Background:Approximately one in four trauma patients admitted to the intensive care unit (ICU) develops an infection, resulting in 20% mortality. In trauma patients, it is difficult to distinguish the systemic inflammation due to injury from infection. Lack of a gold standard for diagnosing infection further complicates recognition and management of sepsis in this population. We developed and piloted an adjudication instrument to analyze infection status in critically injured trauma patients. Methods:Adult trauma patients admitted to the ICU (January-October 2022) were included. Our multidisciplinary adjudication committee of six clinical experts collaboratively developed the case report form (CRF) and infection status form. The CRFs have structured clinical data, and the infection status form includes the likelihood of infection on a Likert scale, site, and type of infection. Two adjudicators were randomly assigned to independently review the CRF and complete the infection status form. If both provided concordant responses, consensus was achieved. If there was a discrepancy in responses, a third adjudicator was assigned to review. Results:40 patients underwent adjudication of infection status. Concordance between the two primary adjudicators was found in 82.5% (33/40). Of these, infection was identified in 18.2% (6/33). In all cases, adjudicators assessed a lung source of bacterial infection. Seven cases were reviewed by a third adjudicator, and infection was identified in 85.7% (6/7). Conclusions:In the absence of a gold standard for the diagnosis of infection in critically injured trauma patients, an adjudication process can be an effective way to standardize the assessment of a study event or endpoint. Level of evidence:Diagnostic tests or criteria; level II.

BACKGROUND:In patients receiving pressure modes of mechanical ventilation, plateau pressure can be higher than peak inspiratory pressure when the patient has a strong drive to breathe. This report provides comprehensive evidence to support this observation. METHODS:Peak inspiratory pressure, plateau pressure, esophageal pressure, and tidal volume were observed at various levels of pressure support in a patient with absent cortical function but preserved brainstem function who was receiving mechanical ventilation. RESULTS:Positive end-expiratory pressure was 5 cm H2O for all pressure support settings. At pressure support of 0 cm H2O, plateau pressure was 13 cm H2O; peak inspiratory pressure was 5 cm H2O. The difference between plateau pressure and peak inspiratory pressure (8 cm H2O) reflected the patient's inspiratory effort. The driving pressure (8 cm H2O) generated a tidal volume of 619 mL. At pressure support of 10 cm H2O, plateau pressure was 12 cm H2O; peak inspiratory pressure was 15 cm H2O. The difference between plateau pressure and peak inspiratory pressure was -3 cm H2O, indicating absent inspiratory effort apart from triggering the breath. The driving pressure (7 cm H2O) generated a tidal volume of 563 mL. CONCLUSION:When plateau pressure can be accurately measured, the difference between plateau pressure and peak inspiratory pressure can be used at the bedside to evaluate a patient's respiratory drive. Ensuring protective goals by routinely monitoring plateau pressure regardless of the mode of mechanical ventilation is critical.

Acute pulmonary injury can occur in response to any number of inciting factors. The body's response to these insults is much less diverse and usually categorizable as one of several patterns of disease defined by histopathology, with corresponding patterns on chest CT. Common patterns of acute injury include diffuse alveolar damage, organizing pneumonia, acute eosinophilic pneumonia, and hypersensitivity pneumonitis. The ultimate clinical diagnosis is multidisciplinary, requiring a detailed history and relevant laboratory investigations from referring clinicians, identification of injury patterns on imaging by radiologists, and sometimes tissue evaluation by pathologists. In this review, several clinical diagnoses will be explored, grouped by imaging pattern, with a representative clinical presentation, a review of the current literature, and a discussion of typical imaging findings. Additional information on terminology and disambiguation will be provided to assist with comprehension and standardization of descriptions. The focus will be on the acute phase of illness from presentation to diagnosis; treatment methods and chronic sequela of acute disease are beyond the scope of this review.

Background Although previous trials suggest that systemic corticosteroids improve survival in ARDS, the optimal dose remains uncertain. Research Question Which corticosteroid dose offers the greatest efficacy, safety, or both in ARDS? Study Design and Methods We conducted a model-based dose-response network meta-analysis (NMA) that pooled randomized controlled trials (RCTs) of dexamethasone, hydrocortisone, and methylprednisolone, converting regimens to cumulative methylprednisolone-equivalent doses. For short-term mortality, we fitted agent-specific dose-response curves and estimated the 95% effective dose (ED95) as a near-maximal dose. A Bayesian equal-dose NMA compared treatment effects at ED95 and at a nonspecific dose of NMA. Certainty of evidence was assessed using Confidence in Network Meta-Analysis. Results Six thousand five hundred two participants from 28 RCTs were analyzed. ED95 (cumulative methylprednisolone-equivalent doses) was 840 mg for dexamethasone and 1,400 mg for methylprednisolone. At ED95, dexamethasone reduced short-term mortality by 87 deaths per 1,000 patients vs placebo (95% credible interval [CrI], 148 fewer-7 fewer; low certainty) and methylprednisolone reduced mortality by 98 deaths per 1,000 patients vs placebo (95% CrI, 172 fewer-26 fewer; low certainty). Hydrocortisone, primarily evaluated at lower cumulative doses, showed an ED95 of 270 mg methylprednisolone-equivalent doses, based on a log-linear model, with a mortality reduction of 73 deaths per 1,000 patients vs placebo (95% CrI, 152 fewer-22 more; low certainty). Escalating to pulse-dose regimens provided no additional benefit. In the equal-dose NMA, dexamethasone and methylprednisolone improved ventilator-free days vs placebo, whereas hydrocortisone did not. No meaningful differences were observed in safety outcomes across agents. Interpretation Our results suggest that dexamethasone and methylprednisolone, when administered at ED95, are associated with lower mortality and more ventilator-free days in patients with ARDS. Hydrocortisone’s lower mortality benefit likely reflects suboptimal doses in RCTs; its log-linear dose response suggests potential for greater benefit at higher doses.

Acute respiratory distress syndrome due to non-pulmonary causes exhibits prominent endothelial activation which is challenging to assess in critically ill patients. Preclinical in vivo models of sepsis and ARDS have failed to yield useful therapies in humans, perhaps due to interspecies differences in inflammatory responses. Use of microphysiological systems (MPS) offer improved fidelity to human biological responses and better predict pharmacological responses than traditional culture. We adapted a lung endothelial MPS based on the LumeNEXT platform to evaluate the effect of plasma from critically ill sepsis patients on endothelial permeability, adhesion molecule expression and inflammatory cytokine production. Lumens incubated with sepsis plasma exhibited areas of contraction, loss of cellular coverage, and luminal defects. Sepsis plasma-incubated lumens had significantly increased permeability compared to lumens incubated with healthy donor plasma. ICAM-1 expression increased significantly in lumens incubated with sepsis plasma compared with those incubated with healthy control plasma, while concentrations of IL-6, IL-18, and soluble VEGF-R1 increased in sepsis plasma before and after incubation in the MPS compared with healthy control plasma. Use of the lung endothelial MPS may enable interrogation of specific mechanisms of endothelial dysfunction that promote ARDS in sepsis patients.

SESSION TITLE: ECMO and ARDS in COVID-19 InfectionsSESSION TYPE: Rapid Fire Original InvPRESENTED ON: 10/17/2022 12:15 pm - 1:15 pmPURPOSE: Veno-venous extracorporeal membrane oxygenation (VV-ECMO) is an important salvage therapy for patients with severe COVID-19 associated acute respiratory distress syndrome (ARDS). Whether gas exchange after initiation of ECMO predicts survival remains unknown. The present study aims to investigate if gas exchange parameters are associated with survival during ECMO support of COVID-19 associated ARDS.METHODS: We retrospectively evaluated all ARDS patients initiated on VV-ECMO according to ELSO guidelines between 2018 and 2021 at a tertiary academic medical center. ECMO sweep and ventilator fraction of inspire oxygen (FiO2) were catalogued every eight hours for all patients and compared between COVID-19 survivors and non-survivors at Days 0, 7, 14, 21, and 28 of ECMO using the Mann-Whitney U test. Cohort characteristics were compared between patients with and without COVID-19 using the chi-squared test for categorical comparisons and the Mann-Whitney U test for comparison of non-parametric continuous variables. Statistical significance was considered as p<0.05 for all tests.RESULTS: Forty-two ARDS patients were initiated on VV-ECMO during the study period, including 30 patients with COVID-19. Mortality was similar between patients with and without COVID-19 (43.3% vs 41.7%, p=0.92). ECMO duration (31 [33.5] vs 9.5 [7.0] days, p=0.002), median sweep (7.0 [4.5] vs 4.3 [4.0], p< 0.001), and median ventilator FiO2 (0.55 [0.50] vs 0.45 [25], p < 0.001) were significantly increased in patients with COVID-19 compared to those without. Among COVID-19 patients, median sweep did not differ between survivors and non-survivors at Day 0 (3.5 [1.0] vs 4.0 [1.0], p=0.20), Day 7 (6.0 [3.0] vs 7.5 [2.3], p=0.38), Day 14 (6.0 [2.5] vs 8.0 [3.3], p=0.14), Day 21 (8.0 [3.5] vs 9.0 [3.0], p= 0.97), or Day 28 (7.5 [3.5] vs 8.0 [3.0], p=0.74). Median ventilator FiO2 was significantly lower in COVID-19 survivors compared to non-survivors at Day 28 (0.50 [0.16] vs 0.81 [0.40], p=0.03), but not at Day 0 (0.75 [0.52] vs 0.60 [0.25], p= 0.98), Day 7 (0.90 [0.50] vs 1 [0.45], p = 0.54), Day 14 (0.90 [0.50] vs 1 [0.08], p=0.08), or Day 21 (0.80 [0.10] vs 0.90 [0.40], p=0.62).CONCLUSIONS: Survival was similar between ARDS patients with and without COVID-19 despite significantly increased ECMO duration and gas exchange support in patients with COVID-19. Early gas exchange parameters after initiation of ECMO were not associated with survival in patients with COVID-19. At Day 28 of ECMO, COVID-19 survivors had significantly lower ventilator FiO2 requirements compared to non-survivors.CLINICAL IMPLICATIONS: Gas exchange parameters did not discriminate survivors from non-survivors until day 28 of ECMO in patients with COVID-19 associated ARDS. Given the need for increased gas exchange support and duration of ECMO therapy in this population, gas exchange parameters prior day 28 of ECMO may not be suitable markers for prognostication.DISCLOSURES: No relevant relationships by Andrew DavisNo relevant relationships by Malcolm DeCampNo relevant relationships by Hilary FaustNo relevant relationships by James MaloneyNo relevant relationships by Daniel McCarthyNo relevant relationships by Michael Peliska SESSION TITLE: ECMO and ARDS in COVID-19 Infections SESSION TYPE: Rapid Fire Original Inv PRESENTED ON: 10/17/2022 12:15 pm - 1:15 pm PURPOSE: Veno-venous extracorporeal membrane oxygenation (VV-ECMO) is an important salvage therapy for patients with severe COVID-19 associated acute respiratory distress syndrome (ARDS). Whether gas exchange after initiation of ECMO predicts survival remains unknown. The present study aims to investigate if gas exchange parameters are associated with survival during ECMO support of COVID-19 associated ARDS. METHODS: We retrospectively evaluated all ARDS patients initiated on VV-ECMO according to ELSO guidelines between 2018 and 2021 at a tertiary academic medical center. ECMO sweep and ventilator fraction of inspire oxygen (FiO2) were catalogued every eight hours for all patients and compared between COVID-19 survivors and non-survivors at Days 0, 7, 14, 21, and 28 of ECMO using the Mann-Whitney U test. Cohort characteristics were compared between patients with and without COVID-19 using the chi-squared test for categorical comparisons and the Mann-Whitney U test for comparison of non-parametric continuous variables. Statistical significance was considered as p<0.05 for all tests. RESULTS: Forty-two ARDS patients were initiated on VV-ECMO during the study period, including 30 patients with COVID-19. Mortality was similar between patients with and without COVID-19 (43.3% vs 41.7%, p=0.92). ECMO duration (31 [33.5] vs 9.5 [7.0] days, p=0.002), median sweep (7.0 [4.5] vs 4.3 [4.0], p< 0.001), and median ventilator FiO2 (0.55 [0.50] vs 0.45 [25], p < 0.001) were significantly increased in patients with COVID-19 compared to those without. Among COVID-19 patients, median sweep did not differ between survivors and non-survivors at Day 0 (3.5 [1.0] vs 4.0 [1.0], p=0.20), Day 7 (6.0 [3.0] vs 7.5 [2.3], p=0.38), Day 14 (6.0 [2.5] vs 8.0 [3.3], p=0.14), Day 21 (8.0 [3.5] vs 9.0 [3.0], p= 0.97), or Day 28 (7.5 [3.5] vs 8.0 [3.0], p=0.74). Median ventilator FiO2 was significantly lower in COVID-19 survivors compared to non-survivors at Day 28 (0.50 [0.16] vs 0.81 [0.40], p=0.03), but not at Day 0 (0.75 [0.52] vs 0.60 [0.25], p= 0.98), Day 7 (0.90 [0.50] vs 1 [0.45], p = 0.54), Day 14 (0.90 [0.50] vs 1 [0.08], p=0.08), or Day 21 (0.80 [0.10] vs 0.90 [0.40], p=0.62). CONCLUSIONS: Survival was similar between ARDS patients with and without COVID-19 despite significantly increased ECMO duration and gas exchange support in patients with COVID-19. Early gas exchange parameters after initiation of ECMO were not associated with survival in patients with COVID-19. At Day 28 of ECMO, COVID-19 survivors had significantly lower ventilator FiO2 requirements compared to non-survivors. CLINICAL IMPLICATIONS: Gas exchange parameters did not discriminate survivors from non-survivors until day 28 of ECMO in patients with COVID-19 associated ARDS. Given the need for increased gas exchange support and duration of ECMO therapy in this population, gas exchange parameters prior day 28 of ECMO may not be suitable markers for prognostication. DISCLOSURES: No relevant relationships by Andrew Davis No relevant relationships by Malcolm DeCamp No relevant relationships by Hilary Faust No relevant relationships by James Maloney No relevant relationships by Daniel McCarthy No relevant relationships by Michael Peliska

OBJECTIVES:. Circulating nucleic acids, alone and in complex with histones as nucleosomes, have been proposed to link systemic inflammation and coagulation after trauma to acute kidney injury (AKI). We sought to determine the association of circulating nucleic acids measured at multiple time points after trauma with AKI risk. DESIGN:. We conducted a prospective cohort study of trauma patients, collecting plasma on presentation and at 6, 12, 24, and 48 hours, defining AKI over the first 6 days by Kidney Disease Improving Global Outcomes serum creatinine and dialysis criteria. We determined kinetics of plasma mitochondrial DNA (mtDNA), nuclear DNA (nDNA), and nucleosome levels across time points and associations with AKI using multivariable linear mixed-effects models, adjusted for injury characteristics and blood transfusions. We evaluated the association of presentation nucleic acid damage-associated molecular patterns (DAMP) concentrations with subsequent AKI, adjusting for injury severity using multivariable logistic regression. SETTING:. Academic level I trauma center. PATIENTS:. Trauma patients (n = 55) requiring intensive care for greater than or equal to 24 hours after presentation. INTERVENTIONS:. None. MEASUREMENTS AND MAIN RESULTS:. AKI developed in 17 patients (31%), a median of 12.0 hours (interquartile range, 6.2–24.1 hr) after presentation. mtDNA demonstrated a time-varying association with AKI (p = 0.022, interaction with time point), with differences by AKI status not emerging until 24 hours (β = 0.97 [95% CI, 0.03–1.90] log copies/uL; p = 0.043). Patients who developed AKI had higher nDNA across all time points (overall β = 1.41 log copies/uL [0.86–1.95 log copies/uL]; p < 0.001), and presentation levels were significantly associated with subsequent AKI (odds ratio [OR], 2.55 [1.36–4.78] per log copy/uL; p = 0.003). Patients with AKI had higher nucleosome levels at presentation (β = 0.32 [0.00–0.63] arbitrary unit; p = 0.048), a difference that was more pronounced at 24 hours (β = 0.41 [0.06–0.76]; p = 0.021) and 48 hours (β = 0.71 [0.35–1.08]; p < 0.001) (p = 0.075, interaction with time point). CONCLUSIONS:. Plasma nucleic acid DAMPs have distinct kinetics and associations with AKI in critically ill trauma patients. nDNA at presentation predicts subsequent AKI and may be amenable to targeted therapies in this population.

BACKGROUND: Critically ill patients who develop ARDS have substantial associated morbidity and mortality. Circulating mitochondrial DNA (mtDNA) released during critical illness causes endothelial dysfunction and lung injury in experimental models. This study hypothesized that elevated plasma mtDNA is associated with ARDS in critically ill patients with trauma and sepsis. METHODS: Plasma mtDNA concentrations were measured at ED presentation and approximately 48 h later in separate prospective cohorts of critically ill patients with trauma and sepsis. ARDS was classified according to the Berlin definition. The association of mtDNA with ARDS was tested by using multivariable logistic regression, adjusted for covariates previously shown to contribute to ARDS risk in each population. RESULTS: ARDS developed in 41 of 224 (18%) trauma patients and in 45 of 120 (38%) patients with sepsis. Forty-eight-hour mtDNA levels were significantly associated with ARDS (trauma: OR, 1.58/log copies/mu L; 95% CI, 1.14-2.19 [P = .006]; sepsis: OR, 1.52/log copies/mu L; 95% CI, 1.12-2.06 [P = .007]). Plasma mtDNA on presentation was not significantly associated with ARDS in either cohort. In patients with sepsis, 48-h mtDNA was more strongly associated with ARDS among those with a nonpulmonary infectious source (OR, 2.20/log copies/mu L; 95% CI, 1.36-3.55 [P = .001], n = 69) than those with a pulmonary source (OR, 1.04/log copies/mu L; 95% CI, 0.68-1.59 [P = .84], n = 51; P = .014 for interaction). CONCLUSIONS: Plasma mtDNA levels were associated with incident ARDS in two critical illness populations. Given supportive preclinical data, our findings suggest a potential link between circulating mtDNA and lung injury and merit further investigation as a potentially targetable mediator of ARDS.

OBJECTIVES:Microvascular thrombosis contributes to acute respiratory distress syndrome pathophysiology and has been demonstrated in coronavirus disease 2019-associated acute respiratory distress syndrome. Clinical laboratory measurements of coagulation and disseminated intravascular coagulation, such as coagulation factor function, platelet count, and fibrinogen, may not fully reflect the extent of microvascular thrombosis present in these patients. We investigated thromboelastography in patients with coronavirus disease 2019-associated acute respiratory distress syndrome with the objective of characterizing suspected coagulopathy and impaired fibrinolysis.DESIGN:Retrospective observational cohort study.SETTING:Single-center academic medical center.PATIENTS:Ten patients with polymerase chain reaction-confirmed coronavirus disease 2019 disease complicated by acute respiratory distress syndrome.INTERVENTIONS:Measurement of thromboelastography (n = 10) and thrombolysis with alteplase (n = 4).MEASUREMENTS AND MAIN RESULTS:Hypercoagulability and decreased or absent fibrinolysis were demonstrated by thromboelastography. Thrombocytopenia and hypofibrinogenemia were not observed, while seven of 10 patients had elevated d-dimer values. For patients who received thrombolytic therapy, repeat thromboelastography demonstrated improvements in coagulation index and lysis at 30 minutes reflecting reduced hypercoagulability and increased fibrinolysis. One major bleeding complication was detected following thrombolysis. Eight of 10 patients survived and were successfully extubated, and six of 10 have since been discharged.CONCLUSIONS:In coronavirus disease 2019 patients with acute respiratory distress syndrome in whom thromboelastography was performed, hypercoagulability and impaired fibrinolysis were observed. In the context of autopsy studies demonstrating pulmonary microvascular thromboses in coronavirus disease 2019 patients, noninvasive detection of hypercoagulability and deficient fibrinolysis in coronavirus disease 2019 acute respiratory distress syndrome using thromboelastography could improve understanding and management of coronavirus disease 2019.

Faust, Hilary; Wang, Yiyue; Forker, Caitlin; Dunn, Thomas; Zhang, Peggy; Lanken, Paul; Sims, Carrie; Yehya, Nadir; Christie, Jason; Meyer, Nuala; Reilly, John; Mangalmurti, Nilam; Shashaty, Michael Author Information

RBC transfusion is associated with increased morbidity and mortality in critically ill patients. Endothelial cell necroptosis and subsequent damage‐associated molecular pattern (DAMP) release has been identified as a mechanism of injury following RBC transfusion. Mounting evidence implicates the pro‐inflammatory pattern recognition receptor, Receptor for Advanced Glycation End Products (RAGE), in initiating cell death programmes such as necroptosis. Here, we demonstrate the role of RAGE in endothelial necroptosis, as deletion of RAGE attenuates necroptotic cell death in response to TNFα, LPS or CpG‐DNA. We show direct interaction of RAGE with the critical mediator of necroptosis, Receptor Interacting Protein Kinase 3 (RIPK3), during necroptosis. Furthermore, we observe decreased plasma High Mobility Group Box 1 (HMGB1) and RIPK3 levels in RAGE deficient mice compared to WT mice post‐transfusion, substantiating the role for RAGE in transfusion‐induced DAMP release in vivo. Collectively, these findings underscore RAGE as an essential mediator of regulated necrosis and post‐transfusion DAMP release. Further studies to understand the role of RAGE and the necroptotic pathway in transfusion‐induced organ injury may offer key targets to mitigate transfusion‐related risks, including the risk of ARDS, in susceptible hosts.

INTRODUCTION: Sulfhemoglobin is a rare dyshemoglobin resulting from incorporation of sulfur into the oxidized form of iron in the hemoglobin moiety.Sulfhemoglobin is unable to bind oxygen for the life of the erythrocyte, leading to discrepant pulse oximetry and arterial oxygen tension (PaO2).Oxygenation of the tissues is only mildly affected due to the right shift of the oxyhemoglobin dissociation curve for the remaining oxyhemoglobin molecules.Occupational exposures, medications, and sulfideproducing intestinal flora have been implicated in its development.Sulfhemoglobin and methemoglobin share similar presentations of cyanosis, hypoxia without hypoxemia, and absorptive peak wavelengths on co-oximetry, and thus distinguishing the difference can be a diagnostic challenge.