Published papers

Background: Acute kidney injury (AKI) is common in sepsis and a urine output <0.5 mL/kg/h associated with increased mortality is incorporated into AKI diagnosis. We aimed to identify the urine-output threshold associated with increased AKI incidence and hypothesized that a higher urine output than a specified threshold, which differs from the predominantly used 0.5 mL/kg/h threshold, would be associated with an increased AKI incidence. Methods: This was a post-hoc analysis of a nationwide prospective observational study. This study included adult patients newly diagnosed with sepsis and requiring intensive care. Urine output on the day of sepsis diagnosis was categorized as low, moderate, or high (<0.5, 0.5-1.0, and >1.0 mL/kg/h, respectively), and we compared AKI incidence, renal replacement therapy (RRT) requirement, and 28-day survival by category. Estimated probabilities for these outcomes were also compared after adjusting for patient background and hourly fluid administration. Results: Among 172 eligible patients, AKI occurred in 46.3%, 48.3%, and 53.1% of those with high, moderate, and low urine output, respectively. The probability of AKI was lower in patients with high urine output than in those with low output (43.6% vs 56.5%; P =.028), whereas RRT requirement was lower in patients with high and moderate urine output (11.7% and 12.8% vs 49.1%; P <.001). Patients with low urine output demonstrated significantly lower survival (87.7% vs 82.8% and 67.8%; P =.018). Cubic spline curves for AKI, RRT, and survival prediction indicated different urine-output thresholds, including <1.2 to 1.3 mL/kg/h for AKI and <0.6 to 0.8 mL/kg/h for RRT and mortality risk. Conclusions: Urine output >1.0 mL/kg/h on the day of sepsis diagnosis was associated with lower AKI incidence. The urine-output threshold was higher for developing AKI than for RRT requirement or mortality.

Background: Despite improvements in surgical techniques and perioperative management, the incidence of postoperative surgical site infection after pancreatoduodenectomy remains high. This study aim to assess whether broad-spectrum antibiotic prophylaxis can reduce complications after pancreatoduodenectomy compared with standard care antibiotics. Methods: Data of patients who underwent pancreatoduodenectomy between July 2010 and March 2022 were extracted from a nationwide Japanese inpatient database. First- and second-generation cephalosporins were designated as narrow-spectrum, and third- and fourth-generation cephalosporins and piperacillin–tazobactam as broad-spectrum antibiotics. Patients who received either narrow- or broad-spectrum antibiotics on the day of surgery were included in the analysis. Using propensity-score stabilized inverse probability of treatment weighting, the postoperative complications were compared between patients who received antimicrobial prophylaxis with narrow-spectrum antibiotics versus broad-spectrum antibiotics. Results: From among 45 099 eligible patients, 36 742 (81.5%) and 8357 (18.5%) patients received narrow- and broad-spectrum antibiotics, respectively. After stabilized inverse probability of treatment weighting, the use of broad-spectrum antibiotics bore a significant association with the reduction in intra-abdominal infections [risk difference (RD), −7.4; 95% confidence interval (CI), −8.7 to −6.0], postoperative pancreatic fistula (RD, −3.0; 95% CI, −4.0 to −1.9), post-pancreatectomy hemorrhage (RD, −1.5; 95% CI, −1.9 to −1.1). The use of broad-spectrum antibiotics was also associated with a shorter postoperative length of hospital stay and lower total hospitalization costs. The proportion of Clostridioides difficile infection did not differ between the groups. Conclusions: The administration of broad-spectrum antibiotics as antimicrobial prophylaxis was associated with better in-hospital postoperative outcomes compared with narrow-spectrum in patients undergoing pancreatoduodenectomy.

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.

Introduction Chlorhexidine alcohol (1.0%–2.0%) is currently recommended as a skin disinfectant to be used prior to catheterisation for preventing catheter-related infections. However, chlorhexidine alcohol has various side effects and has little antibacterial effect on methicillin-resistant Staphylococcus aureus (MRSA). Therefore, MRSA remains a concern for catheter-related bloodstream infection (CRBSI) prevention. Olanedine, containing 1.5% olanexidine gluconate in aqueous solution, was developed in Japan in 2015 and is structurally similar to chlorhexidine. Olanexine has been used as a disinfectant against various gram-positive and gram-negative bacteria and MRSA. This study aims to compare the efficacy of 1.5% aqueous olanexidine gluconate and 1% chlorhexidine alcohol as skin antiseptics for the prevention of catheter-related infections. Methods and analysis This Apollo study is an open-label, multicentre, non-inferiority, two-arm, parallel-group, randomised controlled trial conducted at 21 intensive care units (ICUs) and high-care units (HCUs) in Japan. All patients scheduled to be admitted to the ICU or HCU of a facility participating in this study, who require central venous catheter insertion are eligible. Eligible patients will be assigned to either the 1.5% aqueous olanexidine gluconate or 1% chlorhexidine alcohol group by randomisation in a ratio of 1:1 with stratification by centres. The antibacterial agents are to be used as a skin disinfectant before and during catheter placement. The primary endpoint is the proportion of catheter-related infections, defined as a composite of catheter-related sepsis without bacteraemia and CRBSI. A total of 1980 patients will be included in this study. Ethics and dissemination This clinical trial was approved by the Institutional Review Board of Jichi Medical University and the ethics committees of the participating institutions. The study results will be disseminated through conferences, peer-reviewed publications and meetings with interested parties.

Background: Inhaled molecular hydrogen gas (H2) has been shown to improve outcomes in animal models of cardiac arrest (CA). H2 inhalation is safe and feasible in patients after CA. We investigated whether inhaled H2 would improve outcomes after out-of-hospital CA (OHCA). Methods: HYBRID II is a prospective, multicentre, randomised, double-blind, placebo-controlled trial performed at 15 hospitals in Japan, between February 1, 2017, and September 30, 2021. Patients aged 20–80 years with coma following cardiogenic OHCA were randomly assigned (1:1) using blinded gas cylinders to receive supplementary oxygen with 2% H2 or oxygen (control) for 18 h. The primary outcome was the proportion of patients with a 90-day Cerebral Performance Category (CPC) of 1 or 2 assessed in a full-analysis set. Secondary outcomes included the 90-day score on a modified Rankin scale (mRS) and survival. HYBRID II was registered with the University Hospital Medical Information Network (registration number: UMIN000019820) and re-registered with the Japan Registry for Clinical Trials (registration number: jRCTs031180352). Findings: The trial was terminated prematurely because of the restrictions imposed on enrolment during the COVID-19 pandemic. Between February 1, 2017, and September 30, 2021, 429 patients were screened for eligibility, of whom 73 were randomly assigned to H2 (n = 39) or control (n = 34) groups. The primary outcome, i.e., a CPC of 1 or 2 at 90 days, was achieved in 22 (56%) and 13 (39%) patients in the H2 and control groups (relative risk compared with the control group, 0.72; 95% CI, 0.46–1.13; P = 0.15), respectively. Regarding the secondary outcomes, median mRS was 1 (IQR: 0–5) and 5 (1–6) in the H2 and control groups, respectively (P = 0.01). An mRS score of 0 was achieved in 18 (46%) and 7 (21%) patients in the H2 and control groups, respectively (P = 0.03). The 90-day survival rate was 85% (33/39) and 61% (20/33) in the H2 and control groups, respectively (P = 0.02). Interpretation: The increase in participants with good neurological outcomes following post-OHCA H2 inhalation in a selected population of patients was not statistically significant. However, the secondary outcomes suggest that H2 inhalation may increase 90-day survival without neurological deficits. Funding: Taiyo Nippon Sanso Corporation. Translation: For the Japanese translation of the abstract see Supplementary Materials section.

Purpose: We examined the effect of a high-target mean arterial pressure (MAP) on septic shock in a previously underrepresented region. Methods: A multicentre, pragmatic, open-label, randomised controlled trial was conducted in 29 hospitals in Japan, where the prevalence of chronic hypertension among older individuals is 66.9%. Patients who were diagnosed with septic shock, aged ≥ 65 years, and admitted to an intensive care unit were randomised 1:1 to the high (target MAP = 80–85 mmHg) or control (target MAP = 65–70 mmHg) groups from 1 July 2021 to 12 December 2023. The target MAP was maintained for 72 h or until vasopressors were no longer required. The primary outcome was the 90-day all-cause mortality. Secondary outcomes included organ support-free days and adverse events. Results: The trial was terminated early on the basis of the interim analysis results, suggesting the harm of the high-target strategy. Of the 518 patients, 258 were in the high-target group, and 260 were in the control group. By 90 days after randomisation, 101 patients (39.3%) in the high-target group and 74 (28.6%) in the control group had died from any cause (risk difference = 10.7; 95% confidence interval, 2.6–18.9). Renal replacement therapy-free days at 28 days were shorter in the high-target group. No clinical benefits for any outcome were observed in any subpopulation, including those with known chronic hypertension. Conclusion: Among older patients with septic shock, high-target MAP significantly increased mortality compared with standard care. Trial registration: UMIN Clinical Trials Registry; UMIN000041775; 13 September 2020.

Background: Angiography has been conducted as a hemostatic procedure for trauma patients. While several complications, such as tissue necrosis after embolization, have been reported, little is known regarding subsequent acute kidney injury (AKI) due to contrast media. To elucidate whether emergency angiography would introduce kidney dysfunction in trauma victims, we compared the incidence of AKI between patients who underwent emergency angiography and those who did not. Methods: A retrospective cohort study was conducted using a nationwide trauma database (2004–2019), and adult trauma patients were included. The indication of emergency angiography was determined by both trauma surgeons and radiologists, and AKI was diagnosed by treating physicians based on a rise in serum creatinine and/or fall in urine output according to any published standard criteria. Incidence of AKI was compared between patients who underwent emergency angiography and those who did not. Propensity score matching was conducted to adjust baseline characteristics including age, comorbidities, mechanism of injury, vital signs on admission, Injury Severity Scale (ISS), degree of traumatic kidney injury, surgical procedures, and surgery on the kidney, such as nephrectomy and nephrorrhaphy. Results: Among 230,776 patients eligible for the study, 14,180 underwent emergency angiography. The abdomen/pelvis was major site for angiography (10,624 [83.5%]). Embolization was performed in 5,541 (43.5%). Propensity score matching selected 12,724 pairs of severely injured patients (median age, 59; median ISS, 25). While the incidence of AKI was rare, it was higher among patients who underwent emergency angiography than in those who did not (140 [1.1%] vs. 67 [0.5%]; odds ratio = 2.10 [1.57–2.82]; p < 0.01). The association between emergency angiography and subsequent AKI was observed regardless of vasopressor usage or injury severity in subgroup analyses. Conclusions: Emergency angiography in trauma patients was probably associated with increased incidence of AKI. The results should be validated in future studies.

Purpose: While follow-up CT and prophylactic embolization with angiography are often conducted during non-operative management (NOM) for BLSI, particularly in a high-grade injury, the utility of early repeated CT for preventing unexpected hemorrhage remains unclear. This study aimed to elucidate whether early follow-up computerized tomography (CT) within 7 days after admission would decrease unexpected hemostatic procedures on pediatric blunt liver and spleen injury (BLSI). Methods: A post-hoc analysis of a multicenter observational cohort study on pediatric patients with BLSI (2008–2019) was conducted on those who underwent NOM, in whom the timing of follow-up CT were decided by treating physicians. The incidence of unexpected hemostatic procedure (laparotomy and/or emergency angiography for ruptured pseudoaneurysm) and complications related to BLSI were compared between patients with and without early follow-up CT within 7 days. Inverse probability weighting with propensity scores adjusted patient demographics, comorbidities, mechanism and severity of injury, initial resuscitation, and institutional characteristics. Results: Among 1320 included patients, 552 underwent early follow-up CT. Approximately 25% of patients underwent angiography on the day of admission. The incidence of unexpected hemostasis was similar between patients with and without early repeat CT (8 [1.4%] vs. 6 [0.8%]; adjusted OR, 1.44 [0.62–3.34]; p = 0.40). Patients with repeat CT scans more frequently underwent multiple angiographies (OR, 2.79 [1.32–5.88]) and had more complications related to BLSI, particularly bile leak (OR, 1.73 [1.04–2.87]). Conclusion: Follow-up CT scans within 7 days was not associated with reduced unexpected hemostasis in NOM for pediatric BLSI.

Study objective: To elucidate the clinical utility of the Clinical Frailty Scale score for predicting poor neurologic functions in patients resuscitated from out-of-hospital cardiac arrest (OHCA). Methods: This was a prospective, multicenter, observational study conducted between 2019 and 2021. The study included adults with nontraumatic OHCA admitted to the intensive care unit after return of spontaneous circulation (ROSC). Pre-arrest high Clinical Frailty Scale score was defined as 5 or more. Favorable neurologic outcomes defined as a Cerebral Performance Category score of 2 or less at 30 days after admission were compared between patients with and without high Clinical Frailty Scale scores. Multivariable logistic regression analyses fitted with generalized estimating equations were performed to adjust for patient characteristics, out-of-hospital information, and resuscitation content and account for within-institution clustering. Results: Of 9,909 patients with OHCA during the study period, 1,216 were included, and 317 had a pre-arrest high Clinical Frailty Scale score. Favorable neurologic outcomes were fewer among patients with high Clinical Frailty Scale scores. The high Clinical Frailty Scale score group showed a lower percentage of favorable neurologic outcomes after OHCA than the low Clinical Frailty Scale score group (6.1% vs 24.4%; adjusted odds ratio, 0.45 [95% confidence interval 0.22 to 0.93]). This relationship remained in subgroups with cardiogenic OHCA, with ROSC after hospital arrival, and without a high risk of dying (Clinical Frailty Scale score of 7 or less), whereas the neurologic outcomes were comparable regardless of pre-arrest frailty in those with noncardiogenic OHCA and with ROSC before hospital arrival. Conclusions: Pre-arrest high Clinical Frailty Scale score was associated with unfavorable neurologic functions among patients resuscitated from OHCA. The Clinical Frailty Scale score would help predict clinical consequences following intensive care after ROSC.

Background: Advances in healthcare and the development of various technologies have improved disease-free longevity. Although the number of healthy centenarians is gradually increasing, studies on postinjury functions among centenarians are lacking. Therefore, we aimed to determine the clinical predictors of mortality and unfavorable functions after injury among centenarians. Method: A retrospective study was conducted using a nationwide trauma database, and data from patients aged ≥ 100 years across ≥ 250 institutions during 2019–2022 were analyzed. Patient demographics, comorbidities, mechanism of injury, injury severity, vital signs on arrival, and pre- and in-hospital treatments were compared between survivors and non-survivors as well as between survivors who had and did not have the ability to live independently at discharge, which was defined as Glasgow Outcome Scale (GCS) score of ≤ 3. Independent predictors of in-hospital mortality and unfavorable functions after injury were examined using a generalized estimating equation model to account for institutional and regional differences in the management and characteristics of centenarians. Results: Of the 409 centenarians, 384 (93.9%) survived to discharge. Although 208 (50.9%) patients had lived independently before the injury, only 91 (22.2%) could live independently at discharge. All patients had blunt injury, and fall from standing was the most frequent (86.6%) mechanism. The injury severity score was 10 ± 5, and surgery/angiography was performed in < 2% of the centenarians, except for fracture fixation in the extremity/pelvis, which was conducted in 225 (55.0%) patients. The adjusted model revealed three independent predictors of in-hospital mortality: male gender, mechanism of injury other than fall from standing, and GCS score on arrival. In contrast, only injury severity in the extremity/pelvis was an independent predictor of unfavorable functions after injury. Conclusion: Male gender, mechanisms of injury other than fall from standing, and GCS on arrival were associated with higher in-hospital mortality. Injury severity in the extremity/pelvis was related to dependent living after injury among centenarians.

Background: Pediatric trauma patients often have disability after successful resuscitation for hemorrhage. Clinical characteristics related to dependency on living following injury were elucidated among pediatric patients without traumatic brain injury. Methods: This retrospective cohort study used the 2019–2021 Japan Trauma Data Bank and included pediatric patients aged ≤16 years without head injury (Abbreviated Injury Scale [AIS] ≥ 2). The unfavorable function was defined as dependency in daily life at discharge (Glasgow Outcome Scale ≤ 3), and predictors for unfavorable functional outcomes were examined using a generalized estimating equations (GEE) model, including age, sex, physical disability before injury, injury mechanism, transportation time, prehospital procedures, vital signs on arrival, surgery in each body region, transfusion, AIS in each region, and institutions. Furthermore, these factors were analyzed separately in toddler/preschool (≤5 years), school age (6–11 years), and adolescence (12–16 years). Results: Among 1,412 patients eligible for the study, 137 had an unfavorable physical function at discharge. The GEE model revealed that female sex, physical disability before injury, prehospital transfusion, lower Glasgow Coma Score (GCS) score on arrival, neck surgery, and higher AIS in the neck and extremity/pelvis were independently associated with unfavorable function at discharge. In age-specific analyses, physical disability before injury strongly predicted worse functional outcomes in toddlers/preschoolers, whereas higher AIS in the chest and lower systolic blood pressure on arrival were additional predictors of dependent living among adolescents. Conclusions: Severe neck/extremity/pelvis injury and lower GCS on arrival are associated with unfavorable functional outcomes in patients with pediatric trauma.

Background: Fungal infections are significant complications of severe coronavirus disease 2019 (COVID-19). Although various risk factors for poor outcomes in patients with COVID-19 have been identified, clinical and treatment factors associated with fungal infections in patients with severe COVID-19 remain unclear. This study aimed to elucidate clinical factors associated with fungal infections during severe COVID-19 treatment. Methods: This was a post hoc analysis of the J-RECOVER study, a multicenter retrospective observational study involving patients with COVID-19 who required admission at 66 hospitals between January and September 2020. Inclusion criteria were ages ≥ 18 years, COVID-19 diagnosis with reverse-transcription polymerase chain reaction, and treatment with mechanical ventilation (MV). Patients who received antifungal drugs before MV were excluded. Potential predictors were identified through univariate analysis of patient and treatment characteristics between patients with- and those without fungal infection, which was defined as antifungal agent use for ≥ 5 days. To account for facility-specific data clustering, generalized estimating equations (GEE) were employed as adjusted analyses to calculate the relative risks of potentially associated factors. Two sensitivity analyses were performed with modified definitions for the two groups: patients who received antifungal drugs for ≤ 4 days were excluded, and fungal infection was re-defined as antifungal drug use for ≥ 14 days. Results: Among 4,915 patients in the J-RECOVER study, 559 adults with COVID-19 who required MV were included. Fungal infections occurred in 57 (10.2%) patients. Univariate analyses identified age, age ≥ 65 years, D-dimer level, remdesivir use, steroid use, and duration of steroid therapy as potential predictors of fungal infections. Multivariate analysis using GEE on these six factors revealed that only the duration of steroid use was significantly associated with an increased risk of fungal infection (odds ratio [OR] for a day increase: 1.01; 95% confidence interval [CI]: 1.00–1.01; p < 0.001). The two sensitivity analyses similarly showed that the duration of steroid use was associated with fungal infection (odds ratio for a day increase: 1.01; 95% CI: 1.00–1.01; p < 0.001 for both). Conclusions: In patients with severe COVID-19 requiring MV, each additional day of steroid use was associated with prolonged use of antifungal medications for ≥ 5 days.

Background: A health-economic evaluation related to COVID-19 is urgently needed to allocate healthcare resources efficiently; however, relevant medical cost data in Japan concerning COVID-19 are scarce. Methods: This cross-sectional study investigated the healthcare cost for hospitalized COVID-19 patients in 2021 at Keio University Hospital. We calculated the healthcare costs during hospitalization using hospital claims data and investigated the variables significantly related to the healthcare cost with multivariable analysis. Results: The median healthcare cost per patient for the analyzed 330 patients was Japanese yen (JPY) 1,304,431 (US dollars ~ 11,871) (interquartile range: JPY 968,349–1,954,093), and the median length of stay was 10 days. The median healthcare cost was JPY 798,810 for mild cases; JPY 1,113,680 for moderate I cases; JPY 1,643,909 for moderate II cases; and JPY 6,210,607 for severe cases. Healthcare costs increased by 4.0% for each additional day of hospitalization; 1.26 times for moderate I cases, 1.64 times for moderate II cases, and 1.84 times for severe cases compared to mild cases; and 2.05 times for cases involving ICU stay compared to those not staying in ICU. Conclusions: We clarified the healthcare cost for hospitalized COVID-19 patients by severity in a Japanese university hospital. These costs contribute as inputs for forthcoming health economic evaluations for strategies for preventing and treating COVID-19.

Background The updated Surviving Sepsis Campaign guidelines recommend a 1-hour window for completion of a sepsis care bundle; however, the effectiveness of the hour-1 bundle has not been fully evaluated. The present study aimed to evaluate the impact of hour-1 bundle completion on clinical outcomes in sepsis patients. Methods This was a multicenter, prospective, observational study conducted in 17 intensive care units in tertiary hospitals in Japan. We included all adult patients who were diagnosed as having sepsis by Sepsis-3 and admitted to intensive care units from July 2019 to August 2020. Impacts of hour-1 bundle adherence and delay of adherence on risk-adjusted in-hospital mortality were estimated by multivariable logistic regression analyses. Results The final study cohort included 178 patients with sepsis. Among them, 89 received bundle-adherent care. Completion rates of each component (measure lactate level, obtain blood cultures, administer broad-spectrum antibiotics, administer crystalloid, apply vasopressors) within 1 hour were 98.9%, 86.2%, 51.1%, 94.9%, and 69.1%, respectively. Completion rate of all components within 1 hour was 50%. In-hospital mortality was 18.0% in the patients with and 30.3% in the patients without bundle-adherent care (p = 0.054). The adjusted odds ratio of non-bundle-adherent versus bundle-adherent care for in-hospital mortality was 2.32 (95% CI 1.09–4.95) using propensity scoring. Non-adherence to obtaining blood cultures and administering broad-spectrum antibiotics within 1 hour was related to in-hospital mortality (2.65 [95% CI 1.25–5.62] and 4.81 [95% CI 1.38–16.72], respectively). The adjusted odds ratio for 1-hour delay in achieving hour-1 bundle components for in-hospital mortality was 1.28 (95% CI 1.04–1.57) by logistic regression analysis. Conclusion Completion of the hour-1 bundle was associated with lower in-hospital mortality. Obtaining blood cultures and administering antibiotics within 1 hour may have been the components most contributing to decreased in-hospital mortality.

Background: Despite the benefits of extracorporeal cardiopulmonary resuscitation (ECPR) in cohorts of selected patients with cardiac arrest (CA), extracorporeal membrane oxygenation (ECMO) includes an artificial oxygenation membrane and circuits that contact the circulating blood and induce excessive oxidative stress and inflammatory responses, resulting in coagulopathy and endothelial cell damage. There is currently no pharmacological treatment that has been proven to improve outcomes after CA/ECPR. We aimed to test the hypothesis that administration of hydrogen gas (H2) combined with ECPR could improve outcomes after CA/ECPR in rats. Methods: Rats were subjected to 20 min of asphyxial CA and were resuscitated by ECPR. Mechanical ventilation (MV) was initiated at the beginning of ECPR. Animals were randomly assigned to the placebo or H2 gas treatment groups. The supplement gas was administered with O2 through the ECMO membrane and MV. Survival time, electroencephalography (EEG), brain functional status, and brain tissue oxygenation were measured. Changes in the plasma levels of syndecan-1 (a marker of endothelial damage), multiple cytokines, chemokines, and metabolites were also evaluated. Results: The survival rate at 4 h was 77.8% (7 out of 9) in the H2 group and 22.2% (2 out of 9) in the placebo group. The Kaplan–Meier analysis showed that H2 significantly improved the 4 h-survival endpoint (log-rank P = 0.025 vs. placebo). All animals treated with H2 regained EEG activity, whereas no recovery was observed in animals treated with placebo. H2 therapy markedly improved intra-resuscitation brain tissue oxygenation and prevented an increase in central venous pressure after ECPR. H2 attenuated an increase in syndecan-1 levels and enhanced an increase in interleukin-10, vascular endothelial growth factor, and leptin levels after ECPR. Metabolomics analysis identified significant changes at 2 h after CA/ECPR between the two groups, particularly in d-glutamine and d-glutamate metabolism. Conclusions: H2 therapy improved mortality in highly lethal CA rats rescued by ECPR and helped recover brain electrical activity. The underlying mechanism might be linked to protective effects against endothelial damage. Further studies are warranted to elucidate the mechanisms responsible for the beneficial effects of H2 on ischemia–reperfusion injury in critically ill patients who require ECMO support.

Background: The use of resuscitative endovascular balloon occlusion of the aorta (REBOA) for hemorrhagic shock in the torso has become increasingly common as a bridge to definitive hemostasis. Hydrogen molecules, distributed throughout the bloodstream, alleviate ischemic injury but cannot reach ischemic organs during REBOA use. This study investigates whether intra-aortic irrigation with hydrogen-dissolved saline under REBOA use delivers hydrogen to the intestine in a swine hemorrhagic shock model. Methods: We induced volume-regulated hemorrhagic shock in a 40 kg female swine. Following this, hydrogen-dissolved saline irrigation was initiated through an intra-aortic catheter positioned distal to the REBOA balloon. Hydrogen concentration in the portal vein was determined in four models: controlled hemorrhagic shock with full REBOA inflation during the standard occlusion time, uncontrolled hemorrhagic shock with liver injury and full REBOA inflation during the extended occlusion time, uncontrolled hemorrhagic shock with liver injury and partial REBOA inflation during the extended occlusion time, and as the control model, controlled hemorrhagic shock with full REBOA inflation during the standard occlusion time with normal saline irrigation without hydrogen. Results: Hydrogen concentration in the portal vein was found to be 0.224 mg/L (13.998%) in the controlled hemorrhagic shock model with full REBOA inflation, 0.049 mg/L (3.063%) in the uncontrolled hemorrhagic shock model with liver injury and full REBOA inflation, 0.018 mg/L (1.125%) in the uncontrolled hemorrhagic shock model with liver injury and partial REBOA inflation, and 0.002 mg/L (0.015%) in the control model. These results demonstrate the presence of hydrogen in the portal vein under different REBOA applications. Conclusions: Increased hydrogen concentration in the portal vein indicated that hydrogen was delivered to the intestine. These findings suggest an approach for drug administration during REBOA use. However, further investigations are required to establish its application in clinical settings.

Background: Information on hyperoxemia among patients with trauma has been limited, other than traumatic brain injuries. This study aimed to elucidate whether hyperoxemia during resuscitation of patients with trauma was associated with unfavorable outcomes. Methods: A post hoc analysis of a prospective observational study was carried out at 39 tertiary hospitals in 2016–2018 in adult patients with trauma and injury severity score (ISS) of > 15. Hyperoxemia during resuscitation was defined as PaO2 of ≥ 300 mmHg on hospital arrival and/or 3 h after arrival. Intensive care unit (ICU)-free days were compared between patients with and without hyperoxemia. An inverse probability of treatment weighting (IPW) analysis was conducted to adjust patient characteristics including age, injury mechanism, comorbidities, vital signs on presentation, chest injury severity, and ISS. Analyses were stratified with intubation status at the emergency department (ED). The association between biomarkers and ICU length of stay were then analyzed with multivariate models. Results: Among 295 severely injured trauma patients registered, 240 were eligible for analysis. Patients in the hyperoxemia group (n = 58) had shorter ICU-free days than those in the non-hyperoxemia group [17 (10–21) vs 23 (16–26), p < 0.001]. IPW analysis revealed the association between hyperoxemia and prolonged ICU stay among patients not intubated at the ED [ICU-free days = 16 (12–22) vs 23 (19–26), p = 0.004], but not among those intubated at the ED [18 (9–20) vs 15 (8–23), p = 0.777]. In the hyperoxemia group, high inflammatory markers such as soluble RAGE and HMGB-1, as well as low lung-protective proteins such as surfactant protein D and Clara cell secretory protein, were associated with prolonged ICU stay. Conclusions: Hyperoxemia until 3 h after hospital arrival was associated with prolonged ICU stay among severely injured trauma patients not intubated at the ED. Trial registration: UMIN-CTR, UMIN000019588. Registered on November 15, 2015.

Background: Supraphysiologic oxygen administration causes unfavorable clinical outcomes in various diseases, including traumatic brain injury, post–cardiac arrest syndrome, and acute lung injury. Accidental hypothermia is a critical illness that reduces oxygen demands, and excessive oxygen is likely to emerge. This study aimed to determine whether hyperoxia would be associated with increased mortality in patients with accidental hypothermia. Methods: A post-hoc analysis of a nationwide multicenter prospective observational study (ICE-CRASH study) on patients with accidental hypothermia admitted in 2019–2022 was conducted. Adult patients without cardiac arrest whose core body temperature was < 32 °C and whose arterial partial pressure of oxygen (PaO2) was measured at the emergency department were included. Hyperoxia was defined as a PaO2 level of 300 mmHg or higher, and 28-day mortality was compared between patients with and without hyperoxia before rewarming. Inverse probability weighting (IPW) analyses with propensity scores were performed to adjust patient demographics, comorbidities, etiology and severity of hypothermia, hemodynamic status and laboratories on arrival, and institution characteristics. Subgroup analyses were conducted according to age, chronic cardiopulmonary diseases, hemodynamic instability, and severity of hypothermia. Results: Of the 338 patients who were eligible for the study, 65 had hyperoxia before rewarming. Patients with hyperoxia had a higher 28-day mortality rate than those without (25 (39.1%) vs. 51 (19.5%); odds ratio (OR) 2.65 (95% confidence interval 1.47–4.78); p < 0.001). IPW analyses with propensity scores revealed similar results (adjusted OR 1.65 (1.14–2.38); p = 0.008). Subgroup analyses showed that hyperoxia was harmful in the elderly and those with cardiopulmonary diseases and severe hypothermia below 28 °C, whereas hyperoxia exposure had no effect on mortality in patients with hemodynamic instability on hospital arrival. Conclusions: Hyperoxia with PaO2 levels of 300 mmHg or higher before initiating rewarming was associated with increased 28-day mortality in patients with accidental hypothermia. The amount of oxygen to administer to patients with accidental hypothermia should be carefully determined. Trial Registration: The ICE-CRASH study was registered at the University Hospital Medical Information Network Clinical Trial Registry on April 1, 2019 (UMIN-CTR ID, UMIN000036132).

Background Supraphysiological oxygen administration causes unfavourable clinical outcomes in various diseases. This study aimed to determine whether hyperoxia would be associated with increased mortality in patients with severe infection. Methods A post-hoc analysis of a nationwide multicentre prospective observational study on sepsis (SPICE Study) was conducted, including adult patients admitted to the intensive care unit with available arterial partial pressure of oxygen (PaO2) at the treatment initiation for severe infection. Hyperoxia was defined as a PaO2 level of ≥300 mm Hg and in-hospital mortality was compared between patients with and without hyperoxia. Results Of the 563 patients eligible for the study, 49 had hyperoxia at treatment initiation for severe infection. The in-hospital all-cause mortality rates of patients with and without hyperoxia were 14 (29.2%) and 90 (17.6%), respectively. Inverse probability weighting analyses with propensity scores revealed the association between hyperoxia and increased in-hospital mortality rate (28.8% vs 18.8%; adjusted OR 1.75 (1.03 to 2.97); p=0.038), adjusting for patient demographics, comorbidities, site of infection, severity of infection, haemodynamic and respiratory status, laboratory data and location of patient at infection development. Acute lung injury developed more frequently in patients with hyperoxia on the following days after infection treatment, whereas sepsis-related mortality was comparable regardless of hyperoxia exposure. Conclusion Hyperoxia with PaO2 ≥300 mm Hg at treatment initiation of severe infection was associated with an increased in-hospital mortality rate in patients requiring intensive care. The amount of oxygen to administer to patients with severe infection should be carefully determined.

Introduction: Post-contrast acute kidney injury (PC-AKI) is a major complication of contrast media usage; risks for PC-AKI are generally evaluated before computed tomography (CT) with contrast at the emergency department (ED). Although persistent hypotension (systolic blood pressure [sBP] <80 mm Hg for 1 h) is associated with increased PC-AKI incidence, it remains unclear whether transient hypotension that is haemodynamically stabilized before CT is a risk of PC-AKI. We hypothesized that hypotension on ED arrival would be associated with higher PC-AKI incidence even if CT with contrast was performed after patients are appropriately resuscitated. Methods: This multicentre retrospective observational study was conducted at three tertiary care centres during 2013-2014. We identified 280 patients who underwent CT with contrast at the ED. Patients were classified into two groups based on sBP on arrival (<80 vs. ≥80 mm Hg); hypotension was considered as transient because CT with contrast has always been performed after patients were stabilized at participating hospitals. PC-AKI incidence was compared between the groups; inverse probability weighting (IPW) was conducted to adjust background characteristics. Results: Eighteen patients were excluded due to chronic haemodialysis, cardiac arrest on arrival, or death within 72 h; 262 were eligible for this study. PC-AKI incidence was higher in the transient hypotension group than the normotension group {7/27 (28.6%) vs. 24/235 (10.2%), odds ratio (OR) 3.08 (95% confidence interval [CI] 1.18-8.03), p = 0.026}, which was confirmed by IPW (OR 3.25 [95% CI 1.99-5.29], p < 0.001). Conclusion: Transient hypotension at the ED was associated with PC-AKI development.