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Abstract This study aimed to investigate the incidence and significance of disseminated intravascular coagulation (DIC) in coronavirus disease 2019 (COVID-19). A multicenter cohort study was conducted using large-scale COVID-19 registry data. The patients were classified into DIC and non-DIC groups based on the diagnosis on admission (day 1) and on any of the days 1, 4, 8, and 15. In total, 23,054 patients were divided into DIC (n = 264) and non-DIC (n = 22,790) groups on admission. Thereafter, 1654 patients were divided into 181 patients with DIC and 1473 non-DIC patients based on the DIC diagnosis on any of the days from 1 to 15. DIC incidence was 1.1% on admission, increasing to 10.9% by day 15. DIC diagnosis on admission had moderate predictive performance for developing multiple organ dysfunction syndrome (MODS) on day 4 and in-hospital death and was independently associated with MODS and in-hospital death. DIC diagnosis on any of the days from 1 to 15, especially days 8 and 15, was associated with lower survival probability than those without DIC and showed significant association with in-hospital death. In conclusion, despite its low incidence, DIC, particularly late-onset DIC, plays a significant role in the pathogenesis of poor prognosis in patients with COVID-19.

Abstract Background The development of disseminated intravascular coagulation (DIC) in patients with sepsis has been repeatedly confirmed as a factor associated with poor prognosis. Anticoagulant therapy has been expected to improve sepsis patient outcomes, whereas no randomized controlled trials have demonstrated the survival benefit of anticoagulant therapies in non-specific overall sepsis. Patient selection based on the component of “high disease severity” in addition to “sepsis with DIC” has recently proved important in identifying appropriate targets for anticoagulant therapy. The aims of this study were to characterize “severe” sepsis DIC patients and to identify the patient population benefiting from anticoagulant therapy. Methods This retrospective sub-analysis of a prospective multicenter study included 1,178 adult patients with severe sepsis from 59 intensive care units in Japan from January 2016 to March 2017. We examined the association of patient outcomes, including organ dysfunction and in-hospital mortality, with the DIC score and prothrombin time-international normalized ratio (PT-INR), one of the components of the DIC score, using multivariable regression models including the cross-product term between these indicators. Multivariate Cox proportional hazard regression analysis with non-linear restricted cubic spline including a three-way interaction term (anticoagulant therapy × the DIC score × PT-INR) was also performed. Anticoagulant therapy was defined as the administration of antithrombin, recombinant human thrombomodulin, or their combination. Results In total, we analyzed 1013 patients. The regression model showed that organ dysfunction and in-hospital mortality deteriorated with higher PT-INR values in the range of

Background Supraphysiological oxygen administration causes unfavourable clinical outcomes in various diseases. This study aimed to determine whether hyperoxia would be associated with increased mortality in patients with severe infection.Methods A post-hoc analysis of a nationwide multicentre prospective observational study on sepsis (SPICE Study) was conducted, including adult patients admitted to the intensive care unit with available arterial partial pressure of oxygen (PaO2) at the treatment initiation for severe infection. Hyperoxia was defined as a PaO2 level of ≥300 mm Hg and in-hospital mortality was compared between patients with and without hyperoxia.Results Of the 563 patients eligible for the study, 49 had hyperoxia at treatment initiation for severe infection. The in-hospital all-cause mortality rates of patients with and without hyperoxia were 14 (29.2%) and 90 (17.6%), respectively. Inverse probability weighting analyses with propensity scores revealed the association between hyperoxia and increased in-hospital mortality rate (28.8% vs 18.8%; adjusted OR 1.75 (1.03 to 2.97); p=0.038), adjusting for patient demographics, comorbidities, site of infection, severity of infection, haemodynamic and respiratory status, laboratory data and location of patient at infection development. Acute lung injury developed more frequently in patients with hyperoxia on the following days after infection treatment, whereas sepsis-related mortality was comparable regardless of hyperoxia exposure.Conclusion Hyperoxia with PaO2 ≥300 mm Hg at treatment initiation of severe infection was associated with an increased in-hospital mortality rate in patients requiring intensive care. The amount of oxygen to administer to patients with severe infection should be carefully determined.Trial registration number University Hospital Medical Information Network Clinical Trial Registry (UMIN000027452).

Abstract Disseminated intravascular coagulation (DIC) is one of the major organ dysfunctions associated with sepsis. This retrospective secondary analysis comprised data from a prospective multicenter study to investigate the age-related differences in the survival benefit of anticoagulant therapy in sepsis according to the DIC diagnostic criteria. Adult patients with severe sepsis based on the Sepsis-2 criteria were enrolled and divided into the following groups: (1) anticoagulant group (patients who received anticoagulant therapy) and (2) non-anticoagulant group (patients who did not receive anticoagulant therapy). Patients in the former group were administered antithrombin, recombinant human thrombomodulin, or their combination. The increases in the risk of hospital mortality were suppressed in the high-DIC-score patients aged 60–70 years receiving anticoagulant therapy. No favorable association of anti-coagulant therapy with hospital mortality was observed in patients aged 50 years and 80 years. Furthermore, anticoagulant therapy in the lower-DIC-score range increased the risk of hospital mortality in patients aged 50–60 years. In conclusion, anticoagulant therapy was associated with decreased hospital mortality according to a higher DIC score in septic patients aged 60–70 years. Anticoagulant therapy, however, was not associated with a better outcome in relatively younger and older patients with sepsis.

Abstract Aim This study aimed to investigate the association of early vasopressor initiation with improved septic shock outcomes. Methods This multicenter observational study was conducted in 17 intensive care units in Japan and included adult patients with sepsis admitted to the intensive care unit from July 2019 to August 2020 and treated with vasopressor therapy. Patients were divided into the early vasopressor group (≤1 h from sepsis recognition) and the delayed vasopressor group (>1 h). The impact of early vasopressor administration on risk‐adjusted in‐hospital mortality was estimated using logistic regression analyses adjusted by an inverse probability of treatment weighting analysis with propensity scoring. Results Among the 97 patients, 67 received vasopressor therapy within 1 h from sepsis recognition and 30 received vasopressor after 1 h. In‐hospital mortality was 32.8% in the early vasopressor group and 26.7% in the delayed vasopressor group (p = 0.543). The adjusted odds ratio for in‐hospital mortality was 0.76 (95% confidence interval 0.17–3.29) when comparing patients in the early vasopressor with those in the delayed vasopressor group. The fit curve from the mixed‐effects model showed a relatively lower trend toward an infusion volume over time in the early vasopressor group than in the delayed vasopressor group. Conclusion Our study did not reach a definitive conclusion for early vasopressor administration. However, early vasopressor administration may help avoid volume overload in the long course of sepsis care.

IntroductionTrauma activates the innate immune system to modulate hemostasis and minimize the damage caused by physiological bodily responses, including the activation of coagulation. Sufficiently severe trauma overwhelms physiological responses and elicits the systemic inflammatory response syndrome, which leads to the onset of disseminated intravascular coagulation (DIC), characterized by dysregulated inflammatory coagulofibrinolytic responses. Impaired anticoagulant mechanisms, including antithrombin, constitutes the pathology of DIC, while the dynamics of antithrombin and relevance to outcomes in trauma-induced coagulopathy have not been fully elucidated. This study investigated the associations of antithrombin activity with DIC onset and outcomes in severely injured patients.MethodsThis retrospective sub-analysis of a multicenter, prospective study included patients with an injury severity score ≥16. We characterized trauma patients with low antithrombin activity (antithrombin 85%). Antithrombin activity at 3 h showed good predictive performance for in-hospital mortality, and a multivariable Cox proportional-hazard regression model with a cross-product term between the antithrombin and DIC showed that the in-hospital mortality in patients with DIC increased with decreased antithrombin activity. A multivariable logistic regression model showed that the odds for the development of MODS in patients with DIC increased with lower antithrombin values.ConclusionDecreased antithrombin activity in trauma-induced coagulopathy is associated with poor outcomes through worsening of DIC.

Background: Starting infusion at a rate based on the Baxter formula is the global standard. However, with this infusion formula, an excessive amount of fluid may be stored inside the body (fluid creep), which may lead to severe respiratory disorders or abdominal compartment syndrome. The present study explored whether the Baxter formula or the Modified Brooke formula is more beneficial for resuscitation in extensively burned patients. Methods: The study design was a randomized controlled trial. One group received conventional intervention based on the Baxter formula, and the other received intervention using the infusion method by the Modified Brooke formula. Thirty-nine patients were enrolled in this study by admission to each hospital for 3 years. Of the 39 cases, 3 dropped out according to the study protocol, so 36 cases were analyzed, and 17 patients in the Modified Brooke formula group and 19 in the Baxter formula group were used for the analyses in this study. Results: There were no statistically significant differences between the 2 groups in the age, gender, body weight, burn severity, infusion volume required within 2 days after admission, serum creatinine, and acute kidney injury based on the KDIGO guideline within 48 h after arrival at the hospital, daily P/F ratio within 1 week after hospitalization, survival rate on the 28th day, and discharge survival rate. There were no cases of abdominal compartment syndrome during the observation period. The Modified Brooke formula group failed to achieve the target urine output corresponding to the infusion volume within 8 h after arrival, especially in ≥40% TBSA burn patients, but it did not become a clinical problem. Conclusion: We were unable to conclusively demonstrate that the Modified Brooke formula blocked the occurrence of “fluid creep” in extensively burned patients. However, it was suggested that starting the initial resuscitation at half the conventional volume might contribute to an improved physiological condition in the acute phase of major burns.

BackgroundPatients successfully resuscitated from cardiac arrest often develop organ dysfunction caused by systemic inflammation and increased coagulation, leading to disseminated intravascular coagulation (DIC). The involvement of histones in DIC and organ dysfunction in patients with sepsis and trauma has been previously reported, raising the probability that histones may also be associated with pathophysiology in patients after cardiac arrest and resuscitation. This study evaluated the relationship between histones and organ dysfunction related to coagulofibrinolytic changes in patients with post-cardiac arrest syndrome (PCAS).MethodsThis prospective single-center observational study assessed 35 adult patients with PCAS who were divided into two groups, i.e., 15 patients with multiple organ dysfunction syndrome (MODS) and 20 patients without MODS. MODS was defined as a sequential organ failure assessment score of ≥12. The plasma levels of histones and coagulofibrinolytic markers, including soluble fibrin, tissue-type plasminogen activator, plasminogen activator inhibitor-1, plasmin-alpha 2-plasmin inhibitor complex (PIC), and soluble thrombomodulin, were measured in patients with PCAS immediately after admission to the emergency department, and 3 and 24 h after arriving at the hospital.ResultsPCAS patients with MODS had higher DIC scores [4 (3.0–5.0) vs. 1 (0.0–3.0), p = 0.012] and higher mortality rates (66.7% vs. 20.0%, p = 0.013) than those without MODS. Moreover, patients with MODS exhibited higher histone levels than those without MODS during the early phase of the post-resuscitation period. Severe endothelial injury and higher thrombin and plasmin generation were observed in the MODS group. Plasma levels of histones were positively correlated with those of soluble fibrin immediately after resuscitation (rho = 0.367, p = 0.030) and PIC 3 h after arriving at the hospital (rho = 0.480, p = 0.005). This correlation was prominent in the patient population with MODS (soluble fibrin: rho = 0.681, p = 0.005, PIC: rho = 0.742, p = 0.002).ConclusionsThis study demonstrated that elevated histone levels were associated with increased levels of thrombin, and subsequent plasmin generation in PCAS patients, especially those with MODS. Further studies are required to elucidate the causal relationship between histones and organ dysfunction related to DIC in PCAS.

Abstract Trauma patients die from massive bleeding due to disseminated intravascular coagulation (DIC) with a fibrinolytic phenotype in the early phase, which transforms to DIC with a thrombotic phenotype in the late phase of trauma, contributing to the development of multiple organ dysfunction syndrome (MODS) and a consequently poor outcome. This is a sub-analysis of a multicenter prospective descriptive cross-sectional study on DIC to evaluate the effect of a DIC diagnosis on the survival probability and predictive performance of DIC scores for massive transfusion, MODS, and hospital death in severely injured trauma patients. A DIC diagnosis on admission was associated with a lower survival probability (Log Rank P

Abstract Background Information on hyperoxemia among patients with trauma has been limited, other than traumatic brain injuries. This study aimed to elucidate whether hyperoxemia during resuscitation of patients with trauma was associated with unfavorable outcomes. Methods A post hoc analysis of a prospective observational study was carried out at 39 tertiary hospitals in 2016–2018 in adult patients with trauma and injury severity score (ISS) of > 15. Hyperoxemia during resuscitation was defined as PaO2 of ≥ 300 mmHg on hospital arrival and/or 3 h after arrival. Intensive care unit (ICU)-free days were compared between patients with and without hyperoxemia. An inverse probability of treatment weighting (IPW) analysis was conducted to adjust patient characteristics including age, injury mechanism, comorbidities, vital signs on presentation, chest injury severity, and ISS. Analyses were stratified with intubation status at the emergency department (ED). The association between biomarkers and ICU length of stay were then analyzed with multivariate models. Results Among 295 severely injured trauma patients registered, 240 were eligible for analysis. Patients in the hyperoxemia group (n = 58) had shorter ICU-free days than those in the non-hyperoxemia group [17 (10–21) vs 23 (16–26), p < 0.001]. IPW analysis revealed the association between hyperoxemia and prolonged ICU stay among patients not intubated at the ED [ICU-free days = 16 (12–22) vs 23 (19–26), p = 0.004], but not among those intubated at the ED [18 (9–20) vs 15 (8–23), p = 0.777]. In the hyperoxemia group, high inflammatory markers such as soluble RAGE and HMGB-1, as well as low lung-protective proteins such as surfactant protein D and Clara cell secretory protein, were associated with prolonged ICU stay. Conclusions Hyperoxemia until 3 h after hospital arrival was associated with prolonged ICU stay among severely injured trauma patients not intubated at the ED. Trial registration UMIN-CTR, UMIN000019588 . Registered on November 15, 2015.

Abstract Previous studies have shown inconsistent prognostic accuracy for mortality with both quick sequential organ failure assessment (qSOFA) and the systemic inflammatory response syndrome (SIRS) criteria. We aimed to validate the accuracy of qSOFA and the SIRS criteria for predicting in-hospital mortality in patients with suspected infection in the emergency department. A prospective study was conducted including participants with suspected infection who were hospitalised or died in 34 emergency departments in Japan. Prognostic accuracy of qSOFA and SIRS criteria for in-hospital mortality was assessed by the area under the receiver operating characteristic (AUROC) curve. Of the 1060 participants, 402 (37.9%) and 915 (86.3%) had qSOFA ≥ 2 and SIRS criteria ≥ 2 (given thresholds), respectively, and there were 157 (14.8%) in-hospital deaths. Greater accuracy for in-hospital mortality was shown with qSOFA than with the SIRS criteria (AUROC: 0.64 versus 0.52, difference + 0.13, 95% CI [+ 0.07, + 0.18]). Sensitivity and specificity for predicting in-hospital mortality at the given thresholds were 0.55 and 0.65 based on qSOFA and 0.88 and 0.14 based on SIRS criteria, respectively. To predict in-hospital mortality in patients visiting to the emergency department with suspected infection, qSOFA was demonstrated to be modestly more accurate than the SIRS criteria albeit insufficiently sensitive. Clinical Trial Registration: The study was pre-registered in the University Hospital Medical Information Network Clinical Trials Registry (UMIN000027258).

Background: There is no one-size-fits-all empiric antimicrobial therapy for sepsis because the pathogens vary according to the site of infection and have changed over time. Therefore, updating knowledge on the spectrum of pathogens is necessary for the rapid administration of appropriate antimicrobials. Objective: The aim of this study was to elucidate the current spectrum of pathogens and its variation by site of infection in sepsis. Methods: This was a prospective nationwide cohort study of consecutive adult patients with sepsis in 59 intensive care units in Japan. The spectrum of pathogens was evaluated in all patients and in subgroups by site of infection. Regression analyses were conducted to evaluate the associations between the pathogens and mortality. Results: The study cohort comprised 1184 patients. The most common pathogen was Escherichia coli (21.5%), followed by Klebsiella pneumoniae (9.0%). However, the pattern varied widely by site of infection; for example, gram-positive bacteria were the dominant pathogen in bone/soft tissue infection (55.7%) and cardiovascular infection (52.6%), but were rarely identified in urinary tract infection (6.4%). In contrast, gram-negative bacteria were the predominant pathogens in abdominal infection (38.4%) and urinary tract infection (72.0%). The highest mortality of 47.5% was observed in patients infected with methicillin-resistant Staphylococcus aureus, which was significantly associated with an increased risk of death (odds ratio 1.88, 95% confidence interval 1.22–2.91). Conclusions: This study revealed the current spectrum of pathogens and its variation based on the site of infection, which is essential for empiric antimicrobial therapy against sepsis.

Abstract Current research regarding the association between body mass index (BMI) and altered clinical outcomes of sepsis in Asian populations is insufficient. We investigated the association between BMI and clinical outcomes using two Japanese cohorts of severe sepsis (derivation cohort, Chiba University Hospital, n = 614; validation cohort, multicenter cohort, n = 1561). Participants were categorized into the underweight (BMI

Abstract Background Frailty is associated with morbidity and mortality in patients admitted to intensive care units (ICUs). However, the characteristics of frail patients with suspected infection remain unclear. We aimed to investigate the characteristics and outcomes of frail patients with suspected infection in ICUs. Methods This is a secondary analysis of a multicenter cohort study, including 22 ICUs in Japan. Adult patients (aged ≥16 years) with newly suspected infection from December 2017 to May 2018 were included. We compared baseline patient characteristics and outcomes among three frailty groups based on the Clinical Frailty Scale (CFS) score: fit (score, 1–3), vulnerable (score, 4), and frail (score, 5–9). We conducted subgroup analysis of patients with sepsis defined as per Sepsis-3 criteria. We also produced Kaplan–Meier survival curves for 90-day survival. Results We enrolled 650 patients with suspected infection, including 599 (92.2%) patients with sepsis. Patients with a median CFS score of 3 (interquartile range [IQR] 3–5) were included: 337 (51.8%) were fit, 109 (16.8%) were vulnerable, and 204 (31.4%) were frail. The median patient age was 72 years (IQR 60–81). The Sequential Organ Failure Assessment scores for fit, vulnerable, and frail patients were 7 (IQR 4–10), 8 (IQR 5–11), and 7 (IQR 5–10), respectively (p = 0.59). The median body temperatures of fit, vulnerable, and frail patients were 37.5 °C (IQR 36.5 °C–38.5 °C), 37.5 °C (IQR 36.4 °C–38.6 °C), and 37.0 °C (IQR 36.3 °C–38.1 °C), respectively (p

Abstract Background Elderly patients have a blunted host response, which may influence vital signs and clinical outcomes of sepsis. This study was aimed to investigate whether the associations between the vital signs and mortality are different in elderly and non-elderly patients with sepsis. Methods This was a retrospective observational study. A Japanese multicenter sepsis cohort (FORECAST, n = 1148) was used for the discovery analyses. Significant discovery results were tested for replication using two validation cohorts of sepsis (JAAMSR, Japan, n = 624; SPH, Canada, n = 1004). Patients were categorized into elderly and non-elderly groups (age ≥ 75 or

Abstract Background Diagnosing sepsis remains difficult because it is not a single disease but a syndrome with various pathogen- and host factor-associated symptoms. Sepsis-3 was established to improve risk stratification among patients with infection based on organ failures, but it has been still controversial compared with previous definitions. Therefore, we aimed to describe characteristics of patients who met sepsis-2 (severe sepsis) and sepsis-3 definitions. Methods This was a multicenter, prospective cohort study conducted by 22 intensive care units (ICUs) in Japan. Adult patients (≥ 16 years) with newly suspected infection from December 2017 to May 2018 were included. Those without infection at final diagnosis were excluded. Patient’s characteristics and outcomes were described according to whether they met each definition or not. Results In total, 618 patients with suspected infection were admitted to 22 ICUs during the study, of whom 530 (85.8%) met the sepsis-2 definition and 569 (92.1%) met the sepsis-3 definition. The two groups comprised different individuals, and 501 (81.1%) patients met both definitions. In-hospital mortality of study population was 19.1%. In-hospital mortality among patients with sepsis-2 and sepsis-3 patients was comparable (21.7% and 19.8%, respectively). Patients exclusively identified with sepsis-2 or sepsis-3 had a lower mortality (17.2% vs. 4.4%, respectively). No patients died if they did not meet any definitions. Patients who met sepsis-3 shock definition had higher in-hospital mortality than those who met sepsis-2 shock definition. Conclusions Most patients with infection admitted to ICU meet sepsis-2 and sepsis-3 criteria. However, in-hospital mortality did not occur if patients did not meet any criteria. Better criteria might be developed by better selection and combination of elements in both definitions. Trial registration UMIN000027452

Abstract Background Predisposing conditions and risk modifiers instead of causes and risk factors have recently been used as alternatives to identify patients at a risk of acute respiratory distress syndrome (ARDS). However, data regarding risk modifiers among patients with non-pulmonary sepsis is rare. Methods We conducted a secondary analysis of the multicenter, prospective, Focused Outcomes Research in Emergency Care in Acute Respiratory Distress Syndrome, Sepsis and Trauma (FORECAST) cohort study that was conducted in 59 intensive care units (ICUs) in Japan during January 2016–March 2017. Adult patients with severe sepsis caused by non-pulmonary infection were included, and the primary outcome was having ARDS, defined as meeting the Berlin definition on the first or fourth day of screening. Multivariate logistic regression modeling was used to identify risk modifiers associated with ARDS, and odds ratios (ORs) and their 95% confidence intervals were reported. The following explanatory variables were then assessed: age, sex, admission source, body mass index, smoking status, congestive heart failure, chronic obstructive pulmonary disease, diabetes mellitus, steroid use, statin use, infection site, septic shock, and acute physiology and chronic health evaluation (APACHE) II score. Results After applying inclusion and exclusion criteria, 594 patients with non-pulmonary sepsis were enrolled, among whom 85 (14.3%) had ARDS. Septic shock was diagnosed in 80% of patients with ARDS and 66% of those without ARDS (p = 0.01). APACHE II scores were higher in patients with ARDS [26 (22–33)] than in those without ARDS [21 (16–28), p < 0.01]. In the multivariate logistic regression model, the following were independently associated with ARDS: ICU admission source [OR, 1.89 (1.06–3.40) for emergency department compared with hospital wards], smoking status [OR, 0.18 (0.06–0.59) for current smoking compared with never smoked], infection site [OR, 2.39 (1.04–5.40) for soft tissue infection compared with abdominal infection], and APACHE II score [OR, 1.08 (1.05–1.12) for higher compared with lower score]. Conclusions Soft tissue infection, ICU admission from an emergency department, and a higher APACHE II score appear to be the risk modifiers of ARDS in patients with non-pulmonary sepsis.

Anti-glomerular basement membrane disease (anti-GBM disease) associated with renal and lung lesions has a poor prognosis. Diffuse alveolar hemorrhage (DAH) is a complication that worsens anti-GBM disease prognosis. We report a rescue case using veno-venous extracorporeal membrane oxygenation (VV-ECMO) for diffuse alveolar hemorrhage due to isolated pulmonary anti-GBM disease; a rare anti-GBM syndrome. A 30-year-old Japanese female with no past medical history. Presented with acute hypoxemic respiratory failure requiring mechanical ventilation. Progressive deterioration and refractory hypoxemia prompted therapy with VV-ECMO. Serum anti-GBM antibody confirmed the diagnosis of anti-GBM disease. Multi-modal systemic therapy with pulse-dosed methylprednisolone, plasma exchange, and rituximab resulted in significant clinical improvement. VV-ECMO for 10 days was uncomplicated. Renal replacement therapy was not required. The patient was extubated on day 18 and discharged from the hospital after 45 days. VV-ECMO supportive therapy for DAH with refractory respiratory failure was demonstrated to be effective pending definitive diagnostic and therapeutic management in this case of isolated pulmonary anti-GBM disease.

Background The updated Surviving Sepsis Campaign guidelines recommend a 1-hour window for completion of a sepsis care bundle; however, the effectiveness of the hour-1 bundle has not been fully evaluated. The present study aimed to evaluate the impact of hour-1 bundle completion on clinical outcomes in sepsis patients. Methods This was a multicenter, prospective, observational study conducted in 17 intensive care units in tertiary hospitals in Japan. We included all adult patients who were diagnosed as having sepsis by Sepsis-3 and admitted to intensive care units from July 2019 to August 2020. Impacts of hour-1 bundle adherence and delay of adherence on risk-adjusted in-hospital mortality were estimated by multivariable logistic regression analyses. Results The final study cohort included 178 patients with sepsis. Among them, 89 received bundle-adherent care. Completion rates of each component (measure lactate level, obtain blood cultures, administer broad-spectrum antibiotics, administer crystalloid, apply vasopressors) within 1 hour were 98.9%, 86.2%, 51.1%, 94.9%, and 69.1%, respectively. Completion rate of all components within 1 hour was 50%. In-hospital mortality was 18.0% in the patients with and 30.3% in the patients without bundle-adherent care (p = 0.054). The adjusted odds ratio of non-bundle-adherent versus bundle-adherent care for in-hospital mortality was 2.32 (95% CI 1.09–4.95) using propensity scoring. Non-adherence to obtaining blood cultures and administering broad-spectrum antibiotics within 1 hour was related to in-hospital mortality (2.65 [95% CI 1.25–5.62] and 4.81 [95% CI 1.38–16.72], respectively). The adjusted odds ratio for 1-hour delay in achieving hour-1 bundle components for in-hospital mortality was 1.28 (95% CI 1.04–1.57) by logistic regression analysis. Conclusion Completion of the hour-1 bundle was associated with lower in-hospital mortality. Obtaining blood cultures and administering antibiotics within 1 hour may have been the components most contributing to decreased in-hospital mortality.

Background: Traumatic brain injury (TBI)-associated coagulopathy is a widely recognized risk factor for secondary brain damage and contributes to poor clinical outcomes. Various theories, including disseminated intravascular coagulation (DIC), have been proposed regarding its pathomechanisms; no consensus has been reached thus far. This study aimed to elucidate the pathophysiology of TBI-induced coagulopathy by comparing coagulofibrinolytic changes in isolated TBI (iTBI) to those in non-TBI, to determine the associated factors, and identify the clinical significance of DIC diagnosis in patients with iTBI.Methods: This secondary multicenter, prospective study assessed patients with severe trauma. iTBI was defined as Abbreviated Injury Scale (AIS) scores ≥4 in the head and neck, and ≤2 in other body parts. Non-TBI was defined as AIS scores ≥4 in single body parts other than the head and neck, and the absence of AIS scores ≥3 in any other trauma-affected parts. Specific biomarkers for thrombin and plasmin generation, anticoagulation, and fibrinolysis inhibition were measured at the presentation to the emergency department (0 h) and 3 h after arrival.Results: We analyzed 34 iTBI and 40 non-TBI patients. Baseline characteristics, transfusion requirements and in-hospital mortality did not significantly differ between groups. The changes in coagulation/fibrinolysis-related biomarkers were similar. Lactate levels in the iTBI group positively correlated with DIC scores (rho = −0.441, p = 0.017), but not with blood pressure (rho = −0.098, p = 0.614). Multiple logistic regression analyses revealed that the injury severity score was an independent predictor of DIC development in patients with iTBI (odds ratio = 1.237, p = 0.018). Patients with iTBI were further subdivided into two groups: DIC (n = 15) and non-DIC (n = 19) groups. Marked thrombin and plasmin generation were observed in all patients with iTBI, especially those with DIC. Patients with iTBI and DIC had higher requirements for massive transfusion and emergency surgery, and higher in-hospital mortality than those without DIC. Furthermore, DIC development significantly correlated with poor hospital survival; DIC scores at 0 h were predictive of in-hospital mortality.Conclusions: Coagulofibrinolytic changes in iTBI and non-TBI patients were identical, and consistent with the pathophysiology of DIC. DIC diagnosis in the early phase of TBI is key in predicting the outcomes of severe TBI.

Thromboplasminflammation in coronavirus disease 2019 (COVID-19) coagulopathy consists of angiotensin II (Ang II)-induced coagulopathy, activated factor XII (FXIIa)- and kallikrein, kinin system-enhanced fibrinolysis, and disseminated intravascular coagulation (DIC). All three conditions induce systemic inflammation via each pathomechanism-developed production of inflammatory cytokines. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) downregulates angiotensin-converting enzyme 2, leading to an increase in Ang II levels. Ang II-induced coagulopathy comprising platelet activation, thrombin generation, plasminogen activator inhibitor-1 expression and endothelial injury causes thrombosis via the angiotensin II type 1 receptor. SARS-CoV-2 RNA and neutrophil extracellular trap (NET) DNA activate FXII, resulting in plasmin generation through FXIIa- and kallikrein-mediated plasminogen conversion to plasmin and bradykinin-induced tissue-type plasminogen activator release from the endothelium via the kinin B2 receptor. NETs induce immunothrombosis at the site of infection (lungs), through histone- and DNA-mediated thrombin generation, insufficient anticoagulation control, and inhibition of fibrinolysis. However, if the infection is sufficiently severe, immunothrombosis disseminates into the systemic circulation, and DIC, which is associated with the endothelial injury, occurs. Inflammation, and serine protease networks of coagulation and fibrinolysis, militate each other through complement pathways, which exacerbates three pathologies of COVID-19 coagulopathy. COVID-19 coagulopathy causes microvascular thrombosis and bleeding, resulting in multiple organ dysfunction and death in critically ill patients. Treatment targets for improving the prognosis of COVID-19 coagulopathy include thrombin, plasmin, and inflammation, and SARS-CoV-2 infection. Several drugs are candidates for controlling these conditions; however, further advances are required to establish robust treatments based on a clear understanding of molecular mechanisms of COVID-19 coagulopathy.

Abstract Background Time to antibiotic administration is a key element in sepsis care; however, it is difficult to implement sepsis care bundles. Additionally, sepsis is different from other emergent conditions including acute coronary syndrome, stroke, or trauma. We aimed to describe the association between time to antibiotic administration and outcomes in patients with severe sepsis and septic shock in Japan. Methods This prospective observational study enrolled 1184 adult patients diagnosed with severe sepsis based on the Sepsis-2 criteria and admitted to 59 intensive care units (ICUs) in Japan between January 1, 2016, and March 31, 2017, as the sepsis cohort of the Focused Outcomes Research in Emergency Care in Acute Respiratory Distress Syndrome, Sepsis and Trauma (FORECAST) study. We compared the characteristics and in-hospital mortality of patients administered with antibiotics at varying durations after sepsis recognition, i.e., 0–60, 61–120, 121–180, 181–240, 241–360, and 361–1440 min, and estimated the impact of antibiotic timing on risk-adjusted in-hospital mortality using the generalized estimating equation model (GEE) with an exchangeable, within-group correlation matrix, with “hospital” as the grouping variable. Results Data from 1124 patients in 54 hospitals were used for analyses. Of these, 30.5% and 73.9% received antibiotics within 1 h and 3 h, respectively. Overall, the median time to antibiotic administration was 102 min [interquartile range (IQR), 55–189]. Compared with patients diagnosed in the emergency department [90 min (IQR, 48–164 min)], time to antibiotic administration was shortest in patients diagnosed in ICUs [60 min (39–180 min)] and longest in patients transferred from wards [120 min (62–226)]. Overall crude mortality was 23.4%, where patients in the 0–60 min group had the highest mortality (28.0%) and a risk-adjusted mortality rate [28.7% (95% CI 23.3–34.1%)], whereas those in the 61–120 min group had the lowest mortality (20.2%) and risk-adjusted mortality rates [21.6% (95% CI 16.5–26.6%)]. Differences in mortality were noted only between the 0–60 min and 61–120 min groups. Conclusions We could not find any association between earlier antibiotic administration and reduction in in-hospital mortality in patients with severe sepsis.

Abstract Background Rapid detection, early resuscitation, and appropriate antibiotic use are crucial for sepsis care. Accurate identification of the site of infection may facilitate a timely provision of appropriate care. We aimed to investigate the relationship between misdiagnosis of the site of infection at initial examination and in-hospital mortality. Methods This was a secondary-multicenter prospective cohort study involving 37 emergency departments. Consecutive adult patients with infection from December 2017 to February 2018 were included. Misdiagnosis of the site of infection was defined as a discrepancy between the suspected site of infection at initial examination and that at final diagnosis, including those infections remaining unidentified during hospital admission, whereas correct diagnosis was defined as site concordance. In-hospital mortality was compared between those misdiagnosed and those correctly diagnosed. Results Of 974 patients included in the analysis, 11.6% were misdiagnosed. Patients diagnosed with lung, intra-abdominal, urinary, soft tissue, and CNS infection at the initial examination, 4.2%, 3.8%, 13.6%, 10.9%, and 58.3% respectively, turned out to have an infection at a different site. In-hospital mortality occurred in 15%. In both generalized estimating equation (GEE) and propensity score-matched models, misdiagnosed patients exhibited higher mortality despite adjustment for patient background, site infection, and severity. The adjusted odds ratios (misdiagnosis vs. correct diagnosis) for in-hospital mortality were 2.66 (95% CI, 1.45–4.89) in the GEE model and 3.03 (95% CI, 1.24–7.38) in the propensity score-matched model. The difference in the absolute risk in the GEE model was 0.11 (0.04–0.18). Conclusions Among patients with infection, misdiagnosed site of infection is associated with a > 10% increase in in-hospital mortality.

Abstract Background Accurate and early identification of infection sites might help to drive crucial decisions regarding the treatment of sepsis. We aimed to determine the clinical and etiological features of infection according to sites among patients with severe sepsis in Japan. Methods This secondary analysis of a multicenter, prospective cohort study included 59 intensive care units (ICU) and proceeded between January 2016 and March 2017. The study cohort comprised 1184 adults (≥ 16 years) who were admitted to an ICU with severe sepsis and septic shock diagnosed according to the sepsis-2 criteria. Sites of infection diagnosed by physicians in charge at the time of arrival comprised the lung, abdomen, urinary tract, soft tissue, bloodstream, central nervous system (CNS), and undifferentiated infections. The primary outcome was in-hospital mortality. Results The most common sites of infection were the lungs (31.0%), followed by intra-abdominal sites (26.3%), the urinary tract (18.4%), and soft tissue (10.9%). The characteristics of the patients with severe sepsis across seven major suspected infection sites were heterogeneous. Septic shock was more frequent among patients with intra-abdominal (72.2%) and urinary tract (70.2%) infections than other sites. The in-hospital mortality rate due to severe sepsis and septic shock of a pooled sample was 23.4% (range, 11.9% [urinary tract infection] to 47.6% [CNS infection]). After adjusting for clinical background, sepsis severity, and stratification according to the presence or absence of shock, variations in hospital mortality across seven major sites of infection remained essentially unchanged from those for crude in-hospital mortality; adjusted in-hospital mortality rates ranged from 7.7% (95%CI, − 0.3 to 15.8) for urinary tract infection without shock to 58.3% (95%CI, 21.0–95.7) for CNS infection with shock in a generalized estimating equation model. Intra-abdominal and urinary tract infections were statistically associated with less in-hospital mortality than pneumonia. Infections of the CNS were statistically associated with higher in-hospital mortality rates than pneumonia in a logistic regression model, but not in the generalized estimating equation model. Conclusions In-hospital mortality and clinical features of patients with severe sepsis and septic shock were heterogeneous according to sites of infection.

Trauma-induced coagulopathy is classified into primary and secondary coagulopathy, with the former elicited by trauma and traumatic shock itself and the latter being acquired coagulopathy induced by anemia, hypothermia, acidosis, and dilution. Primary coagulopathy consists of disseminated intravascular coagulation and acute coagulopathy of trauma shock (ACOTS). The pathophysiology of ACOTS is the suppression of thrombin generation and neutralization of plasminogen activator inhibitor-1 mediated by activated protein C that leads to hypocoagulation and hyperfibrinolysis in the circulation. This review tried to clarify the validity of activated protein C hypothesis that constitutes the main pathophysiology of the ACOTS in experimental trauma models. Keywords: Activated protein C, Coagulopathy, Disseminated intravascular coagulation, Thrombin, Trauma

Background: In recent years, the use of veno-arterial extracorporeal membrane oxygenation (VA-ECMO) in patients with cardiopulmonary arrest who do not respond to conventional resuscitation, has increased. However, despite the development of VA-ECMO, the outcomes of resuscitated patients remain poor. The poor prognosis may be attributed to deterioration owing to the post-cardiac arrest syndrome (PCAS); this includes the systemic inflammatory response and coagulation activation caused by the extracorporeal circulation (VA-ECMO circuit) itself. This study aimed to evaluate the coagulofibrinolytic changes caused by VA-ECMO and to identify predictive factors of poor prognosis.Methods: We analyzed 151 cases of PCAS with witnessed cardiac arrest. As biomarkers, platelet counts, prothrombin time ratio, fibrin/fibrinogen degradation products, fibrinogen, antithrombin, and lactate were recorded from blood samples from the time of delivery to the third day of hospitalization. The maximum (max) and minimum (min) values of each factor during the study period were calculated. To evaluate the impact of VA-ECMO on patients with PCAS, we performed propensity score matching between the patients who received and did not receive VA-ECMO. Sub-analysis was performed for the group with VA-ECMO.Results: There were significant differences in all baseline characteristics and demographics except the time from detection to hospital arrival, percentage of cardiopulmonary resuscitations (CPR) by witnesses, and the initial rhythm between the groups. Propensity score matching adjusted for prehospital factors demonstrated that the patients who received VA-ECMO developed significantly severe coagulation disorders. In a sub-analysis, significant differences were noted in the prothrombin time ratio min, fibrinogen max, antithrombin max, and lactate min between survivors and non-survivors. In particular, the prothrombin time ratio min and antithrombin max were strongly correlated with poor outcome.Conclusion: In the present study, significant coagulopathy was observed in patients who received VA-ECMO for CPR. In particular, in patients receiving VA-ECMO, the minimum prothrombin time ratio and maximum antithrombin by day 3 of hospitalization were strongly correlated with poor outcomes. These results suggest that VA-ECMO-induced coagulopathy can be a promising therapeutic target for patients resuscitated by VA-ECMO.

This study aimed to assess the value of quick sequential organ failure assessment (qSOFA) combined with other risk factors in predicting in-hospital mortality in patients presenting to the emergency department with suspected infection. This post-hoc analysis of a prospective multicenter study dataset included 34 emergency departments across Japan (December 2017 to February 2018). We included adult patients (age ≥16 years) who presented to the emergency department with suspected infection. qSOFA was calculated and recorded by senior emergency physicians when they suspected an infection. Different types of sepsis-related risk factors (demographic, functional, and laboratory values) were chosen from prior studies. A logistic regression model was used to assess the predictive value of qSOFA for in-hospital mortality in models based on the following combination of predictors: 1) qSOFA-Only; 2) qSOFA+Age; 3) qSOFA+Clinical Frailty Scale (CFS); 4) qSOFA+Charlson Comorbidity Index (CCI); 5) qSOFA+lactate levels; 6) qSOFA+Age+CCI+CFS+lactate levels. We calculated the area under the receiver operating characteristic curve (AUC) and other key clinical statistics at Youden's index, where the sum of sensitivity and specificity is maximized. Following prior literature, an AUC >0.9 was deemed to indicate high accuracy; 0.7-0.9, moderate accuracy; 0.5-0.7, low accuracy; and 0.5, a chance result. Of the 951 patients included in the analysis, 151 (15.9%) died during hospitalization. The AUC for predicting in-hospital mortality was 0.627 (95% confidence interval [CI]: 0.580-0.673) for the qSOFA-Only model. Addition of other variables only marginally improved the model's AUC; the model that included all potentially relevant variables yielded an AUC of only 0.730 (95% CI: 0.687-0.774). Other key statistic values were similar among all models, with sensitivity and specificity of 0.55-0.65 and 0.60-0.75, respectively. In this post-hoc data analysis from a prospective multicenter study based in Japan, combining qSOFA with other sepsis-related risk factors only marginally improved the model's predictive value.

BACKGROUND:Dysglycemia is frequently observed in patients with sepsis. However, the relationship between dysglycemia and outcome is inconsistent. We evaluate the clinical characteristics, glycemic abnormalities, and the relationship between the initial glucose level and mortality in patients with sepsis. METHODS:This is a retrospective sub-analysis of a multicenter, prospective cohort study. Adult patients with severe sepsis (Sepsis-2) were divided into groups based on blood glucose categories (

Abstract Background Sepsis is a leading cause of death and long-term disability in developed countries. A comprehensive report on the incidence, clinical characteristics, and evolving management of sepsis is important. Thus, this study aimed to evaluate the characteristics, management, and outcomes of patients with severe sepsis in Japan. Methods This is a cohort study of the Focused Outcomes Research in Emergency Care in Acute Respiratory Distress Syndrome, Sepsis, and Trauma (FORECAST) study, which was a multicenter, prospective cohort study conducted at 59 intensive care units (ICUs) from January 2016 to March 2017. We included adult patients with severe sepsis based on the sepsis-2 criteria. Results In total, 1184 patients (median age 73 years, interquartile range (IQR) 64–81) with severe sepsis were admitted to the ICU during the study period. The most common comorbidity was diabetes mellitus (23%). Moreover, approximately 63% of patients had septic shock. The median Sepsis-related Organ Failure Assessment (SOFA) score was 9 (IQR 6–11). The most common site of infection was the lung (31%). Approximately 54% of the participants had positive blood cultures. The compliance rates for the entire 3-h bundle, measurement of central venous pressure, and assessment of central venous oxygen saturation were 64%, 26%, and 7%, respectively. A multilevel logistic regression model showed that closed ICUs and non-university hospitals were more compliant with the entire 3-h bundle. The in-hospital mortality rate of patients with severe sepsis was 23% (21–26%). Older age, multiple comorbidities, suspected site of infection, and increasing SOFA scores correlated with in-hospital mortality, based on the generalized estimating equation model. The length of hospital stay was 24 (12–46) days. Approximately 37% of the patients were discharged home after recovery. Conclusion Our prospective study showed that sepsis management in Japan was characterized by a high compliance rate for the 3-h bundle and low compliance rate for central venous catheter measurements. The in-hospital mortality rate in Japan was comparable to that of other developed countries. Only one third of the patients were discharged home, considering the aging population with multiple comorbidities in the ICUs in Japan. Trial registration UMIN-CTR, UMIN000019742. Registered on 16 November 2015.

Abstract Background The pathophysiological mechanisms of acute coagulopathy of trauma-shock (ACOTS) are reported to include activated protein C-mediated suppression of thrombin generation via the proteolytic inactivation of activated Factor V (FVa) and FVIIIa; an increased fibrinolysis via neutralization of plasminogen activator inhibitor-1 (PAI-1) by activated protein C. The aims of this study are to review the evidences for the role of activated protein C in thrombin generation and fibrinolysis and to validate the diagnosis of ACOTS based on the activated protein C dynamics. Methods We conducted systematic literature search (2007–2017) using PubMed, the Cochrane Database of Systematic Reviews (CDSR), and the Cochrane Central Register of Controlled Trials (CENTRAL). Clinical studies on trauma that measured activated protein C or the circulating levels of activated protein C-related coagulation and fibrinolysis markers were included in our study. Results Out of 7613 studies, 17 clinical studies met the inclusion criteria. The levels of activated protein C in ACOTS were inconsistently decreased, showed no change, or were increased in comparison to the control groups. Irrespective of the activated protein C levels, thrombin generation was always preserved or highly elevated. There was no report on the activated protein C-mediated neutralization of PAI-1 with increased fibrinolysis. No included studies used unified diagnostic criteria to diagnose ACOTS and those studies also used different terms to refer to the condition known as ACOTS. Conclusions None of the studies showed direct cause and effect relationships between activated protein C and the suppression of coagulation and increased fibrinolysis. No definitive diagnostic criteria or unified terminology have been established for ACOTS based on the activated protein C dynamics.

Abstract Background No single anticoagulant has been proven effective for sepsis-associated disseminated intravascular coagulation (DIC). Thus, the concomitant use of antithrombin concentrate and recombinant thrombomodulin has been conceived. This observational study was conducted to investigate the efficacy and safety of this combination therapy. Methods A total of 510 septic DIC patients who received antithrombin substitution were retrospectively analyzed. Among them, 228 were treated with antithrombin and recombinant thrombomodulin (combination therapy) and the rest were treated with antithrombin alone (monotherapy). Propensity score matching created 129 matched pairs, and 28-day all-cause mortality, DIC scores, the sequential organ failure assessment (SOFA) scores, and the incidence of bleeding were compared. Results A log-rank test revealed a significant association between combination therapy and a lower 28-day mortality rate (hazard ratio 0.49, 95% confidence interval 0.29–0.82, P = 0.006) in the matched pairs. The DIC scores and the SOFA scores in the combination therapy group were significantly lower than those in the monotherapy group on Day 4 and Day 7. The incidence of bleeding did not differ between the groups (2.11 vs. 2.31%, P = 1.000). Conclusions The current study demonstrated the potential benefit of adding recombinant thrombomodulin to antithrombin. The co-administration of these two anticoagulants was associated with reduced mortality among patients with sepsis-induced DIC without increasing the risk of bleeding.

Case. We report a case of severe methemoglobinemia due to sodium nitrite poisoning. A 28-year-old man was brought to our emergency department because of transient loss of consciousness and cyanosis. He was immediately intubated and ventilated with 100% oxygen. A blood test revealed a methemoglobin level of 92.5%. Outcome. We treated the patient with gastric lavage, activated charcoal, and methylene blue (2 mg/kg) administered intravenously. Soon after receiving methylene blue, his cyanosis resolved and the methemoglobin level began to decrease. After relocation to the intensive care unit, his consciousness improved and he could recall ingesting approximately 15 g sodium nitrite about 1 hour before he was brought to our hospital. The patient was discharged on day 7 without neurologic impairment. Conclusion. Severe methemoglobinemia may be fatal. Therefore, accurate diagnosis of methemoglobinemia is very important so that treatment can be started as soon as possible.