The Last 100 Years of Sepsis
http://www.100md.com
《美国呼吸和危急护理医学》
Department of Intensive Care, Erasme Hospital, Free University of Brussels, Belgium
Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado at Denver and Health Sciences Center, Denver, Colorado
ABSTRACT
Over the last 100 years, huge advances have been made in the field of sepsis in terms of pathophysiology, epidemiology, diagnosis, monitoring, and therapeutics. Here, we offer our perspective of the key changes and current situation in each of these areas. Despite these changes, mortality rates remain unacceptably high and continued progress, particularly in early diagnosis and therapy, is urgently needed.
Key Words: endotoxin cytokines epidemiology septic shock immunomodulation
The last 100 years have seen great advances in our understanding of sepsis, a term derived from the ancient Greek for rotten flesh and putrefaction. In the 1680s, some of the first descriptions of bacteria, Leeuwenhoek's "animalcules," were made, but it was another 200 years before the link between bacteria and infection finally began to be realized by some of the founders of modern microbiology and medicine, including Koch, Pasteur, Semmelweis, and Lister. Finally, in 1914, Schottmueller reported that the release of pathogenic germs into the bloodstream was responsible for systemic symptoms and signs (1), changing our modern understanding of the term "sepsis."
PATHOPHYSIOLOGY OF SEPSIS
The pathogenesis of sepsis involves a complex process of cellular activation resulting in the release of proinflammatory mediators, such as cytokines, activation of neutrophils, monocytes, and microvascular endothelial cells, involvement of neuroendocrine reflexes, and activation of the complement, coagulation, and fibrinolytic systems. Initiation of sepsis occurs as microbial components are recognized by soluble or cell-bound pattern recognition molecules or receptors, such as CD14 and Toll-like receptors (TLRs), activation of which induces the transcription of inflammatory and immune response genes, often via nuclear factor-B–mediated mechanisms, resulting in the release of a number of endogenous mediators. Cytokines, a family of cell signaling peptides with pro- and antiinflammatory properties, are some of the best known and most studied endogenous mediators associated with the development of organ system dysfunction in sepsis.
Two of the first cytokines to be implicated in sepsis were tumor necrosis factor (TNF-) and interleukin 1 (IL-1). TNF-, first identified in 1975 (2), is involved in leukocyte adhesion, local inflammation, neutrophil activation, generation of fever, suppression of erythropoiesis, decrease in fatty acid synthesis, and suppression of albumin synthesis, among others. The final critical steps demonstrating that these cytokines were involved in the development of severe sepsis came from studies showing that there was a correlation between the magnitude of circulating TNF- levels and patient outcome (3, 4), and then the observation that the injection of IL-1 or TNF- into animals can reproduce all the hemodynamic and biochemical features of severe sepsis and organ failure. Furthermore, blocking the effects of TNF and IL-1 in models of severe infection prevented complications and improved outcomes. Other cytokines and proinflammatory mediators that are currently attracting considerable interest for their putative contribution to sepsis include high-mobility group box 1, HMGB1, protein, a late mediator of systemic inflammation (5), and macrophage migration inhibitory factor, MIF (6).
An important advance in sepsis pathophysiology has been the growing realization of the links between the coagulation system and the immune response to sepsis (7), which led to the development of the only specific antisepsis treatment currently available, recombinant human activated protein C (8). Detailed reviews of mediators involved in sepsis can be found elsewhere (9).
Role of Endotoxin and Other Bacterial Toxins: Does the Type of Organism Matter
Endotoxin was first identified more than 100 years ago, but it was not until 1951 that Borden and Hall first suggested that it might have a role in the development of septic shock (10). Experimental studies using endotoxin administration soon followed and these models do reproduce many features of septic shock; however, they are usually characterized by a low cardiac output (hypokinetic state) and a high vascular resistance, a hemodynamic syndrome not characteristic of human septic shock. Already in 1911, Rolleston (11) had underlined that the clinical presentation of Escherichia coli infections in humans was different from E. coli administration in animals. In 1945, Altschule and colleagues first reported their experience with endotoxin administration in humans (12). Other investigators (13, 14) have since used this model, which has helped identify a number of the key characteristics of sepsis, although the human model also has its limitations. Evidence for a pathogenic role of endotoxin came from the report by Taveira da Silva and colleagues (15) of the effects of accidental self-administration of endotoxin by a lab technician.
One of the difficulties with determining the precise role of endotoxin in sepsis has been the difficulty in being able to measure endotoxin levels accurately. The development of the Limulus test in 1970 (16) marked a key step forward, but this assay can be activated by fungi, making it relatively nonspecific (17). A recently developed chemiluminescent assay, the endotoxin activity assay, may provide a means of identifying endotoxemia reliably and rapidly, although this test needs further validation (18).
Endotoxin is frequently found in the blood of acutely ill patients with sepsis, even in the absence of demonstrable gram-negative infection (19), possibly as a result of bacterial translocation from the gut. Even patients with heart failure may have circulating endotoxin (20). Nevertheless, endotoxin levels are associated with a higher incidence of complications (21) and have been shown to be an early predictor of bacteremia in febrile patients (22).
Other bacterial toxins, such as peptidoglycans or lipoteichoic acid, can be released by gram-positive microorganisms and induce the production of mediators associated with sepsis (23). Although early studies in patients attempted to relate the hemodynamic presentation with the type of microorganism (gram-positive vs. gram-negative), the results of these studies were inconsistent (24, 25), and it became apparent that the hemodynamic response is not related to the type of organism (26). This does not mean, however, that the specific causative organism does not matter; although the innate immune response generated by the host may be similar for all microorganisms, there also appear to be adaptive pathogen-specific responses (27, 28).
DEFINITIONS OF SEPSIS
Recent consensus conferences defined sepsis as the systemic response to infection. However, many would argue that sepsis is a maladaptive response, and defining it simply as "the host response to an infection" does not necessarily convey this negative connotation.
Bone and colleagues (29) proposed the term "sepsis syndrome," defined as hypothermia (temperature < 96°F) or hyperthermia (> 101°F), tachycardia (> 90 beats/min), tachypnea (> 20 breaths/min), clinical evidence of an infection site, and at least one end organ demonstrating inadequate perfusion or dysfunction. This terminology associated sepsis with some form of organ dysfunction, but since sepsis is already a syndrome, "sepsis syndrome" was somewhat redundant and later evolved into the term "severe sepsis." A consensus conference organized by the American College of Chest Physicians (ACCP) and the Society of Critical Care Medicine (SCCM) in 1991 (30) referred to systemic inflammatory response syndrome (SIRS) that could occur in association with an infection, which would then be called sepsis. To meet the SIRS criteria, patients needed to satisfy at least two of the following: fever or hypothermia, tachycardia, tachypnea or hyperventilation, and leukocytosis or leukopenia. However, many intensive care physicians remained concerned about a lack of a common definition for sepsis (31), and with a need to reexplore these concepts, a sepsis definitions conference was held in 2001, sponsored by the SCCM, the ACCP, the American Thoracic Society, the European Society of Intensive Care Medicine, and the Surgical Infection Society (32). The conference participants concluded that the diagnostic criteria for SIRS were overly sensitive and nonspecific, and that an expanded list of signs and symptoms of sepsis (Table 1) would better reflect the clinical response to infection (32). Hence, to summarize current definitions:
Infection: a pathologic process caused by the invasion of normally sterile tissue, fluid, or body cavity by pathogenic or potentially pathogenic microorganisms
Sepsis: infection, documented or suspected, and some of the signs and symptoms of an inflammatory response (Table 1)
Severe sepsis: sepsis complicated by organ dysfunction
Septic shock: severe sepsis plus acute circulatory failure characterized by persistent arterial hypotension despite adequate volume administration, unexplained by causes other than sepsis
EPIDEMIOLOGY OF SEPSIS
The last 100 years have seen considerable changes in the epidemiology of sepsis. However, as definitions have changed during this period and laboratory and imaging techniques have improved, it is only possible to draw fairly general conclusions. Current estimates suggest that that some 750,000 cases of severe sepsis occur annually in the United States, with a mortality rate of around 29% (33). The recent Sepsis Occurrence in Acutely Ill Patients (SOAP) study across Europe reported that more than 35% of intensive care unit (ICU) patients had sepsis at some point during their ICU stay, with a mortality rate of 27% (34). The rates of sepsis appear to be increasing in hospitals worldwide. Using the National Hospital Discharge Survey database, Martin and coworkers (35) reported an increase in frequency of severe sepsis in the United States from 83 cases per 100,000 population in 1979 to 240 cases per 100,000 population in 2000. In a review of relevant publications from 1958 to 1997, Friedman and colleagues noted a reduction in reported mortality rates from septic shock (36). Nevertheless, although the risk of death per individual case may be falling, the overall number of patients dying from sepsis mortality rates is growing as more patients are affected.
The primary infectious site causing sepsis has changed with time, from the abdomen as primary source before 1990 to the lungs in more recent years (36). Recent studies indicate that pneumonia is the most common infection associated with sepsis today ( 40%), followed by intraabdominal infection (20%), catheters and primary bacteremias (15%), and the urinary tract (10%) (33, 37–41). The microbiology of severe sepsis and septic shock has also altered over time. Although in the past gram-negative organisms were most commonly implicated, increasingly gram-positive organisms are isolated (36), such that roughly similar numbers of gram-positive and gram-negative organisms are now associated with sepsis. Sepsis can also be caused by a fungal or parasitic infection, and in about one-third of patients, no infectious agent is identified (8), usually either because sampling is impossible (e.g., some patients have community-acquired lung infection without sputum production) or because culture remains negative in patients who are already receiving antimicrobial drugs.
DIAGNOSIS OF SEPSIS
The diagnosis of sepsis is difficult, particularly in the ICU where signs of sepsis may be present in the absence of a real infection. The SIRS criteria included only fever (or hypothermia), tachycardia, tachypnea, and raised (or decreased) white blood cell count (30), but the list of possible signs and symptoms is much longer (Table 1). Unfortunately, none of these criteria are really specific. Various candidates have been put forward as potential "markers" of sepsis, but none has enough specificity to qualify as the marker. As indicated earlier, endotoxin is often found in the blood of critically ill patients, so that measurements of these levels have limited diagnostic value. Acute phase reactants like C-reactive protein may be more helpful and have some prognostic value, particularly when considering sequential measurements (42). Procalcitonin (PCT) may be more reliable (43), although PCT may also increase in nonseptic conditions, such as after cardiopulmonary bypass or in pancreatitis. Here again, the time course may be more helpful than a single value. Recently, supporting the key link between coagulation and inflammation, a modified activated partial thromboplastin time waveform has been proposed as a rapid and specific technique to identify patients with sepsis (44). Despite much research in the last decades, we still rely on a nonspecific combination of clinical signs and biochemical abnormalities to diagnose sepsis.
CHARACTERIZATION OF SEPSIS
One of the key problems in the diagnosis and definition of sepsis is the heterogeneity of this disease process. For example, a previously healthy young patient with meningococcemia and severe disseminated intravascular coagulation is markedly different from an elderly patient on steroids for advanced chronic obstructive pulmonary disease who arrives in the ICU with another episode of lung infection or the patient on their third course of chemotherapy for leukemia with a gram-negative bacteremia of unknown origin.
These different factors that contribute to the development of and outcome from sepsis can be grouped according to the PIRO classification (predisposing factors, infectious factors, host response, and organ [dys]function; Table 2) (32, 45).
Predisposing Factors
Age participates in modifying the host response to sepsis, as infections in neonates, children, and adults may be quite different. Past history is another feature, as patients with particular comorbidities (e.g., cirrhosis) or receiving immunosuppressive drugs may have different characteristics. Genetic factors likely play an important role in determining who develops sepsis, as well as its severity, and also modulate the response to treatment (46). Most genetic traits associated with severe infection are associated with defects in innate immune responses; some, such as complement deficiencies (47) have been recognized for some time, with others more recently described, including neutrophil defects (48), alterations in pattern recognition molecules, such as CD14 and TLRs (49, 50), and variations in cytokine expression (51–53).
Infection
Infection is characterized by the type of organism(s) and the likely source of infection. The site of infection also has prognostic value, For example, infections from the urinary tract are usually less severe than intraabdominal or pulmonary sources. In the PROWESS (Protein C Worldwide Evaluation in Severe Sepsis) trial (8), patients with urinary tract infections as a source of severe sepsis had a 28-d all-cause mortality rate of 21% compared with patients with a pulmonary source of sepsis who had a mortality rate of 34% (p < 0.01). The quantity and virulence of the infecting organisms are also important in determining outcomes. However, although these aspects are well known, classifying the relative importance of infections on outcome is difficult. Cohen and colleagues (54) recently generated a grading system for bacteremia, meningitis, pneumonia, skin and soft tissue infections, peritonitis, and urinary tract infections. For each infection site and organism, a two-digit code was generated according to the mortality rate associated with that infection (from 1, 5%, to 4, > 30%), and the level of evidence available to support the mortality risk (level A representing evidence from more than five studies with greater than 100 patients, through to level E where there was insufficient evidence from case reports). This Grading System for Site and Severity of Infection needs to be validated, but could be a useful means of better characterizing the risks associated with infections caused by various organisms in different sites. The timing of onset of infection may also influence outcomes. A recent study showed that patients who developed septic shock within 24 hours of ICU admission were more severely ill, but had better outcomes, than patients who became hypotensive later during their ICU stay (55).
Response
The host response to infection varies between patients and with time in the same patient (56). The degree of host response can be assessed according to the presence or absence of various clinical and laboratory features and to the degree of elevation of factors such as white cell count, C-reactive protein, and PCT. However, none of these are specific for sepsis and may be altered in other conditions. In addition, there is a time lag before changes are seen in such markers. Advances in genomic and proteomic techniques may permit more accurate characterization of each individual's immune response status.
Organ Dysfunction
Outcome from sepsis is correlated to the degree of organ dysfunction (40, 57), which can be assessed with various scoring systems, one of the most common being the Sequential Organ Failure Assessment score (58). This scoring system is different from the Acute Physiology and Chronic Health Evaluation II (APACHE II) (59) or the simplified acute physiology score, SAPS (60), scores that evaluate the risk of mortality, but do not individualize the various degrees of organ dysfunction.
FEATURES OF SEPSIS
Hemodynamic Alterations
Hyperkinetic shock.
Early clinical studies identified hypodynamic and hyperdynamic shock (so-called cold and warm forms, respectively). Some of these studies even attempted to relate these patterns to the source of infection (e.g., urinary vs. other sources) or type of microorganism (gram-positive vs. gram-negative), but failed to show consistent results (24, 25, 61). Later studies, conducted after better fluid resuscitation was implemented, indicated that septic shock is typically hyperdynamic (62); hypokinetic shock is only present before adequate fluid resuscitation or in rare cases where myocardial depression is severe, such as in some cases of meningococcemia.
Decreased vascular reactivity and myocardial depression.
Decreased vascular reactivity was demonstrated by Groeneveld and colleagues (63), who noted that patients who die of septic shock have a persistent defect in peripheral vascular tone irrespective of cardiac index. Myocardial depression is also a key feature. Parker and coworkers (64) used radionuclide studies and found a transient acute fall in ejection fraction, explaining how ventricular dilation in a setting of myocardial depression can maintain stroke volume and cardiac output. In the 1980s, a number of studies also focused attention on right ventricular function. Although left ventricular ejection is facilitated by the low systemic resistance that accompanies severe sepsis, afterload to the right ventricle is typically increased as a result of pulmonary hypertension, making myocardial depression easier to demonstrate for the right ventricle (65).
Metabolic Alterations
Many studies have addressed the question of vascular shunting versus metabolic alterations to account for the alterations in cellular metabolism in septic shock. Some studies refer to a defective oxygen consumption in septic shock (66). Fink (67) introduced the concept of "cytopathic hypoxia" to account for an abnormal cellular metabolism even after resuscitation appears to be complete. It is likely that hemodynamic and metabolic alterations coexist.
MANAGEMENT OF SEPSIS
Infection Control
Infection control has become more sophisticated as imaging and culture techniques have improved, enabling more accurate determination of infection site, facilitating surgical intervention where necessary, and causative microorganism, facilitating appropriate early antimicrobial treatment. In addition, the choice of antimicrobials has increased hugely since the discovery of penicillin in 1928.
Should Fever Be Treated
Fever is a known cardinal sign of sepsis and was for many years considered to be a harmful effect and widely treated with antipyretic agents. Controversial studies by Kluger and colleagues in 1975 in poikilothermic animals suggested an improved outcome in animals developing a fever after bacterial injection (68). Although short-term studies have indicated that avoiding fever may decrease the severity of acute lung injury (69), more prolonged animal experiments have suggested that control of fever may be detrimental (68) and the release of heat shock proteins in fever may have important protective effects (70). A multicenter study in patients with severe sepsis reported that ibuprofen, a cyclooxygenase inhibitor, was well tolerated and could decrease oxygen consumption but did not reduce mortality (71); although this study did not specifically target the treatment of fever, it adds to the controversy on this subject.
Hemodynamic Management
The hemodynamic management of shock was summarized by Weil and Shubin in 1969 in the following VIP mnemonic (72): Ventilation (adequate oxygenation), Infusion (of fluids, blood, etc.), and Pump (administration of vasoactive agents as required). However, although this approach remains the cornerstone to the management of the patient with severe sepsis, many aspects of optimal hemodynamic resuscitation remain uncertain. For example, which fluids should be used, how much, and titrated to which endpoints Which is the optimal vasopressor When should intotropic support be offered These questions and many others remain largely undefined.
Initial resuscitation is primarily based on the correction of arterial hypotension. Various vasopressor substances, including norepinephrine, metaraminol, phenylephrine, mephentermine, and even angiotensin, have been proposed and used for this purpose. In 1964, Udhoji and Weil compared the effects of angiotensin, levarterenol, and metaraminol in the treatment of shock (73). The need to maintain cardiac output was soon recognized and early reports suggested adding isoproterenol for this purpose. MacCannell and coworkers (74) first proposed the administration of dopamine in 1966, for its combined vasoconstrictor and inotropic effects associated with a possible improved distribution of blood flow. However, it is still unclear whether one drug is superior to the other. A prospective, randomized, double-blinded European study is ongoing to evaluate the effects of dopamine versus norepinephrine as the initial vasopressor agent in shock.
In the last decade or so, it has been reported that plasma concentrations of vasopressin are inappropriately low in patients with septic shock (75), and it has been suggested that low doses of vasopressin may be a beneficial adjunct to standard vasopressor therapy in such patients (76, 77). However, large, randomized, controlled trials are needed to confirm whether or not vasopressin has a place in the hemodynamic management of patients with septic shock.
In the 1970s, the importance of maintaining cardiac output and oxygen delivery (DO2) was recognized (78). Shoemaker and colleagues (79) and others recommended maintaining DO2 at predetermined supranormal levels, but this strategy was later recognized as being potentially harmful (80). More recent studies suggest that therapy should be tailored according to the patient's needs (81), with blood lactate and mixed venous oxygen saturation (SO2) forming part of the management algorithm (82). Rivers and colleagues (83) reported that patients who received 6 hours of early goal-directed therapy aimed at maintaining central venous oxygen saturation (ScvO2) greater than 70% had better outcomes than those who received standard therapy with very similar treatment goals except for the use of ScvO2 data to drive therapeutic decisions.
Attempts to influence the distribution of blood flow have been disappointing. In particular, the beneficial effects of low doses of dopamine on renal function were not substantiated (84), although it was widely used for many years. Some studies have even suggested that interventions resulting in vasodilating effects may improve the microcirculation (85).
Hemodynamic Monitoring
The introduction of the pulmonary artery catheter in 1970 (86) helped physicians better characterize the hemodynamic alterations in septic patients. Although the use of the the pulmonary artery catheter has helped to define the hemodynamic patterns of sepsis, its value in determining therapy has been challenged in the last decade (87). Regional monitoring systems have been developed and may be preferable. The gut has been the focus of considerable attention and interest, with gastric tonometry an attractive possibility, but this technique has practical limitations (88). Sublingual capnometry provides information that is equivalent to that of gastric tonometry (89). The sublingual region may also enable direct visualization of the microcirculatory defects (90, 91), and persistence of these alterations, as observed using orthogonal polarization spectral imaging, has been associated with worse outcomes (91). The study of microcirculatory changes and their possible correction with outcome could result in improved treatment strategies that can be targeted at the underlying abnormality (92, 93).
Metabolic parameters to monitor hemodynamic status are limited. Blood lactate levels were first proposed by Broder and Weil in 1964 (94). They were shown to have prognostic value, and in the 1980s repeated measurements were shown to be helpful (95). However, although high lactate levels were initially considered to reflect tissue hypoxia, a number of studies have indicated this may not necessarily be the case especially in sepsis, and altered cellular metabolism may result in high pyruvate and lactate levels. Hence, the interpretation of high lactate levels in sepsis can be complex (96).
Role of Steroids
Steroids were first proposed in the treatment of severe infections as early as 1954 (97). Various effects were described, including an increase in adenylate cyclase, effects on the complement and coagulation systems, improved reticuloendothelial system function, and better cellular phagocytic function. Decreased permeability alterations were also described (98). Beneficial hemodynamic effects were associated with an increase in arterial pressure and cardiac output, in part attributed to an inhibited release of the then popular "myocardial depressant factor."
Clinical reports emerged in the early 1970s from Motsay and colleagues (99) and others suggesting beneficial effects of massive doses of steroids, typically 30 mg/kg of methylprednisolone or 6 mg/kg of dexamethasone. Some studies reported beneficial hemodynamic effects associated with an increase in cardiac output, a reduction in systemic vascular resistance, an improvement in hepatosplanchnic perfusion, and even an increase in 2,3 diphosphoglycerate that could increase the peripheral delivery of oxygen to the tissues (100). The clinical studies were, however, of limited size and quality and yielded controversial results in outcome (101, 102). An important prospective, randomized, placebo-controlled study by Schumer (102) reported improved survival rates with large dose of steroids in septic shock, and Hoffman and coworkers (103) showed a beneficial effect of steroids in typhoid fever. However, two prospective randomized studies (104, 105) of high-dose corticosteroid therapy in patients with the sepsis syndrome showed no beneficial effects, and combined with the results of a meta-analysis (106), seemed to put an end to the use of steroids in sepsis.
However, the steroid story was not over. Although animal studies had emphasized the importance of an adequate adrenal response to permit survival from severe infections, this concept was finally put forward clinically by Sibbald and coworkers in 1977 (107) when they showed that several patients, despite having severe bacterial infections and no history to support Addison's disease, had low plasma cortisol levels and a lesser response to a corticotropin test than would be expected. Could this so-called relative adrenal insufficiency be corrected with replacement doses of steroids Several studies (summarized in Reference 108) have indeed suggested an improved outcome in patients with septic shock treated with moderate doses of hydrocortisone 200 to 300 mg/d, rather than the large doses used in the past. In 2002, Annane and colleagues (109) published the results of an important multicenter French study including 299 patients randomized to receive moderate-dose hydrocortisone or placebo for 7 d. Although there was no significant effect on survival overall, there was a significant reduction in mortality in the (predefined) subgroup of patients with a suboptimal response to an adrenocorticotropic hormone test. The significance was, however, obtained only after adjustment for several factors. Nevertheless, in view of the other recent studies, the Surviving Sepsis Campaign Guidelines for the management of severe sepsis and septic shock (110) recommend the use of moderate doses of hydrocortisone, pending the results of a large multicenter study (Corticus) being conducted in Europe. Although Annane and colleagues (110) observed a survival benefit only in patients with a suboptimal response to a corticotropin test, the need for this test is still questionable. Likewise, the addition of oral fludrocortisone, as in the study by Annane and colleagues, is still questionable.
Immunomodulating Therapies
A large number of immunomodulatory agents have been studied in experimental and clinical studies (Table 3). Antiendotoxin strategies were the first to be investigated as the structure of endotoxin was identified in the 1960s and have perhaps been more extensively investigated than any other area in this field. However, the vast majority of the clinical trials of immunomodulatory agents have shown relatively little success, despite often promising preclinical results. The reasons behind these apparent failures are varied. It is possible that some strategies may have had limited efficacy in discrete patient populations, but nevertheless failed to show a significant improvement in survival rate. For example, the use of bactericidal/permeability-increasing protein did not decrease mortality in children with meningococcemia but may have diminished some sepsis related morbidities, such as the need for amputations (111).
Another major limitation to the immunomodulatory approach is that it aims at antagonizing a response that is not necessarily maladaptive. As an example, blocking TNF- with anti-TNF antibodies or soluble fusion protein complexes that include TNF receptors may help some individuals with an overwhelming host response, but may be harmful in patients with an appropriate, controlled response. Animal models have also shown that antiinflammatory strategies could be beneficial in very acute models of endotoxin administration, but harmful in models of more localized intraabdominal infections (112).
One agent has shown benefit in sepsis: drotrecogin alfa (activated). The PROWESS study (8) demonstrated that a dose of 24 μg/kg of body weight/hour for 96 h of drotrecogin alfa (activated) reduced mortality rates from 30.8% in the placebo group to 24.7% in the treatment group, which equated to one additional life saved for every 16 patients treated. Subgroup analyses indicated that this was largely due to the effect on patients with greater disease severity (i.e., APACHE II score 25), and a subsequent randomized, placebo-controlled study (the Administration of Drotrecogin Alfa [Activated] in Early Stage Severe Sepsis [ADDRESS] trial) in patients with a lower risk of death (defined by an APACHE II score < 25 or single-organ failure) showed no statistically significant differences in 28-d mortality between the placebo group and the treatment group (113). Another study in children with severe sepsis was also stopped for futility. Nevertheless, despite these results, the high costs, and increased risks of bleeding, drotrecogin alfa (activated) does appear to reduce mortality rates in patients with severe sepsis and a high risk of death (i.e., multiple-organ failure or high APACHE II score).
The fact that studies with other natural anticoagulants, including tissue factor pathway inhibitor (114) and antithrombin (115), did not reduce mortality rates raises questions about the mechanism of action of drotrecogin alfa (activated) and the importance of coagulation alterations in contributing to organ dysfunction and mortality associated with sepsis. Indeed, the mechanisms of action of drotrecogin alfa (activated) appear to extend beyond its anticoagulant activity, and include diminishing neutrophil chemotaxis and endothelial activation through interaction with the endothelial protein C receptor, which is present on endothelial cells, neutrophils, and monocytes (116, 117).
CONCLUSIONS: HAS PROGRESS BEEN MADE IN SEPSIS
The story of sepsis over the past 100 years has been a fascinating tale of discovery. Great strides have been made in terms of understanding the extra- and intracellular events that contribute to organ system dysfunction. There has also been progress in management, with several studies suggesting reduced mortality rates (35, 36) as a result of improved supportive and pharmacologic management of these critically ill patients. Widely publicized evidence-based guidelines have been published to help the clinician manage the patient with severe sepsis (110). However, mortality rates still remain unacceptably high, and it is apparent that much remains to be done to advance our understanding and treatment of this important and increasingly frequent medical problem.
FOOTNOTES
Originally Published in Press as DOI: 10.1164/rccm.200510-1604OE on October 20, 2005
Conflict of Interest Statement: J-L.V. received honoraria and grants from Brahms, Chiron, Eli Lilly, Eisai, GlaxoSmithKline, Toray, and Pfizer. E.A. received consulting fees from Eli Lilly in 2002 and 2003; he served as the principal investigator of the Eli Lilly-sponsored ADDRESS study, an international multicenter clinical trial that investigated the utility of rhAPC in patients with sepsis at lower risk of mortality. He also served as principal investigator of the Chorin-sponsored OPTIMIST study, which examined the utility of Rificogin in patients with sepsis.
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Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado at Denver and Health Sciences Center, Denver, Colorado
ABSTRACT
Over the last 100 years, huge advances have been made in the field of sepsis in terms of pathophysiology, epidemiology, diagnosis, monitoring, and therapeutics. Here, we offer our perspective of the key changes and current situation in each of these areas. Despite these changes, mortality rates remain unacceptably high and continued progress, particularly in early diagnosis and therapy, is urgently needed.
Key Words: endotoxin cytokines epidemiology septic shock immunomodulation
The last 100 years have seen great advances in our understanding of sepsis, a term derived from the ancient Greek for rotten flesh and putrefaction. In the 1680s, some of the first descriptions of bacteria, Leeuwenhoek's "animalcules," were made, but it was another 200 years before the link between bacteria and infection finally began to be realized by some of the founders of modern microbiology and medicine, including Koch, Pasteur, Semmelweis, and Lister. Finally, in 1914, Schottmueller reported that the release of pathogenic germs into the bloodstream was responsible for systemic symptoms and signs (1), changing our modern understanding of the term "sepsis."
PATHOPHYSIOLOGY OF SEPSIS
The pathogenesis of sepsis involves a complex process of cellular activation resulting in the release of proinflammatory mediators, such as cytokines, activation of neutrophils, monocytes, and microvascular endothelial cells, involvement of neuroendocrine reflexes, and activation of the complement, coagulation, and fibrinolytic systems. Initiation of sepsis occurs as microbial components are recognized by soluble or cell-bound pattern recognition molecules or receptors, such as CD14 and Toll-like receptors (TLRs), activation of which induces the transcription of inflammatory and immune response genes, often via nuclear factor-B–mediated mechanisms, resulting in the release of a number of endogenous mediators. Cytokines, a family of cell signaling peptides with pro- and antiinflammatory properties, are some of the best known and most studied endogenous mediators associated with the development of organ system dysfunction in sepsis.
Two of the first cytokines to be implicated in sepsis were tumor necrosis factor (TNF-) and interleukin 1 (IL-1). TNF-, first identified in 1975 (2), is involved in leukocyte adhesion, local inflammation, neutrophil activation, generation of fever, suppression of erythropoiesis, decrease in fatty acid synthesis, and suppression of albumin synthesis, among others. The final critical steps demonstrating that these cytokines were involved in the development of severe sepsis came from studies showing that there was a correlation between the magnitude of circulating TNF- levels and patient outcome (3, 4), and then the observation that the injection of IL-1 or TNF- into animals can reproduce all the hemodynamic and biochemical features of severe sepsis and organ failure. Furthermore, blocking the effects of TNF and IL-1 in models of severe infection prevented complications and improved outcomes. Other cytokines and proinflammatory mediators that are currently attracting considerable interest for their putative contribution to sepsis include high-mobility group box 1, HMGB1, protein, a late mediator of systemic inflammation (5), and macrophage migration inhibitory factor, MIF (6).
An important advance in sepsis pathophysiology has been the growing realization of the links between the coagulation system and the immune response to sepsis (7), which led to the development of the only specific antisepsis treatment currently available, recombinant human activated protein C (8). Detailed reviews of mediators involved in sepsis can be found elsewhere (9).
Role of Endotoxin and Other Bacterial Toxins: Does the Type of Organism Matter
Endotoxin was first identified more than 100 years ago, but it was not until 1951 that Borden and Hall first suggested that it might have a role in the development of septic shock (10). Experimental studies using endotoxin administration soon followed and these models do reproduce many features of septic shock; however, they are usually characterized by a low cardiac output (hypokinetic state) and a high vascular resistance, a hemodynamic syndrome not characteristic of human septic shock. Already in 1911, Rolleston (11) had underlined that the clinical presentation of Escherichia coli infections in humans was different from E. coli administration in animals. In 1945, Altschule and colleagues first reported their experience with endotoxin administration in humans (12). Other investigators (13, 14) have since used this model, which has helped identify a number of the key characteristics of sepsis, although the human model also has its limitations. Evidence for a pathogenic role of endotoxin came from the report by Taveira da Silva and colleagues (15) of the effects of accidental self-administration of endotoxin by a lab technician.
One of the difficulties with determining the precise role of endotoxin in sepsis has been the difficulty in being able to measure endotoxin levels accurately. The development of the Limulus test in 1970 (16) marked a key step forward, but this assay can be activated by fungi, making it relatively nonspecific (17). A recently developed chemiluminescent assay, the endotoxin activity assay, may provide a means of identifying endotoxemia reliably and rapidly, although this test needs further validation (18).
Endotoxin is frequently found in the blood of acutely ill patients with sepsis, even in the absence of demonstrable gram-negative infection (19), possibly as a result of bacterial translocation from the gut. Even patients with heart failure may have circulating endotoxin (20). Nevertheless, endotoxin levels are associated with a higher incidence of complications (21) and have been shown to be an early predictor of bacteremia in febrile patients (22).
Other bacterial toxins, such as peptidoglycans or lipoteichoic acid, can be released by gram-positive microorganisms and induce the production of mediators associated with sepsis (23). Although early studies in patients attempted to relate the hemodynamic presentation with the type of microorganism (gram-positive vs. gram-negative), the results of these studies were inconsistent (24, 25), and it became apparent that the hemodynamic response is not related to the type of organism (26). This does not mean, however, that the specific causative organism does not matter; although the innate immune response generated by the host may be similar for all microorganisms, there also appear to be adaptive pathogen-specific responses (27, 28).
DEFINITIONS OF SEPSIS
Recent consensus conferences defined sepsis as the systemic response to infection. However, many would argue that sepsis is a maladaptive response, and defining it simply as "the host response to an infection" does not necessarily convey this negative connotation.
Bone and colleagues (29) proposed the term "sepsis syndrome," defined as hypothermia (temperature < 96°F) or hyperthermia (> 101°F), tachycardia (> 90 beats/min), tachypnea (> 20 breaths/min), clinical evidence of an infection site, and at least one end organ demonstrating inadequate perfusion or dysfunction. This terminology associated sepsis with some form of organ dysfunction, but since sepsis is already a syndrome, "sepsis syndrome" was somewhat redundant and later evolved into the term "severe sepsis." A consensus conference organized by the American College of Chest Physicians (ACCP) and the Society of Critical Care Medicine (SCCM) in 1991 (30) referred to systemic inflammatory response syndrome (SIRS) that could occur in association with an infection, which would then be called sepsis. To meet the SIRS criteria, patients needed to satisfy at least two of the following: fever or hypothermia, tachycardia, tachypnea or hyperventilation, and leukocytosis or leukopenia. However, many intensive care physicians remained concerned about a lack of a common definition for sepsis (31), and with a need to reexplore these concepts, a sepsis definitions conference was held in 2001, sponsored by the SCCM, the ACCP, the American Thoracic Society, the European Society of Intensive Care Medicine, and the Surgical Infection Society (32). The conference participants concluded that the diagnostic criteria for SIRS were overly sensitive and nonspecific, and that an expanded list of signs and symptoms of sepsis (Table 1) would better reflect the clinical response to infection (32). Hence, to summarize current definitions:
Infection: a pathologic process caused by the invasion of normally sterile tissue, fluid, or body cavity by pathogenic or potentially pathogenic microorganisms
Sepsis: infection, documented or suspected, and some of the signs and symptoms of an inflammatory response (Table 1)
Severe sepsis: sepsis complicated by organ dysfunction
Septic shock: severe sepsis plus acute circulatory failure characterized by persistent arterial hypotension despite adequate volume administration, unexplained by causes other than sepsis
EPIDEMIOLOGY OF SEPSIS
The last 100 years have seen considerable changes in the epidemiology of sepsis. However, as definitions have changed during this period and laboratory and imaging techniques have improved, it is only possible to draw fairly general conclusions. Current estimates suggest that that some 750,000 cases of severe sepsis occur annually in the United States, with a mortality rate of around 29% (33). The recent Sepsis Occurrence in Acutely Ill Patients (SOAP) study across Europe reported that more than 35% of intensive care unit (ICU) patients had sepsis at some point during their ICU stay, with a mortality rate of 27% (34). The rates of sepsis appear to be increasing in hospitals worldwide. Using the National Hospital Discharge Survey database, Martin and coworkers (35) reported an increase in frequency of severe sepsis in the United States from 83 cases per 100,000 population in 1979 to 240 cases per 100,000 population in 2000. In a review of relevant publications from 1958 to 1997, Friedman and colleagues noted a reduction in reported mortality rates from septic shock (36). Nevertheless, although the risk of death per individual case may be falling, the overall number of patients dying from sepsis mortality rates is growing as more patients are affected.
The primary infectious site causing sepsis has changed with time, from the abdomen as primary source before 1990 to the lungs in more recent years (36). Recent studies indicate that pneumonia is the most common infection associated with sepsis today ( 40%), followed by intraabdominal infection (20%), catheters and primary bacteremias (15%), and the urinary tract (10%) (33, 37–41). The microbiology of severe sepsis and septic shock has also altered over time. Although in the past gram-negative organisms were most commonly implicated, increasingly gram-positive organisms are isolated (36), such that roughly similar numbers of gram-positive and gram-negative organisms are now associated with sepsis. Sepsis can also be caused by a fungal or parasitic infection, and in about one-third of patients, no infectious agent is identified (8), usually either because sampling is impossible (e.g., some patients have community-acquired lung infection without sputum production) or because culture remains negative in patients who are already receiving antimicrobial drugs.
DIAGNOSIS OF SEPSIS
The diagnosis of sepsis is difficult, particularly in the ICU where signs of sepsis may be present in the absence of a real infection. The SIRS criteria included only fever (or hypothermia), tachycardia, tachypnea, and raised (or decreased) white blood cell count (30), but the list of possible signs and symptoms is much longer (Table 1). Unfortunately, none of these criteria are really specific. Various candidates have been put forward as potential "markers" of sepsis, but none has enough specificity to qualify as the marker. As indicated earlier, endotoxin is often found in the blood of critically ill patients, so that measurements of these levels have limited diagnostic value. Acute phase reactants like C-reactive protein may be more helpful and have some prognostic value, particularly when considering sequential measurements (42). Procalcitonin (PCT) may be more reliable (43), although PCT may also increase in nonseptic conditions, such as after cardiopulmonary bypass or in pancreatitis. Here again, the time course may be more helpful than a single value. Recently, supporting the key link between coagulation and inflammation, a modified activated partial thromboplastin time waveform has been proposed as a rapid and specific technique to identify patients with sepsis (44). Despite much research in the last decades, we still rely on a nonspecific combination of clinical signs and biochemical abnormalities to diagnose sepsis.
CHARACTERIZATION OF SEPSIS
One of the key problems in the diagnosis and definition of sepsis is the heterogeneity of this disease process. For example, a previously healthy young patient with meningococcemia and severe disseminated intravascular coagulation is markedly different from an elderly patient on steroids for advanced chronic obstructive pulmonary disease who arrives in the ICU with another episode of lung infection or the patient on their third course of chemotherapy for leukemia with a gram-negative bacteremia of unknown origin.
These different factors that contribute to the development of and outcome from sepsis can be grouped according to the PIRO classification (predisposing factors, infectious factors, host response, and organ [dys]function; Table 2) (32, 45).
Predisposing Factors
Age participates in modifying the host response to sepsis, as infections in neonates, children, and adults may be quite different. Past history is another feature, as patients with particular comorbidities (e.g., cirrhosis) or receiving immunosuppressive drugs may have different characteristics. Genetic factors likely play an important role in determining who develops sepsis, as well as its severity, and also modulate the response to treatment (46). Most genetic traits associated with severe infection are associated with defects in innate immune responses; some, such as complement deficiencies (47) have been recognized for some time, with others more recently described, including neutrophil defects (48), alterations in pattern recognition molecules, such as CD14 and TLRs (49, 50), and variations in cytokine expression (51–53).
Infection
Infection is characterized by the type of organism(s) and the likely source of infection. The site of infection also has prognostic value, For example, infections from the urinary tract are usually less severe than intraabdominal or pulmonary sources. In the PROWESS (Protein C Worldwide Evaluation in Severe Sepsis) trial (8), patients with urinary tract infections as a source of severe sepsis had a 28-d all-cause mortality rate of 21% compared with patients with a pulmonary source of sepsis who had a mortality rate of 34% (p < 0.01). The quantity and virulence of the infecting organisms are also important in determining outcomes. However, although these aspects are well known, classifying the relative importance of infections on outcome is difficult. Cohen and colleagues (54) recently generated a grading system for bacteremia, meningitis, pneumonia, skin and soft tissue infections, peritonitis, and urinary tract infections. For each infection site and organism, a two-digit code was generated according to the mortality rate associated with that infection (from 1, 5%, to 4, > 30%), and the level of evidence available to support the mortality risk (level A representing evidence from more than five studies with greater than 100 patients, through to level E where there was insufficient evidence from case reports). This Grading System for Site and Severity of Infection needs to be validated, but could be a useful means of better characterizing the risks associated with infections caused by various organisms in different sites. The timing of onset of infection may also influence outcomes. A recent study showed that patients who developed septic shock within 24 hours of ICU admission were more severely ill, but had better outcomes, than patients who became hypotensive later during their ICU stay (55).
Response
The host response to infection varies between patients and with time in the same patient (56). The degree of host response can be assessed according to the presence or absence of various clinical and laboratory features and to the degree of elevation of factors such as white cell count, C-reactive protein, and PCT. However, none of these are specific for sepsis and may be altered in other conditions. In addition, there is a time lag before changes are seen in such markers. Advances in genomic and proteomic techniques may permit more accurate characterization of each individual's immune response status.
Organ Dysfunction
Outcome from sepsis is correlated to the degree of organ dysfunction (40, 57), which can be assessed with various scoring systems, one of the most common being the Sequential Organ Failure Assessment score (58). This scoring system is different from the Acute Physiology and Chronic Health Evaluation II (APACHE II) (59) or the simplified acute physiology score, SAPS (60), scores that evaluate the risk of mortality, but do not individualize the various degrees of organ dysfunction.
FEATURES OF SEPSIS
Hemodynamic Alterations
Hyperkinetic shock.
Early clinical studies identified hypodynamic and hyperdynamic shock (so-called cold and warm forms, respectively). Some of these studies even attempted to relate these patterns to the source of infection (e.g., urinary vs. other sources) or type of microorganism (gram-positive vs. gram-negative), but failed to show consistent results (24, 25, 61). Later studies, conducted after better fluid resuscitation was implemented, indicated that septic shock is typically hyperdynamic (62); hypokinetic shock is only present before adequate fluid resuscitation or in rare cases where myocardial depression is severe, such as in some cases of meningococcemia.
Decreased vascular reactivity and myocardial depression.
Decreased vascular reactivity was demonstrated by Groeneveld and colleagues (63), who noted that patients who die of septic shock have a persistent defect in peripheral vascular tone irrespective of cardiac index. Myocardial depression is also a key feature. Parker and coworkers (64) used radionuclide studies and found a transient acute fall in ejection fraction, explaining how ventricular dilation in a setting of myocardial depression can maintain stroke volume and cardiac output. In the 1980s, a number of studies also focused attention on right ventricular function. Although left ventricular ejection is facilitated by the low systemic resistance that accompanies severe sepsis, afterload to the right ventricle is typically increased as a result of pulmonary hypertension, making myocardial depression easier to demonstrate for the right ventricle (65).
Metabolic Alterations
Many studies have addressed the question of vascular shunting versus metabolic alterations to account for the alterations in cellular metabolism in septic shock. Some studies refer to a defective oxygen consumption in septic shock (66). Fink (67) introduced the concept of "cytopathic hypoxia" to account for an abnormal cellular metabolism even after resuscitation appears to be complete. It is likely that hemodynamic and metabolic alterations coexist.
MANAGEMENT OF SEPSIS
Infection Control
Infection control has become more sophisticated as imaging and culture techniques have improved, enabling more accurate determination of infection site, facilitating surgical intervention where necessary, and causative microorganism, facilitating appropriate early antimicrobial treatment. In addition, the choice of antimicrobials has increased hugely since the discovery of penicillin in 1928.
Should Fever Be Treated
Fever is a known cardinal sign of sepsis and was for many years considered to be a harmful effect and widely treated with antipyretic agents. Controversial studies by Kluger and colleagues in 1975 in poikilothermic animals suggested an improved outcome in animals developing a fever after bacterial injection (68). Although short-term studies have indicated that avoiding fever may decrease the severity of acute lung injury (69), more prolonged animal experiments have suggested that control of fever may be detrimental (68) and the release of heat shock proteins in fever may have important protective effects (70). A multicenter study in patients with severe sepsis reported that ibuprofen, a cyclooxygenase inhibitor, was well tolerated and could decrease oxygen consumption but did not reduce mortality (71); although this study did not specifically target the treatment of fever, it adds to the controversy on this subject.
Hemodynamic Management
The hemodynamic management of shock was summarized by Weil and Shubin in 1969 in the following VIP mnemonic (72): Ventilation (adequate oxygenation), Infusion (of fluids, blood, etc.), and Pump (administration of vasoactive agents as required). However, although this approach remains the cornerstone to the management of the patient with severe sepsis, many aspects of optimal hemodynamic resuscitation remain uncertain. For example, which fluids should be used, how much, and titrated to which endpoints Which is the optimal vasopressor When should intotropic support be offered These questions and many others remain largely undefined.
Initial resuscitation is primarily based on the correction of arterial hypotension. Various vasopressor substances, including norepinephrine, metaraminol, phenylephrine, mephentermine, and even angiotensin, have been proposed and used for this purpose. In 1964, Udhoji and Weil compared the effects of angiotensin, levarterenol, and metaraminol in the treatment of shock (73). The need to maintain cardiac output was soon recognized and early reports suggested adding isoproterenol for this purpose. MacCannell and coworkers (74) first proposed the administration of dopamine in 1966, for its combined vasoconstrictor and inotropic effects associated with a possible improved distribution of blood flow. However, it is still unclear whether one drug is superior to the other. A prospective, randomized, double-blinded European study is ongoing to evaluate the effects of dopamine versus norepinephrine as the initial vasopressor agent in shock.
In the last decade or so, it has been reported that plasma concentrations of vasopressin are inappropriately low in patients with septic shock (75), and it has been suggested that low doses of vasopressin may be a beneficial adjunct to standard vasopressor therapy in such patients (76, 77). However, large, randomized, controlled trials are needed to confirm whether or not vasopressin has a place in the hemodynamic management of patients with septic shock.
In the 1970s, the importance of maintaining cardiac output and oxygen delivery (DO2) was recognized (78). Shoemaker and colleagues (79) and others recommended maintaining DO2 at predetermined supranormal levels, but this strategy was later recognized as being potentially harmful (80). More recent studies suggest that therapy should be tailored according to the patient's needs (81), with blood lactate and mixed venous oxygen saturation (SO2) forming part of the management algorithm (82). Rivers and colleagues (83) reported that patients who received 6 hours of early goal-directed therapy aimed at maintaining central venous oxygen saturation (ScvO2) greater than 70% had better outcomes than those who received standard therapy with very similar treatment goals except for the use of ScvO2 data to drive therapeutic decisions.
Attempts to influence the distribution of blood flow have been disappointing. In particular, the beneficial effects of low doses of dopamine on renal function were not substantiated (84), although it was widely used for many years. Some studies have even suggested that interventions resulting in vasodilating effects may improve the microcirculation (85).
Hemodynamic Monitoring
The introduction of the pulmonary artery catheter in 1970 (86) helped physicians better characterize the hemodynamic alterations in septic patients. Although the use of the the pulmonary artery catheter has helped to define the hemodynamic patterns of sepsis, its value in determining therapy has been challenged in the last decade (87). Regional monitoring systems have been developed and may be preferable. The gut has been the focus of considerable attention and interest, with gastric tonometry an attractive possibility, but this technique has practical limitations (88). Sublingual capnometry provides information that is equivalent to that of gastric tonometry (89). The sublingual region may also enable direct visualization of the microcirculatory defects (90, 91), and persistence of these alterations, as observed using orthogonal polarization spectral imaging, has been associated with worse outcomes (91). The study of microcirculatory changes and their possible correction with outcome could result in improved treatment strategies that can be targeted at the underlying abnormality (92, 93).
Metabolic parameters to monitor hemodynamic status are limited. Blood lactate levels were first proposed by Broder and Weil in 1964 (94). They were shown to have prognostic value, and in the 1980s repeated measurements were shown to be helpful (95). However, although high lactate levels were initially considered to reflect tissue hypoxia, a number of studies have indicated this may not necessarily be the case especially in sepsis, and altered cellular metabolism may result in high pyruvate and lactate levels. Hence, the interpretation of high lactate levels in sepsis can be complex (96).
Role of Steroids
Steroids were first proposed in the treatment of severe infections as early as 1954 (97). Various effects were described, including an increase in adenylate cyclase, effects on the complement and coagulation systems, improved reticuloendothelial system function, and better cellular phagocytic function. Decreased permeability alterations were also described (98). Beneficial hemodynamic effects were associated with an increase in arterial pressure and cardiac output, in part attributed to an inhibited release of the then popular "myocardial depressant factor."
Clinical reports emerged in the early 1970s from Motsay and colleagues (99) and others suggesting beneficial effects of massive doses of steroids, typically 30 mg/kg of methylprednisolone or 6 mg/kg of dexamethasone. Some studies reported beneficial hemodynamic effects associated with an increase in cardiac output, a reduction in systemic vascular resistance, an improvement in hepatosplanchnic perfusion, and even an increase in 2,3 diphosphoglycerate that could increase the peripheral delivery of oxygen to the tissues (100). The clinical studies were, however, of limited size and quality and yielded controversial results in outcome (101, 102). An important prospective, randomized, placebo-controlled study by Schumer (102) reported improved survival rates with large dose of steroids in septic shock, and Hoffman and coworkers (103) showed a beneficial effect of steroids in typhoid fever. However, two prospective randomized studies (104, 105) of high-dose corticosteroid therapy in patients with the sepsis syndrome showed no beneficial effects, and combined with the results of a meta-analysis (106), seemed to put an end to the use of steroids in sepsis.
However, the steroid story was not over. Although animal studies had emphasized the importance of an adequate adrenal response to permit survival from severe infections, this concept was finally put forward clinically by Sibbald and coworkers in 1977 (107) when they showed that several patients, despite having severe bacterial infections and no history to support Addison's disease, had low plasma cortisol levels and a lesser response to a corticotropin test than would be expected. Could this so-called relative adrenal insufficiency be corrected with replacement doses of steroids Several studies (summarized in Reference 108) have indeed suggested an improved outcome in patients with septic shock treated with moderate doses of hydrocortisone 200 to 300 mg/d, rather than the large doses used in the past. In 2002, Annane and colleagues (109) published the results of an important multicenter French study including 299 patients randomized to receive moderate-dose hydrocortisone or placebo for 7 d. Although there was no significant effect on survival overall, there was a significant reduction in mortality in the (predefined) subgroup of patients with a suboptimal response to an adrenocorticotropic hormone test. The significance was, however, obtained only after adjustment for several factors. Nevertheless, in view of the other recent studies, the Surviving Sepsis Campaign Guidelines for the management of severe sepsis and septic shock (110) recommend the use of moderate doses of hydrocortisone, pending the results of a large multicenter study (Corticus) being conducted in Europe. Although Annane and colleagues (110) observed a survival benefit only in patients with a suboptimal response to a corticotropin test, the need for this test is still questionable. Likewise, the addition of oral fludrocortisone, as in the study by Annane and colleagues, is still questionable.
Immunomodulating Therapies
A large number of immunomodulatory agents have been studied in experimental and clinical studies (Table 3). Antiendotoxin strategies were the first to be investigated as the structure of endotoxin was identified in the 1960s and have perhaps been more extensively investigated than any other area in this field. However, the vast majority of the clinical trials of immunomodulatory agents have shown relatively little success, despite often promising preclinical results. The reasons behind these apparent failures are varied. It is possible that some strategies may have had limited efficacy in discrete patient populations, but nevertheless failed to show a significant improvement in survival rate. For example, the use of bactericidal/permeability-increasing protein did not decrease mortality in children with meningococcemia but may have diminished some sepsis related morbidities, such as the need for amputations (111).
Another major limitation to the immunomodulatory approach is that it aims at antagonizing a response that is not necessarily maladaptive. As an example, blocking TNF- with anti-TNF antibodies or soluble fusion protein complexes that include TNF receptors may help some individuals with an overwhelming host response, but may be harmful in patients with an appropriate, controlled response. Animal models have also shown that antiinflammatory strategies could be beneficial in very acute models of endotoxin administration, but harmful in models of more localized intraabdominal infections (112).
One agent has shown benefit in sepsis: drotrecogin alfa (activated). The PROWESS study (8) demonstrated that a dose of 24 μg/kg of body weight/hour for 96 h of drotrecogin alfa (activated) reduced mortality rates from 30.8% in the placebo group to 24.7% in the treatment group, which equated to one additional life saved for every 16 patients treated. Subgroup analyses indicated that this was largely due to the effect on patients with greater disease severity (i.e., APACHE II score 25), and a subsequent randomized, placebo-controlled study (the Administration of Drotrecogin Alfa [Activated] in Early Stage Severe Sepsis [ADDRESS] trial) in patients with a lower risk of death (defined by an APACHE II score < 25 or single-organ failure) showed no statistically significant differences in 28-d mortality between the placebo group and the treatment group (113). Another study in children with severe sepsis was also stopped for futility. Nevertheless, despite these results, the high costs, and increased risks of bleeding, drotrecogin alfa (activated) does appear to reduce mortality rates in patients with severe sepsis and a high risk of death (i.e., multiple-organ failure or high APACHE II score).
The fact that studies with other natural anticoagulants, including tissue factor pathway inhibitor (114) and antithrombin (115), did not reduce mortality rates raises questions about the mechanism of action of drotrecogin alfa (activated) and the importance of coagulation alterations in contributing to organ dysfunction and mortality associated with sepsis. Indeed, the mechanisms of action of drotrecogin alfa (activated) appear to extend beyond its anticoagulant activity, and include diminishing neutrophil chemotaxis and endothelial activation through interaction with the endothelial protein C receptor, which is present on endothelial cells, neutrophils, and monocytes (116, 117).
CONCLUSIONS: HAS PROGRESS BEEN MADE IN SEPSIS
The story of sepsis over the past 100 years has been a fascinating tale of discovery. Great strides have been made in terms of understanding the extra- and intracellular events that contribute to organ system dysfunction. There has also been progress in management, with several studies suggesting reduced mortality rates (35, 36) as a result of improved supportive and pharmacologic management of these critically ill patients. Widely publicized evidence-based guidelines have been published to help the clinician manage the patient with severe sepsis (110). However, mortality rates still remain unacceptably high, and it is apparent that much remains to be done to advance our understanding and treatment of this important and increasingly frequent medical problem.
FOOTNOTES
Originally Published in Press as DOI: 10.1164/rccm.200510-1604OE on October 20, 2005
Conflict of Interest Statement: J-L.V. received honoraria and grants from Brahms, Chiron, Eli Lilly, Eisai, GlaxoSmithKline, Toray, and Pfizer. E.A. received consulting fees from Eli Lilly in 2002 and 2003; he served as the principal investigator of the Eli Lilly-sponsored ADDRESS study, an international multicenter clinical trial that investigated the utility of rhAPC in patients with sepsis at lower risk of mortality. He also served as principal investigator of the Chorin-sponsored OPTIMIST study, which examined the utility of Rificogin in patients with sepsis.
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