Paolo Denti (1), Alexandra Dresner (2), Sandra Castel (1), Jennifer Norman (1), Lubbe Wiesner (1)
(1) Division of Clinical Pharmacology, University of Cape Town, South Africa; (2) Department of Anaesthesia, University of Cape Town, South Africa
Objectives: Cefazolin is a time-dependent antibiotic used as prophylaxis during surgical operations. For its efficacy, perioperative plasma concentrations need to be maintained above target [1]. The objective of this study is to describe the pharmacokinetics of Cefazolin in small children during cardiac surgery, characterizing in particular the effect of the cardiopulmonary bypass (CPB), with or without the use of a priming dose.
Methods: Twenty-two children undergoing cardiac surgery requiring CPB (age 1-94 months, weight 2-22 kg) were recruited in an observational study. Cefazolin 50 mg/kg was administered IV before the surgery and then every 4 to 6 hours. For 7 children, a further dose of cefazolin was added to the priming volume of the CPB circuit. Throughout the surgery, 10 to 15 blood samples were drawn from each patient, focusing on the time of sternal incision and closure, doses, and the initiation and conclusion of CPB. A nonlinear mixed-effect model was developed in NONMEM to interpret the data.
Results: A 3-compartment model with first-order elimination fit the data best. The effect of the CPB circuit during the surgery was modelled as a separate compartment, connected and disconnected from the rest of the model at the recorded times. The model correctly predicted increasing concentrations when connecting a CPB circuit primed with an extra dose, and vice-versa. The size of the CPB compartment was proportional to the priming volume. All other clearance and volume parameters were adjusted by body size using allometric scaling [2], significantly improving the fit. Clearance was found to mature, increasing with post-menstrual age [2]. The estimate of mature clearance for a 12 kg child was 1 L/h, with children born at term having 40% of this value and reaching 75% by 1 year of age. These effects explained most of the variability observed.
Conclusions: The pharmacokinetics of cefazolin in children undergoing CPB surgery was described and the main sources of variability identified in body weight and age. Although all children in the study were above the target (8 µg/mL), the model predicted the lowest concentration following the connection of a CPB not primed with extra cefazolin. The model can inform dosing strategy, strength and frequency, by adjusting for body weight and age, particularly for very small or pre-term babies.
References:
[1] F. H. Edwards, R. M. Engelman, P. Houck, D. M. Shahian, and C. R. Bridges, “The Society of Thoracic Surgeons Practice Guideline Series: Antibiotic Prophylaxis in Cardiac Surgery, Part I: Duration.,” Ann. Thorac. Surg., vol. 81, no. 1, pp. 397–404, Jan. 2006.
[2] N. Holford, Y. Heo, and B. Anderson, “A pharmacokinetic standard for babies and adults.,” J. Pharm. Sci., pp. 1–12, May 2013.
Reference: PAGE 23 () Abstr 3259 [www.page-meeting.org/?abstract=3259]
Poster: Drug/Disease modeling - Infection