Course Authors
John E. Morley, M.D.
During the last three years, Dr. Morley has received grant/research support from Vivus, Merck & Co., Upjohn, B.B raun McGaw, Bayer Corp and Nestec, Ltd. He has also served on the Speakers' Bureau for LXN, Organon, Ross, Pharmacia & Upjohn, Glaxo Wellcome, Hoechst Marion Roussel, Searle, Merck & Co., Roche, Bristol-Myers Squibb, Novartis, Pratt, B. Braun McGaw, Pfizer and Parke-Davis.
This article was also published in Aging Successfully Vol. XI: 2, 2001.
This activity is made possible by an unrestricted educational grant from the Novartis Foundation for Gerontology.
Estimated course time: 1 hour(s).
Albert Einstein College of Medicine – Montefiore Medical Center designates this enduring material activity for a maximum of 1.0 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.
In support of improving patient care, this activity has been planned and implemented by Albert Einstein College of Medicine-Montefiore Medical Center and InterMDnet. Albert Einstein College of Medicine – Montefiore Medical Center is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.
Upon completion of this Cyberounds®, you should be able to:
List the signs and symptoms of sepsis
Discuss the risk factors for sepsis
Discuss the state-of-the-art management of sepsis.
Sepsis is the clinical syndrome of systemic inflammation, coagulopathy and, often, hypotension produced by the immune response of a person to infection. Over 700,000 cases of severe sepsis occur in the United States each year. Sepsis (infection) occurs in approximately one in five of all hospital admissions and can progress to severe sepsis with hypotension and poor blood flow to major organs or, eventually, septic shock with hypotension that is not responsive to fluid resuscitation and organ failure.
In 1991, the Consensus Conference of the American College of Chest Physicians and the Society of Critical Care Medicine put forward a new term, Systemic Inflammatory Response Syndrome (SIRS), to recognize that the "sepsis syndrome" could frequently occur in persons who suffered insults other than infection.
Systemic Inflammatory Response Syndrome was defined as the widespread inflammatory response that occurs following a variety of insults such as infection, trauma, pancreatitis or burns.(1) SIRS is extremely common in hospitalized patients, occurring in over half of patients in a general medical ward and up to 90% in an intensive care unit.
Between 1991 and 1997, there was a marked increase in sepsis in hospitalized older Americans based on Medicare data.(2) This increase has been most prominent in older African-American men. Sepsis is now the tenth leading cause of death among older adults in the United States. Over the last decade, there has been not only an increase in the occurrence of sepsis but also an increase in the consequent death rate. Salvie and colleagues(3) studied the factors associated with sepsis mortality in the elderly. Major predictive factors of death included age, being male, diabetes, hospitalization for cancer, disability that interferes with activities of daily living and cognitive impairment.
While death rates from severe sepsis are highly variable, the overall death rate is approximately one-third of all cases -- between 5 to 35% of young patients vs. 37 to 50% of older persons.(4) One year after an episode of severe sepsis, less than one-third of persons are still alive. Recently, it has been estimated that sepsis is responsible for $5 to $10 billion of the United States health care budget.
History of Sepsis(5)
As long ago as 2735 B.C., the Chinese Emperor Sheng Nung wrote about the use of herbal medicines to treat fever. Subsequently, numerous infections that resulted in sepsis altered the course of history -- for example, the "Black Death" of the bubonic plague epidemic in Europe, the deaths of New World natives when first exposed to Europeans and the loss of wounded war veterans in the U.S. Civil War.
The concept of anti-sepsis was first proposed by John Pringle, the Surgeon General of the British army in the 18th century. Nearly a hundred years later, Ignaz Semmelweis introduced antiseptic techniques for the care of women during the birthing process. As a result, the death rate from puerperal fever dropped sharply from 13.6% to 1.5%. In 1879, the French physician Louis Pasteur identified the streptococcus bacteria as the cause of puerperal sepsis. Thirteen years later, Richard Pfeiffer recognized that bacteria released "endotoxin" in the body of the host. The recognition by Sir Alexander Fleming that a mold could be toxic to bacteria (i.e., the discovery of penicillin) ushered in the era of antibiotics to treat bacterial infections.
Toward the end of the twentieth century, it became clear that sepsis results in the release of a host of inflammatory mediators such as tumor necrosis factor-aand interleukin-1. These mediators, in turn, stimulate the production of nitric oxide which provokes hypotension, while other mediators produce capillary injury and, eventually, organ dysfunction. Damage to the endothelium leads to activation of the coagulation cascade with the production of thrombin. This coagulopathy leads to microvascular thrombosis and multi-organ failure and consumes endogenous regulators of thrombolysis such as protein-C and antithrombin III. As a consequence, continued endothelial damage, organ ischemia and damage and, ultimately, death occur in many patients.
Figure 1. The Sepsis Cascade: An Interaction of Inflamation, Coagulation, & Impaired Fibrinolysis.
Click to see full sized image
Clinical Features
The hallmark clinical manifestations of both sepsis and SIRS are two or more of the following conditions:
- Temperature >38ºC or <36ºC
- Tachycardia >90 beats per minute
- Respiratory rate >20 per minute or a PaCO2 <32 mm Hg
- White blood cell count >12,000 mm3 or <4,000/mm3 or >10% immature (band) forms ("left shift").
The other symptoms and signs associated with sepsis include the signs of peripheral vasodilation, hypotension and altered mental status.(1) Mental status changes include lack of attention, decreased orientation, confusion, agitation, lethargy and, eventually, coma. Prior to the development of hypotension, patients with sepsis may have a high output cardiac state with a wide pulse pressure associated with a tachycardia.
Prolonged sepsis is also associated with neuromuscular weakness, the so-called critical illness polymyopathy. Severe muscle wasting (cachexia) can occur with sepsis.(6) Cytokines provoke muscle catabolism (the breakdown of myofibrillar proteins), which, in turn, releases amino acids into the circulation. Clinically, aside from muscle wasting and weakness, which slows ambulation and rehabilitation, sepsis can also cause respiratory muscle weakness, with delayed weaning from the ventilator and an increased propensity to develop pneumonia.
Gastrointestinal manifestations of sepsis include jaundice, gastrointestinal bleeding and slowed gastrointestinal motility. Decreased urine output and, eventually, severe renal failure are not rare in persons with sepsis. Both hyper- and hypoglycemia may occur, as well as lactic acidosis and electrolyte abnormalities.
The reduced levels of protein-C and antithrombin III, as well as a marked decline in platelet numbers, lead to the coagulopathy which can present with organ pain secondary to ischemia, gangrene of the digits, purpura and bleeding from multiple sites.(7)
Older persons often tend to have atypical responses to sepsis. These patients may fail to mount a fever and may even present early on with hypothermia. Thus, the classical chills and sweating of sepsis are often absent. Leukopenia is common as well. The older person may only have a left shift.
At the beginning of sepsis, older persons are much more likely to present with delirium. This delirium may take the form of lack of attention or non-responsiveness. Thus, for example, a demented patient who screams frequently may stop screaming. New onset of falls in an older person may be the only evidence of a sepsis-associated delirium. The peripheral vasodilation of sepsis can result in an older person presenting with syncope.
Older persons classically have less tissue reserve and so are more vulnerable to stressors. Thus, organ dysfunction such as renal, respiratory or cardiac failure may present earlier in the course of sepsis. Older persons are also more likely to develop septic shock and multiple organ dysfunction syndrome (MODS). In addition, older persons more commonly have genitourinary, gut or respiratory sites of infection and it is more likely, therefore, that they have sepsis caused by a gram-negative bacillus. Finally, older persons can show markedly prolonged rehabilitation times from severe sepsis. Indeed, sepsis may be the event that precipitates their entry into a nursing home.
Factors Contributing to the Development of Sepsis
The reasons for the increased occurrence of sepsis and septic shock are uncertain but the increase in the number of risk factors for sepsis may play a major role. As we all recognize, the population is aging and older persons have a variety of changes in their immune system that put them at increased risk for developing infections. This is particularly true in older persons with multiple diseases.
In addition, we know that older persons are particularly prone to develop weight loss and malnutrition, both of which can produce a further decline in their immune system and a decrease in CD4+ lymphocytes. The decline in the CD4+ to CD8+ ratio results in an inability to mount an adequate host response to infections. Unusual infections, as is seen in patients with acquired immunodeficiency syndrome (AIDS), are the direct result of the decline. Sakkinen and colleagues,(8) examining a subgroup of the Cardiovascular Health Study, all of whom were over 65 years of age, found that older women had lower protein-C levels. This would put older women at particular risk for developing severe coagulopathies during sepsis.
Diseases specifically increasing the risk of sepsis include diabetes mellitus, malignancy and AIDS. Diabetes occurs in almost one in five older persons. Half of the persons with diabetes are over 60 years. Alcoholics are also at increased risk for sepsis, as are patients who acquire a second nosocomial infection for whom there is an increased risk of death from sepsis.
Iatrogenic factors may be particularly responsible for the increase in sepsis in older persons. Urinary catheters are associated with more than one febrile episode every hundred patient days(9) and are associated with a highly significant death rate in older persons. Insertion of intravenous catheters, particularly in the jugular, leads to an increased risk of sepsis death. Because it is often difficult to maintain peripheral venous access in older persons, these patients are at increased risk of receiving central venous catheters.
With multiple diseases and atypical presentations, older persons are more likely to have invasive procedures that put them at increased risk of sepsis. They often receive antibiotics because of recurrent infections and so are more likely to develop resistant microorganisms. The use of cytotoxic and immunosuppressive agents to treat malignancies and autoimmune disorders further increases the chances of an older person developing sepsis. Infections often occur in unusual places in older persons leading to the diagnosis being missed early in the disease process. Figure 2 gives the common sites for infection in older persons.
Figure 2. Common Sites of Infection in Older Persons.
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Treatment
The primary treatment in a person with sepsis is appropriate antibiotics.(10) This requires identification of the organism as early as possible. Appropriate antibiotic therapy has been shown to halve the subsequent mortality. Anti-microbial therapy in patients with fungal septicemia also appears to reduce the mortality rate.
Dennis Sullivan at the University of Arkansas(7) has pointed out that we tend to starve older persons while they are in the hospital. Persons with sepsis should get 25 to 30 kcal/kg daily with 1.5 to 2.0 g/kg coming from protein. In general, enteral nutrition is preferred to parenteral nutrition because of its reduction in stress ulcers, costs and gut protection. It is possible that immunomodulatory formulas may be preferred over regular formulas.
In an attempt to attenuate the ongoing inflammatory cascade of sepsis, numerous agents have been tested.(11) Two meta-analyses failed to find any value in utilizing corticosteroids during sepsis and suggested they may even be harmful. There is no evidence to support other anti-inflammatory agents such as ibuprofen, pentoxifylline or prostaglandin E1. Oxygen scavengers, interferon, TNF-a; and growth hormone have not been shown to be useful in the management of sepsis. Antithrombin III, an inhibitor of a number of coagulation factors, showed promise in treating sepsis in some placebo-controlled small trials, but a large, multi-center, prospective, double-blind study failed to demonstrate a significant improvement in survival.(12)
A recent, large, double-blind randomized trial (the Protein-C Worldwide Evaluation in Severe Sepsis [PROWESS], the abstract of which may be viewed at http://www.nejm.org [March 8]), examined the effect of recombinant human activated protein-C (drotrecogin alfa) in 1690 patients.(13) This drug appears to be able to reverse the cascade of inflammation, coagulation, and fibrinolysis that occurs with sepsis. The average age of the patients was 60.5 years with approximately a quarter being over 75 years of age and 56% over 60 years of age. By 28 days, 30.8% of the placebo group died compared to 24.7% of the drotrecogin alfa group. The absolute reduction in the risk of death was 6.1%. Overall, serious adverse side effects were equal in both groups, though, as might be expected, there was an increase in bleeding episodes in the drotrecogin alfa group. Drotrecogin alfa reduced levels of interleukin-6, a marker of inflammation, and of D-dimer, a marker of coagulopathy. Outcomes were similar in persons over 60 years of age compared to those under 60 years of age.
Summary
Sepsis remains a condition with extremely high fatality rates in older persons. Early recognition of infection and treatment with empiric antibiotics remain the cornerstone of appropriate treatment. Adequate nutrition support needs to be given to all patients. A recent study utilizing activated protein-C has shown that mortality can be further decreased by using this compound in persons with severe sepsis.