Effect of intensive insulin therapy on the somatotropic axis in critically ill children

Abstract

INTRODUCTION Critical illness evokes a ‘catabolic’ response within the growth hormone (GH)/insulin-like growth factor-I (IGF-I) axis. Despite improving patient outcome, intensive insulin therapy (IIT) in critically ill adults unexpectedly lowered IGF-I and increased GH, possibly explained by concomitant malnutrition. In the pediatric intensive care unit (PICU), targeting blood glucose levels to age-adjusted normal fasting values also reduced morbidity and mortality, despite increased incidence of (brief) hypoglycemia. Hormonal responses in children may differ from adults and higher amounts of feeding are administered in critically ill children. We therefore hypothesized that IIT in PICU patients could reactivate the somatotropic axis. METHODS This was a pre-planned subanalysis of all 700 pediatric critically ill patients included in a prospective, randomized study on IIT. Patients were randomly assigned to target blood glucose levels of 50-80 mg/dL in infants (age <1 year, n=317) and 70-100 mg/dL in children (age ≥1 year, n=383) with insulin infusion throughout ICU stay (IIT), or to insulin infusion only to prevent blood glucose from exceeding 215 mg/dL (conventional insulin therapy, CIT). We analyzed blood samples taken upon PICU admission, day 3 and day 7 from patients who were still in PICU on these days. In addition, using a nested case-control design, samples taken before and after hypoglycemia were analyzed in 63 patients experiencing hypoglycemia and in 63 matched patients without hypoglycemia. Circulating insulin, C-peptide, GH, IGF-I, IGF-binding protein (IGFBP)-1, IGFBP-3 and acid labile subunit (ALS) were determined by radio-immunoassays (RIA). Bio-available IGF-I was quantified using a kinase receptor activation assay. In the nested case-control study, we also quantified circulating cortisol and glucagon. RESULTS On day 3 and day 7, circulating insulin was somewhat higher (p=0.026 and p=0.004) whereas C-peptide was >10-fold lower (all p<0.001) in the IIT group than in the CIT group. On day 3, IIT increased circulating GH (p=0.041), while there was no difference on day 7. Total IGF-I was unaltered. In contrast, bio-available IGF-I was lower on day 3 (p=0.002), but not on day 7, in the IIT group. IIT also decreased IGFBP-3 and ALS levels on day 3 (p=0.001 and p=0.007) and day 7 (p=0.003 and p=0.038) as compared with CIT. In contrast, IGFBP-1 levels were increased by IIT on day 3 only (p=0.044). Multivariate logistic regression analysis suggested that only the lowering of portal insulin, as reflected by C-peptide, may have mediated an important part of the mortality benefit. In the nested case-control study, after “hypoglycemia”, only IGFBP-1 remained high in the cases whereas it decreased in controls (p=0.055). No changes in cortisol or glucagon occurred with hypoglycemia. CONCLUSION While improving outcome of PICU patients, IIT further accentuated the illness-associated ‘catabolic’ response within the somatotropic axis, despite feeding. Too low blood glucose targets may have played a role. However, the elimination of the portal insulin effect by exogenous insulin, as reflected by C-peptide, may also explain the changes within the GH axis. This C-peptide effect appeared to statistically explain at least part of the survival benefit with IIT.status: publishe