Recent developments in the treatment of sepsis

Despite advances in supportive care, septic shock remains a major cause of morbidity and mortality. With the identification of the systemic inflammatory response as a major component in the pathogenesis of the septic shock syndrome, much of the recent work has focused on modulating this response. This includes antiendotoxin therapies in patients with Gram-negative sepsis, and therapies to modulate the pro-inflammatory mediators produced in response to infection, such as TNF-alpha, platelet-activating factor and complement. High-flow haemofiltration has the potential advantage of clearing both endotoxin and pro-inflammatory mediators. Antithrombotic strategies have been investigated and have yielded the first major success in the treatment of sepsis with activated protein C. Nitric oxide produces the cardiovascular features of sepsis and investigators have looked at both reducing its production and mopping up the excess. Attempts to reduce apoptosis have been a new focus in the treatment of sepsis. There have also been recent developments in supportive care suggesting a role for vasopressin and replacement corticosteroid therapy.     

Anti-inflammatory therapies in sepsis and septic shock

Despite advances in supportive care, the morbidity and mortality rate resulting from sepsis and septic shock remain high (30 - 50%). A central hypothesis driving sepsis research in recent years is that this syndrome is the result of excessive inflammation. Therapies designed to inhibit the inflammatory response were first shown to be markedly beneficial in animal models of sepsis and then tested in numerous clinical trials involving thousands of patients. Three broad anti-inflammatory strategies have been investigated. First, glucocorticoids in high doses administered at the onset of sepsis were studied. This approach proved unsuccessful. More recently, however, glucocorticoids in lower doses have been found to have a beneficial effect in patients with septic shock. Whether the mechanism of this treatment benefit is through inhibition of inflammation, or by counteracting a relative steroid refractoriness occurring during sepsis, remains unknown. The next focus of research were agents active against the endotoxin molecule. However, as with the experience with glucocorticoids, this approach lacked a consistent pattern of efficacy. It is unclear if this lack of efficacy is the result of endotoxin being a poor therapeutic target, or from testing agents which lacked the appropriate biological activity. Most recently, clinical trials in sepsis have focused on inhibiting specific host pro-inflammatory mediators (e.g., TNF, interleukins). While individual trials of inhibitors of these pro-inflammatory mediators failed to show a convincing benefit, pooling the results of these trials suggest that this approach has a marginal effect, supporting a role for excessive inflammation in sepsis. An unanswered question is reconcilling the very favourable effects obtained with anti-inflammatory treatments in animal models with the marginal results in humans. Further clinical and laboratory research is needed and may provide insight into more effective ways to use the anti-inflammatory agents already tested, or to investigate other potentially more effective anti-inflammatory agents in this syndrome.     

Anti-inflammatory therapies in sepsis and septic shock

Despite advances in supportive care, the morbidity and mortality rate resulting from sepsis and septic shock remain high (30 - 50%). A central hypothesis driving sepsis research in recent years is that this syndrome is the result of excessive inflammation. Therapies designed to inhibit the inflammatory response were first shown to be markedly beneficial in animal models of sepsis and then tested in numerous clinical trials involving thousands of patients. Three broad anti-inflammatory strategies have been investigated. First, glucocorticoids in high doses administered at the onset of sepsis were studied. This approach proved unsuccessful. More recently, however, glucocorticoids in lower doses have been found to have a beneficial effect in patients with septic shock. Whether the mechanism of this treatment benefit is through inhibition of inflammation, or by counteracting a relative steroid refractoriness occurring during sepsis, remains unknown. The next focus of research were agents active against the endotoxin molecule. However, as with the experience with glucocorticoids, this approach lacked a consistent pattern of efficacy. It is unclear if this lack of efficacy is the result of endotoxin being a poor therapeutic target, or from testing agents which lacked the appropriate biological activity. Most recently, clinical trials in sepsis have focused on inhibiting specific host pro-inflammatory mediators (e.g., TNF, interleukins). While individual trials of inhibitors of these pro-inflammatory mediators failed to show a convincing benefit, pooling the results of these trials suggest that this approach has a marginal effect, supporting a role for excessive inflammation in sepsis. An unanswered question is reconcilling the very favourable effects obtained with anti-inflammatory treatments in animal models with the marginal results in humans. Further clinical and laboratory research is needed and may provide insight into more effective ways to use the anti-inflammatory agents already tested, or to investigate other potentially more effective anti-inflammatory agents in this syndrome.     

Advances in sepsis therapy

During the past 3 years new insights have been gained into the fundamental elements that underlie the pathogenesis of sepsis, and after years of frustrating failures, progress in the basic understanding of sepsis has translated into successful new therapies. These new treatment strategies have significantly improved the outcome of patients experiencing the puzzling syndrome of severe sepsis. More effective supportive therapies with early, goal-oriented therapy including volume resuscitation, catecholamine therapy and transfusion improve the chances for survival in septic shock. Novel endocrine management with hydrocortisone replacement therapy for relative adrenal insufficiency in septic shock patients and strict blood glucose control provide a survival advantage in critically ill patients. Administering appropriate antimicrobial therapy, nutritional support and ventilation protocols with low tidal volumes have now been shown to benefit septic patients. Finally, human recombinant activated protein C (drotrecogin alfa), which ameliorates sepsis-induced disseminated intravascular coagulation and exerts several other favourable effects on endothelial cells, has been shown to reduce mortality in patients with severe sepsis. On the basis of newly discovered pathophysiological mechanisms of sepsis, several other adjuvant therapies for sepsis are in various stages of preclinical and clinical development. Individualised and optimal supportive care with efforts to reverse the precipitating cause of sepsis remains the mainstay of therapy for severe sepsis. How these new and often expensive regimens will fit into the standard treatment approach to sepsis remains to be defined by future clinical investigations.     

New perspectives on immunomodulatory therapy for bacteraemia and sepsis

Systemic immune dysregulation is generally acknowledged to be the fundamental molecular mechanism that underlies the pathophysiology of severe sepsis and septic shock. In the presence of a systemic infection, microbial pathogens and their soluble mediators induce generalised immune activation and coagulation activation, leading to severe sepsis and septic shock. For decades, immune-based therapies have been devised with the specific intent of inhibiting the pro-inflammatory events that are thought to precipitate the septic process. Despite a clear therapeutic rationale based upon the available experimental evidence, anti-inflammatory therapies targeting the innate or acquired immune response have largely been unsuccessful in clinical trials of sepsis. Compelling evidence now exists that a prolonged state of sepsis-induced immune suppression follows the initial period of stabilisation and resuscitation in many critically ill patients. Sepsis-related immune suppression is evidenced by histological findings of markedly enhanced lymphocytic and monocytic apoptosis, poor response to neoantigens and recall antigens, and increased incidence of infections by opportunistic pathogens. Candidiasis, cytomegalovirus activation and secondary infections by relatively avirulent bacterial pathogens such as Stenotrophomonas and Acinetobacter spp. are commonplace in septic patients during prolonged Intensive Care Unit stays. Immunological tools to detect sepsis-induced immunosuppression are now available, and novel immunoadjuvants are in development to re-establish immune competence in sepsis patients. The intelligent use of immunomodulatory agents in sepsis will necessitate a personalised medicine approach to treat each patient at the appropriate time and with the optimal therapy.     

Pharmacological utility of melatonin in the treatment of septic shock: experimental and clinical evidence

Sepsis is a major cause of mortality in critically ill patients and develops as a result of the host response to infection. In recent years, important advances have been made in understanding the pathophysiology and treatment of sepsis. Mitochondria play a central role in the intracellular events associated with inflammation and septic shock. One of the current hypotheses for the molecular mechanisms of sepsis is that the enhanced nitric oxide (NO) production by mitochondrial nitric oxide synthase (mtNOS) leads to excessive peroxynitrite (ONOO-) production and protein nitration, impairing mitochondrial function. Despite the advances in understanding of its pathophysiology, therapy for septic shock remains largely symptomatic and supportive. Melatonin has well documented protective effects against the symptoms of severe sepsis/shock in both animals and in humans; its use for this condition significantly improves survival. Melatonin administration counteracts mtNOS induction and respiratory chain failure, restores cellular and mitochondrial redox status, and reduces proinflammatory cytokines. Melatonin clearly prevents multiple organ failure, circulatory failure, and mitochondrial damage in experimental sepsis, and reduces lipid peroxidation, indices of inflammation and mortality in septic human newborns. Considering these effects of melatonin and its virtual absence of toxicity, the use of melatonin (along with conventional therapy) to preserve mitochondrial bioenergetics as well as to limit inflammatory responses and oxidative damage should be seriously considered as a treatment option in both septic newborn and adult patients. This review summarizes the data that provides a rationale for using melatonin in septic shock patients.     

Cytokine modulation in sepsis and septic shock

Sepsis and septic shock are a major cause of morbidity and mortality in patients admitted to the intensive care unit. Since the introduction of antibiotic therapy, the mortality associated with sepsis has remained within the 30- 50% range. Sepsis constitutes the systemic response to infection. This response encompasses both pro-inflammatory and anti-inflammatory phases that are marked by the sequential generation of pro- and anti-inflammatory cytokines. Among the most important pro-inflammatory cytokines are TNF-alpha and IL-1beta. The pro-inflammatory effects of such cytokines are inhibited by soluble receptors/receptor antagonists and anti-inflammatory cytokines including IL-10 and transforming growth factor-beta. Modulation of the activity of both pro- and anti-inflammatory cytokines to improve outcome in patients with sepsis has been subject of multiple clinical studies. This review will examine clinical trials evaluating several strategies for blocking or attenuating TNF-alpha and IL-1beta activity. This review will also survey the current state of experimental therapies involving IL-10, transforming growth factor-beta, granulocyte colony-stimulating factor and IFN-phi. Finally, newer developments related to less known cytokines such as macrophage migration inhibitory factor and high mobility group 1 protein will be evaluated.     

Novel therapies for microvascular permeability in sepsis

Sepsis is characterized physiologically by an aberrant systemic inflammatory response and microvascular dysfunction. While appropriate antibiotics and supportive care are essential in the management of the septic patient, therapies targeting specific aspects of the pathophysiology could have a significant impact on the morbidity and mortality associated with both sepsis and its sequlea, including acute lung injury (ALI). We have characterized several mediators of endothelial cell (EC) barrier function that may serve as novel therapies for sepsis-induced microvascular dysfunction including simvastatin, adenosine triphosphate (ATP), sphingosine 1-phosphate (S1P), and activated protein C (APC). Notably, APC is already available for the treatment of severe sepsis, however, to date its mechanism of action has been unclear. While distinct in many ways, we have found that these agonists have in common the ability to induce dynamic rearrangement of the EC actin cytoskeleton that corresponds to barrier protection. In addition, we have extended our in vitro findings to relevant animal models of endotoxin-induced acute lung injury and have confirmed beneficial effects of both simvastatin and S1P which are associated with evidence of decreased vascular permeability in this setting. Moreover, our data also indicate that APC effects in sepsis may be largely due to augmentation of EC barrier function affecting decreased microvascular permeability. We speculate that the administration of direct modulators of EC barrier function and microvascular permeability, such as those described here, may ultimately become the standard of care for the septic patient.     

Urosepsis: from the intensive care viewpoint

A recent survey conducted by the Competence Network Sepsis (SepNet) revealed that severe sepsis and/or septic shock occurs in 75000 inhabitants (110 per 100,000) and sepsis occurs in 79000 inhabitants (116 per 100,000) in Germany annually. The prevalence of urosepsis in this survey was 7%. Early diagnosis of sepsis prior to the onset of clinical deterioration is of particular interest because this would increase the possibility of early and specific treatment, which in turn is the major determining factor of mortality in septic patients. Treatment of urosepsis consists of source control, early antimicrobial therapy as well as supportive and adjunctive therapy. For supportive therapy, adequate volume loading is the most important step in the treatment of patients with urosepsis in order to restore and maintain oxygen transport and tissue oxygenation. Therefore, supportive treatment should focus on adequate volume resuscitation and appropriate use of inotropes/vasopressors. The PROWESS study is the first investigation demonstrating the decrease in mortality in patients with sepsis following administration of activated protein C (APC). Thus, administration of APC to patients with two-organ failure or an APACHE II score > or =25 within the first 24 h after the first sepsis-induced organ failure is a part of adjunctive therapy. Additionally, current data support low-dose hydrocortisone therapy in patients with vasopressor-dependent severe septic shock. Time to initiation of therapy is crucial for surviving sepsis. Implementing new medical evidence in this context into daily clinical intensive care remains a major hurdle.     

Treatment of sepsis: past and future avenues

In recent years, the concept has emerged that the host's inflammatory response contributes substantially to the development of septic shock and organ failure. Experimental observations prompted large scale randomised clinical trials with a variety of agents such as glucocorticoids, ibuprofen, antiendotoxin monoclonal antibodies, antagonists of platelet-activating factor, of bradykinin or of interleukin-1 receptor, and monoclonal anti-tumour necrosis factor (TNF) antibodies or soluble dimeric TNF receptor fusion proteins. All these major studies of immunomodulators in sepsis have yielded disappointing results despite showing promise during preliminary clinical studies. However, these recent failures do not mean that septic shock will forever remain an insurmountable medical challenge. Many lessons have been learned from these studies. and certain mistakes in their study design will be avoided in the future. Our understanding of the pathophysiology of sepsis and septic shock is increasing markedly; potential new treatment strategies are available and could be explored to improve the outcome of patients with sepsis.     

The role of the endothelium in modulating vascular control in sepsis and related conditions

The majority of deaths amongst critically ill patients requiring intensive care are attributable to sepsis and its sequelae: septic shock, the systemic inflammatory response syndrome (SIRS) and the acute respiratory distress syndrome (ARDS). Patients within the ICU who develop these conditions and fail to survive succumb to multiple organ dysfunction syndrome (MODS). ARDS is considered to be the pulmonary component of MODS and is characterized by pulmonary hypertension, often in the setting of systemic hypotension. Endothelial cells, normally responsible for modulating vascular tone, becomes dysfunctional in sepsis. Pro-thrombotic, pro-inflammatory and vasoactive mediators are released including nitric oxide (NO), endothelins (ETs) and products of cyclo-oxygenase metabolism. It is probably the disordered production of these mediators in vascular beds that results in MODS. This review highlights recent research in this area with particular emphasis on possible therapeutic options.     

PACAP inhibit the release and cytokine activity of HMGB1 and improve the survival during lethal endotoxemia

The pathogenesis of sepsis is mediated in part by bacterial endotoxin (lipopolysaccharide; LPS), which stimulates macrophages/monocytes to sequentially release early (e.g., TNF-alpha, IL-1beta) and late [e.g., high mobility group box 1 (HMGB1) protein] pro-inflammatory cytokines. Specifically targeting early mediators has not been effective clinically, in part, because peak mediator activity often has passed before therapy can be initiated. Recent discovery of HMGB1 as a late mediator of lethal sepsis has provided a new target for the treatment of septic shock. Here, we demonstrate that pituitary adenylate cyclase-activating polypeptide (PACAP), an endogenous neuropeptide, significantly attenuated circulating HMGB1 levels and increased survival in animals with established endotoxemia, even if treatment began after acute cytokine response has occurred. In vitro, PACAP suppressed LPS-induced HMGB1 release from macrophages/monocytes, even when given 2-4 h after LPS stimulation. PACAP also suppressed HMGB1 release induced by TNF-alpha or IFN-gamma. Moreover, PACAP inhibits HMGB1-induced cytokine release in vitro and in vivo. These results indicate that PACAP inhibits the release and pro-inflammatory activity of HMGB1 and improves survival during lethal endotoxemia, which confirms this peptide as a candidate for therapy of septic shock.     

内皮素和一氧化氮对脓毒性休克实验模型中器官损伤，肠系膜缺血和存活的影响

The development of potent drugs to treat cardiopulmonary failure in sepsis, such as antibiotics and new immunomodulatory therapeutic approaches have not prevented sepsis from being a major health problem. Dysfunction of the vascular endothelium is an early event in septic shock. The recognition of endothelium-derived substances, such as nitric oxide and endothelin, important mediators of systemic inflammatory response syndrome,led to the proposal that pharmacological inhibition of nitric oxide and endothelin production could represent a useful strategy in the treatment of septic shock. Splanchnic ischemia and translocation of endotoxin from the gut to the circulation contributes significantly to the high mortality rate in sepsis-related syndromes. This vasoconstriction in the splanchnic circulation can be partially blocked by inducible nitric oxide synthase inhibitor aminoguanidine or endothelin receptor antagonist bosentan in experimental models of septic shock. It can be suggested that endothelin and nitric oxide may affect survival. Although septic shock is a highly complex pathophysiological state, the course of septic shock has different phases with different characteristics which need different (special) treatment strategy. The inhibition of nitric oxide production during hyperdynamic,earlier phase of sepsis combined with the blockade of endothelin receptors at a later stage during the hypodynamic,late phase appears to be a novel promising strategy for the therapy of septic shock. The aim of this review is to discuss the role of nitric oxide and endothelin in sepsis and the potential therapeutic implications of blockade of nitric oxide and endothelin as a target in treatment of human septic shock. Briefly the importance of timing of intervention is also emphasized.     

Targeting the bombesin/gastrin-releasing peptide receptor to treat sepsis

Sepsis is a complex, multifactorial syndrome that can develop into conditions of different severity, described as septic shock or severe sepsis. In spite of the great progress in understanding the mechanisms involved in the pathogenesis and management of sepsis, only a few therapeutic strategies were able to show a decrease in the mortality from septic shock. Although sepsis consists on a systemic inflammatory response, the anti-inflammatory therapies have failed to improve the outcome of critically ill patients. Here the role of gastrin-releasing peptide in immune processes is reviewed and the data that have prompted the recent patent for GRP receptor antagonists RC-3095 as a therapeutic agent on inflammatory conditions are described.     

Current treatment of sepsis and endotoxaemia

This article reviews the new criteria for selecting the proper antimicrobial agent and dosage regimen for standard treatment of severe sepsis, with the intention of preventing septic shock. After introducing new concepts on the pathogenesis of sepsis and septic shock, the authors analyse the parameters of β-lactam antibacterial activity, the antibiotic-induced release of bacterial endotoxin and the interrelationships between pharmacokinetics and pharmacodynamics of antibiotics in the search for an optimum dosage regimen of antimicrobial mono- or polytherapy for severely ill septic patients admitted to the intensive care unit. The mortality rate resulting from severe bacterial sepsis, particularly that associated with shock, still approaches 50% in spite of appropriate antimicrobial therapy and optimum supportive care. Bacterial endotoxins that are part of the cell wall are one of the cofactors in the pathogenesis of sepsis and septic shock and are often induced by antimicrobial chemotherapy, even if administered rationally. Not all antimicrobial agents are equally capable of inducing septic shock; this is dependent on their mechanism of action rather than on the causative pathogen species. The quantity of endotoxin released depends on the drug dose and whether filaments or spheroplast formation predominate. Some antibiotics, such as carbapenems, ceftriaxone, cefepime, glycopeptides, aminoglycosides and quinolones, do not have the propensity to provoke septic shock because their rapid bactericidal activity induces mainly spheroplast or fragile spheroplast-like bacterial forms.     

Current treatment of sepsis and endotoxaemia

This article reviews the new criteria for selecting the proper antimicrobial agent and dosage regimen for standard treatment of severe sepsis, with the intention of preventing septic shock. After introducing new concepts on the pathogenesis of sepsis and septic shock, the authors analyse the parameters of beta-lactam antibacterial activity, the antibiotic-induced release of bacterial endotoxin and the interrelationships between pharmacokinetics and pharmacodynamics of antibiotics in the search for an optimum dosage regimen of antimicrobial mono- or polytherapy for severely ill septic patients admitted to the intensive care unit. The mortality rate resulting from severe bacterial sepsis, particularly that associated with shock, still approaches 50% in spite of appropriate antimicrobial therapy and optimum supportive care. Bacterial endotoxins that are part of the cell wall are one of the cofactors in the pathogenesis of sepsis and septic shock and are often induced by antimicrobial chemotherapy, even if administered rationally. Not all antimicrobial agents are equally capable of inducing septic shock; this is dependent on their mechanism of action rather than on the causative pathogen species. The quantity of endotoxin released depends on the drug dose and whether filaments or spheroplast formation predominate. Some antibiotics, such as carbapenems, ceftriaxone, cefepime, glycopeptides, aminoglycosides and quinolones, do not have the propensity to provoke septic shock because their rapid bacterial activity induces mainly spheroplast or fragile spheroplast-like bacterial forms.     

Melatonin in bacterial and viral infections with focus on sepsis: a review

Melatonin is a versatile molecule, synthesized not only by the pineal gland, but also in small amounts by many other organs like retina, gastrointestinal tract, thymus, bone marrow, lymphocytes etc. It plays an important role in various functions of the body like sleep and circadian rhythm regulation, immunoregulatory mechanism, free radical scavenger, antioxidant functions, oncostatic actions, control of reproductive functions, regulation of mood etc. Melatonin has also been found to be effective in combating various bacterial and viral infections. Its administration has been shown to be effective in controlling chlamydial infections, infections induced by Mycobacterium tuberculosis, and also in many viral infections. Molecular mechanisms of anti microbial actions of melatonin have suggested to be due to effects on free radical formation, direct regulation of duplication of bacteria, depletion of intracellular substrates like iron etc. Besides, it is effective in sepsis as demonstrated in various animal models of septic shock. Melatonin's protective action against sepsis is suggested to be due to its antioxidant, immunomodulating and inhibitory actions against the production and activation of pro-inflammatory mediators. Use of melatonin has been beneficial in treating premature infants suffering from severe respiratory distress syndrome and septic shock. It has a potential therapeutic value in treating septic shock and associated multi organ failure in critically ill patients in addition to its antimicrobial and antiviral actions. The patents related to melatonin's use for treatment of bacterial infections and its use in clinical disorders are included.     

Septic shock: new pharmacotherapy options or better trial design?

Introduction: Over the last two decades, many of the mechanisms underlying the pathophysiology of sepsis have been uncovered, but this has not led to the development of effective therapies for sepsis. Despite improvements in the general care of critically ill patients in recent years, mortality rates for patients with severe sepsis and septic shock remain high at 30 to 50% and there is an urgent need to develop new, effective therapeutic strategies.

Areas covered: Attempts to develop a therapy for sepsis have focused on modulating this immune response. Past and present clinical research in this field are reviewed and promising candidates and approaches for the future are discussed.

Expert opinion: Many reasons have been put forward over the years to explain the many negative results from trials of immunomodulatory therapies. Future studies need to be designed to specifically target patients who can benefit from the intervention being studied rather than at the sepsis population in general. The timing of administration of potential therapies also needs to be taken more into consideration.     

Genetic insights into sepsis: what have we learned and how will it help?

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.     

Nitric oxide and cardiovascular dysfunction in 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 perfusion 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.