by the iNO alert. At the time of the alert, the median PaO₂-to-FIO₂ ratio was 64 mm Hg (range, 55-107 mm Hg), the median age-adjusted oxygenation index was 73 (range, 51-96), and the median Murray score was 3.4 (range, 3-3.75), indicating severe respiratory failure. Median time from iNO alert to ECMO initiation was 81 hours (range, -2-292 hours). Survival to hospital discharge was 83% in those managed with ECMO., Conclusion: Automated alerts may be useful for identifying patients with severe ARDS who may be ECMO candidates., Level of Evidence: Diagnostic test, level V.

Objectives: Venovenous extracorporeal gas exchange is increasingly used in awake, spontaneously breathing patients as a bridge to lung transplantation. Limited data are available on a similar use of extracorporeal gas exchange in patients with acute respiratory distress syndrome. The aim of this study was to investigate the use of extracorporeal gas exchange in awake, spontaneously breathing sheep with healthy lungs and with acute respiratory distress syndrome and describe the interactions between the native lung (healthy and diseased) and the artificial lung (extracorporeal gas exchange) in this setting., Design: Laboratory investigation., Setting: Animal ICU of a governmental laboratory., Subjects: Eleven awake, spontaneously breathing sheep on extracorporeal gas exchange., Interventions: Sheep were studied before (healthy lungs) and after the induction of acute respiratory distress syndrome via IV injection of oleic acid. Six gas flow settings (1-10 L/min), resulting in different amounts of extracorporeal CO2 removal (20-100% of total CO2 production), were tested in each animal before and after the injury., Measurements and Main Results: Respiratory variables and gas exchange were measured for every gas flow setting. Both healthy and injured sheep reduced minute ventilation according to the amount of extracorporeal CO2 removal, up to complete apnea. However, compared with healthy sheep, sheep with acute respiratory distress syndrome presented significantly increased esophageal pressure variations (25 ± 9 vs 6 ± 3 cm H2O; p < 0.001), which could be reduced only with very high amounts of CO2 removal (> 80% of total CO2 production)., Conclusions: Spontaneous ventilation of both healthy sheep and sheep with acute respiratory distress syndrome can be controlled via extracorporeal gas exchange. If this holds true in humans, extracorporeal gas exchange could be used in awake, spontaneously breathing patients with acute respiratory distress syndrome to support gas exchange. A deeper understanding of the pathophysiology of spontaneous breathing during acute respiratory distress syndrome is however warranted in order to be able to propose extracorporeal gas exchange as a safe and valuable alternative to mechanical ventilation for the treatment of patients with acute respiratory distress syndrome.

Background: Acute respiratory distress syndrome (ARDS) prevalence and related outcomes in burned military casualties from Iraq and Afghanistan have not been described previously. The objective of this article was to report ARDS prevalence and its associated in-hospital mortality in military burn patients., Methods: Demographic and physiologic data were collected retrospectively on mechanically ventilated military casualties admitted to our burn intensive care unit from January 2003 to December 2011. Patients with ARDS were identified in accordance with the new Berlin definition of ARDS. Subjects were categorized as having mild, moderate, or severe ARDS. Multivariate logistic regression identified independent risk factors for developing moderate-to-severe ARDS. The main outcome measure was the prevalence of ARDS in a cohort of patients burned as a result of recent combat operations., Results: A total of 876 burned military casualties presented during the study period, of whom 291 (33.2%) required mechanical ventilation. Prevalence of ARDS in this cohort was 32.6%, with a crude overall mortality of 16.5%. Mortality increased significantly with ARDS severity: mild (11.1%), moderate (36.1%), and severe (43.8%) compared with no ARDS (8.7%) (p < 0.001). Predictors for the development of moderate or severe ARDS were inhalation injury (odds ratio [OR], 1.90; 95% confidence interval [CI], 1.01-3.54; p = 0.046), Injury Severity Score (ISS) (OR, 1.04; 95% CI, 1.01-1.07; p = 0.0021), pneumonia (OR, 198; 95% CI, 1.07-3.66; p = 0.03), and transfusion of fresh frozen plasma (OR, 1.32; 95% CI, 1.01-1.72; p = 0.04). Size of burn was associated with moderate or severe ARDS by univariate analysis but was not an independent predictor of ARDS by multivariate logistic regression (p > 0.05). Age, size of burn, and moderate or severe ARDS were independent predictors of mortality., Conclusion: In this cohort of military casualties with thermal injuries, nearly a third required mechanical ventilation; of those, nearly one third developed ARDS, and nearly one third of patients with ARDS did not survive. Moderate and severe ARDS increased the odds of death by more than fourfold and ninefold, respectively., Level of Evidence: Epidemiologic/prognostic study, level III.

Introduction: The clinical use of serial quantitative computed tomography (CT) to characterize lung disease and guide the optimization of mechanical ventilation in patients with acute respiratory distress syndrome (ARDS) is limited by the risk of cumulative radiation exposure and by the difficulties and risks related to transferring patients to the CT room. We evaluated the effects of tube current-time product (mAs) variations on quantitative results in healthy lungs and in experimental ARDS in order to support the use of low-dose CT for quantitative analysis., Methods: In 14 sheep chest CT was performed at baseline and after the induction of ARDS via intravenous oleic acid injection. For each CT session, two consecutive scans were obtained applying two different mAs: 60 mAs was paired with 140, 15 or 7.5 mAs. All other CT parameters were kept unaltered (tube voltage 120 kVp, collimation 32 × 0.5 mm, pitch 0.85, matrix 512 × 512, pixel size 0.625 × 0.625 mm). Quantitative results obtained at different mAs were compared via Bland-Altman analysis., Results: Good agreement was observed between 60 mAs and 140 mAs and between 60 mAs and 15 mAs (all biases less than 1%). A further reduction of mAs to 7.5 mAs caused an increase in the bias of poorly aerated and nonaerated tissue (-2.9% and 2.4%, respectively) and determined a significant widening of the limits of agreement for the same compartments (-10.5% to 4.8% for poorly aerated tissue and -5.9% to 10.8% for nonaerated tissue). Estimated mean effective dose at 140, 60, 15 and 7.5 mAs corresponded to 17.8, 7.4, 2.0 and 0.9 mSv, respectively. Image noise of scans performed at 140, 60, 15 and 7.5 mAs corresponded to 10, 16, 38 and 74 Hounsfield units, respectively., Conclusions: A reduction of effective dose up to 70% has been achieved with minimal effects on lung quantitative results. Low-dose computed tomography provides accurate quantitative results and could be used to characterize lung compartment distribution and possibly monitor time-course of ARDS with a lower risk of exposure to ionizing radiation. A further radiation dose reduction is associated with lower accuracy in quantitative results.

Background: Prone positioning (PP) improves oxygenation and may provide a benefit in patients with acute respiratory distress syndrome (ARDS). This approach adds significant challenges to patients in intensive care by limiting access to the endotracheal or tracheostomy tube and vascular access. PP also significantly complicates burn care by making skin protection and wound care more difficult. We hypothesize that PP improves oxygenation and can be performed safely in burn patients with ARDS., Methods: PP was implemented in a burn intensive care unit for 18 patients with severe refractory ARDS. The characteristics of these patients were retrospectively reviewed to evaluate the impact of PP on Pao2:FiO2 ratio (PFR) during the first 48 hours of therapy. Each patient was considered his or her own control before initiation of PP, and trends in PFR were evaluated with one-way analysis of variance. Secondary measures of complications and mortality were also evaluated., Results: Mean PFR before PP was 87 (± 38) with a mean sequential organ failure assessment score of 11 (± 4). PFR improved during 48 hours in 12 of 14 survivors (p < 0.05). Mean PFR was 133 (± 77) immediately after PP, 165 (± 118) at 6 hours, 170 (± 115) at 12 hours, 214 (± 126) at 24 hours, 236 (± 137) at 36 hours, and 210 (± 97) at 48 hours. At each measured time interval except the last, PFR significantly improved. There were no unintended extubations. Facial pressure ulcers developed in four patients (22%). Overall, 14 survived 48 hours (78%), 12 survived 28 days (67%), and six survived to hospital discharge (33%)., Conclusions: PP improves oxygenation in burn patients with severe ARDS and was safely implemented in a burn intensive care unit. Mortality in this population remains high, warranting investigation into additional complementary rescue therapies., Level of Evidence: Therapeutic study, level IV., (Copyright © 2012 by Lippincott Williams & Wilkins.)

Background: Toxic industrial chemicals (TICs) are potential terrorist weapons. Several TICs, such as chlorine, act primarily on the respiratory tract, but knowledge of the pathophysiology and treatment of these injuries is inadequate. This study aims to characterize the acute respiratory distress syndrome (ARDS) caused by chlorine gas (Cl2) inhalation in a large-animal model., Methods: Anesthetized female sheep were ventilated with 300 L of a Cl2/air/oxygen mixture for 30 minutes. In phase 1 (n = 35), doses were 0 ppm (Group 1, n = 6); 120 ppm (Group 2, n = 6); 240 to 350 ppm (Group 3, n = 11); and 400 to 500 ppm (Group 4, n = 12). In phase 2 (n = 17), doses were 0 ppm (Group 5, n = 5); 60 ppm (Group 6, n = 5); and 90 ppm (Group 7, n = 7), and the multiple inert gas elimination technique (MIGET) was used to characterize the etiology of hypoxemia. Computed tomography (CT) scans were performed daily for all animals., Results: In Phase 1, lung function was well maintained in Group 1; Cl2 caused immediate and sustained acute lung injury (PaO2-to-FiO2 ratio, PFR<3.0) in Group 2 and ARDS (PFR<2.0) in Groups 3 and 4. All animals in Groups 1 and 2 survived 96 hours. Kaplan-Meier analysis showed dose-related differences in survival (log-rank test, p < 0.0001). Logistic regression identified 280 ppm as the lethal dose 50%. CT and histopathology demonstrated lesions of both small airways and alveoli. In Phase 2, MIGET showed diversion of blood flow from normal to true-shunt lung compartments and, transiently, to poorly ventilated compartments., Conclusions: Cl2 causes severe, dose-related lung injury, with features seen in both smoke inhalation and in ARDS secondary to systemic disease. This model will be used to test new therapeutic modalities.

Background: Our goal was to evaluate computed tomographic (CT) scans of the chest as a means of stratifying smoke inhalation injury (SII) severity., Methods: Twenty anesthetized sheep underwent graded SII: group I, no smoke; group II, 5 smoke units; group III, 10 units; and group IV, 16 units. CT scans were obtained at 6, 12, and 24 hours after injury. Each quadrant of each slice was scored subjectively: 0 = normal, 1 = interstitial markings, 2 = ground-glass appearance, and 3 = consolidation. The sum of all scores was the radiologist's score (RADS) for that scan. Computerized analysis of three-dimensional reconstructed scans was also performed, based on Hounsfield unit ranges: hyperinflated, -1,000 to -900; normal, -899 to -500; poorly aerated, -499 to -100; and nonaerated, -99 to +100. The fraction of abnormal lung tissue (FALT) was computed from poorly aerated, nonaerated, and total volumes. Mean gray-scale density (DENS) was also computed., Results: SII resulted in severity- and time-related changes in oxygenation (alveolar-arterial gradient), ventilation (respiratory rate-pressure product), DENS, FALT, and RADS. Ordinal logistic regression generated a predictive model for severity of injury (r2 = 0.623, p = 0.001), retaining RADS at 24 hours and rejecting the other variables., Conclusion: At 24 hours, CT scanning enabled SII severity stratification; qualitative evaluation (RADS) outperformed current semiautomated methods (DENS, FALT).

The article presents a study on the differences of airway pressure release ventilation (APRV) and conventional mechanical ventilation (CMV) in the early management of smoke inhalation injury in swine. The researchers used tiletamine/zolazepam to anesthetize female non-pregnant Yorkshire pigs. They found that APRV seemed not to be of benefit when compared to CMV in the management of acute respiratory distress syndrome (ARDS) during the first 48 hours.