Pathophysiology of septic shock and multiple organ dysfunction syndrome and various therapeutic approaches with special emphasis on immunoglobulins

Abstract

The pathophysiology of sepsis and septic shock is dominated by an imbalance of pro- and antiinflammatory mediators produced by toxin-activated inflammatory cells. Both the overshooting of proinflammatory mediators as well as the development of immune paralysis are deleterious to the patient. Available therapeutic approaches with monoclonal antibodies and antagonists targeted against toxins and mediators have focused mainly on inhibition of overshooting proinflammation: the results, however, have been disappointing. Due to these disappointing results of specific antiinflammatory regimens, adjuvant treatment of sepsis and septic shock with intravenous immunoglobulins (IVIgs) has regained interest although this indication has at best been validated in part. Likely beneficial mechanisms of action may include the improvement of serum bactericidal activity due to neutralizing and opsonizing IgG and IgM antibodies as well as stimulation of phagocytosis and neutralization of bacterial endo- and exotoxins; another attractive mode of action may represent Ig-mediated modification and specific suppression of proinflammatory cytokine release from endotoxin- and superantigen-activated blood cells. For the total group of patients with sepsis and septic shock, a reduction in mortality by IVIg could not be documented; however, in the SBITS study with 653 patients included, a moderate improvement in sepsis morbidity and multiple organ dysfunction syndrome was demonstrated. In defined sepsis sub-groups, a reduction in mortality by IVIg has been seen in each small, not yet confirmed trial. Thus, IVIg is not a magic bullet of sepsis treatment, but it may reduce morbidity and thereby may be useful in the therapeutic mosaic of sepsis treatment.