Effects of esketamine on postoperative rebound pain in patients undergoing unilateral total knee arthroplasty: a single-center, randomized, double-blind, placebo-controlled trial protocol.

Introduction: Rebound pain, transient and acute postoperative pain after the disappearance of regional block anesthesia, has been a concern in recent years. Insufficient preemptive analgesia and hyperalgesia induced by regional block are the main mechanisms. At present, the evidence for the treatment of rebound pain is limited. The esketamine, as an antagonist of the N-methyl-D-aspartate receptor, has been proven to prevent hyperalgesia. Therefore, this trial aims to evaluate the impact of esketamine on postoperative rebound pain in patients undergoing total knee arthroplasty. Methods/design: This study is a single-center, prospective, double-blind, randomized, placebo-controlled trial. Participants who plan to undergo total knee arthroplasty will be randomly assigned to the esketamine group (N = 178) and placebo group (N = 178) in a ratio of 1:1. This trial aims to evaluate the impact of esketamine on postoperative rebound pain in patients undergoing total knee arthroplasty. The primary outcome of this trial is the incidence of rebound pain within 12 h after the operation in the esketamine group and the placebo group. The secondary outcome will be to compare (1) the incidence of rebound pain 24 h after the operation; (2) the time to enter the pain cycle for the first time within 24 h after the procedure; (3) the first time of rebound pain occurred within 24 h after surgery; (4) the modified rebound pain score; (5) NRS score under rest and exercise at different time points; (6) the cumulative opioid consumption at different time points; (7) patient's prognosis and knee joint function evaluation; (8) blood glucose and cortisol concentration; (9) patient's satisfaction score; (10) adverse reactions and adverse events. Discussion: The effect of ketamine on preventing postoperative rebound pain is contradictory and uncertain. The affinity of esketamine to the N-methyl-D-aspartate receptor is about four times higher than levo-ketamine, the analgesic effect is 3 times higher than levo-ketamine, and there are fewer adverse mental reactions. To our knowledge, there is no randomized controlled trial to verify the impact of esketamine on postoperative rebound pain in patients undergoing total knee arthroplasty. Therefore, this trial is expected to fill an important gap in relevant fields and provide novel evidence for individualized pain management. Clinical Trial Registration: http://www.chictr.org.cn, identifier ChiCTR2300069044.

Effects of NBP on postoperative cognitive dysfunction in rats via Nrf 2/ARE pathway.

OBJECTIVE: Postoperative cognitive dysfunction (POCD) is a common postoperative disease that threatens patients' quality of life, especially elderly patients. With the popularity of anesthesia/surgery, POCD has received more attention worldwide. The objective of this research is to evaluate 3-n-Butylphthalide (NBP)'s protective effect on postoperative cognitive function in rats and its related mechanisms. METHODS: Tibial fracture models of senile rats of POCD were established and divided into blank control group, solvent group, NBP group, Nrf 2 agonist group, and Nrf 2 inhibitor group. The changes in the cognitive abilities of rats were systematically evaluated by the Morris water maze test. After hematoxylin-eosin (HE) staining of the hippocampus, the morphological and structural changes of hippocampal neurons were observed by light microscopy. The expressions of apoptosis-related proteins were analyzed by immunohistochemistry and Western blot was used to detect the expressions of Nrf 2,HO-1,Mfn1,Mfn2,Drp1 proteins. Moreover, the changes in the morphology of mitochondria were observed by transmission electron microscopy. RESULTS: Through the water maze test, we observed that the incidence of postoperative cognitive impairment in the NBP, agonist, and inhibitor groups was substantially lower as compared to the blank control group and solvent group (P < 0.05). The expressions of Nrf 2, HO-1, Mfn1, Mfn2, and Drp1 proteins in the NBP group were upregulated in comparison to the blank control group and the solvent group. The expressions of related proteins in the inhibitor group were substantially lower in comparison to the NBP group. CONCLUSIONS: NBP can affect the postoperative cognitive function of rats by activating the Nrf 2/ARE signaling pathway.

Ultrasound-guided posterior quadratus lumborum block can reduce postoperative opioid consumption and promote rapid recovery in patients undergoing sutureless laparoscopic partial nephrectomy: A triple-blind, randomized, controlled study.

Purpose: We hypothesized that posterior quadratus lumborum block would reduce postoperative opioid consumption and improve the quality of recovery in patients undergoing sutureless laparoscopic partial nephrectomy. Materials and methods: The study included 60 patients, ages 18-65 with American Society of Anesthesiologists scores of I-II scheduled for elective sutureless laparoscopic partial nephrectomy. Before general anesthesia, 60 participating patients were randomly allocated to receive a 30-ml injection posterior to the quadratus lumborum muscle with either 0.375% ropivacaine (n = 30) or normal saline (n = 30). The primary outcomes included cumulative opioid consumption within 12 h postoperatively and quality of postoperative recovery at 48 h. Secondary outcomes included the Numerical Rating Scale (NRS), opioid consumption by period, first time to press the analgesic pump, number of patients needing rescue analgesia, blood glucose and cortisol concentrations, early postoperative recovery indicators, and adverse events. Results: There were 48 patients included in the final analysis. The intervention group had lower cumulative consumption of sufentanil within 12 h postoperatively and higher quality of postoperative recovery scores at 48 h postoperatively compared with the control group (p < 0.001). The NRS at resting and movement of the intervention group was lower at 0 h, 6 h, and 12 h after surgery than in the control group (p < 0.05). At prespecified intervals (0 to 2 h, 2 to 6 h, 6 to 12 h, 12 to 24 h, and 24 to 48 h) after surgery, the intervention group had lower consumption of sufentanil compared with the control group (p < 0.05). The intervention group took longer to press the analgesic pump for the first time within 48 h after surgery compared with the control group (p < 0.001). The postoperative blood glucose and cortisol concentrations in the intervention group were lower than in the control group (p < 0.05). The times to first excretion, ambulation, and discharge were shorter in the intervention group compared with the control group (p < 0.05). There was no significant difference in adverse events between the two groups. Conclusions: Our trial demonstrated that patients who received posterior quadratus lumborum block had significantly lower opioid consumption within 12 h postoperatively and had a better quality of recovery at 48 h postoperatively. Therefore, we recommend posterior quadratus lumborum block as an option for postoperative analgesia in patients undergoing sutureless laparoscopic partial nephrectomy. Trial Registration: http://www.chictr.org.cn, identifier ChiCTR2100053439.

Mechanisms of Dexmedetomidine in Neuropathic Pain.

Dexmedetomidin is a new-generation, highly selective α2 adrenergic receptor agonist with a large number of advantages, including its sedative and analgesic properties, its ability to inhibit sympathetic nerves, its reduced anesthetic dosage, its hemodynamic stability, its mild respiratory depression abilities, and its ability to improve postoperative recognition. Its safety and effectiveness, as well as its ability to provide a certain degree of comfort to patients, make it a useful anesthetic adjuvant for a wide range of clinical applications. For example, dexmedetomidine is commonly used in patients undergoing general anesthesia, and it also exerts sedative effects during tracheal intubation or mechanical ventilation in intensive care unit patients. In recent years, with the deepening of clinical research on dexmedetomidine, the drug is still applied in the treatment of spastic pain, myofascial pain, neuropathic pain, complex pain syndrome, and chronic headache, as well as for multimodal analgesia. However, we must note that the appropriateness of patient and dose selection should be given attention when using this drug; furthermore, patients should be observed for adverse reactions such as hypotension and bradycardia. Therefore, the safety and effectiveness of this drug for long-term use remain to be studied. In addition, basic experimental studies have also found that dexmedetomidine can protect important organs, such as the brain, heart, kidney, liver, and lung, through various mechanisms, such as antisympathetic effects, the inhibition of apoptosis and oxidative stress, and a reduction in the inflammatory response. Moreover, the neuroprotective properties of dexmedetomidine have received the most attention from scholars. Hence, in this review, we mainly focus on the characteristics and clinical applications of dexmedetomidine, especially the role of dexmedetomidine in the nervous system and the use of dexmedetomidine in the relief of neuropathic pain.

Maternally inherited coronary heart disease is associated with a novel mitochondrial tRNA mutation.

BACKGROUND: Coronary heart disease (CHD) is the most common cause of mortality globally, yet mitochondrial genetic mutations associated with CHD development remain incompletely understood. METHODS: The subjects from three Chinese families with LHON underwent clinical, genetic, molecular, and biochemical evaluations. Biochemical characterizations included measuring the effects of the15910C > T mutation on tRNAThr levels, enzymatic activity of electron transport chain complexes, membrane permeability, and the mitochondria-mediated generation of both reactive oxygen species (ROS) and adenosine triphosphate (ATP). RESULTS: We characterize mitochondrial genetic mutations in a three-generation Chinese family exhibiting signs of maternally inherited CHD. Of the 24 different family members in this pedigree we assessed, CHD was detected in 6, with variable severity and age of first appearance. When we sequenced the mitochondrial genomes of these individuals, we found a tRNAThr 15910C > T mutation of the Eastern Asian haplogroup M7b'c. This mutation is predicted to destabilize the strongly conserved (24C-10G) base-pairing, thereby disrupting tRNAThr functionality. When we performed Northern blotting, we detected we observed a 37.5% reduction in tRNAThr levels at baseline in cybrid cell lines bearing the 15910C > T mutation. When we conducted western blot analysis, we detected a ~ 24.96% decrease in mitochondrial translation rates in these same cells. CONCLUSIONS: In the present report, Together these findings suggest a possible link between this 15910C > T tRNAThr mutation and CHD, potentially offering new avenues for future disease intervention.

Skullcapflavone I protects cardiomyocytes from hypoxia-caused injury through up-regulation of lincRNA-ROR.

Myocardial infarction (MI) is a serious heart disease in which cardiomyocytes are damaged, caused by hypoxia. This study explored the possible protective activity of Skullcapflavone I (SF I), a flavonoid isolated from the root of Scutellaria baicalensis Georgi, on hypoxia-stimulated cardiomyocytes cell injury in vitro. Viability and apoptosis of H9c2 cells and primary cardiomyocytes were tested using cell counting kit-8 (CCK-8) assay and Guava Nexin Reagent, respectively. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) was used to measure the long non-coding RNA regulator of reprogramming (lincRNA-ROR) expression. si-ROR was transfected to knockdown lincRNA-ROR. Western blotting was conducted to assess the protein levels of key molecules related to cell proliferation, apoptosis, and mitogen-activated protein kinase/extracellular signal-regulated kinase (MEK/ERK) pathway. We discovered that hypoxia stimulation obviously reduced H9c2 cell and primary cardiomyocytes' viability and proliferation, but promoted cell apoptosis. SF I treatment mitigated the cell viability and proliferation inhibition, as well as cell apoptosis caused by hypoxia. Moreover, SF I promoted the hypoxia-caused up-regulation of lincRNA-ROR in H9c2 cells and primary cardiomyocytes. Knockdown of lincRNA-ROR reversed the influence of SF I on hypoxia-stimulated H9c2 cells and primary cardiomyocytes. Besides, SF I activated MEK/ERK pathway in H9c2 cells and primary cardiomyocytes via up-regulating lincRNA-ROR. To sum up, our research verified the beneficial activity of SF I on hypoxia-caused cardiomyocytes injury. SF I protected cardiomyocytes from hypoxia-caused injury through up-regulation of lincRNA-ROR and activation of MEK/ERK pathway.

The Application and Analytical Pathway of Dexmedetomidine in Ischemia/Reperfusion Injury.

Ischemia/reperfusion cerebral injury can cause serious damage to nerve cells. The injured organelles are cleared by autophagy eventually, which is critical for cell survival. Dexmedetomidine is neuroprotective in various ischemia/reperfusion models. Mitochondrial calcium uniporter (MCU) is the most important channel of mitochondrial Ca2+ influx into mitochondria, where Ca2+ has a potential effect on mitochondrial autophagy. However, the role of MCU in the changes of mitophagy and autophagy caused by dexmedetomidine is unknown. In this study, we constructed an in vitro I/R model by subjecting the oxygen and glucose deprivation/reperfusion model to SH-SY5Y cells to mimic the cerebral I/R injury. We found that postconditioning with dexmedetomidine and 3-methyladenine (3MA, an autophagy inhibitor) increased the cell survival meanwhile reduced the production of autophagic vesicles and the expression of LC3 and Beclin 1. This process also increased the expression of BCL-2, P62, and TOM20. After applied with spermine (MCU-specific agonist), the expression of autophagy proteins by dexmedetomidine was reversed, and the same changes were also observed in immunofluorescence. The results of our study suggested that dexmedetomidine can inhibit MCU and reduce excessive mitophagy and autophagy for conferring protection against I/R injury.

Alpha 1-antitrypsin ameliorates ventilator-induced lung injury in rats by inhibiting inflammatory responses and apoptosis.

Mechanical ventilation is extensively used to treat patients with lung injury but may result in ventilator-induced lung injury (VILI). The present study investigated the protective effect of alpha 1-antitrypsin (AAT) on VILI. Adult male rats were subjected to sham, ventilation + saline, or ventilation + AAT treatment and lung injuries were evaluated. Peripheral blood and bronchoalveolar lavage fluid (BALF) were obtained to assess systemic and local inflammatory responses, respectively. Mechanical ventilation resulted in lung injury, as evidenced by histological abnormalities as well as elevations in PaO2/FiO2 ratio, the wet-to-dry weight ratio, and the BALF level of proteins. The intravenous administration of AAT significantly improved these parameters of lung function, suggesting a protective role of AAT in VILI. Mechanistically, ventilator-induced inflammation was effectively reduced by AAT, as evidenced by decreases in BALF neutrophil counts, BALF cytokines, and serum adhesion factors. In contrast, anti-inflammatory interleukin-10 in BALF was increased in response to AAT. AAT treatment also inhibited the expression of nuclear factor-κB, Bax, and cleaved caspase-3 while promoting Bcl-2 expression in ventilator-injured lung tissues. AAT treatment can ameliorate VILI by inhibiting inflammatory mediator production and apoptosis. Impact statement Mechanical ventilation has been commonly used to treat patients with lung injury but may result in ventilator-induced lung injury (VILI). Few effective treatment options are currently available to reduce VILI. Alpha 1-antitrypsin (AAT) is an inhibitor of serine protease with anti-inflammatory and antiapoptotic properties, suggesting a possible role in attenuating lung injury. The present study demonstrates that AAT inhibits the development of VILI by modulating inflammation- and apoptosis-related protein expression. Therefore, AAT may be a novel therapeutic agent for acute respiratory distress syndrome patients undergoing mechanical ventilation.