Abstract
For many years, basic research with relatively straightforward pathophysiologic approaches has driven clinical trials using molecules that supposedly interfere positively with inflammatory processes. However, most of these trials have failed to demonstrate any outcome benefit. Indeed, we need to revisit current paradigms and to think about the possibility that outcome may be predetermined in severe sepsis or septic shock. In addition, an early diagnosis of sepsis prior to the onset of clinical decline is also of particular interest to health practitioners because this information increases the possibilities for early and specific treatment of this life threatening condition. Indeed, the time to initiate therapy is thought to be crucial and the major determent factor in surviving sepsis. Despite substantial progress in sepsis therapy, the gap between the discovery of new effective medical molecules and their implementation in the daily clinical practice of the intensive care unit remains a major hurdle. Fortunately, ongoing research continues to provide new information on the management of sepsis, in particular, severe sepsis or septic shock. High quality and effective management tools are necessary to bring evidence-based therapy to the bedside. On this basis, new therapies could be tested to reduce mortality rates with respect to recently published studies.
Keywords
sepsis; mortality; therapy;
1. Introduction
Intensive care unit (ICU) mortality rate for severe sepsis and septic shock is ranging from 25%–70% when complicated by shock and multiple organ failure.1, 2, 3, 4 So far, the treatment of severe sepsis and septic shock consists of source control, early antimicrobial therapy, and supportive and adjunctive therapies. Further reduction in mortality may be achievable through knowledge and use of the expanding field of adjunctive therapy, e.g., the early administration of appropriate antibiotic therapy and source control, early-goal directed management of hypotension and perfusion abnormalities with fluid resuscitation and vasoactive agents support, and the use of lung protective ventilator support strategies, as necessary.5
The prominent role of inflammatory molecules and pathways suggests a possible therapeutic role in the management of severe sepsis and septic shock. However, numerous trials, irrespective of unsuccessful ones, which targeted at inhibiting various essential inflammatory mediators and receptors involved in the sepsis syndrome, e.g., shock and multiple organ failure, have failed to show a reduction in mortality, thus raising the question whether mortality in sepsis actually derives from an uncontrolled proinflammatory response. Corticosteroids and activated drotrecogin alfa are to date the only drugs that have demonstrated mortality benefits in large randomized controlled trials. This could be due to their broad based attempts at modulating the inflammatory response to infection. However, despite decades of experimental animal and human trials, the role of corticosteroid therapy, even with the evaluation of hypothalamic-pituitary-adrenal axis in sepsis remains uncertain and sometimes controversial.5, 6, 7, 8, 9, 10, 11, 12 Thus, in this review, we attempt to focus our attention on adjunctive sepsis therapies, which are based on animal studies in the literature, with emphasis on mortality outcome.
2. Recent clinical relevance
2.1. Corticosteroids
A remarkable finding in the recently published Corticosteroid Therapy of Septic Shock (CORTICUS) trial of hydrocortisone therapy in septic shock was a large and significant reduction of shock in those treated with steroids, yet Day 28 mortality rate was similar compared with those receiving placebo.13 This relatively stable mortality rate, which persists despite better mechanistic understanding, more rapid, targeted, and aggressive resuscitation14 as well as more rigorous supportive therapies, suggests that relatively constant pathways still lead to death in some patients. It seems that the mechanisms underlying organ failure and death still remain difficult to assess and to counteract. For instance, inflammatory processes interacting with a metabolic failure continue to be key issues.15, 16
2.2. Hydroxyethyl starch
A recent study on hydroxyethyl starch (HES) 130/0.4 that fulfilled the inclusion criteria, was carried out in the form of a randomized clinical trial (RCT) in adults requiring acute volume therapy and admission to ICU or emergency unit for comparing HES with non-HES fluid.17 Despite its lack of evidence in severely ill patients, HES 130/0.4 has been given to more than 24 million patients worldwide according to a certain manufacturer.18 In one-third of 73 Scandinavian ICUs that participated in a survey published in 2008, colloids were used as first-line fluid for resuscitation and HES 130/0.4 was the preferred colloid in the majority of ICUs.18 However, previous two large randomized studies reveal that the use of 10% HES 200/0.5 and 6% HES 200/0.6–0.66 is associated with acute renal failure in severe sepsis patients as compared with Ringer's lactate or gelatin.19, 20 In view of these data, the safest options of colloidal fluid resuscitation in sepsis for early hemodynamic stabilization appear to consider the modification of fluid gelatin and albumin used in combination with crystalloids or crystalloids on own expense.
2.3. Vasopressin
In addition, a recent large-scale multicenter study performed in patients with septic shock, called the Vasopressin and Septic Shock Trial (VASST), indicated that a combination therapy consisting of low-dose arginine vasopressin (AVP, ≤ 1.8 U/hour) and norepinephrine (NE) infusion is equally safe and efficacious as treatment with NE alone.21 At the same mean arterial pressure, AVP infusion offered a significant reduction in NE requirement. A prior subgroup analysis manifests that in patients with less severe sepsis (requirement of <15 mg/minute NE at randomization), the overall mortality on Days 28 and 90 is similar. The treatment with AVP plus NE markedly decreases 90-day mortality compared with NE infusion alone (35.8% vs. 46.1%). It seems that AVP treatment in the early stage of sepsis is potentially superior to whatever treatment in the last resort. However, an effective dose of AVP for patients with grave severity of shock remains a vitally important issue in these patients because of the staggeringly high mortality rate. More recently, Torgersen and colleauges22 have reported that in patients with severe septic shock administration of a higher dose of AVP (0.067 U/minute) than used in the VASST trial could result in a more effective restoration of cardiovascular function. Although the number of patients randomized into Torgersen's study is sufficient to provide useful hemodynamic information, it is not adequate enough to test for differences in survival outcome.23 Thus, randomized controlled trials that are adequately powered to test for survival differences in severely ill patients are still warrantable.
2.4. Glycemic control
The importance of glycemic control also surges as an interest of a European sepsis trial in which cardiac surgery patients were randomized to receive intensive insulin therapy versus ordinary glucose management.24 Although the study demonstrates that increased benefit in the intensive insulin group,24 concerns regarding glucose loading which overtakes standard practice in glucose administration in the control group somewhat tempers these findings.25 In fact, in the trial by the same group in medical ICU patients, no significant difference in mortality with the use of intensive or conventional insulin therapy has been shown26; intensive insulin therapy decreased the rate of death among patients who remained in the ICU for 3 days or more but increased the rate of death among patients whose stay lasted fewer than 3 days.26, 27 The mechanisms by which intensive insulin therapy benefits surgical patients are not known, but they could include the induction of euglycemia, the benefaction form increased insulin levels, or both.28 However, the appropriate target glucose range and insulin dose in patients with sepsis were unknown, because these trials were not conducted in specifically studied patients with sepsis. Actually, among the mixed medical and surgical subjects in these RCTs, 950 could be identified as having sepsis at the time of admission to the ICU.26 Though how intensive insulin therapy affects patients with sepsis remains unclear, it is doubtless that glycemic control offers an intuitive sense.
2.5. Genetic aspect
Obviously, critical care physicians have all been frustrated by the common scenario in which two patients of similar age and having similar comorbidities are treated in an identical manner, yet only one of whom survives, while the other progresses to multiple organ system failure and succumbs. The answer to why one does survive and the other patient does not may be that they are different in genetic make-up. In other words, our genes may affect the way we respond to infection. While no clear “sepsis gene” has yet been identified, genetic factors undoubtedly play an important role in the pathophysiology of sepsis.29 A recent study demonstrates that a class-defining 100-gene signature depicted for each individual patient using mosaics generated by the Gene Expression Dynamics Inspector.30 Composite mosaics are generated representing the average expression patterns for each of the previously published, genome-wide, expression-based sub-classes (subclasses A, B, and C) having clinically relevant phenotypic differences. This study shows that respective sensitivities, specificities, positive predictive values, and negative predictive values of the sub-classification strategy are ≥84% across the three subclasses. The authors conclude that this study provides initial evidence (proof of concept) for a clinically feasible and robust stratification strategy for pediatric septic shock based on a 100-gene signature and gene expression mosaics. However, there is a major barrier that needed to be solved. That is the application of genomic data in the field of critical care medicine has been the translation, interpretation, and acceptance of these complex data by clinicians. Hopefully, further research in this area will lead to a more individualized approach to the management of critically ill patients with sepsis and septic shock, taking into account both the genetic makeup of the host, as well as the characteristics of the immune response.
3. Individual animal study
3.1. Apoptosis
While it is generally accepted that sepsis is an inflammatory state resulting from the systemic response to infection, “apoptosis” is implicated to be an important mechanism of the death of lymphocytes, gastrointestinal and lung epithelial cells, and vascular endothelial cells associated with the development of multiple organ failure in sepsis. The pivotal role of cell apoptosis is now highlighted by multiple studies demonstrating that prevention of cell apoptosis can improve survival in clinically relevant animal models of sepsis. Apoptosis is regulated by the caspase family of cysteine proteases and is triggered in response to proapoptotic stimuli and that result in disassembly of the cell. As inhibition of caspase family members represents a novel approach to disease treatment, some pharmaceutical companies have developed compounds that inhibit activation of caspase. Hotchkiss and coworkers31 have reported that treatment with the broad-spectrum caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp fluoromethylketone (z-VAD-fmk) decreases lymphocyte apoptosis, decreases blood bacterial counts, and improves survival in mice with cecal ligation and puncture (CLP)-induced sepsis. In a related study, Kawasaki and others32 have noted that z-VAD-fmk decreases apoptosis on pulmonary endothelial cells and epithelial cells and elevates the survival rate in a lipopolysaccharide (LPS)-induced acute lung injury mouse model. However, Méthot and coauthors33 have warned us that the ability of low potency caspase inhibitors such as z-VAD-fmk to improve survival in CLP-induced sepsis is not always a result of inhibition of active caspase-3, although a caspase-3–specific reversal inhibitor, if any, would represent a potential therapeutic approach in sepsis.
3.2. Nuclear factor-kappa B pathway
It is clear that the nuclear factor-kappa B (NF-κB) pathway is linked to the dysregulated inflammation that is characteristic of sepsis. Thus, the NF-κB pathway would then appear to be a logical therapeutic target for the treatment of critically ill patients with sepsis.34 Several recent studies have led to questions surrounding this kind of therapeutic strategy.35 For example, given its critical role in the innate and adaptive immune responses to infection, inhibition of NF-κB may worsen pathogen clearance and increase the risk of mortality from overwhelming infection. Alternatively, NF-κB plays an important antiapoptotic role (see below)—inhibition may then have unintended and untoward effects on cell survival and function. Finally, other studies suggest that NF-κB has a critical anti-inflammatory function in preventing an overwhelming host inflammatory response to infectious challenge.36, 37, 38, 39 Obviously, further studies, both in the preclinical and clinical settings will be necessary to further validate this therapeutic approach.
3.3. Levosimendan
It is well recognized that sepsis accounts for the majority of ICU mortality, predominantly via the development of multiple organ failure (MOF). Myocardial dysfunction, which often affects both ventricles, is a well-recognized manifestation of septic organ dysfunction. The role of “levosimendan” in sepsis and septic shock has recently been thoroughly reviewed by Pinto and colleagues.40 The theoretical benefits of levosimendan in treatment of septic shock, such as calcium-sensitizing action, opening of KATP channels (resulting in improved tissue oxygenation and organ protection) along with the anti-inflammatory action of levosimendan, have been supported by vast experimental data.41, 42, 43, 44, 45 Morelli and others46, 47 have previously conducted two prospective, randomized clinical studies assessing levosimendan in patients with sepsis and reported improved cardiac performance and global oxygen transport in addition to decreased pulmonary dysfunction.
3.4. Immunomodulators
Despite advancements in our understanding of innate and adaptive immunity, applying this knowledge to the treatment of sepsis has proven difficult. Many factors modulate innate and adaptive immune responses and link the two branches of immunity during infection. Recently, type 1 interferons (IFNs) are shown to act downstream of Toll-like receptor signaling48 to induce a specific gene activation signature, including induction of chemokines such as CXCL10. Type 1 IFNs also serve as a link between the innate and adaptive immune systems,49 participating in autoimmunity50 and viral51 and bacterial infection.52, 53 During endotoxicosis or highly lethal bacterial infections where systemic inflammation predominates, mice deficient in IFN-α/βreceptor (IFNAR) display decreased systemic inflammation and improved outcome. However, human sepsis mortality often occurs during a prolonged period of immunosuppression and not from exaggerated inflammation. Kelly-Scumpia and others54 used a low lethality cecal ligation and puncture (CLP) model of sepsis to determine the role of type I IFNs in host defense during sepsis. Despite increased endotoxin resistance, they found IFNAR–/–and chimeric mice which lacked IFNAR in hematopoietic cells display increased mortality to CLP. This was not associated with an altered early systemic inflammatory response, except for decreased CXCL10 production. IFNAR–/–mice display persistently elevated peritoneal bacterial counts compared with wild-type mice, reduced peritoneal neutrophil recruitment, and recruitment of neutrophils with poor phagocytic function despite normal to enhanced adaptive immune function during sepsis. Importantly, CXCL10 treatment in IFNAR–/–mice improves survival and decreases peritoneal bacterial loads, and CXCL10 increases mouse and human neutrophil phagocytosis. Using a low lethality sepsis model, they identify a critical role of type I IFN–dependent CXCL10 in host defense during polymicrobial sepsis by increasing neutrophil recruitment and function. Other pleiotropic molecules such as complement C5a receptors and High Mobility Group Box 1 can also show immunomodulatory effects on host defense and inflammation depending on the severity of the septic insult.55 These studies highlight the plasticity of immunomodulatory signaling cascades and their ability to participate in either detrimental systemic inflammatory cascades or protective host defense responses depending on the bacterial burden.
4. Conclusion
The “one size fits all” approach that has been utilized in the clinical design of these studies will not work in the future. We need to address the role of host factors, such as age, gender, presence of comorbidities, and genetic predisposition in determining the individual response to therapy. When designing clinical trials, critically ill patients should be stratified according to severity of illness in order to maximize the signal-to-noise ratio of new therapeutic agents. Ideally, those patients who would generally survive with standard therapy alone should not be included in such studies. In addition, we need to recognize that immunomodulation as a therapeutic strategy encompasses both augmentation of the immune response in critically ill patients with the immunoparalysis phenotype, as well as suppression of the immune response in those patients with a predominantly proinflammatory phenotype. It is likely that one particular therapeutic agent directed against any one mediator is not likely to be successful. Given the inherent complexity and redundancy of the host inflammatory response, future management strategies will likely encompass the use of multiple, synergistic agents acting upon different steps in the mediator cascade.