Fospropofol disodium (fospropofol), a water-soluble prodrug of propofol, reduces injection pain and anesthetic requirements but frequently causes paresthesia. Intravenous lidocaine has been shown to alleviate dexamethasone-induced paresthesia, yet its effect on fospropofol-related symptoms remains uncertain. We combined preclinical and clinical studies, first evaluating the safety and pharmacological changes of fospropofol premixed with lidocaine through in vitro and in vivo experiments and then conducting a randomized controlled trial in adult surgical patients to evaluate whether the lidocaine premixing strategy affects the occurrence of fospropofol-induced paresthesia. In the preclinical study, the findings indicated that mixture of fospropofol and lidocaine remained physicochemically stable, with faster onset and longer sedation duration compared with fospropofol alone, without additional adverse effects. In the clinical trial, 74 patients received fospropofol dissolved in either 20 mL of normal saline or 0.75% lidocaine and 72 were included in the primary outcome analysis of paresthesia. This adverse reaction occurred in 83.3% of patients in both groups, mainly within 40-60 s after administration. No group differences were observed in plasma inflammatory markers and phosphate; however, phosphate levels increased postadministration in both groups. This study provides important guidance for clinical practice, showing that premixing lidocaine does not effectively alleviate paresthesia induced by fospropofol.
Postoperative cognitive dysfunction (POCD) is a common neurologic complication that occurs after surgery, which prolongs the hospital stay of patients to a certain extent, increases the occurrence of complications, and even leads to the patient's death. Intravenous lidocaine can reduce perioperative inflammatory response in patients undergoing surgery, but its effect on postoperative cognitive function has not been systematically evaluated. Notably, prior findings regarding the impact of intravenous lidocaine on postoperative cognitive function have been variable. Therefore, on this basis, this study explored the effects of intravenous lidocaine on postoperative cognitive function of patients undergoing general anesthesia through a systematic review and meta-analysis. Pubmed, Cochrane Library, Embase, Medline, Wanfang Medical Database, China Biomedical Literature Database, and China Academic Journals Full-Text Database were searched from inception to February 2024 for relevant studies that investigated effect of intravenous lidocaine on POCD in patients undergoing general anesthesia surgery. Key data obtained from the referenced literature included the prevalence of POCD, scores from the Mini-Mental State Examination (MMSE), and perioperative serum concentrations of neuron-specific enolase (NSE) and central nervous specific protein (S-100β) protein, serving as biomarkers for central nervous system specificity. Meta-analysis of data was performed using RevMan5.3 software. The software Trial Sequential Analysis (version 0.9) (TSA) was used to analyze high-quality literature focusing on POCD outcome indicators to explore the reliability of the results of meta-analysis. Twenty-five studies were included for quality evaluation and data analysis. The studies compared the effect of intravenous lidocaine on the incidence of POCD in patients undergoing surgery at different time points. Subgroup analysis was used to investigate the incidence of POCD at different time points. The results showed that intravenous lidocaine significantly reduced the incidence of POCD at 1, 3, 7, 9 days and 1 year after surgery compared with the control group (on the first day postoperatively: odds ratio (OR) = 0.48, 95% CI: 0.32-0.69, P < 0.001; postoperative day 3: OR = 0.42, 95% CI: 0.25-0.72, P = 0.002; postoperative day 7: OR = 0.34, 95% CI: 0.21-0.55, P < 0.001; postoperative day 9: OR = 0.32, 95% CI: 0.17-0.61, P < 0.001; 1 year postoperatively: OR = 0.39, 95% CI: 0.28-0.54, P < 0.001). The incidence of POCD in patients undergoing general anesthesia at postoperative day 1 with lidocaine was analyzed sequentially. The results showed that with the increase of the included sample size, the Z-curve still did not exceed the TSA boundary and did not reach the required information size. Fourteen studies compared MMSE scores before, 1, 2, 3, and 7 days after surgery between the 2 groups. The results showed that the MMSE score of lidocaine group was significantly higher than that of control group on the first and third postoperative day, with statistical significance (P < 0.05). Compared with the control group, the serum concentrations of neuron-specific enolase and central nervous specific protein in the lidocaine group significantly decreased postoperatively and on the first and third day postoperatively. Perioperative intravenous lidocaine may improve postoperative cognitive function and reduce the incidence of POCD. However, limited to the current situation of low quality and small sample size, TSA analysis suggests the need for larger high-quality sample to confirm the accuracy of our findings. This is a systematic review, equivalent to a review, and does not require clinical trial registration. We have registered on PROSPERO. CRD42023493992.
Current therapeutic research, clinical and experimental •
In patients undergoing gastrointestinal surgery, enhancing perioperative cognitive function and facilitating expedited postoperative recovery are critical components for achieving swift rehabilitation. Intravenous administration of lidocaine has been shown to mitigate the perioperative inflammatory response in surgical patients; however, its influence on postoperative cognitive performance remains unassessed. Consequently, this study was conducted to investigate the impact of intravenous lidocaine on postoperative cognitive function in participants undergoing laparoscopic surgery for colorectal cancer. We performed a prospective, randomized controlled trial at The First People's Hospital of Changde City and Zhongshan People's Hospital to assess the impact of intravenous lidocaine on postoperative cognitive dysfunction (POCD) in patients undergoing laparoscopic radical resection for colorectal carcinoma. The primary endpoints of our investigation included Mini-Mental State Examination (MMSE) scores measured preoperatively and 7 days postoperatively, as well as the incidence of POCD at the 7-day mark following surgery. Secondary outcomes comprised an evaluation of recovery parameters in the postanesthesia care unit, overall length of hospitalization, and the prevalence of postoperative complications in both study cohorts. The occurrence of POCD at day 7 postsurgery was significantly lower in the lidocaine group compared to the placebo group ( < 0.05). When stratified by age, both elderly patients (≥65 years) and nonelderly patients in the lidocaine group exhibited a significantly reduced incidence of POCD on the seventh day postoperatively compared to the placebo group ( < 0.05). Preoperative MMSE scores were comparable between the two groups; however, on the seventh day after surgery, the lidocaine group had significantly higher MMSE scores than the placebo group ( < 0.05). In the nonelderly cohort, MMSE scores were also significantly elevated in the lidocaine group compared to the placebo group at day 7 postsurgery ( < 0.05). Mediation analysis indicated that lidocaine's influence on the incidence of POCD on the seventh postoperative day was partially mediated by propofol. Furthermore, there were no significant differences observed in intraoperative medication, postoperative recovery, or perioperative adverse events between the groups ( > 0.05). Perioperative administration of intravenous lidocaine has been shown to significantly enhance cognitive function on the seventh postoperative day following laparoscopic colorectal surgery. The mediating influence of propofol on the association between lidocaine and the occurrence of POCD at this time point was determined to be 10%.
Lidocaine and its active metabolites are metabolized mainly by the liver, and liver-compromised may slow the metabolism of lidocaine and its active metabolites. In addition to excessive lidocaine, accumulated active metabolites may also lead to lidocaine-related toxicity in liver-compromised patients. This study aimed to describe the population pharmacokinetics of lidocaine and its active metabolites in partial hepatectomy patients and propose a novel drug regimen involving lidocaine-weighted active metabolites. The concentrations of lidocaine and its active metabolites from thirty-five patients underwent partial hepatectomy were analysed by non-linear mixed-effects models. The mean loading dose was 86.07 mg, and the median continuous infusion dose was 57.97 mg/h. A population pharmacokinetic model fitting the plasma concentrations of lidocaine and its active metabolites was built to explore the factors affecting the concentrations of lidocaine and its active metabolites. A two-compartment model with first-order elimination was used to determine the concentrations of lidocaine and its active metabolites. The different dosing simulations revealed that the selected appropriate loading dose did not exceed 1.5 mg/kg, and the continuous infusion dose of lidocaine should preferably not surpass 1.5 mg/kg/h in Chinese hepatectomy patients. The simulation results of long-term infusion of lidocaine during the postoperative stage after liver resection that showed there was a significant accumulation of MEGX after more than 24 hours of lidocaine infusion, and when the infusion rate reached 1 mg/kg/h, the MEGX concentration exceeded 5 µg/mL. This study proposes for the first time the integration of lidocaine concentration with active metabolites and simulation-based dosing recommendations. During the 24-hour medication period for Chinese hepatectomy patients, the recommended safe dosage includes a loading dose not exceeding 1.5 mg/kg and an infusion dose not exceeding 1.5 mg/kg/h. Monitoring of active metabolites, in addition to lidocaine is also necessary for continuous infusion of lidocaine. The trial is registered at chictr.org.cn (ChiCTR2100042730).