Published papers

BACKGROUND: Most patients hospitalized after cardiac arrest (CA) die because of neurological injury. The systemic inflammatory response after CA is associated with neurological injury and mortality but remains poorly defined. METHODS: We determine the innate immune network induced by clinical CA at single-cell resolution. FINDINGS: Immune cell states diverge as early as 6 h post-CA between patients with good or poor neurological outcomes 30 days after CA. Nectin-2+ monocyte and Tim-3+ natural killer (NK) cell subpopulations are associated with poor outcomes, and interactome analysis highlights their crosstalk via cytokines and immune checkpoints. Ex vivo studies of peripheral blood cells from CA patients demonstrate that immune checkpoints are a compensatory mechanism against inflammation after CA. Interferon γ (IFNγ)/interleukin-10 (IL-10) induced Nectin-2 on monocytes; in a negative feedback loop, Nectin-2 suppresses IFNγ production by NK cells. CONCLUSIONS: The initial hours after CA may represent a window for therapeutic intervention in the resolution of inflammation via immune checkpoints. FUNDING: This work was supported by funding from the American Heart Association, Brigham and Women's Hospital Department of Medicine, the Evergreen Innovation Fund, and the National Institutes of Health.

AIM: We sought to investigate the relationship between mechanical cardiopulmonary resuscitation (CPR) during in-hospital cardiac arrest and survival to hospital discharge. METHODS: Utilizing the prospectively collected American Heart Association's Get With The Guidelines database, we performed an observational study. Data from 153 institutions across the United States were reviewed with a total of 351,125 patients suffering cardiac arrest between 2011 and 2019 were screened. After excluding patients with cardiac arrests lasting less than 5 minutes, and patients who had incomplete data, a total of 111,143 patients were included. Our primary exposure was mechanical vs. manual CPR, and the primary outcome was survival to hospital discharge. Multivariate logistic regression models and propensity weighted analyses were used. RESULTS: 11.8% of patients who received mechanical CPR survived to hospital discharge versus 16.9% in the manual CPR group. Patients who received mechanical CPR had a lower probability of survival to discharge compared to patients who received manual CPR (OR 0.66 95% CI 0.58-0.75; p < 0.001). This association persisted with multi-variable adjustment (OR 0.57 95% CI 0.46-0.70, p < 0.0001) and propensity weighted analysis (OR 0.68 95% CI 0.44-0 0.92, p < 0.0001). Mechanical CPR was associated with decrease likelihood of return of spontaneous circulation after multivariate adjustment (OR 0.68, 95% CI 0.60-0.76; p < 0.001). CONCLUSIONS: Mechanical CPR was associated with a decreased likelihood of survival to hospital discharge and ROSC compared to manual CPR. This finding should be interpreted within the context of important limitations of this study and randomized trials are needed to better investigate this relationship.

INTRODUCTION: Post-cardiac arrest brain injury (PCABI) is the primary determinant of clinical outcomes for patients who achieve return of spontaneous circulation after cardiac arrest (CA). There are limited neuroprotective therapies available to mitigate the acute pathophysiology of PCABI. METHODS: Neuroprotection was one of six focus topics for the Wolf Creek XVII Conference held on June 14-17, 2023 in Ann Arbor, Michigan, USA. Conference invitees included international thought leaders and scientists in the field of CA resuscitation from academia and industry. Participants submitted via online survey knowledge gaps, barriers to translation, and research priorities for each focus topic. Expert panels used the survey results and their own perspectives and insights to create and present a preliminary unranked list for each category that was debated, revised and ranked by all attendees to identify the top 5 for each category. RESULTS: Top 5 knowledge gaps included developing therapies for neuroprotection; improving understanding of the pathophysiology, mechanisms, and natural history of PCABI; deploying precision medicine approaches; optimizing resuscitation and CPR quality; and determining optimal timing for and duration of interventions. Top 5 barriers to translation included patient heterogeneity; nihilism & lack of knowledge about cardiac arrest; challenges with the translational pipeline; absence of mechanistic biomarkers; and inaccurate neuro-triage and neuroprognostication. Top 5 research priorities focused on translational research and trial optimization; addressing patient heterogeneity and individualized interventions; improving understanding of pathophysiology and mechanisms; developing mechanistic and outcome biomarkers across post-CA time course; and improving implementation of science and technology. CONCLUSION: This overview can serve as a guide to transform the care and outcome of patients with PCABI. Addressing these topics has the potential to improve both research and clinical care in the field of neuroprotection for PCABI.

Post-cardiac arrest brain injury (PCABI) is the leading cause of death and disability following cardiac arrest (CA). Nicotinamide adenine dinucleotide (NAD+) depletion after CA contributes to neuronal injury, while nicotinamide mononucleotide (NMN) replenishes NAD+ and may provide neuroprotection via sirtuin activation. This study aimed to investigate the effects of systemic NMN administration on neurological function, survival, and sirtuin-3 (SIRT3) levels in the brain post-CA. In adult male mice (C57BL/6NCrSlc, 10-15 weeks old), 10-min CA was induced by intravenous potassium chloride injection followed by cardiopulmonary resuscitation. NMN (60 mg/kg body weight) or normal saline (control) was randomly administered by intraperitoneal injection immediately after the return of spontaneous circulation (ROSC) and 24 and 48 h post-CA. Brain NAD+ and adenosine triphosphate (ATP) levels, neurological function score (NFS), survival, histological neuronal injury, and brain gene expression and protein levels were measured. Brain NAD+ levels decreased at 2 h post-ROSC and NMN significantly increased brain NAD+ and ATP levels. At 48 h post-CA, surviving mice in the NMN group exhibited significantly higher NFS (control: 8 [IQR: 4-12] vs. NMN: 12 [IQR: 9-12], p = 0.03) and less severe hippocampal neuronal injury compared with controls. Moreover, the NMN group showed significantly higher 7-day survival rate (control: 22.2% [4/18] vs. NMN: 61.1% [11/18], p = 0.03) and brain SIRT3 levels (control: 17.7 ± 3.6 vs. NMN: 34.5 ± 4.4 pg/mg protein, p = 0.01). In conclusion, systemic NMN administration after ROSC attenuates PCABI. The increased brain ATP levels and SIRT3 upregulation may suggest the usefulness of NMN for improving mitochondrial function and contributing to neuroprotection. NAD+ supplementation with NMN is a promising therapeutic approach against PCABI.

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).

＜文献概要＞Point　1 水素は抗酸化・抗炎症作用を含む多面的効果を有する。2 水素の吸入は全身臓器に速やかにかつ簡便に水素を導入する方法である。3 腎性高血圧モデルラットに対する毎日1時間の水素吸入は,自律神経機能障害を改善することで降圧効果を示す。

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 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. 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.

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).

Immunophenotyping of out-of-hospital cardiac arrest (OHCA) patients is of increasing interest but has challenges. Here, we describe steps for the design of the clinical cohort, planning patient enrollment and sample collection, and ethical review of the study protocol. We detail procedures for blood sample collection and cryopreservation of peripheral blood mononuclear cells (PBMCs). We detail steps to modulate immune checkpoints in OHCA PBMC ex vivo. This protocol also has relevance for immunophenotyping other types of critical illness. For complete details on the use and execution of this protocol, please refer to Tamura et al. (2023).1.

BACKGROUND: 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. METHODS: 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. RESULTS: The survival rate at 6 hours after fluid resuscitation was 80% in H2 gas-treated rats and 30% in control gas-treated rats (p < 0.05). 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. CONCLUSIONS: 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.

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.