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The study was approved by the Institutional Ethics Committee of the Erasmus University Medical Center, Rotterdam, The Netherlands. Both BIS, derived from the EEG, and the cAAI, derived from auditory evoked potentials, have been evaluated as tools to measure depth of anesthesia.
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As pharmacodynamics endpoints both BIS and composite A-line ARX index (cAAI) were used. This wake-up test consists of waking up patients during and immediately after completion of spinal procedures after which anesthesia is reinduced to allow for completion of surgery and therefore allows for a unique combination of both awake and anesthetic observations in the same individual. Scoliosis surgery provides a unique setting to study the PK and PD of propofol because during this type of surgery an intraoperative wake-up test is applied to reduce the risk of motor deficit or paraplegia. In this study we aimed to derive a population PK-PD model for propofol in adolescents undergoing idiopathic scoliosis surgery using two different PD endpoints. Moreover, whereas in adults different PD endpoints have been used in PKPD models, in children only Bispectral Index (BIS) and Comfort scores have been used to describe the time course of propofol effects in relation to the dose. However, even though adolescents are known to differ from both children and adults because of physiologic changes due to unique hormonal profiles and changes in body size and composition, only one PKPD model in (obese) adolescents was reported. To date, also a limited number of PKPD models in children have been published on the propofol dose-response relationship in children undergoing different types of surgery, and on the depth of sedation in non-ventilated children in the ICU. For adults, population models are available describing propofol PK PD during various types of surgery, different co-morbidities, and for patients admitted to the ICU. While propofol pharmacokinetics (PK) are widely studied, there is a relative paucity of pharmacodynamic data. Propofol is frequently used for induction and maintenance of anesthesia in adults and children, as it has desirable pharmacokinetic and pharmacodynamic properties. This may imply that BIS and cAAI measure fundamentally different endpoints in the brain. Large differences were demonstrated between both monitors. ConclusionsĪ population PKPD model for propofol in adolescents was developed that successfully described the time course of propofol concentration, BIS and cAAI in individuals upon undergoing scoliosis surgery with intraoperative wake-up test and reinduction of anesthesia. The delay in PD effect in relation to plasma concentration was best described by a two compartment effect-site model with a ke o of 0.102 min − 1, ke 12 of 0.121 min − 1 and ke 21 of 0.172 min − 1. For the sigmoidal Emax model, the propofol concentration at half maximum effect (EC 50) was 3.51 and 2.14 mg/L and Hill coefficient 1.43 and 6.85 for BIS and cAAI, respectively. The time courses of propofol concentrations, BIS and cAAI values during anesthesia, intra-operative wakeup and reduction of anesthesia were best described by a two-compartment PK model linked to an inhibitory sigmoidal Emax PD model. A propofol PKPD model was developed using NONMEM. BIS and cAAI were continuously measured and blood samples collected. Methodsįourteen adolescents (9.8–20.1 years) were evaluated during standardized propofol-remifentanil anesthesia for idiopathic scoliosis surgery with an intraoperative wake-up test with reinduction of anesthesia. In this study we derived a PK-PD model for propofol in adolescents undergoing idiopathic scoliosis surgery with an intraoperative wake-up test with reinduction of anesthesia using both Bispectral Index (BIS) and composite A-line ARX index (cAAI) as endpoints. In adolescents limited data are available on the pharmacokinetics (PK) and pharmacodynamics (PD) of propofol.