**4. Clinical scores**

**2. Sepsis in emergency department**

60 Biomarker - Indicator of Abnormal Physiological Process

intervention [9].

of sepsis.

**3. Diagnosis**

Sepsis is a complex clinical syndrome that still represents a major challenge for today's medicine. In fact, despite the current possibilities of treatment, sepsis remains burdened by a high prevalence in the population and above all by a severe prognosis, representing one of the pathologies with the highest rate of morbidity and mortality. It is responsible for about onethird of all hospital admissions, and about 50% of ICU admissions. Mortality would reach

In this complex scenario, the emergency doctor plays a key role. In fact, it depends on early diagnosis and treatment, the two factors that are recognized today as fundamental in the correct management of the septic patient as it is able to improve the prognosis. The enigmatic and often heterogeneous nature of sepsis, the absence of specific clinical and laboratory elements causes the lack of valid diagnostic tools, strongly influencing early

The recent literature has therefore placed great attention in the search for all clinical and laboratory factors, which can help in the rapid identification of sepsis and in the stratification of the risk of such patients, in order to make the treatment as aggressive as possible in terms of timeliness and effectiveness. More than two decades ago, sepsis was defined by the combination of an SIRS and an infection. This criterion, therefore useful for the correct diagnosis of sepsis, is also endowed with prognostic capacity, proving to be effective for the gravity stratification of patients with suspected infection due to the linking of these criteria with the presence of organ damage. However, the role of SIRS has been recently revised because although it has high prognostic power, it has little specificity being involved in a wide variety of pathologies regardless the presence of infection, in which the differential diagnosis often becomes difficult. Furthermore, it has been calculated that a certain number of patients with sepsis may not present SIRS criteria (about 1 in 8) [10]. The "Third International Consensus Definitions for Sepsis and Septic Shock" (Sepsis-3) [7] has therefore decided to go beyond the concept of SIRS, emphasizing rather the role of the organism's response to infection and organ damage (identified by a SOFA value ≥2) in the pathogenesis

Sepsis diagnosis is established on the basis of patient's symptoms and clinical signs combined with radiological examinations and laboratory tests such as the search for biomarkers and identification of the microorganism responsible for the infection. In cases of sepsis, delay in diagnosis and antibiotic therapy affects the mortality of critically ill patients. Establishing diagnosis and therapy is very important but to hinder their definition it is difficult in differentiating sepsis from non-infectious stimuli in SIRS situations, symptoms and clinical signs, radiological and laboratory tests used for the diagnosis of sepsis are those reported in the previously reported tables, used in the definition of sepsis itself. The use of clinical scores, blood cultures

and biomarkers for the diagnosis of sepsis will be discussed later.

40%, of which 25% of deaths would occur within 48 h of entry into ICU [8].

Since 2004, worldwide, the "Surviving Sepsis Campaign", consisting of a multidisciplinary team of specialists, periodically deals with the preparation and updating of documents on the general management of the septic patient and some specific aspects, such as timing and the optimal choice of antibiotic therapy, blood pressure support, glycemic control and oxygenation. In particular, at the last revision, the bundle of measures are implemented within the first hours after admission of the patient to reduce mortality was well defined [11].

At the same time, over the years, the need arose, especially in an intensivist environment, to identify those factors capable of predicting clinical severity and, in particular, the risk of death; for this purpose, many patient severity scores have been proposed and validated, useful from the moment of diagnosis to stratify the patient's clinical severity and, indirectly, to assess the risk of mortality [12].

The ideal prognostic score should have high sensitivity and high predictive value, be able to predict early mortality or clinical evolution, be rapidly usable, available everywhere, economic, objective and non-observer-dependent. Currently, no clinical score has all these characteristics. In particular, the two basic requirements of a prognostic system are the power of discrimination and calibration [13].

There are several works that have evaluated in the emergency medicine settings, the applicability of different gravity scores. In particular, simpler models to be calculated than those commonly used in Intensive Care Unit (ICU) have been proposed [11]. In 2003, Shapiro et al. have proposed the adoption of a new prognostic model, called Mortality in Emergency Department Sepsis (MEDS), as a method for stratifying patients afferent in emergency medicine with suspected sepsis [14]. Sankoff et al. resumed the MEDS score and carried out a multi-center prospective study to verify its reproducibility and validity [15]. The MEDS is the only score designed to be used in the septic patient in settings different from ICU. Numerous prognostic models born to be used in ICU were subsequently applied in different care settings, primarily in emergency medicine.

In one of the best known studies, Jones et al. have proposed the adoption of the Sequential Organ Failure Assessment (SOFA) score as a tool to predict the outcome of patients with severe sepsis with signs of hypoperfusion or septic shock. The authors considered all patients over the age of 18 with sepsis and evidence of hypoperfusion (systolic BP <90 mmHg or lactate levels>4 mmol/L); calculated the SOFA score at time zero and after 72 h (delta SOFA). The outcome of the study was to evaluate in-hospital mortality, the possible correlation between the difference in SOFA between admission and after 72 h, and finally mortality. The authors have shown a good correlation between the SOFA score at the entrance and the delta SOFA with the risk of in-hospital mortality. The limit of the work, similar to the studies on the MEDS score, is that it is an experience conducted only in a single center, which should be validated and extended to several centers to obtain a useful risk assessment tool [16, 17]. Alan E Jones et al. also demonstrated the usefulness of SOFA as a predictive prognosis score in patients with sepsis, and in particular in patients with severe sepsis with signs of hypoperfusion already on arrival in the emergency room [16].

The SOFA score (**Table 3**) is therefore a prognostic score, used for the prediction of mortality, based on the degree of dysfunction of six different systems and apparatuses, involved in the pathophysiology of the sepsis response. In particular, the respiratory, cardiovascular, renal, neurological, coagulative and hepatic systems are examined. The alteration of each of them indicates a condition of particular gravity, and the progression of the number of systems involved represents a negative prognostic variable. Thus, values < 9 predict mortality <33%, values between 9 and 11 a mortality of 40–50% and values>11 of 95%. Only one work assessed the accuracy of different prognostic models in septic patient assessment in a care setting of this kind [18]. The study, conducted in a single center, evaluated five different prognostic models MEDS, APACHE II, SAPS II, SOFA score (at time 0 and 24 h) and the Charlson index. The outcome examined was 28-day mortality, the number of patients examined was 140. The most accurate result was the 24-hour SOFA; however, also the SOFA at time 0, the maximum SOFA and increasing values of SOFA were related to mortality. It is useful to underline that the patients enrolled in the study already had a diagnosis of sepsis-septic shock with a mortality equal to 29%, much higher than the previously reported jobs (close to that of the IT departments). It is therefore reasonable to think that for a population of this kind, the use of a score

validated in ICU (such as SOFA) may be more reliable than models validated in emergency

Biomarkers Utility for Sepsis Patients Management http://dx.doi.org/10.5772/intechopen.76107 63

The shorter version of SOFA score, the qSOFA, evaluates only three clinical variables that are easily obtainable "bedside" which are systolic arterial pressure ≤ 100 mmHg, respiratory rate ≥ 22 times/min and alteration of the mental state (GCS ≤ 13 or other alteration). A ≥ 2 qSOFA would allow rapid detection of the septic patient and would be associated with 10% mortality. However, recent scientific studies have questioned the role of qSOFA, comparing it with the previous SIRS diagnostic criteria. In particular, a qSOFA ≥2 would seem to have high specificity but low sensitivity compared to a SIRS ≥2 value in the recognition of organ

Blood culture is the "gold standard" exam to diagnose sepsis because it allows the etiological agent to be determined and provides the clinician with useful information for targeted

Several factors can influence the effectiveness and clinical significance of blood culture. In the pre-analytical phase, the withdrawal methods and the number of samples are very important. The sampling must be done when the first suspicions of infection arise and above all before the administration of any antibiotic, otherwise the therapy should be discontinued for a few hours or taken before the next administration of the antibiotic. In most episodes of bacteremia, it is necessary to collect two or three blood culture sets within 24 h to identify the pathogen, in case a single sample set is taken the probability of not identifying a patient with sepsis is about 35–40% [19]. An important factor for the accuracy of the diagnosis is the volume of blood present in the blood culture flask, in fact it is necessary to inoculate at least three colony forming units (CFU) per milliliter to get 100% positive; however, it is considered that in adult patients, in sepsis, the concentration per milliliter of blood is normally 0.1–1 CFU/mL, while in pediatric age the

Therefore, in the adult, the ideal amount of blood will therefore be 5–10 mL per vial and for pediatric patients of 1–5 mL. The ratio between the volume of the sample and that of the culture broth must allow the growth of many microorganisms, this ratio is 1:5–1:10 even if with the addition of substances that disable the inhibitory factors the optimal ratio is 1:5 [22–24].

The Clinical and Laboratory Standards Institute (CLSI) established that 5 days of incubation are sufficient to detect 95% growth of clinically significant bacteria (CLSI, 2007). Several studies have shown that in 97.5% of blood cultures containing a pathogen are positive after 3 days

In the case of suspected endocarditis supported by demanding bacteria, or yeast septicemia or in pediatric patients, the incubation times are prolonged. Moreover, a possible administration of a therapy prior to sampling or the presence of a pathogen with particular nutritional needs lowers the ability of the investigation to identify the microorganism, in fact it has been shown

Another important factor for a successful blood culture is incubation time.

that the levels of analytical sensitivity vary between 8 and 88% [27].

damage, and this could limit its use as a screening method [9].

bacterial load is equal to 10–100 CFU/mL [20, 21].

using automated systems [25, 26].

medicine (such as MEDS) .

**5. Blood cultures**

therapy [11].


Abbreviations: FiO<sup>2</sup> : fraction of inspired oxygen; MAP: mean arterial pressure; PaO<sup>2</sup> : partial pressure of oxygen. a Catecholamine doses are given as ug/kg/min for at least 1 h.

b Glasgow Coma Scale scores range from 3 to 15; higher score indicates better neurological function.

**Table 3.** Sequential (sepsis-related) organ failure assessment score [7].

validated in ICU (such as SOFA) may be more reliable than models validated in emergency medicine (such as MEDS) .

The shorter version of SOFA score, the qSOFA, evaluates only three clinical variables that are easily obtainable "bedside" which are systolic arterial pressure ≤ 100 mmHg, respiratory rate ≥ 22 times/min and alteration of the mental state (GCS ≤ 13 or other alteration). A ≥ 2 qSOFA would allow rapid detection of the septic patient and would be associated with 10% mortality. However, recent scientific studies have questioned the role of qSOFA, comparing it with the previous SIRS diagnostic criteria. In particular, a qSOFA ≥2 would seem to have high specificity but low sensitivity compared to a SIRS ≥2 value in the recognition of organ damage, and this could limit its use as a screening method [9].
