Abstract
Critical illness is associated with dramatic changes in metabolism driven by immune, endocrine, and adrenergic mediators. These changes involve early activation of catabolic processes leading to increased energetic substrate availability; later on, they are followed by a hypometabolic phase characterized by deranged mitochondrial function. In sepsis and ARDS, these rapid clinical changes are reflected in metabolomic profiles of plasma and other fluids, suggesting that metabolomics could one day be used to assist in the diagnosis and prognostication of these syndromes. Some metabolites, such as lactate, are already in clinical use and define patients with septic shock, a high-mortality subtype of sepsis. Larger-scale metabolomic profiling may ultimately offer a tool to identify subgroups of critically ill patients who may respond to therapy, but further work is needed before this type of precision medicine is readily employed in the clinical setting.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Similar content being viewed by others
References
Allingstrup M, Afshari A (2015) Selenium supplementation for critically ill adults. Cochrane Database Syst Rev (7):CD003703. https://doi.org/10.1002/14651858.CD003703.pub3
Annane D, Sébille V, Charpentier C et al (2002) Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA 288(7):862–871. https://doi.org/10.1001/jama.288.7.862
Annane D, Renault A, Brun-Buisson C et al (2018) Hydrocortisone plus fludrocortisone for adults with septic shock. N Engl J Med 378(9):809–818. https://doi.org/10.1056/NEJMoa1705716
Bellani G, Laffey JG, Pham T et al (2016) Epidemiology, patterns of care, and mortality for patients with acute respiratory distress syndrome in intensive care units in 50 countries. JAMA 315(8):788–800. https://doi.org/10.1001/jama.2016.0291
Besecker BY, Exline MC, Hollyfield J et al (2011) A comparison of zinc metabolism, inflammation, and disease severity in critically ill infected and noninfected adults early after intensive care unit admission. Am J Clin Nutr 93(6):1356–1364. https://doi.org/10.3945/ajcn.110.008417
Calfee CS, Gallagher D, Abbott J, Thompson BT, Matthay MA, Network NA (2012) Plasma angiopoietin-2 in clinical acute lung injury: prognostic and pathogenetic significance. Crit Care Med 40(6):1731–1737. https://doi.org/10.1097/CCM.0b013e3182451c87
Calfee CS, Delucchi K, Parsons PE et al (2014) Subphenotypes in acute respiratory distress syndrome: latent class analysis of data from two randomised controlled trials. Lancet Respir Med 2(8):611–620. https://doi.org/10.1016/S2213-2600(14)70097-9
Calfee CS, Delucchi KL, Sinha P et al (2018) Acute respiratory distress syndrome subphenotypes and differential response to simvastatin: secondary analysis of a randomised controlled trial. Lancet Respir Med 6(9):691–698. https://doi.org/10.1016/S2213-2600(18)30177-2
Casaer MP, Van den Berghe G (2014) Nutrition in the acute phase of critical illness. N Engl J Med 370(25):2450–2451. https://doi.org/10.1056/NEJMc1404896
Casaer MP, Mesotten D, Hermans G et al (2011) Early versus late parenteral nutrition in critically ill adults. N Engl J Med 365(6):506–517. https://doi.org/10.1056/NEJMoa1102662
Cooper MS (2003) Corticosteroid Insufficiency in acutely Ill patients. N Engl J Med:8
Dolinay T, Kim YS, Howrylak J et al (2012) Inflammasome-regulated cytokines are critical mediators of acute lung injury. Am J Respir Crit Care Med 185(11):1225–1234. https://doi.org/10.1164/rccm.201201-0003OC
Eckerle M, Ambroggio L, Puskarich MA et al (2017) Metabolomics as a driver in advancing precision medicine in sepsis. Pharmacotherapy 37(9):1023–1032. https://doi.org/10.1002/phar.1974
Englert JA, Rogers AJ (2016) Metabolism, metabolomics, and nutritional support of patients with sepsis. Clin Chest Med 37(2):321–331. https://doi.org/10.1016/j.ccm.2016.01.011
Famous KR, Delucchi K, Ware LB et al (2017) Acute respiratory distress syndrome subphenotypes respond differently to randomized fluid management strategy. Am J Respir Crit Care Med 195(3):331–338. https://doi.org/10.1164/rccm.201603-0645OC
Ferguson ND, Fan E, Camporota L et al (2012) The Berlin definition of ARDS: an expanded rationale, justification, and supplementary material. Intensive Care Med 38(10):1573–1582. https://doi.org/10.1007/s00134-012-2682-1
Fleischmann C, Scherag A, Adhikari NKJ et al (2016) Assessment of global incidence and mortality of hospital-treated sepsis. Current estimates and limitations. Am J Respir Crit Care Med 193(3):259–272. https://doi.org/10.1164/rccm.201504-0781OC
Gaieski DF, Edwards JM, Kallan MJ, Carr BG (2013) Benchmarking the incidence and mortality of severe sepsis in the United States. Crit Care Med 41(5):1167–1174. https://doi.org/10.1097/CCM.0b013e31827c09f8
Hermans G, Casaer MP, Clerckx B et al (2013) Effect of tolerating macronutrient deficit on the development of intensive-care unit acquired weakness: a subanalysis of the EPaNIC trial. Lancet Respir Med 1(8):621–629. https://doi.org/10.1016/S2213-2600(13)70183-8
ICU Outcomes. Philip R. Lee Institute for Health Policy Studies Accessed 24 Apr 2022. https://healthpolicy.ucsf.edu/icu-outcomes
Investigators RC, Gordon AC, Mouncey PR et al (2021) Interleukin-6 receptor antagonists in critically ill patients with Covid-19. N Engl J Med 384(16):1491–1502. https://doi.org/10.1056/NEJMoa2100433
Jansen TC, van Bommel J, Schoonderbeek FJ et al (2010) Early lactate-guided therapy in intensive care unit patients: a multicenter, open-label, randomized controlled trial. Am J Respir Crit Care Med 182(6):752–761. https://doi.org/10.1164/rccm.200912-1918OC
Jones AE, Shapiro NI, Trzeciak S et al (2010) Lactate clearance vs central venous oxygen saturation as goals of early sepsis therapy: a randomized clinical trial. JAMA 303(8):739–746. https://doi.org/10.1001/jama.2010.158
Kalil AC, Patterson TF, Mehta AK et al (2021) Baricitinib plus Remdesivir for hospitalized adults with Covid-19. N Engl J Med 384(9):795–807. https://doi.org/10.1056/NEJMoa2031994
Khardori R, Castillo D (2012) Endocrine and metabolic changes during sepsis. Med Clin North Am 96(6):1095–1105. https://doi.org/10.1016/j.mcna.2012.09.005
Langley RJ, Tsalik EL, van Velkinburgh JC et al (2013) An integrated clinico-metabolomic model improves prediction of death in sepsis. Sci Transl Med 5(195):195ra95. https://doi.org/10.1126/scitranslmed.3005893
Langley RJ, Tipper JL, Bruse S et al (2014) Integrative “omic” analysis of experimental bacteremia identifies a metabolic signature that distinguishes human sepsis from systemic inflammatory response syndromes. Am J Respir Crit Care Med 190(4):445–455. https://doi.org/10.1164/rccm.201404-0624OC
Manzanares W, Dhaliwal R, Jiang X, Murch L, Heyland DK (2012) Antioxidant micronutrients in the critically ill: a systematic review and meta-analysis. Crit Care Lond Engl 16(2):R66. https://doi.org/10.1186/cc11316
Marik PE, Pastores SM, Annane D et al (2008) Recommendations for the diagnosis and management of corticosteroid insufficiency in critically ill adult patients: consensus statements from an international task force by the American College of Critical Care Medicine. Crit Care Med 36(6):1937–1949. https://doi.org/10.1097/CCM.0b013e31817603ba
Masiero E, Agatea L, Mammucari C et al (2009) Autophagy is required to maintain muscle mass. Cell Metab 10(6):507–515. https://doi.org/10.1016/j.cmet.2009.10.008
Matthay MA, Zemans RL, Zimmerman GA et al (2019) Acute respiratory distress syndrome. Nat Rev Primer 5(1):18. https://doi.org/10.1038/s41572-019-0069-0
Metwaly SM, Winston BW (2020) Systems biology ARDS research with a focus on metabolomics. Metabolites 10(5). https://doi.org/10.3390/metabo10050207
Metwaly S, Cote A, Donnelly SJ et al (2021) ARDS metabolic fingerprints: characterization, benchmarking, and potential mechanistic interpretation. Am J Physiol Lung Cell Mol Physiol 321(1):L79–L90. https://doi.org/10.1152/ajplung.00077.2021
Mickiewicz B, Vogel HJ, Wong HR, Winston BW (2013) Metabolomics as a novel approach for early diagnosis of pediatric septic shock and its mortality. Am J Respir Crit Care Med 187(9):967–976. https://doi.org/10.1164/rccm.201209-1726OC
Mickiewicz B, Duggan GE, Winston BW et al (2014) Metabolic profiling of serum samples by 1H nuclear magnetic resonance spectroscopy as a potential diagnostic approach for septic shock. Crit Care Med 42(5):1140–1149. https://doi.org/10.1097/CCM.0000000000000142
Mikkelsen ME, Miltiades AN, Gaieski DF et al (2009) Serum lactate is associated with mortality in severe sepsis independent of organ failure and shock. Crit Care Med 37(5):1670–1677. https://doi.org/10.1097/CCM.0b013e31819fcf68
Piel DA, Gruber PJ, Weinheimer CJ et al (2007) Mitochondrial resuscitation with exogenous cytochrome c in the septic heart. Crit Care Med 35(9):2120–2127. https://doi.org/10.1097/01.ccm.0000278914.85340.fe
Pool R, Gomez H, Kellum JA (2018) Mechanisms of organ dysfunction in sepsis. Crit Care Clin 34(1):63–80. https://doi.org/10.1016/j.ccc.2017.08.003
Preiser JC, Ichai C, Orban JC, Groeneveld ABJ (2014) Metabolic response to the stress of critical illness. Br J Anaesth 113(6):945–954. https://doi.org/10.1093/bja/aeu187
Puskarich MA, Finkel MA, Karnovsky A et al (2015) Pharmacometabolomics of l-carnitine treatment response phenotypes in patients with septic shock. Ann Am Thorac Soc 12(1):46–56. https://doi.org/10.1513/AnnalsATS.201409-415OC
Puskarich MA, Jennaro TS, Gillies CE et al (2021) Pharmacometabolomics identifies candidate predictor metabolites of an L-carnitine treatment mortality benefit in septic shock. Clin Transl Sci. https://doi.org/10.1111/cts.13088
RECOVERY Collaborative Group, Horby P, Lim WS et al (2021) Dexamethasone in hospitalized patients with Covid-19. N Engl J Med 384(8):693–704. https://doi.org/10.1056/NEJMoa2021436
Rogers AJ, McGeachie M, Baron RM et al (2014) Metabolomic derangements are associated with mortality in critically ill adult patients. PLoS One 9(1):e87538. https://doi.org/10.1371/journal.pone.0087538
Rogers AJ, Contrepois K, Wu M et al (2017) Profiling of ARDS pulmonary edema fluid identifies a metabolically distinct subset. Am J Physiol Lung Cell Mol Physiol 312(5):L703–L709. https://doi.org/10.1152/ajplung.00438.2016
Rogers AJ, Guan J, Trtchounian A et al (2019) Association of elevated plasma interleukin-18 level with increased mortality in a clinical trial of statin treatment for acute respiratory distress syndrome. Crit Care Med 47(8):1089–1096. https://doi.org/10.1097/CCM.0000000000003816
Rogers AJ, Leligdowicz A, Contrepois K et al (2021) Plasma metabolites in early sepsis identify distinct clusters defined by plasma lipids. Crit Care Explor 3(8):e0478. https://doi.org/10.1097/CCE.0000000000000478
Rubenfeld GD, Caldwell E, Peabody E et al (2005) Incidence and outcomes of acute lung injury. N Engl J Med 353(16):1685–1693. https://doi.org/10.1056/NEJMoa050333
Rudd KE, Johnson SC, Agesa KM et al (2020) Global, regional, and national sepsis incidence and mortality, 1990-2017: analysis for the global burden of disease study. Lancet Lond Engl 395(10219):200–211. https://doi.org/10.1016/S0140-6736(19)32989-7
Rydzak T, Groves RA, Zhang R et al (2022) Metabolic preference assay for rapid diagnosis of bloodstream infections. Nat Commun 13:2332. https://doi.org/10.1038/s41467-022-30048-6
Sair M, Etherington PJ, Peter Winlove C, Evans TW (2001) Tissue oxygenation and perfusion in patients with systemic sepsis. Crit Care Med 29(7):1343–1349. https://doi.org/10.1097/00003246-200107000-00008
Schmidt C, Höcherl K, Schweda F, Bucher M (2007) Proinflammatory cytokines cause down-regulation of renal chloride entry pathways during sepsis. Crit Care Med 35(9):2110–2119. https://doi.org/10.1097/01.ccm.0000281447.22966.8b
Shapiro NI, Howell MD, Talmor D et al (2005) Serum lactate as a predictor of mortality in emergency department patients with infection. Ann Emerg Med 45(5):524–528. https://doi.org/10.1016/j.annemergmed.2004.12.006
Singer M, De Santis V, Vitale D, Jeffcoate W (2004) Multiorgan failure is an adaptive, endocrine-mediated, metabolic response to overwhelming systemic inflammation. Lancet 364(9433):545–548. https://doi.org/10.1016/S0140-6736(04)16815-3
Singer M, Deutschman CS, Seymour CW et al (2016) The third international consensus definitions for sepsis and septic shock (Sepsis-3). JAMA 315(8):801–810. https://doi.org/10.1001/jama.2016.0287
Sinha P, Delucchi KL, McAuley DF, O’Kane CM, Matthay MA, Calfee CS (2020) Development and validation of parsimonious algorithms to classify acute respiratory distress syndrome phenotypes: a secondary analysis of randomised controlled trials. Lancet Respir Med 8(3):247–257. https://doi.org/10.1016/S2213-2600(19)30369-8
Sprung CL, Annane D, Keh D et al (2008) Hydrocortisone therapy for patients with septic shock. N Engl J Med 358(2):111–124. https://doi.org/10.1056/NEJMoa071366
Thompson BT, Chambers RC, Liu KD (2017) Acute respiratory distress syndrome. N Engl J Med 377(6):562–572. https://doi.org/10.1056/NEJMra1608077
Tomazini BM, Maia IS, Cavalcanti AB et al (2020) Effect of dexamethasone on days alive and ventilator-free in patients with moderate or severe acute respiratory distress syndrome and COVID-19: the CoDEX randomized clinical trial. JAMA 324(13):1307–1316. https://doi.org/10.1001/jama.2020.17021
Vanhorebeek I, Gunst J, Derde S et al (2011) Insufficient activation of autophagy allows cellular damage to accumulate in critically ill patients. J Clin Endocrinol Metab 96(4):E633–E645. https://doi.org/10.1210/jc.2010-2563
Venkatesh B, Finfer S, Cohen J et al (2018) Adjunctive glucocorticoid therapy in patients with septic shock. N Engl J Med 378:797. https://doi.org/10.1056/NEJMoa1705835
Villar J, Ferrando C, Martínez D et al (2020) Dexamethasone treatment for the acute respiratory distress syndrome: a multicentre, randomised controlled trial. Lancet Respir Med 8(3):267–276. https://doi.org/10.1016/S2213-2600(19)30417-5
Viswan A, Ghosh P, Gupta D, Azim A, Sinha N (2019) Distinct metabolic endotype mirroring acute respiratory distress syndrome (ARDS) subphenotype and its heterogeneous biology. Sci Rep 9(1):2108. https://doi.org/10.1038/s41598-019-39017-4
Wasyluk W, Wasyluk M, Zwolak A (2021) Sepsis as a pan-endocrine illness-endocrine disorders in septic patients. J Clin Med 10(10):2075. https://doi.org/10.3390/jcm10102075
Zinter MS, Spicer A, Orwoll BO et al (2016) Plasma angiopoietin-2 outperforms other markers of endothelial injury in prognosticating pediatric ARDS mortality. Am J Physiol Lung Cell Mol Physiol 310(3):L224–L231. https://doi.org/10.1152/ajplung.00336.2015
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2022 The Author(s), under exclusive license to Springer Nature Switzerland AG
About this chapter
Cite this chapter
Pacheco-Navarro, A.E., Rogers, A.J. (2022). The Metabolomics of Critical Illness. In: Ghini, V., Stringer, K.A., Luchinat, C. (eds) Metabolomics and Its Impact on Health and Diseases. Handbook of Experimental Pharmacology, vol 277. Springer, Cham. https://doi.org/10.1007/164_2022_622
Download citation
DOI: https://doi.org/10.1007/164_2022_622
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-031-26858-8
Online ISBN: 978-3-031-26859-5
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)