Pharmacokinetics Of Remifentanil Used For General Anesthesia In Patients With Hepatic Dysfunction And Evaluation Of The TCI System

Remifentanil (REM) is a new selective mu opioid receptor agonist of 5-10times higher pharmacological potency than alfentanil. Unlike other opioids,remifentanil is rapidly hydrolysed by nonspecific plasma and tissue esterases.Itsmetabolism by nonspecific esterases results in rapid and uniform clearanceleading to highly Predictable onset and offset of action. Its elimination half-life is3-10 minutes and plasma cleabance is about 40ml/kg/min, this imparts brevity ofaction, precise and rapidly titratable effects, non-cumulative opioid effects andrapid recovery after cessation of administration. The onset of action ofremifentanil is similar to that of alfentanil, although its offset is considerablymore rapid and independent of the duration of infusion. Its brevity of actionensures not only a rapid resolution of adverse effects but also a rapideffect.Therefore, This study is to investigate the pharmacokinetics ofRemifentanil used for general anesthesia in patients with hepatic dysfunctionand evaluation of the TCI system, and provide theoretical bases for rationaladministration of remifentanil during clinical anesthesia.1. Material and Method1.1 Material This study included 20 patients scheduled to undergo upperabdominal surgery under the general anesthesia(ASAⅠ～Ⅱ,aged 20～58 years).They were divided into two groups: hepatic dysfunction group(groupâ… ,n=10)and normal hepatic function group (groupâ…¡, n=10).Anesthesia was induced withpropofol 2mg·kg^-1and TCI of remefentanil of which the target concentration wasset at 4ng·ml^-1. Intubation was facilitated with Vecuronium 0.1mg·kg^-1,anesthesiawas maintained with propofol-TCI of remifentanil-Veuronium,targetconcentration of Remifentanil was adjusted to fit the surgical stimulation whilepropofol remained steady at 60ug·kg^-1.min^-1 during the surgeries.The TCI systemwas composed TCI-I infusion pump with the pharmacokinetics model andparameters by minto.BP,HR, SPO₂, were monitored throughout anesthesia.1.2 Monitoring of Pharmacokinetics1.2.1 Determination of hemodynamics during anesthesia SBP,DBP,MAP,HR,SPO₂and ECG were monitored continuously during anesthesia, andrecorded at before injection, at 1,10 min after-intubation and at 1,10 minafter-extubation. The adverse reactions were recorded during anesthesia.1.2.2 Time of loss conscionsness, extubation(from end of anesthesia to extubationof the trachea), and response to verbal commands("open your eyes" asked in anormal tone) were recorded.1.3.1 The concentration of REM in plasma was determined by HPLC with UVdetection.Remifentanil was extracted with chlorobutane following the precipitation withmethanol. The compound was back extracted into 0.01mol·L^-1HCI again. Theseparation was performed on a Hypersil CN(4.6mm 250mm, 5um) with a mobilephase of 0.02mol·L^-1NaH₂PO₄-acetonitrile (70:30) (including 0.01%triethylamine) at a flow rate of 1.5mL·min^-1. The detection wave length was at210nm.1.3.2 Collection of blood samplesApproximately 3ml blood samples were drawn into heparinized tubes at0,30,60,90,120,180min after injection. The blood samples were centrifuged keptfrozen at 4～6°Cuntil further analysis.1.3.3 Comparing. Measured with target concentrations, the medianperformance error(MDPE), mean absolute performance error (MDAPE), wobble and divergence were calculated.1.4 Statistics analysisThe data were expressed as X±S,Statistical package (SPSS 10.0) Was used forprocessing data, a=0.05 was considered that the differencehas statisticalsignificant.2.Results2.1 Patient's general conditions between two groups were similar. There were nosignificant differences in hemodynamic values and SpO₂ of different time pointbetween two groups.2.2 Recovery profile including the time of response to verbal autonomousbreathing, extubation, orientation recovery, discharging form PACU and theunexpected events during the operation were no significant differences.2.3 compared with target concentrations, the measured concentrations ofremifentenil were no significant differences(P＞0.05). The TCI of remifentenilMDPE:MDAPE and Wobble were-20.18%, 20.18%,21.4%.3.Conclusions3.1 There wre no significant differences in hemodynamic values and SpO₂ ofdifferent time point between the hepatic dysfunction and normal hepaticfunction.3.2 Recovery profile including the time of response to verbal autonomousbreathing, extubation,orientation recovery, discharging from PACU and theunexpected events during the operation were no significant differences, whichshow that it was safe in the hepatic dysfunction and normal hepatic function.3.3 The measured remifentanil blood concentration was lower than thepredetermined blood concentration. TCI-I is able to maintain the measuredremifentanil whole blood concentration accurately and stably during theadministration of remifentanil.