Study On Pharmacokinetics And Pharmacodynamics Of Cisatracurium In Patients With Congenital Heart Defects

Background and aims:The neuromuscular blocking agent cisatracurium is frequently used adjunctively in anesthesia to facilitate endotracheal intubation and to provide muscle relaxation during surgery. However, the pharmacokinetics (PK) and pharmacodynamics (PD) of cisatracurium in patients with congenital heart defects (CHD) remain underexplored. The lack of PK/PD information in this specific population raises serious concerns about administration of cisatracurium with a regular dose (0.15 mg/kg). Here we aimed to determine the PK/PD of cisatracurium in patients with CHD, such as ventricular septal defect (VSD) and atrial septal defect (ASD) and to assess the effects of CHD on the PK/PD profiles of cisatracurium.Methods:1. A total of 42 patients were included in the clinical trial. These patients were divided into three groups, namely, control (n= 15), VSD (n= 12), and ASD (n= 15) groups. Patients in the control group were diagnosed with inguinal hernia. Patients in the VSD and ASD groups suffered from VSDs and ASDs, respectively.2. Each patient was administered 0.15 mg/kg cisatracurium by intravenous bolus injection. Arterial blood samples were collected before (time 0) and at 1,2,4,8,12,16, and 20 minutes after cisatracurium administration. Quantification of cisatracurium was performed using an UPLC-QTOF/MS system. Each of the three PK models (i.e., conventional one-compartment model, conventional two-compartment models and modified two-compartment model) was fitted to the data of mean plasma concentrations versus time. The model with the smallest Akaike information criterion (AIC) value was regarded as the best model. Subsequently, the best PK model was fitted to individual PK data to derive PK parameters for each subject. Model construction and parameter estimation were performed using WinNonlin software.3. The neuromuscular block response to cisatracurium was monitored by train-of-four stimulation (TOF) technique. Each of three PK/PD models (i.e., model 1, indirect link Emax model; model 2, indirect link sigmoid Emax model; and model 3, direct link sigmoid Emax model) was constructed and fitted to the data of mean neuromuscular block effect versus time. The model with the smallest AIC value was regarded as the best model. Subsequently, the best PK/PD model was fitted to individual PD data to derive PD parameters for each subject. Model construction and parameter estimation were performed using WinNonlin software.Results:A modified two-compartment model was best fitted to the PK data. The model suggested that septal defects significantly lowered the rate of cisatracurium distribution from central to peripheral compartment. The inter-compartment rate constants k12 and k21 were significantly reduced (35-60%, p<0.05) in VSD and ASD patients as compared to control patients. Consistently, septal defects caused a marked increase (160-175%, p< 0.001) in the distribution half-life value (Ti/2α). Besides, significantly delayed pharmacodynamic responses to cisatracurium were observed in patients with septal defects. The onset time (i.e., the time to maximal neuromuscular block effect) was prolonged from 2.2 min to 5.0 min. PK/PD modeling revealed that reduced concentrations of cisatracurium in the effect compartment due to poorer distribution were the main cause to the lagged pharmacodynamic response.Conclusion:Cisatracurium PK/PD were significantly altered in patients with congenital heart defects. Our study should be of use in clinical practice for the administration of cisatracurium to patients with CHD.