Efficacy and safety of remimazolam besylate in bronchoscopy for adults: A multicenter, randomized, double-blind, positive-controlled clinical study.

Background: With the development of fiberoptic bronchoscopy in the diagnosis and treatment of various pulmonary diseases, the anesthesia/sedation requirements are becoming more demanding, posing great challenges for patient safety while ensuring a smooth examination/surgery process. Remimazolam, a brand-new ultra-short-acting anesthetic, may compensate for the shortcomings of current anesthetic/sedation strategies in bronchoscopy. Methods: This study was a prospective, multicenter, randomized, double-blind, parallel positive controlled phase 3 clinical trial. Subjects were randomized to receive 0.2 mg/kg remimazolam besylate or 2 mg/kg propofol during bronchoscopy to evaluate the efficacy and safety of remimazolam. Results: A total of 154 subjects were successfully sedated in both the remimazolam group and the propofol group, with a success rate of 99.4% (95%CI of the adjusted difference -6.7 × 10%-6% to -5.1 × 10%-6%). The sedative effect of remimazolam was noninferior to that of propofol based on the prespecified noninferiority margin of -5%. Compared with the propofol group, the time of loss of consciousness in the remimazolam group (median 61 vs. 48s, p < 0.001), the time from the end of study drug administration to complete awakening (median 17.60 vs. 12.80 min, p < 0.001), the time from the end of bronchoscopy to complete awakening (median 11.00 vs. 7.00 min, p < 0.001), the time from the end of study drug administration to removal of monitoring (median 19.50 vs. 14.50 min, p < 0.001), and the time from the end of bronchoscopy to removal of monitoring (median 12.70 vs. 8.60 min, p < 0.001) were slightly longer. The incidence of Adverse Events in the remimazolam group and the propofol group (74.8% vs. 77.4%, p = 0.59) was not statistically significant, and none of them had Serious Adverse Events. The incidence of hypotension (13.5% vs. 29.7%, p < 0.001), hypotension requiring treatment (1.9% vs. 7.7%, p = 0.017), and injection pain (0.6% vs. 16.8%, p < 0.001) were significantly lower in the remimazolam group than in the propofol group. Conclusion: Moderate sedation with 0.2 mg/kg remimazolam besylate is effective and safe during bronchoscopy. The incidence of hypotension and injection pain was less than with propofol, but the time to loss of consciousness and recovery were slightly longer. Clinical Trial Registration: clinicaltrials.gov, ChiCTR2000039753.

The promising role of PAX1 (aliases: HUP48, OFC2) gene methylation in cancer screening.

BACKGROUND: Paired-box gene 1 (PAX1), a member of the PAX family, plays a role in pattern formation during embryogenesis, and might be essential for development of the vertebral column. METHODS: PAX1 is silenced by methylation in several cancers and is considered a tumor suppressor gene. Our previous studies reported PAX1 as hypermethylated in cervical cancer tissues, thereby suggesting it as a potential screening marker. Recently, an increasing number of studies have confirmed PAX1 methylation as a promising biomarker in cervical cancer based on its excellent discriminatory ability between high-grade cervical lesions and normal tissues, resulting in a reduced necessity for referral for colposcopy and biopsy. Additionally, PAX1 is also hypermethylated in other tumors, including those associated with epithelial ovarian cancer, esophageal squamous cell carcinoma, head and neck squamous cell carcinoma, and endometrial carcinoma, and shows relatively good sensitivity and specificity for the detection of these tumors. RESULTS: This review summarizes reports of PAX1 methylation and its promising role in cancer screening, especially that associated with cervical cancer. CONCLUSION: According to current evidence, combined testing for human papillomavirus and PAX1 methylation analysis represents an efficacious cervical cancer-screening protocol.

Pharmacokinetic and pharmacodynamic study of dexmedetomidine in elderly patients during spinal anesthesia.

OBJECTIVE: The application of dexmedetomidine in patient sedation is generally accepted, though its clinical application is limited because of the lack of information detailing the specific properties among diverse populations of patients. The aim of this study was to compare the pharmacokinetic and pharmacodynamic characteristics of dexmedetomidine between elderly and young patients during spinal anesthesia. METHODS: 34 subjects (elderly group: n = 15; young group: n = 19) with spinal anesthesia were enrolled in the present study following the inclusion/exclusion criteria detailed below. All subjects received intravenous infusion of dexmedetomidine with a loading dose of 0.5 µg x kg⁻¹ for 10 minutes and a maintenance dose of 0.5 µg x kg⁻¹ x h⁻¹ for 50 minutes. Plasma concentrations of dexmedetomidine were detected by the HPLC-MS/MS method and pharmacokinetic parameters were calculated using WinNolin software. RESULTS: There was no significant difference between the elderly and young subjects in major pharmacokinetic parameters. There was a marked gender difference in the Cmax (peak plasma concentration) and tmax (time to reach Cmax) between genders in elderly subjects, though in this cohort the other pharmacokinetic parameters were not significantly different. In the young subjects there were no noteworthy variations between genders in pharmacokinetic parameters. There was no significant difference between the two groups in BISAUC(0-t) (the area under the bispectral index-time curve from time 0 to t hours), BISmin (the minimum value of the bispectral index after drug delivery), and or tmin-BIS (bispectral index for the minimum value of time). SBP (systolic blood pressure), DBP (diastolic blood pressure), HR (heart rate), and SpO2(pulse oxygen saturation) developed substantive differences in a time-dependent manner, but there were no statistically significant differences in these four indicators in the time*group at three time points (1 hour, 2 hours, and 3 hours after drug administration); while SBP was significantly different between the groups, this differential declined in a time-dependent manner, and there were no significant attendant differences in the D-value. The observed values and D-values of DBP and HR were similar in the groups, but the observed value and D-value of SpO2did differ. There were 14 drug-related adverse events in the young group, and 26 drug-related adverse events in the elderly group, a 46% differential. The percentage of patients who requiring intervention during surgery was 68.75% (11/16) in the elderly group and 36.84% (7/19) in the young group, with no significant difference between the two groups once age was factored in (p = 0.06). None of the pharmacodynamic indices, however, correlated with the key pharmacokinetic parameters (Cmax, AUC(0→t), AUC(0→∞)) of dexmedetomidine. CONCLUSIONS: The clearance of dexmedetomidine in elderly patients showed a declining trend compared to young patients. Interventions in the elderly group were more frequent than in the young group, and the elderly group showed significant adverse effects. It is suggested that elderly patients who use dexmedetomidine may benefit from a different dose. However, further research with a larger population size is required to confirm these findings.

Immune-Mediated Metabolic Kynurenine Pathways Are Involved in the Postoperative Cognitive Dysfunction after Cardiopulmonary Bypass.

Postoperative cognitive dysfunction (POCD) after cardiopulmonary bypass is a serious complication that can lead to personality changes, memory loss, reduction in the ability to learn, and other central nervous system dysfunctions. In recent years, there have been improvements in measures to protect the brain during surgery, although the incidence of cognitive dysfunction after cardiac surgery remains high (33 to 83% short-term and 20 to 60% long-term cognitive dysfunction). Despite the large amount of basic and clinical research on the incidence of POCD, its exact pathogenesis and complexity are not clear. Many studies have shown that the kynurenine pathway (KP) and cognitive function in humans are closely related. Some reports also show that the imbalance of some metabolites of the KP such as kynurenic acid and quinolinic acid (QUIN), which act in dynamic equilibrium under physiologic conditions, have effects on the central nervous system and can significantly affect cognitive function. Further studies have shown that inflammatory mediators may act on key enzymes of the KP causing KP-induced disorders. Severe inflammatory reaction occurs in patients undergoing cardiopulmonary bypass, which triggers metabolic pathways that are closely related to changes in cognitive function. In this review, we summarize that inflammation-induced metabolic kynurenine (KYN) pathway disorders are likely to have an important role in incidence of POCD after CPB surgery.

Preoperative cognitive intervention reduces cognitive dysfunction in elderly patients after gastrointestinal surgery: a randomized controlled trial.

BACKGROUND: Preoperative conditions may play a significant role in postoperative cognitive dysfunction (POCD) development in elderly patients. We aimed to investigate whether preoperative cognitive training could lower the incidence of POCD one week after surgery. MATERIAL AND METHODS: A total of 141 ASA I-III elderly patients who underwent gastrointestinal surgery were enrolled into the study. Patients were randomized into either the Intervention group (69 analyzed) or the Control group (72 analyzed). Patients in the intervention group were instructed and trained in a cognition mnemonic skill for a total of three 1-hour sessions with the method of loci (MoL). Controls did not receive any cognitive training during hospitalization. All patients were tested using neuropsychological battery tests (NPTs) on admission and one week after surgery. RESULTS: The incidence of POCD in the intervention group (15.9%) was significantly lower than in the controls (36.1%) (P<0.05). Patients' performance in Brief Visuospatial Memory Test-Revised and Symbol-Digit Modalities Test were improved by the cognitive training. Increasing age, longer length of anesthesia and surgery, and lack of cognitive training were associated with a significantly higher risk of POCD (P<0.05). CONCLUSIONS: Cognitive training with MoL can reduce the decline of early postoperative cognitive function in elderly patients undergoing major gastrointestinal surgery.

Role of SLCO1B1, ABCB1, and CHRNA1 gene polymorphisms on the efficacy of rocuronium in Chinese patients.

This study explored the role of SLCO1B1, ABCB1, and CHRNA1 gene polymorphisms on the efficacy and duration of action of rocuronium in Chinese patients. Two hundred seven unrelated Chinese patients scheduled for elective surgery were recruited, and 200 completed the study. Their ABCB1, SLCO1B1, and CHRNA1 genotypes were determined. Demographic and clinical non-genetic data also were collected. The SLCO1B1, ABCB1, and CHRNA1 variants did not affect the onset time of rocuronium. Clinical duration and recovery time of rocuronium were prolonged in patients with the ABCB1 rs1128503TT and SLCO1B1 rs2306283 AG and GG genotypes. We demonstrate that the SLCO1B1 and ABCB1 gene variants could affect the pharmacodynamics of rocuronium. The ABCB1 rs1128503 C>T genotype was the most important factor on the efficacy of rocuronium.

Tramadol combined with fentanyl in awake endotracheal intubation.

OBJECTIVE: To explore the feasibility and dosage of tramadol combined with fentanyl in awake endotracheal intubation. METHODS: Using Dixon's up-and-down sequential design, the study enrolled patients from each of the 20-49, 50-60 and 70-and-above age groups scheduled for elective surgery under general anesthesia. The feasibility and dosage of tramadol combined with fentanyl in awake endotracheal intubation, guided by fiberoptic bronchoscopy, were verified. RESULTS: After intravenous injection with fentanyl 2.2 µg/kg and tramadol 2.0 mg/kg in the 20-49 age group, fentanyl 1.6 µg/kg and tramadol 1.9 mg/kg in the 50-69 age group and fentanyl 1 µg/kg and tramadol 1.8 mg/kg in those at the age of 70 or above, the patients achieved conscious sedation without obvious respiratory depression. Meanwhile, under these dosages, the patients could easily tolerate the thyrocricocentesis airway surface anesthesia and fiberoptic bronchoscope guided tracheal intubation. Postoperative follow-up showed that most patients had memory of the intubation process but without significant discomfort. No awake endotracheal intubation-related side effect was noted. CONCLUSIONS: Fiberoptic bronchoscope guided nasotracheal intubation can be successfully completed with background administration of fentanyl and tramadol. However, the specific dosages need to be tailored in different age of patients.

Surgery upregulates high mobility group box-1 and disrupts the blood-brain barrier causing cognitive dysfunction in aged rats.

AIM: Postoperative cognitive dysfunction (POCD) is a growing and largely underestimated problem without defined etiology. Herein, we sought to determine the relationship between cognitive decline, blood-brain barrier (BBB) permeability, and inflammation, namely high mobility group box-1 (HMGB1), after surgery in aged rats. METHODS: Aged rats were randomly assigned as surgery group (n = 45, splenectomy under general anesthesia), anesthesia (n = 45, 2% isoflurane for 2 h), and naïve control (n = 15). Markers of inflammation were measured in plasma and brain. Blood-brain barrier ultrastructure and permeability were measured by transmission electron microscope (TEM) and IgG immunohistochemistry. Cognitive function was assessed in a reversal learning version of the Morris water maze (MWM). RESULTS: Surgical trauma under general anesthesia caused distinct changes in systemic and central proinflammatory cytokines. Levels of HMGB1 and the receptor for advanced glycation end products (RAGE) were significantly upregulated in the hippocampus of operated animals. Immunohistochemistry and TEM showed BBB disruption induced by surgery and anesthesia. These molecular changes were associated with cognitive impairment in latency with the MWM up to postoperative day 3. CONCLUSIONS: HMGB1 and RAGE signaling appear pivotal mediators of surgery-induced cognitive decline and may contribute to the changes in BBB permeability after peripheral surgical trauma.

[Effect of isoflurane delayed preconditioning on myocardial ischemia reperfusion injury in rabbits].

OBJECTIVE: To investigate the protective effect of isoflurane delayed preconditioning on myocardial ischemia reperfusion injury and the potential mechanism in rabbits. METHODS: Thirty New Zealand male white rabbits were randomly assigned to 3 groups: Control group; I/R group; and 2.0% isoflurane group. Isoflurane group was exposed to 2.0% isoflurane-100% oxygen for 2 hours. Control group and I/R group were exposed to 100% oxygen for 2 hours and served as untreated controls. Twenty-four hours later I/R group and isoflurane group underwent 40 minutes of coronary occlusion followed by 2 hours of reperfusion. Blood samples were taken from the arterial line at 20 minutes before the occlusion(T1), 20 minutes after the occlusion(T2), 40 minutes after the occlusion(T3), 1 hours after the reperfusion(T4), and 2 hours after the reperfusion(T5) to determine the plasma level of TNF-alpha. At the end of the reperfusion, infarct size and area at risk were defined by Evans and TTC staining. The heart was harvested and levels of the p38MAPK activity were determined by Western blot, and ultrastructures were observed under the electron microscope. RESULTS: The p38MAPK activity of isoflurane group was significantly lower than that of I/R group (P<0.05). Isoflurane significantly (P<0.05) reduced the infarct size(19.7%+/-2.8% in isoflurane group) of the left ventricular area at risk as compared with the controls (37.8%+/-1.7% in I/R group).The injury of I/R group was worse than that of isoflurane group under the light microscope. Isoflurane group had a lower level of TNF-alpha than I/R group. CONCLUSION: Isoflurane can inhibit p38MAPK activity during myocardial ischemia reperfusion and modulate the cytokine expression, which may be one of the molecular mechanisms of isoflurane delayed preconditioning on cardioprotection.