Endocrine, Metabolic & Immune Disorders-Drug Targets (Formerly Current Drug Targets - Immune, Endocrine & Metabolic Disorders) - Volume 6, Issue 2, 2006

Sepsis: From the Bench to the Bedside The term sepsis derives from the Greek sepsis, which means putrefaction. The pathogenesis and clinical manifestations of sepsis result from a complex interaction between the host and the infecting microorganism. Evolving at different stages of a continuum process it places the physician before a major challenge, a medical emergency associated with high morbidity and mortality [1-3]. Despite its importance and the progress of our understanding of the sepsis pathogenesis, how to define and recognize sepsis at the bedside, and how to use similar concepts in evaluating new therapeutic strategies are still matters of debate. Bone et al. have proposed a diagnostic system based on progressive stages of the sepsis disease: bacteremia (presence of positive blood cultures); sepsis (clinical evidence suggestive of infection plus signs of a systemic response to infection); sepsis syndrome (clinical diagnosis of sepsis plus the evidence of an altered organ perfusion); and septic shock [4]. In a consensus conference sponsored of the American College of Chest Physicians and the Society of Critical Care it was recognized that a wide range of insults could lead to a similar clinical picture through common pathways. They proposed the term Systemic Inflammatory Response Syndrome (SIRS) to encompass the clinical manifestations following pancreatitis, burns, trauma and others, with the term sepsis being restricted to the SIRS triggered by infections [5, 6]. Recently, several intensive care societies revisited the definitions for sepsis and related conditions. They concluded that "the concepts of sepsis, severe sepsis, and septic shock remain useful to clinicians and researchers", and expanded the list of signs and symptoms of sepsis. They proposed, however, a developing staging system for sepsis, similar to others used in clinical medicine, stratifying patients by their baseline risk and potential to respond to therapy. The classification is called PIRO, for predisposition conditions, the nature and extend of the insult, the nature and magnitude of the host response and the degree of the organ dysfunction [7]. The pathogenesis of sepsis is a fascinating area of investigation, and our understanding of its underlying mechanisms has improved markedly in recent years [1, 8, 9], specially in bacterial recognition and cellular signaling [10,11]. Perhaps in no other disease, even infectious, are the protective and deleterious responses so closely related. Indeed, they are part of the same process, and as such may not fit into a good or bad dychotomic response. Certainly, this is an important reason for the failure of many pathogenesis-oriented target adjunctive therapies [12]. It is interesting to note that the host-response to bacteria and their products is modulated by the ongoing septic process. In this context, it has been proposed that an anti-inflammatory response should proceed the initial inflammatory response [13], or that both would occur at a different balance in different tissues [14] during sepsis. The experimental work has been fundamental for the development and testing of sepsis concepts. From the chemical studies of LPS, its biological activities, the importance of the host-response in mediating its activity, which ultimately led to discovery of the LPS-gene, much of what we know from about sepsis derives from seminal experimental work. However, a great task has been to translate the basic knowledge into the clinical setting that is, by nature, much more complex. Our therapeutic approach to sepsis has improved in the recent years. While the appropriate use of antibiotics remains the main stone of the therapy, supportive therapy has gained renewed importance and new strategies based on pathophysiology are in use nowadays. Surely, as our understanding of pathogenesis improves, new targets will be identified. It is important to emphasize the existence of a number of time-dependent interventions that reduce mortality from sepsis. A surviving sepsis campaign was launched few years ago aiming to increase awareness and improve outcome in severe sepsis, by using education and monitoring of the standards of care as strategy [15]. In this issue of the Endocrine, Metabolic & Immune Disorders " Drug Targets we aimed to provide a comprehensive overview of sepsis, from the bench to the bedside. I thank the invited authors that brought excellent reviews, mostly based on their own data, offering a wide scope of experimental and clinical work, covering the pathogenesis of sepsis and its clinical therapy. REFERENCES [1] Salomao, R.; Rigato, O.; Pignatari, A. C.; Freudenberg, M. and Galanos, C. (1999) Infection, 27, 1- 11. [2] Angus, D.C.; Linde-Zwirble, W.T.; Lidicker, J.; Clermont, G.; Carcillo, J. and Pinsky, M.R. (2001) Crit. Care Med., 29(7),1303-10. [3] Martin, G.S.; Mannino, D.M.; Eaton, S. and Moss, M. (2003) N. Engl. J. Med., 348(16),1546-54. [4] Bone, R.C. (1991) Ann. Intern. Med., 114(4), 332-3......

An analysis of current literature on sexual dimorphism in response to trauma-hemorrhage revealed conflicting reports on the role of gender in outcomes of trauma patients. In contrast, results obtained from experimental studies clearly support the suggestion that gender plays a significant role in post injury pathogenesis. As discussed in this review, experimental studies suggest that the suppression of immune and cardiac function is severe in males and ovariectomized females; however, both immune and cardiac functions are maintained in proestrus females. Furthermore, findings from a number of studies have shown that the depletion of male sex hormones by castration or by blocking the interaction between male sex steroids and their receptors in males prevented the suppression of both immune and cardiac functions following trauma-hemorrhage. Moreover, administration of estrogen in males and ovariectomized females also prevented the suppression of immune and cardiac functions following trauma-hemorrhage. Thus, these experimental findings collectively suggest that female sex hormones (i.e., estrogen) produce salutary effects following trauma-hemorrhage whereas male sex steroids (i.e. 5α-dihydrotestosterone, 5α-DHT) are suppressive to immune and cardiac functions under those conditions. Such dramatic differences in the outcome of trauma-hemorrhage in proestrus females and males clearly suggest that the prevailing sex hormonal levels at the time of injury play a critical role in shaping the host response to trauma-hemorrhage. While a definitive cause for the conflicting data obtained in the clinical setting remains to be established, the discrepancy could be due to the differences in the hormonal levels at the time of injury. Since there is no information on hormonal status in the clinical studies, it is difficult to ascertain the role of sex hormones in post trauma pathogenesis. Therefore, in order to establish the role of gender in the outcome of trauma patients, more planned studies are needed in which the levels of sex hormones should be measured at the time of hospital admission. Furthermore, more studies, both in the clinical and experimental settings, should be performed to determine the mechanism by which the sex hormones improve immune and organ functions following trauma-hemorrhage. The findings obtained from these studies will help in designing innovative therapeutic approaches for the treatment of trauma patients.

Septic shock is a major cause of death following trauma and a persistent problem in surgical patients. It is a challenge to the critical care medicine specialist and carries an unacceptably high mortality rate, despite adequate antibiotic and vasopressor therapy. The prevalent hypothesis regarding its mechanism is that the syndrome is caused by an excessive defensive and inflammatory response. During the acute phase some signalling mechanisms are activated, particularly hormone release, which function to restore the host homeostasis that has been disturbed by the infection. Since the neuroendocrine and immune systems are functionally related, so the exposure to antigens induces a synchronized response, which allows the organism to successfully endure immunology changes. An important characteristic of this communication includes the appearance of proteins released into the circulation by activated immune cells. These proteins, called cytokines can enter the circulation and reach neuroendocrine organs, where they act either themselves or through the release of intermediates such as prostaglandin, catecholamines and nitric oxide. The synthesis of nitric oxide may be induced in brain as a consequence of infection and may alter the function of the hypothalamic-pituitary axis. In this review we discuss the physiologic roles of the nitric oxide in central nervous system controlling the regulation of vasopressin and oxytocin during the pathophysiology of sepsis.

Sepsis is the result from a complex bacterial-host interaction, which is an often-fatal response when host protective molecular mechanisms designed to fight invading bacteria surpass the beneficial intensity to the point of causing injury to the host. Increasing evidences have implicated the bacterial translocation (BT) as the main source for the induction of sepsis, although the beneficial effect of BT process has been related to the development of the intestinal immune response by physiological interaction between bacteria and host. In this article, we examined evolving concepts concerning to BT and discussed about its potential role in the promotion of microcirculation injury, moreover, its possible participation in the sepsis induction. According to our data obtained from in-vivo BT animal-model, both bacterial overgrowth and bacterial pathogenic determinants seem to be major predisposing factors for the induction of BT. Besides, translocation of luminal bacteria through the lymphatic via elicits the activation of the GALT inflammatory response contributing to microcirculation injuries, and the haematological via of BT was responsible to the systemic bacterial spread. On other hand, the combination of BT process to the pre-existing host systemic infection played a crucial role in the worsening of the clinical outcome. In our understanding, studies concerning to intestinal immune response and the pathophysiology of bacterial-host interaction, under normal and disease conditions, seems to be the key elements to the development of therapeutic approaches towards sepsis.

Sepsis and septic shock continue to be a major cause of morbidity and mortality in critically ill patients. During the onset of sepsis, several inflammatory mediators, including cytokines, chemokines and nitric oxide are released systemically and mediate most of the pathophysiological events present in sepsis and septic shock, such as cardiovascular dysfunction and target-organ lesions. Polymorphonuclear leukocytes are critical effector cells during the inflammatory process and their migration to the infection focus is extremely important for the local control of bacterial growth and consequently for the prevention of bacterial dissemination. In experimental models and in human sepsis a profound failure of neutrophil migration to the infection focus is observed. It seems that the failure of neutrophil migration is dependent on toll-like receptor 4 (TLR4) and mediated by cytokines and chemokines, which induce the production of nitric oxide that inhibits neutrophil adhesion to venular endothelium and also the neutrophil chemotactic ability.

Sepsis remains one of the leading causes of death in intensive care units, despite recent acquired knowledge on pathophysiology and treatment. Several mediators of inflammation and cellular damage have been implicated in the complex host-pathogen interaction underlying organ damage and multisystem organ failure , which are hallmarks of sepsis and common causes of death. Among such mediators, reactive oxygen/nitrogen species have been increasingly studied in the context of direct cytotoxicity as well as altered cell signaling. While the generation of reactive oxygen species by inflammatory cells in sepsis is well known, recent studies have shown that vascular cells are able to release reactive oxygen intermediates that may be associated with endothelial dysfunction of sepsis. These compounds can activate transcription factors such as NF-κB that sustain inflammatory process or enzymatic systems like poly(ADPribose) polymerase-1, which are involved in apoptosis and cytotoxicity of sepsis. Our laboratory recently showed that platelet-derived exosomes from septic patients carry components of a superoxide-producing NADPH oxidase and can, at least in vitro, induce apoptosis of endothelial and vascular smooth muscle cells by a ROS-dependent pathway. Taken together, these data show that reactive oxygen species are involved in cell signaling and organ injury in sepsis. Efforts must be made to identify the precise contribution of these factors in septic process, in order to clarify the mechanisms associated with the disease. This will certainly lead to discovery of therapeutic strategies that can help us to mitigate vascular dysfunction of sepsis.

Sepsis and septic shock are the major causes of morbidity and mortality in critically ill patients. During the onset of sepsis, a massive inflammatory reaction involving chemical mediators such as cytokines and chemokines and inflammatory cells such as the polymorphonuclear neutrophil and macrophage takes place. In addition to this systemic inflammatory process, sepsis and septic shocks cause a profound decrease in the peripheral vasomotor tone leading to a great decrease in the peripheral resistance. This event is central to derangement of hemodynamic and perfusional parameters. Nitric oxide (NO) is produced by several cell types and has been implicated in a wide range of physiological and pathological processes, with both detrimental and beneficial effects. There is a wealth of data implicating NO as a key player in all cardiac, vascular, renal and pulmonary derangements of sepsis and septic shock. Clinical assays trying to improve sepsis by inhibiting NO formation by NO synthases have met with failure, probably due to the lack of selectivity of inhibitors towards NOS isoforms. Notwithstanding the search for selective inhibitors, a better understanding of the NO molecular effector mechanisms may provide new opportunities for therapy development. Some of these NO effector mechanisms are discussed, including guanylate cyclase, nitrosothiols, potassium channels, reactive oxygen species and gene expression in the context of sepsis. Thus, more research on the relationship between NO and sepsis is clearly needed and warranted and may provide new therapeutic targets to treat sepsis and septic shock.

Sepsis is a complex disease and coagulation derangements are part of this context. The inflammatory storm is ultimately responsible for coagulation derangements. It is characterized by exacerbated coagulation, impaired anticoagulation and decreased fibrin removal. These derangements are implicated in the generation of microcirculation thrombosis, with deposition of microclots and obstruction of circulation, impairing blood flow and contributing to tissue hypoperfusion and consequently, organ dysfunction. This review will address the main issues regarding coagulation disorders in the context of sepsis.

The pathogenesis of sepsis involves complex interaction between the host and the infecting microorganism. Recognition and processing of microorganism antigens are essential functions of the cells of innate immune systems, and will ultimately, through the antigen presentation to the cells of adaptive immunity and the synthesis and secretions of mediators, such as cytokines, drive a coordinated immune response. Neutrophils and monocytes will therefore function as sensing and effectors cells. Fundamental in this process is the ability to discriminate self from non-self molecules. Of major interest in sepsis is that the protective and damaging host responses are part of the same process, that is, the inflammatory response that controls the infection process also underscores many of the pathophysiological events of sepsis. Moreover, this is a dynamic process according to the continuum of sepsis and its complications; up and down regulation of cellular activities may be differently regulated in different tissues, different cells and even in different functions of the same cell. This review will focus on microorganism recognition and signalization in sepsis, with emphasis on the neutrophils and monocytes adaptation during the ongoing disease.

The outcome of patients with sepsis arises from multiple factors affecting both the host and the invading microorganisms. Even within the setting of adequate antimicrobial use, patients still die of sepsis. Thus, strategies focusing on further therapy targets are an important area of interest for basic and clinical research. Although such adjunctive sepsis therapy has failed to achieve consistent better survival rates so far, the progress in understanding of the pathophysiology of sepsis seen in recent years is so profound, that the possibility that a new and effective treatment may arise should be warmly considered. Indeed, it may be considered that efficacious interventions, such as early and vigorous fluid replacement, strict blood glucose control, low-dose corticosteroid reposition, protective mechanical ventilation and activated-protein C are pathogenic-oriented targets of therapy. In this paper we aim to review some aspects of the pathogenesis of sepsis, focusing on possible targets for adjunctive therapy. Published clinical trials and experimental data supporting such trials are commented on.

Small volumes of 7.5% NaCl (2400mOsm/L) have been extensive evaluated in animal models of hemorrhagic shock and in clinical trials of post-traumatic hypotension and as volume support for complex cardiovascular procedures. Hypertonic solutions promote immediate blood volume expansion, restore cardiac output and regional blood flows, improve microcirculation and modulate immune responses, thereby decreasing inflammatory responses triggered by shock and trauma. A large number of very interesting in vivo and in vitro experiments highlighted that hypertonic saline resuscitation may decrease susceptibility to post-traumatic sepsis, modulate trauma and sepsis-induced immune dysfunction, inflammatory response and apoptosis. All those long-term benefits associated with hypertonic resuscitation may be of potential relevance for the management of severe sepsis and septic shock In this review, we describe the mechanisms of action of hypertonic saline based on experimental studies as well as its efficacy and safety based on its clinical use. We believe those studies support the need for additional experimental and clinical studies before the widespread use of hypertonic solutions for the treatment of severe sepsis and septic shock.

Severe sepsis is an ongoing challenge for clinicians and health-care administrators mainly because is associated with a high incidence, mortality rate and costs. In recent years, several epidemiological studies about the incidence of sepsis have come out in different and prestigious journals. However, it is not advisable to draw direct conclusions from those studies considering methodological flaws or even different approaches. Hence, we have to be familiar with those obstacles and know how to overcome them. This review paper highlights the methods which have been used in these studies and depicts the results of occurrence rate or incidence of sepsis in countries and in intensive care units.

The mortality rate of severe sepsis is still high (20 to 65%) despite the advances in critical care. The most important determinant of the prognosis in this condition is the occurrence of multiple organ dysfunction syndrome (MODS). The lung is the most frequently identified organ to fail in sepsis and is also the most frequent primary site of infection. The development of acute respiratory distress syndrome (ARDS) is common in those cases. The current understanding of the pathogenesis of ARDS suggests that the degree of inflammatory response and its sustained leukocyte activation may determine the clinical evolution of ARDS. The way that mechanical ventilation is delivered is responsible for the start and/or the perpetuation of a pro-inflammatory cascade activation that, due to the loss of the alveolar compartmentalization in ARDS, can reach the bloodstream and induce MODS. On the other hand, during sepsis, the alveolar compartmentalization is lost, allowing the passage of cytokines, released to the bloodstream by any other organ, to the pulmonary endothelium. These cytokines, especially IL-1, TNF-α and IL-8, have important roles in the lung dysfunction. Experimental and clinical studies have been demonstrated that ventilation strategies using low tidal volumes and limitation of airway pressures can block cytokines and reduce mortality of patients with respiratory failure. The studies are still insufficient to determine the role of pharmacological therapies in those patients.

Sepsis is an acute and severe disease associated with early and late high mortality, high and growing prevalence, and impressive costs. In October 2002, during the European Society of Intensive Care Medicine annual congress, the Surviving Sepsis Campaign was launched through a "Barcelona Declaration" - a document calling critical care providers, governments, health agencies and lay people to join the fight against sepsis. The aim of the campaign was to reduce the sepsis mortality rate by 25% within 5 years (actually, this deadline has been ended from 2007 to 2009). In 2003, a group of international critical care and infectious disease experts in the diagnosis and management of infection and sepsis met to develop guidelines that the bedside clinician could use to improve the outcome of severe sepsis and septic shock. A comprehensive document created from the committee's deliberations was published in prestigious journals. Thus, the SSC is a global, multi-organizational initiative to fight sepsis and undoubtedly, this campaign is a historic step for critical care medicine. This paper highlights the recommendations and the strategies proposed by SSC to implement them in intensive care units.