Reconstructing asynchrony for mechanical ventilation using a hysteresis loop virtual patient model.

BACKGROUND: Patient-specific lung mechanics during mechanical ventilation (MV) can be identified from measured waveforms of fully ventilated, sedated patients. However, asynchrony due to spontaneous breathing (SB) effort can be common, altering these waveforms and reducing the accuracy of identified, model-based, and patient-specific lung mechanics. METHODS: Changes in patient-specific lung elastance over a pressure-volume (PV) loop, identified using hysteresis loop analysis (HLA), are used to detect the occurrence of asynchrony and identify its type and pattern. The identified HLA parameters are then combined with a nonlinear mechanics hysteresis loop model (HLM) to extract and reconstruct ventilated waveforms unaffected by asynchronous breaths. Asynchrony magnitude can then be quantified using an energy-dissipation metric, Easyn, comparing PV loop area between model-reconstructed and original, altered asynchronous breathing cycles. Performance is evaluated using both test-lung experimental data with a known ground truth and clinical data from four patients with varying levels of asynchrony. RESULTS: Root mean square errors for reconstructed PV loops are within 5% for test-lung experimental data, and 10% for over 90% of clinical data. Easyn clearly matches known asynchrony magnitude for experimental data with RMS errors < 4.1%. Clinical data performance shows 57% breaths having Easyn > 50% for Patient 1 and 13% for Patient 2. Patient 3 only presents 20% breaths with Easyn > 10%. Patient 4 has Easyn = 0 for 96% breaths showing accuracy in a case without asynchrony. CONCLUSIONS: Experimental test-lung validation demonstrates the method's reconstruction accuracy and generality in controlled scenarios. Clinical validation matches direct observations of asynchrony in incidence and quantifies magnitude, including cases without asynchrony, validating its robustness and potential efficacy as a clinical real-time asynchrony monitoring tool.

3D kernel-density stochastic model for more personalized glycaemic control: development and in-silico validation.

BACKGROUND: The challenges of glycaemic control in critically ill patients have been debated for 20 years. While glycaemic control shows benefits inter- and intra-patient metabolic variability results in increased hypoglycaemia and glycaemic variability, both increasing morbidity and mortality. Hence, current recommendations for glycaemic control target higher glycaemic ranges, guided by the fear of harm. Lately, studies have proven the ability to provide safe, effective control for lower, normoglycaemic, ranges, using model-based computerised methods. Such methods usually identify patient-specific physiological parameters to personalize titration of insulin and/or nutrition. The Stochastic-Targeted (STAR) glycaemic control framework uses patient-specific insulin sensitivity and a stochastic model of its future variability to directly account for both inter- and intra-patient variability in a risk-based insulin-dosing approach. RESULTS: In this study, a more personalized and specific 3D version of the stochastic model used in STAR is compared to the current 2D stochastic model, both built using kernel-density estimation methods. Fivefold cross validation on 681 retrospective patient glycaemic control episodes, totalling over 65,000 h of control, is used to determine whether the 3D model better captures metabolic variability, and the potential gain in glycaemic outcome is assessed using validated virtual trials. Results show that the 3D stochastic model has similar forward predictive power, but provides significantly tighter, more patient-specific, prediction ranges, showing the 2D model over-conservative > 70% of the time. Virtual trial results show that overall glycaemic safety and performance are similar, but the 3D stochastic model reduced median blood glucose levels (6.3 [5.7, 7.0] vs. 6.2 [5.6, 6.9]) with a higher 61% vs. 56% of blood glucose within the 4.4-6.5 mmol/L range. CONCLUSIONS: This improved performance is achieved with higher insulin rates and higher carbohydrate intake, but no loss in safety from hypoglycaemia. Thus, the 3D stochastic model developed better characterises patient-specific future insulin sensitivity dynamics, resulting in improved simulated glycaemic outcomes and a greater level of personalization in control. The results justify inclusion into ongoing clinical use of STAR.

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.

The Clinical Utilisation of Respiratory Elastance Software (CURE Soft): a bedside software for real-time respiratory mechanics monitoring and mechanical ventilation management.

BACKGROUND: Real-time patient respiratory mechanics estimation can be used to guide mechanical ventilation settings, particularly, positive end-expiratory pressure (PEEP). This work presents a software, Clinical Utilisation of Respiratory Elastance (CURE Soft), using a time-varying respiratory elastance model to offer this ability to aid in mechanical ventilation treatment. IMPLEMENTATION: CURE Soft is a desktop application developed in JAVA. It has two modes of operation, 1) Online real-time monitoring decision support and, 2) Offline for user education purposes, auditing, or reviewing patient care. The CURE Soft has been tested in mechanically ventilated patients with respiratory failure. The clinical protocol, software testing and use of the data were approved by the New Zealand Southern Regional Ethics Committee. RESULTS AND DISCUSSION: Using CURE Soft, patient's respiratory mechanics response to treatment and clinical protocol were monitored. Results showed that the patient's respiratory elastance (Stiffness) changed with the use of muscle relaxants, and responded differently to ventilator settings. This information can be used to guide mechanical ventilation therapy and titrate optimal ventilator PEEP. CONCLUSION: CURE Soft enables real-time calculation of model-based respiratory mechanics for mechanically ventilated patients. Results showed that the system is able to provide detailed, previously unavailable information on patient-specific respiratory mechanics and response to therapy in real-time. The additional insight available to clinicians provides the potential for improved decision-making, and thus improved patient care and outcomes.

Classification-based deep neural network vs mixture density network models for insulin sensitivity prediction problem.

Model-based glycemic control (GC) protocols are used to treat stress-induced hyperglycaemia in intensive care units (ICUs). The STAR (Stochastic-TARgeted) glycemic control protocol - used in clinical practice in several ICUs in New Zealand, Hungary, Belgium, and Malaysia - is a model-based GC protocol using a patient-specific, model-based insulin sensitivity to describe the patient's actual state. Two neural network based methods are defined in this study to predict the patient's insulin sensitivity parameter: a classification deep neural network and a Mixture Density Network based method. Treatment data from three different patient cohorts are used to train the network models. Accuracy of neural network predictions are compared with the current model- based predictions used to guide care. The prediction accuracy was found to be the same or better than the reference. The authors suggest that these methods may be a promising alternative in model-based clinical treatment for patient state prediction. Still, more research is needed to validate these findings, including in-silico simulations and clinical validation trials.

Structural priors represented by discrete cosine transform improve EIT functional imaging.

Structural prior information can improve electrical impedance tomography (EIT) reconstruction. In this contribution, we introduce a discrete cosine transformation-based (DCT-based) EIT reconstruction algorithm to demonstrate a way to incorporate the structural prior with the EIT reconstruction process. Structural prior information is obtained from other available imaging methods, e.g., thorax-CT. The DCT-based approach creates a functional EIT image of regional lung ventilation while preserving the introduced structural information. This leads to an easier interpretation in clinical settings while maintaining the advantages of EIT in terms of bedside monitoring during mechanical ventilation. Structural priors introduced in the DCT-based approach are of two categories in terms of different levels of information included: a contour prior only differentiates lung and non-lung region, while a detail prior includes information, such as atelectasis, within the lung area. To demonstrate the increased interpretability of the EIT image through structural prior in the DCT-based approach, the DCT-based reconstructions were compared with reconstructions from a widely applied one-step Gauss-Newton solver with background prior and from the advanced GREIT algorithm. The comparisons were conducted both on simulation data and retrospective patient data. In the simulation, we used two sets of forward models to simulate different lung conditions. A contour prior and a detail prior were derived from simulation ground truth. With these two structural priors, the reconstructions from the DCT-based approach were compared with the reconstructions from both the one-step Gauss-Newton solver and the GREIT. The difference between the reconstructions and the simulation ground truth is calculated by the ℓ2-norm image difference. In retrospective patient data analysis, datasets from six lung disease patients were included. For each patient, a detail prior was derived from the patient's CT, respectively. The detail prior was used for the reconstructions using the DCT-based approach, which was compared with the reconstructions from the GREIT. The reconstructions from the DCT-based approach are more comprehensive and interpretable in terms of preserving the structure specified by the priors, both in simulation and retrospective patient data analysis. In simulation analysis, the ℓ2-norm image difference of the DCT-based approach with a contour prior decreased on average by 34% from GREIT and 49% from the Gauss-Newton solver with background prior; for reconstructions of the DCT-based approach with detail prior, on average the ℓ2-norm image difference is 53% less than GREIT and 63% less than the reconstruction with background prior. In retrospective patient data analysis, the reconstructions from both the DCT-based approach and GREIT can indicate the current patient status, but the DCT-based approach yields more interpretable results. However, it is worth noting that the preserved structure in the DCT-based approach is derived from another imaging method, not from the EIT measurement. If the structural prior is outdated or wrong, the result might be misleadingly interpreted, which induces false clinical conclusions. Further research in terms of evaluating the validity of the structural prior and detecting the outdated prior is necessary.

Identification of dental root canals and their medial line from micro-CT and cone-beam CT records.

BACKGROUND: Shape of the dental root canal is highly patient specific. Automated identification methods of the medial line of dental root canals and the reproduction of their 3D shape can be beneficial for planning endodontic interventions as severely curved root canals or multi-rooted teeth may pose treatment challenges. Accurate shape information of the root canals may also be used by manufacturers of endodontic instruments in order to make more efficient clinical tools. METHOD: Novel image processing procedures dedicated to the automated detection of the medial axis of the root canal from dental micro-CT and cone-beam CT records are developed. For micro-CT, the 3D model of the root canal is built up from several hundred parallel cross sections, using image enhancement, histogram based fuzzy c-means clustering, center point detection in the segmented slice, three dimensional inner surface reconstruction, and potential field driven curve skeleton extraction in three dimensions. Cone-beam CT records are processed with image enhancement filters and fuzzy chain based regional segmentation, followed by the reconstruction of the root canal surface and detecting its skeleton via a mesh contraction algorithm. RESULTS: The proposed medial line identification and root canal detection algorithms are validated on clinical data sets. 25 micro-CT and 36 cone-beam-CT records are used in the validation procedure. The overall success rate of the automatic dental root canal identification was about 92% in both procedures. The algorithms proved to be accurate enough for endodontic therapy planning. CONCLUSIONS: Accurate medial line identification and shape detection algorithms of dental root canal have been developed. Different procedures are defined for micro-CT and cone-beam CT records. The automated execution of the subsequent processing steps allows easy application of the algorithms in the dental care. The output data of the image processing procedures is suitable for mathematical modeling of the central line. The proposed methods can help automate the preparation and design of several kinds of endodontic interventions.

Differentiating Phenotypes of Coronavirus Disease-2019 Pneumonia by Electric Impedance Tomography.

Introduction: Coronavirus disease-2019 (COVID-19) pneumonia has different phenotypes. Selecting the patient individualized and optimal respirator settings for the ventilated patient is a challenging process. Electric impedance tomography (EIT) is a real-time, radiation-free functional imaging technique that can aid clinicians in differentiating the "low" (L-) and "high" (H-) phenotypes of COVID-19 pneumonia described previously. Methods: Two patients ("A" and "B") underwent a stepwise positive end-expiratory pressure (PEEP) recruitment by 3 cmH2O of steps from PEEP 10 to 25 and back to 10 cmH2O during a pressure control ventilation of 15 cmH2O. Recruitment maneuvers were performed under continuous EIT recording on a daily basis until patients required controlled ventilation mode. Results: Patients "A" and "B" had a 7- and 12-day long trial, respectively. At the daily baseline, patient "A" had significantly higher compliance: mean ± SD = 53 ± 7 vs. 38 ± 5 ml/cmH2O (p < 0.001) and a significantly higher physiological dead space according to the Bohr-Enghoff equation than patient "B": mean ± SD = 52 ± 4 vs. 45 ± 6% (p = 0.018). Following recruitment maneuvers, patient "A" had a significantly higher cumulative collapse ratio detected by EIT than patient "B": mean ± SD = 0.40 ± 0.08 vs. 0.29 ± 0.08 (p = 0.007). In patient "A," there was a significant linear regression between the cumulative collapse ratios at the end of the recruitment maneuvers (R 2 = 0.824, p = 0.005) by moving forward in days, while not for patient "B" (R 2 = 0.329, p = 0.5). Conclusion: Patient "B" was recognized as H-phenotype with high elastance, low compliance, higher recruitability, and low ventilation-to-perfusion ratio; meanwhile patient "A" was identified as the L-phenotype with low elastance, high compliance, and lower recruitability. Observation by EIT was not just able to differentiate the two phenotypes, but it also could follow the transition from L- to H-type within patient "A." Clinical Trial Registration: www.ClinicalTrials.gov, identifier: NCT04360837.

Estimating Enhanced Endogenous Glucose Production in Intensive Care Unit Patients with Severe Insulin Resistance.

BACKGROUND: Critically ill ICU patients frequently experience acute insulin resistance and increased endogenous glucose production, manifesting as stress-induced hyperglycemia and hyperinsulinemia. STAR (Stochastic TARgeted) is a glycemic control protocol, which directly manages inter- and intra- patient variability using model-based insulin sensitivity (SI). The model behind STAR assumes a population constant for endogenous glucose production (EGP), which is not otherwise identifiable. OBJECTIVE: This study analyses the effect of estimating EGP for ICU patients with very low SI (severe insulin resistance) and its impact on identified, model-based insulin sensitivity identification, modeling accuracy, and model-based glycemic clinical control. METHODS: Using clinical data from 717 STAR patients in 3 independent cohorts (Hungary, New Zealand, and Malaysia), insulin sensitivity, time of insulin resistance, and EGP values are analyzed. A method is presented to estimate EGP in the presence of non-physiologically low SI. Performance is assessed via model accuracy. RESULTS: Results show 22%-62% of patients experience 1+ episodes of severe insulin resistance, representing 0.87%-9.00% of hours. Episodes primarily occur in the first 24 h, matching clinical expectations. The Malaysian cohort is most affected. In this subset of hours, constant model-based EGP values can bias identified SI and increase blood glucose (BG) fitting error. Using the EGP estimation method presented in these constrained hours significantly reduced BG fitting errors. CONCLUSIONS: Patients early in ICU stay may have significantly increased EGP. Increasing modeled EGP in model-based glycemic control can improve control accuracy in these hours. The results provide new insight into the frequency and level of significantly increased EGP in critical illness.

Detection of Different COVID-19 Pneumonia Phenotypes with Estimated Alveolar Collapse and Overdistention by Bedside Electrical Impedance Tomography.

COVID-19 induced acute respiratory distress syndrome (ARDS) could have two different phenotypes, which was reported to have different response and outcome to the typical ARDS positive end-expiration pressure (PEEP) treatment. The identification of the different phenotypes in terms of the recruitability can help improve the patient outcome. In this contribution we conducted alveolar overdistention and collapse analysis with the long term electrical impedance tomography monitoring data on two severe COVID-19 pneumonia patients. The result showed different patient reactions to the PEEP trial, revealed the progressive change in the patient status, and indicted a possible phenotype transition in one patient. It might suggest that EIT can be a practical tool to identify phenotypes and to provide progressive information of COVID-19 pneumonia.

Model-based PEEP titration versus standard practice in mechanical ventilation: a randomised controlled trial.

BACKGROUND: Positive end-expiratory pressure (PEEP) at minimum respiratory elastance during mechanical ventilation (MV) in patients with acute respiratory distress syndrome (ARDS) may improve patient care and outcome. The Clinical utilisation of respiratory elastance (CURE) trial is a two-arm, randomised controlled trial (RCT) investigating the performance of PEEP selected at an objective, model-based minimal respiratory system elastance in patients with ARDS. METHODS AND DESIGN: The CURE RCT compares two groups of patients requiring invasive MV with a partial pressure of arterial oxygen/fraction of inspired oxygen (PaO2/FiO2) ratio ≤ 200; one criterion of the Berlin consensus definition of moderate (≤ 200) or severe (≤ 100) ARDS. All patients are ventilated using pressure controlled (bi-level) ventilation with tidal volume = 6-8 ml/kg. Patients randomised to the control group will have PEEP selected per standard practice (SPV). Patients randomised to the intervention will have PEEP selected based on a minimal elastance using a model-based computerised method. The CURE RCT is a single-centre trial in the intensive care unit (ICU) of Christchurch hospital, New Zealand, with a target sample size of 320 patients over a maximum of 3 years. The primary outcome is the area under the curve (AUC) ratio of arterial blood oxygenation to the fraction of inspired oxygen over time. Secondary outcomes include length of time of MV, ventilator-free days (VFD) up to 28 days, ICU and hospital length of stay, AUC of oxygen saturation (SpO2)/FiO2 during MV, number of desaturation events (SpO2 < 88%), changes in respiratory mechanics and chest x-ray index scores, rescue therapies (prone positioning, nitric oxide use, extracorporeal membrane oxygenation) and hospital and 90-day mortality. DISCUSSION: The CURE RCT is the first trial comparing significant clinical outcomes in patients with ARDS in whom PEEP is selected at minimum elastance using an objective model-based method able to quantify and consider both inter-patient and intra-patient variability. CURE aims to demonstrate the hypothesized benefit of patient-specific PEEP and attest to the significance of real-time monitoring and decision-support for MV in the critical care environment. TRIAL REGISTRATION: Australian New Zealand Clinical Trial Registry, ACTRN12614001069640. Registered on 22 September 2014. (https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=366838&isReview=true) The CURE RCT clinical protocol and data usage has been granted by the New Zealand South Regional Ethics Committee (Reference number: 14/STH/132).

Effectiveness of Parameters in Quantifying Root Canal Morphology Change after Instrumentation with the Aid of a Microcomputed Tomography.

The objective of this study was to analyse the effectiveness of some parameters which characterise the change in morphology in human root canals subjected to ProTaper rotary enlargement with the help of an X-ray microfocus computed tomography (MCT) and to introduce a novel parameter that is effective in quantifying changes in root canal morphology. Ten each straight and curved root canals with mature apices chosen from extracted human upper incisor and canine teeth were scanned with MCT before and after canal shaping using ProTaper rotary instruments in order to facilitate three-dimensional digital reconstruction and quantitative gauging of relevant instrumental parameters and changes therein (surface area and volume). Root canal geometry change and the effectiveness of shaping were quantified with Structure Model Index change (ΔSMI) and surface area change to volume change ratio (ΔSA/ΔV). These two parameters were also tested on simulated canals. Postinstrumentation cross-sectional changes were also analysed, but only on the plastic blocks. Statistical analysis of parameters was carried out to verify the significance of results. Analysis of cross-sectional shape of postinstrumented resin simulated canals showed statistically significant decrease in Form Factor (p<0.05) and statistically significant increase in Eccentricity (p<0.005). ΔSMI did not show significant difference between straight and curved canals. SMI values showed bidirectional change during root enlargement which questions the reliability of this metric in analysing instrumentation. Statistically significant (p<0.005) deviations in ΔSA/ΔV were quantified as 1.92 and 3.22 for straight and curved human canals, respectively. Instrumentation-induced canal geometry change was determined to be more pronounced in curved canals using the novel parameter ΔSA/ΔV. This has been proven as being a statistically accurate and reproducible parameter for quantitative characterisation of root canal geometry change and differentiation of preparational efficacy for both straight and curved root canals.

Generalisability of a Virtual Trials Method for Glycaemic Control in Intensive Care.

BACKGROUND: Elevated blood glucose (BG) concentrations (Hyperglycaemia) are a common complication in critically ill patients. Insulin therapy is commonly used to treat hyperglycaemia, but metabolic variability often results in poor BG control and low BG (hypoglycaemia). OBJECTIVE: This paper presents a model-based virtual trial method for glycaemic control protocol design, and evaluates its generalisability across different populations. METHODS: Model-based insulin sensitivity (SI) was used to create virtual patients from clinical data from three different ICUs in New Zealand, Hungary, and Belgium. Glycaemic results from simulation of virtual patients under their original protocol (self-simulation) and protocols from other units (cross simulation) were compared. RESULTS: Differences were found between the three cohorts in median SI and inter-patient variability in SI. However, hour-to-hour intra-patient variability in SI was found to be consistent between cohorts. Self and cross-simulation results were found to have overall similarity and consistency, though results may differ in the first 24-48 h due to different cohort starting BG and underlying SI. CONCLUSIONS AND SIGNIFICANCE: Virtual patients and the virtual trial method were found to be generalisable across different ICUs. This virtual trial method is useful for in silico protocol design and testing, given an understanding of the underlying assumptions and limitations of this method.

Adaptation of the hypothalamic blood flow to chronic nitric oxide deficiency is independent of vasodilator prostanoids.

The aim of our study was to investigate the adaptation of the hypothalamic circulation to chronic nitric oxide (NO) deficiency in rats. Hypothalamic blood flow (HBF) remained unaltered during chronic oral administration of the NO synthase (NOS) inhibitor N(G)-nitro-l-arginine methyl ester (l-NAME, 1 mg/ml drinking water) although acute NOS blockade by intravenous l-NAME injection (50 mg/kg) induced a dramatic HBF decrease. In chronically NOS blocked animals, however, acute l-NAME administration failed to influence the HBF. Reversal of chronic NOS blockade by intravenous l-arginine infusion evoked significant hypothalamic hyperemia suggesting the appearance of a compensatory vasodilator mechanism in the absence of NO. In order to clarify the potential involvement of vasodilator prostanoids in this adaptation, cyclooxygenase (COX) mRNA and protein levels were determined in the hypothalamus, but none of the known isoenzymes (COX-1, COX-2, COX-3) showed upregulation after chronic NOS blockade. Furthermore, levels of vasodilator prostanoid (PGI(2), PGE(2) and PGD(2)) metabolites were also not elevated. Interestingly, however, hypothalamic levels of vasoconstrictor prostanoids (TXA(2) and PGF(2alpha)) decreased after chronic NOS blockade. COX inhibition by indomethacin but not by diclofenac decreased the HBF in control animals. However, neither indomethacin nor diclofenac induced an altered HBF-response after chronic l-NAME treatment. Although urinary excretion of PGI(2) and PGE(2) metabolites markedly increased during chronic NOS blockade, indicating COX activation in the systemic circulation, we conclude that the adaptation of the hypothalamic circulation to the reduction of NO synthesis is independent of vasodilator prostanoids. Reduced release of vasoconstrictor prostanoids, however, may contribute to the normalization of HBF after chronic loss of NO.

Safety, efficacy and clinical generalization of the STAR protocol: a retrospective analysis.

BACKGROUND: The changes in metabolic pathways and metabolites due to critical illness result in a highly complex and dynamic metabolic state, making safe, effective management of hyperglycemia and hypoglycemia difficult. In addition, clinical practices can vary significantly, thus making GC protocols difficult to generalize across units.The aim of this study was to provide a retrospective analysis of the safety, performance and workload of the stochastic targeted (STAR) glycemic control (GC) protocol to demonstrate that patient-specific, safe, effective GC is possible with the STAR protocol and that it is also generalizable across/over different units and clinical practices. METHODS: Retrospective analysis of STAR GC in the Christchurch Hospital Intensive Care Unit (ICU), New Zealand (267 patients), and the Gyula Hospital, Hungary (47 patients), is analyzed (2011-2015). STAR Christchurch (BG target 4.4-8.0 mmol/L) is also compared to the Specialized Relative Insulin and Nutrition Tables (SPRINT) protocol (BG target 4.4-6.1 mmol/L) implemented in the Christchurch Hospital ICU, New Zealand (292 patients, 2005-2007). Cohort mortality, effectiveness and safety of glycemic control and nutrition delivered are compared using nonparametric statistics. RESULTS: Both STAR implementations and SPRINT resulted in over 86 % of time per episode in the blood glucose (BG) band of 4.4-8.0 mmol/L. Patients treated using STAR in Christchurch ICU spent 36.7 % less time on protocol and were fed significantly more than those treated with SPRINT (73 vs. 86 % of caloric target). The results from STAR in both Christchurch and Gyula were very similar, with the BG distributions being almost identical. STAR provided safe GC with very few patients experiencing severe hypoglycemia (BG < 2.2 mmol/L, <5 patients, 1.5 %). CONCLUSIONS: STAR outperformed its predecessor, SPRINT, by providing higher nutrition and equally safe, effective control for all the days of patient stay, while lowering the number of measurements and interventions required. The STAR protocol has the ability to deliver high performance and high safety across patient types, time, clinical practice culture (Christchurch and Gyula) and clinical resources.

An open architecture patient monitoring system using standard technologies.

Computer-aided bedside patient monitoring is applied in areas where real-time vital function analysis takes place. Modern bedside monitoring requires not only the networking of bedside monitors with a central monitor but also other standard communication interfaces. In this paper, a novel approach to patient monitoring is introduced. A patient monitoring system was developed and implemented based on an existing industry standard communication network, using standard hardware components and software technologies. The open architecture system design offers scalability, standard interfaces, and flexible signal interpretation possibilities.

Daily evolution of insulin sensitivity variability with respect to diagnosis in the critically ill.

INTRODUCTION: This study examines the likelihood and evolution of overall and hypoglycemia-inducing variability of insulin sensitivity in ICU patients based on diagnosis and day of stay. MATERIALS AND METHODS: An analysis of model-based insulin sensitivity for n=390 patients in a medical ICU (Christchurch, New Zealand). Two metrics are defined to measure the variability of a patient's insulin sensitivity relative to predictions of a stochastic model created from the same data for all patients over all days of stay. The first selectively captures large increases related to the risk of hypoglycemia. The second captures overall variability. Distributions of per-patient variability scores were evaluated over different ICU days of stay and for different diagnosis groups based on APACHE III: operative and non-operative cardiac, gastric, all other. Linear and generalized linear mixed effects models assess the statistical significance of differences between groups and over days. RESULTS: Variability defined by the two metrics was not substantially different. Variability was highest on day 1, and decreased over time (p<0.0001) in every diagnosis group. There were significant differences between some diagnosis groups: non-operative gastric patients were the least variable, while cardiac (operative and non-operative) patients exhibited the highest variability. CONCLUSIONS: This study characterizes the variability and evolution of insulin sensitivity in critically ill patients, and may help inform the clinical management of metabolic dysfunction in critical care.

Efficient inhomogeneity compensation using fuzzy c-means clustering models.

Intensity inhomogeneity or intensity non-uniformity (INU) is an undesired phenomenon that represents the main obstacle for magnetic resonance (MR) image segmentation and registration methods. Various techniques have been proposed to eliminate or compensate the INU, most of which are embedded into classification or clustering algorithms, they generally have difficulties when INU reaches high amplitudes and usually suffer from high computational load. This study reformulates the design of c-means clustering based INU compensation techniques by identifying and separating those globally working computationally costly operations that can be applied to gray intensity levels instead of individual pixels. The theoretical assumptions are demonstrated using the fuzzy c-means algorithm, but the proposed modification is compatible with a various range of c-means clustering based INU compensation and MR image segmentation algorithms. Experiments carried out using synthetic phantoms and real MR images indicate that the proposed approach produces practically the same segmentation accuracy as the conventional formulation, but 20-30 times faster.

Pilot study of the SPRINT glycemic control protocol in a Hungarian medical intensive care unit.

INTRODUCTION: Stress-induced hyperglycemia increases morbidity and mortality. Tight control can reduce mortality but has proven difficult to achieve. The SPRINT (Specialized Relative Insulin and Nutrition Tables) protocol is the only protocol that reduced both mortality and hypoglycemia by modulating both insulin and nutrition, but it has not been tested in independent hospitals. METHODS: SPRINT was used for 12 adult intensive care unit patients (949 h) at Kálmán Pándy Hospital (Gyula, Hungary) as a clinical practice assessment. Insulin recommendations (0-6 U/h) were administered via constant infusion rather than bolus delivery. Nutrition was administered per local standard protocol, weaning parenteral to enteral nutrition, but was modulated per SPRINT recommendations. Measurement was every 1 to 2 h, per protocol. Glycemic performance is assessed by percentage of blood glucose (BG) measurements in glycemic bands for the cohort and per patient. Safety from hypoglycemia is assessed by numbers of patients with BG < 2.2 (severe) and %BG < 3.0 and < 4.0 mmol/liter (moderate and light). Clinical effort is assessed by measurements per day. Results are median (interquartile range). RESULTS: There were 742 measurements over 1088 h of control (16.4 measurements/day), which is similar to clinical SPRINT results (16.2/day). Per-patient hours of control were 65 (50-95) h. Initial per-patient BG was 10.5 (7.9-11.2) mmol/liter. All patients (100%) reached 6.1 mmol/liter. Cohort BG was 6.3 (5.5-7.5) mmol/liter, with 42.2%, 65.1% and 77.6% of BG in the 4.0-6.1, 4.0-7.0, and 4.0-8.0 mmol/liter bands. Per-patient, median percentage time in these bands was 40.2 (26.7-51.5)%, 62.5 (46.0-75.7)%, and 74.7 (61.6.8-87.8)%, respectively. No patients had BG < 2.2 mmol/liter, and the %BG < 4.0 mmol/liter was 1.9%. These results were achieved using 3.0 (3.0-5.0) U/h of insulin with 7.4 (4.4-10.2) g/h of dextrose administration (all sources) for the cohort. Per-patient median insulin administration was 3.0 (3.0-3.0) U/h and 7.1 (3.4-9.6) g/h dextrose. Higher carbohydrate nutrition formulas than were used in SPRINT are offset by slightly higher insulin administration in this study. CONCLUSIONS: The glycemic performance shows that using the SPRINT protocol to guide insulin infusions and nutrition administration provided very good glycemic control in initial pilot testing, with no severe hypoglycemia. The overall design of the protocol was able to be generalized with good compliance and outcomes across geographically distinct clinical units, patients, and clinical practice.

Induced L2-norm minimization of glucose-insulin system for Type I diabetic patients.

Using induced L2-norm minimization, a robust controller was developed for insulin delivery in Type I diabetic patients. The high-complexity nonlinear diabetic patient Sorensen-model was considered and Linear Parameter Varying methodology was used to develop open-loop model and robust H(∞) controller. Considering the normoglycaemic set point (81.1 mg/dL), a polytopic set was created over the physiologic boundaries of the glucose-insulin interaction of the Sorensen-model. In this way, Linear Parameter Varying model formalism was defined. The robust control was developed considering input and output multiplicative uncertainties with two additional uncertainties from those used in the literature: sensor noise and worst-case design for meal disturbance (60 g carbohydrate). Simulation scenario on large meal absorption illustrates the applicability of the robust LPV control technique, while patient variability is tested with real data taken from the SPRINT clinical protocol on ICU patients.