By Mark Greener

Medical Journalist and Healthcare Communications Consultant

Severe sepsis and septic shock pose major problems for ICUs. Despite the best efforts of healthcare professionals, despite all the high technology at their disposal, despite being relatively common, mortality from sepsis remains stubbornly high.

In the major pharmaceutical markets, 1.5 million people develop sepsis each year. Thirty per cent of those patients who develop organ failure through sepsis are dead within a month. A further 20 per cent die within six months. Indeed, sepsis kills around 100,000 people in the USA annually. In Europe, an analysis presented at the Conference of the European Society of Intensive Care Medicine in October estimated that severe sepsis and septic shock kills up to 146 000 people a year.

Against this background, the report in March that a new drug - drotrecogin - reduced mortality in severe sepsis represents a major breakthrough. However, a quarter of patients still died despite drotrecogin. Fortunately, as this tour illustrates, a number of other specific drugs currently in development should help improve this bleak outlook.

Sepsis is at the most severe end of a spectrum of infection-related diseases. The invaluable online Merck Manual offers some useful definitions. Microbiologists describe bacteria in the blood as bacteraemia. Sepsis - the condition previously known as septicaemia - describes a serious localised or generalised infection, accompanied by inflammation. Septic shock arises when sepsis leads to low blood flow (hypoperfusion) and low blood pressure (hypotension) that doesn't respond to fluid therapy.

However, the chapter adds that numerous factors other than bacterial infections - including pancreatitis, burns, and trauma - can cause a similar shock syndrome. In all these, the release of numerous mediators triggers acute inflammation. This condition is described as the systemic inflammatory response syndrome. Indeed, the University of Queensland's useful introduction to septic shock explains that the release of these substances leads to under-perfusion and tissue hypoxia (lack of oxygen), which causes the cardiovascular abnormalities and multiple organ dysfunctions that typify septic shock. If you want to learn more, Healthsquare.com offers an explanation tailored towards the general public .

Until recently, sepsis treatment relied on antibiotics and supportive therapies to maintain organ function. As a press release announcing a discussion of drotrecogin at this year's Society of Critical Care Medicine annual meeting notes: There is no drug therapy currently approved in the US to treat sepsis. Following the promising results with drotrecogin that's about to change.

Eli Lilly's recombinant activated protein C (drotrecogin) is an undisputed breakthrough. Protein C is antithrombotic, profibrinolytic, anti-inflammatory and a cornerstone of the body's defences against severe infection. Sepsis, however, overwhelms these defences and consumes circulating protein C. The severe inflammation in sepsis means that activated protein C concentrations are insufficient to counter coagulation and inflammation.

Against this background, results from the PROWESS (Recombinant human protein C Worldwide Evaluation in Severe Sepsis) study, published in the New England Journal of Medicine, found that drotrecogin alfa (Xigris) reduced deaths in people with severe sepsis by 19.4 per cent. Mortality over 28 days fell from 30.8 per cent in the placebo group to 24.7 per cent among those treated with drotrecogin.

Drotrecogin will, undoubtedly, be launched with a chorus of approval and considerable market noise. In this case, the drug appears to be worthy of the hype.

Nevertheless, a quarter of patients still die, despite drotrecogin. Fortunately, a number of other companies are working on drugs that take different approaches to managing septic shock.

For example, nitric oxide (NO) is an important mediator in several biological systems. And in the vasculature, NO dilates blood vessels. The inflammatory cascade that leads to sepsis seems to trigger NO overproduction. The resulting vasodilatation results in excessively low blood pressure and reduced blood flow to organs. As a result, NO contributes to organ failure.

NO also seems to facilitate microbes' movement from the intestines into the blood, a process called bacterial translocation. This movement can increase the risk of sepsis, for example following surgery.

Against this background, Medinox is currently assessing the small molecule NO-antagonist NOX-100 in Phase I/IIa clinical trials for sepsis. According to the pages covering NOX-100 on the Medinox website, the agent improved haemodynamics, protected against organ failure, prevented bacterial translocation, and reduced mortality in animal models.

Apoptosis - programmed cell death - also plays a central role in sepsis. A group of enzymes known as caspases modulate cell survival by controlling apoptosis. The family of caspases genes encodes proteases that kill cells. Idun Pharmaceuticals are assessing caspase inhibitors for several potential indications, including sepsis.

You can learn more about these important enzymes, which play a role in numerous diseases - including heart attacks, stroke, liver failure and many others - by pointing your browser at Idun's scientific background pages. Their disease programme pages offer some insights into the possible clinical applications for caspase inhibitors. This is an area with which most of you should have at least a passing acquaintance. The applications could touch on many therapeutic areas.

As a final example, lipoproteins in the blood bind and remove bacterial toxins. However, lipoprotein levels are low in the severely ill. Earlier this year, GSK and Sepsicure entered a licensing agreement to develop a lipid emulsion that the body converts into lipoproteins that binds endotoxin, a common trigger for sepsis. For example, bacteria release endotoxin during translocation from the bowel to the blood. The lipid emulsion should help slow the progression of sepsis. The Rogosin Institute at Cornell University discovered the compound - GR 270773 - and set up Sepsicure to commercialise the idea

Sepsis is an especially difficult condition for even highly skilled ICU staff to manage. Apart from being serious in its own right, many people who develop sepsis are already weakened by illness or injury. So it's unlikely than mortality will ever be eliminated in this vulnerable group. But the new drugs mentioned in this tour should markedly improve outcomes in this deadly disease.

Do you have any comments on this article? Please contact Mark directly at greenermj@aol.com

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