Net reclassification index in comparison of prognostic value of disseminated intravascular coagulation diagnostic criteria by Japanese Society on Thrombosis and Hemostasis and International Society on Thrombosis and Haemostasis: a multicenter prospective cohort study.

BACKGROUND: We compared the prognostic value of the Japanese Society on Thrombosis and Hemostasis (JSTH) disseminated intravascular coagulation (DIC) diagnostic criteria with that of the International Society on Thrombosis and Haemostasis (ISTH) DIC diagnostic criteria for 28-day in-hospital mortality. METHODS: We conducted a multicenter prospective cohort study involving two hematology departments, four emergency departments, and one general medicine department in Japan between August 2017 and July 2021. We assessed three ISTH DIC diagnostic criteria categories using low cutoff levels of D-dimer (low D-dimer), high cutoff levels of D-dimer (high D-dimer), and fibrinogen/fibrin degradation products (FDP) as fibrin-related markers. The main outcome was diagnosis-based category additive net reclassification index (NRI). RESULTS: A total of 222 patients were included: 82 with hematopoietic disorders, 86 with infections, and 54 with other diseases. The 28-day in-hospital mortality rate was 14% (n = 31). The DIC rates diagnosed by the JSTH, ISTH-low D-dimer, high D-dimer, and FDP DIC diagnosis were 52.7%, 47.3%, 42.8%, and 27.0%, respectively. The overall category additive NRI by JSTH DIC diagnosis vs. ISTH-low D-dimer, high D-dimer, and FDP DIC diagnosis were - 10 (95% confidence interval [CI]: -28 to 8, p = 0.282), - 7.8 (95% CI: -26 to 10, p = 0.401), and - 11 (95% CI: -26 to 3, p = 0.131), respectively. CONCLUSIONS: JSTH criterion showed the highest sensitivity for DIC diagnosis that did not improve but reflected the same prognostic value for mortality evaluated using ISTH DIC diagnosis criteria. This finding may help clinicians to use JSTH DIC criterion as an early intervention strategy in patients with coagulopathy.

Prognostic value of serum high mobility group box 1 protein and histone H3 levels in patients with disseminated intravascular coagulation: a multicenter prospective cohort study.

BACKGROUND: We compared the prognostic value of serum high mobility group box 1 protein (HMGB1) and histone H3 levels with the International Society on Thrombosis and Haemostasis (ISTH) disseminated intravascular coagulation (DIC) scores for 28-day in-hospital mortality in patients with DIC caused by various underlying diseases. METHODS: We conducted a multicenter prospective cohort study including two hematology departments, four emergency departments, and one general medicine department in Japan, between August 2017 and July 2021. We included patients diagnosed with DIC by the ISTH DIC scoring system. RESULTS: Overall, 104 patients were included: 50 with hematopoietic disorders, 41 with infections, and 13 with the other diseases. The 28-day in-hospital mortality rate was 21%. The receiver operator characteristic (ROC) curve showed that a DIC score of 6 points, serum HMGB1 level of 8 ng/mL, and serum histone H3 level of 2 ng/mL were the optimal cutoff points. The odds ratios of more than these optimal cutoff points of the DIC score, serum HMGB1, and histone H3 levels were 1.58 (95% confidence interval [CI]: 0.60 to 4.17, p = 0.36), 5.47 (95% CI: 1.70 to 17.6, p = 0.004), and 9.07 (95% CI: 2.00 to 41.3, p = 0.004), respectively. The area under the ROC curve of HMGB1 (0.74, 95% CI: 0.63 to 0.85) was better than that of the ISTH DIC scores (0.55, 95% CI: 0.43 to 0.67, p = 0.03), whereas that of histone H3 was not (0.71, 95% CI: 0.60 to 0.82, p = 0.07). Calibration and net reclassification plots of HMGB1 identified some high-risk patients, whereas the ISTH DIC scores and histone H3 did not. The category-free net reclassification improvement of HMGB1 was 0.45 (95% CI: 0.01 to 0.90, p = 0.04) and that of histone H3 was 0.37 (95% CI: - 0.05 to 0.78, p = 0.08). CONCLUSIONS: Serum HMGB1 levels have a prognostic value for mortality in patients with DIC. This finding may help physicians develop treatment strategies.

Early recognition of sepsis-induced coagulopathy using the C2PAC index: a ratio of soluble type C lectin-like receptor 2 (sCLEC-2) level and platelet count.

C-type lectin-like receptor 2 (CLEC-2) is a platelet-activated receptor expressed on the surface of platelet membranes. Soluble CLEC-2 (sCLEC-2) has been receiving attention as a predictive marker for thrombotic predisposition. The present study examined the relationship between sCLEC-2 level and degree of coagulation disorder in septic patients. Seventy septic patients were divided into the sepsis-induced disseminated intravascular coagulation (DIC) (SID) group (n = 44) and non-SID group (n = 26). The sCLEC-2 levels were compared between the two groups. Because we suspected that the sCLEC-2 level was affected by the platelet count, we calculated the sCLEC-2/platelet count ratio (C2PAC index). We further divided septic patients into four groups using the Japanese Association for Acute Medicine (JAAM) DIC scoring system (DIC scores: 0-1, 2-3, 4-5, and 6-8). The C2PAC index was significantly higher in the SID group (2.6 ± 1.7) compared with the non-SID group (1.2 ± 0.5) (P < .001). The C2PAC indexes in the four JAAM DIC score groups were 0.9 ± 0.3, 1.1 ± 0.3, 1.7 ± 0.7, and 3.6 ± 1.0, respectively, and this index increased significantly as the DIC score increased (P < .001). According to the receiver-operating curve analysis, the area under the curve (AUC) and optimal cutoff value for the diagnosis of SID were 0.8051 and 1.4 (sensitivity, 75.0%; specificity, 76.9%), respectively. When the C2PAC index and D-dimer level, one of the main fibrinolytic markers, were selected as predictive markers for SID diagnosis in stepwise multiple logistic regression analysis, it was possible to diagnose SID with a high probability (AUC, 0.9528; sensitivity, 0.9545; specificity, 0.8846). The C2PAC index is a useful predictor of SID progression and diagnosis in septic patients.

HMGB1 and its membrane receptors as therapeutic targets in an intravesical substance P-induced bladder pain syndrome mouse model.

HMGB1, a nuclear protein, once released to the extracellular space, promotes somatic and visceral pain signals. We thus analyzed the role of HMGB1 in an intravesical substance P-induced bladder pain syndrome (BPS) mouse model. Intravesical administration of substance P caused referred hyperalgesia/allodynia in the lower abdomen and hindpaw without producing severe urothelial damage, which was prevented by an anti-HMGB1-neutralizing antibody, thrombomodulin α capable of inactivating HMGB1 and antagonists of RAGE or CXCR4. The HMGB1 inactivation or RAGE blockade also reversed the established bladder pain symptoms. HMGB1 and RAGE are thus considered to serve as therapeutic targets for BPS.

New diagnostic strategy for sepsis-induced disseminated intravascular coagulation: a prospective single-center observational study.

INTRODUCTION: Inflammation and coagulation are closely interrelated pathophysiologic processes in the pathogenesis of sepsis. However, the diagnostic criteria of sepsis and disseminated intravascular coagulation (DIC) are different. This study aimed to define a biomarker panel to predict sepsis-induced DIC in emergency department patients. METHODS: Eighty-two patients who were admitted to the emergency department of a tertiary university hospital were included in this study. The inclusion criteria were as follows: (1) age >18 years; (2) ≥1 systemic inflammatory response syndrome (SIRS) criteria. Patients were excluded if they lacked biomarker data or apparent clinical manifestations. Eleven biomarkers were assayed from blood drawn on ED admission. Receiver operating curve (ROC) analysis including the area under the ROC and multivariable logistic regression were used to identify an optimal combination of biomarkers to create a diagnostic panel. The derived formula for weighting biomarker values was used to determine the severity of sepsis-induced DIC, which was divided into three categories: mild, moderate, and severe. We also investigated the ability of this classification to predict secondary outcome measures of rates of sepsis and DIC, DIC score, acute physiology and chronic health evaluation (APACHE) II score, sequential organ failure score (SOFA) score, and 28-day all-cause mortality. RESULTS: Among the 11 biomarkers tested, the optimal 2-marker panel comprised presepsin and protein C. The area under the curve for the accuracies of predicting sepsis and DIC from these two biomarkers were 0.913 and 0.880, respectively. When patients were divided according to the severity of sepsis-induced DIC, all secondary outcomes except for mortality were significantly higher depending on the severity (P < .0001). The overall mortality rates of mild, moderate, and severe sepsis-induced DIC were 7.14%, 15.4%, and 28.6%, respectively (P = .0994). CONCLUSIONS: A biomarker panel of presepsin and protein C is predictive of the severity of sepsis-induced DIC in suspected ED patients. These criteria for sepsis-induced DIC are very simple, easy to implement, and can be used in intensive care units as a point-of-care test.

Presepsin as a powerful monitoring tool for the prognosis and treatment of sepsis: a multicenter prospective study.

Presepsin is a protein whose levels increase specifically in the blood of patients with sepsis. It is proposed as a diagnostic and prognostic marker for assessing the degree of sepsis severity. The present multicenter prospective study compared the clinical utility of presepsin with other conventional sepsis biomarkers including procalcitonin, interleukin-6, and C-reactive protein for evaluating the severity of sepsis during follow-up. Patients with sepsis (n = 103) admitted to the emergency room or intensive care unit were enrolled in this study and classified into 3 diagnostic groups: sepsis, severe sepsis, and septic shock. Blood samples were obtained from each patient on admission and after 1, 3, 5, and 7 days. The patients were further divided into the favorable and unfavorable prognosis groups on the basis of several indicators of sepsis severity (i.e., Sequential Organ Failure Assessment score, and Acute Physiology and Chronic Health Evaluation II score). The patients in the favorable prognosis group exhibited significant decreases in all biomarker levels on days 3 and 7 after admission. In the unfavorable prognosis group, only presepsin levels did not decrease significantly during follow-up. The period of antibiotics treatment in the unfavorable prognosis group was significantly longer than those in the favorable prognosis group (P < 0.05). The unfavorable prognosis group had significantly higher 28-day mortality than the favorable prognosis group (P < 0.05). Therefore, the results suggest that presepsin levels correlated with the severity of sepsis during follow-up in comparison with other conventional sepsis biomarkers.

Successful transition from intravenous to inhalation anesthesia for respiratory management of coronavirus disease pneumonia: A case report.

Background: In patients with coronavirus disease pneumonia, strong spontaneous breathing increases pulmonary vascular permeability and induces self-inflicted lung injury, prolonging the intensive care unit stay and worsening prognosis. Therefore, spontaneous respiration must be strictly controlled. Case Presentation: A 48-year-old man was admitted for respiratory management of severe coronavirus disease pneumonia. Despite immediate ventilatory management, ventilatory failure and air leak syndrome developed, necessitating venovenous extracorporeal membrane oxygenation, intravenous sedation, and muscle relaxation. Over time, the patient's inspiratory effort worsened and the requirement for transvenous anesthesia increased. Therefore, management was switched to inhalation anesthesia after discontinuation of all transvenous anesthetics, maintaining morphine-only analgesia. Subsequent management enabled effective control of spontaneous respiration, allowing eventual discontinuation of inhalation anesthesia, venovenous extracorporeal membrane oxygenation, and ventilation. Conclusion: Management of spontaneous respiration in coronavirus disease pneumonia can be complicated by resistance to transvenous anesthesia; however, the use of an inhaled anesthetic may present a valuable alternative.

CG02N Analyzer Accurately Measures Fibrinogen Level in Whole Blood in the Presence of Low- or High-Dose Heparin.

Rapid fibrinogen (Fbg) evaluation is important in patients with massive bleeding during severe trauma and those undergoing major surgery. However, there are only a few studies on the point-of-care Fbg analyzer. In this study, we aimed to investigate the accuracy of Fbg level measured using CG02N, with whole blood contained in lithium-heparinized syringes with two different concentrations of heparin. Blood samples were collected in lithium-heparinized tubes, namely PREZA-PAK®II (low-dose heparin group [LG], 7 IU/mL) and Pro-Vent® Plus (high-dose heparin group [HG], 70.5 IU/mL). The Fbg levels in LG and HG were compared with those of citrated plasma Fbg (standard-Fbg). Strong correlations with respect to the Fbg level were observed between standard-Fbg and LG or HG (r = 0.968, p < 0.0001; r = 0.970, p < 0.0001, respectively). We demonstrated that the Fbg level in whole-blood samples was accurately assessed by CG02N and not affected by low- or high-dose heparin.

The Restrictive Red Blood Cell Transfusion Strategy for Critically Injured Patients (RESTRIC) trial: a cluster-randomized, crossover, non-inferiority multicenter trial of restrictive transfusion in trauma.

BACKGROUND: The efficacies of fresh frozen plasma and coagulation factor transfusion have been widely evaluated in trauma-induced coagulopathy management during the acute post-injury phase. However, the efficacy of red blood cell transfusion has not been adequately investigated in patients with severe trauma, and the optimal hemoglobin target level during the acute post-injury and resuscitation phases remains unclear. Therefore, this study aimed to examine whether a restrictive transfusion strategy was clinically non-inferior to a liberal transfusion strategy during the acute post-injury phase. METHODS: This cluster-randomized, crossover, non-inferiority multicenter trial was conducted at 22 tertiary emergency medical institutions in Japan and included adult patients with severe trauma at risk of major bleeding. The institutions were allocated a restrictive or liberal transfusion strategy (target hemoglobin levels: 7-9 or 10-12 g/dL, respectively). The strategies were applied to patients immediately after arrival at the emergency department. The primary outcome was 28-day survival after arrival at the emergency department. Secondary outcomes included transfusion volume, complication rates, and event-free days. The non-inferiority margin was set at 3%. RESULTS: The 28-day survival rates of patients in the restrictive (n = 216) and liberal (n = 195) strategy groups were 92.1% and 91.3%, respectively. The adjusted odds ratio for 28-day survival in the restrictive versus liberal strategy group was 1.02 (95% confidence interval: 0.49-2.13). Significant non-inferiority was not observed. Transfusion volumes and hemoglobin levels were lower in the restrictive strategy group than in the liberal strategy group. No between-group differences were noted in complication rates or event-free days. CONCLUSIONS: Although non-inferiority of the restrictive versus liberal transfusion strategy for 28-day survival was not statistically significant, the mortality and complication rates were similar between the groups. The restrictive transfusion strategy results in a lower transfusion volume. TRIAL REGISTRATION NUMBER: umin.ac.jp/ctr: UMIN000034405, registration date: 8 October 2018.

Usefulness of presepsin in the diagnosis of sepsis in a multicenter prospective study.

The clinical usefulness of presepsin for discriminating between bacterial and nonbacterial infections (including systemic inflammatory response syndrome) was studied and compared with procalcitonin (PCT) and interleukin-6 (IL-6) in a multicenter prospective study. Suspected sepsis patients (n = 207) were enrolled into the study. Presepsin levels in patients with systemic bacterial infection and localized bacterial infection were significantly higher than in those with nonbacterial infections. In addition, presepsin, PCT, and IL-6 levels in patients with bacterial infectious disease were significantly higher than in those with nonbacterial infectious disease (P < 0.0001, P < 0.0001, and P < 0.0001, respectively). The area under the receiver operating characteristic curve was 0.908 for presepsin, 0.905 for PCT, and 0.825 for IL-6 in patients with bacterial infectious disease and those with nonbacterial infectious disease. The cutoff value of presepsin for discrimination of bacterial and nonbacterial infectious diseases was determined to be 600 pg/ml, of which the clinical sensitivity and specificity were 87.8 % and 81.4 %, respectively. Presepsin levels did not differ significantly between patients with gram-positive and gram-negative bacterial infections. The sensitivity of blood culture was 35.4 %; that for presepsin was 91.9 %. Also there were no significant differences in presepsin levels between the blood culture-positive and -negative groups. Consequently, presepsin is useful for the diagnosis of sepsis, and it is superior to conventional markers and blood culture.

Glial fibrillary acidic protein level on admission can predict severe traumatic brain injury in patients with severe multiple trauma: A single-center retrospective observational study.

Objective: This study aimed to clarify whether the glial fibrillary acidic protein (GFAP) and soluble protein-100ß (S100ß) can predict severe traumatic brain injury (TBI) in patients with severe multiple trauma. Methods: This is a single-center retrospective observational study of 179 patients with severe multiple trauma. The GFAP and S100ß were measured upon patient arrival at the hospital. We divided the patients into the severe TBI group (with a Traumatic Coma Data Bank classification of ≥III), the non-severe TBI group (non-TBI group [absence of abnormality on the computed tomography scan and extracranial injury], and the mild to moderate TBI group [TCDB classification I and II]). We compared biomarker levels between the two groups and then evaluated the accuracy of predicting severe TBI using a receiver operating characteristic curve. Results: A total of 41 patients had severe TBI, and 138 had non-severe TBI. Mean GFAP levels were significantly higher in the severe TBI group (median, 6000 pg/mL; interquartile range [IQR], 651-15,548 pg/mL) than in the non-severe TBI group (median, 149 pg/mL; IQR, 0-695 pg/mL) (p < 0.0001). In contrast, there was no significant difference in S100ß levels between the severe TBI group (median, 64 pg/mL; IQR, 0-536 pg/mL) and non-severe TBI group (median, 117 pg/mL; IQR, 0-403 pg/mL) (p = 0.637). The area under the receiver operating characteristic curve was 0.810 (p < 0.0001) for GFAP and 0.476 (p = 0.908) for S100ß. For the GFAP, the optimal cutoff value for detecting severe TBI was 947 pg/mL (sensitivity, 75.6%; specificity, 78.3%). Conclusions: In patients with severe multiple trauma, the GFAP level at hospital arrival could predict severe TBI, whereas the S100ß level was not a useful predictor.

Relationship between serum zinc level and sepsis-induced coagulopathy.

BACKGROUND: We investigated whether a decrease in the serum zinc level (SZL) among patients with sepsis admitted to the intensive care unit (ICU) was related to sepsis-induced coagulopathy. METHODS: All patients (≥20 years) with a diagnosis of sepsis defined by Sepsis-3 criteria, presenting to the ICU between June 2016 and July 2017, were enrolled. Demographic characteristics and the Sequential Organ Failure Assessment (SOFA) and Japanese Association of Acute Medicine (JAAM) disseminated intravascular coagulation (DIC) scores were recorded. Blood samples were collected upon admission and analyzed for SZL. RESULTS: One hundred patients with sepsis (median age, 70 years) were enrolled. Patients with SOFA scores ≥8 had a significantly lower SZL compared to those with SOFA scores <8 (p < 0.001). The SZL in the DIC group (JAAM DIC score ≥4) was significantly lower than that in the non-DIC group (JAAM DIC score <4) (p < 0.001). Analysis of receiver operating characteristic (ROC) curves for prediction of sepsis-induced DIC based on SZL in patients with sepsis showed a cut-off value of 25 µg/dL for zinc level and a sensitivity of 63% and a specificity of 72% with AUC of 0.7 (p = 0.0065). CONCLUSION: We observed that SZL reflects organ failure, particularly coagulopathy, in patients with sepsis.

Effects of evidence-based ICU care on long-term outcomes of patients with sepsis or septic shock (ILOSS): protocol for a multicentre prospective observational cohort study in Japan.

INTRODUCTION: Sepsis is not only the leading cause of death in the intensive care unit (ICU) but also a major risk factor for physical and cognitive impairment and mental disorders, known as postintensive care syndrome (PICS), reduced health-related quality of life (HRQoL) and even mental health disorders in patient families (PICS-family; PICS-F). The ABCDEF bundle is strongly recommended to overcome them, while the association between implementing the bundle and the long-term outcomes is also unknown. METHODS AND ANALYSIS: This is a multicentre prospective observational study at 26 ICUs. All consecutive patients between 1 November 2020 and 30 April 2022, who are 18 years old or older and expected to stay in an ICU for more than 48 hours due to sepsis or septic shock, are enrolled. Follow-up to evaluate survival and PICS/ PICS-F will be performed at 3, 6 and 12 months and additionally every 6 months up to 5 years after hospital discharge. Primary outcomes include survival at 12 months, which is the primary outcome, and the incidence of PICS defined as the presence of any physical impairment, cognitive impairment or mental disorders. PICS assessment scores, HRQoL and employment status are evaluated. The association between the implementation rate for the ABCDEF bundle and for each of the individual elements and long-term outcomes will be evaluated. The PICS-F, defined as the presence of mental disorders, and HRQoL of the family is also assessed. Additional analyses with data up to 5 years follow-up are planned. ETHICS AND DISSEMINATION: This study received ethics approvals from Saiseikai Utsunomiya Hospital (2020-42) and all other participating institutions and was registered in the University Hospital Medical Information Network Clinical Trials Registry. Informed consent will be obtained from all patients. The findings will be published in peer-reviewed journals and presented at scientific conferences. TRIAL REGISTRATION NUMBER: UMIN000041433.

Oral Health of COVID-19 Patients Using Extracorporeal Membrane Oxygenation: A Clinical Study of 19 Cases.

The oral health of coronavirus disease 2019 (COVID-19) patients in the intensive care unit (ICU) is an important issue in treatment of respiratory failure. We retrospectively investigated the oral health history of severe COVID-19 patients who received extracorporeal membrane oxygenation (ECMO) from April 2020 to December 2020 using the oral assessment guide from Fukuoka University (OAG-F). Nineteen consecutive patients (median age: 62 years) were divided into two groups according to survival (survivors, n = 12; non-survivors, n = 7). A univariate analysis revealed no significant differences between the groups in sex, age, body mass index (BMI), or the number of remaining teeth, whereas the ECMO assistance of non-survivors (median: 34 days) was prolonged in comparison to survivors (median: 8 days; p < 0.05). Among the factors of OAG-F, significant differences were observed between the groups in the conditions of the saliva, mucous membrane, and gingiva. The total scores in non-survivors (median: 19) were significantly higher in comparison to survivors (Median: 15.5), suggesting that the frequency of oral health deterioration was higher in non-survivors (p < 0.05). Taken together, these findings suggest that poor oral health is associated with mortality in COVID-19 patients receiving ECMO in the ICU.

Validating plasminogen activator inhibitor-1 as a poor prognostic factor in sepsis.

AIM: Our previous report indicated that plasminogen activator inhibitor-1 (PAI-1) levels of ≥83 ng/mL in patients with sepsis tended to be associated with disseminated intravascular coagulation (DIC), suppressed fibrinolysis, multiple organ dysfunction, and mortality. Therefore, the present study aimed to validate whether 83 ng/mL was a useful cut-off value for using PAI-1 levels to predict a poor prognosis in sepsis. METHODS: Patients with sepsis were included in this single-center retrospective study. The patients were classified as having high or low PAI-1 values (<83 ng/mL versus ≥83 ng/mL), and were compared in terms of their pre-DIC state, intensive care unit-free days, continuous renal replacement therapy-free days, ventilator-free days, catecholamine-free days, and 28-day survival rate. RESULTS: The high PAI-1 group included 61 patients (54%) and the low PAI-1 group included 52 patients (46%). The high PAI-1 group had significantly higher frequencies of a pre-DIC state within 1 week (P = 0.009). There was no significant difference in ventilator-free days. However, the high PAI-1 group had significantly lower values for intensive care unit-free days (P = 0.01), continuous renal replacement therapy-free days (P = 0.02), and catecholamine-free days (P = 0.02). The high PAI-1 group also had a significantly lower 28-day survival rate based on the Kaplan-Meier analysis (log-rank, P = 0.03). CONCLUSION: Patients with sepsis and PAI-1 levels of ≥83 ng/mL had elevated risks of coagulopathy, organ failure, and mortality. Thus, these results suggest that 83 ng/mL could be a useful cut-off value for prognostication based on PAI-1 levels in this setting.

Involvement of the cystathionine-γ-lyase/Cav3.2 pathway in substance P-induced bladder pain in the mouse, a model for nonulcerative bladder pain syndrome.

Hydrogen sulfide (H2S) formed by cystathionine-γ-lyase (CSE) enhances the activity of Cav3.2 T-type Ca2+ channels, contributing to the bladder pain accompanying hemorrhagic cystitis caused by systemic administration of cyclophosphamide (CPA) in mice. Given clinical and fundamental evidence for the involvement of the substance P/NK1 receptor systems in bladder pain syndrome (BPS)/interstitial cystitis (IC), we created an intravesical substance P-induced bladder pain model in mice and analyzed the possible involvement of the CSE/Cav3.2 pathway. Bladder pain/cystitis was induced by i.p. CPA or intravesical substance P in female mice. Bladder pain was evaluated by counting nociceptive behavior and by detecting referred hyperalgesia in the lower abdomen and hindpaw. The isolated bladder tissue was weighed to estimate bladder swelling and subjected to histological observation and Western blotting. Intravesical substance P caused profound referred hyperalgesia accompanied by little bladder swelling or edema 6-24 h after the administration, in contrast to i.p. CPA-induced nociceptive behavior/referred hyperalgesia with remarkable bladder swelling/edema and urothelial damage. The bladder pain and/or cystitis symptoms caused by substance P or CPA were prevented by the NK1 receptor antagonist. CSE in the bladder was upregulated by substance P or CPA, and the NK1 antagonist prevented the CPA-induced CSE upregulation. A CSE inhibitor, a T-type Ca2+ channel blocker and gene silencing of Cav3.2 abolished the intravesical substance P-induced referred hyperalgesia. The intravesical substance P-induced pain in mice is useful as a model for nonulcerative BPS, and involves the activation of the NK1 receptor/CSE/H2S/Cav3.2 cascade.

Usefulness of plasminogen activator inhibitor-1 as a predictive marker of mortality in sepsis.

BACKGROUND: Sepsis is one of the most significant causes of mortality in intensive care units. It indicates crosstalk between inflammation and coagulation. In this study, we aimed to identify prognostic markers among sepsis biomarkers and coagulation/fibrinolysis markers. METHODS: Patients with sepsis according to the Sepsis-3 criteria were enrolled from January 2013 to September 2015. Univariate and multivariate logistic regression analyses were performed to identify an independent predictive marker of 28-day mortality among sepsis biomarkers and coagulation/fibrinolysis markers on ICU admission. Receiver operating characteristic analysis was performed; the optimal cutoff value of 28-day mortality was calculated using the predictive marker. Patients were classified into two groups according to the cutoff level of the predictive marker. Patient characteristics were compared between the groups. RESULTS: A total of 186 patients were enrolled in this study; the 28-day mortality was 19.4% (36/186). PAI-1 was identified as the only independent predictive marker of 28-day mortality by univariate and multivariate logistic regression. The area under the curve was 0.72; the optimal cutoff level was 83 ng/ml (sensitivity, 75%; specificity, 61%). Patients were classified into a higher group (PAI-1 level ≥83 ng/ml; n = 85) and a lower group (PAI-1 level <83 ng/ml; n = 101). All disseminated intravascular coagulation (DIC) scores and Sequential Organ Failure Assessment score were significantly higher in the higher group than in the lower group. CONCLUSIONS: PAI-1 can predict prognosis in sepsis patients. PAI-1 reflects DIC with suppressed fibrinolysis and organ failure, with microthrombi leading to microcirculatory dysfunction.

Adsorption of Nafamostat Mesilate on AN69ST Membranes: A Single-Center Retrospective and In Vitro Study.

We examined whether AN69ST (acrylonitrile and methallyl sulfonate copolymer) membranes adsorb nafamostat mesilate. This study retrospectively analyzed 87 continuous hemodiafiltration sessions in vivo. We divided the continuous hemodiafiltration sessions into AN69ST and non-AN69ST groups using the nafamostat mesilate dose and activated clotting time as indicators of nafamostat mesilate adsorption onto the membrane. Furthermore, we studied the in vitro adsorption of nafamostat mesilate from nafamostat mesilate solutions onto four different hemodialysis membranes. This in vivo study shows that nafamostat mesilate doses were significantly higher, but activated clotting times were shorter (P < 0.001) in the AN69ST group than in the non-AN69ST group. These results suggest that AN69ST adsorbs nafamostat mesilate. Further, the in vitro experiments show that nafamostat mesilate adsorbs AN69ST on membranes significantly more than the other membranes tested. These in vitro and clinical findings provide evidence that AN69ST may adsorb nafamostat mesilate.