Chapter 79: Sepsis & Septic Shock

Sepsis is one of the leading causes of morbidity and mortality in the United States. Centers for Disease Control and Prevention (CDC) estimates that more than 1.7 million adults in America develop sepsis each year. Sepsis and septic shock cause approximately 270,000 deaths annually, have fatality rates of 30% to 50% in older patients, and are estimated to cost more than 30 billion dollars each year. The incidence of infections that result in sepsis continues to rise with the increased incidence of antibiotic-resistant organisms along with the increased use of immunosuppressive drugs, intravenous and urinary catheters, and prosthetic implants.

Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. Evidence of organ dysfunction includes clinical and laboratory abnormalities of the respiratory system, coagulation, liver, cardiovascular system, nervous system, and kidneys (Table 79–1).

A subset of patients with sepsis can develop septic shock, which is defined by profound cellular abnormalities and inadequate organ perfusion. Clinically, septic shock can be identified in patients with sepsis who also have persistent hypotension (mean arterial blood pressure below 65 mm Hg) and elevated serum lactate despite adequate intravenous fluids.

Bacteremia is an associated term, defined as the presence of bacteria in the blood stream. Approximately 25% of patients with sepsis have detectable bacteremia. The remaining 75% without bacteremia have organ system infections, most often in the respiratory tract, urinary tract, gall bladder or intestine. Sepsis without bacteremia may also occur as a result of infection with viruses, fungi, or protozoa.

Sepsis results from the interaction of the infectious agent, usually bacteria, with the host’s immune, cardiovascular, neuronal, metabolic, and coagulation systems. Some degree of inflammatory response to infection is normal, but when this response is dysregulated, an excess of pro- and anti-inflammatory mediators leads to organ dysfunction.

Sepsis caused by gram-negative bacteria is mediated primarily by endotoxin, also known as lipopolysaccharide (LPS). The main effects of LPS are caused by its lipid A component. Lipid A combines with LPS-binding protein, and together are bound by Toll receptor 4 (TLR4), a pattern recognition receptor (PRRs) on the surface of macrophages and other innate immune cells, as well as B cells. When macrophage TLR4 is activated, this stimulates the production of interleukin-1 (IL-1), tumor necrosis factor (TNF), and IL-6. These cytokines cause fever, alter the endothelial cells to cause vascular leak, and recruit and activate inflammatory white blood cells. Nitric oxide is also released, causing vasodilation and hypotension, contributing to hypotension (see Chapter 58). Figure 79–1 describes the processes that occur in endotoxin-mediated septic shock. The effects of endotoxin are discussed in more detail in Chapter 7 on Bacterial Pathogenesis.

Endotoxin also activates the coagulation cascade, causing disseminated intravascular coagulation (DIC). Endotoxin initiates DIC by stimulating endothelial cells to produce tissue factor. The end result of this cascade is the formation of thrombi (composed of fibrin) in capillaries throughout the body, blocking the flow of blood, and resulting in anoxia of vital organs. Petechial hemorrhages and purpuric lesions occur when blood leaks into the tissue spaces at the site of endothelial cells damaged by anoxia (Figure 79–2).

Sepsis caused by gram-positive bacteria is not mediated by endotoxin because these bacteria do not contain LPS. Rather, there are surface components such as peptidoglycan and teichoic acid that stimulate the macrophage, through PRRs other than TLR4, to produce the inflammatory mediators mentioned above. Similarly, some fungi, viruses, and protozoa have elements that can trigger macrophages to generate the same effect.

Often sepsis is marked by an elevation in total blood leukocytes, especially neutrophils, but it can be accompanied by a reduction in the number and function of leukocytes, particularly B and T lymphocytes. This limits the adaptive host response, enhances the severity of the infection, and further augments the impact of sepsis.

A predisposition to sepsis occurs in the very young (neonatal sepsis), the very old, those with reduced host defenses, and people with chronic diseases such as diabetes, chronic hepatitis, and kidney failure.

Neonatal sepsis is the result of the infant’s immature immune system coupled with carriage of the bacteria in the female genital tract that are transmitted during the passage through the birth canal. The most common causes are Group B streptococci (Streptococcus agalactiae), Escherichia coli, and Listeria monocytogenes.

The clinical manifestations of sepsis often include fever and elevated neutrophils along with signs of organ system dysfunction, including hypoxemia, low platelets, abnormal liver function, hypotension, mental status changes, and kidney injury (see Table 79–1). In septic shock, hypotension is severe enough to require vasopressors to maintain the mean arterial pressure at 65 mm Hg. Petechial hemorrhages and purpuric rash can occur as well, which indicate activation of the coagulation cascade.

Sepsis can be caused by a variety of pathogens (Table 79–2). Bacteria cause the vast majority of cases of sepsis and septic shock. However, viruses such as Ebola virus, influenza virus, hantavirus, yellow fever virus, and dengue virus (dengue hemorrhagic fever) can also cause the clinical features of sepsis. In addition, yeasts, such as Candida albicans, and protozoa, such as Plasmodium falciparum, can also cause a sepsis syndrome.

Among the bacteria, Gram-negative rods, such as Enterobacteriaceae (e.g. E. coli, Enterobacter, Klebsiella, Serratia, and Proteus) and Pseudomonas are common causes of endotoxin-mediated sepsis. Neisseria meningitidis causes meningococcemia, a common cause of septic shock in young adults.

Gram-positive bacteria, such as Staphylococcus aureus and Enterococcus faecalis, are important causes of sepsis. Streptococcus pneumoniae is also an important cause of sepsis, especially in asplenic patients. Both S. aureus and Group A streptococci (Streptococcus pyogenes) cause toxic shock syndrome mediated by superantigens (see Chapters 7 and 58). Group B streptococci (S. agalactiae) are the most common cause of neonatal sepsis. The gram-positive rod, Listeria, also causes neonatal sepsis.

Uncommon bacteria that cause sepsis in the United Sates include Rickettsia rickettsiae (Rocky Mountain spotted fever), Salmonella typhi (typhoid fever), Francisella tularensis (tularemia), Bacillus anthracis (anthrax), and Vibrio vulnificus. Yersinia pestis causes plague that can progress to life-threatening septic shock.

To identify the microbiologic cause of sepsis, blood cultures are the mainstay of diagnosis of blood stream infections. Urinalysis and urine cultures should also be done. Other sites of infection, including skin lesions and sputum, should be cultured. Approximately 25% of septic patients will not have a causative organism identified by culture.

Sepsis is a life-threatening emergency. It is essential to administer broad-spectrum bactericidal antibiotics intravenously to cover the most likely organisms. Antibiotics should be started directly after blood cultures are drawn. The goal is to initiate intravenous antibiotics within the first hour after the diagnosis of sepsis or septic shock is made. The prevalence of antibiotic-resistant organisms should be considered when choosing the antimicrobial drug regimen.

One suggested antibiotic regimen includes vancomycin plus either a third or fourth generation cephalosporin, such as ceftazidime or cefepime, or piperacillin/tazobactam, or a carbapenem such as imipenem. An aminoglycoside or a fluoroquinolone can be added.

In addition to antimicrobial therapy, treatment of sepsis is similar to treatment of other causes of distributive hypotensive shock. Intravenous fluids, particularly crystalloid solutions, are used to raise blood volume. If fluids are ineffective, hypotension can also be treated with vasopressors, such as norepinephrine. Oxygen supplementation, assisted breathing using a ventilator, and/or dialysis for kidney failure may be necessary.

None of these measures will be successful without identifying and removing the source of the infection. In general, a foreign body (e.g. intravenous catheters) that is infected should be removed as soon as is safely possible, and any abscess should be drained and cultured.

There are vaccines against N. meningitidis, S. pneumoniae, S. typhi, influenza virus, and yellow fever virus. There is no vaccine against the enteric gram-negative rods, Pseudomonas, S. aureus, or E. faecalis.

Preventive antibiotics are given to those who develop immunosuppression and to pregnant women who test positive for group B streptococcus carriage to prevent sepsis in these highly susceptible patients. Prompt removal of unnecessary intravenous and urinary catheters is important because these provide an entry point for bacteria and fungi into the bloodstream. Appropriate hospital infection control practices play an important role in preventing health-care associated episodes of sepsis.