Propofol pharmacology in patients with brain tumours

M.M. Sahinovic, D. Eleveld, M.M.R.F. Struys, A.R. Absalom
Department of Anesthesiology, University of Groningen, University Medical Center Groningen, The Netherlands

Background and Goal of the Study: Although some animal and patient studies suggest that brain tumours and associated treatments alter the pharmacokinetics (PK) and pharmacodynamics (PD) of the anaesthetic drugs(1), the evidence is conflicting.(2) PK/PD models developed in patients without brain pathology are widely used for target controlled infusion (TCI) of propofol during brain tumour excision operations. The goal of this study was to determine if the presence of a frontal brain tumour influences propofol pharmacokinetics and dynamics and PK/PD model performance. 

Material and Methods: Twenty patients with a frontal brain tumour and 20 control patients received a propofol infusion to achieve an “induction1-emergence-induction2”anaesthetic sequence. No opioids were administered. Arterial propofol plasma concentration was measured every 4 minutes and at each of the transitions of conscious state. These measurements and continuously recorded BIS values were analysed by non-linear mixed effects modelling to generate a new PK and a PD propofol model. We investigated the effect of different model adaptations on PK and PD performance. Subsequently we back-calculated the propofol concentrations predicted by the Marsh, Schnider and Eleveld models, and calculated the predictive performance of these models in terms of the Varvel criteria i.e. in terms of median prediction error (MdPE) and median absolute prediction error (MdAPE).(3)

Results and Discussion: Hierarchical PK model development resulted in a three-compartment allometric model scaled to total-body-weight. Patients with brain tumours showed 40% higher propofol clearance than control patients. In patients with brain tumours, MdPEpk was -3.83%, and MdAPEpk 21.1%. Predictive performance of the Schnider model (MdPEpk –20.0%, MdAPEpk 23.4%) and Eleveld volunteer model (MdPEpk -8.58%, MdAPEpk 21.6%) were good. The Marsh model performed less well (MdPEpk -14.3%, MdAPEpk 41.4%) as did the Eleveld patient model (MdPEpk -30.8%, MdAPEpk 32.1%).
Hierarchical PD model development found that ke0 (0.108 min-1), Ce50 (2.77 ml/l) and the γ (1.49) did not significantly differ between the two groups. Lower baseline BIS value were found in patients with brain tumours (90.2 vs 95.1).

Conclusion: Frontal brain tumours are associated with differences in the pharmacokinetics and pharmacodynamics of propofol. Caution and good clinical judgment should be exerted when using current propofol TCI in patients with frontal brain tumours.

Reference:
1. 	Archer DP, Priddy RE, Tang TK, Sabourin MA, Samanani N. The influence of cryogenic brain injury on the pharmacodynamics of pentobarbital. Evidence for a serotonergic mechanism. Anesthesiology. 1991 Oct;75(4):634–9. 
2. 	Sahinovic MM, Beese U, Heeremans EH, Kalmar AF, van Amsterdam K, Steenbakkers RJHM, et al. Bispectral index values and propofol concentrations at loss and return of consciousness in patients with frontal brain tumours and control patients. Br J Anaesth. 2014 Jan;112(1):110–7. 
3. 	Varvel J, Donoho DL, Shafer SL. Measuring the predictive performance of computer-controlled infusion pumps. J Pharmacokinet Biopharm. 1992 Feb;20(1):63–94.