Biologic Mechanisms Underlying the Heterogeneous Response to Tight Glycemic Control among Differentially Inflamed Patients in the HALF-PINT Trial.

Abstract

Rationale: Tight glycemic control with insulin (TGC) has not consistently shown benefit in critically ill patients. We previously reported that the subset of children with a hyperinflammatory subphenotype benefitted from TGC in the HALF-PINT study of hyperglycemic children with heart and lung failure and the IIT-SBPP study in severely burned pediatric patients. However, whether this effect was mediated through a reduction in inflammation or some other biological process is not fully understood.

Objectives: To deepen the understanding of inflammatory subphenotypes and explore the biological mechanisms underlying heterogeneous response to TGC.

Methods: Plasma cytokine measurements and whole blood transcriptomics from 740 blood samples collected on pre- and post- treatment study days 0, 2, and 4 from 293 HALF-PINT participants (n=250 hypoinflammatory and n=43 hyperinflammatory) were used to identify cytokine and gene expression signatures of differential responses to TGC.

Measurements and results: Patients with hyperinflammatory subphenotype had greater baseline expression of genes relating to inflammation, cell cycle activity, and immunometabolism. Hyperinflammatory patients treated to a target glucose range of 80-110 mg/dL experienced greater reduction in inflammatory cytokines, innate immune gene expression, and heme metabolism gene expression, as well as an increase in lymphocyte gene expression, compared to those treated to a target range of 150-180 mg/dL. Causal mediation testing indicated that these changes partly explained the observed mortality benefit of TGC in the hyperinflammatory subgroup of patients.

Conclusions: These findings expand our understanding of the biology underlying inflammatory subphenotypes, and provide biological insight into the mortality benefit of TGC in hyperinflammatory children.