Search

OBJECTIVES:. Hyper- and hypoinflammatory subphenotypes discovered in patients with acute respiratory distress syndrome predict clinical outcomes and therapeutic responses. These subphenotypes may be important in broader critically ill patient populations with acute respiratory failure regardless of clinical diagnosis. We investigated subphenotyping with latent class analysis in an inclusive population of acute respiratory failure, derived a parsimonious model for subphenotypic predictions based on a small set of variables, and examined associations with clinical outcomes. DESIGN:. Prospective, observational cohort study. SETTING:. Single-center, academic medical ICU. PATIENTS:. Mechanically ventilated patients with acute respiratory failure. MEASUREMENTS AND MAIN RESULTS:. We included 498 patients with acute respiratory failure (acute respiratory distress syndrome: 143, at-risk for acute respiratory distress syndrome: 198, congestive heart failure: 37, acute on chronic respiratory failure: 23, airway protection: 61, and multifactorial: 35) in our derivation cohort and measured 10 baseline plasma biomarkers. Latent class analysis considering clinical variables and biomarkers determined that a two-class model offered optimal fit (23% hyperinflammatory subphenotype). Distribution of hyperinflammatory subphenotype varied among acute respiratory failure etiologies (acute respiratory distress syndrome: 31%, at-risk for acute respiratory distress syndrome: 27%, congestive heart failure: 22%, acute on chronic respiratory failure 0%, airway protection: 5%, and multifactorial: 14%). Hyperinflammatory patients had higher Sequential Organ Failure Assessment scores, fewer ventilator-free days, and higher 30- and 90-day mortality (all p < 0.001). We derived a parsimonious model consisting of angiopoietin-2, soluble tumor necrosis factor receptor-1, procalcitonin, and bicarbonate and classified subphenotypes in a validation cohort (n = 139). Hyperinflammatory patients (19%) demonstrated higher levels of inflammatory biomarkers not included in the model (p < 0.01) and worse outcomes. CONCLUSIONS:. Host-response subphenotypes are observable in a heterogeneous population with acute respiratory failure and predict clinical outcomes. Simple, biomarker-based models can offer prognostic enrichment in patients with acute respiratory failure. The differential distribution of subphenotypes by specific etiologies of acute respiratory failure indicates that subphenotyping may be more relevant in patients with hypoxemic causes of acute respiratory failure and not in patients intubated for airway protection or acute on chronic decompensation.

OBJECTIVES:. Preclinical studies from our laboratory demonstrated therapeutic effects of enteral dextrose administration in the acute phase of sepsis, mediated by the intestine-derived incretin hormone glucose-dependent insulinotropic peptide. The current study investigated the effects of an early enteral dextrose infusion on systemic inflammation and glucose metabolism in critically ill septic patients. DESIGN:. Single-center, double-blind, placebo-controlled randomized pilot clinical trial (NCT03454087). SETTING:. Tertiary-care medical center in Pittsburgh, PA. PATIENTS:. Critically ill adult patients within 48 hours of sepsis diagnosis and with established enteral access. INTERVENTIONS:. Participants were randomized 1:1 to receive a continuous water (placebo) or enteral dextrose infusion (50% dextrose; 0.5 g/mL) at 10 mL per hour for 24 hours. MEASUREMENTS AND MAIN RESULTS:. We randomized 58 participants between June 2018 and January 2020 (placebo: n = 29, dextrose: n = 29). Protocol adherence was high with similar duration of study infusion in the placebo (median duration, 24 hr [interquartile range, 20.9–24 hr]) and dextrose (23.9 hr [23–24 hr]) groups (p = 0.59). The primary outcome of circulating interleukin-6 at end-infusion did not differ between the dextrose (median, 32 pg/mL [19–79 pg/mL]) and placebo groups (24 pg/mL [9–59 pg/mL]; p = 0.13) with similar results in other measures of the systemic host immune response. Enteral dextrose increased circulating glucose-dependent insulinotropic peptide (76% increase; 95% CI [35–119]; p < 0.01) and insulin (53% [17–88]; p < 0.01) compared with placebo consistent with preclinical studies, but also increased blood glucose during the 24-hour infusion period (153 mg/dL [119–223] vs 116 mg/dL [91–140]; p < 0.01). Occurrence of emesis, ICU and hospital length of stay, and 30-day mortality did not differ between the placebo and enteral dextrose groups. CONCLUSIONS:. Early infusion of low-level enteral dextrose in critically ill septic patients increased circulating levels of insulin and the incretin hormone glucose-dependent insulinotropic peptide without decreasing systemic inflammation.