The TOX-RAGE axis mediates inflammatory activation and lung injury in severe pulmonary infectious diseases.

Thymocyte selection-associated high-mobility group box (TOX) is a transcription factor that is crucial for T cell exhaustion during chronic antigenic stimulation, but its role in inflammation is poorly understood. Here, we report that TOX extracellularly mediates drastic inflammation upon severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection by binding to the cell surface receptor for advanced glycation end-products (RAGE). In various diseases, including COVID-19, TOX release was highly detectable in association with disease severity, contributing to lung fibroproliferative acute respiratory distress syndrome (ARDS). Recombinant TOX-induced blood vessel rupture, similar to a clinical signature in patients experiencing a cytokine storm, further exacerbating respiratory function impairment. In contrast, disruption of TOX function by a neutralizing antibody and genetic removal of RAGE diminished TOX-mediated deleterious effects. Altogether, our results suggest an insight into TOX function as an inflammatory mediator and propose the TOX-RAGE axis as a potential target for treating severe patients with pulmonary infection and mitigating lung fibroproliferative ARDS.

The agreement between jugular bulb and cerebrospinal fluid lactate levels in patients with out-of-hospital cardiac arrest.

We investigated the agreement between the jugular bulb (JB) and cerebrospinal fluid (CSF) lactate levels. The study was conducted from July 2021 to June 2023 as a prospective observational cohort study at a single center. The right jugular vein was accessed, and the placement of JB catheter tip was confirmed using lateral cervical spine X-ray. A lumbar catheter was inserted between the 3rd and 4th lumbar spine of the patient. Lactate levels were measured immediately, 24 h, 48 h, and 72 h after ROSC. In patients with a good neurological prognosis, kappa between JB and CSF lactate levels measured immediately, at 24 h, 48 h, and 72 h after ROSC were 0.08, 0.36, 0.14, - 0.05 (p = 0.65, 0.06, 0.48, and 0.75, respectively). However, in patients with a poor neurological prognosis, kappa between JB and CSF lactate levels measured immediately, at 24 h, 48 h, and 72 h after ROSC were 0.38, 0.21, 0.22, 0.12 (p = 0.001, 0.04, 0.04, and 0.27, respectively). This study demonstrated that JB lactate levels exhibited significant agreement with arterial lactate levels, compared to CSF lactate levels. Therefore, this should be considered when using JB lactate to monitor cerebral metabolism.

Cerebrospinal Fluid Dynamics and Partial Pressure of Carbon Dioxide as Prognostic Indicators in Hypoxic-Ischemic Brain Injury Following Cardiac Arrest.

Changes in cerebrospinal fluid (CSF) dynamics can have adverse effects on neuronal function. We hypothesized that patients with hypoxic-ischemic brain injury (HIBI) showing poor neurological outcomes after cardiac arrest (CA) would exhibit changes in CSF dynamics, leading to abnormalities in gas diffusion within the CSF. Therefore, we investigated the prognostic value of the CSF partial pressure of carbon dioxide (PcsfCO2) in CA survivors who underwent targeted temperature management (TTM). We retrospectively analyzed the 6-month neurological outcomes, CSF, and arterial blood gas parameters of 67 CA survivors. Patients were divided into good and poor neurological outcome groups, and the predictive value of PcsfCO2 for poor neurological outcomes was assessed using receiver operating characteristic curve analysis. Among all patients, 39 (58.2%) had poor neurological outcomes. Significant differences in PcsfCO2 levels between the groups were observed, with lower PcsfCO2 levels on Day 1 showing the highest predictive value at a cutoff of 30 mmHg (area under the curve, sensitivity, and specificity were 0.823, 77.8%, and 79.0%, respectively). These results suggest that PcsfCO2 might serve not only as a unique marker for the severity of hypoxic-ischemic brain injury (HIBI), independent of extracorporeal CO2 levels, but also as an objective indicator of changes in CSF dynamics. This study highlights the potential prognostic and diagnostic utility of PcsfCO2 during TTM in CA survivors, emphasizing its importance in evaluating CSF dynamics and neurological recovery post CA. However, larger multicenter studies are warranted to address potential limitations associated with sample size and outcome assessment methods.

Distribution and elimination kinetics of midazolam and metabolites after post-resuscitation care: a prospective observational study.

Administration of sedatives for post-resuscitation care can complicate the determination of the optimal timing to avoid inappropriate, pessimistic prognostications. This prospective study aimed to investigate the distribution and elimination kinetics of midazolam (MDZ) and its metabolites, and their association with awakening time. The concentrations of MDZ and its seven metabolites were measured immediately and at 4, 8, 12, and 24 h after the discontinuation of MDZ infusion, using liquid chromatography-tandem mass spectrometry. The area under the time-plasma concentration curve from 0 to 24 h after MDZ discontinuation (AUClast) was calculated based on the trapezoidal rule. Of the 15 enrolled patients, seven awakened after the discontinuation of MDZ infusion. MDZ and three of its metabolites were major compounds and their elimination kinetics followed a first-order elimination profile. In the multivariable analysis, only MDZ was associated with awakening time (AUClast: R2 = 0.59, p = 0.03; AUCinf: R2 = 0.96, p < 0.001). Specifically, a 0.001% increase in MDZ AUC was associated with a 1% increase in awakening time. In the individual regression analysis between MDZ concentration and awakening time, the mean MDZ concentration at awakening time was 16.8 ng/mL. The AUC of MDZ is the only significant factor associated with the awakening time.

Blood-brain barrier permeability for the first 24 hours in hypoxic-ischemic brain injury following cardiac arrest.

BACKGROUND: This study aimed to explore the changes in blood-brain barrier (BBB) permeability and intracranial pressure (ICP) for the first 24 h after the return of spontaneous circulation (ROSC) and their association with injury severity of cardiac arrest. METHODS: This prospective study analysed the BBB permeability assessed using the albumin quotient (Qa) and ICP every 2 h for the first 24 h after ROSC. The injury severity of cardiac arrest was assessed using Pittsburgh Cardiac Arrest Category (PCAC) scores. The primary outcome was the time course of changes in the BBB permeability and ICP for the first 24 h after ROSC and their association with injury severity (PCAC scores of 1-4). RESULTS: Qa and ICP were measured 274 and 197 times, respectively, in 32 enrolled patients. Overall, the BBB permeability increased progressively over time after ROSC, and then it increased significantly at 18 h after ROSC compared with the baseline. In contrast, the ICP revealed non-significant changes for the first 24 h after ROSC. The Qa in the PCAC 2 group was < 0.01, indicating normal or mild BBB disruption at all time points, whereas the PCAC 3 and 4 groups showed a significant increase in BBB permeability at 14 and 22 h, and 12 and 14 h after ROSC, respectively. CONCLUSION: BBB permeability increased progressively over time for the first 24 h after ROSC despite post-resuscitation care, whereas ICP did not change over time. BBB permeability has an individual pattern when stratified by injury severity.

Comparison of modified quick sequential organ failure assessment models as triage tools for febrile patients.

Object: Effective triage of febrile patients in the emergency department is crucial during times of overcrowding to prioritize care and allocate resources, especially during pandemics. However, available triage tools often require laboratory data and lack accuracy. We aimed to develop a simple and accurate triage tool for febrile patients by modifying the qSOFA score. Methods: We retrospectively analyzed data from 7,303 febrile patients and created modified versions of qSOFA using factors identified through multivariable analysis. The performance of these modified qSOFAs in predicting in hospital mortality and intensive care unit (ICU) admission was compared using the area under the receiver operating characteristic curve (AUROC). Results: Through multivariable analysis, the identified factors were age (A), male sex (M), SpO2 (S), and lactate levels (L). The AUROCs of ASqSOFA (for in-hospital mortality: 0.812; 95% CI: 0.789-0.835, for ICU admission: 0.794; 95% CI: 0.771-0.817), which included age and SpO2 with qSOFA, were simple and not inferior to other more complex models (e.g., ASMqSOFA, ASLqSOFA, and ASMLqSOFA). ASqSOFA also displayed significantly higher AUROC than other triage scales, such as the modified early warning score and Korean triage and acuity scale. The optimal cut-off score of ASqSOFA for the outcome was 2 and the score for redistribution to a lower-level emergency department was 0. Conclusion: We demonstrated that ASqSOFA can be employed as a simple and efficient triage tool for emergency febrile patients to aid in resource distribution during overcrowding. It may also be applicable in pre-hospital settings for febrile patient triage.