On the Problem of Patient-Specific Endogenous Glucose Production in Neonates on Stochastic Targeted Glycemic Control

Abstract

Background: Both stress and prematurity can induce hyperglycemia in the neonatal intensive care unit, which, in turn, is associated with worsened outcomes. Endogenous glucose production (EGP) is the formation of glucose by the body from substrates and contributes to blood glucose (BG) levels. Due to the inherent fragility of the extremely low birth weight (ELBW) neonates, true fasting EGP cannot be explicitly determined, introducing uncertainty into glycemic models that rely on quantifying glucose sources. Stochastic targeting, or STAR, is one such glycemic control framework. Methods: A literature review was carried out to gather metabolic and EGP values on preterm infants with a gestational age (GA) <32 weeks and a birth weight (BW) <2 kg. The data were analyzed for EGP trends with BW, GA, BG, plasma insulin, and glucose infusion (GI) rates. Trends were modeled and compared with a literature-derived range of population constant EGP models using clinically validated virtual trials on retrospective clinical data. Results: No clear relationship was found for EGP and BW, GA, or plasma insulin. Some evidence of suppression of EGP with increasing GI or BG was seen. Virtual trial results showed that population-constant EGP models fit clinical data best and gave tighter control performance to a target band in virtual trials. Conclusions: Variation in EGP cannot easily be quantified, and EGP is sufficiently modeled as a population constant in the neonatal intensive care insulin-nutrition-glucose model. Analysis of the clinical data and fitting error suggests that ELBW hyperglycemic preterm neonates have unsuppressed EGP in the higher range than that seen in literature.

Insulin kinetics and the Neonatal Intensive Care Insulin–Nutrition–Glucose (NICING) model

“…This variability could also result from accumulated patient-specific deviation from other model parameters, however given kidney clearance ( ) and diffusion between compartments ( ) are an order of magnitude smaller, this effect is not likely to be significant. The high variability in the results is similar to the large variability in endogenous glucose production seen in previous work [39], and likely a reflection of patient condition and metabolic maturity in this very premature cohort. Patient-specific deviations in hepatic insulin clearances may thus result in a bias in the overall SI profile for some patients, but are not likely to affect short-term changes in SI.…”

“…Previous reviews of literature show that endogenous glucose production (EGP) is generally higher in premature infants (median 2.2 mg/kg/min [39] vs. mean ~ 1.4…”

“…The values given, with the exception of those derived in this study, are predominantly derived from literature, and are originally presented and discussed in [37,39].…”

“…As trades off mathematically with SI and cannot be directly measured in this cohort, the adult value of 0.003/min is assumed. Glucose enters the system via exogenous ( ) inputs (parenteral and enteral) and endogenous glucose production (EGP = 0.033 mmol/kg/min) by the liver [39]. , is the volume of distribution of glucose in plasma in litres and is based on gestational age [37].…”

“…While the key glucose dynamics have been previously published [39,40], this study uses a previously published methodology from adults [41] and a novel data set of C-peptide concentrations from a very low birth weight (<1500g) cohort to evaluate diffusion of insulin between plasma and the interstitial fluid, and total liver and kidney clearance of insulin. In addition, the assumptions around insulin distribution volumes in the plasma and interstitial compartments are examined, and kidney glomerular filtration rate (GFR) is used to provide a patient specific value for renal clearance of insulin.…”