Frontal electroencephalogram based drug, sex, and age independent sedation level prediction using non-linear machine learning algorithms.

Brain monitors which track quantitative electroencephalogram (EEG) signatures to monitor sedation levels are drug and patient specific. There is a need for robust sedation level monitoring systems to accurately track sedation levels across all drug classes, sex and age groups. Forty-four quantitative features estimated from a pooled dataset of 204 EEG recordings from 66 healthy adult volunteers who received either propofol, dexmedetomidine, or sevoflurane (all with and without remifentanil) were used in a machine learning based automated system to estimate the depth of sedation. Model training and evaluation were performed using leave-one-out cross validation methodology. We trained four machine learning models to predict sedation levels and evaluated the influence of remifentanil, age, and sex on the prediction performance. The area under the receiver-operator characteristic curve (AUC) was used to assess the performance of the prediction model. The ensemble tree with bagging outperformed other machine learning models and predicted sedation levels with an AUC = 0.88 (0.81-0.90). There were significant differences in the prediction probability of the automated systems when trained and tested across different age groups and sex. The performance of the EEG based sedation level prediction system is drug, sex, and age specific. Nonlinear machine-learning models using quantitative EEG features can accurately predict sedation levels. The results obtained in this study may provide a useful reference for developing next generation EEG based sedation level prediction systems using advanced machine learning algorithms. Clinical trial registration: NCT02043938 and NCT03143972.

Comparison of haemodynamic- and electroencephalographic-monitored effects evoked by four combinations of effect-site concentrations of propofol and remifentanil, yielding a predicted tolerance to laryngoscopy of 90.

This prospective study evaluates haemodynamic and electroencephalographic effects observed when administering four combinations of effect-site concentrations of propofol (CePROP) and remifentanil (CeREMI), all yielding a single predicted probability of tolerance of laryngoscopy of 90% (PTOL = 90%) according to the Bouillon interaction model. We aimed to identify combinations of CePROP and CeREMI along a single isobole of PTOL that result in favourable hypnotic and haemodynamic conditions. This knowledge could be of advantage in the development of drug advisory monitoring technology. 80 patients (18-90 years of age, ASA I-III) were randomized into four groups and titrated towards CePROP (Schnider model, ug⋅ml-1) and CeREMI (Minto model, ng⋅ml-1) of respectively 8.6 and 1, 5.9 and 2, 3.6 and 4 and 2.0 and 8. After eleven minutes of equilibration, baseline measurements of haemodynamic endpoints and bispectral index were compared with three minutes of responsiveness measurements after laryngoscopy. Before laryngoscopy, bispectral index differed significantly (p < 0.0001) between groups in concordance with CePROP. Heart rate decreased with increasing CeREMI (p = 0.001). The haemodynamic and arousal responses evoked by laryngoscopy were not significantly different between groups, but CePROP = 3.6 µg⋅ml-1 and CeREMI = 4 ng⋅ml-1 evoked the lowest median value for ∆HR and ∆SAP after laryngoscopy. This study provides clinical insight on the haemodynamic and hypnotic consequences, when a model based predicted PTOL is used as a target for combined effect-site controlled target- controlled infusion of propofol and remifentanil. Heart rate and bispectral index were significantly different between groups despite a theoretical equipotency for PTOL, suggesting that each component of the anaesthetic state (immobility, analgesia, and hypnotic drug effect) should be considered as independent neurophysiological and pharmacological phenomena. However, claims of (in)accuracy of the predicted PTOL must be considered preliminary because larger numbers of observations are required for that goal.

Test of neural inertia in humans during general anaesthesia.

BACKGROUND: Neural inertia is defined as the tendency of the central nervous system to resist transitions between arousal states. This phenomenon has been observed in mice and Drosophila anaesthetized with volatile anaesthetics: the effect-site concentration required to induce anaesthesia in 50% of the population (C50) was significantly higher than the effect-site concentration for 50% of the population to recover from anaesthesia. We evaluated this phenomenon in humans using propofol or sevoflurane (both with or without remifentanil) as anaesthetic agents. METHODS: Thirty-six healthy volunteers received four sessions of anaesthesia with different drug combinations in a step-up/step-down design. Propofol or sevoflurane was administered with or without remifentanil. Serum concentrations of propofol and remifentanil were measured from arterial blood samples. Loss and return of responsiveness (LOR-ROR), response to pain (PAIN), Patient State Index (PSI) and spectral edge frequency (SEF) were modeled with NONMEM®. RESULTS: For propofol, the C50 for induction and recovery of anaesthesia was not significantly different across the different endpoints. For sevoflurane, for all endpoints except SEF, significant differences were found. For some endpoints (LOR and PAIN) the difference was significant only when sevoflurane was combined with remifentanil. CONCLUSIONS: Our results nuance earlier findings with volatile anaesthetics in mice and Drosophila. Methodological aspects of the study, such as the measured endpoint, influence the detection of neural inertia. A more thorough definition of neural inertia, with a robust methodological framework for clinical studies is required to advance our knowledge of this phenomenon. CLINICAL TRIAL REGISTRATION: NCT 02043938.

Dexmedetomidine pharmacokinetic-pharmacodynamic modelling in healthy volunteers: 1. Influence of arousal on bispectral index and sedation.

BACKGROUND: Dexmedetomidine, a selective α 2 -adrenoreceptor agonist, has unique characteristics, such as maintained respiratory drive and production of arousable sedation. We describe development of a pharmacokinetic-pharmacodynamic model of the sedative properties of dexmedetomidine, taking into account the effect of stimulation on its sedative properties. METHODS: In a two-period, randomized study in 18 healthy volunteers, dexmedetomidine was delivered in a step-up fashion by means of target-controlled infusion using the Dyck model. Volunteers were randomized to a session without background noise and a session with pre-recorded looped operating room background noise. Exploratory pharmacokinetic-pharmacodynamic modelling and covariate analysis were conducted in NONMEM using bispectral index (BIS) monitoring of processed EEG. RESULTS: We found that both stimulation at the time of Modified Observer's Assessment of Alertness/Sedation (MOAA/S) scale scoring and the presence or absence of ambient noise had an effect on the sedative properties of dexmedetomidine. The stimuli associated with MOAA/S scoring increased the BIS of sedated volunteers because of a transient 170% increase in the effect-site concentration necessary to reach half of the maximal effect. In contrast, volunteers deprived of ambient noise were more resistant to dexmedetomidine and required, on average, 32% higher effect-site concentrations for the same effect as subjects who were exposed to background operating room noise. CONCLUSIONS: The new pharmacokinetic-pharmacodynamic models might be used for effect-site rather than plasma concentration target-controlled infusion for dexmedetomidine in clinical practice, thereby allowing tighter control over the desired level of sedation. CLINICAL TRIAL REGISTRATION: NCT01879865.

Dexmedetomidine pharmacodynamics in healthy volunteers: 2. Haemodynamic profile.

BACKGROUND: Dexmedetomidine, a selective α 2 -adrenoreceptor agonist, has unique characteristics, with little respiratory depression and rousability during sedations. We characterized the haemodynamic properties of dexmedetomidine by developing a pharmacokinetic-pharmacodynamic (PKPD) model with a focus on changes in mean arterial blood pressure (MAP) and heart rate. METHODS: Dexmedetomidine was delivered i.v. to 18 healthy volunteers in a step-up fashion by target-controlled infusion using the Dyck model. Exploratory PKPD modelling and covariate analysis were conducted in NONMEM. RESULTS: Our model adequately describes dexmedetomidine-induced hypotension, hypertension, and bradycardia, with a greater effective concentration for the hypertensive effect. Changes in MAP were best described by a double-sigmoidal E max model with hysteresis. Covariate analysis revealed no significant covariates apart from age on the baseline MAP in the population pharmacokinetic model used to develop this PKPD model. Simulations revealed good general agreement with published descriptive studies of haemodynamics after dexmedetomedine infusion. CONCLUSIONS: The present integrated PKPD model should allow tighter control over the desired level of sedation, while limiting potential haemodynamic side-effects. CLINICAL TRIAL REGISTRATION: NCT01879865.

Pharmacokinetic and pharmacodynamic interactions in anaesthesia. A review of current knowledge and how it can be used to optimize anaesthetic drug administration.

This review describes the basics of pharmacokinetic and pharmacodynamic drug interactions and methodological points of particular interest when designing drug interaction studies. It also provides an overview of the available literature concerning interactions, with emphasis on graphic representation of interactions using isoboles and response surface models. It gives examples on how to transform this knowledge into clinically and educationally applicable (bedside) tools.

Probability to tolerate laryngoscopy and noxious stimulation response index as general indicators of the anaesthetic potency of sevoflurane, propofol, and remifentanil.

BACKGROUND: The probability to tolerate laryngoscopy (PTOL) and its derivative, the noxious stimulation response index (NSRI), have been proposed as measures of potency of a propofol-remifentanil drug combination. This study aims at developing a triple drug interaction model to estimate the combined potency of sevoflurane, propofol, and remifentanil in terms of PTOL. We compare the predictive performance of PTOL and the NSRI with various anaesthetic depth monitors. METHODS: Data from three previous studies (n=120) were pooled and reanalysed. Movement response after laryngoscopy was observed with different combinations of propofol-remifentanil, sevoflurane-propofol, and sevoflurane-remifentanil. A triple interaction model to estimate PTOL was developed. The NSRI was derived from PTOL. The ability of PTOL and the NSRI to predict observed tolerance of laryngoscopy (TOL) was compared with the following other measures: (i) effect-site concentrations of sevoflurane, propofol, and remifentanil (CeSEVO, CePROP, and CeREMI); (ii) bispectral index; (iii) two measures of spectral entropy; (iv) composite variability index; and (v) surgical pleth index. RESULTS: Sevoflurane and propofol interact additively, whereas remifentanil interacts in a strongly synergistic manner. The effect-site concentrations of sevoflurane and propofol at a PTOL of 50% (Ce50; se) were 2.59 (0.13) vol % and 7.58 (0.49) µg ml(-1). A CeREMI of 1.36 (0.15) ng ml(-1) reduced the Ce50 of sevoflurane and propofol by 50%. The common slope factor was 5.22 (0.52). The PTOL and NSRI predict the movement response to laryngoscopy best. CONCLUSIONS: The triple interaction model estimates the potency of any combination of sevoflurane, propofol, and remifentanil expressed as either PTOL or NSRI.

Optimizing intravenous drug administration by applying pharmacokinetic/pharmacodynamic concepts.

This review discusses the ways in which anaesthetists can optimize anaesthetic-analgesic drug administration by utilizing pharmacokinetic and pharmacodynamic information. We therefore focus on the dose-response relationship and the interactions between i.v. hypnotics and opioids. For i.v. hypnotics and opioids, models that accurately predict the time course of drug disposition and effect can be applied. Various commercial or experimental drug effect measures have been developed and can be implemented to further fine-tune individual patient-drug titration. The development of advisory and closed-loop feedback systems, which combine and integrate all sources of pharmacological and effect monitoring, has taken the existing kinetic-based administration technology forwards closer to total coverage of the dose-response relationship.

Study of the time course of the clinical effect of propofol compared with the time course of the predicted effect-site concentration: Performance of three pharmacokinetic-dynamic models.

BACKGROUND: In the ideal pharmacokinetic-dynamic (PK-PD) model for calculating the predicted effect-site concentration of propofol (Ce(PROP)), for any Ce(PROP), the corresponding hypnotic effect should be constant. We compared three PK-PD models (Marsh PK with Shüttler PD, Schnider PK with fixed ke0, and Schnider PK with Minto PD) in their ability to maintain a constant bispectral index (BIS), while using the respective effect-site-controlled target-controlled infusion (TCI) algorithms. METHODS: We randomized 60 patients to Group M (Marsh's model with k(e0)=0.26 min(-1)), Group S1 or Group S2 (Schnider's model with a fixed k(e0)=0.456 min(-1) or a k(e0) adapted to a fixed time-to-peak effect=1.6 min, respectively). All patients received propofol at a constant rate until loss of consciousness. The corresponding Ce(PROP), as calculated by the respective models, was set as a target for effect-site-controlled TCI. We observed BIS for 20 min. We hypothesized that BIS remains constant, if Ce(PROP) remains constant over time. RESULTS: All patients in Group M woke up, one in Group S1 and none in Group S2. In Groups S1 and S2, BIS remained constant after 11 min of constant Ce(PROP), at a more pronounced level of hypnotic drug effect than intended. CONCLUSIONS: Targeting Ce(PROP) at which patients lose consciousness with effect-site-controlled TCI does not translate into an immediate constant effect.

A comparison of bispectral index and ARX-derived auditory evoked potential index in measuring the clinical interaction between ketamine and propofol anaesthesia.

We evaluated the effects of a bolus (0.4 mg.kg-1) and continuous infusion (1 mg.kg-1.h-1) of ketamine on Bispectral Index (BIS) and A-Line(R) ARX Index (AAI) during propofol anaesthesia. We included 15 ASA I patients scheduled for general anaesthesia. Induction was performed by infusion of propofol at 100 ml.h-1 until loss of consciousness. Both BIS and AAI monitors responded appropriately at that time. The calculated effect site concentration of propofol at loss of consciousness was maintained by means of a computer controlled infusion system. A 'pseudo' steady-state effect site concentration was reached after 4 min. After 1 min of baseline measurements, ketamine was administered. BIS values increased from the 3rd to the 8th min after the administration of ketamine. The AAI showed no significant increase or decrease, but between-patient variability increased.