Population pharmacokinetic model-based dosing proposal for ampicillin prophylaxis in cardiac surgery patients with cardiopulmonary bypass.

The aim of this study was to describe and quantify pharmacokinetics of ampicillin used prophylactically in cardiac surgery both with and without cardiopulmonary bypass (CPB) using population pharmacokinetic analysis in order to propose an optimal dosing strategy. Adult patients undergoing cardiac surgery and treated with prophylactic dose of 2 g ampicillin were enrolled to this prospective study. Blood samples were collected according to the study protocol and ampicillin plasma concentrations were measured using HPLC/UV system. A three-stage population pharmacokinetic model using nonlinear mixed-effects modelling approach was developed. Totally 273 blood samples obtained from 20 patients undergoing cardiac surgery with the use of the CPB and 20 patients without CPB use were analyzed. Two-comparmental model best fits ampicillin concentration-time data. Mean ± SD body weight-normalized ampicillin central and peripheral volume of distribution was 0.12 ± 0.02 L/kg and 0.15 ± 0.03 L/kg, respectively, while mean ± SD ampicillin clearance in typical patient with eGFR of 1.5 mL/s/1.73 m2 was 1.17 ± 0.05 L/h. The use of CPB did not significantly affect the pharmacokinetics of ampicillin. When administering 2 g of ampicillin before surgery, an additional dose should be administered to reach the PK/PD target of fT > MIC = 50% if the operation lasts longer than 430 min in patients with moderate to severe renal impairment, 320 min in patients with mild renal impairment, 220 min in patients with normal renal function status or 140 min in patients with an augmented renal clearance.

Population Pharmacokinetics of Prophylactic Cefazolin in Cardiac Surgery with Standard and Minimally Invasive Extracorporeal Circulation.

The objectives of this study were to develop a population pharmacokinetic model of prophylactically administered cefazolin in patients undergoing cardiac surgery with and without the use of the cardiopulmonary bypass of both existing types-standard (ECC) and minimallyu invasive extracorporeal circulation (MiECC)-and to propose cefazoline dosing optimization based on this model. A total of 65 adult patients undergoing cardiac surgery were recruited to this clinical trial. A prophylactic cefazolin dose of 2 g was intravenously administered before surgery. Blood samples were collected using a rich sampling design and cefazolin serum concentrations were measured using the HPLC/UV method. The pharmacokinetic population model was calculated using a nonlinear mixed-effects modeling approach, and the Monte Carlo simulation was used to evaluate the PK/PD target attainment. The population cefazolin central volume of distribution (Vd) of 4.91 L increased by 0.51 L with each 1 m2 of BSA, peripheral Vd of 22.07 L was reduced by 0.77 L or 0.79 L when using ECC or MiECC support, respectively, while clearance started at 0.045 L/h and increased by 0.49 L/h with each 1 mL/min/1.73 m2 of eGFR. ECC/MiECC was shown to be covariate of cefazolin Vd, but without relevance to clinical practice, while eGFR was most influential for the PK/PD target attainment. The standard dose of 2 g was sufficient for PK/PD target attainment throughout surgery in patients with normal renal status or with renal impairment. In patients with augmented renal clearance, an additive cefazolin dose should be administered 215, 245, 288 and 318 min after the first dose at MIC of 4, 3, 2 and 1.5 mg/L, respectively.

The effect of continuous elimination methods on the hemostatic profile of a cardiac surgery patient monitored using thromboelastography.

INTRODUCTION: This work is focused on mapping issues of hemostasis in patients during continuous renal replacement therapy, or the possible impact of the use of anticoagulants. METHODS: The study included 30 consecutive patients requiring continuous renal replacement therapy following cardiac surgery in the period of 2009 to 2012. Patients were placed into 2 branches according to the selected method of anticoagulation (regional citrate anticoagulation-RCA, unfractionated heparin UFH). According to the given scheme (t1-t7) thromboelastography and laboratory testing related to the testing of blood clotting during continuous renal replacement therapy were performed. RESULTS: The average lifespan of a hemofilter during continuous renal replacement is 58.13 ± 9.968 hours. During continuous renal replacement therapy there are significant changes in the initiation of coagulation according to thromboelastographic parameters (R, K, alpha angle) in both branches of anticoagulation. The maximum image changes in hemostasis occur around 24 hours (t4) from the start of the procedure. The nature of the changes is the procoagulant activity in these parameters. In the branch of regional citrate anticoagulation a higher value of functional fibrinogen is apparent. There was no significant difference in the activation of native blood between UFH and RCA. CONCLUSIONS: During continuous renal replacement therapy significant changes occur in the thromboelastographic image and the laboratory parameters in blood clotting. The nature of the change is the procoagulant activity. The question remains about the complexity of the changes that TEG is not able to detect, especially in the cellular area.