Adequacy of open-loop Target Controlled Infusion devices during anesthesia
Monia Guidi (1) (2), Alena Simalatsar (1) (3), Sandro Carrara (4), Thierry Buclin (1)
(1) Division of Clinical Pharmacology, University Hospital and University of Lausanne (CHUV), Lausanne, Switzerland, (2) School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Geneva, Switzerland, (3) Institute of Systems Engineering, University of Applied Sciences and Arts - Western Switzerland, Sion, Switzerland, (4) Laboratory of Integrated Systems, Ecole Polytechnique Federale de Lausanne (EPFL), Lausanne, Switzerland
Objectives: Open-loop Target Controlled Infusion (TCI) devices are largely used in clinical practice to aid optimization of propofol dosage for induction and maintenance of anesthesia. Propofol infusion rates are adjusted aiming to a defined target, based on model-predicted plasma or brain concentrations. Pharmacokinetic models used in TCI pumps were developed on small groups of healthy volunteers [1]. However, clinical conditions may markedly alter propofol pharmacokinetics and actual propofol levels could significantly differ from predicted ones, leading to important under- or over-exposure. The aim of our analysis was to assess the adequacy of TCI-predicted propofol dosage in virtual individuals simulated using a comprehensive population model developed on a large population of patients [2].
Methods: A virtual male patient (70 kg, 170 cm, 36 y) with changing propofol target brain concentration of 6 à 4 à 5 mg/L during a 15 min surgical operation was chosen. TCI dosage scheme, i.e. propofol infusion doses and durations required to achieve these targets, was retrieved applying the model of Schnider et al. [1] as implemented in the BasePrimea pump (Fresenius Kabi, Germany). The equilibration time between target brain and plasma concentrations was extracted. The comprehensive population model with between-subject variability developed in 660 patients by Eleveld et al. [2] was then used to simulate plasma propofol concentrations in 1000 individuals with the same characteristics as the index patient. Median plasma concentrations with 90% prediction interval (PI90%) were calculated and compared to the target brain concentrations at equilibrium according to TCI prediction. The percentage of virtual patients reaching propofol levels above 15 mg/L (maximum allowed in TCI) was also estimated.
Results: Median (PI90%) plasma concentrations of 5.6 (3.7–8.1), 3.7 (2.6–5.3) and 4.6 (3.3–6.5) mg/L were calculated when the target levels of 6, 4 and 5 mg/L, respectively, were reached according to TCI predictions. Furthermore, 12% of virtual patients were found with concentrations exceeding 15 mg/L within the first minute of propofol infusion.
Conclusions: Due to between-patient variability, current TCI pumps might deliver inadequate propofol dosages to patients with possible clinical consequences. Our simulations show a potential for a closed-loop control of drug administration based on real-time propofol measurement to improve automated anesthesia delivery.
References:
[1] Schnider TW & al. Anesthesiol 1998;88:1170-82.
[2] Eleveld DJ & al. Anesth Analg 2014;118:1221-37.
