Efficacy,Safety And Pharmacokinetics Of Remazolam Besylate In ICU Patients

Objective:To explore the optimal dose of remimazolam besylate for mild to moderate sedation in critically ill patients.To investigate the efficacy and safety of individualized optimal dose of remimazolam besylate in critically ill patients.To analyze the pharmacokinetics of remimazolam besylate in critically ill patients.Methods:This is a prospective,open,single-center,self-controlled observational study,which selected 85 patients who met the inclusion criteria and were admitted to the Department of Intensive Care Medicine of Gansu Provincial People’s Hospital from September 2021 to October 2022,and finally completed the trial in 44 cases.Dixon’s up-and-down sequential method was used to determine the individual optimal dose of Remazolam benzilate in patients,and sedation level was evaluated according to Richmond agitation-sedation scale（RASS）.The target RASS score for sedation was 0--2,so that patients could maintain light to moderate sedation depth.After determining the optimal dose,the elution period of propofol was set to ensure that the blood concentration of Remazolam benzoate was not affected during the test period.Enter the trial period after the washout period:The optimal dose of Remazolam benzoate was continuously pumped into the patient,and vital signs were monitored and recorded at baseline（T0）,0min（T1）,6h（T2）,12h（T3）,18h（T4）,and 24h（T5）,as well as the occurrence of related therapeutic and adverse events.The sampling time points were set according to the literature（0min,1min,5min,10min,15min,20min,30min,45min,1h,2h,3h,6h,9h,12h,15h,18h,21h,24h after medication withdrawal and 10min,20min,30min,1h after drug withdrawal,2h）,sample collection and blood samples were obtained,and Liquid chromatography-tandem mass spectrometry（LC-MS/MS）was used to determine the concentration of Remazolam benzene sulfonate in plasma.The pharmacokinetic parameters of Remazolam besylate were calculated by using Data analysie system（DAS）2.0 software.Results:1.Remimazolam besylate can achieve mild to moderate sedation level in the dose range of0.05-0.20 mg·kg^-1·h^-1after 24-hour continuous pumping in critically ill patients,and the optimal individualized dose is 0.131±0.043 mg·kg^-1·h^-1.2.Remimazolam benesulfonate had little effect on hemodynamics and respiratory mechanics parameters during the experimental period.The incidence of delirium was 29.5%,and the incidence of adverse reactions such as nausea,vomiting and hypersensitivity was 0%.The requirement for rescue propofol was 11.4%.3.Pharmacokinetic parameters of remimazolam besylate at different doses are as follows:（1）AUC_（0-t）（Area under the blood concentration-time curve at 0-t）at 0.05mg·kg^-1·h^-1remimazolam besylate:（2376.07±596.11）μg·min·L^-1,Elimination half-life(t_1/2):70.98±10.87 min,Time to reach maximum concentration(T_max):4 min,Clearance（Cl）:（1.53±0.52）L·kg^-1,Apparent volume of distribution（V_z）:（0.005±0.036）L·min^-1·kg^-1,C_max:（156.1±12.3）μg·L^-1;（2）When 0.10mg·kg^-1·h^-1remimazolam besylate AUC_（0-t）:（5149.62±1215.19）μg·min·L^-1,t_1/2:73.54±12.54min,T_max:4 min,V_z:（1.13±0.45）L·kg^-1,Cl:（0.007±0.015）L·min^-1·kg^-1,C_max:（403.0±56.4）μg·L^-1;（3）When 0.15mg·kg^-1·h^-1remimazolam besylate AUC_（0-t）:（8567.23±1476.21）μg·min·L^-1,t_1/2:68.98±15.63min,T_max:2 min,Vz:（1.78±0.64）L·kg^-1,Cl:（0.009±0.023）L·min^-1·kg^-1,C_max:（636.9±87.4）μg·L^-1;（4）When 0.20mg·kg^-1·h^-1remimazolam besylate AUC_（0-t）:（11235.35±1653.32）μg·min·L^-1,t_1/2:75.24±14.64min,T_max:2 min,V_z:（1.54±0.37）L·kg^-1,Cl:（0.010±0.023）L·min^-1·kg^-1,C_max:（977.0±75.0）μg·L^-1.Conclusions:1.Remimazolam besylate is safe and well tolerated for 24 hours continuous intravenous infusion in critically ill patients.2.Different doses of remimazolam besylate have no significant effect on hemodynamics and respiratory parameters of patients.Compared with the propofol group during the washout period,the adverse reactions of remimazolam besylate during the trial period did not increase.3.In severe patients,the t_1/2of remimazolam besylate is slightly prolonged,and the Cl concentration is lower.It is suggested that a lower dose of remimazolam besylate can be given for severe patients,and the dose can be adjusted according to the RASS score.