The technology of tongue and hard palate contact detection: a review.

The tongue and hard palate play an essential role in the production of sound during continuous speech. Appropriate tongue and hard palate contacts will ensure proper sound production. Electropalatography, also known as EPG, is a device that can be used to identify the location of the tongue and hard palate contact. It can also be used by a speech therapist to help patients who have a speech disorder. Among the group with the disease are cleft palate, Down syndrome, glossectomy, and autism patients. Besides identifying the contact location, EPG is a useful medical device that has been continuously developed based on the patient's needs and treatment advancement. This article reviews the technology of electropalatography since the early introduction of the device. It also discusses the development process and the drawbacks of the previous EPG systems, resulting in the EPG's upgraded system and technology. This review suggests additional features that can be useful for the future development of the EPG. The latest technology can be incorporated into the EPG system to provide a more convenient method. There are some elements to be considered in the development of EPG's new technology that were discussed in this study. The elements are essential to provide more convenience for the patient during speech therapy. New technology can accelerate the growth of medical devices, particularly on the development of speech therapy equipment that should be based on the latest technological advancements available. Thus, the advanced EPG system suggested in this article may expand the usage of the EPG and serve as a tool to provide speech therapy treatment services and not limited to monitoring only.

Levels and Diagnostic Value of Model-based Insulin Sensitivity in Sepsis: A Preliminary Study.

BACKGROUND AND AIMS: Currently, there is a lack of real-time metric with high sensitivity and specificity to diagnose sepsis. Insulin sensitivity (SI) may be determined in real-time using mathematical glucose-insulin models; however, its effectiveness as a diagnostic test of sepsis is unknown. Our aims were to determine the levels and diagnostic value of model-based SI for identification of sepsis in critically ill patients. MATERIALS AND METHODS: In this retrospective, cohort study, we analyzed SI levels in septic (n = 18) and nonseptic (n = 20) patients at 1 (baseline), 4, 8, 12, 16, 20, and 24 h of their Intensive Care Unit admission. Patients with diabetes mellitus Type I or Type II were excluded from the study. The SI levels were derived by fitting the blood glucose levels, insulin infusion and glucose input rates into the Intensive Control of Insulin-Nutrition-Glucose model. RESULTS: The median SI levels were significantly lower in the sepsis than in the nonsepsis at all follow-up time points. The areas under the receiver operating characteristic curve of the model-based SI at baseline for discriminating sepsis from nonsepsis was 0.814 (95% confidence interval, 0.675-0.953). The optimal cutoff point of the SI test was 1.573 × 10-4 L/mu/min. At this cutoff point, the sensitivity was 77.8%, specificity was 75%, positive predictive value was 73.7%, and negative predictive value was 78.9%. CONCLUSIONS: Model-based SI ruled in and ruled out sepsis with fairly high sensitivity and specificity in our critically ill nondiabetic patients. These findings can be used as a foundation for further, prospective investigation in this area.

Laser-induced changes of in vitro erythrocyte sedimentation rate.

The study of the effects of low-level laser (LLL) radiation on blood is important for elucidating the mechanisms behind the interaction of LLL radiation and biologic tissues. Different therapy methods that involve blood irradiation have been developed and used for clinical purposes with beneficial effects. The aim of this study was to compare the effects of different irradiation protocols using a diode-pumped solid-state LLL (λ = 405 nm) on samples of human blood by measuring the erythrocyte sedimentation rate (ESR). Human blood samples were obtained through venipuncture into tubes containing EDTA as an anticoagulant. Every sample was divided into two equal aliquots to be used as an irradiated sample and a non-irradiated control sample. The irradiated aliquot was subjected to a laser beam with a wavelength of 405 nm and an energy density of 72 J/cm2. The radiation source had a fixed irradiance of 30 mW/cm2. The ESR change was observed for three different experimental protocols: irradiated whole blood, irradiated red blood cells (RBCs) samples re-suspended in non-irradiated blood plasma, and non-irradiated RBCs re-suspended in irradiated blood plasma. The ESR values were measured after laser irradiation and compared with the non-irradiated control samples. Irradiated blood plasma in which non-radiated RBCs were re-suspended was found to result in the largest ESR decrease for healthy human RBCs, 51%, when compared with RBCs re-suspended in non-irradiated blood plasma. The decrease in ESR induced by LLL irradiation of the plasma alone was likely related to changes in the plasma composition and an increase in the erythrocyte zeta potential upon re-suspension of the RBCs in the irradiated blood plasma.

Effects of low-level laser irradiation on human blood lymphocytes in vitro.

Low-level laser irradiation (LLLI) has various effects on cultured human lymphocytes in vitro, but little is known about such effects in whole blood. This study investigated whether LLLI affected lymphocyte count in human whole blood in vitro. A total number of 130 blood samples were collected from apparently healthy adult patients through venipuncture into tubes containing EDTA. Each sample was divided into two equal aliquots to be used as a non-irradiated control sample and an irradiated sample. The irradiated aliquot was subjected to laser wavelengths of 405, 589, and 780 nm with different fluences of 36, 54, 72, and 90 J/cm2, at a fixed irradiance of 30 mW/cm2. A paired student t test was used to compare between non-irradiated and irradiated samples. The lymphocyte counts were measured using a computerized hematology analyzer and showed a significant (P < 0.02) maximum increase (1.6%) at a fluence of 72 J/cm2 when compared with non-irradiated samples. This increase in lymphocyte count upon irradiation was confirmed by flow cytometry. At a wavelength of 589 nm and fluence of 72 J/cm2, irradiation of whole blood samples showed a significant increase in CD45 lymphocytes and natural killer (NK) (CD16, CD56) cells, but no significant changes in CD3 T lymphocytes, T-suppressor (CD3, CD8) cells, T-helper (CD3, CD4) cells, and CD19 B lymphocytes when compared with their non-irradiated counterparts. Our results clearly demonstrate that NK cell count is altered by irradiation, which ultimately affects the whole lymphocyte count significantly.

Erythrocyte sedimentation rate of human blood exposed to low-level laser.

This study is designed to investigate in vitro low-level laser (LLL) effects on rheological parameter, erythrocyte sedimentation rate (ESR), of human blood. The interaction mechanism between LLL radiation and blood is unclear. Therefore, research addresses the effects of LLL irradiation on human blood and this is essential to understanding how laser radiation interacts with biological cells and tissues. The blood samples were collected through venipuncture into EDTA-containing tubes as an anticoagulant. Each sample was divided into two equal aliquots to be used as a non-irradiated sample (control) and an irradiated sample. The aliquot was subjected to doses of 36, 54, 72 and 90 J/cm(2) with wavelengths of 405, 589 and 780 nm, with a radiation source at a fixed power density of 30 mW/cm(2). The ESR and red blood cell count and volume are measured after laser irradiation and compared with the non-irradiated samples. The maximum reduction in ESR is observed with radiation dose 72 J/cm(2) delivered with a 405-nm wavelength laser beam. Moreover, no hemolysis is observed under these irradiation conditions. In a separate protocol, ESR of separated RBCs re-suspended in irradiated plasma (7.6 ± 2.3 mm/h) is found to be significantly lower (by 51 %) than their counterpart re-suspended in non-irradiated plasma (15.0 ± 3.7 mm/h). These results indicate that ESR reduction is mainly due to the effects of LLL on the plasma composition that ultimately affect whole blood ESR.

A simplified low-cost phantom for image quality assessment of dental cone beam computed tomography unit.

INTRODUCTION: A standardised testing protocol for evaluation of a wide range of dental cone beam computed tomography (CBCT) performance and image quality (IQ) parameters is still limited and commercially available testing tool is unaffordable by some centres. This study aims to assess the performance of a low-cost fabricated phantom for image quality assessment (IQA) of digital CBCT unit. METHODS: A customised polymethyl methacrylate (PMMA) cylindrical phantom was developed for performance evaluation of Planmeca ProMax 3D Mid digital dental CBCT unit. The fabricated phantom consists of four different layers for testing specific IQ parameters such as CT number accuracy and uniformity, noise and CT number linearity. The phantom was scanned using common scanning protocols in clinical routine (90.0 kV, 8.0 mA and 13.6 s). In region-of-interest (ROI) analysis, the mean CT numbers (in Hounsfield unit, HU) and noise for water and air were determined and compared with the reference values (0 HU for water and -1000 HU for air). For linearity test, the correlation between the measured HU of different inserts with their density was studied. RESULTS: The average CT number were -994.1 HU and -2.4 HU, for air and water, respectively and the differences were within the recommended acceptable limit. The linearity test showed a strong positive correlation (R2 = 0.9693) between the measured HU and their densities. CONCLUSION: The fabricated IQ phantom serves as a simple and affordable testing tool for digital dental CBCT imaging.

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.

Enhancement of Tech-Sil25 Maxillofacial Silicone Mechanical Properties after Artificial Weathering through Addition of Nanoparticles.

Purpose: To evaluate the effect of nanosilica and nanoalumina addition in Tech-sil25 maxillofacial silicone before and after exposure to artificial weathering conditions. Materials and Methods: A total of 144 samples were divided into four groups, a control group (n = 12) and three test groups, nanosilica (NS) (n = 36), nanoalumina (NA) (n = 36), and a hybrid nanoparticle (HySA) (n = 60) at different weight percentages (1, 2, and 3 wt. %) was added to Tech-sil25. Samples were exposed to artificial weathering for 100 hours, and subjected to characterizations involving tear strength, shore A hardness, roughness, and tensile strength tests. The data were analyzed using descriptive and inferential statistics using a one-way ANOVA test to determine the level of significance between the groups. Results: After 100 hours of artificial weathering, the one-way ANOVA result shows a highly significant increase in tensile and tear strengths with a minimal increase in hardness and roughness observed in samples containing 2% nanosilica (NS) followed by hybrid nanoparticle (HySA) of 1% nanoalumina (NA) + 1% nanosilica (NS) compared with a control group and other groups. Conclusions: The addition of nanosilica (NS), nanoalumina (NA), and a hybrid nanoparticle (HySA) to the Tech-sil25 maxillofacial silicone improved its mechanical properties. The combination of several filler reinforcements is essential for enhancing silicone's antiaging properties of silicone and maintaining some of its mechanical properties to prolong the service life.

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.

Assessment of Glycemic Control Protocol (STAR) Through Compliance Analysis Amongst Malaysian ICU Patients.

PURPOSE: This paper presents an assessment of an automated and personalized stochastic targeted (STAR) glycemic control protocol compliance in Malaysian intensive care unit (ICU) patients to ensure an optimized usage. PATIENTS AND METHODS: STAR proposes 1-3 hours treatment based on individual insulin sensitivity variation and history of blood glucose, insulin, and nutrition. A total of 136 patients recorded data from STAR pilot trial in Malaysia (2017-quarter of 2019*) were used in the study to identify the gap between chosen administered insulin and nutrition intervention as recommended by STAR, and the real intervention performed. RESULTS: The results show the percentage of insulin compliance increased from 2017 to first quarter of 2019* and fluctuated in feed administrations. Overall compliance amounted to 98.8% and 97.7% for administered insulin and feed, respectively. There was higher average of 17 blood glucose measurements per day than in other centres that have been using STAR, but longer intervals were selected when recommended. Control safety and performance were similar for all periods showing no obvious correlation to compliance. CONCLUSION: The results indicate that STAR, an automated model-based protocol is positively accepted among the Malaysian ICU clinicians to automate glycemic control and the usage can be extended to other hospitals already. Performance could be improved with several propositions.

Model-based glycemic control in a Malaysian intensive care unit: performance and safety study.

Background: Stress-induced hyperglycemia is common in critically ill patients. A few forms of model-based glycemic control have been introduced to reduce this phenomena and among them is the automated STAR protocol which has been used in the Christchurch and Gyulá hospitals' intensive care units (ICUs) since 2010. Methods: This article presents the pilot trial assessment of STAR protocol which has been implemented in the International Islamic University Malaysia Medical Centre (IIUMMC) Hospital ICU since December 2017. One hundred and forty-two patients who received STAR treatment for more than 20 hours were used in the assessment. The initial results are presented to discuss the ability to adopt and adapt the model-based control framework in a Malaysian environment by analyzing its performance and safety. Results: Overall, 60.7% of blood glucose measurements were in the target band. Only 0.78% and 0.02% of cohort measurements were below 4.0 mmol/L and 2.2 mmol/L (the limitsfor mild and severe hypoglycemia, respectively). Treatment preference-wise, the clinical staff were favorable of longer intervention options when available. However, 1 hourly treatments were still used in 73.7% of cases. Conclusion: The protocol succeeded in achieving patient-specific glycemic control while maintaining safety and was trusted by nurses to reduce workload. Its lower performance results, however, give the indication for modification in some of the control settings to better fit the Malaysian environment.

Performance of Stochastic Targeted Blood Glucose Control Protocol by virtual trials in the Malaysian intensive care unit.

BACKGROUND AND OBJECTIVE: Blood glucose variability is common in healthcare and it is not related or influenced by diabetes mellitus. To minimise the risk of high blood glucose in critically ill patients, Stochastic Targeted Blood Glucose Control Protocol is used in intensive care unit at hospitals worldwide. Thus, this study focuses on the performance of stochastic modelling protocol in comparison to the current blood glucose management protocols in the Malaysian intensive care unit. Also, this study is to assess the effectiveness of Stochastic Targeted Blood Glucose Control Protocol when it is applied to a cohort of diabetic patients. METHODS: Retrospective data from 210 patients were obtained from a general hospital in Malaysia from May 2014 until June 2015, where 123 patients were having comorbid diabetes mellitus. The comparison of blood glucose control protocol performance between both protocol simulations was conducted through blood glucose fitted with physiological modelling on top of virtual trial simulations, mean calculation of simulation error and several graphical comparisons using stochastic modelling. RESULTS: Stochastic Targeted Blood Glucose Control Protocol reduces hyperglycaemia by 16% in diabetic and 9% in nondiabetic cohorts. The protocol helps to control blood glucose level in the targeted range of 4.0-10.0 mmol/L for 71.8% in diabetic and 82.7% in nondiabetic cohorts, besides minimising the treatment hour up to 71 h for 123 diabetic patients and 39 h for 87 nondiabetic patients. CONCLUSION: It is concluded that Stochastic Targeted Blood Glucose Control Protocol is good in reducing hyperglycaemia as compared to the current blood glucose management protocol in the Malaysian intensive care unit. Hence, the current Malaysian intensive care unit protocols need to be modified to enhance their performance, especially in the integration of insulin and nutrition intervention in decreasing the hyperglycaemia incidences. Improvement in Stochastic Targeted Blood Glucose Control Protocol in terms of uen model is also a must to adapt with the diabetic cohort.

Surface modifications of human tooth using Nd:YAG laser for dental applications.

Ablation using Nd:YAG laser has potential in resulting a rough effect on tooth surfaces. The objective of this study is to perform a comparative evaluation of the roughness structure of enamel using the Cynosure Cynergy Nd:YAG laser and 37% phosphoric acid. The results obtained for laser-etched with a pulse width of 300ms show roughed and porous surface with greater depth. Both show remarkable graininess on the surface and fewer indentations. Comparison of the elemental compositions demonstrated that calcium has higher composition when exposed to laser-etch compared to acid-etch. The atomic percentages of calcium in sample A for acid-etched and laser-etched are 5.08 and 9.61, respectively. While acid-etched and laser-etched for sample B are 3.98 and 12.84, respectively. Other elements are not profoundly affected by the technique used in this study. However, carbon and oxygen show inconsistent results for both of the samples. Thus, Nd:YAG laser provides significant effects on the tooth surface but does not primarily modify the element compositions of the tooth. Therefore, Nd:YAG laser can potentially be implemented for etching procedure as a replacement of acid etching technique.

In Vitro Mean Red Blood Cell Volume Change Induced by Diode Pump Solid State Low-Level Laser of 405 nm.

OBJECTIVE: This study was conducted to investigate the effects of low-level laser (LLL) doses on human red blood cell volume. The effects of exposure to a diode pump solid state (DPSS) (λ = 405 nm) laser were observed. BACKGROUND DATA: The response of human blood to LLL irradiation gives important information about the mechanism of interaction of laser light with living organisms. Materials and methods Blood samples were collected into ethylenediaminetetraacetic acid (EDTA)-containing tubes, and each sample was divided into two equal aliquots, one to serve as control and the other for irradiation. The aliquot was subjected to laser irradiation for 20, 30, 40, or 50 min at a fixed power density of 0.03 W/cm(2). Mean cell volume (MCV) and red blood cell (RBC) counts were measured immediately after irradiation using a computerized hemtoanalyzer. RESULTS: Significant decrease in RBC volume (p < 0.05, p < 0.0001, p < 0.0001, and p < 0.05, respectively) was induced with variation in laser doses.The highest response was observed with an exposure time of 40 min. This result was reproduced in RBCs suspended in a buffered NaCl solution. In contrast to this finding, laser-induced RBC volume change was completely abolished by suspending RBCs in a solution containing a higher concentration of EDTA. CONCLUSIONS: It was suggested that LLL can reduce RBC volume possibly because of the increased free intracellular Ca(+2) concentrations, which activate Ca(+2)-dependent K(+) channels with consequent K(+) ion efflux and cell shrinkage.

Peripheral venous blood oxygen saturation can be non-invasively estimated using photoplethysmography.

Measurement of peripheral venous oxygen saturation (SvO2) is currently performed using invasive catheters or direct blood draw. The purpose of this study was to non-invasively determine SvO2 using a variation of pulse oximetry techniques. Artificial respiration-like modulations applied to the peripheral vascular system were used to infer regional SvO2 using photoplethysmography (PPG) sensors. To achieve this modulation, an artificial pulse generating system (APG) was developed to generate controlled, superficial perturbations on the finger using a pneumatic digit cuff. These low pressure and low frequency modulations affect blood volumes in veins to a much greater extent than arteries due to significant arterial-venous compliance differences. Ten healthy human volunteers were recruited for proof-ofconcept testing. The APG was set at a modulation frequency of 0.2 Hz (12 bpm) and 45-50 mmHg compression pressure. Initial analysis showed that induced blood volume changes in the venous compartment could be detected by PPG. Estimated arterial oxygen saturation (97% [IQR=96.1%-97.4%]) matches published values (95%-99%). Estimated venous oxygen saturation (93.2% [IQR=91.-93.9%]) agrees with reported ranges (92%-95%) measured in peripheral regions. The median difference between the two saturations was 3.6%, while the difference between paired measurements in each subject was statistically significant (p=0.002). These results demonstrate the feasibility of this method for real-time, low cost, non-invasive estimation of SvO2. Further validation of this method is warranted.

A model-based control protocol for transition from ICU to HDU: Robustness analysis.

The robustness of a model-based control protocol as a less intensive TGC protocol using insulin Glargine for provision of basal insulin is simulated in this study. To quantify the performance and robustness of the protocol to errors, namely physiological variability and sensor errors, an in-silico Monte Carlo analysis is performed. Actual patient data from Christchurch Hospital, New Zealand were used as virtual trial patients.

Stochastic targeted (STAR) glycemic control: design, safety, and performance.

INTRODUCTION: Tight glycemic control (TGC) has shown benefits but has been difficult to achieve consistently. STAR (Stochastic TARgeted) is a flexible, model-based TGC approach that directly accounts for intra- and interpatient variability with a stochastically derived maximum 5% risk of blood glucose (BG) below 72 mg/dl. This research assesses the safety, efficacy, and clinical burden of a STAR TGC controller modulating both insulin and nutrition inputs in virtual and clinical pilot trials. METHODS: Clinically validated virtual trials using data from 370 patients in the SPRINT (Specialized Relative Insulin and Nutrition Titration) study were used to design the STAR protocol and test its safety, performance, and required clinical effort prior to clinical pilot trials. Insulin and nutrition interventions were given every 1-3 h as chosen by the nurse to allow them to manage workload. Interventions were designed to maximize the overlap of the model-predicted (5-95(th) percentile) range of BG outcomes with the 72-117 mg/dl band and thus provide a maximum 5% risk of BG <72 mg/dl. Interventions were calculated using clinically validated computer models of human metabolism and its variability in critical illness. Carbohydrate intake (all sources) was selected to maximize intake up to 100% of the American College of Chest Physicians/Society of Critical Care Medicine (ACCP/SCCM) goal (25 kg/kcal/h). Insulin doses were limited (8 U/h maximum), with limited increases based on current rate (0.5-2.0 U/h). Initial clinical pilot trials involved 3 patients covering ~450 h. Approval was granted by the Upper South A Regional Ethics Committee. RESULTS: Virtual trials indicate that STAR provides similar glycemic control performance to SPRINT with 2-3 h (maximum) measurement intervals. Time in the 72-126 mg/dl and 72-145 mg/dl bands was equivalent for all controllers, indicating that glycemic outcome differences between protocols were only shifted in this range. Safety from hypoglycemia was improved. Importantly, STAR using 2-3 h (maximum) intervention intervals reduced clinical burden up to 30%, which is clinically very significant. Initial clinical trials showed glycemic performance, safety, and management of inter- and intrapatient variability that matched or exceeded the virtual trial results. CONCLUSIONS: In virtual trials, STAR TGC provided tight control that maximized the likelihood of BG in a clinically specified glycemic band and reduced hypoglycemia with a maximum 5% (or lower) expected risk of light hypoglycemia (BG <72 mg/dl) via model-based management of intra- and interpatient variability. Clinical workload was self-managed and reduced up to 30% compared with SPRINT. Initial pilot clinical trials matched or exceeded these virtual results.

Pilot proof of concept clinical trials of Stochastic Targeted (STAR) glycemic control.

INTRODUCTION: Tight glycemic control (TGC) has shown benefits but has been difficult to achieve consistently. STAR (Stochastic TARgeted) is a flexible, model-based TGC approach directly accounting for intra- and inter- patient variability with a stochastically derived maximum 5% risk of blood glucose (BG) < 4.0 mmol/L. This research assesses the safety, efficacy, and clinical burden of a STAR TGC controller modulating both insulin and nutrition inputs in pilot trials. METHODS: Seven patients covering 660 hours. Insulin and nutrition interventions are given 1-3 hourly as chosen by the nurse to allow them to manage workload. Interventions are calculated by using clinically validated computer models of human metabolism and its variability in critical illness to maximize the overlap of the model-predicted (5-95th percentile) range of BG outcomes with the 4.0-6.5 mmol/L band while ensuring a maximum 5% risk of BG < 4.0 mmol/L. Carbohydrate intake (all sources) was selected to maximize intake up to 100% of SCCM/ACCP goal (25 kg/kcal/h). Maximum insulin doses and dose changes were limited for safety. Measurements were made with glucometers. Results are compared to those for the SPRINT study, which reduced mortality 25-40% for length of stay ≥3 days. Written informed consent was obtained for all patients, and approval was granted by the NZ Upper South A Regional Ethics Committee. RESULTS: A total of 402 measurements were taken over 660 hours (~14/day), because nurses showed a preference for 2-hourly measurements. Median [interquartile range, (IQR)] cohort BG was 5.9 mmol/L [5.2-6.8]. Overall, 63.2%, 75.9%, and 89.8% of measurements were in the 4.0-6.5, 4.0-7.0, and 4.0-8.0 mmol/L bands. There were no hypoglycemic events (BG < 2.2 mmol/L), and the minimum BG was 3.5 mmol/L with 4.5% < 4.4 mmol/L. Per patient, the median [IQR] hours of TGC was 92 h [29-113] using 53 [19-62] measurements (median, ~13/day). Median [IQR] results: BG, 5.9 mmol/L [5.8-6.3]; carbohydrate nutrition, 6.8 g/h [5.5-8.7] (~70% goal feed median); insulin, 2.5 U/h [0.1-5.1]. All patients achieved BG < 6.1 mmol/L. These results match or exceed SPRINT and clinical workload is reduced more than 20%. CONCLUSIONS: STAR TGC modulating insulin and nutrition inputs provided very tight control with minimal variability by managing intra- and inter- patient variability. Performance and safety exceed that of SPRINT, which reduced mortality and cost in the Christchurch ICU. The use of glucometers did not appear to impact the quality of TGC. Finally, clinical workload was self-managed and reduced 20% compared with SPRINT.

Tight glycemic control in critical care--the leading role of insulin sensitivity and patient variability: a review and model-based analysis.

Tight glycemic control (TGC) has emerged as a major research focus in critical care due to its potential to simultaneously reduce both mortality and costs. However, repeating initial successful TGC trials that reduced mortality and other outcomes has proven difficult with more failures than successes. Hence, there has been growing debate over the necessity of TGC, its goals, the risk of severe hypoglycemia, and target cohorts. This paper provides a review of TGC via new analyses of data from several clinical trials, including SPRINT, Glucontrol and a recent NICU study. It thus provides both a review of the problem and major background factors driving it, as well as a novel model-based analysis designed to examine these dynamics from a new perspective. Using these clinical results and analysis, the goal is to develop new insights that shed greater light on the leading factors that make TGC difficult and inconsistent, as well as the requirements they thus impose on the design and implementation of TGC protocols. A model-based analysis of insulin sensitivity using data from three different critical care units, comprising over 75,000h of clinical data, is used to analyse variability in metabolic dynamics using a clinically validated model-based insulin sensitivity metric (S(I)). Variation in S(I) provides a new interpretation and explanation for the variable results seen (across cohorts and studies) in applying TGC. In particular, significant intra- and inter-patient variability in insulin resistance (1/S(I)) is seen be a major confounder that makes TGC difficult over diverse cohorts, yielding variable results over many published studies and protocols. Further factors that exacerbate this variability in glycemic outcome are found to include measurement frequency and whether a protocol is blind to carbohydrate administration.

What makes tight glycemic control tight? The impact of variability and nutrition in two clinical studies.

INTRODUCTION: Tight glycemic control (TGC) remains controversial while successful, consistent, and effective protocols remain elusive. This research analyzes data from two TGC trials for root causes of the differences achieved in control and thus potentially in glycemic and other outcomes. The goal is to uncover aspects of successful TGC and delineate the impact of differences in cohorts. METHODS: A retrospective analysis was conducted using records from a 211-patient subset of the GluControl trial taken in Liege, Belgium, and 393 patients from Specialized Relative Insulin Nutrition Titration (SPRINT) in New Zealand. Specialized Relative Insulin Nutrition Titration targeted 4.0-6.0 mmol/liter, similar to the GluControl A (N = 142) target of 4.4-6.1 mmol/liter. The GluControl B (N = 69) target was 7.8-10.0 mmol/liter. Cohorts were matched by Acute Physiology and Chronic Health Evaluation II score and percentage males (p > .35); however, the GluControl cohort was slightly older (p = .011). Overall cohort and per-patient comparisons (median, interquartile range) are shown for (a) glycemic levels achieved, (b) nutrition from carbohydrate (all sources), and (c) insulin dosing for this analysis. Intra- and interpatient variability were examined using clinically validated model-based insulin sensitivity metric and its hour-to-hour variation. RESULTS: Cohort blood glucose were as follows: SPRINT, 5.7 (5.0-6.6) mmol/liter; GluControl A, 6.3 (5.3-7.6) mmol/liter; and GluControl B, 8.2 (6.9-9.4) mmol/liter. Insulin dosing was 3.0 (1.0-3.0), 1.5 (0.5-3), and 0.7 (0.0-1.7) U/h, respectively. Nutrition from carbohydrate (all sources) was 435.5 (259.2-539.1), 311.0 (0.0-933.1), and 622.1 (103.7-1036.8) kcal/day, respectively. Median per-patient results for blood glucose were 5.8 (5.3-6.4), 6.4 (5.9-6.9), and 8.3 (7.6-8.8) mmol/liter. Insulin doses were 3.0 (2.0-3.0), 1.5 (0.8-2.0), and 0.5 (0.0-1.0) U/h. Carbohydrate administration was 383.6 (207.4-497.7), 103.7 (0.0-829.4), and 207.4 (0.0-725.8) kcal/day. Overall, SPRINT gave approximately 2x more insulin with a 3-4x narrower, but generally non-zero, range of nutritional input to achieve equally TGC with less hypoglycemia. Specialized Relative Insulin Nutrition Titration had much less hypoglycemia (<2.2 mmol/liter), with 2% of patients, compared to GluControl A (7.7%) and GluControl B (2.9%), indicating much lower variability, with similar results for glucose levels <3.0 mmol/liter. Specialized Relative Insulin Nutrition Titration also had less hyperglycemia (>8.0 mmol/liter) than groups A and B. GluControl patients (A+B) had a approximately 2x wider range of insulin sensitivity than SPRINT. Hour-to-hour variation was similar. Hence GluControl had greater interpatient variability but similar intrapatient variability. CONCLUSION: Protocols that dose insulin blind to carbohydrate administration can suffer greater outcome glycemic variability, even if average cohort glycemic targets are met. While the cohorts varied significantly in model-assessed insulin resistance, their variability was similar. Such significant intra- and interpatient variability is a further significant cause and marker of glycemic variability in TGC. The results strongly recommended that TGC protocols be explicitly designed to account for significant intra- and interpatient variability in insulin resistance, as well as specifying or having knowledge of carbohydrate administration to minimize variability in glycemic outcomes across diverse cohorts and/or centers.