Systemic sepsis from gram-negative bacteria is now a common problem in hospital settings worldwide. It is associated with a high morbidity and frequently fatal sequellae. The advent in the 1960s of modern, potent antibiotics against the gram-positive bacteria revealed a new major threat to the survival of critically ill surgical patients (12). Attention was focused on Gram-negative sepsis and its hemodynamic manifestations. The subsequent advances in cardiovascular and respiratory supportive therapy unmasked the physiologic disorders associated with Gram-negative sepsis and lead to the description of a progressive and sequential failure of multiple organ systems as the final common pathway of bacterial infection (13, 14).
By the end of the 1970s however, the multiple organ failure syndrome was becoming distinctly separated from septicemia, and physicians started to describe a group of patients who manifested the clinical symptoms and outcome of sepsis, and yet had persistant negative blood culture and did not demonstrate a convincing focus of infection.
Following the observation that intensive antibiotherapy could sometimes enhance the clinical symptoms, attention was focused on a component of gram-negative bacterial cell wall: Lipopolysaccharides (LPS) that could be liberated in large amount in the circulation following bacterial lysis by the therapeutic agents (15). The observation that mortality rate correlated well with blood concentration of LPS in patients suffering from gram-negative infection (16), along with observations on animal models and administration to healthy volunteers (17), provided support for the role of LPS in the development of the multiple organ failure syndrome. Lipopolysaccharides have now been implicated in the pathogenesis of Gram negative sepsis, endotoxic shock, adult respiratory distress syndrome (ARDS) and multiple organ failure syndrome.
LPS molecules consist of a lipid core (lipid A) attached to a polysaccharide moiety. The lipid A region is believed to mediate most of the biological effects of LPS and can alone reproduce its toxicity. A 2-keto-3-deoxyoctonate links the lipid A region to the oligosaccharide region called the O-antigen (18, 19). This O-antigen is the only variable region in the LPS molecule and is responsible for the heterogeneity of the response between LPS from different strains of bacteria.
Exposure to low doses of LPS has been hypothesized to be fairly frequent as the gastro-intestinal tract, and more specifically the colon, contains an indigenous bacterial flora with a large number of Gram-negative species. Disturbances of the gastro-intestinal barrier can result in an influx of Gram-negative bacteria first in the liver via the portal vein, and then to the general circulation (20, 21). The liver appears to play a critical role in preventing systemic endotoxemia by the activity of the resident macrophages (kupffer cells) that clear LPS from the general circulation (22).
Gram negative septicemia, and its common treatment with antibiotics can produce a 50 to 2000 fold increase in the blood level of free LPS as a result of the bacterial wall lysis (15, 23). This increase in LPS concentration in the blood leads to numerous pathophysiological alterations. The most comonly reported adverse effects are hypotension with decreased cardiac output, increased pulmonary arterial pressure and vascular permeability in the lungs, disseminated intravascular coagulation, complement activation, and sequential damage to the heart, lungs, kidneys and liver. This is known as the "multiple organ failure syndrome".
It is clear now that many of the adverse effects are dependant on the generation of endogenous mediators. A multitude of mediators have been implicated, including arachidonic acid metabolites, PAF, cytokines such as TNF-a, interferon and various interleukines, reactive oxygen metabolites, and components of the coagulation cascade (1).
The discovery of the importance of lipopolysaccharide and endogenous cytokines in the pathogenesis of the multi-organ failure syndrome have lead to numerous therapeutical attempts to block the process. However, clinical trials of anti-endotoxin monoclonal antibodies have not shown them to have any therapeutic benefit and anti-interleukin-1 and anti-tumor necrosis factor-alpha therapies have demonstrated efficacy when administered preventively in animal models, but not clinically in human trials (13, 24, 27).
