eMedicine Specialties > Emergency Medicine > Infectious Diseases

Shock, Septic

Author: Michael R Filbin, MD, Clinical Instructor, Department of Emergency Medicine, Massachusetts General Hospital
Contributor Information and Disclosures

Updated: Aug 12, 2009

Introduction

Background

The basis of sepsis is the presence of infection and a subsequent systemic inflammatory response to that infection that results in physiologic alterations that occur at the capillary endothelial level. Systemic inflammatory response syndrome (SIRS) is a term that was developed in an attempt to describe the clinical manifestations that result from this inflammatory cascade, or systemic response to infection. Meeting SIRS criteria is considered having at least 2 of the following 4 clinical parameters abnormal: (1) body temperature, (2) heart rate, (3) respiratory rate, and (4) peripheral leukocyte count.

Sepsis syndromes are clinically defined on a spectrum of increasing disease severity as sepsis, severe sepsis, and septic shock. Sepsis is the presence of SIRS in the setting of infection. Severe sepsis is infection with evidence of end-organ dysfunction as a result of hypoperfusion. Septic shock is severe sepsis with persistent hypotension despite fluid resuscitation and resulting tissue hypoperfusion.

Bacteremia is defined as the presence of viable bacteria within the liquid component of blood. Bacteremia may be primary (without an identifiable focus of infection) or, more often, secondary (with an intravascular or extravascular focus of infection). While sepsis is commonly associated with bacterial infection, bacteremia is not a necessary ingredient in the activation of the inflammatory response that results in severe sepsis. In fact, septic shock is associated with culture-positive bacteremia in only 30-50% of cases.^2,3,4,5

Pathophysiology

The physiologic response to infection includes the activation of host defense mechanisms that result in the influx of activated neutrophils and monocytes, the release of inflammatory mediators, local vasodilation and increased endothelial permeability, and activation of coagulation pathways. Sepsis is characterized by a similar response to infection, although on a systemic level, resulting in diffuse endothelial dysfunction. In the case of bacterial infection, the inciting event is the interaction with the host immune cells of endotoxins contained within the bacterial cell wall of gram-negative organisms. In gram-positive organisms, this interaction occurs with either cell wall components or exotoxins released by the organism.

As a result of these interactions, cellular activation occurs with the release of cytokine and noncytokine mediators, the most notorious of which are tumor necrosis factor-alpha (TNF-alpha), interleukin 1 (IL-1), and interleukin 6 (IL-6). These factors are implicated in the diffuse activation of a systemic inflammatory response. As a result, mediators with vasodilatory and endotoxic properties are released systemically, including prostaglandins, thromboxane A2, and nitric oxide. This results in vasodilation and endothelial damage, which leads to hypoperfusion and capillary leak. In addition, cytokines activate the coagulation pathway, resulting in capillary microthrombi and end-organ ischemia.^6,7

The following systems and mediators are stimulated in septic shock:

• Arachidonic acid metabolites (eg, leukotrienes, prostaglandins, thromboxanes)
• The complement system
• IL-1 and IL-6
• TNF-alpha
• The coagulation cascade
• The fibrinolytic system
• Catecholamines
• Glucocorticoids
• Prekallikrein
• Bradykinin
• Histamines
• Beta-endorphins
• Enkephalins
• Adrenocorticoid hormone
• Circulating myocardial depressant factor(s)

The complex interplay of inflammatory cells and mediators leads to dysfunction of capillary endothelium that results in vasodilation and capillary leak. This further initiates a cascade of endothelial injury, global tissue hypoxia, microthrombus formation, abnormal oxygen utilization due to mitochondrial dysfunction, all which lead to organ dysfunction and eventual failure. The insidious nature of sepsis is that microcirculatory dysfunction can occur while global hemodynamic parameters such as blood pressure may remain normal.⁸

Frequency

United States

The National Center for Health Statistics published a large retrospective analysis using the National Hospital Discharge Survey of 500 nonfederal US hospitals with more than 10 million cases of sepsis over a 22-year period. Septicemia accounted for 1.3% of all hospitalizations, and the incidence of sepsis has increased 3-fold, between 1979 and 2000, from 83 cases to 240 cases per year per 100,000 population. The reasons for this likely include an increasingly elderly population, increased recognition of disease, increased performance of invasive procedures and organ transplantation, increased use of immunosuppressive agents and chemotherapy, increased use of indwelling lines and devices, and increase in chronic diseases such as end-stage renal disease and HIV. Of note, in 1987, gram-positive organisms surpassed gram-negative organisms as the most common cause of sepsis, which holds true today.⁹

Angus et al published linked data from several sources related to hospital discharge from all hospitals from 7 large states. Hospital billing codes were used to identify patients with infection and organ dysfunction, consistent with the definition of severe sepsis. This method yielded 300 annual cases per 100,000 population, 2.3% of hospital discharges, or an estimated 750,000 cases annually in the United States.¹⁰ A more recent large survey of emergency department visits showed that severe sepsis accounts for more than 500,000 ED visits annually (0.7% of total visits), the majority of patients presented to EDs without an academic affiliation, and that mean ED length of stay is approximately 5 hours.¹¹

Mortality/Morbidity

The mortality rate of severe sepsis and septic shock is frequently quoted as anywhere from 20-50%. Given that there is a spectrum of disease from sepsis to severe sepsis to septic shock, mortality varies depending on the degree of illness. Factors that are consistently associated with increased mortality in sepsis include advanced age, comorbid conditions, and clinical evidence of organ dysfunction.^10,12 Simply meeting SIRS criteria without evidence of organ dysfunction has not been shown to predict increased mortality, although increasing number of SIRS criteria met has been associated with higher mortality.¹³

The National Center for Health Statistics study showed a reduction in hospital mortality rates from 28% to 18% for septicemia over the years; however, more overall deaths occurred due to the increased incidence of sepsis. The study by Angus et al, which likely more accurately reflects the incidence of severe sepsis and septic shock, reported a mortality rate of about 30%.¹⁰

The morbidity of sepsis is significant given that tissue hypoperfusion leads to organ dysfunction and failure. Acute respiratory distress syndrome (ARDS) is a significant sequela of severe sepsis and one that results in mortality rates that approach 50%. It also leads to prolonged intensive care unit (ICU) length of stay and increased incidence of ventilator-associated pneumonia. Other significant complications of septic shock include myocardial dysfunction, acute renal failure and chronic dysfunction, disseminated intravascular coagulation (DIC), and liver failure. Prolonged tissue hypoperfusion can lead to long-term neurologic and cognitive sequelae as well.⁷

Race

One large epidemiologic study showed that the risk of septicemia in the nonwhite population is almost twice that of the white population, with the highest risk to black men. Potential reasons for this include issues relating to access to health care and increased prevalence of underlying medical conditions.⁹

Sex

Epidemiologic data have shown that the age-adjusted incidence and mortality of septic shock is consistently greater in men. However, it is not clear whether this difference can be attributed to an underlying higher prevalence of comorbid conditions, a higher incidence of lung infection in men, or whether women are inherently protected against the inflammatory injury that occurs in severe sepsis.^9,10

Age

A strong correlation exists between advanced age and the incidence and mortality of septic shock, with a sharp increase in the number of cases in patients older than 50 years.^10,12

Clinical

History

Symptoms of sepsis usually are nonspecific and include fever, chills, rigors, fatigue, malaise, nausea, vomiting, difficulty breathing, anxiety, or confusion. These symptoms are not pathognomonic for sepsis syndromes and may be present in a wide variety of other conditions. Alternatively, typical symptoms of systemic inflammation may be absent in severe sepsis, especially in elderly individuals.

The following localizing symptoms are some of the most useful clues to the etiology sepsis:

• Head and neck infections - Severe headache, neck stiffness, altered mental status, earache, sore throat, sinus pain or tenderness, cervical or submandibular lymphadenopathy
• Chest and pulmonary infections - Cough (especially if productive), pleuritic chest pain, dyspnea
• Abdominal and GI infections - Abdominal pain, nausea, vomiting, diarrhea
• Pelvic and genitourinary infections - Pelvic or flank pain, vaginal or urethral discharge, dysuria, frequency, urgency
• Bone and soft-tissue infections - Focal pain or tenderness, focal erythema, edema, fluctuance

Physical

The hallmark of severe sepsis and septic shock are changes that occur at the microvascular and cellular level with diffuse activation of inflammatory and coagulation cascades, vasodilation and maldistribution of perfusing blood, capillary endothelial leak, and dysfunctional utilization of oxygen and nutrients at the cellular level. The challenge for the clinician is recognize that this process is underway when it may not be clearly manifest in the vital signs or clinical examination.

The American College of Chest Physicians/Society of Critical Care Medicine in 1992 defined the systemic inflammatory response syndrome (SIRS) as a group of vital signs and a laboratory value that if abnormal may indicate that sepsis physiology is occurring at the microvascular and cellular level.¹ Meeting SIRS criteria is defined by the having at least 2 of the following 4 abnormalities:

• Temperature higher than 38°C or lower than 36°C
• Heart rate greater than 90 beats per minute
• Respiratory rate greater than 20 breaths per minute
• WBC count higher than 12,000/mm³ or lower than 4,000/mm³ or with more than 10% immature forms (bands)

Of course, a patient can have either severe sepsis or septic shock without meeting SIRS criteria, and conversely, SIRS criteria may be present in the setting of many other illnesses. One large observational study demonstrated that, in the setting of suspected infection, just meeting SIRS criteria without evidence of organ dysfunction did not predict increased mortality, which emphasizes the importance of identifying organ dysfunction over the presence of SIRS criteria.¹² However, there is evidence that suggests that meeting increasing number of SIRS criteria is associated with increased mortality.

Fever is a common feature of sepsis. An inquiry should be made about fever onset (abrupt or gradual), duration, and maximal temperature. These features have been associated with increased infectious burden and severity of illness. However, note that simply mounting a fever is an insensitive indicator of sepsis. In fact, hypothermia is more predictive of illness severity.

Tachycardia is a common feature of sepsis and indicative of a systemic response to a stressor. Tachycardia is the physiologic mechanism of increasing cardiac output and increasing oxygen delivery to tissues. It is an indicator of hypovolemia and the need for intravascular fluid repletion. It may also result from fever itself. Narrow pulse pressure and tachycardia are also considered the earliest signs of shock.

Increased respiratory rate is also a common and often unappreciated feature of sepsis. Stimulation of the medullary ventilatory center by endotoxins and other inflammatory mediators has been proposed as a cause. As tissue hypoperfusion ensues, the respiratory rate also increases in order to compensate for metabolic acidosis. The patient often feels short of breath or appears mildly anxious. Of note, tachypnea is the most predictive of the SIRS criteria of adverse outcome. This is likely because tachypnea is also an indicator of pulmonary organ dysfunction, and a feature commonly associated with pneumonia and ARDS, all of which are associated with increased mortality in sepsis.

Altered mental status is a common feature of sepsis syndromes. It is considered a sign of organ dysfunction and is associated with increased mortality. Mild disorientation or confusion is especially common in elderly individuals. Other manifestations include apprehension, anxiety, and agitation. Profound cases may involve obtundation or comatose states. The cause of these mental status abnormalities is not entirely understood, but, in addition to cerebral hypoperfusion, altered amino acid metabolism has been proposed as a cause.

The physical examination should first involve assessment of the patient's general condition, including an assessment of airway, breathing, and circulation (ABCs) and mental status. Attention should be paid to skin color and temperature. Pallor, grayish, or mottled skin are signs of poor tissue perfusion seen in septic shock. Skin is often warm in early septic shock as peripheral dilation and increased cardiac output occur (warm shock). As septic shock progresses, depletion of intravascular volume and decreased cardiac output lead to cool, clammy extremities and delayed capillary refill. Petechiae or purpura can be associated with disseminated intravascular coagulation (DIC) and are an ominous sign.

It is important in septic shock to perform a thorough physical examination in order to elucidate any potential source of infection. This is particularly important in cases where a site of infection can be removed or drained as in certain intra-abdominal infections, soft tissue abscesses and fasciitis, or perirectal abscesses. The following physical findings suggest a focal (usually bacterial) infection:

• CNS infection - Profound depression in mental status, meningismus
• Head and neck infections - Inflamed or swollen tympanic membranes, sinus tenderness, nasal congestion or exudate, pharyngeal exudate, stridor, cervical lymphadenopathy
• Chest and pulmonary infections - Localized rales or evidence of consolidation
• Cardiac infections - Any new murmur, especially in patients with a history of intravenous drug use
• Abdominal and gastrointestinal infections - Focal tenderness, guarding or rebound, rectal tenderness or swelling
• Pelvic and genitourinary infections - Costovertebral angle tenderness, pelvic tenderness, cervical motion pain, adnexal tenderness or masses, cervical discharge
• Bone and soft-tissue infections - Focal skin erythema and associated pain or tenderness, fluctuance, pain with joint range of motion, joint effusions and associated warmth/erythema
• Skin infections - Petechiae, purpura, erythema, fluctuance

Causes

Sepsis is a disease seen most frequently in elderly persons and in those with comorbid conditions that predispose to infection, such as diabetes or any immunocompromising disease. The latter are at especially high risk, including those with cancer on chemotherapeutic agents, those with end-stage renal or liver disease, those with advanced HIV, or those on steroids for any other immunocompromising agent for chronic conditions. Patients with indwelling catheters or devices are also at high risk.

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