中田 孝明

OBJECTIVES: The pharmacokinetics of vancomycin and meropenem in patients treated with continuous online hemodiafiltration (OL-HDF) are not well understood. CASE: We evaluated dialytic clearance and serum concentrations of vancomycin and meropenem by OL-HDF in a critically ill patient with soft tissue infection. The mean clearance of OL-HDF and mean serum concentrations during continuous OL-HDF were 155.2 mL/min and 23.1 μg/mL for vancomycin and 145.6 mL/min and 22.7 μg/mL for meropenem. CONCLUSION: Vancomycin and meropenem showed high clearance rates during continuous OL-HDF. However, continuous infusion of these agents at high doses maintained therapeutic serum concentrations.

BACKGROUND: A substantial number of sepsis patients require specialized care, including multidisciplinary care, close monitoring, and artificial organ support in the intensive care unit (ICU). However, the efficacy of ICU management on clinical outcomes remains insufficiently researched. Therefore, we tested the hypothesis that ICU admission would increase the survival rate among sepsis patients. METHODS: We conducted a retrospective study using the nationwide medical claims database of sepsis patients in Japan from 2010 to 2017 with propensity score matching to adjust for baseline imbalances. Patients aged over 20 years, with a combined diagnosis of presumed serious infection and organ failure, were included in this study. The primary outcome studied was the in-hospital mortality among non-ICU and ICU patients. In addition to propensity score matching, we performed a multivariable logistic regression analysis for the primary outcome. As the treatment policy was not extracted from the database, we performed sensitivity analyses to determine mortality differences in adults (20 ≤ age ≤ 64), independent patients, patients without malignant tumors, based on the assumption that treatment intensity is likely to increase in those population. RESULTS: Among 1,167,901 sepsis patients (974,289 in non-ICU and 193,612 in ICU settings), the unadjusted in-hospital mortality was 22.5% among non-ICU patients and 26.2% among ICU patients (3.7% [95% CI 3.5-3.9]). After propensity score matching, the in-hospital mortality was 29.2% among non-ICU patients and 25.8% among ICU patients ([Formula: see text] 3.4% [95% CI [Formula: see text] 3.7 to [Formula: see text] 3.1]). In-hospital mortality with a multivariable regression analysis ([Formula: see text] 5.0% [95% CI [Formula: see text] 5.2 to [Formula: see text] 4.8]) was comparable with the results of the propensity score matching analysis. In the sensitivity analyses, the mortality differences between non-ICU and ICU in adults, independent patients, and patients without malignant tumors were [Formula: see text] 2.7% [95% CI [Formula: see text] 3.3 to [Formula: see text] 2.2], [Formula: see text] 5.8% [95% CI [Formula: see text] 6.4 to [Formula: see text] 5.2], and [Formula: see text] 1.3% [95% CI [Formula: see text] 1.7 to [Formula: see text] 1.0], respectively. CONCLUSIONS: Herein, using the nationwide medical claims database, we demonstrated that ICU admission was potentially associated with decreasing in-hospital mortality among sepsis patients. Further investigations are warranted to validate these results and elucidate the mechanisms favoring ICU management on clinical outcomes.

Sepsis is the leading cause of death worldwide. Considering regional variations in the characteristics of patients with sepsis, a better understanding of the epidemiology in Japan will lead to further development of strategies for the prevention and treatment of sepsis. To investigate the epidemiology of sepsis, we conducted a systematic literature review of PubMed between 2003 and January 2023. Among the 78 studies using a Japanese administrative database, we included 20 that defined patients with sepsis as those with an infection and organ dysfunction. The mortality rate in patients with sepsis has decreased since 2010, reaching 18% in 2017. However, the proportion of inpatients with sepsis is increasing. A study comparing short-course (≤7 days) and long-course (≥8 days) antibiotic administration showed lower 28-day mortality in the short-course group. Six studies on the treatment of patients with septic shock reported that low-dose corticosteroids or polymyxin B hemoperfusion reduced mortality, whereas intravenous immunoglobulins had no such effect. Four studies investigating the effects of treatment in patients with sepsis-associated disseminated intravascular coagulation demonstrated that antithrombin may reduce mortality, whereas recombinant human soluble thrombomodulin does not. A descriptive study of medical costs for patients with sepsis showed that the effective cost per survivor decreased over an 8-year period from 2010 to 2017. Sepsis has a significant impact on public health, and is attracting attention as an ongoing issue. Further research to determine more appropriate prevention methods and treatment for sepsis should be a matter of priority.

目的:Advanced Surgical Skills for Exposure in Trauma(ASSET)コースは米国外科学会が開発したご遺体を用いた外傷トレーニングコースの1つである。世界各国で開催されており,わが国では2016年に初開催された。本コースでは,外傷症例のディスカッションを行い,手術手技を1日で学ぶ。わが国における本コースの有用性が明らかでないため,アンケート調査結果を分析した。方法:過去9回,76名の受講者に対してアンケートを行い,以下の各項目(全体評価,プログラムのトピックスと内容,必要性との合致性,教育の形式,実際の臨床への有用性,新しい知識/技術の習得,満足度など)を分析した。さらに解剖学的に役立った部位も調査した。結果:5段階評価にて平均4.3～4.8と高評価であった。役立った部位は,頸部や上肢を選ぶ受講生が多かった。結論:ASSTコースにも長所,短所があるものの,アンケート調査結果は高評価であり,今後も継続的な普及が望まれる。(著者抄録)

目的:Advanced Surgical Skills for Exposure in Trauma(ASSET)コースは米国外科学会が開発したご遺体を用いた外傷トレーニングコースの1つである。世界各国で開催されており,わが国では2016年に初開催された。本コースでは,外傷症例のディスカッションを行い,手術手技を1日で学ぶ。わが国における本コースの有用性が明らかでないため,アンケート調査結果を分析した。方法:過去9回,76名の受講者に対してアンケートを行い,以下の各項目(全体評価,プログラムのトピックスと内容,必要性との合致性,教育の形式,実際の臨床への有用性,新しい知識/技術の習得,満足度など)を分析した。さらに解剖学的に役立った部位も調査した。結果:5段階評価にて平均4.3～4.8と高評価であった。役立った部位は,頸部や上肢を選ぶ受講生が多かった。結論:ASSTコースにも長所,短所があるものの,アンケート調査結果は高評価であり,今後も継続的な普及が望まれる。(著者抄録)

OBJECTIVES: The aim of this study was to reveal the neurological outcomes of choking-induced out-of-hospital cardiac arrest (OHCA) and evaluate the presence of witnesses, cardiopulmonary resuscitation (CPR) performed by a witness (bystander-witnessed CPR), and the proportion of patients with favourable neurological outcomes by the time from CPR by emergency medical services (EMS) to the return of spontaneous circulation (ROSC) (CPR-ROSC time). METHODS: We retrospectively analysed the SOS-KANTO 2012 database, which included data of 16,452 OHCAs in Japan. We selected choking-induced OHCA patients aged ≥ 20 years. We evaluated the neurological outcomes at 1 month with the Cerebral Performance Category (CPC). We defined favourable neurological outcomes (CPCs: 1-2) and present the outcomes with descriptive statistics. RESULTS: Of 1,045 choking-induced OHCA patients, 18 (1.7%) had a favourable neurological outcome. Of 1,045 OHCAs, 757 (72.6%) were witnessed, and 375 (36.0%) underwent bystander-witnessed CPR. Of the 18 OHCAs with favourable outcomes, 17 (94.4%) were witnessed, and 11 (61.1%) underwent bystander-witnessed CPR. With a CPR-ROSC time of 0-5 minutes, the proportion of patients with favourable neurological outcomes was 29.7%, ranging from 0% to 6% in the following time groups. CONCLUSIONS: The neurological outcome of choking-induced OHCA was poor. The neurological outcomes deteriorated rapidly from 5 minutes after the initiation of CPR by EMS. The presence of witnesses and bystander-witnessed CPR may be factors that contribute to improved outcomes, but the effects were not remarkable. As another approach to reduce deaths due to choking, citizen education for the prevention of choking may be effective.

BACKGROUND: The appropriate duration of antibiotic treatment in patients with bacterial sepsis remains unclear. The purpose of this study was to evaluate the association of a shorter course of antibiotics on 28-day mortality in comparison with a longer course using a national database in Japan. METHODS: We conducted a post hoc analysis from the retrospective observational study of patients with sepsis using a Japanese claims database from 2010 to 2017. The patient dataset was divided into short-course (≤ 7 days) and long-course (≥ 8 days) groups according to the duration of initial antibiotic administration. Subsequently, propensity score matching was performed to adjust the baseline imbalance between the two groups. The primary outcome was 28-day mortality. The secondary outcomes were re-initiated antibiotics at 3 and 7 days, during hospitalization, administration period, antibiotic-free days, and medical cost. RESULTS: After propensity score matching, 448,146 pairs were analyzed. The 28-day mortality was significantly lower in the short-course group (hazard ratio, 0.94; 95% CI, 0.92-0.95; P < 0.001), while the occurrence of re-initiated antibiotics at 3 and 7 days and during hospitalization were significantly higher in the short-course group (P < 0.001). Antibiotic-free days (median [IQR]) were significantly shorter in the long-course group (21 days [17 days, 23 days] vs. 17 days [14 days, 19 days], P < 0.001), and short-course administration contributed to a decrease in medical costs (coefficient $-212, 95% CI; - 223 to - 201, P < 0.001). Subgroup analyses showed a significant decrease in the 28-day mortality of the patients in the short-course group in patients of male sex (hazard ratio: 0.91, 95% CI; 0.89-0.93), community-onset sepsis (hazard ratio; 0.95, 95% CI; 0.93-0.98), abdominal infection (hazard ratio; 0.92, 95% CI; 0.88-0.97) and heart infection (hazard ratio; 0.74, 95% CI; 0.61-0.90), while a significant increase was observed in patients with non-community-onset sepsis (hazard ratio; 1.09, 95% CI; 1.06-1.12). CONCLUSIONS: The 28-day mortality was significantly lower in the short-course group, even though there was a higher rate of re-initiated antibiotics in the short course.

Symptoms of adverse reactions to vaccines evolve over time, but traditional studies have focused only on the frequency and intensity of symptoms. Here, we attempt to extract the dynamic changes in vaccine adverse reaction symptoms as a small number of interpretable components by using non-negative tensor factorization. We recruited healthcare workers who received two doses of the BNT162b2 mRNA COVID-19 vaccine at Chiba University Hospital and collected information on adverse reactions using a smartphone/web-based platform. We analyzed the adverse-reaction data after each dose obtained for 1,516 participants who received two doses of vaccine. The non-negative tensor factorization revealed four time-evolving components that represent typical temporal patterns of adverse reactions for both doses. These components were differently associated with background factors and post-vaccine antibody titers. These results demonstrate that complex adverse reactions against vaccines can be explained by a limited number of time-evolving components identified by tensor factorization.

心停止(cardiac arrest:CA)症例に対するCPR(cardiopulmonary resuscitation)の進歩はめざましく,PCAS(post-cardiac arrest syndrome)の病態とcytokine stormのかかわりが,近年明らかにされた。また,救急医療における進歩の傍ら常に考えなければならない問題が,救急医療領域でのmedical futilityである。本稿ではmedical futilityを回避するための予後予測をふまえつつ,PCASに対するtherapeutic temperature managementの適応と,cytokine stormの制御に関して解説する。(著者抄録)

Rapid and precise prehospital recognition of acute coronary syndrome (ACS) is key to improving clinical outcomes. The aim of this study was to investigate a predictive power for predicting ACS using the machine learning-based prehospital algorithm. We conducted a multicenter observational prospective study that included 10 participating facilities in an urban area of Japan. The data from consecutive adult patients, identified by emergency medical service personnel with suspected ACS, were analyzed. In this study, we used nested cross-validation to evaluate the predictive performance of the model. The primary outcomes were binary classification models for ACS prediction based on the nine machine learning algorithms. The voting classifier model for ACS using 43 features had the highest area under the receiver operating curve (AUC) (0.861 [95% CI 0.775-0.832]) in the test score. After validating the accuracy of the model using the external cohort, we repeated the analysis with a limited number of selected features. The performance of the algorithms using 17 features remained high AUC (voting classifier, 0.864 [95% CI 0.830-0.898], support vector machine (radial basis function), 0.864 [95% CI 0.829-0.887]) in the test score. We found that the machine learning-based prehospital algorithms showed a high predictive power for predicting ACS.

The mortality of coronavirus disease 2019 (COVID-19) is strongly correlated with pulmonary vascular pathology accompanied by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection-triggered immune dysregulation and aberrant activation of platelets. We combined histological analyses using field emission scanning electron microscopy with energy-dispersive X-ray spectroscopy analyses of the lungs from autopsy samples and single-cell RNA sequencing of peripheral blood mononuclear cells to investigate the pathogenesis of vasculitis and immunothrombosis in COVID-19. We found that SARS-CoV-2 accumulated in the pulmonary vessels, causing exudative vasculitis accompanied by the emergence of thrombospondin-1-expressing noncanonical monocytes and the formation of myosin light chain 9 (Myl9)-containing microthrombi in the lung of COVID-19 patients with fatal disease. The amount of plasma Myl9 in COVID-19 was correlated with the clinical severity, and measuring plasma Myl9 together with other markers allowed us to predict the severity of the disease more accurately. This study provides detailed insight into the pathogenesis of vasculitis and immunothrombosis, which may lead to optimal medical treatment for COVID-19.

敗血症診療において,感染巣へのアプローチは抗菌薬投与と並んで重要な治療項目の1つである。そのためにはまず感染巣の検索が必須であり,明らかでない場合には疑われる感染巣に合わせた適切な画像検査を選択する必要がある。感染源が明らかになった場合には基本的にはドレナージ術が検討されるが,一方で感染性膵壊死については早期の侵襲的なアプローチは必ずしも推奨されない。また近年は内視鏡などを用いたより低侵襲なドレナージ術が広まっており,初期にはこれらの治療法から開始して徐々にステップアップする戦略も視野に入れる。(著者抄録)

Machine learning can predict outcomes and determine variables contributing to precise prediction, and can thus classify patients with different risk factors of outcomes. This study aimed to investigate the predictive accuracy for mortality and length of stay in intensive care unit (ICU) patients using machine learning, and to identify the variables contributing to the precise prediction or classification of patients. Patients (n = 12,747) admitted to the ICU at Chiba University Hospital were randomly assigned to the training and test cohorts. After learning using the variables on admission in the training cohort, the area under the curve (AUC) was analyzed in the test cohort to evaluate the predictive accuracy of the supervised machine learning classifiers, including random forest (RF) for outcomes (primary outcome, mortality; secondary outcome, length of ICU stay). The rank of the variables that contributed to the machine learning prediction was confirmed, and cluster analysis of the patients with risk factors of mortality was performed to identify the important variables associated with patient outcomes. Machine learning using RF revealed a high predictive value for mortality, with an AUC of 0.945 (95% confidence interval [CI] 0.922-0.977). In addition, RF showed high predictive value for short and long ICU stays, with AUCs of 0.881 (95% CI 0.876-0.908) and 0.889 (95% CI 0.849-0.936), respectively. Lactate dehydrogenase (LDH) was identified as a variable contributing to the precise prediction in machine learning for both mortality and length of ICU stay. LDH was also identified as a contributing variable to classify patients into sub-populations based on different risk factors of mortality. The machine learning algorithm could predict mortality and length of stay in ICU patients with high accuracy. LDH was identified as a contributing variable in mortality and length of ICU stay prediction and could be used to classify patients based on mortality risk.

BACKGROUND: Sepsis is the leading cause of death worldwide. Although the mortality of sepsis patients has been decreasing over the past decade, the trend of medical costs and cost-effectiveness for sepsis treatment remains insufficiently determined. METHODS: We conducted a retrospective study using the nationwide medical claims database of sepsis patients in Japan between 2010 and 2017. After selecting sepsis patients with a combined diagnosis of presumed serious infection and organ failure, patients over the age of 20 were included in this study. We investigated the annual trend of medical costs during the study period. The primary outcome was the annual trend of the effective cost per survivor, calculated from the gross medical cost and number of survivors per year. Subsequently, we performed subgroup and multiple regression analyses to evaluate the association between the annual trend and medical costs. RESULTS: Among 50,490,128 adult patients with claims, a total of 1,276,678 patients with sepsis were selected from the database. Yearly gross medical costs to treat sepsis gradually increased over the decade from $3.04 billion in 2010 to $4.38 billion in 2017, whereas the total medical cost per hospitalization declined (rate = - $1075/year, p < 0.0001). While the survival rate of sepsis patients improved during the study period, the effective cost per survivor significantly decreased (rate = - $1806/year [95% CI - $2432 to - $1179], p = 0.001). In the subgroup analysis, the trend of decreasing medical cost per hospitalization remained consistent among the subpopulation of age, sex, and site of infection. After adjusting for age, sex (male), number of chronic diseases, site of infection, intensive care unit (ICU) admission, surgery, and length of hospital stay, the admission year was significantly associated with reduced medical costs. CONCLUSIONS: We demonstrated an improvement in annual cost-effectiveness in patients with sepsis between 2010 and 2017. The annual trend of reduced costs was consistent after adjustment with the confounders altering hospital expenses.

BACKGROUND: There is currently limited evidence to guide prehospital identification of patients with cardiopulmonary arrest on arrival (CPAOA) to hospital who have potentially favourable neurological function. This study aimed to develop a simple scoring system that can be determined at the contact point with emergency medical services to predict neurological outcomes. METHODS: We analysed data from patients with CPAOA using a regional Japanese database (SOS-KANTO), from January 2012 to March 2013. Patients were randomly assigned into derivation and validation cohorts. Favourable neurological outcomes were defined as cerebral performance category 1 or 2. We developed a new scoring system using logistic regression analysis with the following predictors: age, no-flow time, initial cardiac rhythm and arrest place. The model was internally validated by assessing discrimination and calibration. RESULTS: Among 4907 patients in the derivation cohort and 4908 patients in the validation cohort, the probabilities of favourable outcome were 0.9% and 0.8%, respectively. In the derivation cohort, age ≤70 years (OR 5.11; 95% CI 2.35 to 11.14), no-flow time ≤5 min (OR 4.06; 95% CI 2.06 to 8.01) and ventricular tachycardia or fibrillation as initial cardiac rhythm (OR 6.66; 95% CI 3.45 to 12.88) were identified as predictors of favourable outcome. The ABC score consisting of Age, information from Bystander and Cardiogram was created. The areas under the receiver operating characteristic curves of this score were 0.863 in the derivation and 0.885 in the validation cohorts. Positive likelihood ratios were 6.15 and 6.39 in patients with scores >2 points and were 11.06 and 17.75 in those with 3 points. CONCLUSION: The ABC score showed good accuracy for predicting favourable neurological outcomes in patients with CPAOA. This simple scoring system could potentially be used to select patients for extracorporeal cardiopulmonary resuscitation and minimise low-flow time.

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.

BACKGROUND: Heart rate (HR) predicts outcomes in patients with acute coronary syndrome (ACS), whereas the impact of HR on outcomes after out-of-hospital cardiac arrest (OHCA) remains unclear. This study aimed to investigate the impact of HR after resuscitation on outcomes after OHCA and whether the impact differs with OHCA etiology.Methods and Results: Of 16,452 patients suffering from OHCA, this study analyzed 741 adults for whom HR after resuscitation was recorded by 12-lead electrocardiogram upon hospital arrival. Etiology of OHCA was categorized into 3 groups: ACS, non-ACS, and non-cardiac. Patients in each etiology group were further divided into tachycardia (>100 beats/min) and non-tachycardia (≤100 beats/min). The impact of HR on outcomes was evaluated in each group. Among the 741 patients, the mean age was 67.6 years and 497 (67.1%) patients were male. The primary outcome - 3-month all-cause mortality - was observed in 55.8% of patients. Tachycardia after resuscitation in patients with ACS was significantly associated with higher all-cause mortality at 3 months (P=0.002), but there was no significant association between tachycardia and mortality in non-ACS and non-cardiac etiology patients. In a multivariate analysis model, the incidence of tachycardia after resuscitation independently predicted higher 3-month all-cause mortality in OHCA patients with ACS (hazard ratio: 2.17 [95% confidence interval: 1.05-4.48], P=0.04). CONCLUSIONS: Increased HR after resuscitation was associated with higher mortality only in patients with ACS.