Sepsis is defined as a life-threatening organ dysfunction caused by a dysregulated host response to infection. Septic shock should be considered a subset of sepsis in which underlying circulatory, cellular, and metabolic abnormalities contribute to a greater risk of mortality than that posed by sepsis alone [1]. Both sepsis and septic shock represent a major growing global burden and a challenge for emergency physicians because of their increasing incidence and great pathophysiological, molecular, genetic, and clinical complexity ^[1][2][3][1,2,3]. The incidence of sepsis and septic shock has continuously increased since the first consensus definition (Sepsis-1) in 1991, reaching around 49 million cases of sepsis and 11 million sepsis-related deaths worldwide in 2017 ^[4][5][4,5]. These data led the World Health Organization (WHO) to declare sepsis a global health priority [5]. This alarming increase in incidence can be attributed to different factors: (i) the advanced average age among patients, especially in western countries; (ii) the increased number of invasive procedures; (iii) the wide usage of immunosuppressive drugs and chemotherapy; and (iv) antibiotic resistance [6]. Despite significant advancements in therapeutic management, septic patients have a high risk of in-hospital mortality (IHM), accounting for approximately 20% of all-cause deaths globally, rendering this combined ailment one of the highest-mortality conditions encountered in the emergency department (ED) ^[5][7][8][9][5,7,8,9].

The frequency of identifiable microorganisms in sepsis/septic shock has varied over time, with a current preponderance of Gram-positive bacteria and an increased clinical and epidemiological significance of fungal sepsis. Among the Gram-positive bacteria, the most frequently isolated pathogens are Staphylococcus aureus and Streptococcus pneumoniae, whereas among the Gram-negative bacteria, those most commonly identified are Escherichia coli, Klebsiella, and Pseudomonas spp. Among the fungal infections associated with the condition, the predominant role is played by Candida spp., which can often be identified in immunosuppressed or neoplastic patients undergoing long-term treatment with chemotherapeutic and immunosuppressive drugs [10]. The main sites of infection related to sepsis are the respiratory tract/pulmonary parenchyma (43%); the urinary system (16%); the abdomen (14%); the head, which is associated with a fever of unknown origin (FUO) (14%); and other sites/causes (13%) ^[6][10][6,10].

From a pathogenetic standpoint, sepsis is currently considered the result of several mechanisms that simultaneously involve a wide range of pro- and anti-inflammatory mediators [11]. Furthermore, sepsis-related cellular modifications have recently been defined, and the importance of microcirculation has been emphasized in the progression from sepsis to septic shock [12]. In this context, the endothelium has been identified as the fundamental functional unit in the pathophysiology of sepsis due to its role in the regulation of microcirculation and the modulation of coagulation mechanisms and inflammatory and anti-inflammatory signaling processes ^[12][13][12,13]. The glycocalyx is a component of the endothelial membrane consisting of proteoglycans and glycoproteins [14]. It mediates different functions, such as the construction of a mechanical barrier regulating vascular permeability, the activation of leukocytes and platelet adhesion, and the modulation of the inflammatory/anti-inflammatory response. Damage to the glycocalyx’s morpho-functional integrity (known as “glycocalyx shedding”) can occur due to oxidizing agents, cytokines, exotoxins, and bacterial endotoxins. This event leads to leukocyte diapedesis and increased vascular permeability with the production of oedema, which raises interstitial pressure and worsens tissue perfusion [14].

According to the third international consensus on sepsis and septic shock (Sepsis-3), sepsis should be suspected in patients with infections stemming from any infective source [1]. In these subjects, a quick Sequential Organ Failure Assessment (qSOFA) should be considered, for which a result ≥ 2 indicates patients who are at higher risk of in-hospital death. However, the 2021 guidelines discourage the use of qSOFA as the sole screening tool, recommending the use of the National Early Warning Score (NEWS) or systemic inflammatory response syndrome (SIRS) score instead due to their better sensitivity vs. qSOFA in predicting patient’s outcome [2]. A diagnosis of sepsis is confirmed in the case of a Sequential Organ Failure Assessment (SOFA) score ≥ 2. Septic shock is defined by the need for a vasopressor to maintain a patient’s mean arterial pressure (MAP) ≥ 65 mmHg and serum lactate level ≥ 2 mmol/L [1].

Antimicrobial therapy is the first pillar of sepsis/septic shock treatment. The administration of a prompt, empiric, antimicrobial therapy at the time of sepsis’s identification and after the collection of the appropriate cultures is a crucial step in pharmacological management. Microbiological samples should be assessed as soon as possible on admission to the ED and include blood and fluid or tissue from other sites deemed proper based on a clinical evaluation (e.g., urine or cerebrospinal fluid). Indeed, particularly in cases of septic shock, every hour of delay is associated with a significant increase in mortality ^[2][15][16][2,15,16]. The choice of empiric antimicrobial therapy based on clinical (i.e., site of infection, previous antibiotic use, immunosuppression, and risk factors for resistant organisms) and epidemiological criteria is fundamental. Initially, regarding septic shock, multidrug antimicrobial regimens with a wide spectrum of activity should be used (e.g., carbapenems and anti-Gram-negative antimicrobials with dual coverage). Dual coverage for Gram-negative organisms might be appropriate in cases of high suspicion for multidrug-resistant organisms (e.g., Pseudomonas aeruginosa or Acinetobacter baumanii). Dual coverage for Gram-positive organisms and methicillin-resistant Staphylococcus aureus (MRSA) should be considered for patients with a high risk of infection due to these pathogens [17]. Since efficacy depends on the peak of the antimicrobic blood level and the length of time during which this level remains above the minimum inhibitory concentration (MIC) for the identified pathogen, appropriate drug dosing is crucial. An initial loading dose may be the best strategy to achieve a therapeutic blood level more rapidly, with further dosing based on renal/liver function and consultation with an infectious disease physician ^[15][16][17][15,16,17].

However, the urgent need to establish antimicrobial treatment should be carefully pondered in terms of potential harm related to drugs administered to patients without an infection ^[2][18][19][2,26,27]. Different studies have proposed comparisons between 1 h vs. 3 h bundles with respect to antimicrobial administration ^{[15][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38]}[15,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46]. Current guidelines propose the administration of antimicrobials immediately, ideally within 1 h, in patients for whom sepsis is highly suspected with/without shock or when sepsis is possible and shock is detectable. 

Procalcitonin (PCT), a peptide precursor of calcitonin, is widely used for differentiating bacterial vs. non-bacterial infections or other inflammatory conditions ^[39][40][41][47,48,49]. In the last few years, different authors have proposed PCT as a marker to guide physicians in terms of starting antimicrobial treatment in patients with an unclear clinical presentation ^{[42][43][44][45][46]}[50,51,52,53,54]. However, as expressed in SSC guidelines, PCT associated with clinical evaluation was less effective than clinical evaluation alone with respect to deciding when to start antimicrobials [2]. 

2.2. Fluids

The second pillar of treatment is fluid resuscitation. Sepsis is accompanied by severe vasoplegia, which is secondary to the shedding of the glycocalyx, an affliction that may lead to distributive shock. The effective support of hemodynamic functions is essential for the survival of patients with sepsis/septic shock ^[47][89]. In the past, the “ideal” treatment for a septic patient was based on massive volume replenishment ^[48][49][90,91].

23.2.1. Type of Fluids

The two main types of resuscitation fluids are isotonic crystalloids and colloids. The following paragraphs will describe the main features of these therapies.

Crystalloids

Crystalloids are divided into two main categories (i.e., chloride-rich solutions and balanced crystalloids); according to the previous guidelines, they should be considered the fluids of choice in patients with sepsis/septic shock ^[2][50][2,96]. The administration of balanced crystalloids for the fluid resuscitation of septic patients is preferable for two reasons: (i) they have an electrolytic composition closer to that of plasma, and (ii) chloride-rich solutions are associated with a high risk of hyperchloremic acidosis (especially in large volumes).

Colloids

In the past, the fluids of choice were colloids (e.g., hydroxyethyl-starch (HES), gelatines, and dextrans), as higher-weight molecules were thought to reduce extravascular leakage and increase long-term intravascular volume ^[7][51][52][7,98,99]. However, since the integrity of the glycocalyx is altered in septic patients, the actual intravascular volume of these fluids is apparently less than expected ^[52][53][54][99,100,101]. Moreover, no data have consistently demonstrated the superiority of colloids over crystalloids with respect to reducing mortality for sepsis [7]. Albumin The use of albumin in sepsis treatment has been largely debated ^[55][105]. Despite the theoretical advantage of albumin over crystalloids in maintaining oncotic pressure, multiple RCTs and meta-analyses have reported that albumin infusion did not improve either short- or long-term mortality ^{[56][57][58][59][60]}[106,107,108,109,110].

2.2.2. Amount of Fluids

The total amount of fluid that should be administered in septic patients for proper resuscitation is still debated. The SSC suggests (but previously strongly recommended) treating septic subjects with at least 30 mL/kg of intravenous (IV) crystalloids within the first 3 h [2]. This volume has been strongly debated in the last years ^{[61][62][63][64][65]}[111,112,113,114,115], for which the common conclusion was to perform an individualized treatment targeted toward “glycocalyx resuscitation” according to fluid tolerance (FT) and fluid responsiveness (FR) ^[66][67][116,117]. FT can be expressed as the degree to which a patient can tolerate the administration of fluids without the onset of organ dysfunction ^[68][118]. FR is commonly defined as a stroke volume (SV) increase of at least 10% following a fluid bolus of 200–500 mL in 10–15 min ^[69][70][71][119,120,121].

2.3. Vasoactive Agents

The use of inotropic drugs represents one of the cornerstones of septic shock treatment. The pathogenesis of this severe and life-threatening condition is closely related to the loss of vasomotor tone with consequent systemic vasodilation and hypotension ^[47][72][89,128]. Since an MAP of 60 to 65 mmHg is considered a threshold for an increased risk of morbidity and mortality, the SSC recommends an MAP target of 65 mmHg and indicates norepinephrine (NE) as the first-choice drug [2]. Recent RCTs have proposed a “permissive hypotension” (MAP 60–65 mmHg) in patients ≥65 years with septic shock showing no differences in 90-day mortality, whereas higher blood pressure values (≥65 mmHg) do not seem to add further benefits ^[73][74][129,130]. NE is an α-1/β-1 adrenergic agonist that predominantly manifests its effects at the vascular level, enhancing vascular filling pressure and redistributing blood flow via its venoconstrictive effect ^[75][131]. In addition, it improves myocardial contractility and cardiac output (increasing preload) while having a minor impact on heart rate ^[76][132]. Ideally, an inotropic drug assessment should occur within the first hour if fluid infusion alone is not sufficient to reach the desired MAP [2]. Various studies have demonstrated that early NE administration (at a dose of 0.1–1.2 μg/kg/min) may improve the outcomes of septic patients, although the results remain controversial. In particular, it has been shown to be effective in shortening length of stay (LOS) and reducing mortality ^{[77][78][79][80][81][82][83][84]}[133,134,135,136,137,138,139,140]. Vasopressin (VP) may be considered a second-line choice for septic shock treatment [2]. According to the SSC’s recommendations, it can be administered (at a dose of 0.25–0.5 μg/kg/min) in addition to NE to obtain the target MAP by decreasing the dosage of the latter and reducing the side effects due to adrenergic overload [2]. Epinephrine should be considered as a third-line treatment for septic shock, and its use should be limited to those cases with inadequate MAP levels despite NE and VP administration [2]. As for VP, it can be used concomitantly with NE. Due to its important β-adrenergic effect, the use of epinephrine is indicated to a greater extent in cases of cardiac dysfunction ^[85][147]. 

2.4. Oxygenation and Ventilation Support

3.4. Oxygenation and Ventilation Support

23.4.1. Oxygen

Oxygen represents the most common treatment administered to any patient with a medical emergency, including those with sepsis/septic shock ^[2][86][2,154]. In clinical practice, oxygen is overused, often leading to hypoxemia, which may negatively impact patients’ survival. While several studies have demonstrated a correlation between hypoxemia and increased mortality in patients who have suffered from a stroke, traumatic brain injury, or cardiac arrest, this relation is not clear in subjects with sepsis/septic shock ^[87][155]. The latest SCC guidelines do not provide any recommendations for the preferential use of oxygen therapy or targets (generally defined as PaO₂ 55 to 70 mmHg; SpO₂ 88 to 92%) for adults [2].

23.4.2. Ventilation

Since the publication of SSC guidelines, no new data regarding the benefit of non-invasive ventilation (NIV) over mechanical ventilation (MV) have been collected or reviewed; thus, no updated recommendations can be provided. Two recent systematic reviews explored the use of low-tidal-volume ventilation (LTVV), proposing a reduction in tidal volume from 10 to 6 mL/kg for septic patients at the ED ^[88][89][157,158]. Both studies concluded that the use of LTVV is associated with improved clinical outcomes for mechanically ventilated ED patients.

23.4.3. High-Flow Nasal Cannula

An HFNC provides heated and humidified oxygen at high flow rates, generating low levels of positive pressure in the upper airways. Treatment with an HFNC induces multiple effects, including increased oxygenation, lower respiratory rates, and reduced inspiratory effort, thus improving survival rates for patients with acute hypoxic respiratory failure ^[90][91][160,161]. Despite the increasing use of HFNCs for critically ill patients, there are no consistent data on their efficacy with respect to sepsis/septic shock as their use was quite limited when the SCC guidelines were issued. Despite the low quality of the evidence, the SSC suggested HFNC application rather than NIV in septic patients with acute hypoxic respiratory failure [2].

2.5. Other Treatments

3.5. Other Treatments

23.5.1. Heparin

Since critically ill patients are at high risk for deep vein thrombosis and pulmonary embolism, heparin should be included in the treatment of these cases. Furthermore, sepsis/septic shock might induce disseminated intravascular coagulation, a life-threatening complication characterized by the suppression of fibrinolysis, which often leads to multiple organ failure ^[92][165]. The SSC guidelines strongly recommended venous thromboembolism (VTE) prophylaxis via administrating low-molecular-weight heparin (LMWH) instead of unfractionated heparin (UFH) [2].

Emergency Physician’s Point of View

VTE prophylaxis should be administered to sepsis/septic shock patients, preferably using LMWH (rather than UFH); mechanical prophylaxis may be advised for the treatment of patients with absolute contraindications to heparin treatment.

23.5.2. Insulin

Stress hyperglycemia, due to increased glucocorticoid and catecholamine release and insulin resistance, is a common effect and may worsen septic patients’ outcome ^{[93][94][95][96]}[172,173,174,175]. In critically ill patients, insulin infusion should always be selected over oral anti-diabetic treatments ^[97][176].

Emergency Physician’s Point of View

According to the SSC guidelines, glycemic control (with a glucose target between 144 to 180 mg/dL), preferably via insulin administration, is highly recommended for septic patients [2].

23.5.3. Proton Pump Inhibitors

In its 2016 guidelines, the SSC strongly recommended the use of stress ulcer prophylaxis for septic patients [1]. This recommendation was downgraded in 2021 because of weak evidence regarding the benefit–risk ratio [2]. Various studies have demonstrated that proton pump inhibitors (PPIs) do not significantly improve critical patients’ prognosis, leading to a modest reduction in gastrointestinal (GI) bleeding ^[98][99][179,180].

Emergency Physician’s Point of View

The current evidence does not provide any further information about PPI assessment for stress ulcer prophylaxis in patients with sepsis/septic shock. Therefore, in line with the SSC’s guidelines, PPI treatment should be pursued.

23.5.4. Renal Replacement Therapy

Acute kidney injury (AKI) is defined as an increase in serum creatinine by ≥0.3 mg/dL within 48 h or by ≥1.5 mg/dL from the baseline values within the previous 7 days or a decrease in urine volume < 0.5 mL/kg/h after 6 h, and it should be stratified for severity according to serum creatinine or urine output ^[100][183]. AKI is a common complication affecting about 40% and up to 64% of septic and septic shock patients, respectively, thus increasing mortality rates ^{[101][102][103]}[184,185,186]. RRT is commonly required in septic AKI associated with other absolute indications for dialysis (e.g., severe metabolic acidosis, refractory fluid overload, electrolyte imbalance, and uremic complications) ^[2][104][2,187].

Emergency Physician’s Point of View

Even though AKI is a common complication in septic patients, sepsis alone is not an indication for RRT.

23.5.5. Steroids

Since a pro-inflammatory state and the cytokine cascade are thought to contribute significantly to the manifestation of sepsis, various studies have proposed the use of steroid treatments; however, the data supporting the use of these drugs remain inconclusive ^{[105][106][107]}[192,193,194]. So far, only hydrocortisone (at a dose of 200 mg/die) has been suggested by the SSC for adult septic shock patients not reaching the target MAP despite vasopressor administration ^{[2][108][109]}[2,195,196].

Emergency Physician’s Point of View

Despite the role of steroids emphasized by Fong et al., the routine table use of glucocorticoids (alone or in combination with fludrocortisone) in septic shock management is not adequately supported by the current evidence. The use of hydrocortisone may be considered for patients with a vasopressor-resistant, inadequate MAP.

23.5.6. Sodium Bicarbonate

Sepsis and septic shock may induce acidosis through different pathophysiological mechanisms, which mainly lead to lactic or metabolic acidosis ^{[110][111][112]}[198,199,200]. The role of sodium bicarbonate in these conditions has been largely debated, but no clear results have been obtained. In particular, the role of bicarbonate therapy in patients with lactic acidosis is controversial. Most experts believe that this treatment is appropriate in cases of severe lactic acidosis with acidemia (arterial pH < 7.1) which may lead to hemodynamic instability as a result of reduced left ventricular contractility, arterial vasodilation, and impaired responsiveness to catecholamines ^[113][201].

Emergency Physician’s Point of View

Despite controversial evidence, sodium bicarbonate is a reasonable treatment for septic patients with severe metabolic/lactic acidosis (bicarbonate levels <5 mEq/L and/or pH < 7.1) or an AKI stage 2 or 3. Therefore, this therapy should be indicated as a bridge to be crossed before the main pillars of treatment begin to be effective.

23.5.7. Acetaminophen

This drug effectively reduces temperature in non-neurocritical ill patients but does not change mortality or other outcomes; therefore, it should not be considered one of the main pillars of sepsis treatment ^[114][115][207,208].

Emergency Physician’s Point of View

Acetaminophen is not considered a pillar of sepsis treatment and should be administered as a symptomatic drug.