Triggering Infections

Sepsis does not arise on its own. It stems from another medical condition, such as an infection in the lungs, urinary tract, skin, abdomen (eg, appendicitis) or other part of the body. Invasive medical procedures like the insertion of a vascular catheter can introduce bacteria into the bloodstream and bring on the condition (NIGMS, 2013).

Many different types of microbes can cause sepsis, including bacteria, fungi, and viruses, but bacteria are the most common culprits. Severe cases often result from a body-wide infection that spreads through the bloodstream, but sepsis can also stem from a localized infection (NIGMS, 2013).

The causative organisms for sepsis have evolved over many years. Originally sepsis was described as a disease specifically related to Gram-negative bacteria. This is because sepsis was thought to be a response to endotoxin—a molecule felt to be relatively specific for Gram-negative bacteria. In fact, some of the original studies of sepsis showed that Gram-negative bacteria were among the most common causes of sepsis. This resulted in a number of trials that focused on Gram-negative therapies, and even highly specific therapies for endotoxin, which were felt to be potentially useful treatments for sepsis.

It is now recognized that sepsis can be caused by any bacteria, as well as from fungal and viral organisms. More recent epidemiology studies show that Gram-positive organisms superseded Gram-negatives in the early to mid-1980s as the most common cause of sepsis in the United States. According to the most recent estimates, there are approximately 200,000 cases of Gram-positive sepsis and approximately 150,000 cases of Gram-negative sepsis each year (Martin, 2012).

While bacterial causes of sepsis have increased, fungal causes of sepsis have grown at an even more rapid pace. This may represent a general increase in nosocomial (hospital-acquired) cases of sepsis, or it may reflect our effective treatment of bacterial infections, which thus allowed fungal infections to grow without competition. While there has been an overall increase in the number of fungal nosocomial infections, we have also observed shifts away from the most common Candida albicans organism to the more recalcitrant torulopsis, glabrata, and krusei subspecies (Martin, 2012).

Answer: D

The likelihood that a local infection will progress to sepsis varies according to its source and location. For example, pulmonary or abdominal infections are 8 times more likely to develop into sepsis than are urinary tract infections (Munford, 2008). The most common sites of infection that lead to sepsis are:

• Lungs
• Abdomen
• Kidney
• Bloodstream (Mayo Clinic, 2013)

Obviously, most infections do not trigger a septic reaction. Two people can have infections in the same tissues, caused by the same microbe, yet one person will develop sepsis and the other person will not. This difference indicates that other factors, beyond the type of tissue and the kind of microbe, are involved in the development of sepsis.

What are these other causative factors?

One clue is the source of the bacteria that most commonly cause sepsis. Bacteria that cause classic infectious diseases, such as Neisseria meningitides (meningitis) or Streptococcus pyogenes (strep throat), lead to sepsis less frequently than do bacteria that are considered commensal (normal flora), such as Staphylococcus aureus or the enterococci. Commensal bacteria are notorious for causing systemic disease in people who have weakened antimicrobial defenses—AIDS patients, immunosuppressed patients, or patients with damaged epithelia or endothelia. The fact that normal flora bacteria are also the most common causes of sepsis suggests that sepsis is most readily triggered in people who have weakened antimicrobial defenses. Whereas the normal flora are usually a help to our body’s digestive system, the bacteria can become deadly when the body isn’t able to keep the normal flora controlled.

To develop sepsis, a microbial infection is necessary but not sufficient: it appears that a patient also needs a pre-existing susceptibility. Support for this idea can be seen in large surveys of ICU patients. These surveys found that “approximately 70% to 80% of the cases of severe sepsis in adults occurred in individuals who were already hospitalized for other reasons” (Munford & Suffredini, 2009).

Answer: B

Spread of the Inflammatory Reaction

Normally, an inflammatory reaction remains localized, but a septic reaction travels via the vascular system to spread inflammation throughout the body. In sepsis, pro-inflammatory molecules can be found in high concentrations throughout the blood stream (Munford, 2008).

The body’s immune system reacts to an invading organism in several ways. The initial and appropriate response to an infection is called the innate immune response. It is activated immediately, is not specific to any antigen, and reacts similarly to a variety of organisms. The adaptive immune response requires some time to react to an infection and it attacks only the pathogen that induced the response (Schulte et al., 2013). The first innate immune response in the body is like a general sending out the quick masses of army men to fight an invader, and the adaptive immune response takes the general time to develop a more specific strategy such as sending out specific snipers to fight the now-identified invader.

Your immune system is absolutely amazing! During the innate immune response, blood vessels dilate in the infected tissue to increase circulation, which allows white blood cells (WBCs) to arrive at the scene of attack. The activation of this first line of cellular defense results in an excessive release of cytokines and other inflammatory regulators, which causes massive vasodilation and hypotension (Schulte et al., 2013). Increased tissue permeability also allows the helpful WBCs and immune cells to enter tissue and identify the invading pathogens. Sepsis has been shown to develop when the innate immune response becomes amplified and dysfunctional, leading to an imbalance between pro-inflammatory and anti-inflammatory responses. It is the innate immune response that plays a major role in sepsis pathophysiology.

Cytokines regulate a variety of inflammatory responses, including the migration of immune cells to the infection, which is a crucial step in containing a localized infection and preventing it from becoming systemic. In the army analogy, the cytokines are like special forces, which go into the invading camp and identify the enemy. However, an uncontrolled cytokine release may lead to vasodilation, increased capillary permeability, and breakdown of normal epithelial cell walls that ideally serve as protective barriers. The resulting leakage syndrome can cause hypotension, hemoconcentration, macromolecular extravasation, and edema, which are frequent findings in septic patients.

Whereas normally the epithelium is a protective barrier, if injured it allows pathogens and their products to further invade the host, to disturb regulatory mechanisms, and, ultimately, to cause organ dysfunctions. Evidence has indicated that immune and inflammatory responses are tightly interwoven with physiologic processes within the human host (eg, coagulation, metabolism, neuroendocrine activation). An inflammation-induced disruption of the coagulation system, for instance, significantly worsens the effects of sepsis and can result in lethal disseminated intravascular coagulation (DIC) (Schulte et al., 2013).

Traditionally, sepsis was viewed as an excessive systemic pro-inflammatory reaction to an infection. More recently it has been proposed that the early phase of hyper-inflammation is followed or overlapped by a prolonged state of immunosuppression, referred to as sepsis-induced immunoparalysis. This immunoparalytic state is characterized by impaired innate and adaptive immune responses and may play a central role in tissue damage, multiple organ failure, and death induced by sepsis (Schulte et al., 2013). What causes the immunosuppression is still being researched and may include nutritional status, toxins in the body, and genetics.

Pro-Inflammatory Molecules in the Circulation

Three components of the body’s response to infection are the cytokines, activated complement, and activated coagulation factors. All of these components are inherently part of the body’s nature defense mechanism and, when functioning properly, protect the body beautifully from foreign pathogens. You are quite a miracle when all systems work correctly. Given the fact that there are 10 times more microorganisms on your body than cells in your body, it is amazing we all aren’t sick (Wenner, 2007). When the components and process becomes dysfunctional, sepsis can occur.

Cytokines

One aspect of the body’s normal response to infection, and key to the propagation of a septic reaction, are the cytokines. As in the normal response to an infection, the septic reaction begins with inflammatory cells, mainly macrophages in the local tissues and neutrophils in the bloodstream. When the macrophages recognize invading microbes, they react by producing pro-inflammatory molecules called cytokines. Think of them as the alarm system for the body to announce when there is an invader.

The cytokines include interleukins, interferons, tumor necrosis factor, transforming growth factor, and other lymphokines, chemokines, and growth factors. (A cytokine’s name often reflects its particular functions.) In most cases, cytokines act locally, either on the producing cell itself or on neighboring cells. However, when manufactured in large quantities, as in sepsis, cytokines are swept into the circulation and cause trouble in distant parts of the body by sending out the alarm for war against invaders that may not be in those tissues (Abbas et al., 2011).

Answer: A

Near the infection, neighboring endothelial cells respond to the sudden surge of cytokines by producing adherence molecules. Meanwhile, neutrophils are being attracted from the bloodstream. The neutrophils stick to the activated endothelial cells and then begin to produce even more pro-inflammatory cytokines. These initial processes take place in all types of infections from small facial blemishes those that become septic.

Activated Complement

A second aspect of the body’s normal response to infection is the triggering of the complement system. The complement system is a sequential set (a cascade) of protein activations that helps to immobilize and break down pathogens. When activated, the complement proteins identify and label foreign molecules. Some complement components lyse membranes of foreign cells. In addition, activated complement proteins multiply the effects of the local immune reactions by putting yet more cytokines into play (Neviere, 2013a). Your body is quite amazing in that this is happening automatically while you are reading this course. Your body fights pathogens all day, every day, and mostly you will never be aware of it because this system works so brilliantly.

Activated Coagulation Factors

A third hallmark of the normal inflammatory response to an infection is the local activation of the blood coagulation system. This leads to the deposit of fibrin by the coagulation cascade into a sticky mesh that helps to fence in and restrict the spread of microbes from the vicinity.

A consequence of the coagulation reactions is the activation of bradykinin. Bradykinin is a circulating peptide that dilates blood vessels and makes capillaries leaky. An increase in the local concentration of bradykinin adds to the vasodilation and capillary leakage that is being caused by histamine and prostaglandins. Histamine is released by mast cells in response to the activation of complement proteins, and prostaglandins are released by activated neutrophils, mast cells, and endothelial cells. As a result, local tissues begin to swell with a protein-rich edema fluid (Neviere, 2013a).

Answer: D

Weakened Inflammation Control Mechanisms

Sepsis begins as the typical inflammatory response to an infection. Like any inflammation, it starts with the local mobilization of macrophages and neutrophils and the activation of the complement and coagulation systems. An array of pro-inflammatory cytokines is produced, and there is local edema.

At this point, however, the septic reaction diverges from the body’s usual reaction, because in sepsis the final half of the typical inflammatory response—the winding down and ending—never happens. According to Neviere (2013a):

Sepsis has been referred to as a process of malignant intravascular inflammation. It is considered malignant because it is uncontrolled, unregulated, and self-sustaining. It is considered intravascular because it represents the bloodborne spread of what is usually a cell-to-cell interaction in the interstitial space. It is considered inflammatory because all characteristics of the septic response are exaggerations of the normal inflammatory response.

A Typical Inflammatory Reaction

. . . the body’s systemic responses to injury and infection normally prevent inflammation within organs distant from a site of infection.

Munford, 2008

When working properly, the innate immune mechanisms are rapidly mobilized into the region of a new infection. At the height of the response, invading microbes are overwhelmed, deactivated, and destroyed. Next, local debris is removed; the pro-inflammatory molecules, the activated complement, and the activated clotting factors are neutralized; and the production of new pro-inflammatory molecules stops. In other words, a typical inflammatory response has a rising phase leading to peak invader-destroying activity and then the activity automatically tapers off and ends.

The inflammatory response must be terminated because it is imprecise and it causes collateral damage by injuring or destroying nearby tissues as well as the invading microbes. Therefore, in a typical inflammatory reaction, when the local attack is over, the activated cells and molecules are neutralized by a wave of deactivation molecules.

Deactivators are produced as normal components of the cleanup operation. Within cells, suppressor factors decrease the manufacture and secretion of pro-inflammatory cytokines. At the same time, outside the cells, a newly secreted class of anti-inflammatory cytokines opposes the activated pro-inflammatory molecules. In addition, specific restorative compounds (lipoxins, resolvins, protectins) are secreted to stabilize and encourage the repair of local cells.

The typical response to an infection includes other protective mechanisms. To shield distant tissues from the unavoidable destruction caused by immune reactions, the local pro-inflammatory response sets off counterbalancing systemic anti-inflammatory responses. For example, local infections lead to an increased systemic circulation of cortisol, epinephrine, prostaglandins, and many proteases, all of which inhibit immune reactions throughout the body.

An Atypical Inflammatory Reaction

In a typical inflammatory reaction, the local pro-inflammatory processes are balanced by systemic anti-inflammatory processes and are automatically terminated within a short time. In sepsis, however, cytokine production continues unending and the circulatory spread of the cytokines then causes increased cytokine production at distant sites.

Sepsis is an atypical inflammatory reaction in which the pro- and anti-inflammatory balance is off-balance, with the pro-inflammatory processes dominating.

Answer: C

A well-studied example is the amount of protein C in the blood. One of the anticoagulation pathways that normally keep the coagulation system under control depends on the availability of sufficient activated protein C. A characteristic of patients with sepsis is that they have an unusually low level of activated protein C in their circulation. This deficit allows the coagulation system to deposit fibrin, making it more likely that small clots will form throughout the vascular system (Shapiro et al., 2010).

Answer: B

If unopposed by protein C-dependent blockades, the continuous stimulation of the coagulation system will sometimes lead to DIC, with eventual clot formation, impaired tissue perfusion, and thrombosis of small vessels. These events intensify the inflammatory response and a vicious cycle occurs (Jui, 2010).

Many checks and balances keep a typical inflammatory response local. In a patient who develops sepsis, some of these restraints have been weakened. This allows a wave of destructive inflammation to wash through the vasculature of the whole body. Whether an infection turns septic is determined more by the body’s ability to control inflammatory reactions than by the particular organism causing the infection (Neviere, 2013a).

Inflammatory Effects of Particular Molecules

In certain cases of sepsis, there is an additional force contributing to the system-wide spread of inflammation. Molecules produced by some microbes accelerate the septic reaction, making it especially rapid and severe (Neviere, 2013a). As in any war, the enemy also has strategies, and in the case of human biologic warfare within our bodies, bacteria produce chemicals that can enhance our release of cytokines. Generally cytokines help to notify that an enemy (pathogen) has entered our body; however, when they are released in larger quantities they become destructive and create an over-reactive response. It’s a clever strategy of the enemy to scatter our own soldiers, creating chaos within our ranks.

Classic examples are the bacterial toxins:

• Endotoxin is a lipopolysaccharide in the cell wall of Gram-negative bacteria. When it gets into the circulation, endotoxin strongly activates the coagulation and complement systems throughout the body.
• Exotoxins are another class of sepsis-worsening molecules that are produced by Gram-positive bacteria. Exotoxins are superantigens, meaning that they bypass the standard immune activation process and directly trigger host cells to pour out cytokines. This happens in toxic shock syndrome, a form of septic shock in which staphylococcal exotoxins have gotten into the patient’s circulation and triggered a rapidly progressing and debilitating sepsis.

Effects of the Spreading Inflammatory Reaction

The effects of spreading inflammatory reaction include endothelial damage, organ damage, adult respiratory distress syndrome (ARDS), progression to shock, and progression to death.

Endothelial Damage

The endothelium is involved in the control of vascular tone, platelet reactivity, coagulation, and permeability. The endothelial cells that line blood vessels, called vascular endothelial cells, are the gatekeepers between the bloodstream and the body’s tissues. A healthy vascular endothelium protects against excessive/abnormal inflammation and coagulation. The transition from a normal to a dysfunctional endothelium is associated with abnormal vasomotor activity, the development of a pro-coagulant surface, and an acceleration of the inflammation process (Bacon et al., 2011). An early indicator of sepsis is damage to these vascular endothelial cells and can manifest in hypotension.

A normal inflammatory reaction activates local endothelial cells but it also damages those same cells. Sepsis multiplies this effect by activating and damaging endothelial cells in patches throughout the entire vascular system. In sepsis there are many places in the body where the barrier between the bloodstream and the surrounding tissues has become leaky and crowded with immune cells, which is what creates redness and inflammation as signs of infection (Ely & Goyette, 2005).

Answer: A

Organ Damage

Sepsis can evolve to multiple organ dysfunction syndrome (MODS), which has a mortality rate of between 30% and 50% (Nesseler, 2012). Damage to the vascular endothelium causes edema and the collection of neutrophils and macrophages. In damaged regions, gas exchange is reduced, nutrients cannot diffuse into the tissues, and waste products cannot diffuse out. An organ with significant damage to its vascular endothelium ends up poorly perfused and ischemic. Such an organ will function poorly (organ dysfunction) or it will fail altogether. As sepsis continues, it causes increasing organ dysfunction and then organ failure, and the risk of the patient dying doubles for each organ that fails (Shapiro et al., 2010).

Lungs

The lungs are usually an early casualty in sepsis, regardless of the location of the initial infection. The surface area of the vascular endothelium of the lungs is large, and when a septic reaction begins disrupting endothelial areas in the body the lungs are likely to suffer significant damage. The surface area of one lung has been said to be the size of a tennis court! This can help you visualize the potential surface area for gas exchange but also potential tissue damage.

Regions of the lung with damaged endothelia become filled with neutrophils and macrophages, as if the dead soldiers of a lost battle spread across a battlefield. Interstitial spaces develop edema, fibrin is deposited, and surfactant is reduced. These regions of the lung become heavy and poorly compliant and local gas exchange is minimal.

To make matters worse, the phenomenon of hypoxic pulmonary vasoconstriction (HPV) is damaged in sepsis. As a protective mechanisms, your amazing lungs have the ability to close off circulation to any damaged areas to conserve energy. HPV is a protective mechanism that normally redirects arterial blood away from any nonfunctioning parts of the lung to better ventilated areas (Wang et al., 2012). In sepsis, however, circulating inflammatory molecules reduce the ability of lung arterioles to constrict. Without HPV, blood will continue to flow through useless regions of the lung, and the body’s growing systemic hypoxemia worsens (Neviere, 2013a).

Increasing lung dysfunction eventually leads to lung failure. In sepsis, lung failure takes the form of acute respiratory distress syndrome, or ARDS.

Answer: B

ARDS comes on quickly; it can appear in minutes to hours after the onset of sepsis. The condition presents as the sudden appearance of severe hypoxemia. The lungs become fluid-filled and poorly compliant, making breathing more difficult. A chest x-ray will show new bilateral diffuse or pulmonary infiltrates, and mechanical ventilation is usually required (Jui, 2010).

Sepsis is the most frequent cause of ARDS, and ARDS develops in approximately half of all patients with severe sepsis or septic shock. On average, ARDS has a mortality rate of 30% to 40%, but in sepsis, ARDS has a mortality rate >50%. The most frequent etiology is pneumonia, followed by nonpulmonary infections.

There is no specific preventive treatment against the development of ARDS in patients with sepsis. Novel therapies are being studied, but no promising results have been reported. It seems that early detection of patients with sepsis who are at risk of developing ARDS is one way to achieve better results in the earliest phase. Indeed, one of the most important preventive strategies is to ensure adequate management of sepsis, including source control and early appropriate antibiotic therapy (de Haro, 2013).

Heart

In a patient without pre-existing cardiac problems, the heart can generally endure a bout of sepsis. Sepsis causes leaky capillaries, which reduces blood volume and lowers blood pressure. At first, the vascular system responds with arterial constriction and increased vascular tone. This helps the heart to maintain a normal cardiac output.

As the sepsis continues however, the heart muscle begins to weaken due to the depressant effect of some of the circulating inflammatory molecules; however, the weakened ventricles also stretch, so the dilated ventricles pump extra blood with each stroke. The additional stroke volume partly compensates for the heart’s decreased pumping power. In this way, the cardiac output (blood volume pumped per minute) can remain fairly constant or even increase during a bout of sepsis. In a patient with existing cardiac problems, however, the heart is not as able to endure this stress, often causing complete heart failure.

Kidneys

Like the lung, kidney function is entirely dependent on maintaining a significant area of intact vascular endothelium. When the septic reaction invades the kidneys, neutrophils and macrophages begin to fill the interstitial tissue and the endothelial cells of the blood vessels are activated and damaged. At the same time, the kidneys, like all body tissues, become underperfused and hypoxic. At first, kidney dysfunction appears as a reduced glomerular filtration rate and an increase in serum creatinine levels. If the sepsis continues, acute tubular necrosis develops, which can eventually lead to acute renal failure (Neviere, 2013a).

Gastrointestinal Tract

The spreading hypoperfusion of sepsis limits the oxygen supply to the intestines. Without oxygen, anaerobic metabolism is activated releasing ketones and lactate, which causes a drop in pH inside the gut.

Hypoxia and acidosis stress the epithelium that lines the gastrointestinal tract, and its natural barrier functions (including protection against gut microbes) are weakened. Bacteria and toxic molecules from the gut lumen slip through the gut wall and into the bloodstream and the lymphatics spreading throughout the rest of the body. This is why the normal flora, which once was helpful to the body, can become the enemy.

Sepsis typically causes small painless erosions in the mucosa (especially in the upper GI tract), resulting in a continual seepage of blood. In severe sepsis or septic shock, the hypoperfusion can also immobilize the intestines, which then develop paralytic ileus (Neviere, 2013a).

Answer: C

Liver

One of the main functions of the liver is clearance of infectious agents and their products, but sepsis can induce liver damage. Just as sepsis destroys the endothelial cells of all organs, sepsis damages hepatocytes and the hypotension through the body can disrupt blood flow to the liver itself, creating hypoxia and cell death. The sepsis-induced liver dysfunction leads to a spillover of bacteria, bacterial toxins, and debris into the circulation. Elevated liver enzymes and coagulation defects may occur. A decreased ability to excrete toxins such as ammonia can lead to encephalopathy (Nesseler et al., 2012).

Nervous System

In sepsis with so many chemicals and molecules of inflammation in the bloodstream, the brain can become toxic. Sepsis often causes acute brain dysfunction, characterized by fluctuating mental status changes, inattention, and disorganized thinking. The effects on the brain are caused by both inflammatory and non-inflammatory processes, which may induce significant alterations in vulnerable areas of the brain (Sonneville, 2013). The problems begin when circulating inflammatory molecules disrupt the endothelium of the blood vessels along the blood–brain barrier (BBB). The leaky BBB lets inflammatory molecules, along with infiltrating white cells, into the neural tissue. Subsequently, edema and collections of cells around arterioles hinder the entry of oxygen and nutrients and the exit of metabolic wastes. In this situation, neurons shut down and cerebral functions slow.

Brain dysfunction during sepsis is frequently complicated with other factors from previous conditions including withdrawal syndrome, drug overdoses, and severe metabolic disturbances. Currently, the treatment of sepsis-associated encephalopathy consists mainly of general management of sepsis and prevention of aggravating factors, including metabolic disturbances, drug overdoses, anticholinergic medications, withdrawal syndromes, and Wernicke’s encephalopathy caused by thiamine deficiency (Sonneville et al., 2013).

Among the other neural problems, septic patients can develop a long-lasting peripheral neuropathy that is similar to the neuropathy seen in other critical illnesses (Ely & Goyette, 2005).

Progression to Shock

Severe sepsis occurs when organ dysfunction progresses to organ failure. If arteries fail to constrict, septic shock occurs. In septic shock, episodes of hypotension cannot be reversed by giving more fluids.

Severe sepsis often progresses to shock. Of every 4 patients in the emergency department with sepsis, 1 patient will develop shock within 72 hours, even after having received appropriate and timely antibiotic therapy (Glickman et al., 2010).

In septic shock, blood vessels can no longer constrict sufficiently to maintain an adequate blood pressure. Three processes contribute to the unresponsiveness of the arterial wall muscles in septic shock which cause hypotension:

• High levels of lactic acid can cause arterial muscles to be unable to respond when stimulated.
• Sepsis suppresses the release of vasopressin (ADH), a pituitary hormone that, among other functions, maintains arterial constriction.
• Sepsis causes endothelial cells to produce excess nitric oxide, which is a vasodilator. (Shapiro et al., 2010)

Progression to Death

The best available information suggests that death in sepsis most often results from the irreversible failure of a number of organ systems rather than from the failure of any one particular organ or system. However, in those cases where death can be attributed to the failure of a single system, it is usually the cardiovascular, respiratory, or central nervous system (Vincent et al., 2011).

Answer: B