P.L. Gambús (1), M.J. Garrido (2), J. Fernández-Candil (1), R. Valero (1), I.F. Trocóniz (2) and N. Fábregas (1)
(1)Department of Anesthesiology, Hospital CLINIC, University of Barcelona, Barcelona; (2) Department of Pharmacy and Pharmaceutical Technology, University of Navarra, Pamplona. SPAIN.
Objective: The characterization of the influence of Chronic Therapy with Phenytoin (CPT) in the Pharmacokinetics (PK) and Pharmacodynamics (PD) of Rocuronium in patients undergoing intracraneal surgery. Background: Rocuronium bromide is a non depolarizing neuromuscular blocking agent (NMBA) widely used in anesthesia. Chronic therapy with phenytoin (lasting longer than 15 days) is known to affect the time course of effect of most NMBA requiring increments in dosing to achieve the same level of effect than patients without phenytoin therapy. This phenomenon could possibly be explained by PK or PD reasons, however in the case of rocuronium it has not been reported yet.
Methods: Under IRB approval and informed consent, 16 patients undergoing surgical craniotomy were included. All patients were routinely monitorized and anesthetized with propofol and remifentanil to provide adequate hypnosis and analgesia. In each patient, an arterial line was inserted for hemodynamic control and for blood sampling. In addition, a microdialysis catheter was also inserted in the quadriceps muscle to allow the quantification of rocuronium concentrations in tissue. The effect was quantified by means or electromiography and the percentage of T1 with respect to supramaximal response (T1%), was the parameter used as effect measure. Rocuronium was administered as a bolus (weight adjusted) followed by a continuous infusion, which was adjusted to maintain a response of TOF. Data were recorded online on a computer by means using the software S5-Collect (DatexOhmeda). Nonlinear mixed effect modeling, using the program NONMEM (version V), was used to estimate the parameters of the PK and PD models.
Results: The best description, according to the value of the objective function and the standard errors (SE) of the parameters, was a two compartment model. Basic PK parameters were: Vc of 5.45 L (0.42) and CL of 0.17 L/min (0.04). When CPT was incorporated into the model as a categorical covariate associated to the clearance, the value of this parameter was increased (1.06 vs 0.17 L/min). A sigmoid EMAX model was linked to the PK using an effect site compartment with a value (SE) for ke0 of 0.11 (0.008) min-1. The influence of CPT on ke0 or C50 was not significant.
Conclusions: Clearance of rocuronium in patients under CPT was higher (almost 90%) than in control patients (without phenytoin therapy). PD parameters for rocuronium did not change with CPT, although for vecuronium an increase in the C50 has been reported in the literature [1].
References:
[1] Wright PMC, McCarthy G, Szenohradszky J,et al. Anesthesiology. 2004; 100(3): 626-33.
Reference: PAGE 14 (2005) Abstr 816 [www.page-meeting.org/?abstract=816]
Poster: poster