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Background: The pathogenesis of sepsis is thought to be linked to a dysregulated immune response, particularly that involving neutrophils. We have developed a granulocyte adsorption column as a "decoy organ," which relocates the massive inflammation in organs in the body to a blood purification column. This study was conducted to assess the safety and experimental effectiveness of granulocyte monocyte adsorption apheresis-direct hemoperfusion (G1-DHP) in the treatment of patients with sepsis, using a prospective, multicenter design., Methods: The study included patients diagnosed with sepsis and with an APACHE II score ranging from 17 to 34. A total of five G1-DHP were performed within 3 days of patient enrollment. The primary endpoint was the change in sequential organ failure assessment (SOFA) score from enrollment to 7 days, and the safety endpoints were adverse events and mortality at 28 days., Results: G1-DHP was performed on 82 patients. The median (interquartile range) SOFA score decreased from 10 (8-11) to 4 (3-7) after 7 days (n = 70; p < 0.01). Granulocytes, mainly neutrophils, were adsorbed, and the neutrophil-to-lymphocyte ratio significantly improved (p < 0.01). Notable improvements were observed in the SOFA scores for circulation and renal function. The acute physiology and chronic health evaluation II score of the 77 patients evaluated for mortality was 27, and the 28-day mortality rate was 7.8%., Conclusions: This study confirmed that G1-DHP can be safely used as an adjunct to standard sepsis treatment regimens. Although further investigations are required, G1-DHP is a promising supplemental therapy for sepsis., Trial Registration: jRCT1080225183 (Japan Registry of Clinical Trials identifier)., (© 2025 The Author(s). Artificial Organs published by International Center for Artificial Organ and Transplantation (ICAOT) and Wiley Periodicals LLC.)

Background: Acute kidney injury (AKI) is a complication often observed in critically ill patients, indicating a worsening prognosis. However, factors predicting AKI in subarachnoid hemorrhage (SAH) patients are unclear. This study aims to elucidate the predictors of AKI occurrence., Methods: All patients with SAH admitted to the intensive care unit between 2013 and 2019 were included. Patients with very severe SAH who are unsuitable to receive aggressive treatment, those who previously received a contrast medium at another medical institution within 24 hours before admission, and those on maintenance dialysis were excluded. We retrospectively examined blood tests conducted upon admission, oral medications administered, and the total amount of contrast medium used after initiating treatment to investigate their association with AKI occurrence., Results: Of the 254 SAH patients treated during the relevant period, 195 (median age 64 years, 72 males) met the inclusion/exclusion criteria, and 32 patients (16.3%) developed AKI. When multivariate analysis was performed using sex, uric acid level, and hemoglobin, which obtained P < 0.01 in the univariate analysis, as variables, only uric acid level was found as an independent predictor of AKI (odds ratio, 1.501; 95% confidence interval, 1.109-2.033, P value of 0.009). There was no difference in the occurrence of AKI between survivors and nonsurvivors (12/163 vs. 2/32, P = 0.824)., Conclusions: AKI occurred in 16.3% of the patients with SAH. Patients who developed AKI had significantly higher uric acid levels. SAH with high uric acid levels warrants attention for AKI., (Copyright © 2024 Elsevier Inc. All rights reserved.)

We present two critical cases of life-threatening postpartum hemorrhage (PPH) due to amniotic fluid embolism (AFE) complicated by disseminated intravascular coagulopathy (DIC). These cases are the first to show the effectiveness of resuscitative endovascular balloon occlusion of the aorta (REBOA) for patient survival. In Case 1, the patient, experiencing critical conditions with severe PPH and DIC despite conventional treatments, including rapid blood transfusion and fibrinogen concentrate, was air-transferred to our hospital, where REBOA was promptly employed before hysterectomy was completed. Case 2 involved an ambulance-transferred patient with massive PPH and DIC despite conventional treatments. Prehospital REBOA was performed to prevent cardiac arrest during transfer, and hysterectomy was performed in the hospital. Given the rapid deterioration associated with AFE, REBOA can serve as a bridge until complete hemostasis to maintain vital signs and control bleeding in patients unresponsive to standard therapies before hemostatic interventions or during transfer., (© 2024 Japan Society of Obstetrics and Gynecology.)

Pregnancy-associated atypical hemolytic-uremic syndrome (p-aHUS) refers to a pregnancy that leads to thrombotic microangiopathy (TMA). This disease is associated with adverse maternal outcomes. We encountered a case of p-aHUS, in which treatment with ravulizumab, a long-acting C5 inhibitor, resulted in a favorable clinical course and recovery of renal function. The patient was a 31-year-old woman with no apparent medical history. She developed TMA on the third postpartum day and was initially treated with steroids, plasma exchange, and hemodialysis (HD). On the seventh day of treatment initiation, she was diagnosed with p-aHUS, and treatment with ravulizumab was started. Following administration, her platelet count increased, and her acute kidney injury improved. Consequently, HD was discontinued after six sessions, and the patient was discharged on the 28th day of treatment initiation and continued her recovery at home. Similar to eculizumab, ravulizumab is an effective treatment for p-aHUS. Early administration of ravulizumab after diagnosis of p-aHUS may contribute to favorable clinical outcomes and recovery of renal function, as observed in the present case., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2024, Miyazaki et al.)

Platelet transfusion has various challenges, and platelet-derived extracellular vesicles have been reported to have more significant procoagulant activity than platelets themselves. Furthermore, platelet products derived from platelet-rich plasma and platelet lysates (PLs) have gained attention for their physiological activity and potential role as drug delivery vehicles owing to the properties of their membranes. We aimed to investigate the characteristics of the fractions isolated through ultracentrifugation from mouse-washed PLs and assess the potential clinical applications of these fractions as a therapeutic approach for bleeding conditions. We prepared PLs from C57BL/6 mouse-washed platelets and isolated three different fractions (20K-vesicles, 100K-vesicles, and PLwo-vesicles) using ultracentrifugation. There was a notable difference in particle size distribution between 20K-vesicles and 100K-vesicles, particularly in terms of the most frequent diameter. The 20K-vesicles exhibited procoagulant activity with concentration dependence, whereas PLwo-vesicles exhibited anticoagulant activity. PLwo-vesicles did not exhibit thrombin generation capacity, and the addition of PLwo-vesicles to Microparticle Free Plasma extended the time to initiate thrombin generation by 20K-vesicles and decreased the peak thrombin value. In a tail-snip bleeding assay, pre-administration of 20K-vesicles significantly shortened bleeding time. PL-derived 20K-vesicles exhibited highly potent procoagulant activity, making them potential alternatives to platelet transfusion.

Metformin-associated lactic acidosis (MALA) is a severe side effect of metformin treatment. We encountered an exceedingly rare case of MALA in a patient taking metformin at recommended doses who had no risk factors except for advanced age. A 77-year-old male with a diagnosis of lactic acidosis was referred to our facility. He was taking 250 mg/day of metformin for diabetes. Although he had no pre-existing chronic kidney disease, he developed acute kidney injury upon admission, leading to the diagnosis of MALA based on the test results and history of metformin use. His lactic acidosis improved without extracorporeal treatment through metformin discontinuation and proper circulatory management. When encountering patients with unexplained lactic acidosis, it is important to consider MALA as part of the differential diagnosis and to confirm the patient's medication history. Specifically, when metformin use is identified, attention should be directed toward the potential for MALA., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Fukuda et al.)

An aberrant right subclavian artery (ARSA) is a rare developmental anomaly wherein the right subclavian artery arises from the descending aorta as a fourth branch of the aortic arch. We present the case of ARSA in an 81-year-old woman who was injured in a motorcycle accident. The patient had a history of asymptomatic cerebral infarction, type 2 diabetes mellitus, and rheumatoid arthritis. She was diagnosed with spleen and liver injury, left renal injury, along with fractures in the rib, pelvic, vertebrae, and right tibia. On the 3 rd hospitalization day, activated partial thromboplastin time (APTT) prolongation was observed, followed by sudden massive hematemesis and shock on the 39 th day. We indicate sudden hematemesis and ARSA bleeding as the cause. We performed compression with a Sengstaken-Blakemore tube and coil embolization for hemostasis. Our findings show that the bleeding was mainly caused by nasogastric tube compression, prolonged APTT, and acquired hemophilia A., Competing Interests: There are no conflicts of interest., (Copyright: © 2023 Journal of Emergencies, Trauma, and Shock.)

Acetaminophen may cause liver damage in a dose-dependent way: we experienced a case where an intravenous injection of 3 g/day of acetaminophen, which is less than the recommended maximum dose, was thought to have caused acute liver failure in a 73-year-old female. Four courses of postoperative adjuvant chemotherapy were given, without liver damage until the third course. After the administration of the fourth course, the patient experienced nausea and vomiting. She was admitted to the hospital with a diagnosis of enteritis a week later. At the time of admission, there was no liver impairment. For abdominal pain caused by enteritis, acetaminophen was administered intravenously over two days, totaling 4,000 mg. On the third day, acute liver failure developed, and N-acetylcysteine was administered. There was no improvement after the introduction of treatment; hence, 1,000 mg/day of steroid pulse therapy was administered. The patient's liver function started to improve, and she was discharged from the hospital two weeks later. This case suggests that the amount of acetaminophen used per unit of body weight may be unintentionally greater for adults with a small physique; thus, physicians should provide sufficient monitoring to discover side effects early and ensure there is appropriate use., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Fukuda et al.)

This is a report of an extremely rare case of an atypical hemolytic uremic syndrome (aHUS) that appears to have been triggered by acute pancreatitis. A 68-year-old man was examined at a medical institution because of sudden lower abdominal pain. The patient was diagnosed with acute pancreatitis on computed tomography. Hemoglobinuria and laboratory findings indicative of intravascular hemolysis were noted. Biochemical analysis revealed normal results for von Willebrand factor activity, antiplatelet antibodies, and ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin type 1 motif, member 13), and stool culture was negative for Shiga-toxin-producing Escherichia coli , leading to the diagnosis of aHUS. Treatment for acute pancreatitis resulted in improvement in the laboratory findings, and the patient's progress was monitored without treatment intervention for aHUS. On day 2 of hospitalization, the abdominal symptoms and hemoglobinuria resolved without any subsequent recurrence. In the absence of any complications, the patient was transferred back to the initial hospital on day 26 of hospitalization. When hemolytic anemia or thrombocytopenia of unknown etiology is observed, aHUS should be suspected, and clinicians should be aware that acute pancreatitis may be a potential cause of aHUS., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Kajiyama et al.)

Rhabdomyolysis accompanying influenza virus infection is a notable extrapulmonary complication. We experienced a case of influenza type A followed by rhabdomyolysis and systemic capillary leak syndrome (SCLS). A 57-year-old man with no significant past medical history was diagnosed as having influenza type A six hours after fever onset, and treatment with oseltamivir was started. Shock, rhabdomyolysis, and acute kidney injury (AKI) progressed rapidly. At 53 hours after starting the oral treatment, intensive care was initiated, including ventilation management. In the acute phase, a large-dose replacement was given for the SCLS and continuous renal replacement therapy for AKI; both eventually healed without sequelae., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Fukuda et al.)

Introduction: To date, the prognosis of patients with sepsis and underlying chronic kidney disease (CKD) had been poor. However, the impact of preseptic renal function on the short-term prognosis of patients with extremely severe septic shock with acute kidney injury (AKI) that requires renal replacement therapy (RRT) is unclear., Methods: Of the septic shock cases treated at the intensive care unit for ≥48 h, 131 adults who were diagnosed as septic AKI and underwent continuous venovenous hemodiafiltration were retrospectively analyzed. The relationships of demographic, clinical, and laboratory data with mortality were evaluated, and the independent risk factors for death were identified., Results: The median age of the subjects was 73 (range, 63-80) years, and 76 (58%) were men. The rate of mortality was significantly higher among patients with CKD (n = 42) than in those without CKD (n = 89) (43% vs. 22%, p < 0.016). On univariate and multivariate logistic regression analyses, the associated factors and independent predictors of death were Sequential Organ Failure Assessment score (odds ratios [ORs] 1.151, 95% confidence intervals [CIs] 1.026-1.293, p = 0.017, and OR 1.129, 95% CI 1.003-1.271, respectively); baseline estimated glomerular filtration rate (OR 0.986, 95% CI 0.975-0.997, p = 0.016, and OR 0.983, 95% CI 0.970-0.996, respectively); and lactic acid (OR 1.094, 95% CI 1.005-1.190, p = 0.038, and OR 1.110 CI 1.015-1.215, respectively)., Conclusion: Reduced baseline renal function may be a factor for poor short-term prognosis in severe septic AKI cases requiring RRT., (© 2022 S. Karger AG, Basel.)

Introduction: Patients with severe coronavirus disease 2019 (COVID-19) receiving ventilation or pulmonary support via veno-venous extracorporeal membrane oxygenation (VV-ECMO) can be infected with drug-resistant bacteria. When introducing VV-ECMO, the changes in serum antibiotic concentration should be considered due to an increased volume of distribution (Vd). However, no pharmacokinetic study has assessed teicoplanin (TEIC) treatment in patients with COVID-19 receiving VV-ECMO., Case Presentation: A 71-year-old man diagnosed with COVID-19 visited a primary hospital. His oxygenation conditions worsened despite treatment with favipiravir and methylprednisolone as well as oxygen therapy. After his transfer to our center, tracheal intubation and steroid pulse therapy were initiated. Seven days after admission, VV-ECMO was performed. TEIC was administered for secondary bacterial infection. The serum TEIC concentration remained within the therapeutic range, indicating that VV-ECMO did not significantly affect TEIC pharmacokinetics. VV-ECMO was discontinued 17 days after admission. However, he developed multi-organ disorder and died 42 days after admission., Conclusion: As TEIC prevents viral invasion, it may be used with ECMO in patients with COVID-19 requiring ventilation; however, the altered pharmacokinetics of TEIC, such as increased Vd, should be considered. Therefore, TEIC pharmacokinetics in VV-ECMO should be assessed in future studies with an appropriate number of patients., Competing Interests: Conflicts of interest None declared., (© 2022 Nobuhisa Hirayu, Atsuo Nakamura, Toshio Morita, Osamu Takasu, published by Sciendo.)

Objective: Disseminated intravascular coagulation plays a key role in the pathophysiology of sepsis. Thrombomodulin is essential in the protein C system of coagulation cascade, and functional polymorphisms influence the human thrombomodulin gene ( THBD ). Therefore, we conducted a multicenter study to evaluate the influence of such polymorphisms on the pathophysiology of sepsis. Methods: A collaborative case-control study in the intensive care unit (ICU) of each of five tertiary emergency centers. The study included 259 patients (of whom 125 displayed severe sepsis), who were admitted to the ICU of Chiba University Hospital, Chiba, Japan between October 2001 and September 2008 (discovery cohort) and 793 patients (of whom 271 patients displayed severe sepsis), who were admitted to the five ICUs between October 2008 and September 2012 (multicenter validation cohort). To assess the susceptibility to severe sepsis, we further selected 222 critically ill patients from the validation cohort matched for age, gender, morbidity, and severity with the patients with severe sepsis, but without any evidence of sepsis. Results: We examined whether the eight THBD single nucleotide polymorphisms (SNPs) were associated with susceptibility to and/or mortality of sepsis. Higher mortality on severe sepsis in the discovery and combined cohorts was significantly associated with the CC genotype in a THBD promoter SNP (-1920 * C/G; rs2239562) [odds ratio [ OR ] 2.709 (1.067-6.877), P = 0.033 and OR 1.768 (1.060-2.949), P = 0.028]. Furthermore, rs2239562 SNP was associated with susceptibility to severe sepsis [ OR 1.593 (1.086-2.338), P = 0.017]. Conclusions: The data demonstrate that rs2239562, the THBD promoter SNP influences both the outcome and susceptibility to severe sepsis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Watanabe, Takasu, Teratake, Sakamoto, Ikeda, Kotani, Kitamura, Ohmori, Teratani, Honda, Hatano, Mayer, Schneider and Oda.)

Objective: To report a case of drug-induced immune hemolytic anemia (DIIHA) that was suspected to have been caused by cefmetazole., Case Summary: A 93-year-old woman with no previous history of liver complications underwent a contrast-enhanced computed tomography scan, which resulted in a diagnosis of acute cholecystitis. The patient experienced intravascular hemolysis and rapid progression of anemia after being exposed to 2 g/day of cefmetazole. After 48 hours of cefmetazole administration, the patient was transferred to the intensive care unit (ICU) of our facility. In view of the severe autoimmune hemolytic anemia, the patient was started on steroid immunosuppression. The patient's condition further deteriorated for 13 hours after treatment and showed increased lactic acidosis and decreased consciousness, thus, the patient was intubated and managed on a ventilator. Lactic acidosis was not easily controlled, and the patient required continuous renal replacement therapy within 15 hours of ICU admission. Blood pressure was unable to be maintained even with the use of catecholamine, and the patient subsequently died 28 hours after ICU admission. Blood taken immediately after death was used to perform a drug-dependent antibody test where DIIHA due to cefmetazole was diagnosed., Conclusion: If there is rapid progression of anemia following drug administration, the possibility of DIIHA needs to be considered. If DIIHA is suspected, identification and immediate discontinuation of the causal drug are essential, and a drug-dependent antibody test should be considered.

Background: A carbapenem-resistant Enterobacteriaceae (CRE) outbreak occurred in an advanced emergency medical service center [hereafter referred to as the intensive care unit (ICU)] between 2016 and 2017., Aim: Our objective was to evaluate the infection control measures for CRE outbreaks., Methods: CRE strains were detected in 16 inpatients located at multiple sites. Environmental cultures were performed and CRE strains were detected in 3 of 38 sites tested. Pulsed-field gel electrophoresis (PFGE), multilocus sequence typing (MLST), and detection of β-lactamase genes were performed against 25 CRE strains., Findings: Molecular typing showed the PFGE patterns of two of four Klebsiella pneumoniae strains were closely related and the same MLST (ST2388), and four of five Enterobacter cloacae strains were closely related and same MLST (ST252). Twenty-three of 25 CRE strains harbored the IMP-1 β-lactamase gene and 15 of 23 CRE strains possessed IncFIIA replicon regions. Despite interventions by the infection control team, new inpatients with the CRE strain continued to appear. Therefore, the ICU was partially closed and the inpatients with CRE were isolated, and the ICU staff was divided into two groups between inpatients with CRE and non-CRE strains to avoid cross-contamination. Although the occurrence of new cases dissipated quickly after the partial closure, a few months were required to eradicate the CRE outbreak., Conclusion: Our data suggest that the various and combined measures that were used for infection control were essential in stopping this CRE outbreak. In particular, partial closure to isolate the ICU and division of the ICU staff were effective.

Background: Shock and organ damage occur in critically ill patients in the emergency department because of biological responses to invasion, and cytokines play an important role in their development. It is important to predict early multiple organ dysfunction (MOD) because it is useful in predicting patient outcomes and selecting treatment strategies. This study examined the accuracy of biomarkers, including interleukin (IL)-6, in predicting early MOD in critically ill patients compared with that of quick sequential organ failure assessment (qSOFA)., Methods: This was a multicenter observational sub-study. Five universities from 2016 to 2018. Data of adult patients with systemic inflammatory response syndrome who presented to the emergency department or were admitted to the intensive care unit were prospectively evaluated. qSOFA score and each biomarker (IL-6, IL-8, IL-10, tumor necrosis factor-α, C-reactive protein, and procalcitonin [PCT]) level were assessed on Days 0, 1, and 2. The primary outcome was set as MOD on Day 2, and the area under the curve (AUC) was analyzed to evaluate qSOFA scores and biomarker levels., Results: Of 199 patients, 38 were excluded and 161 were included. Patients with MOD on Day 2 had significantly higher qSOFA, SOFA, and Acute Physiology and Chronic Health Evaluation II scores and a trend toward worse prognosis, including mortality. The AUC for qSOFA score (Day 0) that predicted MOD (Day 2) was 0.728 (95% confidence interval [CI]: 0.651-0.794). IL-6 (Day 1) showed the highest AUC among all biomarkers (0.790 [95% CI: 0.711-852]). The combination of qSOFA (Day 0) and IL-6 (Day 1) showed improved prediction accuracy (0.842 [95% CI: 0.771-0.893]). The combination model using qSOFA (Day 1) and IL-6 (Day 1) also showed a higher AUC (0.868 [95% CI: 0.799-0.915]). The combination model of IL-8 and PCT also showed a significant improvement in AUC., Conclusions: The addition of IL-6, IL-8 and PCT to qSOFA scores improved the accuracy of early MOD prediction., (© 2021. The Author(s).)

This study aimed to examine the beneficial effects of a novel prophylactic barbiturate therapy, step-down infusion of barbiturates, using thiamylal with normothermia (NOR+sdB), on the poor outcome in the patients with severe traumatic brain injuries (sTBI), in comparison with mild hypothermia (MD-HYPO). From January 2000 to March 2019, 4133 patients with TBI were admitted to our hospital. The inclusion criteria were: a Glasgow coma scale (GCS) score of ≤8 on admission, age between 20 and 80 years, intracranial hematoma requiring surgical evacuation of the hematoma with craniotomy and/or external decompression, and patients who underwent management of body temperature and assessed their outcome at 6-12 months. Finally, 43 patients were included in the MD-HYPO (n = 29) and NOR+sdB (n = 14) groups. sdB was initiated intraoperatively or immediately after the surgical treatment. There were no significant differences in patient characteristics, including age, sex, past medical history, GCS on admission, type of intracranial hematoma, and length of hospitalization between the two groups. Although NOR+sdB could not improve the patient's poor outcome either at discharge from the intensive care unit (ICU) or at 6-12 months after admission, the treatment inhibited composite death at discharge from the ICU. The mean value of the maximum intracranial pressure (ICP) in the NOR+sdB group was <20 mmHg throughout the first 120 h. NOR+sdB prevented composite death in the ICU in patients with sTBI, and we may obtain novel insights into the beneficial role of prophylactic barbiturate therapy from suppression of the elevated ICP during the first 120 h.

Competing Interests: There are no conflicts of interest to declare.

Introduction: Few studies have discussed whether physician-staffed helicopter emergency medical services (HEMS) provide temporal and geographical benefits for patients in remote locations compared to ground emergency medical services (GEMS). Our study seeks to clarify the significance of HEMS for patients with severe trauma by comparing the mortality of patients transported directly from crash scenes by HEMS or GEMS, taking geographical factors into account., Methods: Using medical records from a single center, collected from January 2014 to December 2018, we retrospectively identified 1674 trauma patients. Using propensity score analysis, we selected adult patients with an injury severity score ≥16, divided them into groups depending on their transport to the hospital by HEMS or GEMS, and compared their mortality within 24 h of hospitalization. For propensity score-matched groups, we analyzed distance and time., Results: Of the 317 eligible patients, 202 were transported by HEMS. In the propensity score matching analysis, there was no significant difference in mortality between the HEMS and GEMS groups: 8.7% vs. 5.8%, odds ratio (OR), 1.547 (95% confidence interval [CI], 0.530-4.514). The inverse probability of treatment weighting (IPTW): 11% vs. 7.8%, OR, 1.080 (95% CI, 0.640-1.823); stabilized IPTW: 11% vs. 7.8%, OR, 1.080 (95% CI, 0.502-2.324); and truncated IPTW: 10% vs. 6.4%, OR, 1.143 (95% CI, 0.654-1.997). The distance from the crash scene to the hospital was farther in the HEMS group, and it took a longer period of time to arrive at the hospital (P < 0.001)., Conclusions: HEMS may provide equal treatment opportunities and minimize trauma deaths for patients transported from a greater distance to an emergency medical center compared to GEMS for patients transported from nearby regions., Competing Interests: Declaration of Competing Interest There are no conflicts of interest for all authors in this study., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Predicting multiple organ dysfunction (MOD) in the late phase of critical illnesses is essential. Cytokines are considered biomarkers that can predict clinical outcomes; however, their predictive value for late-phase MOD is unknown. This study aimed to identify the biomarker with the highest predictive value for late-phase MOD., Methods: This observational study prospectively evaluated data on adult patients with systemic inflammatory response syndrome, those who presented to the emergency department or were admitted to intensive care units in five tertiary hospitals (n = 174). Seven blood biomarkers levels (interleukin-6 [IL-6], IL-8, IL-10, tumor-necrosis factor-α, white blood cells, C-reactive protein, and procalcitonin) were measured at three timepoints (days 0, 1, and 2). The area under the receiver operating characteristic curve (AUC) was analyzed to evaluate predictive values for MOD (primary outcome, MOD on day 7 [late-phase]; secondary outcome, MOD on day 3 [early-phase])., Results: Of the measured 7 biomarkers, blood IL-6 levels on day 2 had the highest predictive value for MOD on day 7 using single timepoint data (AUC 0.825, 95% confidence interval [CI] 0.754-0.879). Using three timepoint biomarkers, blood IL-6 levels had the highest predictive value of MOD on day 7 (AUC 0.838, 95% CI 0.768-0.890). Blood IL-6 levels using three timepoint biomarkers had also the highest predictive value for MOD on day 3 (AUC 0.836, 95% CI 0.766-0.888)., Conclusion: Of the measured biomarkers, blood IL-6 levels had the highest predictive value for MOD on days 3 and 7. Blood IL-6 levels predict early- and late-phase MOD in critically ill patients., Competing Interests: This work was supported by Roche Diagnostics K.K. The funding source had no role in the study design, data analysis, or preparation of the manuscript. Authors T.S., T.N., H.O., M.N., T.M., and T.S. received honoraria for advisory board from Roche Diagnostics K.K., and authors T.M., O.T., K.M., J.S., and S.O. received honoraria for advisory board and research funding for this study from Roche Diagnostics K.K. Authors M.Y. and Y.T. declare no conflict of interests for this article. Authors T.S., T.N., H.O., M.N., T.M., and T.S. received honoraria for advisory board from Roche Diagnostics K.K., and authors T.M., O.T., K.M., J.S., and S.O. received honoraria for advisory board and research funding for this study from Roche Diagnostics K.K. Authors M.Y. and Y.T. declare no conflict of interests for this article., (Copyright © 2020 by the Shock Society.)

Objectives: Several inflammation markers have been reported to be associated with unfavorable clinical outcomes in critically ill patients. We aimed to elucidate whether serum interleukin-6 concentration considered with Sequential Organ Failure Assessment score can better predict mortality in critically ill patients., Design: A prospective observational study., Setting: Five university hospitals in 2016-2018., Patients: Critically ill adult patients who met greater than or equal to two systemic inflammatory response syndrome criteria at admission were included, and those who died or were discharged within 48 hours were excluded., Interventions: Inflammatory biomarkers including interleukin (interleukin)-6, -8, and -10; tumor necrosis factor-α; C-reactive protein; and procalcitonin were blindly measured daily for 3 days. Area under the receiver operating characteristic curve for Sequential Organ Failure Assessment score at day 2 according to 28-day mortality was calculated as baseline. Combination models of Sequential Organ Failure Assessment score and additional biomarkers were developed using logistic regression, and area under the receiver operating characteristic curve calculated in each model was compared with the baseline., Measurements and Main Results: Among 161 patients included in the study, 18 (11.2%) did not survive at day 28. Univariate analysis for each biomarker identified that the interleukin-6 (days 1-3), interleukin-8 (days 0-3), and interleukin-10 (days 1-3) were higher in nonsurvivors than in survivors. Analyses of 28-day mortality prediction by a single biomarker showed interleukin-6, -8, and -10 at days 1-3 had a significant discrimination power, and the interleukin-6 at day 3 had the highest area under the receiver operating characteristic curve (0.766 [0.656-0.876]). The baseline area under the receiver operating characteristic curve for Sequential Organ Failure Assessment score predicting 28-day mortality was 0.776 (0.672-0.880). The combination model using additional interleukin-6 at day 3 had higher area under the receiver operating characteristic curve than baseline (area under the receiver operating characteristic curve = 0.844, area under the receiver operating characteristic curve improvement = 0.068 [0.002-0.133]), whereas other biomarkers did not improve accuracy in predicting 28-day mortality., Conclusions: Accuracy for 28-day mortality prediction was improved by adding serum interleukin-6 concentration to Sequential Organ Failure Assessment score., Competing Interests: Drs. Sasaki, Shibusawa, Nakada, Otsubo, Nabeta, and Moriguchi received honoraria for advisory board from Roche Diagnostics K.K., and Drs. Sasaki, Mayumi, Takasu, Matsuda, and Oda received honoraria for advisory board and research funding for this study from Roche Diagnostics K.K. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2021 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine.)

Introduction: FOLFOX therapy is the main chemotherapy regimen for colorectal cancer. Peripheral neuropathy, hematotoxicity, and digestive symptoms are known to be the most frequent adverse events. Hyperammonemia and lactic acidosis rarely occur simultaneously during treatment with FOLFOX therapy; the number of case reports is limited worldwide. We report a case of disturbance of consciousness, considered to be caused by hyperammonemia and lactic acidosis that occurred during treatment with mFOLFOX6 therapy that was administered as postoperative adjuvant treatment for rectal cancer., Patient Concerns: This case was of a 71-year-old man who had been receiving oral treatment for chronic kidney disease and diabetes mellitus. Laparoscopic low anterior resection and artificial anal construction surgery were performed for stage III rectal cancer. As adjuvant postoperative therapy, mFOLFOX6 therapy was started but was followed by a disturbance of consciousness., Diagnoses: Results of the blood tests revealed notable hyperammonemia (ammonia level, 1,163 μg/dl) and lactic acidosis (pH 7.207; lactate, 17.56 mmol/L); however, imaging diagnosis did not reveal intracranial lesions that could cause disturbance of consciousness., Interventions: For hyperammonemia, branched-chain amino acid agents and Ringers solution supplementation were administered. For acidosis, 7% sodium hydrogen carbonate was administered as treatment., Outcomes: The disturbance of consciousness improved within 12 hours of initiating the treatment, and the patient was discharged with no sequelae on 7th day after hospitalization., Conclusion: In patients with chronic kidney disease, FOLFOX regimen may confer risks of hyperammonemia and lactic acidosis.

Background: Diabetic ketoacidosis (DKA) is seen relatively frequently in the emergency department (ED). DKA is characterized by hyperglycemia, acidosis, and ketonemia, and sodium glucose transporter 2 inhibitors (SGLT2i) represent a new diabetes medication that has been associated with euglycemic DKA (eu-DKA)., Case Presentation: A 71-year-old female who was being treated for type 2 diabetes with canagliflozin, metformin, and saxagliptin orally presented to the ED for evaluation of reduced oral intake, malaise, nausea, and abdominal pain. Although her blood glucose was not severely elevated (259 mg/dL), there was notable ketoacidosis (pH 6.89; CO 2 , 11.4 mmHg; HCO 3 , 1.9 mEq/L; base excess, - 31.3 mmol/L; 3-hydroxybutyric acid > 10,000 μmol/L) was observed. The uncontrolled acidosis improved following 3 days of continuous renal replacement therapy, but elevated urinary glucose continued for more than 10 days. Ringer's lactated fluid supplementation was continued for management of polyurea and glucosuria. Urinary glucose turned negative on day 16, and there was improvement in the patient's overall state; hence, she was discharged on day 18., Conclusion: Although it is difficult to diagnose eu-DKA because of the absence of substantial blood glucose abnormalities in the ED, there is a need to consider eu-DKA when evaluating acidosis in a patient treated with SGLT2i. Moreover, even after discontinuing the SGLT2i, attention should be given to the possibility of continuing glucosuria. Regular measurements of urinary glucose should be obtained, and the patient should be monitored for dehydration.

Introduction: Hemorrhagic shock and encephalopathy syndrome (HSES) is a type of acute encephalopathy mainly seen in infants. It is a syndrome encompassing an onset of high fever, disturbance of consciousness, convulsion, and shock that rapidly progresses to watery diarrhea and liver and renal dysfunctions. It is extremely rare in adults, and the number of reports is limited worldwide. We report the case of an adult patient with HSES, which occurred after influenza A infection., Patient Concerns: A 52-year-old man visited his family doctor 2 days after he noticed fever and was diagnosed with influenza A using an influenza rapid diagnosis kit; he underwent treatment on an outpatient basis. He was immediately hospitalized after developing fever, abdominal pain, malaise, and shock 16 hours after the commencement of the treatment. Abrupt acute brain swelling was noted 24 hours after hospitalization., Diagnoses: The antibody titer to influenza A (H3N2) was 1:40. Computed tomography obtained 24 hours after treatment initiation confirmed acute cerebral edema and cerebral herniation. Electroencephalogram at that time showed a flat line., Interventions: For the treatment of influenza A, laninamivir 150 mg was started immediately after the diagnosis by the family doctor, and 600 mg dose was given daily after hospitalization (or since 24 hours after the treatment initiation). For the management of shock, dobutamine 3 μg/kg/min and noradrenaline up to 0.2 μg/kg/min were used together with bolus infusion., Outcomes: The patient was declared brain dead on his 6th hospital day and he died on his 27th hospital day., Conclusion: Drastic courses such as that in our case with HSES can follow influenza infections even in adults.

Background: Acute subdural hematoma (ASDH) is a serious traumatic disease, and predictive methods for hematoma growth are necessary to decide whether emergent operation is necessary. This study aimed to evaluate the incidence of "leakage" using computed tomography angiography (CTA) in patients with ASDH and to identify its prognostic value., Methods: Sixty-seven patients with ASDH were examined using CTA (mean age 64.1 ± 20.6 years; 24 men) by analyzing two serial scans (CTA phase and delayed phase). We defined a positive leakage sign as a > 10% increase in Hounsfield units (HU) in the region of interest. Hematoma expansion was determined using plain CT after 24 h in patients who did not undergo emergent surgery., Results: Of the 67 patients, conservative therapy was administered to 35 patients; of these patients, 9 showed hematoma expansion, and 8 of these 9 patients (88.9%) showed positive leakage signs. The sensitivity and specificity of leakage signs to hematoma expansion in the no-surgery group were 88.8% and 76.1%, respectively. All positive leakage signs were found within 4.5 h of injury; patients showing negative leakage signs showed a decreased tendency towards hematoma 24 h after injury. Patients presenting with positive leakage signs had poor outcomes., Conclusions: The results indicated that the leakage sign is a sensitive predictor of hematoma expansion and poor outcomes in ASDH. If the hematoma is small but leakage sign-positive, strict observation is necessary and aggressive surgery may improve outcomes.

We examined the clinical characteristics and outcomes of patients who had fallen from ladders and statistically analyzed the prognostic factors, highlighting the impact of the coexistence of head injuries on their prognoses. The clinical records of patients who had experienced ladder-related falls who were admitted to the Advanced Emergency Medical Service Center at Kurume University Hospital between April 2013 and August 2015 were retrospectively reviewed. A total of 86 patients were enrolled. The mean patient age was 69.2 years, and 82 patients were male. The median fall height was 2.55 m. Sixty patients fell during non-professional use of the ladder. Forty-four patients experienced some type of head injury. Although the older patients had more frequent complications with head injuries, the height of the fall was not related statistically. The group of patients with head injuries exhibited trends of older age, lower Glasgow Coma Scale scores, higher Injury Severity Score, and poorer outcomes than those of the group of patients without head injuries. Multivariate analysis showed that head injury and non-professional use were independent risk factors for poor outcomes. Our results revealed that ladder-related falls with head injury can occur when older people are working at home, even if they have fallen from a low height. Especially when older men work with the ladder at home, local community-based education and guidance for the prevention of ladder-related fall injuries are needed.

Hematoma expansion is an important consideration in patients with traumatic brain injury (TBI). No precise methods are available, however, for predicting the expansion of TBI-related hematoma. We aimed to establish a more sensitive predictor for contusional hematoma expansion based on the presence of leakage signs on computed tomography angiography (CTA). Thirty-three patients with pure contusion were included in the analysis (age: 64.1 ± 20.6 years; 24 men and 7 women). We compared Hounsfield unit (HU) values within set regions of interest (diameter, 10 mm) between serial CTA phase and delayed-phase CT images (5 min after CTA phase). Positive leakage signs were defined as >10% increases in HU value. Hematoma expansion was determined using plain CT at 24 h in patients who did not undergo emergent surgery. Glasgow Coma Scale (GCS) scores measured at admission and 24 h after admission were also compared. Leakage signs predicted hematoma expansion with high specificity (100%) and sensitivity (92.8%). Patients with positive leakage signs had significant decreases in GCS scores 24 h after the scan (GCS change: positive group, -0.92 ± 0.59; negative group, 1.14 ± 0.82). Positive leakage signs were clearly associated with surgical hematoma removal. Five patients without hematoma who had positive leakage signs at admission exhibited significant expansion of hematomas 24 h later. Our results indicate that leakage signs had high sensitivity in the prediction of contusional hematoma expansion and were significantly associated with delayed neurological deterioration and the necessity of surgical removal.

Background: Hyperfibrinolysis is a critical complication in severe trauma. Hyperfibrinolysis is traditionally diagnosed via elevated D-dimer or fibrin/fibrinogen degradation product levels, and recently, using thromboelastometry. Although hyperfibrinolysis is observed in patients with severe isolated traumatic brain injury (TBI) on arrival at the emergency department (ED), it is unclear which factors induce hyperfibrinolysis. The present study aimed to investigate the factors associated with hyperfibrinolysis in patients with isolated severe TBI., Methods: We conducted a multicentre retrospective review of data for adult trauma patients with an injury severity score ≥ 16, and selected patients with isolated TBI (TBI group) and extra-cranial trauma (non-TBI group). The TBI group included patients with an abbreviated injury score (AIS) for the head ≥ 4 and an extra-cranial AIS < 2. The non-TBI group included patients with an extra-cranial AIS ≥ 3 and head AIS < 2. Hyperfibrinolysis was defined as a D-dimer level ≥ 38 mg/L on arrival at the ED. We evaluated the relationships between hyperfibrinolysis and injury severity/tissue injury/tissue perfusion in TBI patients by comparing them with non-TBI patients., Results: We enrolled 111 patients in the TBI group and 126 in the non-TBI group. In both groups, patients with hyperfibrinolysis had more severe injuries and received transfusion more frequently than patients without hyperfibrinolysis. Tissue injury, evaluated on the basis of lactate dehydrogenase and creatine kinase levels, was associated with hyperfibrinolysis in both groups. Among patients with TBI, the mortality rate was higher in those with hyperfibrinolysis than in those without hyperfibrinolysis. Tissue hypoperfusion, evaluated on the basis of lactate level, was associated with hyperfibrinolysis in only the non-TBI group. Although the increase in lactate level was correlated with the deterioration of coagulofibrinolytic variables (prolonged prothrombin time and activated partial thromboplastin time, decreased fibrinogen levels, and increased D-dimer levels) in the non-TBI group, no such correlation was observed in the TBI group., Conclusions: Hyperfibrinolysis is associated with tissue injury and trauma severity in TBI and non-TBI patients. However, tissue hypoperfusion is associated with hyperfibrinolysis in non-TBI patients, but not in TBI patients. Tissue hypoperfusion may not be a prerequisite for the occurrence of hyperfibrinolysis in patients with isolated TBI.

The objective of this study is to retrospectively assess long-term outcomes and late complications of pancreatic trauma. We studied 14 patients with pancreatic trauma who were treated at the Advanced Emergency Medical Service Center, Kurume University Hospital, between 1981 and 2012 and discharged alive. Relevant data were extracted from patient records and a retrospective patient questionnaire and blood test were completed to evaluate pancreatic function. The median patient age at the time of the survey was 49 years; the median post-injury period was 23 years and 5 months. The comorbidity rates for pancreatic endocrine and exocrine dysfunctions were 35.7% and 33.3%, respectively. No new-onset diabetes mellitus (DM) was seen within 3 years of trauma, except in 1 patient who underwent pancreaticoduodenectomy. DM developed >15 years after trauma in 2 patients each in the pancreatectomy and non-pancreatectomy groups. Diarrhea exacerbated by fat intake was seen in 3 and 1 patient in the pancreatectomy and non-pancreatectomy groups, respectively. Both complications were more common in the pancreatectomy group, but without statistical significance. Although post-surgical pancreatic dysfunction may be absent at discharge, treatment for pancreatic trauma should take into account the possibility that pancreatectomy may accelerate DM onset.

Introduction: In the early phase of trauma, fibrinogen (Fbg) plays an important role in clot formation. However, to the best of our knowledge, few studies have analysed methods of predicting the need for massive transfusion (MT) based on Fbg levels using multiple logistic regression. Therefore, the present study aimed to evaluate whether Fbg levels on admission can be used to predict the need for MT in patients with trauma., Methods: We conducted a retrospective multicentre observational study. Patients with blunt trauma with ISS ≥16 who were admitted to 15 tertiary emergency and critical care centres in Japan participating in the J-OCTET were enrolled in the present study. MT was defined as the transfusion of packed red blood cells (PRBC) ≥10 units or death caused by bleeding within 24h after admission. Patients were divided into non-MT and MT groups. Multiple logistic-regression analysis was used to assess the predictive value of the variables age, sex, vital signs, Glasgow Coma Scale (GCS) score, and Fbg levels for MT. We also evaluated the discrimination threshold of MT prediction via receiver operating characteristic curve (ROC) analysis for each variable., Results: Higher heart rate (HR; per 10 beats per minutes [bpm]), systolic blood pressure (SBP; per 10mm Hg), GCS, and Fbg levels (per 10mg/dL) were independent predictors of MT (odds ratio [OR] 1.480, 95% confidence interval [CI] 1.326-1.668; OR 0.851, 95% CI 0.789-0.914; OR 0.907, 95% CI 0.855-0.962; and OR 0.931, 95% CI 0.898-0.963, respectively). The optimal cut-off values for HR, SBP, GCS, and Fbg levels were ≥100 bpm (sensitivity 62.4%, specificity 79.8%), ≤120mm Hg (sensitivity 61.5%, specificity 70.5%), ≤12 points (sensitivity 63.3%, specificity 63.6%), and ≤190mg/dL (sensitivity 55.1%, specificity 78.6%), respectively., Conclusions: Our findings suggest that vital signs, GCS, and decreased Fbg levels can be regarded as predictors of MT. Therefore, future studies should consider Fbg levels when devising models for the prediction of MT., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Objectives: To evaluate the utility of the conventional lethal triad in current trauma care practice and to develop novel criteria as indicators of treatment strategy., Design: Retrospective observational study., Settings: Fifteen acute critical care medical centers in Japan., Patients: In total, 796 consecutive trauma patients who were admitted to emergency departments with an injury severity score of greater than or equal to 16 from January 2012 to December 2012., Interventions: None., Measurements and Main Results: All data were retrospectively collected, including laboratory data on arrival. Sensitivities to predict trauma death within 28 days of prothrombin time international normalized ratio greater than 1.50, pH less than 7.2, and body temperature less than 35°C were 15.7%, 17.5%, and 15.9%, respectively, and corresponding specificities of these were 96.4%, 96.6%, and 93.6%, respectively. The best predictors associated with hemostatic disorder and acidosis were fibrin/fibrinogen degradation product and base excess (the cutoff values were 88.8 µg/mL and -3.05 mmol/L). The optimal cutoff value of hypothermia was 36.0°C. The impact of the fibrin/fibrinogen degradation product and base excess abnormality on the outcome were approximately three- and two-folds compared with those of hypothermia. Using these variables, if the patient had a hemostatic disorder alone or a combined disorder with acidosis and hypothermia, the sensitivity and specificity were 80.7% and 66.8%., Conclusions: Because of the low sensitivity and high specificity, conventional criteria were unsuitable as prognostic indicators. Our revised criteria are assumed to be useful for predicting trauma death and have the potential to be the objective indicators for activating the damage control strategy in early trauma care.

Background: A vancomycin-intermediate Staphylococcus aureus (VISA) (vancomycin minimum inhibitory concentration: 4mg/L) outbreak occurred in an advanced emergency medical service centre [hereafter referred to as the intensive care unit (ICU)] between 2013 and 2014., Aim: Our objective was to evaluate the infection control measures that were successful., Methods: Seventeen VISA strains were isolated from the sputum of 15 inpatients and the skin of two inpatients. Fourteen VISA strains were recognized as colonization. However, three VISA strains were isolated from the sputum of three inpatients with pneumonia. Environmental cultures were performed and VISA strains were detected in five of 65 sites. Pulsed-field gel electrophoresis (PFGE) and multi-locus sequence typing (MLST) was performed on 21 VISA strains., Findings: Molecular typing including PFGE and MLST showed that the patterns of 19 VISA strains were identical and those of the other two VISA strains were possibly related. This meant that a horizontal transmission of VISA strains had occurred in the ICU. In August 2013, the infection control team began interventions. However, new inpatients with VISA strains continued to appear. Therefore, in October 2013, the ICU was partially closed in order to try to prevent further horizontal transmission, and existing inpatients with the VISA strain were isolated. Although new cases quickly dissipated after the partial closure, it took approximately five months to eradicate the VISA outbreak., Conclusion: Our data suggest that despite the employment of various other infection control measures, partial closure of the ICU was essential in terminating this VISA outbreak., (Copyright © 2016 The Healthcare Infection Society. Published by Elsevier Ltd. All rights reserved.)

Elevated D-dimer level in trauma patients is associated with tissue damage severity and is an indicator of hyperfibrinolysis during the early phase of trauma. To investigate the interacting effects of fibrinogen and D-dimer levels on arrival at the emergency department for massive transfusion and mortality in severe trauma patients in a multicenter retrospective study. This study included 519 adult trauma patients with an injury severity score ≥16. Patients with ≥10 units of red cell concentrate transfusion and/or death during the first 24 h were classified as having a poor outcome. Receiver operating characteristic curve analysis for predicting poor outcome showed the optimal cut-off fibrinogen and D-dimer values to be 190 mg/dL and 38 mg/L, respectively. On the basis of these values, patients were divided into four groups: low D-dimer (<38 mg/L)/high fibrinogen (>190 mg/dL), low D-dimer (<38 mg/L)/low fibrinogen (≤190 mg/dL), high D-dimer (≥38 mg/L)/high fibrinogen (>190 mg/dL), and high D-dimer (≥38 mg/L)/low fibrinogen (≤190 mg/dL). The survival rate was lower in the high D-dimer/low fibrinogen group than in the other groups. Moreover, the survival rate was lower in the high D-dimer/high fibrinogen group than in the low D-dimer/high fibrinogen and low D-dimer/low fibrinogen groups. High D-dimer level on arrival is a strong predictor of early death or requirement for massive transfusion in severe trauma patients, even with high fibrinogen levels.

Cecal ligation and puncture (CLP) models exhibiting polymicrobial sepsis are considered as the gold standard in sepsis research. However, despite meticulous research being conducted in this field, only few treatment drugs are available, indicating that CLP sepsis models do not completely mimic human sepsis models. The greatest flaw in CLP models is abscess formation because the localization of inflammation caused by abscess formation increases the survival rate. Therefore, by resecting intraperitoneal adipose tissue, we developed a mouse CLP model wherein abscess formation was unlikely. Survival rates at 7 days postoperatively were compared using the Kaplan-Meier method for an intraperitoneal adipose tissue resection group (resection group, n=34), an intraperitoneal adipose tissue non-resection group (non-resection group, n=35) and a sham group (n=10). Results indicated that the survival rate was significantly higher in the non-resection group compared with the resection group. Intraperitoneal macroscopic findings in the non-resection group revealed the localization of inflammation caused by abscesses formation covered in adipose tissue. The survival rate for the sham group was 100%. Measurement of interleukin 6 (IL-6) indicated that during the 12 h after the creation of the CLP model, the median level of IL-6 was 1300 (552-3000) pg ml(-1) in the non-resection group (n=19) and 3000 (1224-8595) pg ml(-1) in the resection group (n=19). Meanwhile, for the sham group, IL-6 values were below measurement sensitivity in most cases (9/10 mice). Thus our results suggest that, in CLP models, intraperitoneal adipose tissue has an important role in abscess formation and is strongly related to the survival rate.

We performed high-dose loading (12 mg/kg every 12 h for 48 h; 4 doses total) of teicoplanin (TEIC) in patients with severe methicillin-resistant Staphylococcus aureus (MRSA) infections, with the goal of achieving target serum concentration (TEICc) ≥ 15 mg/l within 48 h of starting administration. The safety and effectiveness of the fixed, early-stage administration method were evaluated across a range of kidney dysfunction severity levels. TEIC high-dose loading was administered to 106 patients with MRSA infection from February 2010 to February 2013. After high-dose loading, maintenance doses based on therapeutic drug monitoring (TDM) of TEICc were administered via 30-min intravenous drips, every 24 h. Subjects were divided into 4 groups based on kidney function and renal replacement therapy (RRT) status for safety and effectiveness evaluation: group 1 (G1) did not undergo RRT and exhibited creatinine clearance (Ccr; ml/min/m(2)) >50, group 2 (G2) exhibited Ccr ≤ 50, group 3 (G3) underwent continuous RRT (CRRT), and group 4 (G4) underwent intermittent RRT (IRRT). TEICc was measured after 24, 48, 72, and 144 h, immediately before TEIC administration. Target TEICc was reached in all groups, and bacteriological effectiveness and utility were high in G1, G2, and G3. The maximum TEICc (≥ 28.0 mg/l) and serum albumin (≤ 1.84 g/dl) were associated with organ toxicity. Fixed high-dose loading of TEIC achieved the target therapeutic range (≥ 15 mg/l) within 48 h of the start of administration regardless of kidney dysfunction, and exhibited sufficient utility., (Copyright © 2015 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Objective: Autophagy is the regulated catabolic process for recycling damaged or unnecessary organelles, which plays crucial roles in cell survival during nutrient deficiency, and innate immune defense against pathogenic microorganisms. Autophagy has been also reported to be involved in various conditions including inflammatory diseases. IRGM (human immunity-related GTPase) has an important function in eliminating Mycobacterium tuberculosis from host cells via autophagy. We examined the association between genetic polymorphism and clinical course/outcome in severely septic patients., Methods: The study included 125 patients with severe sepsis/septic shock (SS) and 104 non-sepsis patients who were admitted to the intensive care unit (ICU) of Chiba University Hospital between October 2001 and September 2008 (discovery cohort) and 268 SS patients and 454 non-sepsis patients who were admitted to ICUs of five Japanese institutions including Chiba University Hospital between October 2008 and September 2012 (multi-center validation cohort). Three hundred forty seven healthy volunteers who consented to this study were also included. Genotyping was performed for a single-nucleotide polymorphism (SNP) within the coding region of IRGM, IRGM(+313) (rs10065172). Lipopolysaccharide challenge of whole blood from randomly selected healthy volunteers (n = 70) was performed for comparison of IRGM mRNA expression among different genotypes., Results: No significant difference in genotypic distributions (CC/CT/TT) at the IRGM(+313) locus was observed among the three subject groups (SS, non-sepsis, and healthy volunteers) in either cohort. When mortality were compared, no significant difference was observed in the non-sepsis group, while TT homozygotes exhibited a significantly higher mortality than the CC+CT genotype category in the SS group for both cohorts (P = 0.043, 0.037). Lipopolysaccharide challenge to whole blood showed a significant suppression of IRGM mRNA expression in TT compared with the CC+CT genotype category (P = 0.019)., Conclusions: The data suggest that the IRGM(+313), an autophagy-related polymorphic locus, influences outcome in severely septic patients, with the possible involvement of autophagy in sepsis exacerbation.

Introduction: To test the hypothesis that the administration of antithrombin concentrate improves disseminated intravascular coagulation (DIC), resulting in recovery from DIC and better outcomes in patients with sepsis, we conducted a prospective, randomized controlled multicenter trial at 13 critical care centers in tertiary care hospitals., Methods: We enrolled 60 DIC patients with sepsis and antithrombin levels of 50 to 80% in this study. The participating patients were randomly assigned to an antithrombin arm receiving antithrombin at a dose of 30 IU/kg per day for three days or a control arm treated with no intervention. The primary efficacy end point was recovery from DIC on day 3. The analysis was conducted with an intention-to-treat approach. DIC was diagnosed according to the Japanese Association for Acute Medicine (JAAM) scoring system. The systemic inflammatory response syndrome (SIRS) score, platelet count and global markers of coagulation and fibrinolysis were measured on day 0 and day 3., Results: Antithrombin treatment resulted in significantly decreased DIC scores and better recovery rates from DIC compared with those observed in the control group on day 3. The incidence of minor bleeding complications did not increase, and no major bleeding related to antithrombin treatment was observed. The platelet count significantly increased; however, antithrombin did not influence the sequential organ failure assessment (SOFA) score or markers of coagulation and fibrinolysis on day 3., Conclusions: Moderate doses of antithrombin improve DIC scores, thereby increasing the recovery rate from DIC without any risk of bleeding in DIC patients with sepsis., Trial Registration: UMIN Clinical Trials Registry (UMIN-CTR) UMIN000000882.

Rationale: The mechanistic basis for cardiac and renal dysfunction in sepsis is unknown. In particular, the degree and type of cell death is undefined., Objectives: To evaluate the degree of sepsis-induced cardiomyocyte and renal tubular cell injury and death., Methods: Light and electron microscopy and immunohistochemical staining for markers of cellular injury and stress, including connexin-43 and kidney-injury-molecule-1 (Kim-1), were used in this study., Measurements and Main Results: Rapid postmortem cardiac and renal harvest was performed in 44 septic patients. Control hearts were obtained from 12 transplant and 13 brain-dead patients. Control kidneys were obtained from 20 trauma patients and eight patients with cancer. Immunohistochemistry demonstrated low levels of apoptotic cardiomyocytes (<1-2 cells per thousand) in septic and control subjects and revealed redistribution of connexin-43 to lateral membranes in sepsis (P < 0.020). Electron microscopy showed hydropic mitochondria only in septic specimens, whereas mitochondrial membrane injury and autophagolysosomes were present equally in control and septic specimens. Control kidneys appeared relatively normal by light microscopy; 3 of 20 specimens showed focal injury in approximately 1% of renal cortical tubules. Conversely, focal acute tubular injury was present in 78% of septic kidneys, occurring in 10.3 ± 9.5% and 32.3 ± 17.8% of corticomedullary-junction tubules by conventional light microscopy and Kim-1 immunostains, respectively (P < 0.01). Electron microscopy revealed increased tubular injury in sepsis, including hydropic mitochondria and increased autophagosomes., Conclusions: Cell death is rare in sepsis-induced cardiac dysfunction, but cardiomyocyte injury occurs. Renal tubular injury is common in sepsis but presents focally; most renal tubular cells appear normal. The degree of cell injury and death does not account for severity of sepsis-induced organ dysfunction.

Context: Severe sepsis is typically characterized by initial cytokine-mediated hyperinflammation. Whether this hyperinflammatory phase is followed by immunosuppression is controversial. Animal studies suggest that multiple immune defects occur in sepsis, but data from humans remain conflicting., Objectives: To determine the association of sepsis with changes in host innate and adaptive immunity and to examine potential mechanisms for putative immunosuppression., Design, Setting, and Participants: Rapid postmortem spleen and lung tissue harvest was performed at the bedsides of 40 patients who died in intensive care units (ICUs) of academic medical centers with active severe sepsis to characterize their immune status at the time of death (2009-2011). Control spleens (n = 29) were obtained from patients who were declared brain-dead or had emergent splenectomy due to trauma; control lungs (n = 20) were obtained from transplant donors or from lung cancer resections., Main Outcome Measures: Cytokine secretion assays and immunophenotyping of cell surface receptor-ligand expression profiles were performed to identify potential mechanisms of immune dysfunction. Immunohistochemical staining was performed to evaluate the loss of immune effector cells., Results: The mean ages of patients with sepsis and controls were 71.7 (SD, 15.9) and 52.7 (SD, 15.0) years, respectively. The median number of ICU days for patients with sepsis was 8 (range, 1-195 days), while control patients were in ICUs for 4 or fewer days. The median duration of sepsis was 4 days (range, 1-40 days). Compared with controls, anti-CD3/anti-CD28-stimulated splenocytes from sepsis patients had significant reductions in cytokine secretion at 5 hours: tumor necrosis factor, 5361 (95% CI, 3327-7485) pg/mL vs 418 (95% CI, 98-738) pg/mL; interferon γ, 1374 (95% CI, 550-2197) pg/mL vs 37.5 (95% CI, -5 to 80) pg/mL; interleukin 6, 3691 (95% CI, 2313-5070) vs 365 (95% CI, 87-642) pg/mL; and interleukin 10, 633 (95% CI, -269 to 1534) vs 58 (95% CI, -39 to 156) pg/mL; (P < .001 for all). There were similar reductions in 5-hour lipopolysaccharide-stimulated cytokine secretion. Cytokine secretion in sepsis patients was generally less than 10% that in controls, independent of age, duration of sepsis, corticosteroid use, and nutritional status. Although differences existed between spleen and lung, flow cytometric analysis showed increased expression of selected inhibitory receptors and ligands and expansion of suppressor cell populations in both organs. Unique differences in cellular inhibitory molecule expression existed in immune cells isolated from lungs of sepsis patients vs cancer patients and vs transplant donors. Immunohistochemical staining showed extensive depletion of splenic CD4, CD8, and HLA-DR cells and expression of ligands for inhibitory receptors on lung epithelial cells., Conclusions: Patients who die in the ICU following sepsis compared with patients who die of nonsepsis etiologies have biochemical, flow cytometric, and immunohistochemical findings consistent with immunosuppression. Targeted immune-enhancing therapy may be a valid approach in selected patients with sepsis.

The splenic white pulp (WP) consists of CD20-positive lymph follicles (LFs) and CD3-positive periarteriolar lymphoid sheaths. Atrophy of the WP associated with a prolonged period of sepsis is a well-known pathological finding at autopsy. On the other hand, dense subendothelial leukocyte infiltration in the trabecular veins is also commonly observed in autopsy specimens of septic spleen. However, the characteristics and significance of this finding have not yet been well studied. In this study, autopsy spleens obtained from 55 sepsis and 45 non-sepsis patients were compared to determine the clinicopathological characteristics of subendothelial leukocyte infiltration in the trabecular veins, and its pathological significance was discussed. Severe and mild subendothelial leukocyte infiltration in the trabecular veins was observed in 45.5% of sepsis patients, but was absent in non-sepsis patients. Several clinicopathological characteristics of subendothelial leukocyte infiltration were identified. Firstly, the majority of infiltrated cells were lymphocytes. Secondly, both incidence and degree of infiltration were decreased at the late phase of sepsis accompanied by atrophy of the WP. Thirdly, types and compositions of infiltrated leukocytes reflected the histological findings of the spleen. Thus, the percentage of CD20-positive cells in the infiltrating cells into the subendothelium was proportional to the relative size of the CD20-positive area in the specimen, and the percentage of MUM1-p-positive cells in the infiltrating cells was proportional to the frequency of appearance of MUM1-p-positive cells in the red pulp. The CD20-positive area approximated the relative size of the WP in the septic cases, while the frequency of appearance of MUM1-p-positive cells was indicative of the differentiation levels of LFs into plasma cells upon antigen stimulation. Lastly, the intense subendothelial infiltration of CD20-positive cells was specific for the early stage of sepsis, and the morphological characteristics of these CD20-positive cells suggested their association with the marginal zone. Based on these clinicopathological characteristics and the fact that leukocyte infiltration into the subendothelium of trabecular veins became undetectable as atrophy of the WP progressed, it was suggested that the infiltrating cells had migrated from the WP, and this cell infiltration is an early activated immunological reaction in the spleen. Furthermore, the presence of possible efflux or drainage routes in the subendothelial spaces of trabecular veins was suggested.

CD10 and MUM1 are representative B cell differentiation markers. Follicular lymphoma (FL) is usually positive for CD10 and negative for MUM1. In this study, however, we compared 22 FLs with peculiar phenotype CD10-MUM1+ with 119 typical CD10+MUM1- FLs. All CD10-MUM1+ FL patients exhibited follicular structure with follicular dendritic meshwork, and a high rate of somatic hypermutation and ongoing mutation, similar to typical FL. However, CD10-MUM1+ FLs were encountered frequently in the elderly compared with CD10+MUM1- typical FLs (67.0 versus 58.7 years, P < .01), showed high grade (grade 3A or 3B) morphology (91% versus 17%, P < .001), diffuse proliferation (59% vs 19%, P < .001), and lacked BCL2/IGH translocation (5% versus 92.5%, P < .001), which is the most characteristic aberration in FL, and 88% showed BCL6 gene abnormalities (translocation or amplification). Our results indicate that CD10-MUM1+ FL is different from typical FL with respect to biologic and clinical features.

The present study was conducted to investigate whether there was any effect of carbohydrate sources on the magnitude of differences in growth and tissue weights found between germ-free and conventional environments in the chicken. Germ-free and conventional birds were allowed free access to a purified diet in which glucose or fructose was used as a sole carbohydrate source from 7 to 17 days of age. Growth performance and visceral weights were measured at the end of the experiment. The results indicated that there was no difference in growth, feed intake, or feed efficiency between the two environments, but that feeding fructose increased feed intake and decreased feed efficiency compared with feeding glucose. The conventional birds had heavier visceral organ weights including liver, jejuno-ileum, and cecum than did the germ-free counterparts. Feeding fructose resulted in lighter liver weight and heavier weights of jejuno-ileum and cecum than feeding glucose. It was concluded that consuming fructose might increase the lower gut weight of the chicken, as was found by the association with normal microflora, but might not affect overall growth compared with consuming glucose.

An experiment was conducted to investigate the effect of diet type on enhanced protein synthesis by the gut microflora in the chick intestine. Both germ-free (GF) and conventional (CV) White Leghorn chicks were fed ad libitum from 4 to 14 d of age either a nonpurified diet or a purified diet having 19% crude protein and 12.1 kJ/g metabolizable energy value. At 14 d of age, protein synthesis was measured in duodenum, jejunoileum and ceca after a large dose of L-[4-3H]phenylalanine injected intravenously via a wing vein. The results showed that wet tissue weights for all intestinal sections were significantly greater in CV birds than in GF counterparts with consistently larger differences between the two environments in chicks fed the nonpurified diet than in those fed the purified diet. Protein synthesis in all intestinal sections was significantly enhanced by the presence of gut microflora in terms of both fractional rate (%/d) and absolute rate [mg/(100 g BW.d)]. The effect of diet type on fractional and absolute rates of protein synthesis was most remarkable in ceca where the significant difference between GF and CV states was found only in chicks fed the nonpurified diet but not in those fed the purified diet.