Abstract
Sepsis-induced metabolic dysfunction is associated with mortality, but the signatures that differentiate variable clinical outcomes among survivors are unknown. Our aim was to determine the relationship between host metabolism and chronic critical illness (CCI) in patients with septic shock. We analyzed metabolomics data from mechanically ventilated patients with vasopressor-dependent septic shock from the placebo arm of a recently completed clinical trial. Baseline serum metabolites were measured by liquid chromatography-mass spectrometry and 1H-nuclear magnetic resonance. We conducted a time-to-event analysis censored at 28 days. Specifically, we determined the relationship between metabolites and time to extubation and freedom from vasopressors using a competing risk survival model, with death as a competing risk. We also compared metabolite concentrations between CCI patients, defined as intensive care unit level of care ≥ 14 days, and those with rapid recovery. Elevations in two acylcarnitines and four amino acids were related to the freedom from organ support (subdistributional hazard ratio < 1 and false discovery rate < 0.05). Proline, glycine, glutamine, and methionine were also elevated in patients who developed CCI. Our work highlights the need for further testing of metabolomics to identify patients at risk of CCI and to elucidate potential mechanisms that contribute to its etiology.
Highlights
A total of 52 patients from the Rapid Administration of Carnitine in Sepsis (RACE) trial were randomized to the placebo arm and had a baseline blood sample taken within 36 h of the onset of mechanical ventilation
Acylcarnitines data generated by LC-MS/MS were available for 47 patients and corresponding data generated by NMR were available for all but one patient (Figure 1)
Time-to-event analysis we demonstrated that serum concentrations of short chain acylcarnitines (C2 and C5) and four amino acids are related to liberation from mechanical ventilation and vasopressors over 28 days
Summary
Survivors of sepsis experience highly variable clinical trajectories [5], with some patients rapidly recovering (within days) and others developing chronic critical illness (CCI) and suffering profound morbidity, long-term sequela, and an increased risk of late mortality [6,7,8]. The poor outcomes of this latter phenotype are driven in part by the initial sepsis-induced organ injury and dependence on mechanical ventilation or other organ support measures [9]. These patients have prolonged stays in the intensive care unit (ICU), characterized by cascading, late-onset organ failures [10]
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