Exploring the impact of dexmedetomidine on short-term outcomes in critically ill sepsis-associated encephalopathy patients.

OBJECTIVE: Dexmedetomidine has demonstrated potential in preclinical medical research as a protective agent against inflammatory injuries and a provider of neuroprotective benefits. However, its effect on the short-term prognosis of patients with sepsis-associated encephalopathy remains unclear. This study aims to explore the underlying value of dexmedetomidine in these patients. PATIENTS AND METHODS: This study enrolled patients with sepsis-associated encephalopathy from the Medical Information Mart for Intensive Care (MIMIC)-IV database, and they were divided into two groups based on dexmedetomidine therapy during hospitalization. Propensity score matching (PSM) and inverse probability of treatment weighting (IPTW) were utilized to balance the inter-group baseline differences. Kaplan-Meier (KM) curves with log-rank test and subgroup analysis were also employed. The primary outcome was 28-day mortality, and the secondary outcomes were in-hospital mortality, intensive care unit (ICU) stay time, hospital stay time, and the incidence of ventilator-associated pneumonia (VAP). RESULTS: After PSM, 1,075 pairs of patients were matched. In contrast to the non-dexmedetomidine cohort, the dexmedetomidine cohort did not exhibit a shortened ICU [4.65 (3.16, 8.55) vs. 6.14 (3.66, 11.04), p<0.001] and hospital stay duration [10.04 (6.55, 15.93) vs. 12.76 (7.92, 19.95), p<0.001], and there was an elevated incidence of VAP [90 (8.4%) vs. 135 (12.6%), p=0.002]. The log-rank test for the KM curves of dexmedetomidine use and 28-day mortality was statistically significant (p<0.001). The results showed that dexmedetomidine was associated with improved 28-day mortality [hazard ratio (HR) 0.46, 95% confidence interval (CI) 0.35-0.61, p<0.001] and in-hospital mortality (HR 0.50, 95% CI 0.37-0.67, p<0.001) after adjusting for various confounders. In the following subgroup analysis, dexmedetomidine infusion was associated with decreased 28-day mortality in most subgroups. CONCLUSIONS: Dexmedetomidine administration was significantly associated with reduced short-term mortality among patients with sepsis-associated encephalopathy in the ICU. However, it also prolonged ICU and hospital stays and increased the incidence of VAP.

Comparative study between remifentanil (or fentanyl) and dexmedetomidine for the analgesia of rhinoplasty: A meta-analysis of randomized controlled trials.

BACKGROUND: Remifentanil (or fentanyl) and dexmedetomidine may have some potential to improve the analgesia of rhinoplasty, and this meta-analysis aims to compare their efficacy for the analgesia of rhinoplasty. METHODS: PubMed, Embase, Web of Science, EBSCO, and Cochrane Library databases were systematically searched, and we included randomized controlled trials (RCTs) assessing the analgesic effect of remifentanil (or fentanyl) versus dexmedetomidine for rhinoplasty. RESULTS: Four RCTs were finally included in the meta-analysis. In patients undergoing rhinoplasty, remifentanil (or fentanyl) infusion and dexmedetomidine infusion resulted in similar good patient satisfaction (odd ratio [OR] = 2.71; 95% confidence interval [CI] = 0.63 to 11.64; P = .18), good surgeon satisfaction (OR = 1.68; 95% CI = 0.02 to 181.40; P = .83), extubation time (mean difference [MD] = 7.56; 95% CI = -11.00 to 26.12; P = .42), recovery time (MD = -2.25; 95% CI = -23.41 to 18.91; P = .83), additional analgesic requirement (OR = 0.16; 95% CI = 0 to 8.65; P = .37) and adverse events (OR = 8.50; 95% CI = 0.47 to 153.30; P = .15). CONCLUSIONS: Remifentanil (or fentanyl) and dexmedetomidine may have comparable analgesia for patients undergoing rhinoplasty.

Intravenous infusion of dexmedetomidine during the surgery to prevent postoperative delirium and postoperative cognitive dysfunction undergoing non-cardiac surgery: a meta-analysis of randomized controlled trials.

BACKGROUND: Dexmedetomidine plays a pivotal role in mitigating postoperative delirium and cognitive dysfunction while enhancing the overall quality of life among surgical patients. Nevertheless, the influence of dexmedetomidine on such complications in various anaesthesia techniques remains inadequately explored. As such, in the present study, a meta-analysis was conducted to comprehensively evaluate its effects on postoperative delirium and cognitive dysfunction. METHODS: A number of databases were searched for randomised controlled trials comparing intravenous dexmedetomidine to other interventions in preventing postoperative delirium and cognitive dysfunction in non-cardiac and non-neurosurgical patients. These databases included PubMed, Embase, and Cochrane Library. Statistical analysis and graphing were performed using Review Manager, STATA, the second version of the Cochrane risk-of-bias tool for randomised controlled trials, and GRADE profiler. MAIN RESULTS: This meta-analysis comprised a total of 24 randomised controlled trials, including 20 trials assessing postoperative delirium and 6 trials assessing postoperative cognitive dysfunction. Across these 24 studies, a statistically significant positive association was observed between intravenous administration of dexmedetomidine and a reduced incidence of postoperative delirium (RR: 0.55; 95% CI 0.47 to 0.64, p < 0.00001, I2 = 2%) and postoperative cognitive dysfunction (RR: 0.60; 95% CI 0.38 to 0.96, p = 0.03, I2 = 60%). Subgroup analysis did not reveal a significant difference in the incidence of postoperative delirium between the general anaesthesia and non-general anaesthesia groups, but a significant difference was observed in the incidence of postoperative cognitive dysfunction. Nonetheless, when the data were pooled, it was evident that the utilisation of dexmedetomidine was associated with an increased incidence of hypotension (RR: 1.42; 95% CI 1.08 to 1.86, p = 0.01, I2 = 0%) and bradycardia (RR: 1.66; 95% CI 1.23 to 2.26, p = 0.001, I2 = 0%) compared with other interventions. However, there was no significantly higher occurrence of hypertension in the DEX groups (RR = 1.35, 95% CI 0.81-2.24, p = 0.25, I2 = 0%). CONCLUSION: Compared with other interventions, intravenous dexmedetomidine infusion during non-cardiac and non-neurosurgical procedures may significantly reduce the risk of postoperative delirium and cognitive dysfunction. The results of subgroup analysis reveal a consistent preventive effect on postoperative delirium in both general and non-general anaesthesia groups. Meanwhile, continuous infusion during general anaesthesia was more effective in reducing the risk of cognitive dysfunction. Despite such findings, hypotension and bradycardia were more frequent in patients who received dexmedetomidine during surgery.

Dexmedetomidine for Preventing Sleep Disturbance after Ambulatory Anesthesia: A Case Report.

Propofol anesthesia may impact a patient's sleep quality in the immediate postprocedure timeframe. We describe a 24-year-old man presenting for gastrostomy-jejunostomy tube replacement who reported debilitating sleep-onset disturbances after 3 previous anesthetic exposures for the same procedure. Review of the patient's records revealed the recurring use of propofol infusion. We proposed using dexmedetomidine infusion to potentially avoid another extended sleep disturbance. Following a dexmedetomidine-centered plan, the patient reported experiencing his usual sleep pattern without side-effects for 5 consecutive days postprocedure. This case highlights the potential for propofol-induced sleep disturbance in the ambulatory setting, which may be avoided with dexmedetomidine administration.

Trial watch: dexmedetomidine in cancer therapy.

Dexmedetomidine (DEX) is a highly selective α2-adrenoceptor agonist that is widely used in intensive and anesthetic care for its sedative and anxiolytic properties. DEX has the capacity to alleviate inflammatory pain while limiting immunosuppressive glucocorticoid stress during major surgery, thus harboring therapeutic benefits for oncological procedures. Recently, the molecular mechanisms of DEX-mediated anticancer effects have been partially deciphered. Together with additional preclinical data, these mechanistic insights support the hypothesis that DEX-induced therapeutic benefits are mediated via the stimulation of adaptive anti-tumor immune responses. Similarly, published clinical trials including ancillary studies described an immunostimulatory role of DEX during the perioperative period of cancer surgery. The impact of DEX on long-term patient survival remains elusive. Nevertheless, DEX-mediated immunostimulation offers an interesting therapeutic option for onco-anesthesia. Our present review comprehensively summarizes data from preclinical and clinical studies as well as from ongoing trials with a distinct focus on the role of DEX in overcoming (tumor microenvironment (TME)-imposed) cancer therapy resistance. The objective of this update is to guide clinicians in their choice toward immunostimulatory onco-anesthetic agents that have the capacity to improve disease outcome.

The effect of dexmedetomidine, remifentanil and metoral in reducing patient bleeding during rhinoplasty surgery.

INTRODUCTION: Rhinoplasty is one of the most common surgeries in the ENT department. Rhinoplasty hemorrhage is one of the complications that different strategies have been used to reduce it. Reduction of bleeding reduces the risk of complications such as hemolytic and non-hemolytic reactions, acute lung damage, viral and bacterial infections, hypothermia and coagulation disorders. Therefore, the aim of this study was to compare the effect of dexmedetomidine, remifentanil and metoral in reducing patient bleeding during rhinoplasty surgery. MATERIALS AND METHODS: This randomized, double-blind trial was performed on rhinoplasty patients. Rhinoplasty candidates who had the inclusion and exclusion criteria were divided into three groups of remifentanil, metoral and dexmedetomidine according to the random number table. Then 0.5 mg/kg/h of dexmedetomidine in the first group was administered, followed by 100-150 kg/h remifentanil in the second group and 50 mg metoral in the third group. Mean blood pressure, heart rate, mean bleeding and surgeon satisfaction were recorded in designed form. Data were analyzed by Spss-22 software. RESULTS: The mean blood pressure of patients in remifentanil group was lower than the other two groups (P = 0.03). In all three times during surgery, recovery and overall time, the amount of bleeding in the remifentanil group was found to be less than the other two groups. Furthermore, the rate of bleeding in the dexmedetomidine group was found to be less than the metoral group (P = 0.03, P = 0.02). The surgeon's satisfaction score in the remifentanil group was higher than the other two groups. Satisfaction score was higher in dexmedetomidine group than metoral group (P = 0.03). The recovery time in the metoral group was shorter than the other two groups (P = 0.02). CONCLUSION: Remifentanil caused a good and appropriate reduction of blood pressure in rhinoplasty surgery, causing less bleeding and higher satisfaction.

Dexmedetomidine Alleviates Propofol Infusion Syndrome-Induced Myocardial Injury through Inhibiting Ferroptosis Associated with Accumulation of Reactive Oxygen Species.

OBJECTIVE: To observe the effect of dexmedetomidine (Dex) on propofol infusion syndrome (PRIS)-induced myocardial injury and explore the roles of ferroptosis and accumulation of reactive oxygen species (ROS). METHODS: Eighteen male Sprague-Dawley rats were evenly divided into the control group, model group and test group (n=6/group) based on a computer-generated random number table. The PRIS-induced myocardial injury model was prepared in the model group and test group through a 12 h-caudal vein infusion of 1% propofol medium and long chain fat emulsion injection at a rate of 20 mg·Kg-1·h-1 for the first 6 h and 40 mg·Kg-1·h--1 for the last 6 h, and meanwhile the test group was treated by Dex. The control group received the same amount of normal saline through the caudal vein. The following indicators were compared between the three groups including myocardial pathological results, enzymatic changes of myocardial injury, ferroptosis of myocardial cells and accumulation of ROS. RESULTS: Dex alleviated the myocardial pathological injury caused by propofol infusion. Propofol infusion caused time-dependent enzymatic changes of myocardial injury and Dex alleviated these enzymatic changes. Dex alleviated the ferroptosis of myocardial cells and accumulation of ROS caused by propofol infusion. CONCLUSIONS: Dex could alleviate PRIS-induced myocardial injury by inhibiting ferroptosis associated with accumulation of ROS. Combined sedation using propofol and Dex might be a potential strategy for the prevention and treatment of PRIS-induced cardiotoxicity.

Dexmedetomidine and Perioperative Arrhythmias.

The highly selective α2-adrenoceptor agonist dexmedetomidine is a commonly used sedative drug for patients undergoing anesthesia and intensive care treatment. Several studies have indicated that dexmedetomidine may have a potential role in preventing and treating perioperative tachyarrhythmias. However, the specific effect and mechanism of action of dexmedetomidine in this context remain unclear. Dexmedetomidine is known to regulate the electrophysiologic function of the myocardium by inhibiting the function of the sinus node and atrioventricular node, as well as affecting myocardial repolarization. This paper aims to provide a theoretical basis for the prevention and treatment of perioperative arrhythmias by summarizing the effects of dexmedetomidine on myocardial electrophysiologic function and its impact on different types of arrhythmias.

Perioperative intravenous infusion of dexmedetomidine for alleviating postpartum depression after cesarean section: A meta-analysis and systematic review.

The efficacy of perioperative dexmedetomidine (DEX) infusion as a precaution against postpartum depression (PPD) in women undergoing cesarean section has not been substantiated systematically. A literature search for RCTs on DEX against PPD was retrieved in the following databases from inception to January 3, 2024: PubMed, Embase, Web of Science, the Cochrane Library, CNKI, Wanfang, CBM, VIP, etc. A total of 13 RCTs with 1711 participants were included. Meta-analysis was performed by RevMan5.3 and Stata16 using a random-effects model. EPDS scores were significantly decreased in the DEX group within one week or over one week postpartum compared to the control group (SMD = -1.25, 95 %CI: -1.73 to -0.77; SMD = -1.08, 95 %CI: -1.43 to -0.73). The prevalence of PPD was significantly inferior to the control at both time points (RR = 0.36, 95 %CI: 0.24 to 0.54; RR = 0.39, 95 %CI: 0.26 to 0.57). Univariate meta-regression suggested that age influenced the heterogeneity of the EPDS scores (P = 0.039), and DEX infusion dose was a potential moderator (P = 0.074). The subgroup analysis results of PPD scores at both time points were consistent, showing that: ① Mothers younger than 30 years old had better sensitivity to DEX for treating PPD. ② The anti-PPD efficacy of continuous infusion of DEX by PCIA was superior to both single infusion and combined infusion. ③ DEX showed a better anti-PPD effect when the total infusion dose was ≤ 2 µg/kg. Moreover, DEX improved analgesia and sleep quality, provided appropriate sedation, and reduced the incidence of nausea, vomiting, and chills. The current evidence confirmed the prophylaxis and superiority of DEX for PPD. More high-quality, large-scale RCTs are required for verifying the reliability and formulating administration methods.

Effects of Dexmedetomidine on Cognitive Function, Oxidative Stress and Brain Protection in Patients Undergoing Craniocerebral Surgery.

BACKGROUND: The protective mechanism of dexmedetomidine on the brains of patients undergoing craniocerebral surgery remains unclear. The aim of this study was to examine the impact of dexmedetomidine on cognitive function, oxidative stress, and brain protection in such patients. METHODS: Fifty-four patients who underwent craniocerebral surgery at our hospital from January 2020 to June 2023 were retrospectively selected as study subjects. They were divided into two groups: the control group (n = 27) and the study group (n = 27), based on different auxiliary anesthesia protocols. Patients in the study group received dexmedetomidine before anesthesia induction, using a midline intravenous pump to assist anesthesia, while the control group received an equivalent amount of normal saline. The remaining anesthesia induction and maintenance protocols were consistent for both groups. Cognitive function was assessed using the Mini Mental State Examination (MMSE) before and 1 day after surgery for both groups. Oxidative stress indicators, including malondialdehyde (MDA), glutathione peroxidase (GSH-Px), and superoxide dismutase (SOD) levels in the serum of both groups, were measured using enzyme-linked immunosorbent assay (ELISA). Additionally, changes in postoperative brain injury indicators, namely neuron-specific enolase (NSE) and central nervous system-specific protein (S100ß), were detected and compared in the serum of both groups. Concurrently, postoperative adverse reactions were recorded for both groups. RESULTS: The MMSE scale scores of both groups of patients 24 hours after surgery were significantly lower than those before surgery. However, the MMSE scale scores of the study group patients were notably higher than those in the control group, with a statistically significant difference (p < 0.05). One hour after surgery, the serum levels of MDA, GSH-Px, and SOD in both groups of patients were significantly elevated compared to pre-surgery levels. Yet, the study group exhibited significantly lower levels of MDA, GSH-Px, and SOD in comparison to the control group, and these differences were statistically significant (p < 0.05). The serum levels of NSE and S100ß in both groups were markedly higher than preoperative levels 24 hours after surgery. However, the study group demonstrated significantly lower levels of serum NSE and S100ß compared to the control group, with a statistically significant difference (p < 0.05). The incidence of postoperative complications in the study group was 7.41% (2/27), indicating a decreasing trend compared to 18.52% (5/27) in the control group. However, this difference did not reach statistical significance (χ2 = 1.477, p = 0.224). CONCLUSION: Dexmedetomidine-assisted anesthesia in craniocerebral surgery can effectively enhance postoperative cognitive function, mitigate oxidative stress, and facilitate overall postoperative recovery for patients. The intervention exhibits a favorable safety profile with no reported serious adverse reactions, establishing it as a relatively safe and reliable approach.

Prevention of post-operative delirium using an overnight infusion of dexmedetomidine in patients undergoing cardiac surgery: a pragmatic, randomized, double-blind, placebo-controlled trial.

BACKGROUND: After cardiac surgery, post-operative delirium (PoD) is acknowledged to have a significant negative impact on patient outcome. To date, there is no valuable and specific treatment for PoD. Critically ill patients often suffer from poor sleep condition. There is an association between delirium and sleep quality after cardiac surgery. This study aimed to establish whether promoting sleep using an overnight infusion of dexmedetomidine reduces the incidence of delirium after cardiac surgery. METHODS: Randomized, pragmatic, multicentre, double-blind, placebo controlled trial from January 2019 to July 2021. All adult patients aged 65 years or older requiring elective cardiac surgery were randomly assigned 1:1 either to the dexmedetomidine group or the placebo group on the day of surgery. Dexmedetomidine or matched placebo infusion was started the night after surgery from 8 pm to 8 am and administered every night while the patient remained in ICU, or for a maximum of 7 days. Primary outcome was the occurrence of postoperative delirium (PoD) within the 7 days after surgery. RESULTS: A total of 348 patients provided informed consent, of whom 333 were randomized: 331 patients underwent surgery and were analysed (165 assigned to dexmedetomidine and 166 assigned to placebo). The incidence of PoD was not significantly different between the two groups (12.6% vs. 12.4%, p = 0.97). Patients treated with dexmedetomidine had significantly more hypotensive events (7.3% vs 0.6%; p < 0.01). At 3 months, functional outcomes (Short-form 36, Cognitive failure questionnaire, PCL-5) were comparable between the two groups. CONCLUSION: In patients recovering from an elective cardiac surgery, an overnight infusion of dexmedetomidine did not decrease postoperative delirium. Trial registration This trial was registered on ClinicalTrials.gov (number: NCT03477344; date: 26th March 2018).

THE PROTECTIVE EFFECT OF DEXMEDETOMIDINE ON THE LIVER INJURY IN SEPSIS THROUGH INHIBITION OF NECROPTOSIS.

ABSTRACT: Background: Sepsis-induced liver injury leads to extensive necroptosis in hepatocytes, which is the main factor of liver dysfunction. This study aims to investigate the protective effect of dexmedetomidine (DEX) on septic liver and to explore whether its molecular mechanism is related to the modulation of necroptosis. Methods: The model of septic liver injury was induced by cecal ligation and puncture (CLP) in rats. DEX and necrostatin-1(Nec-1), a specific antagonist of necroptosis, were administered 1 h before CLP. The levels of arterial blood gas, serum aspartate aminotransferase, and alanine aminotransferase were measured at 6, 12 and 24 h after CLP. The survival rate was observed 24 h after CLP. Liver pathological changes and apoptosis, the contents of IL-6 and TNF-α in liver tissue homogenates, the ROS content in liver tissue, and the expression levels of RIP1, RIP3, MLKL, and HMGB1 were detected. Results: At 6, 12, and 24 h after CLP, the levels of aspartate aminotransferase, and alanine aminotransferase levels increased, and liver enzyme levels gradually increased with the progression of sepsis. In arterial blood gas analysis, P a O 2 gradually decreased and lactic acid concentration gradually increased during these three periods. The morphological impairment of liver tissues, increased apoptosis, elevated inflammatory factors (IL-6 and TNF-α), increased ROS level, and necroptosis components (RIP1, RIP3, MLKL, and HMGB1) were all observed in sepsis rats. However, these injuries can be ameliorated by pretreatment with DEX. Meanwhile, Nec-1 pretreatment also reduced the expression of RIP1, RIP3, MLKL, HMGB1, and ROS level. Conclusion: Our study suggests that DEX alleviates septic liver injury, and the mechanism is associated with the inhibition of necroptosis.

Comparative Study Between Dexmedetomidine with Bupivacaine and Bupivacaine Alone in Erector Spinae Plane Block for Postoperative Pain Control of Posterior Lumbosacral Spine Fixation Surgeries: A Randomized Controlled Trial.

Background: As posterior lumbosacral spine fixation surgeries are common spine procedures done nowadays due to different causes and mostly accompanied with moderate-to-severe postoperative pain, so should find effective postoperative analgesia for these patients. This study aimed to observe analgesic effect of dexmedetomidine combined with bupivacaine versus bupivacaine alone for erector spinae plane block ESPB for postoperative pain control of posterior lumbosacral spine fixation surgeries. Methods: Double-blind randomized controlled study including 90 patients who were randomly allocated into 3 groups (30 patients for each): Dexmedetomidine combined with bupivacaine (DB group), bupivacaine (B group), and saline (control) (S group). US-guided ESPB was performed preoperatively bilaterally in all patients of the 3 groups. All patients received intravenous patient-controlled postoperative analgesia with morphine and 1 gm intravenous paracetamol every 8 hours. Primary clinical outcomes were active (while mobilization) and passive (at rest) visual analog scale (VAS) pain score at first 24 hours measured every 2 hours, opioid consumption (number of PCA presses), and need for rescue analgesia. Other clinical outcomes included active and passive VAS pain score at second 24 hours, measured every 4 hours, opioid consumption, need for rescue analgesia, postoperative opioid side effects, and intraoperative dexmedetomidine side effects as bradycardia and hypotension. Results: Active and passive VAS pain scores, postoperative opioid consumption, need for rescue analgesia, and postoperative opioid side effects were significantly lower in DB group when compared to other groups (B and S groups). There were no additional intraoperative dexmedetomidine side effects as bradycardia and hypotension. The estimated effect-size r was -0.58 and Cohen's d was -1.46. Conclusion: Addition of dexmedetomidine to bupivacaine 0.25% in ESPB for postoperative pain control in patients of posterior lumbosacral spine fixation surgeries resulted in lower active and passive VAS pain scores, decreased postoperative opioid consumption, need for rescue analgesia and postoperative opioid side effects without additional intraoperative dexmedetomidine side effects. Clinicaltrialsgov Identifier: NCT05590234.

Suppression of cerebral ischemia injury induced blood brain barrier breakdown by dexmedetomidine via promoting CCN1.

BACKGROUND: Blood-brain barrier (BBB) could aggravate cerebral ischemia injury. Dexmedetomidine (Dex) has been believed to play a protective role in cerebral ischemia injury-induced BBB injury. METHODS: Middle cerebral artery occlusion (MCAO) and oxygen-glucose deprivation (OGD) models were established to simulate cerebral ischemia injury. Animal experiments included 4 groups, Sham, MCAO, MCAO+Dex, MCAO+Dex+sh-CCN1. Generally applicable gene set enrichment analysis was performed to analyze gene expression difference. Total collagen content and Evans blue staining were performed to measure infarct ratio and BBB breakdown, respectively. The cell apoptosis, mRNA and protein expression were measured through flow cytometry, PCR, and western blotting, respectively. The levels of IL-1ß, TNF-α, and IL-6 in serum were measured with commercial ELISA kits. RESULTS: Dex greatly promoted the expression level of CCN1. Dex suppressed cerebral ischemia injury, increased tight junction protein expression, improved the memory ability and neurological function of MCAO rats through targeting CCN1. The significant increase of inflammatory factors in the serum of MCAO rats were suppressed by Dex. Dex suppressed OGD induced increase of HRP permeability and promoting tight junction protein expression in vitro through regulating CCN1. The neurological function evaluation was performed with Neurological Severity Score (NSS) and Longa Score Scale. CONCLUSIONS: Dex could remarkably alleviate cerebral ischemia injury by inhibiting BBB breakdown, inflammatory response, and promoting neurological function and tight junction protein expression via up-regulating CCN1. This study might provide a novel therapeutic target for the prevention and treatment of cerebral ischemia injury-induced BBB.

Effectiveness of dexmedetomidine during surgery under general anaesthesia on patient-centred outcomes: a systematic review and Bayesian meta-analysis protocol.

INTRODUCTION: Dexmedetomidine is a promising pharmaceutical strategy to minimise opioid use during surgery. Despite its growing use, it is uncertain whether dexmedetomidine can improve patient-centred outcomes such as quality of recovery and pain. METHODS AND ANALYSIS: We will conduct a systematic review and meta-analysis following the recommendations of the Cochrane Handbook for Systematic Reviews. We will search MEDLINE, Embase, CENTRAL, Web of Science and CINAHL approximately in October 2023. We will include randomised controlled trials evaluating the impact of systemic intraoperative dexmedetomidine on patient-centred outcomes. Patient-centred outcome definition will be based on the consensus definition established by the Standardised Endpoints in Perioperative Medicine initiative (StEP-COMPAC). Our primary outcome will be the quality of recovery after surgery. Our secondary outcomes will be patient well-being, function, health-related quality of life, life impact, multidimensional assessment of postoperative acute pain, chronic pain, persistent postoperative opioid use, opioid-related adverse events, hospital length of stay and adverse events. Two reviewers will independently screen and identify trials and extract data. We will evaluate the risk of bias of trials using the Cochrane Risk of Bias Tool (RoB 2.0). We will synthesise data using a random effects Bayesian model framework, estimating the probability of achieving a benefit and its clinical significance. We will assess statistical heterogeneity with the tau-squared and explore sources of heterogeneity with meta-regression. We have involved patient partners, clinicians, methodologists, and key partner organisations in the development of this protocol, and we plan to continue this collaboration throughout all phases of this systematic review. ETHICS AND DISSEMINATION: Our systematic review does not require research ethics approval. It will help inform current clinical practice guidelines and guide development of future randomised controlled trials. The results will be disseminated in open-access peer-reviewed journals, presented at conferences and shared among collaborators and networks. PROSPERO REGISTRATION NUMBER: CRD42023439896.

Activating astrocytic α2A adrenoceptors in hippocampus reduces glutamate toxicity to attenuate sepsis-associated encephalopathy in mice.

BACKGROUND: Glutamate metabolism disorder is an important mechanism of sepsis-associated encephalopathy (SAE). Astrocytes regulate glutamate metabolism. In septic mice, α2A adrenoceptor (α2A-AR) activation in the central nervous system provides neuroprotection. α2A-ARs are expressed abundantly in hippocampal astrocytes. This study was performed to determine whether hippocampal astrocytic α2A-AR activation confers neuroprotection against SAE and whether this protective effect is astrocyte specific and achieved by the modulation of glutamate metabolism. METHODS: Male C57BL/6 mice with and without α2A-AR knockdown were subjected to cecal ligation and puncture (CLP). They were treated with intrahippocampal guanfacine (an α2A-AR agonist) or intraperitoneal dexmedetomidine in the presence or absence of dihydrokainic acid [DHK; a glutamate transporter 1 (GLT-1) antagonist] and/or UCPH-101 [a glutamate/aspartate transporter (GLAST) antagonist]. Hippocampal tissue was collected for the measurement of astrocyte reactivity, GLT-1 and GLAST expression, and glutamate receptor subunit 2B (GluN2B) phosphorylation. In vivo real-time extracellular glutamate concentrations in the hippocampus were measured by ultra-performance liquid chromatography tandem mass spectrometry combined with microdialysis, and in vivo real-time hippocampal glutamatergic neuron excitability was assessed by calcium imaging. The mice were subjected to the Barnes maze and fear conditioning tests to assess their learning and memory. Golgi staining was performed to assess changes in the hippocampal synaptic structure. In vitro, primary astrocytes with and without α2A-AR knockdown were stimulated with lipopolysaccharide (LPS) and treated with guanfacine or dexmedetomidine in the presence or absence of 8-bromo- cyclic adenosine monophosphate (8-Br-cAMP, a cAMP analog). LPS-treated primary and BV2 microglia were also treated with guanfacine or dexmedetomidine. Astrocyte reactivity, PKA catalytic subunit, GLT-1 an GLAST expression were determined in primary astrocytes. Interleukin-1ß, interleukin-6 and tumor necrosis factor-alpha in the medium of microglia culture were measured. RESULTS: CLP induced synaptic injury, impaired neurocognitive function, increased astrocyte reactivity and reduced GLT-1 and GLAST expression in the hippocampus of mice. The extracellular glutamate concentration, phosphorylation of GluN2B at Tyr-1472 and glutamatergic neuron excitability in the hippocampus were increased in the hippocampus of septic mice. Intraperitoneal dexmedetomidine or intrahippocampal guanfacine administration attenuated these effects. Hippocampal astrocytes expressed abundant α2A-ARs; expression was also detected in neurons but not microglia. Specific knockdown of α2A-ARs in hippocampal astrocytes and simultaneous intrahippocampal DHK and UCPH-101 administration blocked the neuroprotective effects of dexmedetomidine and guanfacine. Intrahippocampal administration of DHK or UCPH-101 alone had no such effect. In vitro, guanfacine or dexmedetomidine inhibited astrocyte reactivity, reduced PKA catalytic subunit expression, and increased GLT-1 and GLAST expression in primary astrocytes but not in primary astrocytes that received α2A-AR knockdown or were treated with 8-Br-cAMP. Guanfacine or dexmedetomidine inhibited microglial reactivity in BV2 but not primary microglia. CONCLUSIONS: Our results suggest that neurocognitive protection against SAE after hippocampal α2A-AR activation is astrocyte specific. This protection may involve the inhibition of astrocyte reactivity and alleviation of glutamate neurotoxicity, thereby reducing synaptic injury. The cAMP/protein kinase A (PKA) signaling pathway is a potential cellular mechanism by which activating α2A-AR modulates astrocytic function.