Closed-loop target-controlled infusion systems: stability and performance aspects.

OBJECTIVE: This article addresses the design of a robust autopilot for the delivery of intravenous anesthesia drugs. METHODS: A mathematical framework that expresses the pharmacological variability of a patient population into uncertainty bounds is proposed. These bounds can be effectively used to tune the parameters of a controller to ensure its stability, a key design aspect related to the safety of the overall system. RESULTS: The proposed method is applied to the control of propofol, a powerful hypnotic agent used for sedation and anesthesia. Simulations show that the controller remains stable for all patients considered and that performance are clinically acceptable. CONCLUSION: This methodology can be an important step forward in the design and regulatory approval of such systems.

NREM sleep staging using WAV(CNS) index.

OBJECTIVE: Visual scoring of 30-s epochs of sleep data is not always adequate to show the dynamic structure of sleep in sufficient details. It is also prone to considerable inter- and intra-rater variability. Moreover, it involves considerable training and experience, and is very tedious, time-consuming, labor-intensive and costly. Hence, automatic sleep staging is needed to overcome these limitations. Since naturally occurring NREM sleep and anesthesia have been reported to possess various underlying neurophysiological similarities, EEG-based depth-of-anesthesia monitors have started to penetrate into sleep research. This study investigates the ability of WAV(CNS) index (as implemented in NeuroSENSE depth-of-anesthesia monitor) to detect NREM sleep stages and wake state for full overnight PSG data. METHODS: Full overnight PSG sleep data, obtained from 24 adolescents, was scored by a registered PSG technologist for different sleep stages. Retrospective analysis was performed on a single frontal channel using the WAV(CNS) algorithm. Non-parametric descriptive statistics were used to examine the relationship between WAV(CNS) index and sleep stages. RESULTS: A strong correlation (ρ = 0.9458) was found between the WAV(CNS) index and NREM sleep stages, with WAV(CNS) index values decreasing with increasing sleep stages. Moreover, there was no significant overlap between different NREM sleep stages as classified by the WAV(CNS) index, which was able to significantly differentiate (P < 0.001) between all pairs of Awake and different NREM stages. CONCLUSIONS: This study demonstrates that changes in the depth of natural NREM sleep are reflected sensitively by changes in the WAV(CNS) index. Hence, WAV(CNS) index may serve as an automatic real-time indicator of depth of natural sleep with high temporal resolution, and can possibly be of great use for automated sleep staging in routine/postoperative somnographic studies.

Dynamic behavior of BIS, M-entropy and neuroSENSE brain function monitors.

OBJECTIVES: The objective of this paper is to assess the suitability of brain function monitors for use in closed-loop anesthesia or sedation delivery. In such systems, monitors used as feedback sensors should preferably be Linear and Time Invariant (LTI) in order to limit sensor-induced uncertainty which can cause degraded performance. In this paper, we evaluate the suitability of the BIS A2000 (Aspect Medical Systems, MA), the M-Entropy Monitor (GE HealthCare), and the NeuroSENSE Monitor (NeuroWave Systems Inc, OH), by verifying whether their dynamic behavior conforms to the LTI hypothesis. METHODS: We subjected each monitor to two different composite EEG signals containing step-wise changes in cortical activity. The first signal was used to identify Linear Time-Invariant (LTI) models that mathematically capture the dynamic behavior of each monitor. The identification of the model parameters was carried out using standard Recursive Least Squares (RLS) estimation. The second signal was used to assess the performance of the model, by comparing the output of the monitor to the simulated output predicted by the model. RESULTS: While a LTI model was successfully derived for each monitor using the first signal, only the model derived for NeuroSENSE was capable to reliably predict the monitor output for the second input signals. This indicates that some algorithmic processes within the BIS A2000 and M-Entropy are non-linear and/or time variant. CONCLUSION: While both BIS and M-Entropy monitors have been successfully used in closed-loop systems, we were unable to obtain a unique LTI model that could capture their dynamic behavior during step-wise changes in cortical activity. The uncertainty in their output during rapid changes in cortical activity impose limitations in the ability of the controller to compensate for rapid changes in patients' cortical state, and pose additional difficulties in being able to provide mathematically proof for the stability of the overall closed-loop system. Conversely, the NeuroSENSE dynamic behavior can be fully captured by a linear and time invariant transfer function, which makes it better suited for closed-loop applications.

Quantifying cortical activity during general anesthesia using wavelet analysis.

This paper reports on a novel method for quantifying the cortical activity of a patient during general anesthesia as a surrogate measure of the patient's level of consciousness. The proposed technique is based on the analysis of a single-channel (frontal) electroencephalogram (EEG) signal using stationary wavelet transform (SWT). The wavelet coefficients calculated from the EEG are pooled into a statistical representation, which is then compared to two well-defined states: the awake state with normal EEG activity, and the isoelectric state with maximal cortical depression. The resulting index, referred to as the wavelet-based anesthetic value for central nervous system monitoring (WAV(CNS)), quantifies the depth of consciousness between these two extremes. To validate the proposed technique, we present a clinical study which explores the advantages of the WAV(CNS) in comparison with the BIS monitor (Aspect Medical Systems, MA), currently a reference in consciousness monitoring. Results show that the WAV(CNS) and BIS are well correlated (r = 0.969) during periods of steady-state despite fundamental algorithmic differences. However, in terms of dynamic behavior, the WAV(CNS) offers faster tracking of transitory changes at induction and emergence, with an average lead of 15-30 s. Furthermore, and conversely to the BIS, the WAV(CNS) regains its preinduction baseline value when patients are responding to verbal command after emergence from anesthesia. We conclude that the proposed analysis technique is an attractive alternative to BIS monitoring. In addition, we show that the WAV(CNS) dynamics can be modeled as a linear time invariant transfer function. This index is, therefore, well suited for use as a feedback sensor in advisory systems, closed-loop control schemes, and for the identification of the pharmacodynamic models of anesthetic drugs.

Quantifying uncertainty bounds in anesthetic PKPD models.

A major challenge faced when designing controllers to automate anesthetic drug delivery is the large variability that exists between and within patients. This intra- and inter-patient variability have been reported to lead to instability. Hence, defining and quantifying uncertainty bounds provides a mean to validate the control design, ensure its stability and assess performance. In this work, the intra- and inter-patient variability measured from thiopental induction data is used to define uncertainty bounds. It is shown that these bounds can be reduced by up to 40% when using a patient-specific model as compared to a population-normed model. It is also shown that identifying only the overall static gain of the patient system already decreases significantly this uncertainty.