Accurate end systole detection in dicrotic notch-less arterial pressure waveforms.

Identification of end systole is often necessary when studying events specific to systole or diastole, for example, models that estimate cardiac function and systolic time intervals like left ventricular ejection duration. In proximal arterial pressure waveforms, such as from the aorta, the dicrotic notch marks this transition from systole to diastole. However, distal arterial pressure measures are more common in a clinical setting, typically containing no dicrotic notch. This study defines a new end systole detection algorithm, for dicrotic notch-less arterial waveforms. The new algorithm utilises the beta distribution probability density function as a weighting function, which is adaptive based on previous heartbeats end systole locations. Its accuracy is compared with an existing end systole estimation method, on dicrotic notch-less distal pressure waveforms. Because there are no dicrotic notches defining end systole, validating which method performed better is more difficult. Thus, a validation method is developed using dicrotic notch locations from simultaneously measured aortic pressure, forward projected by pulse transit time (PTT) to the more distal pressure signal. Systolic durations, estimated by each of the end systole estimates, are then compared to the validation systolic duration provided by the PTT based end systole point. Data comes from ten pigs, across two protocols testing the algorithms under different hemodynamic states. The resulting mean difference ± limits of agreement between measured and estimated systolic duration, of [Formula: see text] versus [Formula: see text], for the new and existing algorithms respectively, indicate the new algorithms superiority.

Next-generation, personalised, model-based critical care medicine: a state-of-the art review of in silico virtual patient models, methods, and cohorts, and how to validation them.

Critical care, like many healthcare areas, is under a dual assault from significantly increasing demographic and economic pressures. Intensive care unit (ICU) patients are highly variable in response to treatment, and increasingly aging populations mean ICUs are under increasing demand and their cohorts are increasingly ill. Equally, patient expectations are growing, while the economic ability to deliver care to all is declining. Better, more productive care is thus the big challenge. One means to that end is personalised care designed to manage the significant inter- and intra-patient variability that makes the ICU patient difficult. Thus, moving from current "one size fits all" protocolised care to adaptive, model-based "one method fits all" personalised care could deliver the required step change in the quality, and simultaneously the productivity and cost, of care. Computer models of human physiology are a unique tool to personalise care, as they can couple clinical data with mathematical methods to create subject-specific models and virtual patients to design new, personalised and more optimal protocols, as well as to guide care in real-time. They rely on identifying time varying patient-specific parameters in the model that capture inter- and intra-patient variability, the difference between patients and the evolution of patient condition. Properly validated, virtual patients represent the real patients, and can be used in silico to test different protocols or interventions, or in real-time to guide care. Hence, the underlying models and methods create the foundation for next generation care, as well as a tool for safely and rapidly developing personalised treatment protocols over large virtual cohorts using virtual trials. This review examines the models and methods used to create virtual patients. Specifically, it presents the models types and structures used and the data required. It then covers how to validate the resulting virtual patients and trials, and how these virtual trials can help design and optimise clinical trial. Links between these models and higher order, more complex physiome models are also discussed. In each section, it explores the progress reported up to date, especially on core ICU therapies in glycemic, circulatory and mechanical ventilation management, where high cost and frequency of occurrence provide a significant opportunity for model-based methods to have measurable clinical and economic impact. The outcomes are readily generalised to other areas of medical care.

Evolution of insulin sensitivity and its variability in out-of-hospital cardiac arrest (OHCA) patients treated with hypothermia.

INTRODUCTION: Therapeutic hypothermia (TH) is often used to treat out-of-hospital cardiac arrest (OHCA) patients who also often simultaneously receive insulin for stress-induced hyperglycaemia. However, the impact of TH on systemic metabolism and insulin resistance in critical illness is unknown. This study analyses the impact of TH on metabolism, including the evolution of insulin sensitivity (SI) and its variability, in patients with coma after OHCA. METHODS: This study uses a clinically validated, model-based measure of SI. Insulin sensitivity was identified hourly using retrospective data from 200 post-cardiac arrest patients (8,522 hours) treated with TH, shortly after admission to the intensive care unit (ICU). Blood glucose and body temperature readings were taken every one to two hours. Data were divided into three periods: 1) cool (T <35°C); 2) an idle period of two hours as normothermia was re-established; and 3) warm (T >37°C). A maximum of 24 hours each for the cool and warm periods was considered. The impact of each condition on SI is analysed per cohort and per patient for both level and hour-to-hour variability, between periods and in six-hour blocks. RESULTS: Cohort and per-patient median SI levels increase consistently by 35% to 70% and 26% to 59% (P <0.001) respectively from cool to warm. Conversely, cohort and per-patient SI variability decreased by 11.1% to 33.6% (P <0.001) for the first 12 hours of treatment. However, SI variability increases between the 18th and 30th hours over the cool to warm transition, before continuing to decrease afterward. CONCLUSIONS: OCHA patients treated with TH have significantly lower and more variable SI during the cool period, compared to the later warm period. As treatment continues, SI level rises, and variability decreases consistently except for a large, significant increase during the cool to warm transition. These results demonstrate increased resistance to insulin during mild induced hypothermia. Our study might have important implications for glycaemic control during targeted temperature management.

Reducing the impact of insulin sensitivity variability on glycaemic outcomes using separate stochastic models within the STAR glycaemic protocol.

BACKGROUND: The metabolism of critically ill patients evolves dynamically over time. Post critical insult, levels of counter-regulatory hormones are significantly elevated, but decrease rapidly over the first 12-48 hours in the intensive care unit (ICU). These hormones have a direct physiological impact on insulin sensitivity (SI). Understanding the variability of SI is important for safely managing glycaemic levels and understanding the evolution of patient condition. The objective of this study is to assess the evolution of SI over the first two days of ICU stay, and using this data, propose a separate stochastic model to reduce the impact of SI variability during glycaemic control using the STAR glycaemic control protocol. METHODS: The value of SI was identified hourly for each patient using a validated physiological model. Variability of SI was then calculated as the hour-to-hour percentage change in SI. SI was examined using 6 hour blocks of SI to display trends while mitigating the effects of noise. To reduce the impact of SI variability on achieving glycaemic control a new stochastic model for the most variable period, 0-18 hours, was generated. Virtual simulations were conducted using an existing glycaemic control protocol (STAR) to investigate the clinical impact of using this separate stochastic model during this period of increased metabolic variability. RESULTS: For the first 18 hours, over 80% of all SI values were less than 0.5 × 10(-3) L/mU x min, compared to 65% for >18 hours. Using the new stochastic model for the first 18 hours of ICU stay reduced the number of hypoglycaemic measurements during virtual trials. For time spent below 4.4, 4.0, and 3.0 mmol/L absolute reductions of 1.1%, 0.8% and 0.1% were achieved, respectively. No severe hypoglycaemic events (BG < 2.2 mmol/L) occurred for either case. CONCLUSIONS: SI levels increase significantly, while variability decreases during the first 18 hours of a patients stay in ICU. Virtual trials, using a separate stochastic model for this period, demonstrated a reduction in variability and hypoglycaemia during the first 18 hours without adversely affecting the overall level of control. Thus, use of multiple models can reduce the impact of SI variability during model-based glycaemic control.

A multi-scale cardiovascular system model can account for the load-dependence of the end-systolic pressure-volume relationship.

BACKGROUND: The end-systolic pressure-volume relationship is often considered as a load-independent property of the heart and, for this reason, is widely used as an index of ventricular contractility. However, many criticisms have been expressed against this index and the underlying time-varying elastance theory: first, it does not consider the phenomena underlying contraction and second, the end-systolic pressure volume relationship has been experimentally shown to be load-dependent. METHODS: In place of the time-varying elastance theory, a microscopic model of sarcomere contraction is used to infer the pressure generated by the contraction of the left ventricle, considered as a spherical assembling of sarcomere units. The left ventricle model is inserted into a closed-loop model of the cardiovascular system. Finally, parameters of the modified cardiovascular system model are identified to reproduce the hemodynamics of a normal dog. RESULTS: Experiments that have proven the limitations of the time-varying elastance theory are reproduced with our model: (1) preload reductions, (2) afterload increases, (3) the same experiments with increased ventricular contractility, (4) isovolumic contractions and (5) flow-clamps. All experiments simulated with the model generate different end-systolic pressure-volume relationships, showing that this relationship is actually load-dependent. Furthermore, we show that the results of our simulations are in good agreement with experiments. CONCLUSIONS: We implemented a multi-scale model of the cardiovascular system, in which ventricular contraction is described by a detailed sarcomere model. Using this model, we successfully reproduced a number of experiments that have shown the failing points of the time-varying elastance theory. In particular, the developed multi-scale model of the cardiovascular system can capture the load-dependence of the end-systolic pressure-volume relationship.

Physical Artificial Arterial Pulse System for Development and Testing of PPG-Based Sensors.

A physical system to generate a PPG-mimicking signal was designed and validated using everyday low-cost components to aid in medical sensor design. The pulse waveform was created by driving a working fluid into a silicone tube and changing the pressure within it. The corresponding waveform mimics a PPG signal through an artery, is adaptable, and repeatable. The working fluid is interchangeable allowing for change of blood analyte concentrations for development and testing of PPG-based sensors. The system was validated by black ink water compared to water and air compared to water testing to confirm optical transparency of the tube. The produced PPG signal, pulse rate and pressure change were compared to that seen in subjects. Optical transparency for 660 nm - 1550 nm wavelengths of light was validated with the signal, pulse rate and total compliance matching subject data. Thus, the system can mimic arterial pulses, creating a valid PPG signal that can be detected by PPG-based sensors.Clinical Relevance- Provides a low-cost, adaptable, physical PPG signal generator for research and development of optical medical sensor technologies.

Electrode-Skin Impedance Model Parameter Estimation in the Frequency-Domain.

This paper presents a method for identifying parameter values for a double parallel resistor/constant-phase-element model of the electrode-skin interface for individual silver and silver/silver chloride electrodes. The impedance of each electrode was measured in five from 1 Hz-10 kHz. Phase features of these data were used to guide initial estimates for parameter values which were refined using a least squares algorithm. Resultant model impedances were compared with experimental data across a typical biosignal bandwidth (1 Hz-500 Hz). The method was effective in estimating component values in most datasets, and resulted in a mean relative RMS error of 7 % (σ = 8.3%) across the biosignal bandwidth.Clinical relevance- This work establishes a feature-based method for finding component parameter estimates for an electrode contact impedance model.

Investigation of Narrow-band NIR LED Spectral Response Towards a Non-invasive Glucose Sensor.

Spectroscopy is utilised extensively in medical sensing technology. Typically, hand-held spectroscopy equipment uses miniature narrow-band light emitting diodes (LEDs) and photodiodes to emit and detect light, respectively. Photodiodes typically absorb light across a wide spectra so measurements can be corrupted by surrounding light. LEDs in the visible spectrum have a narrower spectral response and can be used in place of a traditional photodiode. However, the absorption characteristics of near infrared (NIR) spectrum LEDs is unknown. A discrete, low-cost spectrophotometer was designed to assess spectral response for 8 narrow band NIR LEDs. The normalised and raw spectral response determined the optimum detector for 1050 nm - 1300 nm is the 1450 nm LED, and the optimum detector for 1450 nm - 1650 nm emissions is the 1650 nm LED.Clinical relevance - Understanding the spectral response of narrow-band LEDs in the NIR spectrum will aid development of NIR hand-held spectroscopy medical devices.

Second pilot trials of the STAR-Liege protocol for tight glycemic control in critically ill patients.

BACKGROUND: Critically ill patients often present increased insulin resistance and stress-induced hyperglycemia. Tight glycemic control aims to reduce blood glucose (BG) levels and variability while ensuring safety from hypoglycemia. This paper presents the results of the second Belgian clinical trial using the customizable STAR framework in a target-to-range control approach. The main objective is reducing measurement frequency while maintaining performance and safety of the glycemic control. METHODS: The STAR-Liege 2 (SL2) protocol targeted the 100-140 mg/dL glycemic band and offered 2-hourly and 3-hourly interventions. Only insulin rates were adjusted, and nutrition inputs were left to the attending clinicians. This protocol restricted the forecasted risk of BG < 90 mg/dL to a 5% level using a stochastic model of insulin sensitivity to assess patient-specific responses to insulin and its future likely variability to optimize insulin interventions. The clinical trial was performed at the Centre Hospitalier Universitaire de Liege and included 9 patients. Results are compared to 24-hour pre-trial and 24-hour post-trial, but also to the results of the first pilot trial performed in Liege, STAR-Liege 1 (SL1). This trial was approved by the Ethics Committee of the Medical Faculty of the University of Liege (Liege, Belgium). RESULTS: During the SL2 trial, 91 measurements were taken over 194 hours. BG levels were tightly distributed: 54.9% of BG within 100-140 mg/dL, 40.7% were ≥ 140 mg/dL and 4.4% were < 100 mg/dL with no BG < 70 mg/dL. Comparing these results with 24-hour pre-trial and post-trial shows that SL2 reduced high and low BG levels and reduced glycemic variability. Nurses selected 3-hourly measurement only 5 of 16 times and overrode 12% of 91 recommended interventions (35% increased insulin rates and 65% decreased insulin rates). SL1 and SL2 present similar BG levels distribution (p > 0.05) with significantly reduced measurement frequency for SL2 (p < 0.05). CONCLUSIONS: The SL2 protocol succeeded in reducing clinical workload while maintaining safety and effectiveness of the glycemic control. SL2 was also shown to be safer and tighter than hospital control. Overall results validate the efficacy of significantly customizing the STAR framework.

Pilot study of a model-based approach to blood glucose control in very-low-birthweight neonates.

BACKGROUND: Hyperglycemia often occurs in premature, very low birthweight infants (VLBW) due to immaturity of endogenous regulatory systems and the stress of their condition. Hyperglycemia in neonates has been linked to increased morbidities and mortality and occurs at increasing rates with decreasing birthweight. In this cohort, the emerging use of insulin to manage hyperglycemia has carried a significant risk of hypoglycemia. The efficacy of blood glucose control using a computer metabolic system model to determine insulin infusion rates was assessed in very-low-birth-weight infants. METHODS: Initial short-term 24-hour trials were performed on 8 VLBW infants with hyperglycemia followed by long-term trials of several days performed on 22 infants. Median birthweight was 745 g and 760 g for short-term and long-term trial infants, and median gestational age at birth was 25.6 and 25.4 weeks respectively. Blood glucose control is compared to 21 retrospective patients from the same unit who received insulin infusions determined by sliding scales and clinician intuition. This study was approved by the Upper South A Regional Ethics Committee, New Zealand (ClinicalTrials.gov registration NCT01419873). RESULTS: Reduction in hyperglycemia towards the target glucose band was achieved safely in all cases during the short-term trials with no hypoglycemic episodes. Lower median blood glucose concentration was achieved during clinical implementation at 6.6 mmol/L (IQR: 5.5 - 8.2 mmol/L, 1,003 measurements), compared to 8.0 mmol/L achieved in similar infants previously (p < 0.01). No significant difference in incidence of hypoglycemia during long-term trials was observed (0.25% vs 0.25%, p = 0.51). Percentage of blood glucose within the 4.0 - 8.0 mmol/L range was increased by 41% compared to the retrospective cohort (68.4% vs 48.4%, p < 0.01). CONCLUSIONS: A computer model that accurately captures the dynamics of neonatal metabolism can provide safe and effective blood glucose control without increasing hypoglycemia. TRIAL REGISTRATION: ClinicalTrials.gov registration NCT01419873.

Low cost circulatory pressure acquisition and fluid infusion rate measurement system for clinical research.

Acquiring patient physiological waveforms is useful for studying hemodynamic management and developing medical monitoring systems. A low cost, Arduino controlled data acquisition system acquires arterial pressure waveforms (Edwards Lifesciences TruWave compatible) and measures fluid infusion rate using hanging scales. This system can be used at the same time as a clinical monitor, enabling recording of patient arterial pressure and fluid delivery for clinical research. The system is powered via a USB connection, which additionally provides serial output, aiding compatibility and customisation. A simple software user interface, developed in Python, shows outputs. Each data acquisition system, including all necessary connection cables costs ~US$90 and is multiple-use.

Low-cost stimulation resistant electromyography.

Surface Electromyography (sEMG) is the non-invasive measurement of skeletal muscle contraction bio-potentials. Measuring sEMG of a stimulated muscle can prove particularly difficult due to large scale and long lasting stimulation-induced artefacts: if an sEMG device does not account for such artefacts, its measurements can be swamped and components damaged. sEMG has been used in a wide range of clinical and biomedical fields, providing measures such as muscular fatigue and subject intent. The recording of sEMG can prove difficult due to signal contamination such as movement artefact and mains interference. There are very few commercial sEMG devices that contain protection against large stimulation voltages or measures to reduce artefact transient times. Furthermore, most commercial or research level designs are not open source; these designs are effectively an inflexible black box to researchers and developers. This research presents the design, test and validation of an open source sEMG design, able to record muscle bio-potentials concurrently to electrical stimulation. The open source, low-cost nature of the design provides accessibility to researchers without the time and cost associated with design development. The design has been tested on the forearms of four able-bodied subjects during 25 Hz constant current stimulation, and has been shown to record subject volitional sEMG and M-wave without saturation.

Preload & Frank-Starling curves, from textbook to bedside: Clinically applicable non-additionally invasive model-based estimation in pigs.

BACKGROUND: Determining physiological mechanisms leading to circulatory failure can be challenging, contributing to the difficulties in delivering effective hemodynamic management in critical care. Continuous, non-additionally invasive monitoring of preload changes, and assessment of contractility from Frank-Starling curves could potentially make it much easier to diagnose and manage circulatory failure. METHOD: This study combines non-additionally invasive model-based methods to estimate left ventricle end-diastolic volume (LEDV) and stroke volume (SV) during hemodynamic interventions in a pig trial (N = 6). Agreement of model-based LEDV and measured admittance catheter LEDV is assessed. Model-based LEDV and SV are used to identify response to hemodynamic interventions and create Frank-Starling curves, from which Frank-Starling contractility (FSC) is identified as the gradient. RESULTS: Model-based LEDV had good agreement with measured admittance catheter LEDV, with Bland-Altman median bias [limits of agreement (2.5th, 97.5th percentile)] of 2.2 ml [-13.8, 22.5]. Model LEDV and SV were used to identify non-responsive interventions with a good area under the receiver-operating characteristic (ROC) curve of 0.83. FSC was identified using model LEDV and SV with Bland-Altman median bias [limits of agreement (2.5th, 97.5th percentile)] of 0.07 [-0.68, 0.56], with FSC from admittance catheter LEDV and aortic flow probe SV used as a reference method. CONCLUSIONS: This study provides proof-of-concept preload changes and Frank-Starling curves could be non-additionally invasively estimated for critically ill patients, which could potentially enable much clearer insight into cardiovascular function than is currently possible at the patient bedside.

Predicting fluid-response, the heart of hemodynamic management: A model-based solution.

BACKGROUND: Intravenous fluid infusions are an important therapy for patients with circulatory shock. However, it is challenging to predict how patients' cardiac stroke volume (SV) will respond, and thus identify how much fluids should be delivered, if any. Model-predicted SV time-profiles of response to fluid infusions could potentially be used to guide fluid therapy. METHOD: A clinically applicable model-based method predicts SV changes in response to fluid-infusions for a pig trial (N = 6). Validation/calibration SV, SVmea, is from an aortic flow probe. Model parameters are identified in 3 ways: fitting to SVmea from the entire infusion, SVflfit, from the first 200 ml, SVfl200, or from the first 100 ml, SVfl100. RMSE compares error of model-based SV time-profiles for each parameter identification method, and polar plot analysis assesses trending ability. Receiver-operating characteristic (ROC) analysis evaluates ability of model-predicted SVs, SVfl200 and SVfl100, to distinguish non-responsive and responsive infusions, using area-under the curve (AUC), and balanced accuracy as a measure of performance. RESULTS: RMSE for SVflFit, SVfl200, and SVfl100 was 1.8, 3.2, and 6.5 ml, respectively, and polar plot angular limit of agreement from was 11.6, 28.0, and 68.8°, respectively. For predicting responsive and non-responsive interventions SVfl200, and SVfl100 had ROC AUC of 0.64 and 0.69, respectively, and balanced accuracy was 0.75 in both cases. CONCLUSIONS: The model-predicted SV time-profiles matched measured SV trends well for SVflFit, SVfl200, but not SVfl100. Thus, the model can fit the observed SV dynamics, and can deliver good SV prediction given a sufficient parameter identification period. This trial is limited by small numbers and provides proof-of-method, with further experimental and clinical investigation needed. Potentially, this method could deliver model-predicted SV time-profiles to guide fluid therapy decisions, or as part of a closed-loop fluid control system.

Tube-load model: A clinically applicable pulse contour analysis method for estimation of cardiac stroke volume.

BACKGROUND AND OBJECTIVES: Accurate, reproducible, and reliable real-time clinical measurement of stroke volume (SV) is challenging. To accurately estimate arterial mechanics and SV by pulse contour analysis, accounting for wave reflection, such as by a tube-load model, is potentially important. This study tests for the first time whether a dynamically identified tube-load model, given a single peripheral arterial input signal and pulse transit time (PTT), provides accurate SV estimates during hemodynamic instability. METHODS: The model is tested for 5 pigs during hemodynamic interventions, using either an aortic flow probe or admittance catheter for a validation SV measure. Performance is assessed using Bland-Altman and polar plot analysis for a series of long-term state-change and short-term dynamic events. RESULTS: The overall median bias and limits of agreement (2.5th, 97.5th percentile) from Bland-Altman analysis were -10% [-49, 36], and -1% [-28,20] for state-change and dynamic events, respectively. The angular limit of agreement (maximum of 2.5th, 97.5th percentile) from polar-plot analysis for state-change and dynamic interventions was 35.6∘, and 35.2∘, respectively. CONCLUSION: SV estimation agreement and trending performance was reasonable given the severity of the interventions. This simple yet robust method has potential to track SV within acceptable limits during hemodynamic instability in critically ill patients, provided a sufficiently accurate PTT measure.

Organ failure and tight glycemic control in the SPRINT study.

INTRODUCTION: Intensive care unit mortality is strongly associated with organ failure rate and severity. The sequential organ failure assessment (SOFA) score is used to evaluate the impact of a successful tight glycemic control (TGC) intervention (SPRINT) on organ failure, morbidity, and thus mortality. METHODS: A retrospective analysis of 371 patients (3,356 days) on SPRINT (August 2005 - April 2007) and 413 retrospective patients (3,211 days) from two years prior, matched by Acute Physiology and Chronic Health Evaluation (APACHE) III. SOFA is calculated daily for each patient. The effect of the SPRINT TGC intervention is assessed by comparing the percentage of patients with SOFA ≤5 each day and its trends over time and cohort/group. Organ-failure free days (all SOFA components ≤2) and number of organ failures (SOFA components >2) are also compared. Cumulative time in 4.0 to 7.0 mmol/L band (cTIB) was evaluated daily to link tightness and consistency of TGC (cTIB ≥0.5) to SOFA ≤5 using conditional and joint probabilities. RESULTS: Admission and maximum SOFA scores were similar (P = 0.20; P = 0.76), with similar time to maximum (median: one day; IQR: 13 days; P = 0.99). Median length of stay was similar (4.1 days SPRINT and 3.8 days Pre-SPRINT; P = 0.94). The percentage of patients with SOFA ≤5 is different over the first 14 days (P = 0.016), rising to approximately 75% for Pre-SPRINT and approximately 85% for SPRINT, with clear separation after two days. Organ-failure-free days were different (SPRINT = 41.6%; Pre-SPRINT = 36.5%; P < 0.0001) as were the percent of total possible organ failures (SPRINT = 16.0%; Pre-SPRINT = 19.0%; P < 0.0001). By Day 3 over 90% of SPRINT patients had cTIB ≥0.5 (37% Pre-SPRINT) reaching 100% by Day 7 (50% Pre-SPRINT). Conditional and joint probabilities indicate tighter, more consistent TGC under SPRINT (cTIB ≥0.5) increased the likelihood SOFA ≤5. CONCLUSIONS: SPRINT TGC resolved organ failure faster, and for more patients, from similar admission and maximum SOFA scores, than conventional control. These reductions mirror the reduced mortality with SPRINT. The cTIB ≥0.5 metric provides a first benchmark linking TGC quality to organ failure. These results support other physiological and clinical results indicating the role tight, consistent TGC can play in reducing organ failure, morbidity and mortality, and should be validated on data from randomised trials.

Validation of a model-based virtual trials method for tight glycemic control in intensive care.

BACKGROUND: In-silico virtual patients and trials offer significant advantages in cost, time and safety for designing effective tight glycemic control (TGC) protocols. However, no such method has fully validated the independence of virtual patients (or resulting clinical trial predictions) from the data used to create them. This study uses matched cohorts from a TGC clinical trial to validate virtual patients and in-silico virtual trial models and methods. METHODS: Data from a 211 patient subset of the Glucontrol trial in Liege, Belgium. Glucontrol-A (N = 142) targeted 4.4-6.1 mmol/L and Glucontrol-B (N = 69) targeted 7.8-10.0 mmol/L. Cohorts were matched by APACHE II score, initial BG, age, weight, BMI and sex (p > 0.25). Virtual patients are created by fitting a clinically validated model to clinical data, yielding time varying insulin sensitivity profiles (SI(t)) that drives in-silico patients.Model fit and intra-patient (forward) prediction errors are used to validate individual in-silico virtual patients. Self-validation (tests A protocol on Group-A virtual patients; and B protocol on B virtual patients) and cross-validation (tests A protocol on Group-B virtual patients; and B protocol on A virtual patients) are used in comparison to clinical data to assess ability to predict clinical trial results. RESULTS: Model fit errors were small (<0.25%) for all patients, indicating model fitness. Median forward prediction errors were: 4.3, 2.8 and 3.5% for Group-A, Group-B and Overall (A+B), indicating individual virtual patients were accurate representations of real patients. SI and its variability were similar between cohorts indicating they were metabolically similar.Self and cross validation results were within 1-10% of the clinical data for both Group-A and Group-B. Self-validation indicated clinically insignificant errors due to model and/or clinical compliance. Cross-validation clearly showed that virtual patients enabled by identified patient-specific SI(t) profiles can accurately predict the performance of independent and different TGC protocols. CONCLUSIONS: This study fully validates these virtual patients and in silico virtual trial methods, and clearly shows they can accurately simulate, in advance, the clinical results of a TGC protocol, enabling rapid in silico protocol design and optimization. These outcomes provide the first rigorous validation of a virtual in-silico patient and virtual trials methodology.

Data captured using low-cost active electromyography.

Surface electromyography (sEMG) data was captured for three able-body subjects, from their right biceps brachii using the POLE sensor outlined in "Low-cost active electromyography" [1]. Data was captured for 45 seconds per subject, resulting in 12-21 contractions per subject. The raw data files, along with a sinusoidal waveform have been provided. This allows users of the POLE sensor to verify their low-cost sEMG device has been populated and configured correctly. This data also allows researchers/developers to compare their results against this low-cost, low noise sEMG device. The frequency content of the raw sEMG data is also of interest; this is calculated by applying a fast Fourier transform (FFT). The process applied to perform these algorithms is supplied in a MATLAB script.

Clinically applicable model-based method, for physiologically accurate flow waveform and stroke volume estimation.

BACKGROUND AND OBJECTIVES: Cardiovascular dysfunction can be more effectively monitored and treated, with accurate, continuous, stroke volume (SV) and/or cardiac output (CO) measurements. Since direct measurements of SV/CO are highly invasive, clinical measures are often discrete, or if continuous, can require recalibration with a discrete SV measurement after hemodynamic instability. This study presents a clinically applicable, non-additionally invasive, physiological model-based, SV and CO measurement method, which does not require recalibration during or after hemodynamic instability. METHODS AND RESULTS: The model's ability to predict flow profiles and SV is assessed in an animal trial, using endotoxin to induce sepsis in 5 pigs. Mean percentage error between beat-to-beat SV measured from an aortic flow probe and estimated by the model was -2%, while 90% of estimations fell within -24.2% and +27.9% error. Error between estimated and measured changes in mean SV following interventions was less than 30% for 4 out of the 5 pigs. Correlations between model estimated and probe measured flow, for each pig and hemodynamic interventions, was r2 = 0.58 - 0.96, with 21 of the 25 pig intervention stages having r2  >  0.80. CONCLUSION: The results demonstrate the model accurately estimates and tracks changes in flow profiles and resulting SV, without requiring model recalibration.

Incorporating pulse wave velocity into model-based pulse contour analysis method for estimation of cardiac stroke volume.

BACKGROUND AND OBJECTIVES: Stroke volume (SV) and cardiac output (CO) are important metrics for hemodynamic management of critically ill patients. Clinically available devices to continuously monitor these metrics are invasive, and less invasive methods perform poorly during hemodynamic instability. Pulse wave velocity (PWV) could potentially improve estimation of SV and CO by providing information on changing vascular tone. This study investigates whether using PWV for parameter identification of a model-based pulse contour analysis method improves SV estimation accuracy. METHODS: Three implementations of a 3-element windkessel pulse contour analysis model are compared: constant-Z, water hammer, and Bramwell-Hill methods. Each implementation identifies the characteristic impedance parameter (Z) differently. The first method identifies Z statically and does not use PWV, and the latter two methods use PWV to dynamically update Z. Accuracy of SV estimation is tested in an animal trial, where interventions induce severe hemodynamic changes in 5 pigs. Model-predicted SV is compared to SV measured using an aortic flow probe. RESULTS: SV percentage error had median bias and [(IQR); (2.5th, 97.5th percentiles)] of -0.5% [(-6.1%, 4.7%); (-50.3%, +24.1%)] for the constant-Z method, 0.6% [(-4.9%, 6.2%); (-43.4%, +29.3%)] for the water hammer method, and 0.8% [(-6.5, 8.6); (-37.1%, +47.6%)] for the Bramwell-Hill method. CONCLUSION: Incorporating PWV for dynamic Z parameter identification through either the Bramwell-Hill equation or the water hammer equation does not appreciably improve the 3-element windkessel pulse contour analysis model's prediction of SV during hemodynamic changes compared to the constant-Z method.