(744a) Modeling Stress-Induced Hormone Effects On Glucose-Insulin Dynamics in Critically Ill Patients

In the U.S., 5 million patients are admitted annually to intensive care units (ICUs) [1]. Critical care patients commonly suffer from stress hyperglycemia, resulting from a decrease in insulin dependent glucose uptake or/and relative lack of insulin secretion. Clinical evidence has shown that targeted glucose control could help reduce morbidity and mortality rate in ICUs [2]. However, the complex interaction of factors impacting patient glucose dynamics is challenging, where stress-induced hormone levels, e.g., epinephrine, cortisol, and glucagon, play pivotal roles in maintaining glucose homeostasis in ICU patients. Thus in order to efficiently and successfully control ICU patient’s glucose level, it is necessary to exam the impact of these hormones on glucose-insulin dynamics. The focus of this work is to synthesize a patient-tailorable ICU model of glucose-insulin interactions including stress hormones.  This involves the integration of epinephrine and cortisol models into the extended minimal model [3] to address changes in glucose-insulin dynamics resulting from trauma, stress, and inflammation.  As an inflammation surrogate, we use lipopolysaccharide (LPS) challenge.

We synthesized a composite model starting from the extended minimal model (EMM) of Roy [3], which is more relevant to diabetic patients than ICU patients. The model’s main structure includes the dynamics of free fatty acid and elevated metabolism, in addition to glucose-insulin interactions [3]. To capture the dynamics of pancreatic insulin secretion, a key characteristic of non-diabetic ICU patients, a three-state pancreas model was constructed from the biological mechanism of pancreatic insulin release [4,5]. The non-diabetic EMM successfully captures both glucose and insulin data from intravenous glucose tolerance tests. Two-compartment pharmacokinetic models are incorporated to capture the dynamics of epinephrine and cortisol in the body upon exogenous infusion [6, 7]. The steady state responses from the simulation are in agreement with 9 different epinephrine infusion studies; dynamic fit is also consistent with transient response data. Endogenous epinephrine and cortisol productions are calibrated against LPS challenge.

Elevated plasma epinephrine and cortisol concentrations decrease pancreatic insulin secretion and increase insulin resistance (decrease in insulin dependent glucose uptake). Epinephrine also increases hepatic glucose production. By incorporating these stress-induced hormonal effects, the resulting patient model provides a superior characterization of the glycemic response of trauma in ICU patients.  Furthermore, this composite model can be used within a model-based control system to provide decision support to clinicians working to maintain targeted glucose control without hypoglycemia.

Reference:

1. Angus, D.C., Kelly, M.A., Schmitz, R.J., White, A., Popovich, J. (2000) “Current and Projected Workforce Requirements for Care of the Critically Ill and Patients With Pulmonary Disease: Can We Meet the Requirements of an Aging Population?” Journal of the American Medical Association.  284(21):2762-2770
2. Van den Berghe, G. et al (2001) "Intensive Insulin Therapy in Critically Ill Patients." New England Journal of Medicine.345: 1359-1367
3. Roy, A. (2008). Dynamic Modeling of Free Fatty Acid, Glucose, and Insulin During Rest and Exercise in Insulin Dependent Diabetes Mellitus Patients. Ph.D dissertation, University of Pittsburgh.
4. Bergman, R.N., Phillips, L.S., Cobelli, C. (1981) “Physiological Evaluation of Factors controlling Glucose Tolerance in Man”. J. Clin. Invest. 68:1456-1467
5. Pedersen, M.G., Toffolo, G.M., Cobelli, C. (2010). “Cellular Modeling: Insight into Oral Minimal Models of Insulin Secretion”. Am. J. Phys. Endocrinol Metab. 298: E597-E601
6. Rosen S.G., Linares O.A., Sanfield J.A., Zech L.A., Lizzio V.P., Halter J.B.(1989) “Epinephrinekinetics in humans: Radiotracer methodology”. J Clin Endocrinol Metab. 69(4):753-61
7. Mager, M.E, Jusko, W.J.(2002) “Quantitative Structure-Pharmacokinetic/ Pharmacodynamic Relationships of Corticosteroids in Man”. J. of Pharmaceutical Science. 91(11):2441-2451