Diseases 2.0 – Bringing you the latest updates on disease pathophysiology and treatment
Commentary by Andrew McKinstry MD PGY-1
Faculty Peer Reviewed
For anyone who has stepped into an ICU, the septic patient is a familiar sight. Despite advances in research and management, including goal directed therapy and recombinant human activated protein C (Xigris), sepsis continues to be a major cause of mortality in the critical care setting, with an estimated 215,000 deaths annually, and costing roughly 16.7 billion dollars per year. Despite these staggering human and monetary costs, the nature of and mechanisms involved in sepsis remain either unknown or hotly contested. The continuing research into this problem is on the verge of producing a number of promising insights and interventions, from insights into the nature of the syndrome to new pharmaceutical solutions and systems-based interventions.
While sepsis is a well-documented syndrome, there is debate among sepsis researchers whether sepsis is actually a number of different processes with a common late-stage presentation. While this could seem a largely academic debate, a mechanistic understanding of sepsis would be important in determining biomarkers for use in early detection of the syndrome. Recently, procalcitonin emerged as a possible candidate for a sepsis biomarker. Studies as early as 1993 described procalcitonin as an infection variable, and a few studies early this decade showed higher levels of procalcitonin in septic states than other inflammatory states. Further investigation found that while is was another good indicator of systemic inflammation, calcitonin was not specific for sepsis to be useful as a diagnostic test. Research groups at Duke University and Henry Ford Hospital, at the University of Zurich and members of the SPEEDI trial in Copenhagen are now in the process of throwing a wide net in search of sepsis biomarkers using high-throughput protein screening.
The available armamentarium against sepsis is limited to recombinant human activated protein C (APC) which targets one of the dysregulated systems in sepsis, coagulation, and likely affects what is the major dysregulation of sepsis, inflammation. APC has been shown to improve all-cause mortality in severe sepsis, though is ineffective and potentially harmful in less severe sepsis due to a high complication risk. Looking down the pipeline, at least two other drugs that target the hypercoaguable state in sepsis are in late phase trials. Recombinant human soluble thrombomodulin and recombinant anti-thrombin are in trials for treatment of DIC in sepsis, with the hope that they might provide a similar improvement in mortality with fewer hemorrhagic complications associated with APC.
Current drug research in sepsis is primarily focused on correction of inflammatory dysfunction, and coagulation dysfunction. Earlier theories of sepsis categorized it as a purely hyperinflammatory state, and unsuccessful experimental therapies focused on broad reduction of inflammation systemically. Coritcosteroid treatment has been shown to be ineffective, and there was a mixed picture for the efficacy of monoclonal anti-TNF antibodies in sepsis. While there was a meta-analysis of trials using monoclonal anti-TNF antibodies in severe sepsis suggests some efficacy, none of the individual trials showed any significant improvement in outcome.
Current theories on mechanisms of sepsis postulate a complex, heterogenous dysfunction of inflammatory processes- a cytokine storm that can lead to a mixed hyper- and hypoinflammatory state. In animal models of bacterial sepsis, blockade of IL-22 resulted in improved bacterial clearance in the liver and kidneys with reduced kidney damage, a possible future therapy aimed at prevention of end-organ damage in sepsis. Similarly, in translational studies blocking function of IL-27, subjects showed an increase in survival- another potential target for future therapies. Hemodiafiltration using a membrane that filters cytokines shows some promise in treating the cytokine storm of sepsis- human trials have shown decreased markers of end-organ damage, though no survival benefit has yet been demonstrated. Statins, the wonder drugs that seem to have no end of new uses, also show some potential in treatment of sepsis. Prior statin use has been shown to decrease the rate of severe sepsis in hospitalized patients, and statin use in patients with multi-organ dysfunction have been shown to have improved survival.
The ability of relatively small amounts of lipopolysaccharide (LPS) from gram-negative bacteria to induce a septic-shock-like condition has long been known, but the discovery in the last decade of the receptor through which LPS induces a vasodilatory state, Toll-like Receptor 4 (TLR4), presented a promising drug-target. Eritorian is a TLR4 antagonist currently in Phase III trials for treatment of severe sepsis, and TAK-242, a small molecule cytokine inhibitor of TLR4 signaling, is also in late phase trials.
Last but not least, some of the most significant advances in treatment of sepsis have not come from new pharmaceutical interventions, but in improved delivery of care. Early goal-directed therapy was hugely successful in improving sepsis outcomes, but now researchers at the University of Pittsburgh are performing a head-to-head comparison between goal directed therapy (which requires a central venous line with all of its associated complications) to protocolized care (which does not require a central line) in the treatment of septic patients. Who knows, depending on the results of that study, maybe next year in the ICU, not every sepsis patient will need that central line that they have now.
Given the variety of research and the number of late-phase trials currently underway, the clinical approach to sepsis will likely have a number of significant changes in the next five years. Improved diagnostic tests will help ensure earlier interventions, improved protocols will improve the quality of interventions, and new pharmaceuticals will be available for treatment of both complications of sepsis and the dysfunctional inflammatory state of sepsis itself. Continued success in sepsis research may mean that at some point in the no-so-distant future, a sepsis diagnosis will be as simple as a blood test, and pharmaceutical treatment will be as straight forward as antibiotics and an inflammatory modulator. In the mean time, though, make sure those fluids are hanging.
Reviewed by Laura Evans MD, NYU Division of Pulmonary and Critical Care Medicine
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One comment on “Diseases 2.0: Sepsis”
Nice discussion of the septic syndrome and potential etiologies and therapies. Clearly the inflammatory component starting with release of microbial products interacting with Toll-like receptors on monocyte-macrophages, followed by the release of numerous cytokines having a large variety of functions sseems central to the pathophysiology. The work of Mervyn Singer at the Imperial College in London suggests that host cell mitochondrial damage by cytokines may be the extreme and ultimate result in the most severe cases of sepsis and septic shock and is then associated with an inability of cells to utilizze oxygen with the hemodynamic paramters found in patients, presumably being an attempt, often ineffective, to combat the cellular relatively anaerobic state. That is still controversial.
Re clinical mgt of septic patients, it is impt to stress that at present there is only one treatment parameter that has been proven to significantly reduce mortality in bacterial sepsis and that has been demonstrated in many clinical trials since 1964–that is, the earliest possible use of an “effective” antibiotic regimen, defined as one that proves active (by standardized in vitro senstivity testing) against the ultimately isolated pathogen, That gets into the need to optimize all the clinical diagnostic aspects forthe patient re the most likely bacterial etiogic agent(s) and the best selection of the proper early empiric regimen of antibiotic(s).
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