Published papers

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.

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.

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.

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.

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.

AIM: 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). METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.