Background

Sepsis syndrome represents the body’s host response to an infection. The causative agent and the host’s activated inflammatory cascade overwhelm the body’s defenses and regulatory systems, leading to disruption in homeostasis. Tachycardia, tachypnea, fever, and immune system activation are common manifestations. If the body is unable to overcome this insult, cellular injury, tissue damage, shock, multiorgan failure, or death may ensue.

In 1992, the American College of Chest Physicians/Society of Critical Care Medicine issued a consensus statement to establish uniform criteria defining the sepsis syndromes.¹ For the first time, this allowed a common nomenclature for disease classification and systematic comparisons across studies of septic patients. Systemic inflammatory response syndrome (SIRS) is defined as two or more of the following: tachycardia, tachypnea, hyperthermia or hypothermia, high or low white blood cell count, or bandemia; sepsis is the combination of infection plus SIRS; severe sepsis is sepsis plus organ dysfunction; and septic shock is severe sepsis plus hypotension, defined as a systolic blood pressure below 90 mm Hg, not responsive to a fluid challenge (Box 138-1). The importance of this nomenclature is to provide clinicians and researchers with a common classification. Efforts to validate this classification scheme in the emergency department (ED) population have demonstrated that the term sepsis, when it is characterized by fulfilling of the SIRS criteria alone, is perhaps overly sensitive and nonspecific and does not convey an increased mortality risk, although it should prompt further evaluation.² However, organ dysfunction and shock were shown to be significant predictors of adverse outcome. Newer efforts have proposed the PIRO approach, which may help better understand and prognosticate the severity of illness.^3,4 Assessment of predisposing conditions, infection source, response of the host, and organ dysfunction is proposed to help improve classification. The clinician should approach the septic patient with goals to determine who they are (e.g., underlying comorbidities), what infection they have, how they are responding, and where/if organ dysfunction is present.

Bacteremia is often present, but positive cultures are not obligatory in the diagnosis of sepsis. In several prospective studies, only 17 to 27% of patients with sepsis, 25 to 53% of patients with severe sepsis, and 69% of patients with septic shock actually had positive blood cultures.5–7 Culture-negative and culture-positive septic populations have similar outcomes in patients with similar severity of illness.⁸ Pneumonia, abdominal abscess with viscus perforation, and pyelonephritis are common primary causes of sepsis. Gram-positive organisms account for 25 to 50% of infections, gram-negative organisms for 30 to 60%, and fungi for 2 to 10%. The distribution varies with the study and, more important, with host factors such as the status of the host immune system, age of the patient, recent hospitalizations, and presence of indwelling vascular catheters.

The health status of the host is a crucial risk factor in the development and progression of sepsis.⁹ Elders and those with multiple comorbidities are overwhelmed more easily by systemic infection. Chemotherapy-induced neutropenia, acquired immunodeficiency syndrome, and steroid dependency increase susceptibility to sepsis. Increased use of indwelling devices such as intravascular catheters, prosthetic devices, and endotracheal tubes contributes to the risk of systemic infection and sepsis.

Epidemiology

Sepsis is now the tenth most common cause of death in the United States.¹⁰ It is estimated that 571,000 cases of severe sepsis present to U.S. EDs each year.¹¹ Mortality rates from sepsis are estimated between 20 and 50%.^12–14 Sepsis accounts for 4 of 1000 ED visits in the United States.¹⁴ The incidence of sepsis as a reason for hospitalization is rising disproportionately among elders compared with the young (Fig. 138-1). The incidence of sepsis in patients younger than 65 years is less than 5 in 100,000, whereas it is 26 in 100,000 in those 65 years or older.¹² The cost of caring for septic patients is estimated to be $17 billion per year in the United States. Hospital discharge data have shown that the incidence of sepsis is increasing as identification improves and the population ages. Estimates have suggested that the incidence will rise 1.5% per annum or more. The number of ED visits for sepsis has risen proportionally with the rise in ED volume during the past 15 years.¹⁴ Recent research has confirmed the long-held belief that respiratory and genitourinary infections are the most common causes of sepsis.¹¹

Pathophysiology

Sepsis results from the complex interaction of detection molecules, signaling molecules, and numerous inflammatory and coagulation mediators in response to infection. More than 30% of patients with sepsis do not have a definite microbiologic diagnosis.¹⁵ Although our understanding of the pathophysiologic process of sepsis has evolved in the past two decades, it remains incomplete.¹⁶ The initial host response is to mobilize inflammatory cells, particularly neutrophils and macrophages, to the site of infection. These inflammatory cells then release circulating molecules, including cytokines, which trigger a cascade of other inflammatory mediators that result in a coordinated host response. Synthesis of the components of the cascade is increased at many steps along the pathway. If these mediators are not appropriately regulated, sepsis will occur. In the setting of ongoing toxin release, a persistent inflammatory response occurs with ongoing mediator activation, cellular hypoxia, tissue injury, shock, multiorgan failure, and potentially death.

Mediators of Sepsis

Host response and pathogen characteristics are both important in the pathogenesis of sepsis. More than 100 discrete markers have been identified and attributed to the sepsis cascade, but the true culprits have not been clearly identified.1,17 A pathogen is sensed by pattern recognition receptors, most notably toll-like receptors, located on the surface of the white blood cell.¹⁶ The resulting host-pathogen interaction activates the inflammatory and coagulation cascades.^18–21 The subsequent inflammatory signaling occurs through cytokines, chemokines, and other soluble mediators, including increased circulating levels of the interleukins IL-1, IL-6, and IL-8 and tumor necrosis factor alpha (TNF-α). Activation of the clotting cascade results in increased D-dimer levels and decreased circulating levels of protein C.²²

In benign conditions, a self-limited response helps clear the pathogen. If the innate immune response is inadequate, mediators create a procoagulant state. Coagulation and fibrinolytic components are proinflammatory, precipitating a worsening cycle of procoagulant and proinflammatory mediators. This cascade ultimately creates end-organ damage and disseminated intravascular coagulation (DIC). If it is not effectively reversed, the process leads to cellular hypoxia, organ dysfunction, shock, and death.

The primary mediators are cytokines that are primarily proinflammatory, anti-inflammatory, or growth promoting. The molecular mechanisms by which they are regulated are not well understood. The initial cytokine, TNF-α, is found in serum approximately 90 minutes after the administration of endotoxin to healthy volunteers. IL-6 and IL-8 reach peak levels at approximately 120 minutes. The main proinflammatory cytokines are IL-1, TNF, and IL-8. The primary anti-inflammatory cytokines are IL-10, IL-6, transforming growth factor beta, soluble receptors to TNF, and IL-1 receptor antagonist (IL-1RA). If the resultant inflammatory response is adequate, the infection is controlled and cleared. If the response is deficient or excessive, however, a persistent and worsening cascade is produced, ultimately leading to shock, organ failure, and potentially death.

Instability in vascular tone is becoming increasingly important in understanding of the pathophysiologic mechanism of sepsis. Vasopressin, also known as antidiuretic hormone, is a naturally occurring hormone that is essential for cardiovascular stability. It is produced as a prohormone in the hypothalamus. The hormone is stored in the pituitary gland and released in response to stressors such as pain, hypoxia, hypovolemia, and hyperosmolality.²³ In severe sepsis, there is a brief rise in circulating vasopressin levels followed by a prolonged and severe suppression. This pattern of secretion is different from other forms of shock, in which vasopressin levels remain elevated. Vasopressin has numerous physiologic effects, including vasoconstriction of the systemic vasculature, osmoregulation, and maintenance of normovolemia.

Nitric oxide (NO) is a gas that has an important role in septic shock, regulating vascular tone by an indirect effect on smooth muscle cells. NO also contributes to platelet adhesion, insulin secretion, neurotransmission, tissue injury, and inflammation and cytotoxicity. Its half-life is short (6-10 seconds), and it easily diffuses into cells. Although its mechanisms of action are not well understood, it seems to be a key mediator of sepsis. Animal data show that nitric oxide synthase, the enzyme that produces NO, is upregulated in cases of sepsis.²⁴ Enhanced NO production is thought to contribute to the profound vasodilation found in patients in septic shock.

In the setting of ongoing inflammatory activation, the mediators of sepsis continue to be produced and the cascade is perpetuated. Unless it is appropriately and rapidly controlled, the ultimate effect is a sequence of events starting with cellular dysfunction and ultimately leading to tissue damage, organ dysfunction, and death.

Organ System Dysfunction

The organ dysfunction that results from sepsis is central to the pathogenesis of the disease. A 3000-patient ED-based study demonstrated that organ dysfunction with septic shock portends increasingly worse outcomes.² Patients with suspected infection alone had a mortality rate of 2.1%, whereas the presence of SIRS criteria and suspected infection had a mortality rate of only 1.3% (Fig. 138-2A). However, the mortality rate was 9% for those patients with severe sepsis (sepsis plus organ dysfunction) and 28% for those with septic shock. The risk of death from sepsis approximately doubles for each organ that fails. The mortality rate for patients with no organ dysfunctions was 1%; rates for dysfunction of a single organ, two organs, three organs, and four or more organs were 6%, 13%, 26%, and 53%, respectively (Fig. 138-2B).

Novel Concepts

In recent years, there has been increasing evidence that genetics are a risk factor for outcome of sepsis.30,31 The impact of genetics on future treatment modalities for sepsis remains unclear, but the prospect of customized genetic therapy for sepsis is a promising early development.

Symptoms and Signs

The approach to a patient with sepsis relies on identification of the presence of a systemic infection and localization of the source of the initial infection. This allows appropriate and aggressive treatment directed to the source of infection. Often, the source is not readily apparent, but early identification of the septic state allows implementation of broad-spectrum antibiotics that may be potentially lifesaving.

The septic patient manifests signs of systemic infection through tachycardia, tachypnea, hyperthermia or hypothermia, and, if severe, hypotension. A septic patient will often have flushed skin with warm, well-perfused extremities secondary to the early vasodilation and hyperdynamic state. Alternatively, the severely hypoperfused patient with an advanced shock state may appear mottled and cyanotic. Very early in the patient’s presentation, vital sign changes such as tachycardia and tachypnea may be the only early indicators of sepsis. If the patient is in shock, a rapid assessment that excludes other causes, such as hypovolemic or cardiogenic shock, is essential to the proper initial treatment. A complete detailed clinical examination will help the physician determine the cause of the shock state (see Chapter 6). The aforementioned are “classic” signs; however, these findings may not be manifested in a septic patient, and signs and symptoms may be subtle.

Both underlying comorbidities and the etiology of sepsis should be considered. Risk factors such as immunocompromised states (acquired immunodeficiency syndrome, malignant disease, diabetes, splenectomy, and concurrent chemotherapy), older age, debilitation or high-risk environments for iatrogenic infections (such as long-term care facilities), and multiple comorbidities should be considered.

The respiratory system is the most common source of infection in the septic patient. A history of a productive cough, fevers, chills, upper respiratory symptoms, and throat and ear pain should be sought. Both the presence of pneumonia and the findings of tachypnea or hypoxia have been found to be predictors of death in patients with sepsis.³² Physical examination should also include detailed evaluation for focal infection, such as exudative tonsillitis, sinus tenderness, tympanic membrane injection, and crackles or dullness on lung auscultation. Also, pharyngeal thrush should be noticed as a potential marker of an immunocompromised state.