Current Pharmaceutical Design - Volume 14, Issue 19, 2008

Sepsis is a common and devastating syndrome that causes over 200,000 deaths per year in the United States, and the incidence of sepsis is increasing at an alarming rate. The manifestations of sepsis result from the complex interaction between microbe and host. Microbial invasion triggers a robust but tightly regulated host inflammatory response. However, when this response becomes amplified and dysregulated, a cascade of maladaptive events ensue, culminating in tissue hypoperfusion, multiple organ failure, and even death. Past clinical trials targeting either selected microbial products or host inflammatory responses have produced disappointing results. However, exciting new research has provided novel insights into disease pathogenesis in sepsis, opening the door to the development of innovative therapeutic strategies in the treatment of patients with this syndrome. In this Special Issue, we will review clinical manifestations and pathogenic mechanisms in sepsis, with a particular emphasis on novel mediators and pathways involved. Drs. Hodgin and Moss [1] will discuss the changing epidemiology of sepsis and how these changes have impacted both causes of sepsis and clinical outcomes. Dr. Crouser and colleagues [2] provide an introduction to novel inflammatory targets in sepsis, including host derived molecules that activate toll receptor signaling cascades. These authors highlight the importance of other fundamental processes in disease pathogenesis, including mechanistic links between sepsis-induced inflammation, mitochondrial dysfunction, and multiple organ failure. Dr. Ayala and associates [3] discuss the critical role of apoptosis in sepsis, including effects on organ function and immunity. Activation of the coagulation cascade is a hallmark of sepsis, and compelling evidence indicates that microvascular thrombosis contributes to pathophysiologic events in sepsis. Wang and colleagues [4] outline mechanisms of abnormal coagulation in sepsis and review the findings of clinical trials aimed at disrupting coagulation cascades. The septic response is associated with a profound state of immune suppression, which is temporally associated with reprogramming of leukocyte immune responses. Putative mediators of leukocyte reprogramming in sepsis include inhibitors of pathogen recognition receptors, anti-inflammatory cytokines, ligands of nuclear hormone receptors, pro-apoptotic molecules, and epigenetic changes of key regulatory genes. Drs. Lyn-Kew and Standiford [5] discuss molecular mechanisms of impaired innate and acquired immunity in sepsis, and explore novel approaches to reverse these deleterious events in both animal models and patients with sepsis. Sepsis-induced alterations in corticosteroid responses are common and of substantial clinical importance. Dr. Annane [6] reviews causes of abnormal corticosteroid responses in sepsis, and discusses the merits of glucocorticoid therapy in this patient population. Patients with sepsis also have marked impairment in glucose metabolism, which is partially attributable to a relative state of insulin resistance. Implications of hyperglycemia include persistent inflammation, cellular toxicity, and impairment in leukocyte antimicrobial function. Dr. Van Cromphaut and colleagues [7] define mechanisms involved, and discuss the impact of insulin therapy on cellular responses and clinical outcomes in critically ill patients, including patients with sepsis. The influence of genetic variations on gene expression patterns in sepsis is an intense area of research. Dr. Wurfel [8] provides an informative summary of common sequence variations in genes involved in innate immunity, inflammation, and coagulation, and how these genetic factors influence disease susceptibility and expression in sepsis. In the final article of this Issue, Drs. Kaul, Collins, and Hyzy [9] address the important topic of antimicrobial therapy in sepsis, including an overview of evolving patterns of antimicrobial resistance and the status of new classes of antimicrobial agents in development. Collectively, this Special Issue of Current Pharmaceutical Design provides a timely and comprehensive update of new directions in sepsis research that may ultimately fuel a real paradigm shift in our approach to the treatment of this deadly disease. References [1] Hodgin KE, Moss M. The Epidemiology of Sepsis. Curr Pharm Des 2008; 14(19): 1833-1839. [2] Crouser E, Exline M, Knoell D, Wewers MD. Sepsis: Links Between Pathogen Sensing and Organ Damage. Curr Pharm Des 2008; 14(19): 1840-1852. [3] Ayala A, Perl M, Venet F, Lomas-Neira J, Swan R, Chung C-S. Apoptosis in Sepsis: Mechanisms, Clinical Impact and Potential Therapeutic Targets. Curr Pharm Des 2008; 14(19): 1853-1859. [4] Wang L, Bastarache JA, Ware LB.The Coagulation Cascade in Sepsis. Curr Pharm Des 2008; 14(19): 1860-1869. [5] Lyn-Kew K.L, Standiford TJ. Immunosuppression in Sepsis. Curr Pharm Des 2008; 14(19): 1870-1881. [6] Annane D. Adrenal Insufficiency in Sepsis. Curr Pharm Des 2008; 14(19): 1882-1886. [7] Van Cromphaut SJ, Vanhorebeek I, Van den Berghe G. Glucose Metabolism and Insulin Resistance in Sepsis. Curr Pharm Des 2008; 14(19): 1887-1899. [8] Wurfel MM. Genetic Insights into Sepsis: What Have We Learned and How Will It Help? Curr Pharm Des 2008; 14(19): 1900-1911. [9] Kaul DR, Collins C, Hyzy RC. New Development in Antimicrobial Use in Sepsis. Curr Pharm Des 2008; 14(19): 1912-1920.

Sepsis is a common and devastating syndrome that represents a significant healthcare burden worldwide. The average annual cost to care for patients with sepsis has been estimated to being $16.7 billion. Uniform definitions have been developed for the spectrum of sepsis syndrome, including the systemic inflammatory response syndrome (SIRS), sepsis, severe sepsis and septic shock. SIRS describes the clinical manifestations derived from an acute yet nonspecific illness, whereas an infectious etiology is required for the diagnosis of sepsis. As sepsis progresses, organ system dysfunction becomes apparent (severe sepsis) with the final development of fluid refractory cardiovascular dysfunction (septic shock). Pulmonary, gastrointestinal, genitourinary, and primary bloodstream infections account for the majority of infectious sources in septic patients. Since 1987, gram positive bacteria have become the most common organisms responsible for the development of sepsis. Several risk factors for the development of sepsis have been identified including male sex, race, age, comorbid medical conditions, alcohol abuse, and a lower socioeconomic status. Seasonal variations also exist, with sepsis being more common in the winter months. Fortunately, the case fatality rates for both sepsis and severe sepsis have diminished over the last two decades. However, patients who survive their episode of sepsis continue to have increased morbidity and mortality up to five years after their initial illness.

The host's inflammatory response to sepsis can be divided into two phases, the initial detection and response to the pathogen initiated by the innate immune response, and the persistent inflammatory state characterized by multiple organ dysfunction syndrome (MODS). New therapies aimed at pathogen recognition receptors (PRRs) particularly the TLRs and the NOD-like receptors offer hope to suppress the initial inflammatory response in early sepsis and to bolster this response in late sepsis. The persistence of MODS after the initial inflammatory surge can also be a determining factor to host survival. MODS is due to the cellular damage and death induced by sepsis. The mechanism of this cell death depends in part upon mitochondrial dysfunction. Damaged mitochondria have increased membrane permeability prompting their autophagic removal if few mitochondria are involved but apoptotic cell death may occur if the mitochondrial losses are more extensive. In addition. severe loss of mitochondria results in low cell energy stores, necrotic cell death, and increased inflammation driven by the release of cell components such as HMGB1. Therapies, which aim at improving cellular energy reserves such as the promotion of mitochondrial biogenesis by insulin, may have a role in future sepsis therapies. Finally, both the inflammatory responses and the susceptibility to organ failure may be modulated by nutritional status and micronutrients, such as zinc, Therapies aimed at micronutrient repletion may further augment approaches targeting PRR function and mitochondrial viability.

The inability of present therapies to mitigate the devastating effects of sepsis and multiple organ failure in the critically ill patient indicates that more knowledge of the pathophysiology of sepsis is needed if we are to develop better, more effective interventions. This review will examine the concept that a portion of the immune and organ dysfunctions encountered in the septic rodent/ patient is a reflection of not only the types of cells stimulating/ mediating the apoptotic response, but also the varying capacity of the target cell in a given tissue/ organ to perceive these death receptor stimuli as either an apoptotic, inflammatory and/or necrotic signal. We hope the discussion of such studies provides not only new insight into the pathobiology of sepsis, but also suggests possible therapeutic targets for the management of this devastating condition.

Intravascular and extravascular fibrin formation are characteristic findings in patients with sepsis, suggesting that the activation of coagulation and the inhibiton of fibrinolysis are important in the pathogenesis of sepsis. Activation of coagulation during sepsis is primarily driven by the tissue factor (TF) pathway, while inhibition of fibrinolysis is primarily due to increases in plasminogen activator inhibitor -1(PAI-1). Downregulation of the anticoagulant Protein C pathway also plays an important role in the modulation of coagulation and inflammation in sepsis. Recent advances in the understanding of pathogenetic mechanisms of coagulation and fibrinolysis in sepsis may have therapeutic implications. Recombinant human activated protein C (rhAPC) is currently the only pharmacologic therapy that has been shown to reduce mortality in adults with severe sepsis, highlighting the importance of coagulation and fibrinolysis as a therapeutic target in sepsis. This review summarizes recent basic and clinical findings with regard to the role of the coagulation cascade in sepsis and explores potential therapeutic targets in the coagulation and fibrinolytic pathways in the management of sepsis.

The often fatal sepsis syndrome is characterized by the systemic release of inflammatory mediators, which is regulated and counterbalanced by the coordinated expression of anti-inflammatory molecules. The magnitude of sepsis-induced tissue injury and subsequent risk of infectious complications is dictated by the balance between the expression of pro- and anti-inflammatory mediators. As our understanding of the pathophysiology of sepsis continues to evolve, we have gained a greater appreciation for the profound effects that sepsis and similar states of overwhelming stress have on host innate and adaptive immunity. Impaired leukocyte function in sepsis has important clinical consequences, as high mortality rates have been observed in patients who display evidence of sepsis-induced immune dysregulation. Functional defects in leukocytes isolated from patients with sepsis include diminished expression of important cell surface molecules, dysregulated cytokine production, alterations in antigen-presenting ability, and accelerated apoptosis. In this article, we review the current literature supporting the notion that dysregulation of host immunity occurs during sepsis syndrome, and describe novel therapeutic interventions directed at augmenting host immunity during sepsis.

The role of the hypothalamic-pituitary adrenal axis in the host response to infection is crucial. The initial inflammatory response to sepsis activates the endogenous release of cortisol, which in turn modulates the synthesis and release of both pro- and antiinflammatory mediators to restrict inflammation in infected tissues. However, a number of factors, including vascular or ischemic damage, inflammation and apoptosis within the hypothalamic-pituitary adrenal axis, as well as use of drugs that alter cortisol metabolism, may cause adrenal insufficiency. One major problem ICU physicians are faced with is the diagnosis of sepsis-induced adrenal insufficiency at the bedside. A multidisciplinary international task force has recently recommended that sepsis induced adrenal insufficiency is best recognized by basal cortisol of less than 10μg/dl or change in cortisol of less than 9μg/dl after administration of corticotrophin. The diagnostic value of measuring salivary free cortisol in this setting remains to be investigated. While sepsis adrenal insufficiency is undoubtedly associated with a poor prognosis, the indication and practical modalities of corticosteroids therapy remained controversial. Based on the two largest randomised, placebo-controlled trials, many investigators, myself included, contend that septic shock patients with hypotension poorly responsive to fluid replacement and vasopressors should receive a seven day treatment with the combination of hydrocortisone at a dose of 200 mg per day and fludrocortisone at the dose of 50 μg per day.

Hyperglycemia is a common feature of the critically ill in general and of patients with sepsis in particular. Even a moderate degree of hyperglycemia appears detrimental for the outcome of critically ill patients, since maintenance of normoglycemia (blood glucose levels ≤110 mg/dL) with intensive insulin therapy has shown to improve survival and reduce morbidity in prolonged critically ill patients in both surgical and medical intensive care units, as revealed by two large randomized controlled studies. Subsequently, questions have been raised regarding the efficacy and safety of this intervention, above all in the major subpopulation of intensive care patients presenting with sepsis, who are particularly susceptible to hypoglycemia as well. Adequately powered and executed randomized controlled trials addressing explicitly the impact of hyperglycemia, tight blood glucose control and the inherently increased risk of hypoglycemia on mortality and morbidity in patients with sepsis are presently lacking. However, the available literature suggests a causal link between hyperglycemia and adverse outcome in sepsis and a benefit of intensive insulin therapy in sepsis equal to the benefit found in critical illness without sepsis and critical illness in general. Though a high frequency of hypoglycemia may be noted during insulin treatment of patients with sepsis, the present observations define hypoglycemia as a marker of disease severity rather than a harmful treatment side-effect. Prevention of cellular glucose toxicity by strict glycemic control appears to play a predominant role, but other metabolic and nonmetabolic, anti-inflammatory effects of insulin seem to contribute to the clinical benefits realized.

Sepsis and septic shock, are complex disorders that are a major cause of mortality in the intensive care unit. In spite of major advances in our understanding of the pathophysiology of sepsis, accurate prediction of susceptibility to sepsis, multi-organ dysfunction, and death, even in the setting of a seemingly similar burden of infection, continues to challenge critical care clinicians. Evidence from family-based studies and recent gene-association studies suggest that a significant portion of the apparent variability in susceptibility is due to genetic factors. Common sequence variations in genes coding for innate immune effectors, inflammatory mediators, and modulators of coagulation have received particular attention. This review will summarize and integrate the results of studies testing for associations between sequence variations in genes from these functional classes and susceptibility to sepsis and related clinical outcomes. The important insights on sepsis pathophysiology provided by these studies will be discussed along with the relevance of these findings to the design of future diagnostic approaches and therapeutic trials.

Over the past decade, trends in antimicrobial resistance, epidemiology, and drug development have occurred that affect both the empiric and definite selection of antimicrobials in the septic patient. The rapid spread of highly pathogenic community-associated methicillin resistant Staph aureus (MRSA) requires clinicians to consider the inclusion of empiric coverage for MRSA even in community- acquired sepsis. Moreover, vancomycin appears to be losing its effectiveness, and while a number of new agents with broad gram positive activity have been licensed, none have emerged as clearly superior. An alarming increase in the number of hospital-acquired infections due to multi-drug resistant gram negative bacteria has also occurred, and few new gram negative drugs are in development. Clinicians, faced with Pseudomonas aeruginosa or Acinetobacter baumanii isolates resistant to all commonly used drugs, must resort to toxic older drugs such as colistin or therapy combining drugs not effective as monotherapy. Based on a desire to limit overall antimicrobial use, a re-evaluation of older data in both the neutropenic and non-neutropenic host has called into question the common practice of using combination therapy for some gram negative infections. An emerging consensus advocates emphasizing local unit specific antimicrobial sensitivity data in selecting empiric therapy and determining if combination therapy is required. New antifungal drugs and a better understanding of the risk factors for infection with Candida spp. has altered the approach to empiric and definitive treatment of Candida infections in the septic patient.