Pharmacometabolomics identifies candidate predictor metabolites of an L-carnitine treatment mortality benefit in septic shock

for the RACE Investigators

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

Abstract

Sepsis-induced metabolic dysfunction contributes to organ failure and death. L-carnitine has shown promise for septic shock, but a recent phase II study of patients with vasopressor-dependent septic shock demonstrated a non-significant reduction in mortality. We undertook a pharmacometabolomics study of these patients (n = 250) to identify metabolic profiles predictive of a 90-day mortality benefit from L-carnitine. The independent predictive value of each pretreatment metabolite concentration, adjusted for L-carnitine dose, on 90-day mortality was determined by logistic regression. A grid-search analysis maximizing the Z-statistic from a binomial proportion test identified specific metabolite threshold levels that discriminated L-carnitine responsive patients. Threshold concentrations were further assessed by hazard ratio and Kaplan-Meier estimate. Accounting for L-carnitine treatment and dose, 11 1H-NMR metabolites and 12 acylcarnitines were independent predictors of 90-day mortality. Based on the grid-search analysis numerous acylcarnitines and valine were identified as candidate metabolites of drug response. Acetylcarnitine emerged as highly viable for the prediction of an L-carnitine mortality benefit due to its abundance and biological relevance. Using its most statistically significant threshold concentration, patients with pretreatment acetylcarnitine greater than or equal to 35 µM were less likely to die at 90 days if treated with L-carnitine (18 g) versus placebo (p = 0.01 by log rank test). Metabolomics also identified independent predictors of 90-day sepsis mortality. Our proof-of-concept approach shows how pharmacometabolomics could be useful for tackling the heterogeneity of sepsis and informing clinical trial design. In addition, metabolomics can help understand mechanisms of sepsis heterogeneity and variable drug response, because sepsis induces alterations in numerous metabolite concentrations.

Original languageEnglish (US)
Pages (from-to)2288-2299
Number of pages12
JournalClinical and translational science
Volume14
Issue number6
Early online dateJul 3 2021
DOIs
StatePublished - Jul 3 2021

Bibliographical note

Funding Information:
This study was supported by the National Institute of General Medical Sciences (NIGMS) via R01GM103799 (A.E.J.), K23GM113041 (M.A.P.) and R01GM111400 (K.A.S.). C.E.G.’s and T.S.J.’s contributions were supported, in part, by the Michigan Institute for Data Science “Propelling Original Data Science” grant from the University of Michigan; T.S.J. also received support from the American Foundation of Pharmaceutical Education. The content is solely the responsibility of the authors and does not necessarily represent the official views of NIGMS or the NIH.

Funding Information:
This study was supported by the National Institute of General Medical Sciences (NIGMS) via R01GM103799 (A.E.J.), K23GM113041 (M.A.P.) and R01GM111400 (K.A.S.). C.E.G.?s and T.S.J.?s contributions were supported, in part, by the Michigan Institute for Data Science ?Propelling Original Data Science? grant from the University of Michigan; T.S.J. also received support from the American Foundation of Pharmaceutical Education. The content is solely the responsibility of the authors and does not necessarily represent the official views of NIGMS or the NIH. The authors acknowledge the contributions of the RACE Trial Investigators group; Nathan I. Shapiro, MD, MPH (Department of Emergency Medicine, Beth Israel Deaconess Medical Center, Boston, MA); Faheem W. Guirgis, MD (Department of Emergency Medicine, University of Florida College of Medicine?Jacksonville, FL); Michael Runyon, MD, MPH (Department of Emergency Medicine, Carolinas Medical Center, Charlotte, NC); Jason Y. Adams, MD (Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Internal Medicine, University of California, Davis, CA); Robert Sherwin, MD (Department of Emergency Medicine, Wayne State University, Detroit, MI); Ryan Arnold, MD (Department of Emergency Medicine, Christiana Care Health System, Wilmington, DE); Brian W. Roberts, MD, MSc (Department of Emergency Medicine, Cooper University Hospital, Cooper Medical School of Rowan University, Camden, NJ); Michael C. Kurz, MD, MS (Department of Emergency Medicine, The University of Alabama School of Medicine at Birmingham, Birmingham, AL); Henry E. Wang, MD, MS (Department of Emergency Medicine, The University of Texas Health Science Center at Houston, Houston, TX); Jeffrey A. Kline, MD (Department of Emergency Medicine, Indiana University School of Medicine, Indianapolis, IN); D. Mark Courtney, MD (Department of Emergency Medicine, Northwestern University, Chicago, IL); Stephen Trzeciak, MD, MPH (Department of Medicine, Cooper University Hospital, Cooper Medical School of Rowan University, Camden, NJ); Sarah A. Sterling, MD (Department of Emergency Medicine, The University of Mississippi Medical Center, Jackson, MS); Utsav Nandi, MD (Department of Emergency Medicine, The University of Mississippi Medical Center, Jackson, MS); Deepti Patki, MS (Department of Emergency Medicine, The University of Mississippi Medical Center, Jackson, MS); and Kert Viele, PhD (Berry Consultants, Austin, TX).

Publisher Copyright:
© 2021 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics

PubMed: MeSH publication types

  • Journal Article
  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

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