K. Randall Young, Jr., MD
Professor of Medicine
Department of Medicine, Division of Pulmonary/Allergy/Critical Care
The University of Alabama at Birmingham
Birmingham, Alabama

In accordance with the Accreditation Council for Continuing Medical Education Standards for Commercial Support, Dr. Young has no commercial affiliations to disclose.

The University of Alabama School of Medicine is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians.

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Severe sepsis is the leading cause of death in noncoronary intensive care unit (ICU) patients and the 10th cause of death overall in the United States. The complex condition afflicts 750,000 people annually and claims 500 lives every day, with case mortality rates of 20% to 50%.

Incidence is highest among elderly Americans. In spite of advances in understanding the pathogenesis of sepsis and improvements in therapeutics, the frequency of severe sepsis is projected to increase by 1.5% per annum as the US population ages. Costs for each sepsis case average $21,000, with an annual total cost of nearly $17 billion (Crit Care Med. 2001;29[7]:1472-1474).

In 1992, the American College of Chest Physicians and Society of Critical Care Medicine defined sepsis as “a progressive injurious process [that] includes sepsis-associated organ dysfunction,” and introduced the term systemic inflammatory response syndrome (SIRS) (Crit Care Med. 1992;20:864-874). Sepsis is infection with >2 SIRS criteria, including changes in heart rate, respiration, thermoregulation, and leukocyte count — common signs of other critical illnesses.

Updated Guidelines

In 2003, critical care and infectious diseases experts from 11 international organizations undertook a comprehensive literature review, including assessment of adult and pediatric management. Under the auspices of the Surviving Sepsis Campaign — a worldwide effort to decrease relative mortality and systematically implement therapies known to improve outcomes — the consensus group published new guidelines in 2004 for management of severe sepsis and septic shock. The group defined severe sepsis as infection-induced organ dysfunction or hypoperfusion abnormalities and septic shock as severe sepsis with hypotension refractory to fluid resuscitation (Crit Care Med. 2004;32[3]:858-873).

“A variety of noninfectious insults, such as burns, trauma, major surgery, or multiple blood transfusions, also can provoke an inflammatory reaction with release of potent circulating mediators that combine to alter the body’s physiology. The result is often devastating,” says K. Randall Young, Jr, MD, director of UAB’s Division of Pulmonary, Allergy, and Critical Care Medicine. Common sites of infection in hospitalized patients include intravenous lines, surgical drains and wounds, and decubitis ulcers. Osteomyelitis may accompany sepsis in children. Also at high risk are patients with compromised vascular flow, including people with diabetes, and individuals who are immunocompromised as a result of organ transplantation, cancer, AIDS, or other disorders. “ With such a heterogeneous patient population, unpredictable disease progression, and unclear etiology and pathogenesis, severe sepsis is a complex clinical syndrome,” Young says.

Although sepsis is often confirmed by positive blood culture, cultures may be negative in individuals receiving antibiotics. Altered mental status and hyperventilation are often the earliest signs of sepsis. In severe sepsis, organ dysfunction can manifest in the cardiovascular, renal, respiratory, hepatic, circulatory, and central nervous system, with unexplained metabolic acidosis.

Subtle changes in mental status, minor increases or decreases in white cell count or neutrophils, and elevated blood glucose levels are early manifestations of sepsis. “It is critical to recognize sepsis early to identify and control infection, initiate aggressive resuscitation, and deal with circulating mediators, such as tumor necrosis factor-a, interleukin-1 (IL-1), IL-6, and IL-8 receptor antagonists,” says Young. New treatment approaches require a thorough understanding by physician and bedside personnel of common infectious and noninfectious causes of fever in at-risk patients, including the elderly and patients with uremia, who do not always exhibit febrile symptoms (N Engl J Med. 2003;348:138-150).

Management strategies for patients with sepsis and lung injury include early and appropriate use of antimicrobials, a cornerstone of therapy; fluid resuscitation for hemodynamic optimization; low-volume ventilation; steroid replacement; intensive glucose control; vasoconstrictors; and in the event of organ dysfunction following antibiotics and hemodynamic resuscitation, recombinant human activated protein C (Xigris). Corticosteroids are administered when septic shock occurs with relative adrenal insufficiency.

Aggressive resuscitation strategies to stabilize hemodynamics and address infection reduce mortality by 16%, with recombinant human activated protein C demonstrating a 6% absolute survival benefit. Steroid supplementation, when needed, produces a 10% survival benefit (Acad Emerg Med. 2005;12[4]352-359).

Sepsis protocols help ensure simultaneous and immediate coverage of all bases as hospital standard of care. “We have learned you cannot delay, testing one antibiotic and then another. There is a limited window early in the care of sepsis patients when you must have the right antibiotic on board, even before the responsible organism is identified,” Young says.

“Ultimately, early sepsis recognition occurs at the bedside by those caring for the patient,” Young says, emphasizing the importance of a UAB team approach that focuses on early recognition and aggressive intervention in the care of at-risk patients. UAB educates nurses and other personnel in high-risk environments, such as the ICU and Emergency Department, about early signs of sepsis. Nursing protocols and decision analysis are based on tracking vital signs.

“More effective electronic capture of vital signs will enable us to calculate algorithms based on that medical information,” he says. “This will allow us to define at-risk patient groups who need careful observation and rapid intervention. Data confirm our best chance for successful treatment is intervening very early.”

New therapies have proven effective for the subset of patients with severe sepsis. UAB participated in the landmark 2001 multicenter trial, Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis (PROWESS), of drotrecogin alfa (activated) or recombinant human activated protein C, which led to approval by the Food and Drug Administration for treatment of severe sepsis in adult patients with a high risk of death. Because PROWESS also found an increased risk of bleeding with activated protein C, there remains some debate about appropriate use of this agent and its potential adverse side (N Engl J Med. 2001;344:699-709). Therefore, the drug is often restricted to seriously ill patients meeting Acute Physiology and Chronic Health Evaluation (APACHE II) scoring system criteria for sepsis (N Engl J Med. 2003;348:138-150).

A recent trial led by Edward Abraham, MD, chair of the UAB Department of Medicine, and his former University of Colorado Health Sciences Center colleagues also suggests that human activated protein C is not effective in patients at low risk for death (N Engl J Med. 2005;353:1332-1341).

“Investigators and clinicians have made substantial headway devising and implementing early and aggressive protocol-driven therapies for sepsis,” says Young. “There is progress to be made in early recognition of subtle signs and symptoms. Although we are beginning to decrease mortality, the incidence of sepsis is increasing. As our population becomes more susceptible with age, we are in a race against the clock.”

Sepsis with signs of organ dysfunction in one or more systems:
1. Cardiovascular
2. Renal
3. Respiratory
4. Hepatic
5. Central nervous system
6. Hemostasis
7. Unexplained metabolic acidosis

Early Sepsis Recognition
1. Educational intervention in high-risk environments
2. Nursing protocols
3. Decision analysis systems based on tracking vital signs

Standard Of Care For Severe Sepsis
1. Initial resuscitation
2. Intravenous antibiotic therapy
3. Source control
4. Fluid resuscitation
5. Vasopressor therapy
6. Inotropic therapy
7. Drotrecogin alfa (activated) when indicated
8. Mechanical ventilation
9. Adrenal steroid replacement therapy as needed
10. Sedation/analgesia
11. Intensive glucose control
12. Renal replacement
13. Adequate nutrition
14. Hematological support
15. Stress ulcer prophylaxis

Source: Crit Care Med. 2004;32(3)858-873

For more information:

Dr. Randall Young
1-800-UAB-MIST
mist@uabmc.edu

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