Combination of Hydrogen Inhalation and Hypothermic Temperature Control After Out-of-Hospital Cardiac Arrest: A Post hoc Analysis of the Efficacy of Inhaled Hydrogen on Neurologic Outcome Following Brain Ischemia During PostCardiac Arrest Care II Trial.

OBJECTIVE: The Efficacy of Inhaled Hydrogen on Neurologic Outcome Following Brain Ischemia During Post-Cardiac Arrest Care (HYBRID) II trial (jRCTs031180352) suggested that hydrogen inhalation may reduce post-cardiac arrest brain injury (PCABI). However, the combination of hypothermic target temperature management (TTM) and hydrogen inhalation on outcomes is unclear. The aim of this study was to investigate the combined effect of hydrogen inhalation and hypothermic TTM on outcomes after out-of-hospital cardiac arrest (OHCA). DESIGN: Post hoc analysis of a multicenter, randomized, controlled trial. SETTING: Fifteen Japanese ICUs. PATIENTS: Cardiogenic OHCA enrolled in the HYBRID II trial. INTERVENTIONS: Hydrogen mixed oxygen (hydrogen group) versus oxygen alone (control group). MEASUREMENTS AND MAIN RESULTS: TTM was performed at a target temperature of 32-34°C (TTM32-TTM34) or 35-36°C (TTM35-TTM36) per the institutional protocol. The association between hydrogen + TTM32-TTM34 and 90-day good neurologic outcomes was analyzed using generalized estimating equations. The 90-day survival was compared between the hydrogen and control groups under TTM32-TTM34 and TTM35-TTM36, respectively. The analysis included 72 patients (hydrogen [ n = 39] and control [ n = 33] groups) with outcome data. TTM32-TTM34 was implemented in 25 (64%) and 24 (73%) patients in the hydrogen and control groups, respectively ( p = 0.46). Under TTM32-TTM34, 17 (68%) and 9 (38%) patients achieved good neurologic outcomes in the hydrogen and control groups, respectively (relative risk: 1.81 [95% CI, 1.05-3.66], p < 0.05). Hydrogen + TTM32-TTM34 was independently associated with good neurologic outcomes (adjusted odds ratio 16.10 [95% CI, 1.88-138.17], p = 0.01). However, hydrogen + TTM32-TTM34 did not improve survival compared with TTM32-TTM34 alone (adjusted hazard ratio: 0.22 [95% CI, 0.05-1.06], p = 0.06). CONCLUSIONS: Hydrogen + TTM32-TTM34 was associated with improved neurologic outcomes after cardiogenic OHCA compared with TTM32-TTM34 monotherapy. Hydrogen inhalation is a promising treatment option for reducing PCABI when combined with TTM32-TTM34.

Protective Effects of Hydrogen Gas Inhalation for Hindlimb Ischaemia-Reperfusion Injury in a Mouse Model.

OBJECTIVE: Ischaemia-reperfusion (I/R) injury is a severe post-operative complication that triggers an inflammatory response and causes severe damage. Hydrogen gas has anti-oxidant and anti-apoptotic properties and has been shown to be safe in humans. The study aimed to investigate whether hydrogen gas protects against skeletal muscle I/R injury. METHODS: Experimental basic research using mice. A total of 160 eight to 10 week old albino laboratory bred strain of house mice (25.8 ± 0.68 g) were used in this study. The mice were cable tied to the hindlimb under anaesthesia and then placed in an anaesthesia box filled with air and 2% isoflurane (control group); 80 mice were additionally subjected to 1.3% hydrogen gas in this mix (hydrogen group). After two hours, the cable ties were removed to initiate reperfusion, and hydrogen inhalation lasted for six hours in the hydrogen group. After six hours, the mice were taken out of the box and kept in cages under standard conditions until time for observation at 16 different time points after reperfusion: zero, two, four, six, eight, and 10 hours and one, two, three, four, five, six, seven, 14, 21, and 28 days. Five mice were sacrificed using excess anaesthesia at each time point, and the bilateral hindlimb tissues were harvested. The inflammatory effects of the I/R injury were assessed by evaluating serum interleukin-6 concentrations using enzyme linked immunosorbent assay, as well as histological and immunohistochemical analyses. Untreated mice with I/R injury were used as controls. RESULTS: Hydrogen gas showed protective effects associated with a reduction in inflammatory cell infiltration (neutrophils, macrophages, and lymphocytes), a reduced area of damaged muscle, maintenance of normal muscle cells, and replacement of damaged muscle cells with neoplastic myocytes. CONCLUSION: Inhalation of hydrogen gas had a protective effect against hindlimb I/R injury in mice, in part by reducing inflammatory cell infiltration and in part by preserving normal muscle cells.

Urine Output and Development of Acute Kidney Injury in Sepsis: A Multicenter Observational Study.

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.

Delta Shock Index and higher incidence of emergency surgery in older adults with blunt trauma.

PURPOSE: Vital signs are important for predicting clinical outcomes in patients with trauma. However, their accuracy can be affected in older adults because hemodynamic changes are less obvious. This study aimed to examine the usefulness of changes in vital signs during transportation in predicting the need for hemostatic treatments in older patients with trauma. METHODS: This retrospective cohort study was conducted using data from the Japan Trauma Data Bank (2004-2019). Patients aged ≥ 65 years who were hemodynamically stable at the scene were included in this study. The incidence of emergency surgery within 12 h after hospital arrival was compared between patients with delta Shock Index (dSI) > 0.1 and those with dSI ≤ 0.1. Predicting ability was examined after adjusting for patient demographics, comorbidities, vital signs at the scene and on hospital arrival, Injury Severity Score, and abbreviated injury scale in each region. RESULTS: Among the 139,242 patients eligible for the study, 3,701 underwent urgent hemostatic surgery within 12 h. Patients with dSI > 0.1 showed a significantly higher incidence of emergency surgery than those with dSI ≤ 0.1 (871/16,549 [5.3%] vs. 2,830/84,250 [3.4%]; odds ratio (OR), 1.60 [1.48-1.73]; adjusted OR, 1.22 [1.08-1.38]; p = 0.001). The relationship between high dSI and a higher incidence of intervention was observed in patients with hypertension and those with decreased consciousness on arrival. CONCLUSION: High dSI > 0.1 was significantly associated with a higher incidence of urgent hemostatic surgery in older patients.

Door-to-Needle Time for Extracorporeal Cardiopulmonary Resuscitation and Neurological Outcomes in Out-of-Hospital Cardiac Arrest: A Nationwide Study.

BACKGROUND: Extracorporeal cardiopulmonary resuscitation (ECPR) is an option for refractory cardiac arrest, and immediate initiation after indication is recommended. However, the practical goals of ECPR preparation (such as the door-to-needle time) remain unclear. This study aimed to elucidate the association between the door-to-needle time and neurological outcomes of out-of-hospital cardiac arrest. METHODS AND RESULTS: This is a post hoc analysis of a nationwide multicenter study on out-of-hospital cardiac arrest treated with ECPR at 36 institutions between 2013 and 2018 (SAVE-J [Study of Advanced Cardiac Life Support for Ventricular Fibrillation with Extracorporeal Circulation in Japan] II study). Adult patients without hypothermia (≥32 °C) in whom circulation was not returned at ECPR initiation were included. The probability of favorable neurological function at 30 days (defined as Cerebral Performance Category ≤2) was estimated using a generalized estimating equations model, in which institutional, patient, and treatment characteristics were adjusted. Estimated probabilities were then calculated according to the door-to-needle time with 3-minute increments, and a clinical threshold was assumed. Among 1298 patients eligible for this study, 136 (10.6%) had favorable neurological function. The estimated probability of favorable outcomes was highest in patients with 1 to 3 minutes of door-to-needle time (12.9% [11.4%-14.3%]) and remained at 9% to 10% until 27 to 30 minutes. Then, the probability dropped gradually with each 3-minute delay. A 30-minute threshold was assumed, and shorter door-to-extracorporeal membrane oxygenation/low-flow time and fewer adverse events related to cannulation were observed in patients with door-to-needle time <30 minutes. CONCLUSIONS: The probability of favorable functions after out-of-hospital cardiac arrest decreased as the door-to-needle time for ECPR was prolonged, with a rapid decline after 27 to 30 minutes. REGISTRATION: URL: https://center6.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000041577; Unique identifier: UMIN000036490.

Therapeutic Apheresis Using a ß2-Microglobulin Removal Column Reduces Circulating Tumor Cell Count.

An elevated serum ß2-microglobulin (ß2M) level is indicative of impaired glomerular filtration and prerenal diseases, such as malignant tumors, autoimmune disorders, and liver diseases. An elevated serum ß2M level has been shown to promote metastasis via the induction of epithelial-mesenchymal transition (EMT) in cancer cells. However, the therapeutic potential of targeting ß2M remains unclear. Here, we aimed to investigate the efficacy of Filtor, a small polymethyl methacrylate fiber-based ß2M removal column, in reducing the ß2M level and suppressing cancer cell-induced EMT and metastasis. We assessed the effects of Filtor on the changes in metastasis based on the number of circulating tumor cells (CTCs), which reflects the post-EMT cancer cell population. We performed therapeutic apheresis using Filtor on a male patient with sinonasal neuroendocrine carcinoma, a female patient with a history of colorectal cancer, and another female patient with a history of pancreatic ductal adenocarcinoma. Significantly low serum ß2M levels and CTC counts were observed immediately and 4 weeks after treatment compared with those in the pretreatment phase. Moreover, the CTC count immediately after therapeutic intervention was markedly reduced, likely because Filtor had trapped CTCs directly. These findings suggest that therapeutic apheresis with Filtor can prevent cancer metastasis and recurrence by directly removing CTCs.