Brain concentrations of anaesthetic agents: the implications of epilepsy surgery

We read with interest the paper by Van Hese et al. [1] and discussed it at our virtual journal club. This innovative study measured the concentrations of propofol and remifentanil in brain and blood samples taken from patients undergoing brain surgery for epilepsy control under total intravenous anaesthesia (TIVA), and compared these with the concentrations predicted by the Marsh and Minto pharmacokinetic models built into TIVA pumps in order to assess the accuracy of these modelling predictions. We wish to congratulate the authors on undertaking a challenging and novel study, the first to measure actual concentrations of anaesthetic drugs in brain tissue. It is of clinical importance that more is known about effect-site and plasma concentrations, particularly as interest in the influence of appropriate anaesthetic dose on postoperative outcomes continues to build. The finding that themeasured brain and blood concentrations of both remifentanil and propofol were substantially different from predicted concentrations is a cause for concern. An important limitation in the study by Van Hese et al. is that it cannot be assumed that the brain tissue samples are representative of the wider population. Although patients undergoing oncological neurosurgery were not included in the brain concentration analysis on the basis that malignancy might alter cerebral pharmacokinetics, we suggest that structural abnormalities commonly targeted in epilepsy surgery (including benign tumours, vascular malformations and hippocampal sclerosis) may similarly alter drug distribution [2]. Such anatomical considerations are important because, although the study by Van Hese et al. makes the methodological assumption that all brain tissues have equal influence on consciousness, the effects of anaesthetic agents are known to occur at specific receptors in particular locations. These include, for example, GABAA receptors in the pre-optic area of the hypothalamus in the case of propofol, and μ receptors in the peri-aqueductal grey matter in the case of remifentanil [3]. Furthermore, the effect of neurosurgery itself, including localised inflammation and disruption of the blood-brain barrier, should not be discounted. It should also be noted that many medications prescribed to patients with refractory epilepsy, including phenytoin and valproate, affect both drug metabolism and protein binding [4], which may further influence plasma and brain concentrations. Despite these limitations, obtaining brain samples from relevant locations in healthy individuals in a non-invasive fashion would be impossible. Therefore, we feel this study comes as close as is feasible to the ideal. However, in interpreting the generalisability of the findings, it would be helpful to know the specific operations performed and the pharmacological therapies that the patients were receiving peri-operatively andwewonder if the authors would be able to provide this information. While there was a trend towards the Minto model overestimating brain concentrations of remifentanil, and theMarsh model under-estimating brain propofol concentration, there was considerable variation in error between patients [1]. Though likely to be influenced by the small sample size, this finding indicates that pharmacokinetic models are no substitute for clinical assessment, and that predicted drug concentrations should be integrated with other clinical and physiological information when interpreting depth of anaesthesia, as recommended in the Association of Anaesthetists/Society for Intravenous Anaesthesia guideline [5]. While the study by Van Hese et al. may not therefore be immediately practice changing, it emphasises the need for expertise in the delivery of TIVA, including an appreciation of the limits of monitoringmodalities and the influence of patient factors. As TIVA becomes increasingly commonplace, this timely paper highlights an important need for further research to aid a better understanding of pharmacokinetics. Future models could include not only height, age, sex and weight, but specific patient baseline characteristics, such as comorbidities and the effect of interacting drugs, which could be used to design a truly tailored total intravenous anaesthetic.