2019年02月, 北海道大学医学部, 平成30年度 フラテ研究奨励賞　　　　　　　　　　　　　　　
和田剛志

Complication frequency of mechanical chest compression devices: A single-center, blinded study using retrospective data
Takumi Tsuchida, Takashi Kamiishi, Hiroaki Usubuchi, Akiko Semba, Masaki Takahashi, Asumi Mizugaki, Mariko Hayamizu, Mineji Hayakawa, Takeshi Wada
Resuscitation Plus, 20, 100786, 100786, Elsevier BV, 2024年12月
研究論文（学術雑誌）

Simultaneous prognostic score validation in patients with out-of-hospital cardiac arrest by a post-hoc analysis based on national multicenter registry.
Takumi Tsuchida, Kota Ono, Masaki Takahashi, Mariko Hayamaizu, Asumi Mizugaki, Kunihiko Maekawa, Takeshi Wada, Mineji Hayakawa
Scientific reports, 14, 1, 18745, 18745, 2024年08月13日, ［国際誌］
英語, 研究論文（学術雑誌）, Using a nationwide multicenter prospective registry in Japan's data, we calculated prognostic and predictive scores, including the Out-of-Hospital Cardiac Arrest (OHCA); Cardiac Arrest Hospital Prognosis (CAHP); Nonshockable rhythm, Unwitnessed arrest, Long no-flow or Long low-flow period, blood PH < 7.2, Lactate > 7.0 mmol/L, End-stage chronic kidney disease on dialysis, Age ≥ 85 years, Still resuscitation, and Extracardiac cause (NULL-PLEASE); revised post-Cardiac Arrest Syndrome for Therapeutic hypothermia (rCAST); and MIRACLE2 scores, for adult patients with cardiac arrest. The MIRACLE2 score was validated with the modified MIRACLE2 score, which excludes information of pupillary reflexes. Each score was calculated only for the cases with no missing data for the variables used. These scores' accuracies were compared using neurological outcomes 30 days after out-of-hospital cardiac arrest (OOHCA). Patients with a cerebral performance category scale of 1 or 2 were designated as having favorable neurological outcomes. Each score's discrimination ability was evaluated by the receiver operating characteristic curve's area under the curve (AUC). To assess in detail in areas of high specificity and high sensitivity, which are areas of interest to clinicians, partial AUCs were also used. The analysis included 11,924 hospitalized adult patients. The AUCs of the OHCA, MIRACLE2, CAHP, rCAST, and NULL-PLEASE scores for favorable neurological outcomes were 0.713, 0.727, 0.785, 0.761, and 0.831, respectively. The CAHP and NULL-PLEASE scores were significantly more accurate than the rest. Accuracies did not differ significantly between the CAHP and NULL-PLEASE scores. The NULL-PLEASE score was significantly better at discriminating favorable neurological prognoses at 30 days in patients with OOHCA compared to other scoring systems.

Practical approach to thrombocytopenia in patients with sepsis: a narrative review.
Kasumi Satoh, Takeshi Wada, Akihito Tampo, Gaku Takahashi, Kota Hoshino, Hironori Matsumoto, Takayuki Taira, Satoshi Kazuma, Takamitsu Masuda, Takashi Tagami, Hiroyasu Ishikura
Thrombosis journal, 22, 1, 67, 67, 2024年07月22日, ［国際誌］
英語, 研究論文（学術雑誌）, Thrombocytopenia frequently occurs in patients with sepsis. Disseminated intravascular coagulation (DIC) may be a possible cause of thrombocytopenia owing to its high prevalence and association with poor outcomes; however, it is important to keep the presence of other diseases in mind in sepsis practice. Thrombotic microangiopathy (TMA), which is characterized by thrombotic thrombocytopenic purpura, Shiga toxin-producing Escherichia coli hemolytic uremic syndrome (HUS), and complement-mediated HUS, is characterized by thrombocytopenia, microangiopathic hemolytic anemia, and organ damage. TMA has become widely recognized in recent years because of the development of specific treatments. Previous studies have reported a remarkably lower prevalence of TMA than DIC; however, its epidemiology is not well defined, and there may be cases in which TMA is not correctly diagnosed, resulting in poor outcomes. Therefore, it is important to differentiate DIC from TMA. Nevertheless, differentiating between DIC and TMA remains a challenge as indicated by previous reports that most patients with TMA can be diagnosed as DIC using the universal coagulation scoring system. Several algorithms to differentiate sepsis-related DIC from TMA have been suggested, contributing to improving the care of septic patients with thrombocytopenia; however, it may be difficult to apply these algorithms to patients with coexisting DIC and TMA, which has recently been reported. This review describes the disease characteristics, including epidemiology, pathophysiology, and treatment, of DIC, TMA, and other diseases with thrombocytopenia and proposes a novel practical approach flow, which is characterized by the initiation of the diagnosis of TMA in parallel with the diagnosis of DIC. This practical flow also refers to the longitudinal diagnosis and treatment flow with TMA in mind and real clinical timeframes. In conclusion, we aim to widely disseminate the results of this review that emphasize the importance of incorporating consideration of TMA in the management of septic DIC. We anticipate that this practical new approach for the diagnostic and treatment flow will lead to the appropriate diagnosis and treatment of complex cases, improve patient outcomes, and generate new epidemiological evidence regarding TMA.

Proposal and Validation of a Clinically Relevant Modification of the Japanese Association for Acute Medicine Disseminated Intravascular Coagulation Diagnostic Criteria for Sepsis.
Kazuma Yamakawa, Yutaka Umemura, Katsunori Mochizuki, Tadashi Matsuoka, Takeshi Wada, Mineji Hayakawa, Toshiaki Iba, Yasuhiro Ohtomo, Kohji Okamoto, Toshihiko Mayumi, Toshiaki Ikeda, Hiroyasu Ishikura, Hiroshi Ogura, Shigeki Kushimoto, Daizoh Saitoh, Satoshi Gando
Thrombosis and haemostasis, 2024年05月10日, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND:  Japanese Association for Acute Medicine (JAAM) disseminated intravascular coagulation (DIC) criteria were launched nearly 20 years ago. Following the revised conceptual definition of sepsis and subsequent omission of systemic inflammatory response syndrome (SIRS) score from the latest sepsis diagnostic criteria, we omitted the SIRS score and proposed a modified version of JAAM DIC criteria, the JAAM-2 DIC criteria. OBJECTIVES:  To validate and compare performance between new JAAM-2 DIC criteria and conventional JAAM DIC criteria for sepsis. METHODS:  We used three datasets containing adult sepsis patients from a multicenter nationwide Japanese cohort study (J-septic DIC, FORECAST, and SPICE-ICU registries). JAAM-2 DIC criteria omitted the SIRS score and set the cutoff value at ≥3 points. Receiver operating characteristic (ROC) analyses were performed between the two DIC criteria to evaluate prognostic value. Associations between in-hospital mortality and anticoagulant therapy according to DIC status were analyzed using propensity score weighting to compare significance of the criteria in determining introduction of anticoagulants against sepsis. RESULTS:  Final study cohorts of the datasets included 2,154, 1,065, and 608 sepsis patients, respectively. ROC analysis revealed that curves for both JAAM and JAAM-2 DIC criteria as predictors of in-hospital mortality were almost consistent. Survival curves for the anticoagulant and control groups in the propensity score-weighted prediction model diagnosed using the two criteria were also almost entirely consistent. CONCLUSION:  JAAM-2 DIC criteria were equivalent to JAAM DIC criteria regarding prognostic and diagnostic values for initiating anticoagulation. The newly proposed JAAM-2 DIC criteria could be potentially alternative criteria for sepsis management.

冷凍倉庫内で受傷した腹部骨盤腔外傷,低体温症,そして凝固破綻 救えなかったか?　　　　　　　　　　　　　　　
村上 壮一, 和田 剛志, 方波見 謙一, 高岡 憲敬, 林 真理子, 三浦 巧, 海老原 裕磨, 倉島 庸, 七戸 俊明, 平野 聡
日本外傷学会雑誌, 38, 2, 227, 227, (一社)日本外傷学会, 2024年04月
日本語

Effect of gender on 28-day survival rates and transfusion volume in severe trauma patients: a multicenter observational study
Takumi Tsuchida, Asumi Mizugaki, Shohei Tanaka, Akiko Semba, Takuma Nakajima, Takeshi Wada
Shock, Ovid Technologies (Wolters Kluwer Health), 2024年03月25日
研究論文（学術雑誌）, Abstract

Background

This study clarified the relationship between sex with survival and transfusion volume in severe trauma cases.

Methods

A multicenter, collaborative post-hoc analysis of patients with trauma in Japan was conducted. Patients aged ≥18 years with severe trauma indicated by an Injury Severity Score (ISS) of 16 or higher were enrolled. Patients were matched and analyzed by gender based on propensity score with factors determined at the time of injury. Subgroup analysis was performed on patients younger than 50 years and older than 50 years. The significance level was defined as p < 0.05.

Results

The 1,189 patients included in this registry were divided into adjusted groups of 226 male and female patients each. In the main analysis, 28-day survival rates in females were significantly higher than those in males (p = 0.046). In the subgroup analyses, there was no statistically significant prognostic effect of gender. Secondary outcomes, including transfusion volume, showed no significant gender-based variations. Logistic regression analyses consistently demonstrated that female sex was a significant favorable prognostic factor in all ages. This was true for the over-50 group on subgroup analysis, but no significant gender-prognosis relationship was identified in the under-50 age group. High ISS were associated with poorer outcomes across all age groups.

Conclusion

In severe trauma, survival at 28 days was significantly lower in males. However, this trend was not observed in patients aged ˂50 years. Factors other than sex hormones may be responsible for differences in posttraumatic outcomes by gender.

Efficacy of antithrombin administration for patients with sepsis: A systematic review, meta‐analysis, and meta‐regression
Takumi Tsuchida, Yuto Makino, Takeshi Wada, Noritaka Ushio, Takaaki Totoki, Naoki Fujie, Shunsuke Yasuo, Tadashi Matsuoka, Hiroyuki Koami, Kazuma Yamakawa, Toshiaki Iba
Acute Medicine & Surgery, 11, 1, Wiley, 2024年01月
研究論文（学術雑誌）, Abstract

Aims

There have been inconsistent reports regarding the effect of antithrombin on sepsis; furthermore, there are limited reports on how dosage affects therapeutic efficacy. Thus, we aimed to perform a systematic review and meta‐analysis of the use of antithrombin for sepsis and a meta‐regression analysis of antithrombin dosage.

Methods

We included randomized controlled trials (RCTs) and observational studies of adult patients with sepsis who received antithrombin. Outcomes included all‐cause mortality and serious bleeding complications. Statistical analyses and data synthesis were performed using a random‐effects model; further, meta‐regression and funnel plots were used to explore heterogeneity and biases.

Results

Seven RCTs and six observational studies were included. Most patients in the RCTs and observational studies had severe sepsis and septic‐disseminated intravascular coagulation (DIC), respectively. A meta‐analysis using RCTs showed no significant differences in mortality between the antithrombin and control groups. However, the meta‐analysis of observational studies indicated a trend of decreasing mortality rates with antithrombin administration (odds ratio [OR], 0.79; 95% confidence interval [CI], 0.68–0.92; p = 0.002). Bleeding complications were significantly higher in the antithrombin group than in the control group in both study types (OR, 1.90; 95% CI, 1.52–2.37; p < 0.01). The meta‐regression analysis showed no correlation between antithrombin dosage and mortality.

Conclusion

A meta‐analysis of RCTs confirmed no survival benefit of antithrombin, whereas that of observational studies, which mostly focused on septic DIC, showed a significant beneficial effect on improving outcomes. Indications of antithrombin should be considered based on its beneficial and harmful effects.

院外心停止蘇生後における神経学的予後不良群の長期予後　　　　　　　　　　　　　　　
早水 真理子, 土田 拓見, 水柿 明日美, 高氏 修平, 本間 慶憲, 斉藤 智誉, 吉田 知由, 方波見 謙一, 和田 剛志, 前川 邦彦, 早川 峰司
日本救急医学会雑誌, 34, 12, 731, 731, (一社)日本救急医学会, 2023年12月
日本語

原因不明の血小板減少症への診断的アプローチが遅れて脳出血に至ったヘパリン起因性血小板減少症の一例　　　　　　　　　　　　　　　
加藤 諄, 本間 慶憲, 斉藤 智誉, 吉田 知由, 方波見 謙一, 和田 剛志, 前川 邦彦, 早川 峰司
日本救急医学会雑誌, 34, 12, 782, 782, (一社)日本救急医学会, 2023年12月
日本語

Variation in coagulation factor activity levels cause discrepancies between activated partial thromboplastin time and anti-Xa activity for heparin monitoring: a retrospective observational study
Tomoyo Saito, Mineji Hayakawa, Osamu Kumano, Yoshinori Honma, Mone Murashita, Jun Kato, Syouki Fukui, Masaki Takahashi, Yuki Takahashi, Takumi Tsuchida, Asumi Mizugaki, Shuhei Takauji, Mariko Hayamizu, Tomonao Yoshida, Kenichi Katabami, Takeshi Wada, Kunihiko Maekawa
Journal of Intensive Care, 11, 1, Springer Science and Business Media LLC, 2023年11月16日
研究論文（学術雑誌）, Abstract

Background

Unfractionated heparin (UFH) is primarily monitored using activated partial thromboplastin time (APTT). However, the recent introduction of anti-activated factor X (anti-Xa) activity testing has provided a direct evaluation of Xa inhibition by anticoagulants. This study aimed to investigate discrepancies between APTT and anti-Xa activity during UFH monitoring in critically ill patients and explore their underlying causes.

Methods

This study analyzed 271 pairs of laboratory test results from blood samples of 99 critically ill patients receiving continuous intravenous UFH. Theoretical APTT values were calculated using fitted curve equations from spiked sample measurements with anti-Xa activity. Samples were categorized into three groups based on the measurement of the APTT/theoretical APTT ratio: the lower group (< 80%), the concordant group (80–120%), and the upper group (> 120%).

Results

The overall concordance rate between APTT and anti-Xa activity was 45%, with a 55% discrepancy rate. The lower group frequently showed apparent heparin overdoses, while coagulation factor activities in the lower and upper groups were higher and lower, respectively, than those in the concordant group. Particularly, the lower group exhibited higher factor VIII activity levels than the upper and concordant groups.

Conclusions

Discrepancies between APTT and anti-Xa activity were frequently observed, influenced by changes in coagulation factors activity levels. The lower and upper groups were classified as pseudo-heparin-resistant and coagulopathy types, respectively. Accurate monitoring of heparin in critically ill patients is crucial, especially in cases of pseudo-heparin resistance, where APTT values may wrongly indicate inadequate heparin dosing despite sufficient anti-Xa activity. Understanding these discrepancies is important for managing heparin therapy in critically ill patients.

Trial registration: Not applicable.

Phenotypes of Disseminated Intravascular Coagulation.
Takeshi Wada, Satoshi Gando
Thrombosis and haemostasis, 2023年10月03日, ［国際誌］
英語, 研究論文（学術雑誌）, Two phenotypes of disseminated intravascular coagulation (DIC) are systematically reviewed. DIC is classified into thrombotic and fibrinolytic phenotypes characterized by thrombosis and hemorrhage, respectively. Major pathology of DIC with thrombotic phenotype is the activation of coagulation, insufficient anticoagulation with endothelial injury, and plasminogen activator inhibitor-1-mediated inhibition of fibrinolysis, leading to microvascular fibrin thrombosis and organ dysfunction. DIC with fibrinolytic phenotype is defined as massive thrombin generation commonly observed in any type of DIC, combined with systemic pathologic hyperfibrinogenolysis caused by underlying disorder that results in severe bleeding due to excessive plasmin formation. Three major pathomechanisms of systemic hyperfibrinogenolysis have been considered: (1) acceleration of tissue-type plasminogen activator (t-PA) release from hypoxic endothelial cells and t-PA-rich storage pools, (2) enhancement of the conversion of plasminogen to plasmin due to specific proteins and receptors that are expressed on cancer cells and endothelial cells, and (3) alternative pathways of fibrinolysis. DIC with fibrinolytic phenotype can be diagnosed by DIC diagnosis followed by the recognition of systemic pathologic hyperfibrin(ogen)olysis. Low fibrinogen levels, high fibrinogen and fibrin degradation products (FDPs), and the FDP/D-dimer ratio are important for the diagnosis of systemic pathologic hyperfibrin(ogen)olysis. Currently, evidence-based treatment strategies for DIC with fibrinolytic phenotypes are lacking. Tranexamic acid appears to be one of the few methods to be effective in the treatment of systemic pathologic hyperfibrin(ogen)olysis. International cooperation for the elucidation of pathomechanisms, establishment of diagnostic criteria, and treatment strategies for DIC with fibrinolytic phenotype are urgent issues in the field of thrombosis and hemostasis.

Differences in acute outcomes of suicide patients by psychiatric disorder: Retrospective observational study
Takumi Tsuchida, Masaki Takahashi, Asumi Mizugaki, Hisashi Narita, Takeshi Wada
Medicine, 102, 38, e35065, e35065, Ovid Technologies (Wolters Kluwer Health), 2023年09月22日
研究論文（学術雑誌）, Suicide is a social problem with significant economic losses, the victims of which are mainly from the productive population. There are numerous reports on the assessment of suicide risk, but most focus on long-term management. Therefore, factors influencing the severity of physical impairments in the acute phase and the prognosis of suicidal patients have not been sufficiently investigated. This is a single-center retrospective observational study. We collected data on suicidal patients admitted to our emergency department. The effect of age, gender, psychiatric history, method of suicide, alcohol consumption, and hospital admission on the outcome of suicide was assessed. Outcomes were assessed using the hospital mortality scale and the cerebral performance category scale for in-hospital mortality within 28 days. Methods of suicide with a high mortality rate (hanging, jumping, carbon monoxide poisoning, and burns) were defined as lethal methods. A detailed risk assessment of outcomes was performed for patients with schizophrenia, mood disorders, and somatoform disorders. We identified 340 suicide patients from computerized medical records and analyzed 322 records without missing data. The non-survivor group predominantly comprised older adults, men, and patients without a history of psychiatric treatment. Contrastingly, more patients drank alcohol before suicide in the survivor group. In the subgroup analysis, patients with schizophrenia had unfavorable neurological outcomes. Patients with mood disorders had worse in-hospital mortality than other psychiatric patients, as did patients who chose the lethal method. By disease, patients with stress-related and somatoform disorders tended to have higher survival rates, although their psychiatric hospitalization rates were lower. Conversely, patients with mood disorders had a higher rate of hospital visits but a lower survival rate. The results suggest that usual outpatient treatment alone may not be sufficient to reduce suicide mortality in patients with mood disorders who are considered to be at high risk of suicide.

Early restricted oxygen therapy after resuscitation from cardiac arrest (ER-OXYTRAC): protocol for a stepped-wedge cluster randomised controlled trial.
Ryo Yamamoto, Kazuma Yamakawa, Akira Endo, Koichiro Homma, Yasunori Sato, Ryo Takemura, Takeshi Yamagiwa, Keiki Shimizu, Daiki Kaito, Masayuki Yagi, Taku Yonemura, Takayuki Shibusawa, Ginga Suzuki, Takahiro Shoji, Naoya Miura, Jiro Takahashi, Chihiro Narita, Saori Kurata, Kazunobu Minami, Takeshi Wada, Yoshihisa Fujinami, Yohei Tsubouchi, Mai Natsukawa, Jun Nagayama, Wataru Takayama, Ken Ishikura, Kyoko Yokokawa, Yasuo Fujita, Hirofumi Nakayama, Hideki Tokuyama, Kota Shinada, Takayuki Taira, Shoki Fukui, Noritaka Ushio, Masaki Nakane, Eisei Hoshiyama, Akihito Tampo, Hisako Sageshima, Hiroki Takami, Shinichi Iizuka, Hitoshi Kikuchi, Jun Hagiwara, Takashi Tagami, Yumi Funato, Junichi Sasaki, Study Group Er-Oxytrac
BMJ open, 13, 9, e074475, 2023年09月15日, ［国際誌］
英語, 研究論文（学術雑誌）, INTRODUCTION: Cardiac arrest is a critical condition, and patients often experience postcardiac arrest syndrome (PCAS) even after the return of spontaneous circulation (ROSC). Administering a restricted amount of oxygen in the early phase after ROSC has been suggested as a potential therapy for PCAS; however, the optimal target for arterial partial pressure of oxygen or peripheral oxygen saturation (SpO2) to safely and effectively reduce oxygen remains unclear. Therefore, we aimed to validate the efficacy of restricted oxygen treatment with 94%-95% of the target SpO2 during the initial 12 hours after ROSC for patients with PCAS. METHODS AND ANALYSIS: ER-OXYTRAC (early restricted oxygen therapy after resuscitation from cardiac arrest) is a nationwide, multicentre, pragmatic, single-blind, stepped-wedge cluster randomised controlled trial targeting cases of non-traumatic cardiac arrest. This study includes adult patients with out-of-hospital or in-hospital cardiac arrest who achieved ROSC in 39 tertiary centres across Japan, with a target sample size of 1000. Patients whose circulation has returned before hospital arrival and those with cardiac arrest due to intracranial disease or intoxication are excluded. Study participants are assigned to either the restricted oxygen (titration of a fraction of inspired oxygen with 94%-95% of the target SpO2) or the control (98%-100% of the target SpO2) group based on cluster randomisation per institution. The trial intervention continues until 12 hours after ROSC. Other treatments for PCAS, including oxygen administration later than 12 hours, can be determined by the treating physicians. The primary outcome is favourable neurological function, defined as cerebral performance category 1-2 at 90 days after ROSC, to be compared using an intention-to-treat analysis. ETHICS AND DISSEMINATION: This study has been approved by the Institutional Review Board at Keio University School of Medicine (approval number: 20211106). Written informed consent will be obtained from all participants or their legal representatives. Results will be disseminated via publications and presentations. TRIAL REGISTRATION NUMBER: UMIN Clinical Trials Registry (UMIN000046914).

Delayed neurologic improvement and long-term survival of patients with poor neurologic status after out-of-hospital cardiac arrest: a retrospective cohort study in Japan
Mariko Hayamizu, Akira Kodate, Hisako Sageshima, Takumi Tsuchida, Yoshinori Honma, Asumi Mizugaki, Tomonao Yoshida, Tomoyo Saito, Kenichi Katabami, Takeshi Wada, Kunihiko Maekawa, Mineji Hayakawa
Resuscitation, 109790, 109790, Elsevier BV, 2023年04月
研究論文（学術雑誌）

Sepsis-related coagulopathy treatment based on the disseminated intravascular coagulation diagnostic criteria: a post-hoc analysis of a prospective multicenter observational study.
Takeshi Wada, Kazuma Yamakawa, Daijiro Kabata, Toshikazu Abe, Seitaro Fujishima, Shigeki Kushimoto, Toshihiko Mayumi, Hiroshi Ogura, Daizoh Saitoh, Atsushi Shiraishi, Yasuhiro Otomo, Satoshi Gando
Journal of intensive care, 11, 1, 8, 8, 2023年03月05日, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: The development of disseminated intravascular coagulation (DIC) in patients with sepsis has been repeatedly confirmed as a factor associated with poor prognosis. Anticoagulant therapy has been expected to improve sepsis patient outcomes, whereas no randomized controlled trials have demonstrated the survival benefit of anticoagulant therapies in non-specific overall sepsis. Patient selection based on the component of "high disease severity" in addition to "sepsis with DIC" has recently proved important in identifying appropriate targets for anticoagulant therapy. The aims of this study were to characterize "severe" sepsis DIC patients and to identify the patient population benefiting from anticoagulant therapy. METHODS: This retrospective sub-analysis of a prospective multicenter study included 1,178 adult patients with severe sepsis from 59 intensive care units in Japan from January 2016 to March 2017. We examined the association of patient outcomes, including organ dysfunction and in-hospital mortality, with the DIC score and prothrombin time-international normalized ratio (PT-INR), one of the components of the DIC score, using multivariable regression models including the cross-product term between these indicators. Multivariate Cox proportional hazard regression analysis with non-linear restricted cubic spline including a three-way interaction term (anticoagulant therapy × the DIC score × PT-INR) was also performed. Anticoagulant therapy was defined as the administration of antithrombin, recombinant human thrombomodulin, or their combination. RESULTS: In total, we analyzed 1013 patients. The regression model showed that organ dysfunction and in-hospital mortality deteriorated with higher PT-INR values in the range of < 1.5 and that this trend was more pronounced with higher DIC scores. Three-way interaction analysis demonstrated that anticoagulant therapy was associated with better survival outcome in patients with a high DIC score and high PT-INR. Furthermore, we identified a DIC score ≥ 5 and PT-INR ≥ 1.5 as the clinical threshold for identification of optimal targets for anticoagulant therapy. CONCLUSIONS: The combined use of the DIC score and PT-INR helps in selecting the optimal patient population for anticoagulant therapy in sepsis-induced DIC. The results obtained from this study will provide valuable information regarding the study design of randomized controlled trials examining the effects of anticoagulant therapy for sepsis. TRIAL REGISTRATION: UMIN-CTR, UMIN000019742. Registered on November 16, 2015.

Gender-related differences in the coagulofibrinolytic responses and long-term outcomes in patients with isolated traumatic brain injury: A 2-center retrospective study
Takumi Tsuchida, Takeshi Wada, Ryuta Nakae, Yu Fujiki, Takahiro Kanaya, Yasuhiro Takayama, Go Suzuki, Yasutaka Naoe, Shoji Yokobori
Medicine, 102, 6, e32850, e32850, Ovid Technologies (Wolters Kluwer Health), 2023年02月10日
研究論文（学術雑誌）

Sepsis-induced disseminated intravascular coagulation: an international estrangement of disease concept.
Noritaka Ushio, Takeshi Wada, Yuichiro Ono, Kazuma Yamakawa
Acute medicine & surgery, 10, 1, e00843, 2023年, ［国際誌］
英語, 研究論文（学術雑誌）, Disseminated intravascular coagulation (DIC) is an acquired syndrome characterized by widespread intravascular activation of coagulation, which can be caused by infectious and noninfectious insults, such as trauma, postcardiac arrest syndrome, and malignant diseases. At present, diagnosis and treatment of DIC clearly differ between Japan and Western countries; in Japan, DIC has long been considered a therapeutic target, and much evidence on DIC has been published. However, there has recently been no international consensus on whether DIC should be a therapeutic target with anticoagulant therapy. This review describes the coagulofibrinolytic system abnormalities associated with sepsis and discusses related management strategies. It also explores the reasons why DIC is perceived differently in different regions. There is a major discrepancy between diagnostic and treatment options in Japan, which are based on holistic assessments of trials, as well as the results of post hoc subgroup analyses and observational studies, and those in Western countries, which are based mainly on the results of sepsis mega trials, especially randomized controlled trials. The differences might also be due to various patient factors in each region, especially racial characteristics in thrombolytic mechanisms, and differences in interpretation of evidence for candidate drugs. Hence, Japanese researchers need to distribute their high-quality clinical research data not only to Japan but also to the rest of the world.

Hyperfibrinolysis and fibrinolysis shutdown in patients with traumatic brain injury.
Ryuta Nakae, Yasuo Murai, Takeshi Wada, Yu Fujiki, Takahiro Kanaya, Yasuhiro Takayama, Go Suzuki, Yasutaka Naoe, Hiroyuki Yokota, Shoji Yokobori
Scientific reports, 12, 1, 19107, 19107, 2022年11月09日, ［国際誌］
英語, 研究論文（学術雑誌）, Traumatic brain injury (TBI) is associated with coagulation/fibrinolysis disorders. We retrospectively evaluated 61 TBI cases transported to hospital within 1 h post-injury. Levels of thrombin-antithrombin III complex (TAT), D-dimer, and plasminogen activator inhibitor-1 (PAI-1) were measured on arrival and 3 h, 6 h, 12 h, 1 day, 3 days and 7 days after injury. Multivariate logistic regression analysis was performed to identify prognostic factors for coagulation and fibrinolysis. Plasma TAT levels peaked at admission and decreased until 1 day after injury. Plasma D-dimer levels increased, peaking up to 3 h after injury, and decreasing up to 3 days after injury. Plasma PAI-1 levels increased up to 3 h after injury, the upward trend continuing until 6 h after injury, followed by a decrease until 3 days after injury. TAT, D-dimer, and PAI-1 were elevated in the acute phase of TBI in cases with poor outcome. Multivariate logistic regression analysis showed that D-dimer elevation from admission to 3 h after injury and PAI-1 elevation from 6 h to 1 day after injury were significant negative prognostic indicators. Post-TBI hypercoagulation, fibrinolysis, and fibrinolysis shutdown were activated consecutively. Hyperfibrinolysis immediately after injury and subsequent fibrinolysis shutdown were associated with poor outcome.

病院の規模が院外心停止患者の予後に与える影響　　　　　　　　　　　　　　　
土田 拓見, 大野 浩太, 前川 邦彦, 和田 剛志, 早水 真理子, 早川 峰司
日本集中治療医学会雑誌, 29, Suppl.1, 461, 461, (一社)日本集中治療医学会, 2022年11月
日本語

Optimal target blood pressure in elderly with septic shock (OPTPRESS) trial: study protocol for a randomized controlled trial.
Akira Endo, Kazuma Yamakawa, Takashi Tagami, Yutaka Umemura, Kyosuke Takahashi, Hiroki Nagasawa, Yuichi Araki, Mitsuaki Kojima, Toshiki Sera, Masayuki Yagi, Ryo Yamamoto, Jiro Takahashi, Masaki Nakane, Chikashi Takeda, Chihiro Narita, Satoshi Kazuma, Hiroko Okura, Hiroyuki Takahashi, Takeshi Wada, Shu Tahara, Ayaka Matsuoka, Todani Masaki, Atsushi Shiraishi, Keiichiro Shimoyama, Yuta Yokokawa, Rintaro Nakamura, Hisako Sageshima, Yuichiro Yanagida, Kunihiko Takahashi, Yasuhiro Otomo
Trials, 23, 1, 799, 799, 2022年09月24日, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Hemodynamic stabilization is a core component in the resuscitation of septic shock. However, the optimal target blood pressure remains debatable. Previous randomized controlled trials suggested that uniformly adopting a target mean arterial pressure (MAP) higher than 65 mmHg for all adult septic shock patients would not be beneficial; however, it has also been proposed that higher target MAP may be beneficial for elderly patients, especially those with arteriosclerosis. METHODS: A multicenter, pragmatic single-blind randomized controlled trial will be conducted to compare target MAP of 80-85 mmHg (high-target) and 65-70 mmHg (control) in the resuscitation of septic shock patients admitted to 28 hospitals in Japan. Patients with septic shock aged ≥65 years are randomly assigned to the high-target or control groups. The target MAP shall be maintained for 72 h after randomization or until vasopressors are no longer needed to improve patients' condition. To minimize the adverse effects related to catecholamines, if norepinephrine dose of ≥ 0.1 μg/kg/min is needed to maintain the target MAP, vasopressin will be initiated. Other therapeutic approaches, including fluid administration, hydrocortisone use, and antibiotic choice, will be determined by the physician in charge based on the latest clinical guidelines. The primary outcome is all-cause mortality at 90 days after randomization. DISCUSSION: The result of this trial will provide great insight on the resuscitation strategy for septic shock in the era of global aged society. Also, it will provide the better understanding on the importance of individualized treatment strategy in hemodynamic management in critically ill patients. TRIAL REGISTRATION: UMIN Clinical Trials Registry; UMIN000041775. Registered 13 September 2020.

Effects of tranexamic acid on coagulofibrinolytic markers during the early stage of severe trauma: A propensity score-matched analysis.
Satoshi Gando, Atsushi Shiraishi, Takeshi Wada, Kazuma Yamakawa, Seitaro Fujishima, Daizoh Saitoh, Shigeki Kushimoto, Hiroshi Ogura, Toshikazu Abe, Toshihiko Mayumi, Junichi Sasaki, Joji Kotani, Naoshi Takeyama, Ryosuke Tsuruta, Kiyotsugu Takuma, Shin-Ichiro Shiraishi, Yasukazu Shiino, Taka-Aki Nakada, Kohji Okamoto, Yuichiro Sakamoto, Akiyoshi Hagiwara, Satoshi Fujimi, Yutaka Umemura, Yasuhiro Otomo
Medicine, 101, 32, e29711, 2022年08月12日, ［国際誌］
英語, 研究論文（学術雑誌）, Tranexamic acid (TXA) reduces the risk of bleeding trauma death without altering the need for blood transfusion. We examined the effects of TXA on coagulation and fibrinolysis dynamics and the volume of transfusion during the early stage of trauma. This subanalysis of a prospective multicenter study of severe trauma included 276 patients divided into propensity score-matched groups with and without TXA administration. The effects of TXA on coagulation and fibrinolysis markers immediately at (time point 0) and 3 hours after (time point 3) arrival at the emergency department were investigated. The transfusion volume was determined at 24 hours after admission. TXA was administered to the patients within 3 hours (median, 64 minutes) after injury. Significant reductions in fibrin/fibrinogen degradation products and D-dimer levels from time points 0 to 3 in the TXA group compared with the non-TXA group were confirmed, with no marked differences noted in the 24-hour transfusion volumes between the 2 groups. Continuously increased levels of soluble fibrin, a marker of thrombin generation, from time points 0 to 3 and high levels of plasminogen activator inhibitor-1, a marker of inhibition of fibrinolysis, at time point 3 were observed in both groups. TXA inhibited fibrin(ogen)olysis during the early stage of severe trauma, although this was not associated with a reduction in the transfusion volume. Other confounders affecting the dynamics of fibrinolysis and transfusion requirement need to be clarified.

Association of Histones With Coagulofibrinolytic Responses and Organ Dysfunction in Adult Post-cardiac Arrest Syndrome
Asumi Mizugaki, Takeshi Wada, Takumi Tsuchida, Satoshi Gando
Frontiers in Cardiovascular Medicine, 9, 885406, 885406, Frontiers Media SA, 2022年06月28日, ［国際誌］
英語, 研究論文（学術雑誌）, Background

Patients successfully resuscitated from cardiac arrest often develop organ dysfunction caused by systemic inflammation and increased coagulation, leading to disseminated intravascular coagulation (DIC). The involvement of histones in DIC and organ dysfunction in patients with sepsis and trauma has been previously reported, raising the probability that histones may also be associated with pathophysiology in patients after cardiac arrest and resuscitation. This study evaluated the relationship between histones and organ dysfunction related to coagulofibrinolytic changes in patients with post-cardiac arrest syndrome (PCAS).

Methods

This prospective single-center observational study assessed 35 adult patients with PCAS who were divided into two groups, i.e., 15 patients with multiple organ dysfunction syndrome (MODS) and 20 patients without MODS. MODS was defined as a sequential organ failure assessment score of ≥12. The plasma levels of histones and coagulofibrinolytic markers, including soluble fibrin, tissue-type plasminogen activator, plasminogen activator inhibitor-1, plasmin-alpha 2-plasmin inhibitor complex (PIC), and soluble thrombomodulin, were measured in patients with PCAS immediately after admission to the emergency department, and 3 and 24 h after arriving at the hospital.

Results

PCAS patients with MODS had higher DIC scores [4 (3.0–5.0) vs. 1 (0.0–3.0), p = 0.012] and higher mortality rates (66.7% vs. 20.0%, p = 0.013) than those without MODS. Moreover, patients with MODS exhibited higher histone levels than those without MODS during the early phase of the post-resuscitation period. Severe endothelial injury and higher thrombin and plasmin generation were observed in the MODS group. Plasma levels of histones were positively correlated with those of soluble fibrin immediately after resuscitation (rho = 0.367, p = 0.030) and PIC 3 h after arriving at the hospital (rho = 0.480, p = 0.005). This correlation was prominent in the patient population with MODS (soluble fibrin: rho = 0.681, p = 0.005, PIC: rho = 0.742, p = 0.002).

Conclusions

This study demonstrated that elevated histone levels were associated with increased levels of thrombin, and subsequent plasmin generation in PCAS patients, especially those with MODS. Further studies are required to elucidate the causal relationship between histones and organ dysfunction related to DIC in PCAS.

Age-related differences in the survival benefit of the administration of antithrombin, recombinant human thrombomodulin, or their combination in sepsis.
Takeshi Wada, Kazuma Yamakawa, Daijiro Kabata, Toshikazu Abe, Hiroshi Ogura, Atsushi Shiraishi, Daizoh Saitoh, Shigeki Kushimoto, Seitaro Fujishima, Toshihiko Mayumi, Toru Hifumi, Yasukazu Shiino, Taka-Aki Nakada, Takehiko Tarui, Yasuhiro Otomo, Kohji Okamoto, Yutaka Umemura, Joji Kotani, Yuichiro Sakamoto, Junichi Sasaki, Shin-Ichiro Shiraishi, Kiyotsugu Takuma, Ryosuke Tsuruta, Akiyoshi Hagiwara, Tomohiko Masuno, Naoshi Takeyama, Norio Yamashita, Hiroto Ikeda, Masashi Ueyama, Satoshi Fujimi, Satoshi Gando
Scientific reports, 12, 1, 9304, 9304, 2022年06月03日, ［国際誌］
英語, 研究論文（学術雑誌）, Disseminated intravascular coagulation (DIC) is one of the major organ dysfunctions associated with sepsis. This retrospective secondary analysis comprised data from a prospective multicenter study to investigate the age-related differences in the survival benefit of anticoagulant therapy in sepsis according to the DIC diagnostic criteria. Adult patients with severe sepsis based on the Sepsis-2 criteria were enrolled and divided into the following groups: (1) anticoagulant group (patients who received anticoagulant therapy) and (2) non-anticoagulant group (patients who did not receive anticoagulant therapy). Patients in the former group were administered antithrombin, recombinant human thrombomodulin, or their combination. The increases in the risk of hospital mortality were suppressed in the high-DIC-score patients aged 60-70 years receiving anticoagulant therapy. No favorable association of anti-coagulant therapy with hospital mortality was observed in patients aged 50 years and 80 years. Furthermore, anticoagulant therapy in the lower-DIC-score range increased the risk of hospital mortality in patients aged 50-60 years. In conclusion, anticoagulant therapy was associated with decreased hospital mortality according to a higher DIC score in septic patients aged 60-70 years. Anticoagulant therapy, however, was not associated with a better outcome in relatively younger and older patients with sepsis.

Residual persistence of cytotoxicity lymphocytes and regulatory T cells in patients with severe coronavirus disease 2019 over a 1-year recovery process.
Yumi Mitsuyama, Kazuma Yamakawa, Katsuhide Kayano, Miho Maruyama, Yutaka Umemura, Takeshi Wada, Satoshi Fujimi
Acute medicine & surgery, 9, 1, e803, 2022年, ［国際誌］
英語, 研究論文（学術雑誌）, AIM: To clarify the immune cellular changes in critically ill patients recovering from coronavirus disease 2019 (COVID-19). METHODS: The immune response of peripheral blood mononuclear cells from patients with severe COVID-19 in different stages of recovery (3, 6, and 12 months from hospitalization) was evaluated by single-cell mass cytometry. Immunological changes in patients were compared with those in age-matched healthy donors. RESULTS: Three patients with severe COVID-19 were compared with four healthy donors. In the patients, there was an increase in the cell density of CD4- and CD8-positive T lymphocytes, and B cells, over the course of the recovery period. CD4- and CD8-positive T lymphocytes expressing T-bet and granzyme B (Gzm B) in patients were abundant during all recovery periods. The level of regulatory T cells remained high throughout the year. The levels of natural killer (NK) cells in patients were higher than in those in the healthy donors, and the frequency of CD16+ NK cells expressing Gzm B increased throughout the year. CONCLUSION: Patients recovering from severe COVID-19 showed persistence of cytotoxic lymphocytes, NK cells, and regulatory T cells throughout the posthospitalization year of recovery.

Association of antithrombin with development of trauma-induced disseminated intravascular coagulation and outcomes.
Takeshi Wada, Atsushi Shiraishi, Satoshi Gando, Daijiro Kabata, Kazuma Yamakawa, Seitaro Fujishima, Daizoh Saitoh, Shigeki Kushimoto, Hiroshi Ogura, Toshikazu Abe, Toshihiko Mayumi, Yasuhiro Otomo
Frontiers in immunology, 13, 1026163, 1026163, 2022年, ［国際誌］
英語, 研究論文（学術雑誌）, INTRODUCTION: Trauma activates the innate immune system to modulate hemostasis and minimize the damage caused by physiological bodily responses, including the activation of coagulation. Sufficiently severe trauma overwhelms physiological responses and elicits the systemic inflammatory response syndrome, which leads to the onset of disseminated intravascular coagulation (DIC), characterized by dysregulated inflammatory coagulofibrinolytic responses. Impaired anticoagulant mechanisms, including antithrombin, constitutes the pathology of DIC, while the dynamics of antithrombin and relevance to outcomes in trauma-induced coagulopathy have not been fully elucidated. This study investigated the associations of antithrombin activity with DIC onset and outcomes in severely injured patients. METHODS: This retrospective sub-analysis of a multicenter, prospective study included patients with an injury severity score ≥16. We characterized trauma patients with low antithrombin activity (antithrombin <80% on hospital arrival, n = 75) in comparison with those who had normal antithrombin activity (antithrombin ≥80%, n = 200). Global markers of coagulation and fibrinolysis, molecular biomarkers for thrombin generation (soluble fibrin [SF]), and markers of anticoagulation (antithrombin) were evaluated to confirm the associations of antithrombin with DIC development and outcomes, including in-hospital mortality and the multiple organ dysfunction syndrome (MODS). RESULTS: Patients with low antithrombin activity had higher prevalence of shock, transfusion requirements, and in-hospital mortality. Higher DIC scores and more severe organ dysfunction were observed in the low AT group compared to that in the normal AT group. Antithrombin activity on arrival at the hospital was an independent predictor of the development of DIC in trauma patients, and levels of SF increased with lower antithrombin values (antithrombin activity > 85%). Antithrombin activity at 3 h showed good predictive performance for in-hospital mortality, and a multivariable Cox proportional-hazard regression model with a cross-product term between the antithrombin and DIC showed that the in-hospital mortality in patients with DIC increased with decreased antithrombin activity. A multivariable logistic regression model showed that the odds for the development of MODS in patients with DIC increased with lower antithrombin values. CONCLUSION: Decreased antithrombin activity in trauma-induced coagulopathy is associated with poor outcomes through worsening of DIC.

Neutrophil phenotypes implicated in the pathophysiology of post-traumatic sepsis.
Asumi Mizugaki, Takeshi Wada, Takumi Tsuchida, Yoshitaka Oda, Katsuhide Kayano, Kazuma Yamakawa, Shinya Tanaka
Frontiers in medicine, 9, 982399, 982399, 2022年, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: The disruption of immune homeostasis after trauma is a major cause of post-traumatic organ dysfunction and/or sepsis. Recently, a variety of neutrophil phenotypes with distinct functions have been identified and suggested as involved in various clinical conditions. The association between neutrophil phenotypes and post-traumatic immunodeficiency has also been reported, yet the specific neutrophil phenotypes and their functional significance in post-traumatic sepsis have not been fully clarified. Therefore, we sought to investigate neutrophil phenotypic changes in a murine model, as these may hold prognostic value in post-traumatic sepsis. MATERIALS AND METHODS: Third-degree burns affecting 25% of the body surface area were used to establish trauma model, and sepsis was induced 24 h later through cecal ligation and puncture (CLP). The Burn/CLP post-traumatic sepsis model and the Sham/CLP control model were established to assess the immunological status after trauma. Histopathological evaluation was performed on the spleen, liver, kidneys, and lung tissues. Immunological evaluation included the assessment of neutrophil markers using mass cytometry as well as cytokine measurements in serum and ascitic fluid through multiplex analysis using LUMINEX®. RESULTS: The Burn/CLP group had a lower survival rate than the Sham/CLP group. Histopathological examination revealed an impaired immune response and more advanced organ damage in the Burn/CLP group. Furthermore, the Burn/CLP group exhibited higher levels of transforming growth factor-beta 1 in the blood and generally lower levels of cytokines than the Sham/CLP group. CD11b, which is involved in neutrophil adhesion and migration, was highly expressed on neutrophils in the Burn/CLP group. The expression of CD172a, which is related to the inhibition of phagocytosis, was also upregulated on neutrophils in the Burn/CLP group. The expression of sialic acid-binding lg-like lectin F and CD68 also differed between the two groups. CONCLUSION: Different neutrophil phenotypes were observed between Burn/CLP and Sham/CLP groups, suggesting that neutrophils are implicated in the immune imbalance following trauma. However, further studies are needed to prove the causal relationships between neutrophil phenotypes and outcomes, including survival rate and organ dysfunction.

Antithrombin activity levels for predicting long-term outcomes in the early phase of isolated traumatic brain injury.
Masaki Takahashi, Takeshi Wada, Ryuta Nakae, Yu Fujiki, Takahiro Kanaya, Yasuhiro Takayama, Go Suzuki, Yasutaka Naoe, Shoji Yokobori
Frontiers in immunology, 13, 981826, 981826, 2022年, ［国際誌］
英語, 研究論文（学術雑誌）, Coagulopathy management is an important strategy for preventing secondary brain damage in patients with traumatic brain injury (TBI). Antithrombin (AT) is a natural anticoagulant that controls coagulation and inflammation pathways. However, the significance of AT activity levels for outcomes in patients with trauma remains unclear. This study aimed to investigate the relationship between AT activity levels and long-term outcomes in patients with TBI; this was a sub-analysis of a prior study that collected blood samples of trauma patients prospectively in a tertiary care center in Kawaguchi City, Japan. We included patients with isolated TBI (iTBI) aged ≥16 years admitted directly to our hospital within 1 h after injury between April 2018 and March 2021. General coagulofibrinolytic and specific molecular biomarkers, including AT, were measured at 1, 3, 6, 12, and 24 h after injury. We analyzed changes in the AT activity levels during the study period and the impact of the AT activity levels on long-term outcomes, the Glasgow Outcome Scale-Extended (GOSE), 6 months after injury. 49 patients were included in this study; 24 had good neurological outcomes (GOSE 6-8), and 25 had poor neurological outcomes (GOSE 1-5). Low AT activity levels were shown within 1 h after injury in patients in the poor GOSE group; this was associated with poor outcomes. Furthermore, AT activity levels 1 h after injury had a strong predictive value for long-term outcomes (area under the receiver operating characteristic curve of 0.871; 95% CI: 0.747-0.994). Multivariate logistic regression analysis with various biomarkers showed that AT was an independent factor of long-term outcome (adjusted odds ratio: 0.873; 95% CI: 0.765-0.996; p=0.043). Another multivariate analysis with severity scores showed that low AT activity levels were associated with poor outcomes (adjusted odds ratio: 0.909; 95% CI: 0.822-1.010; p=0.063). We demonstrated that the AT activity level soon after injury could be a predictor of long-term neurological prognosis in patients with iTBI.

Protocol for a Sepsis Model Utilizing Fecal Suspension in Mice: Fecal Suspension Intraperitoneal Injection Model.
Takumi Tsuchida, Takeshi Wada, Asumi Mizugaki, Yoshitaka Oda, Katsuhide Kayano, Kazuma Yamakawa, Shinya Tanaka
Frontiers in medicine, 9, 765805, 765805, 2022年, ［国際誌］
英語, 研究論文（学術雑誌）, Background: Various animal models of sepsis have been developed to optimize sepsis treatment. However, therapeutic agents that were successful in animal models were rarely effective in human clinical trials. The cecal ligation and puncture (CLP) model is currently the gold standard for sepsis studies. However, its limitations include the high variability among researchers and the difficulty in comparing animals with different cecum shapes and sizes. In this study, we established a protocol for the creation of a simple and accessible sepsis rodent model using fecal suspensions that minimized differences in technical effects among researchers and individual differences in animals. Methods: A mouse model of sepsis using fecal suspension intraperitoneal injection (FSI) was created using fresh stool excreted within 24 h. The collected fresh stool was dissolved in saline solution and filtered. The obtained fecal suspension was injected intraperitoneally into the mice. Moreover, fecal suspensions with different concentrations were prepared, and the survival rates were compared among the fecal suspensions for each concentration. To assess the validity of the FSI as a sepsis model, CLP and FSI with similar mortality rates were compared pathologically, physiologically, immunologically, and bacteriologically. Histopathological comparison was evaluated by hematoxylin-eosin and Gram staining of the parenchymal organs. Physiological evaluation was performed by comparing the respiratory rate, body temperature, and blood gas analysis results. Immunological assessment was performed using multiplex analysis. Bacteriological comparisons were performed by culturing ascites fluid. Results: The FSI model increased mortality in proportion to the fecal suspension concentration. The mortality rate was reduced with antibiotic administration. In various comparative experiments conducted using the FSI and CLP models, both models showed findings consistent with sepsis. Furthermore, the FSI model showed less variability among the individuals in each test. Conclusion: This is the first detailed and accurate report of a protocol for creating a sepsis model using fecal suspension. The FSI model is a minimally invasive and accessible sepsis rodent model. Its clinical validity as a sepsis model was proven via histological, physiological, microbiological, and immunological evaluation methods. The FSI model minimizes individual differences between mice and helps to conduct accurate studies after the onset of sepsis.

Prolonged enhancement of cytotoxic T lymphocytes in the post-recovery state of severe COVID-19.
Yumi Mitsuyama, Kazuma Yamakawa, Katsuhide Kayano, Miho Maruyama, Takeshi Wada, Satoshi Fujimi
Journal of intensive care, 9, 1, 76, 76, 2021年12月20日, ［国際誌］
英語, We evaluated the peripheral blood immune responses of lymphocytes in severe Coronavirus disease 2019 (COVID-19) patients in different stages of recovery using single-cell mass cytometry. The patients with prolonged hospitalization did not show recovery of B lymphocyte counts and CD4-positive T lymphocyte counts but did show abundant CD8-positive T lymphocytes. CD4 and CD8 T cells expressing high levels of T-bet and Granzyme B were more abundant in post-recovery patients. This study showed that cytotoxic Th1 and CD8 T cells are recruited to the peripheral blood long after recovery from COVID-19.

胃気腫症を認め後腹膜膿瘍を伴う敗血症性ショックに対して緊急開腹手術による治療が奏功した一例　　　　　　　　　　　　　　　
本間 慶憲, 早川 峰司, 前川 邦彦, 和田 剛志, 方波見 謙一, 吉田 知由, 斎藤 智誉, 早水 真理子, 水柿 明日美, 定本 圭弘, 執行 亜希子
日本救急医学会雑誌, 32, 12, 2579, 2579, (一社)日本救急医学会, 2021年11月
日本語

Fibrinolytic system activation immediately following trauma was quickly and intensely suppressed in a rat model of severe blunt trauma.
Mineji Hayakawa, Takumi Tsuchida, Yoshinori Honma, Asumi Mizugaki, Takayoshi Ooyasu, Tomonao Yoshida, Tomoyo Saito, Kenichi Katabami, Takeshi Wada, Kunihiko Maekawa
Scientific reports, 11, 1, 20283, 20283, 2021年10月13日, ［国際誌］
英語, 研究論文（学術雑誌）, In severe trauma, excessive fibrinolytic activation is associated with an increase in the transfusion volume and mortality rate. However, in the first several hours after a blunt trauma, changes in fibrinolytic activation, suppression, and activation-suppression balance have not yet been elucidated, which the present study aimed to clarify. Anesthetized 9-week-old male Wistar S/T rats experienced severe blunt trauma while being placed inside the Noble-Collip drum. Rats were randomly divided into four groups of seven. The no-trauma group was not exposed to any trauma; the remaining groups were analysed 0, 60, and 180 min after trauma. Immediately following trauma, total tissue-plasminogen activator (tPA) levels significantly increased in the plasma, and the balance of active tPA and active plasminogen activator inhibitor-1 (PAI-1) significantly tipped toward fibrinolytic activation. After trauma, both tPA and PAI-1 levels increased gradually in various organs and active and total PAI-1 levels increased exponentially in the plasma. Total plasma tPA levels 60 min after trauma returned quickly to levels comparable to those in the no-trauma group. In conclusion, fibrinolytic activation was observed only immediately following trauma. Therefore, immediately after trauma, the fibrinolytic system was activated; however, its activation was quickly and intensely suppressed.

心停止蘇生後の低リン血症は予後不良因子である　　　　　　　　　　　　　　　
高橋 正樹, 和田 剛志, 中嶋 拓磨, 執行 亜希子, 田中 祥平, 田原 就, 吉田 知由, 方波見 謙一, 前川 邦彦, 早川 峰司
日本集中治療医学会雑誌, 28, Suppl.2, 451, 451, (一社)日本集中治療医学会, 2021年09月
日本語

The Japanese Clinical Practice Guidelines for Management of Sepsis and Septic Shock 2020 (J-SSCG 2020).
Moritoki Egi, Hiroshi Ogura, Tomoaki Yatabe, Kazuaki Atagi, Shigeaki Inoue, Toshiaki Iba, Yasuyuki Kakihana, Tatsuya Kawasaki, Shigeki Kushimoto, Yasuhiro Kuroda, Joji Kotani, Nobuaki Shime, Takumi Taniguchi, Ryosuke Tsuruta, Kent Doi, Matsuyuki Doi, Taka-Aki Nakada, Masaki Nakane, Seitaro Fujishima, Naoto Hosokawa, Yoshiki Masuda, Asako Matsushima, Naoyuki Matsuda, Kazuma Yamakawa, Yoshitaka Hara, Masaaki Sakuraya, Shinichiro Ohshimo, Yoshitaka Aoki, Mai Inada, Yutaka Umemura, Yusuke Kawai, Yutaka Kondo, Hiroki Saito, Shunsuke Taito, Chikashi Takeda, Takero Terayama, Hideo Tohira, Hideki Hashimoto, Kei Hayashida, Toru Hifumi, Tomoya Hirose, Tatsuma Fukuda, Tomoko Fujii, Shinya Miura, Hideto Yasuda, Toshikazu Abe, Kohkichi Andoh, Yuki Iida, Tadashi Ishihara, Kentaro Ide, Kenta Ito, Yusuke Ito, Yu Inata, Akemi Utsunomiya, Takeshi Unoki, Koji Endo, Akira Ouchi, Masayuki Ozaki, Satoshi Ono, Morihiro Katsura, Atsushi Kawaguchi, Yusuke Kawamura, Daisuke Kudo, Kenji Kubo, Kiyoyasu Kurahashi, Hideaki Sakuramoto, Akira Shimoyama, Takeshi Suzuki, Shusuke Sekine, Motohiro Sekino, Nozomi Takahashi, Sei Takahashi, Hiroshi Takahashi, Takashi Tagami, Goro Tajima, Hiroomi Tatsumi, Masanori Tani, Asuka Tsuchiya, Yusuke Tsutsumi, Takaki Naito, Masaharu Nagae, Ichiro Nagasawa, Kensuke Nakamura, Tetsuro Nishimura, Shin Nunomiya, Yasuhiro Norisue, Satoru Hashimoto, Daisuke Hasegawa, Junji Hatakeyama, Naoki Hara, Naoki Higashibeppu, Nana Furushima, Hirotaka Furusono, Yujiro Matsuishi, Tasuku Matsuyama, Yusuke Minematsu, Ryoichi Miyashita, Yuji Miyatake, Megumi Moriyasu, Toru Yamada, Hiroyuki Yamada, Ryo Yamamoto, Takeshi Yoshida, Yuhei Yoshida, Jumpei Yoshimura, Ryuichi Yotsumoto, Hiroshi Yonekura, Takeshi Wada, Eizo Watanabe, Makoto Aoki, Hideki Asai, Takakuni Abe, Yutaka Igarashi, Naoya Iguchi, Masami Ishikawa, Go Ishimaru, Shutaro Isokawa, Ryuta Itakura, Hisashi Imahase, Haruki Imura, Takashi Irinoda, Kenji Uehara, Noritaka Ushio, Takeshi Umegaki, Yuko Egawa, Yuki Enomoto, Kohei Ota, Yoshifumi Ohchi, Takanori Ohno, Hiroyuki Ohbe, Kazuyuki Oka, Nobunaga Okada, Yohei Okada, Hiromu Okano, Jun Okamoto, Hiroshi Okuda, Takayuki Ogura, Yu Onodera, Yuhta Oyama, Motoshi Kainuma, Eisuke Kako, Masahiro Kashiura, Hiromi Kato, Akihiro Kanaya, Tadashi Kaneko, Keita Kanehata, Ken-Ichi Kano, Hiroyuki Kawano, Kazuya Kikutani, Hitoshi Kikuchi, Takahiro Kido, Sho Kimura, Hiroyuki Koami, Daisuke Kobashi, Iwao Saiki, Masahito Sakai, Ayaka Sakamoto, Tetsuya Sato, Yasuhiro Shiga, Manabu Shimoto, Shinya Shimoyama, Tomohisa Shoko, Yoh Sugawara, Atsunori Sugita, Satoshi Suzuki, Yuji Suzuki, Tomohiro Suhara, Kenji Sonota, Shuhei Takauji, Kohei Takashima, Sho Takahashi, Yoko Takahashi, Jun Takeshita, Yuuki Tanaka, Akihito Tampo, Taichiro Tsunoyama, Kenichi Tetsuhara, Kentaro Tokunaga, Yoshihiro Tomioka, Kentaro Tomita, Naoki Tominaga, Mitsunobu Toyosaki, Yukitoshi Toyoda, Hiromichi Naito, Isao Nagata, Tadashi Nagato, Yoshimi Nakamura, Yuki Nakamori, Isao Nahara, Hiromu Naraba, Chihiro Narita, Norihiro Nishioka, Tomoya Nishimura, Kei Nishiyama, Tomohisa Nomura, Taiki Haga, Yoshihiro Hagiwara, Katsuhiko Hashimoto, Takeshi Hatachi, Toshiaki Hamasaki, Takuya Hayashi, Minoru Hayashi, Atsuki Hayamizu, Go Haraguchi, Yohei Hirano, Ryo Fujii, Motoki Fujita, Naoyuki Fujimura, Hiraku Funakoshi, Masahito Horiguchi, Jun Maki, Naohisa Masunaga, Yosuke Matsumura, Takuya Mayumi, Keisuke Minami, Yuya Miyazaki, Kazuyuki Miyamoto, Teppei Murata, Machi Yanai, Takao Yano, Kohei Yamada, Naoki Yamada, Tomonori Yamamoto, Shodai Yoshihiro, Hiroshi Tanaka, Osamu Nishida
Journal of intensive care, 9, 1, 53, 53, 2021年08月25日, ［国際誌］
英語, The Japanese Clinical Practice Guidelines for Management of Sepsis and Septic Shock 2020 (J-SSCG 2020), a Japanese-specific set of clinical practice guidelines for sepsis and septic shock created as revised from J-SSCG 2016 jointly by the Japanese Society of Intensive Care Medicine and the Japanese Association for Acute Medicine, was first released in September 2020 and published in February 2021. An English-language version of these guidelines was created based on the contents of the original Japanese-language version. The purpose of this guideline is to assist medical staff in making appropriate decisions to improve the prognosis of patients undergoing treatment for sepsis and septic shock. We aimed to provide high-quality guidelines that are easy to use and understand for specialists, general clinicians, and multidisciplinary medical professionals. J-SSCG 2016 took up new subjects that were not present in SSCG 2016 (e.g., ICU-acquired weakness [ICU-AW], post-intensive care syndrome [PICS], and body temperature management). The J-SSCG 2020 covered a total of 22 areas with four additional new areas (patient- and family-centered care, sepsis treatment system, neuro-intensive treatment, and stress ulcers). A total of 118 important clinical issues (clinical questions, CQs) were extracted regardless of the presence or absence of evidence. These CQs also include those that have been given particular focus within Japan. This is a large-scale guideline covering multiple fields; thus, in addition to the 25 committee members, we had the participation and support of a total of 226 members who are professionals (physicians, nurses, physiotherapists, clinical engineers, and pharmacists) and medical workers with a history of sepsis or critical illness. The GRADE method was adopted for making recommendations, and the modified Delphi method was used to determine recommendations by voting from all committee members.As a result, 79 GRADE-based recommendations, 5 Good Practice Statements (GPS), 18 expert consensuses, 27 answers to background questions (BQs), and summaries of definitions and diagnosis of sepsis were created as responses to 118 CQs. We also incorporated visual information for each CQ according to the time course of treatment, and we will also distribute this as an app. The J-SSCG 2020 is expected to be widely used as a useful bedside guideline in the field of sepsis treatment both in Japan and overseas involving multiple disciplines.

Simultaneous external validation of various cardiac arrest prognostic scores: a single-center retrospective study.
Takumi Tsuchida, Kota Ono, Kunihiko Maekawa, Takeshi Wada, Kenichi Katabami, Tomonao Yoshida, Mineji Hayakawa
Scandinavian journal of trauma, resuscitation and emergency medicine, 29, 1, 117, 117, 2021年08月14日, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: This study aimed to compare and validate the out-of-hospital cardiac arrest (OHCA); cardiac arrest hospital prognosis (CAHP); non-shockable rhythm, unwitnessed arrest, long no-flow or long low-flow period, blood pH < 7.2, lactate > 7.0 mmol/L, end-stage chronic kidney disease, age ≥ 85 years, still resuscitation, and extracardiac cause (NULL-PLEASE) clinical; post-cardiac arrest syndrome for therapeutic hypothermia (CAST); and revised CAST (rCAST) scores in OHCA patients treated with recent cardiopulmonary resuscitation strategies. METHODS: We retrospectively collected data on adult OHCA patients admitted to our emergency department between February 2015 and July 2018. OHCA, CAHP, NULL-PLEASE clinical, CAST, and rCAST scores were calculated based on the data collected. The predictive abilities of each score were tested using the area under the curve (AUC) of the receiver operating characteristic (ROC) curve. RESULTS: We identified 236 OHCA patients from computer-based medical records and analyzed 189 without missing data. In OHCA patients without bystander witnesses, CAHP and OHCA scores were not calculated. Although the predictive abilities of the scores were not significantly different, the NULL-PLEASE score had a large AUC of ROC curve in various OHCA patients. Furthermore, in patients with bystander-witnessed OHCA, the NULL-PLEASE score had large partial AUCs of ROC from sensitivity 0.8-1.0 and specificity 0.8-1.0. CONCLUSIONS: The NULL-PLEASE score had a high, comprehensive predictive ability in various OHCA patients. Furthermore, the NULL-PLEASE score had a high predictive ability for good and poor neurological outcomes in patients with bystander-witnessed OHCA.

Pathomechanisms Underlying Hypoxemia in Two COVID-19-Associated Acute Respiratory Distress Syndrome Phenotypes: Insights from Thrombosis and Hemostasis.
Satoshi Gando, Takeshi Wada
Shock (Augusta, Ga.), 2021年06月24日, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: The pathomechanisms of hypoxemia and treatment strategies for type H and type L acute respiratory distress syndrome (ARDS) in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-induced coronavirus disease 2019 (COVID-19) have not been elucidated. MAIN TEXT: SARS-CoV-2 mainly targets the lungs and blood, leading to ARDS, and systemic thrombosis or bleeding. Angiotensin II-induced coagulopathy, SARS-CoV-2-induced hyperfibrin(ogen)olysis, and pulmonary and/or disseminated intravascular coagulation due to immunothrombosis contribute to COVID-19-associated coagulopathy. Type H ARDS is associated with hypoxemia due to diffuse alveolar damage-induced high right-to-left shunts. Immunothrombosis occurs at the site of infection due to innate immune inflammatory and coagulofibrinolytic responses to SARS-CoV-2, resulting in microvascular occlusion with hypoperfusion of the lungs. Lung immunothrombosis in type L ARDS results from neutrophil extracellular traps containing platelets and fibrin in the lung microvasculature, leading to hypoxemia due to impaired blood flow and a high ventilation/perfusion (VA/Q) ratio. COVID-19-associated ARDS is more vascular centric than the other types of ARDS. D-dimer levels have been monitored for the progression of microvascular thrombosis in COVID-19 patients. Early anticoagulation therapy in critical patients with high D-dimer levels may improve prognosis, including the prevention and/or alleviation of ARDS. CONCLUSIONS: Right-to-left shunts and high VA/Q ratios caused by lung microvascular thrombosis contribute to hypoxemia in type H and L ARDS, respectively. D-dimer monitoring-based anticoagulation therapy may prevent the progression to and/or worsening of ARDS in COVID-19 patients.

Effects of The Prone Position on Regional Neutrophilic Lung Inflammation According To 18F-FDG PET In An Experimental Ventilator-Induced Lung Injury Model.
Susumu Nakahashi, Hiroshi Imai, Nobutake Shimojo, Yasuhiro Magata, Takahiro Einama, Mineji Hayakawa, Takeshi Wada, Yuji Morimoto, Satoshi Gando
Shock (Augusta, Ga.), 57, 2, 298, 308, 2021年06月08日, ［国際誌］
英語, 研究論文（学術雑誌）, ABSTRACT: Ventilator-induced lung injury (VILI) can be life-threatening and it is important to prevent the development of VILI. It remains unclear whether the prone position affects neutrophilic inflammation in the lung regions in vivo, which plays a crucial role in the pathogenesis of VILI. This study aimed to assess the relationship between the use of the prone position and the development of VILI-associated regional neutrophilic lung inflammation. Regional neutrophilic lung inflammation and lung aeration during low tidal volume mechanical ventilation were assessed using in vivo 2-deoxy-2-[ (18)F] fluoro-D-glucose (18F-FDG) positron emission tomography and computed tomography in acutely experimentally injured rabbit lungs (lung injury induced by lung lavage and excessive ventilation). Direct comparisons were made among three groups: control, supine, and prone position. After approximately 7 hours, tissue-normalized 18F-FDG uptake differed significantly between the supine and prone positions (SUP: 0.038 ± 0.014 vs. PP: 0.029 ± 0.008, P = 0.038), especially in the ventral region (SUP: 0.052 ± 0.013 vs. PP: 0.026 ± 0.007, P = 0.003). The use of the prone position reduced lung inhomogeneities, which was demonstrated by the correction of the disproportionate rate of voxel gas over the given lung region. The progression of neutrophilic inflammation was affected by the interaction between the total strain (for aeration) and the inhomogeneity. The prone position is effective in slowing down the progression of VILI-associated neutrophilic inflammation. Under low-tidal-volume ventilation, the main drivers of the its effect may be homogenization of lung tissue and that of mechanical forces.

Disseminated intravascular coagulation immediately after trauma predicts a poor prognosis in severely injured patients.
Takeshi Wada, Atsushi Shiraishi, Satoshi Gando, Kazuma Yamakawa, Seitaro Fujishima, Daizoh Saitoh, Shigeki Kushimoto, Hiroshi Ogura, Toshikazu Abe, Toshihiko Mayumi, Junichi Sasaki, Joji Kotani, Naoshi Takeyama, Ryosuke Tsuruta, Kiyotsugu Takuma, Norio Yamashita, Shin-Ichiro Shiraishi, Hiroto Ikeda, Yasukazu Shiino, Takehiko Tarui, Taka-Aki Nakada, Toru Hifumi, Kohji Okamoto, Yuichiro Sakamoto, Akiyoshi Hagiwara, Tomohiko Masuno, Masashi Ueyama, Satoshi Fujimi, Yutaka Umemura, Yasuhiro Otomo
Scientific reports, 11, 1, 11031, 11031, 2021年05月26日, ［国際誌］
英語, 研究論文（学術雑誌）, Trauma patients die from massive bleeding due to disseminated intravascular coagulation (DIC) with a fibrinolytic phenotype in the early phase, which transforms to DIC with a thrombotic phenotype in the late phase of trauma, contributing to the development of multiple organ dysfunction syndrome (MODS) and a consequently poor outcome. This is a sub-analysis of a multicenter prospective descriptive cross-sectional study on DIC to evaluate the effect of a DIC diagnosis on the survival probability and predictive performance of DIC scores for massive transfusion, MODS, and hospital death in severely injured trauma patients. A DIC diagnosis on admission was associated with a lower survival probability (Log Rank P < 0.001), higher frequency of massive transfusion and MODS and a higher mortality rate than no such diagnosis. The DIC scores at 0 and 3 h significantly predicted massive transfusion, MODS, and hospital death. Markers of thrombin and plasmin generation and fibrinolysis inhibition also showed a good predictive ability for these three items. In conclusion, a DIC diagnosis on admission was associated with a low survival probability. DIC scores obtained immediately after trauma predicted a poor prognosis of severely injured trauma patients.

Pathophysiology of Coagulopathy Induced by Traumatic Brain Injury Is Identical to That of Disseminated Intravascular Coagulation With Hyperfibrinolysis.
Takeshi Wada, Atsushi Shiraishi, Satoshi Gando, Kazuma Yamakawa, Seitaro Fujishima, Daizoh Saitoh, Shigeki Kushimoto, Hiroshi Ogura, Toshikazu Abe, Toshihiko Mayumi, Junichi Sasaki, Joji Kotani, Naoshi Takeyama, Ryosuke Tsuruta, Kiyotsugu Takuma, Shin-Ichiro Shiraishi, Yasukazu Shiino, Taka-Aki Nakada, Kohji Okamoto, Yuichiro Sakamoto, Akiyoshi Hagiwara, Satoshi Fujimi, Yutaka Umemura, Yasuhiro Otomo
Frontiers in medicine, 8, 767637, 767637, 2021年, ［国際誌］
英語, 研究論文（学術雑誌）, Background: Traumatic brain injury (TBI)-associated coagulopathy is a widely recognized risk factor for secondary brain damage and contributes to poor clinical outcomes. Various theories, including disseminated intravascular coagulation (DIC), have been proposed regarding its pathomechanisms; no consensus has been reached thus far. This study aimed to elucidate the pathophysiology of TBI-induced coagulopathy by comparing coagulofibrinolytic changes in isolated TBI (iTBI) to those in non-TBI, to determine the associated factors, and identify the clinical significance of DIC diagnosis in patients with iTBI. Methods: This secondary multicenter, prospective study assessed patients with severe trauma. iTBI was defined as Abbreviated Injury Scale (AIS) scores ≥4 in the head and neck, and ≤2 in other body parts. Non-TBI was defined as AIS scores ≥4 in single body parts other than the head and neck, and the absence of AIS scores ≥3 in any other trauma-affected parts. Specific biomarkers for thrombin and plasmin generation, anticoagulation, and fibrinolysis inhibition were measured at the presentation to the emergency department (0 h) and 3 h after arrival. Results: We analyzed 34 iTBI and 40 non-TBI patients. Baseline characteristics, transfusion requirements and in-hospital mortality did not significantly differ between groups. The changes in coagulation/fibrinolysis-related biomarkers were similar. Lactate levels in the iTBI group positively correlated with DIC scores (rho = -0.441, p = 0.017), but not with blood pressure (rho = -0.098, p = 0.614). Multiple logistic regression analyses revealed that the injury severity score was an independent predictor of DIC development in patients with iTBI (odds ratio = 1.237, p = 0.018). Patients with iTBI were further subdivided into two groups: DIC (n = 15) and non-DIC (n = 19) groups. Marked thrombin and plasmin generation were observed in all patients with iTBI, especially those with DIC. Patients with iTBI and DIC had higher requirements for massive transfusion and emergency surgery, and higher in-hospital mortality than those without DIC. Furthermore, DIC development significantly correlated with poor hospital survival; DIC scores at 0 h were predictive of in-hospital mortality. Conclusions: Coagulofibrinolytic changes in iTBI and non-TBI patients were identical, and consistent with the pathophysiology of DIC. DIC diagnosis in the early phase of TBI is key in predicting the outcomes of severe TBI.

Thromboplasminflammation in COVID-19 Coagulopathy: Three Viewpoints for Diagnostic and Therapeutic Strategies.
Satoshi Gando, Takeshi Wada
Frontiers in immunology, 12, 649122, 649122, 2021年, ［国際誌］
英語, 研究論文（学術雑誌）, Thromboplasminflammation in coronavirus disease 2019 (COVID-19) coagulopathy consists of angiotensin II (Ang II)-induced coagulopathy, activated factor XII (FXIIa)- and kallikrein, kinin system-enhanced fibrinolysis, and disseminated intravascular coagulation (DIC). All three conditions induce systemic inflammation via each pathomechanism-developed production of inflammatory cytokines. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) downregulates angiotensin-converting enzyme 2, leading to an increase in Ang II levels. Ang II-induced coagulopathy comprising platelet activation, thrombin generation, plasminogen activator inhibitor-1 expression and endothelial injury causes thrombosis via the angiotensin II type 1 receptor. SARS-CoV-2 RNA and neutrophil extracellular trap (NET) DNA activate FXII, resulting in plasmin generation through FXIIa- and kallikrein-mediated plasminogen conversion to plasmin and bradykinin-induced tissue-type plasminogen activator release from the endothelium via the kinin B2 receptor. NETs induce immunothrombosis at the site of infection (lungs), through histone- and DNA-mediated thrombin generation, insufficient anticoagulation control, and inhibition of fibrinolysis. However, if the infection is sufficiently severe, immunothrombosis disseminates into the systemic circulation, and DIC, which is associated with the endothelial injury, occurs. Inflammation, and serine protease networks of coagulation and fibrinolysis, militate each other through complement pathways, which exacerbates three pathologies of COVID-19 coagulopathy. COVID-19 coagulopathy causes microvascular thrombosis and bleeding, resulting in multiple organ dysfunction and death in critically ill patients. Treatment targets for improving the prognosis of COVID-19 coagulopathy include thrombin, plasmin, and inflammation, and SARS-CoV-2 infection. Several drugs are candidates for controlling these conditions; however, further advances are required to establish robust treatments based on a clear understanding of molecular mechanisms of COVID-19 coagulopathy.

Coagulopathy Induced by Veno-Arterial Extracorporeal Membrane Oxygenation Is Associated With a Poor Outcome in Patients With Out-of-Hospital Cardiac Arrest.
Takumi Tsuchida, Takeshi Wada, Satoshi Gando
Frontiers in medicine, 8, 651832, 651832, 2021年, ［国際誌］
英語, 研究論文（学術雑誌）, Background: In recent years, the use of veno-arterial extracorporeal membrane oxygenation (VA-ECMO) in patients with cardiopulmonary arrest who do not respond to conventional resuscitation, has increased. However, despite the development of VA-ECMO, the outcomes of resuscitated patients remain poor. The poor prognosis may be attributed to deterioration owing to the post-cardiac arrest syndrome (PCAS); this includes the systemic inflammatory response and coagulation activation caused by the extracorporeal circulation (VA-ECMO circuit) itself. This study aimed to evaluate the coagulofibrinolytic changes caused by VA-ECMO and to identify predictive factors of poor prognosis. Methods: We analyzed 151 cases of PCAS with witnessed cardiac arrest. As biomarkers, platelet counts, prothrombin time ratio, fibrin/fibrinogen degradation products, fibrinogen, antithrombin, and lactate were recorded from blood samples from the time of delivery to the third day of hospitalization. The maximum (max) and minimum (min) values of each factor during the study period were calculated. To evaluate the impact of VA-ECMO on patients with PCAS, we performed propensity score matching between the patients who received and did not receive VA-ECMO. Sub-analysis was performed for the group with VA-ECMO. Results: There were significant differences in all baseline characteristics and demographics except the time from detection to hospital arrival, percentage of cardiopulmonary resuscitations (CPR) by witnesses, and the initial rhythm between the groups. Propensity score matching adjusted for prehospital factors demonstrated that the patients who received VA-ECMO developed significantly severe coagulation disorders. In a sub-analysis, significant differences were noted in the prothrombin time ratio min, fibrinogen max, antithrombin max, and lactate min between survivors and non-survivors. In particular, the prothrombin time ratio min and antithrombin max were strongly correlated with poor outcome. Conclusion: In the present study, significant coagulopathy was observed in patients who received VA-ECMO for CPR. In particular, in patients receiving VA-ECMO, the minimum prothrombin time ratio and maximum antithrombin by day 3 of hospitalization were strongly correlated with poor outcomes. These results suggest that VA-ECMO-induced coagulopathy can be a promising therapeutic target for patients resuscitated by VA-ECMO.

日本版敗血症診療ガイドライン2020
江⽊ 盛時, ⿊⽥ 泰弘, ⼭⽥ 亨, ⼭⽥ 博之, ⼭元 良, 吉⽥ 健史, 吉⽥ 悠平, 吉村 旬平, 四本 ⻯⼀, ⽶倉 寛, 和⽥ 剛志, 渡邉 栄三, ⼩⾕ 穣治, ⻘⽊ 誠, 浅井 英樹, 安部 隆国, 五⼗嵐 豊, 井⼝ 直也, ⽯川 雅⺒, ⽯丸 剛, 磯川 修太郎, 板倉 隆太, 今⻑⾕ 尚史, 志⾺ 伸朗, 井村 春樹, ⼊野⽥ 崇, 上原 健司, ⽣塩 典敬, 梅垣 岳志, 江川 裕⼦, 榎本 有希, 太⽥ 浩平, ⼤地 嘉史, ⼤野 孝則, ⾕⼝ 巧, ⼤邉 寛幸, 岡 和幸, 岡⽥ 信⻑, 岡⽥ 遥平, 岡野 弘, 岡本 潤, 奥⽥ 拓史, ⼩倉 崇以, ⼩野寺 悠, ⼩⼭ 雄太, 鶴⽥ 良介, ⾙沼 関志, 加古 英介, 柏浦 正広, 加藤 弘美, ⾦⾕ 明浩, ⾦⼦ 唯, ⾦畑 圭太, 狩野 謙⼀, 河野 浩幸, 菊⾕ 知也, ⼟井 研⼈, 菊地 ⻫, 城⼾ 崇裕, ⽊村 翔, ⼩網 博之, ⼩橋 ⼤輔, ⿑⽊ 巌, 堺 正仁, 坂本 彩⾹, 佐藤 哲哉, 志賀 康浩, ⼟井 松幸, 下⼾ 学, 下⼭ 伸哉, 庄古 知久, 菅原 陽, 杉⽥ 篤紀, 鈴⽊ 聡, 鈴⽊ 祐⼆, 壽原 朋宏, 其⽥ 健司, ⾼⽒ 修平, 中⽥ 孝明, ⾼島 光平, ⾼橋 ⽣, ⾼橋 洋⼦, ⽵下 淳, ⽥中 裕記, 丹保 亜希仁, ⾓⼭ 泰⼀朗, 鉄原 健⼀, 徳永 健太郎, 富岡 義裕, 中根 正樹, 冨⽥ 健太朗, 富永 直樹, 豊﨑 光信, 豊⽥ 幸樹年, 内藤 宏道, 永⽥ 功, ⻑⾨ 直, 中村 嘉, 中森 裕毅, 名原 功, 藤島 清太郎, 奈良場 啓, 成⽥ 知⼤, ⻄岡 典宏, ⻄村 朋也, ⻄⼭ 慶, 野村 智久, 芳賀 ⼤樹, 萩原 祥弘, 橋本 克彦, 旗智 武志, ⼩倉 裕司, 細川 直登, 浜崎 俊明, 林 拓也, 林 実, 速⽔ 宏樹, 原⼝ 剛, 平野 洋平, 藤井 遼, 藤⽥ 基, 藤村 直幸, 舩越 拓, 升⽥ 好樹, 堀⼝ 真仁, 牧 盾, 增永 直久, 松村 洋輔, 真⼸ 卓也, 南 啓介, 宮崎 裕也, 宮本 和幸, 村⽥ 哲平, 柳井 真知, 松嶋 ⿇⼦, ⽮野 隆郎, ⼭⽥ 浩平, ⼭⽥ 直樹, ⼭本 朋納, 吉廣 尚⼤, ⽥中 裕, ⻄⽥ 修, 松⽥ 直之, ⼭川 ⼀⾺, 原 嘉孝, ⼤下 慎⼀郎, ⻘⽊ 善孝, 稲⽥ ⿇⾐, 梅村 穣, ⽮⽥部 智昭, 河合 佑亮, 近藤 豊, 斎藤 浩輝, 櫻⾕ 正明, 對東 俊介, 武⽥ 親宗, 寺⼭ 毅郎, 東平 ⽇出夫, 橋本 英樹, 林⽥ 敬, 安宅 ⼀晃, ⼀⼆三 亨, 廣瀬 智也, 福⽥ ⿓将, 藤井 智⼦, 三浦 慎也, 安⽥ 英⼈, 阿部 智⼀, 安藤 幸吉, 飯⽥ 有輝, ⽯原 唯史, 井上 茂亮, 井⼿ 健太郎, 伊藤 健太, 伊藤 雄介, 稲⽥ 雄, 宇都宮 明美, 卯野⽊ 健, 遠藤 功⼆, ⼤内 玲, 尾崎 将之, ⼩野 聡, 射場 敏明, 桂 守弘, 川⼝ 敦, 川村 雄介, ⼯藤 ⼤介, 久保 健児, 倉橋 清泰, 櫻本 秀明, 下⼭ 哲, 鈴⽊ 武志, 関根 秀介, 垣花 泰之, 関野 元裕, ⾼橋 希, ⾼橋 世, ⾼橋 弘, ⽥上 隆, ⽥島 吾郎, 巽 博⾂, ⾕ 昌憲, ⼟⾕ ⾶⿃, 堤 悠介, 川崎 達也, 内藤 貴基, ⻑江 正晴, ⻑澤 俊郎, 中村 謙介, ⻄村 哲郎, 布宮 伸, 則末 泰博, 橋本 悟, ⻑⾕川 ⼤祐, 畠⼭ 淳司, 久志本 成樹, 原 直⼰, 東別府 直紀, 古島 夏奈, 古薗 弘隆, 松⽯ 雄⼆朗, 松⼭ 匡, 峰松 佑輔, 宮下 亮⼀, 宮武 祐⼠, 森安 恵実
日本集中治療医学会雑誌, 27, Suppl., 263, 263, 一般社団法人 日本集中治療医学会, 2020年12月
日本語,

日本集中治療医学会と日本救急医学会は，合同の特別委員会を組織し，2016年に発表した日本版敗血症診療ガイドライン（J-SSCG2016）の改訂を行った。本ガイドライン（J－SSCG2020）の目的は，J-SSCG2016と同様に，敗血症・敗血症性ショックの診療において，医療従事者が患者の予後改善のために適切な判断を下す支援を行うことである。改訂に際し，一般臨床家だけでなく多職種医療者にも理解しやすく，かつ質の高いガイドラインとすることによって，広い普及を目指した。J-SSCG2016ではSSCG2016にない新しい領域（ICU-acquiredweakness（ICU-AW）とPost-Intensive Care Syndrome（PICS），体温管理など）を取り上げたが，J-SSCG2020では新たに注目すべき4領域（Patient-and Family-Centered Care，Sepsis Treatment System，神経集中治療，ストレス潰瘍）を追加し，計22 領域とした。重要な117の臨床課題（クリニカルクエスチョン：CQ）をエビデンスの有無にかかわらず抽出した。これらのCQには，日本国内で特に注目されているCQも含まれる。多領域にわたる大規模ガイドラインであることから，委員24名を中心に，多職種（看護師，理学療法士，臨床工学技士，薬剤師）および患者経験者も含めたワーキンググループメンバー，両学会の公募によるシステマティックレビューメンバーによる総勢226名の参加・協力を得た。また，中立的な立場で横断的に活躍するアカデミックガイドライン推進班を2016年版に引き続き組織した。将来への橋渡しとなることを企図して，多くの若手医師をシステマティックレビューチーム・ワーキンググループに登用し，学会や施設の垣根を越えたネットワーク構築も進めた。作成工程においては，質の担保と作業過程の透明化を図るために様々な工夫を行い，パブリックコメント募集は計2回行った。推奨作成にはGRADE方式を取り入れ，修正Delphi法を用いて全委員の投票により推奨を決定した。結果，117CQに対する回答として，79個のGRADEによる推奨，5個のGPS（Good Practice Statement），18個のエキスパートコンセンサス，27個のBQ（Background Question）の解説，および敗血症の定義と診断を示した。新たな試みとして，CQごとに診療フローなど時間軸に沿った視覚的情報を取り入れた。J-SSCG2020は，多職種が関わる国内外の敗血症診療の現場において，ベッドサイドで役立つガイドラインとして広く活用されることが期待される。なお，本ガイドラインは，日本集中治療医学会と日本救急医学会の両機関誌のガイドライン増刊号として同時掲載するものである。

A multicenter prospective validation study on disseminated intravascular coagulation in trauma-induced coagulopathy.
Satoshi Gando, Atsushi Shiraishi, Takeshi Wada, Kazuma Yamakawa, Seitaro Fujishima, Daizoh Saitoh, Shigeki Kushimoto, Hiroshi Ogura, Toshikazu Abe, Yasuhiro Otomo
Journal of thrombosis and haemostasis : JTH, 18, 9, 2232, 2244, 2020年09月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Trauma-induced coagulopathy (TIC) may progress to disseminated intravascular coagulation (DIC) due to dysregulated inflammatory and coagulofibrinolytic responses to trauma. OBJECTIVES: We explored how DIC and TIC elicit the same coagulofibrinolytic changes which lead to massive transfusion. METHODS: Severely injured trauma patients with an injury severity score ≥ 16 were prospectively included. Platelet counts, global markers of coagulation and fibrinolysis and specific markers of thrombin and plasmin generation, anticoagulation, endothelial injury, and inhibition of fibrinolysis were measured at presentation to the emergency department (0 hour) and 3 hour after arrival. The patients were subdivided into those with and without DIC and those with and without TIC using the 0-hour data. Time courses of specific markers and the frequency of massive transfusion were evaluated. The association of various variables with DIC development was also confirmed. RESULTS: Two hundred and seventy-six patients were eligible for the analyses. The severity of injury (odds ratio; 1.038, P = .022) and thrombin generation (odds ratio; 1.014, P = .024) were associated with the development of DIC. Both DIC and TIC patients showed increased thrombin generation, insufficient anticoagulation controls, endothelial injury and increased fibrinolysis followed by elevated plasminogen activator inhibitor-1 levels at 0 and 3 hours. The frequency of massive transfusion was higher in both DIC (33.6% vs 7.9%, P < .001) and TIC (50.0% vs 13.3%, P < .001) patients than in those without DIC or TIC, respectively. CONCLUSIONS: Disseminated intravascular coagulation and TIC evoked the same coagulofibrinolytic responses in severely injured trauma patients immediately after trauma and needed massive transfusion.

Microparticles and Nucleosomes Are Released From Parenchymal Cells Destroyed After Injury in a Rat Model of Blunt Trauma
Mineji Hayakwa, Takayoshi Ooyasu, Yoshihiro Sadamoto, Tomoyo Saito, Tomonao Yoshida, Kenichi Katabami, Takeshi Wada, Kunihiko Maekawa, Masahiro Ieko
Clinical and Applied Thrombosis/Hemostasis, 26, SAGE Publications Inc., 2020年
英語, 研究論文（学術雑誌）, We investigated the relationships between circulating procoagulants and trauma severity, including cellular destruction, and the effects of thrombin generation on procoagulants in a rat blunt trauma model. The rats were subjected to tumbling blunt trauma, where they were tumbled for 0, 250, 500, or 1000 revolutions. Creatine kinase, nucleosome, and microparticle plasma levels increased gradually with trauma severity. Strong interrelationships were observed among creatine kinase, nucleosome, and microparticle levels. Time to initiation of thrombin generation shortened with increasing trauma severity. In accordance with trauma severity, prothrombin activity decreased, but the thrombin generation ratio increased. Time to initiation of thrombin generation and the thrombin generation ratio correlated with creatine kinase levels. In an in vitro study, a homogenized muscle solution, which included massive nucleosomes and microparticles, showed accelerated thrombin generation of plasma from healthy subjects. Procoagulants, such as microparticles and nucleosomes, are released from destroyed parenchymal cells immediately after external traumatic force, activating the coagulation cascade. The procoagulants shorten the time to initiation of thrombin generation. Furthermore, although coagulation factors are consumed, the thrombin generation ratio increases.

Relationship Between Severity of Fibrinolysis Based on Rotational Thromboelastometry and Conventional Fibrinolysis Markers
Tomoyo Saito, Mineji Hayakawa, Yoshinori Honma, Asumi Mizugaki, Tomonao Yoshida, Kenichi Katabami, Takeshi Wada, Kunihiko Maekawa
Clinical and Applied Thrombosis/Hemostasis, 26, 107602962093300, 107602962093300, SAGE Publications, 2020年01月01日
研究論文（学術雑誌）, The association between severity of fibrinolysis, ascertained by rotational thromboelastometry to diagnose hyperfibrinolysis in patients with out-of-hospital cardiac arrest (OHCA), and conventional fibrinolysis markers (ie, tissue-plasminogen activator [t-PA], plasminogen, α₂-plasmin inhibitor [α₂-PI], and plasminogen activator inhibitor [PAI]) with key roles in the fibrinolytic system was investigated. This prospective observational study included 5 healthy volunteers and 35 patients with OHCA from the Hokkaido University Hospital. Blood samples were drawn immediately upon admission to the emergency department. Assessments of the extrinsic pathway using tissue factor activation (EXTEM) and of fibrinolysis by comparison with EXTEM after aprotinin addition (APTEM) were undertaken. Conventional coagulation and fibrinolysis markers were measured in the stored plasma samples. Significant hyperfibrinolysis observed in EXTEM disappeared in APTEM. Patients exhibited significantly higher levels of fibrinogen/fibrin degradation products, plasmin–α₂-PI complex, and t-PA but lower levels of fibrinogen, plasminogen, and α₂-PI than healthy controls. The PAI level was unchanged. Fibrinolytic parameters of EXTEM correlated with levels of lactate and conventional fibrinolysis markers, especially t-PA. Increased t-PA activity and decreased plasminogen and α₂-PI significantly correlated with increased severity of fibrinolysis (hyperfibrinolysis).

Early administration of fibrinogen concentrate is associated with improved survival among severe trauma patients: a single-centre propensity score-matched analysis.
Yuki Itagaki, Mineji Hayakawa, Kunihiko Maekawa, Tomoyo Saito, Akira Kodate, Yoshinori Honma, Asumi Mizugaki, Tomonao Yoshida, Takayoshi Ohyasu, Kenichi Katabami, Takeshi Wada
World journal of emergency surgery : WJES, 15, 7, 7, 2020年, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Background: Fibrinogen plays an important role in haemostasis during the early phase of trauma, and low fibrinogen levels after severe trauma are associated with haemostatic impairment, massive bleeding, and poor outcomes. Aggressive fibrinogen supplementation may improve haemostatic function, as fibrinogen levels deteriorate before other routine coagulation parameters in this setting. Therefore, we evaluated whether early administration of fibrinogen concentrate (FC) was associated with improved survival in severe trauma patients. Methods: This single-centre retrospective study evaluated patients with severe trauma (injury severity score ≥ 16) who were admitted to our emergency department between January 2010 and July 2018. The exclusion criteria included age < 18 years, cardiac arrest before emergency department arrival, cervical spinal cord injury not caused by a high-energy accident, and severe burn injuries. The FC and control groups included trauma patients who received and did not receive FC within 1 h after emergency department arrival, respectively. Propensity scores were used to balance the two groups based on the trauma and injury severity score (TRISS), heart rate at emergency department admission, and age. The primary outcome was the in-hospital survival rate. Results: The propensity scoring model had a c-statistic of 0.734, the Hosmer-Lemeshow chi-squared value was 7.036 (degrees of freedom = 8), and the non-significant p value of 0.533 indicated a good model fit. The propensity score matching created 31 matched pairs of patients, who had appropriately balanced characteristics. The FC group had a significantly higher in-hospital survival rate than the control group (log-rank p = 0.013). The FC group also used significantly higher amounts of red blood cells and fresh frozen plasma within 6 h after emergency department admission. However, the two groups had similar transfusion amounts between 6 and 24 h after emergency department admission. Conclusions: The present study revealed that early FC administration was associated with a favourable survival rate among severe trauma patients. Therefore, FC may be useful for the early management of trauma-induced coagulopathy and may improve outcomes in this setting.

Trauma-induced coagulopathy: The past, present, and future: A comment.
Takeshi Wada, Kazuma Yamakawa
Journal of thrombosis and haemostasis : JTH, 17, 9, 1571, 1574, 2019年09月, ［査読有り］, ［国際誌］
英語

Altered monocyte and NK cell phenotypes correlate with posttrauma infection.
Seshadri A, Brat GA, Yorkgitis BK, Giangola M, Keegan J, Nguyen JP, Li W, Nakahori Y, Wada T, Hauser C, Salim A, Askari R, Lederer JA
The journal of trauma and acute care surgery, 87, 2, 337, 341, 2019年08月, ［査読有り］

Disseminated intravascular coagulation in cardiac arrest and resuscitation.
Gando S, Wada T
Journal of thrombosis and haemostasis : JTH, 17, 8, 1205, 1216, 2019年08月, ［査読有り］

Diagnosis of sepsis-induced disseminated intravascular coagulation and coagulopathy.
Toshiaki Iba, Yutaka Umemura, Eizo Watanabe, Takeshi Wada, Kei Hayashida, Shigeki Kushimoto
Acute medicine & surgery, 6, 3, 223, 232, 2019年07月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Disseminated intravascular coagulation (DIC) is a frequent complication in sepsis. Once patients develop DIC, the mortality rate increases significantly. Moreover, recent studies have suggested that coagulation disorder plays a significant role in the development of organ dysfunction in sepsis. Thus, the early detection of DIC is vital in sepsis care, and the Japanese Association for Acute Medicine established a set of original diagnostic criteria in 2006 (JAAM DIC). Since then, the usefulness of the JAAM DIC has been repeatedly reported, and these criteria have been widely adopted in emergency and critical care settings in Japan. Different criteria have also been released by the International Society on Thrombosis and Haemostasis (ISTH overt-DIC), and the latter criteria are presently considered to be the international standard. Compared with the JAAM DIC, the ISTH overt-DIC criteria are stricter and the timing of diagnosis is later. This discrepancy is because of conceptual differences. As many physicians think sepsis-associated DIC is the target of anticoagulant therapies in Japan, the JAAM DIC criteria were designed to allow the early initiation of treatment. As other countries do not provide DIC-specific treatments, early diagnosis is not necessary, and this situation has led to a significant gap. However, as overt-DIC is a late-phase coagulation disorder, a need for early detection has been advocated, and members of the ISTH have recently proposed the category of sepsis-induced coagulopathy. In this review, we introduce the strengths and weaknesses of the major criteria including JAAM-DIC, ISTH overt-DIC, sepsis-induced coagulopathy, and Japanese Society on Thrombosis and Haemostasis-DIC.

Sepsis-associated disseminated intravascular coagulation and its differential diagnoses.
Toshiaki Iba, Eizo Watanabe, Yutaka Umemura, Takeshi Wada, Kei Hayashida, Shigeki Kushimoto, Hideo Wada
Journal of intensive care, 7, 32, 32, 2019年, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Disseminated intravascular coagulation (DIC) is a common complication in sepsis. Since DIC not only promotes organ dysfunction but also is a strong prognostic factor, its diagnosis at the earliest possible timing is important. Thrombocytopenia is often present in patients with DIC but can also occur in a number of other critical conditions. Of note, many of the rare thrombocytopenic diseases require prompt diagnoses and specific treatments. To differentiate these diseases correctly, the phenotypic expressions must be considered and the different disease pathophysiologies must be understood. There are three major players in the background characteristics of thrombocytopenia: platelets, the coagulation system, and vascular endothelial cells. For example, the activation of coagulation is at the core of the pathogenesis of sepsis-associated DIC, while platelet aggregation is the essential mechanism in thrombotic thrombocytopenic purpura and endothelial damage is the hallmark of hemolytic uremic syndrome. Though each of the three players is important in all thrombocytopenic diseases, one of the three dominant players typically establishes the individual features of each disease. In this review, we introduce the pathogeneses, symptoms, diagnostic measures, and recent therapeutic advances for the major diseases that should be immediately differentiated from DIC in sepsis.

Disseminated intravascular coagulation with increased fibrinolysis during the early phase of isolated traumatic brain injury
Takeshi Wada, Satoshi Gando, Kunihiko Maekaw, Kenichi Katabami, Hisako Sageshima, Mineji Hayakawa, Atsushi Sawamura
Critical Care, 21, 1, 219, BioMed Central Ltd., 2017年08月22日, ［査読有り］
英語, 研究論文（学術雑誌）, Background: There is evidence to demonstrate that the coagulopathy which occurs in patients with traumatic brain injury coincides with disseminated intravascular coagulation (DIC). We hypothesized that DIC with increased fibrinolysis during the early stage of isolated traumatic brain injury (iTBI) affects the outcome of the patients and that hypoperfusion contributes to hyperfibrinolysis in the DIC. Methods: This retrospective study included 92 patients with iTBI who were divided into DIC and non-DIC groups according to the Japanese Association Acute Medicine DIC scoring system. The DIC patients were subdivided into those with and without hyperfibrinolysis. The platelet counts and global markers of coagulation and fibrinolysis were measured. Systemic inflammatory response syndrome (SIRS), organ dysfunction (assessed by the Sequential Organ Failure Assessment score), tissue hypoperfusion (assessed by the lactate levels) and the transfusion volume were also evaluated. The outcome measure was all-cause hospital mortality. Results: DIC patients showed consumption coagulopathy, lower antithrombin levels and higher fibrin/fibrinogen degradation products (FDP) and D-dimer levels than non-DIC patients. All of the DIC patients developed SIRS accompanied by organ dysfunction and required higher blood transfusion volumes, leading to a worse outcome than non-DIC patients. These changes were more prominent in DIC with hyperfibrinolysis. A higher FDP/D-dimer ratio suggests that DIC belongs to the fibrinolytic phenotype and involves fibrin(ogen)olysis. The mean blood pressures of the patients with and without DIC on arrival were identical. Hypoperfusion and the lactate levels were not identified as independent predictors of hyperfibrinolysis. Conclusions: DIC, especially DIC with hyperfibrinolysis, affects the outcome of patients with iTBI. Low blood pressure-induced tissue hypoperfusion does not contribute to hyperfibrinolysis in this type of DIC.

Disseminated intravascular coagulation with increased fibrinolysis during the early phase of isolated traumatic brain injury
Takeshi Wada, Satoshi Gando, Kunihiko Maekaw, Kenichi Katabami, Hisako Sageshima, Mineji Hayakawa, Atsushi Sawamura
CRITICAL CARE, 21, BIOMED CENTRAL LTD, 2017年08月, ［査読有り］
英語, 研究論文（学術雑誌）, Background: There is evidence to demonstrate that the coagulopathy which occurs in patients with traumatic brain injury coincides with disseminated intravascular coagulation (DIC). We hypothesized that DIC with increased fibrinolysis during the early stage of isolated traumatic brain injury (iTBI) affects the outcome of the patients and that hypoperfusion contributes to hyperfibrinolysis in the DIC.
Methods: This retrospective study included 92 patients with iTBI who were divided into DIC and non-DIC groups according to the Japanese Association Acute Medicine DIC scoring system. The DIC patients were subdivided into those with and without hyperfibrinolysis. The platelet counts and global markers of coagulation and fibrinolysis were measured. Systemic inflammatory response syndrome (SIRS), organ dysfunction (assessed by the Sequential Organ Failure Assessment score), tissue hypoperfusion (assessed by the lactate levels) and the transfusion volume were also evaluated. The outcome measure was all-cause hospital mortality.
Results: DIC patients showed consumption coagulopathy, lower antithrombin levels and higher fibrin/fibrinogen degradation products (FDP) and D-dimer levels than non-DIC patients. All of the DIC patients developed SIRS accompanied by organ dysfunction and required higher blood transfusion volumes, leading to a worse outcome than non-DIC patients. These changes were more prominent in DIC with hyperfibrinolysis. A higher FDP/D-dimer ratio suggests that DIC belongs to the fibrinolytic phenotype and involves fibrin(ogen)olysis. The mean blood pressures of the patients with and without DIC on arrival were identical. Hypoperfusion and the lactate levels were not identified as independent predictors of hyperfibrinolysis.
Conclusions: DIC, especially DIC with hyperfibrinolysis, affects the outcome of patients with iTBI. Low blood pressure-induced tissue hypoperfusion does not contribute to hyperfibrinolysis in this type of DIC.

Differences in coagulofibrinolytic changes between post-cardiac arrest syndrome of cardiac causes and hypoxic insults: a pilot study.
Wada T, Gando S, Mizugaki A, Kodate A, Sadamoto Y, Murakami H, Maekawa K, Katabami K, Ono Y, Hayakawa M, Sawamura A, Jesmin S, Ieko M
Acute medicine & surgery, 4, 3, 371, 372, 2017年07月, ［査読有り］

Fibrin/fibrinogen degradation products (FDP) at hospital admission predict neurological outcomes in out-of-hospital cardiac arrest patients
Yuichi Ono, Mineji Hayakawa, Kunihiko Maekawa, Akira Kodate, Yoshihiro Sadamoto, Naoki Tominaga, Hiromoto Murakami, Tomonao Yoshida, Kenichi Katabami, Takeshi Wada, Hisako Sageshima, Atsushi Sawamura, Satoshi Gando
RESUSCITATION, 111, 62, 67, ELSEVIER IRELAND LTD, 2017年02月, ［査読有り］
英語, 研究論文（学術雑誌）, Objective: This study aimed to test the hypothesis that coagulation, fibrinolytic markers and disseminated intravascular coagulation (DIC) score (International Society on Thrombosis and Haemostasis) at hospital admission of out-of-hospital cardiac arrest (OHCA) patients can predict neurological outcomes 1 month after cardiac arrest.
Methods: In this retrospective, observational analysis, data were collected from the Sapporo Utstein Registry and medical records at Hokkaido University Hospital. We included patients who experienced OHCA with successful return of spontaneous circulation (ROSC) between 2006 and 2012 and were transferred to Hokkaido University Hospital. From medical records, we collected information about the following coagulation and fibrinolytic factors at hospital admission: platelet count; prothrombin time; activated partial thromboplastin time; plasma levels of fibrinogen, D-dimer, fibrin/fibrinogen degradation products (FDP), and antithrombin; and calculated DIC score. Favorable neurological outcomes were defined as a cerebral performance category 1-2.
Results: We analyzed data for 315 patients. Except for fibrinogen level, all coagulation variables, fibrinolytic variables, and DIC score were associated with favorable neurological outcomes. In the receiver operating characteristic curve analysis, FDP level had the largest area under the curve (AUC; 0.795). In addition, the AUC of FDP level was larger than that of lactate level.
Conclusions: All of the coagulation and fibrinolytic markers, except for fibrinogen level, and DIC score at hospital admission, were associated with favorable neurological outcomes. Of all of the variables, FDP level was most closely associated with favorable neurological outcomes in OHCA patients who successfully achieved ROSC. (C) 2016 Elsevier Ireland Ltd. All rights reserved.

Coagulofibrinolytic Changes in Patients with Post-cardiac Arrest Syndrome.
Wada T
Frontiers in medicine, 4, 156, 2017年, ［査読有り］

Disseminated intravascular coagulation with the fibrinolytic phenotype predicts the outcome of patients with out-of-hospital cardiac arrest
Takeshi Wada, Satoshi Gando, Yuichi Ono, Kunihiko Maekawa, Kenichi Katabami, Mineji Hayakawa, Atsushi Sawamura
Thrombosis Journal, 14, 1, 43, BioMed Central Ltd., 2016年09月21日, ［査読有り］
英語, 研究論文（学術雑誌）, Background: We tested the hypothesis that disseminated intravascular coagulation (DIC) during the early phase of post-cardiopulmonary resuscitation (CPR) is associated with systemic inflammatory response syndrome (SIRS), multiple organ dysfunction syndrome (MODS) and affects the outcome of out-of-hospital cardiac arrest (OHCA) patients. Methods: A review of the computer-based medical records of OHCA patients was retrospectively conducted and included 388 patients who were divided into DIC and non-DIC patients based on the Japanese Association for Acute Medicine DIC diagnostic criteria. DIC patients were subdivided into two groups: those with and without hyperfibrinolysis. Pre-hospital factors, platelet count, coagulation and fibrinolysis markers and lactate levels within 24 h after resuscitation were evaluated. The outcome measure was all-cause hospital mortality. Results: DIC patients exhibited lower platelet counts, prolonged prothrombin time, decreased levels of fibrinogen and antithrombin associated with increased fibrinolysis than those without DIC. DIC patients more frequently developed SIRS and MODS, followed by worse outcomes than non-DIC patients. The same changes were observed in DIC patients with hyperfibrinolysis who showed a higher prevalence of MODS, leading to worse outcome than those without hyperfibrinolysis. Logistic regression analyses showed that lactate levels predicted hyperfibrinolysis and DIC is an independent predictor of patient death. Survival probabilities of DIC patients during hospital stay were significantly lower than non-DIC patients. The area under the receiver operating characteristic curve of DIC for the prediction of death was 0.704. Conclusions: The fibrinolytic phenotype of DIC during the early phase of post-CPR more frequently results in SIRS and MODS, especially in patients with hyperfibrinolysis, and affects the outcome of OHCA patients.

Septic DIC の病態と Immunothrombosis
丸藤哲, 和田剛志, 小野雄一, 前川邦彦, 方波見謙一, 早川峰司, 澤村淳
ICUとCCU, 40, 171, 178, 2016年, ［査読有り］
日本語, 研究論文（学術雑誌）

Activated protein C does not increase in the early phase of trauma with disseminated intravascular coagulation: Comparison with acute coagulopathy of trauma-shock
Subrina Jesmin, Satoshi Gando, Takeshi Wada, Mineji Hayakawa, Atsushi Sawamura
Journal of Intensive Care, 4, 1, 1, BioMed Central Ltd., 2016年, ［査読有り］
英語, We hypothesized that activated protein C does not increase in disseminated intravascular coagulation (DIC) after trauma and that the same is true for acute coagulopathy of trauma-shock (ACOTS). Activated protein C levels were prospectively measured in 57 trauma patients: 30 with DIC and 27 without DIC. Normal to more decreased activated protein C levels were observed in DIC patients than in the controls and non-DIC patients. The activated protein C levels in ACOTS patients were similar to those in DIC patients. In conclusion, activated protein C does not increase in either DIC or ACOTS in the early phase of trauma.

Should laryngeal tubes or masks be used for out-of-hospital cardiac arrest patients?
Yuichi Ono, Mineji Hayakawa, Kunihiko Maekawa, Asumi Mizugaki, Kenichi Katabami, Takeshi Wada, Atsushi Sawamura, Satoshi Gando
AMERICAN JOURNAL OF EMERGENCY MEDICINE, 33, 10, 1360, 1363, W B SAUNDERS CO-ELSEVIER INC, 2015年10月, ［査読有り］
英語, 研究論文（学術雑誌）, Objective: Few studies have compared airway management via laryngeal masks (LM) or laryngeal tubes (LT) in patients with out-of-hospital cardiac arrest (OHCA). This study evaluated whether LT insertion by emergency medical service (EMS) personnel affected ventilation and outcomes in OHCA patients (vs. the standard LM treatment).
Methods: This prospective, cluster-randomized, and open-label study evaluated data that were collected by the Sapporo Fire Department between June 2012 and January 2013. We selected the 14 EMS teams that treated the greatest number of OHCA patients in Sapporo, Japan during 2011, and randomized the teams into Groups A and B. In the first study period (June 2012 to September 2012), Group A treated OHCA patients via LT and Group B treated OHCA patients via LM. In the second period (October 2012 to January 2013), Group A treated OHCA patients via LM and Group B treated OHCA patients via LT. If necessary, both groups were allowed to use an esophageal obturator airway (EOA) kit. The primary endpoints were time from cardiopulmonary resuscitation to device insertion and the rate of successful pre-hospital ventilation. The secondary endpoints were return of spontaneous circulation and survival and favorable neurological outcomes at 1 month after cardiac arrest.
Results: LT was used in 148 OHCA patients and LM was used in 165 OHCA patients. Our intention-to-treat analyses revealed no significant differences in the primary and secondary outcomes of the LT-and LM-treated groups.
Conclusion: Prehospital advanced airway management via LT provides similar outcomes to those of LM in OHCA patients. (C) 2015 Elsevier Inc. All rights reserved.

Effects of prehospital epinephrine administration on neurological outcomes in patients with out-of-hospital cardiac arrest
Yuichi Ono, Mineji Hayakawa, Takeshi Wada, Atsushi Sawamura, Satoshi Gando
Journal of Intensive Care, 3, 1, 29, BioMed Central Ltd., 2015年06月24日, ［査読有り］
英語, 研究論文（学術雑誌）, Background: To determine if the effects of epinephrine administration on the outcome of out-of-hospital cardiac arrest (OHCA), patients are associated with the duration of cardiopulmonary resuscitation (CPR) performed by Emergency Medical Service (EMS) personnel. Methods: This retrospective, nonrandomized, observational analysis used the All-Japan Utstein Registry, a prospective, nationwide population-based registry of all OHCA patients transported to the hospital by EMS staff as the data source. We stratified all OHCA patients for quartile of EMSs' CPR duration. Group 1 consisted of patients who fell under the 25th percentile of EMSs' CPR duration (under 15 min)
group 2, patients who fell into the 25th to 50th percentile (between 15 and 19 min)
group 3, patients who fell into the 50th to 75th percentile (between 20 and 26 min)
and group 4, patients who fell at or above the 75th percentile (over 26 min). The primary endpoint was a favorable neurological outcome 1 month after cardiac arrest. The secondary endpoints were ROSC before arrival at the hospital and 1-month survival. Results: A total of 383,811 patients aged over 18 years who had experienced OHCA between 2006 and 2010 in Japan, when stratified for quartile of EMSs' CPR duration, the epinephrine administration increased the rate of return of spontaneous circulation (ROSC) approximately tenfold in all groups. However, the beneficial effects of epinephrine administration on 1-month survival disappeared in patients on whom EMSs' CPR had been performed for more than 26 min, and the beneficial effects of epinephrine administration on neurological outcomes were observed only in patients on whom EMSs' CPR had been performed between 15 and 19 min (odds ratio, 1.327, 95 % confidence intervals, 1.017-1.733 P = 0.037). Conclusions: Epinephrine administration is associated with an increase of ROSC and with improvement in the neurological outcome on which EMSs' CPR duration is performed between 15 and 19 min.

Pharmacokinetics and the optimal regimen for levofloxacin in critically ill patients receiving continuous hemodiafiltration
Takeshi Wada, Masaki Kobayashi, Yuichi Ono, Asumi Mizugaki, Kenichi Katabami, Kunihiko Maekawa, Daisuke Miyamoto, Yuichiro Yanagida, Mineji Hayakawa, Atsushi Sawamura, Ken Iseki, Satoshi Gando
Journal of Intensive Care, 3, 1, 22, BioMed Central Ltd., 2015年05月08日, ［査読有り］
英語, The aim of this study was to establish the pharmacokinetics of levofloxacin (LVFX) and determine the optimal dose of this drug in critically ill patients receiving continuous hemodiafiltration (CHDF). The results of in vivo and in vitro studies showed the pharmacokinetics of LVFX total clearance (CLtotal) according to the creatinine clearance (CLCre), dialysate flow (QD), and ultrafiltrate flow (QF), to be as follows: CLtotal (l/h) = 0.0836 × CLCre (ml/min) + 0.013 × body weight (kg) + 0.94(QD + QF) (l/h). The optimal dose of LVFX was expressed by the following formula: 50 × CLtotal. These results demonstrate that the usual dose of LVFX (500 mg) was sufficient for the patients evaluated in this study.

Rapid Evaluation of Fibrinogen Levels Using the CG02N Whole Blood Coagulation Analyzer
Mineji Hayakawa, Satoshi Gando, Yuichi Ono, Asumi Mizugaki, Kenichi Katabami, Kunihiko Maekawa, Daisuke Miyamoto, Takeshi Wada, Yuichiro Yanagida, Atsushi Sawamura
SEMINARS IN THROMBOSIS AND HEMOSTASIS, 41, 3, 267, 271, THIEME MEDICAL PUBL INC, 2015年04月, ［査読有り］
英語, 研究論文（学術雑誌）, Rapid evaluation of fibrinogen (Fbg) levels is essential for maintaining homeostasis in patients with massive bleeding during severe trauma and major surgery. This study evaluated the accuracy of fibrinogen levels measured by the CG02N whole blood coagulation analyzer (A&T Corporation, Kanagawa, Japan) using heparinized blood drawn for blood gas analysis (whole blood-Fbg). A total of 100 matched pairs of heparinized blood samples and citrated blood samples were simultaneously collected from patients in the intensive care unit. Whole blood-Fbg results were compared with those of citrated plasma (standard-Fbg). The whole blood coagulation analyzer measured fibrinogen levels within 2 minutes. Strong correlations between standard-Fbg and whole blood-Fbg were observed (=0.91, p<0.001). Error grid analysis showed that 88% of the values were clinically acceptable, and 12% were in a range with possible effects on clinical decision-making; none were in a clinically dangerous range without appropriate treatment. Using a fibrinogen cutoff value of 1.5 g/L for standard-Fbg, the area under the receiver operating characteristic curve of whole blood-Fbg was 0.980 (95% confidence interval 0.951-1.000, p<0.001). The whole blood coagulation analyzer can rapidly measure fibrinogen levels in heparinized blood and could be useful in critical care settings where excessive bleeding is a concern.

NOBLE-COLLIP DRUM TRAUMA INDUCES DISSEMINATED INTRAVASCULAR COAGULATION BUT NOT ACUTE COAGULOPATHY OF TRAUMA-SHOCK
Mineji Hayakawa, Satoshi Gando, Yuichi Ono, Takeshi Wada, Yuichiro Yanagida, Atsushi Sawamura, Masahiro Ieko
SHOCK, 43, 3, 261, 267, LIPPINCOTT WILLIAMS & WILKINS, 2015年03月, ［査読有り］
英語, 研究論文（学術雑誌）, Background: There are two opposing possibilities for the main pathogenesis of trauma-induced coagulopathy: an acute coagulopathy of trauma shock and disseminated intravascular coagulation with the fibrinolytic phenotype. Objective: The objective of this study was to clarify the main pathogenesis of trauma-induced coagulopathy using a rat model of Noble-Collip drum trauma. Methods: Eighteen rats were divided into the control, trauma 0, and trauma 30 groups. The trauma 0 and 30 groups were exposed to Noble-Collip drum trauma. Blood samples were drawn without, immediately after, and 30 min after Noble-Collip drum trauma in the control, trauma 0, and trauma 30 groups, respectively. Coagulation and fibrinolysis markers were measured. Thrombin generation was assessed according to a calibrated automated thrombogram. Results: Spontaneous thrombin bursts resulting from circulating procoagulants were observed in the nonstimulated thrombin generation assay immediately after trauma. Soluble fibrin levels (a marker of thrombin generation in the systemic circulation) were 50-fold greater in the trauma groups than in the control group. The resultant coagulation activation consumed platelets, coagulation factors, and antithrombin. Endogenous thrombin potential and factor II ratio were significantly negatively correlated with antithrombin levels, suggesting insufficient control of thrombin generation by antithrombin. High levels of active tissue-type plasminogen activator induced hyperfibrin(ogen)olysis. Soluble thrombomodulin increased significantly. However, activated protein C levels did not change. Conclusions: The systemic thrombin generation accelerated by insufficient antithrombin control leads to the consumption of platelets and coagulation factors associated with hyperfibrin(ogen)olysis. These changes are collectively termed disseminated intravascular coagulation with the fibrinolytic phenotype.

Fibrinogen level deteriorates before other routine coagulation parameters and massive transfusion in the early phase of severe trauma: a retrospective observational study.
Hayakawa M, Gando S, Ono Y, Wada T, Yanagida Y, Sawamura A
Seminars in Thrombosis and Hemostasis, 41, 1, 35, 42, 2015年02月, ［査読有り］
英語, 研究論文（学術雑誌）

Fibrinogen Level Deteriorates before Other Routine Coagulation Parameters and Massive Transfusion in the Early Phase of Severe Trauma: A Retrospective Observational Study
Mineji Hayakawa, Satoshi Gando, Yuichi Ono, Takeshi Wada, Yuichiro Yanagida, Atsushi Sawamura
SEMINARS IN THROMBOSIS AND HEMOSTASIS, 41, 1, 35, 42, THIEME MEDICAL PUBL INC, 2015年02月, ［査読有り］
英語, 研究論文（学術雑誌）, In trauma, hemostatic functions should bemaintained appropriately to prevent massive bleeding. This study elucidated the time-dependent changes in platelet count and coagulation variables, and the effects of disseminated intravascular coagulation (DIC) on these changes during the early phase of trauma. Trauma patients with an injury severity score >= 16 were enrolled. The critical levels of platelet count and coagulation variables were defined according to recent trauma guidelines. Massive transfusion was defined as >10 units red cell concentrate. The time from arrival at the emergency department to reaching the critical levels and meeting the criteria for massive transfusion were evaluated. Eighty trauma patients were enrolled; 35 were diagnosed with DIC on arrival. Among all patients, fibrinogen levels reached the critical level earliest among routine coagulation parameters; other routine coagulation parameters deteriorated after the patients met the criteria for massive transfusion. Routine coagulation parameters reached their critical levels earlier in DIC patients than patients without DIC. Massive transfusion was performed more frequently in DIC patients, who met the criteria earlier. During the early phase of trauma, fibrinogen levels deteriorate earlier than other routine coagulation parameters, especially in DIC patients.

4D flow preliminary investigation of a direct carotid cavernous fistula due to a ruptured intracavernous aneurysm
Shunsuke Nakagawa, Yasuo Murai, Takeshi Wada, Kojiro Tateyama
BMJ Case Reports, 2015, BMJ Publishing Group, 2015年01月22日, ［査読有り］
英語, 研究論文（学術雑誌）, Inadequate information is available about the cerebral blood flow and surgical strategies of a direct aneurysmal carotid cavernous fistula (daCCF). We report a quantitative analysis of flow velocity and volume using preoperative time-resolved phase-contrast MRI (fourdimensional (4D) flow MRI) in a daCCF. This is the first report of 4D flow findings with a daCCF. A 55-year-old woman developed a sudden headache and bruit of the right orbit, and MRI suggested the presence of a daCCF. Quantitative analysis using preoperative 4D flow MRI revealed the flow volume of the right internal carotid artery. The daCCF was successfully treated by high- flow bypass using a radial artery graft and internal carotid artery trapping. Postoperative angiography showed a complete obliteration of the daCCF. Studies to collect data from additional cases are required so that 4D flow findings can be further used in the management of daCCFs.

Spontaneous Angiographic Regression of Cerebral Arteriovenous Malformations: Angiographic Disappearance is not the Real Cure
Fumihiro Matano, Yasuo Murai, Shunsuke Nakagawa, Takeshi Wada, Takayuki Kitamura, Akira Teramoto
TURKISH NEUROSURGERY, 25, 1, 168, 173, TURKISH NEUROSURGICAL SOC, 2015年01月, ［査読有り］
英語, 研究論文（学術雑誌）, Angiographically occult arteriovenous malformations (AOAVMs) are poorly understood. AOAVMs include spontaneous regression of cerebral AVMs. Here we discuss spontaneous angiographical regression of cerebral arteriovenous malformations (SRAVM). We present the case of a 34-year-old male patient with SRAVM in whom an arteriovenous (AV) shunt remnant was revealed by intraoperative indocyanine green videoangiography (ICG-VAG). Preoperative angiography indicated spontaneous regression of AVM. We reviewed the literature for articles having specific citations or case histories of SRAVMs. On the basis of our ICG-VAG findings, we confirmed the possibility of an AV shunt remnant being present in patients with SRAVMs. In addition to our own case, we reviewed previously reported cases and analyzed the data from 132 patients with SRAVMs. Ninety-five (72%) such patients received conservative therapy without surgical removal, and 37 (28%) were treated surgically. Only three patients in whom an SRAVM recanalized after 39, 31, and 16 months have been reported. The rate of recanalization in SRAVM including 3 previously reported cases and the present case, is 3.0% (4/132). Intraoperative ICG-VAG can reveal more SRAVMs that recanalize within a short period even if AV shunts are not depicted by angiography. Therefore, surgical removal of the AOAVM should be considered in cases with low surgical risk.

Effects of rikkunshito (traditional Japanese medicine) on enteral feeding and the plasma ghrelin level in critically ill patients: A pilot study
Mineji Hayakawa, Yuichi Ono, Takeshi Wada, Yuichiro Yanagida, Atsushi Sawamura, Hiroshi Takeda, Satoshi Gando
Journal of Intensive Care, 2, 1, 53, BioMed Central Ltd., 2014年09月02日, ［査読有り］
英語, 研究論文（学術雑誌）, Background: Rikkunshito is a traditional Japanese medicine that has been widely prescribed for patients with various gastrointestinal symptoms. Recently, the prokinetic effects of Rikkunshito in patients with a variety of diseases have attracted attention in Japan. The prokinetic effects of Rikkunshito are believed to result from an increase of active ghrelin, which is most abundant in the stomach and which has a gastrokinetic function. The aim of the present pilot study was to investigate the effects of Rikkunshito on intragastric enteral feeding and plasma ghrelin levels in critically ill patients. Methods: The study population consisted of critically ill patients who were projected to require intragastric tube feeding for more than 7 days. The patients were prospectively assigned to one of two treatment groups and were randomized to receive either Rikkunshito (2.5 g) or metoclopramide (10 mg) every 8 h. All patients received standard enteral nutrition. Patients in both groups were begun on intragastric tube feeding according to our institution's feeding protocol. Results: All patients were undergoing mechanical ventilation at the time of enrollment. The portions of enteral nutrition provided to the target amount and the quantity of gastric discharge were not statistically significantly different between the two groups. The Rikkunshito group reached 50% of the target amount of enteral feeding significantly earlier than the metoclopramide group, although the proportion of patients in whom enteral feeding was successful did not differ significantly between the two groups. Patients in the Rikkunshito group showed significantly higher plasma levels of active ghrelin compared to those in the metoclopramide group. Conclusions: The administration of Rikkunshito increased the plasma level of active ghrelin, and induced prokinetic effects that were greater than those observed following treatment with metoclopramide in critically ill patients.

Effectiveness of end-expiratory lung volume measurements during the lung recruitment maneuver for patients with atelectasis
Susumu Nakahashi, Satoshi Gando, Takehiko Ishikawa, Takeshi Wada, Yuichiro Yanagida, Nobuhiko Kubota, Shinji Uegaki, Mineji Hayakawa, Atsushi Sawamura
JOURNAL OF CRITICAL CARE, 28, 4, 534.e1, 5, W B SAUNDERS CO-ELSEVIER INC, 2013年08月, ［査読有り］
英語, 研究論文（学術雑誌）, Purpose: The aim of this study was to determine whether the relative change in the end-expiratory lung volume (EELV) obtained by the recruitment maneuver (RM) can serve as an indicator of the change in the P/F ratio.
Materials and Methods: The effects of the intermittent stepwise increases in the RM (peak inspiratory pressure, 45, 50, and 55 cm H2O) were compared in 21 patients with atelectasis under mechanical ventilation. The EELV, the ratio of arterial oxygen concentration to the fraction of inspired oxygen P/F ratio, and relative change rate (Delta) in these parameters were evaluated after each RM.
Results: A greater improvement in the EELV (1157 +/- 344 mL vs 1469 +/- 396 mL) and P/F ratio (250 +/- 99 vs 320 +/- 92) was observed after the RM. The Delta EELV was correlated with the Delta P/F ratio (rho = 0.73, P < .01) and was identified as an accurate predictor of the improvement of the Delta P/F ratio by the receiver operating characteristic curve (the area under the curve, 0.93; P < .01).
Conclusions: These results suggest that the Delta EELV obtained by intermittent stepwise RM can serve as an indicator of the change in the P/F ratio. (c) 2013 Elsevier Inc. All rights reserved.

Effectiveness of end-expiratory lung volume measurements during the lung recruitment maneuver for patients with atelectasis
Susumu Nakahashi, Satoshi Gando, Takehiko Ishikawa, Takeshi Wada, Yuichiro Yanagida, Nobuhiko Kubota, Shinji Uegaki, Mineji Hayakawa, Atsushi Sawamura
JOURNAL OF CRITICAL CARE, 28, 4, 534E1, 5, W B SAUNDERS CO-ELSEVIER INC, 2013年08月, ［査読有り］
英語, 研究論文（学術雑誌）, Purpose: The aim of this study was to determine whether the relative change in the end-expiratory lung volume (EELV) obtained by the recruitment maneuver (RM) can serve as an indicator of the change in the P/F ratio.
Materials and Methods: The effects of the intermittent stepwise increases in the RM (peak inspiratory pressure, 45, 50, and 55 cm H2O) were compared in 21 patients with atelectasis under mechanical ventilation. The EELV, the ratio of arterial oxygen concentration to the fraction of inspired oxygen P/F ratio, and relative change rate (Delta) in these parameters were evaluated after each RM.
Results: A greater improvement in the EELV (1157 +/- 344 mL vs 1469 +/- 396 mL) and P/F ratio (250 +/- 99 vs 320 +/- 92) was observed after the RM. The Delta EELV was correlated with the Delta P/F ratio (rho = 0.73, P < .01) and was identified as an accurate predictor of the improvement of the Delta P/F ratio by the receiver operating characteristic curve (the area under the curve, 0.93; P < .01).
Conclusions: These results suggest that the Delta EELV obtained by intermittent stepwise RM can serve as an indicator of the change in the P/F ratio. (c) 2013 Elsevier Inc. All rights reserved.

Normal prothrombinase activity, increased systemic thrombin activity, and lower antithrombin levels in patients with disseminated intravascular coagulation at an early phase of trauma: Comparison with acute coagulopathy of trauma-shock
Yuichiro Yanagida, Satoshi Gando, Atsushi Sawamura, Mineji Hayakawa, Shinji Uegaki, Nobuhiko Kubota, Taeko Homma, Yuichi Ono, Yoshinori Honma, Takeshi Wada, Subrina Jesmin
SURGERY, 154, 1, 48, 57, MOSBY-ELSEVIER, 2013年07月, ［査読有り］
英語, 研究論文（学術雑誌）, Background. We tested the hypotheses that an increase in systemic thrombin activity occurs in both disseminated intravascular coagulation (DIG) with the fibrinolytic phenotype and in acute coagulopathy of trauma shock (ACoTS), and that the patients diagnosed as having ACoTS overlap or are identical with those diagnosed as having DIG.
Methods. We made a prospective study of 57 trauma patients, including 30 patients with DIG and 27 patients without DIG. Patients with ACoTS, defined as a prothrombin time ratio >1.2, were also investigated. We included 12 healthy volunteers as controls. The levels of soluble fibrin, antithrombin, prothrombinase activity, soluble thrombomodulin, and markers of fibrin(ogen)olysis were measured on days 1 and 3 after the trauma. The systemic inflammatory response syndrome and the Sequential Organ Failure Assessment were scored to evaluate the extent of inflammation and organ dysfunction.
Results. Patients with DIG showed more systemic inflammation and greater Sequential Organ Failure Assessment scores and were transfused with more blood products than the patients without DIG. On day 1, normal prothrombinase activity, increased soluble fibrin, lesser levels of antithrombin, and increased soluble thrombomodulin were observed in patients with DIG in comparison with controls and non-DIG patients. These changes were more prominent in patients with DIC who met the overt criteria for DIC established by the International Society on Thrombosis and Haemostasis. Multiple regression analysis showed that antithrombin is an independent predictor of high soluble fibrin in DIG patients. Greater levels of fibrin and fibrinogen degradation products, D-dimer, and the fibrin and fibrinogen degradation products/D-dimer ratio indicated increased fibrin(ogen)olysis in DIG patients. Almost all ACoTS patients overlapped with the DIG patients. The changes in the measured variables in ACoTS patients coincided with those in DIG patients.
Conclusion. Normal prothrombinase activity and insufficient control of coagulation give rise to systemic increase in thrombin generation and its activity in patients with DIG with the fibrinolytic phenotype at an early phase of trauma. The same is true in patients with ACoTS, and shutoff of thrombin generation was not observed.

Coagulofibrinolytic changes in patients with disseminated intravascular coagulation associated with post-cardiac arrest syndrome- Fibrinolytic shutdown and insufficient activation of fibrinolysis lead to organ dysfunction
Takeshi Wada, Satoshi Gando, Asumi Mizugaki, Yuichiro Yanagida, Subrina Jesmin, Hiroyuki Yokota, Masahiro Ieko
THROMBOSIS RESEARCH, 132, 1, E64, E69, PERGAMON-ELSEVIER SCIENCE LTD, 2013年07月, ［査読有り］
英語, 研究論文（学術雑誌）, Introduction: Post-cardiac arrest syndrome (PCAS) is often associated with disseminated intravascular coagulation (DIC), thus leading to the development of multiple organ dysfunction syndrome (MODS). The aim of this study was to examine the pathophysiological relationships between coagulation, fibrinolysis and fibrinolytic shutdown by evaluating the levels of coagulofibrinolytic markers, including soluble fibrin, thrombin-activatable fibrinolysis inhibitor (TAFI), tissue plasminogen activator-plasminogen activator inhibitor-1 complex (tPAIC), plasmin-alpha2 plasmin inhibitor complex (PPIC), neutrophil elastase and fibrin degradation product by neutrophil elastase (EXDP).
Materials and Methods: Fifty-two resuscitated patients were divided into two groups: 22 DIC and 30 non-DIC patients.
Results: The levels of soluble fibrin, PPIC, tPAIC, EXDP and neutrophil elastase in the DIC patients with PCAS were significantly higher than those observed in the non-DIC patients. The values of the tPAIC and JAAM DIC scores were found to be independent predictors of increased SOFA scores in the DIC patients. The MODS patients demonstrated significantly higher levels of soluble fibrin and tPAIC; however, the levels of TAFI and EXDP were identical between the patients with and without MODS. In addition, positive correlations were observed between the levels of tPAIC and EXDP in the patients with non-MODS; however, no correlations were observed between these markers in the MODS patients.
Conclusions: Thrombin activation and fibrinolytic shutdown play important roles in the development of organ dysfunction in PCAS patients. Neutrophil elastase-mediated fibrinolysis cannot overcome the fibrinolytic shutdown that occurs in DIC patients with PCAS, thus resulting in the development of MODS. (C) 2013 Elsevier Ltd. All rights reserved.

The role of angiogenic factors and their soluble receptors in acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) associated with critical illness
Takeshi Wada, Subrina Jesmin, Satoshi Gando, Yuichiro Yanagida, Asumi Mizugaki, Sayeeda Nusrat Sultana, Sohel Zaedi, Hiroyuki Yokota
JOURNAL OF INFLAMMATION-LONDON, 10, 1, 6, BIOMED CENTRAL LTD, 2013年02月, ［査読有り］
英語, 研究論文（学術雑誌）, Background: Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are characterized by a disruption of the endothelium and alveolar epithelial barriers involving increased microvascular permeability, thus resulting in the set of protein-rich pulmonary edema. Angiogenic factors and their receptors, including vascular endothelial growth factor (VEGF)/VEGF-receptor (VEGFR) and the angiopoietin (Ang)/Tie2 signaling pathways, play pivotal roles in both angiogenesis and microvascular permeability. The aim of the study was to assess the relationship between angiogenic factors, their soluble receptors and ALI/ARDS associated with critically ill patients, including sepsis, severe trauma, and post-cardiac arrest syndrome (PCAS).
Methods: One hundred fifty-nine critically ill patients, including 50 patients with sepsis, 57 patients with severe trauma and 52 resuscitated after out-of-hospital cardiac arrest, were divided into three subgroups: including 25 ALI patients, 101 ARDS patients and 22 non-ALI/ARDS patients. The serum levels of angiogenic factors were measured at the time of admission (day 1), as well as day 3 and day 5 and then were compared among the ALI, ARDS and non-ALI/ARDS groups. Their predictive values for developing ALI/ARDS and 28-day mortality were evaluated.
Results: Higher levels of sVEGFR1 and Ang2 were observed in the ALI and ARDS patients than in the non-ALI/ARDS patients during the entire study period. The Ang2/Ang1 ratio in the ARDS group was also significantly higher than that in the non-ALI/ADRS group. The sVEGFR2 levels in the ARDS group on day 1 were significantly lower than those of the non-ALI/ADRS group. In addition, significant positive correlations were seen between the sVEGFR1, Ang2, Ang2/Ang1, and the development of ALI/ARDS in critical illness. There were also significant negative correlations between the minimal value of sVEGFR2, the maximal value of Ang1 and the ALI/ARDS group. In particular, sVEGFR2 and Ang2 were independent predictors of developing ALI/ARDS. Moreover, Ang2 and sVEGFR2 also independently predicted the mortality in ALI/ARDS patients.
Conclusions: Angiogenic factors and their soluble receptors, particularly sVEGFR2 and Ang2, are thus considered to be valuable predictive biomarkers in the development of ALI/ARDS associated with critical illness and mortality in ALI/ARDS patients.

Angiogenic factors and their soluble receptors predict organ dysfunction and mortality in post-cardiac arrest syndrome
Takeshi Wada, Subrina Jesmin, Satoshi Gando, Yuichiro Yanagida, Asumi Mizugaki, Sayeeda N. Sultana, Sohel Zaedi, Hiroyuki Yokota
Critical Care, 16, 5, R171, 2012年09月29日, ［査読有り］
英語, 研究論文（学術雑誌）, Introduction: Post-cardiac arrest syndrome (PCAS) often leads to multiple organ dysfunction syndrome (MODS) with a poor prognosis. Endothelial and leukocyte activation after whole-body ischemia/reperfusion following resuscitation from cardiac arrest is a critical step in endothelial injury and related organ damage. Angiogenic factors, including vascular endothelial growth factor (VEGF) and angiopoietin (Ang), and their receptors play crucial roles in endothelial growth, survival signals, pathological angiogenesis and microvascular permeability. The aim of this study was to confirm the efficacy of angiogenic factors and their soluble receptors in predicting organ dysfunction and mortality in patients with PCAS.Methods: A total of 52 resuscitated patients were divided into two subgroups: 23 survivors and 29 non-survivors. The serum levels of VEGF, soluble VEGF receptor (sVEGFR)1, sVEGFR2, Ang1, Ang2 and soluble Tie2 (sTie2) were measured at the time of admission (Day 1) and on Day 3 and Day 5. The ratio of Ang2 to Ang1 (Ang2/Ang1) was also calculated. This study compared the levels of angiogenic factors and their soluble receptors between survivors and non-survivors, and evaluated the predictive value of these factors for organ dysfunction and 28-day mortality.Results: The non-survivors demonstrated more severe degrees of organ dysfunction and a higher prevalence of MODS. Non-survivors showed significant increases in the Ang2 levels and the Ang2/Ang1 ratios compared to survivors. A stepwise logistic regression analysis demonstrated that the Ang2 levels or the Ang2/Ang1 ratios on Day 1 independently predicted the 28-day mortality. The receiver operating characteristic curves of the Ang2 levels, and the Ang2/Ang1 ratios on Day 1 were good predictors of 28-day mortality. The Ang2 levels also independently predicted increases in the Sequential Organ Failure Assessment (SOFA) scores.Conclusions: We observed a marked imbalance between Ang1 and Ang2 in favor of Ang2 in PCAS patients, and the effect was more prominent in non-survivors. Angiogenic factors and their soluble receptors, particularly Ang2 and Ang2/Ang1, are considered to be valuable predictive biomarkers in the development of organ dysfunction and poor outcomes in PCAS patients. © 2012 Wada et al.
licensee BioMed Central Ltd.

Using angiogenic factors and their soluble receptors to predict organ dysfunction in patients with disseminated intravascular coagulation associated with severe trauma
Takeshi Wada, Subrina Jesmin, Satoshi Gando, Sayeeda N. Sultana, Sohel Zaedi, Hiroyuki Yokota
Critical Care, 16, 2, R63, 2012年04月20日, ［査読有り］
英語, 研究論文（学術雑誌）, Introduction: Disseminated intravascular coagulation (DIC) is characterized by the concomitant activation of coagulofibrinolytic disorders and systemic inflammation associated with endothelial dysfunction-induced microvascular permeability. Angiogenic factors, including vascular endothelial growth factor (VEGF), angiopoietin (Ang), and their receptors, play crucial roles in angiogenesis and microvascular permeability. The aim of the study was to assess the relationship between angiogenic factors, their soluble receptors and organ dysfunction associated with DIC after severe trauma.Materials and methods: A total of 57 patients with severe trauma were divided into two subgroups
30 DIC patients and 27 non-DIC patients. The DIC was diagnosed based on the Japanese Association for Acute Medicine (JAAM) DIC and the International Society on Thrombosis and Haemostasis (ISTH) overt DIC criteria. The serum levels of angiogenic factors were measured at the time of admission (Day 1), Day 3 and Day 5. This study compared levels of these angiogenic factors between the two DIC groups, and evaluated their predictive value for organ dysfunction.Results: DIC patients, especially those with ISTH DIC, showed higher Sequential Organ Failure Assessment (SOFA) scores and lactate levels. There were lower levels of VEGF, Ang1 and the soluble Tie2 in the ISTH DIC patients than the non-DIC patients. The levels of soluble VEGF receptor-1 (sVEGFR1), Ang2 and the Ang2/Ang1 ratio in the ISTH DIC patients were higher than in non-DIC patients. The relationship between the presence of massive transfusion and angiogenic factors indicated the same results. The levels of sVEGFR1, Ang2 and the Ang2/Ang1 ratio correlated with the SOFA scores. In particular, sVEGFR1 and Ang2 were independent predictors of an increase in the SOFA score. The lactate levels independently predicted increases in the levels of sVEGFR1 and Ang2. The decrease in the platelet counts also independently predicted the increase in Ang2 levels in DIC patients.Conclusions: Angiogenic factors and their soluble receptors, particularly sVEGFR1 and Ang2, are considered to play pivotal roles in the development of organ dysfunction in DIC associated with severe trauma. DIC-induced tissue hypoxia and platelet consumption may play crucial roles in inducing sVEGFR1 and Ang2, and in determining the prognosis of the severity of organ dysfunction. © 2012 Wada et al.
licensee BioMed Central Ltd.

Time-Dependent Alterations of VEGF and Its Signaling Molecules in Acute Lung Injury in a Rat Model of Sepsis
Subrina Jesmin, Sohel Zaedi, A. M. Shahidul Islam, S. Nusrat Sultana, Yoshio Iwashima, Takeshi Wada, Naoto Yamaguchi, Michiaki Hiroe, Satoshi Gando
INFLAMMATION, 35, 2, 484, 500, SPRINGER/PLENUM PUBLISHERS, 2012年04月, ［査読有り］
英語, 研究論文（学術雑誌）, Molecular mechanisms of sepsis-associated acute lung injury (ALI) are poorly defined. Since vascular endothelial growth factor (VEGF) is a potent vascular permeability and mitogenic factor, it might contribute to the development of ALI in sepsis. Thus, using lipopolysaccharide (LPS)-induced (15 mg/kg, intraperitoneal) endotoxemic rat model, we studied the timeline (1, 3, 6, and 10 h) of pulmonary VEGF expression and its signaling machinery. Levels of pulmonary VEGF and its angiogenic-mediating receptor, Flk-1, were downregulated by LPS in a time-dependent manner; levels of plasma VEGF and its permeability-mediating receptor, Flt-1, in contrast, was upregulated with time. In addition, blockade of Flt-1 could improve the downregulated pulmonary VEGF level and attenuate the elevated plasma and pulmonary levels of TNF-alpha, followed by improvement of arterial oxygenation and wet-to-dry weight ratio of the lung. Expression of signaling, pro- and or apoptotic factors after LPS administration were as follows: phosphorylated Akt, a downstream molecule was downregulated time dependently; endothelial nitric oxide synthase levels were significantly reduced; pro-apoptotic markers caspase 3 and Bax were upregulated whereas levels of Bcl-2 were downregulated. The present findings show that VEGF may play a role through the expression of Flt-1 in LPS-induced ALI. Moreover, downregulation of VEGF signaling cascade may account for LPS-induced apoptosis and impaired physiological angiogenesis in lung tissues, which in turn may contribute to the development of ALI induced by LPS.

Using angiogenic factors and their soluble receptors to predict organ dysfunction in patients with disseminated intravascular coagulation associated with severe trauma
Takeshi Wada, Subrina Jesmin, Satoshi Gando, Sayeeda N. Sultana, Sohel Zaedi, Hiroyuki Yokota
CRITICAL CARE, 16, 2, BIOMED CENTRAL LTD, 2012年, ［査読有り］
英語, 研究論文（学術雑誌）, Introduction: Disseminated intravascular coagulation (DIC) is characterized by the concomitant activation of coagulofibrinolytic disorders and systemic inflammation associated with endothelial dysfunction-induced microvascular permeability. Angiogenic factors, including vascular endothelial growth factor (VEGF), angiopoietin (Ang), and their receptors, play crucial roles in angiogenesis and microvascular permeability. The aim of the study was to assess the relationship between angiogenic factors, their soluble receptors and organ dysfunction associated with DIC after severe trauma.
Materials and methods: A total of 57 patients with severe trauma were divided into two subgroups; 30 DIC patients and 27 non-DIC patients. The DIC was diagnosed based on the Japanese Association for Acute Medicine (JAAM) DIC and the International Society on Thrombosis and Haemostasis (ISTH) overt DIC criteria. The serum levels of angiogenic factors were measured at the time of admission (Day 1), Day 3 and Day 5. This study compared levels of these angiogenic factors between the two DIC groups, and evaluated their predictive value for organ dysfunction.
Results: DIC patients, especially those with ISTH DIC, showed higher Sequential Organ Failure Assessment (SOFA) scores and lactate levels. There were lower levels of VEGF, Ang1 and the soluble Tie2 in the ISTH DIC patients than the non-DIC patients. The levels of soluble VEGF receptor-1 (sVEGFR1), Ang2 and the Ang2/Ang1 ratio in the ISTH DIC patients were higher than in non-DIC patients. The relationship between the presence of massive transfusion and angiogenic factors indicated the same results. The levels of sVEGFR1, Ang2 and the Ang2/Ang1 ratio correlated with the SOFA scores. In particular, sVEGFR1 and Ang2 were independent predictors of an increase in the SOFA score. The lactate levels independently predicted increases in the levels of sVEGFR1 and Ang2. The decrease in the platelet counts also independently predicted the increase in Ang2 levels in DIC patients.
Conclusions: Angiogenic factors and their soluble receptors, particularly sVEGFR1 and Ang2, are considered to play pivotal roles in the development of organ dysfunction in DIC associated with severe trauma. DIC-induced tissue hypoxia and platelet consumption may play crucial roles in inducing sVEGFR1 and Ang2, and in determining the prognosis of the severity of organ dysfunction.

Effects of intrapulmonary percussive ventilation for acute respiratory failure.
Nakahashi S, Hayakawa M, Katabami K, Wada T, Sawamura A, Ishikawa T, Gando S
Journal of Japanese Society of Intensive Care Medicine., 19, 2, 191, 196, 2012年, ［査読有り］
ICU患者の急性呼吸不全に対する肺内高頻度振動換気法（経気道的陽圧加圧振動法）の血液ガス改善効果の主要因は、同法に特有の”振動”である事を明らかにした前向き介入試験報告である。

Imbalance Between Macrophage Migration Inhibitory Factor and Cortisol Induces Multiple Organ Dysfunction in Patients with Blunt Trauma
Mineji Hayakawa, Kenichi Katabami, Takeshi Wada, Yousuke Minami, Masahiro Sugano, Hidekazu Shimojima, Nobuhiko Kubota, Shinji Uegaki, Atsushi Sawamura, Satoshi Gando
INFLAMMATION, 34, 3, 193, 197, SPRINGER/PLENUM PUBLISHERS, 2011年06月, ［査読有り］
英語, 研究論文（学術雑誌）, Migration inhibitory factor (MIF) is associated with multiple organ dysfunction syndrome (MODS) in patients with systemic inflammatory response syndrome (SIRS). Our purposes were to determine the serum MIF, cortisol, and tumor narcosis factor-alpha (TNF-alpha) and to investigate the influences of the balance between the levels of MIF and cortisol in patients with blunt trauma. The cortisol levels were identical between the patients with and without MODS. However, the MIF and TNF-alpha levels in the patients with MODS were statistically higher than those of the patients without MODS. The cortisol/MIF ratios in the patients with MODS were statistically higher than those of the patients without MODS. The results show that MIF and TNF-alpha play an important role together in posttraumatic inflammatory response. An excessive serum MIF elevation overrides the anti-inflammatory effects of cortisol and leads to persistent SIRS followed by MODS in blunt trauma patients.

SIVELESTAT (SELECTIVE NEUTROPHIL ELASTASE INHIBITOR) IMPROVES THE MORTALITY RATE OF SEPSIS ASSOCIATED WITH BOTH ACUTE RESPIRATORY DISTRESS SYNDROME AND DISSEMINATED INTRAVASCULAR COAGULATION PATIENTS
Mineji Hayakawa, Kenichi Katabami, Takeshi Wada, Masahiro Sugano, Hirokatsu Hoshino, Atsushi Sawamura, Satoshi Gando
SHOCK, 33, 1, 14, 18, LIPPINCOTT WILLIAMS & WILKINS, 2010年01月, ［査読有り］
英語, 研究論文（学術雑誌）, Neutrophil elastase plays an important role in the development of acute respiratory distress syndrome (ARDS) and disseminated intravascular coagulation (DIC) in sepsis. Sivelestat is a selective neutrophil elastase inhibitor. It is possible that sivelestat improves the outcome of septic patients associated with ARDS and DIC. A retrospective data analysis of septic patients associated with ARDS and DIC was conducted to investigate the effects of sivelestat. Observational period was 5 days after admission to intensive care unit (ICU). The study included 167 septic patients associated with ARDS and DIG. Control group included 133 patients without sivelestat, and sivelestat group included 34 patients started to deadministered sivelestat on the admission to ICU. The lung injury scores and Pao(2)/Fio(2) ratio of the sivelestat group were significantly more severe than those of the control group from days 1 to 4. On day 5, the lung injury score and Pao(2)/Fio(2) ratio of the sivelestat group improved to the same levels of those of the control group. The DIC score of sivelestat group improved on day 3 in comparison to day 1, and those of control group remained unchanged until day 4. The length of ICU stay of the sivelestat group was significantly shorter than that of the control group. A stepwise multiple logistic-regression analysis showed the sivelestat administration to be an independent predictor of survival of the septic patients associated with both ARDS and DIC. The length of ICU stay of the sivelestat group was significantly shorter than that of the control group. In addition, sivelestat administration was found to be an independent predictor of survival of those patients.

Application of the Japanese Association for Acute Medicine disseminated intravascular coagulation diagnostic criteria for patients at an early phase of trauma
Atsushi Sawamura, Mineji Hayakawa, Satoshi Gando, Nobuhiko Kubota, Masahiro Sugano, Takeshi Wada, Ken-ichi Katabami
THROMBOSIS RESEARCH, 124, 6, 706, 710, PERGAMON-ELSEVIER SCIENCE LTD, 2009年12月, ［査読有り］
英語, 研究論文（学術雑誌）, Introduction: To validate the diagnostic criteria for disseminated intravascular coagulation (DIC) established by the Japanese Association for Acute Medicine (JAAM) at an early stage of trauma and to evaluate the hypothesis that the JAAM criteria can diagnose DIC with a higher sensitivity than the International Society on Thrombosis and Haemostasis (ISTH) overt DIC criteria.
Materials and Methods: Based on a review of medical records, the data of 314 trauma patients were retrospectively obtained at 4 time points within 24 hr after arrival to the Emergency Department.
Results: One hundred and forty-one JAAM DIC patients (44.9%) showed differences in the prevalence of massive bleeding and multiple organ dysfunction syndrome (MODS), and the outcome in comparison to the non-DIC patients. A stepwise logistic regression analysis showed that the maximum JAAM DIC scores independently predicted the patient death. All of the patients who developed ISTH overt DIC could be identified by the JAAM DIC criteria at early time points. The mortality rate and the incidence of massive bleeding and MODS of the patients with the ISTH overt DIC were higher than those only met the JAAM DIC criteria. Stepwise increases in the ISTH overt DIC scores and the incidence of the overt DIC were observed in accordance with the increases in the JAAM DIC scores. While the mortality rates were identical, there were marked differences in the incidence of MODS and Sequential Organ Failure Assessment scores between the DIC patients associated with trauma and sepsis.
Conclusions: The results show that the JAAM scoring system has acceptable validity for the DIC diagnosis at an early phase of trauma, and also that the scoring system can diagnose DIC with a higher sensitivity than the criteria of the ISTH overt DIC. Bleeding as well as MODS may affect the prognosis of the patients associated with DIC. (C) 2009 Elsevier Ltd. All rights reserved.

Disseminated intravascular coagulation with a fibrinolytic phenotype at an early phase of trauma predicts mortality
Atsushi Sawamura, Mineji Hayakawa, Satoshi Gando, Nobuhiko Kubota, Masahiro Sugano, Takeshi Wada, Ken-ichi Katabami
THROMBOSIS RESEARCH, 124, 5, 608, 613, PERGAMON-ELSEVIER SCIENCE LTD, 2009年11月, ［査読有り］
英語, 研究論文（学術雑誌）, Introduction: Disseminated intravascular coagulation (DIC) with an antifibrinolytic phenotype is characterized by microvascular thrombosis leading to poor outcome at the late-stage of trauma. To test the hypothesis that DIC with a fibrinolytic phenotype at an early stage of trauma also contributes to a poor outcome due to severe bleeding, we conducted a retrospective. cohort study.
Materials and Methods: The subjects included 314 consecutive severe trauma patients. A systematic review of medical records of the patients was conducted to provide the base line characteristics and DIC-related variables. The data of these variables were obtained at 4 time points within 24 hr after arrival to the emergency department (ED): Time Point 1, immediately after arrival to the ED to 4 hr after arrival; Time Point 2, 4 to 8 hr after arrival; Time Point 3, 8 to 16 hr after arrival; Time Point 4, 16 to 24 hr after arrival.
Results: Nonsurvivors (87.3%, 48/55) met the Japanese Association for Acute Medicine (JAAM) DIC criteria showing lower fibrinogen levels, a prolonged prothrombin time, and higher fibrin/fibrinogen degradation products (FDP) and D-dimer levels in comparison to those of the 289 survivors. The FDP/D-dimer ratio and lactate level were significantly higher in the nonsurvivors than those of the survivors. Lower fibrinogen levels and higher FDP/D-dimer ratio suggest fibrinogenolysis in DIC of the nonsurvivors. Furthermore a stepwise logistic regression analysis showed that the JAAM DIC score, levels of fibrinogen, FDP and lactate at Time Point 1 are independent predictors of death. Low levels of fibrinogen and high FDP but not D-dimer predict massive bleeding at an early stage of trauma. The optimal cutoff points for the prediction of death and massive bleeding were fibrinogen (1.90, 1.90 g/L) and FDP (35.2, 68.7 mg/L), respectively.
Conclusions: DIC with a fibrinolytic phenotype modified through fibrinogenolysis at an early phase of trauma contributes to poor prognosis due to massive bleeding. Tissue hypoperfusion may be involved in the pathogenesis of this type of DIC. (C) 2009 Elsevier Ltd. All rights reserved.

ヘパリンモニタリング:まだ,APTTですか?抗Xa活性測定の勧め
斉藤智誉, 水柿明日美, 高氏修平, 早水真理子, 本間慶憲, 吉田知由, 方波見謙一, 和田剛志, 前川邦彦, 早川峰司, 日本集中治療医学会学術集会(Web), 51st, 2024年

【外傷性凝固障害と外傷性DIC】外傷性凝固障害と外傷性DICにおけるトロンビン産生 臨床的検討
高橋 正樹, 和田 剛志, Thrombosis Medicine, 13, 1, 19, 24, 2023年03月
外傷による侵襲を受けると,生体内では止血や組織修復のための生理的防御反応として,トロンビン産生が亢進する.トロンビン産生を評価する指標にはトロンビン産生試験や可溶性フィブリン,アンチトロンビンなどがあり,外傷患者でトロンビン産生が亢進することは,これまで多くの臨床研究で示されてきた.トロンビンの過剰産生は血管内皮細胞に存在する抗凝固機構の破綻を招き,更なるトロンビン産生を引き起こす.外傷性DICとは,トロンビン産生が制御できなくなった病的状態であり,患者予後の悪化へとつながる.(著者抄録), (株)先端医学社, 日本語

原因の診断と治療が遅れたNew-onset refractory status epileticusの1例
前川邦彦, 高橋正樹, 松本悠, 水柿明日美, 早水真理子, 本間慶憲, 斉藤智誉, 吉田知由, 方波見謙一, 和田剛志, 早川峰司, 日本集中治療医学会学術集会(Web), 50th, 2023年

ヘパリンモニタリングにおける抗活性化第X因子活性と活性化部分トロンボプラスチン時間の不一致
斉藤智誉, 水柿明日美, 早水真理子, 本間慶憲, 吉田知由, 方波見謙一, 和田剛志, 前川邦彦, 早川峰司, 日本集中治療医学会学術集会(Web), 50th, 2023年

外傷性凝固障害におけるアンチトロンビンの動態とDIC発症,予後との関係
和田剛志, 白石淳, 丸藤哲, 加葉田大志朗, 山川一馬, 藤島清太郎, 齋藤大蔵, 久志本成樹, 小倉裕司, 真弓俊彦, 大友康裕, 日本血栓止血学会誌, 34, 2, 2023年

【循環器集中治療の最前線】重症疾患に合併したDIC　　　　　　　　　　　　　　　
土田 拓見, 和田 剛志, 循環器内科, 93, 1, 40, 46, 2023年01月
(有)科学評論社, 日本語

【徹底ガイドDICのすべて 2022-'23】基礎病態と治療 頭部外傷　　　　　　　　　　　　　　　
高橋 正樹, 和田 剛志, 救急・集中治療, 34, 2, 740, 747, 2022年07月
＜ここがポイント!＞▼重症頭部外傷ではDICに一致した消費性凝固障害、全身臓器への播種性微小血栓形成、病的線溶亢進が認められる。▼損傷脳から循環血液中への直接的な組織因子の放出と、血管内皮細胞活性化/傷害が凝固亢進の機序として重要である。▼損傷脳由来のt-PAおよびu-PAの放出が病的線溶亢進の一因である。▼頭部外傷後の凝固障害の病態を理解したうえで、血液製剤などによる凝固異常の是正が二次性脳損傷の回避、予後改善につながる。▼トラネキサム酸が重症頭部外傷の予後を改善させる薬剤として注目されており、さらなるエビデンスの蓄積が待たれる。(著者抄録), (株)総合医学社, 日本語

【徹底ガイドDICのすべて 2022-'23】基礎病態と治療 心停止後症候群　　　　　　　　　　　　　　　
土田 拓見, 和田 剛志, 救急・集中治療, 34, 2, 755, 761, 2022年07月
＜ここがポイント!＞▼心停止後症候群の構成要素の一つである全身性虚血/再灌流障害に伴う徴候の一つとしてDICを合併する。▼組織因子の血流への曝露に起因するトロンビン産生、内皮細胞傷害による抗凝固機構の破綻が過剰な凝固反応を促進するが、plasminogen activator inhibitor-1(PAI-1)による線溶遮断が凝固と線溶の不均衡をひき起こし、微小循環不全から臓器不全を発症し予後不良につながる。▼DICの本態は損傷細胞由来のヒストン、および活性化好中球から放出されるneutrophil extracellular traps(NETs)であり、NETsの主成分であるヒストンがさらにNETs放出を促進して相乗的に病態が進展する。▼現在までのところ、心停止後症候群に対する線溶療法、抗凝固療法の有用性は示されていない。(著者抄録), (株)総合医学社, 日本語

播種性血管内凝固の診断と治療　　　　　　　　　　　　　　　
高橋 正樹, 和田 剛志, 集中治療医学レビュー, 2022-'23, 287, 293, 2022年05月
(株)総合医学社, 日本語

【敗血症診療を知る-J-SSCG2020のポイント】敗血症におけるDIC診断と治療
和田 剛志, 射場 敏明, 医学のあゆみ, 279, 12-13, 1175, 1179, 2021年12月
「日本版敗血症診療ガイドライン2020(J-SSCG2020)」での播種性血管内凝固症候群(DIC)診療に関するクリニカルクエスチョン(CQ)においては、前版J-SSCG2016での診断および治療に加え、近年関心が高まっているDICの鑑別について言及した。(1)診断:診断基準は複数存在するが、それぞれの基準が作成された目的や求められる役割の相違などを理解し、診断基準間の優劣を判断することなく目的に応じて使い分ける必要がある。(2)鑑別:血栓性微小血管症(TMA)などDICに類似した血液検査異常をきたす疾患では特異的な治療アルゴリズムが必要な病態が存在し、これらはDICと並存しうるため「敗血症性DICの診療では常にDIC類似疾患の鑑別/並存を念頭に入れる」という心構えが必要である。(3)治療:近年の研究結果から検討対象患者を"敗血症性DIC"に限定し評価した結果、2つの薬剤に関して使用が弱く推奨され、2つの薬剤に関して標準治療として使用しないことが弱く推奨された。この"弱い推奨"の意味を正しく理解したうえでの抗凝固療法の適応検討や治療薬選択が望まれる。(著者抄録), 医歯薬出版(株), 日本語

外傷性凝固障害はDICなのか、それとも活性化プロテインC仮説なのか 過去の病態論争と現在のコンセンサス、そして未来の方向性
和田 剛志, 日本外傷学会雑誌, 35, 3, 209, 218, 2021年07月
外傷性凝固障害(TIC)は外傷そのものにより誘導される一次性凝固障害と,貧血,低体温,アシドーシスなどによる二次性凝固障害の複合的病因で発症する.TICの主病態は,損傷細胞/組織由来の分子パターンに起因するトロンビン産生亢進と消費性凝固障害,すなわち播種性血管内凝固症候群(DIC)であると古くから考えられてきたが,活性化プロテインC(APC)上昇に起因する凝固抑制および線溶亢進を病態の中心に据えるacute traumatic coagulopathy(ATC)が一次性凝固障害の主病態であるとする主張(APC仮説)がDICに否定的な欧米の外傷外科医よりなされている.APC仮説は疑義の多い病態概念であり,十数年にわたりTIC病態を巡る論争が繰り広げられてきた.本総説では,これまでの論争の争点を振り返りつつ現在の国際的コンセンサスを整理し,TICを診療する我々が歩むべき方向性を提示する.(著者抄録), (一社)日本外傷学会, 日本語

重症熱傷における予後予測因子の検討
高橋 正樹, 水柿 明日美, 吉田 知由, 方波見 謙一, 和田 剛志, 前川 邦彦, 早川 峰司, 日本救急医学会雑誌, 32, 6, 295, 302, 2021年06月
【目的】重症熱傷は致死率の高い疾患であり,初療時に予後を的確に評価することが重要である。今回我々は,重症熱傷患者の在院死亡を予測する因子を後方視的に検討した。【対象】2010年4月から2020年3月の間に,北海道大学病院救急科に入院した成人重症熱傷患者を対象とした。重症熱傷の基準は,(1)2度以上熱傷面積25% total body surface area(TBSA)以上,(2)3度熱傷面積10%TBSA以上,(3)24時間以上の人工呼吸器管理を要した気道熱傷,のいずれかを満たすものとした。来院時心肺停止および外来死亡例,他院で24時間以上加療された症例は除外した。【結果】52名が参入基準を満たし,生存群が32名,死亡群が20名であった。既知の予後予測指標および搬入時血液検査を基に,在院死亡を予測するreceiver operating characteristic曲線下面積を算出すると,乳酸脱水素酵素(LDH)が0.960と最大で,次いで熱傷予後指数(PBI)が0.913,abbreviated burn severity index(ABSI)が0.898であった。【結語】重症熱傷において,LDHが予後予測に有用であり,カットオフ値を500IU/Lとすることで,在院死亡を予測できる可能性を示した。LDHは測定が簡便かつ客観的であり,他指標と併せて,熱傷の重症度評価の一助となりうる。(著者抄録), (一社)日本救急医学会, 日本語

日本版敗血症診療ガイドライン2020
江木 盛時, 小倉 裕司, 矢田部 智昭, 安宅 一晃, 井上 茂亮, 射場 敏明, 垣花 泰之, 川崎 達也, 久志本 成樹, 黒田 泰弘, 小谷 穣治, 志馬 伸朗, 谷口 巧, 鶴田 良介, 土井 研人, 土井 松幸, 中田 孝明, 中根 正樹, 藤島 清太郎, 細川 直登, 升田 好樹, 松嶋 麻子, 松田 直之, 山川 一馬, 原 嘉孝, 大下 慎一郎, 青木 善孝, 稲田 麻衣, 梅村 穣, 河合 佑亮, 近藤 豊, 斎藤 浩輝, 櫻谷 正明, 對東 俊介, 武田 親宗, 寺山 毅郎, 東平 日出夫, 橋本 英樹, 林田 敬, 一二三 亨, 廣瀬 智也, 福田 龍将, 藤井 智子, 三浦 慎也, 安田 英人, 阿部 智一, 安藤 幸吉, 飯田 有輝, 石原 唯史, 井手 健太郎, 伊藤 健太, 伊藤 雄介, 稲田 雄, 宇都宮 明美, 卯野木 健, 遠藤 功二, 大内 玲, 尾崎 将之, 小野 聡, 桂 守弘, 川口 敦, 川村 雄介, 工藤 大介, 久保 健児, 倉橋 清泰, 櫻本 秀明, 下山 哲, 鈴木 武志, 関根 秀介, 関野 元裕, 高橋 希, 高橋 世, 高橋 弘, 田上 隆, 田島 吾郎, 巽 博臣, 谷 昌憲, 土谷 飛鳥, 堤 悠介, 内藤 貴基, 長江 正晴, 長澤 俊郎, 中村 謙介, 西村 哲郎, 布宮 伸, 則末 泰博, 橋本 悟, 長谷川 大祐, 畠山 淳司, 原 直己, 東別府 直紀, 古島 夏奈, 古薗 弘隆, 松石 雄二朗, 松山 匡, 峰松 佑輔, 宮下 亮一, 宮武 祐士, 森安 恵実, 山田 亨, 山田 博之, 山元 良, 吉田 健史, 吉田 悠平, 吉村 旬平, 四本 竜一, 米倉 寛, 和田 剛志, 渡邉 栄三, 青木 誠, 浅井 英樹, 安部 隆国, 五十嵐 豊, 井口 直也, 石川 雅巳, 石丸 剛, 磯川 修太郎, 板倉 隆太, 今長谷 尚史, 井村 春樹, 入野田 崇, 上原 健司, 生塩 典敬, 梅垣 岳志, 江川 裕子, 榎本 有希, 太田 浩平, 大地 嘉史, 大野 孝則, 大邉 寛幸, 岡 和幸, 岡田 信長, 岡田 遥平, 岡野 弘, 岡本 潤, 奥田 拓史, 小倉 崇以, 小野寺 悠, 小山 雄太, 貝沼 関志, 加古 英介, 柏浦 正広, 加藤 弘美, 金谷 明浩, 金子 唯, 金畑 圭太, 狩野 謙一, 河野 浩幸, 菊谷 知也, 菊地 斉, 城戸 崇裕, 木村 翔, 小網 博之, 小橋 大輔, 齊木 巌, 堺 正仁, 坂本 彩香, 佐藤 哲哉, 志賀 康浩, 下戸 学, 下山 伸哉, 庄古 知久, 菅原 陽, 杉田 篤紀, 鈴木 聡, 鈴木 祐二, 壽原 朋宏, 其田 健司, 高氏 修平, 高島 光平, 高橋 生, 高橋 洋子, 竹下 淳, 田中 裕記, 丹保 亜希仁, 角山 泰一朗, 鉄原 健一, 徳永 健太郎, 富岡 義裕, 冨田 健太朗, 富永 直樹, 豊崎 光信, 豊田 幸樹年, 内藤 宏道, 永田 功, 長門 直, 中村 嘉, 中森 裕毅, 名原 功, 奈良場 啓, 成田 知大, 西岡 典宏, 西村 朋也, 西山 慶, 野村 智久, 芳賀 大樹, 萩原 祥弘, 橋本 克彦, 旗智 武志, 浜崎 俊明, 林 拓也, 林 実, 速水 宏樹, 原口 剛, 平野 洋平, 藤井 遼, 藤田 基, 藤村 直幸, 舩越 拓, 堀口 真仁, 牧 盾, 増永 直久, 松村 洋輔, 真弓 卓也, 南 啓介, 宮崎 裕也, 宮本 和幸, 村田 哲平, 柳井 真知, 矢野 隆郎, 山田 浩平, 山田 直樹, 山本 朋納, 吉廣 尚大, 田中 裕, 西田 修, 日本版敗血症診療ガイドライン2020特別委員会, 日本救急医学会雑誌, 32, S1, S1, S411, 2021年02月
日本集中治療医学会と日本救急医学会は,合同の特別委員会を組織し,2016年に発表した日本版敗血症診療ガイドライン(J-SSCG)2016の改訂を行った。本ガイドライン(J-SSCG2020)の目的は,J-SSCG2016と同様に,敗血症・敗血症性ショックの診療において,医療従事者が患者の予後改善のために適切な判断を下す支援を行うことである。改訂に際し,一般臨床家だけでなく多職種医療者にも理解しやすく,かつ質の高いガイドラインとすることによって,広い普及を目指した。J-SSCG2016ではSSCG2016にない新しい領域[ICU-acquircd weakness(ICU-AW)とpost-intensive care syndrome(POCS),体温管理など]を取り上げたが,J-SSCG2020では新たに注目すべき4領域(Patient-and Family-Centered Care, sepsis treatment system,神経集中治療,ストレス潰瘍)を追加し,計22領域とした。重要な118の臨床課題(clinical question:CQ)をエビデンスの有無にかかわらず抽出した。これらのCQには,本邦で特に注目されているCQも含まれる。多領域にわたる大規模ガイドラインであることから,委員25名を中心に,多職種(看護師,理学療法士,臨床工学技士,薬剤師)および患者経験者も含めたワーキンググループメンバー,両学会の公募によるシステマティックレビューメンバーによる総勢226名の参加・協力を得た。また,中立的な立場で横断的に活躍するアカデミックガイドライン推進班をJ-SSCG2016に引き続き組織した。将来への橋渡しとなることを企図して,多くの若手医師をシステマティックレビューチーム・ワーキンググループに登用し,学会や施設の垣根を越えたネットワーク構築も進めた。作成工程においては,質の担保と作業過程の透明化を図るために様々な工夫を行い,パブリックコメント募集は計2回行った。推奨作成にはGRADE方式を取り入れ,修正Delphi法を用いて全委員の投票により推奨を決定した。結果,118CQに対する回答として,79個のGRADEによる推奨,5個のGPS(good practice statement),18個のエキスパートコンセンサス,27個のBQ(background question)の解説,および敗血症の定義と診断を示した。新たな試みとして,CQごとに診療フローなど時間軸に沿った視覚的情報を取り入れた。J-SSCG2020は,多職種が関わる国内外の敗血症診療の現場において,ベッドサイドで役立つガイドラインとして広く活用されることが期待される。なお,本ガイドラインは,日本集中治療医学会と日本救急医学会の両機関誌のガイドライン増刊号として同時掲載するものである。(著者抄録), (一社)日本救急医学会, 日本語

【どんな薬剤・合併症・病態・患者背景にも対応できる 周術期の薬の使い方パーフェクトガイド】(第5章)病態に応じた周術期での注意点 播種性血管内凝固症候群(DIC)　　　　　　　　　　　　　　　
土田 拓見, 和田 剛志, 薬事, 63, 3, 559, 566, 2021年02月
＜Key Points＞・播種性血管内凝固症候群(DIC)患者の治療で最も優先すべきは基礎疾患の治療である。・DICは、凝固線溶状態をリアルタイムに把握し、DICスコアを繰り返し評価することによるDIC診断に基づいて適切に治療介入を行う必要がある。・敗血症に対する抗凝固療法の効果はDICを伴う重症患者に限定的である可能性がある。・周術期において出血傾向があり輸血基準に適合する場合には、補充療法により出血のコントロールを行う。(著者抄録), (株)じほう, 日本語

日本版敗血症診療ガイドライン2020
江木 盛時, 小倉 裕司, 矢田部 智昭, 安宅 一晃, 井上 茂亮, 射場 敏明, 垣花 泰之, 川崎 達也, 久志本 成樹, 黒田 泰弘, 小谷 穣治, 志馬 伸朗, 谷口 巧, 鶴田 良介, 土井 研人, 土井 松幸, 中田 孝明, 中根 正樹, 藤島 清太郎, 細川 直登, 升田 好樹, 松嶋 麻子, 松田 直之, 山川 一馬, 原 嘉孝, 大下 慎一郎, 青木 善孝, 稲田 麻衣, 梅村 穣, 河合 佑亮, 近藤 豊, 斎藤 浩輝, 櫻谷 正明, 對東 俊介, 武田 親宗, 寺山 毅郎, 東平 日出夫, 橋本 英樹, 林田 敬, 一二三 亨, 廣瀬 智也, 福田 龍将, 藤井 智子, 三浦 慎也, 安田 英人, 阿部 智一, 安藤 幸吉, 飯田 有輝, 石原 唯史, 井手 健太郎, 伊藤 健太, 伊藤 雄介, 稲田 雄, 宇都宮 明美, 卯野木 健, 遠藤 功二, 大内 玲, 尾崎 将之, 小野 聡, 桂 守弘, 川口 敦, 川村 雄介, 工藤 大介, 久保 健児, 倉橋 清泰, 櫻本 秀明, 下山 哲, 鈴木 武志, 関根 秀介, 関野 元裕, 高橋 希, 高橋 世, 高橋 弘, 田上 隆, 田島 吾郎, 巽 博臣, 谷 昌憲, 土谷 飛鳥, 堤 悠介, 内藤 貴基, 長江 正晴, 長澤 俊郎, 中村 謙介, 西村 哲郎, 布宮 伸, 則末 泰博, 橋本 悟, 長谷川 大祐, 畠山 淳司, 原 直己, 東別府 直紀, 古島 夏奈, 古薗 弘隆, 松石 雄二朗, 松山 匡, 峰松 佑輔, 宮下 亮一, 宮武 祐士, 森安 恵実, 山田 亨, 山田 博之, 山元 良, 吉田 健史, 吉田 悠平, 吉村 旬平, 四本 竜一, 米倉 寛, 和田 剛志, 渡邉 栄三, 青木 誠, 浅井 英樹, 安部 隆国, 五十嵐 豊, 井口 直也, 石川 雅巳, 石丸 剛, 磯川 修太郎, 板倉 隆太, 今長谷 尚史, 井村 春樹, 入野田 崇, 上原 健司, 生塩 典敬, 梅垣 岳志, 江川 裕子, 榎本 有希, 太田 浩平, 大地 嘉史, 大野 孝則, 大邉 寛幸, 岡 和幸, 岡田 信長, 岡田 遥平, 岡野 弘, 岡本 潤, 奥田 拓史, 小倉 崇以, 小野寺 悠, 小山 雄太, 貝沼 関志, 加古 英介, 柏浦 正広, 加藤 弘美, 金谷 明浩, 金子 唯, 金畑 圭太, 狩野 謙一, 河野 浩幸, 菊谷 知也, 菊地 斉, 城戸 崇裕, 木村 翔, 小網 博之, 小橋 大輔, 齊木 巌, 堺 正仁, 坂本 彩香, 佐藤 哲哉, 志賀 康浩, 下戸 学, 下山 伸哉, 庄古 知久, 菅原 陽, 杉田 篤紀, 鈴木 聡, 鈴木 祐二, 壽原 朋宏, 其田 健司, 高氏 修平, 高島 光平, 高橋 生, 高橋 洋子, 竹下 淳, 田中 裕記, 丹保 亜希仁, 角山 泰一朗, 鉄原 健一, 徳永 健太郎, 富岡 義裕, 冨田 健太朗, 富永 直樹, 豊崎 光信, 豊田 幸樹年, 内藤 宏道, 永田 功, 長門 直, 中村 嘉, 中森 裕毅, 名原 功, 奈良場 啓, 成田 知大, 西岡 典宏, 西村 朋也, 西山 慶, 野村 智久, 芳賀 大樹, 萩原 祥弘, 橋本 克彦, 旗智 武志, 浜崎 俊明, 林 拓也, 林 実, 速水 宏樹, 原口 剛, 平野 洋平, 藤井 遼, 藤田 基, 藤村 直幸, 舩越 拓, 堀口 真仁, 牧 盾, 増永 直久, 松村 洋輔, 真弓 卓也, 南 啓介, 宮崎 裕也, 宮本 和幸, 村田 哲平, 柳井 真知, 矢野 隆郎, 山田 浩平, 山田 直樹, 山本 朋納, 吉廣 尚大, 田中 裕, 西田 修, 日本版敗血症診療ガイドライン2020特別委員会, 日本集中治療医学会雑誌, 28, Suppl., S1, S411, 2021年02月
日本集中治療医学会と日本救急医学会は,合同の特別委員会を組織し,2016年に発表した日本版敗血症診療ガイドライン(J-SSCG)2016の改訂を行った。本ガイドライン(J-SSCG2020)の目的は,J-SSCG2016と同様に,敗血症・敗血症性ショックの診療において,医療従事者が患者の予後改善のために適切な判断を下す支援を行うことである。改訂に際し,一般臨床家だけでなく多職種医療者にも理解しやすく,かつ質の高いガイドラインとすることによって,広い普及を目指した。J-SSCG2016ではSSCG2016にない新しい領域[ICU-acquircd weakness(ICU-AW)とpost-intensive care syndrome(POCS),体温管理など]を取り上げたが,J-SSCG2020では新たに注目すべき4領域(Patient-and Family-Centered Care, sepsis treatment system,神経集中治療,ストレス潰瘍)を追加し,計22領域とした。重要な118の臨床課題(clinical question:CQ)をエビデンスの有無にかかわらず抽出した。これらのCQには,本邦で特に注目されているCQも含まれる。多領域にわたる大規模ガイドラインであることから,委員25名を中心に,多職種(看護師,理学療法士,臨床工学技士,薬剤師)および患者経験者も含めたワーキンググループメンバー,両学会の公募によるシステマティックレビューメンバーによる総勢226名の参加・協力を得た。また,中立的な立場で横断的に活躍するアカデミックガイドライン推進班をJ-SSCG2016に引き続き組織した。将来への橋渡しとなることを企図して,多くの若手医師をシステマティックレビューチーム・ワーキンググループに登用し,学会や施設の垣根を越えたネットワーク構築も進めた。作成工程においては,質の担保と作業過程の透明化を図るために様々な工夫を行い,パブリックコメント募集は計2回行った。推奨作成にはGRADE方式を取り入れ,修正Delphi法を用いて全委員の投票により推奨を決定した。結果,118CQに対する回答として,79個のGRADEによる推奨,5個のGPS(good practice statement),18個のエキスパートコンセンサス,27個のBQ(background question)の解説,および敗血症の定義と診断を示した。新たな試みとして,CQごとに診療フローなど時間軸に沿った視覚的情報を取り入れた。J-SSCG2020は,多職種が関わる国内外の敗血症診療の現場において,ベッドサイドで役立つガイドラインとして広く活用されることが期待される。なお,本ガイドラインは,日本集中治療医学会と日本救急医学会の両機関誌のガイドライン増刊号として同時掲載するものである。(著者抄録), (一社)日本集中治療医学会, 日本語

出血性病態とトラネキサム酸(第3回) CRASH-3試験とトラネキサム酸
和田 剛志, Thrombosis Medicine, 10, 4, 299, 303, 2020年12月
＜Points＞○CRASH-3試験は、軽症・中等症、および両側対光反射が残存している頭部外傷患者において、トラネキサム酸投与は頭部外傷関連死を有意に減少させることを示した。○軽症・中等症患者では、治療開始時間が早いほどトラネキサム酸による予後改善効果が期待できたが、重症症例では受傷から治療開始の時間によらず、トラネキサム酸投与による予後改善効果は認められなかった。○トラネキサム酸はできるだけ早く投与されるべきである。トラネキサム酸は、受傷後早期にピークに達する組織型プラスミノゲンアクチベータ(t-PA)を抑制し抗線溶作用を発揮するのに対し、遅れてピークを迎えるウロキナーゼ型プラスミノゲンアクチベータ(u-PA)に対しては作用を増強する。○CRASH-3試験を含むトラネキサム酸の効果を検証した大規模研究結果から、トラネキサム酸は「線溶亢進」の病態を有する疾患に有用であり、すべての出血性疾患に効果を発揮するわけではないことが推察される。(著者抄録), (株)先端医学社, 日本語

日本版敗血症診療ガイドライン2020:Now Open! 敗血症性DICの診断と治療　　　　　　　　　　　　　　　
射場 敏明, 久志本 成樹, 梅村 穣, 渡邉 栄三, 和田 剛志, 林田 敬, 日本版敗血症診療ガイドライン2020特別委員会, 日本救急医学会雑誌, 31, 11, 919, 919, 2020年11月
(一社)日本救急医学会, 日本語

【災害医療2020 大規模イベント、テロ対応を含めて】(第IV章)災害現場での医療判断と対応 各種ショックへの対応　　　　　　　　　　　　　　　
和田 剛志, 土田 拓見, 日本医師会雑誌, 149, 特別1, S150, S154, 2020年06月
(公社)日本医師会, 日本語

線溶亢進型DIC(第4回) 心停止蘇生と線溶亢進型DIC
和田 剛志, Thrombosis Medicine, 10, 2, 138, 142, 2020年06月
＜Points＞●心停止蘇生では自然免疫炎症反応と凝固線溶反応が相乗的に作用し病的自然免疫凝固炎症反応(dysregulated inflammation & coagulofibrinolytic responses)を発症する。●活性化好中球から放出されるNETsと損傷細胞から放出されるヒストンが病的自然免疫凝固炎症反応の病態の中心を担う。●心停止蘇生早期では血管内皮細胞からのt-PA放出によるfibrinolytic phenotypeの播種性血管内凝固(DIC)を発症するが、t-PAに遅れて上昇するplasminogen activator inhibitor-1(PAI-1)により線溶遮断が起こりthrombotic phenotypeのDICに移行する。●Dダイマーやフィブリン・フィブリノゲン分解産物(FDP)は、心停止蘇生において凝固線溶異常を引き起こす血管内皮細胞障害の重症度を間接的に反映する臨床的に有用なマーカーである。(著者抄録), (株)先端医学社, 日本語

救急・集中治療領域におけるDIC診療 正しい凝固・線溶検査の理解に基づく病態の理解　　　　　　　　　　　　　　　
和田 剛志, 日本血栓止血学会誌, 31, 2, 207, 207, 2020年05月
(一社)日本血栓止血学会, 日本語

【集中治療医学レビュー 最新主要文献と解説 2020-'21】I章 集中治療管理 血液凝固線溶系管理　　　　　　　　　　　　　　　
和田 剛志, 集中治療医学レビュー, 2020-'21, 64, 70, 2020年03月
世界が注目したSCARLET試験の結果は、「遺伝子組換えトロンボモジュリンは凝固異常を伴う重症敗血症患者の生命予後を改善させない」というものであったが、この結果だけで薬剤の効果がないと結論付けることはできない。「敗血症かつ播種性血管内凝固症候群(disseminated intravascular coagulation:DIC)かつ重症(臓器不全合併)」が、抗凝固療法の恩恵を受ける患者群であることが明らかにされてきており、SCARLETはこの患者群から外れた軽症症例を試験に組み込んでいた可能性がある。新たな患者選択基準で行われる質の高い臨床研究の結果が待たれる。感染症に血小板減少を合併する症例では、DIC以外にも血栓性微小血管症を鑑別する必要がある。特に補体/凝固制御因子異常で発症する非典型溶血性尿毒症症候群は特異的治療薬エクリズマブが有効であるため、早期診断・治療開始が重要である。トラネキサム酸の頭部外傷に対する効果を検証したCRASH-3試験の結果が公表された。受傷後早期のトラネキサム酸投与は、有害事象を増やすことなく安全に頭部外傷患者の死亡率減少に寄与することが示された。外傷による大量出血を想定したCRASH-2試験とともに、外傷に対するトラネキサム酸の有用性を証明した貴重な研究結果である。(著者抄録), (株)総合医学社, 日本語

外尿道口の出血を伴わない尿道損傷の1例
執行亜希子, 早川峰司, 田中祥平, 中嶋拓磨, 高橋正樹, 田原就, 土田拓見, 定本圭弘, 川原翔太, 本間慶憲, 大安孝允, 早水真理子, 斉藤智誉, 吉田知由, 方波見謙一, 和田剛志, 前川邦彦, 日本集中治療医学会北海道支部学術集会プログラム・抄録集(Web), 4th, 2020年

敗血症と血管内皮細胞障害(第1回) 敗血症と血管内皮細胞障害
和田 剛志, Thrombosis Medicine, 9, 4, 361, 365, 2019年12月
＜Points＞(1)血管内皮細胞は止血と円滑な循環の維持の他、栄養素、代謝産物、老廃物などの物質交換にも関与しているダイナミックな細胞である(2)血管内皮細胞の機能発現に重要な役割を果たすグリコカリックスへの関心が高まっており、電子顕微鏡技術の発達などにより、その構造や機能解明が可能となってきた(3)血栓性微小血管障害(TMA)の一つ、非典型溶血性尿毒症症候群(aHUS)は補体/凝固制御機能の異常で発症する。(4)血管内皮細胞障害を共通の病態にもつTMA(aHUS)と播種性血管内凝固症候群(DIC)の併存を念頭に置く必要がある。(著者抄録), (株)先端医学社, 日本語

【ICU治療指針 II】血液・凝固線溶系疾患と管理 血液・凝固線溶系疾患 好中球減少
土田 拓見, 和田 剛志, 救急・集中治療, 31, 3, 974, 977, 2019年12月
＜POINT＞●好中球が1,500/μL未満に減少した際に、好中球減少と定義される。●好中球数が1,000/μL未満になった場合に、発熱する頻度が増加するとされる。●発熱性好中球減少症は、「好中球数が500/μL未満、あるいは1,000/μL未満で、48時間以内に500/μL未満に減少すると予測される状態で、かつ腋窩温37.5℃以上の発熱を生じた状態」と定義される。●発熱性好中球減少症と診断した際には、リスクに応じて適切な抗菌薬治療が必要となる。(著者抄録), (株)総合医学社, 日本語

【ICU治療指針 II】血液・凝固線溶系疾患と管理 血液・凝固線溶系管理 血液・凝固線溶系の検査と評価
土田 拓見, 和田 剛志, 救急・集中治療, 31, 3, 981, 985, 2019年12月
＜POINT＞●凝固線溶系マーカーの結果を組合せることで、病態の評価が可能となる。●多くの凝固線溶系マーカーは、測定機器や施設によって基準値が異なる。(著者抄録), (株)総合医学社, 日本語

【死戦期における血液凝固線溶系の病態生理】重症頭部外傷の血液凝固線溶系
和田 剛志, Thrombosis Medicine, 9, 1, 23, 29, 2019年03月
重症頭部外傷に合併する凝固線溶異常は、患者をまさに「死戦期」に追い詰める激烈な併存病態である。その病態の本体は過剰なトロンビン産生に起因する播種性血管内凝固症候群であり、血管内皮細胞活性化/傷害による抗凝固機構の破綻が凝固亢進に拍車をかける。頭部外傷では凝固亢進に伴う二次性の線溶亢進に加え損傷脳からの直接的なtissue-type plasminogen activator(t-PA)の放出が過剰な線溶亢進の原因となる。また、血小板機能低下も出血傾向を助長する。頭部外傷に特化した凝固異常補正の治療指針は存在しないが、外傷性凝固障害の病態理解に基づく適切なdamage control resuscitationが重症頭部外傷患者の「死戦期」からの脱出、および予後改善につながるものと期待される。(著者抄録), (株)先端医学社, 日本語

【血栓止血の臨床-研修医のために[第2版]】血小板減少を伴う血栓性疾患 DICの治療 感染症、救命救急領域、外科領域
和田 剛志, 日本血栓止血学会誌, 30, 1, 218, 222, 2019年02月
＜ポイント＞・外来微生物由来のpathogen-associated molecular patterns(PAMPs)同様に、自己損傷細胞/組織由来のdamage-associated molecular patterns(DAMPs)はパターン認識受容体(pattern recognition receptors:PRRs)に認識され自然免疫炎症反応が誘導される。・感染における凝固線溶変化は、生体恒常性維持のための生理的生体反応であり、immunothrombosis(免疫血栓)という概念で理解する。・外傷性凝固障害(trauma-induced coagulopathy:TIC)の主病態は線溶亢進型DICである。(著者抄録), (一社)日本血栓止血学会, 日本語

基礎病態と治療 頭部外傷
和田剛志, 救急・集中治療, 30, 261‐266, 2018年11月20日
日本語

基礎病態と治療 心停止後症候群
和田剛志, 救急・集中治療, 30, 273‐278, 2018年11月20日
日本語

集中治療管理 血液凝固線溶系管理　　　　　　　　　　　　　　　
和田 剛志, 集中治療医学レビュー, 2018-'19, 66, 72, 2018年02月
敗血症病態における凝固線溶異常の関与の重要性および治療対象としての意義が、本邦のみならず世界に浸透してきたことを反映し、敗血症の国際ガイドラインで初めて播種性血管内凝固症候群(disseminated intravascular coagulation:DIC)に言及された。本邦で開発されたDIC治療薬である遺伝子組換えトロンボモジュリンの効果を検証する国際第三相試験の結果が注目される。外傷に合併する凝固障害の主病態は「線溶亢進型DIC」で決着しつつある。外傷に対するビスコエラスティックデバイス使用、トラネキサム酸に関して血栓症などの副作用、頭部外傷への有用性などの議論が依然として続いている。直接作用型経口抗凝固薬に対する特異的中和薬のエビデンスが集積され臨床応用が進んでいる。(著者抄録), (株)総合医学社, 日本語

PICS 集中治療後症候群 ICUケア・環境とPICS 環境因子と治療介入因子の調整によるPICS予防
和田剛志, Intensivist, 10, 1, 47‐60, 2018年01月01日
日本語

外傷性凝固障害の病態と対応 頭部外傷の凝固線溶変化
和田剛志, Thrombosis Medicine, 7, 4, 257‐264, 2017年12月01日
日本語

ショック時の多臓器障害症候群を考える 神経内分泌系・自律神経系・免疫系の連関は多臓器不全に関与する?
和田剛志, 救急・集中治療, 29, 5-6, 391‐396, 2017年05月20日
日本語

ボストン研究留学記
和田 剛志, 日本血栓止血学会誌, 28, 6, 760, 762, 2017年
一般社団法人 日本血栓止血学会, 日本語

神経内分泌系・自律神経系・免疫系の連関は多臓器不全に関与する? (ショック管理 : ショックと臓器障害連関のメカニズム) -- (ショック時の多臓器障害症候群を考える)
和田 剛志, 救急・集中治療, 29, 5, 391, 396, 2017年
総合医学社, 日本語

"PHONE FIRST" IS ASSOCIATED WITH DECREASED INTACT SURVIVAL IN OUT-OF-HOSPITAL CARDIAC ARREST
Kunihiko Maekawa, Mineji Hayakawa, Yuichi Ono, Tomonao Yoshida, Kenichi Katabami, Takeshi Wada, AtsUshi Sawamura, Satoshi Gando, CRITICAL CARE MEDICINE, 44, 12, 2016年12月
LIPPINCOTT WILLIAMS & WILKINS, 英語, 研究発表ペーパー・要旨（国際会議）

RETHINKING NW: WHEN IT WORKS, IT WORKS. WHEN IT DOESN'T, IT REALLY DOESN'T.
Kunihiko Maekawa, Mineji Hayakawa, Yuichi Ono, Tomonao Yoshida, Kenichi Katabami, Takeshi Wada, AtsUshi Sawamura, Satoshi Gando, CRITICAL CARE MEDICINE, 44, 12, 2016年12月
LIPPINCOTT WILLIAMS & WILKINS, 英語, 研究発表ペーパー・要旨（国際会議）

救急治療薬―ここが知りたい,何故使うか,どう使うか 救急現場における治療薬への課題 抗血小板薬,抗凝固薬使用中の急性出血への対応
和田剛志, 救急医学, 40, 12, 1543‐1552, 2016年11月10日
日本語

重症多発外傷患者における脳脂肪塞栓症の検討　　　　　　　　　　　　　　　
澤村 淳, 小館 明, 定本 圭弘, 村上 博基, 水柿 明日美, 方波見 謙一, 前川 邦彦, 宮本 大輔, 小野 雄一, 和田 剛志, 早川 峰司, 丸藤 哲, 日本外傷学会雑誌, 30, 2, 230, 230, 2016年05月
(一社)日本外傷学会, 日本語

PLATELET COUNT, AND GLOBAL MARKERS OF COAGULATION AND FIBRINOLYSIS DURING EARLY PHASE OF OUT-OF-HOSPITAL CARDIAC ARREST AND RESUSCITATION
S. Gando, T. Wada, Y. Ono, K. Maekawa, THROMBOSIS RESEARCH, 141, S59, S59, 2016年05月
PERGAMON-ELSEVIER SCIENCE LTD, 英語, 研究発表ペーパー・要旨（国際会議）

Septic DICの病態とImmunothrombosis (特集 救急・集中治療領域における凝固・線溶異常と対策)
丸藤 哲, 和田 剛志, 小野 雄一, 前川 邦彦, 方波見 謙一, 早川 峰司, 澤村 淳, ICUとCCU = Japanese journal of intensive care medicine : 集中治療医学, 40, 3, 171, 179, 2016年03月
医学図書出版, 日本語

ゾニサミド使用後に高体温を呈した2例
吉田 知由, 早川 峰司, 本間 多恵子, 小野 雄一, 和田 剛志, 柳田 雄一郎, 澤村 淳, 丸藤 哲, 日本集中治療医学会雑誌, 22, 6, 519, 522, 2015年11月
抗痙攣薬であるゾニサミドは、副作用として発汗障害を認めることが知られており、小児てんかんの分野での報告は散在するが、成人症例での報告は少ない。今回、頭部外傷の急性期から亜急性期にゾニサミドを使用した成人症例で、発汗障害からの高体温を来し、感染症などとの鑑別に苦慮した症例を2例経験した。症例1は21歳の男性、自動車事故で受傷し、入院22日目からゾニサミド300mg/dayの使用を開始した。その後39℃の高体温を認めたが感染徴候はなく、ゾニサミドを減量したところ3日後に解熱した。症例2は25歳の男性、自動車事故で受傷し、入院3日目からゾニサミド300mg/dayを使用していた。40℃近い高体温の持続を認めたためゾニサミドを中止したところ、3日後に解熱した。今回、ゾニサミドが原因と思われる高体温症例を経験したが、成人症例と言えどもゾニサミドによる発汗障害からの高体温を来しうるため、高体温時の鑑別として忘れてはならない。(著者抄録), (一社)日本集中治療医学会, 日本語

急性期DIC―診断・治療の最前線 急性期DICの診断 ベッドサイドにおける診断基準の使い方
和田剛志, 救急医学, 39, 11, 1527‐1534, 2015年10月10日
日本語

救急で出会う けいれん・てんかんにどう対応する?急性症候性発作って何?
和田剛志, レジデントノート, 17, 10, 1905, 1911, 2015年10月
(1)急性症候性発作は原因を有する点で「てんかん」と区別され、治療や予後も異なる(2)けいれんの原因は中枢神経とは限らず、全身の検索が必要である(3)頻度は多くないものの脳梗塞でもけいれんをきたしうる(4)思い込みで対応すると治療の機を逸する可能性がある(著者抄録), (株)羊土社, 日本語

3D-CTA診断が可能であったクモ膜下出血症例の検討　　　　　　　　　　　　　　　
澤村 淳, 小舘 旭, 村上 博基, 水柿 明日美, 前川 邦彦, 方波見 謙一, 小野 雄一, 宮本 大輔, 和田 剛志, 早川 峰司, 丸藤 哲, 日本救急医学会雑誌, 26, 8, 383, 383, 2015年08月
(一社)日本救急医学会, 日本語

Role of activated protein c and soluble fibrin in the early phase of trauma with disseminated intravascular coagulation: comparison with acute coagulopathy of trauma-shock
S. Gando, A. Sawamura, M. Hayakawa, T. Wada, Y. Yanagida, D. Miyamoto, K. Maekawa, Y. Ono, A. Mizugaki, S. Jesmin, JOURNAL OF THROMBOSIS AND HAEMOSTASIS, 13, 327, 327, 2015年06月
WILEY-BLACKWELL, 英語, 研究発表ペーパー・要旨（国際会議）

外傷性脳内出血症例のpitfall　　　　　　　　　　　　　　　
澤村 淳, 水柿 明日美, 方波見 謙一, 前川 邦彦, 小野 雄一, 宮本 大輔, 和田 剛志, 柳田 雄一郎, 早川 峰司, 丸藤 哲, 日本外傷学会雑誌, 29, 2, 197, 197, 2015年05月
(一社)日本外傷学会, 日本語

sepsis―最新知見と治療戦略 DICと抗凝固療法
和田剛志, 救急医学, 39, 2, 185, 191, 2015年02月10日
(株)へるす出版, 日本語

PHARMACOKINETICS OF LEVOFLOXACIN IN CRITICALLY-ILL PATIENTS RECEIVING CONTINUOUS HEMODIAFILTRATION
Takeshi Wada, Masaki Kobayashi, Daisuke Miyamoto, Yuichiro Yanagida, Mineji Hayakawa, Atsushi Sawamura, Ken Iseki, Satoshi Gando, CRITICAL CARE MEDICINE, 42, 12, 2014年12月
LIPPINCOTT WILLIAMS & WILKINS, 英語, 研究発表ペーパー・要旨（国際会議）

THE OVERPRODUCTION OF NITRIC OXIDE INDUCED BY ANGIOGENIC AND COAGULATION FACTORS LEADS TO MULTIPLE ORGAN DYSFUNCTION SYNDROME ASSOCIATED WITH POST-CARDIAC ARREST SYNDROME
T. Wada, S. Jesmin, A. Mizugaki, K. Katabami, Y. Ono, K. Maekawa, D. Miyamoto, Y. Yanagida, M. Hayakawa, A. Sawamura, S. Gando, INTENSIVE CARE MEDICINE, 40, S272, S272, 2014年09月
SPRINGER, 英語, 研究発表ペーパー・要旨（国際会議）

基礎病態と治療 心停止後症候群
和田剛志, 救急・集中治療, 26, 5-6, 824, 828, 2014年07月08日
日本語

神経内分泌反応と炎症・凝固反応 神経内分泌・自律神経反応と炎症反応
丸藤哲, 和田剛志, Thromb Med, 4, 1, 5, 14, 2014年03月01日
日本語

神経内分泌反応と炎症・凝固反応 神経内分泌・自律神経反応と凝固線溶反応
丸藤哲, 和田剛志, Thromb Med, 4, 1, 15, 19, 2014年03月01日
日本語

神経内分泌反応と炎症・凝固反応 コリン作動性抗炎症反応経路と敗血症,臓器不全
和田剛志, Thromb Med, 4, 1, 28, 33, 2014年03月01日
日本語

ゾニサミド使用後に高体温を呈した2例　　　　　　　　　　　　　　　
吉田 知由, 本間 多恵子, 小野 雄一, 和田 剛志, 柳田 雄一郎, 早川 峰司, 澤村 淳, 丸藤 哲, 日本集中治療医学会雑誌, 21, Suppl., [DP, 106, 2014年01月
(一社)日本集中治療医学会, 日本語

Surgery Provides A Better Clinical Outcome Following Severe Traumatic Brain Injury
Atsushi Sawamura, Takeshi Wada, Yu-ichi Ono, Daisuke Miyamoto, Yuichiro Yanagida, Masahiro Sugano, Mineji Hayakawa, Satoshi Gando, CRITICAL CARE MEDICINE, 41, 12, 2013年12月
LIPPINCOTT WILLIAMS & WILKINS, 英語, 研究発表ペーパー・要旨（国際会議）

EFFCTS OF RIKKUNSHITO (TRADITIONAL JAPANESE MEDICINE KAMPO) ON ENTERAL FEEDLNG AND PLASMA GHRELIN CONCENTRATION IN CRITICALLY ILL PATIENTS: A DOUBLE-BLIND, RANDMIZED, CONTROLLED TRIAL
Y. Yanagida, M. Hayakawa, H. Yamamoto, T. Wada, M. Sugano, A. Sawamura, S. Gando, INTENSIVE CARE MEDICINE, 39, S242, S243, 2013年10月
SPRINGER, 英語, 研究発表ペーパー・要旨（国際会議）

Normal prothrombinase activity, systemic thrombin activation, and lower antithrombin levels in patients with DIC at an early phase of trauma: comparison with Acute Coagulopathy of Trauma-Shock (ACOTS)
S. Gando, Y. Yanagida, A. Sawamura, M. Hayakawa, N. Kubota, T. Wada, Y. Ono, H. Yamamoto, JOURNAL OF THROMBOSIS AND HAEMOSTASIS, 11, 1049, 1049, 2013年07月
WILEY-BLACKWELL, 英語, 研究発表ペーパー・要旨（国際会議）

橈骨動脈グラフトを用いた多発内頸動脈瘤による頸動脈-海綿静脈洞瘻の治療-4D-flow MRI脳血流解析を含めて-
中川俊祐, 村井保夫, 和田剛志, 展広智, 立山幸次郎, 喜多村孝幸, 寺本明, 水成隆之, 小林士郎, 吉田陽一, 日本脳神経外科救急学会プログラム・抄録集, 18th, 72, 72, 2013年
(NPO)日本脳神経外科救急学会, 日本語

院外心肺停止患者に対するECPR施行時脳低温療法の検討　　　　　　　　　　　　　　　
松本 学, 水柿 明日美, 和田 剛志, 田上 隆, 白石 振一郎, 増野 智彦, 宮内 雅人, 辻井 厚子, 布施 明, 横田 裕行, 日本集中治療医学会雑誌, 20, Suppl., 292, 292, 2013年01月
(一社)日本集中治療医学会, 日本語

ORGAN SPECIFIC EXPRESSION OF VASCULAR ENDOTHELIAL GROWTH FACTOR (VEGF) IN LIPOPOLYSACCHARIDE (LPS)-INDUCED ENDOTOXEMIA
Subrina Jesmin, Yuichiro Yanagida, Takeshi Wada, Nobutake Shimojo, Taro Mizutani, Satoshi Gando, CRITICAL CARE MEDICINE, 40, 12, U65, U65, 2012年12月
LIPPINCOTT WILLIAMS & WILKINS, 英語, 研究発表ペーパー・要旨（国際会議）

ANGIOGENIC FACTORS AND THEIR SOLUBLE RECEPTORS PREDICT ORGAN DYSFUNCTION AND MORTALITY IN POST-CARDIAC ARREST SYNDROME (PCAS)
Takeshi Wada, Subrina Jesmin, Satoshi Gando, Yuichiro Yanagida, Asumi Higashiyama, Sayeeda Sultana, Sohel Zaedi, Hiroyuki Yokota, CRITICAL CARE MEDICINE, 40, 12, U160, U160, 2012年12月
LIPPINCOTT WILLIAMS & WILKINS, 英語, 研究発表ペーパー・要旨（国際会議）

I sepsis・SIRSの概念と定義,病態 Q3 Surviving Sepsis CampaignとSSCG2008からさらなる改訂へ
和田剛志, 丸藤哲, 救急・集中治療, 24, 9-10, 1015, 1019, 2012年10月23日
日本語

ANGIOGEMIC FACTORS AND THEIR SOLUBLE RECEPTORS IN ACUTE LUNG INJURY (ALI/ACUTE RESPIRATORY DISTRESS SYNDROME (ARDS) IN CRITICALLY ILL PATIENTS
T. Wada, S. Jesmin, S. Gando, A. Mizugaki, Y. Yanagida, H. Yokota, INTENSIVE CARE MEDICINE, 38, S247, S247, 2012年10月
SPRINGER, 英語, 研究発表ペーパー・要旨（国際会議）

AMELIORATION OF ACUTE LIVER INJURY THROUGH THE SUPPRESSION OF UPREGULATED LEVELS OF ENDOTHELIN-1 AND TNF-A IN A RAT MODEL OF ENDOTOXEMIA WITH THE BLOCKADE OF PROTEASE ACTIVATED RECEPTOR-2 (PAR2)
S. Jesmin, T. Wada, S. Zaedi, N. Shimojo, S. N. Sultana, M. Moroi, T. Watanebe, S. Gando, INTENSIVE CARE MEDICINE, 38, S104, S104, 2012年10月
SPRINGER, 英語, 研究発表ペーパー・要旨（国際会議）

Elastase-mediated fibrinolysis in disseminated intravascular coagulation (DIC) associated with sepsis
Takeshi Wada, Satoshi Gando, Yuichiro Yanagida, Shinji Uegaki, Nobuhiko Kubota, Mineji Hayakawa, Atsushi Sawamura, Subrina Jesmin, THROMBOSIS RESEARCH, 130, S184, S184, 2012年10月
PERGAMON-ELSEVIER SCIENCE LTD, 英語, 研究発表ペーパー・要旨（国際会議）

Angiogenic factors and their soluble receptors for predicting organ dysfunction in disseminated intravascular coagulation associated with sepsis
Takeshi Wada, Jesmin Subrina, Satoshi Gando, BRITISH JOURNAL OF ANAESTHESIA, 108, 76, 77, 2012年03月
OXFORD UNIV PRESS, 英語, 研究発表ペーパー・要旨（国際会議）

IABP導入前後にBIS値の変動を認めた脳低体温療法の一症例
太田好紀, 和田剛志, 小野雄一, 白石振一郎, 松本学, 斉藤徳子, 村田広茂, 増野智彦, 新井正徳, 横田裕行, 日本集中治療医学会雑誌, 19, Supplement, 2012年

TIME-DEPENDENT ALTERATIONS OF VEGF AND ITS SIGNALING MOLECULES IN ACUTE LUNG INJURY IN A RAT MODEL OF SEPSIS
T. Wada, S. Jesmin, S. Zaedi, S. Gando, INTENSIVE CARE MEDICINE, 37, S9, S9, 2011年09月
SPRINGER, 英語, 研究発表ペーパー・要旨（国際会議）

心外閉塞性ショックの病態と治療 (特集 ショックの病態と治療) -- (各種ショックの病態と治療)
和田 剛志, 横田 裕行, 救急医学, 35, 4, 434, 437, 2011年04月
へるす出版, 日本語

PR3-ANCA-ASSOCIATED MICROSCOPIC POLYANGITIS IN A PATIENT WITH SEPSIS
Takeshi Wada, Mineji Hayakawa, Satoshi Gando, CRITICAL CARE MEDICINE, 38, 12, U286, U286, 2010年12月
LIPPINCOTT WILLIAMS & WILKINS, 英語, 研究発表ペーパー・要旨（国際会議）

腰動脈引き抜き損傷による偽性腰動脈瘤の1例
和田剛志, 澤村淳, 方波見謙一, 菅野正寛, 早川峰司, 丸藤哲, 日本救急医学会雑誌, 21, 9, 799-803 (J-STAGE), 803, 2010年09月15日
日本語

鈍的外傷患者における FDP(fibrin/fibrinogen degradation products) 高値と大量出血の関連性
早川 峰司, 和田 剛志, 菅野 正寛, 下嶋 秀和, 上垣 慎二, 澤村 淳, 丸藤 哲, 日本救急医学会雑誌, 21, 4, 165, 171, 2010年04月15日
鈍的外傷による早期の死亡は大量出血によるものが大半である。その原因として，臓器損傷や血管損傷による直接的な出血と凝固障害を原因とする出血の2つの側面がある。今回，鈍的外傷患者では治療開始前の搬入直後に線溶亢進が認められ，その線溶亢進が凝固障害による大量出血と関係があるとの仮設を立て，受傷現場から直接搬入された鈍的外傷患者を対象に搬入直後の凝固線溶系の検査結果と大量出血の関係を後ろ向きに検討した。2005 年1 月1 日から2006 年12 月31 日の間に，受傷現場から北海道大学病院先進急性期医療センターに直接搬入となったabbreviated injury scale が3 以上の損傷を含む鈍的外傷症例を対象とした。対象患者の診療録から，患者背景，搬入直後の血液検査結果，輸血量などの情報を後ろ向きに収集し，大量出血群と非大量出血群に分類した。83 名が参入基準を満たした。大量出血群は17 症例，非大量出血群66 症例であった。fibrin/fibrinogen degradation products（FDP）とD-dimer に関しては，両群とも著明な高値を示し，大量出血群が非大量出血群と比較して統計学的な有意差を認めていた。ロジスティック回帰分析ではFDPのみが大量出血の独立した予測変数として選択された。大量出血予測に関するreceiver operating characteristic 曲線では，FDPが最も大きな曲線下面積を示した。鈍的外傷患者では，搬入直後にフィブリン/ フィブリノゲン分解に伴うFDPの異常高値を示しており，FDP>64.1μg/ml をカットオフ値とすることで，外傷早期の線溶亢進を原因とする大量出血を予測しうることを示した。鈍的外傷患者の搬入直後のFDP値に注目することにより，外傷早期の凝固障害に対して速やかに対応できる可能性がある。Introduction: Early death after blunt trauma is caused by massive bleeding. Our previous report demonstrated thatdisseminated intravascular coagulation with a fibrinolytic phenotype from the time of admission to the emergencydepartment until 4 hours thereafter contributes to a poor prognosis due to massive bleeding.Objective: Fibrinolysis at admission to the emergency department immediately after blunt trauma may predict massivebleeding. This study retrospectively investigated the relationship between coagulation and fibrinolysis, and massivebleeding at an early phase in patients presenting with blunt trauma.Methods: All patients with blunt trauma admitted to the emergency department, associated with, at least, one of the abbreviatedinjury scales ≥3 from January 2005 to December 2006 were enrolled in the study. The clinical backgroundsof the patients and the measured variables were retrospectively collected.Results: Eighty-three patients; 17 patients with massive bleeding and 66 patients without massive bleeding, were includedin this study. Fibrin/fibrinogen degradation products (FDP) and D-dimer levels markedly increased in bothgroups. FDP and D-dimer in the massive bleeding group were statistically higher than those in the non-massivebleeding group. A stepwise logistic regression analysis showed FDP to be an independent predictor of massivebleeding. The receiver operating characteristic curve analysis for massive bleeding showed FDP to have the largestarea under the curve and that the optimal cutoff point of FDP in order to predict massive bleeding was >64.1 μg/ml.Conclusion: Increased fibrin/fibrinogen degradation resulting in high FDP levels at an early phase of trauma istherefore considered to predict massive bleeding. The optimal cutoff point of FDP to predict massive bleeding was>64.1 μg/ml., 日本救急医学会, 日本語

甲状腺クリーゼと診断した4例の検討
和田剛志, 澤村淳, 菅野正寛, 平安山直美, 久保田信彦, 星野弘勝, 早川峰司, 丸藤哲, 日本集中治療医学会雑誌, 17, 2, 191, 195, 2010年04月01日
甲状腺クリーゼと診断した4例を経験した。1例は来院前に心肺停止となり，蘇生後低酸素脳症により不幸な転帰となったが，他3例は迅速な診断と治療により良好な経過をたどった。4例すべてに心不全徴候を認めたが，甲状腺治療薬が心不全や全身状態を悪化させる可能性があるため，治療に際しては十分な循環動態の監視が必要と考えられた。また，外傷後の異常な頻脈と発熱持続を認める場合，甲状腺機能評価を視野に入れた治療が必要と考えられた。, The Japanese Society of Intensive Care Medicine, 日本語

敗血症を契機に発症したため診断に苦慮したPR3‐ANCA陽性顕微鏡的多発血管炎の1例
和田剛志, 澤村淳, 方波見謙一, 菅野正寛, 久保田信彦, 早川峰司, 丸藤哲, ICUとCCU, 34, 3, 243, 247, 2010年03月10日
医学図書出版, 日本語

鈍的大動脈損傷に対する胸部下行大動脈置換術中に発症した脂肪塞栓症候群の1例
中田 麻子, 早川 峰司, 和田 剛志, 菅野 正寛, 星野 弘勝, 澤村 淳, 丸藤 哲, 日本救急医学会雑誌, 21, 1, 42, 49, 2010年01月15日
鈍的大動脈損傷に対する胸部下行大動脈置換術中に発症した脂肪塞栓症候群の1例を経験した。本症例では，術中から術後の急性呼吸不全と重度の全身性炎症反応症候群（systemic in-flammatory response syndrome; SIRS）の原因解明に難渋し，脂肪塞栓症候群の診断が遅延した。患者は 26 歳の男性。歩行中に乗用車にはねられ受傷した。当院搬入時は意識清明であった。画像診断で胸部下行大動脈損傷と右大腿骨骨幹部骨折を認めた。大腿骨骨折に対し創外固定を行った後，即日，人工血管置換術を施行した。ヘパリン投与後，経皮的心肺補助装置を導入し分離肺換気を開始した前後に，気道から淡血性泡沫状の分泌物を多量に認めはじめ，急速に酸素化能が悪化した。術後も手術侵襲のみでは説明が困難な SIRS と呼吸不全が遷延した。術後 5 日目に前胸部に点状出血があることに気づき，脂肪塞栓症候群を疑いステロイド治療を開始した。呼吸，循環動態はすみやかに改善した。意識障害が遷延し，第21病日にmagnetic resonance imaging（MRI）を撮影したところ，T2 star 強調画像や磁化率強調画像で，両側大脳白質や皮質下白質，脳梁，内包，視床，中脳から橋，小脳などに無数の微細な低信号を認め，脂肪塞栓症候群に典型的な画像であった。本症例では，脂肪塞栓症候群の特徴の一つである呼吸不全が人工血管置換術中に発症したため脂肪塞栓症候群の診断が遅延した。, 日本救急医学会, 日本語

FIBRINOGENOLYSIS DURING THE EARLY STAGE OF TRAUMA PREDICTS THE OCCURRENCE OF MASSIVE BLEEDING IN PATIENTS WITH BLUNT TRAUMA
M. Hayakawa, T. Wada, K. Katabami, M. Sugano, N. Henzan, H. Hoshino, A. Sawamura, S. Gando, INTENSIVE CARE MEDICINE, 35, 10, 10, 2009年09月
SPRINGER, 英語, 研究発表ペーパー・要旨（国際会議）

急性期DIC診断基準による外傷早期のDICによる大量出血の予見は可能か?
早川峰司, 方波見謙一, 三浪陽介, 和田剛志, 菅野正寛, 下嶋秀和, 久保田信彦, 上垣慎二, 澤村淳, 丸藤哲, 日本救急医学会雑誌, 20, 8, 506, 2009年08月15日
日本語

鈍的外傷による偽性腰動脈瘤の一例
和田剛志, 澤村淳, 方波見謙一, 三浪陽介, 菅野正寛, 下嶋秀和, 久保田信彦, 上垣慎二, 早川峰司, 丸藤哲, 日本救急医学会雑誌, 20, 8, 479, 2009年08月15日
日本語

生体肝移植術後に出現したPRES(Posterior Reversible Encephalopathy Syndrome)の二症例
澤村淳, 方波見謙一, 三浪陽介, 和田剛志, 菅野正寛, 下嶋秀和, 上垣慎二, 久保田信彦, 早川峰司, 丸藤哲, 日本救急医学会雑誌, 20, 8, 527, 2009年08月15日
日本語

妊婦の劇症型A群溶血性連鎖球菌感染症の1例
方波見謙一, 三浪陽介, 和田剛志, 菅野正寛, 下嶋秀和, 久保田信彦, 上垣慎二, 早川峰司, 澤村淳, 丸藤哲, 日本救急医学会雑誌, 20, 8, 689, 2009年08月15日
日本語

急性循環不全を呈した劇症型心筋症の一例
菅野正寛, 澤村淳, 方波見謙一, 和田剛志, 平安山直美, 久保田信彦, 星野弘勝, 早川峰司, 石川岳彦, 丸藤哲, 北海道外科雑誌, 54, 1, 78, 79, 2009年06月20日
日本語

妊婦劇症型A群溶血性連鎖球菌感染症の一例
方波見謙一, 早川峰司, 和田剛志, 菅野正寛, 平安山直美, 久保田信彦, 星野弘勝, 澤村淳, 石川岳彦, 丸藤哲, 北海道外科雑誌, 54, 1, 81, 2009年06月20日
日本語

指摘されていなかった過去の右横隔膜ヘルニアに嵌頓した肝挫傷の一例
方波見謙一, 早川峰司, 和田剛志, 菅野正寛, 平安山直美, 久保田信彦, 星野弘勝, 澤村淳, 丸藤哲, 日本外傷学会雑誌, 23, 2, 201, 2009年04月20日
日本語

偽性腰動脈瘤の手術中に偶然発見された外傷性肝管損傷の1例
和田剛志, 澤村淳, 方波見謙一, 菅野正寛, 平安山直美, 久保田信彦, 星野弘勝, 早川峰司, 丸藤哲, 日本外傷学会雑誌, 23, 2, 201, 2009年04月20日
日本語

外傷急性期のフィブリノーゲン溶解と出血予測
早川峰司, 方波見謙一, 和田剛志, 澤村淳, 丸藤哲, 日本外傷学会雑誌, 23, 2, 162, 2009年04月20日
日本語

モニタリングの基本 III 代謝・体液系モニタリング 凝固線溶系
丸藤哲, 澤村淳, 早川峰司, 久保田信彦, 平安山直美, 菅野正寛, 和田剛志, 方波見謙一, 救急医学, 33, 3, 311, 315, 2009年03月10日
日本語

急性呼吸不全患者に対するIntrapulmonary Percussive Ventilationの効果
中橋奨, 早川峰司, 方波見謙一, 和田剛志, 菅野正寛, 平安山直美, 星野弘勝, 澤村淳, 石川岳彦, 丸藤哲, 日本集中治療医学会雑誌, 16, Supplement, 251, 2009年01月20日
日本語

SepsisによるARDS・DICに対する好中球エラスターゼ阻害薬sivelestatの効果
早川峰司, 方波見謙一, 和田剛志, 菅野正寛, 平安山直美, 久保田信彦, 星野弘勝, 澤村淳, 丸藤哲, 日本集中治療医学会雑誌, 16, Supplement, 162, 2009年01月20日
日本語

敗血症を契機に発症したと思われるPR3‐ANCA陽性顕微鏡的多発血管炎の1例
和田剛志, 澤村淳, 方波見謙一, 菅野正寛, 平安山直美, 久保田信彦, 星野弘勝, 早川峰司, 石川岳彦, 丸藤哲, 日本集中治療医学会雑誌, 16, Supplement, 301, 2009年01月20日
日本語

注射用抗菌薬Ciprofloxacin(CPFX)の敗血症における免疫能に及ぼす影響
澤村淳, 方波見謙一, 和田剛志, 菅野正寛, 平安山直美, 久保田信彦, 星野弘勝, 早川峰司, 石川岳彦, 丸藤哲, 日本集中治療医学会雑誌, 16, Supplement, 224, 2009年01月20日
日本語

救急集中治療における血小板・凝固線溶系モニタリングの実際
丸藤 哲, 澤村 淳, 早川 峰司, 星野 弘勝, 久保田 信彦, 平安山 直美, 菅野 正寛, 和田 剛志, 方波見 謙一, 日本救急医学会雑誌, 20, 1, 1, 15, 2009年01月15日
出血傾向・血栓傾向を呈する病態，各種凝固線溶療法，血液浄化装置・補助体外循環装置等，血小板・凝固線溶系モニタリングが要求される疾患・病態，治療法，そして医療機器が救急集中治療域では数多い。このように救急集中治療に携わる医師にとり，血栓止血学の知識とその理解に基づく血小板・凝固線溶系モニタリングは，救急疾患や重症病態の診断とそれらの集中治療の実践に必須である。本稿では血小板・凝固線溶系モニタリングが必要な病態，治療法，医療機器を述べ，それらに使用される血小板，凝固線溶系モニタリングと機器を使用したモニタリングの実際を解説した。, Japanese Association for Acute Medicine, 日本語

SIVELESTAT IMPROVES MORTALITY RATE OF SEPTIC PATIENTS ASSOCIATED WITH ARDS AND DIC.
Mineji Hayakawa, Kenichi Katabami, Takeshi Wada, Masahiro Sugano, Naomi Henzan, Nobuhiko Kubota, Hirokatsu Hoshino, Atsushi Sawamura, Satoshi Gando, CRITICAL CARE MEDICINE, 36, 12, A142, A142, 2008年12月
LIPPINCOTT WILLIAMS & WILKINS, 英語, 研究発表ペーパー・要旨（国際会議）

THE RESPONSE OF ANTITHROMBIN III ACTIVITY AFTER SUPPLEMENTATION DECREASES IN PROPORTION TO THE SEVERITY OF SEPSIS AND LIVER DYSFUNCTION.
Mineji Hayakawa, Naomi Henzan, Kenichi Katabami, Takeshi Wada, Masahiro Sugano, Nobuhiko Kubota, Horokatsu Hoshino, Atsushi Sawamura, Satoshi Gando, CRITICAL CARE MEDICINE, 36, 12, A111, A111, 2008年12月
LIPPINCOTT WILLIAMS & WILKINS, 英語, 研究発表ペーパー・要旨（国際会議）

注射用抗菌薬Ciprofloxacin(CPFX)のSepsisにおける免疫能に及ぼす影響
澤村淳, 方波見謙一, 和田剛志, 菅野正寛, 平安山直美, 久保田信彦, 星野弘勝, 早川峰司, 石川岳彦, 丸藤哲, 日本外科感染症学会雑誌, 5, 5, 594, 2008年10月05日
日本語

鼻出血による出血性ショックで発症した海綿静脈洞内内頚動脈瘤の一例
和田剛志, 早川峰司, 方波見謙一, 菅野正寛, 平安山直美, 久保田信彦, 星野弘勝, 澤村淳, 丸藤哲, 日本救急医学会雑誌, 19, 8, 566, 2008年08月15日
日本語

速乾性擦式手指消毒剤ウェルパス(R)誤飲により食道炎を併発した1例
方波見謙一, 早川峰司, 和田剛志, 菅野正寛, 平安山直美, 久保田信彦, 星野弘勝, 澤村淳, 石川岳彦, 丸藤哲, 日本救急医学会雑誌, 19, 8, 629, 2008年08月15日
日本語

鈍的大動脈損傷に対する下行大動脈置換術中に発症した脂肪塞栓症候群の1例
中田麻子, 方波見謙一, 和田剛志, 菅野正寛, 平安山直美, 久保田信彦, 星野弘勝, 早川峰司, 澤村淳, 丸藤哲, 日本救急医学会雑誌, 19, 8, 668, 2008年08月15日
日本語

歯学部 外科学講義 救急医療　　　　　　　　　　　　　　　
北海道大学歯学部

歯学部 外科学講義 心肺蘇生法　　　　　　　　　　　　　　　
北海道大学歯学部

救急医学分野 心肺蘇生/心停止後症候群　　　　　　　　　　　　　　　
北海道大学医学部

救急医学分野 外傷学　　　　　　　　　　　　　　　
北海道大学医学部

救急医学分野 臓器不全II　　　　　　　　　　　　　　　
北海道大学医学部

救急医学分野 救急診断学・救急治療学　　　　　　　　　　　　　　　
北海道大学医学部

救急医学分野 救急症候学　　　　　　　　　　　　　　　
北海道大学医学部

救急医学分野 生体侵襲と生体反応　　　　　　　　　　　　　　　
北海道大学医学部

救急医学分野 心肺脳蘇生法I・II　　　　　　　　　　　　　　　
北海道大学医学部

膠原病・アレルギー：アナフィラキシーショック　　　　　　　　　　　　　　　
北海道大学医学部

敗血症後に生じる免疫機能不全への挑戦：顆粒球単球吸着除去による免疫調整療法
科学研究費助成事業
2024年04月01日 - 2027年03月31日
高須 朗, 山川 一馬, 久宗 遼, 和田 剛志, 谷口 高平
日本学術振興会, 基盤研究(C), 大阪医科薬科大学, 24K12168

外傷特異的なメモリー制御性T細胞を介した免疫応答の解明
科学研究費助成事業
2024年04月01日 - 2027年03月31日
山川 一馬, 和田 剛志, 梅村 穣, 谷口 高平
日本学術振興会, 基盤研究(C), 大阪医科薬科大学, 24K12188

ARDSに対する革新的治療戦略：ECMO補助下全肺胞洗浄法の基盤研究
科学研究費助成事業
2024年04月01日 - 2027年03月31日
生塩 典敬, 和田 剛志, 山川 一馬, 谷口 高平
日本学術振興会, 基盤研究(C), 大阪医科薬科大学, 24K12209

敗血症病態における血管内皮グリコカリックス障害の修復促進因子の解明と治療戦略構築
科学研究費助成事業
2023年04月01日 - 2026年03月31日
久宗 遼, 山川 一馬, 谷口 高平, 和田 剛志
日本学術振興会, 基盤研究(C), 大阪医科薬科大学, 23K08433

好中球の異質性が関与する外傷後二次性感染症の病態解明と治療法開発に向けた基盤研究
科学研究費助成事業 基盤研究(C)
2022年04月01日 - 2025年03月31日
斉藤 智誉, 和田 剛志, 山川 一馬
日本学術振興会, 基盤研究(C), 北海道大学, 22K09109

重度侵襲後の遷延性免疫不全PIICSにおける骨髄由来免疫抑制細胞の関与
科学研究費助成事業 基盤研究(C)
2022年04月01日 - 2025年03月31日
三嶋 隆之, 山川 一馬, 和田 剛志, 中村 謙介, 梅村 穣
日本学術振興会, 基盤研究(C), 大阪医科薬科大学, 22K09154

CyTOFを用いた集中治療後症候群の病態解明と予防法開発に向けた基盤研究
科学研究費助成事業 基盤研究(C)
2021年04月 - 2024年03月
前川 邦彦
敗血症モデルとして盲腸結紮穿孔(CLP)と、当研究室で新たにモデルとしての妥当性を検証したfecal suspension intraperitoneal injection(FSI)モデルを作成し、①生存率評価、②サイトカイン/ケモカインのLUMINEXによる網羅的測定のための血漿検体採取・保存、③Cytometry by time-of-flightにより血中免疫細胞評価のための血液検体処理・保存、④臓器障害評価のための肺、肝、腎、脾の摘出、保存、を行った。
1-①：生存率はCLP、FSIでそれぞれ77.5％、CLPで67.5％であり、生存したマウスに対して敗血症誘導1か月後にリポポリサッカライド(LPS)10mg/kgの投与をおこなった。sham損傷後LPS投与では、31％のマウスが死亡したが、予想に反して敗血症後マウスに対するLPS投与ではCLP、FSIともに死亡は確認されなかった。病態機序解明のため、上記②-④を行い、まず免疫学的機序解析のため③の検体測定を行ったが、検体処理過程で実施者の家族にCOVID-19陽性が判明し処理継続が不能となったため、CyTOF用の検体の大半が使用不能となった。そのため、最初からの実験やり直しを検討している。
また敗血症後の免疫変化はLPSによる二次性の侵襲に対して保護的に働いている可能性が示唆されている。実験前の仮説と異なる結果であり、二次性の侵襲をLPS投与ではなく、肺炎を誘導するなど感染症による変化を確認することを検討したい。
日本学術振興会, 基盤研究(C), 北海道大学, 研究分担者, 21K09008

Histone/NETsを標的とした外傷性凝固障害の病態生理解明と治療法の確立
科学研究費助成事業 基盤研究(C)
2020年04月01日 - 2023年03月31日
丸藤 哲, 和田 剛志
多施設共同で集積した外傷症例276症例を対象に、外傷性凝固障害（trauma-induced coagulopathy, TIC）と外傷後の播種性血管内凝固症候群（disseminated intravascular coagulation, DIC）の凝固線溶動態は同一である、と言う仮説の証明を試みた。
TIC/DICの血小板・凝固線溶動態を比較検討し、両者が同一の病態で有ることを以下の結果から証明した。
TIC/DICともに、1）活性化プロテインCが上昇するが、トロンビン制御可能な値ではない、2）その結果外傷直後から大量のトロンビン産生が起こる、3）トロンビン産生により消費性凝固障害が起こり血小板数、アンチトロンビン、プロテインCが減少する、4）外傷直後に血管内皮細胞から遊離したtissue-type plasminogen activator (t-PA)が高値となり線溶亢進が起こるが約3時間の経過を経てplasminogen activator inhibitor-1 (PAI-1)発現が誘導され線溶抑制が生ずる、5）DIC症例は非DIC症例と比較して輸血量、新鮮凍結血漿投与量、濃厚血小板液投与量が多く（いずれもp<0.001）、病院死亡率は明らかに高値である（7.5 vs. 26.7%, p=0.001）。
さらに本研究は、DIC病態が外傷直後から起こる事を証明した事に意義があり、上記結果とともに外傷症例の治療方針に大きな示唆を与えるものと推定される。
これらの結果は、2020年7月開催（online） International Society on Thrombosis and Haemostasis Congressで報告し、同学会機関誌であるJournal of Thrombosis and Haemostais (202018:2232-44)に掲載された。
日本学術振興会, 基盤研究(C), 北海道大学, 20K09280

頭部外傷特異的な免疫応答と二次性感染症におけるインフラマソーム制御機構の解明
科学研究費助成事業 基盤研究(C)
2020年04月01日 - 2023年03月31日
和田 剛志
頭部外傷（TBI）後二次性敗血症モデルを作成し、sham損傷後二次性敗血症モデルと①生存率、②生菌数の比較を行った。①生存率：TBI 87% vs. sham 67%とTBI群の方が生存率が高かった。②腹水中生菌数はTBI群ではsham群と比較して有意に低値であった。以上のことから、過去の報告同様、頭部外傷後に生じる免疫応答はその後の感染症/敗血症に保護的に働いている可能性が確認された。
続いて、LUMINEXによる血清、腹水中のサイトカインの網羅的測定を行った。TBI群では、IL-6、TNFalpha、IL-17に代表される炎症性サイトカインが有意に高値である一方、IL-4、IL-10などの抗炎症性サイトカインは両群間に有意な差は認められなかった。また、TBI群ではT細胞非依存性INF gamma誘導に重要な役割を果たすIL-12P70が高値であり、実際にINF gammaの高値も確認された。
以上より、頭部外傷後に生じる敗血症病態では、顕著な炎症反応活性化が病原体の除去、生存率の改善に寄与している可能性が示唆される。
上記2つのモデルにおける免疫細胞、特に好中球、単球（マクロファージ）をはじめとする自然免疫系の変化の解析をすべく、CyTOF mass cytometry用の検体を収集し、CyTOF測定を行った。今後、クラウドデータベースOMIC上で多次元解析を行い免疫細胞機能変化と上述の病態の関連を検討する予定である。TBIで生じている免疫変化を明らかにすることにより、新たな感染症治療の治療標的を見出すことが期待される。
日本学術振興会, 基盤研究(C), 北海道大学, 20K09260

CyTOF technologyを用いた生体侵襲後免疫変化に起因する臓器不全、敗血症発症の病態解明　　　　　　　　　　　　　　　
2021年04月 - 2022年03月
公益信託丸茂救急医学研究振興基金助成金, 研究代表者

外傷性凝固障害(trauma-induced coagulopathy: TIC)の病態理解に基づく新診断基準の策定　　　　　　　　　　　　　　　
2021年04月 - 2022年03月
JA交通事故医療研究助成, 研究代表者

外傷初期凝固線溶系変化の病態生理解明
科学研究費助成事業 挑戦的萌芽研究
2015年04月01日 - 2018年03月31日
丸藤 哲, 澤村 淳, 早川 峰司, 柳田 雄一郎, 和田 剛志, 宮本 大輔
外傷後の凝固線溶動態解明を目的として前向きおよび後ろ向き研究を実施した。外傷自体が引き起こす凝固線溶系変化があることを確認した。重症外傷では、生理的止血・創傷治癒過程が破綻し病的凝固線溶系変化が起こる。この病態は凝固亢進、凝固制御機能不全、線溶抑制であり、播種性血管内凝固症候群（disseminated intravascular coagulation, DIC）の病態生理に一致する事を基礎実験で確認した。この成果をこれまでの教室の研究内容と合わせて数本の英文総説および英文原著として公表した。これらの結果を臨床症例で確認するために、前向き多施設共同研究を北海道大学が研究主管校として実施した。
日本学術振興会, 挑戦的萌芽研究, 北海道大学, 15K15658

外傷・敗血症における易血栓性(DIC)遺伝子多型の国際比較研究
科学研究費助成事業 基盤研究(B)
2013年04月01日 - 2017年03月31日
丸藤 哲, Jesmin Subrina, 澤村 淳, 早川 峰司, 和田 剛志
昨年度に報告したように、外傷・敗血症症例においてDAMPsであるhistone H3, H4、補体経路活性化産物であるC3a, C5a、凝固線溶系で凝固制御機能の主軸を占めるAPCの測定を実施した。外傷後凝固線溶系変化の病態生理を究明するために、DICとAPCの関係を検討した。外傷後にAPC, SF、sTMを測定し、DIC症例では非DIC症例に比較してこれらが全て有意に低値となることを証明した。この結果は、外傷後DIC症例では血管内皮細胞傷害に伴い凝固制御機能の主軸であるAPCが減少し、これが播種性血管内トロンビン産生を来すことが明らかになった。
日本学術振興会, 基盤研究(B), 北海道大学, 25293364

補体系が関与する生体侵襲下臓器障害の病態解明とその治療体系の確立　　　　　　　　　　　　　　　
血液医学分野 海外留学助成
2016年04月 - 2017年03月
和田剛志
公益財団法人 先進医薬研究振興財団, 研究代表者, 競争的資金

HIF1αが関与する心停止後症候群の病態解明と治療法の確立
科学研究費補助金(若手研究(B))
2013年 - 2014年
和田 剛志
動物実験施設改修工事、移動などの関係で、実際に実験に着手するところまでは到達しなかったが、実験開始後の研究が円滑に進むよう、機器の整備、モデル作成の具体的手順、測定する因子の再検討などを行った。平成26年度初めより、実験を開始する予定である。また、臨床研究として心停止後症候群の一酸化窒素とその合成酵素の測定結果の解析を行った。播種性血管内凝固症候群を発症し臓器不全をきたす群では一酸化窒素の過剰産生が見られ予後不良となることが示されたが、その一酸化窒素の過剰産生は一酸化窒素合成酵素ではなく、血管新生関連因子や凝固因子などにより誘導されている可能性がある、という興味深い結果を得た。この結果はヨーロッパ集中治療学会で発表し、英文誌に投稿予定である。
文部科学省, 若手研究(B), 日本医科大学->北海道大学, 研究代表者, 競争的資金, 25861736

敗血症性におけるHIF-1αを介した低酸素応答と凝固炎症反応連関
科学研究費助成事業
2011年 - 2012年
丸藤 哲, ジェスミン サブリナ, 和田 剛志
Hypoxia-inducible factor1-α(HIF1α)が発現を誘導する血管新生関連因子であるVEGF/VEGFR1/VEGFR2およびangiopoietin(Ang)/Tie2システムの動態とDIC、臓器不全発症との関連を、外傷、敗血症、心停止蘇生後症例で検討し、血管新生関連因子が生体侵襲の種類を問わずに同様の動態を示し、臓器不全発症に関わることを証明した。
日本学術振興会, 挑戦的萌芽研究, 北海道大学, 24659793

Ang/Tie2が関与する敗血症性臓器障害発症機序解明とその制御法の確立
科学研究費補助金(若手研究(B))
2011年 - 2012年
和田 剛志
救急領域で扱う過大生体侵襲に合併する臓器不全の病態解明とその制御法の確立を目指し、主に臨床血液サンプルを用いてVEGFやAng、それらの受容体などの血管新生関連因子と、敗血症、重症外傷、心停止後症候群に合併する臓器不全との関わりを検討した。特にAng2が凝固線溶異常と関連して重要な役割を果たしていることを証明した。この成果は海外4学会、国内6学会で発表、また英文誌4編に発表した。
文部科学省, 若手研究(B), 日本医科大学, 研究代表者, 競争的資金, 23792091

生体侵襲・生体反応相互作用から生じる臓器不全の病態解明とその予防・治療体系の確立
科学研究費助成事業
2009年 - 2012年
丸藤 哲, ジェスミン サブリナ, 澤村 淳, 和田 剛志, 水谷 太郎
生体侵襲と生体反応に基づく臓器不全発症機序の研究をさらに発展させ、神経内分泌反応・凝固線溶反応・免疫炎症反応三者の連関の病態生理を明確にすることにより臓器不全発症機序を体系的かつ網羅的に解明し臓器不全の新たな予防および治療方法の確立を目指した。具体的には神経内分泌反応の賦活あるいは抑制が抗炎症反応と凝固線溶反応制御を通じて臓器不全発症を予防して生体侵襲に対して生体恒常性を維持することにより症例の予後を改善することの証明を試みた。
日本学術振興会, 基盤研究(A), 北海道大学, 21249086

ヒストン/NETsが担う病的自然免疫反応による外傷性凝固障害病態解明研究　　　　　　　　　　　　　　　
一般社団法人 日本損害保険協会, 2022年度交通事故医療研究助成(一般研究)

凝固・補体遺伝子解析による敗血症性播種性血管内凝固症候群と血栓性微小血管症の併存病態解明研究　　　　　　　　　　　　　　　
公益財団法人 武田科学振興財団, 2021年度 医学系研究助成

頭部外傷後免疫応答が関与する慢性外傷性脳症の病態解明と治療法開発に向けた基盤研究　　　　　　　　　　　　　　　
公益財団法人 脳神経財団, 2021年度一般研究助成

CyTOF technologyを用いた外傷免疫機能変化の解明-白血球の「数」から「質」の評価へ　　　　　　　　　　　　　　　
交通事故医療研究助成
和田剛志
日本損害保険協会, 研究代表者, 競争的資金