Top

Scandinavian Journal of Trauma, Resuscitation and Emergency Medicine

Published in:

Open Access 01-12-2019 | Central Nervous System Trauma | Original research

A prospective pilot study using metabolomics discloses specific fatty acid, catecholamine and tryptophan metabolic pathways as possible predictors for a negative outcome after severe trauma

Authors: Luis Servià, Mariona Jové, Joaquim Sol, Reinald Pamplona, Mariona Badia, Neus Montserrat, Manuel Portero-Otin, Javier Trujillano

Published in: Scandinavian Journal of Trauma, Resuscitation and Emergency Medicine | Issue 1/2019

Abstract

Background

We wanted to define metabolomic patterns in plasma to predict a negative outcome in severe trauma patients.

Methods

A prospective pilot study was designed to evaluate plasma metabolomic patterns, established by liquid chromatography coupled to mass spectrometry, in patients allocated to an intensive care unit (in the University Hospital Arnau de Vilanova, Lleida, Spain) in the first hours after a severe trauma (n = 48). Univariate and multivariate statistics were employed to establish potential predictors of mortality.

Results

Plasma of patients non surviving to trauma (n = 5) exhibited a discriminating metabolomic pattern, involving basically metabolites belonging to fatty acid and catecholamine synthesis as well as tryptophan degradation pathways. Thus, concentration of several metabolites exhibited an area under the receiver operating curve (ROC) higher than 0.84, including 3-indolelactic acid, hydroxyisovaleric acid, phenylethanolamine, cortisol, epinephrine and myristic acid. Multivariate binary regression logistic revealed that patients with higher myristic acid concentrations had a non-survival odds ratio of 2.1 (CI 95% 1.1–3.9).

Conclusions

Specific fatty acids, catecholamine synthesis and tryptophan degradation pathways could be implicated in a negative outcome after trauma. The metabolomic study of severe trauma patients could be helpful for biomarker proposal.

Available only for authorised users

Norton R, Kobusingye O. Injuries. N Engl J Med. 2013;368:1723–30. https://doi.org/10.1056/NEJMra1109343.CrossRefPubMed

Vincent J-L, Moreno R. Clinical °review: scoring systems in the critically ill. Crit Care. 2010;14:207. https://doi.org/10.1186/cc8204.CrossRefPubMedPubMedCentral

Serviá L, Badia M, Montserrat N, Trujillano J. Severity scores in trauma patients admitted to ICU. Physiological and anatomic models. Med Intensiva. 2019;43(1):26–34. https://doi.org/10.1016/j.medin.2017.11.008.CrossRefPubMed

Legrand M, Januzzi JL, Mebazaa A. Critical research on biomarkers: what’s new? Intensive Care Med. 2013;39:1824–8. https://doi.org/10.1007/s00134-013-3008-7.CrossRefPubMed

Garcia-Simon M. Prognosis biomarkers of severe sepsis and septic shock by 1H NMR urine metabolomics in the intensive care unit. PLoS One. 2015;10(11):e0140993. https://doi.org/10.1371/journal.pone.0140993 eCollection 2015.CrossRefPubMedPubMedCentral

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;184:647–55. https://doi.org/10.1164/rccm.201103-0474CI.CrossRefPubMedPubMedCentral

Pierrakos C, Vincent J-L. Sepsis biomarkers: a review. Crit Care. 2010;14:R15. https://doi.org/10.1186/cc8872.CrossRefPubMedPubMedCentral

Gordillo-Escobar E, Egea-Guerrero JJ, Rodríguez-Rodríguez A, Murillo-Cabezas F. Usefulness of biomarkers in the prognosis of severe head injuries. Med Int. 2016;40:105–12. https://doi.org/10.1016/j.medin.2015.11.008. CrossRef

Jové M, Portero-Otín M, Naudí A, Ferrer I, Pamplona R. Metabolomics of human brain aging and age-related neurodegenerative diseases. J Neuropathol Exp Neurol. 2014;73:640–57. https://doi.org/10.1097/NEN.0000000000000091.CrossRefPubMed

10.

Parent BA, Seaton M, Sood RF, Gu H, Djukovic D, Raftery D, et al. Use of metabolomics to trend recovery and therapy after injury in critically ill trauma patients. JAMA Surg. 2016;151:e160853. https://doi.org/10.1001/jamasurg.2016.0853.CrossRefPubMed

11.

Jayaraman SP, Anand RJ, DeAntonio JH, Mangino M, Aboutanos MB, Kasirajan V, et al. Metabolomics and precision medicine in trauma: the state of the field. Shock. 2017. https://doi.org/10.1097/SHK.0000000000001093.CrossRef

12.

Baker SP, O’Neill B, Haddon W, Long WB. The injury severity score: a method for describing patients with multiple injuries and evaluating emergency care. J Trauma. 1974;14:187–96.CrossRef

13.

Knaus WA, Wagner DP, Draper EA, Zimmerman JE, Bergner M, Bastos PG, et al. The APACHE III prognostic system. Risk prediction of hospital mortality for critically ill hospitalized adults. Chest. 1991;100:1619–36.CrossRef

14.

Jové M, Mauri-Capdevila G, Suárez I, Cambray S, Sanahuja J, Quílez A, et al. Metabolomics predicts stroke recurrence after transient ischemic attack. Neurology. 2015;84:36–45. https://doi.org/10.1212/WNL.0000000000001093.CrossRefPubMedPubMedCentral

15.

Sana TR, Roark JC, Li X, Waddell K, Fischer SM. Molecular formula and METLIN personal metabolite database matching applied to the identification of compounds generated by LC/TOF-MS. J Biomol Tech. 2008;19:258–66.PubMedPubMedCentral

16.

Xia J, Sinelnikov IV, Han B, Wishart DS. MetaboAnalyst 3.0--making metabolomics more meaningful. Nucleic Acids Res. 2015;43:W251–7. https://doi.org/10.1093/nar/gkv380.CrossRefPubMedPubMedCentral

17.

Knaus WA, Draper EA, Wagner DP, Zimmerman JE. APACHE II: a severity of disease classification system. Crit Care Med. 1985;13:818–29.CrossRef

18.

Lusczek ER, Myers C, Popovsky K, Mulier K, Beilman G, Sawyer R. Plasma metabolomics pilot study suggests age and sex-based differences in the metabolic response to traumatic injury. Injury. 2018. https://doi.org/10.1016/j.injury.2018.09.033.CrossRef

19.

D’Alessandro A, Moore HB, Moore EE, Reisz JA, Wither MJ, Ghasabyan A, et al. Plasma succinate is a predictor of mortality in critically injured patients. J Trauma Acute Care Surg. 2017. https://doi.org/10.1097/TA.0000000000001565.CrossRef

20.

Lusczek ER, Muratore SL, Dubick MA, Beilman GJ. Assessment of key plasma metabolites in combat casualties. J Trauma Acute Care Surg. 2017;82:309–16. https://doi.org/10.1097/TA.0000000000001277.CrossRefPubMed

21.

Dickens AM, Posti JP, Takala RS, Ala-Seppälä HM, Mattila I, Coles JC, et al. Serum metabolites associate with CT findings following TBI. J Neurotrauma. 2018;35:2673–83. https://doi.org/10.1089/neu.2017.5272.CrossRefPubMed

22.

Wolahan SM, Lebby E, Mao HC, McArthur D, Real C, Vespa PM, et al. Novel metabolomic comparison of arterial and jugular venous blood in severe adult TBI patients and the impact of pentobarbital infusion. J Neurotrauma. 2018. https://doi.org/10.1089/neu.2018.5674.CrossRef

23.

Hagos FT, Empey PE, Wang P, Ma X, Poloyac SM, Bayır H, et al. Exploratory application of neuropharmacometabolomics in severe childhood traumatic brain injury. Crit Care Med. 2018. https://doi.org/10.1097/CCM.0000000000003203.CrossRef

24.

Ottens AK, Stafflinger JE, Griffin HE, Kunz RD, Cifu DX, Niemeier JP. Post-acute brain injury urinary signature: a new resource for molecular diagnostics. J Neurotrauma. 2014;31:782–8. https://doi.org/10.1089/neu.2013.3116.CrossRefPubMedPubMedCentral

25.

Fiandaca MS, Mapstone M, Mahmoodi A, Gross T, Macciardi F, Cheema AK, et al. Plasma metabolomic biomarkers accurately classify acute mild traumatic brain injury from controls. PLoS One. 2018;13:e0195318. https://doi.org/10.1371/journal.pone.0195318.CrossRefPubMedPubMedCentral

26.

Pandya U, Polite N, Wood T, Lieber M. Increased total serum random cortisol levels predict mortality in critically ill trauma patients. Am Surg. 2014;80:1112–8.PubMed

27.

Rady MY, Johnson DJ, Patel B, Larson J, Helmers R. Cortisol levels and corticosteroid administration fail to predict mortality in critical illness: the confounding effects of organ dysfunction and sex. Arch Surg. 2005;140:661–8; discussion 669. https://doi.org/10.1001/archsurg.140.7.661.CrossRefPubMed

28.

Gale SC, Sicoutris C, Reilly PM, Schwab CW, Gracias VH. Poor glycemic control is associated with increased mortality in critically ill trauma patients. Am Surg. 2007;73:454–60.PubMed

29.

Gelfand RA, Matthews DE, Bier DM, Sherwin RS. Role of counterregulatory hormones in the catabolic response to stress. J Clin Invest. 1984;74:2238–48. https://doi.org/10.1172/JCI111650.CrossRefPubMedPubMedCentral

30.

Mao H, Wang H, Wang B, Liu X, Gao H, Xu M, et al. Systemic metabolic changes of traumatic critically ill patients revealed by an NMR-based metabonomic approach. J Proteome Res. 2009;8:5423–30. https://doi.org/10.1021/pr900576y.CrossRefPubMed

31.

Naganathar S, De’Ath HD, Wall J, Brohi K. Admission biomarkers of trauma-induced secondary cardiac injury predict adverse cardiac events and are associated with plasma catecholamine levels. J Trauma Acute Care Surg. 2015;79:71–7. https://doi.org/10.1097/TA.0000000000000694.CrossRefPubMed

32.

Johansson PI, Stensballe J, Rasmussen LS, Ostrowski SR. High circulating adrenaline levels at admission predict increased mortality after trauma. J Trauma Acute Care Surg. 2012;72:428–36.CrossRef

33.

Ammar NM, Farag MA, Kholeif TE, Metwally NS, El-Sheikh NM, El Gendy AN, et al. Serum metabolomics reveals the mechanistic role of functional foods and exercise for obesity management in rats. J Pharm Biomed Anal. 2017;142:91–101. https://doi.org/10.1016/j.jpba.2017.05.001.CrossRefPubMed

34.

Shannon HE, Cone EJ, Yousefnejad D. Physiologic effects and plasma kinetics of phenylethanolamine and its N-methyl homolog in the dog. J Pharmacol Exp Ther. 1981;217:379–85.PubMed

35.

Morita I, Kawamoto M, Hattori M, Eguchi K, Sekiba K, Yoshida H. Determination of tryptophan and its metabolites in human plasma and serum by high-performance liquid chromatography with automated sample clean-up system. J Chromatogr. 1990;526:367–74.CrossRef

36.

Cala MP, Agulló-Ortuño MT, Prieto-García E, González-Riano C, Parrilla-Rubio L, Barbas C, et al. Multiplatform plasma fingerprinting in cancer cachexia: a pilot observational and translational study. J Cachexia Sarcopenia Muscle. 2018;9:348–57. https://doi.org/10.1002/jcsm.12270.CrossRefPubMedPubMedCentral

37.

Ristagno G, Fries M, Brunelli L, Fumagalli F, Bagnati R, Russo I, et al. Early kynurenine pathway activation following cardiac arrest in rats, pigs, and humans. Resuscitation. 2013;84:1604–10. https://doi.org/10.1016/j.resuscitation.2013.06.002.CrossRefPubMed

38.

Huttunen R, Syrjänen J, Aittoniemi J, Oja SS, Raitala A, Laine J, et al. High activity of indoleamine 2,3 dioxygenase enzyme predicts disease severity and case fatality in bacteremic patients. Shock. 2010;33:149–54. https://doi.org/10.1097/SHK.0b013e3181ad3195.CrossRefPubMed

39.

Moyer ED, McMenamy RH, Cerra FB, Reed RA, Yu L, Chenier R, et al. Multiple systems organ failure: III contrasts in plasma amino acid profiles in septic trauma patients who subsequently survive and do not survive-effects of intravenous amino acids. J Trauma. 1981;21:263–74.CrossRef

40.

Speziali G, Liesinger L, Gindlhuber J, Leopold C, Pucher B, Brandi J, et al. Myristic acid induces proteomic and secretomic changes associated with steatosis, cytoskeleton remodeling, endoplasmic reticulum stress, protein turnover and exosome release in HepG2 cells. J Proteome. 2018;181:118–30. https://doi.org/10.1016/j.jprot.2018.04.008.CrossRef

41.

Ebbesson SOE, Voruganti VS, Higgins PB, Fabsitz RR, Ebbesson LO, Laston S, et al. Fatty acids linked to cardiovascular mortality are associated with risk factors. Int J Circumpolar Health. 2015;74:28055. https://doi.org/10.3402/ijch.v74.28055.CrossRefPubMed

42.

Udenwobele DI, Su R-C, Good SV, Ball TB, Varma Shrivastav S, Shrivastav A. Myristoylation: an important protein modification in the immune response. Front Immunol. 2017;8:751. https://doi.org/10.3389/fimmu.2017.00751.CrossRefPubMedPubMedCentral

43.

Bortolotti P, Faure E, Kipnis E. Inflammasomes in tissue damages and immune disorders after trauma. Front Immunol. 2018;9:1900. https://doi.org/10.3389/fimmu.2018.01900.CrossRefPubMedPubMedCentral

44.

Posti JP, Dickens AM, Orešič M, Hyötyläinen T, Tenovuo O. Metabolomics profiling as a diagnostic tool in severe traumatic brain injury. Front Neurol. 2017;8:398. https://doi.org/10.3389/fneur.2017.00398.CrossRefPubMedPubMedCentral

45.

Cohen MJ, Serkova NJ, Wiener-Kronish J, Pittet J-F, Niemann CU. 1H-NMR-based metabolic signatures of clinical outcomes in trauma patients--beyond lactate and base deficit. J Trauma. 2010;69:31–40. https://doi.org/10.1097/TA.0b013e3181e043fe.CrossRefPubMed

46.

Stoner HB, Frayn KN, Barton RN, Threlfall CJ, Little RA. The relationships between plasma substrates and hormones and the severity of injury in 277 recently injured patients. Clin Sci. 1979;56:563–73.CrossRef

47.

Nixon JR, Brock-Utne JG. Free fatty acid and arterial oxygen changes following major injury: a correlation between hypoxemia and increased free fatty acid levels. J Trauma. 1978;18:23–6.CrossRef

48.

Kamolz LP, Andel H, Mittlböck M, Winter W, Haslik W, Meissl G, et al. Serum cholesterol and triglycerides: potential role in mortality prediction. Burns. 2003;29:810–5.CrossRef

49.

Sztefko K, Panek J. Serum free fatty acid concentration in patients with acute pancreatitis. Pancreatology. 2001;1:230–6. https://doi.org/10.1159/000055816.CrossRefPubMed

50.

Qi P, Abdullahi A, Stanojcic M, Patsouris D, Jeschke MG. Lipidomic analysis enables prediction of clinical outcomes in burn patients. Sci Rep. 2016;6:38707. https://doi.org/10.1038/srep38707.CrossRefPubMedPubMedCentral

51.

Wang Y, Qian Y, Fang Q, Zhong P, Li W, Wang L, et al. Saturated palmitic acid induces myocardial inflammatory injuries through direct binding to TLR4 accessory protein MD2. Nat Commun. 2017;8:13997. https://doi.org/10.1038/ncomms13997.CrossRefPubMedPubMedCentral

52.

Miedema MD, Maziarz M, Biggs ML, Zieman SJ, Kizer JR, Ix JH, et al. Plasma-free fatty acids, fatty acid-binding protein 4, and mortality in older adults (from the cardiovascular health study). Am J Cardiol. 2014;114:843–8. https://doi.org/10.1016/j.amjcard.2014.06.012.CrossRefPubMedPubMedCentral

53.

Ikeoka DT, Pachler C, Mader JK, Bock G, Neves AL, Svehlikova E, et al. Lipid-heparin infusion suppresses the IL-10 response to trauma in subcutaneous adipose tissue in humans. Obesity (Silver Spring). 2011;19:715–21. https://doi.org/10.1038/oby.2010.227.CrossRef

54.

Qin X, Dong W, Sharpe SM, Sheth SU, Palange DC, Rider T, et al. Role of lipase-generated free fatty acids in converting mesenteric lymph from a noncytotoxic to a cytotoxic fluid. Am J Physiol Gastrointest Liver Physiol. 2012;303:G969–78. https://doi.org/10.1152/ajpgi.00290.2012.CrossRefPubMedPubMedCentral

55.

Hardaway RM, Vasquez Y. A shock toxin that produces disseminated intravascular coagulation and multiple organ failure. Am J Med Sci. 2001;322:222–8.CrossRef

56.

Penn AH, Dubick MA, Torres Filho IP. Fatty acid saturation of albumin used in resuscitation fluids modulates cell damage in shock: in vitro results using a novel technique to measure fatty acid binding capacity. Shock. 2017. https://doi.org/10.1097/SHK.0000000000000865.CrossRef

57.

Jové M, Naudí A, Aledo JC, Cabré R, Ayala V, Portero-Otin M, et al. Plasma long-chain free fatty acids predict mammalian longevity. Sci Rep. 2013;3:3346. https://doi.org/10.1038/srep03346.CrossRefPubMedPubMedCentral

58.

Karpe F, Dickmann JR, Frayn KN. Fatty acids, obesity, and insulin resistance: time for a reevaluation. Diabetes. 2011;60:2441–9. https://doi.org/10.2337/db11-0425.CrossRefPubMedPubMedCentral

59.

Witowski N, Lusczek E, Determan C, Lexcen D, Mulier K, Ostrowski B, et al. A four-compartment metabolomics analysis of the liver, muscle, serum, and urine response to polytrauma with hemorrhagic shock following carbohydrate prefeed. PLoS One. 2015;10:e0124467. https://doi.org/10.1371/journal.pone.0124467.CrossRefPubMedPubMedCentral

Title: A prospective pilot study using metabolomics discloses specific fatty acid, catecholamine and tryptophan metabolic pathways as possible predictors for a negative outcome after severe trauma
Authors: Luis Servià
Mariona Jové
Joaquim Sol
Reinald Pamplona
Mariona Badia
Neus Montserrat
Manuel Portero-Otin
Javier Trujillano
Publication date: 01-12-2019
Publisher: BioMed Central
Keywords: Central Nervous System Trauma
Biomarkers
Published in: Scandinavian Journal of Trauma, Resuscitation and Emergency Medicine / Issue 1/2019
Electronic ISSN: 1757-7241
DOI: https://doi.org/10.1186/s13049-019-0631-5

Keynote webinar | Spotlight on medication adherence

Springer Medicine

A prospective pilot study using metabolomics discloses specific fatty acid, catecholamine and tryptophan metabolic pathways as possible predictors for a negative outcome after severe trauma

Abstract

Background

Methods

Results

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 1/2019

A prospective stepped wedge cohort evaluation of the new national trauma team activation criteria in Sweden – the TRAUMALERT study

Female risk-adjusted survival advantage after injuries caused by falls, traffic or assault: a nationwide 11-year study

Determining optimal needle size for decompression of tension pneumothorax in children – a CT-based study

Emergency department non-invasive cardiac output study (EDNICO): a feasibility and repeatability study

Impact of caller’s degree-of-worry on triage response in out-of-hours telephone consultations: a randomized controlled trial

Outcome, quality of life and direct costs after out-of-hospital cardiac arrest in an urban region of Switzerland