Journal
ANNALS OF THE AMERICAN THORACIC SOCIETY
Volume 12, Issue 1, Pages 46-56Publisher
AMER THORACIC SOC
DOI: 10.1513/AnnalsATS.201409-415OC
Keywords
sepsis; 3-hydroxybutyric acid; ketone bodies; nuclear magnetic resonance; individualized medicine
Categories
Funding
- University of Michigan's College of Pharmacy
- Biochemical Nuclear Magnetic Resonance Core
- Michigan Regional Comprehensive Metabolomics Research Core (AK and Chenomx software) - National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [DK097153]
- American Heart Association [10POST3560001]
- Cannon Foundation [SRG10-004]
- National Institute of General Medical Sciences (NIGMS) [R01GM103799]
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [U24DK097153] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [K23GM113041, R01GM103799] Funding Source: NIH RePORTER
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Rationale: Sepsis therapeutics have a poor history of success in clinical trials, due in part to the heterogeneity of enrolled patients. Pharmacometabolomics could differentiate drug response phenotypes and permit a precision medicine approach to sepsis. Objectives: To use existing serum samples from the phase 1 clinical trial of L-carnitine treatment for severe sepsis to metabolically phenotype L carnitine responders and nonresponders. Methods: Serum samples collected before (T0) and after completion of the infusion (T24, T48) from patients randomized to either L carnitine (12 g) or placebo for the treatment of vasopressor-dependent septic shock were assayed by untargeted H-1-nuclear magnetic resonance metabolomics. The normalized, quantified metabolite data sets of L-carnitine- and placebo-treated patients at each time point were compared by analysis of variance with post-hoc testing for multiple comparisons. Pathway analysis was performed to statistically rank metabolic networks. Measurements and Main Results: Thirty-eight metabolites were identified in all samples. Concentrations of 3-hydroxybutyrate, acetoacetate, and 3-hydroxyisovalerate were different at T0 and over time in L carnitine-treated survivors versus nonsurvivors. Pathway analysis of pretreatment metabolites revealed that synthesis and degradation of ketone bodies had the greatest impact in differentiating L-carnitine treatment response. Analysis of all patients based on pretreatment 3-hydroxybutyrate concentration yielded distinct phenotypes. Using the T0 median 3-hydroxybutyrate level (153 mu M), patients were categorized as either high or low ketone. L Carnitine-treated low-ketone patients had greater use of carnitine as evidenced by lower post-treatment L carnitine levels. The L-carnitine responders also had faster resolution of vasopressor requirement and a trend toward a greater improvement in mortality at 1 year (P = 0.038) compared with patients with higher 3-hydroxybutyrate. Conclusions: The results of this preliminary study, which were not readily apparent from the parent clinical trial, show a unique metabolite profile of L-carnitine responders and introduce pharmacometabolomics as a viable strategy for informing L-carnitine responsiveness. The approach taken in this study represents a concrete example for the application of precision medicine to sepsis therapeutics that warrants further study.
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