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Abstract: Background: Although coagulopathy is often observed in acute respiratory distress syndrome (ARDS), its clinical impact remains poorly understood. Objectives: This study aimed to clarify the coagulopathy parameters that are clinically applicable for prognostication and to determine anticoagulant indications in sepsis-induced ARDS. Method: This study enrolled patients with sepsis-derived ARDS from two nationwide multicenter, prospective observational studies. We explored coagulopathy parameters that could predict outcomes in the Focused Outcome Research on Emergency Care for Acute Respiratory Distress Syndrome, Sepsis, and Trauma (FORECAST) cohort, and the defined coagulopathy criteria were validated in the Sepsis Prognostication in Intensive Care Unit and Emergency Room-Intensive Care Unit (SPICE-ICU) cohort. The correlation between anticoagulant use and outcomes was also evaluated. Results: A total of 181 patients with sepsis-derived ARDS in the FORECAST study and 61 patients in the SPICE-ICU study were included. In a preliminary study, we found the set of prothrombin time-international normalized ratio ≥1.4 and platelet count ≤12 × 10 4 /μL, and thrombocytopenia and elongated prothrombin time (TEP) coagulopathy as the best coagulopathy parameters and used it for further analysis; the odds ratio (OR) of TEP coagulopathy for in-hospital mortality adjusted for confounding was 3.84 (95% confidence interval [CI], 1.66-8.87; P = 0.005). In the validation cohort, the adjusted OR for in-hospital mortality was 32.99 (95% CI, 2.60-418.72; P = 0.002). Although patients without TEP coagulopathy showed significant improvements in oxygenation over the first 4 days, patients with TEP coagulopathy showed no significant improvement (ΔPaO 2 /FiO 2 ratio, 24 ± 20 vs. 90 ± 9; P = 0.026). Furthermore, anticoagulant use was significantly correlated with mortality and oxygenation recovery in patients with TEP coagulopathy but not in patients without TEP coagulopathy. Conclusion: Thrombocytopenia and elongated prothrombin time coagulopathy is closely associated with better outcomes and responses to anticoagulant therapy in sepsis-induced ARDS, and our coagulopathy criteria may be clinically useful., Competing Interests: Conflicts of interest/competing interests: Dr Fujishima reports grants and personal fees from Asahi Kasei Japan Co; personal fees from Takeda Pharmaceutical Co, Ltd; grants from Chugai Pharmaceuticals Co, Ltd; grants from Teijin Pharma Ltd; grants from Otsuka Pharmaceutical Co, Ltd; grants from Mitsubishi Tanabe Pharma; grants from Tsumura & Co; grants from Shionogi Co, Ltd; and grants from Teijin Pharma, Ltd, outside the submitted work. Dr Nakada reports grants from Smart119., (Copyright © 2023 by the Shock Society.)

Abstract: Glycemic control strategies for sepsis have changed significantly over the last decade, but their impact on dysglycemia and its associated outcomes has been poorly understood. In addition, there is controversy regarding the detrimental effects of hyperglycemia in sepsis. To evaluate the incidence and risks of dysglycemia under current strategy, we conducted a preplanned subanalysis of the sepsis cohort in a prospective, multicenter FORECAST study. A total of 1,140 patients with severe sepsis, including 259 patients with pre-existing diabetes, were included. Median blood glucose levels were approximately 140 mg/dL at 0 and 72 h indicating that blood glucose was moderately controlled. The rate of initial and late hyperglycemia was 27.3% and 21.7%, respectively. The rate of early hypoglycemic episodes during the initial 24 h was 13.2%. Glycemic control was accompanied by a higher percentage of initial and late hyperglycemia but not with early hypoglycemic episodes, suggesting that glycemic control was targeted at excess hyperglycemia. In nondiabetic patients, late hyperglycemia (hazard ratio, 95% confidence interval; P value: 1.816, 1.116-2.955, 0.016) and early hypoglycemic episodes (1.936, 1.180-3.175, 0.009) were positively associated with in-hospital mortality. Further subgroup analysis suggested that late hyperglycemia and early hypoglycemic episodes independently, and probably synergistically, affect the outcomes. In diabetic patients, however, these correlations were not observed. In conclusion, a significantly high incidence of dysglycemia was observed in our sepsis cohort under moderate glycemic control. Late hyperglycemia in addition to early hypoglycemia was associated with poor outcomes at least in nondiabetic patients. More sophisticated approaches are necessary to reduce the incidence of these serious complications., Competing Interests: The other authors report no conflicts of interest., (Copyright © 2021 by the Shock Society.)

Introduction: Polymyxin B hemoperfusion (PMX-HP) is an adjuvant therapy for sepsis or septic shock that removes circulating endotoxin. However, PMX-HP has seldom achieved expectations in randomized trials targeting nonspecific overall sepsis patients. If used in an optimal population, PMX-HP may be beneficial. This study aimed to identify the optimal population for PMX-HP in patients with septic shock., Methods: We used a prospective nationwide cohort targeting consecutive adult patients with severe sepsis (Sepsis-2) in 59 intensive care units in Japan. Associations between PMX-HP therapy and in-hospital mortality were assessed using multivariable Cox proportional hazard regression models. To identify best targets for PMX-HP, we developed a non-linear restricted cubic spline model including two-way interaction term (treatment × Acute Physiology and Chronic Health Evaluation [APACHE] II score/Sequential Organ Failure Assessment [SOFA] score) and three-way interaction term (treatment × age × each score)., Results: The final study cohort comprised 741 sepsis patients (92 received PMX-HP, 625 did not). Cox proportional hazards regression model adjusted for the covariates suggested no association between PMX-HP therapy and improved mortality overall. Effect modification of PMX-HP by APACHE II score was statistically significant (P for interaction = 0.189) but non-significant for SOFA score (P for interaction = 0.413). Three-way interaction analysis revealed suppressed risk hazard in the PMX-HP group versus control group only in septic shock patients with high age and in the most severe subset of both scores, whereas increased risk hazard was observed in those with high age but in the lower severity subset of both scores., Conclusions: Our results suggested that although PMX-HP did not reduce in-hospital mortality among overall septic shock patients, it may benefit a limited population with high age and higher disease severity.

Components of neutrophil extracellular traps (NETs) are released into the circulation by neutrophils and contribute to microcirculatory disturbance in sepsis. Removing NET components (DNA, histones, and proteases) from the circulation could be a new strategy for counteracting NET-dependent tissue damage. We evaluated the effect of hemoperfusion with a polymyxin B (PMX) cartridge, which was originally developed for treating gram-negative infection, on circulating NET components in patients with septic shock, as well as the effect on phorbol myristate acetate (PMA)-stimulated neutrophils obtained from healthy volunteers. Ex vivo closed loop hemoperfusion was performed through PMX filters in a laboratory circuit. Whole blood from healthy volunteers (incubated with or without PMA) or from septic shock patients was perfused through the circuit. For in vivo experiment blood samples were collected before and immediately after hemoperfusion with PMX to measure the plasma levels of cell-free NETs. The level of cell-free NETs was assessed by measuring myeloperoxidase-associated DNA (MPO-DNA), neutrophil elastase-associated DNA (NE-DNA), and cell-free DNA (cf-DNA). Plasma levels of MPO-DNA, NE-DNA, and cf-DNA were significantly increased after 2 h of PMA stimulation. When the circuit was perfused with blood from septic shock patients or PMA-stimulated neutrophils from healthy volunteers, circulating levels of MPO-DNA, NE-DNA, and cf-DNA were significantly reduced after 1 and 2 h of perfusion with a PMX filter compared with perfusion without a PMX filter. In 10 patients with sepsis, direct hemoperfusion through filters with immobilized PMX significantly reduced plasma levels of MPO-DNA and NE-DNA. These ex vivo and in vivo findings demonstrated that hemoperfusion with PMX removes circulating NET components. Selective removal of circulating NET components from the blood could be effective for prevention/treatment of NET-related inappropriate inflammation and thrombogenesis in patients with sepsis.

Purpose: Acute respiratory distress syndrome (ARDS) remains a major cause of death. Epidemiology should be continually examined to refine therapeutic strategies for ARDS. We aimed to elucidate demographics, treatments, and outcomes of ARDS in Japan., Methods: This is a prospective cohort study for ARDS. We included adult patients admitted to intensive care units through emergency and critical care departments who satisfied the American-European Consensus Conference (AECC) acute lung injury (ALI) criteria. In addition, the fulfillment of the Berlin definition was assessed. Logistic regression analyses were used to examine the association of independent variables with outcomes., Results: Our study included 166 patients with AECC ALI from 34 hospitals in Japan; among them, 157 (94.6%) fulfilled the Berlin definition. The proportion of patients with PaO2/FIO2 ≤ 100, patients under invasive positive pressure ventilation (IPPV), and in-hospital mortality was 39.2%, 92.2%, and 38.0% for patients with AECC ALI and 38.9%, 96.8%, and 37.6% for patients with Berlin ARDS, respectively. The area of lung infiltration was independently associated with outcomes of ARDS. Low-mid-tidal volume ventilation was performed in 75% of patients under IPPV. Glucocorticoid use was observed in 54% patients, and it was positively associated with mortality., Conclusions: Our study included a greater percentage of patients with ARDS with high severity and found that the overall mortality was 38%. The management of ARDS in Japan was characterized by high the utilization rate of glucocorticoids, which was positively associated with mortality.

In this study, we examined the effects of direct hemoperfusion through filters with immobilized polymyxin B (PMX-DHP) on leukocyte function and plasma levels of cytokines in patients with septic shock. We found that PMX-DHP caused increased expression of C-X-C chemokine receptor 1 (CXCR1) and CXCR2, along with decreased expression of CD64 and CD11b, by circulating neutrophils in patients with septic shock. Plasma levels of cytokines, including interleukin 6 (IL-6), IL-8, IL-10, and high-mobility group box 1, were elevated in patients with septic shock compared with healthy controls, but cytokine levels were not altered by PMX-DHP. These results suggest that PMX-DHP influences neutrophils via a mechanism that does not involve cytokine. Ex vivo perfusion of heparinized blood from patients with sepsis and septic shock through PMX filters in a laboratory circuit caused a significant decrease in neutrophil and monocyte counts. After 120 min of perfusion, neutrophils, monocytes, and lymphocytes were decreased by 78%, 70%, and 10%, respectively, compared with baseline values. Flow cytometric analysis indicated that activated neutrophils with high levels of CD11b/CD64 expression and low levels of CXCR1/CXCR2 expression showed preferential adhesion to PMX filters. Neutrophils isolated from the blood after ex vivo PMX perfusion caused less damage to an endothelial cell monolayer than cells from sham-treated blood, whereas neutrophil phagocytosis of opsonized Escherichia coli was unaffected. These results indicate that PMX-DHP selectively removes activated neutrophils and reduces the ability of circulating cells to cause endothelial damage. Selective removal of activated neutrophils using PMX-DHP may improve the systemic inflammatory response in patients with septic shock.