Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
Reisinger, A.
Lipoproteins and metabolites in sepsis and septic shock in the intensive care unit
Doktoratsstudium der Medizinischen Wissenschaft; Humanmedizin; [ Dissertation ] Medizinische Universität Graz; 2022. pp. 108
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- Autor*innen der Med Uni Graz:
- Betreuer*innen:
- Eller Philipp
- Marsche Gunther
- Sourij Harald
- Altmetrics:
- Abstract:
- Background: Sepsis is a devastating disease and accounts for high mortality and morbidity in patients treated in the intensive care unit (ICU). Lipoproteins, especially the high-density lipoprotein (HDL) particles, play an important role in the innate immune defense. In addition, proton nuclear magnetic resonance (1H NMR) spectroscopy is an emerging technique for targeted and untargeted analyses of metabolites. Aim: To investigate quantitative and qualitative changes of lipoproteins during sepsis, investigate correlations with organ dysfunction and associations with ICU- and 28-day mortality. Methods: Adult patients with sepsis and septic shock, as well as ICU controls without sepsis or bacteremia were enrolled at the ICU of the Department of Internal Medicine at the Medical University of Graz. Sepsis was defined according to the current sepsis-3 criteria with a suspected infection by the treating physician and an increase in the sequential organ failure assessment (SOFA) score by ≥2 points. Septic shock was defined as patients with sepsis, with the need of vasopressor therapy to maintain a mean arterial pressure ≥65mmHg despite adequate fluid resuscitation and/or absence of hypovolemia; and a lactate level of >2 mmol/L. Quantitative assessments of lipoproteins were performed on routine laboratory machines. For qualitative lipoprotein measurements, both the arylesterase activity of the HDL associated paraoxonase (AEA) and cholesterol efflux capacity (CEC) were performed with ApoB-depleted sera. In addition, targeted and untargeted 1H NMR metabolomics were studied. Results: Fifty-three ICU patients with sepsis and 25 ICU controls without sepsis or bacteremia were prospectively enrolled. HDL-C <40mg/dL was more common in sepsis compared to controls (85 vs 52%, p=0.002). Quantitative lipoprotein parameters such as HDL-C were significantly lower in sepsis compared to controls (14 vs 39 mg/dL, p<0.0001), but were not associated with mortality endpoints. The qualitative HDL parameter AEA was significantly lower in sepsis compared to controls at 67 vs 111 mM/min/mL serum (p<0.0001), while the CEC showed a trend towards lower levels in sepsis compared to controls (9 vs 10 %, p=0.091). The AEA was significantly associated with ICU- and 28-day mortality in uni- and multivariable logistic regression analyses in the sepsis cohort. Lipoprotein alterations were confirmed in targeted 1H NMR metabolomic analyses. Furthermore, untargeted 1H NMR metabolomics identified differences of the branched-chain amino acids group, consisting of valine, leucine, and isoleucine. Non-survivors compared to survivors had lower levels of valine (33.0 vs 55.0 normalized signal intensity units (NSI), p=0.002), leucine (53.4 vs 70.8 NSI, p=0.005), and isoleucine (15.2 vs 18.1, p=0.012). Branched-chain amino acids were associated with ICU- and 28-day mortality in uni- and multivariable analyses. Conclusion: Quantity and functionality of lipoproteins are significantly different in ICU patients suffering from sepsis compared to non-sepsis ICU controls. The antioxidative and anti-inflammatory arylesterase activity of the HDL associated paraoxonase, representing parts of the HDL particle functionality, was a strong predictor for ICU- and 28-day mortality in patients with sepsis admitted to the ICU. Furthermore, branched-chain amino acids were additionally identified in metabolomic analyses as significant predictors for mortality endpoints.