Sepsis in Internal Medicine wards: current knowledge, uncertainties and new approaches for management optimization

Abstract

Sepsis represents a global health problem in terms of morbidity, mortality, social and economic costs. Although usually managed in Intensive Care Units, sepsis showed an increased prevalence among Internal Medicine wards in the last decade. This is substantially due to the ageing of population and to multi-morbidity. These characteristics represent both a risk factor for sepsis and a relative contra-indication for the admission to Intensive Care Units. Although there is a lack of literature on the management of sepsis in Internal Medicine, the outcome of these patients seems to be gradually improving. This is due to Internists’ increased adherence to guidelines and “bundles”. The routine use of SOFA score helps physicians in the definition of septic patients, even if the optimal score has still to come. Point-of-care ultrasonography, lactates, procalcitonin and beta-d-glucan are of help for treatment optimization. The purpose of this narrative review is to focus on the management of sepsis in Internal Medicine departments, particularly on crucial concepts regarding diagnosis, risk assessment and treatment.

Key Messages

• Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection.

• The prevalence of sepsis is constantly increasing, affecting more hospital patients than any other disease.

• At least half of patients affected by sepsis are admitted to Internal Medicine wards.

• Adherence to guidelines, routine use of clinical and lab scores and point-of-care ultrasonography are of help for early recognition of septic patients and treatment optimization.

Keywords:

• Sepsis
• Internal Medicine
• SOFA
• qSOFA

1. Introduction

Sepsis is a life-threatening disease that represents a major global healthcare problem, with a steadily increasing incidence in all countries [1,2]. Despite advances in modern medicine, it remains the primary cause of death from infection; it is more common than heart attack, and claims more lives than any cancer [3]. Information on the epidemiology, causes, treatment and prognosis of patients affected by sepsis comes mainly from studies conducted within Intensive Care Unit (ICU) [4,5]. Data derived from these studies constitute most of the evidence on which current guidelines for the management of sepsis are based [6]. Nevertheless, people at higher risk for sepsis, such as the elderly and those affected by chronic illnesses, are more frequently hospitalized outside the ICUs [7,8]. As a matter of fact, sepsis shows a high prevalence among patients admitted to Internal Medicine wards, with high mortality rates, but there is a lack of literature data on this specific population of patients [7,9].

The purpose of this narrative review is to focus on the current evidence regarding the management of sepsis in Internal Medicine departments, particularly on crucial concepts concerning diagnosis, risk assessment and treatment. A prompt recognition of sepsis among these patients may lead to an earlier and more efficient management, possibly with a survival improvement. Moreover, questions that remain still unanswered on the topic have been summarized, underlining the need for research in this setting.

A literature review using the PubMed database with the search terms “sepsis”, “Internal Medicine”, “septic shock”, “sepsis-3”, “surviving sepsis campaign” was conducted up to March 2017. The literature search was limited to publications written in the English language.

2. Definitions

The first definition of sepsis was introduced in 1991, based on the presence of a suspected or proven infection with two or more criteria of the Systemic Inflammatory Response Syndrome (SIRS) (Table 1) [10]. According to this definition, severe sepsis indicated the presence of organ failure (Table 2), while septic shock defined the presence of acute circulatory failure and arterial hypotension (Table 3). In 2001, considering SIRS criteria too sensible and not enough specific, new variables were added to identify systemic response to infection [11].

Table 1. Systemic inflammatory response syndrome (SIRS) criteria.

Two or more of the following

Fever (core temperature >38 °C) or hypothermia (core temperature <36 °C)

Heart rate >90 beats per minute

Respiratory rate >20 breaths per minute or partial pressure of carbon dioxide in arterial blood (PaCO2) < 32 mm Hg

Leukocytosis (white-cell count >12,000 cells/μl) or leukopenia (white-cell count <4000 cells/μl) or >10% immature forms (bands)

Table 2. Diagnostic criteria for severe sepsis.

Sepsis-induced tissue hypoperfusion or organ dysfunction

Sepsis-induced hypotension

Lactate above upper normal laboratory limits

Urine output <0.5 ml/kg/h for more than 2 h despite adequate fluid resuscitation

Acute lung injury with PaO2/FiO2 <250 in the absence of pneumonia as infection source

Acute lung injury with PaO2/FiO2 <200 in the presence of pneumonia as infection source

Creatinine >2.0 mg/dl (176.8 μmol/l)

Bilirubin >2 mg/dl (34.2 μmol/l)

Platelet count <100,000/μl

Coagulopathy (international normalized ratio >1.5)

Table 3. Septic shock criteria.

Refractory hypotension (SBP <90 mm Hg o MAP <70 mm Hg) plus

Persistent hypotension despite 30ml/kg crystalloids infusion or

Need of vasopressor infusion despite adequate volume replacement

Recently, by the release of the new Sepsis-3, sepsis has been defined as a life-threatening organ dysfunction caused by a dysregulated host response to infection, and septic shock as a subset of sepsis in which underlying circulatory and cellular/metabolic abnormalities are profound enough to increase mortality [12]. Consequently, the term severe sepsis has become obsolete and will not be used throughout this manuscript.

3. Epidemiology and burden of disease

Sepsis and sepsis-related complications represent a global health problem with an enormous economic burden in industrialized countries due to a high rate of morbidity and mortality [13]. Incidence of sepsis has been increasing during the last decade being nowadays the tenth cause of death in the general population with an estimated global incidence of 19 million cases per year worldwide [3]. However, given its heterogeneous nature, the lack of a uniform definition and the difficulty of getting an accurate diagnosis, global data on the incidence of sepsis are lacking [14].

The increasing incidence and severity of sepsis could be related to the aging of population, as well as to immunosuppression and multi-resistant infections [1]. On this connection, the majority of cases of sepsis (about 60–80%) have been observed in patients over 65, with a 30-times increase in over 85 years old [4]. At present, most of patients referring to Emergency Departments (ED) share the above-mentioned features (i.e. older age, chronic diseases) and a high proportion of septic patients are hospitalized from ED to non-intensive wards [4].

4. Sepsis in Internal Medicine wards

According to epidemiological data, about two third of patients with sepsis are admitted to Internal Medicine wards [7]. Moreover, patients admitted to Internal Medicine wards are usually elderly (mean age of 67 years), affected by chronic poly-pathology, on poly-pharmacotherapy, often showing cognitive and functional impairment and residing in long-term facilities [8]. Most of them are at high risk for developing infections and consequently sepsis; in fact, those affected by chronic renal failure, chronic liver disease or hospital infections progress most frequently to sepsis [7]. Among these patients, respiratory system, genitourinary and gastrointestinal tracts represent the main site of infection. Urinary sepsis account for lower mortality, while community-acquired pneumonia is most frequently associated with the development of sepsis (48% of cases) and septic shock (5% of cases) [15]. Although in 1990s the majority of sepsis were related to Gram positive bacteria, at present Gram negatives account for about 60% of sepsis events [16,17], even if in approximately 50% of the cases blood cultures remain negative [18].

The prognosis of septic patients admitted to Internal Medicine wards seems to be worse with respect to those directly admitted to ICU from ED [19]. Data from an Australian study showed that 39% of septic patients admitted to medical wards progressed to sepsis and 31.1% of these died in-hospital, while patients directly transferred to ICU showed a slightly lower mortality (28.9%) [20]. With this regard, a survey conducted in 2010 showed that the management of patients with sepsis or septic shock varies depending on the specialty of the physician who handles the case [21]. Specialists in Internal Medicine, Emergency Medicine and Critical Care Medicine show different approaches to the management and treatment of this condition; even the compliance to guidelines varies according to the specialties. These differences could explain the variability of outcomes. Nevertheless, data about the current epidemiology and outcome of sepsis in Internal Medicine wards are lacking [8,22].

5. Pitfalls in diagnosis of sepsis in Internal Medicine wards

Few studies assessed the characteristics of septic patients in Internal Medicine departments [7,20,22]. Although "sepsis" still has a low rate of codification as discharge diagnosis from Internal Medicine wards, the attention paid by Internists to this syndrome is constantly increasing due to an improved identification [23,24].

The compliance to practice guidelines and related bundles for the management of sepsis is variable and there is lack of evidence regarding the effectiveness of current guidelines in improving sepsis-related mortality in Medicine wards. As underlined by Sepsis-3, sepsis requires early recognition and treatment in order to reduce mortality and morbidity [12].

The identification of septic patients requires, first of all, a mindful clinical eye. Classic signs and symptoms of infection could be absent in Internal Medicine patients due to their high rate of multi-morbidity [25]. Thus, physician should carefully consider any sign and/or symptom of organ dysfunction (i.e. reduction of arterial pressure, elevation of pulse frequency and/or respiratory rate, modification of neurological status, reduction in urine output and/or raise of lactates). The six sepsis-target organ systems should be always evaluated: cardiovascular, respiratory, renal, neurological, hepatic, and coagulation [26]. On this connection, establishing a “rapid-response sepsis team” in Internal Medicine departments could be of help, as well as developing formal performance improvement programs, given a suggestion of a mortality benefit [27].

Given that patients admitted to general wards may become septic at any point during their hospitalization, screening for sepsis should be performed longitudinally rather than once [28]. With this regard, the role of ward nurses in detecting abnormal vital signs is pivotal in the early recognition of sepsis [29,30]. Moreover, the application of a nurse-based screening protocol for sepsis identification and notification to physician seems to improve 30-days survival [31].

In Internal Medicine wards, the lack of invasive monitoring and “intensive care environment” can delay the early identification of patients at risk, and there is the need for a scoring system that allows this process [32]. At present, most of the available scoring systems are inappropriate for their use outside ICU [33]. Among these, the most used is the Sequential Organ Failure Assessment (SOFA, originally the Sepsis-related Organ Failure Assessment) score [34], that is now critical, according to the Sepsis-3 task force, for the definition of sepsis. Clinical data used for the development of the Sepsis-3 definitions were derived mainly from the patients hospitalized in ICU. A recent study retrospectively analyzed the performance of the new Sepsis-3 definitions for early assessment of mortality and organ dysfunction outside ICU and positively validated the use of SOFA score to predict unfavourable outcome and to limit misclassification into lower severity [35]. Nevertheless, laboratory tests are needed to calculate this score, which is therefore not a quick tool and remains difficult to use outside ICU [12].

In the context of a resource-limited setting, such as Internal Medicine wards, a frequent evaluation of clinical signs represents the only feasible strategy to monitor treatment response [36]. Noninvasive bedside monitoring includes vital signs (i.e. heart rate, respiratory rate, blood pressure, body temperature), urine output, oxygen saturation, lactate level, mental status, capillary refill time, and skin mottling [37–41]. On the other hand, the management of severely ill patients could be particularly difficult – and challenging at the same time – because the standard targeted approach typical of resource-rich facilities (ICUs) is not reproducible in general medical wards [40]. The stratification of patients on the basis of severity/prognostic scores is helpful to decide to alert the emergency team for the admission to ICU.

Few prognostic scores designed outside the ICU are available in clinical practice. The most common used are the Modified Early Warning Score (MEWS) [42], the Simple Clinical Score (SCS) [43], the Mortality in the Emergency Department Sepsis (MEDS) score [44], and the Rapid Emergency Medicine Score (REMS) [45]. Ghanem-Zoubi and coworkers tested the performance of these scores for the risk stratification of septic patients admitted to Internal Medicine ward: SCS and REMS seemed to be the most appropriate to predict mortality in this setting [33]. However, these scores could be inadequate for older patients because of different risk factors for poor prognosis [8].

Sepsis-3 has given a high emphasis to the early identification of patients with a suspected infection at risk for clinical deterioration, and provided a new bedside index – the quick SOFA score (qSOFA) (Table 4) – for early evaluation of a patient for the likelihood of sepsis [46]. This score can be easily calculated by physician or nurse. The qSOFA showed a high predictivity, particularly when applied to patients treated outside ICU [46]. However, the Sepsis-3 task force is explicitly stating the need for a validation of the new score using non-US databases of patients, and a recent study conducted on a Greek cohort of patients failed to showed high sensitivity of qSOFA for the early prediction of mortality outside ICU [35].

Table 4. Quick SOFA (qSOFA) criteria.

Respiratory rate >22 breath per minute

Altered mental status

Systolic blood pressure <100 mm Hg

Figure 1 shows a proposed flow-chart for the assessment and management of septic patients in Internal Medicine wards.

Figure 1. Proposed flow-chart for the assessment and management of patients affected by sepsis in the Internal Medicine wards. Pre-Management: knowledge of sepsis should be increased by the application of education programs, scoring systems, bundles and protocols. Diagnosis: from the clinical evaluation to the suspicion and to the diagnosis of sepsis. Early treatment: optimal treatment to be started within 3 hours from the clinical suspicion of sepsis. Re-Assessment: evaluation of the response to treatment, in order to decide if the patient could be managed in the Internal Medicine ward or needs to be transferred to ICU [12,83]. qSOFA: quick SOFA; SOFA: Sequential Organ Failure Assessment; POCUS: point-of-care ultrasonography; MAP: mean arterial pressure; NIV: non-invasive ventilation; IVC: Inferior vena cava; ICU: Intensive Care Unit. (1) Performance improvement in clinical suspicion of sepsis: continuous education programs (physicians, nurses, affiliate providers), scoring systems for sepsis alarm (e.g. MEWS, qSOFA), use of bundles, protocol development, ongoing feedback. (2) Risk factors for infection: immunosuppression, chronic poly-pathology, poly-pharmacotherapy, recent antibiotic use, cognitive and functional impairment, malnutrition, recent hospitalization, residing in long-term facilities, etc. (3) Signs of infection: fever, headache, cough, dysuria, abdominal pain, etc. (4) Signs of organ dysfunction: dyspnea, oliguria, hypotension, altered mental status, haemorrhage, jaundice, etc. (5) qSOFA: systolic blood pressure <100 mmHg (1 point), respiratory rate >22 (1 point), altered mental status (1 point). (6) Infection assessment: cultures (blood, urine, etc.) before antibiotic administration, chest X-ray, POCUS, C reactive protein, procalcitonin, other radiological investigations (if indicated). (7) Delta IVC: Inferior Vena Cava Collapsibility Index = [(IVCexp – IVCinsp)/IVCexp] × 100. (8) Lactate clearance: [(lactate initial – lactate 2h)/lactate initial] × 100.

6. Current guidelines: diagnosis, antibiotic treatment and hemodynamic support

The cornerstone of the therapeutic approach to sepsis is represented by the identification of the etiological agent and the source of infection, by its removal, if possible, in combination with an appropriate and early antibiotic therapy [47]. Moreover, maintaining an adequate circulating volume to allow an optimal tissue perfusion is needed to prevent or to reduce organ failure [48].

The identification of the microbiological agent is crucial for the choice of treatment, therefore, clinicians should obtain culture samples (i.e. blood, urine and other clinically relevant sites) before starting antibiotic therapy [11]. In those patients with a central venous catheter (CVC), a difference in positivization time between peripheral and central blood sample (>120 min) showed to have high sensitivity and specificity for diagnosis of catheter-related bloodstream infection (CRBSI) [49].

Failure of initial therapy is associated with increased mortality [50]. By choosing an antibiotic treatment, clinicians should consider the clinical setting, patient’s microbiological history, previous exposure to antibiotics, recent hospitalizations and local ecology in terms of pathogens’ susceptibility [13]. Moreover, Internal Medicine patients should be considered at risk for fungal infections, particularly candidemia [51].

An early antibiotic administration is associated with reduced mortality [52,53], but it does not represent yet the routine clinical practice [54].

The source of infection should be promptly identified and treated [55]. In particular, drainage of abscesses, debridement of necrotic tissue, and removal of potential infected devices should be performed in the 12 h after the diagnosis of sepsis [56]. In case of CRBSI, CVC removal represents the optimal choice [49]; however, catheter characteristics, patient's clinical status and type of pathogen could influence the decision to remove CVC or to start antibiotic lock-therapy [57,58].

All patients with sepsis-induced tissue hypoperfusion should undergo a protocolized quantitative resuscitation [47] consisting in the administration of fluid boluses, vasopressors, inotropic drugs and red cell transfusion in order to target predetermined physiologic goals (early goal-directed therapy, EGDT). Crystalloids represent the first choice fluids, given the harms in terms of kidney impairment produced by colloid solutions [59].

Norepinephrine is the vasopressor to be preferred in case of persistent hypotension despite adequate fluid administration [60]. Adrenaline and vasopressin may be considered as additional agents to norepinephrine; dobutamine infusion is recommended in presence of myocardial dysfunction or ongoing hypoperfusion despite adequate intravascular volume [46].

The use of corticosteroids in sepsis treatment has become over the years more and more controversial, considering that a review on this topic has failed in highlighting significant benefits of hydrocortisone on the outcome [61]. Recently the HYPRESS trial has failed to demonstrate the superiority of hydrocortisone with respect to placebo in reducing the risk of progression to septic shock among patients with sepsis [62].

7. Guidelines: evolution and criticality

Since 2002, the Surviving Sepsis Campaign (SSC) Committee has been working to reduce the overall mortality from sepsis and septic shock through the development and promotion of evidence-based guidelines. These were published in 2004, then revised in 2008 and 2012 [47,63,64]. In January 2017, the fourth revision of the guidelines was published online [6].

Based on the 2012 guidelines, during the first 6 h of treatment all the patients should be treated with EGDT, whose effectiveness has been tested in a small open single-centre study [65]. This strategy has been object of criticism: the measurement of CVP does not own a proven accuracy in predicting fluid-responsiveness [66]; in addition, a CVP >8 mmHg seems to be associated to fluid overload, organ dysfunction and increased risk of death [67]. Moreover, the administration of blood products in patients with Hb >7 g/dl does not increase ScvO2 nor improve the mortality rate of patients with septic shock [68]. Similarly, the administration of inotropic drugs in order to increase ScvO2 without considering left ventricle function is harmful [69]. Hence, EGDT requires an early invasive approach that constitutes a major obstacle to its application in routine clinical practice in ED [70], and even more in Internal Medicine wards.

More than a decade after the publication of the study by Rivers, three large multicenter randomized trials (PROCESS, ARISE and ProMISe – see further) have shown that the measurement of CVP and ScvO2, although safe, does not improve the outcome of patients with sepsis or septic shock [71–73]. Therefore, this approach could be not strictly necessary for the resuscitation of these patients.

The SSC Committee has created a set of recommendations, called sepsis bundles that can be applied to the management of patients with sepsis and septic shock [47]. Sepsis bundles have been revised after the publication of PROCESS, ARISE and ProMISe trials [74]; in the new version, if a persistent hypotension or hyperlactatemia is present, a re-evaluation of intravascular volume and tissue perfusion is recommended. The PROCESS, ARISE and ProMISe trials have created a substantial uncertainty in how to guide clinicians for the management of patients with sepsis and septic shock [75].

In response, the 2016 SSC guidelines has removed standard EGDT resuscitation targets, recommending that sepsis-induced hypoperfusion be treated with at least 30mL/kg of intravenous crystalloids given in 3 h or less [6]; in the absence of the former static EGDT targets (e.g. CVP), a frequent clinical reassessment and the use of dynamic measures of fluid responsiveness (e.g. fluid challenges or passive leg raise test against stroke volume measurements) is emphasized [76]. Thus, the new guidelines moved from a protocolized, quantitative resuscitation strategy to a more patient-centred resuscitation approach guided by hemodynamic assessment including noninvasive monitoring of dynamic variables for fluid responsiveness and ongoing reevaluation of the response to treatment [77].

Thus, septic patients can be treated in Internal Medicine wards, with no absolute need for continuous invasive monitoring, provided that a proper treatment is quickly administered and frequently reassessed. On this connection, a recent observational study, conducted among septic patients admitted to Internal Medicine wards, showed similar results to those of patients admitted to the ICU [22].

8. New approaches in diagnosis and management of sepsis in Internal Medicine wards

The treatment of septic patients managed in Internal Medicine wards requires a less invasive but equally effective approach to assess organ perfusion and oxygenation, in order to support the “decision making” process [46]. On this connection, several non-invasive tools are potentially available to the Internist.

Point of care ultrasonography (POCUS)

POCUS is a flexible and non-invasive method, currently used in the clinical management of critically ill patients [78]. POCUS has been shown to replace, at least in the initial phases, the execution of invasive procedures (i.e. CVC placement). Haydar and colleagues showed that the use of echography-derived information significantly influenced the management of sepsis in ED [79]. In particular, POCUS is helpful for the early identification of septic shock, reducing the diagnostic delay and, consequently, improving patients’ prognosis [80]. On this connection, the assessment of dynamic physiological parameters, such as the inferior vena cava (IVC) collapsibility or lactate clearance, has been proposed as alternatives to the measurement of CVP and ScvO2 [81,82]. According to Coen and co-workers, the assessment of IVC collapsibility in an ED setting is useful to guide fluid administration at least in the early septic shock, avoiding CVC insertion in almost a third of patients, and reserving this procedure to those who, by not responding to fluids, need treatment with vasopressors [83]. Moreover, POCUS represents a valuable tool in the identification of septic source and in monitoring the response to antibiotic therapy [84]. The application of this technique would be desirable in Internal Medicine "sepsis alert" patients.

Lactates

The evaluation of circulating lactate’s levels represents an easily available tool for the Internist. Lactate elevation reflects the pathophysiological changes of sepsis (hypotension, tissue hypoperfusion and organ dysfunction); it defines the diagnosis and prognosis of septic patients [85]. Accordingly, it may be considered an alternative to the more complex and invasive ScvO2 and MAP measurement in the monitoring of septic patients [82]. Moreover, monitoring this parameter has been shown to improve the outcome of critically ill patients [86].

Procalcitonin

Procalcitonin is a marker related to the presence of bacterial infection, the concentration of which is correlated to the severity of infection [87]. The use of procalcitonin could complement the clinical evaluation both in the diagnosis phase and in evaluating the efficacy and duration of antibiotic therapy [88]. Monitoring procalcitonin levels could be of help even in the decision to stop antibiotic therapy, but clinical experience is limited and the potential for harm remains a concern [89].

Beta-d-glucan and anti-mannan antibodies

Blood cultures are essential to rule out invasive fungal infections, although with low performances in terms of time to positivization [90]. Fungal biomarkers and metabolites could be assessed in plasmatic samples to anticipate the diagnosis. The combined detection of mannan and anti-mannan antibodies represents a specific method for the diagnosis of candidemia (80% sensitivity, 85% specificity, >85% negative predictive value) with a mean anticipation of 6 days prior to blood cultures positivization [90]. It can support the diagnosis of candidemia especially in critically ill patients with risk factors for invasive candidiasis [90]. Galactomannan, although the assonance with mannan/anti-mannan, does not represent a test to detect candidiasis, but it is useful for the diagnosis of aspergillus infections.

In recent years, the use of 1,3-β-d-glucan for the diagnosis of invasive fungal infections received a significant emphasis. It constitutes the cell wall of most of fungal species and it is not specific for candida infection. Several detection techniques are available. A cut-off value of 80 pg/ml showed the best sensitivity (>65%), specificity (80%) and negative predictive value (>85%) in diagnosing invasive candidiasis [90]. According to ESCMID guidelines 1,3-β-d-glucan, besides being recommended for the diagnosis of candidemia and invasive candidiasis, is useful to rule out fungal infections. It should be underlined that Internal Medicine patients could frequently show false positivity in association with haemodialysis, gauzes, immunoglobulins and albumin infusions [91]. However, given its high-negative predictive value, the negativization of 1,3-β-d-glucan levels can support the decision to discontinue antimicotic therapy [90,91]. Serial determinations (twice a week) are recommended to monitor 1,3-β-d-glucan circulating levels [90].

Real-time PCR represents an alternative method for the diagnosis of fungal and bacterial infections, with high sensitivity and specificity, although it requires further validation [90].

9. Perspectives

Sepsis-3 opened a new era in the management of sepsis. At present, the challenge for physicians, in particular, for the Internist, is to predict the possibility of a clinical deterioration of a patient with any infection and to aggressively treat infection, as quick as possible. Most physicians do not use the term “septic“ to define a patient with an infection plus changes in vital signs (i.e. tachycardia or fever); they use the term “septic” to define a patient that “looks bad”, whose clinical conditions are severe enough to require a more intensive monitoring or an admission to ICU [92].

Protocols for the early identification of sepsis among Internal Medicine patients are warranted. A number of hospitals are implementing sepsis screening programs among patients admitted to non-ICU wards [93]. However, which is the best method to identify “really sick/septic” patients among patients with any infection? At present, the risk of death seems to be correlated to the presence of organ failure (neurological, respiratory, cardiovascular) [94].

The diffusion of protocols for the early identification and treatment of septic patients among Internal Medicine wards could lead to a more efficient management, with a cooperation between Internists and Intensivists. Moreover, the adherence to guidelines and bundles should produce a quantitative, measurable, improvement in the management and in the outcome of septic patients. The dissemination of a knowledge of sepsis among Internists, particularly among young doctors, represents the real challenge for the future [21].

Abbreviations
qSOFA	=	quick SOFA
SOFA	=	Sequential Organ Failure Assessment
POCUS	=	point-of-care ultrasonography
MAP	=	mean arterial pressure
NIV	=	non-invasive ventilation
IVC	=	Inferior vena cava
ICU	=	Intensive Care Unit

Acknowledgements

The authors are grateful to Ms. Caterina Mirijello for the expert revision of English language.

Disclosure statement

The authors report no conflicts of interest.