Manchester Critical Care Symposium Abstracts: John Marshall Sepsis: The bacterium or the host? Sepsis is defined as the maladaptive systemic host response to invasive infection. This brief definition conceals enormous biologic and conceptual complexity. Microorganisms are an essential part of a healthy multicellular organism, supporting normal development, metabolism, and host defense. However when members of the indigenous flora, or pathogens from the environment invade normally sterile tissues, they evoke a response whose evolutionary role is to limit spread and eliminate the organism. Bacteria release virulence factors such as coagulase from S. aureus that facilitate tissue invasion, and the pathogenicity of infecting organisms and the clinical syndromes resulting from infection show substantial diversity. However uncontrolled microbial proliferation is uncommonly seen during infection, reflecting the effectiveness of host defense mechanisms. The activation of these mechanisms also underlies the clinical syndrome of sepsis. Bacterial or fungal products activate cells of the innate immune system by engaging dedicated cell surface receptors such as members of the Toll-like receptor family. Receptor engagement results in profound alterations in gene transcription, with increased synthesis and release of a large number of protein cytokines, and equally marked inhibition of other genes, particularly genes involved in innate immunity. These products alone, in the absence of infection, can trigger clinical manifestations of sepsis, suggesting that it is the host, rather than the bacterium, that is responsible for the clinical phenotype. That both susceptibility to infection, and the risk of death following infection, are strongly shaped by genetic factors underlines the important role played by this complex host response. Elimination of the organism is a core element of the treatment of sepsis, and fundamental to limiting the host response that, while it facilitates infection control, is also responsible for the morbidity and mortality of the syndrome. Endotoxin as a therapeutic target in critical illness Endotoxin, also known as lipopolysaccharide or LPS, is a complex cell wall lipid that makes up about 10% of the weight of a Gram negative bacterium. It is released when Gram negative bacteria are lysed. However because of the number of Gram negative bacteria in the gastrointestinal tract, a normal human being has approximately 25 grams of bacteria in the gut in a state of health. Since nanogram doses are sufficient to evoke signs and symptoms of sepsis in human volunteers, the absorption of very small quantities of endotoxin from the gut can evoke a clinically evident response. Studies of endotoxemia show that circulating endotoxin can be identified in the majority of patients admitted to an ICU, and that endotoxemia related to systemic hypotension can be seen following a variety of illnesses including congestive heart failure, burns, multiple trauma and pancreatitis. Indeed endotoxin can be detected in the blood following extended vigourous exercise, consistent with the view that the innate immune system exploits a bacterial product, using it as a kind of exogenous hormone. Multiple strategies to remove or localize endotoxin have been evaluated. Endotoxin can be neutralized by antibodies, by the antibiotic polymyxin B, and by the neutrophil protein, BPI. Its binding to plasma proteins can be blocked by lipoproteins such as HDL, and its binding to its receptor complex inhibited by the LPS analog eritoran or by antibodies to CD14. Further the early events in receptor activation can be inhibited by the compound Tak242. None of these approaches has shown clear evidence of efficacy in human sepsis. The reasons are many. Some antibodies may not have been efficacious in vivo. The clinical criteria used to recruit patients do not necessarily identify patients with endotoxemia. Finally there is even evidence that neutralizing endotoxin may be harmful in some patients, especially those with Gram positive infections. An ongoing study (the EUPHRATES trial) is evaluating the efficacy of extracorporeal removal of endotoxin using a polymyxin B column; only patients with significantly elevated endotoxin levels are being recruited. As we learn more about the biology of sepsis, it is likely we will identify effective strategies to inhibit endotoxin activity to improve outcomes in some patients with sepsis. However it is also entirely probably that we will identify a population of patients in whom administration of endotoxin is beneficial. Is critical illness a disease? While the definition of a disease is intuitively simple – a state in which quality of life is diminished because of a derangement of optimal biologic homeostasis – it is enormously challenging to apply to the common disorders of critical illness. While critically ill patients may be admitted to hospital with a definable illness such as pneumococcal pneumonia or closed head injury, their trajectory within the ICU is rarely shaped exclusively, or even primarily by that illness. Pneumococci are readily eliminated using antibiotics, and persistently positive cultures are uncommon. However the adverse clinical condition frequently continues to evolve, and is given names such as sepsis, ARDS, acute kidney injury and others. Are these diseases, are they complications of diseases, or are they complications of the way we manage the diseases? These nuanced differences have important implications for how we manage the critically ill patient. Classical notions of disease are of particular importance early in the course of critical illness as we seek to optimize the management of peritonitis secondary to colonic ischemia, right ventricular failure, or variceal bleeding secondary to end-stage liver disease. Management is disease specific, and generally guided by therapeutic principles that apply to all patients with the disorder, regardless of how ill they are. The concept that ARDS or sepsis is a disease suggests that each has a characteristic pathologic basis, and that targeting elements of the pathologic process can alter the course of the disease. This remains an unsupported hypothesis – perhaps because the diseases are complex, and represent multiple different processes creating a common phenotype, or perhaps because it is conceptually wrong. The notion that the disease of critical illness is at least in part what we do to the patient, while perhaps counter-intuitive and unfamiliar, is proving compelling in practice. That ARDS is a complication of the way we ventilate patients is suggested by the fact that lung protective strategies improve outcome, or that prone positioning is similarly protective. The concept that the sequelae of sepsis are in part a function of the way we give fluids is supported by studies showing that the choice and amount of fluid is critical to survival. In reality the question “Is sepsis a disease?” may be answered both yes and no, but considering it from both perspectives can provide valuable insights to inform patient care.