Abstract
Liver dysfunction (LD) and liver failure are associated with poor outcome in critically ill patients. In patients with severe sepsis or septic shock, LD occurred in nearly 19% of patients. An early diagnosis of LD at time of initial damage of the liver can lead to a better prognosis of these patients because an early start of therapy is possible. We performed a second prospective study with septic patients to test a new cell-based cytotoxicity device (biosensor) to evaluate clinical relevance for early diagnosis of LD and prognostic capacity. In the clinical study, 99 intensive care unit patients were included in two groups. From the patients of the septic group (n = 51, SG), and the control (non-septic) group [n = 49, control group (CG)] were drawn 20 ml blood at inclusion, after 3, and 7 days for testing with the biosensor. Patients’ data were recorded for hospital survival, organ function, and demographic data, illness severity [acute physiology and chronic health evaluation (APACHE) II-, sepsis-related organ failure assessment (SOFA) scores], cytokines, circulating-free deoxyribonucleic acid/neutrophil-derived extracellular traps (cf-DNA/NETs), microbiological results, and pre-morbidity. For the developed cytotoxicity test, the human liver cell line HepG2/C3A was used. Patients’ plasma was incubated in a microtiter plate assay with the test cells and after 6 days incubation the viability (trypan blue staining, XTT-test) and functionality (synthesis of albumin, cytochrome 1A2 activity) was analyzed. An impairment of viability and functionality of test cells was only seen in the SG compared with the CG. The plasma of non-survivors in the SG led to a more pronounced impairment of test cells than the plasma of survivors at inclusion. In addition, the levels of cf-DNA/NETs were significantly higher in the SG at inclusion, after 3, and after 7 days compared with the CG. The SG showed an in-hospital mortality of 24% and the values of bilirubin, APACHE II-, and SOFA scores were markedly higher at inclusion than in the CG. Hepatotoxicity of septic plasma was already detected with the liver cell-based biosensor at inclusion and also in the course of disease. The biosensor may be a tool for early diagnosis of LD in septic patients and may have prognostic relevance.
Highlights
The development of liver dysfunction (LD) and liver failure in intensive care unit (ICU) patients have a relatively high incidence of 11% in all ICU patients and over 19% in patient with septic shock and is associated with increased in-hospital mortality [1,2,3,4].Because physiological and online parameters are unable to diagnose Liver dysfunction (LD) early, laboratory parameters, like transaminases, albumin, and coagulation factors are commonly used, without convincing clinical data for detection of early LD [5]
In a smaller first study, we showed that plasma of septic patients caused an impairment of functionality of hepatocytes in the cytotoxicity test compared with postoperative non-septic controls and healthy volunteers [22]
The septic patients were included in the study on average 0.5 ± 0.8 (0.2/0.8) days after beginning of severe sepsis or septic shock
Summary
The development of liver dysfunction (LD) and liver failure in intensive care unit (ICU) patients have a relatively high incidence of 11% in all ICU patients and over 19% in patient with septic shock and is associated with increased in-hospital mortality [1,2,3,4].Because physiological and online parameters are unable to diagnose LD early, laboratory parameters, like transaminases, albumin, and coagulation factors are commonly used, without convincing clinical data for detection of early LD [5]. The development of liver dysfunction (LD) and liver failure in intensive care unit (ICU) patients have a relatively high incidence of 11% in all ICU patients and over 19% in patient with septic shock and is associated with increased in-hospital mortality [1,2,3,4]. Serum bilirubin is often utilized for diagnosis of (early) LD in critically ill patients [3]; an increase of bilirubin is seen late in patients, 2–3 days after initial impairment of the liver and other organ damages as displayed in sepsis-related organ failure assessment (SOFA)-, and SAPS scores [6]. Experimental and clinical investigations have shown that impaired biliary secretion is the main component of early LD in systemic inflammatory response syndrome and sepsis [8,9,10,11,12]. Hepatotoxicity of inflammatory mediators like nitric oxide, chemokines and cytokines, endogen and exogen toxins like lipopolysaccharides, plasma cascade factors, and hepatic ischemia are the main pathophysiological factors for the development of LD leading to hyperbilirubinemia and intrahepatic cholestasis [3, 5, 10, 12,13,14,15,16,17,18]
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