Sepsis Syndrome

Background

Sepsis syndrome represents the body’s host response to an infection. The causative agent and 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 and Society of Critical Care Medicine issued a consensus statement to establish uniform criteria defining the sepsis syndromes. The goal was to create a common nomenclature for disease classification and systematic comparisons across studies of septic patients. The term 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 sepsis plus hypotension, defined as a systolic blood pressure below 90 mmHg, not responsive to a fluid challenge ( Box 127.1 ). This nomenclature is intended 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 characterized by fulfilling the SIRS criteria alone, is overly sensitive and nonspecific and does not convey an increased mortality risk. SIRS is not specific because it can be present in noninfectious inflammatory states and in localized infections that are not inclined to lead to sepsis, such as streptococcal pharyngitis or viral illnesses. However, organ dysfunction and shock have been shown to portend worse outcomes.

The Third International Consensus Definitions Task Force (SEP-3) is a group who revisited the sepsis definitions and published a set of revised definitions. The quick SOFA (qSOFA) score emerged as a risk stratification tool for the Emergency Department (ED). The qSOFA score uses three clinical criteria with each receiving one point if present: respiratory rate of 22 breaths or less per minute, altered mental status, and hypotension defined by a systolic blood pressure (SBP) 100 mm Hg or less. A qSOFA score of two or greater was associated with an increased risk of mortality. The definitions group proposed using a suspected infection plus a qSOFA of 2 or greater to help identify patients with potential sepsis in the non-ICU setting. Subsequent validation studies have called the accuracy into question; ultimately it appears that it is a reasonable tool that is less sensitive and more specific than the original sepsis criteria. However, consensus is lacking as to whether it should be used to define sepsis.

Bacteremia may be present, but positive cultures are not obligatory in the diagnosis of sepsis. Culture-negative and culture-positive septic populations have similar outcomes in patients with similar illness severity. 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 importantly, 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 an important risk factor in the development and progression of sepsis. Older adults and those with multiple comorbidities may be more susceptible to developing a 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 also contribute to the risk of systemic infection and sepsis.

Pathophysiology

Sepsis results from the complex interaction of detection molecules, signaling molecules, and numerous inflammatory and coagulation mediators in response to infection. Although our understanding of the pathophysiologic process of sepsis has evolved, it remains incomplete. 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.

Organ System Dysfunction

The organ dysfunction that results from sepsis is central to the pathogenesis of the disease. The mortality of patients with sepsis increases as the number of failing organs increases ( Fig. 127.1A ). In one large study, the mortality rate was 1% for sepsis patients with no organ dysfunction, whereas the rates for patients with dysfunction of a single organ, two organs, three organs, and four or more organs were 6%, 13%, 26%, and 53%, respectively (see Fig. 127.1B ).

Neurologic Impairment

Patients with sepsis may display neurologic impairment manifested by altered mental status and lethargy, commonly referred to as septic encephalopathy. The incidence has been reported as between 10% and 70%. The mortality rate in patients with septic encephalopathy is higher than that in septic patients without significant neurologic involvement. Although the pathophysiologic process has not been clearly defined, contributing factors may include direct bacterial invasion, endotoxemia, altered cerebral perfusion or metabolism, metabolic derangements, multiorgan system failure, and iatrogenic injury. In addition, impaired renal or hepatic function in the absence of overt organ failure has been shown to correlate with encephalopathy.

Cardiovascular Dysfunction

Cardiovascular dysfunction is common with sepsis. The cardiovascular dysfunction and failure arise from direct myocardial depression and distributive shock. Gram-negative, gram-positive, and killed organisms can cause myocardial depression. The direct insults of the toxic mediators as well as the mobilization of host mediators of sepsis produce a distributive shock. Early in sepsis, a hyperdynamic state develops, characterized by increased cardiac output and decreased systemic vascular resistance. Although the cardiac output is increased, it is at the expense of ventricular dilation and decreased ejection fraction (EF). Vigorous fluid resuscitation usually increases preload and, secondarily, EF, thereby improving the cardiac index. Much of the cardiovascular compromise from septic shock is reversible, and normal cardiovascular function usually returns within 10 days.

Pulmonary Involvement

Involvement of the lung is often seen in the inflammatory response to infection. These effects are apparent, irrespective of the primary infection that caused sepsis. Early infiltration with neutrophils, surfactant dysfunction, and edema gives way to monocyte infiltration and fibrosis. Significant right-to-left shunting, arterial hypoxemia, and intractable hypoxemia occur. The resulting morbidity is high and is a common endpoint to sepsis-related deaths.

Sepsis produces a highly catabolic state and places significant demands on the respiratory system to maintain the acid-base status. At the same time, airway resistance may be increased, and muscle function is impaired. Irrespective of whether pneumonia is the cause of sepsis, a common pulmonary endpoint is acute respiratory distress syndrome (ARDS). ARDS is defined clinically and correlates with the pathologic finding of diffuse alveolar damage (see Chapter 2 ). Because of alveolar-capillary membrane damage, fluid accumulates in the alveoli. Rather than being a diffuse disease, ARDS is a heterogeneous process that results in interspersed damaged and normal alveoli.

Gastrointestinal Effects

Splanchnic blood flow is dependent on mean arterial pressure because there is relatively little autoregulation. Therefore, hemodynamic dysfunction may have a profound effect on viscus metabolism. A shock state causes significant deleterious effects on a hollow viscus and its oxygen supply. A prolonged ileus may accompany hypoperfusion and persist beyond the perfusion deficit.

Solid organ involvement is also common. Even in the previously normal host, elevations in aminotransferases and bilirubin levels are common early in sepsis. The liver has also been implicated in the pathogenesis of sepsis; some of the mediators of sepsis are produced by the liver.

Endocrine Disorders

An absolute or relative adrenal insufficiency is common in sepsis. Depending on the balance of circulating cytokines, augmentation or suppression of the hypothalamic-pituitary axis is possible. IL-1 and IL-6 both activate the hypothalamic-pituitary-adrenal axis. TNF-α and cortistatin depress pituitary function. Other factors that may contribute to adrenal insufficiency in sepsis include decreased blood flow to the adrenal cortex, decreased pituitary function, and decreased pituitary secretion of adrenocorticotropic hormone due to severe stress. As a result of these interactions, the hypothalamic thermoregulatory mechanism may be reset, and temperature fluctuations may develop.

Hematologic Abnormalities

Sepsis causes abnormalities in many parts of the coagulation system. Endotoxin, TNF-α, and IL-1 are the key mediators. Pathologic activation of the extrinsic (tissue factor–dependent) pathway, protein C, protein S, and fibrinolysis lead to consumption of essential coagulation factors, causing DIC. The activation of the coagulation cascade produces fibrin deposition and microvascular thrombi. If these depositions are not corrected, they can compromise organ perfusion and contribute to organ failure. Tissue factor expression on monocytes is increased. This results in fibrin deposition and perhaps contributes to an increased incidence of multiorgan failure due to microvascular thrombi.

Protein C has been identified as an important modulator of inflammation and coagulation in patients with sepsis. Impairment of the protein C–dependent anticoagulation pathway is critical to the development of the thrombotic complications of sepsis. In healthy people, protein C is activated by a combination of thrombin and thrombomodulin. The activation of protein C results in the downregulation of many portions of the coagulation cascade, including release of tissue factor, inactivation of factors VIIIa and Va, and stimulation of fibrinolysis. It is possible that protein C activation in early sepsis is impaired because of an inflammatory cytokine–mediated downregulation of thrombomodulin. As a result, a consumptive coagulopathy ensues. This leads to increased fibrin deposition and a resulting upregulation of the fibrinolytic pathway, as identified by low plasma levels of the fibrinolytic proteins and increased fibrin split products. This sequence of events leads to consumption of coagulation factors and DIC. In late sepsis, the fibrinolytic system is suppressed.

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 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.

The septic patient may manifest signs of systemic infection through tachycardia, tachypnea, hyperthermia or hypothermia and, if severe, hypotension. Very early in the patient’s presentation, vital sign changes such as tachycardia and tachypnea may be first 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 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 advanced shock may appear cyanotic. A complete detailed clinical examination will help the emergency clinician determine the cause of the shock state (see Chapter 3 ). These are classic signs; however, these findings may not be manifested in a septic patient, and signs and symptoms may be subtle or absent.

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

The respiratory system is the most common source of infection in the septic patient (see Chapter 62 ). A history of a productive cough, fevers, chills, upper respiratory symptoms, sore throat, or ear pain should be sought. Physical examination should also include a 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 noted as a potential marker of an immunocompromised state.

The gastrointestinal system is the second or third (depending on the study) most common source of sepsis. A history of abdominal pain, including its description, location, timing, and modifying factors, should be sought. Further history, including the presence of nausea, vomiting, and diarrhea and time of the last bowel movement should be noted. A careful physical examination, looking for signs of peritoneal irritation, abdominal tenderness, and hyperactive or hypoactive bowel sounds, is critical in identifying the source of abdominal sepsis. Particular attention should be paid to physical findings suggestive of common sources of infection or disease—Murphy sign indicating cholecystitis, pain at McBurney point indicating appendicitis, left lower quadrant pain suggesting diverticulitis, or rectal examination revealing a rectal abscess or prostatitis.

The neurologic system should be evaluated for signs of meningitis, encephalitis, or epidural abscess, including nuchal rigidity, fevers, and change in consciousness (see Chapter 95 ). Lethargy or altered mentation may indicate primary neurologic disease or may be the result of decreased brain perfusion.

The genitourinary (GU) history includes queries about the presence of flank pain, dysuria, polyuria, discharge, Foley catheter placement, and genitourinary instrumentation. However, one must also remember that GU infection is a common source of infection in older patients and is a common offender in patients with nonspecific symptoms. Obstructed nephrolithiasis with associated urinary tract infection is a potentially lethal source of infection that can advance rapidly without decompression by nephrostomy.

Rarely, sexually transmitted infections may be the cause of sepsis. The genital examination could reveal ulcers, discharge, penile or vulvar lesions, or the woody induration of Fournier gangrene. Cervical motion tenderness indicates pelvic inflammatory disease, and adnexal tenderness in a toxic-appearing woman may represent a tubo-ovarian abscess. Tampons are rarely a cause of toxic shock syndrome, but when no other source of septic shock is found, a retained tampon should be considered.

The musculoskeletal history includes the presence of any localizing symptoms to a particular joint. Redness, swelling, and warmth over a joint, especially if there is a decreased range of motion in that joint, may be signs of septic arthritis and may mandate arthrocentesis. The skin should be examined for evidence of cellulitis, abscess, wound infection, or traumatic injury. Deep injuries, foreign bodies, and fasciitis may be difficult to identify clinically. The emergency clinician should look for crepitus, bullae, or skin edema extending beyond areas of erythema that may indicate the presence of an aggressive, gas-forming organism (see Chapter 126 ). Back pain and fever may be signs of an epidural abscess. Local lymphadenopathy, swelling, and streaking should also be noted as signs of an advancing infection. Petechiae and purpura may represent a Neisseria meningitidis infection or DIC. Generalized erythroderma and rash may represent an exotoxin from pathogens such as Staphylococcus aureus and Streptococcus pyogenes .

A history of fevers or chills in the setting of injection drug use, artificial heart valve, or mitral valve prolapse should increase the suspicion for endocarditis. The emergency clinician should suspect endocarditis in the presence of a murmur or other stigmata of endocarditis (e.g., splinter hemorrhages, Roth’s spots, Janeway’s lesions) (see Chapter 69 ).

Emergency clinicians must identify the severity of illness in patients with infection and initiate early resuscitation for those with the potential of becoming critically ill. Although a patient may meet SIRS criteria, this alone has little predictive value in determining the severity of illness and mortality. There are many scoring systems that have been developed to risk-stratify illness severity. Most scoring systems are not clinically relevant and not routinely used. The Mortality in Emergency Department Sepsis (MEDS) score is one proposed method to risk stratify ED patients with sepsis. The MEDS prediction rule assigns point values to specific clinical characteristics ( Table 127.1 ). The total score can be used to assess risk of death. Thus, the greater the number of risk factors, the more likely a patient is to die during hospitalization. Although typically not calculated for all patients, the elements of the score may be identified and considered as a red flag when risk-stratifying a patient.