中田 孝明

Background Timely and effective fluid resuscitation is vital for stabilizing sepsis while avoiding volume overload. We aimed to assess how the administration of a 30 mL/kg bolus fluid affects patients with sepsis within three hours of clinical outcomes. Methods This multicenter observational study included adult patients diagnosed with sepsis in 17 intensive care units at tertiary hospitals in Japan between July 2019 and August 2020. The clinical outcomes of patients with sepsis who received ≥30 mL/kg bolus fluid within three hours (30 × 3 group) were compared with those who received <30 mL/kg fluid (non-30 × 3 group). Results Of 172 eligible patients, 74 (43.0%) belonged to the 30 × 3 group, and 98 (57.0%) belonged to the non-30 × 3 group. The median Sequential Organ Failure Assessment score was 9 (interquartile range (Q1-Q3): 7-11) in the 30 × 3 group and 7 (Q1-Q3: 4-9) in the non-30 × 3 group (P < 0.01). The 28-day mortality rate was 29.7% in the 30 × 3 group and 12.2% in the non-30 × 3 group (P < 0.01). However, the adjusted odds ratio by the inverse probability of treatment weighting analysis with propensity score for the 28-day mortality rate of the 30 × 3 group compared with that in the non-30 × 3 group was 2.17 (95% confidence interval: 0.85-5.54). Among the propensity score-matched patients, the 28-day mortality rate was 30% in the 30 × 3 (n = 70) and non-30 × 3 (n = 95) groups, respectively (P = 0.72). Conclusions Patients with sepsis who received the 30 mL/kg bolus fluid within three hours experienced more severe clinical outcomes. However, it was not associated with the increased odds of the 28-day mortality.

Background The impact of intensive care unit (ICU) case volume on the mortality and medical costs of sepsis has not been fully elucidated. We hypothesized that ICU case volume is associated with mortality and medical costs in patients with sepsis in Japan. Methodology This retrospective nationwide study used the Japanese administrative data from 2010 to 2017. The ICU volume categorization into quartiles was performed according to the annual number of sepsis cases. The primary and secondary outcomes were in-hospital mortality and medical costs, respectively. A mixed-effects logistic model with a two-level hierarchical structure was used to adjust for baseline imbalances. Fractional polynomials were investigated to determine the significance of the association between hospital volume and clinical outcomes. Subgroup and sensitivity analyses were performed for the primary outcome. Results Among 317,365 sepsis patients from 532 hospitals, the crude in-hospital mortality was 26.0% and 21.4% in the lowest and highest quartile of sepsis volume, respectively. After adjustment for confounding factors, in-hospital mortality in the highest quartile was significantly lower than that of the lowest quartile (odds ratio = 0.829; 95% confidence interval = 0.794-0.865; p < 0.001). Investigations with fractional polynomials revealed that sepsis caseload was significantly associated with in-hospital mortality. The highest quartile had higher daily medical costs per person compared to the lowest quartile. Subgroup analyses showed that high-volume ICUs with patients undergoing mechanical ventilation, vasopressor therapy, and renal replacement therapy had a significantly low in-hospital mortality. The sensitivity analysis, excluding patients who were transferred to other hospitals, demonstrated a result consistent with that of the primary test. Conclusions This nationwide study using the medical claims database suggested that a higher ICU case volume is associated with lower in-hospital mortality and higher daily medical costs per person in patients with sepsis.

BACKGROUND: It is important to determine the prevalence and prognosis of community-acquired infection (CAI) and nosocomial infection (NI) to develop treatment strategies and appropriate medical policies in aging society. METHODS: Patients hospitalized between January 2010 and December 2019, for whom culture tests were performed and antibiotics were administered, were selected using a national claims-based database. The annual trends in incidence and in-hospital mortality were calculated and evaluated by dividing the patients into four age groups. RESULTS: Of the 73,962,409 inpatients registered in the database, 9.7% and 4.7% had CAI and NI, respectively. These incidences tended to increase across the years in both the groups. Among the patients hospitalized with infectious diseases, there was a significant increase in patients aged ≥ 85 years (CAI: + 1.04%/year and NI: + 0.94%/year, P < 0.001), while there was a significant decrease in hospitalization of patients aged ≤ 64 years (CAI: -1.63%/year and NI: -0.94%/year, P < 0.001). In-hospital mortality was significantly higher in the NI than in the CAI group (CAI: 8.3%; NI: 14.5%, adjusted mean difference 4.7%). The NI group had higher organ support, medical cost per patient, and longer duration of hospital stay. A decreasing trend in mortality was observed in both the groups (CAI: -0.53%/year and NI: -0.72%/year, P < 0.001). CONCLUSION: The present analysis of a large Japanese claims database showed that NI is a significant burden on hospitalized patients in aging societies, emphasizing the need to address particularly on NI.

OBJECTIVES: We aimed to describe empiric antimicrobial options for patients with community-onset sepsis using nationwide real-world data from Japan. METHODS: This retrospective cohort study used nationwide Japanese data from a medical reimbursement system database. Patients aged ≥20 years with both presumed infections and acute organ dysfunction who were admitted to hospitals from the outpatient department or emergency department between 2010 and 2017 were enrolled. We described the initial choices of antimicrobials for patients with sepsis stratified by intensive care unit (ICU) or ward. RESULTS: There were 1,195,741 patients with community-onset sepsis; of these, 1,068,719 and 127,022 patients were admitted to the wards and ICU, respectively. Third-generation cephalosporins and carbapenem were most commonly used for patients with community-onset sepsis. We found that 1.7% and 6.0% of patients initially used antimicrobials for methicillin-resistant Staphylococcus aureus coverage in the wards and ICU, respectively. Although half of the patients initially used antipseudomonal agents, only a few patients used a combination of antipseudomonal agents. Moreover, few patients initially used a combination of antimicrobials to treat methicillin-resistant Staphylococcus aureus and Pseudomonas sp. CONCLUSION: Third-generation cephalosporins and carbapenem were most frequently used for patients with sepsis. A combination therapy of antimicrobials for drug-resistant bacteria coverage was rarely provided to these patients.

BACKGROUND: The effect of hospital spending on the mortality rate of patients with sepsis has not yet been fully elucidated. We hypothesized that hospitals that consume more medical resources would have lower mortality rates among patients with sepsis. METHODS: This retrospective study used administrative data from 2010 to 2017. The enrolled hospitals were divided into quartiles based on average daily medical cost per sepsis case. The primary and secondary outcomes were the average in-hospital mortality rate of patients with sepsis and the effective cost per survivor among the enrolled hospitals, respectively. A multiple regression model was used to determine the significance of the differences among hospital categories to adjust for baseline imbalances. RESULTS: Among 997 hospitals enrolled in this study, the crude in-hospital mortality rates were 15.7% and 13.2% in the lowest and highest quartiles of hospital spending, respectively. After adjusting for confounding factors, the highest hospital spending group demonstrated a significantly lower in-hospital mortality rate than the lowest hospital spending group (coefficient = -0.025, 95% confidence interval [CI] -0.034 to -0.015; p < 0.0001). Similarly, the highest hospital spending group was associated with a significantly higher effective cost per survivor than the lowest hospital spending group (coefficient = 77.7, 95% CI 73.1 to 82.3; p < 0.0001). In subgroup analyses, hospitals with a small or medium number of beds demonstrated a consistent pattern with the primary test, whereas those with a large number of beds or academic affiliations displayed no association. CONCLUSIONS: Using a nationwide Japanese medical claims database, this study indicated that hospitals with greater expenditures were associated with a superior survival rate and a higher effective cost per survivor in patients with sepsis than those with lower expenditures. In contrast, no correlations between hospital spending and mortality were observed in hospitals with a large number of beds or academic affiliations.

This retrospective cohort study aimed to develop and evaluate a machine-learning algorithm for predicting oliguria, a sign of acute kidney injury (AKI). To this end, electronic health record data from consecutive patients admitted to the intensive care unit (ICU) between 2010 and 2019 were used and oliguria was defined as a urine output of less than 0.5 mL/kg/h. Furthermore, a light-gradient boosting machine was used for model development. Among the 9,241 patients who participated in the study, the proportions of patients with urine output < 0.5 mL/kg/h for 6 h and with AKI during the ICU stay were 27.4% and 30.2%, respectively. The area under the curve (AUC) values provided by the prediction algorithm for the onset of oliguria at 6 h and 72 h using 28 clinically relevant variables were 0.964 (a 95% confidence interval (CI) of 0.963-0.965) and 0.916 (a 95% CI of 0.914-0.918), respectively. The Shapley additive explanation analysis for predicting oliguria at 6 h identified urine values, severity scores, serum creatinine, oxygen partial pressure, fibrinogen/fibrin degradation products, interleukin-6, and peripheral temperature as important variables. Thus, this study demonstrates that a machine-learning algorithm can accurately predict oliguria onset in ICU patients, suggesting the importance of oliguria in the early diagnosis and optimal management of AKI.

INTRODUCTION: The neurologic prognosis of out-of-hospital cardiac arrest (OHCA) patients in whom return of spontaneous circulation (ROSC) is achieved remains poor. The aim of this study was to externally and prospectively validate two scoring systems developed by us: the CAST score, a scoring system to predict the neurological prognosis of OHCA patients undergoing targeted temperature management (TTM), and a simplified version of the same score developed for improved ease of use in clinical settings, the revised CAST (rCAST) score. METHODS: This study was a prospective, multicenter, observational study conducted using the SOS KANTO 2017 registry, an OHCA registry involving hospitals in the Kanto region (including Tokyo) of Japan. The primary outcome was favorable neurological outcome (defined as Cerebral Performance Category score of 1 or 2) at 30 days and the secondary outcomes were favorable neurological outcome at 90 days and survival at 30 and 90 days. The predictive accuracies of the original CAST (oCAST) and rCAST scores were evaluated by using area under the receiver operating characteristic curve (AUC). RESULTS: Of 9909 OHCA patients, 565 showed ROSC and received TTM. Of these, we analyzed the data of 259 patients in this study. The areas under the receiver operating characteristic curve (AUCs) of the oCAST and rCAST scores for predicting a favorable neurological outcome at 30 days were 0.86 and 0.87, respectively, and those for predicting a favorable neurological outcome at 90 days were 0.87 and 0.88, respectively. The rCAST showed a higher predictive accuracy for the neurological outcome as compared with the NULL-PLEASE score. The patients with a favorable neurological outcome who had been classified into the high severity group based on the rCAST tended to have hypothermia at hospital arrival and to not show any signs of loss of gray-white matter differentiation on brain CT. Neurological function at 90 days was correlated with the rCAST (r = 0.63, p < 0.001). CONCLUSIONS: rCAST showed high predictive accuracy for the neurological prognosis of OHCA patients managed by TTM, comparable to that of the oCAST score. The scores on the rCAST were strongly correlated with the neurological functions at 90 days, implying that the rCAST is a useful scale for assessing the severity of brain injury after cardiac arrest.

BACKGROUND: We evaluated the applicability of automated citation screening in developing clinical practice guidelines. METHODS: We prospectively compared the efficiency of citation screening between the conventional (Rayyan) and semi-automated (ASReview software) methods. We searched the literature for five clinical questions (CQs) in the development of the Japanese Clinical Practice Guidelines for the Management of Sepsis and Septic Shock. Objective measurements of the time required to complete citation screening were recorded. Following the first screening round, in the primary analysis, the sensitivity, specificity, positive predictive value, and overall screening time were calculated for both procedures using the semi-automated tool as index and the results of the conventional method as standard reference. In the secondary analysis, the same parameters were compared between the two procedures using the final list of included studies after the second screening session as standard reference. RESULTS: Among the five CQs after the first screening session, the highest and lowest sensitivity, specificity, and positive predictive values were 0.241 and 0.795; 0.991 and 1.000; and 0.482 and 0.929, respectively. In the secondary analysis, the highest sensitivity and specificity in the semi-automated citation screening were 1.000 and 0.997, respectively. The overall screening time per 100 studies was significantly shorter with semi-automated than with conventional citation screening. CONCLUSIONS: The potential advantages of the semi-automated method (shorter screening time and higher discriminatory rate for the final list of studies) warrant further validation. TRIAL REGISTRATION: This study was submitted to the University Hospital Medical Information Network Clinical Trial Registry (UMIN-CTR [UMIN000049366]).

Abstract Background The efficacy of therapeutic drug monitoring (TDM)-based antimicrobial dosing optimization strategies on pharmacokinetics/pharmacodynamics and specific drug properties for critically ill patients is unclear. Here, we conducted a systematic review and meta-analysis of randomized controlled trials to evaluate the effectiveness of TDM-based regimen in these patients. Methods Articles from three databases were systematically retrieved to identify relevant randomized control studies. Version two of the Cochrane tool for assessing risk of bias in randomized trials was used to assess the risk of bias in studies included in the analysis, and quality assessment of evidence was graded using the Grading of Recommendations Assessment, Development, and Evaluation approach. Primary outcome was the 28-day mortality and secondary outcome were in-hospital mortality, clinical cure, length of stay in the intensive care unit (ICU) and target attainment at day 1 and 3. Results In total, 5 studies involving 1011 patients were included for meta-analysis of the primary outcome, of which no significant difference was observed between TDM-based regimen and control groups (risk ratio [RR] 0.94, 95% confidence interval [CI]: 0.77–1.14; I² = 0%). In-hospital mortality (RR 0.96, 95% CI: 0.76–1.20), clinical cure (RR 1.23, 95% CI: 0.91–1.67), length of stay in the ICU (mean difference 0, 95% CI: − 2.18–2.19), and target attainment at day 1 (RR 1.14, 95% CI: 0.88–1.48) and day 3 (RR 1.35, 95% CI: 0.90–2.03) were not significantly different between the two groups, and all evidence for the secondary outcomes had a low or very low level of certainty because the included studies had serious risk of bias, variation of definition for outcomes, and small sample sizes. Conclusion TDM-based regimens had no significant efficacy for clinical or pharmacological outcomes. Further studies with other achievable targets and well-defined outcomes are required. Trial registration: Clinical trial registration; PROSPERO (https://www.crd.york.ac.uk/prospero/), registry number: CRD 42022371959. Registered 24 November 2022.

Predicting out-of-hospital cardiac arrest (OHCA) events might improve outcomes of OHCA patients. We hypothesized that machine learning algorithms using meteorological information would predict OHCA incidences. We used the Japanese population-based repository database of OHCA and weather information. The Tokyo data (2005-2012) was used as the training cohort and datasets of the top six populated prefectures (2013-2015) as the test. Eight various algorithms were evaluated to predict the high-incidence OHCA days, defined as the daily events exceeding 75% tile of our dataset, using meteorological and chronological values: temperature, humidity, air pressure, months, days, national holidays, the day before the holidays, the day after the holidays, and New Year's holidays. Additionally, we evaluated the contribution of each feature by Shapley Additive exPlanations (SHAP) values. The training cohort included 96,597 OHCA patients. The eXtreme Gradient Boosting (XGBoost) had the highest area under the receiver operating curve (AUROC) of 0.906 (95% confidence interval; 0.868-0.944). In the test cohorts, the XGBoost algorithms also had high AUROC (0.862-0.923). The SHAP values indicated that the "mean temperature on the previous day" impacted the most on the model. Algorithms using machine learning with meteorological and chronological information could predict OHCA events accurately.

While the development of prehospital diagnosis scales has been reported in various regions, we have also developed a scale to predict stroke type using machine learning. In the present study, we aimed to assess for the first time a scale that predicts the need for surgical intervention across stroke types, including subarachnoid haemorrhage and intracerebral haemorrhage. A multicentre retrospective study was conducted within a secondary medical care area. Twenty-three items, including vitals and neurological symptoms, were analysed in adult patients suspected of having a stroke by paramedics. The primary outcome was a binary classification model for predicting surgical intervention based on eXtreme Gradient Boosting (XGBoost). Of the 1143 patients enrolled, 765 (70%) were used as the training cohort, and 378 (30%) were used as the test cohort. The XGBoost model predicted stroke requiring surgical intervention with high accuracy in the test cohort, with an area under the receiver operating characteristic curve of 0.802 (sensitivity 0.748, specificity 0.853). We found that simple survey items, such as the level of consciousness, vital signs, sudden headache, and speech abnormalities were the most significant variables for accurate prediction. This algorithm can be useful for prehospital stroke management, which is crucial for better patient outcomes.

【目的】臨床症状と血液検査,画像診断を用いた救急外来を受診する患者における新型コロナウイルス感染症(COVID-19)の診断予測精度を明らかにする。【方法】対象は2021年2月～2022年5月の期間に千葉大学医学部附属病院の救急外来を受診し,SARS-CoV-2抗原定量検査とRT-qPCRを施行した患者とした。Receiver operating characteristic(ROC)曲線の曲線下面積(area under the curve;AUC)を算出して臨床症状と検査所見を用いたCOVID-19の診断予測精度を前方視的に検討した。【結果】解析対象患者213名のうちCOVID-19陽性患者は8名であり,全例でSARS-CoV-2抗原定量検査が陽性であった。COVID-19に特徴的な臨床症状数によるAUCは0.679(95%信頼区間0.470-0.887)であった一方,C-reactive proteinとCOVID-19に特徴的な胸部コンピュータ断層撮影(CT)画像所見数を基にしたAUCはそれぞれ0.839(95%信頼区間0.666-1.000),0.877(95%信頼区間0.721-1.000)であった。【結語】救急外来を受診する患者では,臨床症状よりも血液検査や画像所見を用いたCOVID-19の診断予測精度のほうが高かった。(著者抄録)

INTRODUCTION: Capillary refill time (CRT) is an indicator of peripheral circulation and is recommended in the 2021 guidelines for treating and managing sepsis. STUDY OBJECTIVE: This study developed a portable device to realize objective CRT measurement. Assuming that peripheral blood flow obstruction by the artery occlusion test (AOT) or venous occlusion test (VOT) increases the CRT, the cut-off value for peripheral circulatory failure was studied by performing a comparative analysis with CRT with no occlusion test (No OT). METHODS: Fourteen (14) healthy adults (age: 20-26 years) participated in the study. For the vascular occlusion test, a sphygmomanometer was placed on the left upper arm of the participant in the supine position, and a pressure of 30mmHg higher than the systolic pressure was applied for AOT, a pressure of 60mmHg was applied for VOT, respectively, and no pressure was applied for No OT. The CRT was measured from the index finger of the participant's left hand. RESULTS: Experimental results revealed that CRT was significantly longer in the AOT and did not differ significantly in the VOT. The cut-off value for peripheral circulatory failure was found to be 2.88 seconds based on Youden's index by using receiver operating characteristic (ROC) analysis with AOT as positive and No OT as negative. CONCLUSION: Significant results were obtained in a previous study on the evaluation of septic shock patients when CRT > three seconds was considered abnormal, and the cut-off value for peripheral circulatory failure in the current study validated this.

BACKGROUND: Patients with severe acute kidney injury (AKI) who require continuous venovenous hemodiafiltration (CVVHDF) in intensive care unit (ICU) are at high mortality risk. Little is known about clinical biomarkers for risk prediction, optimal initiation, and optimal discontinuation of CVVHDF. METHODS: This prospective observational study was conducted in seven university-affiliated ICUs. For urinary neutrophil gelatinase-associated lipocalin (NGAL) and plasma IL-6 measurements, samples were collected at initiation, 24 h, 48 h after, and CVVHDF discontinuation in adult patients with severe AKI. The outcomes were deaths during CVVHDF and CVVHDF dependence. RESULTS: A total number of 133 patients were included. Twenty-eight patients died without CVVHDF discontinuation (CVVHDF nonsurvivors). Urinary NGAL and plasma IL-6 at the CVVHDF initiation were significantly higher in CVVHDF nonsurvivors than in survivors. Among 105 CVVHDF survivors, 70 patients were free from renal replacement therapy (RRT) or death in the next 7 days after discontinuation (success group), whereas 35 patients died or needed RRT again (failure group). Urinary NGAL at CVVHDF discontinuation was significantly lower in the success group (93.8 ng/ml vs. 999 ng/ml, p < 0.01), whereas no significant difference was observed in plasma IL-6 between the groups. Temporal elevations of urinary NGAL levels during the first 48 h since CVVHDF initiation were observed in CVVHDF nonsurvivors and those who failed in CVVHDF discontinuation. CONCLUSIONS: Urinary NGAL at CVVHDF initiation and discontinuation was associated with mortality and RRT dependence, respectively. The serial changes of urinary NGAL might also help predict the prognosis of patients with AKI on CVVHDF.

Data collection on adverse reactions in recipients after vaccination is vital to evaluate potential health issues, but health observation diaries are onerous for participants. Here, we present a protocol to collect time series information using a smartphone or web-based platform, thus eliminating the need for paperwork and data submission. We describe steps for setting up the platform using the Model-View-Controller web framework, uploading lists of recipients, sending notifications, and managing respondent data. For complete details on the use and execution of this protocol, please refer to Ikeda et al. (2022).1.