Identifying Altered Metabolic Signatures in Septic Shock: Steps Toward Precision Pharmacotherapy
Creators: name: Jennaro, Theodore
Publisher: name: My University
Year: 2023
Subjects: subject: sepsis
subject: metabolomics
subject: precision medicine
subject: carnitine
subject: organ failure
subject: Internal Medicine and Specialties
subject: Pharmacy and Pharmacology
subject: Health Sciences
subject: Science

description: Sepsis is a life-threatening clinical syndrome characterized by a dysregulated host-response to infection and organ dysfunction. There are variable clinical course trajectories in patients with sepsis, and the precise reasons why the illness resolves in some individuals, causes long-term sequela in others, and is deadly to many remains poorly understood. This heterogeneity has contributed to the litany of failed clinical trials for novel therapeutics such that sepsis therapy remains largely supportive and non-specific. This dissertation leverages patient data and biospecimen from a recently completed clinical trial to investigate the metabolic pathways that drive sepsis mortality and patient response to a metabolic therapeutic, levocarnitine (L-carnitine). Using data from the placebo arm of the trial, I determined that baseline clusters of metabolomics data can identify patient subgroups characterized by differential organ function and mortality. I also modeled the early trajectory of metabolite changes over the first 48-hours of septic shock and found several acylcarnitines and IL-8 were persistently elevated in patients who died. I then found higher concentrations of acylcarnitines and amino acids in serum were related to non-mortality endpoints, including the continued need for vasopressors and mechanical ventilation. With logistic regression models and a grid search methodology of the entire metabolomics dataset from the trial, I discovered a signal that L-carnitine treatment response varies depending on a patient’s baseline metabolic status. Namely, that those patients with elevated acetylcarnitine and/or valine derived a mortality benefit upon having been randomized to high dose L-carnitine over placebo. I also built a population pharmacokinetic model that describes L-carnitine concentrations over time in patients with sepsis. I then validated that renal function is a key patient covariate on the elimination rate of the drug, particularly when renal function estimates were built from equations using serum cystatin C without a patient’s self-identified race. These results add to growing calls to reconsider renal function estimates based on serum creatinine and/or race. In aggregate, this thesis explores sepsis-induced perturbations in metabolism and how they relate to patient outcomes and the pharmacokinetic and clinical response to L-carnitine. This work implicates energetic and mitochondrial metabolic dysfunction, particularly related to the impairment of fatty acid beta-oxidation, in explaining some of the observed heterogeneity in sepsis outcomes and response to treatment. Future pre-clinical and clinical follow-up studies are necessary to understand: 1) the mechanisms driving perturbed host metabolism and the development of sepsis-induced organ dysfunction and 2) if these metabolic measures hold further promise as prognostic and/or predictive biomarkers in patients with sepsis.