Background
In severe sepsis and septic shock, endotoxin (lipopolysaccharides [LPS]), IL-6 and complement-activation product 5a (C5a) trigger inflammatory cascades resulting in multiple organ dysfunction and failure of the cell-mediated immune system (immunoparalysis). This correlates with uncontrolled infection and fatal outcome. We therefore determined whether simultaneous removal of systemic LPS, IL-6 and C5a by selective immunoadsorption (IA) reduces hyperinflammation, reverses immunoparalysis and improves organ functions in patients with severe sepsis and septic shock.
Design
In a prospective, controlled, open-label fashion, 29 patients with severe sepsis or septic shock hospitalized in the ICUs of a university hospital were included in a proof-of-concept trial (ISASS-1). Patients were enrolled between 2002 and 2004 and followed-up for 28 days, until hospital discharge or death.
Methods
In addition to the best supportive ICU care, 11 patients (age 57.8 ± 2.2 years, Acute Physiology and Chronic Health Evaluation II [APACHE-II] score 23.7 ± 1.6) received extra-corporeal LPS-IA, IL-6-IA and C5a-IA on 5 consecutive days for 7.5 hours each. As control, prognostically relevant parameters of 18 contemporary patients (age 55.2 ± 2.6, APACHE II score 22.9 ± 1.2) were followed up.
Results
There was no difference between the study groups at baseline. Target molecules were reduced under IA: IL-6 (361.7 ± 116.0 to 38.2 ± 15.2 pg/ml, P = 0.003), C5a (297.6 ± 43.1 to 79.2 ± 14.5 ng/ml, P < 0.001) and markers of endotoxemia. In IA-treated individuals, IL-6 (P < 0.001), CRP (P = 0.001) and APACHE II score (P = 0.002) was significantly lower at day 7. Monocytic HLA-DR improved in IA patients (P < 0.001) and was unchanged in controls. HLA-DR recovered in all immunoparalytic patients under IA (4993.6 ± 1162 to 15,295.3 ± 2197 molecules/ cell, P = 0.002).
Conclusion
Immunoadsorption is a new, selective approach to target key inflammatory mediators in septic patients. Simultaneous targeting of LPS, IL-6 and C5a reduced major inflammatory mediators, reversed immunoparalysis and improved major disease severity scores.