Keywords: Biological systems and controls, Biomedical system modelling, Experiment design
Abstract: We propose a rapid nonovershooting tracking controller for the continuous infusion of anesthetics and analgesics to prevent overdosing and other harmful side effects on patients. The controller utilizes a state feedback control design methodology for multi-input multi-output systems to achieve a closed-loop eigenstructure that yields a nonovershooting transient response. The method is combined with a global optimization method to achieve a rapid nonovershooting response. The controller uses an extended Kalman filter to estimate system states from measurable outputs, and integral control is added to achieve robust tracking. The performance of the method is simulated on 20 patient models in two groups, and the results are compared against another recent study from the biomedical control literature.

Keywords: Pharmacokinetics and drug delivery
Abstract: In this paper we propose the use of an optimization strategy for the computation of an optimized reference (command) input to be applied to a proportional-integral-derivative (PID) based closed-loop control system for the administration of propofol during the induction phase of general anesthesia. The bispectral index scale (BIS) is the controlled variable. The proposed methodology explicitly takes into account the dynamics of the PID controller in the calculation of the reference input to minimize the induction time of anesthesia while limiting the undershoot of the BIS level. The eectiveness of the proposed methodology is assessed in simulation by means of a Monte Carlo method and the performance is compared with that of an optimally tuned PID controller and with that of a recently devised optimized feedforward control law. The effect of the PID tuning on the obtainable performance is also investigated.

Keywords: Pharmacokinetics and drug delivery
Abstract: In the practice of total intravenous anesthesia, the regulation of the balance between opioid and hypnotic drugs is fundamental since it has a significant impact on depth of hypnosis and hemodynamics. Therefore, in the implementation of a fully automated control system for anesthesia, this aspect must be considered. In a recently devised PID-based control scheme for propofol and remifentanil coadministration, the opioid-hypnotic balance is handled by imposing a ratio between the infusion rates of these two drugs. The anesthesiologist can choose the most suitable balance during each phase of surgery by changing the ratio. The aim of this paper is to evaluate and discuss the benefits that this solution can bring in the clinical practice. In order to do so, the proposed solution has been tested in simulation by using a recently devised open source patient simulator that takes into account both anesthetic and hemodynamic variables. Simulation results show that the proposed approach automatically induces and maintains the desired depth of hypnosis and, furthermore, it gives the anesthesiologist the possibility to better manage the patient's hemodynamics by selecting the most appropriate opioid-hypnotic balance for each situation.

Keywords: Pharmaceutical processes, Biomedical system modelling, Identification and validation
Abstract: Most surgical interventions involve sedating the patient with a cocktail of substances having anesthetic effects. The procedure is usually performed by a medical doctor that continuously monitors and readjusts drug dosage with respect to the patient’s response. Current advances in automatic control and biomedical engineering offer the possibility to reassign the anesthetist’s task to real-time, highly-performant monitoring and control algorithms, with the purpose of providing a risk-free anesthetic experience. The present study combines the well-known benefits of fractional calculus in biomedical applications with the intricate tasks revolving around automatic anesthesia. The proposed fractional order control algorithms are developed based on an open-source patient simulator that combines hemodynamics and anesthesia in a single customizable framework. Testing and validation of the proposed strategy is successfully performed on a group of 24 different patients in the presence of surgical stimulus. The ultimate result is that the hemodynamic characteristics are kept within accepted ranges, while a certain level of anesthesia is achieved.

Keywords: Identification and validation, Biomedical system modelling, Biological systems and controls
Abstract: There is a large variability between individuals in the response to anesthetic drugs, that seriously limits the achievable performance of closed-loop controlled drug dosing. Full individualization of patient models based on early clinical response data has been suggested as a means to improve performance with maintained robustness (safety). We use estimation theoretic analysis and realization theory to characterize practical identifiability of the standard pharmacological model structure from anesthetic induction phase data and conclude that such approaches are not practically feasible.

Keywords: Pharmacokinetics and drug delivery
Abstract: General anaesthesia is a clinical procedure that involves the continuous monitoring of several parameters for the correct application of anaesthetics and associated drugs. Focusing on the automatic control in anaesthesia, this work presents a multiobjective optimization design of controllers based on the Non-dominated Sorting Genetic Algorithm II (NSGA-II) to solve the problem of drug delivery for induction of anaesthesia. Five Proportional-Integral-Derivative (PID) controllers in a decentralized scheme were tuned for one specific patient and tested in a total of 24 simulated patients. Acting over the infusions of Propofol, Remifentanil, Atracurium, Dobutamine, and Sodium Nitroprusside the proposed controllers could maintain the controlled variables in a safe range for surgical procedures.

Keywords: Biomedical system modelling
Abstract: This paper proposes a Model Predictive Control (MPC) approach of both anesthesia and hemodynamic systems. The designed control strategy has been validated on a novel and unique patient simulator. The aim of this paper is to evaluate the feasibility MIMO closed-loop control of anesthesia and hemodynamic variables taking into account the interaction (synergic and antagonistic) between subsystems. The proposed methodology takes into account patient variability, is robust to subsystems interaction and meets the clinical objectives. The algorithm is tested in simulation on a hypnosis-hemodynamic combined model for use during general anesthesia. The preliminary results are promising and show the effectiveness of the control procedure.

Keywords: Pharmacokinetics and drug delivery, Kinetic modelling and control of biological systems, Biomedical system modelling
Abstract: In this paper a control scheme based on a simplified model for the joint action of propofol and remifentanil on the depth of anesthesia, measured by the BIS level, is proposed. The simplified model contains four patient dependent parameters, two of which can be easily estimated from the patient’s BIS response to an initial bolus of propofol. Instead of estimating the remaining necessary parameters, initial guesses are assumed for these parameters in order to compute the drug dosages corresponding to a desired reference BIS level by steady-state model inversion. The dosages are updated by means of a successive retuning procedure that ensures that the patient’s BIS response achieves and maintains the desired reference level. This successive retuning scheme yields betters results than a single retuning procedure by decreasing the settling time at the target BIS value.

Keywords: Pharmacokinetics and drug delivery, Biological systems and controls
Abstract: As a part of the BMS2021 Benchmark Challenge, this paper deals with the design and testing of a closed-loop anesthesia delivery regulation system by exploiting the open-source Matlab-based patient simulator. Because of system inherent complexity together with intra- and inter-patient parameters variability and partially unknown disturbances, traditional model-based approaches may suffer. To overcome these limitations, we opt for a data-driven approach using real-time ultra-local models coupled with the corresponding so-called intelligent controllers. In this way, one maintains the hemodynamic variables while regulating the levels of hypnosis, analgesia, and neuromuscular blockade in anesthesia by automatic delivery of drugs. The performance of the proposed approach has been evaluated in silico by considering a representative dataset composed of 24 patients, the presence of disturbances mimicking both surgical stimulations and actions of ''anesthesiologist in the loop'', including also noise effects and time-varying system delays.

Keywords: Biosignal analysis and interpretation,, Advances in sensing and signal processing
Abstract: Localized tissue bioimpedance is being widely investigated as a technique to identify physiological features in support of health focused applications. In support of this method being translated into wearable systems for continuous monitoring, it is critical to not only collect measurements but also evaluate their quality. This is necessary to reduce errors in equipment or measurement conditions from contributing data artifacts to datasets that will be analyzed. Two methods for artifact identification in resistance measurements of bioimpedance datasets are presented. These methods, based on thresholding and trend detection, are applied to localized knee bioimpedance datasets collected from two knee sites over 7 consecutive days in free-living conditions. Threshold artifacts were identified in 0.04% (longitudinal and transverse) and 0.69% (longitudinal) / 3.50% (transverse) of the total data collected.

Keywords: Experiment design, Devices and sensors, Biosignal analysis and interpretation,
Abstract: Technical details of the construction of the laboratory set-up dedicated for experimentation with body sounds recordings is reported in the paper, together with the feasibility studies focused on multisystem medical inference and long-run mode of work. Presented, exemplary, qualitative and quantitative results show the potential of the construction to uncover the physiological patterns in one- and multidimensional acoustic data, including short- and long-range feedback loops, significant for the circadian rhythm control.

Keywords: Identification and validation, Biomedical system modelling, Devices and sensors
Abstract: This work aims to study postsurgical trauma modeling to characterize the physiological process in postoperative pain assessment in an observational trial. The skin impedance data is proposed to be fitted by derived-Cole models, i.e., single and double dispersion models and a distributed model with an inductive term related to sweat glands. These models are motivated by the biological characteristics of the skin, its physiological stratification and the current intra- and extra-cellular pathways. The correlation between the identified parameters with the patient's pain reported using the numerical rating scale (NRS) is analyzed for one patient for all three models. Following the trial, a statistically significant positive linear relationship was observed between the Anspec-Pro index and NRS (r2 = 0:16, p=0.00), driving the further study of the relationship between the estimated dielectric parameters. The paper focuses to analyze the changes of the coefficients related to the particular clinical data, successfully identified using the non-linear least square procedure. The clinical significance of the results may be related to the individual model parameters for postoperative pain detection, validated on patients.

Keywords: Biomedical imaging systems, Devices and sensors, Advances in sensing and signal processing
Abstract: Video-assisted thoracoscopic surgery (VATS) is the primary minimally invasive excise procedure for the diagnostics of pulmonary lesions. However, these lesions can be difficult to localize during the surgery as the lung collapses. Here we continue our study on the use of radio frequency technology directly during VATS as an intraoperative strategy for the location of pulmonary lesions. Finite Difference Time Domain (FDTD) simulations were used to compare a dipole and a bowtie antenna of different lengths. The results show that the bowtie antenna performs better than a dipole one, even if only marginally.

Keywords: Devices and sensors, Biomedical imaging systems
Abstract: Electrical Impedance Tomography (EIT) uses boundary voltage measurements due to multiple injection current patterns to reconstruct cross-sectional impedance images. Usually, the hardware does not provide any capacitive information and the reconstructed image is only based on conductivity. An approach where each electrode has its own Howland current source is a powerful and innovative architecture in which different current injections can be implemented. However, the potential source of error increases with this new architecture when compared with conventional architectures. This paper enumerates some of the potential errors considering the main modules of the electrode: 1. Howland current source; 2. ADC and DAC converters; and 3. The demodulator. A methodology for verifying ADC and DAC precision and linearity is proposed.

Keywords: Simulation and visualization,, Biomedical system modelling
Abstract: A new inflatable sensor-actuator system is being developed to analyze the in-vivo biomechanical properties of the urethra of a male human. It could provide decision-aids to urologists while treating issues like urethral strictures. Models that could simulate the biomechanical variations of the urethra are important to evaluate the capabilities of the system under development. For the initial study, a simplified axisymmetric Finite Element Method ‘tube’ model was generated. To simulate an ideal inflating actuator (balloon) within this urethra model, a pressure was applied on the inner wall of the tube. From the region over which the pressure was applied, ‘sensor’ measurements were taken from the ‘top’ plane, ‘middle’ plane and a plane lying between these two. The resulting pressure-circumference and pressure-(wall)thickness responses at these measurement planes were determined. A hyperelastic response attributable to biological tissues was obtained. It was found that the resultant circumferential extension and thickness varies at different planes during the actuator inflation. After inflating at the highest chosen pressure, from the initial inner circumference of 25mm, final extensions ranging 45mm to 63mm for the peripheral plane were obtained. Similarly, extensions ranging from 48mm to 68mm were obtained for the other two planes. The pressure-circumference response at the plane lying on the periphery of the inflated region was found to be less compliant than the plane in the center for the model. A range of biomechanical responses were able to be achieved by performing a parametric variation for the chosen mathematical model and geometry in consideration. The study indicates that a larger dataset can be generated to further model a variety of urethral biomechanical responses. These initial simulations provide important information for identification tasks related to the current development. The results show that simulations could be a prospective way to test new sensors prior to real experiments.