Skip to main content
Log in

Prognostic role of urinary ketone body in patients with sepsis-associated encephalopathy without hepatic failure: a retrospective cohort study

  • IM - ORIGINAL
  • Published:
Internal and Emergency Medicine Aims and scope Submit manuscript

Abstract

Sepsis-associated encephalopathy (SAE) is defined as a dysfunction of the central nervous system experienced during sepsis with variable clinical features. The study aims to identify the prognostic role of urinary ketone bodies in relation to clinical outcomes in patients with SAE. The Medical Information Mart for Intensive Care III (MIMIC-III) database was used to conduct a retrospective cohort study. We recruited 427 patients with SAE admitted to the intensive care unit (ICU) from the MIMIC-III database. Patients with SAE were divided into a survival group (380 patients) and a non-survival group (47 patients). We used the Wilcoxon signed-rank test and the multivariate logistic regression analysis to analyze the relationship between the level of urinary ketone bodies and the clinical prognosis in patients with SAE. The primary outcome was the relationship between urinary ketone body levels and 28-day mortality of SAE. The secondary outcomes were the relationship between urinary ketone body levels and length of ICU stays, Simplified Acute Physiology Score II, Sequential Organ Failure Assessment (SOFA), Glasgow Coma Scale, mechanical ventilation, renal replacement therapy, and the use of vasopressors. The 28-day mortality of patients with SAE was 11.0%. Urinary ketone body levels were not significantly associated with the 28-day mortality of patients with SAE. Urinary ketone body levels were associated with SOFA score and the use of vasopressors in patients with SAE. The SOFA score was an independent risk factor for the 28-day mortality in patients with SAE. Urinary ketone body levels were significantly associated with SOFA score and the use of vasopressors in patients with SAE. Furthermore, the SOFA score can predict the prognosis of short-term outcomes of patients with SAE. Therefore, we should closely monitor the changes of urinary ketone bodies and SOFA score and intervene in time.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

Availability of data and materials

The datasets analyzed during the current study are available in https://github.com/MIT-LCP/mimic-code/tree/master/concepts/severityscores.

References

  1. Gofton TE, Young GB (2012) Sepsis-associated encephalopathy. Nature reviews. Neurology 810:557–566

    Google Scholar 

  2. Ji MH, Qiu LL, Tang H et al (2015) Sepsis-induced selective parvalbumin interneuron phenotype loss and cognitive impairments may be mediated by NADPH oxidase 2 activation in mice. J Neuroinflamm 12:182

    Article  Google Scholar 

  3. Iwashyna TJ, Ely EW, Smith DM et al (2010) Long-term cognitive impairment and functional disability among survivors of severe sepsis. JAMA 30416:1787–1794

    Article  Google Scholar 

  4. Mina F, Comim CM, Dominguini D et al (2014) Il1-β involvement in cognitive impairment after sepsis. Mol Neurobiol 492:1069–1076

    Article  Google Scholar 

  5. Eidelman LA, Putterman D, Putterman C et al (1996) The spectrum of septic encephalopathy. Definitions, etiologies, and mortalities. JAMA 2756:470–473

    Article  Google Scholar 

  6. Cahill GF, Jr. (2006) Fuel metabolism in starvation. Annu Rev Nutr 26:1–22

    Article  CAS  PubMed  Google Scholar 

  7. Hawkins RA, Williamson DH, Krebs HA (1971) Ketone-body utilization by adult and suckling rat brain in vivo. Biochem J 1221:13–18

    Article  Google Scholar 

  8. Cotter DG, Schugar RC, Crawford PA (2013) Ketone body metabolism and cardiovascular disease. Am J Physiol Heart Circ Physiol 3048:H1060-1076

    Article  Google Scholar 

  9. Bradshaw PC, Seeds WA, Miller AC et al (2020) COVID-19: proposing a ketone-based metabolic therapy as a treatment to blunt the cytokine storm. Oxid Med Cell Longev 2020:6401341

    Article  PubMed  PubMed Central  Google Scholar 

  10. Youm YH, Nguyen KY, Grant RW et al (2015) The ketone metabolite β-hydroxybutyrate blocks NLRP3 inflammasome-mediated inflammatory disease. Nat Med 213:263–269

    Article  Google Scholar 

  11. Wang X, Song Y, Chen J et al (2020) Subcutaneous administration of β-hydroxybutyrate improves learning and memory of sepsis surviving mice. Neurother: J Am Soc Exp NeuroTher 172:616–626

    Article  Google Scholar 

  12. Fu SP, Li SN, Wang JF et al (2014) BHBA suppresses LPS-induced inflammation in BV-2 cells by inhibiting NF-κB activation. Mediat Inflamm 2014:983401

    Article  Google Scholar 

  13. Goossens C, Weckx R, Derde S et al (2019) Adipose tissue protects against sepsis-induced muscle weakness in mice: from lipolysis to ketones. Crit Care (Lond, Engl) 231:236

    Article  Google Scholar 

  14. Taggart AK, Kero J, Gan X et al (2005) (D)-beta-Hydroxybutyrate inhibits adipocyte lipolysis via the nicotinic acid receptor PUMA-G. J Biol Chem 28029:26649–26652

    Article  Google Scholar 

  15. Wang A, Huen SC, Luan HH et al (2016) Opposing effects of fasting metabolism on tissue tolerance in bacterial and viral inflammation. Cell 1666:1512-1525.e1512

    Article  Google Scholar 

  16. Huang M, Yu Y, Tang X et al (2023) 3-Hydroxybutyrate ameliorates sepsis-associated acute lung injury by promoting autophagy through the activation of GPR109α in macrophages. Biochem Pharmacol 213:115632

    Article  CAS  PubMed  Google Scholar 

  17. Soni S, Martens MD, Takahara S et al (2022) Exogenous ketone ester administration attenuates systemic inflammation and reduces organ damage in a lipopolysaccharide model of sepsis. Biochim Biophys Acta Mol Basis Dis 1868(11):166507

    Article  CAS  PubMed  Google Scholar 

  18. Puchalska P, Crawford PA (2017) Multi-dimensional roles of ketone bodies in fuel metabolism, signaling, and therapeutics. Cell Metab 252:262–284

    Article  Google Scholar 

  19. Byrne NJ, Soni S, Takahara S et al (2020) Chronically elevating circulating ketones can reduce cardiac inflammation and blunt the development of heart failure. Circ Heart Fail 136:e006573

    Article  Google Scholar 

  20. Ji L, He Q, Liu Y et al (2022) Ketone body β-hydroxybutyrate prevents myocardial oxidative stress in septic cardiomyopathy. Oxid Med Cell Longev 2022:2513837

    Article  PubMed  PubMed Central  Google Scholar 

  21. Puchalska P, Crawford PA (2021) Metabolic and signaling roles of ketone bodies in health and disease. Annu Rev Nutr 41:49–77

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Sonneville R, de Montmollin E, Poujade J et al (2017) Potentially modifiable factors contributing to sepsis-associated encephalopathy. Intensive Care Med 438:1075–1084

    Article  Google Scholar 

  23. Yang J, Li Y, Liu Q et al (2020) Brief introduction of medical database and data mining technology in big data era. J Evid Based Med 131:57–69

    Article  Google Scholar 

  24. Zhao L, Li Y, Wang Y et al (2021) Development and validation of a nomogram for the prediction of hospital mortality of patients with encephalopathy caused by microbial infection: a retrospective cohort study. Front Microbiol 12:737066

    Article  PubMed  PubMed Central  Google Scholar 

  25. Johnson AE, Pollard TJ, Shen L et al (2016) MIMIC-III, a freely accessible critical care database. Sci Data 3:160035

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Sprung CL, Peduzzi PN, Shatney CH et al (1990) Impact of encephalopathy on mortality in the sepsis syndrome. The Veterans Administration Systemic Sepsis Cooperative Study group. Crit Care Med 188:801–806

    Article  Google Scholar 

  27. Zhang LN, Wang XT, Ai YH et al (2012) Epidemiological features and risk factors of sepsis-associated encephalopathy in intensive care unit patients: 2008–2011. Chin Med J 1255:828–831

    Google Scholar 

  28. Pandharipande PP, Girard TD, Jackson JC et al (2013) Long-term cognitive impairment after critical illness. N Engl J Med 36914:1306–1316

    Article  Google Scholar 

  29. Chen J, Shi X, Diao M et al (2020) A retrospective study of sepsis-associated encephalopathy: epidemiology, clinical features and adverse outcomes. BMC Emerg Med 201:77

    Article  Google Scholar 

  30. Matsuda J, Kato S, Yano H et al (2020) The Sequential Organ Failure Assessment (SOFA) score predicts mortality and neurological outcome in patients with post-cardiac arrest syndrome. J Cardiol 763:295–302

    Article  Google Scholar 

  31. Martin-Loeches I, Guia MC, Vallecoccia MS et al (2019) Risk factors for mortality in elderly and very elderly critically ill patients with sepsis: a prospective, observational, multicenter cohort study. Ann Intensive Care 91:26

    Article  Google Scholar 

  32. Martin GS, Mannino DM, Moss M (2006) The effect of age on the development and outcome of adult sepsis. Crit Care Med 341:15–21

    Article  Google Scholar 

  33. Suissa L, Flachon V, Guigonis JM et al (2020) Urinary ketone body loss leads to degeneration of brain white matter in elderly SLC5A8-deficient mice. J Cereb Blood Flow Metab: Off J Int Soc Cereb Blood Flow Metab 408:1709–1723

    Article  Google Scholar 

  34. Soeters MR, Serlie MJ, Sauerwein HP et al (2012) Characterization of D-3-hydroxybutyrylcarnitine (ketocarnitine): an identified ketosis-induced metabolite. Metab: Clin Exp 617:966–973

    Article  Google Scholar 

  35. Tamaki T, Node Y, Teramoto A (2008) Changes of the plasma ketone body level and arterial ketone body ratio at the onset of mild aneurysmal subarachnoid hemorrhage. Neurol Res 309:898–902

    Article  Google Scholar 

  36. Manaka D, Okamoto R, Yokoyama T et al (1992) Maintenance of liver graft viability in the state of brain death. Synergistic effects of vasopressin and epinephrine on hepatic energy metabolism in brain-dead dogs. Transplantation 533:545–550

    Article  Google Scholar 

  37. Krentz AJ, Freedman D, Greene R et al (1996) Differential effects of physiological versus pathophysiological plasma concentrations of epinephrine and norepinephrine on ketone body metabolism and hepatic portal blood flow in man. Metab: Clin Exp 4510:1214–1220

    Article  Google Scholar 

Download references

Acknowledgements

The authors would like to thank MIMIC III program for access to the database.

Funding

None.

Author information

Authors and Affiliations

Authors

Contributions

Tian Ruan and Jianbo Yu designed the study. Tian Ruan, Chuanning Liu, and Mu Xu collected and analyzed the data. Ya Wu supervised the data and provided statistical advices. Tian Ruan wrote the paper. Jianbo Yu reviewed the paper. All authors approved the final manuscript.

Corresponding author

Correspondence to Jianbo Yu.

Ethics declarations

Conflict of interest

All authors confirmed that there were no conflicts of interest with the contents of this article.

Ethics approval and consent to participate

All patients in the database are anonymous, and no informed consent is required.

Consent for publication

Not applicable.

Human and animal rights

This article does not contain any studies with human participants or animals performed by any of the authors.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ruan, T., Wu, Y., Liu, C. et al. Prognostic role of urinary ketone body in patients with sepsis-associated encephalopathy without hepatic failure: a retrospective cohort study. Intern Emerg Med (2024). https://doi.org/10.1007/s11739-024-03563-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s11739-024-03563-1

Keywords

Navigation