Introduction

Sepsis (infection) 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 and it is now the tenth leading cause of death. Sepsis occurs in approximately one in five of all hospital admissions and can progress to severe sepsis with hypotension, then septic shock with hypotension unresponsive to fluid resuscitation and organ failure.

In 1991, a new term, Systemic Inflammatory Response Syndrome (SIRS), was put forward to recognize that the "sepsis syndrome" could frequently occur following a variety of insults such as infection, trauma, pancreatitis or burns. SIRS is extremely common in hospitalized patients, afflicting 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 American, most prominently in older African American men. Not only has there been an increase in the occurrence of sepsis but we have also seen an increase in the consequent death rate. Major predictive factors of death included age, being male, diabetes, hospitalization for cancer, disability of 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. One year after an episode of severe sepsis, less than one-third of persons are still alive.

History of Sepsis

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 cholera epidemic in Europe, the deaths of the Native Americans 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, 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-alpha and 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 damage and, ultimately, death occur in many patients.

Clinical features

The hallmark clinical manifestations of both sepsis and SIRS are two or more of the following conditions:

1. Temperature >38ºC or <36ºC
2. Tachycardia >90 beats per minute
3. Respiratory rate >20 per minute or a PaCO2 <32 mm Hg
4. 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 peripheral vasodilation, hypotension and altered mental status (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 (polymyopathy) and severe muscle wasting (cachexia). Cytokines provoke muscle catabolism (the breakdown of myofibrillar proteins), which, in turn, releases amino acids into the circulation. 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.

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

Older persons have a variety of changes in their immune system that make them at increased risk for developing infections. They 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. Similar to AIDS patients, the lowered level of CD4+ makes them particularly susceptible to unusual infections.

One researcher found that older women, moreover, have lower protein-C levels, putting them at risk for developing severe coagulopathies during sepsis.

Diabetes mellitus (which occurs in almost one in five older persons), malignancy and AIDS specifically increase the risk of sepsis. Patients who acquire a second nosocomial infection are at increased risk of death from sepsis.

Iatrogenic factors may be particularly responsible for the increase in sepsis in older persons. Urinary catheters and insertion of intravenous catheters, particularly in the jugular, lead to an increased risk of sepsis death.

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.

Treatment

The primary treatment in a person with sepsis is appropriate antibiotics. This requires identification of the organism as early as possible. Appropriate antibiotic therapy has been shown to halve the subsequent mortality.

In practice, we tend to starve older persons while they are in the hospital. Instead, persons with sepsis should get 25 to 30 kcal/kg daily with 1.5 to 2.0 g/kg coming from protein. Enteral nutrition is preferred to parenteral nutrition.

There is no evidence to support the use of anti-inflammatory agents such as ibuprofen, pentoxifylline or prostaglandin E1. Corticosteroids may even be harmful. Oxygen scavengers, interferon, TNF-alpha and growth hormone and Antithrombin II have not been shown to be useful in the management of sepsis.

A recent, large, double-blind randomized trial PROWESS examined the effect of recombinant human activated protein-C (drotrecogin alfa) in 1690 patients. This recombinant protein appears to be able to reverse, in some patients, the cascade of inflammation, coagulation and fibrinolysis that occurs with sepsis.

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