**2. Sepsis and septic shock in adults**

#### **2.1 Definitions of sepsis and septic shock**

The first definition of sepsis, published in 1992, was based on the presence of a suspected or proven infection with two or more criteria of the systemic inflammatory response syndrome (SIRS) [5]. Sepsis was defined, as the presence of two or more positive SIRS criteria with a confirmed or suspected infection as the underlying cause. If signs of organ dysfunction were seen, the diagnosis was changed to severe sepsis. Septic shock was defined by the presence of acute circulatory failure and arterial hypotension along with features of sepsis. Until recently, the definitions of sepsis, septic shock and organ dysfunction remained the same for more than 20 years (**Figure 1**). Due to the inaccuracies of the past definition and the SIRS criteria, new guidelines were published by the surviving sepsis campaign (SSC) in 2016, a multidisciplinary task force started by the Society of Critical Care Medicine in the United States and the European Society of Intensive Care Medicine [6, 7]. Since there is no gold standard test for sepsis, the task force decided to come up with definitions and clinical criteria that were clear, useful, and valid [3]. Instead of using the SIRS criteria to determine if a patient is in going into sepsis, the new guidelines suggest using the sequential organ failure assessment (SOFA) score and a quick SOFA score for more emergent cases, a topic that will be discussed in length in the next section.

In 2016, the Third International Consensus Definition for Sepsis and Septic Shock (Sepsis-3) defined sepsis as *a life-threatening organ dysfunction resulting from dysregulated host responses to infection*, and defined septic shock as *a subset of sepsis in which underlying circulatory, cellular, and metabolic abnormalities are profound enough to substantially increase the risk of mortality* (**Table 1**) [2]. Septic shock is also *defined as persisting hypotension that requires vasopressors to achieve a mean arterial pressure* ≥65 mmHg *despite adequate fluid resuscitation and a lactic acid level* >2 mmol/L [7]. These new definitions focused on organ dysfunction rather than inflammation.

#### **2.2 SIRS versus SOFA**

The same task force that changed the definition also implemented the use of the sequential organ failure assessment (SOFA) score over the SIRS criteria. Even though SOFA is not considered the gold standard for diagnosis, its use is recommended over SIRS.

SIRS was based on an inflammatory response to an infectious inoculation (**Figure 2**). Throughout its utilization, the surviving sepsis guidelines, specifically the SIRS criteria, were widely criticized. Many thought the definition was not helpful largely because the definition place a large emphasis on inflammation,

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**Figure 1.**

*Sepsis and Septic Shock*

*DOI: http://dx.doi.org/10.5772/intechopen.86800*

causing many patients without bacterial or viral infections to receive empiric antibiotic therapy and over-resuscitation [10]. The SIRS criteria were also thought to be remarkably sensitive, not taking into account any outside factors, multi-drug resistance and the ability to attain source control [3]. Based on the old definition of sepsis using the SIRS criteria, patients may have been incorrectly identified as being septic. One study showed a positive SIRS score in 87% of all ICU admissions, yet 14.3% of those with 2 or more SIRS criteria did not have infection [5, 7]. Moreover, in another study, 12.1% of patients had SIRS-negative sepsis, which is approxi-

*Sepsis and septic shock definitions over the years [9]. Abbreviations: SIRS, systemic inflammatory response syndrome; SOFA, sequential organ failure assessment; and qSOFA, quick sequential organ failure assessment.*

Due to these inaccuracies in the SIRS criteria, the new Sepsis-3 definitions recommend using the SOFA score; however, it is not commonly used or known outside of the critical care world [7]. The SOFA score is an aggregate score, from 0 to 4, for each organ system, including respiratory, coagulation, liver, cardiovascular, renal and central nervous systems [12]. An acute increase in the total score of 2 or more reflects an overall mortality risk in patients suspected of infection [7]. Calculating the SOFA score at the bedside or in a noncritical care unit and in patients who do not have full laboratory testing, is challenging. Since the SOFA score is based on biochemical criteria, the task force developed the clinical qSOFA screening tool which is based on respiratory rate, systolic blood pressure and altered mental state (**Figure 2**) [13]. If 2 of the 3 clinical variables

mately a miss of 1 in 8 patients diagnosed with sepsis [11].

*Sepsis and Septic Shock DOI: http://dx.doi.org/10.5772/intechopen.86800*

#### **Figure 1.**

*Clinical Management of Shock - The Science and Art of Physiological Restoration*

pregnant and pediatric populations.

**2. Sepsis and septic shock in adults**

**2.1 Definitions of sepsis and septic shock**

happened at a faster pace [2]. At the World Health Assembly in 2017, the World Health Organization (WHO) made sepsis a global health priority and passed a resolution to improve the prevention, diagnosis and management of sepsis [4]. In this chapter, we will examine the current definitions of sepsis and septic shock. We will explore the current guidelines in the diagnosis of sepsis. As we delve into the diagnosis, we will discuss the pathophysiology, clinical presentation, risk factors, etiologies, and finally, management strategies and treatments of the adult,

The first definition of sepsis, published in 1992, was based on the presence of a suspected or proven infection with two or more criteria of the systemic inflammatory response syndrome (SIRS) [5]. Sepsis was defined, as the presence of two or more positive SIRS criteria with a confirmed or suspected infection as the underlying cause. If signs of organ dysfunction were seen, the diagnosis was changed to severe sepsis. Septic shock was defined by the presence of acute circulatory failure and arterial hypotension along with features of sepsis. Until recently, the definitions of sepsis, septic shock and organ dysfunction remained the same for more than 20 years (**Figure 1**). Due to the inaccuracies of the past definition and the SIRS criteria, new guidelines were published by the surviving sepsis campaign (SSC) in 2016, a multidisciplinary task force started by the Society of Critical Care Medicine in the United States and the European Society of Intensive Care Medicine [6, 7]. Since there is no gold standard test for sepsis, the task force decided to come up with definitions and clinical criteria that were clear, useful, and valid [3]. Instead of using the SIRS criteria to determine if a patient is in going into sepsis, the new guidelines suggest using the sequential organ failure assessment (SOFA) score and a quick SOFA score for more emergent cases, a topic that will be discussed in length

In 2016, the Third International Consensus Definition for Sepsis and Septic Shock (Sepsis-3) defined sepsis as *a life-threatening organ dysfunction resulting from dysregulated host responses to infection*, and defined septic shock as *a subset of sepsis in which underlying circulatory, cellular, and metabolic abnormalities are profound enough to substantially increase the risk of mortality* (**Table 1**) [2]. Septic shock is also *defined as persisting hypotension that requires vasopressors to achieve a mean arterial pressure* ≥65 mmHg *despite adequate fluid resuscitation and a lactic acid level* >2 mmol/L [7]. These new definitions focused on organ dysfunction rather than

The same task force that changed the definition also implemented the use of the sequential organ failure assessment (SOFA) score over the SIRS criteria. Even though SOFA is not considered the gold standard for diagnosis, its use is recom-

SIRS was based on an inflammatory response to an infectious inoculation (**Figure 2**). Throughout its utilization, the surviving sepsis guidelines, specifically the SIRS criteria, were widely criticized. Many thought the definition was not helpful largely because the definition place a large emphasis on inflammation,

**64**

in the next section.

inflammation.

**2.2 SIRS versus SOFA**

mended over SIRS.

*Sepsis and septic shock definitions over the years [9]. Abbreviations: SIRS, systemic inflammatory response syndrome; SOFA, sequential organ failure assessment; and qSOFA, quick sequential organ failure assessment.*

causing many patients without bacterial or viral infections to receive empiric antibiotic therapy and over-resuscitation [10]. The SIRS criteria were also thought to be remarkably sensitive, not taking into account any outside factors, multi-drug resistance and the ability to attain source control [3]. Based on the old definition of sepsis using the SIRS criteria, patients may have been incorrectly identified as being septic. One study showed a positive SIRS score in 87% of all ICU admissions, yet 14.3% of those with 2 or more SIRS criteria did not have infection [5, 7]. Moreover, in another study, 12.1% of patients had SIRS-negative sepsis, which is approximately a miss of 1 in 8 patients diagnosed with sepsis [11].

Due to these inaccuracies in the SIRS criteria, the new Sepsis-3 definitions recommend using the SOFA score; however, it is not commonly used or known outside of the critical care world [7]. The SOFA score is an aggregate score, from 0 to 4, for each organ system, including respiratory, coagulation, liver, cardiovascular, renal and central nervous systems [12]. An acute increase in the total score of 2 or more reflects an overall mortality risk in patients suspected of infection [7]. Calculating the SOFA score at the bedside or in a noncritical care unit and in patients who do not have full laboratory testing, is challenging. Since the SOFA score is based on biochemical criteria, the task force developed the clinical qSOFA screening tool which is based on respiratory rate, systolic blood pressure and altered mental state (**Figure 2**) [13]. If 2 of the 3 clinical variables



*Abbreviations: MAP, mean arterial pressure; qSOFA, quick SOFA; SOFA, sequential [8] organ failure assessment; and ICU, intensive care unit.*

#### **Table 1.**

*Sepsis-3 terms and definitions [3, 6].*

#### **Figure 2.**

*Comparison of SIRS versus qSOFA [7, 13, 15]. Abbreviations: SIRS, systemic inflammatory response syndrome; SOFA, sequential organ failure assessment; and qSOFA, quick SOFA.*

are positive, the predictive validity is similar to the entire SOFA score when used outside the ICU setting [14].

#### **2.3 Pathophysiology**

Sepsis is a clinical syndrome with an array of disease courses of which is not completely understood. It is characterized by a varied response to infection, started

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*Sepsis and Septic Shock*

**2.4 Etiology**

**2.5 Risk factors**

**2.6 Clinical presentation**

*DOI: http://dx.doi.org/10.5772/intechopen.86800*

tension that results in tissue hypo-perfusion [16].

understood and continue to be an ongoing investigation [2].

Americans rather than females Caucasians respectively [19, 22].

common gram-negative bacteria seen [20].

by recognition of pathogen associated molecular patterns (PAMPs) from invasive microorganisms [16]. PAMPs are conservative antigens that are recognized by four classes of receptors: Toll-like receptors, C-type lectin receptors, retinoic acid inducible gene 1-like receptors and nucleotide-binding oligomerization domain-like receptors [17]. Cell lysis and spillover of intracellular molecules into the extracellular space is seen due to the resulting inflammatory response to the pathogen. The net result is an increased capillary permeability and vasodilation leading to hypo-

In sepsis, a hypercoagulable state is achieved due to the changes in the clotting factors. There is an increase of tissue factor which causes a decrease of antithrombin, subsequently causing an increase in plasma thrombin. At the same time there is decreased production of protein C and an increase in plasminogen activator inhibitor type 1 which all inhibits fibrinolysis. Increased coagulation and hypotension in sepsis can lead to multi organ failure, the most severe and life threatening consequence of sepsis [18]. During severe sepsis, and altered coagulation is almost always seen leading to disseminated intravascular coagulation (DIC). The mechanisms of how cell injury and sepsis-induced organ dysfunction occur are not fully

Sepsis can be caused by any type of infecting organism and can originate from communities, hospitals or other health care facilities [2]. The most common culprit is pneumonia, which accounts for about half of all cases, followed closely by intra-abdominal infections and urinary tract infections [19]. The most common gram positive bacteria seen are *Staphylococcus aureus* and *Streptococcus pneumoniae*, whereas *Escherichia coli*, Klebsiella species, and *Pseudomonas aeruginosa* are the most

Most risk factors for sepsis mainly rely on the patient's predisposition to infection. The main groups of patients are but not limited to; young or old age, patients with immunosuppressive diseases (e.g., AIDS) or ones taking immunosuppressive medications, cancer patients, alcoholics, patients with indwelling catheters, or other patients that have altered skin integrity all predispose them to infection [2, 21]. Age, sex, race, or ethnic groups have an influence on the incidence of severe sepsis. It is seen that sepsis mainly occurs in infants and elderly people, in males and African

In sepsis, a person's response to an infection presents as signs of infection together with acute organ dysfunction, which can lead to multiple organ failure, acidosis, and death [21]. The clinical manifestations of sepsis varies, depending on the where the infection happens, the type of organism, the pattern of acute organ dysfunction, the health status of the patient, and what happens prior to initiation of treatment. Acute organ dysfunction is most commonly seen in the respiratory and cardiovascular systems. Respiratory compromise is classically manifested as acute respiratory distress syndrome (ARDS), which is defined as hypoxemia with bilateral infiltrates of noncardiac origin. Cardiovascular compromise is manifested primarily as hypotension or an elevated serum lactate level [18]. Patients often present to the emergency department with general malaise, fever, tachycardia,

#### *Sepsis and Septic Shock DOI: http://dx.doi.org/10.5772/intechopen.86800*

by recognition of pathogen associated molecular patterns (PAMPs) from invasive microorganisms [16]. PAMPs are conservative antigens that are recognized by four classes of receptors: Toll-like receptors, C-type lectin receptors, retinoic acid inducible gene 1-like receptors and nucleotide-binding oligomerization domain-like receptors [17]. Cell lysis and spillover of intracellular molecules into the extracellular space is seen due to the resulting inflammatory response to the pathogen. The net result is an increased capillary permeability and vasodilation leading to hypotension that results in tissue hypo-perfusion [16].

In sepsis, a hypercoagulable state is achieved due to the changes in the clotting factors. There is an increase of tissue factor which causes a decrease of antithrombin, subsequently causing an increase in plasma thrombin. At the same time there is decreased production of protein C and an increase in plasminogen activator inhibitor type 1 which all inhibits fibrinolysis. Increased coagulation and hypotension in sepsis can lead to multi organ failure, the most severe and life threatening consequence of sepsis [18]. During severe sepsis, and altered coagulation is almost always seen leading to disseminated intravascular coagulation (DIC). The mechanisms of how cell injury and sepsis-induced organ dysfunction occur are not fully understood and continue to be an ongoing investigation [2].
