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Background: Mounting evidence indicates that hydrogen gas (H2) is a versatile therapeutic agent, even at very low, non-combustible concentrations. The Chinese National Health and Medical Commission recently recommended the use of inhaled H2 in addition to O2 therapy in the treatment of COVID-19-associated pneumonia, and its effects extend to anti-tumor, anti-inflammatory and antioxidant actions. Summary: In this review, we highlight key findings from preclinical researchn this review, we have highlighted key findings from preclinical research and recent clinical studies demonstrating that H2 reduces the organ damage caused by ischemia-reperfusion. We have also outlined the critical role this effect plays in a variety of medical emergencies, including myocardial infarction, hemorrhagic shock, and out-of-hospital cardiac arrest, as well as in organ transplantation. H2 is compared with established treatments such as targeted temperature management, and we have also discussed its possible mechanisms of action, including the recently identified suppression of TNF-α-mediated endothelial glycocalyx degradation by inhaled H2. In addition, our new method that enables H2 gas to be easily transported to emergency settings and quickly injected into an organ preservation solution at the site of donor organ procurement have been described. and recent clinical studies demonstrating that H2 reduces the organ damage caused by ischemia–reperfusion. We outline the critical role this effect plays in a variety of medical emergencies, including myocardial infarction, hemorrhagic shock, and out-of-hospital cardiac arrest, as well as in organ transplantation. H2 is compared with established treatments such as targeted temperature management, and we discuss its possible mechanisms of action, including the recently identified suppression of TNF-α-mediated endothelial glycocalyx degradation by inhaled H2 . In addition, we describe our new method that enables H2 gas to be easily transported to emergency settings and quickly injected into an organ preservation solution at the site of donor organ procurement. Conclusion: H2 is an easily administered, inexpensive and well-tolerated agent that is highly effective for a wide range of conditions in emergency medicine, as well as for preserving donated organs.

BACKGROUND: Pro-inflammatory fibroblasts are critical for pathogenesis in rheumatoid arthritis, inflammatory bowel disease, interstitial lung disease, and Sjögren’s syndrome and represent a novel therapeutic target for chronic inflammatory disease. However, the heterogeneity of fibroblast phenotypes, exacerbated by the lack of a common cross-tissue taxonomy, has limited our understanding of which pathways are shared by multiple diseases. METHODS: We profiled fibroblasts derived from inflamed and non-inflamed synovium, intestine, lungs, and salivary glands from affected individuals with single-cell RNA sequencing. We integrated all fibroblasts into a multi-tissue atlas to characterize shared and tissue-specific phenotypes. FINDINGS: Two shared clusters, CXCL10(+)CCL19(+) immune-interacting and SPARC(+)COL3A1(+) vascular-interacting fibroblasts, were expanded in all inflamed tissues and mapped to dermal analogs in a public atopic dermatitis atlas. We confirmed these human pro-inflammatory fibroblasts in animal models of lung, joint, and intestinal inflammation. CONCLUSIONS: This work represents a thorough investigation into fibroblasts across organ systems, individual donors, and disease states that reveals shared pathogenic activation states across four chronic inflammatory diseases. FUNDING: Grant from F. Hoffmann-La Roche (Roche) AG.

Supplemental Digital Content is available in the text, Background: Hydrogen gas (H2) inhalation during hemorrhage stabilizes post-resuscitation hemodynamics, improving short-term survival in a rat hemorrhagic shock and resuscitation (HS/R) model. However, the underlying molecular mechanism of H2 in HS/R is unclear. Endothelial glycocalyx (EG) damage causes hemodynamic failure associated with HS/R. In this study, we tested the hypothesis that H2 alleviates oxidative stress by suppressing xanthine oxidoreductase (XOR) and/or preventing tumor necrosis factor-alfa (TNF-α)-mediated syndecan-1 shedding during EG damage. Methods: HS/R was induced in rats by reducing mean arterial pressure (MAP) to 35 mm Hg for 60 min followed by resuscitation. Rats inhaled oxygen or H2 + oxygen after achieving shock either in the presence or absence of an XOR inhibitor (XOR-I) for both the groups. In a second test, rats received oxygen alone or antitumor necrosis factor (TNF)-α monoclonal antibody with oxygen or H2. Two hours after resuscitation, XOR activity, purine metabolites, cytokines, syndecan-1 were measured and survival rates were assessed 6 h after resuscitation. Results: H2 and XOR-I both suppressed MAP reduction and improved survival rates. H2 did not affect XOR activity and the therapeutic effects of XOR-I and H2 were additive. H2 suppressed plasma TNF-α and syndecan-1 expression; however, no additional H2 therapeutic effect was observed in the presence of anti-TNF-α monoclonal antibody. Conclusions: H2 inhalation after shock stabilized hemodynamics and improved survival rates in an HS/R model independent of XOR. The therapeutic action of H2 was partially mediated by inhibition of TNF-α-dependent syndecan-1 shedding.

Background Outcome prediction for patients with out-of-hospital cardiac arrest (OHCA) has the possibility to detect patients who could have been potentially saved. Advanced machine learning techniques have recently been developed and employed for clinical studies. In this study, we aimed to establish a prognostication model for OHCA with presumed cardiac aetiology using an advanced machine learning technique. Methods and Results Cohort data from a prospective multi-centre cohort study for OHCA patients transported by an ambulance in the Kanto area of Japan between January 2012 and March 2013 (SOS-KANTO 2012 study) were analysed in this study. Of 16,452 patients, data for OHCA patients aged ≥18 years with presumed cardiac aetiology were retrieved, and were divided into two groups (training set: n = 5718, between January 1, 2012 and December 12, 2012; test set: n = 1608, between January 1, 2013 and March 31, 2013). Of 421 variables observed during prehospital and emergency department settings, 35 prehospital variables, or 35 prehospital and 18 in-hospital variables, were used for outcome prediction of 1-year survival using a random forest method. In validation using the test set, prognostication models trained with 35 variables, or 53 variables for 1-year survival showed area under the receiver operating characteristics curve (AUC) values of 0.943 (95% CI [0.930, 0.955]) and 0.958 (95% CI [0.948, 0.969]), respectively. Conclusions The advanced machine learning technique showed favourable prediction capability for 1-year survival of OHCA with presumed cardiac aetiology. These models can be useful for detecting patients who could have been potentially saved.

Summary This protocol aids both new and experienced researchers in designing retrospective clinical and translational studies of acute respiratory decline in hospitalized patients. This protocol addresses (1) the basics of respiratory failure and electronic health record research, (2) defining patient cohorts as “mild, progressive, or severe” instead of “ICU versus non-ICU”, (3) adapting physiological indices, and (4) using biomarker trends. We apply these approaches to inflammatory biomarkers in COVID-19, but this protocol can be applied to any progressive respiratory failure study. For complete details on the use and execution of this protocol, please refer to Mueller et al. (2020)., Graphical abstract, Highlights • Basics of hypoxemic respiratory failure and electronic health records research • Design of patient cohorts that discriminate progressive respiratory failure • Physiological measurements of respiratory failure (P/F, ROX index) • Use of inflammatory biomarker trends to predict respiratory decline, This protocol aids both new and experienced researchers in designing retrospective clinical and translational studies of acute respiratory decline in hospitalized patients. This protocol addresses (1) the basics of respiratory failure and electronic health record research, (2) defining patient cohorts as “mild, progressive, or severe” instead of “ICU versus non-ICU”, (3) adapting physiological indices, and (4) using biomarker trends. We apply these approaches to inflammatory biomarkers in COVID-19, but this protocol can be applied to any progressive respiratory failure study.

A recent clinical study demonstrated that haemodialysis with a dialysate containing hydrogen (H2) improves blood pressure control in end-stage kidney disease. Herein, we examined whether H2 has a salutary effect on hypertension in animal models. We subjected 5/6 nephrectomised rats to inhalation of either H2 (1.3% H2 + 21% O2 + 77.7% N2) or control (21% O2 + 79% N2) gas mixture for 1 h per day. H2 significantly suppressed increases in blood pressure after 5/6 nephrectomy. The anti-hypertensive effect of H2 was also confirmed in rats in a stable hypertensive state 3 weeks after nephrectomy. To examine the detailed effects of H2 on hypertension, we used an implanted telemetry system to continuously monitor blood pressure. H2 exerted an anti-hypertensive effect not only during daytime rest, but also during night-time activities. Spectral analysis of blood pressure variability revealed that H2 improved autonomic imbalance, namely by suppressing the overly active sympathetic nervous system and augmenting parasympathetic nervous system activity; these effects co-occurred with the blood pressure-lowering effect. In conclusion, 1-h daily exposure to H2 exerts an anti-hypertensive effect in an animal model of hypertension.

Purpose: To modify a surgical catheterization method using the bent needle introducer in small animals. Methods: Eight-week-old male Lewis rats were used in the study. A needle introducer was created by bending a 21G injection needle at 45°. The bent needle introducer was used for catheter insertion into the left femoral artery of the rats under anesthesia. As a control, a catheter was directly inserted into the blood vessel without the introducer. The insertion time of each method was measured. Blood pressure and heart rate were measured 24 h after catheter insertion using the telemetry system. Results: Using the introducer, the catheter was successfully inserted within a short time in all rats. Without the introducer, a longer duration was required for catheter insertion. The frequency of the insertion with no catheter-based errors with the introducer tended to be higher than that without the introducer. The mean arterial pressure and heart rate 24 h after catheter insertion in each group were almost the same. Conclusions: We developed a surgical catheterization method using the introducer in small animals. This could potentially reduce the frequency of the insertion with catheter-based errors and insertion time.

In this single-center, retrospective cohort analysis of hospitalized coronavirus disease 2019 (COVID-19) patients, we investigate whether inflammatory biomarker levels predict respiratory decline in patients who initially present with stable disease. Examination of C-reactive protein (CRP) trends reveals that a rapid rise in CRP levels precedes respiratory deterioration and intubation, although CRP levels plateau in patients who remain stable. Increasing CRP during the first 48 h of hospitalization is a better predictor (with higher sensitivity) of respiratory decline than initial CRP levels or ROX indices (a physiological score of respiratory function). CRP, the proinflammatory cytokine interleukin-6 (IL-6), and physiological measures of hypoxemic respiratory failure are correlated, which suggests a mechanistic link. Our work shows that rising CRP predicts subsequent respiratory deterioration in COVID-19 and may suggest mechanistic insight and a potential role for targeted immunomodulation in a subset of patients early during hospitalization., Graphical Abstract, Highlights Rising CRP levels predict intubation in COVID-19 inpatients stable at admission Early CRP trend outperforms initial CRP level in prediction of respiratory failure CRP trend outperforms a physiological index (ROX) in prediction of respiratory failure CRP and IL-6 levels correlate with each other and with hypoxemia (PaO2/FiO2), Mueller et al. demonstrate in hospitalized COVID-19 patients that trending C-reactive protein (CRP), an inflammatory biomarker, is a simple and accessible strategy for predicting respiratory deterioration. An early rise in CRP predicts intubation, and CRP levels correlate with IL-6 levels and physiological measures of hypoxemic respiratory failure.

As treatment of the early, inflammatory phase of sepsis improves, post-sepsis immunosuppression and secondary infection have increased in importance. How early inflammation drives immunosuppression remains unclear. Although IFN-γ typically helps microbial clearance, we found that increased plasma IFN-γ in early clinical sepsis was associated with the later development of secondary Candida infection. Consistent with this observation, we found that exogenous IFN-γ suppressed macrophage phagocytosis of zymosan in vivo, and antibody blockade of IFN-γ after endotoxemia improved survival of secondary candidemia. Transcriptomic analysis of innate lymphocytes during endotoxemia suggested that NKT cells drove IFN-γ production by NK cells via mTORC1. Activation of invariant NKT (iNKT) cells with glycolipid antigen drove immunosuppression. Deletion of iNKT cells in Cd1d(–/–) mice or inhibition of mTOR by rapamycin reduced immunosuppression and susceptibility to secondary Candida infection. Thus, although rapamycin is typically an immunosuppressive medication, in the context of sepsis, rapamycin has the opposite effect. These results implicated an NKT cell/mTOR/IFN-γ axis in immunosuppression following endotoxemia or sepsis. In summary, in vivo iNKT cells activated mTORC1 in NK cells to produce IFN-γ, which worsened macrophage phagocytosis, clearance of secondary Candida infection, and mortality.

The benefits of inhaling hydrogen gas (H2) have been widely reported but its pharmacokinetics have not yet been sufficiently analyzed. We developed a new experimental system in pigs to closely evaluate the process by which H2 is absorbed in the lungs, enters the bloodstream, and is distributed, metabolized, and excreted. We inserted and secured catheters into the carotid artery (CA), portal vein (PV), and supra-hepatic inferior vena cava (IVC) to allow repeated blood sampling and performed bilateral thoracotomy to collapse the lungs. Then, using a hydrogen-absorbing alloy canister, we filled the lungs to the maximum inspiratory level with 100% H2. The pig was maintained for 30 seconds without resuming breathing, as if they were holding their breath. We collected blood from the three intravascular catheters after 0, 3, 10, 30, and 60 minutes and measured H2 concentration by gas chromatography. H2 concentration in the CA peaked immediately after breath holding; 3 min later, it dropped to 1/40 of the peak value. Peak H2 concentrations in the PV and IVC were 40% and 14% of that in the CA, respectively. However, H2 concentration decay in the PV and IVC (half-life: 310 s and 350 s, respectively) was slower than in the CA (half-life: 92 s). At 10 min, H2 concentration was significantly higher in venous blood than in arterial blood. At 60 min, H2 was detected in the portal blood at a concentration of 6.9-53 nL/mL higher than at steady state, and in the SVC 14-29 nL/mL higher than at steady state. In contrast, H2 concentration in the CA decreased to steady state levels. This is the first report showing that inhaled H2 is transported to the whole body by advection diffusion and metabolized dynamically.

We aimed to determine the characteristics of quantitative pupillary response parameters other than amplitude of pupillary light reflex (PLR) early after return of spontaneous circulation (ROSC) and their implications for predicting neurological outcomes early after cardiac arrest (CA). Fifty adults resuscitated after non-traumatic out-of-hospital CA from four emergency hospitals were enrolled. Pupil diameters, PLR, constriction velocity (CV), maximum CV (MCV), dilation velocity (DV), latency of constriction, and Neurological Pupil index (NPi) were quantitatively measured at 0, 6, 12, 24, 48, and 72 h post-ROSC using an automated pupillometer. Change over time of each parameter was compared between favorable (Cerebral Performance Category [CPC] 1 or 2) and unfavorable neurological outcome (CPC 3–5) groups. Prognostic values of 90-day favorable outcome by these parameters and when combined with clinical predictors (witness status, bystander cardiopulmonary resuscitation, initial shockable rhythm, implementation of target temperature management) were tested. Thirteen patients achieved favorable outcome. CV, MCV, DV (P < 0.001), and NPi (P = 0.005) were consistently greater in the favorable group than in the unfavorable outcome group. Change over time was not statistically different between the groups in all parameters. CV, MCV, DV (ρ = 0.96 to 0.97, P < 0.001, respectively), and NPi (ρ = 0.65, P < 0.001) positively correlated with PLR. The prognostic value of 0-hour CV (area under the curve, AUC [95% confidence interval]: 0.92 [0.80–1.00]), DV (0.84 [0.68–0.99]), and NPi (0.88 [0.74–1.00]) was equivalent to that of PLR (0.84 [0.69–0.98]). Prognostic values improved to AUC of 0.95–0.96 when 0-hour PLR, CV, DV, or NPi was combined with clinical predictors. The 0-hour CV, MCV, and NPi showed equivalent prognostic values to PLR alone/in combination with clinical predictors. Using PLR among several quantitative pupillary response parameters for early neurological prognostication of post-CA patients is a simple and effective strategy.

During the course of hospitalization, it is often unclear which COVID-19 patients will progress from non-critical to critical illness. Predicting disease trajectory is crucial for resource allocation and therapeutic intervention. In our single-center retrospective cohort analysis of the first 66 patients admitted for COVID-19 infection, we examined biomarkers of inflammation to distinguish non-critically ill inpatients who remained stable from those that had progressive respiratory failure requiring intubation and ICU transfer. Unlike the typical approach where patients are grouped into the two categories of non-critical and critical illness, COVID-19 patients in our study were classified into three cohorts by severity and stability of respiratory failure: stable non-critical illness (“mild”, 38 [58%]); non-critical illness at admission that progressed to critical illness (“progressive”, 21 [32%]); and critical illness at admission (“severe”, 7 [11%]). We found that while CRP level at admission was weakly associated with future progressive respiratory failure and appeared to have limited clinical utility. The progressive cohort showed modestly increased levels of CRP compared to the mild cohort, with significant overlap (125.0 ± 74 vs. 81.3 ± 57 mg/L, P = 0.05). Despite the limited predictive value of admission CRP levels, these measurements were indeed clinically relevant as they correlated with SOFA score (ρ = 0.41, P < 0.001) and hypoxemic respiratory failure (PaO2/FiO2, r = -0.58, P < 0.001). A closer examination of CRP trend showed that dynamic trend of CRP levels within the first 72 hours of admission rather than the static CRP level at admission showed a much stronger association with respiratory deterioration. Specifically, rise in CRP levels most clearly distinguished mild and progressive cohorts (24-48h post-admission: 170.6 ± 95 vs. 91.0 ± 67 mg/L, P = 0.03; 48-72h post-admission: 185.0 ± 92 vs. 81.6 ± 63 mg/L, P = 0.002). Trends of inflammatory biomarkers, rather than absolute value at admission, may have most value for clinical triage and targeting therapeutic immunomodulation. Further, COVID-19 patients that are aggregated as “critically ill” in cross-sectional studies could represent two distinct inflammatory biomarker profiles and clinical presentations ( i.e., progressive versus severe cohorts). Funding: This work was supported by the American Heart Association Award 2014D007100 (E.Y.K.) and NIAMS T32 AR007530-35 (A.A.M.). Conflict of Interest: The authors declare no competing interests. Ethical Approval: This investigation was approved by the Partners Healthcare Institutional Review Board (Protocol 2014D007100). Opt-out consent was designated for the study.

BACKGROUND Renal dysfunction is associated with increased cardiovascular-related mortality, but its impact on outcome of out-of-hospital cardiac arrest (OHCA) remains unclear. We assessed whether post-OHCA outcome correlated with renal function early after OHCA. Methods and Results: Of the 16,452 registered patients in the SOS-KANTO 2012 Study, 5,112 cardiogenic OHCA adults with creatinine measurement (mean age, 72 years; male, 64%) were examined. First-obtained creatinine was used to assess eGFR. Associations between eGFR groups, ≥60 (n=997), 45-59 (n=1,311), 30-44 (n=1,441), and

It has been reported that hydrogen gas exerts a therapeutic effect in a wide range of disease conditions, from acute illness such as ischemia-reperfusion injury, shock, and damage healing to chronic illness such as metabolic syndrome, rheumatoid arthritis, and neurodegenerative diseases. Antioxidant and anti-inflammatory properties of hydrogen gas have been proposed, but the molecular target of hydrogen gas has not been identified. We established the Center for Molecular Hydrogen Medicine to promote non-clinical and clinical research on the medical use of hydrogen gas through industry-university collaboration and to obtain regulatory approval of hydrogen gas and hydrogen medical devices (http://www.karc.keio.ac.jp/center/center-55.html). Studies undertaken by the Center have suggested possible therapeutic effects of hydrogen gas in relation to various aspects of emergency and critical care medicine, including acute myocardial infarction, cardiopulmonary arrest syndrome, contrast-induced acute kidney injury, and hemorrhagic shock.

Mortality of hemorrhagic shock primarily depends on whether or not the patients can endure the loss of circulating volume until radical treatment is applied. We investigated whether hydrogen (H2) gas inhalation would influence the tolerance to hemorrhagic shock and improve survival.Hemorrhagic shock was achieved by withdrawing blood until the mean arterial blood pressure reached 30-35 mm Hg. After 60 minutes of shock, the rats were resuscitated with a volume of normal saline equal to four times the volume of shed blood. The rats were assigned to either the H2 gas (1.3% H2, 26% O2, 72.7% N2)-treated group or the control gas (26% O2, 74% N2)-treated group. Inhalation of the specified gas mixture began at the initiation of blood withdrawal and continued for 2 hours after fluid resuscitation.The survival rate at 6 hours after fluid resuscitation was 80% in H2 gas-treated rats and 30% in control gas-treated rats (p0.05). The volume of blood that was removed through a catheter to induce shock was significantly larger in the H2 gas-treated rats than in the control rats. Despite losing more blood, the increase in serum potassium levels was suppressed in the H2 gas-treated rats after 60 minutes of shock. Fluid resuscitation completely restored blood pressure in the H2 gas-treated rats, whereas it failed to fully restore the blood pressure in the control gas-treated rats. At 2 hours after fluid resuscitation, blood pressure remained in the normal range and metabolic acidosis was well compensated in the H2 gas-treated rats, whereas we observed decreased blood pressure and uncompensated metabolic acidosis and hyperkalemia in the surviving control gas-treated rats.H2 gas inhalation delays the progression to irreversible shock. Clinically, H2 gas inhalation is expected to stabilize the subject until curative treatment can be performed, thereby increasing the probability of survival after hemorrhagic shock.

To determine whether early lactate reduction is associated with improved survival and good neurologic outcome in patients with out-of-hospital cardiac arrest.Ad hoc data analysis of a prospective, multicenter observational study.Out-of-hospital cardiac arrest patients at 67 emergency hospitals in Kanto, Japan between January 2012 and March 2013.Adult patients with out-of-hospital cardiac arrest admitted to the hospital after successful resuscitation were identified.Blood lactate concentrations were measured at hospital admission and 6 h after hospital admission. Early lactate clearance was defined as the percent change in lactate level 6 h after a baseline measurement.The 543 patients (mean age, 65 ± 16 yr; 72.6% male) had a mean lactate clearance of 42.4% ± 53.7%. Overall 30-day survival and good neurologic outcome were 47.1% and 27.4%, respectively. The survival proportion increased with increasing lactate clearance (quartile 1, 29.4%; quartile 2, 42.6%; quartile 3, 51.5%; quartile 4, 65.2%; p0.001). Multivariate logistic regression analysis showed that lactate clearance quartile was an independent predictor of the 30-day survival and good neurologic outcome. In the Cox proportional hazards model, the frequency of mortality during 30 days was significantly higher for patients with lactate clearance in quartile 1 (hazard ratio, 3.12; 95% CI, 2.14-4.53), quartile 2 (hazard ratio, 2.13; 95% CI, 1.46-3.11), and quartile 3 (hazard ratio, 1.49; 95% CI, 1.01-2.19) than those with lactate clearance in quartile 4. Furthermore, multivariate logistic regression analysis revealed that lactate clearance was a significant predictor of good neurologic outcome at 30 days after hospital admission.Effective lactate reduction over the first 6 hours of postcardiac arrest care was associated with survival and good neurologic outcome independently of the initial lactate level.

Introduction: An emphasis on the chain of survival has contributed to improved outcomes of out-of-hospital cardiac arrest (OHCA). Although immediate recognition of cardiac arrest (CA) and activation of the emergency response system are the first links in the chain of survival, their impact on outcomes is unclear. Hypothesis: Delayed time from collapse to activation of the emergency response system (bystander delay) is associated with an unfavorable neurological outcome after adult OHCA. Methods: Data from the prospective, nationwide, population-based All-Japan Utstein Registry of the Fire and Disaster Management Agency between January 1, 2012 and December 31, 2016 were analyzed. Of the 625,916 eligible cases, 164,256 adult, non-traumatic, witnessed OHCA including bystander delay times (age, 79 [IQR, 67-86] years; 60% male) were studied. The primary outcome measure was favorable neurological outcome 1 month after an OHCA, defined as a score of 1 or 2 on the Cerebral Performance Category Scale. Results: The median bystander delay time of 2.0 [1.0-4.0] min was shorter among patients who achieved a favorable outcome as compared to 3.0 [1.0-6.0] min (P < 0.001) for patients with an unfavorable outcome. In multivariable logistic regression analyses, bystander delay had an OR for favorable neurological outcome of 0.94 [95% CI, 0.93-0.97] after adjusting for age, sex, etiology of arrest, first documented rhythm, provision of bystander CPR, use of public access automated external defibrillator, epinephrine administration, time intervals of activation of the emergency response system and hospital arrival, and collapse to initiation of CPR, and regional location. Similarly, bystander delay was independently associated with reduced neurologically favorable survival among patients who received bystander CPR within one minute of collapse (adjusted OR, 0.97 [0.97-0.98]). Conclusions: Bystander delay was independently associated with decreased odds of neurologically favorable survival, even among patients for whom bystander CPR was immediately performed.

Background: Outcome prediction for patients with out-of-hospital cardiac arrest (OHCA) using prehospital information has been one of the major challenges in resuscitation medicine. Recently, machine learning techniques have been shown to be highly effective in predicting outcomes using clinical registries. In this study, we aimed to establish a prediction model for outcomes of OHCA of presumed cardiac cause using machine learning techniques. Methods: We analyzed data from the All-Japan Utstein Registry of the Fire and Disaster Management Agency between 2005 and 2016. Of 1,423,338 cases, data of OHCA patients aged ≥18 years with presumed cardiac etiology were retrieved and divided into two groups: training set, n = 584,748 (between 2005 and 2013) and test set, n = 223,314 (between 2014 and 2016). The endpoints were neurologic outcome at 1-month and survival at 1-month. Of 47 variables evaluated during the prehospital course, 19 variables (e.g.,sex, age, ECG waveform, and practice of bystander CPR) were used for outcome prediction. Performances of logistic regression, random forests, and deep neural network were examined in this study. Results: For prediction of neurologic outcomes (cerebral performance category 1 or 2) using the test set, the generated models showed area under the receiver operating characteristic curve (AUROC) values of 0.942 (95% confidence interval [CI] 0.941-0.943), 0.947 (95% CI 0.946-0.948), and 0.948 (95% CI 0.948-0.950) in logistic regression, random forest, and deep neural network, respectively. For survival prediction, the generated models showed AUROC values of 0.901 (95% CI 0.900-0.902), 0.913 (95% CI 0.912-0.914), and 0.912 (95% CI 0.911-0.913) in logistic regression, random forest, and deep neural network, respectively. Conclusions: Machine learning techniques using prehospital variables showed favorable prediction capability for 1-month neurologic outcome and survival in OHCA of presumed cardiac cause.

Oxidative stress plays a key role in the pathophysiology of post-cardiac arrest syndrome. Molecular hydrogen reduces oxidative stress and exerts anti-inflammatory effects in an animal model of cardiac arrest. However, its effect on human post-cardiac arrest syndrome is unclear. We consecutively enrolled five comatose post-cardiac arrest patients (three males; mean age, 65 ± 15 years; four cardiogenic, one septic cardiac arrest) and evaluated temporal changes in oxidative stress markers and cytokines with inhaled hydrogen. All patients were treated with target temperature management. Hydrogen gas inhalation (2% hydrogen with titrated oxygen) was initiated upon admission for 18 h. Blood hydrogen concentrations, plasma and urine oxidative stress markers (derivatives of reactive oxygen metabolites, biological antioxidant potential, 8-hydroxy-2'-deoxyguanosine, N ɛ-hexanoyl-lysine, lipid hydroperoxide), and cytokines (interleukin-6 and tumor necrosis factor-α) were measured before and 3, 9, 18, and 24 h after hydrogen gas inhalation. Arterial hydrogen concentration was measurable and it was equilibrated with inhaled hydrogen. Oxidative stress was reduced and cytokine levels were unchanged in cardiogenic patients, whereas oxidative stress was unchanged and cytokine levels were diminished in the septic patient. The effect of inhaled hydrogen on oxidative stress and cytokines in comatose post-cardiac arrest patients remains indefinite because of methodological weaknesses.

Background Hydrogen gas inhalation (HI) ameliorates cerebral and cardiac dysfunction in animal models of post-cardiac arrest syndrome (PCAS). HI for human patients with PCAS has never been studied. Methods and results Between January 2014 and January 2015, 21 of 107 patients with out-of-hospital cardiac arrest achieved spontaneous return of circulation. After excluding 16 patients with specific criteria, 5 patients underwent HI together with target temperature management (TTM). No undesirable effects attributable to HI were observed and 4 patients survived 90 days with a favorable neurological outcome. Conclusions HI in combination with TTM is a feasible therapy for patients with PCAS. (Circ J 2016; 80: 1870-1873).

Introduction and Objective: Early prognostication for cardiogenic out-of-hospital cardiac arrest (OHCA) patients remain challenging. Recently, advanced machine learning techniques have been employed for clinical diagnosis and prognostication for various conditions. Therefore, in this study, we attempted to establish a prognostication model for cardiogenic OHCA using an advanced machine learning technique. Methods and Results: Data of a prospective multi-center cohort study of OHCA patients transported by an ambulance to 67 medical institutions in Kanto area of Japan between January 2012 and March 2013 was used in this study. Data for cardiogenic OHCA patients aged ≥18 years were retrieved and patients were grouped according to the time of calls for ambulances (training set: between January 1, 2012 and December 12, 2012; test set: between January 1, 2013 and March 31, 2013). From among 421 variables observed during the period between calls for ambulances and initial in-hospital treatments of cardiogenic OHCA, 38 prehospital factors or 56 prehospital factors and initial in-hospital factors were used for prognostication, respectively. Prognostication models for 1-year survival were established with random forest method, an advanced machine learning method that aggregates a series of decision trees for classification and regression. After 10-fold internal cross validation in the training set, prognostication models were validated using test set. Area under the receiver operating characteristics curve (AUC) was used to evaluate the prediction performance of models. Prognostication models trained with 38 variables or 56 variables for 1-year survival showed AUC values of 0.93±0.01 and 0.95±0.01, respectively. Conclusions: Prognostication models trained with advanced machine learning technique showed favorable prediction capability for 1-year survival of cardiogenic OHCA. These results indicate that an advanced machine learning technique can be applicable to establish early prognostication model for cardiogenic OHCA.

Background: Molecular hydrogen gas (H 2 ) is known to alleviate ischemia-reperfusion injury; however, the mechanism of action involved remains unknown. Metabolome analysis of tissue subjected to ischemia-reperfusion injury has revealed xanthine oxidoreductase (XOR) as a candidate target molecule for H 2. Purpose: The effects of H 2 and the XOR inhibitor (XORi) on resuscitation after hemorrhagic shock (HS) were examined. Methods: Male Sprague-Dawley rats were subjected to HS by the withdrawal of blood to maintain a mean arterial pressure (MBP) of 35 mmHg for 60 minutes (T0 to T60). They were then resuscitated with lactated Ringer’s solution with 3 times the shed blood volume over 30 minutes (T60 to T90). The animals were randomly assigned into 3 groups: H 2 inhalation (1.3% H 2 ) from T30 (n=6), XORi administration (Topiroxostat 10 mg/kg, orally administered at 60 minutes before induction of HS) (n=5), and control (CTL) (n=5). The rats were observed until 2 hours after fluid resuscitation (T210). Results: Compared to that in the control group, the lactate level at 60 minutes after introduction of HS was lower in the XORi group, while the MBP after 2 hours of fluid resuscitation was higher in the H 2 group. XOR activity in the plasma, liver, kidney, and lung tissue was suppressed in the XORi group, but not in the H 2 group. Increased permeability of the pulmonary vasculature associated with increased levels of plasma inflammatory cytokines and plasma Syndecan-1 (a marker of endothelial glycocalyx degradation) after 2 hours of fluid resuscitation was ameliorated only in the H 2 group. Conclusion: The mechanisms of action possibly differ between H 2 and XORi. XORi confers resistance to ischemia by suppressing anaerobic glycolysis during ischemia. On the other hand, H 2 stabilizes hemodynamics via suppression of inflammation and vascular hyperpermeability after resuscitation.

To clarify whether quantitative assessment of pupillary light reflexes (PLR) can predict the outcome of post-cardiac arrest (CA) patients during the first 72 h after the return of spontaneous circulation (ROSC).Fifty adults resuscitated after non-traumatic out-of-hospital CA (OHCA) (mean age 64.1 years old, 36 males) were enrolled in four emergency hospitals. PLR was sequentially measured at 0, 6, 12, 24, 48, and 72 h after ROSC by an automated portable infrared pupillometry. PLR values for each time point were compared between both survivors and non-survivors, and patients with either favourable (Cerebral Performance Category (CPC) 1 or 2) or unfavourable neurological outcomes.Twenty-three patients survived for 90 days after CA, and 13 patients achieved favourable neurological outcomes. The PLR values of the survivors and patients with favourable neurological outcomes were consistently greater than those of non-survivors (P 0.001) and those with unfavourable neurological outcomes (P 0.001), respectively. The change in PLR over time was not statistically different between the outcome groups. The 0-hour PLR best predicted both 90-day survival (AUC = 0.82, cutoff 3%, sensitivity 0.87, specificity 0.80) and favourable neurological outcomes (AUC = 0.84, cutoff 6%, sensitivity 0.92, specificity 0.74). No patient with a 6-hour PLR less than 3% survived for 90 days after CA.Quantitatively measured PLR was consistently greater in survivors and patients with favourable neurological outcomes during the 72 h after ROSC. Quantitative assessment of PLR at as early as 0 h has a potential role for prognostication in post-CA patients.

Background Hydrogen gas inhalation (HI) improved survival and neurological outcomes in an animal model of post-cardiac arrest syndrome (PCAS). The feasibility and safety of HI for patients with PCAS was confirmed in a pilot study. The objective of this study is to evaluate the efficacy of HI for patients with PCAS. Methods/design The efficacy of inhaled HYdrogen on neurological outcome following BRain Ischemia During post-cardiac arrest care (HYBRID II) trial is an investigator-initiated, randomized, double-blind, placebo-controlled trial designed to enroll 360 adult comatose (Glasgow Coma Scale score

Background Hydrogen gas inhalation (HI) reduced infarct size and mitigated adverse left ventricular (LV) remodeling in a rat model of acute myocardial infarction (AMI). We designed a prospective, open-label, rater-blinded clinical pilot study in patients experiencing ST-elevated MI (STEMI).Methods and Results:The 20 patients with an initial diagnosis of STEMI were assigned to either an HI group (1.3% H2with 26% oxygen) or a control group (26% oxygen). There were no HI-related severe adverse events. In the full analysis set, the cardiac salvage index as evaluated using cardiac magnetic resonance imaging at 7 days after primary percutaneous coronary intervention (PCI), showed no significant between-group difference (HI: 50.0±24.3%; control: 60.1±20.1%; P=0.43). However, the improvement from day 7 in the HI group was numerically greater than that in the control group in some of the surrogate outcomes at 6-month follow-up, including the LV stroke volume index (HI: 9.2±7.1 mL/m2; control: -1.4±7.2 mL/m2; P=0.03) and the LV ejection fraction (HI: 11.0%±9.3%; control: 1.7%±8.3%; P=0.11). Conclusions The first clinical study has shown that HI during PCI is feasible and safe and may also promote LV reverse remodeling at 6 months after STEMI. The study was not powered to test efficacy and a further large-scale trial is warranted. (Clinical trials registration: UMIN00006825).

The Walter Reed National Surgical Quality Improvement Program Data Transfer web module integrates with medical and surgical information systems, and leverages outside standards, such as the National Library of Medicine's RxNorm, to process surgical and risk assessment data. Key components of the project included a needs assessment with nurse reviewers and a data analysis for federated (standards were locally controlled) data sources. The resulting interface streamlines nurse reviewer workflow by integrating related tasks and data.