and the alteration of mental status [7]. Septic shock has a mortality rate that ranges from 30–50% [7]. The early identification of sepsis and septic shock is essential for immediate treatment [1,2] and for the reduction of the patient mortality rate [10,11]. Sepsis can affect people of all ages [2–4]. Therapy for sepsis should be personalized and tailored according to the patient's needs. Many biomarkers such as procalcitonin (PCT) or interleukin (IL)-6 or IL-18 are used in clinical practice to facilitate the diagnosis of sepsis [5,6]. Novel biomarkers such as proadrenomedullin (MR-proADM), kallistatin, testican-1, and presepsin have been introduced to assess the severity of sepsis and to predict the organ damage and the risk of imminent death [5]. As of now, a golden standard biomarker in terms of the diagnosis and prognosis for sepsis and septic shock has not been found. The aim of our narrative review is to evaluate the role of MR-proADM as a biomarker of sepsis in the context of emergency medicine and to summarize the current knowledge about MR-proADM in sepsis and septic shock as a potential biomarker to achieve an early diagnosis and to predict the long-term mortality of patients directly in the ED.

#### **2. Literature Research**

We performed an electronic literature review to investigate the role of MR-proADM in sepsis and septic shock. We searched papers on PubMed®, Cochrane®, UptoDate®, and Web of Science®. No ethical approval was necessary to perform this review. The principal words we included in the search were "severe sepsis" OR "sepsis", OR "septic shock", AND "procalcitonin", AND/OR "pro-adrenomedullin", OR "MR-proADM", AND/OR "IL-6", AND/OR "systemic inflammation", AND/OR "organ failure", AND/OR "infections", AND "diagnostic biomarkers" AND "prognostic biomarkers", OR "bacteria-induced sepsis", AND/OR Emergency Department (ED) OR Emergency Medicine. Our search was based on clinical trials, meta-analysis, randomized controlled trials, reviews, and systematic reviews if available. We extracted data from comprehensive studies based on the new definition of sepsis and septic shock and reviewed the role of serum MR-proADM as a diagnostic and/or prognostic biomarker according to the available literature. We summarized the main studies, exploring the role of MR-proADM with the investigated cut-off value (nmol/L) (when available). No exclusion criteria (patient age, gender, comorbidities, admission to ICU, etc.) were applied. We also searched studies performed in the context of emergency medicine/ED. Papers were initially selected by title and abstract and then by the availability of the full text. We reviewed the results of the studies on the basis of the total number of patients, levels of MD-proADM, outcomes, management in the ED or Intensive Care Unit (ICU), and use of MD-proADM or other biomarkers or stratification scores of the severity of the patient's condition. We investigated a total of 16 manuscripts from 2013 to 2021. The limitation of our review is the heterogeneity of the studies (type of patients included, design of study, endpoints).

#### **3. Role of MR-proADM in ICU and in ED**

Several authors have investigated the role of MR-proADM in patients with sepsis and septic shock. MR-proADM is a stable and detectable fragment of 48-amino acids derived from ADM (a 52-amino acid peptide and member of the calcitonin family) that is mainly produced by vascular endothelial cells and smooth muscle cells. ADM and MR-proADM have effects on vasodilatation (on artery and vein), natriuresis, bronchodilatation, and they have influences on cardiac contractility and glomerular filtration [11], which are involved in some clinical manifestations of sepsis and septic shock as refractory hypotension. MRproADM has a half-life that is longer than ADM and can be more easily detected in blood compared to ADM, which is rapidly cleared from the circulation.

Most of the reported studies found that MR-proADM was a reliable biomarker that could serve as an early predictor of high mortality risk. In fact, levels of MR-proADM can potentially reflect the severity of organ dysfunction, even in the first stages of the disease, in the progression of systemic inflammatory response, in the movement from sepsis to septic shock, and in the mortality risk of septic patients [11,12]. A prospective observational study

conducted with 213 septic patients showed that MR-proADM was able to predict system dysfunction (respiratory, coagulation, renal, neurological, and cardiovascular) and was well-correlated with Sequential Organ Failure Assessment (SOFA) score components [13]. The same results were obtained by Onal et al. [11], who concluded that MR-proADM could be a good alternative to SOFA score. L. Buendgens and his team [14] designed a prospective study to assess the role of MR-proADM in a cohort of 203 ICU patients and 66 healthy controls that they followed for a period of 26 months. They demonstrated that MR-proADM values were higher in critically ill patients—especially in those with sepsis progression—with a close correlation with other markers of systemic inflammation and endothelial dysfunction. Moreover, MR-proADM levels correlated with scores for disease severity (Acute Physiology and Chronic Health Disease Classification System (APACHE II), SOFA, and Simplified Acute Physiology Score (SAPS2)). The best cut-off value that was found by these authors to identify patients at high mortality risk was of 1.4 nmol/L [14]. Similar results were also reported by Gonzales Del Castillo et al. [15] in a larger study of 684 patients admitted to the ED for a suspected infection.

The abovementioned authors found that MR-proADM was able to identify those hiding an underlying severe condition and who were at high risk for delayed or insufficient initial treatment. In addition, authors compared several biomarkers (MR-proADM, Creactive protein (CRP), PCT, and lactate) and clinical scores (SOFA, quick SOFA, and National early warning score (NEWS)), concluding that MR-proADM could help identify patients with low NEWS or quick SOFA values but who were at high risk for sepsis progression, helping in the initial treatment choices [15]. A prospective observational study of 657 patients with an acute infection conducted by Haang et al. [16] reported that the combination of MR-proADM and SOFA-score would better improve the stratification risk of patients for 30-day mortality (area under the curve (AUC) 0.87) than the SOFA-score alone (AUC 0.81). The authors defined a MR-proADM threshold value of 1.75 nmol/L as a prognostic value for 30-day mortality (sensitivity 81%, specificity 75%, and negative predictive value 98%) [16].

Spoto et al. [2] conducted a study on 571 septic patients and reported that MR-proADM has a strong correlation with a high risk of 90-day mortality, with a cut-off of 3.39 nmol/L for septic patients and a cut-off value of 4.33 nmol/L for shock patients. In another prospective study of 209 patients with a clinical sepsis diagnosis, S. Spoto [17] et al. showed that MR-proADM had an important function in predicting the development of organ failure over 24 h [17]. Significant evidence of MR-proADM prognostic reliability was also provided by a prospective observational study conducted in a sample of 326 patients with sepsis or septic shock by Andaluz-Ojeda [18] and his coworkers. Their results showed that MR-proADM was an optimal biomarker for the early identification of patients who had a high-risk of mortality, even if these patients who initially had a moderate clinical severity [18]. Such evidence further strengthens the role of MR-proADM as a prognostic factor for mortality in critical illness, but this evidence also shows how its inclusion in the first evaluation of septic patients with a moderate clinical condition is able to predict later organ dysfunction. Schuetz et al. [19] conducted a prospective, multicenter study including 7132 patients and revealed that MR-proADM improved the models that predict ICU admission for patients with sepsis and septic shock. In a cohort of 128 septic patients in the ED, Travaglino et al. [20] proved that MR-proADM was correlated with the APACHE score. Chris-Crain et al. [21] proved that MR-proADM was a good prognostic biomarker in critically ill patients with sepsis. However, a neat cut-off value for the identification of septic patients with a high mortality risk has not yet been found, and more studies are needed to finally set a threshold that can be standardized.

#### **4. Discussion**

Sepsis and septic shock are medical emergencies that require a proper diagnosis and appropriate management from the moment of admission to the ED. In fact, sepsis and septic shock carry a high mortality risk for patients [7,10,16]. Many factors contribute to the

complexity of these conditions. Among them, the over-activation and dysregulation of the innate immune system in response to a blood microbial invasion is a topic of great interest in order to better define the most targeted therapeutic strategy. The innate immune system expresses some receptors that are able to recognize the signaling of damage or infection as damage-associated molecular patterns (DAMPs) or pathogen-associated molecular patterns (PAMPs). DAMPs and PAMPs, which are binding receptors of the innate immune cells, lead to the release of many pro-inflammatory cytokines and molecules such as tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-1β (IL-1β) followed by the release of acute phase proteins such as CRP, PCT, and MR-proADM [22]. In the context of the ED, it is important to have easily measurable biomarkers that can produce an indication level of the patient's severity level in order to modulate the priority and the intensity of the patient's care. Literature studies [5,6] have investigated the role, both diagnostic and prognostic, of some biomarkers such as PCT, IL-6, IL-18, presepsin, etc., in patients with sepsis and septic shock without finding conclusive results. MR-proADM seems to be a good biomarker in assessing a patient's initial state, evolution, and prognosis. Moreover, MR-proADM may be a good alternative to the sequential organ failure assessment (SOFA) score. In the context of the ED, especially in the case of overcrowding, the administration of a simple blood test may be more practical compared to the collection of a multitude of data to calculate a score. MD-proADM has shown a strong ability to predict localized bacterial infections and to make a differentiatial diagnosis of sepsis from SIRS in patients with hematologic malignancies [23]. More studies are underway to explore the pathophysiological profile of MD-proADM regarding the release kinetics and the blood clearance time in order to reduce the risk of false-positive or -negative results and to avoid confounding and misleading mistakes in interpretation.

Moreover, the best cut-off value of MR-proADM for the early diagnosis of sepsis and for predicting patient prognosis has not yet been clarified. More studies are required to better define it for use in clinical practice and directly in the ED.

Some other molecules proposed as ideal predictor biomarkers of sepsis include CD64, the soluble receptors of myeloid cells (sTREM)-1, the soluble urokinase-type plasminogen activator receptor (suPAR), and pentraxin-3, but they are still far from application in the ED. Recent advances in technology are now focusing on microbiome and non-coding RNAs [22], some of which, for example miR-21, contribute to inflammatory responses and multi-organ dysfunction (i.e., kidney, lung, and liver) during sepsis [24,25]. Moreover, several models and scoring systems involving the combination of biomarkers are in progress [26–29]. They seem to have interesting diagnostic and prognostic performance, but they need confirmation through more trials. Our review has some limitations. The analyzed studies often extrapolated conclusions about MR-proADM based on a combination of different biomarkers and/or scores and not from the analysis of MR-proADM alone. Moreover, most of research studies included in the present work were not conducted in the ED and were conducted in the ICU. The population sample and design of the studies were often not homogeneous. Due to these considerations, it is essential to perform more studies in the context of ED and to identify good biomarkers or a combination of biomarkers and their cut off values that are able to promptly recognize the different phenotypes of septic patients in order to stratify the most urgent patients in order to improve the quality of care and survival, starting directly from the ED. The summary of studies exploring the role of MR-proADM can be seen in Table 1.

#### **Table 1.** Summary of studies exploring the role of proadrenomedullin (MR-proADM).

#### **5. Conclusions**

Data extracted from this narrative literature review showed that MR-proADM may be helpful as a prognostic biomarker to stratify the mortality risk in cases of sepsis and septic shock with different degrees of organ damages directly in the ED. Sepsis and septic shock are conditions of high complexity and high mortality-risk. In the ED, early diagnosis is crucial to provide early treatment and to improve patient survival. Diagnosis and prognosis are often the result of a combination of several tests. In our opinion, testing MR-proADM directly in the ED could help emergency physicians to facilitate the subsequent clinical management and intensive treatment of septic patients with better patient survival results.

**Author Contributions:** Conceptualization, A.P. and A.S.; methodology, S.C. and F.V.; software, M.C. (Marcello Candelli) and M.C. (Marcello Covino); validation, A.P., F.F. and Y.L.; formal analysis, M.C. and G.T.; investigation, T.d.C. and P.T.; resources, C.Z.; data curation, M.C.S.; writing—original draft preparation, A.S., S.C. and F.V.; writing—review and editing, A.P. and A.S.; visualization, Y.L.; supervision, F.F. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research received no external funding.

**Institutional Review Board Statement:** Not applicable.

**Informed Consent Statement:** Not applicable.

**Data Availability Statement:** Not applicable.

**Conflicts of Interest:** The authors declare no conflict of interest.

#### **References**

## *Article* **Diagnostic Accuracy and Prognostic Value of Neutrophil-to-Lymphocyte and Platelet-to-Lymphocyte Ratios in Septic Patients outside the Intensive Care Unit**

**Silvia Spoto 1 , Domenica Marika Lupoi 1 , Emanuele Valeriani 1 , Marta Fogolari 2,\*, Luciana Locorriere 1 , Giuseppina Beretta Anguissola 1 , Giulia Battifoglia 1 , Damiano Caputo 3 , Alessandro Coppola 3 , Sebastiano Costantino 1 , Massimo Ciccozzi 4 and Silvia Angeletti 2**

**Abstract:** *Background and Objectives*: The aim of this study was to evaluate the diagnostic accuracy and prognostic value of neutrophil-to-lymphocyte (NLR) and platelet-to-lymphocyte (PLR) ratios and to compare them with other biomarkers and clinical scores of sepsis outside the intensive care unit. *Materials and methods*: In this retrospective study, 251 patients with sepsis and 126 patients with infection other than sepsis were enrolled. NLR and PLR were calculated as the ratio between absolute values of neutrophils, lymphocytes, and platelets by complete blood counts performed on whole blood by *Sysmex* XE-9000 (Dasit, Italy) following the manufacturer's instruction. *Results*: The best NLR value in diagnosis of sepsis was 7.97 with sensibility, specificity, AUC, PPV, and NPV of 64.26%, 80.16%, 0.74 (*p* < 0.001), 86.49%, and 53.18%, respectively. The diagnostic role of NLR significantly increases when PLR, C-reactive protein (PCR), procalcitonin (PCT), and mid-regional pro-adrenomedullin (MR-proADM) values, as well as systemic inflammatory re-sponse syndrome (SIRS), sequential organ failure assessment (SOFA), and quick-sequential organ failure assessment (qSOFA) scores, were added to the model. The best value of NLR in predicting 90-day mortality was 9.05 with sensibility, specificity, AUC, PPV, and NPV of 69.57%, 61.44%, 0.66 (*p* < 0.0001), 28.9%, and 89.9%, respectively. Sensibility, specificity, AUC, PPV, and NPV of NLR increase if PLR, PCR, PCT, MR-proADM, SIRS, qSOFA, and SOFA scores are added to NLR. *Conclusions*: NLR and PLR represent a widely useful and cheap tool in diagnosis and in predict-ing 90-day mortality in patients with sepsis.

**Keywords:** neutrophil-to-lymphocyte; platelet-to-lymphocyte; C-reactive protein; procalcitonin; MRproAdrenomedullin; systemic inflammatory response syndrome; sequential organ failure assessment; quick-sequential organ failure assessment; sepsis; septic shock

#### **1. Introduction**

Sepsis is a systemic syndrome induced by infection and leading to a widespread inflammation up to septic shock, multi organ failure, and death [1,2]. Patients with bacteriemia, sepsis, and septic shock presented a high mortality rate ranging from 25% to 30% and 40% to 50%, respectively [3,4]. Patients' prognosis and mortality rate, however,

**Citation:** Spoto, S.; Lupoi, D.M.; Valeriani, E.; Fogolari, M.; Locorriere, L.; Beretta Anguissola, G.; Battifoglia, G.; Caputo, D.; Coppola, A.; Costantino, S.; et al. Diagnostic Accuracy and Prognostic Value of Neutrophil-to-Lymphocyte and Platelet-to-Lymphocyte Ratios in Septic Patients outside the Intensive Care Unit. *Medicina* **2021**, *57*, 811. https://doi.org/10.3390/ medicina57080811

Academic Editor: Win Sen Kuan

Received: 30 June 2021 Accepted: 31 July 2021 Published: 7 August 2021

**Publisher's Note:** MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

**Copyright:** © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

are strictly affected by a timely performed clinical and laboratory diagnosis as well as by proper therapeutic management [5–7].

Blood cultures represent the gold standard for microbiological diagnosis of sepsis [6]. Unfortunately, they yielded positive results in just a third of cases and may require several days for positivization even if newer and more expensive molecular techniques are used (e.g., polymerase chain reaction and mass spectroscopy) [8–18].

To overcome these issues, several scores such as SIRS and qSOFA were introduced in clinical practice to help diagnosis, disease severity stratification, and prognostic evaluation [5,19,20]. Adding laboratory biomarkers increases the usefulness of these scores in guiding clinical and therapeutic choices [12–26]. Among these, C-reactive protein (PCR, ≥ 5 mg/dL), procalcitonin (PCT, ≥0.5 ng/mL), and mid-regional pro-adrenomedullin (MR-proADM, ≥1.50 nmol/L) showed the highest diagnostic and prognostic power, but they were expensive and not widely available [15,26–29]. Conversely, the neutrophil-tolymphocyte ratio (NLR) represents a widely available, inexpensive, and easily performed marker that has been recently evaluated for its diagnostic and prognostic role in sepsis. NLR early expresses the relationship between innate (neutrophils) and adaptive cellular immune response (lymphocytes) during pathological states. [30]. Mean NLR values below 2 (1,6) are representative of healthy people (without differences in sex category or race) [30,31], while it may increase up to values of >10 in sepsis and >20 in septic shock, with good sensibility and specificity [30–44]. NLR seems to also vary in relation to different bacterial pathogens, with the lowest and highest values in Gram-positive and Gram-negative or polymicrobial sepsis, respectively [37–39].

NLR, however, may be affected by some clinical condition or therapies resulting in false positive (e.g., corticosteroids) or false negative (e.g., chemotherapy, radiotherapy, antibiotic therapy, Cachexia) results [31].

Along with NLR, the monocyte-to-lymphocyte ratio (MLR), the platelet-to-lymphocyte ratio (PLR), and the mean platelet volume-to-platelet count (MPV/PC) ratio have been studied recently, but the results are contrasting [30–39].

The aim of this study was to evaluate the diagnostic accuracy and prognostic value of NLR, PLR, and MLR in patients with sepsis and septic shock outside the intensive care unit (ICU) and to compare them with C-reactive protein (CRP), PCT, MR-proADM, *SIRS*, qSOFA, and SOFA scores.

Furthermore, we evaluated the role of NLR in aetiological diagnosis of sepsis and on length of stay stratification.

#### **2. Materials and Methods**

The study was approved on 23 July 2016 by the Ethical Committee of the University Hospital Campus Bio-Medico of Rome (28.16 TS Com Et CBM). All methods were performed in accordance with the relevant guidelines and regulations. Informed consent was not required for the retrospective design of the study.

#### *2.1. Patients Selection and Study Design*

Consecutive patients with clinically suspected sepsis or septic shock admitted to the Diagnostic and Therapeutic Medicine Department and General Surgery of the University Hospital Campus Bio-Medico of Rome were retrospectively enrolled between May 2014 and February 2021.

Exclusion criteria were age < 18 years and pregnancy.

The control group included patients with infection, but without sepsis admitted to the Diagnostic and Therapeutic Medicine Department between May 2014 and February 2021.

Diagnosis of sepsis was performed according to the Third Consensus Conference Criteria of 2016 when qSOFA or SOFA scores were ≥2 from the baseline in the presence of an infection.

Bloodstream infection was defined as any positive blood culture for pathogens. Pneumonia was defined based on a positive pathogen respiratory culture and other Infectious

Diseases Society of America (IDSA) diagnostic criteria [45]. Patients with positive urine cultures were identified as cases based on the CDC National Healthcare Safety Network (NHSN) UTI case definitions [46].

Baseline patients' characteristics were retrospectively collected form medical records including demographic information (age, sex category), presence of comorbidities (cardiovascular, pulmonary, kidney, liver disease), immune status (active malignancy or other causes of an immunosuppression), immunosuppressive treatments (corticosteroids, antibiotics), laboratory values (complete blood count, NLR, PLR, MLR, PCR, PCT, MR-proADM), and clinical scores (e.g., SIRS, qSOFA, SOFA).

#### *2.2. Laboratory and Microbiological Parameters*

Complete blood counts (CBCs) were performed on whole blood by *Sysmex* XE-9000 (Dasit, Italy) following the manufacturer's instruction. NLR, PLR, and MLR were calculated by the ratio between absolute values of neutrophils, lymphocytes, monocytes, respectively, and that of platelets.

CRP protein was measured by Alinity c (Abbott, diagnostics) following the manufacturer's instruction.

PCT and MR-proADM plasma concentrations were measured by an automated Kryptor analyzer, using a time-resolved amplified cryptate emission (TRACE) technology assay (Kryptor PCT; Brahms AG; Hennigsdorf, Germany) with commercially available immunoluminometric assays (Brahms) [5,21,25,26].

Blood specimens from patients were collected in BACTEC bottles containing anaerobic or aerobic broth and resins. Blood culture bottles were incubated in BACTEC FX instrument (Becton Dickinson, Meylan, France) until they were positive for bacterial growth or for a maximum of 5 days. Positive samples were cultivated in selective agar media. Growing colonies were identified by MALDI-TOF (Brahms) [5,21,25,26]. Selective and non-selective media were used for microbiological cultures.

#### *2.3. Statistical Analysis*

Data were analysed using Med-Calc <IP_ADDRESS> statistical package (MedCalc Software, Mariakerke, Belgium). Receiver operating characteristic (ROC) analysis was performed among independent variables associated with sepsis to define the cutoff point for NLR, PLR, plasma PCR, PCT, MR-proADM, SIRS, SOFA, and qSOFA score values. ROC curves and areas under the curve (AUCs) were calculated for all markers and compared in patients with sepsis or septic shock versus control patients.

χ2 for proportions test was used to compare the relative percentage of patients with positivity and/or negativity to SIRS criteria, SOFA score, qSOFA score, and other demographic characteristics of septic patients and control patients.

Positive predictive value (PPV) and negative predictive value (NPV) were calculated for each variable, based on sensitivity, specificity, and disease prevalence. Younden Index was used for cut-off selection.

The multivariate logistic regression model is performed to evaluate the association between all evaluable laboratory markers and 90-day mortality.

Mann–Whitney test was used for median values' comparison. *p*-value < 0.05 was considered significant.

#### **3. Results**

#### *3.1. Baseline Patients' Characteristics*

Demographic and clinical characteristics of patients with sepsis (251 patients) and the control group (126 patients) are reported in Table 1.

Patients with sepsis were younger than the control group (73 vs. 80, *p* = 0.001), while roughly half of the patients in both groups were male (52.6 vs. 50.4%, *p* = 0.771).

The vast majority of baseline patients' characteristics were similar between septic patients and control group (Table 1), except for the presence of presence of cancer and chronic lung disease that was more (36.7% vs. 23.8%, *p* = 0.016) and less frequent (23.1 vs. 34.1, *p* = 0.031), respectively, in the former.

In septic patients, median SIRS, qSOFA, and SOFA scores' values were 2 (IQR, 1 to 3), 2 (IQR, 1 to 2), and 4 (IQR, 2 to 6), respectively. One hundred out of 251 patients (39.8%) had septic shock and 47 out of 251 patients (18.7%) required ICU transfer during hospitalization.

The median length of stay was higher in septic patients than the control group (15 days (IQR, 11 to 26) vs. 10 days (IQR 7 to 13), *p* ≤ 0.001) and a significantly higher proportion of patients with sepsis died during 90-day follow-up (27.5% vs. 0.8%, *p* < 0.001).

#### *3.2. Diagnostic Role of NLR*

For the diagnosis of sepsis, the best value of NLR was 7.97 with sensibility of 64.26%, specificity of 80.16%, AUC of 0.74 (*p* < 0.001), PPV of 86.49%, and NPV of 53.18%. The ROC curve is reported in Figure 1A. In Table 2, the diagnostic role of NLR is compared with

that of PLR, PCR, PCT, and MR-proADM, as well as with that of SIRS, q-SOFA, and SOFA scores. MLR did not reach a significant role in the diagnosis of sepsis.

**Figure 1.** (**A**) Receiver operating characteristic (ROC) curve analysis, showing neutrophil-to-lymphocyte (NLR) ability to differentiate Scheme 7.97. (**B**) ROC curve analysis, showing NLR ability in to predict 90-day mortality in septic patients; the best value of NRL was 9.05.

**Table 2.** Diagnostic role of NLR by ROC curve analysis.

Area under the curve (AUC); positive predictive value (PPV); negative predictive value (NPV). NLR, neutrophil-tolymphocyte; PLR, platelet-to-lymphocyte; PCR, C-reactive protein; PCT, procalcitonin; MR-proADM, mid-regional pro-adrenomedullin; SIRS, systemic inflammatory response syndrome; SOFA, sequential organ failure assessment.

The diagnostic role of NLR significantly increases when PCR, PCT, and MR-proADM values, as well as SIRS, qSOFA, and SOFA scores, were added to the model (Table 3).

When just PCT and MR-proADM are considered in the diagnosis of sepsis, the model reached a PPV of 96% and a NPV of 69%. PPV and NPV for SIRS ≥2, qSOFA ≥2, and SOFA ≥2 were 96.77% and 43.3%, 99.23 and 50.21%, and 82.94% and 54.21%, respectively.

The best values of PPV and NPV are reached when NLR, PLR, and SIRS scores (99.7% and 94%, respectively), or NLR, PLR, and qSOFA scores (99.9% and 95.6%, respectively), are included in the model.

NLR, MLR, and PLR did not show a significant role in aetiological diagnosis of sepsis. Conversely, our results confirm the role of PCT in aetiological diagnosis of sepsis with higher values in Gram-negative versus Gram-positive bacteria (*p* = 0.0022). Furthermore, MR-proADM values are significantly higher in Gram-negative (*p* = 0.037) and polymicrobial (*p* = 0.037) than Gram-positive sepsis.

**Table 3.** Comparison of the diagnostic role of NLR with other inflammatory markers or clinical scores: positive predictive value (PPV) and negative predictive value (NPV).

\* Cut-off values: NLR, 7.97; PLR, 370.59; PCR, 37.88 mg/dL; PCT, 0.41 ng/mL; MRproADM, 1.83 ng/mL; SIRS, q-SOFA, SOFA ≥ 2. NLR, neutrophil-to-lymphocyte; PLR, platelet-to-lymphocyte; PCR, C-reactive protein; PCT, procalcitonin; MR-proADM, mid-regional pro-adrenomedullin; SIRS, systemic inflammatory response syndrome; SOFA, sequential organ failure assessment.

#### *3.3. Role of NLR in Predicting 90-Day Mortality*

The best value of NLR in predicting 90-day mortality was 9.05, with sensibility, specificity, AUC, PPV, and NPV of 69.57%, 61.44%, 0.66 (*p* < 0.0001), 28.9%, and 89.9%, respectively. The ROC curve is reported in Figure 1B.

The prognostic role of NLR in comparison with that of PLR, PCR, PCT, and MR-proADM values, as well as with that of SIRS, qSOFA, and SOFA scores, is listed in Table 4.

**Table 4.** Role of NLR in predicting 90-day mortality.

Area under the curve (AUC); positive predictive value (PPV); negative predictive value (NPV). NLR, neutrophilto-lymphocyte; PCR, C-reactive protein; PCT, procalcitonin; MR-proADM, mid-regional pro-adrenomedullin; SIRS, systemic inflammatory response syndrome; SOFA, sequential organ failure assessment.

Sensibility, specificity, AUC, PPV, and NPV of NLR increase if PLR, PCR, PCT, MRproADM, SIRS, qSOFA, and SOFA scores are added to NLR (Table 5).

MLR was not statistically significant in the 90-day mortality prediction.

Multivariate logistic regression model including all evaluable laboratory markers showed as just MR-proADM is significantly associated with 90-day mortality (Table 6).

**Table 5.** Improvement of the prognostic role of NLR with further biomarkers or clinical scores: positive predictive value (PPV) and negative predictive value (NPV) reached by the association of different biomarkers and clinical scores.

\* Cut-off values: NLR, 9.05; MRproADM, 3.21 ng/mL; SIRS, q-SOFA, SOFA ≥2. NLR, neutrophil-to-lymphocyte; MR-proADM, mid-regional pro-adrenomedullin; SIRS, systemic inflammatory response syndrome; SOFA, sequential organ failure assessment.

#### **4. Discussion**

The results of this study showed that NLR values of 7.97 had a good diagnostic accuracy, whereas a value of 9.05 allowed a prognostic stratification of patients with sepsis that is increased by the association with PLR values of 370.59. Conversely to PCT and MR-proADM, NLR did not help identify the type of bacterial pathogen responsible for sepsis. MLR evaluation did not yield significant results.

Patients with sepsis presented a higher 90-day mortality (27.5%) and need for ICU transfer (18.7%) than the control group. However, these proportions of patients resulted lower than data available from previous studies, where mortality and ICU transfer reached values as high as 37.5% and 80.8%, respectively [47].

Performing a complete blood count and calculating NLR and PLR in a clinical suspicion of sepsis may, therefore, help the clinician in diagnostic evaluation and prognostic stratification of patients with significant values of sensibility, specificity, PPV, NPV, and AUC (*p* < 0.0001). These latter values were similar to the values of PCT >0.41 and MRproADM >1.83 and are increased by the association with PLR values (PPV of 96% and NPV of 83%) and clinical score of sepsis such as SIRS (PPV of 99.7% and NPV of 94.0%), qSOFA (PPV of 99.9% and NPV of 95.6%), and SOFA (PPV 98.3% and NPV on 91.6%). In our study, the association between NLR and SIRS or qSOFA reached higher diagnostic power than the association between NLR and SOFA. This may be related to the clinical setting; our patients, indeed, were hospitalized in a medical ward and outside the ICU.

Furthermore, the best values of NLR, CRP, PCT, and MR-proADM for a diagnosis of sepsis were lower than the values reported from previous studies (10, 5 mg/dL, 0.5 ng/mL, and 1.5 nmol/L respectively) [5,25,26,28,30–44]. This may be related to a prompt laboratory evaluation performed immediately after the suspicion of sepsis. These biomarkers, indeed, have a turnaround time of less than an hour for complete blood count and one hour for CRP, PCT, and MR-proADM. A prompt availability of these biomarkers may reduce the delay between the diagnosis of sepsis and the administration of an effective treatment.

As for sepsis diagnosis, NLR values of 9.05 showed a good role in prognostic stratification in terms of 90-day mortality. This is increased by its combination with both MR-proADM (PPV of 52% and NPV of 50%) and clinical scores of sepsis such as SIRS (PPV of 95% and NPV of 86%), q-SOFA (PPV of 96% and NPV of 88%), and SOFA (PPV of 94.6% and NPV of 55.7%).

Knowing that, the shorter the time between clinical presentation and diagnosis, the better the patients' prognosis, NLR may ameliorate septic patients' management. This, latter, further increases when the clinical score such as SIRS and qSOFA is used in association with NLR.

The results of our study certainly showed that a prompt and accurate diagnosis of sepsis may be achieved by the use of rapid, cheap, and widely performed biomarkers, as well as in those clinical setting where the use of other biomarkers may be not available or too expensive. Outside the ICU, adding information derived by these biomarkers to clinical score such as SIRS or qSOFA reached a diagnostic accuracy of about 100%.

A limitation of the study is the monocentric enrollment of patients, which should be expanded in the future to be multicentric, thus increasing the number of patients, which is limited to 251 in this first study.

#### **5. Conclusions**

NLR is a good, rapid, cheap, and widely performed biomarker useful in diagnosis and prognostic stratification of patients with sepsis. The association of NLR with other biomarkers and clinical scores further increases these characteristics. Only the association between clinical signs and several biomarkers may help increase the diagnostic sensibility of sepsis and predict disease severity and mortality. Biomarkers must be performed in supporting a clinical diagnosis. We hope that the use of NLR may improve the management and ameliorate the prognosis of patients with sepsis.

**Author Contributions:** Conceptualization, S.S. and S.A.; Methodology, S.S. and S.A.; Software, D.M.L. and E.V.; Validation, L.L., G.B.A., M.F., and E.V.; Formal analysis, S.S. and E.V.; Investigation, D.M.L. and E.V.; Data curation, S.S.; writing—original draft preparation, S.S., S.A., and E.V.; writing—review and editing, S.S., S.A., and E.V.; visualization, M.F., M.C., D.C., A.C., G.B., and S.C.; supervision, S.S., M.C., and S.C.; project administration, S.S. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research received no external funding.

**Institutional Review Board Statement:** The study was conducted according to the guidelines of the Declaration of Helsinki and approved by the Ethical Committee of the University Hospital Campus Bio-Medico of Rome (28.16 TS Com Et CBM).

**Informed Consent Statement:** Informed consent was not required for the retrospective design of the study.

**Data Availability Statement:** The data presented in this study are available on request from the corresponding author. The data are not publicly available due to their containing information that could compromise the privacy of research participants.

**Conflicts of Interest:** The authors declare no conflict of interest.

#### **Abbreviations**

#### **References**

## *Editorial* **Sepsis: New Challenges and Future Perspectives for an Evolving Disease—Precision Medicine Is the Way!**

**Antonio Mirijello 1,\* and Alberto Tosoni 2,\***

Sepsis still remains the leading cause of in-hospital death in the world [1,2]. In the very recent years, this condition became even more evident with the appearance of COVID-19, which has reached an unexpected burden in terms of morbidity and mortality worldwide [3]; the severe form of COVID-19 is characterized by multi-organ failure, mainly secondary to an inappropriate host response, which can be considered a full-fledged sepsis [4]. In addition, SARS-CoV-2 infection has been shown to be an independent risk factor for the development of bloodstream infection (BSI) and sepsis in hospitalized patients [5].

The knowledge in the field of sepsis has accumulated over time. Nevertheless, significant gaps in understanding the pathophysiological aspects and the management possibilities of this deadly condition are still present.

The Special Issue "New Strategies for Treatment of Sepsis" was thought as an opportunity to bring together high-quality manuscripts that showcase the current knowledge on the management of sepsis. We were particularly aware that several unmet needs still needed to be addressed: the comprehension of mechanisms underlying the development and progression of sepsis, the use of new diagnostic tools (including artificial intelligence) for a better and less invasive approach, and the development of antimicrobial strategies in order to effectively fight antimicrobial resistance [1].

The findings reported in the studies published as part of this Special Issue further confirm the potential beneficial role of a deep understanding of mechanisms underlying sepsis, both in reference to the characteristics of microbes and of hosts involved, which in their singularity go to outline different types of sepsis each time. In this way this Special Issue pave the way for future investigations aimed at further dissecting the impact of Precision Medicine as the leading strategy for treatment of sepsis.

Specifically, the article by Rossetti et al. comprehensively analyzed the substantial changes in the homeostasis of micronutrients connected with sepsis and its regulatory processes [6]. In particular, the roles of Vitamin D, Vitamin C, Thiamine and Zinc, all involved in inflammatory or immune response processes, were analyzed. Authors reviewed several studies, many of which have failed to achieve statistical significance or contradict each other. However, the main limitation of these studies, having mortality as outcome, is that the action of micronutrients on seriously ill patients may be less relevant, probably because the severity of organ failure is the result of several metabolic pathways that cannot be easily reverted. Research on this topic should consider reliable and clinically sensitive surrogate outcomes besides mortality, since in seriously ill patients the outcome is too often confused by concomitant factors.

On this connection, the article by Aisa-Alvarez et al. highlighted the antioxidant effect of Vitamin C, Vitamin E, N-acetylcysteine, and Melatonin in patients with septic shock determining the SOFA score and measuring antioxidant markers in plasma [7].

**Citation:** Mirijello, A.; Tosoni, A. Sepsis: New Challenges and Future Perspectives for an Evolving Disease—Precision Medicine Is the Way! *Medicina* **2021**, *57*, 1109. https://doi.org/10.3390/ medicina57101109

Received: 11 October 2021 Accepted: 13 October 2021 Published: 15 October 2021

**Publisher's Note:** MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

**Copyright:** © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

Other secondary outcomes were measured on day 28th including mortality due to any cause, ventilator-free days, ICU-free days, and hospital-free days. The results showed that antioxidant therapy associated with standard therapy reduces multi-organ failure, oxidative stress, and inflammation in patients with septic shock. The strengths of this study are certainly the monitoring of the plasma levels of the micronutrients administered, the evident paucity of treatment-associated side effects, a rapid assessment of patients that allowed to start the administration of micronutrients in a much faster way compared to other comparable studies. Moreover, this is the first study in which the use of Melatonin has been tested in humans with septic shock.

Back to pathophysiological aspects of sepsis, the study by Cutuli et al. analyzed the possibility of both pharmacological and extracorporeal immune modulation in critically ill septic patients [8]. In the last few years, an increasing body of evidence has demonstrated that the administration of immune modulating drugs can mitigate both pro- and antiinflammatory bursts due to an infection and should be considered as a complementary therapy to be associated with appropriate etiologic therapies (e.g., source infection control and antibiotics). However, the real application of this complementary treatment is still a matter of debate due to controversial results between laboratory and clinical trials. Trials may be inconclusive or discordant with each other due to the great heterogeneity of septic patients enrolled [9]. It is mandatory to push towards a personalized approach trying to distinguish the peculiar characteristics of each septic patient, in order to better choose and monitor the therapy to be tested and the effects to be evaluated.

Pursuing a personalized medicine of septic patients, which also includes the differentiation of types of sepsis and the context in which they develop, the article by Bertozzi et al. gives a detailed description of Neutropenic Enterocolitis (NE) and its frequent association with sepsis [10]. NE is an acute alteration of the intestinal mucosa, mainly of the colon, which develops in immunocompromised patients with a history of cancer and chemotherapy in the previous month, particularly treated with those agents that cause mucositis such as taxanes. This condition has an extremely high lethality rate (79% of patients with histologically confirmed NE died after a median survival of 1 day) and septicemia occurs frequently. The demonstration of an altered intestinal mucosal barrier would seem to support the hypothesis of translocation as a prerequisite for subsequent bacteremia, sepsis, and multi-organ failure.

The study by Perrotta et al. describes the case of a patient affected by thrombotic thrombocytopenic purpura (TTP) admitted to an ICU after developing a hospital-acquired SARS-CoV-2 interstitial pneumonia, further complicated by a K. Pneumoniae NDM sepsis [11]. The antibiotic treatment was effective not only for the treatment of sepsis, but also for intestinal decolonization. This is the first report in literature on intestinal decontamination using the ceftazidime/avibactam + aztreonam combination as treatment for Klebsiella pneumoniae NDM sepsis. This article allows a reflection on the risk of bacteremia related to intestinal colonization with KPC-Kp and on the possibility that a specific acquired condition such as SARS-CoV-2 infection may increase this risk, either through a direct mechanism of infection at intestinal level, either following the use of immuno-modulatory therapies, both capable of increasing bacterial translocation in the intestinal tract.

On this connection, again with a view to a personalized medicine that allows managing the infection in the context of the patient's singularity, the study by Murri et al. acquires relevance [12]. It took into consideration the management of candidemia and the frequent overtreatment of this condition. Indeed, overtreatment may be associated with several disadvantages: possible increase in antifungal resistance, drugs-related adverse events and high costs. The intervention of a stewardship program associated with a biomarker such as beta-D-glucan has been shown to be effective in reducing the excessive duration of treatment without impacting length of hospitalization or mortality.

Another thriving line of research concerns diagnostic tools for an early and accurate diagnosis of sepsis, taking into account not only the type of infection and the characteristics of host, but also the context in which the patient is being managed.

Covino et al. retrospectively analyzed a monocentric cohort of patients presenting to ED with fever, over a 10-year period, and subsequently hospitalized [13]. The aim of this study was to ascertain whether PCT determination at ED could improve patient's prognosis with respect to those with no PCT assessment. As main result, in the whole sample of 12.062 evaluated patients, the PCT-guided management was not associated with a better outcome. However, two subgroups of patients showed a clinical benefit from this approach: those who received a final diagnosis of bloodstream infection and those with a qSOFA ≥ 2. At a closer look, this work underlines the importance of PCT in the management of the septic patient, rather than in its early diagnosis.

Even though literature data recommend the use prediction scores to early recognize those patients at risk for sepsis and poor in-hospital outcome, there is still a significant burden of uncertainty on the optimal prognostic score to be used (e.g. qSOFA, SOFA, SIRS, EWS). Sozio and Colleagues focused their research on the most accurate predictor of in-hospital mortality outcome in septic patients presenting to the ED [14]. Their retrospective monocentric study included 1014 patients admitted to two ED in Tuscany, Italy, for suspected sepsis. Among them the diagnosis of sepsis was confirmed in 651 patients, while 363 received an alternative diagnosis. A Bayesian mean multivariate logistic regression model identified septic shock and positive qSOFA as independent risk factors for in-hospital mortality while hyperthermia was a protective factor. In other words, the absence of fever could identify sicker patients who are not able to properly respond to infection (anergy), thus at higher risk of mortality.

Shifting the gaze from the ED setting to that of Internal Medicine departments, the management of patients with a septic state and a bloodstream infection still represents a challenge for the heterogeneity of the population and the scarcity of literature data on the optimal management.

Our research group focused on the prognostic accuracy of delta-PCT (a reduction of PCT > 50% after 48 h, >75% after 72 h, and >85% after 96 h) in predicting mortality of Internal Medicine patients with microbiological identified sepsis [15]. In a sample of 80 patients with at least two available PCT determinations, those patients with Delta-PCT showed a significantly higher proportion of survival both at 28-days and 90-days. Delta-PCT can therefore be used to predict the prognosis of septic patients admitted to internal medicine wards.

The possible application of new diagnostic markers was evaluated by Piccioni et al. who reviewed the current literature on the use of presepsin and proadrenomedullin in the setting of ED [16,17]. Presepsin is a fragment of the soluble form of CD14 (sCD14), after being cleaved by plasma cathepsin D; it contributes to the activation of the innate immune response. Proadrenomedullin derives from the degradation of adrenomedullin into a fragment of 48-amino acids; it is mainly produced by endothelium and smooth muscle cells and exerts its effects on vasodilatation, bronchodilatation, promoting diuresis and myocardial contractility. Levels of these two peptides rise during bloodstream infections, thus they have been proposed in the setting of early identification of septic and critical patients. However, their ability to add significant information compared to those given by PCT is still matter of debate. In any case, given that a single biomarker cannot give an unfailing and absolute answer in the setting of prognostication [9], expanding diagnostic possibilities is warranted.

Similarly, Spoto and Colleagues tested the diagnostic accuracy and prognostic validity of neutrophil-to-lymphocyte (NLR) and platelet-to-lymphocyte (PLR) ratios in comparison with other biomarkers of sepsis in non-ICU wards [18]. They found them good, rapid and cheap biomarkers to help clinician in the identification and prognostic stratification of patients with sepsis.

In summary, the field of sepsis is exceptionally diverse and it is a rapidly growing area of research and development.

 **Author Contributions:** A.M. and A.T. equally worked on the conceptualization, writing, review and editing of the paper. Members of Internal Medicine Sepsis Study Group participated in the writing and revision process. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research received no external funding.

**Conflicts of Interest:** The authors declare no conflict of interest.

#### **References**

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**1. Introduction**

190 Biomedical Science, Engineering and Technology

*Chem. Pharm. Bull. (Tokyo).* 1998; 46(1): 113-119.

inhibitors from Brazilian natural medicine, the leaves of Myrcia multiflora DC. (Myrtaceae): structures of myrciacitrins I and II and myrciaphenones A and B".

> Atherosclerosis, an inflammatory disease which causes thickening and stiffening of arteries, is a major cause of death in the United States (Lloyd-Jones et al., 2010). These deaths occur because of vessel occlusion created by atherosclerotic plaques and thrombus shedding, leading to heart attack, ischemia, or stroke. Atherosclerosis is expected to be the leading cause of death worldwide within 10 years (Lloyd-Jones et al., 2010).

> Inflammation plays a significant role in the initiation and progression of atherosclerosis. The cells that line the arteries, endothelial cells (ECs), mediate the inflammatory process. The forces created by blood flow affect the inflammatory response of ECs and the interaction with blood components. This chapter summarizes the background in our recent studies on the response of ECs to blood forces and the interaction of inflammatory cells.


Meet the editor

Carlos A. Reusser earned a BEng in Naval Electrical Engineering from the Naval Polytechnic Academy (APOLINAV), Chile, in 2001 and served in the Chilean Navy for twenty years. He also received a master's degree in Asset Management and an MSc and Ph.D. in Power Electronics, all from Universidad Tecnica Federico Santa Maria (UTFSM), Chile, in 2010, 2014, and 2020, respectively. From 2011 to 2019, Dr. Reusser was a lecturer at APO-

LINAV. In 2015, he became a lecturer at UTFSM. In 2020, he became an associate professor at Pontificia Universidad Catolica de Valparaiso, Chile. His main research interests include sensorless control, power converters, and electric ship applications.

## Contents


**4. Themes**

The reviewed literature revealed that there are six (6) themes that the nurses use as their coping strategies when caring for MHCUs who are diagnosed with SUDs namely nurses' resilience, peer support, management support, strengthening the multidisciplinary team (MDT) approach, open-door policy as well as education and training. The themes and sub-themes are given in the following **Table 1**:

**Table 1.** *Themes and sub-themes.*

### **4.1 Nurses' resilience**

It is clear from the introduction of this chapter that nurses deal with challenges in their working environment, especially those that are working at mental health establishments, or those who are caring for MHCUs who are diagnosed with SUDs. In this case, we strongly believe that nurses need to strengthen their resilience. Nurses who manage to cope and in some instances even grow in the face of omnipresent stressful experiences are described as resilient [16]. Resilience refers to a person's capacity to withstand or recover quickly from difficult conditions [16]. The same study also refers to resilience as qualities of both the individual (internal protective factors) and the environment (external protective factors) that could support positive development [16]. We also have a strong view that nurses should use both the internal and external protective factors of resilience in order to cope when caring for MHCUs who are diagnosed with SUDs. Resilience can also be defined as the ability of people to adjust to unfavourable conditions in a positive way, and bounce back from hardships and overcome negative life experiences [17]. It is clear from the information, particularly in the introduction that nurses caring for MHCUs who are diagnosed with SUDs are working in unfavourable conditions. However, they should be able to view that situation in a positive way and overcome their negative life experiences of MHCUs diagnosed with SUDs. Most of the nurses when they care for MHCUs who are diagnosed with SUDs feel angry, demotivated and dissatisfied. This resulted in some of the nurses choosing to leave South Africa in search of greener pastures [18]. Based on the above information, nurses need the opportunity to develop resilient attributes in their different specialist areas [18], particularly in the area of mental health and SUDs. Coping skills increase resilience [12].

#### **4.2 Peer support**

Peer support has been mentioned in several studies as nurses' coping strategy when caring for MHCUs diagnosed with SUD [1, 11]. Workplace support provided by peers or colleagues and the organisation is of major importance in the direct delivery of nursing care as a lack of teamwork can compromise patient care [18]. However, it should also be noted that relying on support from outside the workplace can also play an important role in the ability of nurses to cope [18], particularly when they care for MHCUs who are diagnosed with SUDs. Having collegial support from other nurses and interprofessional team members is recommended to manage uncertainty [1]. A qualitative study recently conducted in the NWP found that nurses do not collaborate with one another and as a result, they are unable to deliver quality care to MHCUs diagnosed with SUD. The above information highlights the gap that, it is imperative that nurses have role support which includes the presence of supportive, knowledgeable colleagues with whom to collaborate and gain expertise in practice [1].

#### **4.3 Management support**

Management support is one of the strategies that nurses use when caring for MHCUs diagnosed with SUDs as shown in several studies [1, 11, 19]. Participants of a qualitative study that was conducted in 2016 in the NWP of SA indicated that it would be good if the nurses were supported and motivated by their own management [11]. Nurses mentioned in a study conducted in New Jersey that they have no problem of

### *Nurses' Coping Strategies When Caring for Mental Health Care Users Diagnosed with Substance… DOI: http://dx.doi.org/10.5772/intechopen.107034*

caring for MHCUs diagnosed with SUDs for as long as the MHCU load or nurse-topatient ratio is not too much because these MHCUs can be a handful at times [1]. This shows that the sooner the management supports the nurses by addressing the issue of nurse-to-patient ratio, the better the client outcome and the nurses' improved coping. Strengthening the prevention and treatment initiatives for addressing SUDs requires direct effort and partnership from employers (management), healthcare practitioners and researchers [19]. Managers and supervisors should create learning opportunities with the sole purpose of empowering nurses with relevant skills in providing care to mental health care users [18]. Health care practitioners should work collaboratively with the management of the mental health care institutions where they are working. The researchers should conduct more research that is aimed at assisting the nurses to cope better when they care for MHCUs who are diagnosed with SUDs.

#### **4.4 Strengthening the multidisciplinary team (MDT) approach**

Several studies mentioned strengthening the multidisciplinary team (MDT) approach as one of the strategies used by nurses who are caring for MHCUs diagnosed with SUDs [1, 8]. Nurses in collaboration with other disciplines have collective power to achieve more [10]. Two people are better off than one. Multidisciplinary team (MDT) approach is effective in caring for MHCUs who are diagnosed with SUDs. MDT approach consists of nurses, psychiatrists, pharmacists and dieticians who play a unique role in treating MHCUs who are diagnosed with SUDs [8]. For the purpose of this chapter, we suggest that the word mental health care practitioners be used to refer to MDT. According to the Mental Health Care Act 17 of 2002, mental health care practitioners also include psychologists, social workers and occupational therapists, who have been trained to provide the prescribed mental health care, treatment and rehabilitation services [14], including the care of MHCUs who are diagnosed with SUDs. Both collaboration and support with nurses and interprofessional colleagues will help manage the challenges in care and possibly mitigate the uncertainties in caring for this increasingly common patient population [1].

#### **4.5 Open-door policy**

Open-door policy is mentioned in the literature as one of the effective strategies used by the nurses who are caring for MHCUs diagnosed with SUDs. The practice of restricting the freedom of MHCUs who are diagnosed with SUDs by locking the doors of mental health care units is highly questionable [20] because everyone has the right to freedom of movement [21]. All MHCUs especially those who are diagnosed with SUDs are also protected by this right. The introduction of an open-door ward policy can reduce coercive measures like unnecessary seclusions, involuntary care, treatment and rehabilitation services, as well as incidents of aggression [20]. As a result, authors of this chapter advocate for open-door policy for all MHCUs who are diagnosed with SUDs. This will be in line with Section 21(1) of the Constitution of the Republic of South Africa (RSA) which states that "everyone has the right to freedom of movement. However, it should be noted that the MHCUs who are violent, aggressive, suicidal or homicidal, meaning those who are dangerous to themselves, or other people may be admitted involuntarily or be secluded. This is normally done after prescription by the medical doctor. The main reason for admitting these MHCUs is to protect them and other people such as families and health care practitioners. In this case, it does not mean that the MHCU's rights are violated, this is done to protect them.

#### **4.6 Education and training**

Many studies show that education and training play a major role for the nurses who are caring for MHCUs diagnosed with SUDs [1, 6, 11]. However, literature shows that some nurses do not have the necessary training and education for proper care, treatment and rehabilitation services for MHCUs who are diagnosed with SUDs. For instance, the nurses mentioned in a qualitative study that was conducted in the North West Province (NWP) of South Africa that they were taught at the university or the colleges how to care for, treat and rehabilitate MHCUs who are diagnosed with SUDs. However, the nurses maintained that caring, treating and rehabilitating an MHCU diagnosed with SUDs was not dealt with in greater detail [11]. The authors of this chapter are in agreement with this statement because substance use is presented like any other topic. There is no emphasis on it. Knowledge, skills and experience play a role in the nurses' ability to cope while providing mental health care [18]. Continuous workshops should be done for the nurses to help them deal effectively with the addicted MHCUs [12].

Another important study was conducted by two scientists from Kean University in New Jersey. The findings of the study indicated that nurses reported a lack of knowledge specific to mental disorders and SUD issues and reflected a disconnect in their ability to care for MHCUs with both physiological and psychiatric disorders [1]. The same study continues to mention that for the nurses to cope effectively with the MHCUs who are diagnosed with SUDs, nursing education programs should be created to assist nurses in developing skills in articulating and managing their uncertainty and to use evidence to guide practice [1]. This means that Nursing Education Institutions (NEIs) should also be part of the fight against SUDs.

A mixed methods study was conducted in Nigeria on the *Forex Index and Substance Abuse among Psychiatric Patients*. The findings of the study indicate that the staff in mental health care institutions including the mental health nurses should be trained on techniques of screening and detecting the use of psychoactive substances as well as on how to successfully rehabilitate MHCUs who are diagnosed with SUDs [6]. Education focusing on assessment, prevention and interventions to prevent violence and aggression, should be addressed in educational offerings, both in academia and in the clinical environment [1]. In addition, when the nurses are properly educated and trained on how to care, treat and rehabilitate MHCUs who are diagnosed with SUDs, they will be able to teach MHCUs about the dangers of substance abuse, including but not limited to the psychological and physical effects; the damage to relationships and family lives; and the impact on meeting basic needs such as holding down a job. These nurses who are well trained will also educate the MHCUs regarding treatment options, including those they can use on either an inpatient or outpatient basis and those they can use to stay substance-free long-term. The nurses might also educate MHCU's family members about what to expect from the rehabilitation process and how they can support their loved one's attempt to conquer addiction to the substances.


**2. Materials and Methods**

In this retrospective, cross-sectional study, patients who attended the Department of Ophthalmology, Hiroshima University Hospital, Japan, were evaluated between April 2017 and November 2018. The study received approval from the institution's ethics committee (E—797), and the research adhered to the tenets of the Declaration of Helsinki.

Sixty-one eyes from 50 patients with OHB who had undergone TLE with a fornixbased conjunctival flap using MMC at least 3 months prior to entry were analyzed in this study (OHB group). The eyes with multiple glaucoma surgery were also included in the OHB group. Sixty-five control eyes from 54 glaucoma patients who had no history of prior surgical intervention, except uncomplicated cataract surgery at least 3 months prior to their entry, were concurrently recruited during a similar period (control group). Best-corrected visual acuity (BCVA) and intraocular pressure (IOP; Goldman Applanation Tonometer, Haag-Streit, Köniz, Switzerland) were measured. The anterior segment was observed using slit lamp microscopy. In addition, all eyes with IOLs were using monofocal lenses.

The TOPCON KR-1W wavefront analyzer (Tokyo, Japan) can calculate "corneal" HOAs from the shape of the cornea as well as HOAs of the entire eye. We used the TOPCON KR-1W wavefront analyzer to measure corneal HOAs for a 4 mm pupil diameter without dilating the pupil, and the data were expanded to Zernike polynomials. The magnitude was demonstrated as the mean root square (RMS). Based on our reports, we evaluated corneal wavefront aberrations for coma (C−1 3 and C1 3), spherical aberrations (C0 4), the RMS of the third-order, fourth-order, and total HOAs. The RMS of the third-order Zernike coefficients (the square root of the sum of the squared coefficients of C−3 3, C−1 3, C1 3, and C3 3) was considered a coma-like aberration. The RMS of the fourth-order Zernike coefficients (the square root of the sum of the squared coefficients of C−4 4, C−2 4, C0 4, C2 4, and C4 4) was considered a spherical-like aberration. Finally, the total of HOAs was defined as the RMS of the magnitudes for the third- to fourth-order aberrations. All patients had BCVA of ≥20/40, which was enough to allow fixation on the target of the wavefront analyzer. Aberrometry measurements were automatically measured three times.

For clinical photographic images, we used the TOPCON SL-D8Z slit lamp mounted camera (Tokyo, Japan) to evaluate the anterior ocular segment (×10) from 40 degrees on the temporal side using a diffuser by 50–75 Ws (Watt seconds). OHB was diagnosed if the cornea was covered with bleb under the slit lamp. The dimensional parameters in clinical photographic images were calculated using the NIH image J software (Image J, National Institute of Health, Bethesda, Maryland, USA). The entire corneal area and the area of the bleb over the cornea were measured each as pixels. The ratio of cornea covered by bleb, the ratio of cornea covered by bleb to the entire cornea was calculated as the ratio of the OHB area in the cornea relative to the entire corneal area (Figure 1). We calculated the ratio of the cornea covered by the bleb as follows.

**Figure 1.** Clinical photographic image using slit lamp mounted camera and dimensions measured using NIH image J software. The ratio of cornea covered by bleb is the ratio of area of the cornea covered by bleb to entire cornea area. The red and black lines are the cornea covered by bleb area and entire cornea area, respectively.

The cornea covered by bleb area (pixels)/the entire cornea (pixels) × 100 (%)

The exclusion criteria were BCVA <20/40 and patients with any history of ocular surgery (other than uncomplicated cataract surgery) for the control group. Patients of the OHB group were not excluded for having had glaucoma surgery several times. Additionally, patients of corneal, conjunctival ocular disease observed on a slit-lamp microscopy were also excluded (e.g., pterygium, superficial punctate keratopathy, corneal opacity, and corneal erosion).

#### *Statistical Analysis*

Data were entered in an Excel spreadsheet (Microsoft Corp. Redmond, WA, USA) and analyzed using JMP software (ver. 14, SAS, Inc., Cary, NC, USA). Measurement data were expressed as the mean ± standard deviation with a 95% confidence interval. Continuous data from the two groups were analyzed by an independent *t*-test, whereas discrete data were analyzed using Pearson's chi-square test. The influence of age, IOP, and the ratio of bleb area on aberrations was analyzed using multiple linear regression. BCVA was converted into logMAR units for analysis. Differences were statistically significant when the *p*-value was <0.05.


*Article* **Backward Running: Acute E**ff**ects on Sprint Performance in Preadolescent Boys**

#### **Dimitrios Petrakis 1,**†**, Eleni Bassa 1,\*,**†**, Anastasia Papavasileiou 1, Anthi Xenofondos 2 and Dimitrios A. Patikas 1**

Received: 19 February 2020; Accepted: 20 April 2020; Published: 23 April 2020

**Abstract:** The aim of this study was to examine the acute effect of backward running (BwR) during warm-up on a 20-m sprint of boys' performance, compared to forward running (FwR). Fourteen recreationally active preadolescent boys (aged 12.5 ± 0.5 years) were examined in 3 protocols: warm-up (control condition), warm-up with 3 × 10 m additional BwR sprints and warm-up with 3 × 10 m additional FwR sprints. Participants were evaluated 4 minutes after each protocol on a 20-m sprint and intermediate distances, as well as the rate of perceived exertion (RPE). Sprint speed across 10–20 m was significantly higher for the BwR warm-up compared to the regular warm-up (*p* < 0.05) and a significantly higher RPE after the BwR and FwR protocols compared to the control condition was recorded (*p* < 0.05). No significant difference was detected across the distances 0–5, 5–10, 0–10 and 0–20 m. Although adding 3 × 10-m sprints of BwR or FwR after the warm-up did not enhance performance in a 20 m sprint of preadolescent boys, the positive effect of BwR across 10–20 m distance suggests that BwR could be an alternative means for enhancing performance for certain phases of a sprint for this age. However, preadolescent boys' response to different sprint conditioning exercise stimuli and the optimization of rest time to maximize performance remain to be determined.

**Keywords:** preadolescence; child; post-activation performance enhancement; sprint; warm-up; rate of perceived exertion


**3.2 Information, the key to victory**

To meet all these requirements, information is one of the major foundations for the exercise of the command of the chief. It is the keystone of all military action, to keep the initiative and maintain supremacy on the ground [2].

In fact, information allows the chief to plan the military action, taking into account the means at his disposal, ensuring the transport logistics, and confronting the possible friendly and enemy modes of action in order to determine the manoeuvre that he will conduct.

The management of the information received is reflected "en conduite1 " by the regular rhythm of reports and situation updates to higher or subordinate levels, in order to anticipate threats and maintain a capacity to react as quickly and efficiently as possible in the face of adversity or any obstacle hindering the manoeuvre.

For the decision-making process to run smoothly, the information must be updated regularly because the situation can change very quickly and the leader will have to adapt his analysis accordingly.

Thus, there is no single decision of the military commander in operation, but a continuum of decisions, some of which are almost routine or implicit, while others require extensive analysis. Some decisions are ultimately critical, as they can result in a favourable or tragic outcome to a given situation.


*3.1. Nomenclature and Fundamental Aspects*

Graphene, discovered by Geim and Novoselov in 2004, is relatively a new two dimensional (2D) sheet-like material in which a honeycomb or hexagonal structure with a flat lattice configuration, completely composed of sp2 hybridized carbon atoms that are covalently bound, is densely packed[102,103]. Graphene, an atomic layer of graphite, is the unique carbon's allotrope, where each atom is tightly linked to its neighbors by an only electronic cloud in which a C–C bond distance is 0.142 nm [104]. It is considered as a fundamental basis for all carbon allotropes and as the mother of a graphitic family for all the dimensions.

Graphene-based nanomaterials (GNMs), the first materials reported as examples of 2D nanocarbons, can be classified based on the number of sheet layers, surface modifications, total oxygen content or orientation [105]. Graphene is highly hydrophobic and is prone to agglomeration, owing to the strong van der Waals' interactions between the 2D graphene sheets, leading to low surface area and ineffective use of its outstanding features [106]. These latter are also closely dependent on the graphene availability as a single layer because if the layers are in close vicinity to each other, they are likely to restack or agglomerate due to π–π interactions. Hence, its functionalization is commonly required to surpass these issues. Typically, three types of functionalization approaches through covalent (nucleophilic substitution, electrophilic substitution, condensation and addition), noncovalent (π–π bonding, electrostatic attraction and hydrogen bonding, etc.) or a combination of both interactions can be used, where the aromaticity of graphene can be either lost or preserved [107]. As shown in Figure 3a–e, GNMs can be found in various forms for which the most important ones that will be the focus of the present review are graphene nanosheets (GNS), graphene nanoplatelets (GNP), graphene

oxide (GO), reduced graphene oxide (RGO) and graphene and graphene oxide quantum dots (GQD). In the frame of the present review, the acronym GN will encompass GNS and GNP.

**Figure 3.** Some common forms of graphene: (**a**) graphene oxide, (**b**) pristine graphene, (**c**) functionalized graphene, (**d**) graphene quantum dot and (**e**) reduced graphene oxide. Reproduced with permission from Reference [46]. Licensed under a Creative Commons Attribution 3.0 International License (https://creativecommons.org/licenses/by/3.0/); (**f**) Different properties of graphene and its applications. Reproduced with permission from Reference [108]. Copyright ©2019, Elsevier.

Graphene oxide (GO), commonly prepared from the oxidation of graphite, consists of a few- or a single-layer sheet. GO sheets are rich in various oxygen-containing groups such as hydroxyl, epoxy, carboxyl, carbonyl, phenol, lactone and quinone, which can change the van der Waals interactions. The two former chemical groups are mostly present on the basal plane, whereas the others with small quantities are found at the sheet edges. These functional groups in GO can deeply influence its electrochemical, mechanical and electronic features. Despite the aromaticity of graphene is lost in GO, owing to exploitation of π electrons in the covalent bonding of these oxy groups on graphene backbone, the carbonyl, carboxyl and so forth groups at the edge render them more dispersible in both organic solvents and water [44,107]. The hydrophobic aromatic frameworks and the hydrophilic oxygen-containing groups make GO amphiphilic, allowing its interaction with inorganic and organic molecules.

Reduced graphene oxide (RGO), obtained by the reduction of GO [109], contains fewer oxygen atoms, hence, is less negatively charged [106]. During the reduction, RGO recovers the graphitic arrangements (partial recuperation of the sp2 from sp3 hybridization of GO) through the elimination of the oxygen-containing groups, which have been inserted in the oxidation step, thus, restoring the electronic properties of graphene [110]. This partial reduction and the exposure to some chemicals allow tailoring the conductivity, band-gap and optical features of the material [111,112].

Graphene quantum dots (GQDs), which can be found as single- or multiple layers, display interesting features such as good chemical stability, high surface area, tunable physical characteristics, stable photoluminescence and low toxicity [113,114]. They can be used in optoelectronic, electronic, biomedical, sensors and energy storage. They usually consist of up to 10 layers of 10–60 nm size RGO [46].

Graphene-based nanomaterials possess exceptional electrical, optical, mechanical, electrochemical and thermal features that make them versatile for a wide range of applications and have drawn worldwide attention in both academic and engineering fields [44,105]. They can be employed in industrial applications such as biomedical, solar cells, biosensors, supercapacitors, electromagnetic absorbers, optical devices, integrated circuit, protective coatings, organiclight-emitting diodes, sound transducers, petroleumindustry, automobile components, aerospace, energy storage, nanocomposites and contamination purification in wastewater management, to cite a few (Figure 3f) [107,115,116].


**2. Methodology**

To probe into indigenous ways of "observing, discussing, and making sense," our study employs experiential methodology, specifically walking and storytelling, to engage in affective, place-based, and rhythmic aspects of indigenous knowledge. By experiential methodology, we mean to underscore the dynamic and meaning-creating process, in which humans interact with the world, or things, in our case, the Tayal millet foodscape. In a sense, humans are not only shaped by the environment and foodscape, but also have the power to mold the world. Experiential methodology recognizes that, in different relationships, we as humans make sense and create meanings through constant interactions and processes of perceiving, understanding, reasoning, imagining, and so on [14]. In such a process of co-belonging between humankind and the environment (foodscape), we become sensitive to perceive and to be concerned—a capacity to make ourselves sensitive that precedes all distinctions among the instruments of science, humanities, arts, theology, etc [15].


Scope of the Series

Biomedical engineering is one of the fastest growing interdisciplinary branches of science and industry. The combination of electronics and computer science with biology and medicine has resulted in improved patient diagnosis, reduced rehabilitation time and better quality of life. Nowadays, all medical imaging devices, medical instruments or new laboratory techniques are the result of the cooperation of specialists in various fields. The series of biomedical engineering books covers such areas of knowledge as chemistry, physics, electronics, medicine and biology. This series is intended for doctors, engineers and scientists involved in biomedical engineering or those wanting to start working in this field.

Contents

*by Bartłomiej Płaczek*

Assistance Systems

*and Isabell Steuding*

Interface

*by Gulcicek Dere*

Introductory Chapter: Data Acquisition

Acoustic Monitoring of Joint Health *by Lucy Spain and David Cheneler*

the State of the Cardiovascular System

**Preface XI**

**Chapter 1 1**

**Chapter 2 5**

**Chapter 3 31**

**Chapter 4 51**

**Chapter 5 71**

**Chapter 6 93**

Real-Time Capable Sensor Data Analysis-Framework for Intelligent

*by Ulrich H.P. Fischer, Sabrina Hoppstock, Peter Kußmann*

Control of a Prosthetic Arm Using fNIRS, a Neural-Machine

*by Usama Ali Syed, Zareena Kausar and Neelum Yousaf Sattar*

*by Abdullayev Namiq Tahir and Ahmadova Khadija Ramiz*

Biomedical Applications with Using Embedded Systems

Flicker-Noise Spectroscopy Method in the Problem of Diagnosing


**9. Conclusion**

The use of anaerobic digestion for treatment of solid and liquid organic wastes has vastly increased world-wide. The by-product of this process is the digestate, a liquid or solid material with high nutrient and organic matter content. These properties of the digestate make possible to use it as plant nutrients and to characterize it as a fertilizer. On the other hand, a biomass, reach in recalcitrant molecules is characterized by a high biological stability degree which is suitable for soil improving. The utilization of digestate as fertilizer provides economic and environmental benefits because of its higher stabile organic matter content, the hygienization effect of anaerobic digestion process and the reduced quantity of the artificial fertilizers needs for plant production. Moreover, the alkaline pH of digestate could contribute to the decrease of soil acidification, which is a serious problem of the world. Using digestate in place of artificial fertilizers could contribute to maintain the fertility of soil.

As the results show, the digestate application in solid or liquid form could result significant improvement of the quantity and quality of foods through the even nutrient supply harmonizing with the necessity of plants and through its microelement content in the available forms for plants. In this way, digestate application in agriculture could contribute to the healthy life of humans.

Microbiological activity of soil could be increased by application of digestate which is also an important condition of soil fertility.

Beyond these "classical" application possibilities of digestate, there are new promising alternatives for its utilization which means more opportunities to use this valuable matter for making better our environment and our life.


**2.4. Intra-abdominal infections**

catheter-associated UTIs are fever, lateral lumbar pain, sensitivity in the costovertebral angle, haematuria and delirium with recent onset. After catheter removal, pollakiuria or dysuria

The Infectious Disease Society of America defines asymptomatic bacteriuria as the absence of

cies in a catheterised patient. In most cases of asymptomatic bacteriuria, the treatment led to the temporary sterilisation of urine and not to the eradication of pathogens [19]. Additionally, in 33–50% of patients, after catheter removal, the bacteriuria spontaneously resolved. This is why treating an asymptomatic bacteriuria increases the risk of antimicrobial resistance or of

Some pathogenic bacteria produce biofilms, which consist of an adherent layer of microorganisms and their extracellular products. The biofilm protects the pathogens against the host's defence mechanisms and against antibiotic therapy. Migration to the urinary bladder occurs in 1–3 days. The duration of catheterization is an important risk factor, with almost all patients who are catheterised for more than 30 days developing bacteriuria. These patients are at risk of upper urinary tract inflammation, which increases the risk of bacteraemia. Infections linked to long-term catheterisation are often polymicrobial, which involves a broad-spectrum treatment.

The selection of antibiotics used for the treatment of catheter-associated UTIs depends on the result of the microscopical examination, as well as on the colonial characters. In 60–80% of cases, the causative agent is a Gram-negative bacillus (*E.coli*, *Klebsiella* spp., *Pseudomonas* spp., *Proteus* spp., *Enterobacter* spp.). The remaining 20–40% is caused by Gram-positive bacteria, most often species of staphylococci or enterococci. The empirical treatment has to take the following factors, which increase the risk of antibiotic resistance: the duration of hospitalisation,

Urinary fluoroquinolones (ciprofloxacin and levofloxacin) are administered to patients with mild and moderate infections, who are considered haemodynamically stable and do not present an altered mental status. Moxifloxacin is not recommended, as it does not reach effective urine concentrations. Broad-spectrum cephalosporins, ceftriaxone or cefepime, may also be used. In patients with urosepsis or in those haemodynamically unstable (hypothermia,

or leukopenia under 4000/mm3

In medium clinical forms, ciprofloxacin, 400 mg iv, for every 12 h or levofloxacin 500 mg iv /24 h

The recommended treatments in severe forms include: cefepime 2g iv/12h, ceftazidime 2g iv/8h, imipenem 500 mg iv/6 h, doripenem 500 mg iv/8 h, meropenem 1 g/8 h and piperacillin/tazo-

The treatment of UTIs associated with bladder catheterisation is done with antibiotics for 3 days in women aged over 65 years, from whom the catheter has been removed; otherwise,

the treatment is given for 7 days. The duration of levofloxacin treatment is 5 days.

colony forming units/ml of one or more bacterial spe-

under 33 mmHg,

) piperacillin-tazobactam is

may be present.

22 Current Topics in Intensive Care Medicine

symptoms with the presence of over 105

leukocytosis over 12,000/mm3

or ceftriaxone for 1 g iv/day are administered.

administered.

bactam 3.375 g iv/6 h.

adverse reactions associated with useless antibiotic treatment.

previous administration of antibiotics, and local resistance patterns.

tachycardia over 90/minute, tachypnoea over 20 respirations/minute or Pco2

Intra-abdominal infections include a series of diseases with variable severity, from uncomplicated appendicitis to faecal peritonitis. Uncomplicated infections involve a single organ and may not reach the peritoneum, and they may be solved either by surgical resection or by administration of antibiotics. Complicated intra-abdominal infections are those which extend to the peritoneum causing localised or generalised peritonitis; in order to solve these, the infection source must be solved by both surgery and antibiotic therapy.

The antimicrobial therapy of intra-abdominal infections, which are to be solved percutaneously or by surgery, has the following goals: to accelerate the elimination of the infecting microorganisms, to decrease the recurrence risk of the intra-abdominal infection, to shorten the clinical evolution, to limit the expansion of the infection to the abdominal wall and to decrease the risk of generalisation of the infectious process.

The antibiotic therapy is initiated after hydroelectrolyte rebalance, the restored volemia determining the restoration of the visceral perfusion and a better distribution of the medication. Moreover, this diminishes the side effects of antibiotics, which have been exacerbated by the deficitary perfusion of internal organs.

The empirical antibiotic treatment is initiated in concordance with the most probable microbiological spectrum, the type and density of germs being dependant on the level where the perforation of the digestive tract has occurred. By gastric, duodenal and proximal jejunal perforations, a low number of aerobic Gram-positive and anaerobic Gram-negative bacteria, generally sensitive to cephalosporins, are released into the peritoneum. *Candida albicans* has also been isolated, but antifungal treatment is only required in the case of patients under immunosuppressive treatment or in patients with recurrent intra-abdominal infections. The perforations of the distal small intestine often evolve as localised abscesses and peritonitis only takes place when these are ruptured. The intra-abdominal infections propagated from the colon into the peritoneum are caused by anaerobic or facultative anaerobic Gram-negative bacteria; *Bacteroides fragilis* is sometimes present.

The selection of the antibiotic should then be guided by the results of the cultures from the biological specimens obtained by percutaneous drainage or during the surgical intervention, but until these become available, it is necessary and useful to perform the microscopical examination directly on a Gram-stained smear. If high numbers of Gram-positive cocci are present, these are very likely to be enterococci or other faecal streptococci, which imposes the association of vancomycin.

cerebrospinal fluid (CSF) collection, in cases of expansive intra-cranial processes accompanied by papilledema or focal signs. In this latter situation, computerised tomography (CT) or nuclear magnetic resonance (NMR) examinations should be conducted after blood collection for blood culture and after the first dose of antibiotic, despite the risk of excessive treatment.

Infections and Multidrug-Resistant Pathogens in ICU Patients

http://dx.doi.org/10.5772/intechopen.79229

25

*The antibiotic administration route* in meningitis is intravenous, which is capable to ensure the CSF bactericidal concentrations; the exception is for rifampicin, which may be administered orally and is useful in the treatment of meningitis caused by beta-lactam-resistant pneumo-

*Antibiotic selection*: in the treatment of bacterial meningitis, bactericidal antibiotics able to cross the blood-brain barrier are administered, so that optimal CSF concentrations are ensured regardless of the meningeal inflammation degree (meningeal inflammation favours the penetration of the antibiotic in the sub-arachnoid space at the onset of the disease, but as the inflammation regresses under treatment, the concentration tends to decrease, so that higher

Patients with suspected bacterial meningitis will be initially treated with a broad-spectrum antibiotic concordant to the most probable aetiology, the selection being made depending on the age and comorbidities. After establishing the aetiology and antibiotic susceptibility of the isolated pathogen, the antibiotic therapy will be focused, maintaining the high doses and

The lumbar puncture should be repeated after the first 24–36 h from the initiation of the treat-

The immune competent adult with bacterial meningitis requires an initial antibiotic treatment aiming at meningococcus and pneumococcus, consisting in the association of ceftriaxone (2 g/12 h) or cefotaxime (2 g/6 h) with vancomycin (30–60 mg/kg/day for every 8 or 12 h); third-generation cephalosporins must be administered even if the antibiogram shows that the respective strain presents intermediate sensitivity or resistance, because vancomycin acts

Patients with bacterial meningitis and compromised cell immunity due to pre-existing conditions or immunosuppressive treatment, but with conserved renal function, should be treated with vancomycin (60 mg/kg/day divided into two or three doses) plus cefepime (6 g/day

If a *Listeria* infection is suspected, the empirical treatment may consist in the association between vancomycin and moxifloxacin (400 mg in a single daily dose) plus trimethoprim-

The duration of the antibiotic treatment in meningitis is not standardised, but it should be individualised based upon the clinical response of each patient, but usually 7 days of treatment is sufficient for meningococcal and *H. influenzae* meningitis, 10–14 days for pneumococcal meningitis, 14–21 days for meningitis with *S. agalactiae* and 21 days or more for meningitis with *L. monocytogenes*; meningitis with aerobic Gram-negative bacilli requires antibiotic

ment in order to assess CSF cytological, biochemical and bacteriological changes.

divided into three doses) or meropenem (6 g/day divided into three doses).

coccus and coagulase-negative staphylococci.

intravenous administration.

doses are required as compared to other diseases) [23].

synergically and increases the efficiency of the therapy [24].

sulfamethoxazole (10–20 mg/kg/day divided at 6 or 12 h).

administration for 21 or 14 days after the last CSF sterile culture.

Aerobic and anaerobic Gram-negative cocci may be covered by administration of cefoxitin, ampicillin/sulbactam, piperacillin/tazobactam, imipenem, meropenem, moxifloxacin, while aerobic Gram-negative bacilli may be destroyed with aminoglycosides, second-, third- and fourth-generation cephalosporins, aztreonam, antipseudomonal penicillins or fluoroquinolones (ciprofloxacin, levofloxacin). It must be mentioned that ertapenem is not active on *Pseudomonas aeruginosa* and *Acinetobacter* spp., and in the case of critical patients infected with *P. aeruginosa*, the dose of meropenem must be increased to 1 g administered for every 6 h. Vancomycin-resistant enterococci produce extremely difficult to treat infections, the only useful antibiotic being daptomycin. Tigecycline has been approved for the treatment of complicated intra-abdominal infections caused by *Citrobacter freundii, Enterobacter cloacae, E. coli, Klebsiella oxytoca, Klebsiella pneumoniae, Enterococcus faecalis (*vancomycin-susceptible), MSSA, MRSA and some anaerobic bacteria [22].

The antibiotic, which is active only against Gram-negative bacilli and anaerobic bacteria, is metronidazole, for which no resistance has been reported.

The patients at high risk of unfavourable evolution and reserved prognosis have a high APACHE II score, poor nutritional status, significant cardiovascular diseases, immune suppression induced by medicines or by co-morbidities, while the infection source cannot be controlled. The predictive factors of therapeutic failure include the duration of the evolution prior to hospital admission, more than 2 days of presurgical treatment, as well as the presence of the MDRO. These patients should be treated similarly to those with hospital-acquired infections with carbapenems and vancomycin, but also considering the local antibiotic resistance.

The antibiotic treatment must be administered until the resolution of the clinical signs of infection (normalisation of the thermal curve, restoration of the intestinal transit) and normalisation of the biological inflammatory syndrome.

In cases with recurrent intra-abdominal infections, the diagnosis must be reassessed after 5–7 days of treatment and the investigations should be broadened (echography, CT). Often, the antibiotic therapy must be adjusted or a new surgical intervention is required in order to eliminate the site of infection.