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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.

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.)

Introduction: Extracorporeal Membrane Oxygenation (ECMO) has only recently been described in patients with burn injuries. We report the incidence and type of infections in critically ill burn and non-burn patients receiving ECMO., Methods: A retrospective chart review was performed on all patients at Brooke Army Medical Center who received ECMO between September 2012 and May 2018., Results: 78 patients underwent ECMO. Approximately half were men with a median age of 34 years with a median time on ECMO of 237 h (IQR 121-391). Compared to patients without burns (n = 58), patients with burns (n = 20) had no difference in time on ECMO, but had more overall infections (86 vs. 31 per 1000 days, p = 0.0002), respiratory infections (40 vs. 15 per 1000 days, p = 0.01), skin and soft tissue infections (21 vs. 5 per 1000 days, p = 0.02) and fungal infections (35% vs 10%, p = 0.02). Twenty percent of bacterial burn infections were due to drug resistant organisms., Conclusion: This is the first study to describe the incidence of infection in burn injury patients who are undergoing ECMO. We observed an increase in infections in burn patients on ECMO compared to non-burn patients. ECMO remains a viable option for critically ill patients with burn injuries., (Published by Elsevier Ltd.)

Background: Smoke inhalation and burn injury remain a major source of morbidity and mortality. There is known dysregulation of hemostasis in burn patients, but either hypercoagulation or hypocoagulation states are reported. Sheep are an established animal model for studying burn pathology and provide robust data on hemostatic function at baseline and after injury., Methods: After an IACUC-approved protocol, 15 sheep were anesthetized and subjected to a 40% full thickness burn with smoke inhalation. Blood was sampled at baseline, 1 day postinjury (early effects) and days 2, 3, and 4 (late effects) after injury. Assays at each timepoint assessed: hemostatic function by thromboelastography (TEG), platelet counts and function by flow cytometry and aggregometry, coagulation protein levels, and free hemoglobin. Data were analyzed by the Wilcoxon paired test (nonparametric) with significance set at less than 0.05., Results: By 24 hours postinjury, platelet counts had dropped, whereas the percent activated platelets increased. Absolute platelet functional response to the agonist adenosine diphosphate (ADP) decreased, whereas response to collagen showed no significant difference. On a per platelet basis, ADP response was unchanged, whereas the collagen response was elevated. Prothrombin time and activated partial thromboplastin time were prolonged. TEG parameters decreased significantly from baseline. Fibrinogen and factor V were trending up; coagulation proteins ATIII, factors IX and X were decreased.Late effects were followed in six animals. At day 4, platelet counts remained depressed compared with baseline with a nadir at day 2; responses to agonist on a per platelet basis remained the same for ADP and stayed elevated for collagen. Platelets continued to have elevated activation levels. Fibrinogen and factor V remained significantly elevated, whereas TEG parameters and prothrombin time, factors IX and X returned to near baseline levels., Conclusion: Coagulation parameters and hemostasis are dysregulated in sheep after smoke inhalation and burn. By 24 hours, sheep were hypocoagulable and subsequently became hypercoagulable by day 4. These results suggest a three-stage coagulopathy in burn injuries with a known early consumptive hypercoagulable state which is followed by a relatively hypocoagulable state with increased bleeding risk and then a return to a relatively unknown hypercoagulability with increased susceptibility to thrombotic disorders.

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.

Introduction: Host inflammatory response to any form of tissue injury, including burn, trauma, or shock, has been well documented. After significant burns, cytokines can increase substantially within the first 24 h after injury and may contribute to subsequent organ failure. Hemoadsorption by cytokine-adsorbing columns may attenuate this maladaptive response, thereby improving outcomes. The aim of this study was to investigate the feasibility, technical safety, and efficacy of cytokine and myoglobin removal by early use of a cytokine absorbing column (CytoSorb) in a porcine model of smoke inhalation and burn injury., Methods: Anesthetized female Yorkshire pigs (n = 15) were injured by wood bark smoke inhalation and a 40% total body surface area deep burn and observed for 72 h or death. The animals were randomized to hemoadsorption treatment (n = 9) or a sham group (n = 6) before injury. A 6-h hemoadsorption or sham session was performed on days one, two, and three. Serum cytokines (IL-1b, IL-6, IL-8, IL-10, TNF-alpha) and myoglobin were measured systemically, locally in bronchoalveolar lavage fluid and also in circulating blood before and after the adsorbing column to evaluate single pass clearance by the device., Results: Hemoadsorption caused significant removal of IL-1b, IL-6, IL-10, and myoglobin across the device mainly during the first run, ranging from 22% for IL-6 to 29% for IL-1b and 41% removal rates for myoglobin after 15  min of treatment. Systemic cytokine or myoglobin serum concentrations did not change., Conclusions: In a porcine model of smoke and burn injury, hemoadsorption using the CytoSorb cartridge did not result in significant systemic or pulmonary reductions in the measured cytokines or myoglobin despite efficient transmembrane reductions. Further investigations are needed to optimize the efficiency of mediator clearance to affect both circulating levels and clinically relevant outcomes.

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.)

A prolonged and fulminant inflammatory state, with high levels of pro- and anti-inflammatory mediators, is seen after extensive thermal injury. Blood purification techniques including plasma exchange, continuous venovenous hemofiltration, and adsorbing membranes have the potential to modulate this response, thereby improving outcomes. This article describes the scientific rationale behind blood purification in burns and offers a review of literature regarding its potential application in this patient cohort., (Copyright © 2014 Elsevier Ltd and ISBI. All rights reserved.)

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.

In critically ill intubated patients, assessment of adequacy of ventilation relies on measuring partial pressure of arterial carbon dioxide (PaCO2), which requires invasive arterial blood gas analysis. Alternative noninvasive technologies include transcutaneous CO2 (tPCO2) and end-tidal CO2 (EtCO2) monitoring. We evaluated accuracy of tPCO2 and EtCO2 monitoring in a porcine model of acute lung injury (ALI) due to smoke inhalation and burns. Eight anesthetized Yorkshire pigs underwent mechanical ventilation, wood-bark smoke inhalation injury, and 40% total body surface area thermal injury. tPCO2 was measured with a SenTec system (SenTec AG, Therwil, Switzerland) and EtCO2 with a Capnostream-20 (Oridion Medical, Jerusalem, Israel). These values were compared with PaCO2 measurements from an arterial blood gas analyzer. Paired measurements of EtCO2-PaCO2 (n = 276) and tPCO2-PaCO2 (n = 250) were recorded in the PaCO2 range of 25 to 85 mmHg. Overlapping data sets were analyzed based on respiratory and hemodynamic status of animals. Acute lung injury was defined as PaO2/FIO2 ≤ 300 mmHg; hemodynamic instability was defined as mean arterial pressure ≤ 60 mmHg. Before ALI, EtCO2 demonstrated moderate correlation with PaCO2 (R = 0.45; P < 0.0001), which deteriorated after onset of ALI (R = 0.12; P < 0.0001). Before ALI, tPCO2 demonstrated moderate correlation (R = 0.51, P < 0.0001), which was sustained after onset of ALI (R = 0.78; P < 0.0001). During hemodynamic stability, EtCO2 demonstrated moderate correlation with PaCO2 (R = 0.44; P < 0.0001). During hemodynamic instability, EtCO2 did not correlate with PaCO2 (R = 0.03; P = 0.29). tPCO2 monitoring demonstrated strong correlation with PaCO2 during hemodynamic stability (R = 0.80, P < 0.0001), which deteriorated under hemodynamically unstable conditions (R = 0.39; P < 0.0001). Noninvasive carbon dioxide monitors are acceptable for monitoring trends in PaCO2 under conditions of hemodynamic and pulmonary stability. Under unstable conditions, reevaluation of patient status and increased caution in the interpretation of results are required.

Critical illness and hypovolemia are associated with loss of complexity of the R-to-R interval (RRI) of the electrocardiogram, whereas recovery is characterized by restoration thereof. Our goal was to investigate the dynamics of RRI complexity in burn patients. We hypothesized that the postburn period is associated with a state of low RRI complexity, and that successful resuscitation restores it. Electrocardiogram was acquired from 13 patients (age 55 +/- 5 years, total body surface area burned 36 +/- 6%, 11 +/- 5% full thickness) at 8, 12, 24, and 36 hours during postburn resuscitation. RRI complexity was quantified by approximate entropy (ApEn) and sample entropy (SampEn) that measure RRI signal irregularity, as well as by symbol distribution entropy and bit-per-word entropy that assess symbol sequences within the RRI signal. Data (in arbitrary units) are means +/- SEM. All patients survived resuscitation. Changes in heart rate and blood pressure were not significant. ApEn at 8 hours was abnormally low at 0.89 +/- 0.06. ApEn progressively increased after burn to 1.22 +/- 0.04 at 36 hours. SampEn showed similar significant changes. Symbol distribution entropy and bit-per-word entropy increased with resuscitation from 3.63 +/- 0.22 and 0.61 +/- 0.04 respectively at 8 hours postburn to 4.25 +/- 0.11 and 0.71 +/- 0.02 at 24 hours postburn. RRI complexity was abnormally low during the early postburn period, possibly reflecting physiologic deterioration. Resuscitation was associated with a progressive improvement in complexity as measured by ApEn and SampEn and complementary changes in other measures. Assessment of complexity may provide new insight into the cardiovascular response to burns.

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 PaO2-to-FiO2 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. [ABSTRACT FROM AUTHOR]

Inhalation injury commonly accompanies thermal injury, increasing the likelihood of mortality and multiple organ dysfunction (MOD). Large animal models have given important insight into the pathophysiology of this injury; however recapitulating late MOD has remained difficult. The current report describes experiments using a smoke inhalation and burn model, with follow-up of ambulatory swine for 14days with bronchoscopy, CT scanning, and bronchoalveolar lavage fluid (BALF)/blood collection. Clinically, animals cleared airway damage in the first several days after-injury. This was mirrored with erythematous airways on day 2 after-injury, which resolved by the end of the experiment, as did parenchymal damage seen on CT. An initial rise in the protein content of BALF immediately after-injury was followed by a dramatic increase in the concentration of leukocytes. Circulating neutrophils increased while lymphocytes decreased; both correlated with cell counts in BALF. IL8 levels in BALF increased 30-fold and remained elevated throughout the experiment. IL1ra increased circulation immediately after-injury, and afterwards in BALF. Other cytokines (TNFα, IL12) transiently increased in BALF (and decreased in circulation) on day 2. Taken together, these results display a remarkable capability for the lungs to recover in the absence of intubation, with further evidence of the role of cytokines such as IL8 and IL1ra. The possible exacerbating effects of clinical practices such as ventilation and bronchoscopies should be considered. [ABSTRACT FROM AUTHOR]