Kinetics of Biomarkers of Oxidative Stress in Septic Shock: A Pilot Study

Abstract

Septic shock is a major cause of mortality in ICU patients, its pathophysiology is complex and not properly understood. Oxidative stress seems to be one of the most important mechanisms of shock progression to multiple organ failure. In the present pilot study, we have analysed eight oxidative-stress-related biomarkers in seven consecutive time points (i.e., the first seven days) in 21 septic shock patients admitted to the ICU. Our objective was to describe the kinetics of four biomarkers related to pro-oxidative processes (nitrite/nitrate, malondialdehyde, 8-oxo-2'-deoxyguanosine, soluble endoglin) compared to four biomarkers of antioxidant processes (the ferric reducing ability of plasma, superoxide dismutase, asymmetric dimethylarginine, mid-regional pro-adrenomedullin) and four inflammatory biomarkers (CRP, IL-6, IL-10 and neopterin). Furthermore, we analysed each biomarker's ability to predict mortality at the time of admission and 12 h after admission. Although a small number of study subjects were recruited, we have identified four promising molecules for further investigation: soluble endoglin, superoxide dismutase, asymmetric dimethylarginine and neopterin.

Keywords: antioxidant; asymmetric dimethylarginine; biomarker; neopterin; oxidative stress; sepsis; septic shock; soluble endoglin; superoxide dismutase.

Figure 1

Course of biomarker changes in surviving patients (black points) and in deceased patients (red squares). Seven samples from each timepoint T1–T7 (T1—immediately upon hospital admission, T2—12 h after hospital admission, T3—24 h after hospital admission, T4—morning of the third day (approximately 48 h after hospital admission), T5—morning of the fourth day, T6—morning of the fifth day, T7—morning of the seventh day). Median and interquartile ranges are presented for each time point. * indicates statistical significance at T1, # indicates statistical significance at T2.

Figure 2

The diagram shows the presumed context of pathophysiological processes with sepsis. With sepsis, the host response to infection leads to deregulation of the inflammatory response. This is characterised by elevated CRP and neopterin levels. At the same time, oxidative stress is deregulated by increased ROS and RNS production. An indicator of excessive NO production is an increased NOx level. Opposite antioxidation mechanisms are also activated: SOD catalyses the conversion of the superoxide radical to the less toxic and reactive hydrogen peroxide and ADMA competitively suppresses NO synthesis. The level of plasma antioxidant capacity can be determined as FRAP. Oxidative stress leads to cell damage by lipid peroxidation and nucleic acid damage. The level of these phenomena is described by MDA and 8-OHdG markers, respectively. Endothelial dysfunction also develops. Through the activation of the transcription factor KLF6 and subsequent MMP14 metalloproteinase, a massive release of soluble endoglin from the endothelium occurs. Its function in respect of sepsis has not yet been clearly identified. It is not clear whether it is only due to or causes endothelial dysfunction. Among other things, it increases the production of NO. Damage to membranes, nucleic acids and the endothelium, caused by oxidative stress, leads to tissue damage, subsequent organ dysfunction and the development of multiorgan failure. The level of organ dysfunction correlates to the mortality of patients who are in septic shock.