**5. Blood cultures**

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

**0 1 2 3 4**

respiratory support

Dopamine 5.1–15 or epinephrine ≤0.1 or norepinephrine ≤0.1<sup>b</sup>

6.0–11.9 (102–204) >12 (204)

3.5–4.9 (300–440) >5.0 (440)

: partial pressure of oxygen.

<100 (13.3) with respiratory support

Dopamine >15 or epinephrine >0.1 or norepinephrine >0.1b

≥400 (53.3) <400 (53.3) <300 (40) <200 (26.7) with

/uL ≥150 <150 <100 <50 <20

(33–101)

15 13–14 10–12 6–9 <6

2.0–3.4 (171–299)

Dopamine <5 or dobutamine (any dose)<sup>b</sup>

<1.2 (20) 1.2–1.9 (20–32) 2.0–5.9

MAP <70 mmHg

(110–170)

Urine output, mL/d <500 <200

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

: fraction of inspired oxygen; MAP: mean arterial pressure; PaO<sup>2</sup>

**System Score**

, mmHg

Cardiovascular MAP

≥70 mmHg

62 Biomarker - Indicator of Abnormal Physiological Process

<1.2 (110) 1.2–1.9

Catecholamine doses are given as ug/kg/min for at least 1 h.

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

Respiration

Coagulation Platelets, ×103

Bilirubin, mg/dL (umol/L)

Central nervous system

Glasgow Coma Scale scoreb

Creatinine, mg/dL (umol/L)

Abbreviations: FiO<sup>2</sup>

Renal

a

b

PaO<sup>2</sup> /FiO<sup>2</sup>

(kPa)

Liver

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 therapy [11].

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

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

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 using automated systems [25, 26].

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

A limitation of blood culture is the lack of sensitivity in the search for particular bacteria that are often responsible for community-acquired pneumonia, such as *Mycoplasma pneumoniae*, *Legionella pneumophila* and *Chlamydia pneumoniae* and other germs that are difficult to grow or even non-cultivable such as *Coxiella burnetii*, *Francisella tularensis*, *Bartonella* spp., *Rickettsia* spp. and *Nocardia* spp. [28, 29].

≥ 2 mmol/L. However, according to other authors, the additive prognostic role of lactates to

Biomarkers Utility for Sepsis Patients Management http://dx.doi.org/10.5772/intechopen.76107 65

CRP and PCT are routinely used in patients with suspected first aid infection. CRP, released as an acute phase protein in inflammatory states, has a high specificity but low sensitivity and is therefore used for its negative predictive value. PCT, on the other hand, has been shown to have diagnostic and prognostic value in the management of sepsis. It is released in the course of bacterial infections, being therefore aids in the differential diagnosis, and is also included within the guidelines as a valid aid in guiding antibiotic therapy, representing a "mirror" of

More recently, however, we have focused on the role of adrenomedullin (ADM). It is a peptide that several studies have shown to increase in septic patients [35]. The secretion mechanism depends to a large extent on stimulation by the lipopolysaccharide of bacteria, and its plasma levels derive mainly from secretion by endothelial cells [36]. ADM plays a fundamental role in hyperdynamic response during the early stages of sepsis and its main function is vasodilator [37]. After demonstrating the prognostic role of its precursor MR-proADM [38], thanks to a novel instrument based on a chemiluminescent sandwich detection (in which specific monoclonal antibodies are used against the C-terminal part of the peptide), today, it is possible directly measure the biologically active molecule (Bio-ADM or ADM). Thus, in a study published in 2014, our group showed that ADM values are significantly higher in patients with severe sepsis and septic shock than those with sepsis [39]; in particular, ADM, considered one of the most potent endogenous vasodilators, was found to be closely related to low mean arterial pressure (PAM) values and to the need to use vasopressors, thus detecting septic shock markers. Furthermore, higher values have been correlated with greater probability of death; and finally, the detection of multi-stroke ADM has proved

From what has emerged, considering that sepsis determines endothelial dysregulation, excessive vasodilatation and consecutively collapse of arterial pressure and micro-vascular homeostasis and that ADM has as its main function vasodilator and therefore regulator of vascular tone, new studies currently in progress and still in the experimental phase, are directed to the development of a murine anti-ADM monoclonal antibody (HAM1101) that can become a therapy in septic shock, according to the hypothesis that it can improve the hemodynamics and perfusion of the organs and, consequently, also reduce the incidence of acute renal failure. To date, a humanized antibody has been selected, the HAM8101, which will be the subject of phase III experimental

Establishing diagnosis and therapy is very important but to hinder their definition is the difficulty in differentiating sepsis from non-infectious stimuli in SIRS situations, especially in those critically ill patients who may have developed SIRS for other causes such as pancreatitis, trauma, burns, etc. Therefore, the detection of an accurate biomarker in sepsis is decisive in critical situations with the ability to exclude or confirm an acute bacterial infection, to evaluate the systemic inflammatory response to infection and the host response to the established therapy [41].

• useful in early diagnosis, provide information for a definitive diagnosis or help to identify

the therapeutic response to infection, and for its high prognostic power.

to be fundamental in identifying patients with a worse prognosis [39].

An ideal biological marker must have different characteristics:

qSOFA would not be significant [34].

studies in the near future [39, 40].

a probable diagnosis;

The value of blood culture as a diagnostic test for bacteraemia and sepsis is limited, in fact, it emerges that in 50% of cases, the blood culture is negative even if the diagnosis of sepsis is certain and also the first results are provided after 48 h to conclude analysis with the identification and sensitivity to the pathogen's antibiotics after 5 days or more [1, 30, 31].
