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Community-Acquired Pneumonia and Sepsis
Clin Chest Med 26 (2005) 19 – 28
Community-Acquired Pneumonia and Sepsis Michelle A. Beutz, MD*, Edward Abraham, MD Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Health Sciences Center, Campus Box C272, 4200 East Ninth Avenue, Denver, CO 80262, USA
Despite extensive research, sepsis remains common and lethal. It is the tenth cause of death overall in the United States [1] and a leading cause of death in intensive care units (ICUs) [2]. Mortality rates range from 30% to 70% [3]. The estimated annual economic burden in the United States approaches $17 billion [4]. Sepsis is a frequent sequelae of communityacquired pneumonia (CAP). In a study of 280 patients admitted to the hospital with CAP, Waterer et al [5] found that 31 patients met criteria for septic shock. Ruiz and colleagues [6] demonstrated that in CAP classified as severe, septic shock developed in 32% of patients. A thorough review of CAP necessitates an examination of the relationship between pneumonia and sepsis, with particular consideration of the epidemiology, pathophysiology, and treatment that characterize the concurrence of these two processes.
Definition of sepsis Defining sepsis has proved to be a difficult task and has often engendered controversy. The difficulty arises from the fact that a multiplicity of noninfectious inflammatory processes mimic the systemic manifestations of sepsis, and, even when infection is the source of clinical illness, an etiologic agent
This work was supported in part by grants NO1HR46061, RO1 HL62221, HL07171, and PO1 HL68743 from the National Institutes of Health. Dr. Abraham has received contracts from and been a consultant for Eli Lilly and Chiron. * Corresponding author. E-mail address: [email protected] (M.A. Beutz).
often is not identified. On average, only 30% of patients considered septic have positive blood cultures at the time of diagnosis [7]. In 20% to 30% of patients judged clinically to be septic, no apparent anatomic source of infection is identified [8,9]. Additionally, there is no gold standard laboratory test in sepsis comparable with troponin in myocardial infarction against which definitions and diagnostic criteria can be calibrated. The American College of Chest Physicians/ Society of Critical Care Medicine (ACCP/SCCM) Consensus Conference Committee initially addressed the goal of defining the continuum of sepsis syndromes in guidelines published in 1992 [10]. Their recommendations included the following: The term systemic inflammatory response syn-
drome (SIRS) is the clinical manifestation of the inflammatory response to a wide variety of insults, including infectious and noninfectious etiologies. The syndrome is recognized by the presence of two or more of the following clinical signs: (1) temperature > 38C or < 36C; (2) heart rate > 90 beats per minute; (3) tachypnea manifested as a respiratory rate > 20 breaths per minute or a PaCO2 < 32 mm Hg; and (4) a white blood cell count > 12,000 or < 4000 cells/mm3. The term sepsis describes SIRS when the syndrome is the result of an infectious process. The term severe sepsis is employed to describe sepsis associated with organ dysfunction, hypotension (systolic blood pressure < 90 mm Hg or a reduction from baseline of more than 40 mm Hg), or hypoperfusion. Manifestations of hypoperfusion include, among others, lactic acidosis, oliguria, and acute alteration of mental status.
0272-5231/05/$ – see front matter D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.ccm.2004.10.015
chestmed.theclinics.com
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beutz The term septic shock defines the subset of
patients with severe sepsis who have hypotension with evidence of hypoperfusion that persists despite adequate fluid resuscitation. Patients requiring inotropic or vasopressor support despite fluid resuscitation are considered to be in septic shock. The term multiple organ dysfunction syndrome (MODS) is the presence of altered organ function in an acutely ill patient such that homeostasis cannot be maintained without intervention.
Population-adjusted incidence of sepsis (no./100,000)
Since the 1992 consensus guidelines were issued, they have been the subject of controversy. Criticisms target the high sensitivity and low specificity of the SIRS criteria [11]. In some studies, the SIRS criteria are met by two-thirds of ICU patients and a substantial proportion of ward patients [12,13]; therefore, clinical trials using SIRS criteria alone include a large and heterogeneous group of patients. Individuals with noninfectious inflammatory processes, such as pancreatitis or trauma, may meet the SIRS criteria. Identification of treatment responses in truly septic patients becomes difficult. The 1992 definitions were revisited in 2001 by a combined conference of European and North American experts [14]. The international panel determined that the 1992 definitions should be preserved; however, the panel also acknowledged that, frequently in sepsis, infection is strongly suspected without being microbiologically confirmed. The diagnostic criteria for sepsis were expanded to emphasize that multiple clinical abnormalities often combine to prompt the experienced clinician to judge a patient to be septic. Additionally, the panel proposed exploration of a staging system for sepsis, the ‘‘PIRO’’
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classification, to improve characterization of sepsis pathophysiology and prognosis. Analogous to the tumor, node, metastasis (TNM) system in oncology, the PIRO system would stratify patients based on their Predisposing factors, Infection (or Insult), host Response, and degree of Organ dysfunction. The PIRO concept was proposed as a template, and studies to evaluate its validity as a prognostic or treatment tool have not yet been conducted.
Epidemiology Although the mortality rate from sepsis continues to decrease, several recent epidemiologic studies in the United States and Europe demonstrate that the total number of deaths continues to rise owing to the increasing incidence of sepsis [15,16]. Martin and colleagues recently reviewed discharge data on more than 750 million hospitalizations and identified 10,319,418 cases of sepsis from 1979 to 2000. Over the 22-year period, the incidence of sepsis increased from 82.7 cases per 100,000 population to 240.4 cases per 100,000 population, representing an annualized increase of 8.7% (Fig. 1). During the same period, mortality rates declined from 27.8% percent to 17.9% (Fig. 2). The increasing incidence resulted in a near tripling of in-hospital sepsis deaths [15]. Annane et al demonstrated a similar trend in French ICUs [8]. A review of admissions from 22 Parisian ICUs from 1993 to 2000 demonstrated that the incidence of sepsis increased from 7.0 to 9.7 cases per 100 ICU admissions. During the 8-year period studied, the investigators documented a 5% reduction in crude mortality.
300 Men Women 200
100
0 1979 1981 1983 1985 1987 1989 1991 1993 1995 1997 1999 2001
Fig. 1. Population-adjusted incidence of sepsis according to sex, 1979 to 2000. (From Martin GS, Mannino DM, Eaton S, et al. The epidemiology of sepsis in the United States from 1979 – 2000. N Engl J Med 2003;348(16):1546 – 54; with permission.)
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Proportion of patients with sepsis who died
0.40
0.30
0.20
0.10
0.00 1979 1981 1983 1985 1987 1989 1991 1993 1995 1997 1999 2001
Fig. 2. Overall in-hospital mortality rate among patients hospitalized for sepsis, 1979 to 2000. (From Martin GS, Mannino DM, Eaton S, et al. The epidemiology of sepsis in the United States from 1979 – 2000. N Engl J Med 2003;348(16):1546 – 54; with permission.)
Several demographic trends remain constant in the recent epidemiologic reports [15]. Sepsis more commonly affects males (relative risk [RR], 1.28) and older patients (mean age, 60.8 years), with the mean age of patients increasing over time. In the United States, blacks and other nonwhite groups have an elevated risk of sepsis when compared with whites (mean annual RR, 1.89). Comorbidities such as neoplasms, renal or hepatic failure, and AIDS, which impair host defenses, are common in sepsis. Cancer, chronic obstructive pulmonary disease, and diabetes are the comorbidities most commonly reported [9].
Risk factors for mortality in sepsis Clinical determinants of sepsis outcome include the site and type of infection, the timing and appropriateness of antibiotic therapy, the development of shock and organ dysfunction, and host response. The primary site of infection is most commonly the respiratory tract, predominantly pneumonia. The respiratory tract is the source of sepsis in 40% to 60% of patients, followed by intra-abdominal sources and urinary tract infections [3,8,9,15]. The frequency of sepsis secondary to pneumonia is increasing [8]. Additionally, several factors are associated with increased mortality from pneumonia-related sepsis. Patients with ICU-acquired pneumonia, particularly ventilator-acquired pneumonia (VAP), are at a higher risk for sepsis and have higher mortality than do
patients with CAP [9]. In some series, mechanical ventilation is associated with the highest odds ratio (OR) of dying from sepsis (4.72) [8]. Females demonstrate a lower proportion of sepsis episodes associated with a pulmonary source, which may explain, in part, the lower sepsis mortality rates in women [3]. The incidence of sepsis from gram-positive organisms is increasing. Although gram-negative organisms continue to cause a substantial proportion of sepsis, gram-positive organisms are now responsible for the majority (52.1%) of cases of sepsis in some analyses [15]. Although fungal organisms cause only a small proportion of sepsis, the incidence of fungal sepsis is increasing rapidly (a relative increase of 207% from 1979 to 2000) [15], and it has been associated with the highest mortality risk in several studies [4]. In general, sepsis secondary to nosocomial infections carries a higher mortality than sepsis secondary to community-acquired infections [9]. Positive blood cultures favorably impact survival; if the source or type of infection remains unknown, mortality increases [8,17]. Appropriate antimicrobial therapy is associated with lower mortality in sepsis [18]. Harbarth and coworkers evaluated the initial antibiotic choice for severely septic patients. Antibiotics were categorized as inappropriate if subsequently identified causative organisms were not susceptible to the initial antimicrobial agent. According to this criterion, 23% of patients with severe sepsis received inappropriate antimicrobial therapy during the first 24 hours of admission. The mortality was significantly higher
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in the inadequately treated group (39% versus 24%, P < .001). The degree of organ dysfunction correlates with mortality. Mortality increases along the continuum of SIRS to septic shock. Brun-Buisson et al [19] reported an in-hospital mortality rate of 7% with SIRS alone, 16% with sepsis, 20% with severe sepsis, and 46% with septic shock. Martin and colleagues found that patients without organ failure had an average mortality rate of 15%, whereas patients with three or more failed organ systems had a mortality rate greater than 70% [15]. The incidence of multiple organ system failure secondary to sepsis is increasing [15], as is the number of patients requiring mechanical ventilation, vasopressors, or renal replacement therapy [8]. Based on a requirement for mechanical ventilation, the lung is the organ that most often fails in sepsis (18%) [15]. Genetic risk for pneumonia and sepsis is increasingly recognized as an important determinant of outcome. Strong evidence for the role of genetics in infection was initially provided by adoptee studies demonstrating that, if either natural parent died of infection before age 50 years, an individual’s risk of death from an infection was almost six times greater [20]. Much of the current evidence for a genetic role in infection comes from association studies of single nucleotide polymorphisms (SNP) with susceptibility to infection or outcome. Most of the SNPs that have been studied are within candidate genes hypothesized to mediate inflammation; a majority of these candidate genes are located on the highly polymorphic region of chromosome 6, the major histocompatibility complex (MHC). Examples of cytokines and receptors with polymorphisms that may be associated with an increased risk of sepsis or septic shock include tumor necrosis factor alpha (TNF-a), TNF-b, interleukin-1 (IL-1) receptor antagonist (IL-1ra), IL-10, IL-6, toll-like receptors 2 and 4 (TLR2 and TLR4), CD-14, and lipopolysaccharide binding protein (LBP) [21,22]. The study of septic shock and respiratory failure in CAP performed by Waterer et al demonstrates how an understanding of genetic polymorphisms not only impacts the clinician’s ability to predict who is at risk for septic shock but also furthers knowledge of disease mechanisms [5]. In a prospective analysis of 280 patients admitted with CAP, 31 experienced septic shock, and 103 had respiratory failure. Patients were evaluated for polymorphisms in the TNF-b or TNF-a promoter regions, that is, a guanine to adenine SNP in lymphotoxin-alpha (LTa, also known as TNF-b) at the +250 site and in the TNF-a gene promoter region at the 308 site. Individuals who
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were AA homozygotes at the LTa+250 locus were significantly more likely to have septic shock. Interestingly, the AA (TNF-a hypersecretor) genotype did not correlate with respiratory failure, whereas there was a trend toward an association between GG (TNF-a hyposecretor) LTa+250 homozygotes and respiratory failure. TNF-a 308 polymorphisms were not associated with the development of septic shock in patients with CAP as previously reported [23], possibly owing to linkage disequilibrium. The LTa+250A (TNF-a high secretor) allele is nearly always inherited with the TNF-a 308G (TNF-a low secretor) allele. The study by Waterer et al [5] has ramifications for the current understanding of the inflammatory response to infection in sepsis. In clinical studies of sepsis, hypoxemia has been one of the most frequently cited manifestations of organ dysfunction in SIRS. Nevertheless, Waterer’s finding that hypoxia was not associated with a TNF-hypersecretor genotype, whereas septic shock was associated with such a genotype, suggests that hypoxia may not occur through the same mechanism or reflect the same proinflammatory state as septic shock.
Pathophysiology Initially, sepsis was conceptualized as the phenomenon of an infectious agent overwhelming the innate defenses of a host. There is now general agreement that SIRS and sepsis represent the dysregulation of the host’s immune system as much or more than the direct effects of a virulent invading organism. This dysregulation may involve a hyperimmune as well as a hypoimmune state. During the onset of sepsis, cellular and humoral defense mechanisms are activated. Animal models have shown in the initial phase of sepsis that there is an outpouring of proinflammatory cytokines and chemokines. Endothelial and epithelial cells, as well as macrophages, neutrophils, and lymphocytes, generate proinflammatory mediators, including TNF-a, IL-6, IL-1, and IL-8. Simultaneously, humoral defense mechanisms such as the complement cascade are activated. Through C5a, cytokine and chemokine production is further enhanced. The coagulation system is activated, and disseminated intravascular coagulation may occur. Phagocytic cells respond to various proinflammatory mediators by releasing granular enzymes and producing reactive oxygen species such as H2O2. Ultimately, these overlapping pathways cause microvascular damage and vascular instability [24].
community-acquired pneumonia and sepsis
Although the initial high serum cytokine and chemokine levels are well established in animal models, the pattern is less evident in humans. With the exception of meningococcemia, most human studies have not demonstrated the ‘‘cytokine storm’’ evident in animal models using large doses of endotoxin. The emerging complexity of the human immune response to sepsis is underscored by the failure to improve survival in multiple clinical trials targeting proinflammatory mediators. Evidence is increasingly supporting the concept that, in addition to an initial hyperinflammatory state in which the host may undergo ‘‘bystander’’ damage from its own overwhelming proinflammatory response, sepsis is also characterized by a hypoimmune state in which the host enters a stage of immunosuppression [25]. The latter effect may occur via several mechanisms. First, there can be a shift from an inflammatory (TH1) response to an anti-inflammatory (TH2) response. TH2 cytokines, including IL-4, IL-10, transforming growth factor-b (TGFb), and IL-13, are elevated [24,25]. Second, autopsy studies reveal that, in persons who die of sepsis, a profound loss of immune cells occurs through apoptosis
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[26 – 28]. Specifically, immunohistochemical analyses of spleens from deceased patients reveals progressive loss of B cells, CD4+ T cells, and follicular dendritic cells. Third, some evidence suggests that T cells become anergic, possibly induced by the apoptosis of gastrointestinal epithelial cells, dendritic cells, and other antigen-presenting cells during sepsis [29]. Of note, gut epithelial and lymphocyte apoptosis occurs not only in sepsis of abdominal source but also in a setting of pneumonia-related sepsis [30]. Fourth, macrophages demonstrate decreased expression of MHC class II and costimulatory molecules. Neutrophil function is suppressed, and the innate immune system can lose the ability to kill invading microorganisms effectively [25].
Pathophysiology of sepsis in pneumonia When endothelial and epithelial barriers are injured in the lung in pneumonia, the lung can become not only a target but also a source of inflammation. Cell injury by infecting organisms triggers the cascade of cytokine and chemokine responses. Never-
Pneumonia
Pulmonary Inflammation
Mechanical Ventilation
Ventilator Induced Lung Injury
Surfactant Rupture and Inactivation
Microvascular Injury
Decreased Integrity of the Alveolar-Capillary Membrane
Translocation of Bacteria and Pro-inflammatory Cytokines
Increased Pulmonary Edema and Lymphatic Drainage
Increased Circulating Bacteria and Pro-Inflammatory Cytokines
Increased Systemic Inflammatory Response
Sepsis and/or Multiple Organ Dysfunction Fig. 3. Schematic illustration of the way in which mechanical ventilation may amplify systemic inflammatory response in pneumonia.
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theless, the lung is unique in that, when lung injury advances to a degree requiring mechanical ventilation, ventilator-induced lung injury may amplify endothelial and epithelial barrier injury and accelerate proinflammatory responses. This process may be the result of several mechanisms. First, several investigators have demonstrated in mouse models that high tidal volumes administered without positive endexpiratory pressure (PEEP) produce significant serum elevation of proinflammatory cytokines, such as TNF-a and macrophage inflammatory protein (MIP)-2 [31,32]. Similarly, in human clinical studies, patients receiving conventional ventilation versus low tidal volumes had higher levels of circulating IL-6, TNF-a, IL-1b, and IL-8. The higher serum cytokine levels correlated with higher scores of multisystem organ failure [33]. Second, the loss of integrity of the alveolar-capillary membrane associated with high tidal volume ventilation may promote translocation of bacteria into the systemic circulation. The evidence for increased bacterial translocation includes increases in bacteremia [34] and spleen seeding [32] with high tidal volume ventilation. Several mechanisms may be responsible for the translocation of bacteria and inflammatory mediators into the systemic circulation in association with mechanical ventilation (Fig. 3). The predominant process affecting translocation of bacteria and mediators from the lung is likely the increased permeability of the alveolar-capillary membrane. The permeability may be altered by infection-initiated inflammation as well as by ventilator-induced lung injury allowing direct entry of organisms and cytokines into the circulation [32,34]. A lack of adequate PEEP also may prohibit the compartmentalization of bacteria into distal airways [34]. Additionally, ventilation may inactivate surfactant’s bacteriostatic properties [34]. Repeated alveolar closing and opening in low PEEP ventilation may cause surfactant destruction via surfactant compression and rupture with re-expansion. High tidal volume ventilation strategies correlate with increased surfactant large aggregates and total protein in bronchoalveolar lavage fluid. Ventilation may cause microvascular injury and pulmonary edema, increasing lymphatic flow and accelerating drainage of bacteria and inflammatory mediators into the systemic circulation [34].
Treatment of sepsis in the setting of pneumonia Previously, no specific therapies were shown to improve outcomes in patients with sepsis. In recent
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years, several interventions have shown a positive impact on mortality rates from sepsis in clinical trials, including drotrecogin alfa (activated) (Xigris), moderate-dose corticosteroids, intensive insulin therapy, and early goal-directed therapy (EGDT).
Drotrecogin alfa (activated) Activated protein C is an important modulator of inflammation and coagulation in sepsis. It inhibits inflammation, neutrophil chemotaxis, endothelial activation, and thrombosis. Activated protein C also promotes fibrinolysis. Several observational studies have reported depletion of protein C in patients with sepsis and have correlated low levels with an increased risk of death [35 – 37]. Trials in a baboon model of Escherichia coli sepsis showed that administration of activated protein C was protective [38]; therefore, recombinant human activated protein C (drotrecogin alfa [activated]) was evaluated for human use in a prospective, multicenter, placebocontrolled clinical trial (PROWESS) [39]. A total of 1690 patients were randomized to a 96-hour infusion of placebo or 24 mg/kg/h of drotrecogin alfa (activated). Patients were eligible for enrollment if they had (1) a known or suspected infection, (2) at least three or more signs of SIRS, and (3) evidence of dysfunction in at least one organ system for 24 hours or less. The overall mortality rate in the placebo group was 30.8% compared with 24.7% in the drotrecogin alfa (activated) group (P = .005). This represented an absolute reduction in the risk of death of 6.1% and a reduction in the RR of death of 19.4%. As expected, the primary complication associated with administration of drotrecogin alfa (activated) was bleeding. Severe bleeding episodes (defined as intracranial hemorrhage, any life-threatening bleeding, any bleeding classified as serious by the investigator, or any bleeding that required the administration of at least 3 units of packed red blood cells on 2 consecutive days) occurred in 3.5% of patients receiving drotrecogin alfa (activated) compared with 2.0% of patients receiving placebo ( P = .06). The majority of patients in either group with an episode of severe bleeding had an identifiable predisposition to bleeding. These factors included a history of gastrointestinal ulceration, abnormal laboratory coagulation studies (activated partial-thromboplastin time > 120 seconds or a prolonged prothrombin time with an international normalized ratio > 3.0), thrombocytopenia with a platelet count < 30,000/mm3, or trauma to a blood vessel or highly vascular organ.
community-acquired pneumonia and sepsis
Subgroup analyses were prospectively defined in the PROWESS trial for several characteristics, including the severity of illness using the APACHE II score, the degree and type of organ dysfunction, sex, age, the site and type of infection, and the presence or absence of protein C deficiency. With some notable exceptions, a consistent beneficial effect of drotrecogin alfa (activated) was observed among the subgroups, including patients without protein C deficiency. Nevertheless, whether categorized by APACHE II score or the number of dysfunctional organs, the patients with less severe disease had either less or no apparent benefit from administration of drotrecogin alfa (activated). In particular, a higher 28-day mortality was observed in patients receiving the study drug in the first APACHE II score quartile, in which scores ranged from 3 to 19 (mortality rate of 21.1% for drotrecogin alfa (activated) versus 14.5% for placebo, P = .009) [40]. Additionally, within the subgroup with single organ dysfunction, there was no significant improvement in mortality (P = .469) [40]. Of note, a clinical trial to determine the role of drotrecogin alfa (activated) for lower-severity sepsis (the ADDRESS trial) was halted for futility, implying that drotrecogin alfa (activated) does not have clinically significant benefit in patients with a low risk of death (Edward Abraham, MD, unpublished data, 2004). In the PROWESS trial, drotrecogin alfa (activated) demonstrated particular benefit in patients with pulmonary infection [40]. Respiratory dysfunction was defined as a PaO2/FIO2 < 250 (if the cause of sepsis was not pneumonia) or a PaO2/FIO2 < 200 (if the lung was the source of sepsis). The lung was the most common site of infection in PROWESS (53.6%), and greater than 70% of patients in the treatment and placebo groups required mechanical ventilation [39]. The time to resolution of respiratory dysfunction was significantly shorter in the drotrecogin alfa (activated) group when compared with the placebo group (16.7% versus 11.3% resolved at 7 days) [40]. Based on the results of the PROWESS trial and ensuing subgroup analyses, experts in the treatment of sepsis recommend that drotrecogin alfa (activated) be considered for use in adult patients with recent onset of severe sepsis or septic shock, no significant bleeding risks, and a high risk of death [41].
Corticosteroids The value of steroids in the treatment of patients with severe sepsis and septic shock has generated
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considerable controversy. Corticosteroids were the first anti-inflammatory drugs tested in randomized trials. Short courses of high-dose steroids did not have favorable effects on mortality from sepsis and, in some instances, demonstrated increased mortality as the result of an increased incidence of nosocomial infections and possibly increased organ dysfunction [42,43]. Nevertheless, several small studies documenting the frequency of and increased mortality associated with relative adrenal insufficiency in septic shock provided a strong rationale for prolonged administrated of lower-dose steroids in such patients [44,45]. A multicenter French trial conducted by Annane and colleagues [46] provides further insight into the incidence of adrenal dysfunction in sepsis and the role of steroids in this patient population. Patients with septic shock were randomly assigned to receive either hydrocortisone (50 mg intravenously every 6 hours) and fludrocortisone (50 mg by mouth daily) or placebo for 7 days. All patients had severe septic shock, as evidenced by continued hypotension despite fluid resuscitation and treatment with 5 mg/kg or more of dopamine or other vasoactive agents. All patients required mechanical ventilation and had an additional sepsis-induced organ failure, including hypoxemia, decreased urine output, or elevated lactate. For post hoc analysis, patients were stratified according to their response to a corticotropin (ACTH) stimulation test. Individuals with less than a 9 mg/dL increase in serum cortisol levels in response to corticotropin were identified as nonresponders and considered to have relative adrenal insufficiency. Of the 299 patients analyzed, 229 were ACTH nonresponders (placebo, 115 patients; steroids, 114 patients). A significant survival benefit was demonstrated among nonresponders randomized to steroids. There were 73 deaths in the placebo group (63%) and 60 deaths in the steroids group (53%) (P = .023). Nonresponders treated with steroids also had a shorter median time to withdrawal of vasopressor therapy than did nonresponders treated with placebo (7 versus 10 days). There were no significant differences in the rates of adverse events related to steroids (ie, nosocomial infections, gastrointestinal bleeding, or psychiatric disorders) between the two groups; however, in the group of patients without adrenal insufficiency, the number of deaths was higher in patients who were treated with steroids (22/36 or 61%) than in patients treated with placebo (18/34 or 53%). The difference was not statistically significant but raises concern that the administration of steroids to patients without adrenal insufficiency may be detrimental.
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Administration of moderate-dose corticosteroids should be considered in mechanically ventilated patients with refractory septic shock. In practice, a corticotropin stimulation test should be performed before initiating steroids. Corticosteroids should be continued only in patients who fail to increase serum cortisol levels more than 9 mg/dL in response to corticotropin [41,47].
Intensive insulin therapy Stress hyperglycemia (used to denote an elevation of blood glucose and free fatty acids) occurs in many critically ill patients and is caused by hepatic gluconeogenesis, peripheral insulin resistance, and release of free fatty acids from adipose tissue [48]. Stress hyperglycemia has been hypothesized to represent an adaptive response to severe illness, providing glucose for the brain, organs, red blood cells, and wound healing [41]. Nevertheless, studies performed by Van den Berghe and colleagues [49,50] indicate that even modest hyperglycemia (> 110 mg/dL) has detrimental effects on the development of nosocomial infections, multiple organ dysfunction syndrome, and mortality in critically ill patients. In the initial study, Van den Berghe and coworkers conducted a large prospective randomized controlled trial of intensive blood glucose control in 1548 patients admitted to a surgical ICU [49]. Patients were randomized to conventional therapy (intravenous insulin drip if blood glucose was > 215 mg/dL with maintenance of glucose between 180 and 200 mg/dL) or intensive therapy (continuous intravenous insulin to maintain glucose between 80 and 110 mg/dL). Sixty-three patients (8.0%) in the conventional therapy arm died compared with 35 (4.6%) receiving intensive insulin therapy. The greatest reduction in mortality occurred among patients in the ICU for more than 5 days and was attributed to a decrease in deaths owing to multiple organ failure with a septic focus. In addition to reducing mortality in critically ill patients, intensive insulin therapy had several beneficial effects on morbidity. Patients randomized to tight glucose control had a 46% reduction of bloodstream infections, a 41% decrease in the incidence of acute renal failure requiring hemofiltration or dialysis, 50% fewer red blood cell transfusions, and a 44% reduction in the occurrence of critical-illness polyneuropathy. Of note, the patients receiving intensive insulin therapy were significantly less likely to require prolonged ventilatory support. Ninety-three patients (11.9%) in the conventional treatment group required greater than 14 days of mechanical ventila-
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tion compared with 57 (7.5%) of patients with tight glycemic control (P = .003). The intensive insulin therapy trial raised the question of whether the beneficial effects observed were the result of normoglycemia or the cumulative insulin dose. This issue was addressed by Van den Berghe et al [50]. Using data from the initial trial of intensive insulin therapy, the researchers performed a multivariate logistic regression analysis of the impact of blood glucose versus the insulin dose on morbidity. Strict maintenance of normoglycemia, rather than the total insulin dose, was most significantly associated with a reduction in mortality (P < .0001), critical-illness polyneuropathy (P < .001), bacteremia (P = .02), inflammation (defined as 3 or more days with C reactive protein > 150 mg/L, P = .0006), and anemia requiring red blood cell transfusion (P = .06). In contrast, the actual dose of insulin was a negative predictor for acute renal failure and the need for renal replacement therapy (P = .03).
Early goal-directed therapy Early goal-directed therapy is the effort to balance optimally oxygen delivery and oxygen demand in patients with septic shock before the onset of global tissue hypoxia and multiorgan failure. In a study conducted by Rivers et al [51], 263 enrolled patients were randomized to receive 6 hours of EGDT versus standard therapy. In addition to a target central venous pressure (CVP) between 8 and 12 mm Hg, mean arterial pressure (MAP) 65 mm Hg, and urine output 0.5 mL/kg/h in the standard therapy group, resuscitation endpoints used in the EGDT group to confirm optimal oxygen delivery included normalized values for arterial lactate, base deficit, and pH, and a central venous oxygen saturation (ScvO2) 70%. Patients randomized to EGDT received crystalloid boluses, vasopressors, red blood cell transfusions, and, if necessary, dobutamine until resuscitation endpoints were met. The in-hospital mortality rate was 30.5% in the EGDT group compared with 46.5% in the standard therapy group (P = .009). During the 7 to 72 hours from admission, when compared with patients treated with standard therapy, patients treated with EGDT demonstrated significant improvement in all resuscitation endpoints: ScvO2, lactate, base deficit, and pH. The EGDT group had a mean APACHE II score during the same period that was significantly lower than that in the control group, indicating less severe organ dysfunction.
community-acquired pneumonia and sepsis
More than one-third of patients in both treatment groups carried an admission diagnosis of pneumonia. In patients with baseline respiratory compromise, aggressive fluid resuscitation would be expected to be associated with increased requirements for mechanical ventilation; however, the trial by Rivers and coworkers demonstrated the opposite. Although the patients treated with EGDT received significantly more fluid and blood within the initial 6 hours of admission, there was no significant difference between the EGDT and standard therapy groups in the number of patients requiring mechanical ventilation. Over the ensuing 7 to 72 hours, significantly more fluid was administered to the patients receiving standard therapy. A greater percentage of patients in the standard therapy group required mechanical ventilation during the 7 to 72 hour period (16.8% versus 2.6%, P < .001). The net effect from 0 to 72 hours was a greater requirement for mechanical ventilation in the standard therapy group (70.6% versus 55.6%) despite equal total fluid administration in both groups. Although somewhat counterintuitive, this result underscores the benefit of early fluid resuscitation to optimize oxygen delivery and decrease subsequent organ dysfunction in patients with pneumonia and sepsis.
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Rea Network. Am J Respir Crit Care Med 2003;168: 165 – 72. Alberti C, Brun-Buisson C, Burchardi H, et al. Epidemiology of sepsis and infection in ICU patients from an international multicentre cohort study. Intensive Care Med 2001;28(2):108 – 21. Bone RC, Balk RA, Cerra FB, et al. ACCP/SCCM Consensus Conference: definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Chest 1992;101:1644 – 55. Vincent JL. Dear SIRS, I’m sorry to say that I don’t like you. Crit Care Med 1997;25:372 – 4. Rangel Frausto MS, Pittet D, Costigan M, et al. The natural history of the systemic inflammatory response syndrome (SIRS): a prospective study. JAMA 1995; 273:117 – 23. Salvo I, De Cian W, Musicco M, et al. The Italian SEPSIS study: preliminary results on the incidence and evolution of SIRS, sepsis, severe sepsis, and septic shock. Intensive Care Med 1995;21:S244 – 9. Levy MM, Fink MP, Marshal JC, et al. 2001 SCCM/ ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference. Crit Care Med 2003;31:1250 – 6. Martin GS, Mannino DM, Eaton S, et al. The epidemiology of sepsis in the United States from 1979 through 2000. N Engl J Med 2003;348(16):1546 – 54. The EPISEPSIS Study Group. EPISEPSIS: a reappraisal of the epidemiology and outcome of severe sepsis in French intensive care units. Intensive Care Med 2004;30:580 – 8. Rello J, Ricart M, Mirelis B, et al. Nosocomial bacteremia in a medical-surgical intensive care unit: epidemiologic characteristics and factors influencing mortality in 111 episodes. Intensive Care Med 1994; 20:94 – 8. Harbarth S, Garbino J, Pugin J, et al. Inappropriate initial antimicrobial therapy and its effect on survival in a clinical trial of immunomodulating therapy for severe sepsis. Am J Med 2003;115:529 – 35. Brun-Buisson C, Doyon F, Cartlet J, et al. Bacteremia and severe sepsis in adults: a multicenter prospective survey in ICUs and wards of 24 hospitals. Am J Respir Crit Care Med 1996;154:617 – 24. Sorensen TI, Nielsen GG, Andersen PK, et al. Genetic and environmental influences and premature death in adult adoptees. N Engl J Med 1988;318:727 – 32. Wunderink RG, Waterer GW. Genetics of sepsis and pneumonia. Curr Opin Crit Care 2003;9:384 – 9. Holmes CL, Russell JA, Walley KR. Genetic polymorphisms in sepsis and septic shock. Chest 2003;124: 1103 – 15. Mira JP, Cariou A, Grall F, et al. Association of TNF2, a TNF-a promoter polymorphism, with septic shock susceptibility and mortality: a multicenter study. JAMA 1999;282:561 – 8. Riedemann N, Guo R-F, Ward PA. Novel strategies for the treatment of sepsis. Nat Med 2003;9(5):517 – 24. Hotchkiss RS, Karl IE. The pathophysiology and treatment of sepsis. N Engl J Med 2003;348(2):138 – 50.
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[26] Hotchkiss RS, Swanson PE, Freeman BD, et al. Apoptotic cell death in patients with sepsis, shock, and multiple organ dysfunction. Crit Care Med 1999; 27:1230 – 51. [27] Hotchkiss RS, Tinsley KW, Swanson PE, et al. Sepsisinduced apoptosis causes progressive profound depletion of B and CD4+ T lymphocytes in humans. J Immunol 2001;166:6952 – 63. [28] Hotchkiss RS, Tinsley KW, Swanson PE, et al. Depletion of dendritic cells, but not macrophages, in patients with sepsis. J Immunol 2002;168:2493 – 500. [29] Voll RE, Herrmann M, Roth EA, et al. Immunosuppressive effects of apoptotic cells. Nature 1997;390: 350 – 1. [30] Coopersmith CM, Stromberg PE, Davis CG, et al. Sepsis from Pseudomonas aeruginosa pneumonia decreases intestinal proliferation and induces gut epithelial cell cycle arrest. Crit Care Med 2003;31(6): 1630 – 7. [31] Chiumello DE, Pristine G, Slutsky A. Mechanical ventilation affects local and systemic cytokines in an animal model of acute respiratory distress syndrome. Am J Respir Crit Care Med 1999;160:109 – 16. [32] Schortgen F, Bouadma L, Joly-Guillou M-L, et al. Infectious and inflammatory dissemination are affected by ventilation strategy in rats with unilateral pneumonia. Intensive Care Med 2004;30:693 – 701. [33] Ranieri VM, Giunta F, Suter PM, et al. Mechanical ventilation as a mediator of multisystem organ failure in acute respiratory distress syndrome. JAMA 2000; 284(1):43 – 4. [34] Lin C-Y, Zhang H, Cheng K-C, et al. Mechanical ventilation may increase susceptibility to the development of bacteremia. Crit Care Med 2003;31(5): 1429 – 34. [35] Yan SB, Helterbrand JD, Hartman DL, et al. Low levels of protein C are associated with poor outcomes in severe sepsis. Chest 2001;120:915 – 22. [36] Hesselvik JF, Malm J, Dahlback B, et al. Protein C, protein S, C4b-binding protein in severe infection and septic shock. Throm Haemost 1991;65:126 – 9. [37] Fourrier F, Chopin C, Goudemand J, et al. Septic shock, multiple organ failure, and disseminated intravascular coagulation: compared patterns of antithrombin III, protein C, and protein S deficiencies. Chest 1992;101:816 – 23.
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abraham [38] Taylor Jr FB, Chang A, Esmon CT, et al. Protein C prevents the coagulopathic and lethal effects of Escherichia coli infusion in the baboon. J Clin Invest 1987;79:918 – 25. [39] Bernard GR, Vincent J-L, Laterre P-F, et al. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med 2001;344:699 – 709. [40] Dhainaut J-F, Laterre P-F, Janes JM, et al. Drotrecogin alfa (activated) in the treatment of severe sepsis patients with multiple-organ dysfunction: data from the PROWESS trial. Intensive Care Med 2003;29: 894 – 903. [41] Vincent J-L, Abraham E, Annane D, et al. Reducing mortality in sepsis: new directions. Crit Care 2002;6: S1 – 18. [42] Cronin L, Cook DJ, Carlet J, et al. Corticosteroid treatment for sepsis: a critical appraisal and metaanalysis. Crit Care Med 1995;23:1430 – 9. [43] Lefering R, Neugeauer EA. Steroid controversy in sepsis and septic shock: a meta-analysis. Crit Care Med 1995;23:1294 – 303. [44] Rothwell PM, Udwadia ZF, Lawler PG. Cortisol response to corticotropin and survival in septic shock. Lancet 1991;337:582 – 3. [45] Annane D, Sebille V, Troche G, et al. A 3-level prognostic classification in septic shock based on cortisol levels and cortisol response to corticotropin. JAMA 2000;283:1038 – 45. [46] Annane D, Sebille V, Charpentier C, et al. Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA 2002;288:862 – 71. [47] Abraham E, Evans T. Corticosteroids and septic shock. JAMA 2002;288:886 – 7. [48] McCowen KC, Malhotra A, Bistrian BR. Stress-induced hyperglycemia. Crit Care Clin 2001;17:107 – 24. [49] Van den Berghe G, Wouters P, Weekers F, et al. Intensive insulin therapy in critically ill patients. N Engl J Med 2001;345:1359 – 67. [50] Van den Berghe G, Wouters P, Bouillon R, et al. Outcome benefit of intensive insulin therapy in the critically ill: insulin dose versus glycemic control. Crit Care Med 2003;31(2):359 – 66. [51] Rivers E, Nguyen B, Havstad S, et al. Early goaldirected therapy in the treatment of severe sepsis and septic shock. N Engl J Med 2001;345(19):1368 – 77.
Community-Acquired Pneumonia and Sepsis Michelle A. Beutz, MD*, Edward Abraham, MD Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Health Sciences Center, Campus Box C272, 4200 East Ninth Avenue, Denver, CO 80262, USA
Despite extensive research, sepsis remains common and lethal. It is the tenth cause of death overall in the United States [1] and a leading cause of death in intensive care units (ICUs) [2]. Mortality rates range from 30% to 70% [3]. The estimated annual economic burden in the United States approaches $17 billion [4]. Sepsis is a frequent sequelae of communityacquired pneumonia (CAP). In a study of 280 patients admitted to the hospital with CAP, Waterer et al [5] found that 31 patients met criteria for septic shock. Ruiz and colleagues [6] demonstrated that in CAP classified as severe, septic shock developed in 32% of patients. A thorough review of CAP necessitates an examination of the relationship between pneumonia and sepsis, with particular consideration of the epidemiology, pathophysiology, and treatment that characterize the concurrence of these two processes.
Definition of sepsis Defining sepsis has proved to be a difficult task and has often engendered controversy. The difficulty arises from the fact that a multiplicity of noninfectious inflammatory processes mimic the systemic manifestations of sepsis, and, even when infection is the source of clinical illness, an etiologic agent
This work was supported in part by grants NO1HR46061, RO1 HL62221, HL07171, and PO1 HL68743 from the National Institutes of Health. Dr. Abraham has received contracts from and been a consultant for Eli Lilly and Chiron. * Corresponding author. E-mail address: [email protected] (M.A. Beutz).
often is not identified. On average, only 30% of patients considered septic have positive blood cultures at the time of diagnosis [7]. In 20% to 30% of patients judged clinically to be septic, no apparent anatomic source of infection is identified [8,9]. Additionally, there is no gold standard laboratory test in sepsis comparable with troponin in myocardial infarction against which definitions and diagnostic criteria can be calibrated. The American College of Chest Physicians/ Society of Critical Care Medicine (ACCP/SCCM) Consensus Conference Committee initially addressed the goal of defining the continuum of sepsis syndromes in guidelines published in 1992 [10]. Their recommendations included the following: The term systemic inflammatory response syn-
drome (SIRS) is the clinical manifestation of the inflammatory response to a wide variety of insults, including infectious and noninfectious etiologies. The syndrome is recognized by the presence of two or more of the following clinical signs: (1) temperature > 38C or < 36C; (2) heart rate > 90 beats per minute; (3) tachypnea manifested as a respiratory rate > 20 breaths per minute or a PaCO2 < 32 mm Hg; and (4) a white blood cell count > 12,000 or < 4000 cells/mm3. The term sepsis describes SIRS when the syndrome is the result of an infectious process. The term severe sepsis is employed to describe sepsis associated with organ dysfunction, hypotension (systolic blood pressure < 90 mm Hg or a reduction from baseline of more than 40 mm Hg), or hypoperfusion. Manifestations of hypoperfusion include, among others, lactic acidosis, oliguria, and acute alteration of mental status.
0272-5231/05/$ – see front matter D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.ccm.2004.10.015
chestmed.theclinics.com
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patients with severe sepsis who have hypotension with evidence of hypoperfusion that persists despite adequate fluid resuscitation. Patients requiring inotropic or vasopressor support despite fluid resuscitation are considered to be in septic shock. The term multiple organ dysfunction syndrome (MODS) is the presence of altered organ function in an acutely ill patient such that homeostasis cannot be maintained without intervention.
Population-adjusted incidence of sepsis (no./100,000)
Since the 1992 consensus guidelines were issued, they have been the subject of controversy. Criticisms target the high sensitivity and low specificity of the SIRS criteria [11]. In some studies, the SIRS criteria are met by two-thirds of ICU patients and a substantial proportion of ward patients [12,13]; therefore, clinical trials using SIRS criteria alone include a large and heterogeneous group of patients. Individuals with noninfectious inflammatory processes, such as pancreatitis or trauma, may meet the SIRS criteria. Identification of treatment responses in truly septic patients becomes difficult. The 1992 definitions were revisited in 2001 by a combined conference of European and North American experts [14]. The international panel determined that the 1992 definitions should be preserved; however, the panel also acknowledged that, frequently in sepsis, infection is strongly suspected without being microbiologically confirmed. The diagnostic criteria for sepsis were expanded to emphasize that multiple clinical abnormalities often combine to prompt the experienced clinician to judge a patient to be septic. Additionally, the panel proposed exploration of a staging system for sepsis, the ‘‘PIRO’’
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classification, to improve characterization of sepsis pathophysiology and prognosis. Analogous to the tumor, node, metastasis (TNM) system in oncology, the PIRO system would stratify patients based on their Predisposing factors, Infection (or Insult), host Response, and degree of Organ dysfunction. The PIRO concept was proposed as a template, and studies to evaluate its validity as a prognostic or treatment tool have not yet been conducted.
Epidemiology Although the mortality rate from sepsis continues to decrease, several recent epidemiologic studies in the United States and Europe demonstrate that the total number of deaths continues to rise owing to the increasing incidence of sepsis [15,16]. Martin and colleagues recently reviewed discharge data on more than 750 million hospitalizations and identified 10,319,418 cases of sepsis from 1979 to 2000. Over the 22-year period, the incidence of sepsis increased from 82.7 cases per 100,000 population to 240.4 cases per 100,000 population, representing an annualized increase of 8.7% (Fig. 1). During the same period, mortality rates declined from 27.8% percent to 17.9% (Fig. 2). The increasing incidence resulted in a near tripling of in-hospital sepsis deaths [15]. Annane et al demonstrated a similar trend in French ICUs [8]. A review of admissions from 22 Parisian ICUs from 1993 to 2000 demonstrated that the incidence of sepsis increased from 7.0 to 9.7 cases per 100 ICU admissions. During the 8-year period studied, the investigators documented a 5% reduction in crude mortality.
300 Men Women 200
100
0 1979 1981 1983 1985 1987 1989 1991 1993 1995 1997 1999 2001
Fig. 1. Population-adjusted incidence of sepsis according to sex, 1979 to 2000. (From Martin GS, Mannino DM, Eaton S, et al. The epidemiology of sepsis in the United States from 1979 – 2000. N Engl J Med 2003;348(16):1546 – 54; with permission.)
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Proportion of patients with sepsis who died
0.40
0.30
0.20
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0.00 1979 1981 1983 1985 1987 1989 1991 1993 1995 1997 1999 2001
Fig. 2. Overall in-hospital mortality rate among patients hospitalized for sepsis, 1979 to 2000. (From Martin GS, Mannino DM, Eaton S, et al. The epidemiology of sepsis in the United States from 1979 – 2000. N Engl J Med 2003;348(16):1546 – 54; with permission.)
Several demographic trends remain constant in the recent epidemiologic reports [15]. Sepsis more commonly affects males (relative risk [RR], 1.28) and older patients (mean age, 60.8 years), with the mean age of patients increasing over time. In the United States, blacks and other nonwhite groups have an elevated risk of sepsis when compared with whites (mean annual RR, 1.89). Comorbidities such as neoplasms, renal or hepatic failure, and AIDS, which impair host defenses, are common in sepsis. Cancer, chronic obstructive pulmonary disease, and diabetes are the comorbidities most commonly reported [9].
Risk factors for mortality in sepsis Clinical determinants of sepsis outcome include the site and type of infection, the timing and appropriateness of antibiotic therapy, the development of shock and organ dysfunction, and host response. The primary site of infection is most commonly the respiratory tract, predominantly pneumonia. The respiratory tract is the source of sepsis in 40% to 60% of patients, followed by intra-abdominal sources and urinary tract infections [3,8,9,15]. The frequency of sepsis secondary to pneumonia is increasing [8]. Additionally, several factors are associated with increased mortality from pneumonia-related sepsis. Patients with ICU-acquired pneumonia, particularly ventilator-acquired pneumonia (VAP), are at a higher risk for sepsis and have higher mortality than do
patients with CAP [9]. In some series, mechanical ventilation is associated with the highest odds ratio (OR) of dying from sepsis (4.72) [8]. Females demonstrate a lower proportion of sepsis episodes associated with a pulmonary source, which may explain, in part, the lower sepsis mortality rates in women [3]. The incidence of sepsis from gram-positive organisms is increasing. Although gram-negative organisms continue to cause a substantial proportion of sepsis, gram-positive organisms are now responsible for the majority (52.1%) of cases of sepsis in some analyses [15]. Although fungal organisms cause only a small proportion of sepsis, the incidence of fungal sepsis is increasing rapidly (a relative increase of 207% from 1979 to 2000) [15], and it has been associated with the highest mortality risk in several studies [4]. In general, sepsis secondary to nosocomial infections carries a higher mortality than sepsis secondary to community-acquired infections [9]. Positive blood cultures favorably impact survival; if the source or type of infection remains unknown, mortality increases [8,17]. Appropriate antimicrobial therapy is associated with lower mortality in sepsis [18]. Harbarth and coworkers evaluated the initial antibiotic choice for severely septic patients. Antibiotics were categorized as inappropriate if subsequently identified causative organisms were not susceptible to the initial antimicrobial agent. According to this criterion, 23% of patients with severe sepsis received inappropriate antimicrobial therapy during the first 24 hours of admission. The mortality was significantly higher
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in the inadequately treated group (39% versus 24%, P < .001). The degree of organ dysfunction correlates with mortality. Mortality increases along the continuum of SIRS to septic shock. Brun-Buisson et al [19] reported an in-hospital mortality rate of 7% with SIRS alone, 16% with sepsis, 20% with severe sepsis, and 46% with septic shock. Martin and colleagues found that patients without organ failure had an average mortality rate of 15%, whereas patients with three or more failed organ systems had a mortality rate greater than 70% [15]. The incidence of multiple organ system failure secondary to sepsis is increasing [15], as is the number of patients requiring mechanical ventilation, vasopressors, or renal replacement therapy [8]. Based on a requirement for mechanical ventilation, the lung is the organ that most often fails in sepsis (18%) [15]. Genetic risk for pneumonia and sepsis is increasingly recognized as an important determinant of outcome. Strong evidence for the role of genetics in infection was initially provided by adoptee studies demonstrating that, if either natural parent died of infection before age 50 years, an individual’s risk of death from an infection was almost six times greater [20]. Much of the current evidence for a genetic role in infection comes from association studies of single nucleotide polymorphisms (SNP) with susceptibility to infection or outcome. Most of the SNPs that have been studied are within candidate genes hypothesized to mediate inflammation; a majority of these candidate genes are located on the highly polymorphic region of chromosome 6, the major histocompatibility complex (MHC). Examples of cytokines and receptors with polymorphisms that may be associated with an increased risk of sepsis or septic shock include tumor necrosis factor alpha (TNF-a), TNF-b, interleukin-1 (IL-1) receptor antagonist (IL-1ra), IL-10, IL-6, toll-like receptors 2 and 4 (TLR2 and TLR4), CD-14, and lipopolysaccharide binding protein (LBP) [21,22]. The study of septic shock and respiratory failure in CAP performed by Waterer et al demonstrates how an understanding of genetic polymorphisms not only impacts the clinician’s ability to predict who is at risk for septic shock but also furthers knowledge of disease mechanisms [5]. In a prospective analysis of 280 patients admitted with CAP, 31 experienced septic shock, and 103 had respiratory failure. Patients were evaluated for polymorphisms in the TNF-b or TNF-a promoter regions, that is, a guanine to adenine SNP in lymphotoxin-alpha (LTa, also known as TNF-b) at the +250 site and in the TNF-a gene promoter region at the 308 site. Individuals who
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were AA homozygotes at the LTa+250 locus were significantly more likely to have septic shock. Interestingly, the AA (TNF-a hypersecretor) genotype did not correlate with respiratory failure, whereas there was a trend toward an association between GG (TNF-a hyposecretor) LTa+250 homozygotes and respiratory failure. TNF-a 308 polymorphisms were not associated with the development of septic shock in patients with CAP as previously reported [23], possibly owing to linkage disequilibrium. The LTa+250A (TNF-a high secretor) allele is nearly always inherited with the TNF-a 308G (TNF-a low secretor) allele. The study by Waterer et al [5] has ramifications for the current understanding of the inflammatory response to infection in sepsis. In clinical studies of sepsis, hypoxemia has been one of the most frequently cited manifestations of organ dysfunction in SIRS. Nevertheless, Waterer’s finding that hypoxia was not associated with a TNF-hypersecretor genotype, whereas septic shock was associated with such a genotype, suggests that hypoxia may not occur through the same mechanism or reflect the same proinflammatory state as septic shock.
Pathophysiology Initially, sepsis was conceptualized as the phenomenon of an infectious agent overwhelming the innate defenses of a host. There is now general agreement that SIRS and sepsis represent the dysregulation of the host’s immune system as much or more than the direct effects of a virulent invading organism. This dysregulation may involve a hyperimmune as well as a hypoimmune state. During the onset of sepsis, cellular and humoral defense mechanisms are activated. Animal models have shown in the initial phase of sepsis that there is an outpouring of proinflammatory cytokines and chemokines. Endothelial and epithelial cells, as well as macrophages, neutrophils, and lymphocytes, generate proinflammatory mediators, including TNF-a, IL-6, IL-1, and IL-8. Simultaneously, humoral defense mechanisms such as the complement cascade are activated. Through C5a, cytokine and chemokine production is further enhanced. The coagulation system is activated, and disseminated intravascular coagulation may occur. Phagocytic cells respond to various proinflammatory mediators by releasing granular enzymes and producing reactive oxygen species such as H2O2. Ultimately, these overlapping pathways cause microvascular damage and vascular instability [24].
community-acquired pneumonia and sepsis
Although the initial high serum cytokine and chemokine levels are well established in animal models, the pattern is less evident in humans. With the exception of meningococcemia, most human studies have not demonstrated the ‘‘cytokine storm’’ evident in animal models using large doses of endotoxin. The emerging complexity of the human immune response to sepsis is underscored by the failure to improve survival in multiple clinical trials targeting proinflammatory mediators. Evidence is increasingly supporting the concept that, in addition to an initial hyperinflammatory state in which the host may undergo ‘‘bystander’’ damage from its own overwhelming proinflammatory response, sepsis is also characterized by a hypoimmune state in which the host enters a stage of immunosuppression [25]. The latter effect may occur via several mechanisms. First, there can be a shift from an inflammatory (TH1) response to an anti-inflammatory (TH2) response. TH2 cytokines, including IL-4, IL-10, transforming growth factor-b (TGFb), and IL-13, are elevated [24,25]. Second, autopsy studies reveal that, in persons who die of sepsis, a profound loss of immune cells occurs through apoptosis
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[26 – 28]. Specifically, immunohistochemical analyses of spleens from deceased patients reveals progressive loss of B cells, CD4+ T cells, and follicular dendritic cells. Third, some evidence suggests that T cells become anergic, possibly induced by the apoptosis of gastrointestinal epithelial cells, dendritic cells, and other antigen-presenting cells during sepsis [29]. Of note, gut epithelial and lymphocyte apoptosis occurs not only in sepsis of abdominal source but also in a setting of pneumonia-related sepsis [30]. Fourth, macrophages demonstrate decreased expression of MHC class II and costimulatory molecules. Neutrophil function is suppressed, and the innate immune system can lose the ability to kill invading microorganisms effectively [25].
Pathophysiology of sepsis in pneumonia When endothelial and epithelial barriers are injured in the lung in pneumonia, the lung can become not only a target but also a source of inflammation. Cell injury by infecting organisms triggers the cascade of cytokine and chemokine responses. Never-
Pneumonia
Pulmonary Inflammation
Mechanical Ventilation
Ventilator Induced Lung Injury
Surfactant Rupture and Inactivation
Microvascular Injury
Decreased Integrity of the Alveolar-Capillary Membrane
Translocation of Bacteria and Pro-inflammatory Cytokines
Increased Pulmonary Edema and Lymphatic Drainage
Increased Circulating Bacteria and Pro-Inflammatory Cytokines
Increased Systemic Inflammatory Response
Sepsis and/or Multiple Organ Dysfunction Fig. 3. Schematic illustration of the way in which mechanical ventilation may amplify systemic inflammatory response in pneumonia.
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theless, the lung is unique in that, when lung injury advances to a degree requiring mechanical ventilation, ventilator-induced lung injury may amplify endothelial and epithelial barrier injury and accelerate proinflammatory responses. This process may be the result of several mechanisms. First, several investigators have demonstrated in mouse models that high tidal volumes administered without positive endexpiratory pressure (PEEP) produce significant serum elevation of proinflammatory cytokines, such as TNF-a and macrophage inflammatory protein (MIP)-2 [31,32]. Similarly, in human clinical studies, patients receiving conventional ventilation versus low tidal volumes had higher levels of circulating IL-6, TNF-a, IL-1b, and IL-8. The higher serum cytokine levels correlated with higher scores of multisystem organ failure [33]. Second, the loss of integrity of the alveolar-capillary membrane associated with high tidal volume ventilation may promote translocation of bacteria into the systemic circulation. The evidence for increased bacterial translocation includes increases in bacteremia [34] and spleen seeding [32] with high tidal volume ventilation. Several mechanisms may be responsible for the translocation of bacteria and inflammatory mediators into the systemic circulation in association with mechanical ventilation (Fig. 3). The predominant process affecting translocation of bacteria and mediators from the lung is likely the increased permeability of the alveolar-capillary membrane. The permeability may be altered by infection-initiated inflammation as well as by ventilator-induced lung injury allowing direct entry of organisms and cytokines into the circulation [32,34]. A lack of adequate PEEP also may prohibit the compartmentalization of bacteria into distal airways [34]. Additionally, ventilation may inactivate surfactant’s bacteriostatic properties [34]. Repeated alveolar closing and opening in low PEEP ventilation may cause surfactant destruction via surfactant compression and rupture with re-expansion. High tidal volume ventilation strategies correlate with increased surfactant large aggregates and total protein in bronchoalveolar lavage fluid. Ventilation may cause microvascular injury and pulmonary edema, increasing lymphatic flow and accelerating drainage of bacteria and inflammatory mediators into the systemic circulation [34].
Treatment of sepsis in the setting of pneumonia Previously, no specific therapies were shown to improve outcomes in patients with sepsis. In recent
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years, several interventions have shown a positive impact on mortality rates from sepsis in clinical trials, including drotrecogin alfa (activated) (Xigris), moderate-dose corticosteroids, intensive insulin therapy, and early goal-directed therapy (EGDT).
Drotrecogin alfa (activated) Activated protein C is an important modulator of inflammation and coagulation in sepsis. It inhibits inflammation, neutrophil chemotaxis, endothelial activation, and thrombosis. Activated protein C also promotes fibrinolysis. Several observational studies have reported depletion of protein C in patients with sepsis and have correlated low levels with an increased risk of death [35 – 37]. Trials in a baboon model of Escherichia coli sepsis showed that administration of activated protein C was protective [38]; therefore, recombinant human activated protein C (drotrecogin alfa [activated]) was evaluated for human use in a prospective, multicenter, placebocontrolled clinical trial (PROWESS) [39]. A total of 1690 patients were randomized to a 96-hour infusion of placebo or 24 mg/kg/h of drotrecogin alfa (activated). Patients were eligible for enrollment if they had (1) a known or suspected infection, (2) at least three or more signs of SIRS, and (3) evidence of dysfunction in at least one organ system for 24 hours or less. The overall mortality rate in the placebo group was 30.8% compared with 24.7% in the drotrecogin alfa (activated) group (P = .005). This represented an absolute reduction in the risk of death of 6.1% and a reduction in the RR of death of 19.4%. As expected, the primary complication associated with administration of drotrecogin alfa (activated) was bleeding. Severe bleeding episodes (defined as intracranial hemorrhage, any life-threatening bleeding, any bleeding classified as serious by the investigator, or any bleeding that required the administration of at least 3 units of packed red blood cells on 2 consecutive days) occurred in 3.5% of patients receiving drotrecogin alfa (activated) compared with 2.0% of patients receiving placebo ( P = .06). The majority of patients in either group with an episode of severe bleeding had an identifiable predisposition to bleeding. These factors included a history of gastrointestinal ulceration, abnormal laboratory coagulation studies (activated partial-thromboplastin time > 120 seconds or a prolonged prothrombin time with an international normalized ratio > 3.0), thrombocytopenia with a platelet count < 30,000/mm3, or trauma to a blood vessel or highly vascular organ.
community-acquired pneumonia and sepsis
Subgroup analyses were prospectively defined in the PROWESS trial for several characteristics, including the severity of illness using the APACHE II score, the degree and type of organ dysfunction, sex, age, the site and type of infection, and the presence or absence of protein C deficiency. With some notable exceptions, a consistent beneficial effect of drotrecogin alfa (activated) was observed among the subgroups, including patients without protein C deficiency. Nevertheless, whether categorized by APACHE II score or the number of dysfunctional organs, the patients with less severe disease had either less or no apparent benefit from administration of drotrecogin alfa (activated). In particular, a higher 28-day mortality was observed in patients receiving the study drug in the first APACHE II score quartile, in which scores ranged from 3 to 19 (mortality rate of 21.1% for drotrecogin alfa (activated) versus 14.5% for placebo, P = .009) [40]. Additionally, within the subgroup with single organ dysfunction, there was no significant improvement in mortality (P = .469) [40]. Of note, a clinical trial to determine the role of drotrecogin alfa (activated) for lower-severity sepsis (the ADDRESS trial) was halted for futility, implying that drotrecogin alfa (activated) does not have clinically significant benefit in patients with a low risk of death (Edward Abraham, MD, unpublished data, 2004). In the PROWESS trial, drotrecogin alfa (activated) demonstrated particular benefit in patients with pulmonary infection [40]. Respiratory dysfunction was defined as a PaO2/FIO2 < 250 (if the cause of sepsis was not pneumonia) or a PaO2/FIO2 < 200 (if the lung was the source of sepsis). The lung was the most common site of infection in PROWESS (53.6%), and greater than 70% of patients in the treatment and placebo groups required mechanical ventilation [39]. The time to resolution of respiratory dysfunction was significantly shorter in the drotrecogin alfa (activated) group when compared with the placebo group (16.7% versus 11.3% resolved at 7 days) [40]. Based on the results of the PROWESS trial and ensuing subgroup analyses, experts in the treatment of sepsis recommend that drotrecogin alfa (activated) be considered for use in adult patients with recent onset of severe sepsis or septic shock, no significant bleeding risks, and a high risk of death [41].
Corticosteroids The value of steroids in the treatment of patients with severe sepsis and septic shock has generated
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considerable controversy. Corticosteroids were the first anti-inflammatory drugs tested in randomized trials. Short courses of high-dose steroids did not have favorable effects on mortality from sepsis and, in some instances, demonstrated increased mortality as the result of an increased incidence of nosocomial infections and possibly increased organ dysfunction [42,43]. Nevertheless, several small studies documenting the frequency of and increased mortality associated with relative adrenal insufficiency in septic shock provided a strong rationale for prolonged administrated of lower-dose steroids in such patients [44,45]. A multicenter French trial conducted by Annane and colleagues [46] provides further insight into the incidence of adrenal dysfunction in sepsis and the role of steroids in this patient population. Patients with septic shock were randomly assigned to receive either hydrocortisone (50 mg intravenously every 6 hours) and fludrocortisone (50 mg by mouth daily) or placebo for 7 days. All patients had severe septic shock, as evidenced by continued hypotension despite fluid resuscitation and treatment with 5 mg/kg or more of dopamine or other vasoactive agents. All patients required mechanical ventilation and had an additional sepsis-induced organ failure, including hypoxemia, decreased urine output, or elevated lactate. For post hoc analysis, patients were stratified according to their response to a corticotropin (ACTH) stimulation test. Individuals with less than a 9 mg/dL increase in serum cortisol levels in response to corticotropin were identified as nonresponders and considered to have relative adrenal insufficiency. Of the 299 patients analyzed, 229 were ACTH nonresponders (placebo, 115 patients; steroids, 114 patients). A significant survival benefit was demonstrated among nonresponders randomized to steroids. There were 73 deaths in the placebo group (63%) and 60 deaths in the steroids group (53%) (P = .023). Nonresponders treated with steroids also had a shorter median time to withdrawal of vasopressor therapy than did nonresponders treated with placebo (7 versus 10 days). There were no significant differences in the rates of adverse events related to steroids (ie, nosocomial infections, gastrointestinal bleeding, or psychiatric disorders) between the two groups; however, in the group of patients without adrenal insufficiency, the number of deaths was higher in patients who were treated with steroids (22/36 or 61%) than in patients treated with placebo (18/34 or 53%). The difference was not statistically significant but raises concern that the administration of steroids to patients without adrenal insufficiency may be detrimental.
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Administration of moderate-dose corticosteroids should be considered in mechanically ventilated patients with refractory septic shock. In practice, a corticotropin stimulation test should be performed before initiating steroids. Corticosteroids should be continued only in patients who fail to increase serum cortisol levels more than 9 mg/dL in response to corticotropin [41,47].
Intensive insulin therapy Stress hyperglycemia (used to denote an elevation of blood glucose and free fatty acids) occurs in many critically ill patients and is caused by hepatic gluconeogenesis, peripheral insulin resistance, and release of free fatty acids from adipose tissue [48]. Stress hyperglycemia has been hypothesized to represent an adaptive response to severe illness, providing glucose for the brain, organs, red blood cells, and wound healing [41]. Nevertheless, studies performed by Van den Berghe and colleagues [49,50] indicate that even modest hyperglycemia (> 110 mg/dL) has detrimental effects on the development of nosocomial infections, multiple organ dysfunction syndrome, and mortality in critically ill patients. In the initial study, Van den Berghe and coworkers conducted a large prospective randomized controlled trial of intensive blood glucose control in 1548 patients admitted to a surgical ICU [49]. Patients were randomized to conventional therapy (intravenous insulin drip if blood glucose was > 215 mg/dL with maintenance of glucose between 180 and 200 mg/dL) or intensive therapy (continuous intravenous insulin to maintain glucose between 80 and 110 mg/dL). Sixty-three patients (8.0%) in the conventional therapy arm died compared with 35 (4.6%) receiving intensive insulin therapy. The greatest reduction in mortality occurred among patients in the ICU for more than 5 days and was attributed to a decrease in deaths owing to multiple organ failure with a septic focus. In addition to reducing mortality in critically ill patients, intensive insulin therapy had several beneficial effects on morbidity. Patients randomized to tight glucose control had a 46% reduction of bloodstream infections, a 41% decrease in the incidence of acute renal failure requiring hemofiltration or dialysis, 50% fewer red blood cell transfusions, and a 44% reduction in the occurrence of critical-illness polyneuropathy. Of note, the patients receiving intensive insulin therapy were significantly less likely to require prolonged ventilatory support. Ninety-three patients (11.9%) in the conventional treatment group required greater than 14 days of mechanical ventila-
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tion compared with 57 (7.5%) of patients with tight glycemic control (P = .003). The intensive insulin therapy trial raised the question of whether the beneficial effects observed were the result of normoglycemia or the cumulative insulin dose. This issue was addressed by Van den Berghe et al [50]. Using data from the initial trial of intensive insulin therapy, the researchers performed a multivariate logistic regression analysis of the impact of blood glucose versus the insulin dose on morbidity. Strict maintenance of normoglycemia, rather than the total insulin dose, was most significantly associated with a reduction in mortality (P < .0001), critical-illness polyneuropathy (P < .001), bacteremia (P = .02), inflammation (defined as 3 or more days with C reactive protein > 150 mg/L, P = .0006), and anemia requiring red blood cell transfusion (P = .06). In contrast, the actual dose of insulin was a negative predictor for acute renal failure and the need for renal replacement therapy (P = .03).
Early goal-directed therapy Early goal-directed therapy is the effort to balance optimally oxygen delivery and oxygen demand in patients with septic shock before the onset of global tissue hypoxia and multiorgan failure. In a study conducted by Rivers et al [51], 263 enrolled patients were randomized to receive 6 hours of EGDT versus standard therapy. In addition to a target central venous pressure (CVP) between 8 and 12 mm Hg, mean arterial pressure (MAP) 65 mm Hg, and urine output 0.5 mL/kg/h in the standard therapy group, resuscitation endpoints used in the EGDT group to confirm optimal oxygen delivery included normalized values for arterial lactate, base deficit, and pH, and a central venous oxygen saturation (ScvO2) 70%. Patients randomized to EGDT received crystalloid boluses, vasopressors, red blood cell transfusions, and, if necessary, dobutamine until resuscitation endpoints were met. The in-hospital mortality rate was 30.5% in the EGDT group compared with 46.5% in the standard therapy group (P = .009). During the 7 to 72 hours from admission, when compared with patients treated with standard therapy, patients treated with EGDT demonstrated significant improvement in all resuscitation endpoints: ScvO2, lactate, base deficit, and pH. The EGDT group had a mean APACHE II score during the same period that was significantly lower than that in the control group, indicating less severe organ dysfunction.
community-acquired pneumonia and sepsis
More than one-third of patients in both treatment groups carried an admission diagnosis of pneumonia. In patients with baseline respiratory compromise, aggressive fluid resuscitation would be expected to be associated with increased requirements for mechanical ventilation; however, the trial by Rivers and coworkers demonstrated the opposite. Although the patients treated with EGDT received significantly more fluid and blood within the initial 6 hours of admission, there was no significant difference between the EGDT and standard therapy groups in the number of patients requiring mechanical ventilation. Over the ensuing 7 to 72 hours, significantly more fluid was administered to the patients receiving standard therapy. A greater percentage of patients in the standard therapy group required mechanical ventilation during the 7 to 72 hour period (16.8% versus 2.6%, P < .001). The net effect from 0 to 72 hours was a greater requirement for mechanical ventilation in the standard therapy group (70.6% versus 55.6%) despite equal total fluid administration in both groups. Although somewhat counterintuitive, this result underscores the benefit of early fluid resuscitation to optimize oxygen delivery and decrease subsequent organ dysfunction in patients with pneumonia and sepsis.
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