Cefazolin pharmacokinetics and extent of device binding during cardiopulmonary bypass

Introduction: Cefazolin is administered routinely for antibiotic prophylaxis during cardiac surgery. However there is uncertainty in determining the correct dose due to the impact of critical illness and the cardiopulmonary bypass (CPB) machine on drug pharmacokinetics (PK).

Aims: To quantify cefazolin adsorption to the CPB machine device and incorporate this into a population PK model in children undergoing cardiac surgery supported by CPB.  

Methods: Fifty patients aged 3 days – 13 years were recruited from Starship Children’s Hospital, Auckland, NZ who underwent cardiac surgery supported by CPB. Unbound (678) and total (622) cefazolin concentrations were quantified and population parameters were estimated using non-linear mixed effects modelling. A two-compartment model was used to describe cefazolin distribution in vivo. A third compartment was “switched on” when the CPB machine was connected to the patient. Covariates included age (postmenstrual and postnatal), size (fat free mass) and renal function. A separate ex vivo (benchtop) study quantified cefazolin adsorption to the CPB machine circuitry. 

Results: Population parameter estimates were clearance (CL) 20.1 L/h/70kg 95% CI [16.9, 23.1], intercompartmental CL (Q) 37.7 L/h/70kg 95% CI [21.6, 55.2], volume of distribution (V) of the central compartment (V1) 11.0 L/70kg 95% CI [3.1, 17.7] and V of the peripheral compartment (V2) 25.0 L/70kg 95% CI [17.5, 33.2]. CL was reduced by a factor of 0.66   CI [0.54, 0.80] after connection to the CPB device. The maximum   amount of cefazolin adsorption (Bmax) to the CPB machine was 75.3   mg CI [36.4, 113] for a child circuit over 1 hour.  

Discussion: Adsorption of cefazolin to the machine circuitry is not clinically relevant but can account for some of concentration variability seen in vivo. CPB reduces drug CL beyond what can be explained by age, size and machine ultrafiltration processes.