Validation of recommended protocol for cefazolin (CFZ) infusion during liver surgery: an approach by physiological modelling simulation
F. Lagneau, J. Marty, M. Tod*.
Anaesthesia and Intensive Care Unit, Hôpital Beaujon, Université Paris VII, France
*Pharmacology Unit, Hôpital Avicennes, France
Background and Goal of study: Prophylactic infusion of CFZ is recommended during liver surgery. Recommended doses are independent of patient characteristics. The aim of the study was to evaluate the protocol suitability during liver surgery by simulations using a physiological model.
Materials and Methods: A physiological model for CFZ was implemented in ADAPT II software. Specifically, non linear fixation of CFZ on albumin, hemodynamic consequences of isoflurane inhalation and of liver surgery and consequences of blood loss (clearance, albumin concentration) were implemented. The protocol (2 g followed by 1 g four hours later) was tested in health patient and in case of obesity, renal failure or increased blood loss. Model validation was made by comparing our model predicted free CFZ concentrations in plasma, skin, fat and muscle after a 1 g infusion in a non anesthetized patient to a published physiological model predictions (1).
Results and discussion: CFZ concentrations predicted by our model after a 1 g CFZ bolus were similar to previous published results. During liver surgery, free CFZ concentrations remained up to 1 mcg/ml (CMI) in liver, skin, fat and muscles between skin incision and parietal closure in the four tested situations. Corresponding pharmacokinetic parameters are presented in table.
|
|
Health |
Obese |
Renal failure |
high blood loss |
|
AUCu |
0.03 |
0.02 |
0.03 |
0.1 |
|
AUCt |
0.51 |
0.43 |
0.57 |
0.96 |
|
CL(ml/min) |
71 |
85 |
65 |
76 |
|
Vd (l) |
6.8 |
10 |
7 |
5.5 |
|
fu |
0.06 |
0.05 |
0.06 |
0.1 |
|
T1/2 (min) |
66 |
81 |
74 |
50 |
AUC: area under curve (u: unbound, t: total); CL: total clearance; Vd: volume of distribution; fu: plasma unbound fraction; T1/2: elimination half-time
Conclusions :The model should be improved in order to better predict renal failure consequences. Keeping in mind this reserve, predicted concentrations confirmed the suitability of the protocol in the four tested situations. A decrease in infused doses may be proposed in case of renal failure. The final validation of the model has to be performed by real CFZ dosages in patients during surgery.
Reference: (1) Tsuji et al, Drug Metab Disp, 1985