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This is an interim analysis of the Beta-blocker (Propranolol) use in traumatic brain injury (TBI) based on the high-sensitive troponin status (BBTBBT) study. The BBTBBT is an ongoing double-blind placebo-controlled randomized clinical trial with a target sample size of 771 patients with TBI. We sought, after attaining 50% of the sample size, to explore the impact of early administration of beta-blockers (BBs) on the adrenergic surge, pro-inflammatory cytokines, and the TBI biomarkers linked to the status of high-sensitivity troponin T (HsTnT). Patients were stratified based on the severity of TBI using the Glasgow coma scale (GCS) and HsTnT status (positive vs negative) before randomization. Patients with positive HsTnT (non-randomized) received propranolol (Group-1; n = 110), and those with negative test were randomized to receive propranolol (Group-2; n = 129) or placebo (Group-3; n = 111). Propranolol was administered within 24 h of injury for 6 days, guided by the heart rate (> 60 bpm), systolic blood pressure (≥ 100 mmHg), or mean arterial pressure (> 70 mmHg). Luminex and ELISA-based immunoassays were used to quantify the serum levels of pro-inflammatory cytokines (Interleukin (IL)-1β, IL-6, IL-8, and IL-18), TBI biomarkers [S100B, Neuron-Specific Enolase (NSE), and epinephrine]. Three hundred and fifty patients with comparable age (mean 34.8 ± 9.9 years) and gender were enrolled in the interim analysis. Group 1 had significantly higher baseline levels of IL-6, IL-1B, S100B, lactate, and base deficit than the randomized groups ( p  = 0.001). Group 1 showed a significant temporal reduction in serum IL-6, IL-1β, epinephrine, and NSE levels from baseline to 48 h post-injury ( p  = 0.001). Patients with severe head injuries had higher baseline levels of IL-6, IL-1B, S100B, and HsTnT than mild and moderate TBI ( p  = 0.01). HsTnT levels significantly correlated with the Injury Severity Score (ISS) (r = 0.275, p  = 0.001), GCS (r = − 0.125, p  = 0.02), and serum S100B (r = 0.205, p  = 0.001). Early Propranolol administration showed a significant reduction in cytokine levels and TBI biomarkers from baseline to 48 h post-injury, particularly among patients with positive HsTnT, indicating the potential role in modulating inflammation post-TBI. Trial registration: ClinicalTrials.gov NCT04508244. It was registered first on 11/08/2020. Recruitment started on 29 December 2020 and is ongoing. The study was partly presented at the 23rd European Congress of Trauma and Emergency Surgery (ECTES), April 28–30, 2024, in Estoril, Lisbon, Portugal.

Background Postoperative cognitive dysfunction (POCD) is one of the major complications after surgery, with devastating clinical outcomes. Although POCD is a condition with a multifactorial pathophysiology, blood-brain barrier (BBB) dysfunction and neuronal injury have been shown to play a critical role, especially in the elderly. Previous studies have demonstrated that the choice of anesthetics affect BBB permeability and neuroinflammation. However, most studies are carried out on animals, with limited research undertaken on humans. Therefore, we will compare the effect of intravenous anesthetics and inhaled anesthetics on BBB dysfunction and the change of inflammatory markers after surgery. Methods One hundred and fifty-four patients who are 60 years of age or older undergoing major surgery for more than 2 h will be randomly allocated to two anesthetics groups (intravenous, inhaled) in a 1:1 ratio. In the intravenous anesthetics group (group P), propofol will be infused with a target-controlled infusion (TCI) system throughout the entire surgery. In the inhaled anesthetics group (group G), bolus injection of propofol will be administered for loss of consciousness, and simultaneously sevoflurane will be initiated for the maintenance of anesthesia. The primary outcome is the change in serum S100 calcium binding protein β (S100β) at four time points: before induction of anesthesia, at the end of surgery, 4 h after surgery, postoperative day 1. Secondary outcomes include changes in the inflammatory markers, serum interleukin (IL)-6, IL-8, tumor necrosis factor (TNF)-α, and C-reactive protein; the incidence of delirium; and the change in the cognitive function between groups. In patients pre-scheduled for postoperative intensive care unit admission, the cerebrospinal fluid/serum albumin quotient (Qalb) between the two groups will be compared before and after surgery, and change in inflammatory markers in serum and CSF will be analyzed in relation to the Qalb. Discussion The current study will compare the effect of intravenous versus inhaled anesthetics on blood-brain barrier permeability and, as a result, the difference in neuroinflammation in elderly patients. Also, the study results will provide additional information to develop intraoperative anesthetic strategies to reduce POCD. Trial registration The trial was prospectively registered at Clinical Trials protocol registration with identifier 2310-117-126 on April 9, 2024.

Major depressive disorder (MDD) is a debilitating illness that includes depressive mood. Repetitive Transcranial Magnetic Stimulation (rTMS) is a therapy method used in the treatment of MDD. The purpose of this study was to assess neurotrophic factors, and oxidative stress levels in MDD patients and evaluate the changes in these parameters as a result of rTMS therapy. Twenty-five patients with MDD and twenty-six healthy volunteers with the same demographic characteristics were included in the study. Brain-derived neurotrophic factors were measured photometrically with commercial kits. Oxidative stress parameters were measured by the photometric method. Oxidative stress index (OSI) and disulfide (DIS) levels were calculated with mathematical formulas. In this study, total antioxidant status (TAS), total thiol (TT), and native thiol (NT) antioxidant parameters and brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF), and allopregnanolone (ALLO) levels were reduced in pre-rTMS with regard to the healthy control group; TOS, OSI, DIS, and S100 calcium-binding protein B (S100B) levels were increased statistically significantly ( p  < 0.01). Moreover, owing to TMS treatment; TAS, TT, NT, BDNF, GDNF, and ALLO levels were increased compared to pre-rTMS, while DIS, TOS, OSI, and S100B levels were decreased significantly ( p  < 0.01). The rTMS treatment reduces oxidative stress and restores thiol-disulfide balance in MDD patients. Additionally, rTMS modulates neurotrophic factors and neuroactive steroids, suggesting its potential as an antidepressant therapy. The changes in the biomarkers evaluated may help determine a more specific approach to treating MDD with rTMS therapy.

Background and Objectives: Oxygen is essential for all living organisms and plays a critical role in anesthesia and intensive care practices. However, the notion that unlimited oxygen therapy is harmless is a misconception. Our study investigates the acute effects of different preoxygenation methods on hemodynamic parameters and neurodegenerative biomarkers in patients undergoing laparoscopic cholecystectomy surgery. Materials and Methods: This prospective, randomized, controlled study included 52 patients undergoing elective laparoscopic cholecystectomy under general anesthesia. Patients were divided into two groups: Group I received standard preoxygenation (100% FiO2 for 3 min), while Group II underwent rapid preoxygenation (eight deep breaths over 30 s to 1 min). Hemodynamic parameters (SAP, DAP, MAP, and SpO2) and neurodegenerative biomarkers (pTau, S100B, NSE, NfL, GFAP) were measured after preoxygenation, after intubation, and at the end of surgery. Results: Group I exhibited a significant increase in levels of pTau, S100B, NSE, and GFAP, indicating higher neuronal and glial cell stress compared to Group II (p < 0.001). No significant increase in NfL levels was observed in either group. Hemodynamic parameters (HR, SAP, DAP, MAP) were significantly higher during and after preoxygenation in Group I, suggesting an increased stress response. Group II showed lower levels of acute neurotoxicity and oxidative stress. Conclusions: Our findings indicate that preoxygenation with 100% FiO2 induces stress in neuronal cells, axons, and glial cells, leading to an increase in neurodegenerative biomarkers. Optimizing preoxygenation strategies is crucial to reduce oxidative stress and improve neurological outcomes for surgical patients.

Background Elderly patients are reportedly at higher risk of postoperative cognitive dysfunction (POCD) after inhalational anesthesia with sevoflurane. We hypothesized that the incidence of POCD would be higher in elderly patients undergoing major surgery under inhalational rather than intravenous anesthesia. We also measured plasma S-100β protein concentration as a biomarker of central nervous system injury, and plasma interleukin (IL)-6 and tumor necrosis factor (TNF)-α concentrations to judge the contribution of systemic inflammation to POCD. Methods Ninety patients aged 65–75 years scheduled for resection of an esophageal carcinoma were randomly assigned to one of three groups ( n  = 30) as follows: a group receiving sevoflurane anesthesia (Group S); a group receiving preoperative methylprednisolone before sevoflurane anesthesia (Group S + MP); and a control group maintained with intravenous propofol (Group C). The mini-mental state examination (MMSE) and Montreal cognitive assessment (MoCA) were used to measure patients’ cognitive function the day before surgery, and on the first, third and seventh postoperative days. The plasma concentrations of TNF-α, IL-6 and S-100β protein were measured 10 min before anesthesia, and on the first, third and seventh postoperative days. Results There were no significant differences in the demographic or clinical characteristics, or perioperative hemodynamic status, of the three groups. The MMSE and MoCA scores were significantly lower in Group S than in the propofol control (Group C) and Group S + MP on the first, third and seventh postoperative days ( P <0.05). Throughout the first postoperative week the plasma concentrations of TNF-α, IL-6, and S-100β protein were significantly elevated in Group S compared with Group C ( P <0.05), but were significantly lower in Group S + MP than Group S ( P <0.05). Conclusions The incidence of POCD was higher in elderly patients undergoing major surgery under inhalational anesthesia with sevoflurane than those maintained on intravenous propofol, and lower in elderly patients pro-treating with methylprednisolone. Furthermore, we found elevated plasma concentrations of S-100β protein, TNF-α and IL-6 in those receiving sevoflurane anesthesia. Trial registration ChiCTR-IOR-15007007 (02-09-2015).

Background This study aims to investigate the efficacy and safety of glibenclamide treatment in patients with acute aneurysmal subarachnoid hemorrhage (aSAH). Methods The randomized controlled trial was conducted from October 2021 to May 2023 at two university-affiliated hospitals in Beijing, China. The study included patients with aSAH within 48 h of onset, of whom were divided into the intervention group and the control group according to the random number table method. Patients in the intervention group received glibenclamide tablet 3.75 mg/day for 7 days. The primary end points were the levels of serum neuron-specific enolase (NSE) and soluble protein 100B (S100B) between the two groups. Secondary end points included evaluating changes in the midline shift and the gray matter–white matter ratio, as well as assessing the modified Rankin Scale scores during follow-up. The trial was registered at ClinicalTrials.gov (identifier NCT05137678). Results A total of 111 study participants completed the study. The median age was 55 years, and 52% were women. The mean admission Glasgow Coma Scale was 10, and 58% of the Hunt-Hess grades were no less than grade III. The baseline characteristics of the two groups were similar. On days 3 and 7, there were no statistically significant differences observed in serum NSE and S100B levels between the two groups ( P  > 0.05). The computer tomography (CT) values of gray matter and white matter in the basal ganglia were low on admission, indicating early brain edema. However, there were no significant differences found in midline shift and gray matter–white matter ratio ( P  > 0.05) between the two groups. More than half of the patients had a beneficial outcome (modified Rankin Scale scores 0–2), and there were no statistically significant differences between the two groups. The incidence of hypoglycemia in the two groups were 4% and 9%, respectively ( P  = 0.439). Conclusions Treating patients with early aSAH with oral glibenclamide did not decrease levels of serum NSE and S100B and did not improve the poor 90-day neurological outcome. In the intervention group, there was a visible decreasing trend in cases of delayed cerebral ischemia, but no statistically significant difference was observed. The incidence of hypoglycemia did not differ significantly between the two groups.

ObjectiveTraumatic brain injury (TBI) is a leading cause of morbidity and mortality worldwide. Metformin is reported to have pleiotropic neuroprotective effects through anti-inflammatory, antioxidative, and anti-ischemic activity, and improvements in vascular hemodynamics and endothelial function. The aim of this study is to examine the efficacy and safety of metformin therapy in severe TBI patients.MethodsThis single-blind, parallel-group, randomized controlled trial enrolled adult TBI patients. Of 158 trauma patients assessed, 30 met the eligibility criteria and were randomly allocated in a one-to-one ratio to receive 1 g metformin every 12 h for five consecutive days (intervention group) or to usual management only (control group). For efficacy analysis, temporal profiles of serum levels of S100b, neutrophil to lymphocyte ratio (NLR), and glial fibrillary acidic protein (GFAP) were assessed. For pharmacokinetic analysis, serum concentrations of metformin were evaluated in the intervention group.ResultsThe two study groups were similar in terms of demographics, baseline clinical characteristics, and on-admission biomarkers’ serum levels. Longitudinal analysis of S100b and NLR levels showed statistically significant declines in values toward normal levels in the intervention group (p values of < 0.001 and 0.030, respectively), different from the profiles of the control group (p values of 0.074 and 0.645, respectively). Pharmacokinetic analysis demonstrated that metformin absorption is delayed in TBI patients. No events of hypoglycemia and lactic acidosis occurred.ConclusionsMetformin could potentially be an effective and safe therapeutic intervention in patients with severe TBI. Large-scale, multicentre studies are needed to confirm our encouraging results.

BackgroundPostoperative delirium (POD) is an acute neurocognitive impairment and is commonly observed in older patients with hip fractures. POD is associated with poor outcomes, including increased postoperative complications, prolonged hospitalisation, high costs and increased perioperative mortality. Therefore, reducing the occurrence of POD and improving cognitive abilities in older patients are critical and urgent. Transcutaneous auricular vagus nerve stimulation (TAVNS) is a simple, safe, non-invasive treatment and has great potential to improve cognitive function. This clinical study will evaluate the effectiveness of TAVNS in reducing the incidence of POD in older patients and further elucidate the possible underlying mechanisms.Methods and analysisThis randomised, double-blind, single-centre controlled trial will enroll 154 older patients undergoing hip fracture surgery, who will be randomly assigned to the TAVNS group (n=77), receiving TAVNS from 1 hour before anaesthetic induction to the end of the surgery, or the sham stimulation group (n=77), receiving sham stimulation in the same manner. The primary outcome measure will be the incidence of POD during the first 7 days post-surgery, as assessed by the confusion assessment method for the intensive care unit. The secondary outcomes include the incidence of delayed neurocognitive recovery; serum acetylcholinesterase and butyrylcholinesterase levels; the concentrations of tumour necrosis factor-α, interleukin-1β, interleukin-6 and S100β; unplanned intensive care unit admission rates; the length and cost of hospital stay; the incidence of postoperative complications during hospitalisation; and mortality at 1 month, 6 months and 1 year after surgery.Ethics and disseminationThis study was approved by the Ethics Committee of the Chongqing Traditional Chinese Medicine Hospital on 15 May 2024 (2024-KY-HY-13). The findings will be published in the international peer-reviewed academic journals and presented orally at academic conferences.Trial registration numberChiCTR2400085508.

The effect of volatile anesthetics on postoperative recovery in older adults is still not entirely clear. Thus, we evaluated the effect of desflurane versus sevoflurane anesthesia on speed of postoperative recovery in older adults eligible for same-day discharge. We further evaluated the incidence of postoperative nausea and vomiting (PONV), bispectral index (BIS) values, and S100B concentrations. Single-center, prospective, observer-blinded, randomized clinical trial. Operating room. 190 patients ≥65 years of age and scheduled for minor- to moderate-risk noncardiac surgeries. Goal-directed administration of desflurane versus sevoflurane for maintenance of anesthesia with an intraoperative goal of BIS 50 ± 5. The primary outcome was the time to anesthesia recovery, which was defined as the time between arrival at the post-anesthesia care unit (PACU) and reaching criteria for discharge from PACU, based on modified Aldrete score ≥ 12 points. Modified Aldrete scores were assessed at PACU arrival and thereafter in five-minute intervals. PONV was evaluated during PACU stay and the first three postoperative days, BIS values were recorded during PACU stay, and S100B values were measured before and after surgery, and on the second postoperative day. 95 patients were randomized to receive desflurane, and 95 patients to receive sevoflurane. We did not observe a significant difference in median duration of postoperative recovery between the groups (desflurane: 0 min [0;0]; sevoflurane: 0 min [0;0]; p = 0.245). 77 patients (81.1%) in the desflurane group and 84 patients (88.4%) in the sevoflurane group already had Aldrete scores ≥12 points upon arrival at PACU (p = 0.277). There was also no significant difference in the incidences of PONV (p = 0.606), postoperative BIS values (p = 0.197), and postoperative maximum S100B concentrations (p = 0.821) between the groups. Despite previous reports, we did not observe significant faster recovery times after desflurane anesthesia. Both volatile anesthetics may be appropriate for same-day discharge in older adults. •Older adults are at-risk for prolonged recovery after volatile anesthesia.•The effect of desflurane versus sevoflurane on recovery is not entirely clear.•Postoperative recovery was not significantly faster after desflurane anesthesia.•PONV, delirium and cognitive dysfunction were similar between the groups.

Objective To determine whether maternal allopurinol treatment during suspected fetal hypoxia would reduce the release of biomarkers associated with neonatal brain damage. Design A randomised double-blind placebo controlled multicentre trial. Patients We studied women in labour at term with clinical indices of fetal hypoxia, prompting immediate delivery. Setting Delivery rooms of 11 Dutch hospitals. Intervention When immediate delivery was foreseen based on suspected fetal hypoxia, women were allocated to receive allopurinol 500 mg intravenous (ALLO) or placebo intravenous (CONT). Main outcome measures Primary endpoint was the difference in cord S100ß, a tissue-specific biomarker for brain damage. Results 222 women were randomised to receive allopurinol (ALLO, n=111) or placebo (CONT, n=111). Cord S100ß was not significantly different between the two groups: 44.5 pg/mL (IQR 20.2–71.4) in the ALLO group versus 54.9 pg/mL (IQR 26.8–94.7) in the CONT group (difference in median −7.69 (95% CI −24.9 to 9.52)). Post hoc subgroup analysis showed a potential treatment effect of allopurinol on the proportion of infants with a cord S100ß value above the 75th percentile in girls (ALLO n=5 (12%) vs CONT n=10 (31%); risk ratio (RR) 0.37 (95% CI 0.14 to 0.99)) but not in boys (ALLO n=18 (32%) vs CONT n=15 (25%); RR 1.4 (95% CI 0.84 to 2.3)). Also, cord neuroketal levels were significantly lower in girls treated with allopurinol as compared with placebo treated girls: 18.0 pg/mL (95% CI 12.1 to 26.9) in the ALLO group versus 32.2 pg/mL (95% CI 22.7 to 45.7) in the CONT group (geometric mean difference −16.4 (95% CI −24.6 to −1.64)). Conclusions Maternal treatment with allopurinol during fetal hypoxia did not significantly lower neuronal damage markers in cord blood. Post hoc analysis revealed a potential beneficial treatment effect in girls. Trial registration number NCT00189007, Dutch Trial Register NTR1383.