Sepsis (in Adults): Clinical Guidelines

List of Abbreviations

SBA – systemic antibacterial drugs

AMT – antimicrobial therapy

AM - antimicrobials (J01 - Antibacterials for systemic use)

ESBL - extended-spectrum beta-lactamases

WHO – World Health Organization

HFNO - high-flow nasal oxygen therapy

DIC - disseminated intravascular coagulation syndrome

PCWP - pulmonary capillary wedge pressure

RRT – renal replacement therapy

IMV – invasive mechanical ventilation

IC - invasive candidiasis

CT – computed tomography

MRI – magnetic resonance imaging

MOD - multiple organ dysfunction

NIV – non-invasive ventilation

ICU - intensive care unit

AKI – acute kidney injury

ARDS – acute respiratory distress syndrome

ICU – intensive care unit

BV – blood volume

MOF – multiple organ failure

PCT – procalcitonin

MDRO - multidrug-resistant pathogens

RCTs – Randomized Controlled Trials

MAP – mean arterial pressure

SI - systemic inflammation

SIRS - systemic inflammatory response syndrome

CRP - C-reactive protein

SIRS – systemic inflammatory response syndrome

MODS - multiple organ dysfunction syndrome

SS – septic shock

CVC – central venous catheter

SOFA scale - Sequential Organ Failure Assessment

ECMO – extracorporeal membrane oxygenation

SSC-2016 - 2016 Surviving Sepsis Campaign guidelines

SvO₂ - venous blood oxygen saturation

SSC-2021 - 2021 Surviving Sepsis Campaign guidelines

Terms and Definitions

Local infection - presence of an infectious focus with or without clinical manifestations of systemic inflammatory response syndrome (SIRS).

Bacteremia - isolation of microorganisms from the blood. It is one of the possible, but not mandatory, manifestations of sepsis. Detection of microorganisms in the bloodstream in individuals without clinical and laboratory confirmation of systemic inflammation should in most cases be considered as transient bacteremia not associated with the septic process.

Sepsis - a pathological process based on the body's reaction in the form of generalized (systemic) inflammation to an infection of various origins (bacterial, viral, fungal), leading to newly developed organ dysfunction.

Septic shock - the most severe clinical course of sepsis, characterized by marked circulatory, cellular, and metabolic abnormalities that significantly increase the risk of mortality.

Laboratory diagnostics - a set of methods aimed at analyzing test material using various specialized methods and equipment.

Instrumental diagnostics – diagnostics using various devices, apparatus, and instruments.

Medical intervention - a set of medical examinations and/or procedures performed by a medical worker or other personnel authorized to engage in medical activities, targeting a patient's physical or mental state and having a preventive, diagnostic, therapeutic, rehabilitative, or research orientation.

Surgical treatment is a method of treating diseases by dividing and uniting tissues during a surgical operation.

Source control - eradication of the infection focus using various surgical and technical options.

Intensive care - prevention and treatment of severe, but reversible functional and metabolic disorders that threaten the patient with death, using methods of artificial maintenance or replacement of organ and system functions.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Sepsis - a pathological process based on the body's reaction in the form of generalized (systemic) inflammation to an infection of various origins (bacterial, viral, fungal), leading to newly developed organ dysfunction [1].

Septic shock - the most severe clinical course of sepsis, characterized by marked circulatory, cellular, and metabolic abnormalities that significantly increase the risk of mortality [2].

Local infection - presence of an inflammatory focus of infectious origin of any localization with or without signs of SIRS, but without organ dysfunction.

Evolution of the clinical and diagnostic concept. On May 26, 2017, the 70th World Health Organization (WHO) World Health Assembly for the first time reviewed a report on improving the prevention, diagnosis, and clinical management of sepsis. It was noted that sepsis has a distinct and time-critical clinical course, which, when diagnosed early, is largely treatable with appropriate therapy [3].

The definition of sepsis as an infection accompanied by at least two signs of systemic inflammatory response syndrome (SIRS concept; "Sepsis-2") [4] is outdated. Numerous studies have demonstrated the low specificity of this approach because SIRS often has a compensatory nature.

The key point indicating the development of sepsis—as a new qualitative state—in the presence of an infection focus is the dysregulation of the host response to the infectious agent, manifesting as morphological and/or functional damage to own tissues or organs. The latest consensus definition ("Sepsis-3") notes that the fundamental difference between sepsis and local uncomplicated infection is the development of acute organ dysfunction due to host response dysregulation [1]. Septic shock is regarded not as a link in the chain of progressive systemic inflammation, but as a clinical variant of sepsis with profound circulatory and metabolic disorders. Its criteria include the need for adrenergic and dopaminergic drugs (with predominantly vasopressor action, e.g., norepinephrine**) to maintain mean arterial pressure ≥ 65 mm Hg, and an arterial blood lactate level > 2 mmol/L despite adequate intravenous fluid resuscitation [1, 2].

1.2 Etiology and pathogenesis of the disease or condition (group of diseases or conditions)

The incidence of Gram-negative sepsis is increasing in most large multidisciplinary medical centers worldwide. Results of the EPIC-II study show that Gram-negative bacteria are isolated in 62% and Gram-positive bacteria in 47% of ICU patients with infection [5]. At the same time, the prevalence of Gram-positive infection had previously exceeded 50% in North America, Eastern Europe, Oceania, and Africa [6]. Results of the EPIC-III study indicate an increasing incidence of sepsis, especially in ICUs, caused by extended-spectrum beta-lactamase-producing Enterobacterales as well as carbapenem-resistant and carbapenemase-producing microorganisms. While EPIC-III involved ICUs from 75 countries, significantly expanding the geography of EPIC-II, which included 17 Western countries [7].

The EPIC-II study already noted that the incidence of non-fermenting bacteria (Pseudomonas aeruginosa i Acinetobacter spp.) varies significantly across different regions of the world at 16.9% and 5.6% (Western Europe), 13.3% and 3.9% (North America), 28.1% and 17.4% (Eastern Europe), and 28.7% and 19% (Asia) [7]. Typically, these microorganisms act as causative agents of hospital-acquired sepsis in ICU patients. Their increased clinical significance in the development of severe infections is associated with the increased life expectancy of patients who have survived critical conditions and the unjustifiably frequent use of systemic antibacterial drugs in clinical practice, particularly 3rd-generation cephalosporins, fluoroquinolones, and carbapenems. As a result, the etiological structure of nosocomial sepsis pathogens has become similar in most large ICUs, beginning to be characterized by the first letters of the genus names of the microorganisms – ESKAPE (sounding like "escape"): Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Rseudomonas aeruginosa, Enterobacter spp. [8]. Consequently, based on prevalence and resistance to antimicrobial drugs, especially in the ICU, the top three "leaders" were represented by members of the order Enterobacterales, Acinetobacter baumannii, Pseudomonas aeruginosa[3].

All highlighted bacteria demonstrate increasing resistance to systemic antibacterial drugs. A new, extremely adverse phenomenon is the emergence of multiple and even pan-resistance phenotypes, characterized by resistance to all available systemic antibacterial drugs. Recently, the order Enterobacterales has taken the lead; its representatives live freely in the external environment and the gastrointestinal tract and possess a high capacity for expressing genes that implement resistance mechanisms. According to EPIC-III data, within the overall structure of causative agents, the detection rate of bacteria from the order Enterobacterales in Russia was comparable to their prevalence in Western European ICUs (33% and 33.8%) and North America (33.0% and 31.2%), but lower than in Eastern Europe (43.6%). The prevalence of infections associated with Gram-positive bacteria in the overall etiological structure in the Russian Federation was significantly lower at 23.9%. Among Gram-negative bacteria, in the RIORIT study conducted in Russia, representatives of the order Enterobacterаles also held leading positions as causative agents in ICUs at 52.7%, followed by P. aeruginosa at 29.9%, and Acinetobacter spp. at 15.7% [9]. In turn, among representatives of the order Enterobacterales, K. pneumoniae (34%) and E. coli (28.9%) played the primary role [10, 11].

The role of viruses in the etiology of sepsis. Events and scientific studies over the past 10 years have convincingly proven that viruses can trigger systemic inflammatory syndrome with severe organ dysfunction, including the development of shock and ARDS [12, 13]. The high genome-mutating capacity of these microorganisms has led to the emergence of viruses with a significantly greater ability than classical respiratory viruses to generate an uncoordinated host inflammatory response. Coronaviruses, avian influenza virus H₅N₁, and H₁N₁/California virus [14, 15, 16, 17], and particularly SARS-CoV-2—whose pathogen is prone to mutations, making the pandemic caused by it so difficult to manage [18, 19]—have most prominently asserted themselves in this regard.

Key pathogenesis points. The main driving force in shaping the clinical manifestations of the disease is the endogenous response of the body aimed at limiting the microbial invasion. Loss of control over the endogenous response is accompanied by the development of organ damage and serves as one of the main causes of death. Development of an uncontrolled inflammatory response is facilitated by genetic predisposition, advanced age, severe chronic pathology, and phenotypic characteristics of the pathogen. The pathogenesis of sepsis is described in considerable detail in various monographs and guidelines, including domestic ones [2, 20, 21]. In general, it reduces to the following principal positions.

The role of the host organism. Current concepts of the pathogenesis of sepsis are the result of generalizing a large number of experimental and clinical studies performed in dozens of laboratories across Europe, North America, Asia, and Australia. The formulation of the systemic inflammatory response syndrome concept as the main component of sepsis genesis by R. Bone et al. [22] received stronger justification in subsequent years through the specification of the mechanisms of this pathological process. When the inflammatory component prevails over the anti-inflammatory one and primary barrier structures are damaged in the inflammation zone, inflammatory mediators "break through" into the systemic bloodstream. The inability of regulatory systems to maintain homeostasis, along with the dominance of destructive effects of cytokines and other mediators, leads to systemic structural and functional remodeling of endothelial cells, microcirculatory hemodynamic disorders outside the primary focus, the triggering of disseminated intravascular coagulation syndrome, and the development of organ dysfunction.

Accumulation of new data on sepsis-induced changes in cell morphology, biology, biochemistry, and immunology has shown that the interaction between the host and the microorganism is more complex than previously thought. It is characterized by multifaceted responses of the host to microbial invasion, involving other non-immunological links of pathogenesis in shaping the sepsis phenotype: cardiovascular, hormonal, neuronal, metabolic, and coagulation systems. The severity of the body's reaction to infection is determined by sex, age, genetic factors, concomitant pathology, and "therapeutic aggression," including surgical interventions and certain medications. The resulting organ dysfunction is not always associated with cell death.

Shock development in sepsis is associated with three main mechanisms: a decrease in peripheral vascular tone; early, progressive myocardial dysfunction; and loss of circulating blood volume due to increased vascular permeability and its sequestration in the microcirculatory bed. Most of these disorders are caused by direct or indirect effects of pro-inflammatory cytokines produced by activated leukocytes and endothelial cells. Endotoxin, TNF, IL-1, and IL-6 are the main proximal mediators initiating systemic inflammation, but the leading role in shock formation belongs to nitric oxide (NO). High concentrations of NO cause a drop in peripheral vascular tone combined with a reduced vascular wall response to central and humoral regulatory stimuli [23].

The most typical hemodynamic profile of early septic shock is hyperdynamic—increased cardiac output combined with decreased systemic vascular resistance. Nevertheless, manifestations of myocardial dysfunction in the form of decreased myocardial contractility are already recorded at this point. The maintenance of increased cardiac output in this situation is facilitated by low afterload and endogenous hypercatecholaminemia. This hemodynamic variant of septic shock is typical for patients with preserved myocardial contractile function, without severe hypovolemia or with its rapid correction. Clinically, it corresponds to the "warm shock" phase—dry, hyperemic, warm skin, usually combined with moderate manifestations of organ dysfunction. As the phenomenon of blood volume pooling increases due to microcirculatory disorders and capillary leakage, a decrease in venous return to the heart, in addition to increasing cardiodepression, begins to contribute to the drop in cardiac output. Low cardiac output is associated with severe peripheral circulation disorders, which is accompanied by the formation of the "cold shock" pattern and severe multiple organ dysfunction syndrome—the hypodynamic variant. Two main mechanisms contribute to the development of myocardial depression: proinflammatory mediators (TNF, IL-1) and decreased sensitivity of ß₁-adrenoceptors to catecholamines. In addition, NO is also involved in the implementation of the cardiodepressor effect. The duration of septic shock phases has no clear temporal determination and depends on the specific clinical situation, the characteristics of the infection-host interaction, and the patient's baseline functional background.

The indicated variants represent the extreme points of a wide range of hemodynamic disorders. In real-world management of patients with septic shock, there is a number of intermediate types of circulatory disorders, the appearance of which determines the degree of hypovolemia and the nature of the treatment provided, starting from the pre-hospital stage. In particular, hyperdynamic shock can be combined with hypovolemia, and hypodynamic shock—with both a pronounced blood volume deficit and normovolemia, with various changes in stroke volume.

Peripheral circulation in septic shock. Due to the specific features of the systemic inflammatory response, the microvasculature is the main target and locus of damage in sepsis. With the development of septic shock, microcirculatory disorders are especially pronounced. Even with significantly increased systemic inflammation and oxygen transport to tissues, there is a decrease in the arteriovenous oxygen difference and an increase in lactate content due to decreased peripheral oxygen extraction. One of the reasons for low extraction is a decrease in the number of functioning capillaries. In turn, the inability of capillaries to fulfill their main purpose, which consists in the integration of blood flow and metabolism through oxygen delivery, is associated with a number of events occurring in sepsis: damage to blood flow autoregulation mechanisms, erythrocyte deformation and their increased adhesion to the endothelium, external compression by edematous fluid, microthrombus formation, and finally, the triggering of arteriovenous shunting. It should also be borne in mind that microcirculatory disorders occur even before the appearance of hypotension, and the level of systemic blood pressure in septic shock does not reflect the value of tissue perfusion and does not coincide with the number of functioning capillaries.

Neuroendocrine regulation and systemic inflammation. The stereotypical response of the body to the impact of aggressive factors, termed by H. Selye as the general adaptation syndrome or stress response, aimed at restoring homeostasis and ultimately increasing survival, is certainly involved in septic shock as well. Activation of the hypothalamic-pituitary-adrenal axis is the result of increased secretion of corticotropin-releasing hormone and arginine vasopressin by the paraventricular nuclei of the hypothalamus.

Currently, evidence has accumulated indicating the important role of the development of glucocorticoid receptor resistance. The decrease in their sensitivity is associated with a decrease in their nuclear translocation as a result of the circulation of high concentrations of both free and bound cortisol. A correlation was also established between a decrease in the density of nuclear glucocorticoid receptors and the outcome when blood cortisol levels were high [24].

In addition to a decrease in the number of receptors, the appearance of isoforms incapable of ligand binding also plays a role in the genesis of septic shock. It is believed that polymorphism of genes encoding receptors could also influence the outcome of the interaction. In some patients with septic shock, adrenal dysfunction may be associated with its structural changes—hemorrhage or infarction. Such changes are more common in severe consumption coagulopathy and systemic candidiasis [1].

The role of microbial factor characteristics. Various microorganisms, as well as different bacterial strains within the same genus and species, have an unequal ability to affect cardiac output, the realization of local tissue damage, and dissemination within the body. These differences are determined by the presence of virulence factors that have evolved over hundreds of millions of years of their coexistence with other forms of life on Earth. Specifically, the presence of gene clusters encoding virulence factors distinguishes pathogenic strains from commensals. However, these slow vertical evolutionary changes can subsequently spread rapidly among bacterial populations through horizontal transfer of genetic information. An unequal set of virulence factors is possessed not only by microorganisms belonging to different genera, but even within the same species. Apparently, the expression of virulence factors is influenced by environmental conditions and the process of individual interaction between the host and bacteria, as well as the population density of the latter. The concentration of patients with reduced anti-infective defense observed in general ICUs, hematology departments, transplant units, and burn centers has created new ecological niches for microorganisms. Under these conditions, derepression of genes controlling the synthesis of virulence factors and selection of microorganism populations with a new set of determinants of increased pathogenicity are observed. This circumstance is one of the leading reasons for the increasing incidence of severe life-threatening infections, including septic shock [25,26,27].

Septic shock indicates a decompensated course of the systemic inflammatory response syndrome, which may be indicated by neutrophilia and a shift to immature neutrophils, as well as the development of a persistent tendency toward disseminated thrombosis (the so-called thrombotic phenotype of disseminated intravascular coagulation) due to platelet consumption (development of thrombocytopenia) and natural anticoagulants along with the suppression of overall fibrinolytic activity. After a few days, an immunosuppressive state with a high risk of fatal outcome may occur. Different pathogenetic mechanisms reinforce each other: inflammation causes coagulation, coagulation causes inflammation, and tissue hypoxia enhances both inflammation and coagulation. This leads to the formation of pro-inflammatory and pro-coagulant vicious circles. Many mediators are harmful to the body (e.g., TNF-α), but at the same time they are important for the homeostatic control of infection, and this partly explains why treatments aimed at neutralizing such mediators have been ineffective to date.

Massive endothelial damage, characterized by increased permeability and, consequently, the development of capillary leakage, is an important sign of septic shock. Consequently, protein-rich edematous fluid escapes into tissues, including the lungs, contributing to the development of acute respiratory distress syndrome. In septic shock, damaged endothelial cells synthesize nitric oxide (NO), which is a potent vasodilator. In septic shock, epithelial cells of the lungs and intestine are also damaged. Disruption of the intestinal epithelial barrier promotes the translocation of enteric bacteria and endotoxin, thereby further enhancing the inflammatory manifestations of septic shock.

1.3 Epidemiology of the Disease or Condition

The results of the first unification of diagnostic criteria (Sepsis-1 criteria) provided an insight into the prevalence of sepsis in certain regions of the world. For example, in the USA, severe sepsis was diagnosed more than 700,000 times annually, i.e., about 2,000 cases daily. Septic shock developed in 58% of severe sepsis cases. At the same time, the incidence of sepsis was higher in the winter season—48.6 per 100,000 population, exceeding its prevalence in the autumn-summer period by 16.5%. Characteristically, mortality in the winter months also exceeded the annual average by 13% [28].

Data on the incidence of sepsis in Russia are virtually non-existent. During the only multicenter study RIORIT (Prevalence of Infections in Intensive Care Units) conducted back in 2011, it was established that the proportion of patients with infection in ICUs was 34.1% of all hospitalized patients; septic shock developed in 20.2% of cases among them [9]. Mortality among individuals with various forms of infection in ICUs was 30.4% [29, 30].

The prevalence of sepsis with organ dysfunction in various regions of the world, according to the Sepsis-1 criteria, ranged from 38 to 240 patients per 100,000 population. The wide variation in sepsis prevalence figures is related both to diagnostic criteria and to the characteristics of the population and the healthcare delivery system. It is known that in major hospital centers, the number of patients with sepsis is higher due to the greater prevalence of nosocomial sepsis resulting from high surgical activity and the complexity of performed surgical interventions. A significant difference in the frequency of hospitalizations for sepsis in general wards and in ICUs is associated with the unequal availability of ICU beds in different countries. Sepsis frequently develops as a result of healthcare-associated infections. About half (49%) of sepsis patients in ICUs acquire the infection in the hospital. Mortality among sepsis patients is estimated at 27% in general hospital wards and 42% in ICUs. Overall, mortality in sepsis with MODS is 20–40%, and in septic shock it is 40–80% [31].

More recent studies note an increase in the number of hospitalized patients and an increase in incidence in the general population—288 cases of sepsis per 100,000 residents, with 148 cases accounting for sepsis with organ dysfunction. Extrapolation of these data to the entire world population shows that the development of sepsis probably occurs in 31.5 million people annually. Assuming that mortality in sepsis with MODS, even in countries with high healthcare investment levels, is 26%, approximately 5.3 million people may die annually from this complication. However, it is known that 87% of the world's population lives in low- or middle-income countries in terms of healthcare system investment, while 60–80% of fatalities are recorded precisely in them. The highest mortality and length of stay in ICUs are characteristic of nosocomial sepsis [32].

In 2021, T. Imaeda et al. published the results of assessing the prevalence of sepsis in Japan from 2010 to 2017 using Sepsis-3 criteria. They analyzed 50,490,128 hospitalization cases and revealed that sepsis developed in 2,043,073 people (4%). Over 8 years, the annual increase in sepsis incidence was 0.3%, and the frequency of its development among hospitalized patients reached 4.9% in 2017. Annual sepsis mortality per 1,000 hospital patients increased by 1.8 cases per year and amounted to 7.8/1,000 in 2017 [33].

The treatment of patients upon the development of sepsis sharply increases institutional costs. For example, in China, according to T. Yan et al., the amount of ICU expenses in treating sepsis using international standard protocols increased by 7,214.41 USD (per patient) [34], and the total costs for sepsis treatment in the USA amounted to 20.3 billion USD, or 5.2% of the total combined cost of all hospitalizations, ranking first among the most expensive hospitalizations [35].

1.4 Features of Coding the Disease or Condition

According to the International Statistical Classification of Diseases and Related Health Problems, depending on the clinical situation and according to existing sepsis criteria, the following codes can be used:

A40 – Streptococcal sepsis

A40.0 – Sepsis due to streptococcus, group A

A40.1 – Sepsis due to streptococcus, group B

A40.2 – Sepsis due to streptococcus, group D

A40.3 – Sepsis due to Streptococcus pneumoniae

A40.8 – Other streptococcal sepsis

A40.9 – Streptococcal sepsis, unspecified

A41 – Other sepsis

A41.0 – Sepsis due to Staphylococcus aureus

A41.1 – Sepsis due to other specified staphylococcus

A41.2 – Sepsis due to unspecified staphylococcus

A41.3 – Sepsis due to Haemophilus influenzae

A41.4 – Sepsis due to anaerobes

A41.5 – Sepsis due to other Gram-negative organisms

A41.8 – Other specified sepsis

A41.9 – Sepsis, unspecified

B37.7 — Candidal septicaemia

If it is necessary to identify septic shock, an additional code (R57.2) should be used, and for systemic inflammatory response syndrome of infectious origin with organ dysfunction, R65.1. This category is not used in primary coding. It is intended for use in multiple coding to identify this syndrome arising from any cause. A code from another chapter must be assigned first to indicate the cause or underlying disease.

1.5 Classification of the disease or condition

Currently, the following are distinguished:

1. sepsis with the development or progression of multiple organ dysfunction in response to infection,

2. sepsis with the development of shock accompanied by pronounced circulatory, cellular, and metabolic abnormalities in response to infection.

Prior to 2016, the classification of the septic process proposed by the Consensus Conference of the American College of Chest Physicians and the Society of Critical Care Medicine (ACCP/SCCM) regarded sepsis as the systemic inflammatory response syndrome (SIRS) to microbial invasion. Sepsis combined with organ dysfunction, hypotension, and impaired tissue perfusion was defined as severe sepsis, and septic shock was defined as sepsis with signs of tissue and organ hypoperfusion and arterial hypotension that does not resolve with fluid resuscitation and requires the administration of norepinephrine** or other vasopressor drugs.

This classification is currently considered obsolete.

1.6 Clinical presentation of the disease or condition

Systemic inflammatory response syndrome (SIRS) is a predictable manifestation of the body's response to infection, but its presence does not yet indicate sepsis. The development of the systemic inflammatory process is associated with a temperature reaction (typically fever, much less frequently hypothermia), the release of neutrophils into the circulation from reserve pools and increased leukopoiesis, an increased heart rate and respiratory rate, hyperproduction of acute-phase proteins and a whole pool of metabolic products. This made it possible to outline the systemic inflammatory response syndrome as the initial symptom complex indicating the likelihood of an infectious focus and the risk of developing sepsis.

Organ/system dysfunction/failure. Mediator chaos combined with the development of an uncontrolled inflammatory response, associated with genetic predisposition, age, severe acute or chronic pathology, drug therapy, and pathogen characteristics, involves a broader pool of mediators in the cellular response, forming a diverse phenotype of sepsis with various clinical and laboratory manifestations of the pathological process and impaired function of systems and organs. The severity of organ dysfunction is extremely variable and unstable. It is precisely the presence of a particular organ dysfunction and its severity, in addition to the nosology complicated by sepsis, that determine the specific clinical and laboratory "portrait" of the patient. Subsequently, the clinical picture is complemented by the nature of the treatment provided (surgery), response/non-response to therapy, and the addition of a particular variant of nosocomial infection.

Shock. According to the latest international definitions of sepsis from 2016, the development of septic shock is manifested by pronounced circulatory, cellular, and metabolic disturbances in the form of arterial hypotension and an arterial blood lactate level greater than 2 mmol/L, despite adequate fluid resuscitation affecting the water-electrolyte balance. Septic shock belongs to the distributive type of shock and is characterized by the acute development of inadequate tissue perfusion with the formation of tissue hypoxia as a result of a decrease in systemic oxygen transport and impairment of cellular oxygen utilization mechanisms.

2. Diagnostics, medical indications and contraindications for diagnostic methods

The fastest possible determination of the development of sepsis/septic shock has a key impact on the outcome. According to the modern concept of sepsis (Sepsis-3), it is valid to make such a diagnosis upon identifying the connection of developing (progressing) organ dysfunction with a pre-existing or current inflammatory or purulent disease/process. Accordingly, the main criteria for establishing the development of sepsis/septic shock are: a) the presence of a focus of infection and b) the cumulative manifestations of the body's reaction to this focus in the form of multiple organ dysfunction.

The most characteristic clinical, laboratory, and instrumental criteria reflecting the appearance of a focus of infection are presented below. The main criterion for the aggravation of the systemic response to an inflammatory/purulent process and the progression of organ dysfunction is a rapid deterioration of the patient's condition with an increase in the SOFA score by 2 or more points (App. G.1). In the case of known chronic diseases, the baseline level of organ disorders can be taken as the zero value of organ dysfunction according to SOFA [36].

The criterion for the development of septic shock in a patient with sepsis is the development of hypotension requiring the use of adrenergic and dopaminergic agents with predominant vasopressor action to maintain a mean arterial pressure (MAP) ≥ 65 mm Hg, with an arterial blood lactate level > 2 mmol/L despite adequate intravenous fluid resuscitation affecting the water and electrolyte balance [1].

Therefore, for diagnosis, both anamnestic data and the results of physical examination, laboratory tests, and various instrumental studies performed to locate the source of infection, assess changes in the course of the primary and concomitant diseases, and detect signs of a complicated postoperative period are of great importance.

2.1 Complaints and Anamnesis

Level of trustworthiness of evidence (LTE) 5, Level of recommendation (LR) C

Comments: the main complaints are usually associated with the presence of a primary inflammatory (infectious) focus (pain, discomfort, dysfunction in the causative organ or tissue) + nonspecific complaints associated with intoxication and signs of organ dysfunction. General (nonspecific) complaints and symptoms: weakness, myalgia, malaise, lack of energy, passive behavior; elevated body temperature (fever, chills, sweating).

Complaints and symptoms depending on the involved organs: cough, dyspnea, chest pain; palpitations, arrhythmia; nausea, vomiting, loss of appetite, jaundice of the skin and mucous membranes, dry mouth; abdominal pain, abdominal distension, constipation; headaches, euphoria, agitation, delirium, lethargy, impaired consciousness up to coma; lower back pain, absence or low urine output (diuresis less than 0.5 mL/kg/h for more than 2 consecutive hours); subcutaneous hemorrhage, bleeding gums, epistaxis.

When taking the medical history, pay attention to the presence of a preexisting/current inflammatory or purulent disease/process, and not only surgical, but also, for example, pneumonia.

2.2 Physical Examination

• When sepsis is suspected, it is recommended to perform a physical examination to identify an inflammatory or purulent disease/process, as well as associated organ disorders [2, 37].

Level of trustworthiness of evidence (LTE) 5, Level of recommendation (LR) C

Comments: general inspection of the skin and mucous membranes may reveal hot skin; skin pallor, marmoreal skin; facial flushing, acrocyanosis; jaundice of the sclera and skin; hemorrhagic rash (ranging from punctate petechiae to confluent ecchymoses and large hemorrhagic and necrotic lesions, appearing early, localized on the anterior chest wall, abdomen, and arms) in coagulopathy and thrombocytopenia; enlargement of local lymph nodes, polylymphadenopathy. Sepsis is typically characterized by fever and profuse sweating. Other local signs of infection causing the sepsis may also be present.

Assessment of respiratory status: tachypnea, dyspnea, mixed shortness of breath; changes in percussion findings: shortening/dullness of the percussion sound is detected over areas of lung tissue consolidation and fluid accumulation in the pleural cavity; changes in vocal fremitus: its weakening over areas with pleural effusion, enhancement over areas of lung tissue consolidation/infiltration; changes in lung auscultation findings: weakened, harsh breath sounds, bronchial breathing; appearance of moist rales and crepitation over pneumonic areas.

Physical examination of the heart (auscultation and percussion of the heart, examination of the pulse and apical impulse, etc.): muffling of heart sounds; tachycardia, tachyarrhythmia; enlargement of the relative cardiac dullness boundaries (in the event of myocarditis).

Abdominal examination: pay attention to the presence of peritoneal signs (identifying the primary source of infection) and signs of intra-abdominal hypertension as a factor affecting respiratory and hemodynamic status, renal excretory function, and splanchnic blood flow (in the abdominal organs); sepsis is characterized by splenomegaly and hepatomegaly; abdominal distension (tympanites), decreased or absent bowel sounds, and gastroparesis.

Symptoms and signs of sepsis can be subtle, and organ dysfunction, when it develops, is frequently mistaken for manifestations of other conditions (e.g., delirium tremens, heart disease, pulmonary embolism), especially in postoperative patients. As the condition of a patient with sepsis deteriorates or as septic shock develops, an early symptom—particularly in the elderly—may be confusion or decreased activity. Blood pressure drops, yet the skin remains paradoxically warm. In later stages, the limbs become cool and pale with peripheral cyanosis. Organ dysfunction leads to additional symptoms and signs depending on the affected organ (e.g., oliguria, dyspnea, etc.).

• If sepsis is suspected in an adult patient, the SOFA (Sepsis (sequential) Organ Failure Assessment) scale is recommended to assess the presence and severity of organ dysfunction [38, 39, 40].

Level of Evidence (LE) 4, Grade of Recommendation (GR) C

Comment. Assessing the severity of organ dysfunction using the SOFA scale is a key criterion established by the Sepsis-3 concept [40]. This scale has high informative value with a small number of parameters (App. G.1). It allows for the quantitative determination of the severity of organ-system disorders and is available for use in most domestic medical organizations. Therefore, in international guidelines, this recommendation received the status of "best clinical practice". An increase of 2 or more points on the SOFA scale from baseline in the presence of a suspected or proven site of infection indicates the development of sepsis.

• To assess the presence of organ dysfunction outside the ICU (ICU/ACU) and out-of-hospital for initial screening of the probability of sepsis development in an adult patient, it is recommended to use the simplified SOFA scale (quick SOFA - qSOFA) [41, 42, 43, 44, 45].

Level of Reliable Evidence (LRE) 1, Level of Clinical Recommendations (LCR) A

Comment. The qSOFA scale uses 3 variables (App. G2). Initially (3rd International Consensus Definitions for Sepsis [40]), it was accepted that if any two of them are simultaneously recorded, the risk of an adverse outcome in patients with known or suspected infection is extremely high. However, subsequent studies have shown that for the early detection of infection-induced organ dysfunction, qSOFA is a more specific but less sensitive method than assessment using SIRS or the NEWS scale [42, 43, 44]. The SSC-2021 guidelines [37] note that neither SIRS nor NEWS scales are ideal tools for sepsis screening and should not be used for this purpose. However, a positive qSOFA result should alert the clinician to the likelihood of organ dysfunction potentially related to the formation of an infection source and, accordingly, the possible development of sepsis. This makes it advisable to use it in settings where a more detailed patient examination is impossible for various reasons. A score of two or more on the qSOFA scale indicates a high risk of organ dysfunction, which, in the presence of an infection source, necessitates appropriate organizational and therapeutic actions aimed at confirming or ruling out the development of sepsis.

• In a patient with sepsis, an arterial blood lactate level of more than 2 mmol/L requiring vasopressor therapy to maintain a mean arterial pressure ≥ 65 mmHg (provided there are no signs of hypovolemia) is recommended to be considered a manifestation of septic shock [1, 37].

Level of trustworthiness of evidence (LTE) 5, Level of recommendation (LR) C

Comment. Septic shock is classified as a distributive type of shock, which is based on the maldistribution of circulating blood volume and marked microcirculatory disturbances accompanied by a decrease in systemic vascular resistance. In the development of septic shock, maintaining a mean arterial pressure of 65 mmHg or higher (in the absence of signs of hypovolemia) is achieved using adrenergic and dopaminergic agents (with a predominant vasopressor effect — norepinephrine**, etc.) [1, 37].

2.3 Laboratory Diagnostics

Laboratory diagnostics are performed to assess the severity of inflammation, the degree of vital organ dysfunction, and to identify infectious pathogens along with the determination of their characteristics.

Laboratory changes can be diverse and indicate the presence of:

• liver failure (hypoalbuminemia, prolongation of INR (international normalized ratio) > 1.5 times);

• liver cell cytolysis (increase in blood transaminase activity by more than 2 times) and cholestasis (increase in blood alkaline phosphatase activity);

• acute kidney injury (increased blood creatinine and urea levels, decreased glomerular filtration rate, decompensated metabolic acidosis);

• acute adrenal insufficiency (hyponatremia, hyperkalemia, hypoglycemia);

• non-coronary myocardial injury (increased troponin T level);

• coagulopathy (imbalance between procoagulant and/or anticoagulant systems and/or fibrinolysis, thrombocytosis or thrombocytopenia, thrombopathy possible);

• metabolic and/or respiratory acidosis and compensatory reactions;

• development of ARDS (decreased PaO₂/FiO₂ or SpO₂/FiO₂ ratio);

• blood system response to infectious inflammation (lymphocytosis or lymphopenia, anemia, hemoconcentration).

• In adult patients with suspected sepsis, it is recommended to perform a differential leukocyte count (complete blood count with differential), platelet count, total bilirubin and creatinine levels in the blood, serum C-reactive protein level, acid-base balance, and blood gases, as well as analyze available microbiological test results. If arterial hypotension develops, it is additionally recommended to test blood lactate levels [2, 37].

Level of trustworthiness of evidence (LTE) 5, Level of recommendation (LR) C

Comment. The studied parameters are necessary to assess the presence of SIRS, organ dysfunction, microbial invasion, and to determine the severity of organ dysfunction using the SOFA scale. SIRS is characterized by two or more of the following criteria: temperature >38°C or <36°C, heart rate >90/min, respiratory rate >20/min or hyperventilation (PaCO₂ <32 mmHg), white blood cell count >12×10⁹/L or <4×10⁹/L, or the presence of immature forms >10% [2, 22].

Clinical signs of candidemia are non-specific and do not differ from the symptoms of bacterial sepsis: fever >38 °C refractory to systemic antibacterial therapy is detected in 82% of patients, multiple organ dysfunction syndrome in 48%, and DIC in 13%. Acute disseminated candidiasis can affect virtually all organs and tissues, but the skin and subcutaneous tissue, brain, kidneys, heart, lungs, and organs of vision are most frequently involved in the pathological process.

• To diagnose DIC syndrome in an adult patient with sepsis, it is recommended to use standardized laboratory methods: blood platelet count, blood fibrinogen level, prothrombin (thromboplastin) time in blood or plasma, international normalized ratio (INR), activated partial thromboplastin time (APTT), blood D-dimer concentration, and total blood hemoglobin level [46].

Level of Evidence 5, Grade of Recommendation C.

Comment. Disseminated intravascular coagulation (DIC syndrome) is a pathophysiological process of simultaneous widespread (non-localized) blood clot formation in medium and small blood vessels of various organs and tissues resulting from dysregulation of blood coagulation, anticoagulation, and fibrinolysis. It develops in most critical conditions, including sepsis and septic shock. DIC syndrome is an important element in the pathogenesis of sepsis, aggravating organ dysfunction and worsening the course of the disease. A feature of DIC syndrome in septic shock is the predominance of a thrombotic DIC phenotype, characterized by the consumption of platelets and clotting factors, a marked deficit of natural anticoagulants, and impaired fibrinolytic activity [47]. Timely diagnosis of DIC syndrome using laboratory tests that assess the content of major blood clot substrates (platelets, fibrinogen) as well as the status of extrinsic (prothrombin time, INR) and intrinsic (APTT) coagulation pathways and the severity of anemia ensures the choice of targeted therapy [46]. Integral methods for assessing the hemostatic system (thromboelastography or rotational thromboelastometry (ROTEM)) simplify diagnosis [48, 49]. Appropriate biomarkers, specifically blood procalcitonin and serum C-reactive protein levels, can be used as auxiliary tools for the diagnosis and differential diagnosis of infection, monitoring the efficacy of antimicrobial therapy, and predicting disease outcomes [37].

• In adult patients with suspected sepsis, it is recommended to measure blood procalcitonin levels in addition to clinical evaluation to decide on initiating antimicrobial therapy (if technically feasible and provided this does not delay antimicrobial therapy) [37, 50, 51].

Level of trustworthiness of evidence (LTE) 5, Level of recommendation (LR) C

• In an adult patient with an initial diagnosis of sepsis, provided adequate source control of the infection has been achieved and the optimal duration of therapy has not been established, it is recommended to measure blood procalcitonin (PCT) levels in addition to clinical evaluation to decide on the possibility of discontinuing antimicrobial therapy [37, 50, 51].

Level of trustworthiness of evidence (LTE) 5, Level of recommendation (LR) C

Comment. In recent years, experimental and clinical data on the use of biomarkers for the diagnosis and monitoring of infectious and septic diseases have been intensively accumulating. Currently, PCT best fits the characteristics of an ideal biomarker (high sensitivity and specificity, reproducibility, rapid turnaround time, stability, and reasonable cost) [50]. An increase in blood PCT levels occurs specifically in bacterial infections, and the registered level of this marker correlates with disease severity. In fungal and viral infections, as well as in allergic and autoimmune conditions, procalcitonin levels do not rise significantly, which allows PCT to be used for differential diagnosis [50, 51]. Rapid testing of blood PCT is not always possible, so the absence of results should not delay the initiation of antimicrobial therapy.

Measurement of blood PCT levels is routinely used in many clinics worldwide as part of a package of measures for the diagnosis and differential diagnosis of infection, as well as for determining indications for antibacterial drugs and the adequate duration of antimicrobial therapy. Various algorithms have been developed for this purpose, allowing for a differentiated approach to prescribing systemic antibacterial drugs in patients with suspected infection, as well as for de-escalating antimicrobial therapy, including in severe infections and sepsis. The use of such algorithms can safely reduce the use of systemic antibacterial drugs [50]. It should be noted that the SSC-2021 guidelines do not recommend using PCT in combination with clinical evaluation as a trigger for starting antimicrobial therapy in sepsis. This recommendation is justified by a meta-analysis of three relatively old studies that used diagnostic criteria for sepsis different from modern ones. Furthermore, sepsis is a highly heterogeneous syndrome, and patients with this condition, despite formal standardization, are not always comparable. Therefore, taking into account high-quality research data and the personal experience of several experts, the use of PCT for diagnosing infection (not sepsis!) should be considered an effective approach to objectify indications for starting antimicrobial therapy [51].

A normal blood PCT level (usually ≤0.1 ng/mL) indicates a low probability of bacterial infection and no need for antimicrobial therapy. In doubtful cases, it is recommended to repeat the test in 4–6 hours to rule out the influence of the 'gray zone' effect [52].

During antimicrobial therapy, it is advisable to regularly assess the clinical and laboratory parameters mentioned above, including microbiological data and infection biomarkers (differential leukocyte count, platelet count, total bilirubin, creatinine, procalcitonin, C-reactive protein in the blood, and arterial blood lactate levels), in order to determine treatment efficacy and decide on the possibility of regimen correction, de-escalation, or discontinuation of systemic antibacterial drugs. Thus, a decrease in PCT values by 80% from the peak level or to normal values during therapy indicates its effectiveness. A lack of positive dynamics or an increase in PCT levels compared to baseline may indicate the need to revise the treatment regimen (primarily, the adjustment of antimicrobial therapy) [51].

Along with PCT, other biomarkers, particularly C-reactive protein, may have a certain value in assessing the effectiveness of antimicrobial therapy. Its use is limited by low specificity. An increase in serum C-reactive protein (CRP) during an inflammatory response occurs regardless of the causes of its development. Nevertheless, some authors suggest that CRP can be used in strategies to reduce the consumption of systemic antibacterial drugs [53].

Presepsin has high sensitivity and specificity in the diagnosis of sepsis and can be a useful and valuable biomarker in its early diagnosis [54]. However, it cannot be used as the sole marker in the diagnosis of sepsis [55, 56]

It should be borne in mind that, in addition to clinical and laboratory data, the duration of antimicrobial therapy is determined by the localization of the focus and the degree of its sanitation, as well as the type of pathogen. It is also important to note that biomarkers are merely an adjunct to the clinical assessment of the patient. Decisions to start, modify, or stop antimicrobial therapy should never be made solely on the basis of determining the level of any biomarker, including PCT.

Microbiological diagnostics.

• In adult patients with suspected sepsis or septic shock, it is recommended to collect biological material from the focus(es) of infection, as well as blood samples for microbiological studies before initiating antimicrobial therapy, provided this does not delay the administration of systemic antibacterial drugs by ≥45 min [37, 58].

Level of Reliable Evidence 2, Strength of Recommendation Grade B

• To obtain an optimal blood culture result in adult patients with suspected sepsis or septic shock, it is recommended to collect at least 2 blood samples of 20 ml each (total volume of at least 40-60 ml). For culturing each blood sample, it is recommended to use at least two bottles, between which the collected sample is divided equally. It is recommended to use pairs of bottles for aerobic and anaerobic blood culture. It is not recommended to inoculate blood into a single bottle only, as this practice leads to an insufficient blood volume being cultured and the risk of missing a significant number of bacteremia cases, as well as the inability to rule out sample contamination [57].

Level of trustworthiness of evidence (LTE) 5, Level of recommendation (LR) C

• In adult patients with sepsis, it is recommended to perform a microbiological (culture) study of material obtained from a diagnosed or suspected focus of infection (e.g., sputum, tracheal aspirate, bronchoalveolar lavage, urine, cerebrospinal fluid, peritoneal fluid, drainage discharge, etc.) to identify the pathogen, as well as to determine the susceptibility of microorganisms to antimicrobial chemotherapeutic agents (by disc-diffusion method, gradient diffusion method, dilution methods, using automated analyzers, mass spectrometry methods, or breakpoint concentrations) to ensure targeted antimicrobial therapy [59].

Level of trustworthiness of evidence (LTE) 5, Level of recommendation (LR) C

Commentary. In the international SSC-2021 guidelines [37], the collection of relevant biomaterial samples for microbiological testing prior to starting antimicrobial therapy (unless this delays the administration of systemic antibacterial drugs by ≥45 min) has been designated as "best clinical practice".

Each institution should develop local standard operating procedures for collecting material for microbiological testing, its delivery to the laboratory, the microbiological testing itself, and the reporting of obtained results.

Blood culture is the primary method for detecting bacteremia, which may accompany the infectious process. It allows for the characterization of pathogens and the selection of an adequate therapy regimen. To ensure maximum sensitivity of the method, blood samples for culture should ideally be obtained before the initiation of antimicrobial therapy. If this is not possible, blood for culture should be drawn immediately before administering the next dose of the systemic antibacterial drug, when the drug concentration in the blood is at its minimum [57].

Optimal diagnosis of bacteremia is achieved by using standardized factory-produced bottles with enriched nutrient media containing antimicrobial substance sorbents.

Blood samples to determine the presence of bacteremia are obtained by peripheral venipuncture observing asepsis and antisepsis rules. Sampling from a vascular catheter is allowed only in cases of suspected catheter-related bloodstream infection or, as a last resort, when venipuncture is technically impossible. The use of arterial blood for culture offers no advantages over venous blood.

A well-known limitation of the blood culture method is the duration of the study—even in the best laboratories, at least 6–8 hours pass from the delivery of samples to the laboratory until information on microbial growth is obtained, which is required for microorganism multiplication; additional time is required to identify the pathogen and determine its susceptibility to systemic antibacterial drugs. Given that microbiological laboratories often do not operate around the clock, the total test time reaches several days. At the same time, urgent notification of the attending physician regarding the growth in blood samples, as well as microscopic examination data of the primary blood culture using Gram staining, provide critically important information for optimizing antimicrobial therapy.

It is possible to significantly speed up the identification of the pathogen in a primary blood culture or pure culture of microorganisms by using MALDI-ToF mass spectrometry. In addition, real-time polymerase chain reaction (real-time PCR) molecular methods can be used to accelerate etiological diagnosis and identify certain determinants of antibiotic resistance [60; 61].

The BCID2 reagent kit has also been developed for the detection and identification of microorganism nucleic acids and genes determining resistance to systemic antibacterial drugs in blood culture samples using multiplex PCR for rapid identification of bloodstream infection pathogens (a number of the most common bacteria and yeast fungi) with simultaneous determination of genetic markers of resistance to systemic antibacterial drugs from a positive blood culture (test duration is about 1 hour). Such technologies, combined with antimicrobial stewardship programs, make it possible to transition from empirical to targeted antimicrobial therapy within the first day after diagnosis, which ultimately significantly improves clinical outcomes in patients. Thus, a meta-analysis by T. Timbrook et al. showed that the implementation of this comprehensive approach is accompanied by a statistically significant reduction in the risk of mortality in patients with bloodstream infections (OR 0.64; 95% CI 0.51–0.79), a reduction in the time to effective antimicrobial therapy by 5 hours, and a reduction in hospital stay by an average of 2.5 days [58].

2.4 Instrumental Diagnostics

• In adult sepsis patients with an unclear source of infection, it is recommended to use imaging diagnostic methods for its rapid identification [62].

Level of trustworthiness of evidence (LTE) 5, Level of recommendation (LR) C

Comment. Diagnostic imaging methods for identifying the source of infection include plain radiography, ultrasonography, computed tomography, and magnetic resonance imaging. In complex cases, these technologies are indispensable. Therefore, in Japanese international guidelines, this recommendation was designated as 'best clinical practice' [62]. Imaging methods are useful for clarifying the diagnosis and selecting the optimal treatment method. Meanwhile, it is necessary to consider the risks of X-ray exposure and contrast agent use, as well as potential deterioration of the patient's condition during transportation and the procedure.

The choice of the most effective diagnostic imaging method is determined by the suspected localization of the infectious process (App. A.3.1.)

1. Head and neck.

   Cerebral abscess: contrast-enhanced brain magnetic resonance imaging is the most informative imaging method, as it allows for the detection of inflammation spreading to the tissue adjacent to (surrounding) the abscess [63].

   Neck phlegmon (descending necrotizing mediastinitis): superficially located processes can be detected using ultrasound; however, for identifying deeply located foci, contrast-enhanced soft tissue computed tomography is preferred, as it clearly differentiates fluid collections resulting from infection from blood vessels [64].

2. Thoracic cavity.

   Pneumonia: instrumental diagnostics include radiological imaging methods—targeted chest radiography, chest computed tomography, and lung ultrasound. Targeted chest radiography in the anteroposterior and lateral projections (in the right lateral projection if the localization of the inflammatory process is unknown) is performed in all patients with suspected pneumonia [65, 66].

   Pleural empyema: targeted radiography and pleural ultrasonography are first-line diagnostic methods. Computed tomography with intravenous bolus contrast enhancement is effective for monitoring treatment efficacy [62].

   Mediastinitis: chest computed tomography and chest magnetic resonance imaging are the best diagnostic modalities for diagnosing mediastinitis, including postoperative cases [67,68].

   Infective endocarditis: one of the two major diagnostic criteria (Duke diagnostic criteria) is based on echocardiography results; therefore, transthoracic echocardiography is preferred as the first-line diagnostic method in all patients with suspected infective endocarditis [69]. When necessary, transesophageal echocardiography can be used to clarify the diagnosis [70].

3. Abdominal cavity.

   Gastrointestinal perforation/peritonitis: plain radiography and comprehensive abdominal ultrasonography are performed first. Contrast-enhanced abdominal computed tomography with intravenous bolus is indicated to clarify the presence of organ or bowel ischemia [71].

   Cholecystitis/cholangitis: ultrasound of the gallbladder and bile ducts and abdominal computed tomography are the most frequently used imaging methods. Magnetic resonance cholangiopancreatography can be used as an alternative method to clarify the diagnosis [72].

4. Retroperitoneal space.

   Infected pancreatonecrosis: ultrasound examination of the pancreas is used as a screening method for diagnosing acute pancreatitis and establishing its biliary etiology. Computed tomography of the abdominal cavity and retroperitoneal space with intravenous bolus contrast enhancement is the most informative method for detecting signs of infection in focal fluid collections within the abdominal cavity, omental bursa, and retroperitoneal tissue [73, 74].

   Obstructive urinary tract infection: ultrasound of the urinary tract is performed as the first-line imaging method, while radiography of the kidneys and urinary tract and computed tomography of the kidneys and upper urinary tract with intravenous bolus contrast enhancement are used for the topical diagnosis of the cause of obstruction [75].

5. Necrotizing soft tissue infections.

   In cases of an unclear clinical picture, ultrasound of the soft tissues (one anatomical region) and/or contrast-enhanced computed tomography of the soft tissues is performed, which allows for the detection of edema and fluid accumulation in the soft tissues. However, no imaging method can establish a definitive diagnosis of necrotizing fasciitis, which can only be confirmed during surgery [76].

• In adult patients with sepsis of an unknown source of infection, it is recommended to perform computed tomography of the chest, abdominal cavity, retroperitoneal space, and pelvic organs with intravenous bolus contrast enhancement as early as possible to identify the source [37, 62].

Level of trustworthiness of evidence (LTE) 5, Level of recommendation (LR) C

• In controversial situations in adult patients with sepsis, when performing differential diagnosis of the cause of shock, echocardiography is recommended as an additional method [77].

Level of trustworthiness of evidence (LTE) 5, Level of recommendation (LR) C

Comment. In septic shock, echocardiography typically reveals normal heart chamber dimensions and preserved contractile function, unlike cardiogenic shock, where the ventricles are dilated and zones of akinesia or poor cardiac contractility are registered. In cases of obstructive shock (pulmonary embolism), there is dilatation of the right ventricle and a reduction in the size of the left ventricle [77].

2.5 Other Procedures

• Monitoring in all patients with sepsis should be recommended to focus on evaluating the effectiveness of infection source control measures and ongoing intensive care, including antimicrobial and infusion therapy. Important criteria include assessing the restoration of perfusion, the dynamics of multiple organ dysfunction and systemic inflammatory response syndrome, as well as changes in the clinical picture reflecting the state of the infection focus [37, 78, 79].

Level of trustworthiness of evidence (LTE) 5, Level of recommendation (LR) C

Comment. Improving treatment outcomes for patients with sepsis is associated with various aspects: routine screening for sepsis diagnosis, professional development of physicians and nursing staff in the management of such patients, the use of modern technologies for infection source control and life-support system maintenance, and the ability to timely adjust the treatment program based on the evaluation of the process dynamics [78, 79]. A meta-analysis of 50 observational studies summarizing the impact of various treatment strategy components on mortality showed that a comprehensive approach with increased attention to the problem, rather than individual specific measures, played a key role in improving treatment outcomes for patients with sepsis and septic shock (OR 0.66; 95% CI 0.61–0.72) [80].

• To assess the dynamics of the process and the effectiveness of ongoing therapy, it is recommended that all patients with a confirmed diagnosis of sepsis in the ICU undergo daily dynamic calculations using the SOFA scale [81, 82, 83].

LOD 2, GOR A

Comment. The variety of multiple organ dysfunction variants in terms of syndrome combinations and severity, as well as the multidirectional nature of their development during ongoing intensive care, necessitates the use of an integral quantitative system to individualize therapy approaches, predict the probability of complications, compare treatment outcomes across various medical institutions, and evaluate the effectiveness of introducing new drugs or intensive care methods. From this perspective, utilizing SOFA score calculations allows not only for screening patients with sepsis but also for assessing the dynamics of the disease course and predicting the outcome [81]. Numerous studies have demonstrated that this scale significantly outperforms the qSOFA and SIRS scales in terms of prognostic informativeness, sensitivity, and accuracy [82, 83]. At the same time, dynamic monitoring of the systemic inflammatory response using traditional criteria (temperature reaction, peripheral blood leukocyte count, left shift of the leukocyte formula, etc.) and biomarkers when necessary also provides arguments for assessing the effectiveness of ongoing therapy, especially antimicrobial therapy (see chapters 2.2, 3.1, and 3.2).

• In adult patients with persistent arterial hypotension, it is recommended to prioritize invasive 24-hour blood pressure monitoring with the assessment of mean arterial pressure (MAP). Non-invasive 24-hour blood pressure monitoring on peripheral arteries is performed when invasive monitoring cannot be connected due to technical difficulties or limited resources [84, 85, 86].

Level of Evidence (LoE) 3, Grade of Recommendation (GoR) C

Comment. Blood pressure assessment using the non-invasive measurement method on peripheral arteries is less accurate. Discrepancies with data obtained via invasive measurement are more pronounced in shock states [84, 85, 86]. Catheterization of the radial or femoral artery allows for safe, reliable, and continuous blood pressure measurement and real-time analysis to guide management decisions based on immediate and accurate perfusion pressure data [87]. However, large randomized trials comparing invasive and non-invasive blood pressure monitoring are still lacking. Given the low complication rate and likely higher accuracy of blood pressure measurement, the benefits of arterial catheters outweigh the risks. Nevertheless, potentially limited resources and the lack of high-quality studies have resulted in only a weak recommendation for arterial catheter placement. Arterial catheters should be removed as soon as continuous hemodynamic monitoring is no longer necessary to minimize the risk of complications.

An increase in MAP typically leads to improved tissue perfusion. Although some tissues (such as the brain and kidneys) exhibit autoregulation of blood flow, a MAP below a threshold value (generally understood as 60 mmHg) is associated with impaired organ perfusion: the lower the MAP, the worse the perfusion [88].

Low central venous pressure suggests hypovolemia, but septic shock management guided by central venous pressure values and systolic blood pressure targets does not improve outcomes.

• During intensive care for sepsis, including cases complicated by hypotension, routine pulmonary artery catheterization is not recommended [89, 90].

Level of Reliable Evidence (LRE) 1, Level of Clinical Recommendations (LCR) A

Comment. A pulmonary artery catheter allows monitoring of pulmonary artery wedge pressure (PAWP), stroke volume, cardiac output, and mixed venous oxygen saturation (A12.10.003). Although pulmonary artery catheterization can provide useful information regarding volume status and cardiac function, these benefits may be outweighed by discrepancies in result interpretation, poor correlation of PAWP with clinical response, and lack of impact on outcomes [91, 92]. It has been demonstrated that a strategy based on the use of pulmonary artery catheterization does not improve patient outcomes [89]. A pooled analysis of two multicenter randomized trials—one involving 676 patients with shock or ARDS [94] and the other involving 1000 patients with ARDS [95]—failed to show any benefit of pulmonary artery catheterization regarding mortality (RR 1.02; 95% CI 0.96–1.09) or ICU mortality [90]. This lack of demonstrated benefit must be considered in the context of increased resource utilization. Because numerous clinical trials have failed to demonstrate improved patient outcomes with pulmonary artery catheterization, it is no longer routinely used in the standard management of sepsis and septic shock. Nevertheless, selected patients with sepsis may undergo pulmonary artery catheterization if management decisions depend exclusively on information obtained via prepulmonary thermodilution.

• In sepsis, to assess the efficacy of fluid therapy in restoring tissue perfusion, it is recommended to determine the blood lactate level in arterial or mixed venous blood [96, 97, 98].

Level of Reliable Evidence (LRE) 1, Level of Clinical Recommendations (LCR) A

• In the development of persistent arterial hypotension, it is recommended to use the capillary refill time (blanching test) in addition to other methods to assess tissue perfusion [99, 100, 101].

LMR 3, LGR B

Comment. Arterial blood lactate is an important biomarker of tissue hypoxia, but it is not a direct indicator of tissue perfusion [83]. Achieving a normal arterial blood lactate level in all patients with septic shock is impossible, but its changes may indicate both the efficacy and inefficacy of the therapeutic techniques used [96, 98]. Blood lactate levels should be interpreted taking into account the clinical context and other possible causes of its elevation. Values above 2 mmol/L clearly indicate the presence of hypoperfusion. However, its measurement cannot always be performed on an emergency basis, especially under resource-constrained conditions. In these cases, alternative indicators of organ perfusion can be used to assess the efficacy and safety of fluid therapy: extremity skin temperature, skin mottling, and capillary refill time [99, 100]. The ANDROMEDA-SHOCK study showed that when assessing treatment efficacy, the normalization of capillary refill time is not inferior in informativeness to a decrease in lactate levels [101]. This test is performed easily, non-invasively, and without material costs. However, this approach must be supplemented by a thorough, frequent, and comprehensive examination of the patient to predict or early detect fluid overload. In addition, the presence of comorbid pathology or other pathological processes relevant to the patient should be taken into account [102, 103].

• To individualize fluid therapy during intensive care for sepsis, it is recommended to dynamically assess the patient's responsiveness to fluid challenge [104, 105, 106].

Level of Reliable Evidence (LRE) 1, Level of Clinical Recommendations (LCR) A

Comment. Fluid therapy in sepsis is associated with the risk of fluid accumulation and potential harm related to fluid overload: increased duration of mechanical ventilation, progression of acute kidney injury, and increased mortality. One of the most important principles in managing such patients is the need for continuous reassessment of the response to treatment. To avoid adverse consequences, fluid administration must be based on a careful assessment of intravascular volume status and organ perfusion. Heart rate, central venous pressure, and systolic blood pressure are poor indicators of volume status on their own. Dynamic measures have demonstrated better diagnostic accuracy compared to static parameters for hemodynamic assessment. Dynamic parameters include the assessment of stroke volume (SV), its variations (SVV), pulse pressure variation (PPV), or echocardiographic indicators in response to passive leg raise or fluid bolus administration. The use of static (discretely obtained) hemodynamic parameters is an important element of monitoring that provides an understanding of the circulatory system state at a specific point in time.

A fluid challenge test or passive leg raise test is used to assess tolerance to fluid load. Recording dynamic hemodynamic parameters (pulse pressure variation or stroke volume variation) in response to changes in intrathoracic pressure provides a more objective picture. A systematic review and meta-analysis showed that the use of dynamic parameters to assess the efficacy of fluid therapy is associated with reduced mortality (RR 0.59; 95% CI 0.42–0.83), length of ICU stay (RR -1.16 days; 95% CI 1.97–0.36), and duration of mechanical ventilation [104].

An RCT conducted in Zambia in patients with sepsis and hypotension showed that implementing a fluid therapy protocol guided by jugular venous pressure and arterial blood oxygen saturation was associated with a significantly larger volume of fluid administered in the first 6 hours [median 3.5 L (IQR 2.7–4.0) vs. 2.0 L (IQR 1.0–2.5)] and higher in-hospital mortality (48.1% vs. 33%) compared to standard care [102]. If fluid therapy exceeding 30 mL/kg in volume is required, the decision on additional boluses can be made taking into account stroke volume and/or cardiac output. In resource-limited settings where measurement of these parameters is not possible, the decision to administer additional fluid volume can be made if pulse pressure increases by more than 15% in response to a passive leg raise test performed for 60–90 seconds [104, 106].

3. Treatment, including drug and non-drug therapies, diet therapy, and pain management

Survival in sepsis is most significantly improved by three approaches: early adequate antimicrobial therapy, restoration of adequate cellular perfusion, and timely source control [107]. A specific challenge in caring for patients with surgical sepsis is the need for invasive control of the infection focus, which increases the complexity of care. Timely debridement of the focus combined with adequate antimicrobial therapy is the cornerstone of successful sepsis treatment [108]. Systemic antibacterial therapy is important, but in most cases, it alone cannot provide adequate control over the source of surgical infection, which in sepsis patients cannot always be rapidly identified. Amid growing antimicrobial resistance, evidence suggests that source control is beginning to outweigh the impact of antimicrobial therapy [109].

Overall, in combating surgical infections, source control has a higher priority than the administration of systemic antibacterial drugs [110]. The core concept underlying source control is to do it as "rapidly" as possible and, undoubtedly, in an "appropriate manner".

3.1. Source control

Searching for the source of infection when it is unknown is important at an early stage to develop a treatment plan [111]. When deciding on diagnostic imaging methods, especially CT of each body segment, one must consider the potential for hemodynamic destabilization during transport for the scan, as well as adverse reactions to contrast agents. However, the benefits of verifying a source of sepsis requiring surgical correction are generally believed to outweigh potential risks. It should be remembered that the diagnostic value of contrast-enhanced CT is not identical for all potential sources of infection depending on anatomical localization. In some cases, specific diagnostic methods should be prioritized for each organ.

Invasive diagnostic methods may be used when diagnostic uncertainty persists despite X-ray and sonographic imaging.

• In an adult patient with suspected sepsis, it is recommended to identify or exclude a specific anatomical focus of infection requiring emergency source control, and to perform necessary surgical interventions as soon as possible from the moment the infection source is identified and the diagnosis of sepsis or septic shock is established [112, 113, 114, 115, 116].

LOD 2, GOR A

Comment. Recent observational and cluster randomized trials have shown that infection source control was associated with improved survival [113, 114, 116], and therefore it should be performed as soon as possible [2, 115, 116]. From a clinical standpoint, it is clear that without adequate debridement of the infection focus, a positive outcome in sepsis treatment cannot be expected; thus, in the international SSC-2021 guidelines, this recommendation received "best clinical practice" status. However, currently there are only limited data regarding the optimal timing of surgical debridement of the infection focus. Preferably, this should be done within up to 12 hours, as survival typically declines beyond this timeframe [115-121]. The inability to demonstrate a benefit from source control implemented less than 6 hours from diagnosis may be a consequence of the limited patient sample size and heterogeneity of the intervention. Consequently, any necessary source control intervention in sepsis and septic shock should ideally be carried out as soon as medical and organizational conditions allow [2, 116].

Proper infection source control is a key principle in the treatment of sepsis and septic shock [37, 122, 123]. It may include abscess drainage, removal of infected necrotic tissue and potentially infected devices, as well as definitive source control in ongoing microbial contamination [124].

Sources of infection that can be effectively treated surgically include intra-abdominal abscesses, gastrointestinal perforation, intestinal ischemia or volvulus, cholangitis, cholecystitis, pyelonephritis associated with obstruction or abscess, necrotizing soft tissue infection, other cavity infections (e.g., empyema or septic arthritis), implanted device infections, etc.

Surgical tactics for source debridement in infections of various localizations: operative and technical methods, choice of surgical method and approach, features of drainage, postoperative wound management, etc., are detailed in various Russian and international guidelines, manuals, and publications:

1. skin and soft tissue infections [125, 126, 127, 128];

2. bone and joint infections [129, 130, 131, 132, 133];

3. complicated intra-abdominal infections, pancreatitis [134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146];

4. inflammatory diseases of the spine, brain, and spinal cord [147, 148, 149];

5. ENT pathology: acute purulent otitis media, chronic purulent otitis media, acute sinusitis, acute tonsillopharyngitis, peritonsillar abscess [150-155];

6. lung abscess, pulmonary gangrene, empyema, mediastinitis [156-159];

7. sternal infection, prosthetic valve endocarditis [160-169].

8. acute urological pathology: acute obstructive pyelonephritis, paranephritis (apostematous, renal abscess, renal carbuncle); acute prostatitis with abscess formation; acute orchitis, epididymitis, orchiepididymitis [170].

9. infections in obstetrics and gynecology [171-178].

Necrotic tissue is a source of infection, and early intervention is a basic treatment principle. However, pancreatic necrosis does not fall under this general principle of early intervention. The mortality rate with late interventions is lower than with early surgery; therefore, the benefits of late intervention likely outweigh its harms [75, 146].

Timeliness of surgery implies that the benefit of the intervention is comparable to the risk of its performance. This assumes stabilization of the patient's vital functions through intensive care measures, the pace of which should be as rapid as possible [2]. In necrotizing skin and soft tissue infections, and complicated intra-abdominal infections with abdominal compartment syndrome characterized by a rapidly progressive course and development of septic shock, complete stabilization cannot be achieved until the spread of the infectious process is halted. In these cases, surgery may be considered part of resuscitation measures [111].

When choosing optimal source control methods, one must weigh the benefits and risks of a specific intervention, patient preferences, clinician expertise, and the availability and risks of specific procedures. Preference should be given to the least invasive option that can effectively provide source control. Open surgery should be considered when other interventional approaches initially cannot provide reliable source control, are insufficiently effective, or cannot be performed in a timely manner. The availability of necessary equipment, qualifications, and experience of the medical organization's staff may also play a role in choosing surgical tactics. Overall, the benefits of surgical source debridement outweigh the harms, including those that may be caused by the surgery itself [115, 116].

Clinical experience shows that without proper source control, patients' conditions do not improve despite intensive fluid resuscitation and antibacterial therapy; therefore, prolonged stabilization efforts instead of source control, especially in patients with septic shock, are generally not recommended [2, 179].

• In an adult patient with sepsis, it is recommended to promptly remove intravascular access devices that are a potential source of sepsis or septic shock once alternative vascular access is established [121, 124, 180].

Level of Evidence (LE) 4, Grade of Recommendation (GR) C

Comment. Removal of a potentially infected intravascular access device is considered a core element of proper source control in catheter-related bloodstream infections [124], even considering the risk of complications associated with both the removal of the infected catheter and the placement of new vascular access; therefore, in the international SSC-2021 guidelines, this recommendation received "best clinical practice" status [37].

In the absence of septic shock or fungemia, certain tunnelled catheter infections can be effectively treated with prolonged antimicrobial therapy if catheter removal is not feasible or appropriate [180, 181]; however, catheter removal combined with adequate antimicrobial therapy is the preferred approach in most cases.

3.2. Antimicrobial therapy

• For adult patients with confirmed or suspected septic shock, it is recommended to urgently initiate antimicrobial therapy, preferably within 1 hour of identifying or suspecting sepsis [182, 183, 184].

Level of Reliable Evidence 2, Strength of Recommendation Grade B

Commentary. Early initiation of effective antimicrobial therapy is one of the most critical factors in reducing mortality in patients with sepsis [182, 183]. However, the unwarranted administration of systemic antibacterial drugs should be avoided in patients with clinical symptoms similar to sepsis caused by non-infectious etiologies. Unwarranted administration of systemic antibacterial drugs leads to adverse consequences, such as adverse drug reactions, including Clostridioides difficile infection and the selection of antibiotic resistance [186-188].

The reduction in mortality achieved by the early administration of effective antimicrobial therapy is most significant for patients with septic shock, in whom studies demonstrate a pronounced association between the time to initiation of antimicrobial therapy and mortality.

In a study of 49,331 patients treated in 149 US hospitals, each additional hour from intensive care unit admission to the initiation of antimicrobial therapy resulted in an increased risk of in-hospital mortality (OR 1.04, p<0.001; for patients receiving adrenergic and dopaminergic agents with predominantly vasopressor action — 1.07; 95% CI (1.05–1.09); for patients not receiving adrenergic vasopressor agents — 1.01; 95% CI (0.99–1.04)) [189]. In a California-based study of 35,000 patients, each additional hour from ICU admission was associated with a 1.09-fold increase in the odds of in-hospital mortality (1.07 for patients with "severe sepsis" [lactate ≥ 2 mmol/L, at least 1 episode of hypotension, need for mechanical ventilation, or organ dysfunction]; 1.14-fold for patients with septic shock) [184]. In another US study (10,811 patients), each hour of delay in initiating antimicrobial therapy resulted in a 1.16-fold increase in the odds of in-hospital mortality [190]. Meanwhile, several other studies did not find a significant association between the time of antimicrobial initiation and mortality; however, all the aforementioned studies were observational and had a substantial risk of bias due to small sample size, suboptimal adjustment for risk factors, and other design limitations [156, 191-196].

• For adult patients with suspected sepsis without septic shock, it is recommended to perform an expedited diagnostic workup and, if an infectious cause is proven or suspected, to initiate antimicrobial therapy within 3 hours after sepsis is diagnosed or recognized as the most probable diagnosis [112, 189, 184, 196].

Level of Evidence (LE) 4, Grade of Recommendation (GR) C

Commentary. In patients without septic shock, the relationship between mortality and the timing of antimicrobial therapy is less evident. The results of two randomized controlled trials on this topic have been published: one found no differences in mortality between patient groups with varying times to initiation of systemic antibacterial drugs, while the other showed a statistically insignificant difference in mortality [112, 197]. Overall, observational studies indicate that mortality in sepsis patients without septic shock may potentially increase when the initiation of antimicrobial therapy is delayed by more than 3–5 hours [112, 189, 190, 197].

• For adult patients with a low probability of infection and no signs of shock, it is recommended to continuously monitor the patient's condition without prescribing systemic antibacterial drugs [189, 184, 196].

Level of trustworthiness of evidence (LTE) 5, Level of recommendation (LR) C

Comment. Given the need to initiate effective antimicrobial therapy as early as possible in patients with sepsis and septic shock, the medical organization must have a sufficient range of systemic antibacterial drugs available 24/7. This list should take into account the specifics of the medical care provided by the organization, as well as the local pattern of infection causative agents and their resistance to systemic antibacterial drugs. An example of a basic list of "round-the-clock availability" antibacterial and antifungal drugs for a large multidisciplinary hospital, taking into account the current state of antibiotic resistance in the Russian Federation, is given in App. A.3.2.

• For adult patients at high risk of infection caused by methicillin-resistant Staphylococcus aureus (MRSA), it is recommended to use an empirical antimicrobial therapy regimen that includes systemic antibacterial drugs active against MRSA (vancomycin**, #ceftaroline fosamil**, #linezolid**, #daptomycin**, #telavancin**) (ICD-10 disease code A40-A41). For patients at low risk of MRSA, it is not recommended to include systemic antibacterial drugs active against MRSA in the empirical antimicrobial therapy regimen [197, 198, 199, 200, 201, 202, 203, 472, 473].

LMR 3, LGR B

Comment. Currently, MRSA play a relatively minor role in community-acquired infections in the Russian Federation (8.8% of all community-acquired S. aureus strains in 2018–2020 [https://amrmap.ru/?id=Ykz2U51SH33SH10]). Among nosocomial S. aureus strains, MRSA accounted for 30.3% in 2018–2020 [https://amrmap.ru/?id=NJT1P31eF36eF10]. However, considering the overall decrease in the role of S. aureus in nosocomial infections (7.7% in 2018–2020 [https://amrmap.ru/?id=fYOiz011Y501Y10]), the proportion of MRSA is about 2.3% of all microorganism isolates recovered from nosocomial infections in the Russian Federation.

Available observational data on the impact of including systemic antibacterial drugs active against MRSA in empirical therapy regimens are contradictory. In a number of studies among patients with documented MRSA infection, delaying the administration of MRSA-effective systemic antibacterial drugs for more than 24–48 hours was associated with increased mortality [198–201], whereas in a comparable number of other similar studies, no such association was observed [202–207.]. At the same time, in the general patient population, therapy regimens including systemic antibacterial drugs active against MRSA were associated with higher mortality, especially among patients in whom MRSA was not isolated [208] (this is likely due, at least in part, to the fact that vancomycin** was the most frequently used anti-MRSA drug).

Thus, although failing to cover MRSA in patients with MRSA infection can lead to serious negative consequences for the patient, unjustified empirical use of systemic antibacterial drugs active against MRSA as part of empirical therapy in patients at low risk of MRSA is undesirable. Rapid methods for detecting MRSA in clinical specimens may play a potentially important role in selecting empirical therapy.

Recommended antimicrobial therapy regimens for MRSA infections are presented in App. A.3.4. [61]

More detailed information on the diagnosis and antimicrobial therapy of MRSA infections is provided in the Guidelines "Diagnosis and Antimicrobial Therapy of Infections Caused by Multidrug-Resistant Microorganism Strains" (2022 update) [61].

• For patients with sepsis and a high risk of infection caused by multidrug-resistant Gram-negative pathogens, it is recommended to initiate empirical therapy regimens, preferably combination therapy, active against multidrug-resistant Gram-negative pathogens based on the results of local microbiological monitoring. After obtaining the microbiological culture results, it is recommended to adjust the therapy regimen taking into account the pathogen(s) susceptibility, patient characteristics, and the properties of the systemic antibacterial drugs [208, 209].

Level of Reliable Evidence 2, Strength of Recommendation Grade B

Comment. Considering the extreme relevance of multidrug-resistant Gram-negative pathogens for Russian inpatient facilities [78], when prescribing antimicrobial therapy to a patient with sepsis who has risk factors for multidrug-resistant pathogens, it is necessary to maximize the probability that the initial therapy regimen includes at least one agent active against each of the suspected multidrug-resistant pathogens [50].

A recent systematic review/meta-analysis of 10 randomized clinical trials showed no differences in mortality and other patient-important outcomes of sepsis/septic shock between groups receiving combination therapy and monotherapy (including analysis stratified by patient severity) [209]. However, the largest study included in this meta-analysis compared meropenem** monotherapy and meropenem** plus moxifloxacin** combination therapy in a setting of low antibiotic resistance rates, which naturally makes the conclusions of the entire meta-analysis inapplicable to departments with a high prevalence of multidrug-resistant pathogens [210].

Due to the heterogeneity of patient population characteristics across different medical organizations and departments, as well as the uneven prevalence of various multidrug-resistant pathogens, the choice of initial empiric therapy regimen must be guided by local antimicrobial resistance surveillance data [211].

Since the same risk factors may be characteristic of various multidrug-resistant pathogens, achieving potential coverage of their entire spectrum generally justifies considering an initial combination antimicrobial therapy regimen. The most typical risk factors for infections caused by multidrug-resistant Gram-negative pathogens include: 1) known infection or colonization with multidrug-resistant pathogens within the past year, unfavorable local epidemiology of multidrug-resistant pathogens, nosocomial nature of the infection, use of broad-spectrum systemic antimicrobial drugs (carbapenems, 3rd–4th generation cephalosporins, fluoroquinolones) and/or hospitalization within the preceding 3 months, recent selective intestinal decontamination, and travel to regions with an unfavorable epidemiological situation within the preceding 3 months [78, 212, 213].

Antimicrobial therapy regimens for infections caused by multidrug-resistant Gram-negative strains are presented in App. A.3.5. [61]

More detailed information on the diagnosis and antimicrobial therapy of infections caused by multidrug-resistant Gram-negative strains is provided in the Clinical Guidelines «Diagnosis and Antimicrobial Therapy of Infections Caused by Multidrug-Resistant Microorganism Strains» (2022 update) [61].

• For patients at high risk of invasive candidiasis/candidemia (IC), it is recommended to use an empiric antimicrobial therapy regimen that includes systemic antifungal drugs. For patients at low risk of invasive candidiasis/candidemia, the empiric administration of systemic antifungal drugs is not recommended [216, 217, 218, 219].

Level of Evidence (LE) 4, Grade of Recommendation (GR) C

Comment. Sepsis caused by fungal infection is characterized by a high rate of adverse outcomes [214-216]. Individual observational studies indicate that early administration of adequate antifungal therapy may be associated with lower mortality, but these studies cannot definitively demonstrate a causal relationship between the characteristics of the prescribed antifungal therapy and clinical outcomes [217, 218]. A meta-analysis comparing patient groups receiving and not receiving systemic antifungal drugs empirically showed no differences in short-term mortality. The largest recent trial, «EMPIRICUS», also found no differences in outcomes between patients receiving antifungal therapy (micafungin**) and placebo [219]. Overall, the quality of evidence regarding the role of antifungal therapy in septic patients is low. At the same time, routine empiric use of systemic antifungal drugs can lead to substantial unjustified economic losses.

Patients with high-risk factors for fungal infections, such as patients with febrile neutropenia unresponsive to adequate antimicrobial therapy for 4–7 days, require empiric administration of systemic antifungal drugs [220, 221, 222]. Other risk factors for IC in adult ICU patients that should be taken into account include: central venous catheter use, systemic antibacterial drug use, severe patient condition (median APACHE II – 13, SOFA – 6), surgical treatment or gastrointestinal perforation, infected pancreatic necrosis, mechanical ventilation, total parenteral nutrition, hemodialysis, and the use of glucocorticoids and immunosuppressants. Invasive candidiasis occurs more frequently in older men.

In Russian adult ICUs (ARUs), the main causative agents of IC are C. albicans (42–48%), C. glabrata (14–24%), C. parapsilosis (2–17%), C. tropicalis (5–15%), and C. krusei (5–16%), while C. lusitaniae, C. guilliermondii, C. kefyr, and others are identified less frequently (1–3%). In recent years, outbreaks of nosocomial candidiasis caused by the multidrug-resistant pathogen C. auris have been noted in Russian hospitals. Candida species correlate with susceptibility to systemic antifungal drugs. For example, C. albicans is typically susceptible to fluconazole**, whereas non-albicans Candida species are frequently resistant. In Russian ICUs (ARUs), susceptibility to fluconazole** is reduced in 21% of IC pathogens. C. auris is resistant to fluconazole** and may also be resistant to voriconazole** and amphotericin B**. Resistance to anidulafungin, caspofungin**, and micafungin** is extremely rare.

Candidemia (circulation of Candida spp. in the bloodstream) and acute disseminated candidiasis (ADC – candidemia combined with one or more foci of dissemination or multiple foci of dissemination) account for up to 90% of all IC cases.

Antimicrobial therapy regimens for invasive candidiasis and candidemia (candida septicemia) are presented in App. A.3.6. [61]

• The probability of developing invasive candidiasis in ICU patients without risk factors (neutropenia, hematopoietic stem cell transplantation, liver transplantation, etc.) is low; therefore, routine primary antifungal prophylaxis is not recommended [220, 222].

LOD 2, GOR A

Comment. In ICU patients, an indication for primary antifungal prophylaxis may be recurrent gastrointestinal perforation or infected pancreatic necrosis. In such situations, systemic antifungals are indicated (#fluconazole** 800 mg once daily on the first day, followed by 400 mg daily, or #caspofungin** 70 mg on day 1, then 50 mg/day) (App. A.3.6, ICD-10 disease code B37.7) [214]. Prophylactic administration of nystatin**, natamycin**, and their analogues for invasive mycosis is ineffective and inappropriate, as is the use of fluconazole** at a dose of less than 6 mg/kg per day [221].

• In cases of fever of unknown origin lasting more than 4–6 days, resistant to adequate broad-spectrum systemic antibacterial therapy, combined with two or more risk factors (use of systemic antibacterial drugs, central venous catheter, abdominal surgery, total parenteral nutrition, use of glucocorticoids or immunosuppressants) in ICU (ARU) patients, it is recommended to administer empiric IC therapy [220, 222].

Level of Evidence 5, Grade of Recommendation C.

Comment. In the presence of IC risk factors and clinical signs of septic shock, empiric therapy should be initiated immediately. Early empiric initiation of therapy improves survival in patients with IC: anidulafungin, caspofungin**, and micafungin** (App. A.3.6 [61] When prescribing empiric IC therapy, the central venous catheter should be replaced (not over a guidewire), and blood cultures (≥40 ml per day for an adult patient), samples from potential IC sites, and the distal segment of the central venous catheter should be obtained.

• When Candida spp. are isolated from normally sterile sites (blood, cerebrospinal fluid, etc.) within 24 hours, it is recommended to prescribe a systemic antifungal drug and replace the central venous catheter (not over a guidewire) [61, 220, 222].

Level of Evidence 5, Grade of Recommendation C.

Comment. Anidulafungin, caspofungin**, and micafungin** are drugs of choice for targeted therapy of all variants of invasive candidiasis (IC), except for meningitis and endophthalmitis. Triazole drugs (voriconazole**, fluconazole**) can be prescribed only when a susceptible pathogen is isolated in a patient with a stable condition, as well as for the treatment of candidal meningitis and endophthalmitis. In addition, voriconazole** and fluconazole** are used for de-escalation therapy after patient stabilization with anidulafungin, caspofungin**, or micafungin** [220, 222]. Amphotericin B [liposomal] and amphotericin B [lipid complex] are used in case of inefficacy, intolerance, or unavailability of anidulafungin, caspofungin**, or micafungin**. Amphotericin B**, posaconazole**, and itraconazole are not used for the treatment of IC (App. A.3.6) [61].

Detailed information on the diagnosis and treatment of IC is presented in the Guidelines «Diagnosis and Antimicrobial Therapy of Infections Caused by Multidrug-Resistant Strains of Microorganisms» (2022 update) [61].

• For patients with sepsis, when using beta-lactam antibacterial drugs (ATC J01C Beta-lactam antibacterials, penicillins), after a bolus administration of the first dose, it is recommended to consider continuing their administration as a prolonged or continuous infusion [223, 224, 225].

Level of Evidence (LE) 1, Grade of Recommendation (GR) A.

Comment. The pharmacokinetic parameters of beta-lactam antibacterial drugs may be subject to alterations in sepsis and septic shock, leading to a decrease in their therapeutic concentrations [199]. Unlike conventional intermittent infusion (infusion ≤ 30 min), administration by prolonged or continuous intravenous infusion, or as an extended infusion (systemic antibacterial drug administered over at least half of the dosing interval), ensures a stable concentration of the beta-lactam antibacterial drug that corresponds to the pharmacodynamics of these drugs. Two meta-analyses have shown results confirming a reduction in short-term mortality (RR 0.70; 95% CI 0.57-0.87) with prolonged infusion of beta-lactam antibacterial drugs: penicillins [224, 225]. However, the adverse effects of continuous infusion have not been evaluated by anyone. At the same time, the desired effects were deemed important, whereas the overall quality of evidence was rated as moderate.

Continuous infusion of beta-lactam antibacterial drugs can be implemented if appropriate intravenous access and necessary resources (infusion pumps, extension sets, etc.) are available. Administration of a loading dose of the drug prior to its initiation is necessary to avoid delays in achieving effective concentrations of beta-lactams [227].

The reduction in short-term mortality from prolonged infusion of beta-lactam antibacterial drugs is significant, and the intervention is feasible at a low cost. There are no data indicating worse outcomes with prolonged infusion. Accordingly, it is suggested to use prolonged infusion of beta-lactam antibacterial drugs instead of conventional bolus infusion in patients with sepsis and septic shock, provided the necessary equipment is available. Further evaluation of long-term outcomes, investigation of the impact of this technology on the emergence of antibiotic resistance, and cost comparison between prolonged and bolus infusions of beta-lactam antibacterial drugs are needed [228].

• For patients with sepsis, it is recommended to individualize the dosing regimen of systemic antibacterial drugs based on pharmacokinetic and pharmacodynamic parameters [61, 229, 230].

Level of Evidence 5, Grade of Recommendation C.

Comment. In sepsis and septic shock, pharmacokinetic/pharmacodynamic (PK/PD) parameters of systemic antibacterial drugs are subject to alterations, which can result in plasma concentrations that are too low, leading to clinical inefficacy, or conversely, too high and toxic [231, 232]. Increased renal clearance, acute kidney injury, hypoalbuminemia, renal replacement therapy, and extracorporeal membrane oxygenation are examples of common scenarios affecting the concentration of certain systemic antibacterial drugs [233-238]. Recommendations for dosing systemic antibacterial drugs in these cases, including off-label use regarding conditions coded by ICD-10 within A.40 and A.41, are formulated in the «Guidelines for the Diagnosis and Antimicrobial Therapy of Infections Caused by Multidrug-Resistant Strains of Microorganisms» [61].

Prescribing systemic antibacterial drugs taking into account PK/PD characteristics and using dosing regimens developed for patients with sepsis and septic shock is more likely to lead to effective and safe drug concentrations [239]. Some studies have reported the benefits of such an approach in the treatment of critically ill patients in terms of positive clinical outcomes [240]. PD-based dosing requires additional resources and trained clinical team members [241], adherence to patient-category-specific guidelines [242], the use of therapeutic drug monitoring, devices and dosing software, or special dose calculation nomograms [243].

• For patients with sepsis, it is recommended to perform a daily assessment of the possibility of de-escalating antimicrobial therapy instead of using fixed-duration courses of antimicrobial therapy [244, 245].

Level of trustworthiness of evidence (LTE) 5, Level of recommendation (LR) C

Comment. Exposure to systemic antibacterial drugs is associated with the development of resistance to them, and therefore efforts to reduce both the amount of administered systemic antibacterial drugs and their spectrum of activity are important [244]. This is particularly relevant in empirical therapy focused on broad-spectrum systemic antibacterial drugs, since the causative agent has not yet been identified. As soon as both the pathogen(s) and its susceptibility are known, de-escalation should be performed, i.e., discontinuation of systemic antibacterial drugs that are no longer needed (in case of combination therapy), or switching to a systemic antibacterial drug with a narrower spectrum of activity. Given the adverse social and individual risks associated with continuing unnecessary antimicrobial therapy, thoughtful discontinuation of systemic antibacterial drugs based on the clinical course is advisable. Early discontinuation of all antimicrobial therapy is recommended if infection is ruled out. Ideally, antibacterial de-escalation should be performed as soon as possible, which can be facilitated by rapid diagnostic methods. Direct evidence (13 studies, 1968 patients [245], including 1 RCT [246]) of the effectiveness of this approach has been identified. De-escalation is generally safe, can provide cost savings upon discontinuation of unnecessary systemic antibacterial drugs, and may play an important role in reducing the risk of antimicrobial resistance, toxicity, and adverse effects [247].

• For patients with sepsis, with adequate source control of infection, it is recommended to focus on short courses of antimicrobial therapy. For patients with sepsis and septic shock in whom the optimal duration of antimicrobial therapy has not been established after achieving adequate source control of infection, it is recommended to use a comprehensive assessment of clinical data and procalcitonin levels to decide on the discontinuation of antimicrobial therapy [248, 249, 250].

LE 2, GR A.

Comment. Restricting antimicrobial therapy to a short course is associated with better outcomes and is an important component of the antimicrobial stewardship strategy [248, 251]. The optimal duration of antimicrobial therapy for a particular patient with sepsis or septic shock depends on many factors, including host characteristics, pathogen and virulence, the drug, and the site of infection [252, 253]. Over the past two decades, significant efforts have been made to determine the optimal duration of antimicrobial therapy by comparing "short" courses with traditional ("longer") ones. RCT data are available for specific nosologies, such as pneumonia [254, 255], urinary tract infections [256], bacteremia [257], and intra-abdominal infections [258]. In many studies, the short course was just as effective as the longer course, but was associated with fewer adverse events. However, very few studies have focused exclusively on critically ill patients with sepsis or septic shock, so the overall quality of evidence is considered low.

Given the lack of definitive and generalized data regarding the optimal duration of therapy for critically ill patients, practice continues to vary [259, 260]. However, based on the clear benefit of reducing the duration of unjustified antimicrobial therapy, adult patients with an initial diagnosis of sepsis or septic shock, provided adequate source control is achieved, can be recommended a shorter course of systemic antibacterial drugs, as it is less costly, has fewer adverse effects, and does not adversely affect outcomes.

• When sepsis is suspected but infection is not confirmed, it is recommended to regularly assess the patient's condition and discontinue empirical antimicrobial therapy if an alternative cause of the disease is proven or suspected [37, 122].

Level of Evidence 5, Grade of Recommendation C.

Comment. International guidelines for sepsis and septic shock emphasize the importance of obtaining a complete screening of all media (including blood) for infectious agents prior to initiating systemic antibacterial drugs [123]. The signs and symptoms of sepsis are nonspecific and often mimic many other conditions [261]. Because there is no "gold standard" test for diagnosing sepsis, the attending physician cannot always rapidly differentiate between sepsis and mere worsening of organ dysfunction. In practice, a third or more of patients initially diagnosed with sepsis turn out to have non-infectious conditions [262, 263]. Therefore, the patient's condition and available data should be constantly reassessed to avoid overdiagnosis and to timely discontinue unjustified antimicrobial therapy. In the SSC-2021 guidelines, this recommendation was therefore designated as "best clinical practice" [37].

3.3. Infusion and transfusion therapy

Timely and effective fluid resuscitation is the cornerstone in stabilizing tissue hypoperfusion caused by sepsis and septic shock [37, 122].

• As the first-line fluid resuscitation therapy in the management of sepsis in adult patients, it is recommended to use water-electrolyte balance-influencing solutions (electrolytes) [37].

Level of Evidence 5, Grade of Recommendation C.

• Adult patients with sepsis-induced hypoperfusion are recommended to receive intravenous administration of no more than 30 mL/kg of a water-electrolyte balance-influencing solution (electrolyte) within the first 3 hours of initiating treatment [37].

Level of Evidence 5, Grade of Recommendation C.

• When implementing first-line fluid resuscitation in sepsis, primarily to avoid hyperchloremic acidosis among water-electrolyte balance-influencing solutions (crystalloids), it is recommended to prioritize balanced electrolyte solutions over 0.9% sodium chloride solution** [37, 264].

Level of Evidence 5, Grade of Recommendation C.

• When administering large volumes of water-electrolyte balance-influencing solutions (electrolytes), it is recommended to use albumin** to maintain colloid osmotic pressure [37].

Level of Evidence 5, Grade of Recommendation C.

Comment. There is insufficient evidence to formulate a recommendation regarding the use of restrictive versus liberal fluid therapy in patients with sepsis and septic shock during the first 24 hours if signs of hypoperfusion and hypovolemia persist after initial fluid resuscitation [264-269].

Fluid therapy in sepsis, especially in the early stages of treatment, must be individualized. It is impossible to apply a single formula to all patients, as fluid requirements vary significantly (depending on the source of sepsis and pre-existing cardiovascular dysfunction). This is especially true regarding the suggestion to administer at least 30 mL/kg of fluid within the first 3 hours [37, 122]. A young patient without comorbidities is more likely to tolerate a large fluid load than an elderly patient with severe cardiac or renal pathology.

Modern intensive care of sepsis is based on a personalized approach [240]; therefore, the SSC-2021 recommendation [37] regarding the need for a 30 mL/kg fluid infusion over 3 hours is very general and needs to be specified taking into account early assessment of pulse pressure, signs of hypovolemia, body temperature dynamics, age, and comorbid pathology.

The overall modern trend in fluid therapy is a shift toward a restrictive approach using electrolyte solutions, including in combination with albumin**. It is believed that in septic shock, limiting the fluid volume while starting norepinephrine** infusion early is acceptable [271]. From a modern perspective, restrictive fluid therapy with hemodynamic monitoring is superior to early goal-directed therapy in terms of survival in sepsis and prevention of complications [272, 273]. Acute kidney injury that develops is associated with the systemic inflammatory response rather than insufficient fluid volume.

• When choosing a water-electrolyte balance-influencing solution for the fluid management program, it is recommended to be guided by the patient's blood plasma electrolyte composition. Preference should be given to solutions with an electrolyte composition close to that of healthy human blood plasma [274, 275, 276].

Level of Reliable Evidence (LRE) 1, Level of Clinical Recommendations (LCR) A

Comment. Infusion of balanced solutions is associated with a lower risk of AKI and the need for renal replacement therapy. Volume overload should be avoided due to the potential for worsening acute kidney injury [277]. The use of 5-20% albumin** solutions has a complex history. Interest in it was renewed after 2011, when a meta-analysis of 17 studies on its use in sepsis was published, showing a statistically significant increase in survival [248]. The arguments in favor of using albumin** were strengthened by the emergence in 2014 of meta-analyses by C. Wiedermann and M. Ioannidis [279]. Ultimately, the indications for albumin infusion must be considered from the standpoint of personalized medicine, based on the severity of hypoalbuminemia and capillary leak syndrome [280-283]. An indication for albumin infusion is the cessation of transmembrane loss and a blood albumin level below 25 g/L [284].

Level of Evidence (LE): 5, Grade of Recommendation (GR): C.

Comment. In Russia, the use of all hydroxyethyl starch** solutions in patients with sepsis has not been permitted since 2017 [285].

Level of Evidence (LE) 1, Grade of Recommendation (GR) A.

Comment. The results of a 2015 metaanalysis demonstrated a higher frequency of renal replacement therapy use with gelatin** compared to standard 0.9% sodium chloride solution** (OR 1.27; 95% CI 0.44–3.64) and balanced electrolyte solutions (OR 1.50; 95% CI 0.56–3.96) [286]. However, the quality of evidence was rated as low. A review of RCTs on the use of gelatin** in patients with hypovolemia revealed an increased risk of anaphylaxis (RR 3.01; 95% CI 1.27–7.14) [287]. Furthermore, gelatin**, much like dextran**, can cause hemostasis disorders. At the same time, a number of studies have shown no clear impact of these solutions on mortality in sepsis [264, 286]. Given the increased side effects and higher costs compared to electrolyte solutions, SSC-2021 [37] included a statement against using gelatin** for initial fluid resuscitation in sepsis. This recommendation is considered weak due to the lack of evidence regarding a negative impact on sepsis treatment outcomes.

• In adult patients with sepsis, the decision to perform blood transfusion is recommended to be made taking into account not only the blood total hemoglobin level, but also the state of tissue perfusion [288, 289, 290, 291].

Level of Evidence (LE) 1, Grade of Recommendation (GR) A.

Comment. The blood total hemoglobin level range for initiating red blood cell suspension transfusion is less than 70–80 g/L, and the hematocrit is below 0.25 in the presence of circulatory disorders. However, the approach to blood transfusion should be individualized, guided by a clinical assessment of tissue perfusion, measurements of ScvO₂, and lactate levels. Blood components (red blood cell suspension, packed red blood cells, washed red cells) should be handled with extreme care and caution, carefully weighing the risk/benefit ratio in each case due to the potential for complications [288–291]. Indications for plasma transfusion may include DIC syndrome, hemorrhagic shock, and warfarin** overdose.

3.4. Vasopressor and inotropic therapy

The development of sepsis can be accompanied by a decrease in arterial and venous tone, as well as myocardial contractile function, manifesting as arterial hypotension and/or clinical and laboratory signs of acute heart failure, which necessitates the administration of these drug classes. Early initiation of vasopressor support alongside intensive fluid therapy increases treatment efficacy [292, 293].

• In adult patients with sepsis-induced hypotension, it is recommended to use infusions of adrenergic and dopaminergic agents (with predominantly vasopressor action) to maintain an initial target mean arterial pressure (MAP) of 65 mm Hg [37, 122, 292, 294, 295, 296].

Level of Evidence (LE) 1, Grade of Recommendation (GR) A.

Comment. The SSC-2016 recommendations for initiating intensive care focused on the need to maintain MAP above 65 mm Hg [122]. This recommendation was based mainly on an RCT in septic shock comparing patients who received vasopressor agents to achieve target MAP values above 65–70 mm Hg versus above 80–85 mm Hg [294]. This study found no difference in mortality, but demonstrated a reduced frequency of renal replacement therapy use in patients with chronic hypertension (by 10.5%) at higher MAP targets. At the same time, the high MAP threshold achieved using adrenergic and dopaminergic agents (with predominantly vasopressor action) was associated with a significantly higher risk of atrial fibrillation. A limitation of this study was that MAP values in both arms exceeded the target range. A subsequent meta-analysis of two RCTs confirmed that higher MAP targets did not improve survival in septic shock (RR 1.05; 95% CI 0.9–1.23) [295]. In a recently conducted RCT, a comparison was made between groups of patients aged 65 years and older with septic shock (n=2463) managed with " permissive hypotension" (MAP 60–65 mm Hg) versus a "usual care" group treated with vasopressor agents and MAP targets set by the attending physician [296, 297]. In the former group, the MAP value was 66.7 mm Hg; in the latter, 72.6 mm Hg. The "permissive hypotension" group showed a significantly lower requirement for adrenergic and dopaminergic agents (with predominantly vasopressor action), as assessed by the duration of infusion and cumulative doses of norepinephrine**. Ninety-day mortality was similar between the groups (41% vs. 43.8%). Given the lack of benefits associated with higher MAP targets and the absence of harm for elderly patients with MAP targets of 60–65 mm Hg, SSC-21 experts recommended targeting a MAP of 65 mm Hg in septic shock when vasopressor therapy is required [37].

Although a mean value of 65 mm Hg is recommended as the initial target, the optimal level may be higher in patients with a history of arterial hypertension, atherosclerosis, or chronic kidney disease. Conversely, it may be lower in younger patients without prior vascular problems, in patients with chronically low blood pressure, or in those who maintain adequate tissue perfusion.

• In adult patients, as a first-line agent for blood pressure drops and hypoperfusion not related to hypovolemia, it is recommended to use norepinephrine**—an adrenergic and dopaminergic agent with pronounced vasopressor effects: administered intravenously via continuous infusion (or syringe pump) at an initial dose of 0.1 to 0.3 mcg/kg/min, with subsequent stepwise titration of the dose and infusion rate until a mean arterial pressure of at least 65 mm Hg is reached [37, 122, 297, 298].

Level of Evidence 5, Grade of Recommendation C.

• If, during the treatment of sepsis-induced hypotension in an adult patient, the mean arterial pressure remains inadequate despite the use of norepinephrine**, it is recommended to add epinephrine** (administered intravenously via continuous infusion or syringe pump at a rate of 1 to 10 mcg/min depending on the clinical response) [37, 122, 297, 298].

Level of Evidence 5, Grade of Recommendation C.

• In patients who develop sepsis-induced hypotension and cardiac dysfunction, it is recommended to use either a combination of norepinephrine** and dobutamine**, or epinephrine** alone [37, 122, 297, 298].

Level of Evidence (LE) 1, Grade of Recommendation (GR) A.

Comment. According to the SSC–2021 guidelines [37], the drug of first choice is norepinephrine**. Dopamine** is an alternative to norepinephrine** in a very narrow subpopulation of patients with absolute or relative bradycardia. Low doses of dopamine** (1–5 mcg/kg/min) do not provide genuine nephroprotection and should not be used [299].

A meta-analysis of 11 RCTs demonstrated lower mortality (RR 0.89; 95% CI 0.81–0.98) and a lower risk of arrhythmias (RR 0.48; 95% CI 0.4–0.58) with the use of norepinephrine** compared to dopamine** [297]. Although the β-1 activity of dopamine** may be beneficial for patients with myocardial dysfunction, the high risk of arrhythmias limits its use [298].

The use of pure α-agonist phenylephrine** is limited due to the lack of sufficient clinical trials. There is evidence of mesenteric vasoconstriction during its infusion. In the presence of signs of persistent hypoperfusion despite adequate fluid resuscitation, dobutamine** may be added to the vasopressor support regimen to increase cardiac output [300].

It is advisable to take an individualized approach to initiating vasopressor therapy. Preliminary fluid loading may be used in less severe cases. Infusing solutions concurrently with the administration of vasopressor agents is preferable in cases of life-threatening hypotension or low diastolic blood pressure.

The administration of adrenergic and dopaminergic agents (with predominantly inotropic action) should also be individualized if tissue hypoperfusion is associated with impaired cardiac function proven by instrumental diagnostic methods (e.g., echocardiography). The choice and dose of such an agent should be based on achieving target parameters through individual hemodynamic monitoring with repeated measurements.

• In cases of refractory hypotension in a patient with sepsis (ICD-10 disease codes A40–A41), it is recommended to consider the use of an inotropic agent other than cardiac glycosides—#levosimendan** (at a route of administration and dose corresponding to the product labeling—from 0.05 to 0.2 mcg/kg/min) in the event of reduced myocardial contractility and/or development of diastolic dysfunction confirmed by instrumental diagnostics (echocardiography, etc.) [301, 303, 304, 305].

Level of Reliability of Evidence 1, Level of Credibility of Recommendations C.

Comment. Data from the LeoPARDS trial (n=515) showed that #levosimendan** compared with adrenergic and dopaminergic inotropic agents is associated with a lower likelihood of successful weaning from mechanical ventilation and a higher risk of supraventricular tachyarrhythmia [305]. A meta-analysis of seven RCTs comparing #levosimendan** with dobutamine** demonstrated that #levosimendan** is not superior to dobutamine** in adults with sepsis regarding mortality (0.8; 95% CI 0.48–1.33; p=0.39) [301]. Based on available data showing no benefit and taking into account the potential risk of arrhythmia, high cost, and limited availability, it is not possible to formulate strong recommendations for its use in patients with septic shock. At the same time, in patients with low cardiac output, the use of #levosimendan** (in accordance with the instructions for use and if available in the institution's arsenal) instead of dobutamine** cannot be ruled out, which follows from a number of studies and a meta-analysis performed in 2017 [302, 303, 305]. The results of a meta-analysis performed in 2021 by D.H. Liu et al. [304] also showed that after a 24-hour infusion of #levosimendan** in septic patients with myocardial dysfunction, there was an improvement in cardiac index and a decrease in blood lactate levels compared with dobutamine**. However, overall, the use of #levosimendan** had no effect on either mortality or left ventricular ejection fraction. Therefore, it is recognized that the indications for its use in septic shock remain clearly undefined.

• In the absence of central venous access, the administration of adrenergic and dopaminergic agents to restore mean arterial pressure in an adult patient with sepsis is recommended to be initiated into peripheral veins without waiting for central venous access to be established [37, 122].

Level of Evidence 5, Grade of Recommendation C.

3.5. Respiratory support

Gas exchange disorders are an important link in the pathogenesis of sepsis, which are managed by various methods of respiratory support (ranging from oxygen inhalation, including high-flow nasal cannula oxygen therapy, to various modes of non-invasive and invasive assisted and mechanical ventilation).

Oxygenation targets.

• There is insufficient evidence to recommend favoring solely a conservative or solely a liberal oxygen therapy strategy in sepsis-induced hypoxemic respiratory failure [306, 307].

Level of Evidence (LE) 1, Grade of Recommendation (GR) A.

Comment. Patients receiving mechanical ventilation in the ICU often receive a high fraction of inspired oxygen and have a high partial pressure of oxygen in arterial blood. A conservative oxygen strategy with oxygenation targets typically defined as PaO₂ = 55–70 mmHg; SpO₂ = 88–92% can reduce exposure to a high fraction of oxygen and decrease pulmonary and systemic oxidative injury. Evidence for this approach in septic patients is limited to three randomized trials [306,308,309]. In the ICU-ROX trial, which included 1,000 adult patients undergoing mechanical ventilation in the ICU [308], conservative oxygen therapy compared with liberal oxygen therapy had no significant effect on the primary study endpoint, defined as ventilator-free days. Mortality at 90 and 180 days also did not differ. These findings contrast with the results of a previous single-center trial that was stopped shortly after an unplanned interim analysis. In that trial, conservative oxygen therapy in the ICU was associated with a markedly lower mortality rate compared with conventional oxygen therapy [306]. In a recent systematic review and meta-analysis of 25 randomized controlled trials involving 16,037 patients with sepsis, stroke, trauma, myocardial infarction, or cardiac arrest, as well as patients undergoing emergency surgery, the investigators also found that a conservative oxygen therapy strategy was associated with a lower mortality rate compared with a liberal strategy [307]. However, the LOCO-2 trial, which was terminated early by the data safety monitoring board, reported no difference in 28-day survival in patients with ARDS when comparing liberal and conservative oxygenation strategies [310].

High-flow nasal cannula oxygen therapy (HFNC)

• In patients with hypoxemic respiratory failure caused by sepsis, it is recommended to prefer high-flow nasal cannula oxygen therapy over non-invasive ventilation [311, 312].

LetSD 2, LeRC B.

Comment. Acute hypoxemic respiratory failure may be a consequence of the underlying diseases causing sepsis, such as pneumonia or extrapulmonary infections leading to ARDS. In patients with hypoxemia without hypercapnia, an increased concentration of oxygen in the inspiratory mixture is used, which can be delivered by conventional means using devices such as nasal cannulas, a reservoir face mask, or a Venturi mask.

For patients with severe hypoxemia requiring intensified respiratory support, non-invasive ventilation or high-flow nasal cannula oxygen therapy is used. Both treatment methods help avoid complications associated with tracheal intubation and invasive mechanical ventilation, and promote better patient-ventilator interaction. In addition to improving gas exchange, non-invasive ventilation (NIV) can help reduce the work of breathing in selected patients. However, the use of NIV can be associated with adverse effects such as gastric distension and aspiration of gastric contents, and facial skin damage. The use of NIV may cause patient discomfort related to the inability to eat independently and communicate fully during respiratory support.

High-flow nasal cannula oxygen therapy utilizes a non-invasive interface to deliver a breathing mixture with a high oxygen concentration; it provides heating and humidification of the breathing mixture and a high flow rate to better match the patient's inspiratory demands. The application of high flow leads to the washout of gas from the nasopharyngeal dead space and the generation of moderate positive airway pressure. Through the single inspiratory limb of the HFNC circuit, a gas flow of up to 60 L/min is delivered to achieve an fraction of inspired oxygen (FiO₂) of 95–100%. However, HFNC is less effective compared to NIV in terms of reducing the work of breathing and providing a moderate or higher level of PEEP [311]. Complications with HFNC are possible, but usually do not require discontinuation of therapy.

A direct comparison of strategies using NIV and HFNC, as well as conventional face mask oxygen delivery in acute hypoxemic respiratory failure, has been performed in only one large randomized trial [312]. Although the primary outcome of the intervention, defined as the intubation rate at 28 days, did not differ between the NIV and HFNC patient groups, this trial demonstrated improved 90-day survival with HFNC compared with the NIV group (OR 0.42; 95% CI 0.21–0.85). Patients treated with HFNC also had significantly more ventilator-free days over the 28-day study period [312]. A retrospective analysis revealed that the use of HFNC in patients with severe hypoxemia (PaO₂/FiO₂ ≤ 200 mmHg) from the aforementioned trial resulted in a lower intubation rate compared with patients receiving NIV (35 versus 58 percent, respectively). A systematic review and meta-analysis of nine RCTs [313] showed that HFNC compared with conventional face mask oxygen delivery and NIV reduced the rate of tracheal intubation (RR 0.85; 95% CI 0.74–0.99), but did not affect the risk of death or the length of ICU stay [313–316]. However, the technique of NIV administration was not standardized, and center experience varied.

Despite the low quality of evidence, the benefits of a trial of HFNC instead of non-invasive ventilation in patients with sepsis and non-hypercapnic respiratory failure appear justified. At the same time, patients requiring HFNC for the treatment of acute hypoxemic respiratory failure are at high risk of requiring tracheal intubation, which necessitates close patient monitoring.

Non-invasive ventilation (NIV).

• For hypoxemic respiratory failure induced by sepsis, it is recommended to use mechanical ventilation with tracheal intubation. There is insufficient evidence to recommend using non-invasive ventilation instead [317, 318, 319].

Level of Evidence (LE) 4, Grade of Recommendation (GR) C.

Comment. When directly compared to positive-pressure mechanical ventilation with tracheal intubation (invasive), NIV appears to provide similar physiological benefits, including improved gas exchange and reduced work of breathing in selected patients, while avoiding complications associated with intubation, invasive ventilation, and concomitant sedation. On the other hand, NIV can cause mask-related discomfort, unrecognized patient-ventilator asynchrony due to leaks, and gastric distension. The main risk of NIV in acute respiratory failure is the potential delay in performing necessary tracheal intubation and an increased time interval with a high risk of aspiration. Studies have shown that NIV failure is an independent risk factor for mortality specifically in this population, although careful patient selection can reduce this risk [317, 318].

Patients with hypoxemic respiratory failure caused by sepsis may or may not have a concurrent chronic respiratory disease (e.g., COPD), and the use of NIV to manage patients with exclusively acute hypoxemic respiratory failure ("de novo respiratory failure") is less well studied, but not uncommon. For example, the LUNG SAFE study showed that NIV was used in 15% of ARDS patients with varying efficacy and mortality, depending on ARDS severity [319].

Several small RCTs have demonstrated a benefit from NIV in early or mild ARDS or de novo hypoxemic respiratory failure [320, 321]. Due to the small number of patients studied, low quality of evidence, uncertainty as to whether clinicians can identify patients with hypoxemic respiratory failure in whom NIV may be effective, and observational data suggesting potential harm from NIV in these settings, no definitive recommendation can be made. If NIV is used for patients with sepsis-associated hypoxemic respiratory failure, they should be monitored for an early decrease in the work of breathing and closely monitored for tidal volumes [322].

Lung-protective ventilation in acute respiratory distress syndrome (ARDS).

• In adult patients with ARDS caused by sepsis, it is recommended to use a low tidal volume ventilation strategy (6 mL/kg) rather than a high tidal volume strategy (> 10 mL/kg) [323, 324, 326, 327].

LE 2, GR A.

Comment. Several multicenter RCTs have been conducted in patients with ARDS to evaluate the effects of inspiratory pressure limitation through tidal volume reduction [323, 324, 325, 327]. These studies showed mixed results, which may have been driven by differences in airway pressures between the intervention and control groups [326, 328, 329].

Several meta-analyses indicate a reduction in mortality when using a pressure- and volume-limitation strategy in patients with established ARDS [330, 331]. The largest trial of the volume- and pressure-limitation strategy showed a 9% absolute reduction in mortality in ARDS patients managed with a tidal volume of 6 mL/kg and a target plateau pressure of ≤ 30 cm H₂O compared to those managed with a tidal volume of 12 mL/kg of predicted body weight (PBW) [326].

The use of a lung-protective ventilation strategy in patients with ARDS is supported by clinical trials and has gained widespread acceptance; however, the tidal volume for an individual patient with ARDS requires adjustment based on factors such as plateau pressure, selected positive end-expiratory pressure (PEEP), thoracoabdominal compliance, and patient respiratory effort. Patients with severe metabolic acidosis, high minute ventilation, or short stature may require additional tidal volume adjustment. Some clinicians believe that ventilation with tidal volumes > 6 mL/kg PBW may be safe as long as a plateau pressure of ≤ 30 cm H₂O can be maintained [332]. Plateau pressure is a truly valuable metric only if the patient is passive during an inspiratory hold. Conversely, patients with reduced thoracoabdominal compliance and high pleural pressure may tolerate plateau pressures > 30 cm H₂O well, as their transpulmonary pressure will be lower. At the same time, results from a retrospective study suggest that tidal volume should be reduced even at plateau pressures ≤ 30 cm H₂O [333], as lower plateau pressures were associated with reduced hospital mortality [334]. A recent meta-analysis of individual patient data showed that using a tidal volume that results in a driving pressure reduction of less than 12–15 cm H₂O may be beneficial in patients without spontaneous respiratory efforts [324]. Before recommending this approach, further studies are needed to confirm the efficacy of titrating tidal volume based on driving pressure (plateau pressure minus set PEEP).

Tidal volumes > 6 mL/kg PBW combined with a plateau pressure > 30 cm H₂O in ARDS should be avoided. If the plateau pressure exceeds 30 cm H₂O after reducing the tidal volume to 6 mL/kg PBW, the tidal volume may be further reduced to 4 mL/kg PBW. The clinician should bear in mind that very low tidal volumes can lead to significant patient-ventilator dyssynchrony and patient discomfort. When reducing tidal volume, respiratory rate should be increased to maintain minute ventilation (up to a maximum of 35 breaths/min). Volume- and pressure-limited ventilation may lead to hypercapnia even at the maximum allowable set respiratory rate; this appears to be acceptable and safe in the absence of contraindications (e.g., high intracranial pressure, sickle cell crisis). Neither ventilation mode (pressure-controlled or volume-controlled) has demonstrated superiority over any other that adheres to the same lung protection principles.

• In adult patients with severe ARDS caused by sepsis, it is recommended to target an upper limit plateau pressure of 30 cm H₂O rather than higher plateau pressure levels [327, 325, 328, 329, 336].

LE 2, GR A.

Comment. It should be noted that all three RCTs on which this recommendation is based [325, 327, 328] included patients using the American-European Consensus Conference criteria for acute lung injury and ARDS [337], whereas the current standard is the 2012 Berlin definition and the terms mild, moderate, and severe ARDS (PaO₂/FiO₂ ≤ 300, ≤ 200, and ≤ 100 mmHg, respectively) [326]. These three RCTs compared a strategy of low tidal volume and plateau pressure limitation with a strategy utilizing higher tidal volumes and plateau pressures; pooled data indicate a reduction in mortality (RR 0.83; 95% CI 0.70–0.97) and an increase in ventilator-free days (RR 1.8 days; 95% CI 0.35–3.25) in patients managed with low plateau pressure [37].

Another systematic review including five RCTs also revealed a strong relationship between plateau pressure and mortality [329]. This recommendation is further supported by observational data. A large international observational study, LUNGSAFE, established a correlation between plateau pressure and mortality; however, the relationship was not apparent when plateau pressures were below 20 cm H₂O [336]. Secondary analysis of five observational studies identified a plateau pressure threshold of 29 cm H₂O, above which stepwise increases in plateau pressure were accompanied by an increased risk of death [338]. Based on these data, the recommendation was adopted setting the upper limit of plateau pressure at 30 cm H₂O.

• In adult patients with moderate-to-severe ARDS caused by sepsis, it is recommended to use a high PEEP strategy instead of a low PEEP strategy [339, 340, 341, 342].

LE 2, GR A.

Comment. The application of higher PEEP in patients with ARDS can recruit pulmonary alveoli to participate in gas exchange and increase PaO₂. A meta-analysis was conducted including three multicenter RCTs [339, 340, 341] and one pilot RCT [342] investigating the use of a high-PEEP strategy compared with a low-PEEP strategy combined with low tidal volumes for the management of patients with ARDS. Among patients with ARDS receiving low tidal volumes, no significant benefit was found from the high-PEEP strategy compared with the low-PEEP strategy, with no reduction in mortality (RR = 0.93; 95% CI 0.83–1.03), reduction in ventilator days (RR = 0.00; 95% CI 1.02–1.02), or increase in ventilator-free days (RR = 1.48; 95% CI 0.19–2.76); and no increased risk of barotrauma was identified (RR = 1.49; 95% CI 0.99–2.23) [342].

Patient-level data meta-analysis showed no overall benefit from higher PEEP in all ARDS patients; however, patients with moderate or severe ARDS (PaO₂/FiO₂ ≤ 200) demonstrated a reduction in mortality with higher PEEP use, whereas patients with mild ARDS did not [343]. Analysis of data from two randomized PEEP trials [341, 340] showed that ARDS patients who respond to increased PEEP with improved oxygenation have a lower risk of death; this association was stronger in patients with more severe ARDS (PaO₂/FiO₂ < 150) compared to those with less severe ARDS [344].

The optimal method for selecting a high PEEP level remains unknown. One option is to titrate PEEP based on bedside respiratory system compliance measurements to achieve the best compliance value or the lowest driving pressure, reflecting a favorable balance between lung recruitment and overdistension [345]. A second option involves titrating PEEP via step-by-step increases while the patient receives a tidal volume of 6 mL/kg PBW, until the plateau airway pressure reaches 28 cm H₂O [341]. A third option is to use a PEEP/FiO₂ titration table, where PEEP is titrated based on matching the FiO₂ and PEEP combination required to maintain adequate oxygenation [349, 340, 341]. To prevent lung collapse, a PEEP > 5 cm H₂O is generally required [318]. PEEP titration using esophageal pressure measurements has been evaluated in two studies [349, 348]. While a pilot study showed a benefit from this approach to PEEP selection [348], subsequent results from a multicenter RCT involving 200 patients, which compared PEEP titration based on esophageal pressure measurement (P_ES) versus empirical PEEP titration (high PEEP-low FiO₂), showed no significant difference using the combined primary endpoint of death and ventilator-free days up to day 28 [349].

Low tidal volume in respiratory failure without ARDS

• In adult patients with respiratory failure caused by sepsis (without ARDS), it is recommended to use low rather than high tidal volume ventilation [122, 350].

LEL 2, GOR A.

Commentary. There is no robust evidence base for patients with acute respiratory failure requiring mechanical ventilation who do not meet ARDS criteria. A 2015 systematic review and meta-analysis revealed a reduction in the risk of the combined endpoint, including ARDS and pneumonia, during hospital stay in the low tidal volume ventilation group compared to the high tidal volume ventilation group (RR 0.72; 95% CI 0.52–0.98) [350]. An analysis of three RCTs (1129 patients) showed no difference in mortality with low Vt ventilation (RR 1.07; 95% CI 0.91–1.26), while noting a trend toward a reduced risk of developing ARDS (RR 0.59; 95% CI 0.34–1.02) [37]. Data regarding ventilation strategy in patients with sepsis-induced respiratory failure not meeting ARDS criteria are limited. However, sepsis is an independent risk factor for ARDS, and a delay in diagnosing ARDS may lead to untimely implementation of low tidal volume ventilation. Therefore, it is suggested to use low tidal volume ventilation in all mechanically ventilated sepsis patients. Furthermore, the use of low tidal volume ventilation avoids the risk of ventilator-induced lung injury in sepsis patients in whom ARDS has not been diagnosed.

Alveolar recruitment maneuvers

• In adult patients with moderate-to-severe ARDS caused by sepsis, it is recommended to use traditional alveolar recruitment maneuvers [351, 352, 353].

LE 2, GR A.

• When performing alveolar recruitment maneuvers in adult patients with sepsis, it is not recommended to use the stepwise PEEP titration algorithm [351, 352, 353].

LE 2, GR A.

Comment. There are numerous management strategies for refractory hypoxemia in patients with severe ARDS [351]. Temporary increases in transpulmonary pressure can promote the recruitment of atelectatic alveoli and improve gas exchange [346], but may also lead to overdistension of already aerated lung units, resulting in ventilator-induced lung injury and transient hypotension. Since the publication of the previous SSC-2016 guidelines, two major RCTs have been published that evaluated a "non-traditional" approach to alveolar recruitment. Instead of the "traditional" recruitment maneuver, which involves sustained continuous positive airway pressure (e.g., 30–40 cm H₂O for 30–40 s), both studies performed recruitment by stepwise increases in PEEP followed by stepwise decreases, combined with PEEP titration based on the best static respiratory system compliance [352] or oxygen saturation [353]. When stepwise PEEP recruitment was analyzed separately from studies using traditional recruitment methods, stepwise PEEP recruitment was associated with increased 28-day mortality (RR 1.12; 95% CI 1–1.25), justifying the strong recommendation against using stepwise PEEP titration for recruitment maneuvers [37, 122]. The use of traditional alveolar recruitment maneuvers appears to reduce 28-day mortality (RR 0.79; 95% CI 0.64–0.96) in patients with ARDS [37]. Although recruitment maneuvers initially improve oxygen saturation, this effect may be transient [354].

Selected patients with severe hypoxemia may benefit from alveolar recruitment maneuvers combined with high levels of PEEP, but there is limited evidence to support the routine use of these maneuvers in all patients with ARDS; therefore, these recommendations primarily apply to patients with moderate-to-severe ARDS [354]. Any patient undergoing alveolar recruitment maneuvers must be closely monitored, and if the clinical status deteriorates, the recruitment maneuver should be immediately discontinued.

Prone positioning ventilation.

• In adult patients with severe ARDS caused by sepsis, it is recommended to use prone positioning (prone ventilation) [355, 356, 357].

Level of Evidence (LE) 1, Grade of Recommendation (GR) A.

Commentary. In 2017, a meta-analysis [355] was published showing improved survival in patients with ARDS and a PaO₂/FiO₂ ratio < 200 when prone positioning was used during mechanical ventilation within the first 36 hours after intubation compared with supine positioning, but only provided that the session duration was > 12 hours per day. The meta-analysis demonstrated a reduction in mortality in patients with severe ARDS treated in the prone position compared with the supine position (RR 0.74; 95% CI 0.56–0.99), as well as an improvement in oxygenation assessed by changes in the PaO₂/FiO₂ ratio (median 235; 95% CI 124–345) [355]. Most patients responded to prone positioning with improved oxygenation, and respiratory system compliance could also improve [356, 357, 358]. Although prone positioning may be associated with potentially life-threatening complications, including accidental endotracheal tube dislodgement, this was not significantly evident in the pooled analysis (RR 1.09; 95% CI 0.85–1.39). However, prone positioning was associated with an increased incidence of pressure ulcers (RR 1.22; 95% CI 1.05–1.41) [320, 331], and some patients had contraindications to the prone position [359, 360].

Muscle relaxants.

• For adults with moderate-to-severe sepsis-induced ARDS, it is recommended to use intermittent boluses of neuromuscular blocking agents instead of continuous infusion [361, 362, 363, 364].

LetSD 2, LeRC B.

Comments. The most common indication for the use of neuromuscular blocking agents (NMBAs) in the ICU is to facilitate mechanical ventilation [365]. These drugs can improve chest wall compliance, prevent patient-ventilator dyssynchrony, and lower peak airway pressures [366]. In addition, the use of NMBAs can reduce oxygen consumption by decreasing the work of breathing [367]. The 2016 SSC guidelines provided a weak recommendation for the use of NMBA infusion for 48 hours in moderate-to-severe sepsis-induced ARDS [122]. This recommendation was based on a meta-analysis of 3 studies investigating the use of NMBAs in ARDS [335–337], and the results of this meta-analysis showed a reduction in the risk of death (RR 0.72; 95% CI 0.58–0.91) and barotrauma (RR 0.43; 95% CI 0.2–0.9) with cisatracurium infusion [368, 369, 370]. Since then, several RCTs have been published [370, 371, 372], the largest of which is the ROSE study [373]. Due to significant statistical and clinical heterogeneity, performing a meta-analysis based on all seven studies was considered unfeasible. Continuous infusion of NMBAs did not reduce mortality compared with a strategy of light sedation and bolus administration of NMBAs as needed without continuous infusion (RR 0.99; 95% CI 0.86–1.15). On the other hand, continuous infusion of NMBAs resulted in lower mortality compared with deep sedation and bolus administration of NMBAs as needed (RR 0.71; 95% CI 0.57–0.89). Overall, continuous infusion of NMBAs resulted in a reduced risk of barotrauma (RR 0.55; 95% CI 0.35–0.85), but the effect on ventilator-free days, duration of mechanical ventilation, and ICU-acquired weakness was unclear [374, 375].

Given the uncertainty that still exists regarding these important outcomes and the balance between benefit and potential harm, a weak recommendation was made in favor of intermittent boluses compared with continuous administration of NMBAs. It is important to note that adequate patient sedation and analgesia should be ensured when using NMBAs [375, 376].

Extracorporeal membrane oxygenation (ECMO).

• For adults with severe sepsis-induced ARDS when conventional mechanical ventilation fails, venovenous (VV) ECMO is recommended in centers with the infrastructure for ECMO [377, 378, 379].

LE 2, GR A.

Comment. Veno-venous (VV) extracorporeal membrane oxygenation (ECMO) is used in patients with severe acute respiratory failure to provide gas exchange in conditions of refractory hypoxemia or hypercapnic respiratory acidosis [377]. It can also be used to reduce the aggressiveness of mechanical ventilation. Evidence for the use of VV ECMO in sepsis-induced ARDS is limited; over the past 10 years, two RCTs have been conducted to evaluate the potential efficacy of VV ECMO in severe ARDS [378, 379]. Inclusion criteria for the studies were strict and focused on a population of patients with severe ARDS refractory to conventional ventilation strategies and prone positioning. The quality of evidence in this study, due to its indirect nature, was downgraded to very low quality.

The studies reviewed had methodological limitations. In one study, all intervention participants were treated at a single center, which may have increased the effect size since the center specialized in ECMO treatment [379]. In addition, some of the participants in this study did not receive the intervention [379]. However, one systematic review showed that VV ECMO performed in expert centers reduces mortality in patients with severe ARDS [377].

3.6. Extracorporeal blood purification methods

The kidneys in sepsis are highly vulnerable organs whose function, in addition to the underlying pathology, can be further compromised by the effects of contrast agents, certain systemic antibacterial drugs, dextrans**, furosemide**, and other medications. Extracorporeal blood purification techniques in sepsis can be used not only to replace lost renal function, but also to reduce the severity of the systemic inflammatory response and intoxication.

Therapy aimed at reducing the systemic inflammatory response and intoxication.

• In adult patients with sepsis, it is recommended to consider the possibility of using extracorporeal blood purification methods [37, 380, 381, 382, 383].

Level of Evidence (LE) 1, Grade of Recommendation (GR) A.

Comment. The following methods of extracorporeal blood purification can be used: hemosorption, blood hemofiltration, selective lipopolysaccharide hemosorption, plasmasorption combined with hemofiltration, plasmapheresis, plasma exchange, lipid filtration, plasmodiafiltration, cascade plasma filtration, selective plasma filtration, hemodiafiltration, prolonged hemodiafiltration, continuous hemodiafiltration.

In the development of a dysregulated systemic inflammatory response in sepsis and septic shock, lipopolysaccharide from Gram-negative bacteria plays one of the key roles. In the multicenter randomized controlled LASSO trial, the use of a multimodal lipopolysaccharide hemosorbent was accompanied by a statistically significant improvement in hemodynamics and gas exchange, a decrease in the severity of organ dysfunction and systemic inflammation markers, faster resolution of septic shock, and a reduced need for renal replacement therapy and hospital length of stay. At the same time, there were no significant differences in 28-day mortality: 47.4% compared to 55.0% in the control group [380]. Another large cohort study of 44,177 patients showed that lipopolysaccharide removal resulted in a substantial difference in 28-day mortality compared to the control group: 15% and 19.9%, respectively, in the SOFA 7–9 category (p = 0.041), and 18.6% and 27.4% in the SOFA 10–12 category (p = 0.0008) [381]. International experience with lipopolysaccharide sorption is also summarized in a meta-analysis of 17 RCTs conducted in various countries. It also showed an association of endotoxin sorption with reduced mortality among patients with septic shock [383]. However, although a number of other studies showed a significant reduction in 28-day mortality with cytokine sorption, international experts in the management of sepsis and septic shock noted insufficient quality of such studies, which prevented them from including a recommendation for the mandatory use of specific technologies in the new international guidelines for the management of sepsis and septic shock, also taking into account high financial costs [37, 178, 382, 383, 384, 385, 386]. Nevertheless, the accumulation of experience in extracorporeal blood purification using sorption, plasma-modifying, and hemofiltration therapy methods continues worldwide. The data obtained indicate positive results with an improvement in the clinical course of patients with sepsis and septic shock [386, 387, 388, 389, 390].

The most commonly used methods include: selective hemadsorption of lipopolysaccharides when Gram-negative infection is suspected; selective cytokine hemadsorption for the management of cytokine storm; hemodiafiltration combined with lipopolysaccharide adsorption for the combined treatment of Gram-negative septic shock with systemic inflammatory response, including the use of mass-transfer devices (dialyzers) with enhanced sorption properties, medium and high cutoff points for cytokine storm management and acute kidney injury treatment; plasma exchange with fresh frozen donor plasma (FFP) or selective plasma filtration when an adequate volume of FFP is not available (in the presence of signs of macrophage activation syndrome, disseminated intravascular coagulation syndrome, thrombotic microangiopathy). In cases combining sepsis (septic shock) with hyperbilirubinemia, acute liver injury, or liver failure, high-volume plasma exchange using donor plasma is performed (3–4 plasma volumes), and when the required volume of donor plasma is unavailable, selective plasma exchange (selective plasma filtration) or plasmodiafiltration is used (ASFA-2019, EASL-2017 international guidelines [391]).

Renal replacement therapy.

• In adult patients with sepsis, it is recommended to use renal replacement therapy based on renal indications. [392, 395]

Level of Evidence (LoE) 1, Grade of Recommendation (GoR) B.

Commentary. The following methods may be used for renal replacement therapy: hemodialysis, high-flux intermittent hemodialysis, low-flux intermittent hemodialysis, sustained intermittent hemodialysis, hemodialysis with selective plasma filtration and adsorption, and continuous hemodialysis.

• In adult patients with sepsis and acute kidney injury requiring renal replacement therapy, it is recommended to use both continuous and intermittent renal replacement therapy [383, 392, 393, 394, 395, 396, 397].

Level of Evidence (LoE) 1, Grade of Recommendation (GoR) B.

Commentary. A 2020 systematic review and meta-analysis summarized data on the use of continuous and intermittent renal replacement therapy modalities and showed no significant difference in mortality between patients in these groups [392, 393]. Nevertheless, according to the 2012 KDIGO clinical practice guideline for acute kidney injury [397], continuous modalities (such as continuous hemofiltration, continuous hemodiafiltration, and continuous hemodialysis) remain more preferable in patients with hemodynamic instability, elevated intracranial pressure, or generalized cerebral edema due to various causes. This statement was based on the results of a Cochrane meta-analysis, which established that during continuous RRT, the mean arterial pressure at the end of treatment was significantly higher, and the number of patients requiring vasopressor therapy escalation was significantly lower compared to intermittent dialysis [398]. If continuous procedures (lasting 24 hours or more) are not feasible, extended intermittent procedures are advisable (lasting 6 to 12 hours—sustained intermittent hemodialysis, sustained hemofiltration, sustained hemodiafiltration, and sustained blood ultrafiltration). Once hemodynamic stability is achieved, treatment may be continued in a short intermittent RRT mode (low-flux and high-flux intermittent hemodialysis, intermittent hemofiltration, intermittent hemodiafiltration).

A 2021 meta-analysis based on randomized controlled trial data involving 3,774 patients revealed an association between continuous renal replacement therapy and better renal function recovery [399]. Several studies have shown a reduction in neurological complications with continuous RRT modalities, which is attributed to the increased risk of decreased cerebral perfusion pressure during dialysis (intradialytic hypotension) or increased cerebral edema and intracranial pressure (dialysis disequilibrium syndrome). Dialysis disequilibrium syndrome results from the rapid removal of osmotically active solutes, leading to shifts in intracellular fluid. Both hypotension and disequilibrium syndrome can be avoided with continuous RRT modalities through slow, gradual fluid and solute removal [400–402]. At the same time, several large cohort studies in critically ill patients have demonstrated that ultrafiltration rates within 1.01–1.75 mL/kg/h during continuous RRT modalities are associated with lower 90-day mortality and better renal function recovery [403, 404]. Extended and intermittent regimens also facilitate earlier mobilization of patients once their condition stabilizes, despite persistent severe renal dysfunction.

Several large randomized controlled trials (AKIKI, IDEAL-ICU, STARRT-AKI) comparing early versus delayed initiation of RRT in patients including those with sepsis and septic shock (SOFA >10 points) showed no difference in mortality [395, 396, 405]. The criteria for early initiation in the AKIKI (619 patients) and IDEAL-ICU (488 patients) trials were starting RRT in patients with stage 3 AKI within 6 and 12 hours, respectively, while late initiation involved the appearance of absolute indications for the procedure. In the STARRT-AKI trial (2,927 patients), early initiation was within 12 hours in patients with stage 2 or higher AKI, and late initiation was within 72 hours or upon the appearance of absolute indications for RRT.

However, multivariate analysis in the 2021 randomized AKIKI 2 trial (278 patients) demonstrated that later initiation of RRT—in patients with stage 3 AKI with a blood urea level of 50 mmol/L, or upon the development of significant hyperkalemia, metabolic acidosis, or pulmonary edema—carried a higher risk of 60-day mortality, with a hazard ratio of 1.65 (95% CI 1.09–2.5, p=0.018), compared to patients with stage 3 AKI who started RRT within 72 hours or when urea exceeded 40 mmol/L [406]. Nevertheless, it should be noted that all these studies also utilized immunomodulatory continuous filtration techniques, the use of which was not correlated with the characteristics of the systemic inflammatory response.

The insufficiency of data regarding the benefits of early versus late RRT initiation in patients with sepsis and septic shock, in terms of systemic inflammation criteria, makes it appropriate to apply these modalities guided by the manifestations of sepsis-associated acute kidney injury (App. A.3.7; A.3.8). Nevertheless, according to the 2012 KDIGO AKI guidelines, decision-making regarding RRT initiation should account for the broader clinical context, conditions modifiable by RRT, and laboratory trends rather than threshold values of urea and creatinine alone [397].

3.7. Adjuvant therapy

Mediator chaos, genetic determination, and baseline conditions associated with comorbidities cause patients to exhibit various clinical and pathobiological manifestations at different stages of the septic process. In this regard, the nature and scope of adjunctive therapy are tailored to each individual patient.

Glucocorticoids.

• In adult patients, it is recommended to individualize the decision to prescribe glucocorticoids not only in sepsis-induced hypotension but also in ARDS complicating the course of sepsis [37, 407, 408].

Level of Evidence (LE) 1, Grade of Recommendation (GR) A.

Commentary. In cases of refractory septic shock (ICD-10 codes A40–A41; R57.2), several studies recommend using #hydrocortisone** exclusively at a dose of 200 mg/day (administered as 4 bolus injections or via continuous infusion over 24 hours using a syringe driver) [122, 407, 474].

The choice of hydrocortisone** is dictated by the following effects: it is a synthetic cortisol analog, reduces the synthesis and secretion of pro-inflammatory cytokines and nitric oxide, maintains endothelial integrity, and participates in regulating the body's natural response to stress. Therefore, the primary rationale for its administration is endogenous cortisol deficiency in refractory septic shock, which is defined as a clinical situation where the target blood pressure (>65 mmHg) cannot be achieved with norepinephrine** infusion at a rate exceeding 0.5 mcg/kg/min. However, some specialists rely on higher doses (1 mcg/kg/min and above) [409] at which the required blood pressure level is generally achieved. In this regard, the decision to prescribe hydrocortisone** is made by the attending physician.

It should be taken into account that glucocorticoid receptors may be blocked, and the administration of hydrocortisone** in this case increases mortality [410]. Other adverse drug reactions include an increased risk of hyperglycemia and hypernatremia. However, a meta-analysis by D. Annane et al. [411], which included about 5,000 patients with septic shock, demonstrated a reduction in 28-day and hospital mortality with hydrocortisone** administration. In addition to reduced hospital mortality, a number of studies demonstrate increased 90-day and 180-day survival, as well as a reduction in the duration of shock and mechanical ventilation by 1 day in individuals who received hydrocortisone** for 5–7 days and survived septic shock [37].

P. Marik's compromise approach consists of prescribing hydrocortisone** to patients with septic shock who require norepinephrine** infusion at a rate greater than 0.5 mcg/kg/min to restore target blood pressure. If no effect in the form of reduced norepinephrine** doses is observed within 48 hours, hydrocortisone** is discontinued. Otherwise, its administration is continued for up to 7 days [412].

The SSC-2021 recommendations [122] suggest intravenous glucocorticoids in septic shock with a persistent requirement for vasopressor therapy (norepinephrine** or epinephrine** dose ≥ 0.25 mcg/kg/min, initiation 4 h after starting adrenergic and dopaminergic agents with vasopressor activity): #hydrocortisone** intravenously at a dose of 200 mg/day (50 mg every 6 h or as a continuous infusion). However, this recommendation is considered weak with moderate quality.

Immunoglobulins.

Level of Evidence 5, Grade of Recommendation C.

Comment. Due to the extremely low level of evidence regarding efficacy and the presence of contradictory data, SSC-2021 experts [122] do not recommend routine use of these drugs in the intensive care of sepsis and septic shock. However, a meta-analysis by K.G. Kreymann showed an advantage of early administration of intravenous immunoglobulins in patients with sepsis and septic shock, which led to a decrease in mortality and length of stay in the ICU [413]. It is proposed to consider the administration of immunoglobulins for replacement therapy when their levels decrease.

3.8. Venous thromboembolism prophylaxis

• In adults with sepsis, it is recommended to use pharmacological prophylaxis for venous thromboembolism (VTE) unless there are contraindications to this therapy [122].

Level of Evidence 5, Grade of Recommendation C.

• In sepsis, for VTE prophylaxis among heparin group drugs, it is recommended to use low-molecular-weight heparins instead of unfractionated heparin** [122].

Level of Evidence 5, Grade of Recommendation C.

• In adults with sepsis, it is not recommended to use mechanical VTE prophylaxis in addition to pharmacological prophylaxis [122].

Level of Evidence 5, Grade of Recommendation C.

Comment. Mechanical VTE prophylaxis should be performed only in the presence of contraindications to heparins and a high risk of hemorrhagic complications [414].

Risk factors for hemorrhagic complications during thromboprophylaxis: age > 85 years, previous bleeding episode, hemostatic disorders (platelet count < 50 × 10⁹/L, congenital bleeding disorders), active bleeding of any localization, uncontrolled arterial hypertension (systolic BP > 180 mm Hg and/or diastolic BP > 110 mm Hg), stroke (within the last 3 months), major head or spinal cord injuries, invasive procedures between 4 hours before and 12 hours after surgery, lumbar puncture, or epidural anesthesia.

3.9. Management of disseminated intravascular coagulation in septic shock

• Correction of hemostatic disorders in adults with sepsis over time is recommended to be carried out in a targeted manner, guided by the results of laboratory and instrumental studies [415, 416, 417, 418].

Level of Evidence (LE) 1, Grade of Recommendation (GR) A.

Comment. The individual approach strategy is the basis for treating DIC in sepsis, since uncontrolled use of drugs affecting the coagulant and anticoagulant potential of the blood can bring not only benefit, but also harm. The attitude towards maintaining anticoagulant therapy in sepsis-associated DIC is ambiguous, despite existing randomized controlled trials [415, 416]. A limitation of such studies is that they were mainly conducted in patients with sepsis, but not always with concomitant DIC, and also that therapy was often preceded by thromboprophylaxis, which influenced the evaluation of results. Nevertheless, a trend towards a decrease in the probability of death in septic patients with coagulopathy or DIC during anticoagulant therapy has been noted [417, 418].

• In adults with sepsis, it is recommended to use continuous intravenous infusion of heparin sodium** at a therapeutic dose (1000–2000 IU/hour or 24000–48000 IU/day) with aPTT monitoring, taking into account the likelihood of bleeding, the short half-life of heparin sodium**, and the reversibility of its action [415, 416, 417, 420, 424].

Level of Evidence 5, Grade of Recommendation C.

Comment. The optimal dosing regimen is determined by the physician taking into account the specific clinical situation. The use of heparin sodium** does not aim to necessarily increase the aPTT to 1.5–2.5 times compared to the control. In addition, aPTT monitoring in these cases can be difficult, so clinical observation for signs of bleeding is important. The efficacy of the heparin group (low-molecular-weight drugs) in the treatment of thrombosis is assessed better than that of unfractionated heparin**, but confirmation by high-quality evidence is lacking [424].

In sepsis, antithrombin III levels decrease due to increased vascular permeability (extravasation), consumption during pathologically activated coagulation, cleavage by proteases, and slowed hepatic synthesis due to impaired liver function [420]. When antithrombin III activity drops below 70%, attempts are made to restore it by FFP transfusion or antithrombin III administration to promote the anticoagulant effect of heparin group drugs [422]. However, evidence for the routine use of antithrombin III in sepsis-induced DIC has not been obtained [423]. A large-scale phase 3 study, which also investigated the effect of high doses of antithrombin III on sepsis outcomes, revealed no benefit from its use, but recorded increased bleeding [421].

• Platelet or plasma (plasma component) transfusion in patients with sepsis-induced DIC is recommended primarily for patients with bleeding. In patients with DIC without bleeding, prophylactic platelet transfusion is not recommended unless a high bleeding risk is identified [424].

Level of Evidence 5, Grade of Recommendation C.

Comment. The target platelet count when used for prophylactic purposes is not <50 × 10⁹/L [424]. Antifibrinolytic agents should not be used in patients with DIC with a thrombotic phenotype [424].

3.10. Stress ulcer prophylaxis

• Adult patients with sepsis who have risk factors for gastrointestinal bleeding are recommended to undergo stress ulcer prophylaxis with H₂ receptor blockers or proton pump inhibitors [37, 122, 123].

Level of Evidence 5, Grade of Recommendation C.

Comment. Risk factors for gastrointestinal bleeding include: prolonged mechanical ventilation (more than 48 hours), coagulopathy, liver dysfunction, need for renal replacement therapy, and a high SOFA score. The development of bleeding is associated with damage to mucosal defense mechanisms against gastric acids, oxidative stress, and hypoperfusion. The prescription of these drugs is not indicated in the absence of the specified risk factors, as they increase the likelihood of ventilator-associated pneumonia and Clostridioides difficile infection. Early enteral nutrition prevents the likelihood of bleeding. However, the experts who prepared the update of the SSC-2021 guidelines [37] rated the quality of evidence presented in various studies as moderate, and the recommendation itself as weak.

3.11. Artificial nutrition.

• Adult patients with sepsis who can tolerate enteral nutrition are recommended to start it within 72 hours after diagnosis [37].

Level of Evidence 5, Grade of Recommendation C.

• If tube feeding is predicted to be unfeasible within the next 3–5 days, it is recommended to prescribe total parenteral nutrition in the first 24–48 hours in a gradually increasing volume, observing the prescribed infusion rate of parenteral nutrition solutions as nutritional substrates (amino acids and lipids no more than 0.1 g/kg, glucose no more than 0.5 g/kg per hour) [37, 477].

LetSD 2, LeRC B.

Comment. When managing patients with sepsis, especially those undergoing any form of respiratory support and lacking contraindications specific to the underlying disease that caused the sepsis, priority should be given to enteral nutrition, starting with its trophic variant. Early initiation of enteral nutrition in patients with septic shock and sepsis has potential physiological benefits associated with maintaining gut integrity and preventing bacterial translocation, attenuating inflammatory responses, and modulating metabolic responses that may reduce insulin resistance.

There is no compelling evidence in the literature supporting this proposition. However, given the probable potential benefit and the absence of any apparent harm, early initiation of feeding in patients with sepsis and septic shock is formulated as a weak recommendation. The most common regimens include the following positions.

The required baseline substrate supply in an unstable condition is: energy — 20–25 kcal/kg/day, protein — 1–1.2 g/kg/day; in a stable condition — energy — 30–35 kcal/kg/day, protein — 1.5–2 g/kg/day, micronutrients — at least the daily physiological requirement.

In the first days, it is recommended to avoid prescribing a hypercaloric diet, preferably starting with lower doses (from 500 kcal per day) and increasing the dose if it is tolerated. Preference should be given to standard enteral nutrition formulas with an increased protein content (high-nitrogen formulas).

The need to switch to mixed or total parenteral nutrition is considered after 7 days of ineffective enteral nutrition. Prokinetics such as metoclopramide** or erythromycin may be added to the enteral nutrition regimen. However, one should bear in mind the adverse drug reactions associated with their administration, namely QT-interval prolongation and the development of ventricular arrhythmias.

There are no strong grounds for adding carnitine, arginine, glutamine, selenium, or omega-3 fatty acids to enteral nutrition.

3.12. Glycemic control

• In adult patients with sepsis, it is recommended to initiate insulin therapy at a blood glucose level ≥ 10 mmol/L (180 mg/dL) [37, 425].

LE 2, GR A.

Comment. Glycemic control should be performed when blood glucose levels exceed 9–10 mmol/L in 2 consecutive samples. When blood glucose levels are above 12–13 mmol/L, it is advisable to consider slow intravenous administration of insulin (ATX A10A Insulins and analogues) up to 7 IU/hour, depending on the glycemia level in a particular patient [425].

3.13. Sedation and analgesia

Level of Evidence 5, Grade of Recommendation C.

Comment. The presence of an endotracheal tube in the trachea is not in itself a sufficient indication for administering hypnotics and sedatives. Sedative agents reduce vascular tone and myocardial contractility, and may also alter immune function. When possible, preference should be given to propofol** and dexmedetomidine, avoiding benzodiazepine derivatives and barbiturates. Analgesia, if required, should precede sedation. The arsenal of non-pharmacological methods of sedation should be expanded by creating an appropriate atmosphere in the unit.

4. Medical Rehabilitation and Sanatorium-Resort Treatment

The goal of rehabilitation for patients with sepsis is the restoration and preservation of health and full social and daily activity [426, 427]. Medical rehabilitation is indicated for all patients who have undergone sepsis; the choice of the optimal rehabilitation method depends on the specific disease that caused it [428, 429].

The main objectives of rehabilitation for patients with sepsis are: 1) prevention or reduction of the severity of organ and body system dysfunctions, 2) prevention or reduction of the degree of activity limitations, disease progression, and development of complications, 3) elimination and correction of emotional and psychological disorders, 4) reduction of the severity of disabling consequences of the disease, and adaptation to everyday physical loads [430].

• An individualized rehabilitation program is recommended to be carried out for patients with sepsis daily, lasting from 1 to 3 hours, taking into account the state of consciousness, hemodynamic status, and mobility level, with an emphasis on the respiratory system [431, 432, 433].

LoE 5, GoR C.

Comment. Depending on the patient's ability to participate in rehabilitation measures (severity of condition, level of consciousness), rehabilitation is carried out in active (for patients capable of interacting with medical personnel) and passive (for patients with altered levels of consciousness) modes. The rehabilitation program includes a combination of both simple (positioning) and more complex (muscle electrical stimulation, automated electromyostimulation with verticalization, etc.) techniques implemented both by ICU staff and by a multidisciplinary rehabilitation team, if available in the medical organization [431].

LoE 5, GoR C

Comment. Non-verticalizing positioning has no absolute contraindications and should be used from the 1st day of admission by the on-duty medical staff [435]. In particular, lateral positioning promotes better drainage function and prevents sputum stagnation. Positioning with an elevated head of the bed and in a sitting position increases tidal volume and promotes effective coughing. During positioning, hemodynamic response and individual tolerance must be taken into account. There is no evidence of the superiority of certain physiotherapy methods in sepsis; physiotherapy can be considered as an adjunctive technique to basic surgical care, intensive care, conservative therapy, and rehabilitation.

LoE 5, GoR C

• In septic shock, active rehabilitation measures for mobilization and verticalizing positioning are not recommended [431, 436, 437].

LoE 5, GoR C

Comment. Despite the critical condition of a patient with sepsis/septic shock, it is advisable to use non-verticalizing positioning for the prevention of pressure ulcers and other complications, as well as to implement other rehabilitation methods recommended by the Union of Rehabilitologists of Russia for categories of patients who are or have been on prolonged mechanical ventilation, have a tracheostomy, or have pronounced impairments of consciousness, taking into account the indications and contraindications formulated by them [431].

After the resolution of sepsis and the transfer of patients from the ICU to a specialized department, as well as discharge from the hospital, the medical rehabilitation and sanatorium-resort treatment program are determined by the underlying disease whose course was complicated by the development of sepsis, as well as the nature of the surgical intervention performed [438].

5. Prevention and Dispensary Observation

Prevention of sepsis consists of timely diagnosis and full eradication of existing infectious and inflammatory foci, as well as the prevention of healthcare-associated infections [2, 439, 440].

Issues regarding the diagnosis and surgical tactics of focus sanitization in infections of various localizations (operational and technical methods, choice of surgical method and technique, features of drainage, management of the postoperative wound, etc.) are detailed in various Russian and international guidelines, manuals, and publications, the list of which is presented in Section 3.1 of these clinical guidelines.

Prevention of healthcare-associated infections is presented in the relevant sections of SanPiN 3.3686-21 "Sanitary and epidemiological requirements for the prevention of infectious diseases" (Resolution of the Chief State Sanitary Doctor of the Russian Federation dated February 15, 2021).

• Dispenser observation (follow-up) of patients who have undergone sepsis is recommended to be carried out taking into account the profile of the underlying and comorbid diseases, as well as the nature of the surgical intervention performed [37, 438].

Level of trustworthiness of evidence (LTE) 5, Level of recommendation (LR) C

6. Organization of Medical Care

When providing emergency, including specialized emergency, medical care outside a medical organization, emergency medical teams perform medical evacuation of patients with suspected sepsis to medical organizations if the initial patient assessment reveals: 1) signs of an infectious focus of any localization (pneumonia, purulent wound, etc.), 2) signs of organ dysfunction scoring 2 or more points on the qSOFA scale, arising after the onset of symptoms of the suspected focus.

• In patients with suspected sepsis at the prehospital stage, laboratory and instrumental studies aimed at confirming or excluding the diagnosis are not recommended [37].

Level of trustworthiness of evidence (LTE) 5, Level of recommendation (LR) C

Comment. The diagnosis of sepsis is clinical; any prehospital diagnostic measures that may delay hospitalization are unacceptable. Patients with suspected sepsis are recommended to be hospitalized preferably in a level III multidisciplinary hospital with facilities for emergency diagnosis of the infectious focus and treatment of various pathologies. A patient hospitalized in a hospital lacking such facilities should be transferred as quickly as possible, if feasible, to a medical organization equipped with all modern technologies used in the treatment of sepsis, including the management of the infectious focus. In each region, it is advisable to develop regional emergency transfer rules, a routing protocol for patients with sepsis taking into account regional characteristics, and a mechanism for implementing teleconsultations by the appropriate information and consultation center within whose responsibility zone this medical organization is located.

• A patient delivered to a medical organization with obvious signs of sepsis is recommended to be hospitalized in the intensive care unit of the emergency department (if available) or directly in the ICU to perform intensive care in parallel with diagnostic measures [37].

Level of trustworthiness of evidence (LTE) 5, Level of recommendation (LR) C

Comment. Delayed hospitalization of sepsis patients in the ICU is associated with increased mortality, duration of mechanical ventilation, and length of stay both in the ICU and in the hospital [441]. This conclusion was confirmed by an observational study by L.T. Cardoso et al. (401 patients), which showed a 1.5% increase in ICU mortality for each hour of delay in transfer to the ICU from the emergency department [442]. Another retrospective observational study (14,788 critically ill patients) in the Netherlands also revealed higher in-hospital mortality with longer transfer times from the emergency department to the ICU [443]. A study conducted in the UK (12,380 patients treated in general wards across 48 hospitals) showed that delayed ICU admission resulted in higher 90-day mortality [444].

• If sepsis is suspected in a patient currently in a specialized ward (appearance and/or worsening of multiple organ dysfunction signs with a qSOFA score of 2 or more in the presence of an infectious focus or suspicion of its development), it is recommended to call an anesthesiologist-resuscitologist for a consultation; if the septic cause of the patient's deterioration is confirmed, it is advisable to hospitalize them in the ICU no later than 6 hours from the time of diagnosis [37].

Level of trustworthiness of evidence (LTE) 5, Level of recommendation (LR) C

Comment. If there is a clinical picture of sepsis but the infectious focus is not identified, intensive care measures are carried out while simultaneously continuing the diagnostic search. If emergency surgery is required as part of source control, the patient may first undergo surgical intervention in accordance with the requirements of relevant clinical guidelines, and only thereafter be transferred to the ICU to continue intensive care. Admission to the ICU of sepsis patients receiving palliative care whose treatment excludes advanced organ support is not indicated; the decision on their transfer is made on an individual basis in each case.

• If upon further evaluation the diagnosis of sepsis is not confirmed and organ dysfunction does not progress, it is recommended to transfer the patient to a specialized hospital ward, provided there are no other grounds for the patient's stay in the ICU [37, 445, 446].

Level of trustworthiness of evidence (LTE) 5, Level of recommendation (LR) C

Comment. Signs and symptoms of sepsis are nonspecific and often correspond to other diseases manifested by life support system decompensation [261, 447, 448]. Approximately a third or more of patients initially diagnosed with sepsis turn out to be non-infectious [448, 449, 447]. Their transfer, as well as the transfer of patients recovered from critical illness to a specialized ward, is carried out on grounds generally accepted in medical practice.

• Patients after surviving sepsis are recommended to be discharged from the hospital provided there is clinical stabilization, completion of risk stratification for an adverse outcome, and implementation of the chosen treatment strategy for the underlying disease and its complications in accordance with relevant clinical guidelines [37].

LE 5, GR C

7. Additional Information

Comorbid pathology in a patient can complicate diagnosis and worsen the course of the disease. This is important to consider in cases of polyvalent allergy, history of leukemia, oncological diseases, tuberculosis; primary and secondary immunodeficiency, HIV infection; hepatitis B and C; cardiovascular diseases accompanied by rhythm disorders and myocardial weakness (post-infarction cardiosclerosis, atrial fibrillation/flutter, frequent ventricular extrasystole of bigeminy/trigeminy type, chronic heart failure stage III–IV according to NYHA, etc.), as well as pulmonary diseases (chronic obstructive pulmonary disease, etc.).

Criteria for Evaluating the Quality of Medical Care

References

Appendix A1. Working Group Composition

Bagnenko S.F. (Saint Petersburg) – Academician of the Russian Academy of Sciences, D.Sc. in Medicine, Professor, Board Member of the Russian Society of Surgeons (RSS), Chairman of the Board of the Russian Society of First Aid, Rector of the Academician I.P. Pavlov First Saint Petersburg State Medical University of the Russian Ministry of Health, Chief Freelance Specialist in Emergency Medical Care of the Russian Ministry of Health

Gorobets E.S. (Moscow) – D.Sc. in Medicine, Professor, Member of the Russian Non-Profit Organization "Association of Anesthesiologists-Reanimatologists", Chief Researcher at the N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health

Gusarov V.G. (Moscow) – D.Sc. in Medicine, Associate Professor, Head of the Department of Anesthesiology and Resuscitology, Chief Physician of the Hospital at the N.I. Pirogov National Medical and Surgical Center of the Russian Ministry of Health, Member of the Interregional Association for Clinical Microbiology and Antimicrobial Chemotherapy (MACMACh)

Dekhnich A.V. (Smolensk) – Ph.D. in Medicine, Member of the Interregional Association for Clinical Microbiology and Antimicrobial Chemotherapy (MACMACh), Deputy Director for Research at the Research Institute of Antimicrobial Chemotherapy of the Smolensk State Medical University of the Russian Ministry of Health, Head of the Methodological Verification Center for Antimicrobial Resistance – Reference Center for Clinical Pharmacology.

Dibirov M.D. (Moscow) – D.Sc. in Medicine, Professor, President of the Russian Association of Surgical Infection Specialists (RASSI), Board Member of the Russian Society of Surgeons, Head of the Department of Surgical Diseases and Clinical Angiology at the A.I. Evdokimov Moscow State University of Medicine and Dentistry of the Russian Ministry of Health

Ershova O.N. (Moscow) – D.Sc. in Medicine, Member of the Expert Council of the Russian Sepsis Forum, Professor of the Department of Hygiene, Epidemiology and Infectious Diseases at the Institute of Advanced Training of the Federal Medical-Biological Agency, Member of the Interregional Association for Clinical Microbiology and Antimicrobial Chemotherapy (MACMACh)

Zamyatin M.N. (Moscow) – D.Sc. in Medicine, Professor, Member of the Coordinating Council of the Russian Non-Profit Organization "Association of Anesthesiologists-Reanimatologists", Member of the All-Russian Public Organization of Specialists in Disaster Medicine, Director of the Federal Center for Disaster Medicine at the N.I. Pirogov National Medical and Surgical Center of the Russian Ministry of Health, Head of the Department of Medical Care Organization in Emergencies at the Institute of Professional Education, Chief Anesthesiologist-Reanimatologist at the N.I. Pirogov National Medical and Surgical Center of the Russian Ministry of Health

Zubareva N.A. (Perm) – D.Sc. in Medicine, Professor, Co-Chair of the "Perioperative Medicine" Section of the Russian Society of Surgeons, Member of the Russian Association of Surgical Infection Specialists (RASSI), Chairman of the Perm Regional Branch of the Interregional Association for Clinical Microbiology and Antimicrobial Chemotherapy (MACMACh), Member of the Expert Council of the Russian Sepsis Forum, Professor of the Department of General Surgery No. 1 at the Academician E.A. Wagner Perm State Medical University of the Russian Ministry of Health

Klimko N.N. (Saint Petersburg) – D.Sc. in Medicine, Professor, Member of the Interregional Association for Clinical Microbiology and Antimicrobial Chemotherapy (MACMACh), Head of the Department of Clinical Mycology, Allergology and Immunology at the I.I. Mechnikov North-Western State Medical University of the Russian Ministry of Health

Kozlov R.S. (Smolensk) – Corresponding Member of the Russian Academy of Sciences, D.Sc. in Medicine, Professor, President of the Interregional Association for Clinical Microbiology and Antimicrobial Chemotherapy (MACMACh), Rector of the Smolensk State Medical University of the Russian Ministry of Health, Chief Freelance Specialist in Clinical Microbiology and Antimicrobial Resistance of the Russian Ministry of Health

Korolkov A.Yu. (Saint Petersburg) – D.Sc. in Medicine, Member of the Russian Society of Surgeons, Professor of the Department of General Surgery, Head of the Emergency Surgery Department at the Research Institute of Surgery and Emergency Medicine of the Academician I.P. Pavlov First Saint Petersburg State Medical University of the Russian Ministry of Health

Kulabukhov V.V. (Moscow) – Ph.D. in Medicine, Associate Professor, President of the Interregional Public Organization "Society of Physicians and Nurses 'Sepsis Forum'" (RSF), Member of the Coordinating Council of the Russian Non-Profit Organization "Association of Anesthesiologists-Reanimatologists", Leading Researcher at the N.V. Sklifosovsky Research Institute of Emergency Care of the Moscow Healthcare Department

Polushin Yu.S. (Saint Petersburg) – D.Sc. in Medicine, Professor, Academician of the Russian Academy of Sciences, President of the Russian Non-Profit Organization "Association of Anesthesiologists-Reanimatologists", Honorary President of the All-Russian Public Organization "Federation of Anesthesiologists and Reanimatologists", Head of the Research and Clinical Center of Anesthesiology and Resuscitology at the Academician I.P. Pavlov First Saint Petersburg State Medical University of the Russian Ministry of Health

Popov D.A. (Moscow) – D.Sc. in Medicine, Professor of the Russian Academy of Sciences, Member of the Presidium of the Board of the Interregional Public Organization "Alliance of Clinical Chemotherapists and Microbiologists", Member of the Interregional Association for Clinical Microbiology and Antimicrobial Chemotherapy (MACMACh), Member of the Expert Council of the Russian Sepsis Forum, Professor of the Department of Anesthesiology and Resuscitology with a Course in Clinical Laboratory Diagnostics at the Institute of Professional Education, Head of the Laboratory of Clinical Microbiology and Antimicrobial Therapy at the A.N. Bakulev National Medical Research Center of Cardiovascular Surgery of the Russian Ministry of Health

Revishvili A.Sh. (Moscow) - D.Sc. in Medicine, Professor, Academician of the Russian Academy of Sciences, Chief Freelance Surgeon and Endoscopist of the Ministry of Health of the Russian Federation, Vice-President of the Russian Society of Surgeons, Director of the A.V. Vishnevsky National Medical Research Center of Surgery

Roitman E.V. (Moscow) – D.Sc. in Medicine, President of the National Association of Specialists in Thrombosis, Clinical Hemostaseology and Hemorheology, Professor of the Department of Oncology, Hematology and Radiation Therapy at the Pirogov Russian National Research Medical University of the Russian Ministry of Health

Rudnov V.A. (Yekaterinburg) – D.Sc. in Medicine, Professor, Vice-President of the Interregional Association for Clinical Microbiology and Antimicrobial Chemotherapy (MACMACh), Chairman of the Expert Council of the Russian Sepsis Forum, Member of the Coordinating Council of the Russian Non-Profit Organization "Association of Anesthesiologists-Reanimatologists", Head of the Department of Anesthesiology, Resuscitology and Toxicology at the Ural State Medical University.

Sidorenko S.V. (Saint Petersburg) – Corresponding Member of the Russian Academy of Sciences, D.Sc. in Medicine, Professor, Vice-President of the Interregional Public Organization "Alliance of Clinical Chemotherapists and Microbiologists", Head of the Department of Medical Microbiology and Molecular Epidemiology at the Pediatric Research and Clinical Institute of Infectious Diseases of the Federal Medical-Biological Agency, Professor of the Department of Medical Microbiology at the I.I. Mechnikov North-Western State Medical University of the Russian Ministry of Health

Sokolov D.V. (Saint Petersburg) – Member of the Coordinating Council of the Russian Non-Profit Organization "Association of Anesthesiologists-Reanimatologists", Researcher at the Research and Clinical Center of Anesthesiology and Resuscitology at the Academician I.P. Pavlov First Saint Petersburg State Medical University of the Russian Ministry of Health

Khachatryan N.N. (Moscow) – D.Sc. in Medicine, Professor, Vice-President of the Russian Association of Surgical Infection Specialists (RASSI), Professor of the Department of Surgical Diseases and Clinical Angiology at the A.I. Evdokimov Moscow State University of Medicine and Dentistry of the Russian Ministry of Health

Khrapov K.N. (Saint Petersburg) – Dr. Sc. (Med.), Member of the Russian Non-Profit Organization "Association of Anesthesiologists and Intensivists", Chief Researcher at the Scientific and Clinical Center for Anesthesiology and Intensive Care, Professor at the Department of Anesthesiology and Intensive Care, Pavlov First Saint Petersburg State Medical University of the Russian Ministry of Health

Shabunin A.V. (Moscow) – Dr. Sc. (Med.), Professor, Academician of the RAS, President of the Russian Society of Surgeons, Chief Surgeon and Endoscopist of the Moscow Healthcare Department, Head of the Department of Surgery, Russian Medical Academy of Continuous Professional Education (RMANPO) of the Ministry of Health of the Russian Federation, Chief Medical Officer of the Botkin City Clinical Hospital of the Moscow Healthcare Department

Shlyk I.V. (Saint Petersburg) – Dr. Sc. (Med.), Professor, Deputy President of the Russian Non-Profit Organization "Association of Anesthesiologists and Intensivists", Professor at the Department of Anesthesiology and Intensive Care, Deputy Head for Clinical Work at the Scientific and Clinical Center for Anesthesiology and Intensive Care, Deputy Chief Medical Officer for Anesthesiology and Intensive Care at the Clinic of the Pavlov First Saint Petersburg State Medical University of the Russian Ministry of Health

Yakovlev S.V. (Moscow) – Dr. Sc. (Med.), President of the Interregional Public Organization "Alliance of Clinical Chemotherapists and Microbiologists", Professor at the Department of Hospital Therapy No. 2, Faculty of General Medicine, Sechenov First Moscow State Medical University of the Russian Ministry of Health

All members of the working group declare no conflict of interest regarding the preparation of the clinical guidelines "Sepsis (in Adults)".

Appendix A2. Methodology for Developing Clinical Guidelines

The development of these clinical guidelines was carried out in several stages. First, a multidisciplinary group of specialists dealing with the treatment of severe infections, initiated by the public organization "Russian Sepsis Forum", prepared a draft version of the guidelines. This draft took into account the main provisions of the 2021 international Surviving Sepsis Campaign guidelines (SSC-2021) [111], as well as domestic interdisciplinary methodological guidelines "Diagnosis and Antimicrobial Therapy of Infections Caused by Multidrug-Resistant Microorganism Strains" (2022 update) [65]. The project was approved by the Coordination Council of the "Association of Anesthesiologists and Intensivists" at a meeting held during the 4th Congress "Current Issues in Critical Care Medicine" (May 2022) and supported by the Presidium of the Russian Society of Surgeons. Subsequently, an interdisciplinary working group was formed to finalize the document, consisting of experts from various public organizations: the "Russian Society of Surgeons", the "Association of Anesthesiologists and Intensivists", the "Russian Sepsis Forum", the "Russian Association of Surgeons for Surgical Infections" (RASS), the "Interregional Association for Clinical Microbiology and Antimicrobial Chemotherapy", the Interregional Public Organization "Alliance of Clinical Chemotherapists and Microbiologists", and the Russian Society of Emergency Medical Aid. The outcome of the group's work was a draft of the clinical guidelines, which was posted on July 1, 2022, for public discussion on the websites of the "Russian Society of Surgeons", the "Association of Anesthesiologists and Intensivists", the "Russian Sepsis Forum", and the "Interregional Association for Clinical Microbiology and Antimicrobial Chemotherapy". Comments and suggestions were accepted until August 22, 2022, and were subsequently incorporated into the final edition of the document. Following the active involvement of representatives from the "National Association of Specialists in Thrombosis, Clinical Hemostasiology and Hemorheology" in the discussion, the association was added to the list of public organizations participating in the development of the clinical guidelines. Approval of the final version of the guidelines was carried out first at a remote meeting of the drafting working group, and subsequently by all public organizations that participated in their development.

Determination of the level of reliability of evidence (LRE) was carried out in two directions: in the first, LRE was determined based on the methodological quality and consistency of clinical study results. In the second, the LRE scale was converted based on the methodological quality and consistency of clinical study results.

Target audience for these guidelines:

• anesthesiologist-resuscitologist

• infectious disease specialist

• clinical pharmacologist

• medical microbiologist

• neurosurgery specialist

• nephrologist

• cardiovascular surgeon

• emergency physician

• thoracic surgeon

• transfusiologist

• trauma and orthopedic surgeon

• urologist

• surgeon

• maxillofacial surgeon

Table A.2.1. Scale for grading levels of reliability of evidence (LRE) for diagnostic methods (diagnostic interventions)

Table A.2.2. Scale for grading levels of reliability of evidence (LRE) for prevention, treatment, and medical rehabilitation methods (preventive, therapeutic, and rehabilitation interventions)

Table A.2.3. Scale for grading levels of recommendation validity (LRV) for prevention, diagnostic, treatment, and medical rehabilitation methods, including those based on natural therapeutic factors (preventive, diagnostic, therapeutic, and rehabilitation interventions)

Procedure for updating clinical guidelines.

The guideline update mechanism provides for their revision at least once every three years, as well as upon the emergence of new evidence-based data regarding the diagnosis, treatment, prevention, and rehabilitation of sepsis.

Appendix A3. Reference Materials

Appendix A.3.1. Conditions requiring source control and imaging

Note: * Contrast-enhanced CT

** Transesophageal echocardiography may be performed to clarify the diagnosis when transthoracic echocardiography yields negative results

Appendix A.3.2. Basic list of "round-the-clock available" parenteral antibacterial and systemic antifungal agents for a large multidisciplinary hospital

Appendix A.3.3. Risk factors for antimicrobial resistance of microorganisms

Risk factors for infection caused by ESBL-producing Enterobacteriaceae:

• hospitalization within the preceding 3 months or current hospitalization;

• use of systemic antibacterial drugs (3rd-generation cephalosporins, 4th-generation cephalosporins, fluoroquinolones) for any reason within the preceding 3 months;

• stay in long-term care facilities (nursing home, infant home, hospice);

• hemodialysis;

• comorbidity: diabetes mellitus, liver cirrhosis, chronic kidney disease;

Risk factors for MRSA infections:

• high prevalence of MRSA in the ward where the patient is located;

• prior (within 3 months) hospitalization involving surgical interventions and invasive procedures (especially with implantation of artificial materials and/or devices);

• use of broad-spectrum systemic antibacterial drugs (fluoroquinolones, to a lesser extent 3rd-generation cephalosporins, 4th-generation cephalosporins) for any reason within the preceding 3 months;

• presence of an intravascular catheter;

• MRSA nasal carriage;

• IV drug use;

• presence of trophic ulcers or pressure sores.

Risk factors for infections caused by multidrug-resistant P. aeruginosa:

• prolonged ICU stay;

• prior therapy with cephalosporins, fluoroquinolones, and carbapenems;

• mechanical ventilation > 4 days;

• sternotomy;

• presence of bronchiectasis, cystic fibrosis;

• presence of a urethral catheter.

Risk factors for infections caused by carbapenem-resistant Enterobacteriaceae:

• prior carbapenem therapy;

• high prevalence of carbapenem-resistant Enterobacteriaceae in the ward where the patient is located;

• intestinal colonization of the patient with carbapenem-resistant Enterobacteriaceae.

Appendix A.3.4. Antimicrobial therapy regimens for MRSA infections (ICD-10 disease codes A40-A41)

Appendix A.3.5. Antimicrobial regimens for infections caused by multidrug-resistant Gram-negative pathogens (ICD-10 disease codes A40-A41)

Notes:

*Carbapenem-resistant strains are strains resistant to at least one of the listed carbapenems (ertapenem**, imipenem, meropenem**, doripenem)

MC – medical commission of a medical organization

1. In combination with baseline drugs, 1–2 drugs from this list are used.

2. Examples of antimicrobial combinations in the treatment of infections caused by carbapenem-resistant (CPR) P. aeruginosa:

   • ceftazidime+[avibactam]** + aztreonam or amikacin** or fosfomycin**;

   • ceftolozane+[tazobactam]** + amikacin** or polymyxin B** or colistimethate sodium or fosfomycin**;

   • aztreonam + polymyxin B** or colistimethate sodium or amikacin**;

   • polymyxin B** or colistimethate sodium + meropenem** or doripenem ± fosfomycin**

3. Examples of AMP combinations in the treatment of infections caused by CPR Acinetobacter spp. strains:

   • polymyxin B** or colistimethate sodium + sulbactam or ampicillin+[sulbactam]** or cefepime+[sulbactam] or cefoperazone+[sulbactam]** + tigecycline**;

   • polymyxin B** or colistimethate sodium + sulfamethoxazole + trimethoprim** or tigecycline** ± meropenem** or doripenem;

   • tigecycline** + sulfamethoxazole + trimethoprim** ± amikacin** (± meropenem** or doripenem).

Appendix A.3.6. Antimicrobial therapy regimens for invasive candidiasis (IC) and candidemia (ICD-10 disease code B37.7)

Appendix A.3.7. Stages of acute kidney injury (by KDIGO)

Note: assessment is based on one of two indicators – either changes in creatinine level or urine output rate (diuresis).

Appendix A.3.8. Absolute and relative indications for initiating renal replacement therapy in acute kidney injury

Appendix B. Physician Action Algorithms

Appendix B.1. Screening for suspected sepsis outside the ICU

Appendix B.2. Screening for suspected sepsis in the ICU

Appendix B.3. Intensive care algorithm for sepsis

Appendix B.4. Algorithm for prescribing antibacterial therapy

Appendix C. Patient Information

Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection. If not recognized early and treated promptly, sepsis can lead to septic shock, multiple organ failure, and death. Sepsis can be triggered by any type of infectious pathogen. Antimicrobial resistance to systemic antibacterial drugs is a major factor leading to clinical treatment failure and the rapid development of sepsis and septic shock. Patients with sepsis caused by drug-resistant pathogens face an increased risk of in-hospital mortality.

Sepsis can develop in anyone with an infection, but vulnerable populations are at higher risk, including the elderly, pregnant women, newborns, hospitalized patients, and individuals with HIV/AIDS, liver cirrhosis, cancer, kidney disease, autoimmune disorders, and asplenia.

Sepsis is a medical emergency. However, signs and symptoms of sepsis can vary over time because such a clinical condition can be caused by multiple pathogens and change its presentation at different stages. Warning signs and symptoms include high or low body temperature and chills, altered mental status, difficult/rapid breathing, rapid heart rate, weak pulse/low blood pressure, oliguria, cyanosis or skin mottling, cold extremities, and severe body pain or discomfort. If such signs are identified, medical assistance must be sought immediately.

Appendix G. Assessment Scales, Questionnaires, and Other Evaluation Tools

Appendix G.1. SOFA organ dysfunction scoring system

Russian title: Sequential Organ Failure Assessment (SOFA) score

Original title (if applicable): Sepsis (sequential) Organ Failure Assessment (SOFA)

Source (official developers' website, validation publication): Vincent J.L, Moreno R., Takala J., Willatts S., Mendonça A.De., Bruining H., Reinhart C.K., Suter P.M., Thijs L.G. The SOFA (Sepsis-related Organ Failure Assessment) score to describe organ dysfunction/failure. On behalf of the Working Group on Sepsis-Related Problems of the European Society of Intensive Care Medicine//Intensive Care Med .1996 Jul;22(7):707-10 [38].

Type (underline):

• rating scale

• index

• questionnaire

• other (specify)___________________

Purpose: to assess the severity of organ dysfunction

Content (template):

Key (interpretation):

Points are summed. Total SOFA score = sum of scores for all 6 parameters.

Possible result:

• 0 points – normal,

• 4 points – greatest deviation from normal.

Notes.

• each organ dysfunction is assessed separately over time; PaO₂ in mmHg and FiO₂ in %;

• adrenergic and dopaminergic agents administered for at least 1 hour in mcg/kg/min;

• mean arterial pressure in mmHg = (systolic BP in mmHg) + 2(diastolic BP in mmHg) / 3;

• a score of 2 or more indicates the development of multiple organ dysfunction;

• the higher the score, the greater the organ dysfunction and the more pronounced the multiple organ dysfunction.

Appendix G.2. qSOFA simplified organ dysfunction risk assessment scale

Russian title: Simplified scale for assessing the risk of organ dysfunction qSOFA

Original title (if any): quick Sequential Organ Failure Assessment (qSOFA)

Source (official developer website, validation publication): Angus D.C., Seymour Ch.W., Coopersmith C.M., Deutschman C.S., Klompas M., Levy M.M., Martin G.S., Osborn T.M., Rhee Ch., Watson R.S. A Framework for the Development and Interpretation of Different Sepsis Definitions and Clinical Criteria // Critical Care Medicine 44(3):p e113-e121, March 2016. DOI: 10.1097/CCM.0000000000001730 [41].

Type (underline):

• rating scale

• index

• questionnaire

• other (specify)___________________

Purpose: assessment of the likelihood of organ dysfunction

Content (template):

Key (interpretation):

Points are summed.

Possible result:

• a qSOFA score of 2 or more indicates a high risk of organ dysfunction;

• in the presence of an infection focus and a qSOFA score of 2 or more, appropriate organizational and therapeutic measures should be taken to confirm or rule out the development of sepsis.

Appendix G.3. Glasgow Coma Scale

Russian title: Glasgow Coma Scale

Original title (if any): Glasgow coma scale

Source (official developer website, validation publication): Teasdale G.M., Jennett B. Assessment of coma and impaired consciousness: A practical scale. Lancet, 1974 [468].

Type (underline):

• rating scale

• index

• questionnaire

• other (specify)___________________

Purpose: to assess the level of consciousness

Content (template):

Key (interpretation):

15 points – clear consciousness,

14–13 points – obtundation,

12–9 points – stupor,

8 points – mild coma,

7–6 points – moderate coma,

5 points or less – deep coma.

Note.

Scores are summed up. Possible result from 3 to 15.