Catálogo de publicaciones - libros

Sepsis is a complex syndrome characterized by systemic inflammation in response to infection. It is a significant health problem with an estimated 750,000 new cases in the USA annually []. It is also the third leading cause of death in developed countries, equalling the number of fatalities from acute myocardial infarction. The incidence of sepsis has increased in recent decades and is predicted to continue to rise. The high sepsis-related mortalities and the burden on healthcare systems means there is an urgent need to improve the diagnosis and management of sepsis patients.

Sepsis remains a major cause of death in critically ill patients admitted to the intensive care unit (ICU) []–[]. Infections increase the all-cause mortality during ICU admission from 12.1% in non-infected patients to 43.9% in infected patients []. Timely and effective antimicrobial treatment has crucial importance for prognosis. Delayed correct antimicrobial treatment substantially increases mortality []. The Surviving Sepsis Campaign has optimized multifactorial sepsis treatment in an evidence-based manner, to the benefit of critically ill patients with sepsis [].

The term “hormokine” was proposed to encompass the cytokine-like behavior of hormones, during inflammation and infections []. The concept was based on the finding of a ubiquitous expression of calcitonin peptides (i.e., procalcitonin [PCT], calictonin gene related peptides (CGRPs), and adrenomedullin [ADM]) during sepsis. Calcitonin gene products are prototypes of hormokine mediators and can follow either a classical hormonal expression in neuro-endocrine cells or a cytokine-like ubiquitous expression pathway in various cell types []. The inflammatory release of hormokines can be induced either directly via microbial toxins (e.g., endotoxin) or indirectly via a humoral or cell-mediated host response (e.g., interleukin [IL]-1β, tumor necrosis factor [TNF]-α, IL-6). Parenchymal cells (including liver, kidney, adipocytes, and muscle) provide the largest tissue mass and principal source of circulating hormokines in sepsis []. The greater mRNA induction and peptide release from parenchymal cells in comparison to circulating cells, appears to indicate a tissue-based, rather than a leukocyte-based mechanism of host defense, which is characteristic of hormokines. Lowering of circulating hormokines by specific antibodies improves survival in various animal models of mono- and polymicrobial sepsis. This important finding suggests potential therapeutic use.

As the molecular basis for disease becomes better understood the importance of biomarkers continues to grow. Novel techniques have led to the identification of large numbers of biologically significant compounds that could act as biomarkers. The appeal of these as diagnostic and therapeutic markers is obvious but the choice of marker for everyday clinical practice is not.

For over 100 years clinical medicine has relied on culture-based techniques to define infections in patients. However, over the past 30 years, it has become clear that culture-independent methods more completely describe both microbial diversity and community dynamics and the importance of such interactions in states of health and disease has been revealed [, ], Furthermore, the use of culture-based techniques has clouded our understanding of the pathogenesis of human infections. The concept that one species causes infection by entering the host, defeating the host’s defense system and multiplying to a threshold that allows it to cause injury is probably only applicable for a small subset of microbes, e.g., bioterror agents. The new emerging paradigm in microbial pathogenesis is that many organisms, such as , already exist in bacterial communities of the oro- and nasopharynx of most healthy individuals and that a change in their virulence gene expression and /or an increase in numbers permitting dissemination cause symptoms of infection []. The molecular signals that bring about these shifts in pathogen physiology are not fully understood; however, given the importance of bacterial cell-to-cell signaling (quorum sensing) it is possible that shifts in bacterial community composition may lead to emergence and dominance of pre-existing pathogenic species within the community This hypothesis is supported by the finding that within hours of their admission to the intensive care unit (ICU), critically ill patients exhibit dramatic changes in the bacterial communities colonizing their oro- and nasal pharynx [, ].

It is estimated that four million newborn infants die every year, of these 35% (1.6 million) die from sepsis []. Preterm infants are at greater risk of developing infection (often multiple) between birth and the first month of life compared to term infants. It is estimated that intra-uterine infection, a risk factor for developing severe infection, is present in up to 35% of preterm deliveries [].

Recent studies have demonstrated the importance of microcirculatory alterations in the early stage of sepsis []–[]. The gastrointestinal tract, particularly perfusion of the splanchnic bed and the integrity of the gut mucosa, occupies a key position in the pathogenesis of multiple organ failure (MOF) in sepsis.

Recombinant human activated protein C (rhAPC) has been demonstrated to reduce the mortality rate of adult patients with severe sepsis []. This effect is thought to be related to a reduction in coagulation and, to a lesser extent, to a reduction in the inflammatory response to sepsis. Data from the Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) study demonstrated that the use of rhAPC was associated with a quicker reduction in cardiovascular failure.

The existence of vasoactive peptide hormones was first reported more than 100 years ago []. Since then, several oligo- and polypeptides influencing blood pressure regulation have been identified. Some of these are direct vasoconstrictors, such as vasopressin, angiotensin II, endothelin-1, and neuropeptide Y and are classified as hypertensive agents. Other peptides, e.g., the natriuretic peptides, vasoactive intestinal peptide (VIP), and calcitonin-gene related peptide (CGRP), have direct vasodilatory properties and, thus, lower systemic blood pressure. Adrenomedullin belongs to the vasodilatory peptide hormones and plays a crucial role in the regulation and preservation of cardiovascular, endocrine and immunologic homeostasis [].

Before 1980, the endothelium was considered to be an inert hemostatic barrier. Furchgott and Zawadzki were the first to demonstrate the necessity of the vascular endothelium for vasodilatation to acetylcholine []. If the vascular endothelium was removed, the blood vessel failed to relax in response to acetylcholine, but still responded to glyceryl trinitrate. This endothelium-dependent vaso dilatation is mediated by an endogenous mediator, initially named endothelium-derived relaxing factor (EDRF), but which was subsequently identified as nitric oxide (NO). From this discovery a new era of endothelial research developed. The endothelium is now known to have a key role in the maintenance of vascular homeostasis. It actively regulates vascular tone, platelet aggregation, coagulation, fibrinolysis, and leukocyte activation []. Endothelial function is impaired in critical illness and may be important in the pathophysiology of multiple organ failure (MOF) [].