Effect of clock rhythm on emergence agitation and early postoperative delirium in older adults undergoing thoracoscopic lung cancer surgery: protocol for a prospective, observational, cohort study.

INTRODUCTION: Surgeries conducted at night can impact patients' prognosis, and the mechanism may be related to circadian rhythm, which influence normal physiological functions and pathophysiological changes. Melatonin is primarily a circadian hormone with hypnotic and chronobiotic effects, thereby affecting disease outcomes through influencing the expression of inflammatory factors and biochemical metabolism. This study aims to observe the effects of circadian rhythms on emergence agitation and early postoperative delirium of older individuals undergoing thoracoscopic lung cancer surgery and explore the possible regulatory role of melatonin. METHODS: This prospective, observational, cohort study will involve 240 patients. Patients will be routinely divided into three groups based on the time of the surgery: T1 (8:00-14:00), T2 (14:00-20:00) and T3 group (20:00-08:00). The primary outcome will be the incidence of emergence agitation assessed via the Richmond Agitation and Sedation Scale (RASS) in the post-anesthesia care unit (PACU). Secondary outcomes will include the incidence of early postoperative delirium assessed via the Confusion Assessment Method (CAM) on postoperative day 1, pain status assessed via the numerical rating scale (NRS) in the PACU, sleep quality on postoperative day 1 and changes in perioperative plasma melatonin, clock genes and inflammatory factor levels. Postoperative surgical complications, intensive care unit admission and hospital length of stay will also be evaluated. DISCUSSION: This paper describes a protocol for investigating the effects of circadian rhythms on emergence agitation and early postoperative delirium of older individuals undergoing thoracoscopic lung cancer surgery, as well as exploring the potential regulatory role of melatonin. By elucidating the mechanism by which circadian rhythms impact postoperative recovery, we aim to develop a new approach for achieving rapid recovery during perioperative period. TRIAL REGISTRATION: The study was registered at the Chinese Clinical Trials Registry (ChiCTR2000040252) on November 26, 2020, and refreshed on September 4, 2022.

Efficacy and safety of remimazolam tosilate versus propofol in patients undergoing day surgery: a prospective randomized controlled trial.

BACKGROUND: Remimazolam tosilate (RT) is a novel short-acting GABA (A) receptor agonist that has a rapid recovery from procedural sedation and can be fully reversed by flumazenil. To date, there have been relatively few articles comparing RT and propofol for general anesthesia. This study aimed to assess the efficacy and safety of RT with or without flumazenil compared with propofol in general anesthesia for day surgery. METHODS: 115 patients scheduled for day surgery were randomized into three groups: RT (n = 39), RT + flumazenil (n = 38) and propofol (n = 38). The primary endpoints were anesthesia induction time and time until fully alert. Anesthesia success rate, bispectral index (BIS) values, injection pain, opioid and vasopressor dosages, postoperative recovery profiles and perioperative inflammatory and cognitive changes were assessed. Any adverse events were recorded. RESULTS: Induction times were similar among the three groups (P = 0.437), but the median time until fully alert in patients treated with RT was longer than that of the propofol or RT + flumazenil groups (17.6 min vs. 12.3 min vs. 12.3 min, P < 0.001). The three groups had comparable postoperative recovery quality and inflammatory and cognitive state changes (P > 0.05). Smaller percentages of patients who received RT (26.3%) and RT + flumazenil (31.6%) developed hypotension during anesthesia maintenance compared with propofol (68.4%), and consequently less ephedrine (P < 0.001) and phenylephrine (P = 0.015) were needed in the RT group. Furthermore, serum triglyceride levels were lower (P < 0.001) and injection pain was much less frequent in the RT with or without flumazenil groups compared with the propofol group (5.3% vs. 0% vs. 18.4%). CONCLUSION: RT permits rapid induction and comparable recovery profile compared with propofol in general anesthesia for day surgery, but has a prolonged recovery time without flumazenil. The safety profile of RT was superior to propofol in terms of hypotension and injection pain. TRIAL REGISTRATION: The study was registered at Chinese Clinical Trial Registry http://www.chictr.org.cn/ (Registration date: 19/7/2021; Trial ID: ChiCTR2100048904).

Chronic constriction injury-induced changes in circular RNA expression profiling of the dorsal root ganglion in a rat model of neuropathic pain.

BACKGROUND: The pathogenesis of neuropathic pain (NP) has not been fully elucidated. Gene changes in dorsal root ganglia (DRG) may contribute to the development of NP. Circular RNAs (circRNAs) are a class of endogenous noncoding RNAs that form covalently closed loop structures and are crucial for genetic and epigenetic regulation. However, little is known about circRNA changes in DRG neurons after peripheral nerve injury. METHODS: A sciatic nerve chronic constriction injury (CCI) model was established to induce neuropathic pain. We performed genome-wide circRNA analysis of four paired dorsal root ganglion (DRG) samples (L4-L5) from CCI and negative control (NC) rats using next-generation sequencing technology. The differentially expressed circRNAs (DEcircRNAs) were identified by differential expression analysis, and the expression profile of circRNAs was validated by quantitative PCR. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses were performed to predict the function of DEcircRNAs. RESULTS: A total of 374 DEcircRNAs were identified between CCI and NC rats using circRNA high-throughput sequencing. Among them, 290 were upregulated and 84 were downregulated in the CCI group. The expression levels of nine DEcircRNAs were validated by qPCR. Functional annotation analysis showed that the DEcircRNAs were mainly enriched in pathways and functions, including 'dopaminergic synapse,' 'renin secretion,' 'mitogen-activated protein kinase signaling pathway,' and 'neurogenesis.' Competing endogenous RNA analysis showed that the top 50 circRNAs exhibited interactions with four pain-related microRNAs (miRNAs). Circ:chr2:33950934-33955969 was the largest node in the circRNA-miRNA interaction network. CONCLUSIONS: Peripheral nerve injury-induced neuropathic pain led to changes in the comprehensive expression profile of circRNAs in the DRG of rats. DEcircRNAs may advance our understanding of the molecular mechanisms underlying neuropathic pain.

Modified protocol for Enhanced Recovery After Surgery is beneficial for achalasia patients undergoing peroral endoscopic myotomy: a randomized prospective trial.

INTRODUCTION: Enhanced Recovery After Surgery (ERAS) protocols have been proven to promote postoperative recovery. However, limited evidence is available on ERAS protocols in patients undergoing peroral endoscopic myotomy (POEM). AIM: To study the safety and effectiveness of an ERAS protocol in terms of the standard postoperative length of stay (LOS) and QoR-15 (Quality of Recovery) score of patients undergoing POEM. MATERIAL AND METHODS: Eighty patients were randomly divided into the ERAS or conventional group. The ERAS group received ERAS management, while the conventional group received normal management. The ERAS protocol included sufficient preoperative education, shortening time of preoperative fasting, maintaining intraoperative normothermia, intraoperative fluid management, and improving analgesia. We compared the results between the two groups in term of standard postoperative LOS and cost, QoR-15 score, postoperative pain and complications. RESULTS: Patients showed an improvement in the ERAS group in terms of earlier readiness for hospital discharge (40.21 ±8.42 h vs. 48.63 ±10.42 h; p < 0.001), earlier resumption of oral feeding (31.80 ±8.7 h vs. 42.35 ±10.80 h; p < 0.001), lower VAS, and higher QoR-15 score (139.29 ±2.21 vs. 137.03 ±3.77; p = 0.002) on postoperative day 2. For post-operative complications, there was no significant difference between the two groups. CONCLUSIONS: The ERAS protocol is feasible and safe for POEM, and may decrease standard postoperative LOS, shorten recovery of gastrointestinal function, and improve postoperative patient satisfaction.

Morphine promotes angiogenesis by activating PI3K/Akt/HIF-1α pathway and upregulating VEGF in hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is characterized by the neo-angiogenesis induced by tumor and adjacent cells. It is a leading cancer-related cause of death. Morphine has effects on angiogenesis with pro-angiogenic or anti-angiogenic phonotypes. This study explores the function of morphine on cancer cell growth, angiogenesis and the underlying mechanism in HCC. METHODS: Morphine was used to treat BEL-7402 or HCC-LM3 cells and human umbilical vein endothelial cells (HUVECs) were subsequently incubated in the conditioned media (CM) of HCC cells. The potential effects of cell proliferation, migration and tube formation of CM-treated HUVECs were investigated. Furthermore, the angiogenesis regulated factors of VEGFA, PIGF, ANG-1, ANG-2, FGF-1 and FGF-2 were assessed. siRNA and LY294002 were further used to explore the mechanism mediating the effects of morphine on the angiogenesis pathway. The neovascularization effect by morphine was confirmed through the use of human HCC cancer heterotopic mouse model in vivo. RESULTS: A significantly increased cell proliferation, migration, and tube formation effect of HUVECs induced by the CM from HCC cell lines treated with morphine was observed. More VEGFA secretion in CM from LM3 or BEL-7402 cell lines was found than the controls (P=0.03 and P=0.027, respectively). VEGFA knock-down could significantly reverse cell proliferation, migration and tube formation induced by the CM from HCC cell lines with morphine treatment. Further molecular experiments indicated that VEGFA secretion was activated by morphine potentially through the PI3K/Akt/HIF-1α pathway. Morphine-induced neovascularization was also observed by the IHC of CD31 and VEGFA. CONCLUSIONS: Morphine promotes angiogenesis in hepatocellular carcinoma possibly through the activation of the PI3K/Akt/HIF-1α pathway and VEGFA stimulation.

SET8 suppression mediates high glucose-induced vascular endothelial inflammation via the upregulation of PTEN.

Hyperglycemia-mediated endothelial inflammation participates in the pathogenesis of cardiovascular complications in subjects with diabetes. Previous studies reported that phosphatase and tensin homolog deleted on chromosome ten (PTEN) and SET8 participate in high glucose-mediated endothelial inflammation. In this study, we hypothesize that SET8 regulates PTEN expression, thus contributing to high glucose-mediated vascular endothelial inflammation. Our data indicated that plasma soluble intercellular adhesion molecule-1 (sICAM-1) and endothelial selectin (e-selectin) were increased in patients with diabetes and diabetic rats. PTEN expression was augmented in the peripheral blood mononuclear cells of patients with diabetes and in the aortic tissues of diabetic rats. Our in vitro study indicated that high glucose increased monocyte/endothelial adhesion, endothelial adhesion molecule expression and p65 phosphorylation in human umbilical vein endothelial cells (HUVECs). Moreover, high glucose led to endothelial inflammation via upregulation of PTEN. Furthermore, high glucose inhibited SET8 expression and histone H4 lysine 20 methylation (H4K20me1), a downstream target of SET8. SET8 overexpression reversed the effects of high-glucose treatment. shSET8-mediated endothelial inflammation was counteracted by siPTEN. Furthermore, SET8 was found to interact with FOXO1. siFOXO1 attenuated high glucose-mediated endothelial inflammation. FOXO1 overexpression-mediated endothelial inflammation was counteracted by siPTEN. H4K20me1 and FOXO1 were enriched in the PTEN promoter region. shSET8 increased PTEN promoter activity and augmented the positive effect of FOXO1 overexpression on PTEN promoter activity. Our in vivo study indicated that SET8 was downregulated and FOXO1 was upregulated in the peripheral blood mononuclear cells of patients with diabetes and the aortic tissues of diabetic rats. In conclusion, SET8 interacted with FOXO1 to modulate PTEN expression in vascular endothelial cells, thus contributing to hyperglycemia-mediated endothelial inflammation.

A modified approach for ultrasound-guided axillary venipuncture in the infraclavicular area: A retrospective observational study.

BACKGROUND: Catheterization of the axillary vein in the infraclavicular area has important advantages in patients with long-term, indwelling central venous catheters. The two most commonly used ultrasound-guided approaches for catheterization of the axillary vein include the long-axis/in-plane approach and the short-axis/out-of-plane approach, but there are certain drawbacks to both approaches. We have modified a new approach for axillary vein catheterization: the oblique-axis/in-plane approach. METHODS: This observational study retrospectively collected data from patients who underwent ultrasound-guided placement of an axillary vein infusion port in the infraclavicular area at the Central Venous Access Clinics of Zhongshan Hospital at Fudan University between March 2014 and May 2017. The patients' demographic data, success rate of catheterization, venous catheterization site, and immediate complications associated with catheterization were recorded. RESULTS: Between March 2014 and May 2017, a total of 858 patients underwent placement of an axillary vein infusion port in the infraclavicular area at our center. The ultrasound-guided oblique-axis/in-plane approach was used for all patients, and the venipuncture success rate was 100%. Two cases of accidental arterial puncture and one case of local hematoma formation were reported, and no other complications, such as pneumothorax or nerve damage, were reported. CONCLUSION: The ultrasound-guided oblique-axis/in-plane approach is a safe and reliable alternative to the routine ultrasound-guided approach for axillary venous catheterization.

Effects of resveratrol pretreatment on endoplasmic reticulum stress and cognitive function after surgery in aged mice.

BACKGROUND: Postoperative cognitive dysfunction (POCD) seriously reduces quality of life and is associated with increased morbidity and mortality. The causes and neuropathogenesis of POCD remain largely unknown. Resveratrol, a sirtuin 1 (Sirt1) activator, is a polyphenol compound found in red wine that has protective functions in neuropathology paradigms. Endoplasmic reticulum stress (ERS) is a primary cellular response that activates the unfolded protein response (UPR). ERS and UPR mediate molecular and biochemical mechanisms related to neurodegeneration; however, the roles of ERS and Sirt1 in POCD remain unclear. The properties of resveratrol might be useful in the setting of POCD. METHODS: In the present study, we investigated learning and memory function and ERS pathways in aged mice after surgery under local anesthesia, and we evaluated the effects of resveratrol pretreatment. RESULTS: We found that resveratrol attenuated postoperative learning and memory impairment in aged mice postoperatively but did not alter locomotor activity. Resveratrol significantly decreased postoperative expression of ERS pathway UPR-related proteins and inflammatory mediators including nuclear factor-κB (NF-κB) in the hippocampus. This was accompanied by higher Sirt1 protein expression levels. Pretreatment with resveratrol did not affect the number of hippocampal neurons in aged mice after surgery. CONCLUSION: Overall, resveratrol pretreatment attenuated short-term learning and memory impairment and the ERS pathway UPR in aged mice after surgery under local anesthesia.

Novamin infusion: a new method to cure postoperative shivering with hypothermia.

BACKGROUND: Postoperative shivering is a frequent complication of surgery in developing countries and there is no satisfying method to treat it, let alone to cure it. We studied whether intravenous amino acid (AA) infusion can cure postoperative shivering in the postanesthesia care unit. METHODS: Sixty postanesthesia care unit patients with shivering grade 2 or higher and tympanic temperature <36°C received randomly either infusion of Novamin 18 AAs (2 mL/kg/h), pethidine (0.5 mg/kg), or tramadol (1 mg/kg). Tympanic temperature, shivering grade, and thermal comfort were assessed every 5 min for 60 min. Blood glucose and lactic acid concentrations were measured before and after treatment. Postoperative nausea and vomiting were also recorded. RESULTS: Shivering stopped within 5 min in the pethidine and tramadol groups versus 90% stopped within 15 min in AA group. There were five cases of reshivering in the tramadol group versus none in the AA or pethidine groups. Tympanic temperature increased slowly in all patients but increased significantly faster in the AA group. Thermal comfort improved significantly faster in the AA group versus the other two groups, thermal comfort was significantly higher in the tramadol versus the pethidine group ≥35 min. Blood glucose concentration in AA group increased to 135.18 ± 9.18 mg/dL. There were some cases of nausea and vomiting in pethidine and tramadol groups but none in the AA group. CONCLUSION: Novamin infusion can stop postoperative shivering and alleviates hypothermia and improves thermal comfort more effectively than tramadol and pethidine with less nausea and vomiting and causes a clinically acceptable blood glucose increase with no reshivering episodes.

Impaired spatial learning and memory after sevoflurane-nitrous oxide anesthesia in aged rats is associated with down-regulated cAMP/CREB signaling.

Neurocognitive deficits arising from anesthetic exposure have recently been debated, while studies have shown that the phosphorylation of cyclic AMP response element-binding protein (CREB) in the hippocampus is critical for long-term memory. To better understand the neural effects of inhalational anesthetics, we studied the behavioral and biochemical changes in aged rats that were exposed to sevoflurane (Sev) and nitrous oxide (N2O) for 4 h. Eighteen-month-old rats were randomly assigned to receive 1.3% sevoflurane and 50% nitrous oxide/50% oxygen or 50% oxygen for 4 h. Spatial learning and memory were tested with the Morris water maze 48 h after exposure, and the results showed that sevoflurane-nitrous oxide exposure induced a significant deficit in spatial learning acquisition and memory retention. Experiments revealed that the cAMP and pCREB levels in the dorsal hippocampus were decreased in rats with anesthetic exposure in comparison with control rats 48 h after anesthesia as well as 15 min after the probe trial, but there were no significant differences in CREB expression. Besides these, the current study also found the DG neurogenesis significantly decreased as well as neuronal loss and neuronal apoptosis increased in the hippocampus of rats exposed to Sev+N2O. The current study demonstrated that down-regulation of cAMP/CREB signaling, decrease of CREB-dependent neurogenesis and neuronal survival in the hippocampus contributed to the neurotoxicity and cognitive dysfunction induced by general anesthesia with sevoflurane-nitrous oxide.

Retrieval of Consolidated Spatial Memory in the Water Maze Is Correlated with Expression of pCREB and Egr1 in the Hippocampus of Aged Mice.

OBJECTIVE: To study the relationship of the expression of phosphorylated cyclic AMP response element-binding protein (pCREB) and early growth response protein 1 (Egr1) in the hippocampus of aged mice with retrieval of consolidated spatial memory in a water maze. METHODS: Twenty-four aged mice were allocated into no training or probe test (naïve), no training but exposed to the same probe test (NTPRT), received training and probe test (PRT), and received training but no probe test (NPRT) groups. Twelve mice were trained in a water maze over 14 days. After the final probe trial on day 15, all mice were anesthetized and the brains were removed. pCREB immunoreactivity (pCREB-ir) and Egr1 immunoreactivity (Egr1-ir) in the hippocampal CA1 and CA3 areas were examined. RESULTS: pCREB-ir and Egr1-ir in the CA1 and CA3 areas of the NPRT and PRT groups were significantly higher than those of the naïve and NTPRT groups, and those in the PRT group were significantly higher than in the NPRT group. In all groups, pCREB-ir was significantly higher in the CA3 area compared to the CA1 area, while Egr1-ir was significantly higher in the CA1 area compared to the CA3 area. CONCLUSION: Retrieval, as well as formation, of consolidated spatial memory in the water maze is correlated with expression of pCREB and Egr1 in the hippocampus of aged mice.

Effects of different loading doses of dexmedetomidine on bispectral index under stepwise propofol target-controlled infusion.

BACKGROUND AND PURPOSE: Stepwise propofol target-controlled infusion (TCI) can achieve a less disturbed condition of hemodynamics and respiration. Its combination with dexmedetomidine may have some advantages for patients. We studied the effects of different loading doses of dexmedetomidine on the bispectral index (BIS) under stepwise propofol TCI. METHODS: Forty patients were randomly assigned into groups D(1.0), D(0.5), D(0.25) and D(0), in which dexmedetomidine at 1.0, 0.5, 0.25 or 0 µg•kg(-1) was infused over 10 min followed by 0.5 µg•kg(-1)•h(-1) and stepwise propofol TCI, which was administered with target effect site concentration (Ce) at 0.5 µg•ml(-1), and increased until 2.5 µg•ml(-1) by 1.0 µg•ml(-1) after 5 min reaching target Ce. BIS, heart rate, MAP, pulse oxygen saturation, RR and end-tidal carbon dioxide pressure were recorded before loading dose (T(0)), at 5 min (T(5 min)) and 10 min (T(10 min)) after starting infusion, after 5 min reaching Ce of 0.5, 1.5 and 2.5 µg•ml(-1) (T(p0.5), T(p1.5) and T(p2.5)). RESULTS: BIS values in group D(1.0) were significantly lower compared with those in group D(0) since T(10 min) and those in groups D(0.5) and D(0.25) since T(p0.5). In group D(1.0), heart rate decreased significantly at T(5 min) and T(10 min), heart rate at T(10 min) was significantly lower compared with that in group D(0). MAP remained stable during the loading dose infusion and decreased to some degree after propofol infusion in all groups. Changes in pulse oxygen saturation, RR and end-tidal carbon dioxide pressurewere similar among the groups without respiration depression. CONCLUSION: A loading dose of dexmedetomidine of 1.0 µg•kg(-1), not 0.5 µg•kg(-1) or less, over 10 min followed by 0.5 µg•kg(-1)•h(-1) can definitely decrease the BIS under stepwise propofol TCI with clinically stable blood pressure and without respiration depression, while attention should be paid to decreased heart rate.