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

<b>Rationale:</b> Tight glycemic control (TGC) with insulin has not consistently shown benefit in critically ill patients. We previously reported that the subset of children with a hyperinflammatory subphenotype benefited from TGC in the HALF-PINT (Heart and Lung Failure - Pediatric Insulin Titration) study of hyperglycemic children with heart and lung failure and the IIT-SBPP (Intensive Insulin Treatment - Severely Burned Pediatric Patients) study in severely burned pediatric patients. However, whether this effect was mediated through a reduction in inflammation or some other biologic process is not fully understood. <b>Objectives:</b> To deepen the understanding of inflammatory subphenotypes and explore the biologic mechanisms underlying heterogeneous response to TGC. <b>Methods:</b> 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 (<i>n</i> = 250 hypoinflammatory and <i>n</i> = 43 hyperinflammatory) were used to identify cytokine and gene expression signatures of differential responses to TGC. <b>Measurements and Results:</b> Patients with the 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 reductions in inflammatory cytokines, innate immune gene expression, and heme metabolism gene expression, as well as an increase in lymphocyte gene expression, compared with 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. <b>Conclusions:</b> These findings expand our understanding of the biology underlying inflammatory subphenotypes and provide biologic insight into the mortality benefit of TGC in hyperinflammatory children.