Septic shock, the most severe form of sepsis associated with refractory hypotension and organ dysfunction, is a deadly disease. It still remains as one of the most important causes of mortality in intensive care units (ICUs) nowadays. Although definite advances have been made in the knowledge of pathophysiology and treatment of sepsis and a decline in mortality has been observed, the annual incidence of the disease is increasing 8.7% in the United States, which results in increasing health care costs. The economic burden of sepsis is nearly $17 billion annually in the United States, with mortality ranging from 20% to 50% of severely affected patients (1). Sepsis accounts for 10% of admissions to ICUs, with a peak incidence in the sixth decade of life (2). The augmented incidence in recent years is probably due to progressive aging of the population, improvements in critical care support, and progress in chemotherapy and other immunosuppressive therapies so that individuals with immunosuppression and malignancies now have increased life expectancy, therefore increasing the occurrence of septic episodes during their life course. Because sepsis is a disease associated with high morbidity and mortality, it is very natural that large amounts of resources have been allocated for research of molecules and therapeutic strategies amenable to reduce sepsis complications. Unfortunately, most of the clinical trials evaluating therapeutic approaches and drugs for sepsis have shown miserably negative results. The purpose of this study is to review some of the recent strategies that have been associated with improvement in experimental and clinical sepsis scenarios and may be potentially useful for sepsis treatment in the near future.
CURRENT TREATMENT OF SEPTIC SHOCK
A complete review regarding the standard treatment of septic shock has been recently described elsewhere (3, 4) and is beyond the scope of this article. Thus, we will briefly summarize the recently published guidelines to provide an adequate context for the interventions that are the subjects of this review.
In general, the current treatment of septic shock is based on prompt recognition and management of the disease and support of failing organs, with adequate approach involving early goal-directed therapy (EGDT), broad-spectrum antibiotics, lung-protective ventilation, activated protein C for selected cases, glycemic control, and possibly corticosteroid therapy (4).
The hypothesis associated with the beneficial effect of EGDT is related to cardiovascular dysfunction of septic shock and correction of occult tissue hypoxia that may occur when volemic resuscitation is guided by ordinary hemodynamic objectives. In EGDT study (5), patients with severe sepsis and septic shock were divided into two groups after arrival at the emergency department. The control group was resuscitated according to central venous pressure (8-12 mmHg), diuresis (>0.5 mL kg−1 h−1), and mean arterial pressure (MAP) (65-90 mmHg). The treatment group (EGDT) was resuscitated according to the same parameters and maintenance of central venous oxygen saturation greater than 70%. Strategies to increase central venous oxygen saturation included volemic resuscitation, blood transfusion, and dobutamine up to 20 mcg kg−1 min−1. Early goal-directed therapy was associated in this study with a 16% absolute risk reduction in mortality.
Early antibiotic administration is another cornerstone of sepsis treatment because delays in the antimicrobial therapy are associated with an increased risk of death. A recent study evaluating the medical records of more than 2,000 patients with septic shock demonstrated that each hour of delay in antimicrobial administration during the next 6 h was associated with an average decrease in survival of 7.6%, and, in addition, only 50% of septic shock patients received effective antimicrobial therapy within 6 h of documented hypotension (6). Therefore, the recent Surviving Sepsis Campaign guidelines for treatment of septic shock state that patients must receive antibiotic therapy within the first hour of the diagnosis of sepsis (4).
The occurrence of hyperglycemia and insulin resistance is very common in sepsis. Harmful effects of hyperglycemia may include impairment of neutrophil function, increase in the incidence of infections, and apoptosis induction (3). Studies in surgical and medical critically ill patients demonstrated that achieving normoglycemia is associated with reduced incidence of infections and decreased rate of death among patients that remain in the ICU for at least 3 days (7, 8). However, a recent German study evaluating specifically severe sepsis patients was discontinued after an interim analysis demonstrated lack of benefit of intensive glycemic control and frequent hypoglycemic events in the intensive insulin group (9). Although the precise management of glycemia in septic patients deserves more studies, a reasonable approach seems to be the one recommended by the Surviving Sepsis Campaign, which suggests maintenance of glycemia less than 150 mg dL−1 to avoid the harmful metabolic consequences of excessive hyperglycemia (4).
The link between coagulation and inflammation in sepsis has been demonstrated in the last 20 years or so. Coagulation abnormalities in sepsis include activation of coagulation cascade with formation of microthrombi, consumption of clotting factors, and decrease in activities of protein C and antithrombin. Therefore, several coagulation inhibitors have been tested in patients with sepsis, with prospective randomized controlled studies of tissue factor pathway inhibitor and antithrombin yielding negative results (2). Conversely, activated protein C (drotrecogin α) was shown to be beneficial in sepsis patients with high risk of death, such as those with septic shock and/or more than two organ dysfunctions or Acute Physiology and Chronic Health Evaluation II score greater than 24 (10). This drug is currently considered for use in the first 48 h of sepsis for this specific subgroup of patients provided there is no risk of significant bleeding (4).
Corticosteroids have been used in sepsis for more than 3 decades. In the earlier studies, these drugs were given at high doses for short periods of time to reduce the exacerbated inflammatory response of sepsis. However, the results of these trials were disappointing (11). Nevertheless, in recent years, the use of glucocorticoids for sepsis has been revisited based on the putative role of adrenal insufficiency and peripheral glucocorticoid resistance frequently observed in sepsis. Potential beneficial effects of corticoids include reversal of sepsis-induced adrenal dysfunction and enhancement of vessel responsiveness to vasopressor agents (11). Indeed, a recent study of 300 patients with septic shock refractory to catecholamines treated with 200 mg of hydrocortisone and 50 mcg of fludrocortisone per day reported an early reversal of shock and mortality benefits in the subgroup of patients with adrenal dysfunction (12). In patients with nonrefractory septic shock, however, corticoids may have no benefit as demonstrated in the recently published Corticosteroid Therapy of Septic Shock study and may also be associated with increased incidence of superinfections (13).
POTENTIAL NEW THERAPIES IN SEPSIS
The list of therapies proven ineffective in sepsis is long and discouraging. It includes anti-LPS, ibuprofen, bradykinin antagonists, anticytokines, and unspecific NOS inhibitors. The reasons for these negative results are various but may include the hypothesis that pathophysiologic pathways are redundant in sepsis as well as the importance of several of the molecules blocked in these trials for the host defense and homeostasis of the organism. Thus, the search for the holy grail in sepsis treatment persists, and we will summarize here some of the recent research performed in this topic. The interventions discussed herein are vasopressin supplementation, statins, hemofiltration, and immunoglobulins. The main mechanisms associated with beneficial effects from these treatments in sepsis pathophysiology are depicted in the Figure 1.
Vasopressin (also called arginine vasopressin to differentiate from the synthetic analogs desmopressin and terlipressin) is a nonapeptide hormone also known as antidiuretic hormone. It is produced in the hypothalamic neurons magnocellular and parvocellular located in the supraoptic and paraventricular nuclei (14). The hormone can be released in the systemic circulation through migration of its precursors to posterior pituitary gland, where they are stored in neurosecretory vesicles (15). Vasopressin can also be released somatodendritically within the nuclei of its origin. Stimuli associated with release of the hormone in health include increases in plasma osmolality, decreased arterial pressure, and blood volume (14). On the other hand, conditions commonly present in critically ill patients such as hypoxia and acidosis are inducers of vasopressin release through stimulation of carotid body chemoreceptors (16).
The interactions of vasopressin with three receptors are responsible for their main effects in the organism. V1 receptors are located mainly in vascular smooth muscle cells from the systemic, splanchnic, coronary, and renal circulations. Their activation produces vasoconstriction via elevation of intracellular calcium. V2 receptors are present essentially in the kidney collecting duct cells and are associated with water retention and osmolality control through intracellular cyclic adenosine monophosphate increase. This effect increases the water permeability of these cells by insertion of aquaporin water channels in the apical cell membrane (17). V3 receptors, on the other hand, are responsible for the modulation of vasopressin-induced corticotropin secretion and are located predominantly on the cells of the adenohypophysis.
The role of vasopressin in cardiovascular control is dependent on the complex interplay between this hormone and the other regulators of vascular tonus such as the sympathetic and renin-angiotensin systems. For example, infusion of exogenous vasopressin in healthy volunteers leads only to modest increases in MAP and mild bradycardia (18). On the other hand, administration of vasopressin on individuals with autonomic insufficiency induces significant increments in MAP, which suggests that, under conditions where sympathetic tone and renin-angiotensin system are dysfunctional, vasopressin may act as a backup system for blood pressure control and cardiovascular sympathetic modulation (14).
It is well demonstrated that episodes of profound hypotension such as those caused by hypovolemic shock are associated with large releases of vasopressin in the circulation with concentrations of up to 180 pg mL−1 (normal concentrations are ∼2 pg mL−1) (14, 15). However, in distributive shock, there has been a demonstration of low or normal levels of vasopressin in the circulation mainly after 24 h of sepsis so that a condition of relative vasopressin deficiency has been proposed to these individuals (15, 19). These low hormonal levels may be mediated by depletion of neurohypophyseal stores or inhibition of hormonal synthesis or release. Nitric oxide (NO), a free radical present in large quantities in plasma of septic patients, has been associated with direct inhibition of vasopressin secretion (20). Moreover, septic shock has also been associated with down-regulation of vasopressin receptors (3), and these summarized data have led to investigations regarding vasopressin supplementation in patients with vasodilatory or septic shock.
The effect of exogenous vasopressin has been evaluated in a recent retrospective study in patients with vasodilatory shock. A vasopressin infusion (0.06 U min−1) in this group of patients (with septic shock, postcardiotomy shock, and hypotension induced by overwhelming systemic inflammatory response syndrome) caused increases in MAP, systemic vascular resistance, and stroke volume index, with concomitant decreases in vasoactive drug requirements (21). However, complications of vasopressin use such as decrease in cardiac index, increase in bilirubins and liver enzymes, and decrease in platelet counts during this therapy have been described in this trial as well.
Other small trials of vasopressin use in patients with septic shock have also been described in the literature. Vasopressin infusion (0.04 - 0.20 U min−1) was compared with norepinephrine as a single agent to revert hypotension in a small group of patients with septic shock and was associated with improvements in renal function and in Sequential Organ Failure Assessment score (22). In other studies, terlipressin (a long-action vasopressin analog) was administered in patients with refractory septic shock and was able to restore adequate MAP for up to 5 h (23, 24). Nevertheless, terlipressin has been described as a potent intestinal vasoconstrictor and may possibly induce decreased intestinal perfusion.
Finally, a large randomized clinical trial (Vasopressin Versus Norepinephrine in Septic Shock Study) has now been completed, comparing vasopressin to norepinephrine therapy in 776 patients with vasopressor-dependent septic shock. The preliminary results were announced, and there was no difference in overall mortality, but vasopressin seemed to be beneficial in the less severe subgroup of patients (4, 25). The novel Surviving Sepsis Campaign guidelines suggest that a fixed dosage of 0.03 U min−1 of vasopressin may be added to septic shock patients already receiving norepinephrine, with anticipation of an effect equivalent to norepinephrine alone (4). Given the relative insufficiency of vasopressin described in septic shock patients and the side effects of this therapy, vasopressin infusion can possibly be more useful as a hormonal replacement regimen in patients receiving low doses of norepinephrine instead of a rescue therapy for those with vasopressor-refractory septic shock.
Hemofiltration has many superficial similarities to hemodialysis. In both techniques, access to the circulation is required, and blood passes through an extracorporeal circuit that includes either a dialyzer or a hemofilter. However, the mechanisms by which the composition of the blood is modified diverge markedly. During dialysis, blood flows along one side of a semipermeable membrane as a solution of crystalloids is pumped along the other side of the membrane against the direction of the blood flow (26). Hemofiltration works in a different manner. In the simplest form of the procedure, blood under pressure passes down one side of a highly permeable membrane, allowing both water and high molecular weight substances to go through the membrane by convective flow, as in glomerular filtration (26, 27). During hemofiltration, in contrast to hemodialysis, urea, creatinine, and phosphate are cleared at similar rates, and profound hypophosphatemia may develop unless the patient's phosphate intake is supplemented. Larger molecules such as heparin, insulin, myoglobin, and vancomycin, which are cleared from the blood in only negligible quantities in a dialyzer, are cleared efficiently by the hemofilter (26).
Continuous venous-venous hemofiltration (CVVHF) allows efficient control of fluid balance and azotemia in septic patients with acute renal failure, and it offers additional beneficial effects resulting from the removal of inflammatory mediators such as proinflammatory cytokines (28). Indeed, CVVHF has been shown to remove several proinflammatory mediators, although generally not resulting in decreased plasma levels (29). Ronco et al. (27) proposed the peak concentration hypothesis as the mechanism by which CVVHF can be beneficial in sepsis. This concept refers to the ability of CVVHF to lower peak levels of both the proinflammatory and anti-inflammatory molecules, reducing their toxic effects such as capillary leak, vasoplegia, and immunosuppression (27, 29). By this nonspecific removal of an overshoot of mediators, a new equilibrium might be shaped (27).
The filter's ability to remove solutes is dependent on many factors, including the material, pore size, wall thickness, electrical charge, physical structure, and surface area. Polyacrylonitrile (AN69) membranes have high adsorptive capacities and are more effective in removing TNF, IL-6, and IL-8. In endotoxemic dogs, hemofiltration with AN69 improves cardiac performance when compared with the polysulphone membrane (30).
In hemodynamic-unstable patients evolving the first hours of shock syndrome with acute renal failure, CVVHF has become an important method of artificial renal support (26). However, after multiple-organ-dysfunction installation, the use of intermittent high-blood-flow hemodialysis seems to be as safe and effective as CVVHF, with less hypothermia incidence during the procedure (31). In severe sepsis or septic shock patients without classical indications of renal replacement, the early application of CVVHF with ultrafiltration rates of 2 L h−1 reduces neither the plasmatic concentrations of various proinflammatory mediators nor the extent of subsequent multiple organ dysfunction (32). When dialytic acute renal failure occurs in the early severe sepsis or septic shock, isovolemic CVVHF with ultrafiltration rates of at least 35 mL kg−1 may be associated with improved survival (33). If the ultrafiltration rate is limited due to technical performance of pump-driven machines, a dialysate flow can be added to achieve higher clearances and best outcomes (34). Some recently designed equipment can provide high-precision scales (these devices are equipped with software for online continuous testing and high-volume capacity) and powerful heating systems for maintaining large volumes of infusion solution at sufficient high temperatures. These devices are able to perform pulses of high-volume hemofiltration higher then 85 mL kg−1 of ultrafiltrate, and this procedure improves hemodynamics both during and after therapy (35). Hemofiltration may be a beneficial adjuvant treatment for severe sepsis/septic shock regarding mortality benefits, but it deserves more investigation (35).
Statins are 3-hydroxy-3methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors that are established therapy for cardiovascular disease. Statins are potent inhibitors of HMG-CoA reductase, and treatment with these agents results in reduced intracellular cholesterol levels. These drugs are widely used in clinical practice for their lipid-lowering effects, following the demonstration in clinical trials that treatment with them reduces cardiovascular mortality in patients with and without coronary disease (36).
Reports from observational studies that previous statin treatment reduces the incidence of bacteremia and sepsis in hospitalized patients (as will be discussed later in this section) gave rise to a crescent interest regarding a possible statin-induced protective role during sepsis (37). However, the precise mechanisms by which statins can influence the course of this disease are not completely understood. It is possible that several pathways dependent or independent of cholesterol metabolism may account for their anti-inflammatory effect.
A known anti-inflammatory effect of statins is related to their inhibition of the intracellular signaling (37). This effect is mediated by statin-induced reduction of isoprenylation of isoprenoid molecules, which are nonsterol intermediaries that act as intracellular lipid attachments for posttranslational modifications of a number of cellular proteins (for example, guanosine triphosphate-binding proteins that are closely related to intracellular inflammatory signaling). One of the precursors of this pathway is mevalonate, and HMG-CoA is one of the most important enzymes in its regulation. Therefore, by reducing the isoprenylation, statins may reduce the response magnitude of the signaling pathways (38). In addition, HMG-CoA reductase inhibitors down-regulate the activation of key transcription factors, notably nuclear factor κB and mitogen-activated protein kinase, which are crucial for the expression of proinflammatory mediators. This inhibition affects the expression of cytokines, chemokines, and acute-phase proteins, thus reducing the inflammatory response associated with sepsis (39).
In addition to the effects related to intracellular signaling and cytokine production, statin treatment has been associated with important effects in leukocyte recruitment, with inhibition of expression of adhesion molecules, modulation of immune response by suppression of major histocompatibility complex II expression, and direct interference with lymphocyte-endothelial interactions (36). Other possibly beneficial mechanisms associated with statin treatment comprise induction of heme oxygenase protective pathway and reduction in oxidative stress during sepsis by reducing neutrophil oxidative burst (40).
The mechanisms associated with statin benefits in sepsis have been clearly demonstrated in experimental studies. In LPS-treated rats, simvastatin improves vascular responsiveness and decreases NO overproduction, an important hallmark of sepsis-induced vascular dysfunction (41). Moreover, simvastatin reduces superoxide production from neutrophils of ICU patients with sepsis (40). When administered after treatment, several statin preparations prolong survival in a cecal ligation and puncture mouse model. Possible effects associated with statin treatment in this study included preservation of cardiac function and hemodynamics as assessed by echocardiography and isolated heart preparations (42).
Although there are no prospective randomized studies of statin treatment in patients with sepsis, observational trials depict benefits associated with their use. A retrospective study of 388 patients admitted to the hospital for bacterial infection demonstrated that previous statin use was associated with significantly lower mortality (43). In another observational trial, Almog et al. (44) investigated the rate of severe sepsis in patients hospitalized for severe pneumonia, urinary tract infection, or cellulitis and identified that patients on previous statin use were associated with less evolution for severe sepsis and less overall ICU admission. In a more recent study, the same group evaluated the infection-related mortality of 11,490 patients with atherosclerotic disease and demonstrated that patients using statins had reduced risk of infection-related mortality. In this trial, previous statin use was recognized as an independent beneficial factor for mortality when adjusted for potential confounders (45). Possible drawbacks of these and other statins studies are the observational design, different end points, and different characteristics of the studied groups (37). Therefore, although statins seem to be a promising treatment for patients with sepsis, the lack of prospective controlled randomized trials preclude the use of these agents at bedside so far.
Intravenous immunoglobulin (IVIG) is a blood product prepared from a pool of donors and frequently used for the treatment of neurologic, hematologic, immunologic, nephrologic, and rheumatologic diseases (46). For the purposes of this article, only polyvalent IVIG will be discussed here because monoclonal antibodies will not be considered for this review.
Regarding composition, IVIG preparations contain more than 90% of immunoglobulin G (IgG) and can be divided into those that only contain IgG or those preparations enriched with IgM and IgA. The IgM-enriched preparation (Pentaglobin) contains 38 g L−1 IgG, 6 g L−1 IgM, and 6 g L−1 IgA, whereas the IgG preparations (Flebogamma) commonly contain more than 96% IgG. Because human plasma contains all three immunoglobulin classes, the IgM/A-enriched IVIG has been suggested to be more physiological (47).
The possible mechanisms by which IVIG may protect against severe sepsis and septic shock are dependent on the preparation used and the organism responsible for the infection. Generally, two essential mechanisms may be responsible for the benefits: modulation of the inflammatory response and antibacterial activity.
The antibacterial activity of IVIG is derived from the presence of a broad spectrum of opsonic and neutralizing antibodies against a variety of microbial antigens, including Campylobacter jejuni, oxacillin-resistant Staphylococcus aureus, Pseudomonas aeruginosa, and vancomycin-resistant Enterococcus faecalis (48). In this regard, the presence of IgM in IVIG preparation seems to confer a major protective effect because it is the main component of the primary antibody response, and its pentameric form contributes to a superior efficacy in toxin neutralization and bacterial agglutination when compared with IgG antibodies (47).
Other mechanisms described as important for IVIG protective effect are related to reduction of leukocyte-endothelial interaction and attenuation of microvascular failure in endotoxemia. A recent experimental study with endotoxemic hamsters demonstrated a reduction in venular leakage and attenuation in the decrease in platelet counts after IVIG infusion. Only intravenous IgM was able to reduce leukocyte adhesion to venules and microvascular perfusion failure after 24 h of LPS (49).
Interference with cytokine production may also be part of the pathways inhibited by IVIG during the course of sepsis. It has been demonstrated that IVIG decreases the concentrations of proinflammatory cytokines and increases anti-inflammatory molecules in mononuclear blood cells (50). Interference with the complement system may also account for the reduced inflammation after IVIG because these preparations have been associated with prevention of complement activation after acute inflammatory disorders (48).
The use of IVIG as adjuvant therapy for septic patients is not a modern idea. However, the earliest studies were biased by the small number of patients and the lack of consistent and reproducible definitions of sepsis. In more recent years, larger studies were performed, and the results are inconsistent. Werdan et al. (51) evaluated 652 patients with sepsis and could not demonstrate a positive benefit of IVIG in severe sepsis. However, this trial is only reported as an abstract and has not been completely published yet. In addition, a study of 211 septic and neutropenic patients with hematologic malignancies also failed to demonstrate a survival benefit of IVIG enriched with IgM/IgA (52). Nevertheless, when pooled together in a recently published meta-analysis, there is a trend to survival benefit for patients treated with IVIG (53). The administration of immunoglobulin for pediatric patients was also suggested by the recent Surviving Sepsis Campaign guidelines (4) mainly after a single center study demonstrated reduction in the mortality of neonates with severe sepsis after IVIG administration (54). However, most of the studies with IVIG for treatment of sepsis were performed before the implementation of recent beneficial discoveries such as activated protein C and EGDT. The interaction of an adjuvant anti-inflammatory therapy such as IVIG to approaches that, albeit already used in clinical practice, still do not have their beneficial mechanism completely demonstrated deserves better clarification. Thus, a randomized, prospective, controlled trial of polyvalent Ig in septic shock patients is mandatory.
Beyond conventional treatments, there have been few novel therapies that improve survival during sepsis. Sepsis remains a lethal syndrome despite the recent improvements in treatment discovered in recent years and described in this article. The continuous research in novel agents and therapeutic approaches amenable to sepsis therapy can be useful to further clarify the pathophysiology of the disease and to design clinical studies using these novel inhibitors, which may prove to halt the significant mortality of this condition.
The authors thank all the investigators of the studies who, due to space restrictions, were not mentioned in this article.
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