{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T07:06:53Z","timestamp":1791875213861,"version":"4.3.4"},"reference-count":76,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2022,1,26]],"date-time":"2022-01-26T00:00:00Z","timestamp":1643155200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["R01GM103799"],"award-info":[{"award-number":["R01GM103799"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["R01GM111400"],"award-info":[{"award-number":["R01GM111400"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Sepsis-induced metabolic dysfunction is associated with mortality, but the signatures that differentiate variable clinical outcomes among survivors are unknown. Our aim was to determine the relationship between host metabolism and chronic critical illness (CCI) in patients with septic shock. We analyzed metabolomics data from mechanically ventilated patients with vasopressor-dependent septic shock from the placebo arm of a recently completed clinical trial. Baseline serum metabolites were measured by liquid chromatography-mass spectrometry and 1H-nuclear magnetic resonance. We conducted a time-to-event analysis censored at 28 days. Specifically, we determined the relationship between metabolites and time to extubation and freedom from vasopressors using a competing risk survival model, with death as a competing risk. We also compared metabolite concentrations between CCI patients, defined as intensive care unit level of care \u2265 14 days, and those with rapid recovery. Elevations in two acylcarnitines and four amino acids were related to the freedom from organ support (subdistributional hazard ratio &lt; 1 and false discovery rate &lt; 0.05). Proline, glycine, glutamine, and methionine were also elevated in patients who developed CCI. Our work highlights the need for further testing of metabolomics to identify patients at risk of CCI and to elucidate potential mechanisms that contribute to its etiology.<\/jats:p>","DOI":"10.3390\/jcm11030627","type":"journal-article","created":{"date-parts":[[2022,1,26]],"date-time":"2022-01-26T11:02:53Z","timestamp":1643194973000},"page":"627","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Serum Levels of Acylcarnitines and Amino Acids Are Associated with Liberation from Organ Support in Patients with Septic Shock"],"prefix":"10.3390","volume":"11","author":[{"given":"Theodore S.","family":"Jennaro","sequence":"first","affiliation":[{"name":"Department of Clinical Pharmacy and the NMR Metabolomics Laboratory, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7439-6322","authenticated-orcid":false,"given":"Elizabeth M.","family":"Viglianti","sequence":"additional","affiliation":[{"name":"Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, School of Medicine, University of Michigan, Ann Arbor, MI 48109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0292-0594","authenticated-orcid":false,"given":"Nicholas E.","family":"Ingraham","sequence":"additional","affiliation":[{"name":"Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, Department of Internal Medicine, School of Medicine, University of Minnesota, Minneapolis, MN 55455, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alan E.","family":"Jones","sequence":"additional","affiliation":[{"name":"Department of Emergency Medicine, University of Mississippi Medical Center, Jackson, MS 39216, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0238-7774","authenticated-orcid":false,"given":"Kathleen A.","family":"Stringer","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacy and the NMR Metabolomics Laboratory, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USA"},{"name":"Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, School of Medicine, University of Michigan, Ann Arbor, MI 48109, USA"},{"name":"Michigan Center for Integrative Research in Critical Care (MCIRCC), University of Michigan, Ann Arbor, MI 48109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael A.","family":"Puskarich","sequence":"additional","affiliation":[{"name":"Department of Emergency Medicine, School of Medicine, University of Minnesota, Minneapolis, MN 55415, USA"},{"name":"Department of Emergency Medicine, Hennepin County Medical Center, Minneapolis, MN 55415, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,1,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"801","DOI":"10.1001\/jama.2016.0287","article-title":"The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3)","volume":"315","author":"Singer","year":"2016","journal-title":"JAMA"},{"key":"ref_2","unstructured":"Torio, C.M., and Moore, B.J. (2016). National Inpatient Hospital Costs: The Most Expensive Conditions by Payer, 2013: Statistical Brief #204."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1016\/S0140-6736(19)32989-7","article-title":"Global, regional, and national sepsis incidence and mortality, 1990\u20132017: Analysis for the Global Burden of Disease Study","volume":"395","author":"Rudd","year":"2020","journal-title":"Lancet"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"196","DOI":"10.1186\/s13054-019-2478-6","article-title":"Frequency and mortality of septic shock in Europe and North America: A systematic review and meta-analysis","volume":"23","author":"Vincent","year":"2019","journal-title":"Crit. Care"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1511","DOI":"10.3389\/fimmu.2018.01511","article-title":"Chronic Critical Illness and the Persistent Inflammation, Immunosuppression, and Catabolism Syndrome","volume":"9","author":"Hawkins","year":"2018","journal-title":"Front. Immunol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"502","DOI":"10.1097\/SLA.0000000000003458","article-title":"Current Epidemiology of Surgical Sepsis: Discordance Between Inpatient Mortality and 1-year Outcomes","volume":"270","author":"Brakenridge","year":"2019","journal-title":"Ann. Surg."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1556","DOI":"10.1097\/CCM.0000000000004524","article-title":"National Trends and Variation of Functional Status Deterioration in the Medically Critically Ill","volume":"48","author":"Ingraham","year":"2020","journal-title":"Crit. Care Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"i2375","DOI":"10.1136\/bmj.i2375","article-title":"Late mortality after sepsis: Propensity matched cohort study","volume":"353","author":"Prescott","year":"2016","journal-title":"BMJ"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"446","DOI":"10.1164\/rccm.201002-0210CI","article-title":"Chronic critical illness","volume":"182","author":"Nelson","year":"2010","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/j.jcrc.2018.03.029","article-title":"Late organ failures in patients with prolonged intensive care unit stays","volume":"46","author":"Viglianti","year":"2018","journal-title":"J. Crit. Care"},{"key":"ref_11","first-page":"39","article-title":"Neither vitamin D levels nor supplementation are associated with the development of persistent critical illness: A retrospective cohort analysis","volume":"21","author":"Viglianti","year":"2019","journal-title":"Crit. Care Resusc. J. Australas. Acad. Crit. Care Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"571","DOI":"10.1016\/j.chest.2020.02.071","article-title":"Late Vasopressor Administration in Patients in the ICU: A Retrospective Cohort Study","volume":"158","author":"Viglianti","year":"2020","journal-title":"Chest"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Darden, D.B., Ghita, G.L., Wang, Z., Stortz, J.A., Lopez, M.-C., Cox, M.C., Hawkins, R., Rincon, J., Kelly, L., and Fenner, B. (2021). Chronic Critical Illness Elicits a Unique Circulating Leukocyte Transcriptome in Sepsis Survivors. J. Clin. Med., 10.","DOI":"10.3390\/jcm10153211"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"188","DOI":"10.1093\/gerona\/glab080","article-title":"Older Adults Demonstrate Biomarker Evidence of the Persistent Inflammation, Immunosuppression, and Catabolism Syndrome (PICS) After Sepsis","volume":"77","author":"Mankowski","year":"2022","journal-title":"J. Gerontol. Ser. A"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1718","DOI":"10.1007\/s00134-019-05760-5","article-title":"Elevated urea-to-creatinine ratio provides a biochemical signature of muscle catabolism and persistent critical illness after major trauma","volume":"45","author":"Haines","year":"2019","journal-title":"Intensive Care Med."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Acharjee, A., Hazeldine, J., Bazarova, A., Deenadayalu, L., Zhang, J., Bentley, C., Russ, D., Lord, J.M., Gkoutos, G.V., and Young, S.P. (2022). Integration of Metabolomic and Clinical Data Improves the Prediction of Intensive Care Unit Length of Stay Following Major Traumatic Injury. Metabolites, 12.","DOI":"10.3390\/metabo12010029"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"146","DOI":"10.1097\/00000658-199808000-00002","article-title":"Sequential changes in the metabolic response in severely septic patients during the first 23 days after the onset of peritonitis","volume":"228","author":"Plank","year":"1998","journal-title":"Ann. Surg."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"571","DOI":"10.1097\/00000658-197911000-00003","article-title":"Plasma amino acids as predictors of the severity and outcome of sepsis","volume":"190","author":"Freund","year":"1979","journal-title":"Ann. Surg."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"66","DOI":"10.4161\/viru.26907","article-title":"The role of mitochondrial dysfunction in sepsis-induced multi-organ failure","volume":"5","author":"Singer","year":"2014","journal-title":"Virulence"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"647","DOI":"10.1164\/rccm.201103-0474CI","article-title":"The emerging field of quantitative blood metabolomics for biomarker discovery in critical illnesses","volume":"184","author":"Serkova","year":"2011","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1164\/rccm.201404-0624OC","article-title":"Integrative \"omic\" analysis of experimental bacteremia identifies a metabolic signature that distinguishes human sepsis from systemic inflammatory response syndromes","volume":"190","author":"Langley","year":"2014","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1186\/s13054-019-2456-z","article-title":"Nuclear magnetic resonance-based serum metabolomic analysis reveals different disease evolution profiles between septic shock survivors and non-survivors","volume":"23","author":"Liu","year":"2019","journal-title":"Crit. Care"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1140","DOI":"10.1097\/CCM.0000000000000142","article-title":"Metabolic profiling of serum samples by 1H nuclear magnetic resonance spectroscopy as a potential diagnostic approach for septic shock","volume":"42","author":"Mickiewicz","year":"2014","journal-title":"Crit. Care Med."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1513\/AnnalsATS.201409-415OC","article-title":"Pharmacometabolomics of l-carnitine treatment response phenotypes in patients with septic shock","volume":"12","author":"Puskarich","year":"2015","journal-title":"Ann. Am. Thorac. Soc."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"412","DOI":"10.1097\/SHK.0000000000000997","article-title":"Septic Shock Nonsurvivors Have Persistently Elevated Acylcarnitines Following Carnitine Supplementation","volume":"49","author":"Puskarich","year":"2018","journal-title":"Shock"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2288","DOI":"10.1111\/cts.13088","article-title":"Pharmacometabolomics identifies candidate predictor metabolites of an L-carnitine treatment mortality benefit in septic shock","volume":"14","author":"Puskarich","year":"2021","journal-title":"Clin. Transl. Transl. Sci."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Wang, J., Sun, Y., Teng, S., and Li, K. (2020). Prediction of sepsis mortality using metabolite biomarkers in the blood: A meta-analysis of death-related pathways and prospective validation. BMC Med., 18.","DOI":"10.1186\/s12916-020-01546-5"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"e186076","DOI":"10.1001\/jamanetworkopen.2018.6076","article-title":"Effect of Levocarnitine vs Placebo as an Adjunctive Treatment for Septic Shock: The Rapid Administration of Carnitine in Sepsis (RACE) Randomized Clinical Trial","volume":"1","author":"Jones","year":"2018","journal-title":"JAMA Netw. Open"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"707","DOI":"10.1007\/BF01709751","article-title":"The SOFA (Sepsis-related Organ Failure Assessment) score to describe organ dysfunction\/failure. On behalf of the Working Group on Sepsis-Related Problems of the European Society of Intensive Care Medicine","volume":"22","author":"Vincent","year":"1996","journal-title":"Intensive Care Med."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Gillies, C.E., Jennaro, T.S., Puskarich, M.A., Sharma, R., Ward, K.R., Fan, X., Jones, A.E., and Stringer, K.A. (2020). A Multilevel Bayesian Approach to Improve Effect Size Estimation in Regression Modeling of Metabolomics Data Utilizing Imputation with Uncertainty. Metabolites, 10.","DOI":"10.3390\/metabo10080319"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"11367","DOI":"10.1038\/s41598-019-47761-w","article-title":"Serum amino acid concentrations and clinical outcomes in smokers: SPIROMICS metabolomics study","volume":"9","author":"Labaki","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"McHugh, C.E., Flott, T.L., Schooff, C.R., Smiley, Z., Puskarich, M.A., Myers, D.D., Younger, J.G., Jones, A.E., and Stringer, K.A. (2018). Rapid, Reproducible, Quantifiable NMR Metabolomics: Methanol and Methanol: Chloroform Precipitation for Removal of Macromolecules in Serum and Whole Blood. Metabolites, 8.","DOI":"10.3390\/metabo8040093"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Antonelli, J., Claggett, B.L., Henglin, M., Kim, A., Ovsak, G., Kim, N., Rao, K., Tyagi, O., Watrous, J.D., and Lagerborg, K.A. (2019). Statistical Workflow for Feature Selection in Human Metabolomics Data. Metabolites, 9.","DOI":"10.3390\/metabo9070143"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Everitt, B., and Hothorn, T. (2011). An Introduction to Applied Multivariate Analysis with R, Springer.","DOI":"10.1007\/978-1-4419-9650-3"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Van den Berg, R.A., Hoefsloot, H.C., Westerhuis, J.A., Smilde, A.K., and van der Werf, M.J. (2006). Centering, scaling, and transformations: Improving the biological information content of metabolomics data. BMC Genom., 7.","DOI":"10.1186\/1471-2164-7-142"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"828","DOI":"10.1164\/rccm.201810-2050CP","article-title":"Reappraisal of Ventilator-Free Days in Critical Care Research","volume":"200","author":"Yehya","year":"2019","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"496","DOI":"10.1080\/01621459.1999.10474144","article-title":"A Proportional Hazards Model for the Subdistribution of a Competing Risk","volume":"94","author":"Fine","year":"1999","journal-title":"J. Am. Stat. Assoc."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1016\/0021-9681(87)90171-8","article-title":"A new method of classifying prognostic comorbidity in longitudinal studies: Development and validation","volume":"40","author":"Charlson","year":"1987","journal-title":"J. Chronic. Dis."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1638","DOI":"10.1056\/NEJMoa1609409","article-title":"Levosimendan for the Prevention of Acute Organ Dysfunction in Sepsis","volume":"375","author":"Gordon","year":"2016","journal-title":"N. Engl. J. Med."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"374","DOI":"10.1186\/s13054-019-2663-7","article-title":"The SOFA score\u2014development, utility and challenges of accurate assessment in clinical trials","volume":"23","author":"Lambden","year":"2019","journal-title":"Crit. Care"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1111\/j.2517-6161.1995.tb02031.x","article-title":"Controlling the False Discovery Rate: A Practical and Powerful Approach to Multiple Testing","volume":"57","author":"Benjamini","year":"1995","journal-title":"J. R. Stat. Soc. Ser. B"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1876","DOI":"10.1513\/AnnalsATS.202008-1076OC","article-title":"Comparing Clinical Features and Outcomes in Mechanically Ventilated Patients with COVID-19 and the Acute Respiratory Distress Syndrome","volume":"18","author":"Sjoding","year":"2021","journal-title":"Ann. Am. Thorac. Soc."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1097\/SHK.0000000000000981","article-title":"Evidence for Persistent Immune Suppression in Patients Who Develop Chronic Critical Illness After Sepsis","volume":"49","author":"Stortz","year":"2018","journal-title":"Shock"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"342","DOI":"10.1097\/TA.0000000000001758","article-title":"Benchmarking clinical outcomes and the immunocatabolic phenotype of chronic critical illness after sepsis in surgical intensive care unit patients","volume":"84","author":"Stortz","year":"2018","journal-title":"J. Trauma Acute Care Surg."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"566","DOI":"10.1016\/S2213-2600(16)30098-4","article-title":"Timing of onset and burden of persistent critical illness in Australia and New Zealand: A retrospective, population-based, observational study","volume":"4","author":"Iwashyna","year":"2016","journal-title":"Lancet Respir. Med."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"e86","DOI":"10.1002\/cpbi.86","article-title":"Using MetaboAnalyst 4.0 for Comprehensive and Integrative Metabolomics Data Analysis","volume":"68","author":"Chong","year":"2019","journal-title":"Curr. Protoc. Bioinform."},{"key":"ref_47","unstructured":"R Core Team (2019). R: A Language and Environment for Statistical Computing, R Foundation for Statistical Computing. Available online: https:\/\/www.R-project.org\/."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"4391","DOI":"10.1002\/sim.7501","article-title":"Practical recommendations for reporting Fine-Gray model analyses for competing risk data","volume":"36","author":"Austin","year":"2017","journal-title":"Stat. Med."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"e10128","DOI":"10.15252\/emmm.201810128","article-title":"Sepsis therapies: Learning from 30 years of failure of translational research to propose new leads","volume":"12","author":"Cavaillon","year":"2020","journal-title":"EMBO Mol. Med."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"195ra95","DOI":"10.1126\/scitranslmed.3005893","article-title":"An integrated clinico-metabolomic model improves prediction of death in sepsis","volume":"5","author":"Langley","year":"2013","journal-title":"Sci. Transl. Med."},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Rogers, A.J., McGeachie, M., Baron, R.M., Gazourian, L., Haspel, J.A., Nakahira, K., Fredenburgh, L.E., Hunninghake, G.M., Raby, B.A., and Matthay, M.A. (2014). Metabolomic derangements are associated with mortality in critically ill adult patients. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0087538"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1097\/CCM.0000000000003517","article-title":"Increased Plasma Acetylcarnitine in Sepsis Is Associated with Multiple Organ Dysfunction and Mortality: A Multicenter Cohort Study","volume":"47","author":"Chung","year":"2019","journal-title":"Crit. Care Med."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"20391","DOI":"10.1038\/srep20391","article-title":"Mortality prediction in patients with severe septic shock: A pilot study using a target metabolomics approach","volume":"6","author":"Ferrario","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1097\/CCM.0000000000002074","article-title":"Sepsis Pathophysiology, Chronic Critical Illness, and Persistent Inflammation-Immunosuppression and Catabolism Syndrome","volume":"45","author":"Mira","year":"2017","journal-title":"Crit. Care Med."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1016\/j.ccc.2016.12.001","article-title":"Persistent Inflammation, Immunosuppression and Catabolism Syndrome","volume":"33","author":"Mira","year":"2017","journal-title":"Crit. Care Clin."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1491","DOI":"10.1097\/TA.0b013e318256e000","article-title":"Persistent inflammation and immunosuppression: A common syndrome and new horizon for surgical intensive care","volume":"72","author":"Gentile","year":"2012","journal-title":"J. Trauma Acute Care Surg."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1237","DOI":"10.1002\/jpen.1794","article-title":"Chronic Critical Illness Patients Fail to Respond to Current Evidence-Based Intensive Care Nutrition Secondarily to Persistent Inflammation, Immunosuppression, and Catabolic Syndrome","volume":"44","author":"Rosenthal","year":"2020","journal-title":"J. Parenter. Enter. Nutr."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"e31","DOI":"10.1016\/j.ddmec.2009.02.001","article-title":"Carnitine homeostasis, mitochondrial function, and cardiovascular disease","volume":"6","author":"Sharma","year":"2009","journal-title":"Drug Discov. Today Dis. Mech."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"246","DOI":"10.1089\/sur.2019.192","article-title":"Pre- and Peri-Operative Factors Associated with Chronic Critical Illness in Liver Transplant Recipients","volume":"21","author":"Ingraham","year":"2020","journal-title":"Surg. Infect."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1186\/s13054-020-2768-z","article-title":"Defining persistent critical illness based on growth trajectories in patients with sepsis","volume":"24","author":"Zhang","year":"2020","journal-title":"Crit. Care"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"108508","DOI":"10.1016\/j.abb.2020.108508","article-title":"Altered profiles of serum amino acids in patients with sepsis and septic shock\u2014Preliminary findings","volume":"691","author":"Fleszar","year":"2020","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_62","doi-asserted-by":"crossref","unstructured":"Su, L., Li, H., Xie, A., Liu, D., Rao, W., Lan, L., Li, X., Li, F., Xiao, K., and Wang, H. (2015). Dynamic Changes in Amino Acid Concentration Profiles in Patients with Sepsis. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0121933"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1097\/SHK.0000000000001687","article-title":"Serum Levels of Branched Chain Amino Acids Predict Duration of Cardiovascular Organ Failure in Septic Shock","volume":"56","author":"Puskarich","year":"2021","journal-title":"Shock"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1260","DOI":"10.1038\/s41598-021-81037-6","article-title":"Methionine restriction plus overload improves skeletal muscle and metabolic health in old mice on a high fat diet","volume":"11","author":"Swaminathan","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"740","DOI":"10.1002\/oby.22146","article-title":"The Components of Age-Dependent Effects of Dietary Methionine Restriction on Energy Balance in Rats","volume":"26","author":"Wanders","year":"2018","journal-title":"Obesity"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"292","DOI":"10.1016\/j.copbio.2021.03.001","article-title":"Glutathione and its precursors in cancer","volume":"68","author":"Asantewaa","year":"2021","journal-title":"Curr. Opin. Biotechnol."},{"key":"ref_67","doi-asserted-by":"crossref","unstructured":"Cruzat, V., Macedo Rogero, M., Noel Keane, K., Curi, R., and Newsholme, P. (2018). Glutamine: Metabolism and Immune Function, Supplementation and Clinical Translation. Nutrients, 10.","DOI":"10.20944\/preprints201809.0459.v1"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1111\/1541-4337.12401","article-title":"Dietary Amino Acids and the Gut-Microbiome-Immune Axis: Physiological Metabolism and Therapeutic Prospects","volume":"18","author":"Ma","year":"2019","journal-title":"Compr. Rev. Food Sci. Food Saf."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1007\/s001340000703","article-title":"Plasma glutamine depletion and patient outcome in acute ICU admissions","volume":"27","author":"Bosman","year":"2001","journal-title":"Intensive Care Med."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"591","DOI":"10.1042\/CS20110520","article-title":"Glutamine and glutathione at ICU admission in relation to outcome","volume":"122","author":"Rodas","year":"2012","journal-title":"Clin. Sci."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"514","DOI":"10.1001\/jama.2014.7698","article-title":"High-protein enteral nutrition enriched with immune-modulating nutrients vs standard high-protein enteral nutrition and nosocomial infections in the ICU: A randomized clinical trial","volume":"312","author":"Sztark","year":"2014","journal-title":"JAMA"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1016\/j.clnu.2013.11.017","article-title":"Altered balance of the aminogram in patients with sepsis\u2013the relation to mortality","volume":"33","author":"Hirose","year":"2014","journal-title":"Clin. Nutr."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"R76","DOI":"10.1186\/cc13836","article-title":"Parenteral glutamine supplementation in critical illness: A systematic review","volume":"18","author":"Wischmeyer","year":"2014","journal-title":"Crit. Care"},{"key":"ref_74","first-page":"CD010050","article-title":"Glutamine supplementation for critically ill adults","volume":"9","author":"Tao","year":"2014","journal-title":"Cochrane Database Syst Rev."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"890","DOI":"10.1177\/0148607114567201","article-title":"Consequences of the REDOXS and METAPLUS trials: The end of an era of glutamine and antioxidant supplementation for critically ill patients?","volume":"39","author":"Hofman","year":"2015","journal-title":"J. Parenter. Enter. Nutr."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1186\/s13054-016-1531-y","article-title":"Is the glutamine story over?","volume":"20","author":"Smedberg","year":"2016","journal-title":"Crit. Care"}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/11\/3\/627\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T22:08:16Z","timestamp":1760134096000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/11\/3\/627"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,1,26]]},"references-count":76,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2022,2]]}},"alternative-id":["jcm11030627"],"URL":"https:\/\/doi.org\/10.3390\/jcm11030627","relation":{},"ISSN":["2077-0383"],"issn-type":[{"value":"2077-0383","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,1,26]]}}}