Pharmacometabolomics of L-carnitine treatment response phenotypes in patients with septic shock

Annals of the American Thoracic Society

Volumn 12, Issue 1, 2015, Pages 46-56

  Puskarich, Michael A ^a   Finkel, Michael A ^b   Karnovsky, Alla ^c   Jones, Alan E ^a   Trexel, Julie ^b   Harris, Brooke N ^a   Stringer, Kathleen A ^b,c  

^a UNIVERSITY OF MISSISSIPPI SCHOOL OF MEDICINE   (United States)

^b UNIVERSITY OF MICHIGAN   (United States)

^c UNIVERSITY OF MICHIGAN MEDICAL SCHOOL   (United States)

Author keywords

3 hydroxybutyric acid; Individualized medicine; Ketone bodies; Nuclear magnetic resonance; Sepsis

Indexed keywords

3 HYDROXYBUTYRIC ACID; 3 HYDROXYISOVALERATE; ACETOACETIC ACID; CARNITINE; DRUG METABOLITE; KETONE BODY; UNCLASSIFIED DRUG; ACETOACETIC ACID DERIVATIVE; BETA-HYDROXYISOVALERIC ACID; VALERIC ACID DERIVATIVE; VITAMIN B COMPLEX;

ADULT; AGED; ARTICLE; BLOOD SAMPLING; CLINICAL ARTICLE; CONTROLLED STUDY; DISEASE SEVERITY; FEMALE; HUMAN; MALE; METABOLOMICS; MORTALITY; PHARMACOMETABOLOMICS; PHASE 1 CLINICAL TRIAL (TOPIC); PHENOTYPE; PROTON NUCLEAR MAGNETIC RESONANCE; RANDOMIZED CONTROLLED TRIAL; RANDOMIZED CONTROLLED TRIAL (TOPIC); SEPTIC SHOCK; SURVIVOR; TREATMENT RESPONSE; BLOOD; CLINICAL TRIAL; METABOLISM; MIDDLE AGED; NUCLEAR MAGNETIC RESONANCE SPECTROSCOPY; PHASE 1 CLINICAL TRIAL; PROCEDURES; SHOCK, SEPTIC; TREATMENT OUTCOME;

3-HYDROXYBUTYRIC ACID; ACETOACETATES; AGED; CARNITINE; FEMALE; HUMANS; MAGNETIC RESONANCE SPECTROSCOPY; MALE; METABOLOMICS; MIDDLE AGED; PHENOTYPE; SHOCK, SEPTIC; TREATMENT OUTCOME; VALERATES; VITAMIN B COMPLEX;

EID: 84922469698     PISSN: 23256621     EISSN: None     Source Type: Journal    
DOI: 10.1513/AnnalsATS.201409-415OC     Document Type: Article

References (51)

1. Angus DC, Linde-Zwirble WT, Lidicker J, Clermont G, Carcillo J, Pinsky MR. Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Crit Care Med 2001;29:1303-1310.
2. Yealy DM, Kellum JA, Huang DT, Barnato AE, Weissfeld LA, Pike F, Terndrup T, Wang HE, Hou PC, LoVecchio F, et al.; ProCESS Investigators. A randomized trial of protocol-based care for early septic shock. N Engl J Med 2014;370:1683-1693.
3. Wunderink RG, Walley KR. Update in sepsis and pulmonary infections 2013. Am J Respir Crit Care Med 2014;190:25-31.
4. Liu V, Escobar GJ, Greene JD, Soule J, Whippy A, Angus DC, Iwashyna TJ. Hospital deaths in patients with sepsis from 2 independent cohorts. JAMA 2014;312:90-92.
5. Dellinger RP, Vincent JL, Marshall J, Reinhart K. Important issues in the design and reporting of clinical trials in severe sepsis and acute lung injury. J Crit Care 2008;23:493-499.
6. National Research Council (US), Committee on a Framework for Developing a New Taxonomy of Disease. Toward precision medicine: building a knowledge network for biomedical research and a new taxonomy of disease. Washington, DC: National Academies Press; 2011.
7. Katsnelson A. Momentum grows to make 'personalized' medicine more 'precise'. Nat Med 2013;19:249.
8. Christaki E, Giamarellos-Bourboulis EJ. The beginning of personalized medicine in sepsis: small steps to a bright future. Clin Genet 2014;86: 56-61.
9. Man M, Close SL, Shaw AD, Bernard GR, Douglas IS, Kaner RJ, Payen D, Vincent JL, Fossceco S, Janes JM, et al. Beyond single-marker analyses: mining whole genome scans for insights into treatment responses in severe sepsis. Pharmacogenomics J 2013;13:218-226.
10. Clayton TA, Lindon JC, Cloarec O, Antti H, Charuel C, Hanton G, Provost JP, Le Net JL, Baker D, Walley RJ, et al. Pharmacometabonomic phenotyping and personalized drug treatment. Nature 2006;440:1073-1077.
11. Clayton TA, Baker D, Lindon JC, Everett JR, Nicholson JK. Pharmacometabonomic identification of a significant host-microbiome metabolic interaction affecting human drug metabolism. Proc Natl Acad Sci USA 2009;106:14728-14733.
12. Everett JR, Loo RL, Pullen FS. Pharmacometabonomics and personalized medicine. Ann Clin Biochem 2013;50:523-545.
13. Serkova NJ, Standiford TJ, Stringer KA. The emerging field of quantitative blood metabolomics for biomarker discovery in critical illnesses. Am J Respir Crit Care Med 2011;184:647-655.
14. Psychogios N, Hau DD, Peng J, Guo AC, Mandal R, Bouatra S, Sinelnikov I, Krishnamurthy R, Eisner R, Gautam B, et al. The human serum metabolome. PLoS One 2011;6:e16957.
15. Xia J, Broadhurst DI, Wilson M, Wishart DS. Translational biomarker discovery in clinical metabolomics: an introductory tutorial. Metabolomics 2013;9:280-299.
16. Kaddurah-Daouk R, Weinshilboum RM; Pharmacometabolomics Research Network. Pharmacometabolomics: implications for clinical pharmacology and systems pharmacology. Clin Pharmacol Ther 2014;95:154-167.
17. Collino S, Martin FP, Rezzi S. Clinical metabolomics paves the way towards future healthcare strategies. Br J Clin Pharmacol 2013;75: 619-629.
18. Puskarich MA, Kline JA, Krabill V, Claremont H, Jones AE. Preliminary safety and efficacy of L-carnitine infusion for the treatment of vasopressor-dependent septic shock: a randomized control trial. JPEN J Parenter Enteral Nutr 2013;38:736-743.
19. Langley RJ, Tsalik EL, van Velkinburgh JC, Glickman SW, Rice BJ, Wang C, Chen B, Carin L, Suarez A, Mohney RP, et al. An integrated clinico-metabolomic model improves prediction of death in sepsis. Sci Transl Med 2013;5:195ra195.
20. Seymour CW, Yende S, Scott MJ, Pribis J, Mohney RP, Bell LN, Chen YF, Zuckerbraun BS, Bigbee WL, Yealy DM, et al. Metabolomics in pneumonia and sepsis: an analysis of the GenIMS cohort study. Intensive Care Med 2013;39:1423-1434.
21. 1H nuclear magnetic resonance spectroscopy as a potential diagnostic approach for septic shock. Crit Care Med 2014;42:1140-1149.
22. Jones AE, Shapiro NI, Trzeciak S, Arnold RC, Claremont HA, Kline JA; Emergency Medicine Shock Research Network (EMShockNet) Investigators. Lactate clearance vs central venous oxygen saturation as goals of early sepsis therapy: a randomized clinical trial. JAMA 2010;303:739-746.
23. Jones AE. Lactate clearance for assessing response to resuscitation in severe sepsis. Acad Emerg Med 2013;20:844-847.
24. Víctor VM, Espulgues JV, Hernández-Mijares A, Rocha M. Oxidative stress and mitochondrial dysfunction in sepsis: a potential therapy with mitochondria-targeted antioxidants. Infect Disord Drug Targets 2009;9:376-389.
25. Corbucci GG, Gasparetto A, Antonelli M, Bufi M, Crimi G, Conti G, De Blasi RA, Candiani A, Cooper MB, Jones DA, et al. Effects of L-carnitine administration on mitochondrial electron transport activity present in human muscle during circulatory shock. Int J Clin Pharmacol Res 1985;5:237-241.
26. Crouser ED. Mitochondrial dysfunction in septic shock and multiple organ dysfunction syndrome. Mitochondrion 2004;4:729-741.
27. Harrois A, Huet O, Duranteau J. Alterations of mitochondrial function in sepsis and critical illness. Curr Opin Anaesthesiol 2009;22: 143-149.
28. Levy B, Sadoune LO, Gelot AM, Bollaert PE, Nabet P, Larcan A. Evolution of lactate/pyruvate and arterial ketone body ratios in the early course of catecholamine-treated septic shock. Crit Care Med 2000;28:114-119.
29. 1H-nuclear magnetic resonance (NMR) pharmacometabolomics [abstract]. Am J Respir Crit Care Med 2014;189:A3932.
30. Trzeciak S, McCoy JV, Phillip Dellinger R, Arnold RC, Rizzuto M, Abate NL, Shapiro NI, Parrillo JE, Hollenberg SM; Microcirculatory Alterations in Resuscitation and Shock (MARS) Investigators. Early increases in microcirculatory perfusion during protocol-directed resuscitation are associated with reduced multi-organ failure at 24 h in patients with sepsis. Intensive Care Med 2008;34:2210-2217.
31. Vincent JL, Moreno R, Takala J, Willatts S, De Mendonça A, Bruining H, Reinhart CK, Suter PM, Thijs LG; Working Group on Sepsis-Related Problems of the European Society of Intensive Care Medicine. The SOFA (Sepsis-Related Organ Failure Assessment) score to describe organ dysfunction/failure. Intensive Care Med 1996;22: 707-710.
32. 1H-nuclear magnetic resonance quantitative metabolomics and computational analysis. Am J Physiol Lung Cell Mol Physiol 2011;300:L4-L11.
33. Serkova NJ, Brown MS. Quantitative analysis in magnetic resonance spectroscopy: from metabolic profiling to in vivo biomarkers. Bioanalysis 2012;4:321-341.
34. 1H nuclear magnetic resonance spectroscopy. Anal Biochem 2008;377:16-23.
35. Lacy P, McKay RT, Finkel M, Karnovsky A, Woehler S, Lewis MJ, Chang D, Stringer KA. Signal intensities derived from different NMR probes and parameters contribute to variations in quantification of metabolites. PLoS One 2014;9:e85732.
36. Mercier P, Lewis MJ, Chang D, Baker D, Wishart DS. Towards automatic metabolomic profiling of high-resolution one-dimensional proton NMR spectra. J Biomol NMR 2011;49:307-323.
37. Š idák Z. Rectangular confidence regions for the means of multivariate normal distributions. J Am Stat Assoc 1967;62:626-633.
38. Miyata Y, Shimomura I. Metabolic flexibility and carnitine flux: the role of carnitine acyltransferase in glucose homeostasis. J Diabetes Investig 2013;4:247-249.
39. Nakamura K, Inokuchi R, Doi K, Fukuda T, Tokunaga K, Nakajima S, Noiri E, Yahagi N. Septic ketoacidosis. Intern Med 2014;53: 1071-1073.
40. Famularo G, De Simone C, Trinchieri V, Mosca L. Carnitines and its congeners: a metabolic pathway to the regulation of immune response and inflammation. Ann N Y Acad Sci 2004;1033:132-138.
41. Flanagan JL, Simmons PA, Vehige J, Willcox MD, Garrett Q. Role of carnitine in disease. Nutr Metab (Lond) 2010;7:30.
42. Belikova I, Lukaszewicz AC, Faivre V, Damoisel C, Singer M, Payen D. Oxygen consumption of human peripheral blood mononuclear cells in severe human sepsis. Crit Care Med 2007;35:2702-2708.
43. Brealey D, Brand M, Hargreaves I, Heales S, Land J, Smolenski R, Davies NA, Cooper CE, Singer M. Association between mitochondrial dysfunction and severity and outcome of septic shock. Lancet 2002;360:219-223.
44. Szendroedi J, Phielix E, Roden M. The role of mitochondria in insulin resistance and type 2 diabetes mellitus. Nat Rev Endocrinol 2012;8: 92-103.
45. Seiler SE, Martin OJ, Noland RC, Slentz DH, DeBalsi KL, Ilkayeva OR, An J, Newgard CB, Koves TR, Muoio DM. Obesity and lipid stress inhibit carnitine acetyltransferase activity. J Lipid Res 2014;55: 635-644.
46. Noland RC, Koves TR, Seiler SE, Lum H, Lust RM, Ilkayeva O, Stevens RD, Hegardt FG, Muoio DM. Carnitine insufficiency caused by aging and overnutrition compromises mitochondrial performance and metabolic control. J Biol Chem 2009;284: 22840-22852.
47. Stephens FB, Constantin-Teodosiu D, Greenhaff PL. New insights concerning the role of carnitine in the regulation of fuel metabolism in skeletal muscle. J Physiol 2007;581:431-444.
48. Gasparetto A, Corbucci GG, De Blasi RA, Antonelli M, Bagiella E, D'Iddio S, Trevisani C. Influence of acetyl-L-carnitine infusion on haemodynamic parameters and survival of circulatory-shock patients. Int J Clin Pharmacol Res 1991;11:83-92.
49. Patti GJ, Tautenhahn R, Rinehart D, Cho K, Shriver LP, Manchester M, Nikolskiy I, Johnson CH, Mahieu NG, Siuzdak G. A view from above: cloud plots to visualize global metabolomic data. Anal Chem 2013; 85:798-804.
50. Lewis JP, Yerges-Armstrong LM, Ellero-Simatos S, Georgiades A, Kaddurah-Daouk R, Hankemeier T. Integration of pharmacometabolomic and pharmacogenomic approaches reveals novel insights into antiplatelet therapy. Clin Pharmacol Ther 2013;94:570-573.
51. Yerges-Armstrong LM, Ellero-Simatos S, Georgiades A, Zhu H, Lewis JP, Horenstein RB, Beitelshees AL, Dane A, Reijmers T, Hankemeier T, et al. Purine pathway implicated in mechanism of resistance to aspirin therapy: pharmacometabolomics-informed pharmacogenomics. Clin Pharmacol Ther 2013;94:525-532.