Nicolás Marco-Ariño (1, 2), Itziar Irurzun-Arana (1, 2), Sebastian Jaramillo (3), Pedro L Gambús (3), Iñaki F. Trocóniz (1, 2)
(1) Pharmacometrics and Systems Pharmacology, Departament of Pharmacy and Pharmaceutical Technology, School of Pharmacy, University of Navarra, Pamplona, Spain. (2) IdiSNA; Navarra Institute for Health Research, Pamplona, Spain (3) Systems Pharmacology Effect Control and Modeling Research Group, Department of Anesthesia, Hospital CLINIC de Barcelona, Barcelona, Spain.
Objectives: Movement is an extensively characterised response to noxious stimulus. However, its applicability to assess intraoperative pain has limitations due to the effect of anaesthesia in the response. Previous research has shown that pupil reflex, an indicator of anesthetic depth, could also predict movement after noxious stimuli1,2. The objective of this project is to characterise the effect of remifentanil and potentially propofol on the pupil size over the time course of the operation and to evaluate the pupil size as a predictor of response to movement after anaesthetic and/or nociceptive stimulus, thus enabling anaesthesiologists to optimise dosing during surgery.
Methods: Patients undergoing gynaecological, hysteroscopic and urinary incontinence surgery were recruited for the study. Exclusion criteria included ocular diseases, prescription of drugs affecting the size or reflex of the pupil and morbid obesity (IMC> 35). Pupil diameter was measured multiple times before and after surgery using the AlgiScan (Neurolight, IDMED™) hand-held pupillometer which was also used to delivered a 60 mA tetanic stimulus during 5 seconds in the forearm of the patient. Movement response to the stimulus was evaluated in a categorical scale ranging from 0 (absence) to 3 (strong movement) by the physicians. Propofol and remifentanil concentrations in plasma and effect site were predicted using previously validated PK models. Data were analysed using NONMEM 7.3.
Results: Eighty-seven patients participated in the study (3 males and 84 females) each having a median of 5 (range 3 to 7) measures of pupil size after noxious stimulation during surgery. The first measure was performed in the presence of propofol (1152 observations) and the rest in the presence of propofol and remifentanil (9271 observations). No data from basal pupil size in the absence of anaesthesia was available due to the impossibility to perform the procedure in awake subjects. The median pre-stimulus pupil diameter in the presence of propofol was 4.02mm. A two compartment indirect response model accurately described the effect of the noxious stimulus on the pupil size over the time course of the records (before, during and after perturbation). In this model the administration of the tetanic stimulus modulates a nociceptive compartment whose synthesis and degradation rates are governed by a KSD1 parameter (0.492s-1). The amount in the nociceptive compartment subsequently controls the turnover of the pupil diameter. The pharmacodynamics effects of propofol and remifentanil were sequentially evaluated. The effect of propofol in the pupil size could not be assessed due to the lack of baseline pupil measurements but the pupil diameter in the presence of propofol was estimated in 3.77mm. Remifentanil reduced pupil diameter by modulating the turnover of the nociceptive compartment with an IC50 of 0.481ng/ml and the pupil size with an IC50 of 2.78ng/ml. Precision of the parameter was estimated accurately (RSE <25%) although high inter-individual variability was observed. Model performance was based on goodness of fit plots and visual predictive checks.
Conclusions: A semi-mechanistic pharmacodyamic model to describe the pupil size after a noxious stimulus in the presence of propofol and remifentanil was successfully implemented. Assessment of covariates affecting the model parameters would be performed to reduce the unexplained variability. This model will be further developed to incorporate the movement response
References:
[1] Leslie, K. et al. Prediction of movement during propofol/nitrous oxide anesthesia. Performance of concentration, electroencephalographic, pupillary, and hemodynamic indicators. Anesthesiology 84, 52–63 (1996).
[2] Funcke, S. et al. Validation of Innovative Techniques for Monitoring Nociception during General Anesthesia. Anesthesiology 127, 272–283 (2017).
Reference: PAGE 28 (2019) Abstr 9098 [www.page-meeting.org/?abstract=9098]
Poster: Drug/Disease Modelling - CNS