Effect of cuff inflation with lidocaine, saline, and air on tracheal tube cuff pressure during laparoscopic resection of colorectal neoplasms: a randomized clinical trial.

BACKGROUND: Tracheal tube cuff pressure will increase after pneumoperitoneum when the cuff is inflated with air, high pressure can cause tracheal mucosal damage. This prospective trial aimed to assess if inflating with normal saline or lidocaine can prevent increase of tracheal tube cuff pressure and tracheal mucosal damage in laparoscopic surgeries with general anesthesia. Whether changes of tracheal tube cuff transverse diameter (CD) can predict changes of tracheal tube cuff pressure. METHODS: Ninety patients scheduled for laparoscopic resection of colorectal neoplasms under general anesthesia were randomly assigned to groups air (A), saline (S) or lidocaine (L). Endotracheal tube cuff was inflated with room-temperature air in group A (n = 30), normal saline in group S (n = 30), 2% lidocaine hydrochloride injection in group L (n = 30). After intubation, tracheal tube cuff pressure was monitored by a calibrated pressure transducers, cuff pressure was adjusted to 25 cmH2O (T0.5). Tracheal tube cuff pressure at 15 min after pneumoperitoneum (T1) and 15 min after exsufflation (T2) were accessed. CD were measured by ultrasound at T0.5 and T1, the ability of ΔCD (T1-0.5) to predict cuff pressure was accessed. Tracheal mucous injury at the end of surgery were also recorded. RESULTS: Tracheal tube cuff pressure had no significant difference among the three groups at T1 and T2. ΔCD had prediction value (AUC: 0.92 [95% CI: 0.81-1.02]; sensitivity: 0.99; specificity: 0.82) for cuff pressure. Tracheal mucous injury at the end of surgery were 0 (0, 1.0) in group A, 0 (0, 1.0) in group S, 0 (0, 0) in group L (p = 0.02, group L was lower than group A and S, p = 0.03 and p = 0.04). CONCLUSIONS: Compared to inflation with air, normal saline and 2% lidocaine cannot ameliorate the increase of tracheal tube cuff pressure during the pneumoperitoneum period under general anesthesia, but lidocaine can decrease postoperative tracheal mucosa injury. ΔCD measured by ultrasound is a predictor for changes of tracheal tube cuff pressure. TRIAL REGISTRATION: Chinese Clinical Trial Registry, identifier: ChiCTR2100054089, Date: 08/12/2021.

The effect of different endotracheal tube cuff pressure monitoring systems on postoperative sore throat in patients undergoing tracheal intubation: a randomized clinical trial.

BACKGROUND: Postoperative sore throat (POST) is an unpleasant outcome that can occur as a result of tracheal intubation in adults. Increased pressure from the endotracheal tube (ETT) cuff often leads to local mucosal injury, resulting in sore throat. The purpose of this study was to compare the effect of two different ETT cuff pressure monitoring systems vs. no cuff pressure monitoring on the incidence and severity of POST in adults. METHODS: One hundred and fourteen ASA I-III patients of either gender, aged 18-65 years, and undergoing surgery requiring endotracheal intubation were included in this study. Patients were randomized into three groups: control (C), cuff pressure gauge (G), and automated cuff controller (A). The ETT cuff pressure was not monitored intraoperatively in group C but was monitored using a cuff pressure gauge and an automated cuff controller in groups G and A, respectively. Postoperatively, patients were assessed at 2, 24, and 48 h for the presence and severity of POST, hoarseness and cough. RESULTS: One hundred and eleven patients completed the study. POST occurred in 40.5% of the patients in group G (n = 37) (p = 0.013) and 23.7% of the patients in group A (n = 38) (p < 0.001) within 48 h after surgery, compared to 69.4% in group C (n = 36). There were no significant differences in hoarseness, coughing, and dysphagia across the groups at any time. When comparing groups A and C, individuals in group A exhibited a lower occurrence of significant (grade ≥ 2) POST and hoarseness (10.5% vs. 41.7%, p = 0.002; 26.3% vs. 58.3%, p = 0.005). The incidence of significant cough and dysphagia did not differ substantially across the patient groups within 48 h after surgery. POST scores in group A at 2, 24 h postoperatively were both 0 (0-0), which was significantly lower than those in group C (1 (0-2) at 2 h, p < 0.001 ; 1 (0-1) at 24 h, p = 0.001). POST in group G at 2 h postoperatively was graded as 0 (0-1.5) which was milder than group C (P = 0.024). The severity of hoarseness in group A with scores of 0 (0-2) was superior to that in group C (2 (0-2), p = 0.006) at 2 h postoperatively. CONCLUSIONS: In conclusion, the findings of this study indicated that the occurrence of POST can be reduced by using either the cuff pressure gauge approach or the automated cuff controller method. The automated cuff controller monitoring can potentially decrease the severity of POST and hoarseness. TRIAL REGISTRATION: Chinese Clinical Trial Registry, identifier: ChiCTR2100054089, Date: 08/12/2021.

Effect of subclavian vein diameter combined with perioperative fluid therapy on preventing post-induction hypotension in patients with ASA status I or II.

BACKGROUND: Perioperative hypotension is frequently observed following the initiation of general anesthesia administration, often associated with adverse outcomes. This study assessed the effect of subclavian vein (SCV) diameter combined with perioperative fluid therapy on preventing post-induction hypotension (PIH) in patients with lower ASA status. METHODS: This two-part study included patients aged 18 to 65 years, classified as ASA physical status I or II, and scheduled for elective surgery. The first part (Part I) included 146 adult patients, where maximum SCV diameter (dSCVmax), minimum SCV diameter (dSCVmin), SCV collapsibility index (SCVCI) and SCV variability (SCVvariability) assessed using ultrasound. PIH was determined by reduction in mean arterial pressure (MAP) exceeding 30% from baseline measurement or any instance of MAP < falling below 65 mmHg for ≥ a duration of at least 1 min during the period from induction to 10 min after intubation. Receiver Operating Characteristic (ROC) curve analysis was employed to determine the predictive values of subclavian vein diameter and other relevant parameters. The second part comprised 124 adult patients, where patients with SCV diameter above the optimal cutoff value, as determined in Part I study, received 6 ml/kg of colloid solution within 20 min before induction. The study evaluated the impact of subclavian vein diameter combined with perioperative fluid therapy by comparing the observed incidence of PIH after induction of anesthesia. RESULTS: The areas under the curves (with 95% confidence intervals) for SCVCI and SCVvariability were both 0.819 (0.744-0.893). The optimal cutoff values were determined to be 45.4% and 14.7% (with sensitivity of 76.1% and specificity of 86.7%), respectively. Logistic regression analysis, after adjusting for confounding factors, demonstrated that both SCVCI and SCVvariability were significant predictors of PIH. A threshold of 45.4% for SCVCI was chosen as the grouping criterion. The incidence of PIH in patients receiving fluid therapy was significantly lower in the SCVCI ≥ 45.4% group compared to the SCVCI < 45.4% group. CONCLUSIONS: Both SCVCI and SCVvariability are noninvasive parameters capable of predicting PIH, and their combination with perioperative fluid therapy can reduce the incidence of PIH.

Hydrogen attenuates postoperative pain through Trx1/ASK1/MMP9 signaling pathway.

BACKGROUND: Postoperative pain is a serious clinical problem with a poorly understood mechanism, and lacks effective treatment. Hydrogen (H2) can reduce neuroinflammation; therefore, we hypothesize that H2 may alleviate postoperative pain, and aimed to investigate the underlying mechanism. METHODS: Mice were used to establish a postoperative pain model using plantar incision surgery. Mechanical allodynia was measured using the von Frey test. Cell signaling was assayed using gelatin zymography, western blotting, immunohistochemistry, and immunofluorescence staining. Animals or BV-2 cells were received with/without ASK1 and Trx1 inhibitors to investigate the effects of H2 on microglia. RESULTS: Plantar incision surgery increased MMP-9 activity and ASK1 phosphorylation in the spinal cord of mice. MMP-9 knockout and the ASK1 inhibitor, NQDI-1, attenuated postoperative pain. H2 increased the expression of Trx1 in the spinal cord and in BV-2 cells. H2 treatment mimicked NQDI1 in decreasing the phosphorylation of ASK1, p38 and JNK. It also reduced MMP-9 activity, downregulated pro-IL-1ß maturation and IBA-1 expression in the spinal cord of mice, and ameliorated postoperative pain. The protective effects of H2 were abolished by the Trx1 inhibitor, PX12. In vitro, in BV-2 cells, H2 also mimicked NQDI1 in inhibiting the phosphorylation of ASK1, p38, and JNK, and also reduced MMP-9 activity and decreased IBA-1 expression induced by LPS. The Trx1 inhibitor, PX12, abolished the protective effects of H2 in BV-2 cells. CONCLUSIONS: For the first time, the results of our study confirm that H2 can be used as a therapeutic agent to alleviate postoperative pain through the Trx1/ASK1/MMP9 signaling pathway. MMP-9 and ASK1 may be the target molecules for relieving postoperative pain.

Therapeutic Hypothermia Combined with Hydrogen Sulfide Treatment Attenuated Early Blood-Brain Barrier Disruption and Brain Edema Induced by Cardiac Arrest and Resuscitation in Rat Model.

Brain injury remains a major problem in patients suffering cardiac arrest (CA). Disruption of the blood-brain barrier (BBB) is an important factor leading to brain injury. Therapeutic hypothermia is widely accepted to limit neurological impairment. However, the efficacy is incomplete. Hydrogen sulfide (H2S), a signaling gas molecule, has protective effects after cerebral ischemia reperfusion injury. This study showed that combination of hypothermia and H2S after resuscitation was more beneficial for attenuated BBB disruption and brain edema than that of hypothermia or H2S treatment alone. CA was induced by ventricular fibrillation for 4 min. Hypothermia was performed by applying alcohol and ice bags to the body surface under anesthesia. We used sodium hydrosulphide (NaHS) as the H2S donor. We found that global brain ischemia induced by CA and cardiopulmonary resuscitation (CPR) resulted in brain edema and BBB disruption; Hypothermia or H2S treatment diminished brain edema, decreased the permeability and preserved the structure of BBB during the early period of CA and resuscitation, and more importantly, improved the neurologic function, increased the 7-day survival rate after resuscitation; the combination of hypothermia and H2S treatment was more beneficial than that of hypothermia or H2S treatment alone. The beneficial effects were associated with the inhibition of matrix metalloproteinase-9 expression, attenuated the degradation of the tight junction protein occludin, and subsequently protected the structure of BBB. These findings suggest that combined use of therapeutic hypothermia and hydrogen sulfide treatment during resuscitation of CA patients could be a potential strategy to improve clinical outcomes and survival rate.

Effects of continuous and slow tracheal tube cuff deflation on cough reflex during extubation in noncardiac surgery patients: a randomised clinical trial.

BACKGROUND: The incidence of cough reflex during extubation is 76%. Cough reflex causes severe hemodynamic fluctuations and airway complications. This prospective trial investigated the potential effects of tracheal tube cuff deflation on cough reflex during extubation. METHODS: One hundred and twenty-six patients scheduled for operations within 3 h under general anaesthesia with orotracheal intubation were randomly assigned to one of three groups: control (C), experimental (E) or syringe (S) groups. Patients in group C underwent tracheal tube cuff deflation using a 10-ml syringe in 1 s, patients in group E underwent tracheal tube cuff deflation continuously and slowly in 5 s using a cuff pressure gauge until the pressure was zero and patients in group S underwent tracheal tube cuff deflation using a 10-ml syringe at a speed of 1 ml s-1. The incidence and severity of cough reflexs during extubation and the incidence of postoperative airway complications within 48 h were assessed. RESULTS: Compared with group C (60.0%), the incidence of cough reflex in group E was 9.8% (p < 0.001) and in group S was 12.5% (p < 0.001). The severity of cough reflex was graded as 2 (1-2) in group C, 1 (1-1) in group E and 1 (1-1) in group S (p < 0.001 for group comparisons). The incidence of hoarseness in group C was 0.0%, in group E was 19.5% and in group S was 5.0% (p < 0.05 for all groups, p = 0.009 between group C and E). CONCLUSIONS: Compared with deflating a trachal tube cuff with a 10-ml syringe in 1 s, the use of a 10-ml syringe at a speed of 1 ml s-1 or a cuff pressure guage within 5 s can both reduce the incidence of cough reflex, but deflating with a cuff pressure guage can increase the incidence of postoperative hoarseness. TRIAL REGISTRATION: Chinese Clinical Trial Registry, identifier: ChiCTR2100054089, Date: 08/12/2021.

Risk factors for acute postoperative hypertension in non-cardiac major surgery: a case control study.

PURPOSE: Acute postoperative hypertension (APH) is a common complication during the anesthesia recovery period that can lead to adverse outcomes, including cardiovascular and cerebrovascular accidents. Identification of risk factors for APH will allow for preoperative optimization and appropriate perioperative management. This study aimed to identify risk factors for APH. PATIENTS AND METHODS: In this retrospective single-center study, 1,178 cases were included. Data was entered by two investigators, and consistency analysis was performed by another. Patients were divided into APH and non-APH groups. A predictive model was built by multivariate stepwise logistic regression. The predictive ability of the logistic regression model was tested by drawing the receiver operating characteristic (ROC) curve and calculating the area under the curve (AUC). Hosmer and Lemeshow goodness-of-fit (GOF) test was performed to reflect the goodness of fit of the model. Calibration curve was created to represent the relationship between predicted risk and observed frequency. Sensitivity analysis was performed to evaluate the robustness of the results. RESULTS: Multivariate logistic regression analysis showed that age over 65 years (OR = 3.07, 95% CI: 2.14 ~ 4.42, P < 0.001), female patients (OR = 1.37, 95% CI: 1.02 ~ 1.84, P = 0.034), presence of intraoperative hypertension (OR = 2.15, 95% CI: 1.57 ~ 2.95, P < 0.001), and use of propofol in PACU (OR = 2.14, 95% CI: 1.49 ~ 3.06, P < 0.001) were risk factors for APH. Intraoperative use of dexmedetomidine (OR = 0.66, 95% CI: 0.49 ~ 0.89, P = 0.007) was a protective factor. Higher baseline SBP (OR = 0.90, 95% CI: 0.89 ~ 0.92, P < 0.001) also showed some correlation with APH. CONCLUSIONS: The risk of acute postoperative hypertension increased with age over 65 years, female patients, intraoperative hypertension and restlessness during anesthesia recovery. Intraoperative use of dexmedetomidine was a protective factor for APH.

Pentoxifylline alleviates ischemic white matter injury through up-regulating Mertk-mediated myelin clearance.

BACKGROUND: Vascular dementia (VAD) is the second most common type of dementia lacking effective treatments. Pentoxifylline (PTX), a nonselective phosphodiesterase inhibitor, displays protective effects in multiple cerebral diseases. In this study, we aimed to investigate the therapeutic effects and potential mechanisms of PTX in VAD. METHODS: Bilateral common carotid artery stenosis (BCAS) mouse model was established to mimic VAD. Mouse behavior was tested by open field test, novel object recognition test, Y-maze and Morris water maze (MWM) tests. Histological staining, magnetic resonance imaging (MRI) and electron microscopy were used to define white matter integrity. The impact of PTX on microglia phagocytosis, peroxisome proliferator-activated receptors-γ (PPAR-γ) activation and Mer receptor tyrosine kinase (Mertk) expression was assessed by immunofluorescence, western blotting and flow cytometry with the application of microglia-specific Mertk knockout mice, Mertk inhibitor and PPAR-γ inhibitor. RESULTS: Here, we found that PTX treatment alleviated cognitive impairment in novel object recognition test, Y-maze and Morris water maze tests. Furthermore, PTX alleviated white matter injury in corpus callosum (CC) and internal capsule (IC) areas as shown by histological staining and MRI analysis. PTX-treatment group presented thicker myelin sheath than vehicle group by electron microscopy. Mechanistically, PTX facilitated microglial phagocytosis of myelin debris by up-regulating the expression of Mertk in BCAS model and primary cultured microglia. Importantly, microglia-specific Mertk knockout blocked the therapeutic effects of PTX in BCAS model. Moreover, Mertk expression was regulated by the nuclear translocation of PPAR-γ. Through modulating PPAR-γ, PTX enhanced Mertk expression. CONCLUSIONS: Collectively, our results demonstrated that PTX showed therapeutic potentials in VAD and alleviated ischemic white matter injury via modulating Mertk-mediated myelin clearance in microglia.

Distal radial artery as an alternative approach to forearm radial artery for perioperative blood pressure monitoring: a randomized, controlled, noninferiority trial.

BACKGROUND: The novel distal radial artery (dRA) approach is a popular arterial access route for interventional cardiology and neurointerventions. We explored the dRA as an alternative site to the classic forearm radial artery (RA) for perioperative blood pressure monitoring. We hypothesized that dRA catheterization is noninferior to RA for the first attempt success rate. METHODS: This was a single-center, prospective, randomized controlled, noninferiority study. Adult patients who underwent elective surgery at the Jinling Hospital from May 2021 to August 2021 were enrolled. The primary endpoint was to test the noninferiority of the first attempt success rate between the groups. Secondary endpoints included anatomical characteristics, catheterization time, arterial posterior wall puncture rate, postoperative compression time, dampened arterial pressure waveforms, and complications. RESULTS: Totally, 161 patients who received either dRA (n = 81) or RA (n = 80) catheterization were analyzed. The first attempt success rates were 87.7 and 91.3% in the dRA and RA groups, respectively, with a mean difference of - 3.6% (95% CI, - 13.1 to 5.9%). The dRA diameter and cross-sectional area were significantly smaller than those of the RA (P < 0.001). The subcutaneous depth of dRA was significantly greater than that of the RA (P < 0.001). The dRA had a longer catheterization time (P = 0.008) but a shorter postoperative compression time (P < 0.001). The arterial posterior wall puncture rate of dRA was significantly higher than that of the RA (P = 0.006). The dRA had fewer dampened arterial waveforms than RA (P = 0.030) perioperatively. CONCLUSIONS: The dRA is a rational alternative approach to RA for perioperative arterial pressure monitoring and provides a noninferior first attempt success rate. TRIAL REGISTRATION: This study is registered in the Chinese Clinical Trials Registry (registration number: ChiCTR2100043714 , registration date: 27/02/2021).

Pupil maximum constriction velocity predicts post-induction hypotension in patients with lower ASA status: a prospective observational study.

BACKGROUND: Individuals affected by autonomic dysfunction are at a higher risk of developing hypotension following anesthesia induction. Dynamic pupillometry has previously been employed as a means of assessing autonomic function. This prospective observational study was developed to determine whether pupillary light reflex (PLR) parameters can reliably predict post-induction hypotension (PIH). METHODS: This study enrolled patients with lower ASA status (I-II) undergoing elective surgery. PLR recordings for these patients prior to anesthesia induction were made with an infrared pupil camcorder, with a computer being used to assess Average Constriction Velocity (ACV), Maximum Constriction Velocity (MCV), and Constriction Ratio (CR). PIH was defined by a > 30% reduction in mean arterial pressure (MAP) or any MAP recording < 65 mmHg for at least 1 min from the time of induction until 10 minutes following intubation. Patients were stratified into PIH and non-PIH groups based on whether or not they developed hypotension. RESULTS: This study enrolled 61 total patients, of whom 31 (50.8%) exhibited one or more hypotensive episodes. Patients in the PIH group exhibited significantly smaller ACV (P = 0.003) and MCV values (P < 0.001), as well as a higher CR (P = 0.003). Following adjustment for certain factors (Model 2), MCV was identified as a protective factor for PIH (Odds Ratio: 0.369). Receiver operating characteristic (ROC) analyses revealed that relative to CR (AUC: 0.695, 95% CI: 0.563-0.806; P = 0.004), the reciprocal of MCV (1/MCV) offered greater value as a predictor of PIH (AUC: 0.803,95%CI: 0.681-0.894; P < 0.001). CONCLUSION: These results indicate that pupil maximum constriction velocity is a reliable predictor of post-induction hypotension in individuals of ASA I-II status undergoing elective surgery. TRIAL REGISTRATION: This study was registered with the Chinese Clinical Trial Registry (registration number: ChiCTR2200057164, registration date: 01/03/2022).

Neuroprotective Effect of Hydrogen-Rich Saline in Global Cerebral Ischemia/Reperfusion Rats: Up-Regulated Tregs and Down-Regulated miR-21, miR-210 and NF-κB Expression.

Recently, it has been suggested that molecular hydrogen (H2) can selectively reduce the levels of hydroxyl radicals (.OH), and ameliorate oxidative and inflammatory injuries to organs in global cerebral ischemia reperfusion models. Global cerebral ischemia/reperfusion (I/R) can induce a sudden activation of inflammatory cytokines and later influence the systemic immunoreactivity which may contribute to a worse outcome. Regulatory T cells (Tregs) are involved in several pathological aspects of cerebral I/R. In addition, miRNA took part in the processes of cellular response to hypoxia. Since the expression of a specific set of miRNA called "hypoxamirs" is upregulated by hypoxia. Therefore, the aim of this study was to analyze the effect of HRS on I/R inducing cerebral damage, Tregs, and specific miRNA. Our results showed that rats undergone global cerebral I/R and treated with HRS have milder injury than I/R animals without HRS treatment. miR-210 expression in the hippocampus of the I/R group at 6, 24 and 96 h after reperfusion was significantly increased at each time point, while its expression in the group treated with HRS was significantly decreased. In addition, Tregs number in group I/R was decreased at each time points, while its number in the group treated with HRS was increased at 24 and 96 h after reperfusion. We focus on the relationship among Tregs, TGF-ß1, TNF-α and NF-κB at 24 h, and we found that there is a high correlation among them. Therefore, our results indicated that the brain resuscitation mechanism in the HRS-treated rats may be related with the effect of upregulating the number of Treg cells.

Hydrogen sulphide and mild hypothermia activate the CREB signaling pathway and prevent ischemia-reperfusion injury.

BACKGROUND: Both hydrogen sulphide (H2S) and mild hypothermia have been reported to prevent brain damage caused by reperfusion assault through regulating the N-methyl-D-aspartate receptor (NMDAR). However, the relationship between the two treatments and how they exert neuro-protective effects through NMDARs remain to be elucidated. METHODS: Transient cerebral ischemia was induced using the Pulsinelli four-vessel occlusion method. We used sodium hydrosulphide (NaHS) as the H2S donor. We randomly divided 100 Sprague-Dawley rats into five groups of 20: Sham operation group (Sh), normothermic (36-37 °C) ischemia group (NT), mild hypothermic (32-33 °C) ischemia group (mHT), normothermic ischemia combined with NaHS treatment group (NT + NaHS), and mild hypothermic ischemia combined with NaHS treatment group (mHT + NaHS). After 6 hrs of reperfusion, rats were decapitated and hippocampus samples were immediately collected. We measured NR2A (GluN1), NR2B (GluN2) and p-CREB protein levels using western blotting. We further analyzed BDNF mRNA expression by real-time PCR. Hematoxylin and eosin (HE) staining was used to examine pyramidal cell histology at the CA1 region. All statistical analyses were carried out by ANOVA and LSD t-test as implemented by the SPSS 13.0 software. RESULTS: In the four test groups with ischemia-reperfusion, hippocampal H2S concentration increased following treatment, and administration of NaHS further increased H2S levels. Moreover, administration of both NaHS and mild hypothermia resulted in up-regulation of NR2A and NR2B protein expressions, as well as p-CREB protein and BDNF mRNA levels. At the cellular level, NaHS and mild hypothermia groups exhibited lower damage caused by ischemia-reperfusion in the CA1 region of the hippocampus. The strongest protective effect was observed in rats treated with combined NaHS and mild hypothermia, suggesting their effects were additive. CONCLUSION: Our results support previous findings that hydrogen sulphide and mild hypothermia can prevent ischemia-reperfusion injury. Both treatments caused an up-regulation of NMDA receptors, as well as an elevation in p-CREB protein and BDNF mRNA levels. Thus, hydrogen sulphide and mild hypothermia may provide neuro-protective effect through activating the pro-survival CREB signaling pathway.

[Role of FOXO3a in process of hydrogen-rich saline attenuating global cerebral ischemia-reperfusion injury in rats].

OBJECTIVE: To investigate the role of FOXO3a in process of hydrogen-rich saline attenuating global cerebral ischemia-reperfusion (I/R) injury in rats. METHODS: Seventy-two male Sprague Dawley rats, weighing 280-320 g, were randomly divided into six groups (n = 12 each) : sham operation group (group I), cerebral ischemia-reperfusion group (group II), hydrogen-rich saline group (group III), vehicle group (group IV), JNK inhibitor SP600125 group (group V), JNK inhibitor+hydrogen-rich saline group (group VI). Global cerebral I/R was produced by transesophageal pacing inducing cardiac arrest (CA) method. Cardiopulmonary resuscitation (CPR) and mechanical ventilation was implemented at the end of 4 min for CA. In groups III and VI, hydrogen-rich saline 5 ml/kg was intraperitoneally immediately and 6 hours after reperfusion, while equel volume of nomal saline was injected in the other four groups. The rats in groups V and VI received intracerebroventricular injection of JNK inhibitor SP600125 10 µl 30 min before ischemia, while group IV received intracerebroventricular injection of equal volume of DMSO. Neuro Deficit Score (NDS) was evaluated at 24 h of reperfusion. Then rats were sacrificed, and the global brain tissues were obtained and stained with HE for examination of the changes in pyramidal cells in the CA1 region of hippocampus. The bilateral hippocampi were romoved for detection of the expression of p-JNK, JNK and FOXO3a using Western Blotting. RESULTS: Compared with group I, the expression of p-JNK, nuclear FOXO3a and the level of NDS were significantly up-regulated, and the number of pyramidal cells and was decreased in group II and IV. Compared with group II, the expression of p-JNK, nuclear FOXO3a and the level of NDS were significantly down-regulated, and the number of pyramidal cells was increased in group III, V and VI. CONCLUSION: Hydrogen-rich saline can attenuate global cerebral I/R injure through inhibiting JNK, reducing the expression of FOXO3a.

Hydrogen-rich saline attenuates neuronal ischemia--reperfusion injury by protecting mitochondrial function in rats.

BACKGROUND: Hydrogen, a popular antioxidant gas, can selectively reduce cytotoxic oxygen radicals and has been found to protect against ischemia-reperfusion (I/R) injury of multiple organs. Acute neuronal death during I/R has been attributed to loss of mitochondrial permeability transition coupled with mitochondrial dysfunction. This study was designed to investigate the potential therapeutic effect of hydrogen-rich saline on neuronal mitochondrial injury from global cerebral I/R in rats. MATERIALS AND METHODS: We used a four-vessel occlusion model of global cerebral ischemia and reperfusion, with Sprague-Dawley rats. The rats were divided randomly into six groups (n = 90): sham (group S), I/R (group I/R), normal saline (group NS), atractyloside (group A), hydrogen-rich saline (group H), and hydrogen-rich saline + atractyloside (group HA). In groups H and HA, intraperitoneal hydrogen-rich saline (5 mL/kg) was injected immediately after reperfusion, whereas the equal volume of NS was injected in the other four groups. In groups A and HA, atractyloside (15 µL) was intracerebroventricularly injected 10 min before reperfusion, whereas groups NS and H received equal NS. The mitochondrial permeability transition pore opening and mitochondrial membrane potential were measured by spectrophotometry. Cytochrome c protein expression in the mitochondria and cytoplasm was detected by western blot. The hippocampus mitochondria ultrastructure was examined with transmission electron microscope. The histologic damage in hippocampus was assessed by hematoxylin and eosin staining. RESULTS: Hydrogen-rich saline treatment significantly improved the amount of surviving cells (P < 0.05). Furthermore, hydrogen-rich saline not only reduced tissue damage, the degree of mitochondrial swelling, and the loss of mitochondrial membrane potential but also preserved the mitochondrial cytochrome c content (P < 0.05). CONCLUSIONS: Our study showed that hydrogen-rich saline was able to attenuate neuronal I/R injury, probably by protecting mitochondrial function in rats.

[Effects of mild hypothermia plus ifenprodil on apoptosis inducing factor translocation after global cerebral ischemia-reperfusion in rats].

OBJECTIVE: To explore the effects of mild hypothermia combined with ifenprodil on the survival of neuronal and translocation of apoptosis inducing factor (AIF) following global cerebral ischemia-reperfusion to understand the mechanism of combination in cerebral resuscitation. METHODS: Eighty male SD rats were randomly divided into 5 groups of sham (I), model (II), ifenprodil (III), mild hypothermia (IV) and ifenprodil plus mild hypothermia (V) (n = 16 each). Group I completed all procedures except for ventricular fibrillation (VF) and cardio pulmonary resuscitation (CPR). For groups II and V, the model of global cerebral ischemia-reperfusion was established and VF induced with transoesophageal cardiac pacing; groups III and V received by an intraperitoneal injection of ifenprodil immediately after reperfusion and other groups had an equal volume of distilled water. Rectal temperature was cooled down to (32 ± 1)°C in groups IV and V by rubbing body surface with ethanol in 10 min after reperfusion and maintained 4 hours continuously while other groups at (37 ± 1)°C. In hippocampal CA1 region at 24 hours after reperfusion, the pathomorphological changes and quantity of pyramidal cells were detected with hematoxylin and eosin staining, nuclear translocation of AIF was shown with immunofluorescence technique and the nuclear expression level of AIF was measured with Western blot. RESULTS: Compared with group I (75.0 ± 3.2), the number of pyramidal cells decreased in other groups (P < 0.05); compared with group II (36.0 ± 1.2), the number increased in group III (46.8 ± 1.3), IV (49.0 ± 2.7) and V (61.3 ± 2.60) (P < 0.05). In particular, cell count increased significantly in group V (P < 0.05). Compared to group I, the translocation of AIF form mitochondria to nucleus was detected in other groups; compared with group I (0.022 ± 0.003), the expression level of AIF in the nucleus was higher in other groups (P < 0.05). Compared with group II (1.020 ± 0.029) , the expression levels of AIF in groups III (0.870 ± 0.016), IV (0.820 ± 0.050) and V (0.550 ± 0.050) were lower (P < 0.05). And it decreased significantly in group V (P < 0.05). CONCLUSION: Mild hypothermia plus ifenprodil may alleviate neuronal damage after global cerebral ischemia/reperfusion injury through mitigating its pro-apoptotic role after AIF translocation.

Cold inducible RNA binding protein-regulated mitochondria associated endoplasmic reticulum membranes-mediated Ca2+ transport play a critical role in hypothermia cerebral resuscitation.

Cardiac arrest is a global health issue causing more deaths than many other diseases. Hypothermia therapy is commonly used to treat secondary brain injury resulting from cardiac arrest. Previous studies have shown that CIRP is induced in specific brain regions during hypothermia and inhibits mitochondrial apoptotic factors. However, the specific mechanisms by which hypothermia-induced CIRP exerts its anti-apoptotic effect are still unknown. This study aims to investigate the role of Cold-inducible RNA-binding protein (CIRP) in mitochondrial-associated endoplasmic reticulum membrane (MAM)-mediated Ca2+ transport during hypothermic brain resuscitation.We constructed a rat model of cardiac arrest and resuscitation and hippocampal neuron oxygen-glucose deprivation/reoxygenation model. We utilized shRNA transfection to interfere the expression of CIRP and observe the effect of CIRP on the structure and function of MAM.Hypothermia induced CIRP can reduce the apoptosis of hippocampal neurons, and improve the survival rate of rats. Hypothermia induced CIRP can reduce the expressions of calcium transporters IP3R and VDAC1 in MAM, reduce the concentration of calcium in mitochondria, decrease the expression of ROS, and stabilize the mitochondrial membrane potential. Immunofluorescence and immunocoprecipitation showed that CIRP could directly interact with IP3R-VDAC1 complex, thereby changing the structure of MAM, inhibiting calcium transportation and improving mitochondrial function in vivo and vitro.Both in vivo and in vitro experiments have confirmed that hypothermia induced CIRP can act on the calcium channel IP3R-VDAC1 in MAM, reduce the calcium overload in mitochondria, improve the energy metabolism of mitochondria, and thus play a role in neuron resuscitation. This study contributes to understanding hypothermia therapy and identifies potential targets for brain injury treatment.

Oxytocin ameliorates cognitive impairments by attenuating excitation/inhibition imbalance of neurotransmitters acting on parvalbumin interneurons in a mouse model of sepsis-associated encephalopathy.

Inflammation plays a crucial role in the initiation and progression of sepsis, and it also induces alterations in brain neurotransmission, thereby contributing to the development of sepsis-associated encephalopathy (SAE). Parvalbumin (PV) interneurons are pivotal contributors to cognitive processes in various central dysfunctions including SAE. Oxytocin, known for its ability to augment the firing rate of gamma-aminobutyric acid (GABA)ergic interneurons and directly stimulate inhibitory interneurons to enhance the tonic inhibition of pyramidal neurons, has prompted an investigation into its potential effects on cognitive dysfunction in SAE. In the current study, we administered intranasal oxytocin to the SAE mice induced by lipopolysaccharide (LPS). Behavioral assessments, including open field, Y-maze, and fear conditioning, were used to evaluate cognitive performance. Golgi staining revealed hippocampal synaptic deterioration, local field potential recordings showed weakened gamma oscillations, and immunofluorescence analysis demonstrated decreased PV expression in the cornu ammonis 1 (CA1) region of the hippocampus following LPS treatment, which was alleviated by oxytocin. Furthermore, immunofluorescence staining of PV co-localization with vesicular glutamate transporter 1 or vesicular GABA transporter indicated a balanced excitation/inhibition effect of neurotransmitters on PV interneurons after oxytocin administration in the SAE mice, leading to improved cognitive function. In conclusion, cognitive function improved after oxytocin treatment. The number of PV neurons in the hippocampal CA1 region and the balance of excitatory/inhibitory synaptic transmission on PV interneurons, as well as changes in local field potential gamma oscillations in the hippocampal CA1 region, may represent its specific mechanisms.

Hydrogen alleviates impaired lung epithelial barrier in acute respiratory distress syndrome via inhibiting Drp1-mediated mitochondrial fission through the Trx1 pathway.

Acute respiratory distress syndrome (ARDS) is an acute and severe clinical complication lacking effective therapeutic interventions. The disruption of the lung epithelial barrier plays a crucial role in ARDS pathogenesis. Recent studies have proposed the involvement of abnormal mitochondrial dynamics mediated by dynamin-related protein 1 (Drp1) in the mechanism of impaired epithelial barrier in ARDS. Hydrogen is an anti-oxidative stress molecule that regulates mitochondrial function via multiple signaling pathways. Our previous study confirmed that hydrogen modulated oxidative stress and attenuated acute pulmonary edema in ARDS by upregulating thioredoxin 1 (Trx1) expression, but the exact mechanism remains unclear. This study aimed to investigate the effects of hydrogen on mitochondrial dynamics both in vivo and in vitro. Our study revealed that hydrogen inhibited lipopolysaccharide (LPS)-induced phosphorylation of Drp1 (at Ser616), suppressed Drp1-mediated mitochondrial fission, alleviated epithelial tight junction damage and cell apoptosis, and improved the integrity of the epithelial barrier. This process was associated with the upregulation of Trx1 in lung epithelial tissues of ARDS mice by hydrogen. In addition, hydrogen treatment reduced the production of reactive oxygen species in LPS-induced airway epithelial cells (AECs) and increased the mitochondrial membrane potential, indicating that the mitochondrial dysfunction was restored. Then, the expression of tight junction proteins occludin and zonula occludens 1 was upregulated, and apoptosis in AECs was alleviated. Remarkably, the protective effects of hydrogen on the mitochondrial and epithelial barrier were eliminated after applying the Trx1 inhibitor PX-12. The results showed that hydrogen significantly inhibited the cell apoptosis and the disruption of epithelial tight junctions, maintaining the integrity of the epithelial barrier in mice of ARDS. This might be related to the inhibition of Drp1-mediated mitochondrial fission through the Trx1 pathway. The findings of this study provided a new theoretical basis for the application of hydrogen in the clinical treatment of ARDS.

Hydrogen ameliorates endotoxin-induced acute lung injury through AMPK-mediated bidirectional regulation of Caspase3.

Septic lung injury is characterized by uncontrollable inflammatory infiltrations and acute onset bilateral hypoxemia. Evidence has emerged of the beneficial effect of hydrogen in acute lung injury (ALI), but the underlying mechanism is unclear. In this research, the recovery action of hydrogen on lipopolysaccharide (LPS)-induced ALI in mice and A549 cells was investigated. The 7-day survival rate and body weight of mice were measured after intraperitoneal injection of LPS. Lung function was determined by a whole body plethysmography (WBP) system using the indicators respiratory rate and enhanced pause. Hematoxylin and eosin (HE) staining confirmed the signs of pulmonary edema and inflammatory ooze. Reverse transcription-polymerase chain reaction (RT-PCR) quantification was used to detect the expression of inflammatory factors. Western blotting analysis evaluated the expression levels of involved proteins in the AMP-activated protein kinase (AMPK) pathway. The experimental results confirmed that hydrogen provided an essential solution to the dissipative effects of LPS on survival rate, weight loss and lung function. The LPS-stimulated inflammatory factors, interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α) and interleukin-1ß (IL-1ß) were also suppressed by hydrogen in A549 cells. Western blot analysis showed that hydrogen significantly upregulated the levels of phosphorylated AMPK (p-AMPK) and lowered the LPS-induced increased expression of dynamin-related protein 1 (Drp1) and Caspase3. These findings prove that hydrogen attenuated LPS-treated ALI by activating the AMPK pathway, supporting the feasibility of hydrogen treatment for sepsis.

Use of hypophysin in hypotensive patients with low systemic vascular resistance following cardiopulmonary bypass.

OBJECTIVE: This study aimed to test the effects of hypophysin on hemodynamics and coronary artery caliber of patients with hypotension and decreased systemic vascular resistance (SVR) following cardiopulmonary bypass (CPB). METHODS: Twenty-four patients with mean arterial pressure (MAP) < 60 mmHg, mean aorta pressure < 70 mmHg, SVR < 800 dynes.sec.cm-5, cardiac index (CI) > 2.5 l.min-1.m-2, central venous pressure > 8 mmHg and refractory to dopamine, norepinephrine, and fluid resuscitation were treated with hypophysin at an initial dose of 0.6 IU and a continuous infusion rate of 1 - 4 IU/h till the end of operation. The hemodynamics and the diameter of proximal left main coronary artery were evaluated before incision, before hypophysin administration, 5 min after hypophysin administration, and at the end of operation. RESULTS: MAP, SVR, and the diameter of proximal left main coronary artery increased whereas heart rate, CI, stroke volume index, and mean pulmonary artery pressure had no significant changes after hypophysin administration compared with before hypophysin administration. All hypophysin-treated patients successfully recovered. CONCLUSION: Hypophysin may improve the hemodynamics and dilate the proximal left main coronary artery in hypotensive patients with low SVR following CPB.