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

ABSTRACT: 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) /=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

Pilot Proof of Concept Clinical Trials of Stochastic Targeted (STAR) Glycemic Control

(open access)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

Physiological modeling, tight glycemic control, and the ICU clinician: what are models and how can they affect practice?

Critically ill patients are highly variable in their response to care and treatment. This variability and the search for improved outcomes have led to a significant increase in the use of protocolized care to reduce variability in care. However, protocolized care does not address the variability of outcome due to inter- and intra-patient variability, both in physiological state, and the response to disease and treatment. This lack of patient-specificity defines the opportunity for patient-specific approaches to diagnosis, care, and patient management, which are complementary to, and fit within, protocolized approaches

First pilot trial of the STAR-Liege protocol for tight glycemic control in critically ill patients

peer reviewe

Determination of favorable blood glucose target range for stochastic TARgeted (STAR) glycemic control in Malaysia

Stress-induced hyperglycemia is common in critically ill patients, but there is uncertainty about what constitutes an optimal blood glucose target range for glycemic control. Furthermore, to reduce the rate of hyperglycemic and hypoglycemic events, model-based glycemic control protocols have been introduced, such as the stochastic targeted (STAR) glycemic control protocol. This protocol has been used in the intensive care units of Christchurch and Gyulà Hospital since 2010, and in Malaysia since 2017. In this study, we analyzed the adaptability of the protocol and identified the blood glucose target range most favorable for use in the Malaysian population. Virtual simulation results are presented for two clinical cohorts: one receiving treatment by the STAR protocol itself and the other receiving intensive insulin therapy by the sliding scale method. Performance and safety were analyzed using five clinical target ranges, and best control was simulated at a target range of 6.0–10.0 mmol/L. This target range had the best balance of performance, with the lowest risk of hypoglycemia and the lowest requirement for nursing interventions. The result is encouraging as the STAR protocol is suitable to provide better and safer glycemic control while using a target range that is already widely used in Malaysian intensive care units

The Impact of Parameter Identification Methods on Drug Therapy Control in an Intensive Care Unit

This paper investigates the impact of fast parameter identification methods, which do not require any forward simulations, on model-based glucose control, using retrospective data in the Christchurch Hospital Intensive Care Unit. The integral-based identification method has been previously clinically validated and extensively applied in a number of biomedical applications; and is a crucial element in the presented model-based therapeutics approach. Common non-linear regression and gradient descent approaches are too computationally intense and not suitable for the glucose control applications presented. The main focus in this paper is on better characterizing and understanding the importance of the integral in the formulation and the effect it has on model-based drug therapy control. As a comparison, a potentially more natural derivative formulation which has the same computation speed advantages is investigated, and is shown to go unstable with respect to modelling error which is always present clinically. The integral method remains robust

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

peer reviewedBACKGROUND: 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

Efficacy and safety of SPRINT and STAR protocol on Malaysian critically-ill patients

Abstract—Intensive care unit patients may have a better glycaemic management with the right control protocol. Results of virtual trial performance on Malaysian critically-ill patients adopting a model-derived and model-based control protocol known as SPRINT and STAR are presented in this paper. These ICU patients have been treated by intensive sliding-scale insulin infusion. The effectiveness and safety of glycaemic control are then analysed. Results showed that patient safety improved by 83% with SPRINT and STAR protocol as the number of hypoglycaemic patients significantly reduced (BG<2.2 mmol/L). Percentage of time within desired bands and median BG improves in both SPRINT and STAR. However the improvements are associated with higher number of BG measurements (workload)

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. © 2019 Abu-Samah et al