Significance of body temperature in elderly patients with sepsis.

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 < 75 years). We tested for association between vital signs (body temperature [BT], heart rate, mean arterial pressure, systolic blood pressure, and respiratory rate) and 90-day in-hospital mortality (primary outcome). RESULTS: In the discovery cohort, non-elderly patients with BT < 36.0 °C had significantly increased 90-day mortality (P = 0.025, adjusted hazard ratio 1.70, 95% CI 1.07-2.71). In the validation cohorts, non-elderly patients with BT < 36.0 °C had significantly increased mortality (JAAMSR, P = 0.0024, adjusted hazard ratio 2.05, 95% CI 1.29-3.26; SPH, P = 0.029, adjusted hazard ratio 1.36, 95% CI 1.03-1.80). These differences were not observed in elderly patients in the three cohorts. Associations between the other four vital signs and mortality were not different in elderly and non-elderly patients. The interaction of age and hypothermia/fever was significant (P < 0.05). CONCLUSIONS: In septic patients, we found mortality in non-elderly sepsis patients was increased with hypothermia and decreased with fever. However, mortality in elderly patients was not associated with BT. These results illuminate the difference in the inflammatory response of the elderly compared to non-elderly sepsis patients.

Newly Proposed Sepsis-Induced Coagulopathy Precedes International Society on Thrombosis and Haemostasis Overt-Disseminated Intravascular Coagulation and Predicts High Mortality.

BACKGROUND: Disseminated intravascular coagulation (DIC) has been recognized as an urgent and critical condition in patients with sepsis. Therefore, unfamiliar and time-consuming tests or a complex scoring system are not suitable for diagnosis. Sepsis-induced coagulopathy (SIC), a newly proposed category delineated by a few global coagulation tests, has been established as an early warning sign for DIC. The purpose of this study was to elucidate the characteristics of SIC, especially in relation to the score of the International Society on Thrombosis and Haemostasis (ISTH) for overt DIC. METHOD: A data set for 332 patients with sepsis who were suspected to have DIC, antithrombin activity <70%, and treated with antithrombin substitution was utilized to examine the relationship between SIC and overt DIC. The performance of SIC calculated at baseline (ie, before treatment) as well as on days 2, 4, or 7 was analyzed in terms of its ability to predict 28-day mortality and overt DIC. RESULTS: At baseline, 149 (98.7%) of 151 patients with overt DIC according to the ISTH definition were diagnosed as having SIC. Of the 49, 46 (93.9%) patients who developed overt DIC between days 2 and 4 had received a prior diagnosis of SIC. The sensitivity of baseline SIC for the prediction of death was significantly higher than that of overt DIC (86.8% vs 64.5%, P < .001). The sensitivity of SIC on days 2, 4, and 7 was significantly higher than those of overt DIC (96.1%, 92.3%, and 84.4% vs 67.1%, 57.7%, and 50.0%, P < .001, .001, and .001, respectively), although the specificity of SIC was lower at all time points.

Complementary Role of Hypothermia Identification to the Quick Sequential Organ Failure Assessment Score in Predicting Patients With Sepsis at High Risk of Mortality: A Retrospective Analysis From a Multicenter, Observational Study.

BACKGROUND: Although the quick Sequential Organ Failure Assessment (qSOFA) has been recommended for identifying patients at higher risk of hospital death, it has only a 60% sensitivity for in-hospital mortality. On the other hand, hypothermia associates with increased mortality and organ failure in patients with sepsis. This study aimed to assess the predictive validity of qSOFA for identifying patients with sepsis at higher risk of multiple organ dysfunction or death and the complementary effect of hypothermia. METHODS: Patients with severe sepsis admitted to intensive care units (ICUs) were retrospectively analyzed. The predictive validities of qSOFA (≥2, positive) and the complementary effect of hypothermia (body temperature ≤36.5°C) for the identification of death or multiorgan dysfunction were evaluated. RESULTS: Of the 624 patients, 230 (36.9%) developed multiorgan dysfunction and 144 (23.1%) died within 28 days; 527 (84.5%) had a positive qSOFA. The 28-day mortality rates of patients with positive and negative qSOFA were 25.4% and 10.3%, respectively (P = .001). The rate of positive qSOFA was higher in patients with multiorgan dysfunction (sensitivity, 0.896; specificity, 0.185) and among patients who died within 28 days (sensitivity, 0.931; specificity, 0.181); 10 (6.9%) of 144 deaths were not identified. In cases of positive qSOFA without hypothermia, positive qSOFA + hypothermia, or negative qSOFA with hypothermia, the predictive value for 28-day mortality improved (sensitivity, 0.979). Among the 144 patients who died, only 3 were not identified. CONCLUSION: A qSOFA score ≥2 may identify >90% of 28-day deaths among patients with severe sepsis; hypothermia may complement the predictive ability of qSOFA.

Characteristics and outcomes of frail patients with suspected infection in intensive care units: a descriptive analysis from a multicenter cohort study.

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 < 0.01). The median C-reactive protein levels of fit, vulnerable, and frail patients were 13.6 (IQR 4.6-24.5), 12.1 (IQR 3.9-24.9), 10.5 (IQR 3.0-21.0) mg/dL, respectively (p < 0.01). In-hospital mortality did not statistically differ among the patients according to frailty (p = 0.19). Kaplan-Meier survival curves showed little difference in the mortality rate during short-term follow-up. However, more vulnerable and frail patients died after 30-day than fit patients; this difference was not statistically significant (p = 0.25). Compared with the fit and vulnerable groups, the rate of home discharge was lower in the frail group. CONCLUSION: Frail and vulnerable patients with suspected infection tend to have poor disease outcomes. However, they did not show a statistically significant increase in the 90-day mortality risk.

Impact of Body Temperature Abnormalities on the Implementation of Sepsis Bundles and Outcomes in Patients With Severe Sepsis: A Retrospective Sub-Analysis of the Focused Outcome Research on Emergency Care for Acute Respiratory Distress Syndrome, Sepsis and Trauma Study.

OBJECTIVES: To investigate the impact of body temperature on disease severity, implementation of sepsis bundles, and outcomes in severe sepsis patients. DESIGN: Retrospective sub-analysis. SETTING: Fifty-nine ICUs in Japan, from January 2016 to March 2017. PATIENTS: Adult patients with severe sepsis based on Sepsis-2 were enrolled and divided into three categories (body temperature < 36°C, 36-38°C, > 38°C), using the core body temperature at ICU admission. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Compliance with the bundles proposed in the Surviving Sepsis Campaign Guidelines 2012, in-hospital mortality, disposition after discharge, and the number of ICU and ventilator-free days were evaluated. Of 1,143 enrolled patients, 127, 565, and 451 were categorized as having body temperature less than 36°C, 36-38°C, and greater than 38°C, respectively. Hypothermia-body temperature less than 36°C-was observed in 11.1% of patients. Patients with hypothermia were significantly older than those with a body temperature of 36-38°C or greater than 38°C and had a lower body mass index and higher prevalence of septic shock than those with body temperature greater than 38°C. Acute Physiology and Chronic Health Evaluation II and Sequential Organ Failure Assessment scores on the day of enrollment were also significantly higher in hypothermia patients. Implementation rates of the entire 3-hour bundle and administration of broad-spectrum antibiotics significantly differed across categories; implementation rates were significantly lower in patients with body temperature less than 36°C than in those with body temperature greater than 38°C. Implementation rate of the entire 3-hour resuscitation bundle + vasopressor use + remeasured lactate significantly differed across categories, as did the in-hospital and 28-day mortality. The odds ratio for in-hospital mortality relative to the reference range of body temperature greater than 38°C was 1.760 (95% CI, 1.134-2.732) in the group with hypothermia. The proportions of ICU-free and ventilator-free days also significantly differed between categories and were significantly smaller in patients with hypothermia. CONCLUSIONS: Hypothermia was associated with a significantly higher disease severity, mortality risk, and lower implementation of sepsis bundles.

In-hospital mortality associated with the misdiagnosis or unidentified site of infection at admission.

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.

Implementation of earlier antibiotic administration in patients with severe sepsis and septic shock in Japan: a descriptive analysis of a prospective observational study.

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.

Prognostic Accuracy of Quick SOFA is different according to the severity of illness in infectious patients.

BACKGROUND: Sepsis-3 proposed the quick Sequential Organ Failure Assessment (qSOFA) to identify sepsis patients likely to have poor outcome. The clinical utility of qSOFA still remains controversial because its predictive accuracy for mortality is quite different across the validation studies. We hypothesized that one of the major causes for these controversial findings was the heterogeneity in severity across the studies, and evaluated the association between severity of illness and the prognostic accuracy of qSOFA. MATERIALS AND METHODS: This was a post hoc analysis of a prospective nationwide cohort of consecutive adult patients with sepsis in 59 intensive care units in Japan. Regression trees analysis for survival was used to classify patients according to severity of illness as determined by SOFA score on registration. We conducted receiver operating characteristic (ROC) analyses and evaluated the differences in the area under the ROC curve (AUROC). As a subgroup analysis, we conducted the above evaluations in emergency department (ED) and non-ED patients separately. RESULTS: We included 1114 patients fulfilling the criteria and classified them into three subsets according to severity. The AUROC for mortality was significantly different according to the severity of illness (p = 0.007), with the highest AUROC being in the low-severity subset (patients with SOFA score ≤ 7). Interestingly, our subgroup analysis revealed that a significant difference in the AUROC of qSOFA was observed only in ED patients. CONCLUSION: This study suggested that lower severity of illness was associated with the relatively higher prognostic accuracy of qSOFA, especially in ED patients.

Effect of a Recombinant Human Soluble Thrombomodulin on Mortality in Patients With Sepsis-Associated Coagulopathy: The SCARLET Randomized Clinical Trial.

Importance: Previous research suggested that soluble human recombinant thrombomodulin may reduce mortality among patients with sepsis-associated coagulopathy. Objective: To determine the effect of human recombinant thrombomodulin vs placebo on 28-day all-cause mortality among patients with sepsis-associated coagulopathy. Design, Setting, and Participants: The SCARLET trial was a randomized, double-blind, placebo-controlled, multinational, multicenter phase 3 study conducted in intensive care units at 159 sites in 26 countries. All adult patients admitted to one of the participating intensive care units between October 2012 and March 2018 with sepsis-associated coagulopathy and concomitant cardiovascular and/or respiratory failure, defined as an international normalized ratio greater than 1.40 without other known etiology and a platelet count in the range of 30 to 150 × 109/L or a greater than 30% decrease in platelet count within 24 hours, were considered for inclusion. The final date of follow-up was February 28, 2019. Interventions: Patients with sepsis-associated coagulopathy were randomized and treated with an intravenous bolus or a 15-minute infusion of thrombomodulin (0.06 mg/kg/d [maximum, 6 mg/d]; n = 395) or matching placebo (n = 405) once daily for 6 days. Main Outcome and Measures: The primary end point was 28-day all-cause mortality. Results: Among 816 randomized patients, 800 (mean age, 60.7 years; 437 [54.6%] men) completed the study and were included in the full analysis set. In these patients, the 28-day all-cause mortality rate was not statistically significantly different between the thrombomodulin group and the placebo group (106 of 395 patients [26.8%] vs 119 of 405 patients [29.4%], respectively; P = .32). The absolute risk difference was 2.55% (95% CI, -3.68% to 8.77%). The incidence of serious major bleeding adverse events (defined as any intracranial hemorrhage; life-threatening bleeding; or bleeding event classified as serious by the investigator, with administration of at least 1440 mL [typically 6 units] of packed red blood cells over 2 consecutive days) was 23 of 396 patients (5.8%) in the thrombomodulin group and 16 of 404 (4.0%) in the placebo group. Conclusions and Relevance: Among patients with sepsis-associated coagulopathy, administration of a human recombinant thrombomodulin, compared with placebo, did not significantly reduce 28-day all-cause mortality. Trial Registration: ClinicalTrials.gov Identifier: NCT01598831.

Activated protein C plays no major roles in the inhibition of coagulation or increased fibrinolysis in acute coagulopathy of trauma-shock: a systematic review.

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.

Characteristics, management, and in-hospital mortality among patients with severe sepsis in intensive care units in Japan: the FORECAST study.

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.

The roles of activated protein C in experimental trauma models.

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.

Disseminated intravascular coagulation with increased fibrinolysis during the early phase of isolated traumatic brain injury.

BACKGROUND: There is evidence to demonstrate that the coagulopathy which occurs in patients with traumatic brain injury coincides with disseminated intravascular coagulation (DIC). We hypothesized that DIC with increased fibrinolysis during the early stage of isolated traumatic brain injury (iTBI) affects the outcome of the patients and that hypoperfusion contributes to hyperfibrinolysis in the DIC. METHODS: This retrospective study included 92 patients with iTBI who were divided into DIC and non-DIC groups according to the Japanese Association Acute Medicine DIC scoring system. The DIC patients were subdivided into those with and without hyperfibrinolysis. The platelet counts and global markers of coagulation and fibrinolysis were measured. Systemic inflammatory response syndrome (SIRS), organ dysfunction (assessed by the Sequential Organ Failure Assessment score), tissue hypoperfusion (assessed by the lactate levels) and the transfusion volume were also evaluated. The outcome measure was all-cause hospital mortality. RESULTS: DIC patients showed consumption coagulopathy, lower antithrombin levels and higher fibrin/fibrinogen degradation products (FDP) and D-dimer levels than non-DIC patients. All of the DIC patients developed SIRS accompanied by organ dysfunction and required higher blood transfusion volumes, leading to a worse outcome than non-DIC patients. These changes were more prominent in DIC with hyperfibrinolysis. A higher FDP/D-dimer ratio suggests that DIC belongs to the fibrinolytic phenotype and involves fibrin(ogen)olysis. The mean blood pressures of the patients with and without DIC on arrival were identical. Hypoperfusion and the lactate levels were not identified as independent predictors of hyperfibrinolysis. CONCLUSIONS: DIC, especially DIC with hyperfibrinolysis, affects the outcome of patients with iTBI. Low blood pressure-induced tissue hypoperfusion does not contribute to hyperfibrinolysis in this type of DIC.

Assessment of mortality by qSOFA in patients with sepsis outside ICU: A post hoc subgroup analysis by the Japanese Association for Acute Medicine Sepsis Registry Study Group.

Quick sequential organ failure assessment (qSOFA) was proposed in the new sepsis definition (Sepsis-3). Although qSOFA was created to identify patients with suspected infection and likely to have poor outcomes, the clinical utility of qSOFA to screen sepsis has not been fully evaluated. We investigated the number of patients diagnosed as having severe sepsis who could not be identified by the qSOFA criteria and what clinical signs could complement the qSOFA score. This retrospective analysis of a multicenter prospective registry included adult patients with severe sepsis diagnosed outside the intensive care unit (ICU) by conventional criteria proposed in 2003. We conducted receiver operating characteristic (ROC) analyses to assess the predictive value for in-hospital mortality and compared clinical characteristics between survivors and non-survivors with qSOFA score ≤ 1 point (qSOFA-negative). Among 387 eligible patients, 63 (16.3%) patients were categorized as qSOFA-negative, and 10 (15.9%) of these patients died. The area under the ROC curve for the qSOFA score was 0.615, which was superior to that for the systemic inflammatory response syndrome score (0.531, P = 0.019) but inferior to that for the SOFA score (0.702, P = 0.005). Multivariate logistic regression analysis showed that hypothermia might be associated with poor outcome independently of qSOFA criteria. Our findings suggested that qSOFA had a suboptimal level of predictive value outside the ICU and could not identify 16.3% of patients who were once actually diagnosed with sepsis. Hypothermia might be associated with an increased risk of death that cannot be identified by qSOFA.

Pathophysiology of Trauma-Induced Coagulopathy and Management of Critical Bleeding Requiring Massive Transfusion.

Trauma-induced coagulopathy is caused by multiple factors, such as anemia, hemodilution, hypothermia, acidosis, shock, and serious trauma itself, which affects patient outcomes due to critical bleeding requiring massive transfusion. Disseminated intravascular coagulation (DIC) with the fibrinolytic phenotype directly caused by trauma and/or traumatic shock has been considered to be the primary pathophysiology of trauma-induced coagulopathy. The key to controlling DIC is vigorous treatment of the underlying disorder, that is, trauma itself and hemorrhagic shock. Damage control resuscitation, consisting of damage control surgery, permissive hypotension, and hemostatic resuscitation, aims to control severe trauma and critical bleeding, which is equivalent to managing the underlying disorder of DIC. At present, however, evidence-based practices for damage control resuscitation are lacking. A robust prospective outcome study for damage control resuscitation that considers DIC with the fibrinolytic phenotype as the main pathological condition of trauma-induced coagulopathy affecting patient outcome is essential for improving therapeutic strategies.

Disseminated intravascular coagulation with the fibrinolytic phenotype predicts the outcome of patients with out-of-hospital cardiac arrest.

BACKGROUND: We tested the hypothesis that disseminated intravascular coagulation (DIC) during the early phase of post-cardiopulmonary resuscitation (CPR) is associated with systemic inflammatory response syndrome (SIRS), multiple organ dysfunction syndrome (MODS) and affects the outcome of out-of-hospital cardiac arrest (OHCA) patients. METHODS: A review of the computer-based medical records of OHCA patients was retrospectively conducted and included 388 patients who were divided into DIC and non-DIC patients based on the Japanese Association for Acute Medicine DIC diagnostic criteria. DIC patients were subdivided into two groups: those with and without hyperfibrinolysis. Pre-hospital factors, platelet count, coagulation and fibrinolysis markers and lactate levels within 24 h after resuscitation were evaluated. The outcome measure was all-cause hospital mortality. RESULTS: DIC patients exhibited lower platelet counts, prolonged prothrombin time, decreased levels of fibrinogen and antithrombin associated with increased fibrinolysis than those without DIC. DIC patients more frequently developed SIRS and MODS, followed by worse outcomes than non-DIC patients. The same changes were observed in DIC patients with hyperfibrinolysis who showed a higher prevalence of MODS, leading to worse outcome than those without hyperfibrinolysis. Logistic regression analyses showed that lactate levels predicted hyperfibrinolysis and DIC is an independent predictor of patient death. Survival probabilities of DIC patients during hospital stay were significantly lower than non-DIC patients. The area under the receiver operating characteristic curve of DIC for the prediction of death was 0.704. CONCLUSIONS: The fibrinolytic phenotype of DIC during the early phase of post-CPR more frequently results in SIRS and MODS, especially in patients with hyperfibrinolysis, and affects the outcome of OHCA patients.

Infection site is predictive of outcome in acute lung injury associated with severe sepsis and septic shock.

BACKGROUND AND OBJECTIVE: Sepsis is a leading cause of acute lung injury (ALI); however, the characteristics and outcome of sepsis-associated ALI are poorly understood. We aimed to elucidate factors that predict patient outcome in sepsis-associated ALI. METHODS: Secondary analysis of a multicenter, prospective, observational study was performed. RESULTS: Among 624 patients with severe sepsis and septic shock, 251 (40.2%) fulfilled the definition of American-European Consensus Conference definition of ALI. All-cause 28-day and in-hospital mortalities were 30.7% and 38.6%, respectively. More than 40% of ALI patients had neurological, cardiovascular and haematological dysfunctions or disseminated intravascular coagulation, all of which were associated with higher mortality. We report a significant correlation between infection site and mortality in patients with ALI, but not in those without ALI. The proportion of ALI was significantly higher in pulmonary sepsis; further, a complication of ALI was associated with higher mortality in sepsis from pulmonary and other sources, but not in abdominal sepsis. Among the other sepsis sites, urinary tract, central nervous system, catheter-related and undetermined foci of infection had worse outcomes when associated with ALI. None of the individual severe sepsis bundles, including fluid resuscitation and early antibiotic administration, correlated with mortality. Compliance with a set of sepsis management bundles was associated with better outcomes. CONCLUSION: In severe sepsis and septic shock, the proportion and effect on outcome was not uniform among infection sites. The infection site was predictive of outcome in patients with ALI but not in those without ALI.

HMGB1 Promotes Intraoral Palatal Wound Healing through RAGE-Dependent Mechanisms.

High mobility group box 1 (HMGB1) is tightly connected to the process of tissue organization upon tissue injury. Here we show that HMGB1 controls epithelium and connective tissue regeneration both in vivo and in vitro during palatal wound healing. Heterozygous HMGB1 (Hmgb1+/-) mice and Wild-type (WT) mice were subjected to palatal injury. Maxillary tissues were stained with Mallory Azan or immunostained with anti-HMGB1, anti-proliferating cell nuclear antigen (PCNA), anti-nuclear factor-κB (NF-κB) p50 and anti-vascular endothelial growth factor (VEGF) antibodies. Palatal gingival explants were cultured with recombinant HMGB1 (rHMGB1) co-treated with siRNA targeting receptor for advanced glycation end products (RAGEs) for cell migration and PCNA expression analysis. Measurement of the wound area showed differences between Hmgb1+/- and WT mice on Day 3 after wounding. Mallory Azan staining showed densely packed of collagen fibers in WT mice, whereas in Hmgb1+/- mice weave-like pattern of low density collagen bundles were present. At three and seven days post-surgery, PCNA, NF-κB p50 and VEGF positive keratinocytes of WT mice were greater than that of Hmgb1+/- mice. Knockdown of RAGE prevents the effect of rHMGB1-induced cell migration and PCNA expression in gingival cell cultures. The data suggest that HMGB1/RAGE axis has crucial roles in palatal wound healing.

[Extracorporeal membrane oxygenation for critically ill adults].

Extracorporeal membrane oxygenation therapy (ECMO) is an artificial life support for severe respiratory and/or cardiac failure, and refractory cardiac arrest. It consists of a hollow-fiber membrane that oxygenates the blood and removes carbon dioxide and a centrifugal pump that drain blood from central venous circulation, pump through membrane, and return to the patients. Veno-venous ECMO provides gas change in hemodynamically stable patients with respiratory failure. Veno-arterial ECMO offers hemodynamic support in addition to gas change for cardiac failure or refractory cardiac arrest. We describe the physiological principles and the clinical evidence supporting the use of ECMO in critically ill adult patients.

Hemostasis and thrombosis in trauma patients.

Hemostasis and thrombosis in trauma patients consist of physiological hemostasis for wound healing and the pathological reaction of disseminated intravascular coagulation (DIC). Whole body trauma, isolated brain injury, and fat embolism syndrome, if extremely severe, can cause DIC and affect a patient's prognosis. Shock-induced hyperfibrinolysis causes DIC with the fibrinolytic phenotype, contributing to oozing-type severe bleeding. If uncontrolled, this phenotype progresses to thrombotic phenotype at the late stage of trauma, followed by microvascular thrombosis, leading to organ dysfunction. Another type of pathological hemostatic change is acute coagulopathy of trauma shock (ACOTS), which gives rise to activated protein C-mediated systemic hypocoagulation, resulting in bleeding. ACOTS occurs only in trauma associated with shock-induced hypoperfusion and there is nothing to suggest DIC in this phenomenon. This review will provide information about the recent advances in hemostasis and thrombosis in trauma and will clarify the pathogeneses of the pathological processes observed in trauma patients.