The 90% effective concentration of alfentanil combined with 0.075% ropivacaine for epidural labor analgesia: a single-center, prospective, double-blind sequential allocation biased-coin design.

PURPOSE: More literature studies have reported that alfentanil is safe and effective for labor analgesia. However, there is no unified consensus on the optimal dosage of alfentanil used for epidural analgesia. This study explored the concentration at 90% of minimum effective concentration (EC90) of alfentanil combined with 0.075% ropivacaine in patients undergoing epidural labor analgesia to infer reasonable drug compatibility and provide guidance for clinical practice. METHODS: In this prospective, single-center, double-blind study, a total of 45 singleton term primiparas with vaginal delivery who volunteered for epidural labor analgesia were recruited. The first maternal was administered with 3 µg/mL alfentanil combined with 0.075% ropivacaine with the infusion of 10 mL of the mixture every 50 min at a background dose of 3 mL/h. In the absence of PCEA, a total of 15 mL of the mixture is injected per hour. The subsequent alfentanil concentration was determined on the block efficacy of the previous case, using an up-down sequential allocation with a bias-coin design. 30 min after epidural labor analgesia, the block of patient failed with visual analog score (VAS) > 3, the alfentanil concentration was increased in a 0.5 µg/mL gradient for the next patient, while the block was successful with VAS ≤ 3, the alfentanil concentration was remained or decreased in a gradient according to a randomized response list for the next patient. EC90 and 95% confidence interval were calculated by linear interpolation and prediction model with R statistical software. RESULTS: In this study, the estimated EC90 of alfentanil was 3.85 µg/mL (95% confidence interval, 3.64-4.28 µg/mL). CONCLUSION: When combined with ropivacaine 0.075%, the EC90 of alfentanil for epidural labor analgesia is 3.85 µg/mL in patients undergoing labor analgesia.

A role of GABAA receptor α1 subunit in the hippocampus for rapid-acting antidepressant-like effects of ketamine.

Ketamine can produce rapid-acting antidepressant effects in treatment-resistant patients with depression. Although alterations in glutamatergic and GABAergic neurotransmission in the brain play a role in depression, the precise molecular mechanisms in these neurotransmission underlying ketamine's antidepressant actions remain largely unknown. Mice exposed to FSS (forced swimming stress) showed depression-like behavior and decreased levels of GABA (γ-aminobutyric acid), but not glutamate, in the hippocampus. Ketamine increased GABA levels and decreased glutamate levels in the hippocampus of mice exposed to FSS. There was a correlation between GABA levels and depression-like behavior. Furthermore, ketamine increased the levels of enzymes and transporters on the GABAergic neurons (SAT1, GAD67, GAD65, VGAT and GAT1) and astrocytes (EAAT2 and GAT3), without affecting the levels of enzymes and transporters (SAT2, VGluT1 and GABAAR γ2) on glutamatergic neurons. Moreover, ketamine caused a decreased expression of GABAAR α1 subunit, which was specifically expressed on GABAergic neurons and astrocytes, an increased GABA synthesis and metabolism in GABAergic neurons, a plasticity change in astrocytes, and an increase in ATP (adenosine triphosphate) contents. Finally, GABAAR antagonist bicuculline or ATP exerted a rapid antidepressant-like effect whereas pretreatment with GABAAR agonist muscimol blocked the antidepressant-like effects of ketamine. In addition, pharmacological activation and inhibition of GABAAR modulated the synthesis and metabolism of GABA, and the plasticity of astrocytes in the hippocampus. The present data suggest that ketamine could increase GABA synthesis and astrocyte plasticity through downregulation of GABAAR α1, increases in GABA, and conversion of GABA into ATP, resulting in a rapid-acting antidepressant-like action. This article is part of the Special Issue on 'Ketamine and its Metabolites'.

Perioperative intravenous S(+)-ketamine for acute postoperative pain in adults: study protocol for a multicentre, randomised, open-label, positive-controlled, pragmatic clinical trial (SAFE-SK-A trial).

INTRODUCTION: Postoperative pain remains incompletely controlled for decades. Recently, multimodal analgesia is emerging as a potential approach in the management of postoperative pain. Therein, S(+)-ketamine is appealing as an adjuvant drug in multimodal analgesia due to its unique pharmacological advantages. This pragmatic clinical trial (SAFE-SK-A trial) is designed to investigate the analgesic effect and safety of S(+)-ketamine for acute postoperative pain in adults and explore the optimal strategy of perioperative intravenous S(+)-ketamine in a real-world setting. METHODS AND ANALYSIS: This multicentre, randomised, open-label, positive-controlled, pragmatic clinical trial (SAFE-SK-A study) is planned to conduct in 80 centres from China and recruit a total of 12 000 adult participants undergoing a surgical procedure under general anaesthesia. Patient recruitment started in June 2021 and will end in June 2022. Participants will be randomised in a ratio of 2:1 to either receive perioperative intravenous S(+)-ketamine plus conventional anaesthesia or conventional anaesthesia only. Given the pragmatic nature of the study, no specific restriction as to the administration dosage, route, time, synergistic regimen or basic analgesics. Primary endpoints are the area under the broken line of Numerical Rating Scale (NRS) scores for pain intensity and the total opioid consumption within 48 hours postoperative. Secondary endpoints are postoperative NRS scores, the anaesthesia recovery time, time of first rescue analgesia, the incidence of rescue analgesia, the incidence of postoperative delirium, patient questionnaire for effect, changes from baseline in cognitive function and anxiety and depression, as well as the adverse events and pharmacoeconomic outcomes. The general linear model will be used for the primary endpoint, and appropriate methods will be used for the secondary endpoints. ETHICS AND DISSEMINATION: This trial has been approved by the local Institutional Review Board (S2021-026-02) and conducted following the Declaration of Helsinki. Results of this trial will be publicly disclosed and published in scientific journals. TRIAL REGISTRATION NUMBER: NCT04837170; Pre-results.

[Effect of transcutaneous electrical acupoint stimulation on catheter related bladder discomfort after ureteroscopic lithotripsy].

OBJECTIVE: To verify the efficacy of transcutaneous electrical acupoint stimulation (TEAS) on catheter related bladder discomfort after ureteroscopic lithotripsy. METHODS: Sixty male patients with selective ureteroscopic lithotripsy under general anesthesia were randomly divided into a TEAS group (30 cases, one case dropped off) and a sham TEAS group (30 cases, 2 cases dropped off). Before anesthesia induction, the patients in the TEAS group were treated with TEAS at Guanyuan (CV 4), Zhongji (CV 3), Zusanli (ST 36) and Sanyinjiao (SP 6) for 30 min, with disperse-dense wave, frequency of 2 Hz/ 15 Hz and current intensity of 6 to 10 mA. The patients in the sham TEAS group were treated with the same TEAS device at the same acupoints, but no electrical stimulation was given. After 30 min, anesthesia induction started. The total dosages of propofol and remifentanil in the two groups were recorded, and the time of operation and anesthesia, the time of wake-up and the time of stay in postanesthesia care unit (PACU) were recorded. The postoperative recovery was evaluated 5 min (T1) after wake-up, 1 h (T2), 2 h (T3) and 6 h (T4) after the operation, including the severity of urinary tract irritation and visual analogue scale (VAS) score. The occurrence of adverse reactions was observed, such as nausea and vomiting, dizziness and headache. RESULTS: The dosage of remifentanil in the TEAS group was significantly lower than that in the sham TEAS group (P<0.05); but the dosage of propofol had no significant difference between the two groups (P>0.05). Compared with the sham TEAS group, the incidence of more-than-moderate urinary tract irritation symptoms in the TEAS group was reduced (P<0.05), and the VAS scores 1 and 2 h after operation were reduced (P<0.05). CONCLUSION: The 30-min TEAS at Guanyuan (CV 4), Zhongji (CV 3), Zusanli (ST 36) and Sanyinjiao (SP 6) before anesthesia induction could significantly control the severity of postoperative urinary tract irritation in patients with ureteroscopic lithotripsy, reduce the dosage of anesthetic drugs and relieve postoperative pain.

Penehyclidine hydrochloride attenuates the cerebral injury in a rat model of cardiopulmonary bypass.

This study investigated the effect of penehyclidine hydrochloride (PHC) on regulatory mediators during the neuroinflammatory response and cerebral cell apoptosis following cardiopulmonary bypass (CPB). Forty-eight rats were randomly divided among 4 groups as follows: sham-operation, vehicle, low-dose PHC (0.6 mg·(kg body mass)(-1)), and high-dose PHC (2.0 mg·(kg body mass)(-1)). CPB was performed in the latter 3 groups. The plasma levels of neuron specific enolase (NSE) and S-100B were tested with ELISA. Real-time PCR and Western blotting were used to evaluate the expression levels of matrix metalloproteinase-9 (MMP-9), IL-10, caspase-3, Bcl-2, and p38 in brain tissue. The ultrastructure of hippocampus tissue was examined under an electron microscope. PHC attenuated the increase of plasma NSE and S-100B following CPB. MMP-9, cleaved caspase-3, and phosphorylated p38 expression were substantially increased in the vehicle group compared with the sham-operation group and gradually diminished with increasing doses of PHC. IL-10 and Bcl-2 expression were markedly lower in the vehicle group than in the sham-operation group and gradually recovered with increasing doses of PHC. PHC attenuated the histopathological changes of cerebral injury following CPB. PHC favorably regulates the inflammatory response and reduces markers of neuronal injury following CPB, potentially by reducing p38 and caspase-3 activation.

Penehyclidine hydrochloride preserves the intestinal barrier function in patients undergoing cardiopulmonary bypass.

OBJECTIVE: The study objective was to investigate the protective effect of penehyclidine hydrochloride on intestinal barrier function integrity and its therapeutic potential on endotoxemia and systemic inflammatory response in patients undergoing cardiopulmonary bypass. METHODS: Forty patients undergoing cardiac valve replacement with cardiopulmonary bypass were enrolled in the study. All patients were randomly divided into the penehyclidine hydrochloride or control group (20 patients in each group). Patients in the penehyclidine hydrochloride group received an intravenous injection of 0.05 mg/kg penehyclidine hydrochloride 10 minutes before cardiopulmonary bypass, and those in the control group were given the same volume of saline. Blood samples for blood glucose, lactic acid, intestinal fatty acid binding protein, D-lactate, serum endotoxin (lipopolysaccharide), interleukin-6, and interleukin-10 measurements were collected during the following time points: immediately after anesthesia induction (T0), 10 minutes after the release of aortic-clamping (T1), immediately after weaning from cardiopulmonary bypass (T2), 2 hours postoperatively (T3), 6 hours postoperatively (T4), and 18 hours postoperatively (T5). RESULTS: Blood glucose, lactic acid, intestinal fatty acid binding protein, D-lactate, lipopolysaccharide, interleukin-6, and interleukin-10 were significantly increased at all postoperative time points. At specific postoperative time points, blood glucose, lactic acid, intestinal fatty acid binding protein, D-lactate, lipopolysaccharide, and interleukin-6 were statistically lower in the penehyclidine hydrochloride group than in the control group. Postoperatively, interleukin-10 did not differ between the penehyclidine hydrochloride and control groups. CONCLUSIONS: Penehyclidine hydrochloride preserves intestinal barrier function integrity, attenuates endotoxemia, and inhibits systemic inflammatory response in patients undergoing cardiopulmonary bypass, possibly by improving intestinal microcirculation and depressing stress response.

Probiotics can alleviate cardiopulmonary bypass-induced intestinal mucosa damage in rats.

BACKGROUND: Cardiopulmonary bypass (CPB) is commonly applied to support circulation during heart surgery but frequently causes adverse effects. AIMS: The purpose of this study was to examine the potential of probiotics to improve small intestinal mucosa barrier function after CPB. METHODS: Twenty-four adult male SD rats were randomly divided into sham-operated (S), CPB-operated (CPB), and probiotic-fed (Y) groups. Diamine oxidase (DAO) activity and concentrations of D-lactic acid, endotoxin, TNFα, and IL-6 were measured in portal vein blood. IgA concentrations were determined in plasma and the small intestine. Vena cava blood and tissue samples were used to monitor bacterial growth. Intestinal epithelial ultrastructure was analyzed by transmission electron microscopy (TEM). Occludin and ZO-1 expression levels in the intestinal epithelium were detected by western blotting and immunohistochemistry, respectively. RESULTS: D-lactic acid, endotoxin, TNFα and IL-6 levels, DAO activity, and bacterial translocation rate were increased (P < 0.05) in CPB and Y compared to the S group. The above indices were relatively lower (P < 0.05) in Y than in CPB. Plasma and small intestinal IgA levels were significantly lower (P < 0.05) in CPB, while in Y they were significantly increased (P < 0.05) but lower than in S (P < 0.05). These results were confirmed by TEM. Consistently, occludin and ZO-1 expression levels were significantly higher in Y than in CPB (P < 0.05) but still lower compared to S (P < 0.05). CONCLUSION: Pre-administration of probiotics can improve, to some extent, intestinal barrier function after CPB in rats, and this effect is likely related to inhibition of the CPB-induced inflammatory response, improvement in local intestinal immune function, and increased expression of intestinal epithelial tight junction proteins.

Effects of penehyclidine hydrochloride on rat intestinal barrier function during cardiopulmonary bypass.

AIM: To test the ability of penehyclidine hydrochloride (PHC) to attenuate intestinal injury in a rat cardiopulmonary bypass (CPB) model. METHODS: Male Sprague-Dawley rats were randomly divided into six groups (eight each): sham-operated control; sham-operated low-dose PHC control (0.6 mg/kg); sham-operated high-dose PHC control (2.0 mg/kg); CPB vehicle control; CPB low-dose PHC (0.6 mg/kg); and CPB high-dose PHC (2.0 mg/kg). Blood samples were collected from the femoral artery 2 h after CPB for determination of plasma diamine oxidase (DAO), D-lactate and endotoxin levels. Spleen, liver, mesenteric lymph nodes and lung were removed for biochemical analyses. Intestinal tissue ultrastructure was examined by electron microscopy. RESULTS: In the sham-operated groups, high- and low-dose-PHC had no significant impact on the levels of DAO, D-lactate and endotoxin, or the incidence of intestinal bacterial translocation (BT). Serum levels of DAO, D-lactate, endotoxin and the incidence of intestinal BT were significantly increased in the surgical groups, compared with the sham-operated groups (0.543 ± 0.061, 5.697 ± 0.272, 14.75 ± 2.46, and 0/40 vs 1.038 ± 0.252, 9.377 ± 0.769, 60.37 ± 5.63, and 30/40, respectively, all P < 0.05). PHC alleviated the biochemical and histopathological changes in a dose-dependent manner. Serum levels of DAO, D-lactate, and endotoxin and the incidence of intestinal BT in the high-dose PHC group were significantly lower than in the low-dose PHC group (0.637 ± 0.064, 6.972 ± 0.349, 29.64 ± 5.49, and 14/40 vs 0.998 ± 0.062, 7.835 ± 0.330, 38.56 ± 4.28, and 6/40, respectively, all P < 0.05). CONCLUSION: PHC protects the structure and function of the intestinal mucosa from injury after CPB in rats.