Virtual patient trials of a multi-input stochastic model for tight glycaemic control using insulin sensitivity and blood glucose data

Abstract Objective Safe, effective glycaemic control (GC) requires accurate prediction of future patient insulin sensitivity (SI), balancing the risk of hyper- and hypo-glycaemia. The stochastic targeted (STAR) protocol combines a clinically validated metabolic model and SI metric with a risk-based stochastic approach to optimise patient specific insulin and feed rates. Validated virtual trials comparing a novel 3D stochastic model for prediction of future patient SI using current patient SI and current blood glucose (BG) to an existing 2D stochastic model for SI prediction were conducted. Methods The virtual trials involved 1477 retrospective patients across two hospitals and two GC protocols. They were conducted using five-fold cross-validation to build each stochastic model, ensuring independent test data. Results The 3D stochastic model shifted BG from the 4.4–8.0 mmol/L target band towards the lower 4.4–6.5 mmol/L band, providing a decrease from 12.31 % to 11.19 % in hyperglycaemic hours (BG > 8.0 mmol/L), but only a 0.24 % increase, from 1.01 % to 1.25 %, in light hypoglycaemic hours (BG Conclusions The 3D stochastic model provided greater personalisation and better realised STAR’s design philosophy of minimising hyperglycaemic events for an acceptable clinical risk of 5.0 % BG

[1]  Yeong Shiong Chiew,et al.  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 , 2018, BioMedical Engineering OnLine.

[2]  Richard L. Jones,et al.  Cost analysis of intensive glycemic control in critically ill adult patients. , 2006, Chest.

[3]  Balázs Benyó,et al.  Safety, efficacy and clinical generalization of the STAR protocol: a retrospective analysis , 2016, Annals of Intensive Care.

[4]  J. Dickson,et al.  Humans are Horribly Variable , 2014 .

[5]  Rinaldo Bellomo,et al.  The impact of early hypoglycemia and blood glucose variability on outcome in critical illness , 2009, Critical care.

[6]  G. Van den Berghe,et al.  Analysis of healthcare resource utilization with intensive insulin therapy in critically ill patients* , 2006, Critical care medicine.

[7]  Thomas Desaive,et al.  Multi-input stochastic prediction of insulin sensitivity for tight glycaemic control using insulin sensitivity and blood glucose data , 2019, Comput. Methods Programs Biomed..

[8]  A J Scheen,et al.  Roles of circadian rhythmicity and sleep in human glucose regulation. , 1997, Endocrine reviews.

[9]  James Stephen Krinsley,et al.  Effect of an intensive glucose management protocol on the mortality of critically ill adult patients. , 2004, Mayo Clinic proceedings.

[10]  M Schetz,et al.  Intensive insulin therapy in critically ill patients. , 2001, The New England journal of medicine.

[11]  G. Van den Berghe,et al.  Effect of intensive insulin therapy on insulin sensitivity in the critically ill. , 2007, The Journal of clinical endocrinology and metabolism.

[12]  J. Geoffrey Chase,et al.  Glycemic control in the intensive care unit: A control systems perspective , 2019, Annu. Rev. Control..

[13]  Michael Bailey,et al.  Hypoglycemia and outcome in critically ill patients. , 2010, Mayo Clinic proceedings.

[14]  J. Krinsley,et al.  Glycemic variability: A strong independent predictor of mortality in critically ill patients* , 2008, Critical care medicine.

[15]  H. Gerstein,et al.  Stress hyperglycaemia and increased risk of death after myocardial infarction in patients with and without diabetes: a systematic overview , 2000, The Lancet.

[16]  Timothy W. Evans,et al.  Glucose Control and Mortality in Critically Ill Patients , 2003 .

[17]  Thomas Desaive,et al.  Organ failure and tight glycemic control in the SPRINT study , 2010, Critical care.

[18]  Christopher E. Hann,et al.  A physiological Intensive Control Insulin-Nutrition-Glucose (ICING) model validated in critically ill patients , 2011, Comput. Methods Programs Biomed..

[19]  James Stephen Krinsley,et al.  Association between hyperglycemia and increased hospital mortality in a heterogeneous population of critically ill patients. , 2003, Mayo Clinic proceedings.

[20]  Thomas Desaive,et al.  Validation of a model-based virtual trials method for tight glycemic control in intensive care , 2010, Biomedical engineering online.

[21]  John A Myburgh,et al.  Hypoglycemia and risk of death in critically ill patients. , 2012, The New England journal of medicine.

[22]  Christopher E. Hann,et al.  Tight glycemic control in critical care - The leading role of insulin sensitivity and patient variability: A review and model-based analysis , 2011, Comput. Methods Programs Biomed..

[23]  J. Preiser,et al.  Time in blood glucose range 70 to 140 mg/dl >80% is strongly associated with increased survival in non-diabetic critically ill adults , 2015, Critical Care.

[24]  Christopher E. Hann,et al.  Stochastic modelling of insulin sensitivity variability in critical care , 2006, Biomed. Signal Process. Control..

[25]  J. Chase,et al.  Glycemic Levels in Critically Ill Patients: Are Normoglycemia and Low Variability Associated with Improved Outcomes? , 2012, Journal of diabetes science and technology.

[26]  Christopher E. Hann,et al.  Stochastic modelling of insulin sensitivity and adaptive glycemic control for critical care , 2008, Comput. Methods Programs Biomed..

[27]  A. Malhotra,et al.  Stress-induced hyperglycemia. , 2001, Critical care clinics.

[28]  J. Geoffrey Chase,et al.  Stochastic Targeted (STAR) Glycemic Control: Design, Safety, and Performance , 2012, Journal of diabetes science and technology.

[29]  J. Chase,et al.  Glucose control positively influences patient outcome: A retrospective study. , 2015, Journal of critical care.

[30]  Patricia A. H. Williams,et al.  Energy‐Dense versus Routine Enteral Nutrition in the Critically Ill , 2018, The New England journal of medicine.

[31]  J. Geoffrey Chase,et al.  Generalisability of a Virtual Trials Method for Glycaemic Control in Intensive Care , 2018, IEEE Transactions on Biomedical Engineering.

[32]  A. Day,et al.  Optimal amount of calories for critically ill patients: Depends on how you slice the cake!* , 2011, Critical care medicine.

[33]  Dominic S. Lee,et al.  Implementation and evaluation of the SPRINT protocol for tight glycaemic control in critically ill patients: a clinical practice change , 2008, Critical care.

[34]  J. Geoffrey Chase,et al.  STAR Development and Protocol Comparison , 2012, IEEE Transactions on Biomedical Engineering.

[35]  J. Geoffrey Chase,et al.  Characterisation of the iterative integral parameter identification method , 2011, Medical & Biological Engineering & Computing.

[36]  J. Geoffrey Chase,et al.  A 3D insulin sensitivity prediction model enables more patient-specific prediction and model-based glycaemic control , 2018, Biomed. Signal Process. Control..

[37]  J. Geoffrey Chase,et al.  Stochastic Model Predictive (STOMP) glycaemic control for the intensive care unit: Development and virtual trial validation , 2015, Biomed. Signal Process. Control..

[38]  Christopher E. Hann,et al.  Integral-based identification of patient specific parameters for a minimal cardiac model , 2006, Comput. Methods Programs Biomed..

[39]  Thomas Desaive,et al.  Pilot proof of concept clinical trials of Stochastic Targeted (STAR) glycemic control , 2011, Annals of intensive care.

[40]  Rinaldo Bellomo,et al.  Variability of Blood Glucose Concentration and Short-term Mortality in Critically Ill Patients , 2006, Anesthesiology.

[41]  R. Hovorka,et al.  Improving glycemic control in critically ill patients: personalized care to mimic the endocrine pancreas , 2018, Critical Care.