Itaconate alleviates anesthesia/surgery-induced cognitive impairment by activating a Nrf2-dependent anti-neuroinflammation and neurogenesis via gut-brain axis.

BACKGROUND: Postoperative cognitive dysfunction (POCD) is a common neurological complication of anesthesia and surgery in aging individuals. Neuroinflammation has been identified as a hallmark of POCD. However, safe and effective treatments of POCD are still lacking. Itaconate is an immunoregulatory metabolite derived from the tricarboxylic acid cycle that exerts anti-inflammatory effects by activating the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway. In this study, we investigated the effects and underlying mechanism of 4-octyl itaconate (OI), a cell-permeable itaconate derivative, on POCD in aged mice. METHODS: A POCD animal model was established by performing aseptic laparotomy in 18-month-old male C57BL/6 mice under isoflurane anesthesia while maintaining spontaneous ventilation. OI was intraperitoneally injected into the mice after surgery. Primary microglia and neurons were isolated and treated to lipopolysaccharide (LPS), isoflurane, and OI. Cognitive function, neuroinflammatory responses, as well as levels of gut microbiota and their metabolites were evaluated. To determine the mechanisms underlying the therapeutic effects of OI in POCD, ML385, an antagonist of Nrf2, was administered intraperitoneally. Cognitive function, neuroinflammatory responses, endogenous neurogenesis, neuronal apoptosis, and Nrf2/extracellular signal-related kinases (ERK) signaling pathway were evaluated. RESULTS: Our findings revealed that OI treatment significantly alleviated anesthesia/surgery-induced cognitive impairment, concomitant with reduced levels of the neuroinflammatory cytokines IL-1ß and IL-6, as well as suppressed activation of microglia and astrocytes in the hippocampus. Similarly, OI treatment inhibited the expression of IL-1ß and IL-6 in LPS and isoflurane-induced primary microglia in vitro. Intraperitoneal administration of OI led to alterations in the gut microbiota and promoted the production of microbiota-derived metabolites associated with neurogenesis. We further confirmed that OI promoted endogenous neurogenesis and inhibited neuronal apoptosis in the hippocampal dentate gyrus of aged mice. Mechanistically, we observed a decrease in Nrf2 expression in hippocampal neurons both in vitro and in vivo, which was reversed by OI treatment. We found that Nrf2 was required for OI treatment to inhibit neuroinflammation in POCD. The enhanced POCD recovery and promotion of neurogenesis triggered by OI exposure were, at least partially, mediated by the activation of the Nrf2/ERK signaling pathway. CONCLUSIONS: Our findings demonstrate that OI can attenuate anesthesia/surgery-induced cognitive impairment by stabilizing the gut microbiota and activating Nrf2 signaling to restrict neuroinflammation and promote neurogenesis. Boosting endogenous itaconate or supplementation with exogenous itaconate derivatives may represent novel strategies for the treatment of POCD.

Effect of phenylephrine rescue injection on hypotension after spinal anaesthesia for caesarean delivery when guided by both heart rate and SBP during an early warning window: A randomised controlled trial.

BACKGROUND: Spinal anaesthesia is now the most common technique for caesarean delivery. However, because of the intermittent nature of noninvasive blood pressure (NIBP) measurements, maternal blood pressure may become hypotensive between the measurements. There is thus an inbuilt delay before the anaesthesiologist can intervene to counteract the hypotension. Based on the principle that changes in blood pressure can induce compensatory changes in the heart rate (HR), combining the NIBP with real-time HR, we designed two warning windows to predict hypotension and hypertension. OBJECTIVE: To evaluate whether phenylephrine administration guided by these warning windows would help maintain haemodynamic stability. SETTING: A teaching hospital. DESIGN: A randomised controlled trial. PATIENTS: One hundred and ten pregnant women scheduled for elective caesarean delivery were enrolled, from which, after exclusions, 86 were eligible for the study. INTERVENTIONS: All eligible patients received a continuous intravenous infusion of phenylephrine as soon as spinal anaesthesia was initiated. Thereafter, patients were randomly assigned to two groups. In the test group (Win-Group): rescue phenylephrine administration was triggered by an early warning window of HR above 100 beats per minute (bpm) and SBP 90 to 110 mmHg; pausing the infusion phenylephrine was triggered by a HR lower than 60 bpm and SBP greater than 90 mmHg. In the control group, phenylephrine was guided by BP only when it appeared on the monitor: SBP less than 90 mmHg was the trigger for administering rescue phenylephrine; SBP greater than 110 mmHg was the trigger for pausing the phenylephrine infusion. MAIN OUTCOME MEASURES: The primary outcome was incidence of hypotension. Secondary outcomes were the incidence of hypertension and other adverse haemodynamic events. RESULTS: The incidence of hypotension was significantly lower in the Win-Group than in the BP-Group (27.8 vs. 66.7%, P  = 0.001). The minimum SBP was significantly higher in Win-Group than in BP-Group (93.9 ±â€Š9.49 vs. 86.7 ±â€Š11.16 mmHg, P   =  0.004). There was no significant difference in the incidence of hypertension between groups. CONCLUSION: After spinal anaesthesia for caesarean delivery, when phenylephrine infusion is guided by HR along with BP from a warning window it effectively reduces the incidence of hypotension without any significant effect on incidence of hypertension. TRIAL REGISTRATION: Chictr.org.cn; Identifier: ChiCTR 2100041812.

Preventing Spinal Hypotension During Cesarean Birth With Two Initial Boluses of Norepinephrine in Chinese Parturients: A Randomized, Double-Blind, Controlled Trial.

BACKGROUND: Norepinephrine is effective in preventing spinal hypotension during cesarean birth; however, an optimal regimen has not been determined. We hypothesized that an initial bolus of norepinephrine improves efficacy of spinal hypotension prophylaxis beyond continuous norepinephrine alone. METHODS: In this double-blind, controlled study, 120 patients scheduled for cesarean birth under spinal anesthesia were randomly allocated to receive a norepinephrine bolus at 0.05 or 0.10 µg/kg, followed by norepinephrine infusion at a rate of 0.05 µg·kg -1 ·min -1 . The primary outcome was the frequency of spinal hypotension during cesarean birth. The doses of the rescue drug (phenylephrine), frequency of nausea or vomiting, duration of hypotension, frequency of intraoperative hypertension, frequency of bradycardia, and fetal outcomes were also compared. RESULTS: One-hundred-fifteen patients were included in the analysis. Compared with the 0.05 µg/kg group, the frequency of spinal hypotension was lower in the 0.10 µg/kg group (20.7% vs 45.6%; odds ratio [OR], 0.31; 95% confidence interval (CI), 0.14-0.71; P = .004). Fewer rescue doses of phenylephrine (0 [0,0] vs 0 [0,80]; 95% CI for the difference, 0 (0-0); P = .006) were required, and the frequency of nausea or vomiting was lower (5.2% vs 17.5%; OR, 0.26; 95% CI, 0.07-0.99; P = .04) in the 0.10 µg/kg group. The duration of hypotension was shorter in the 0.10 µg/kg group than that in the 0.05 µg/kg group (0 [0,0] vs 0 [0,2]; 95% CI for the difference, 0 [0-0]; P = .006). The incidence of intraoperative hypertension, frequency of bradycardia, and fetal outcomes were comparable between the 2 groups. CONCLUSIONS: With a fixed-rate norepinephrine infusion of 0.05 µg·kg -1 ·min -1 , the 0.10 µg/kg initial bolus was more effective in reducing the incidence of spinal hypotension compared with the 0.05 µg/kg initial bolus.

Effects of intravenous glucocorticoids on postoperative delirium in adult patients undergoing major surgery: a systematic review and meta-analysis with trial sequential analysis.

BACKGROUND: The effects of intravenous glucocorticoids on postoperative delirium (POD) in adult patients undergoing major surgery remain controversial. Therefore, we conducted this meta-analysis to assess whether intravenous glucocorticoids can decrease POD incidence in the entire adult population undergoing major surgery and its association with patients age, type of surgery, and type of glucocorticoid. METHODS: We searched the relevant literature published before November 3, 2023, through Cochrane Library, PubMed, Embase, and Web of Science. The primary outcome was POD incidence. The risk ratio for the primary outcome was calculated using the Mantel-Haenszel method. The secondary outcomes included 30-day mortality, length of hospital stay, ICU duration, mechanical ventilation duration, and occurrence of glucocorticoid-related adverse effects (e.g., infection and hyperglycemia). This meta-analysis was registered in PROSPERO: CRD42022345997. RESULTS: We included eight randomized controlled studies involving 8972 patients. For the entire adult population undergoing major surgery, intravenous glucocorticoids reduced the POD incidence (risk ratio = 0.704, 95% confidence interval, 0.519-0.955; P = 0.024). However, subgroups defined by type of surgery showed differential effects of glucocorticoids on POD. Intravenous glucocorticoids can not reduce POD incidence in adult patients undergoing cardiac surgery (risk ratio = 0.961, 95% confidence interval, 0.769-1.202; P = 0.728), with firm evidence from trial sequential analysis. However, in major non-cardiac surgery, perioperative intravenous glucocorticoid reduced the incidence of POD (risk ratio = 0.491, 95% confidence interval, 0.338-0.714; P < 0.001), which warrants further studies due to inconclusive evidence by trial sequence analysis. In addition, the use of glucocorticoids may reduce the mechanical ventilation time (weighted mean difference, -1.350; 95% confidence interval, -1.846 to -0.854; P < 0.001) and ICU duration (weighted mean difference = -7.866; 95% confidence interval, -15.620 to -0.112; P = 0.047). CONCLUSIONS: For the entire adult population undergoing major surgery, glucocorticoids reduced the POD incidence. However, the effects of glucocorticoids on POD appear to vary according to the type of surgery. In patients receiving major non-cardiac surgery, glucocorticoid may be an attractive drug in the prevention of POD, and further studies are needed to draw a definitive conclusion. In cardiac surgery, intravenous glucocorticoids have no such effect.

Lower preoperative serum uric acid level may be a risk factor for postoperative delirium in older patients undergoing hip fracture surgery: a matched retrospective case-control study.

BACKGROUND: Postoperative delirium (POD) is a common complication after hip fracture surgery that is associated with various short- and long-term outcomes. The mechanism of POD may be associated with the oxidative stress process. Uric acid has been shown to provide a neuroprotective effect in various neurodegenerative diseases through its antioxidant properties. However, it is unclear whether lower preoperative serum uric acid levels are associated with the development of POD after hip fracture surgery. Therefore, this study assessed the association of lower preoperative uric acid levels in patients with POD during hospitalization. METHODS: This is a matched retrospective case-control study that included 96 older patients (≥65 y) who underwent hip fracture surgery. POD was diagnosed using the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. Patients diagnosed with POD (cases) were matched 1:1 with patients without POD (controls) on the basis of age, sex, and anesthesia type. The relationship between preoperative uric acid and POD was analyzed by multivariable analysis. RESULTS: The POD and non-POD groups each had 48 patients. In the univariate analysis, lower log preoperative serum uric acid value, higher neutrophil-to-lymphocyte ratio, and cerebrovascular disease were more likely in patients with POD than in those with no POD. Multivariable conditional logistic regression analysis showed that lower log preoperative serum uric acid (adjusted odds ratio [aOR], 0.028; confidence interval [CI], 0.001-0.844; p = 0.040), higher neutrophil-to-lymphocyte ratio (aOR, 1.314; 95% CI, 1.053-1.638; p = 0.015), and increased surgery duration (aOR, 1.034; 95% CI, 1.004-1.065; p = 0.024) were associated with increased risk of POD. CONCLUSIONS: Lower preoperative serum uric acid levels may be an independent risk factor for POD after adjustment for possible confounding factors. However, large prospective studies are needed to confirm this finding.

Association of Carotid Plaque and Serum Lipoprotein-Associated Phospholipase A2 (LP-PLA2) with Postoperative Delirium in Geriatric Patients Undergoing Hip Replacement: A Prospective Cohort Study.

BACKGROUND The aim of this study was to investigate the relationships among carotid plaque (CP), serum lipoprotein-associated phospholipase (LP-PLA2), and POD in elderly patients. MATERIAL AND METHODS Sixty-two elderly patients undergoing hip replacement with spinal-epidural anesthesia were divided into CP and non-CP groups based on the preoperative presence or absence of carotid atherosclerotic plaques, as assessed by ultrasound. POD was diagnosed by means of the Confusion Assessment Method (CAM). Blood samples were collected (preoperatively, postoperatively, and postoperative day 2) for the assessment of serum LP-PLA2 by enzyme-linked immunosorbent assay. The CP group was further divided into POD and no-POD subgroups based on the occurrence of POD. RESULTS The incidence of POD was higher in the CP group than in the non-CP group (P0.05), it was higher in the CP group than in the non-CP group postoperatively and on postoperative day 2 (P0.05), but was significantly higher in the POD subgroup than in the no-POD subgroup on postoperative day 2 (P<0.05). Furthermore, the LP-PLA2 level on postoperative day 2 was an independent risk factor for POD (odds ratio: 1.03, 95% confidence interval: 1.00-1.07). CONCLUSIONS The preoperative presence of carotid plaque is closely associated with a higher incidence of POD. The potential mechanism may involve the increased expression of LP-PLA2 in the serum, which can lead to plaque destabilization and subsequent inflammatory cascades.

Anesthetic management of tracheal laceration from traumatic dislocation of the first rib: a case report and literature of the review.

BACKGROUND: Tracheobronchial lacerations from trauma can be life-threatening and present significant challenges for safe anesthetic management. Early recognition of tracheal injuries and prompt airway control can be lifesaving. CASE PRESENTATION: A 56-year-old man with no significant medical history presented with difficulty breathing after a blunt trauma to his chest to the emergency room and was diagnosed with dislocation of the first rib and tracheal laceration after a chest tomography (CT) study. Subcutaneous emphysema in neck area quickly worsened indicating continuous air leak. Emergent surgical repair was scheduled. General anesthesia with maintaining spontaneous ventilation was performed and a 5.5 mm endotracheal tube was placed under the guidance of flexible bronchoscopy. Depth of anesthesia was maintained to achieve a Bispectral Index Score of 40-60. Once the offending first rib was removed, a 7.5 mm endotracheal tube was inserted distal to the laceration site with the guidance of flexible bronchoscopy. Once confirmed location of the endotracheal tube, cisatracurium was administered intravenously and the patient was managed on mechanical ventilation with interval positive pressure ventilation. The operation was successful and he was transferred to the ICU intubated. He then received elective surgical repairs for sternum fracture, multiple rib fractures and hemopneumothorax under general anesthesia on day 5 after the first surgery and was extubated on postoperative day 7. The subsequent course was uneventful. Comprehensive rehabilitation was done for 2 weeks and he was discharged home on postoperative day 41. CONCLUSIONS: Early diagnosis and multidisciplinary collaborations are keys to the successful management of this patient. Flexible bronchoscopy is particularly useful in airway management for urgent trachea tracheal laceration repair.

Nasotracheal intubation-extubation-intubation and asleep-awake-asleep anesthesia technique for deep brain stimulation.

BACKGROUND: The asleep-awake-asleep (AAA) technique and laryngeal mask airway (LMA) is a common general anesthesia technique for deep brain stimulation (DBS) surgery. However, the LMA is not always the ideal artificial airway. In this report, we presented our experiences with nasotracheal intubation-extubation-intubation (IEI) and AAA techniques in DBS surgery for Parkinson's disease (PD) patients to meet the needs of surgery and ensure patients' safety and comfort. CASE PRESENTATION: Three PD patients scheduled for DBS surgery had to receive general anesthesia for various reasons. For the first asleep stage, general anesthesia and nasotracheal intubation was completed with routine methods. During the awake stage, we pulled the nasotracheal tube back right above the epiglottis under fiberoptic bronchoscope (FOB) guidance for microelectrode recording (MER), macrostimulation testing and verbal communication. Once monitoring is completed, we induced anesthesia with rapid sequence induction and utilized the FOB to advance the nasotracheal tube into the trachea again. To minimize airway irritations during the process, we sprayed the airway with lidocaine before any manipulation. The neurophysiologists completed neuromoinitroing successfully and all three patients were satisfied with the anesthesia provided at follow-up. CONCLUSION: Nasotracheal IEI and AAA anesthetic techniques should be considered as a viable option during DBS surgery.

Nicotine-Induced Neuroprotection against Cognitive Dysfunction after Partial Hepatectomy Involves Activation of BDNF/TrkB Signaling Pathway and Inhibition of NF-κB Signaling Pathway in Aged Rats.

Introduction: The main purpose of this study was to investigate the effects and possible mechanisms of nicotine pre-treatment on postoperative cognitive dysfunction (POCD) in aged rats. Methods: Nicotine (0.5 mg/kg) was given i.p. immediately after anesthesia induction. After the Morris water maze test was used to evaluate the rats' spatial learning and memory, serum and hippocampal tissues were harvested 1 and 3 days after intervention. Inflammatory cytokines in the serum were evaluated by Enzyme-linked Immunosorbent Assay (ELISA). Brain-derived neurotrophic factor (BDNF), p-TrkB, neuroinflammation cytokines, NF-κB p65, and cleaved caspase-3 were measured by western blotting; neuronal apoptosis in the hippocampal CA1 region was also evaluated by TUNEL staining. Results: We found that nicotine markedly attenuated the POCD and reduced the elevated levels of inflammatory cytokines in the serum, including IL-1ß and high mobility group box-1 (HMGB1), on postoperative day 1. Additionally, nicotine suppressed the surgery-induced release of IL-1ß, TNF-ɑ, HMGB1, and NF-κB p65 in the hippocampus on postoperative day 1 and day 3. In addition, operated rats displayed lower BDNF and p-TrkB in the hippocampus on postoperative day 1, returning to baseline by postoperative day 3. However, nicotine pre-treatment clearly reversed the surgical stress-induced decrease in both BDNF and p-TrkB expression in the hippocampus. Furthermore, nicotine pre-treatment significantly alleviated the surgery-induced increase in the neuronal apoptosis in the hippocampus on postoperative day 1 and day 3. Conclusions: Our results showed that nicotine-induced neuroprotection against POCD may involve activation of the BDNF/TrkB signaling pathway and inhibition of the NF-κB signaling pathway. Implications: Nicotine has long been considered a potent therapeutic agent for neuroprotection. This study reported the positive effect of nicotine treatment on cognitive dysfunction after partial hepatectomy in aged rats. Furthermore, the underlying mechanism may involve activation of the BDNF/TrkB signaling pathway and inhibition of the NF-κB signaling pathway in the hippocampus.

Case report: perioperative management of caesarean section for a parturient with mitochondrial myopathy.

BACKGROUND: Mitochondrial myopathies represent a group of disorders caused by mitochondrial defects that disrupt energy production. Most patients have issues from infancy to early childhood. Pregnancy in women with mitochondrial myopathy is uncommon and the management for these parturients is full of challenges. CASE PRESENTATION: A 36-year-old woman with mitochondrial myopathy was scheduled for caesarean section under a combined spinal-epidural anaesthesia and multi-model analgesia. The parturient was safe and the delivery was performed safely and smoothly, but there were some complications after surgery due to the complex condition of the patient. After consultation with and treatment from multiple disciplines, both the parturient and neonate were well and discharged. CONCLUSION: It is important that patients with mitochondrial diseases are comprehensively assessed and monitored perioperatively.