Pathophysiology Of Sepsis Essay

Pathophysiology Of Sepsis Essay

Sepsis is one of the major causes of morbidity and mortality, specifically in the Intensive Care Units (ICU) of hospitals. Every year, more than 750,000 patients die from complications of sepsis (Angus 2001). These statistics translate into a mortality rate of between 30% and 60% of patient diagnosed with sepsis (Angus 2001). Pathophysiology Of Sepsis Essay.It is expected that these numbers will continue to rise there are serious characteristics of our population that are on the rise that put patients at increased risk for sepsis and death, including an aging population, increased patients with co-morbidities, increased bacterial resistance and opportunistic infections, increased use of invasive devices for monitoring and therapy, and the increased use of immunosuppressive medications (Mayo Clinic). Pathophysiology Of Sepsis Essay.

Pathophysiology on the tissue level with the presence of biochemical agents

Sepsis begins with the body’s inflammatory process, in which the body recognizes there has been a breach in its immune defenses and an infection is starting somewhere throughout the body. When the microorganisms that are causing the infection enter the bloodstream, the patient becomes septic (Ignatavicius 2012). With the increasing number of infiltrates, the body initiates the inflammatory response, systemic inflammatory response syndrome (SIRS). During this response, the body’s chemical mediators (interleukins, chemokines, tumor necrosis factor receptors) develop a system-wide response to the infection. However, the inflammatory mediators have an uncontrolled response leading to compensatory anti-inflammatory response syndrome (CARS). The body’s response leads to excessive hormonal, tissue, and vascular changes and oxidative stress that further impairs oxygenation and perfusion to the body’s tissues. Pathophysiology Of Sepsis Essay.The patient also experiences vasodilatation and blood pooling, causing coagulopathies. When SIRS and CARS develop, multiple organ dysfunction syndrome (MODS) occurs and death results (Ignatavicius 2012).


Signs and Symptoms

During sepsis, the body’s tissues are reacting to the infection, to prevent its spread from the blood into the tissue. These widespread changes lead to various symptoms, including fever (core body temperature above 38.3 degrees Celsius) or hypothermia (core body temperature below 36 degrees Celsius), a heart rate above 90 beats per minute, a respiratory rate above 20 breaths per minute, an arterial blood gas level of carbon dioxide less than 32, and a white blood cell count either above 12,000/mm3 or below 4,000/mm3 (May Clinic). Pathophysiology Of Sepsis Essay. As the symptoms increase and the body’s tissues react, systemic involvement can include hypotension, pulmonary edema, hypoxemia, acute respiratory distress syndrome (ARDS), disseminated intravascular coagulation (DIC), coagulopathy, and deep vein thrombosis (DVT) (McCance and Huether 2014).

Diagnosis and Treatment

Sepsis can be diagnosed through multiple laboratory tests, including a complete blood count, coagulation profile, electrolyte levels, creatinine and BUN levels, urinalysis and culture, blood culture and blood stain, culture of the primary infection site, and an MRI to localize the infectious etiology (MedlinePlus). It is very important to monitor the patient for early signs and symptoms of sepsis, as an earlier prognosis can lead to earlier treatments and a better outcome. Treatment therapies include antibiotics, fluid therapy, vasopressors, and corticosteroids (McCance and Huether 2014). Antibiotics work to destroy the pathogenic organisms, fluid therapy decreases the risk of hypovolemia and hypotension, vasopressors work when fluid therapy does not, and corticosteroids work to decrease the inflammatory process. If untreated, sepsis develops into severe sepsis, then into septic shock, which will most likely result in death of the patient (McCance and Huether 2014). Pathophysiology Of Sepsis Essay.


Angus DC, et al., Epidemiology of severe sepsis in the United States: Analysis of incidence,
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Donna D. Ignatavicius MS RN ANEF. (2012) Medical-Surgical Nursing: Patient-Centered
Collaborative Care, Single Volume, 7e (Ignatavicius, Medical-Surgical Nursing, Single Vol). 7 Edition. Saunders. p. 820.
McCance, K.L., Huether, S.E. (2014) Pathophysiology: The Biologic Basis for Disease in Adults
and Children, 7th edn., St. Louis, Missouri: Elsevier.
Sepsis – Mayo Clinic . 2014. Sepsis Causes – Diseases and Conditions – Mayo Clinic . [ONLINE]
Available at: [Accessed 02 March 2015].
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[ONLINE] Available at: [Accessed 02 March 2015].

Sepsis has become a major health economic issue, with more patients dying in hospitals due to sepsis related complications compared to breast and colorectal cancer together. Despite extensive research in order to improve outcome in sepsis over the last few decades, results of large multicenter studies were by-and-large very disappointing. This fiasco can be explained by several factors, but one of the most important reasons is the uncertain definition of sepsis resulting in very heterogeneous patient populations, and the lack of understanding of pathophysiology, which is mainly based on the imbalance in the host-immune response. However, this heroic research work has not been in vain. Putting the results of positive and negative studies into context, we can now approach sepsis in a different concept, which may lead us to new perspectives in diagnostics and treatment. While decision making based on conventional sepsis definitions can inevitably lead to false judgment due to the heterogeneity of patients, new concepts based on currently gained knowledge in immunology may help to tailor assessment and treatment of these patients to their actual needs. Summarizing where we stand at present and what the future may hold are the purpose of this review. Pathophysiology Of Sepsis Essay.

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1. Introduction

One of the most challenging tasks in critical care medicine is the treatment of serious infection related multiple organ dysfunction, termed in general as sepsis, severe sepsis, and septic shock. However, sepsis means a very heterogeneous patient population, which varies in etiology and severity; therefore, universally applicable diagnostic criteria and treatment algorhythms are difficult to be defined. This heterogeneity proved to be one of the most difficult hurdles that most prospective randomized trials could not concur; hence, they failed to show either clear survival benefit or positive results of single center studies that were later contradicted by large multicenter trials [1]. Nevertheless, sepsis has become a very important health economic issue all around the world.

Furthermore, treating sepsis is a multidisciplinary task. Early recognition and commencing initial steps of resuscitation are inevitable to give the best possible chance for survival, which has to be started on the primary care level: outside the hospital, in the emergency department or on the wards. In the absence of adequate initial management, providing even the highest level of intensive care would be in vain.

Although the results of prospective randomized clinical trials may be disappointing as far as survival is concerned, it is beyond doubt that we have learned a lot about the pathophysiology of sepsis during performing these studies over the last few decades. Understanding the immunological background of the clinical picture is of utmost importance, which enables the clinician to interpret results of diagnostic tests and rationalize treatment modalities in the most appropriate way.Pathophysiology Of Sepsis Essay.  To highlight a few of the current novelties in sepsis pathophysiology and potential new perspectives is the purpose of this review.

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2. Sepsis Is Not a “Definitive” Disease

In medical school we were brought up in the world of “definitive diagnoses.” This means that patients come in with a certain complaint, the physician after taking medical history, performing physical examination and diagnostic tests, defines the diagnosis and treat the patient accordingly. In the case of a well-defined disease more-or-less the same or similar diagnostic tests and therapeutic interventions are performed all around the world (such as stroke and myocardial infarction). This holds true for most diseases in classical medicine and surgery. However, defining sepsis is not that simple. The term we call “sepsis syndrome” was conceived in a hotel room in Las Vegas in 1980, during the protocol writing of one of the first prospective randomized trials in sepsis, performed by a group of scientists led by the late Roger Bone [2, 3]. Based on the inclusion criteria of this study a statement paper was later published by the same authors titled “Sepsis Syndrome: A Valid Clinical Entity” [3]. However, these classical signs of the “sepsis syndrome,” such as fever/hypothermia, leukocytosis/leukopenia, tachycardia, and hypotension, meant a very large and nonspecific/noninfectious cohort of patients. For this reason, a few years later a consensus conference was brought together and defined the so called “consensus criteria” of sepsis [4], which has also been recently questioned and criticized by Vincent et al. [5].Pathophysiology Of Sepsis Essay.  In the most current Surviving Sepsis Campaign Guideline a more robust, more detailed definition has been created, in order to “save” the previous concept of the Bone-criteria [6].

These efforts clearly show that finding the appropriate definition of sepsis has been a continuous challenge for more than 30 years. The difficulty in defining sepsis originates from its pathophysiology, to be discussed in Section 4. This has been recognized by international societies and currently an international Task Force has been working on a new, pathophysiology based sepsis definition. Nevertheless, in most specialties the disease itself is easily diagnosed by a laboratory or radiological test. However, in the case of sepsis it is different, which makes not just the diagnosis but the interpretation of the results of clinical trials and also epidemiological data very difficult.

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3. Epidemiology

According to recent surveys we treat several folds more critically ill patients on the intensive care units (ICU) worldwide these days as compared to the figures from more than 10 years ago [7]. There seems to be an increase in the incidence of sepsis, with mortality rates of 20–50%, and according to recent data from the United States, sepsis is the single most expensive reason for hospitalization at present [8, 9]. However, it is important to note that reported mortality shows considerable variation across the globe. A recent retrospective analysis from Australia and New Zealand showed an increase in the number of critically ill and septic patients over the last 12 years, with a mortality reduction from more than 30% to less than 20% [7]. In the PROCESS trial from the United States mortality was around 20% [10]. According to these data outcome has improved dramatically over the years. However, results from Europe, both retrospective and prospective, indicate greater mortality of 45–55%, which was also accompanied by a 2- to 3-fold longer ICU and hospital stay [11, 12], as compared to that reported by the two previously mentioned studies. This raises the question of whether the care is better in those countries which reported lower mortality rate or is it the patient selection that causes this difference? Although it is difficult to give a definitive answer, referring to our previous chapter, due to the difficulties in defining sepsis, severe sepsis, and septic shock, one cannot exclude that this difference can be the result of the uncertainties in patient selection, and, in those countries reporting higher mortality rates, sicker patients were included in the “septic shock” cohort.

Indeed, patients with the same diagnosis of “septic shock” could have completely different severity and prognosis.Pathophysiology Of Sepsis Essay.  The same holds true for every potential “insult” in critical care, such as trauma, sterile inflammation (acute pancreatitis), ischemia-reperfusion injury, major surgery, burns, and infection. These conditions share the same feature in their pathophysiology, namely, that it is not the insult per se, but the host’s response, especially the immune response, which determines severity and outcome (Figure 1).

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Figure 1

The “sepsis-triangles”: pathomechanism and treatment. SIRS: systemic inflammatory response syndrome, I-R: ischemia-reperfusion, DO2: oxygen delivery, VO2: oxygen consumption, PAMP: pathogen-associated molecular patterns, DAMP: damage-associated molecular patterns, EC: extra corporeal, and IPPV: intermittent positive pressure ventilation.

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4. Pathophysiology

4.1. From Localized Insult to “Cytokine Storm”

The immune system is a “team effort” that involves many different players interacting with each other as an orchestra. The immune response to pathogens relies on both innate and adaptive components. The first line of defense against invaders consists of physical barriers such as the skin [13, 14], the mucous membranes of our gastrointestinal [15], and respiratory [16] and genitourinary [17] tracts. The second line is the rapid defense by the innate immune system (including complement proteins, sentinel phagocyte cells, and natural killer cells), which plays an activator and a controller role of the adaptive immune system [18]. The innate system acts by broad recognition of antigens, mainly by sensing pathogen-associated molecular patterns (PAMP) of carbohydrates and fatty acids located on the surfaces of common pathogens. By-and-large when a local response spread systemically the activation of several classes of pattern recognition receptors will generate a “cytokine-chemokine storm” [19]. However, very similar molecules are released due to cell injury after trauma, burns, ischemia-reperfusion, pancreatitis, major surgery, and so forth, derived from necrotic cells, mainly from the mitochondria. These are called “damage-associated molecular patterns” (DAMP). It was a very important recognition that after cellular injury similar proteins will be released during bacterial infection, because the genetic background of the bacteria and the mitochondria is very similar [20]. Pathophysiology Of Sepsis Essay. This highlights the fact that the Bone-concept inevitably mixed patients who suffered insults due to PAMP, DAMP, or the mixture of the two.

Activation of neutrophils, macrophages, and monocytes by costimulatory molecules at the site of infection will turn the local adaptive immune system on and give “permission” to the adaptive system to respond to an infectious insult. The aim of the innate response is the eradication of the DAMP and PAMP, which is followed by the adaptive response with the resolution of the immunological process. The adaptive immune response is based on maturation and proliferation, both influenced by the “cytokine signature” of the innate response. In other words, every host has its own “cytokine signature” for a certain insult. Under normal circumstances these processes are well regulated maintaining an even balance between counteracting forces, hence keeping the inflammatory response localized.

However, in the case of an unbalanced (proinflammatory and anti-inflammatory), dysregulated (maturation and proliferation) response, the localized process goes out of control and becomes systemic, in other words the disease of the whole body; hence, it gives way for impairing the function of distant vital organs. This makes the clinical manifestation of critical illness so similar regardless of the insult. To give an example, the same gravity of acute respiratory distress syndrome (ARDS), shock, or deterioration in mental function can occur in pancreatitis, just as well as after major surgery, or due to any type of infection (Figure 2). The adaptive immune system as the third level of defense is based on its memories. It can adapt and protect us against almost any invader.

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Figure 2

The main pillars of systemic inflammatory response. PAMPs: pathogen-associated molecular pattern, DAMPs: damage-associated molecular pattern molecules, MBL: mannose-binding lectin, NOD protein: nucleotide-binding oligomerization domain protein, and NALP: a type a NOD like receptors. For explanation, see text.

In brief the “cytokine signature” of neutrophils and macrophages will give signals to the T and B lymphocytes via the dendritic cells, which after proliferation by maturation will express different cell surface receptors in soluble or membrane bound forms. Pathophysiology Of Sepsis Essay. The adaptive immune response is a soluble matrix, which consists of the cascade-type activation of cytokines, coagulation factors, the release of acute phase proteins, stress hormones, and different chemokines and hormokines, forming a complex network. The key factor of immune resolution is the balance between proinflammatory and anti-inflammatory forces, which is mainly determined by the balance between the relationship of Th1, Th2, Th17, and γΔT to each other, namely, the maturation, magnitude, and the duration of their activity [19].

4.2. Systemic Inflammatory Response Syndrome (SIRS) and Immunoparalysis

Based on the Bone-criteria, systemic inflammatory response syndrome, invented on the Consensus Conference in 1991 [4], initially meant the classical “sepsis syndrome” criteria, without proven infection. The SIRS-criteria have also been criticized for similar reasons as the “sepsis syndrome” definition, but nevertheless this “SIRS-concept” assumed that systemic inflammatory response can occur for an insult without infection.

In the past SIRS was mainly thought to be related to the imbalance between the proinflammatory and anti-inflammatory responses. However, it is more complex. In the context of the innate and adaptive immune responses both proinflammatory and anti-inflammatory processes take place in a parallel fashion. When the proinflammatory and anti-inflammatory forces swing into action, the proinflammatory forces overwhelm the anti-inflammatory process at the beginning. In general we can say that there is a short delay of the anti-inflammatory response as compared to the proinflammatory. This proinflammatory “dominance” lasts for 2 to 4 days, but an oversized response, which means that the localized insult becomes systemic, will lead to different degree of tissue damage, shock, and eventually organ failure.Pathophysiology Of Sepsis Essay.  During the course of disease the adaptive response is initiated by Th1 reaction. In the next phase, the proinflammatory process slowly “turns itself off,” while the adaptive response will switch to a Th2 response. In other words, this later phase helps to survive the proinflammatory process after the eradication of the insult with “restitutio ad integrum” [21]. However, a dysregulated, systemic form of the adaptive response could later induce immunoparalysis, jeopardizing the body’s defense, hence leaving it prone to further, even opportunistic infections. There are many unanswered questions in this process, but discussing these issues in details goes well beyond the scope of this paper [22].

4.3. The Altered Immune Response and Leukocyte Reprogramming

In the later phase, in septic patients and in patients with severe noninfectious SIRS (such as burns, trauma, major surgery, hemorrhage, or ischemia-reperfusion after cardiac arrest), the anti-inflammatory process may overwhelm the proinflammatory forces. This is often referred to as “anergy,” “endotoxin intolerance,” “immunoparalysis,” or “immunodepression,” but these are very general and simplified descriptions of what is really happening. The term cellular reprogramming may be more accurate indicating the cellular changes during this process. In brief, cellular reprogramming means two contradictory parallel cellular processes: cells derived from hematopoietic compartments, such as bone marrow, spleen, lymph nodes, and blood, become hyporeactive. In contrast, cells derived from other tissues and solid organs (like liver, kidney, lung, brain, or gastrointestinal tract) can often be hyperreactive causing hyperinflammation in the particular organs, especially in the infected organ. The inhibition of some signaling pathways parallel with others, which are maintained or enhanced, results in large variety of immune response. Immunosuppression itself does not cause harm but leaves the patient prone to infection. Unfortunately, tests able to measure the degree of immunosuppression are not available all around the clock; hence, the clinician has nothing else to rely on at the bedside than the etiology, clinical picture, and biomarkers in order to detect the onset of a potentially devastating new infection as soon as possible [21, 22]. Pathophysiology Of Sepsis Essay.

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5. Diagnostic Challenges

One of the most common misconceptions in sepsis diagnosis is that we have been searching for specific “marker(s) of sepsis.” However, there is not and there will never be one single marker which is able to diagnose sepsis, mainly due to the very colorful manifestation of sepsis and due to the heterogeneity of patients.

Recognizing the septic patient has two main elements. On the one hand, we have to evaluate vital organ function and the degree of organ dysfunction via objective signs, such as hypotension, hypoperfusion, altered mental status, acid-base imbalance, hypoxemia, lactate levels, renal and liver dysfunction, and thrombocytopenia. Based on these findings we should start supportive therapy without any further delay, and if there is any suspicion of the possibility of an infection, empirical antibiotic therapy should also be started immediately (Figure 1) [16].

In the meantime we have to diagnose the etiology of critical illness. In other words we have to decide whether critical illness is due to infection or not. Because if it is due to infection antibiotics should be started as soon as possible, but if it is not related to a bacterial infection, antibiotics are not just a waste of time and money, but they may also do harm in short and long term. Unfortunately, diagnosing infection in critically ill patients is not easy.

5.1. Conventional Markers of Infection

Clinical signs are the most important in recognizing critical illness, but they cannot prove infection on their own. Conventional (fever/hypothermia, leukocytosis/leukopenia, tachypnoe, tachycardia, and hypotension) indicators, also listed in the classical “sepsis-syndrome” criteria, are very nonspecific, in fact poor indicators of infection. Pathophysiology Of Sepsis Essay. For microbiological proof of infection, although very important, unfortunately results become available 24–48 hours at the earliest after sending the specimen to the laboratory. According to our current concept, it is of utmost importance to start adequate antibiotic therapy as soon as possible, but at least within an hour after the onset of infection caused hypotension; otherwise chances for survival are reducing by the hour [23].

New molecular biology techniques are now available to define the presence of bacterial or fungal DNA within the bloodstream of patients [24, 25]. Highly sophisticated molecular biology based tests such as polymerase chain reaction (PCR), matrix assisted laser desorption/ionization (Maldi/Tof), and peptide nucleic acid fluorescence in situ hybridization (PNAFISH) based pathogen detection can theoretically shorten the recognition of the underlying pathogen to about 8 hours [26]. However, these cannot differentiate between colonization and clinically significant infection. Therefore, we need laboratory tests, which are sensitive and specific enough to show the onset and magnitude of bacterial invasion caused inflammatory response as soon as possible and may also be able to follow the progress of the disease within hours. These biologically active substances are called biomarkers.

5.2. The Role of Biomarkers at the Bedside

There have been several biomarkers developed so far [1], but neither is suitable for all purposes. Every marker has its own merit and limitations. They inevitably can support decision making but they will never be able to differentiate “sepsis” from “SIRS” with a 100% sensitivity and specificity, mainly due to the problems we discussed earlier in details regarding the problems of defining sepsis, and also due to the complex, overlapping pathomechanism of PAMP and DAMP. Pathophysiology Of Sepsis Essay. Nevertheless, there is still an ongoing search for better, new markers of inflammatory response and infection, with promising preliminary results [40].

There are almost 200 so-called sepsis markers; therefore, discussing the features of those cannot be integrated into the current review. We will mainly focus on the two most commonly used markers: procalcitonin (PCT) and C-reactive protein (CRP). However, briefly mentioning the main features of a few other new markers already applied in daily practice, such as soluble CD14 subtype (presepsin) and soluble urokinase-type plasminogen activator receptor (suPAR), may be worthwhile. Higher presepsin concentrations in septic patients were associated with ICU mortality in a recent large multicenter trial [41]. It was also suggested that changes in plasma concentrations may reflect the appropriateness of antibiotic therapy, but this have to be confirmed by future studies [41]. Regarding the suPAR molecule it has been shown to be a very good indicator of severity of the acute disease and shows good correlation with the degree of organ dysfunction in the critically ill but cannot be regarded as a “sepsis marker” due to its low specificity [42].


Any condition inducing DAMP [43] or PAMP could shed the endothelial glycocalyx layer. It has been confirmed in several experimental studies in different septic models that damage of the endothelial glycocalyx layer is reflected in elevated serum syndecan-1 and syndecan-4 levels [44–47], which may be potentially a very interesting marker in the future, but again, it may be nonspecific for bacterial infection only.

Finally, neutrophil-lymphocyte count ratio is a cheap, fast, and easily available tool to diagnose bacteremia and was found to improve bloodstream infection diagnostics in a recent study on the emergency ward [48]. This simple test may also have a potential in the future. Pathophysiology Of Sepsis Essay.

Nevertheless, the two most commonly used markers in infection/sepsis diagnostics and for guiding therapeutic interventions are PCT and CRP [49]. Despite their popularity, there are still many pros and cons without clear answers regarding their usefulness and interpretation in guiding patient management.

Procalcitonin is detectable in the serum within a few (4–6) hours after the onset of bacterial infection. During the “normal” course of an infection it reaches its peak within 24 hours and then starts its decline in the case of adequate treatment with levels reducing by roughly 50% daily according to its half-life [27]. In contrast, CRP moves “slowly,” and under similar circumstances it reaches its maximum value usually within 48 hours. However, levels are generally elevated in most ICU patients, making interpretation of CRP very difficult [50]. The other major problem with CRP on the ICU is that it is lagging way behind the actual events of the inflammatory process. The most important differences between the two markers are summarized in Table 1.  Pathophysiology Of Sepsis Essay.