Semi-mechanistic model of the Haemodynamic effects of propofol and remifentanil administered in combination to patients undergoing general anaesthesia
Maite Garraza-Obaldia (1,2), Zinnia P Parra-Guillén(1,2), Joan Altés (3), Sebastián Jaramillo (4), José Fernando Valencia (5), Pedro L Gambús (4), Iñaki F Troconiz (1,2,6)
(1) Department of Pharmaceutical Technology and Chemistry, School of Pharmacy and Nutrition, University of Navarra, Pamplona, Spain. (2) Navarra Institute for Health Research (IdiSNA), Pamplona, Spain. (3) Medical Department, Predictheon Medical S.L., Barcelona, Spain. (4) Anesthesiology Department, Hospital Clinic de Barcelona, Barcelona, Spain. (5) Biomedical Engineering Program, Universidad de San Buenaventura, Cali, Colombia. (6) Institute of Data Science and Artificial Intelligence, DATAI, University of Navarra, Pamplona, Spain.
Introduction and Objectives. Propofol, a GABA-A receptor agonist hypnotic, and remifentanil, a short-acting opioid analgesic, are the most commonly used drugs for the induction and maintenance of general anaesthesia. Typically, these drugs are administered in infusions guided by plasma or effect-site concentrations, and titrated according to the desired hypnotic and analgesic effects, while avoiding undesirable effects such as haemodynamic changes.
The haemodynamic changes induced by propofol and remifentanil have received considerable attention in recent years in light of the studies that have associated intraoperative changes in mean arterial pressure (MAP) and heart rate (HR) with increased morbidity and mortality in the surgical patient. Nevertheless, the haemodynamic effects of both drugs have not been sufficiently studied. Only a few studies have quantitatively analysed the effects of propofol on MAP and HR, but no studies have analysed the effects of remifentanil or the combination of propofol and remifentanil.
The aim of this study is to develop a population pharmacokinetic/pharmacodynamic model of the effects of the combination of propofol and remifentanil on MAP and HR, including the impact of the surgical stimulus within the quantitative framework.
Methods. A total of 1370 observations of MAP and HR recorded every minute from twenty-five female patients weighing 48 – 88 kg, aging 23 – 82 years, and undergoing different types of gynaecological surgical interventions were analysed. Surgery duration ranged between 3 (urinary incontinence surgery) and 96 minutes (laparoscopic hysterectomy).
Patients received intravenous administrations of propofol and remifentanil achieving different concentration levels through controlled infusions according to PKPD models and parameters reported previously [1,2]. Maximal plasma concentrations achieved for propofol and remifentanil were 15 ug/mL and 11 ng/mL respectively. The time at which the surgery began was recorded and the effect of the associated nociceptive stimulus on the hemodynamic parameters was evaluated during model building as well as the covariates weight, age, intervention, etc.
Both hemodynamic responses were analysed simultaneously using the population approach with nonlinear mixed effects modelling and the software NONMEM 7.4. R Version 4.0.2, with RStudio interface, was used for data formatting and exploration.
Results. The core model was represented by a feedback process that accounted for the dynamics of the responses (MAP and HR). The system undergoes tight (internal)-regulation consisting of feedback driven by the changes of HR with respect to its baseline on the mechanisms controlling the synthesis of MAP. The nociception as the result of the surgical intervention increases MAP, and its dynamic was accounted assuming a bolus input, at the time of the pain stimulus and a mono-exponential decay. Effects of propofol and remifentanil reducing the rate of synthesis of MAP and HR, respectively, were described with inhibitory EMAX models.
The estimates of the system (physiological)-dependent parameters were in accordance with previous models developed in healthy volunteers and measuring additional haemodynamic markers [3, 4]. The estimated typical first-order dissipation rate constant (precision by RSE, %) for HR and MAP was 0.09 min-1 (24 %). In addition, the values of the estimates of IC50 for both drugs were within the expected range based on previous reports [2] with estimated values (RSE, %) of 7.2 ug/mL (35%) and 2.0 ng/mL (41%) for propofol and remifentanil respectively. The painful stimulus increased the rate of synthesis of MAP by 50%, and showed an average dissipation rate of 0.006 min-1. Different diagnostics techniques indicate that data for both responses were well captured by the model.
Conclusions. In this data-driven analysis, we have developed a fully identifiable comprehensive semi-mechanistic model handling simultaneously two relevant variables of the haemodynamic response in a variety of scenarios during routine anaesthesia practice, including drug combinations and the absence/presence of nociceptive stimulus. This model is intended to facilitate anaesthesiologist to personalize drug optimization protocols.
References:
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