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 PaO
2 55 to 70 mmHg; SpO
2 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.