Sepsis: Clinical Guidelines

Applies tochildren2025 editionA39.2, A39.3, A39.4, A40.0…

Clinical Guidelines of the Russian Ministry of Health, pediatric patients. 2025 edition, ICD-10 codes: A39.2, A39.3, A39.4, A40.0….

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Brief for Practice

WhiteCoat Pro editorial summary of the guideline text, 2025 edition. Each item links to the original section — verify against it before prescribing.

Pediatric sepsis is suspected or confirmed infection with life-threatening multiorgan dysfunction caused by dysregulated host response to infection. The guidelines focus on early clinical recognition, assessment of organ dysfunction, prompt antimicrobial therapy, hemodynamic/respiratory support, and source control.

Key points

Diagnosis of sepsis in children: suspected or confirmed infection plus progressive clinical deterioration with signs of multiorgan dysfunction; the main threshold is pSOFA ≥ 2 points. → in text
Septic shock: confirmed sepsis with cardiovascular dysfunction ≥ 1 point, persistent hypotension and lactate > 5 mmol/L despite adequate fluid resuscitation, requiring inotropic support excluding cardiac glycosides. → in text
Bacteremia is not mandatory: positive blood cultures are found in only 30–50% of patients with septic shock. → in text
In septic shock, antibiotics must be initiated within 1 hour of diagnosis; in sepsis without septic shock, within 3 hours. Recommendation grade 3, Evidence level A. → in text
In septic shock during the first hour, fluid resuscitation should not exceed 40 mL/kg, administered in 5–10 mL/kg boluses, only in the absence of signs of fluid overload. Recommendation grade B, Evidence level 2. → in text
First-line drugs for hemodynamic instability in children with septic shock are epinephrine or norepinephrine. Dopamine is not used in septic shock. Recommendation grade B, Evidence level 2. → in text
Source control is mandatory: debridement/drainage as early as possible; procedures should ideally be performed within 6–12 hours of diagnosis following initial hemodynamic stabilization. → in text

Diagnostics

First, assess clinically for infection and risk factors: oncological diseases, asplenia, bone marrow or organ transplantation, central or indwelling venous catheter, immunodeficiency, severe CNS damage, cerebral palsy. Recommendation grade C, Evidence level 5. → in text
Evaluate non-specific signs: temperature > 38.5 °C or < 36.0 °C, capillary refill time > 3 s, systolic blood pressure below age-adjusted normal by > 2 SD, respiratory rate above age-adjusted normal by > 2 SD. → in text
Calculate pSOFA score upon any suspicion of sepsis: at admission, upon transfer to the ICU, and daily thereafter in the ICU. Recommendation grade C, Evidence level 5. → in text
Baseline laboratory tests for all children with suspected sepsis: complete blood count, urinalysis, blood chemistry including electrolytes, calcium, total protein, urea, creatinine, bilirubin, glucose, ALT/AST, CRP. Minimum requirements: at diagnosis, within 1 hour of ICU admission, 72 hours after starting antibiotics, and at the end of treatment. Recommendation grade C, Evidence level 5. → in text
To assess hypoxia and the efficacy of intensive care, acid-base status/blood gases and lactate are measured every 6–12 hours; in septic shock, initial lactate is measured within the first 60 minutes of resuscitation. The lactate threshold for pediatric sepsis is 2.2 mmol/L. Recommendation grade B, Evidence level 3. → in text
In children with suspected sepsis and risk factors, blood cultures for aerobic and anaerobic susceptibility testing are drawn prior to antibiotic administration whenever possible; if antibiotics have already been initiated, draw blood immediately prior to the next dose. Blood volume for cultures is determined by weight, not exceeding 4% of total blood volume; at least two bottles are used. Recommendation grade C, Evidence level 5. → in text
Instrumental diagnostics: Echocardiography for all children with sepsis/septic shock to guide fluid and vasoactive support; chest X-ray and abdominal overview radiograph for respiratory distress; abdominal ultrasound for all patients with sepsis/septic shock. Recommendation grade C, Evidence level 5. → in text

Treatment

Initial empirical therapy consists of one or more broad-spectrum antibiotics targeting likely pathogens; the regimen is adjusted upon pathogen identification and susceptibility testing, including de-escalation. Recommendation grade 5, Evidence level C. → in text
The empirical regimen must cover gram-negative and gram-positive pathogens, and fungi in the presence of risk factors; drug selection depends on the site of infection and local resistance patterns. Recommendation grade 5, Evidence level C. → in text
Fluid resuscitation in septic shock is initiated with balanced electrolyte solutions; 0.9% sodium chloride and albumin are not used for initial volume loading, and hydroxyethyl starches are contraindicated. Recommendation grade C, Evidence level 4–5. → in text
Hemodynamic targets: mean arterial pressure not below the 50th percentile for age, and ≥ 65 mm Hg in children over 12 years; cardiac index 3.5–5.5 L/min/m², stroke volume index 30–60 mL/m², total peripheral vascular resistance index 800–1600 dyn·s·cm⁻⁵/m². → in text
In septic shock, early combination of balanced solution boluses and norepinephrine is justified; if hypotension and low cardiac output syndrome persist despite epinephrine/norepinephrine, dobutamine or levosimendan is added under cardiac output monitoring. The dose for epinephrine is specified as 0.05–0.1 mcg/kg/min. → in text
Oxygen therapy is the first line of intervention for initial stabilization and mild respiratory distress; indications include PaO2 < 60 mm Hg or SpO2 < 93% on room air. Target during CPAP/nasal cannula: FiO2 0.4–0.6 to maintain SpO2 92–95%, flow rate 1 L/kg for the first 10 kg + 0.5 L for each subsequent kg. → in text
Septic shock is an indication for invasive mechanical ventilation. Mechanical ventilation settings: tidal volume 5–8 mL/kg, 4–6 mL/kg in severe lung injury, PEEP 10–15 cm H2O in severe ARDS, plateau pressure ≤ 30 cm H2O; prone positioning ≥ 12 hours/day for refractory severe hypoxemia. → in text
Enteral nutrition is initiated within the first 24–48 hours in the absence of contraindications; by the end of the first week in the ICU, energy delivery should reach at least 70% of calculated requirements, with protein intake of at least 1.5 g/kg/day. Recommendation grade C, Evidence level 4. → in text

When to refer and how to monitor

All children with suspected or confirmed sepsis require emergency hospitalization; septic shock is an absolute indication for hospitalization. → in text
At the pre-hospital stage, a child with signs of localized infection and organ dysfunction must be evacuated to a hospital; laboratory and instrumental investigations that would delay transport should not be performed. → in text
Admission to a multidisciplinary level III pediatric hospital is preferred; if a child is admitted to a facility lacking necessary capabilities, transfer must be arranged as rapidly as possible. → in text
All sepsis patients must be admitted to the ICU, as the diagnosis implies organ dysfunction. Indications for ICU admission in suspected sepsis include hemodynamic instability, sopor, progressive respiratory failure, and the need for respiratory support. → in text
Following stabilization and normalization of hemodynamics with fluid and continuous vasoactive support, the patient should be transferred as early as possible to a specialized pediatric ICU with experience in managing such patients. → in text

Frequently asked questions

What is the main diagnostic criterion for sepsis in a child?

Suspected infection plus organ dysfunction: mpSOFA ≥ 2 points. ICU assessment is performed daily, recording the worst values over 24 hours. → in text

How does septic shock differ from sepsis?

It is sepsis accompanied by cardiovascular dysfunction: persistent hypotension and hyperlactatemia > 5 mmol/L despite adequate fluid resuscitation, requiring inotropic agents other than cardiac glycosides. → in text

When should antibiotics be initiated in pediatric sepsis?

Within 1 hour of diagnosis in septic shock, and within 3 hours in sepsis without shock. Blood cultures should be drawn prior to starting therapy whenever possible. → in text

How much fluid should be administered during the first hour in pediatric septic shock?

No more than 40 mL/kg during the first hour, given in 5–10 mL/kg boluses and only if there are no signs of fluid overload. The initial solution of choice is a balanced electrolyte solution. → in text

Which vasoactive drugs are considered first-line agents in pediatric septic shock?

Epinephrine or norepinephrine. Dopamine is not used in septic shock; if signs of low cardiac output occur despite epinephrine/norepinephrine, dobutamine or levosimendan may be added under cardiac output monitoring. → in text

Status: Applied · approved by the Scientific and Practical Council of the Russian Ministry of Health
Database ID: 953, edition 1 (ID 953_1)
Publication date: October 10, 2025
Age category: children
ICD-10 codes: A39.2 A39.3 A39.4 A40.0 A40.1 A40.2 A40.3 A40.8 A40.9 A41 A42.7 A49.9 B00.7 B37.7 O85 R57.2
Specialties: Anesthesiology and Critical Care Medicine Pediatrics
Developers: Association of Pediatric Anesthesiologists and Critical Care Physicians of Russia
Official text: Russian Ministry of Health Rubricator — 953_1

List of Abbreviations

BP – blood pressure

ALT – alanine aminotransferase

aPTT – activated partial thromboplastin time

AST – aspartate aminotransferase

CHD – congenital heart disease

RRT – renal replacement therapy

IMV – invasive mechanical ventilation

SVRI – systemic vascular resistance index

HNIG – Human normal immunoglobulin [IgG + IgA + IgM]

CT – computed tomography

Med – medication

INR – international normalized ratio

MIC – minimum inhibitory concentration

MRI – magnetic resonance imaging

AKI – acute kidney injury

SVR – systemic vascular resistance

ARDS – acute respiratory distress syndrome

ICU – intensive care unit

BV – blood volume

PT – prothrombin time

FDP – fibrin degradation products

PCT – procalcitonin

MOD – multiple organ dysfunction

MOF – multiple organ failure

PN – parenteral nutrition

PT – prothrombin index

PCR – polymerase chain reaction

RCT – randomized controlled trial

IHA – indirect hemagglutination assay

SV – stroke volume

FFP – fresh frozen plasma

CI – cardiac index

CRP – C-reactive protein

SIRS – systemic inflammatory response syndrome

SS – septic shock

TT – thrombin time

LCE – level of confidence of evidence

US – ultrasound examination

SI – stroke index

SV – stroke volume

GRS – grade of recommendation strength

CVP – central venous pressure

CVC – central venous catheter

CNS – central nervous system

HR – heart rate

RR – respiratory rate

ECG – electrocardiogram

EN – enteral nutrition

mpSOFA – modified pSOFA scale

PEEP – positive end-expiratory pressure – positive end-expiratory pressure

pSOFA – Pediatric Sequential Organ Failure Assessment – pediatric modification of the scale

SOFA – Sequential Organ Failure Assessment

Terms and Definitions

Local infection – presence of an infectious focus with or without clinical manifestations of systemic inflammatory response syndrome – SIRS [1-3].

Sepsis – confirmed or suspected infection with the development of life-threatening multiple organ dysfunction (MOD) of internal organs due to dysregulation of the host response to infection [1-3].

Septic shock (SS) – sepsis with severe circulatory, cellular, and metabolic abnormalities persisting despite adequate fluid resuscitation and vasopressor therapy, and characterized by a higher risk of death compared to sepsis [1-3].

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

As criteria for internal organ dysfunction in children with sepsis / SS, it is advisable to use the pediatric SOFA scale – pSOFA (Pediatric Sequential Organ Failure Assessment), which is designed to assess the functional state of six organ systems: CNS, cardiovascular, respiratory, hematologic, hepatobiliary, and urinary systems [4].

The main criterion for sepsis in children is a progressive worsening of the condition with manifestations of multiple organ dysfunction and a pSOFA score ≥ 2 points against the background of suspected or confirmed infection.

SS is characterized by the need for inotropic agents (ATC C01C: Cardiac stimulants, excluding cardiac glycosides) to maintain the mean arterial pressure corresponding to age-specific reference values according to the pSOFA scale (despite adequate fluid resuscitation) and persistent hyperlactatemia. Cardiovascular dysfunction criteria from the Phoenix Sepsis Score should be used as criteria for SS [2].

The criterion for SS in children is the presence of confirmed infection / sepsis and cardiovascular dysfunction (score of 1 or more on the modified pSOFA scale) manifested by persistent arterial hypotension and hyperlactatemia (greater than 5 mmol/L) despite adequate fluid resuscitation, which requires the administration of inotropic agents, excluding cardiac glycosides (ATC C01C).

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

Sepsis can be caused by bacterial, fungal, viral, and parasitic pathogens, although the host response due to dysregulation of the body's response to infection is primary [5]. Bacteremia is not mandatory for the diagnosis of sepsis; positive blood cultures occur in only 30-50% of patients with septic shock [6].

It has been established that mortality in children with confirmed bacteremia in the absence of organ dysfunction is close to zero and increases to 17% with dysfunction of any organ, confirming the distinction between "infection" and "sepsis", which is defined as infection with organ dysfunction [7].

Pathogenesis

Sepsis has a complex pathogenesis and diverse non-specific clinical manifestations occurring in heterogeneous patient groups, making a simple and objective definition challenging [8].

The pathophysiology of septic shock is not fully understood, but it is believed to involve a complex interaction between the pathogen and the host immune system. While a normal physiological response to localized infection involves the activation of host defense mechanisms resulting in an influx of activated neutrophils and monocytes, release of inflammatory mediators, local vasodilation, increased endothelial permeability, and activation of coagulation pathways, in sepsis/septic shock these reactions occur on a systemic scale, leading to diffuse endothelial destruction, vascular permeability, vasodilation, and microvascular thrombosis in target organs [9]. Gram-positive and Gram-negative bacteria induce numerous pro-inflammatory mediators, including cytokines, which play a key role in the initiation of sepsis and shock [10].

The exact mechanisms of cell damage and, consequently, organ dysfunction in patients with sepsis are also not fully understood. MOD is associated with widespread endothelial and parenchymal cell injury occurring via the following hypothesized mechanisms:

Hypoxic hypoxia – septic circulatory impairment disrupts tissue oxygenation, alters the metabolic regulation of tissue oxygen delivery, and contributes to organ dysfunction.
Direct cytotoxicity – endotoxin, TNF-α, and NO can induce impairment of mitochondrial electron transport, leading to disrupted energy metabolism.
Apoptosis (programmed cell death) – disruption of apoptosis plays a critical role in tissue damage in patients with sepsis.
Immunosuppression. The interaction between pro-inflammatory and anti-inflammatory mediators can lead to imbalance and an inflammatory response; immunodeficiency may predominate, or both may occur simultaneously [11].

1.3 Epidemiology of the Disease or Condition

The prevalence of sepsis in children varies depending on the diagnostic criteria used, study methodology, clinical and demographic characteristics of the population, level of socioeconomic development, and healthcare system [12].

Sepsis and SS are considered the leading cause of death from infection in childhood [13]. At the same time, the prevalence of sepsis in children varies up to 7-fold depending on the tactics used to detect the disease [14]. In the international multicenter SPROUT study, the prevalence and mortality of severe sepsis were evaluated in 6,925 children across 128 pediatric ICUs from 26 countries. The authors reported a high prevalence of sepsis in pediatric ICUs at 8.2%. Furthermore, a wide variation in the prevalence of severe sepsis among children across different continents was observed, ranging from 6.2% in Europe to 23.1% in Africa (p < 0.001). Overall regional mortality varied geographically: 21% in North America, 29% in Europe, 32% in Australia/New Zealand, 40% in Asia, 11% in South America, and 40% in Africa. Significantly, among survivors, one-fifth of children exhibited moderate functional disability after hospital discharge. Overall, it was demonstrated that in a pediatric ICU with 16 beds or more, a child with sepsis is very likely to be present [15].

In a recent meta-analysis on the epidemiology of sepsis, the incidence in children in Europe was 48 cases, and for severe sepsis, 22 cases per 100,000 population per year. Overall, the authors estimated an incidence of 1.2 million cases of pediatric sepsis per year. Pediatric mortality from severe sepsis ranged from 9% to 20%. It should be noted that this systematic review did not include studies from low-income countries, where the incidence and mortality of sepsis in children are likely higher [16]. Overall, mortality from sepsis in children ranges from 4% to 50%, depending on disease severity, risk factors, and geographical location [17]. Importantly, nearly 25% of children surviving sepsis experienced a clinically significant reduction in health-related quality of life – one in three survivors was discharged with a disability, and 24% of previously healthy children were discharged with some form of disability [18].

1.4 Features of Coding the Disease or Condition

In the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision, the diagnosis of "Sepsis" is coded under the following categories:

B37.7 – Candidal sepsis

A39.2 – Acute meningococcemia

A39.3 – Chronic meningococcemia

A39.4 – Meningococcemia, unspecified

A42.7 – Actinomycotic sepsis

O85 – Puerperal 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

The category "Other sepsis (A41)" includes:

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 (gas gangrene (A48.0) excluded)

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

A41.8 – Other specified sepsis

A41.9 – Sepsis, unspecified

A49.9 – Bacterial infection, unspecified

B00.7 – Disseminated herpesviral disease

If the patient has septic shock, an additional code is added to the primary code: R57.2 – Septic shock.

According to the International Classification of Diseases, Eleventh Revision, proposed at the 144th session of the Executive Board in January 2019 and approved at the 72nd World Health Assembly (WHA) in May 2019, the diagnosis of "sepsis" can be classified under the following categories [19]:

01 Certain infectious or parasitic diseases (1A00-1K6Z)

Sepsis due to certain bacteria (1C30-1C35):

1C30 – Sepsis due to group A streptococci

1C31 – Sepsis due to group B streptococci

1C32 – Sepsis due to Staphylococcus aureus

1C33 – Sepsis due to Escherichia coli

1C34 – Sepsis due to anaerobic bacteria

1C35 – Sepsis following complicated delivery

1D30-1D3Z – Meningococcal sepsis

19 Certain conditions originating in the perinatal and neonatal period:

KA70 – Fetus or newborn sepsis

The transition to the new classification has been recommended by the WHO since January 1, 2022; the transition period has been extended until 2027.

1.5 Classification of the disease or condition

Currently, there is no universally accepted classification of sepsis in children. The previously used approach to classifying sepsis based on the presence and localization of the primary infection focus, as well as the type and nature of the pathogen, has completely lost its relevance [5].

1.6 Clinical presentation of the disease or condition

There is no typical clinical picture of sepsis. Symptoms vary depending on the child's age and the localization of the infection focus. Nonspecific symptoms and signs are usually detected, especially in infants.

Sepsis may initially present with nonspecific, non-localized symptoms, such as feeling very unwell in the presence of a normal temperature. If a child has signs or symptoms suggestive of a possible infection, regardless of temperature, sepsis should be considered.

Initial evaluation includes identifying the likely source of infection, detecting risk factors for sepsis (e.g., very young age (< 1 year); recent trauma, surgery, or invasive procedure; immune deficiency due to illness or medication use; maternal infection during the perinatal period (e.g., maternal group B streptococcal infection); indwelling catheter or any skin integrity disruption (e.g., cuts, burns, blisters, or skin infections)), as well as determining clinical red flags such as behavioral, circulatory, or respiratory abnormalities.

Although laboratory tests (e.g., blood cultures, biomarkers) are useful for confirming the diagnosis, the diagnosis must first be established based on clinical evaluation. Diagnostic criteria from international consensus guidelines are primarily intended as research criteria designed to facilitate informative research. Research criteria and clinical evaluation do not always align: up to one-third of patients with clinical sepsis do not meet the research diagnostic criteria.

2. Diagnostics, medical indications and contraindications for diagnostic methods

Diagnostic criteria for sepsis

2.1 History and symptoms

The presence of symptoms of proven or suspected infection is a strong rationale for verifying sepsis in children.

2.2 Physical examination

➣ fever (body temperature > 38.5°C);

➣ hypothermia (body temperature < 36.0°C);

➣ capillary refill time > 3 s;

➣ systolic blood pressure below the age-adjusted norm by two standard deviations;

➣ respiratory rate above the age-adjusted norm by two standard deviations.

Organ function impairment: the severity of organ dysfunction is determined using the pSOFA score (at least one symptom from the four highlighted symptom groups).

2.3 Laboratory diagnostic tests

▪ Leukocytosis (blood leukocyte count > 12 x 10⁹/L).

▪ Leukopenia (blood leukocyte count < 4 x 10⁹/L.

▪ Blood procalcitonin ≥ 0.5 ng/mL.

▪ C-reactive protein > 20 mg/L.

▪ Absolute neutrophil count > 10,000/mm³.

▪ Thrombocytopenia or thrombocytosis.

▪ Blood glucose lability: hypo- (< 2.6 mmol/L) or hyperglycemia (> 10 mmol/L).

▪ Metabolic acidosis, significant base excess (BE > (– 4 mmol/L).

▪ Lactic acidosis (blood lactate level greater than 2 mmol/L).

▪ Positive blood culture results for sterility (isolation of microorganism cultures).

2.4 Organ dysfunction: to assess the severity of organ dysfunction and the probability of a fatal outcome in pediatric sepsis, it is advisable to use the pSOFA (Pediatric Sequential Organ Failure Assessment) score or its modified version (see Appendices G1-G3) [4].

In 2024, the Society of Critical Care Medicine (SCCM), based on an expert panel conclusion, recommended identifying sepsis in children with suspected infection when the Phoenix Sepsis Score is ≥ 2 points, indicating potentially life-threatening organ dysfunction. Unlike the pSOFA score, the Phoenix Sepsis Score is based on evaluating dysfunction criteria across four systems: cardiovascular, respiratory, neurological, and hemostatic.

The diagnosis of "Sepsis" is established in the presence of suspected infection and an mpSOFA score ≥ 2 points. The diagnosis of "Septic shock" is established in the presence of confirmed sepsis and a cardiovascular dysfunction severity score ≥ 1 point [2].

Evaluation using multiple organ dysfunction scores in children admitted to the ICU is performed daily by summing the scores of organ systems (respiratory, cardiovascular, hematologic systems, etc.). For each system, the worst score recorded within 24 hours is selected. As the score increases, the likelihood of an unfavorable course and mortality rises.

2.1 Complaints and Anamnesis

When sepsis is suspected, it is recommended to thoroughly review the patient's medical history and the course of the disease to identify risk factors for sepsis development [1, 2, 17, 20].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comment: risk factors for sepsis in children include oncologic diseases, asplenia, bone marrow transplantation, central or permanent venous lines, solid organ transplantation, immunodeficiency states, severe central nervous system lesions, and cerebral palsy.

2.2 Physical Examination

All children with suspected sepsis are recommended to undergo a physical examination [1, 2, 17, 20, 21].

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5)

Comment: all symptoms of sepsis and septic shock in children are nonspecific and reflect the presence of multiple organ dysfunction.

To assess the severity of the condition and the degree of multiple organ dysfunction in children with sepsis and septic shock, it is recommended to use the pSOFA score [22, 23].

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5)

Comment: the pSOFA score should be evaluated upon any suspicion of sepsis: upon admission to the hospital, upon transfer to the ICU, and every 24 hours of treatment in the ICU.

2.3 Laboratory Diagnostics

All children with suspected sepsis are recommended to undergo the following laboratory tests to verify the systemic (generalized) infectious-inflammatory process and confirm the diagnosis: complete blood count (CBC) with differential, urinalysis, general clinical blood chemistry (levels of sodium, potassium, total and ionized calcium, total protein, urea, creatinine, total bilirubin, glucose, alanine aminotransferase, and aspartate aminotransferase activity in the blood), and serum C-reactive protein. All laboratory tests must be performed at least three times: at the time of diagnosis, within one hour of ICU admission, 72 hours after the start of antibacterial therapy, and after completion of the treatment course [1, 2, 17, 20, 21].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comment: in the event of patient instability and/or sudden deterioration, the decision regarding the need for additional laboratory testing is made individually, taking into account the clinical course of the disease.

All children with sepsis and septic shock are recommended to undergo a coagulation profile (exploratory hemostasis testing) and a platelet count to rule out coagulopathy, determine management tactics, and assess treatment efficacy [24, 25].

GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)

Comment: coagulopathy is a constant companion of severe infections, sepsis, and septic shock, and is associated with an unfavorable outcome.

To assess the severity of tissue hypoxia and the efficacy of intensive care measures, all children with sepsis and septic shock are recommended to undergo acid-base balance and blood gas analysis, along with blood lactate measurement in capillary (venous or arterial) blood every 6–12 hours, provided the necessary equipment is available [26-35].

GCR BLoE 3Level of Evidence B (Level of Confidence of Evidence – 3)

Comment: in children with sepsis and septic shock, several studies have demonstrated that an increase in initial blood lactate levels correlates with increased mortality, while its subsequent decrease correlates with reduced mortality in septic shock [26-28]. In addition, a decrease in blood lactate during intensive care in children with sepsis and septic shock is associated with a shorter duration of hemodynamic support and hospital stay [29-33]. Thus, normalization of lactate clearance indicates successful intensive care, whereas a continuing increase in lactate levels indicates treatment failure. Jan Bakker et al. believe that hyperlactatemia has a stronger association with mortality than any other biochemical marker [34]. The threshold serum lactate level in children with sepsis is considered to be 2.2 mmol/L [16]. It is recommended to perform the initial blood lactate test within the first 60 minutes after the initiation of resuscitation in septic shock, and lactate measured by any method, including whole blood and blood gas measurements (arterial, venous, or capillary), is considered acceptable [35].

In all children with sepsis, it is recommended to measure blood procalcitonin levels every 1–3 days to assess treatment efficacy and make informed decisions regarding the adjustment or discontinuation of antimicrobial therapy [36-39].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comment: an elevated procalcitonin (PCT) level is specific to bacterial infections, and the results obtained correlate with disease severity. In fungal and viral infections, PCT levels do not increase significantly, allowing this test to be used for differential diagnosis. One study evaluated the possibility of reducing antibiotic use in critically ill children with systemic inflammatory response syndrome. The algorithm involved discontinuing antibiotics after 24–48 hours if the PCT level was < 1 ng/mL, the CRP level was < 4 mg/dL, microbiological cultures were negative, and the patient's clinical evaluation showed no focus of infection. Implementation of this algorithm led to a significant reduction in the duration of antibiotic therapy in the patient group whose PCT and CRP levels were below the specified thresholds. This study demonstrated the potential utility of blood PCT determination for ensuring safe antibiotic de-escalation in pediatric patients with a low risk of bacterial infection [36]. PCT is a specific marker of bacterial infection. Its normal concentration (typically ≤ 0.1 ng/mL) indicates a low probability of bacterial infection and no need for antibiotic therapy. In doubtful cases, it is recommended to repeat testing after 4–6 hours to rule out the "grey zone" effect [37].

During antibiotic therapy, clinical and laboratory parameters, including microbiological data and infection biomarkers, should be evaluated daily to determine treatment efficacy and decide on the possibility of regimen adjustment, de-escalation, or discontinuation of antibiotics. A decrease in PCT levels during ongoing therapy indicates its effectiveness. The absence of positive dynamics or an increase in PCT levels compared to baseline indicates the need to revise the treatment regimen (primarily, the adjustment of antibiotic therapy) [38].

Along with PCT, other biomarkers may have a certain value in assessing the effectiveness of antibiotic therapy, in particular, C-reactive protein (CRP). Its use is limited by low specificity. An increase in plasma CRP levels during an inflammatory response occurs regardless of the causes of its development [39].

Microbiological diagnosis of sepsis

In all children with suspected sepsis who have risk factors, it is recommended to perform a microbiological (culture) blood test for sterility with determination of antimicrobial susceptibility to identify the causative agent and determine the tactics of antibacterial therapy [17].

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5)

Comment: microbiological (culture) blood testing for sterility is the primary method for detecting bacteremia, allowing identification of the pathogen, determination of its susceptibility to antibacterial drugs, and selection of an adequate treatment regimen. To ensure maximum sensitivity, blood samples for culture should, whenever possible, be obtained before starting antimicrobial therapy [17]. If this is not possible, blood for culture should be drawn immediately before the administration of the next antibiotic dose, when the concentration of the drug in the blood is at its minimum.

Blood samples for verifying bacteremia are obtained by peripheral venipuncture while observing aseptic and antiseptic rules. Sampling through a vascular catheter is permitted only when catheter-related bloodstream infection is suspected or when venipuncture is technically impossible. The use of arterial blood for culture offers no advantages over venous blood. An important aspect for obtaining optimal blood culture results is taking a sufficient volume of blood for analysis, as well as using an approach that differentiates sample contamination from true bacteremia. The blood volume for culture should not exceed 4% of the circulating blood volume (CBV) and is determined based on the patient's body weight – Table 1 [40].

Table 1. Recommended blood volume for culture in children

Body weight, kg	Total blood sample volume, ml	Number of bottles, pcs.
< 3,9	1	2
4-7,9	3	2
8-13,9	6	2
14-18,9	12	4
19-25,9	16	4
26-39,9	20	4
40-53,9	32	4
> 54	40	4

In patients with higher body weight, the recommended total volume of test samples corresponds to that for adult patients – 40–60 ml.

It is preferable to use blood culture bottles containing antimicrobial-absorbing resins intended for use in pediatric practice [41].

For a single microbiological (culture) blood test for sterility, it is recommended to use at least two bottles, between which the blood sample is evenly distributed. Whenever possible, a single bottle should not be used, as this leads to testing an insufficient volume of blood, creates the risk of missing a significant number of bacteremia cases, and makes it impossible to rule out sample contamination [42].

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 necessary for microorganism multiplication; additional time is required to identify the pathogen and determine its antibiotic susceptibility. 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 about microbial growth, as well as Gram-stain microscopy data of the primary blood culture, provide exceptionally important information for optimizing antibiotic therapy.

Depending on the diagnosed or suspected focus of infection, in addition to the microbiological (culture) blood test for sterility, the prompt collection of appropriate biological material samples for microbiological testing (e.g., sputum, tracheal aspirate, bronchoalveolar lavage, urine, cerebrospinal fluid, drainage discharge, etc.) should be ensured.

It is possible to significantly speed up the pathogen identification result in a primary blood culture or pure culture of microorganisms using MALDI-ToF mass spectrometry [43]. In addition, real-time PCR-based molecular methods can be used to accelerate etiological diagnosis.

In all children with sepsis / septic shock, depending on the identified or suspected focus of infection, it is recommended to perform a microbiological (culture) examination of the corresponding biological material (sputum, lavage fluid, cerebrospinal fluid, urine, pleural fluid, pericardial fluid, etc.) for aerobic and facultatively anaerobic microorganisms to verify the pathogen and determine the tactics of antibacterial therapy [44-47].

Level of Recommendations CLevel of Evidence 3Level of Recommendation C (Level of Evidence – 3)

Comments: It is not recommended to take skin surface swabs for culture in the absence of clinical signs of a localized skin and soft tissue infection. When central nervous system (CNS) infection is suspected, it is advisable to perform microbiological (culture) blood testing for sterility and microbiological (culture) cerebrospinal fluid testing for aerobic and facultatively anaerobic opportunistic microorganisms [46]. In critically ill children who exhibit significant deterioration of circulatory or respiratory function in response to external stimuli, performing a lumbar puncture may be postponed until their condition stabilizes [46, 47].

2.4 Instrumental Diagnostics

To optimize infusion, inotropic, and vasopressor support, all children with sepsis and septic shock are recommended to undergo echocardiography [48, 49].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comment: Timely diagnosis of septic shock in children is complicated by the fact that sepsis develops against the background of physiological characteristics inherent to a child. At the same time, the clinical manifestations of sepsis may overlap with those of hemodynamic disorders in congenital heart defects, the instrumental diagnosis of which may not always be feasible at the initial stage of therapy. Therefore, misdiagnosing septic shock and administering massive fluid therapy in decompensated congenital heart defects can have catastrophic consequences for the patient.

Performing echocardiography prior to initiating hemodynamic support makes it possible to exclude a ductus-dependent critical congenital heart defect, hemodynamically significant pericardial effusion, verify hypovolemia, myocardial dysfunction, peripheral vasodilation, persistent pulmonary hypertension, intra- and extracardiac shunts, as well as the direction of the shunt.

In all children with sepsis and clinical signs of respiratory distress, chest X-ray and plain abdominal radiography are recommended to rule out infiltrative changes in the lungs, pneumothorax, comorbidities, and congenital malformations [1, 2, 17, 20, 21].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comment: Respiratory distress associated with pneumonia is the most common clinical manifestation of early neonatal sepsis, which necessitates radiological imaging to assess the severity of infiltrative changes and rule out potential complications.

In all children with sepsis and septic shock, a comprehensive abdominal ultrasound is recommended to rule out internal organ pathology and ongoing bleeding [1, 2, 17, 20, 21].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comment: In children with sepsis and septic shock, acute abdominal conditions requiring emergency surgery and central nervous system infections must be strictly ruled out, as peritonitis and meningitis are the most common causes of sepsis manifestation in pediatric practice.

In all children with sepsis or suspected sepsis and septic shock, 24-hour bedside monitoring of vital functions and parameters (heart rate, respiratory rate, peripheral arterial blood pressure, blood oxygen saturation, general thermometry, and urine output measurement) is recommended for the timely administration of symptomatic and pathogen-directed therapy [1, 2, 17, 20, 21].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

2.5 Other Procedures

When prescribing medications to children with sepsis and septic shock that are used in accordance with indicators (characteristics) not specified in the drug's instructions for use (off-label), a consultation with a clinical pharmacologist is recommended to prevent adverse drug reactions [50-52]. If it is necessary to prescribe medications in a dosing regimen or for indications not registered in the Russian Federation, a medical committee conclusion is required, subject to obtaining informed consent from the parents or legal representatives of the patient.

poziom wiarygodności zaleceń 5 (poziom wiarygodności dowodów – C)

Comment: A prospective randomized double-blind study demonstrated that the involvement of a clinical pharmacologist in the treatment of patients in the ICU helps reduce the incidence of adverse drug reactions [51, 52].

In accordance with Decree of the Government of the Russian Federation No. 1799 dated October 27, 2023, "On Approval of Requirements for a Medicinal Product Registered in the Territory of the Russian Federation Used in Accordance with Indicators (Characteristics) of the Medicinal Product Not Specified in its Instructions for Use, the Inclusion of Which is Permitted in Standards of Medical Care for Children and Clinical Guidelines," the following requirements apply:

– the efficacy and safety of using the medicinal product in accordance with indicators (characteristics) not specified in its instructions for use are confirmed by research data published in scientific publications and/or clinical case descriptions posted in the Russian Science Citation Index database and/or in "White List" journals for each departure from the instructions regarding indications for use, and/or dosing regimen, and/or route of administration, and/or drug-drug interactions and other types of interactions;

– indication of the efficacy and safety of the medicinal product's use is confirmed by its inclusion in recommendations adopted by international professional organizations.

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

3.1 Conservative Treatment

3.1.1 Antimicrobial Therapy

In children with septic shock, antimicrobial therapy is recommended to be initiated no later than 1 hour after diagnosis [17, 55, 56].

Level of recommendation validity 3 (level of evidentiary reliability – A)

In children with sepsis without signs of septic shock, antimicrobial therapy is recommended to be initiated no later than 3 hours after diagnosis [17, 55, 56].

Level of recommendation validity 3 (level of evidentiary reliability – A)

Comment: antibiotics are the only group of medications whose action is directed specifically against the causative agent of sepsis, and there is a strong biological rationale for initiating antimicrobial therapy as early as possible in patients with sepsis [53]. A number of studies have shown improved outcomes in pediatric sepsis through the implementation of an intensive care bundle that includes early initiation of intravenous antibiotic therapy [53, 54]. There is a correlation between the time of initiation of antibiotic therapy and disease outcome in patients with sepsis and septic shock. A cohort study involving 1,179 patients aged 18 years or younger with sepsis (69% of whom had septic shock) investigated the effect of implementing a diagnostic and treatment bundle (blood culture sampling, antibiotic administration, and intravenous fluid bolus of 20 ml/kg) within 1 hour of diagnosis, demonstrating a statistically significant reduction in mortality. However, the isolated administration of antibiotics within 1 hour of sepsis diagnosis was not accompanied by a statistically significant reduction in mortality [55]. Another retrospective study involving 130 children with sepsis found that delaying antibiotic therapy by 3 hours or more leads to a significant increase in mortality [56]. Thus, initiating antimicrobial therapy within 3 hours of sepsis diagnosis (within 1 hour for septic shock), despite the lack of rigorous evidence, can be considered a recommended intervention in relevant conditions [17]. An important aspect in this regard is also conducting adequate clinical and laboratory diagnostics that allow for the prompt identification of patients with sepsis and the initiation of intensive care for this condition.

Immediately after diagnosis, all children with sepsis / septic shock are recommended to receive empirical antimicrobial therapy using one or more broad-spectrum agents targeting the most likely pathogens. Following pathogen identification and susceptibility testing, adjustment of empirical antimicrobial therapy with potential de-escalation is recommended [57, 58].

Level of recommendation validity 5 (level of evidentiary reliability – C)

Comment: a recent trend has been a significant increase in the proportion of gram-negative bacteria in the structure of nosocomial pathogens. According to the national antimicrobial resistance map (www.amrmap.ru), in 2020–2022 they accounted for 86% of all hospital-acquired infection pathogens in patients under 18 years of age. Specifically, enterobacteria accounted for 52% of all pathogens, Pseudomonas aeruginosa for 25%, and Acinetobacter for 8%. These microorganisms exhibit diverse antibiotic resistance mechanisms that often act in combination, enabling them to effectively withstand most agents currently available in clinical practice. The high frequency of extended-spectrum β-lactamase (ESBL) production in enterobacteria (especially K. pneumoniae) has shifted carbapenems from reserve drugs to the drugs of choice in treating infections caused by these pathogens [57]. Their widespread and frequently irrational use has driven the emergence and spread of carbapenem resistance. Infections caused by carbapenem-resistant non-fermenting gram-negative bacteria, primarily P. aeruginosa and A. baumannii, also present a major challenge. Gram-negative bacterial resistance to carbapenems is driven by various mechanisms and their combinations, including impaired cell wall permeability, efflux pumps, and enzymatic inactivation, where carbapenemase production plays a pivotal role. According to the Ambler classification, beta-lactamases are divided into 4 molecular classes: serine β-lactamases (A, C, D) and metallo-β-lactamases, which feature a zinc atom in their active site (B). AmpC-type enzymes (molecular class C), characteristic of enterobacteria and P. aeruginosa, predominantly exhibit cephalosporin hydrolysis.

Class A includes a range of enzymes with varying substrate profiles, including ESBLs (which confer resistance in enterobacteria to all beta-lactam antibacterials except carbapenems), as well as KPC and GES carbapenemases found in enterobacteria and P. aeruginosa. Class D includes OXA-type carbapenemases characteristic of the order Enterobacterales and Acinetobacter species. Metallo-beta-lactamases are found predominantly in P. aeruginosa (VIM) and enterobacteria (NDM); they possess a broad spectrum of hydrolytic activity, including against carbapenems, but are inactive against monobactams. When microbes produce carbapenems, carbapenem monotherapy is inappropriate, even in the presence of in vitro phenotypic susceptibility. At relatively low MIC values (≤ 8 µg/mL) for meropenem**, combination regimens may be used in certain cases, including high-dose meropenem** combined with amikacin**, fosfomycin**, #tigecycline** (for severe/complicated intra-abdominal infections), or polymyxins as combination partners [59–61].

At high meropenem MICs, combination therapy based on polymyxins may be administered [58]. In cases of enterobacterial resistance to carbapenems mediated by serine carbapenemase production—even with co-production of ESBLs—Ceftazidime + [Avibactam]** demonstrates high efficacy. In the event of metallo-enzyme production (which exhibits high hydrolytic activity, is not inhibited by avibactam) or the simultaneous production of multiple carbapenems with potential co-production of other beta-lactamases, a combination of Ceftazidime + [Avibactam]** and aztreonam administered concurrently and synchronously may be used. This combination is active against ESBL producers as well as serine and metallo-carbapenemases. Ceftazidime + [Avibactam]** also retains activity against a number of P. aeruginosa strains, including those producing molecular class GES serine carbapenemases. Modern hospital isolates of A. baumannii exhibit high-level resistance to most antibiotic classes, including carbapenems and sulbactam. Polymyxins show high in vitro activity, and some isolates may be susceptible to co-trimoxazole**. For infections caused by gram-positive microorganisms, there is an increasing clinical significance of methicillin-resistant staphylococci and multidrug-resistant enterococci, which are resistant to all beta-lactam antibacterials, including penicillins. These microorganisms also show associated resistance to other antibacterial agents (macrolides, aminoglycosides, etc.). Vancomycin** remains the baseline antibiotic for problem coccal infections; however, recent evidence indicates insufficient efficacy of this drug in severe infections caused by staphylococci that are formally susceptible yet exhibit elevated vancomycin** MICs (especially at MIC ≥ 2 µg/mL). In such cases, as well as in staphylococcal and enterococcal resistance to or intolerance of standard therapy, alternative agents are indicated (specifically linezolid**, daptomycin**, and in some cases teicoplanin). Invasive fungal infections show a trend toward increasing clinical importance of Candida non-albicans species with reduced susceptibility to fluconazole**. The most effective drugs in this setting are caspofungin** and micafungin** [58].

When providing empiric antimicrobial therapy for sepsis and septic shock in children, it is recommended to prescribe agents active against gram-negative and gram-positive pathogens, and—in the presence of risk factors—fungi as well [17].

Level of recommendation validity 5 (level of evidentiary reliability – C)

Comment: drug selection is guided by the localization of the infection focus and the susceptibility profile of the most probable causative agents, determined through microbiological monitoring of the primary flora in a specific department and/or facility. Therapy is adjusted once microbiological test results (blood and focal material) become available. Beyond the appropriate choice of drugs based on their spectrum of activity and infection site, the rational antibiotic therapy issue involves a critical yet often overlooked aspect regarding correct antibiotic dosing regimens. Sepsis can cause bidirectional changes in the pharmacokinetics and pharmacodynamics of systemic antimicrobials. Suboptimal concentrations of systemic antimicrobials in the blood and body tissues can lead to reduced or completely absent therapeutic efficacy and the emergence of resistant pathogen strains. Overdosing on certain agents is equally dangerous, as it can cause toxic adverse effects (specifically nephrotoxicity or hepatotoxicity). The ultimate outcome in both cases is worsened clinical treatment results and increased economic costs. The issue of adequate antibiotic dosing is of paramount importance in patients with multiple organ dysfunction syndrome (MODS) or at high risk for developing it, as well as in patients undergoing various extracorporeal detoxification methods. Detailed information regarding current recommended rules and regimens of antibiotic therapy can be found in relevant guidelines [57, 58].

In children with sepsis / septic shock receiving systemic antimicrobials, it is recommended to perform daily evaluations of clinical and laboratory data to de-escalate antimicrobial therapy [57].

Level of recommendation validity 5 (level of evidentiary reliability – C)

Comment: the irrational use of antibiotics in healthcare and agriculture has led to the emergence and spread of microorganisms resistant to systemic antimicrobial drugs, which has become a global problem [62]. Optimizing indications and shortening the duration of antimicrobial therapy helps reduce the risk of side effects when prescribing antibiotics. Several studies in adult patients have shown that effective and safe de-escalation of antimicrobial therapy can be achieved through daily analysis of indicators reflecting the clinical and microbiological efficacy of the ongoing therapy [63, 64]. The implementation of antimicrobial stewardship programs helps reduce the need for systemic antimicrobial drugs without adverse consequences for patients. Such programs may include a range of approaches, such as discontinuing systemic antimicrobial drugs in the absence of signs of infection, switching from intravenous to oral drugs, adapting the activity spectrum of the drugs used to the pathogen susceptibility profile, scheduling the next efficacy assessment or discontinuation date of antibiotic therapy, as well as outpatient parenteral antimicrobial therapy [65]. The de-escalation of antimicrobial therapy should be based on an adequate clinical assessment of the patient's condition and be tailored to the local epidemiological situation and pathogen resistance profile.

The duration of antimicrobial therapy in children with sepsis / septic shock is recommended to be determined based on the site of infection, etiology, efficacy of the ongoing therapy, and the possibility of eliminating the source of infection [16, 17, 66].

Level of recommendation 4 (Evidence level – C)

Comment: the main goal of antimicrobial therapy in children with sepsis is a rapid reduction in microbial load and the prevention of infection recurrence. The optimal duration of antimicrobial therapy may vary depending on the localization of the infection focus, the possibility of its sanitation/drainage, the level of microbial load, the ability to achieve adequate antibiotic concentrations at the focus, pathogen characteristics, the presence of microbial biofilms, and the adequacy of the patient's immune response. Treatment of infective endocarditis, undrained abscesses, and prosthetic joint infections typically requires longer therapy. Pathogen characteristics that may increase the optimal duration of antibiotic therapy include resistance or reduced susceptibility to first-line drugs, as well as a propensity to cause deep and/or refractory infections. Thus, while 7–10 days of therapy are sufficient to treat uncomplicated bacteremia caused by Enterobacteriaceae in immunocompetent patients, S. aureus bacteremia requires a longer course of therapy to achieve a cure. The adequacy of the patient's immune response affects the clearance of infection; therefore, antimicrobial therapy in children with neutropenia is often continued until resolution of neutropenia [66].

3.1.2 Hemodynamic Support

3.1.2.1 Volume Resuscitation

Infusion therapy in children with septic shock during the first hour after diagnosis is recommended to be administered at a volume of no more than 40 ml/kg — 5–10 ml/kg per bolus in the absence of clinical signs of fluid overload [67–69].

GRC BLEL 2Grade of Recommendation B (Level of Evidence – 2)

Comment: three randomized clinical trials on various tactics and strategies of infusion therapy in children with septic shock are known [67–69]. There was no difference in mortality between the restrictive and liberal fluid loading strategies.

In children with sepsis and septic shock, it is recommended to avoid excessive fluid administration to prevent heart failure due to volume overload [70–74].

GRC BLEL 2Grade of Recommendation B (Level of Evidence – 2)

Comment: massive infusion therapy can lead to fluid overload, which is associated with increased mortality [70]. A systematic review and meta-analysis including 44 studies found that fluid overload is associated with increased in-hospital mortality. Survivors had a lower percentage of fluid overload than non-survivors. In addition, fluid overload was associated with an increased risk of prolonged mechanical ventilation (> 48 hours) and acute kidney injury [71]. A study by Han et al. on early intensive care of sepsis and septic shock in children demonstrated that non-survivors received greater mean fluid volumes compared to survivors [72]. Samransamruajkit et al. also found that children with septic shock who died received much larger fluid volumes [73]. Chen et al. established that early fluid overload and infusion therapy in the first 24 hours after admission to the ICU were significantly associated with ICU mortality [74]. In children with sepsis, fluid overload of more than 10% within 24 hours after admission to the intensive care unit is associated with higher mortality, the need for mechanical ventilation, and longer hospital stays [75].

In the absence of arterial hypotension, intravenous bolus fluid administration as the first stage of sepsis treatment in children is not recommended [17].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comment: if it is not possible to provide adequate monitoring, hemodynamic, and respiratory support in children with signs of compensated septic shock and severe fever, infusion therapy should be performed with utmost caution.

In children with septic shock, it is recommended to use only balanced electrolyte solutions (B05XA) as the starting infusion drug [76, 77].

GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)

The use of 0.9% sodium chloride solution** and albumin** for initial fluid loading is not recommended [78].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comment: although RCTs on this issue are lacking, large observational studies demonstrate reduced mortality with the use of balanced crystalloids [76, 77]. The European Resuscitation Council recommends using balanced electrolyte solutions (B05XA) in all cases of circulatory failure in children [78]. A systematic review by Lehr et al. demonstrates evidence of improved blood pH and bicarbonate levels in critically ill children after 4–12 hours of infusion therapy with balanced solutions compared to unbalanced ones [79]. Sankar et al. demonstrate that in children with septic shock, the use of balanced electrolyte solutions (B05XA) compared to 0.9% sodium chloride solution** led to a significant reduction in the incidence or progression of acute kidney injury in the first 7 days of hospital treatment [80].

In a study by Maitland K. et al., bolus administration of albumin** and 0.9% sodium chloride solution** demonstrated higher mortality than the group without bolus therapy, whereas comparing albumin** solution infusion with 0.9% saline (RR 1.02; 95% CI 0.8–1.28) showed no difference in mortality [81].

Qian SY and Liu J. found that in children with sepsis and septic shock, hypoalbuminemia is a risk factor for mortality (p < 0.001). The frequency of hypoalbuminemia was significantly lower in survivors (69.5%) than in non-survivors (94.1%), and mortality negatively correlated with serum albumin concentration (p < 0.05) [82]. Work by Horowitz et al. demonstrates an increased duration of ICU and hospital treatment in the presence of hypoalbuminemia (albumin level < 34 g/L in children aged 7 months and older, < 25 g/L in children under 7 months) [83].

The use of hydroxyethyl starch solutions** in children with sepsis and septic shock is not recommended [17].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comment: the use of 6% hydroxyethyl starch solution** in children is not recommended because their administration is associated with a decrease in platelet count, longer ICU stay, and acute kidney injury [17].

3.1.2.2 Vasopressor and Inotropic Support

In children with sepsis and septic shock, it is recommended to maintain the mean arterial pressure at or above the 50th percentile for the appropriate age group. In children over 12 years of age, the recommended mean arterial pressure is 65 mm Hg [17, 84].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comment: most data obtained from RCTs do not demonstrate specific hemodynamic targets in children. Weiss S.L. et al., when publishing clinical guidelines for the intensive care of septic shock in children, were unable to reach a consensus to recommend a clear MAP target for children due to a lack of evidence. However, according to clinical practice, 37% of the authors of that work reported a target MAP between the 5th and 50th percentiles for age, and 45% reported a target MAP above the 50th percentile for age [17].

In children with sepsis and septic shock, it is recommended to maintain hemodynamic parameters within the following target ranges: cardiac index (CI): 3.5–5.5 L/min/m², stroke volume index: 30–60 mL/m², systemic vascular resistance index (SVRI): 800–1600 dyn·s·cm^-5/m² [85].

GCR ALOE 2Grade of Recommendation A (Level of Evidence – 2)

Comment: Pollack M.M. et al. demonstrated better survival rates in children with septic shock when hemodynamic parameters were maintained within age-specific reference ranges; achieving the therapeutic CI target of 3.3–6.0 L/min/m² led to improved survival [85].

In children with septic shock, it is recommended to use epinephrine** or norepinephrine** as first-line agents for the correction of hemodynamic disorders [17, 86].

GCR BLEL 2Grade of Recommendations B (Level of Evidence – 2)

Comment: a survey of 114 pediatric anesthesiologists-intensivists from 27 countries demonstrated that 94% of respondents also use norepinephrine** as a first-line drug [86]. Early administration of epinephrine** or norepinephrine** reduces the need for fluid loading and decreases the duration of mechanical ventilation [17, 86].

In children with septic shock, early simultaneous bolus administration of balanced electrolyte solutions (B05XA) and norepinephrine** is recommended [87, 88].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comment: early administration of norepinephrine** in children with septic shock resulted in a twofold reduction in infusion volume during the first 24 hours and a significant decrease in the duration of mechanical ventilation compared to patients in whom norepinephrine** was initiated later [86]. Early administration of epinephrine** following initial fluid resuscitation in children with septic shock was associated with better clinical outcomes compared to delayed administration: lower mortality, lower need for mechanical ventilation, and fewer additional fluid boluses compared to the group receiving delayed epinephrine** [87]. Karanvir et al. (2021) demonstrated that early administration of cardiotonic agents (ATC code C01C: cardiac stimulants excl. cardiac glycosides) helped reduce the number of fluid boluses, complications associated with fluid overload, duration of septic shock, and length of stay in the PICU, although mortality rates did not differ significantly between the groups [88]. We fully share the opinion of Davis A.L. et al. (2017), who believe that the earliest possible initiation of cardiotonic agents (ATC code C01C: cardiac stimulants excl. cardiac glycosides) is justified in children with septic shock [20].

In children with septic shock who have persistent arterial hypotension and signs of low cardiac output syndrome despite continuous infusion of epinephrine** and norepinephrine**, combining them with vasodilators (dobutamine**, #levosimendan**) under cardiac output monitoring is recommended [17, 20].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comment: currently, there are no studies evaluating the necessity and clinical efficacy of simultaneously using multiple vasoactive agents (ATC code C01C: cardiac stimulants excl. cardiac glycosides) in children with septic shock to improve myocardial contractility and maintain target blood pressure; however, according to S.L. Weiss et al. (2020), the combined use of cardiac stimulants excl. cardiac glycosides (ATC code C01C)—specifically catecholamines and inodilators—may be justified in children with low cardiac output syndrome and signs of systemic hypoperfusion [17]. This is particularly effective in the presence of clinical signs of hypoperfusion despite age-appropriate blood pressure. In this situation, the use of epinephrine** (0.05–0.1 mcg/kg/min) combined with dobutamine** or #levosimendan** is justified under cardiac output monitoring.

The use of dopamine** in children with septic shock is not recommended [89].

GCR BLEL 2Grade of Recommendations B (Level of Evidence – 2)

Comment: the use of dopamine** is associated with increased mortality (odds ratio [OR], 6.5; 95% CI, 1.1–37.8; p = 0.037) and the manifestation of healthcare-associated infections in children with septic shock (OR, 67.7; 95% CI, 5.0–910.8; p = 0.001) [89].

3.1.3 Respiratory support

Oxygen therapy in children with sepsis and septic shock is recommended as a first-line respiratory support method during initial stabilization and as maintenance therapy for mild respiratory distress to normalize oxygenation parameters [17, 20, 90].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comment: rationale: Oxygen therapy is justified in the presence of acute mixed-etiology hypoxia during initial stabilization and as a method to correct mild-to-moderate hypoxemia in patients with mild respiratory distress [17, 20, 90]. Oxygen therapy can be delivered using a wide variety of devices, the most effective being nasal cannulas for high-flow oxygen delivery and continuous positive airway pressure (CPAP).

Indications: 1) Hypoxemia (PaO₂ < 60 mm Hg, SpO₂ < 93% on room air); 2) Severe anemia; 3) Low cardiac output syndrome (in the absence of cardiogenic shock).

Contraindications: 1) Depressed level of consciousness down to coma; 2) Progressive arterial hypotension; 3) Septic shock; 4) PaO₂/FiO₂ ratio < 300 mm Hg; 5) Decompensated acidosis of any etiology (pH < 7.25); 6) Decompensated respiratory alkalosis.

Starting parameters for oxygen therapy using nasal cannulas for oxygen delivery and continuous positive airway pressure (CPAP): 1) Temperature of the oxygen-air mixture: 34–37^oC; FiO₂ = 0.4–0.6 to maintain SpO₃ = 92–95%; flow rate = 1 L/kg for the first 10 kg + 0.5 L for each subsequent kg of weight (i.e., flow rate = 10 L for a weight of 10 kg and 13 L for a child weighing 16 kg). If respiratory failure progresses, the flow rate should be increased to 2 L/kg for the first 10 kg + 0.5 L for each subsequent kg of weight (i.e., flow rate = 20 L for a weight of 10 kg and 23 L for a child weighing 16 kg). The maximum flow rate is 50 L/min. As a final reserve, increasing FiO₂ is possible. If ineffective and ARDS continues to progress, non-invasive or invasive mechanical ventilation should be used.

In all children with septic shock, invasive mechanical ventilation is recommended to correct severe gas exchange disorders [17, 20, 90].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comment: although there are currently no randomized controlled trials demonstrating the necessity of mandatory endotracheal intubation and mechanical ventilation and their unquestionable efficacy, we believe that the presence of fluid-refractory septic shock is an absolute indication for invasive respiratory support. This is due to the high risk in this patient category of progressing to acute respiratory distress syndrome and multiple organ dysfunction syndrome due to hypoxia, high metabolic rate, lactic acidosis, and fluid overload, the negative effects of which can be mitigated by aggressive respiratory support [91–95]. It should also be noted that chest X-ray findings confirming ARDS very often "lag behind" the clinical picture of disease progression, which can lead to delayed initiation of mechanical ventilation when the adverse course of ARDS is already nearly irreversible [17, 20, 94, 95].

Indications for intubation and invasive mechanical ventilation:

Septic shock.
Impaired consciousness secondary to progressive hypoxemia (in children, this may be equivalent to severe agitation).
Cyanosis and pronounced skin diaphoresis.
Severe tachypnea, appearance of areas of decreased breath sounds on lung auscultation.
Severe hypoxemia (PaO₂ < 60 mm Hg).
Severe hypercapnia (PaCO₂ > 60 mm Hg).
Decompensated respiratory alkalosis (PaCO₂ < 25 mm Hg).
Decrease in PvO₂ below 30 mm Hg.
Decrease in SvO₂ below 60%.
Oxygen extraction ratio greater than 40%.

Ketamine** and fentanyl** are recommended as drugs of choice for sedation and analgesia during endotracheal intubation in children with sepsis and septic shock. Fentanyl** should be administered in small boluses at a dose of 1–2 mcg/kg over 60 seconds. The use of long-acting hypnotic and sedative agents (ATC code N05C) with pronounced cardiodepressive effects should be avoided [20, 96, 97].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comment: anesthesia induction for tracheal intubation in patients with septic shock is very frequently associated with arterial hypotension, hemodynamic instability, and pulmonary edema against the background of systolic-diastolic myocardial dysfunction; therefore, it is preferable to use short-acting drugs (fentanyl**, ketamine**, midazolam**). To prevent hemodynamic disturbances, the administration of epinephrine** in inotropic doses (0.05–0.1 mcg/kg/min) prior to anesthesia induction is justified. If epinephrine** cannot be administered, the use of atropine** is justified, as it reduces the risk of bradiarrhythmia and is not contraindicated in sinus tachycardia [96]. Ketamine** is the primary and safest agent for anesthesia induction in children with septic shock [17, 20, 97]. Its side effects can be mitigated by intravenous bolus administration over 30–60 seconds. The use of atropine** in combination with ketamine** in children with septic shock ensures maximal hemodynamic stability. Fentanyl** is best used for analgesia, particularly in younger children, as it has no significant impact on the patient's hemodynamic status.

The use of non-invasive mechanical ventilation is recommended in children with sepsis in the absence of septic shock and other absolute indications for tracheal intubation and invasive mechanical ventilation [98-102].

GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)

Comment: the use of non-invasive respiratory support in children with sepsis and mild to moderate respiratory distress syndrome allows for the timely initiation of respiratory failure therapy and buys time for reassessment and informed clinical decision-making, taking into account the efficacy of ongoing therapy and the patient's clinical dynamics. It should be emphasized that non-invasive respiratory support is justified only in mild to moderate respiratory distress with distinct clinical improvement of the patient during ongoing therapy [98-102].

The indication for non-invasive respiratory support is the presence of signs of mild to moderate respiratory distress or respiratory failure.

Contraindications for non-invasive respiratory support are: 1) cardiac arrest; 2) hemodynamic instability, need for vasopressors; 3) septic shock; 4) coma, severe CNS disorders; 5) airway obstruction; 6) acute upper gastrointestinal bleeding; 7) intrathoracic pressure syndrome (untreated tension pneumothorax, hydrothorax); 8) decompensated acidosis of any genesis; 9) decompensated respiratory alkalosis.

Pressure-controlled or dual-controlled invasive mechanical ventilation is recommended for all children with septic shock and severe ARDS to reduce ventilator-induced lung injury [101-103].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comment: currently, there are no clear recommendations regarding the use of mechanical ventilation modes in children with sepsis or acute respiratory distress syndrome, as there is not a single randomized controlled trial demonstrating a clear correlation between the ventilation mode used and disease outcome, which is especially true for children with sepsis. Given that ARDS in the setting of sepsis is characterized by a significant decrease in respiratory system compliance and an extremely high risk of secondary lung injury during volume-controlled invasive mechanical ventilation, we recommend using pressure-controlled or dual-controlled ventilation in routine clinical practice [101-103].

In children with sepsis and septic shock requiring mechanical ventilation, it is recommended to use a tidal volume of 5–8 mL/kg to prevent volutrauma [102-104].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comment: during invasive mechanical ventilation in children with sepsis and septic shock, tidal volumes exceeding the upper limit of age-specific reference ranges should be avoided, as this may cause secondary lung injury, hyperventilation, hypocapnia, systemic vasospasm, and hemodynamic disturbances clinically and laboratory manifested by arterial hypotension and progressive lactate acidosis.

In children with sepsis and septic shock requiring mechanical ventilation who have significant pulmonary parenchymal involvement, a tidal volume of 4–6 mL/kg is recommended to prevent secondary lung injury [102-104].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comment: during invasive mechanical ventilation in children with sepsis and septic shock, tidal volumes exceeding the upper limit of age-specific reference ranges should be avoided, as this may cause secondary lung injury, volutrauma, and barotrauma, which will aggravate the pathological process.

To correct critical hypoxemia in children with sepsis, septic shock, and severe ARDS, a moderate increase in the PEEP level to 10–15 cm H₂O is recommended under the control of hemodynamic and oxygenation parameters [17, 101-104].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comment: the use of positive end-expiratory pressure allows for an increase in mean airway pressure, recruitment of collapsed alveoli, and improvement of oxygenation without increasing the fraction of inspired oxygen. However, currently, there is no single study recommending an absolute value for positive end-expiratory pressure in children with acute respiratory distress syndrome. A starting PEEP level of 8 cm H₂O is recommended for patients with moderate ARDS, and 10 cm H₂O or higher for severe ARDS. The use of PEEP above 15 cm H₂O is associated with a high risk of hemodynamic disorders and impaired cerebral venous outflow; therefore, high PEEP values are strictly contraindicated in children with severe traumatic brain injury and intracranial hypertension. Increasing PEEP above 12 cm H₂O is justified only in severe hypoxemia and should be considered a life-saving measure.

During mechanical ventilation in children with sepsis and septic shock, an inspiratory-to-expiratory ratio (I:E) of 1:1.5 to 1:2 is recommended to prevent gas trapping [92, 93, 101, 104].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comment: in children with sepsis, septic shock, and severe hypercapnic respiratory failure, inspiratory and expiratory times should be set taking into account respiratory system compliance, airway resistance, and time constants. The optimal I:E ratio is 1:2. In case of combined hypercapnia and severe hypoxemia, an I:E ratio of 1:1 is justified. Inverse ratio ventilation is not recommended. In the presence of air trapping syndrome or a high risk of its development, the expiratory time should be equal to 3–5 time constants.

In severe hypoxemia in children with sepsis and septic shock, high respiratory rate is not recommended as it may lead to the progression of hypoxemia [104].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comment: the use of a high respiratory rate in patients with hypoxemic respiratory failure can cause the progression of hypoxemia and worsening of gas exchange. This is because as the respiratory rate increases, the convection zone expands and shifts from the conductive airways into the alveolar zone, where gas exchange normally occurs via diffusion. This leads to an increase in physiological dead space, whereas a decrease in respiratory rate is accompanied by an expansion of the diffusive gas exchange zone.

During invasive mechanical ventilation in children with sepsis and septic shock, cuffed endotracheal tubes are recommended to reduce the risk of oxygen-air mixture leakage and unplanned extubation [105-107].

GRC BLEL 2Grade of Recommendation B (Level of Evidence – 2)

Comment: there is compelling evidence that the use of cuffed endotracheal tubes is safe and helps reduce the frequency of airway manipulations [105, 106]. Cuffed tubes are particularly justified in situations where respiratory system compliance is significantly reduced, as air-oxygen mixture leaks around the endotracheal tube will lead to further gas exchange impairments due to the collapse of intact alveoli. During high-frequency oscillatory ventilation, the use of cuffed tubes is also advisable as it improves carbon dioxide elimination, whereas an air-oxygen mixture leak would inevitably require increasing the mean airway pressure and amplitude. The appropriateness of cuffed endotracheal tubes is also supported by the 2020 pediatric advanced life support guidelines, which state that this approach avoids the need to replace an uncuffed endotracheal tube in the event of a large air-oxygen mixture leak and the necessity of increasing mechanical ventilation parameters [107].

During invasive mechanical ventilation in children with sepsis, septic shock, and a PEEP level of less than 10 cm H₂O, SpO₂ values are recommended to be maintained in the range of 92–97% [101, 102].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comment: when ventilating children with sepsis, septic shock, and ARDS, efforts should be made to achieve target blood gas and oxygenation values. In patients with mild-to-moderate ARDS where the applied PEEP does not exceed 10 cm H₂O, pulse oximetry readings should remain within reference ranges, although there is currently no convincing evidence that improving oxygenation leads to a more favorable outcome.

In children with sepsis and septic shock requiring invasive mechanical ventilation with SpO₂ values below 92%, monitoring of central venous oxygen saturation and oxygen status parameters is recommended. Target central venous oxygen saturation values: 65–75% [101–102].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comment: currently, there is insufficient evidence to recommend the concept of permissive hypoxemia for routine clinical practice [108, 109]. All respiratory support strategies should aim to ensure adequate tissue oxygenation while minimizing the fraction of inspired oxygen and invasive mechanical ventilation parameters, as long-term neurological outcomes using the permissive hypoxemia concept have not yet been studied, and clinicians must carefully weigh all potential risks in a given clinical situation.

The use of the permissive hypercapnia concept in children with sepsis and septic shock is recommended only in severe ARDS to minimize ventilator-induced lung injury [101, 102].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comment: the application of the permissive hypercapnia concept in routine clinical practice is a life-saving strategy aimed at minimizing invasive mechanical ventilation parameters to prevent ventilator-induced lung injury. Its use in mild ARDS is not justified [101, 102].

In severe ARDS in children with sepsis and septic shock, it is recommended to maintain pH values in the range of 7.25–7.30 to prevent lung injury [101].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comment: there is compelling data showing that emergency correction of metabolic acidosis using sodium bicarbonate** is strictly indicated to maintain pH above 7.20. This is especially important in cases of sepsis, septic shock, and ARDS, which are very frequently accompanied by decompensated metabolic acidosis that the body attempts to compensate for via respiratory alkalosis. At a pH < 7.2, further progression of metabolic acidosis can lead to a significant drop in pH. This is of major clinical significance when the blood carbon dioxide tension is at the lower limit of compensation, which is approximately 15 mm Hg in an otherwise healthy young person. In the presence of concomitant heart, lung, and kidney diseases, the compensation limit is likely lower. Specifically, in such patients, even a minor further decrease in bicarbonate concentration will not be accompanied by a decrease in blood carbon dioxide partial pressure, which can lead to very rapid decompensation.

During invasive mechanical ventilation in children with sepsis and septic shock, it is recommended to use a plateau pressure not exceeding 30 cm H₂O [101–104].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comment: in severe hypoxemia and severe ARDS, an excessive increase in plateau pressure above 28 cm H₂O will be accompanied by a deterioration in ventilation-perfusion ratios, systemic hemodynamics disorders, and the development of metabolic and lactic acidosis, necessitating the use of cardiotonic agents other than cardiac glycosides (ATC C01C); therefore, the plateau pressure should not exceed 30 cm H₂O. If the plateau pressure exceeds 30 cm H₂O, a step-by-step reduction in inspiratory pressure and positive end-expiratory pressure is indicated, keeping in mind that the target expired tidal volume must be at least 4 mL/kg. If the plateau pressure is below 30 cm H₂O and the expired tidal volume is less than 6 mL/kg, a gradual step-by-step increase in inspiratory pressure and positive end-expiratory pressure is indicated until the target expired tidal volume of 6 mL/kg is reached. If the plateau pressure is < 30 cm H₂O and patient-ventilator dyssynchrony occurs, a step-by-step increase in inspiratory pressure and positive end-expiratory pressure is indicated until the target expired tidal volume of 7–8 mL/kg is reached, while the plateau pressure must not exceed 30 cm H₂O [101–104].

In severe hypoxemia refractory to ongoing therapy in children with sepsis, septic shock, and severe ARDS, prone positioning mechanical ventilation is recommended [110].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comment: in severe hypoxemia, performing both invasive and non-invasive respiratory support in the prone position for 12 or more hours per day is justified, as it helps improve oxygenation and gas exchange. This therapeutic strategy allows collapsed alveoli to be recruited into gas exchange and increases respiratory system compliance [110]. However, this may cause a deterioration in ventilation-perfusion ratios in dependent lung regions, making it necessary to ensure adequate systemic perfusion.

The use of muscle relaxants in children with sepsis and septic shock for ventilator adaptation is recommended only during the initial stabilization phase and ventilator parameter adjustment. The use of long-acting muscle relaxants for patient-ventilator synchronization is not recommended [17, 111].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comment: the most commonly used muscle relaxants, such as suxamethonium iodide** (used from one year of age) or rocuronium bromide**, can provide optimal conditions for endotracheal intubation; however, arterial hypotension may occur even in children with adequate volume and hemodynamic support during fluid therapy and continuous infusion of catecholamines, so their use should be limited. To counteract the adverse effects of muscle relaxants, one should be prepared for intravenous bolus fluid administration and the initiation or dose escalation of cardiotonic agents other than cardiac glycosides (ATC C01C). When prolonged mechanical ventilation is required for analgesia and sedation, fentanyl** and midazolam** are the best choices. A randomized clinical trial evaluating the impact of early muscle relaxant use in children with ARDS found that this tactic may lead to prolonged mechanical ventilation [111].

3.1.4 Nutritional Support

Nutritional support in children with sepsis and septic shock is an integral component of intensive care alongside antibiotic therapy, fluid resuscitation, respiratory support, etc.

In children with sepsis and septic shock, early enteral nutrition (within the first 24–48 hours) is recommended as the optimal method of nutritional support in the absence of contraindications [112, 113].

GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)

In children with sepsis, it is recommended to step-by-step increase enteral nutrition volume to provide at least 70% of the calculated daily energy requirement by the end of the first week of ICU stay, with a recommended minimum protein intake of 1.5 g/kg/day [114, 115].

GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)

Comment: there are no studies addressing nutrition in children with sepsis and septic shock. Indirect data indicate that patients who received early enteral nutrition (EN) had lower mortality compared to those who did not, with children receiving EN at an early age having a twofold lower probability of death [112]. In another single-center randomized trial of 120 children in the ICU, half of the children received EN within 6–24 hours of admission (early group) and the other half more than 24 hours later (late group). No significant differences between the groups were found in treatment duration and outcomes, although the early EN group showed a trend toward increased survival [113]. The benefits of early EN in critically ill children are also supported by other small studies [116–120]. Regarding optimal protein dosage, Mehta N.M. et al. convincingly demonstrated that adequate protein intake during EN was associated with a significant reduction in 60-day mortality and ICU length of stay [114]. Protein targets by the end of the week were 1.9 ± 0.7 g/kg/day, and calorie targets were 69 ± 28 kcal/kg/day. In another prospective study of 76 mechanically ventilated children, the authors also justified a minimum protein dose of 1.5 g/kg/day and a calorie dose of 58 kcal/kg/day [115]. Similar data on the positive effect of early enteral nutrition on outcomes in mechanically ventilated and ARDS children are reported by other authors [121, 122].

In children with septic shock, enteral nutrition is recommended even during the infusion of cardiotonic agents (ATC C01C: Cardiac stimulants, excl. glycosides) provided that hemodynamic parameters are stable [123–125].

GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)

Comment: a series of studies in children with septic shock receiving cardiotonic agents (ATC C01C: cardiac stimulants, excl. glycosides) demonstrated the feasibility of EN without increasing side effects or gastrointestinal complications [123–125].

At the initial stage of septic shock treatment in children, hypocaloric (trophic) EN is recommended, followed by a gradual increase in volume to meet age-specific requirements [126].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comment: trophic nutrition targets the gut rather than the patient's body [126]. Its purpose is to prevent mucosal atrophy and maintain motility. Trophic nutrition continuously stimulates the intestine and reduces the risk of bacterial translocation, which is especially important in sepsis. It has been established that in critically ill children, a stepwise approach to advancing enteral nutrition reduces the time required to achieve nutritional support goals, and trophic nutrition was associated with lower gastrointestinal intolerance [127–131].

Transpyloric nutrition is recommended for children with sepsis or septic shock in whom enteral feeding is contraindicated (e.g., high risk of aspiration) or impossible [132–137].

GCR ALOE 2Grade of Recommendation A (Level of Evidence – 2)

Comment: several studies have proven the safety of postpyloric feeding in critically ill children [132, 133], as well as the ability to achieve target protein and calorie delivery significantly faster [134–137].

Parenteral nutrition in children with sepsis and septic shock is recommended starting from the 2nd–3rd day of ICU treatment only in cases where full enteral nutrition is impossible [17, 138].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comment: Parenteral nutrition (PN) should be administered when enteral nutrition (EN) is impossible or contraindicated. The timing of initiating PN should be individualized. Based on a single RCT, supplemental PN should be delayed until 1 week after ICU admission for patients with a normal baseline nutritional status and a low risk of nutritional deterioration [138]. The PEPaNIC study was conducted in three pediatric ICUs involving 1,440 pediatric and surgical patients who were randomized into 2 groups: an early PN group, where children received EN + PN during the first 24 hours, and a late PN group, where patients received EN, and PN was started only from the 8th day if their caloric intake by that time was < 80% of the EN energy requirement. Furthermore, compared with the early PN group, the late PN group had fewer new infections, a shorter duration of mechanical ventilation, and shorter ICU stays. Meanwhile, supplemental parenteral nutrition is widely used in critically ill children in whom early EN is not performed or is insufficient to achieve nutritional support goals [137, 139-145]. However, following its publication, the PEPaNIC study was heavily criticized [146-148]. The following remarks were made: 1. the study was not blinded; 2. local protocols in the three participating centers differed in their strategies for determining calorie requirements: the Canadian center used indirect calorimetry, the Dutch center used the Schofield equation, and the Belgian center used a "rule of thumb" estimate. Consequently, the target energy doses in the latter two centers clearly exceeded requirements (up to 100 kcal/kg/day), making the groups non-representative; 3. the very large number of patients included in the study was achieved while accounting for a high degree of heterogeneity regarding age (0–17 years), primary diagnoses (postoperative surgical and non-surgical), nutritional status and requirements, as well as the use of quite different nutritional strategies and products; 4. the necessity of administering PN from the first day regardless of indications, age, or tolerance to EN contrasts with modern clinical nutrition concepts and is questionable in many children—more than half of the children in the early PN group were discharged from the ICU on the 4th day, meaning a large number of patients included in the study received PN without strict indications; 5. the results obtained in the early PN group could to a significant extent be related to overfeeding—by the 8th day, they were receiving over 90 kcal/kg/day, compared to 57 kcal/kg/day in the late PN group, which may have contributed to unfavorable outcomes; 6. Finally, almost 40% of patients participating in the PEPaNIC study had infections already upon admission, so the high rate of pre-existing infections may have led to difficulties in recognizing newly emerging infections. Thus, the findings of the PEPaNIC study should be interpreted with caution. These results should hardly be extrapolated to all critically ill children and should not lead to the complete abandonment of PN until the 8th day as a universal strategy in all critically ill children [149].

3.1.5 Extracorporeal and Intracorporeal Therapy

Renal Replacement Therapy

In children with sepsis / septic shock, it is recommended to use renal replacement therapy both to replace renal function and to correct hypervolemia when diuretic therapy is ineffective [17, 150, 151].

GCR CLoE 3Grade of Recommendation C (Level of Evidence – 3)

For children with sepsis or septic shock and acute kidney injury requiring renal replacement therapy, it is recommended to use continuous renal replacement therapy, intermittent renal replacement therapy, and peritoneal dialysis [151–158].

GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)

Comment: acute kidney injury (AKI) associated with sepsis and septic shock is common in children and is associated with adverse short- and long-term treatment outcomes, carries the risk of incomplete renal function recovery with the development of chronic kidney disease, and increases mortality among hospitalized patients [17, 150, 151, 159–163].

Critically ill children are very susceptible to fluid accumulation, and fluid overload in children with sepsis and septic shock is accompanied by worsening treatment outcomes, including increased organ dysfunction, the need for prolonged mechanical ventilation, longer hospital stays, and higher mortality [164–167].

The use of various RRT modalities in sepsis and septic shock involves action in several directions: correction of electrolyte disturbances and hyperazotemia, elimination of metabolic acidosis, potential removal of cytokines, and removal of excess fluid when diuretic therapy is ineffective, or a combination of these strategies.

Conservative therapy with fluid restriction and diuretic use is not always sufficiently effective. In these situations, RRT can be useful for managing fluid overload and preventing further fluid overload in patients requiring large fluid volumes to ensure adequate nutrition, including parenteral administration of systemic antibacterial drugs (ATC code J01), systemic antifungal drugs (J02), hypnotics and sedatives (ATC code N05C), and other medications [168, 169].

Currently, there are no randomized controlled trials conducted in children that could answer the question of when to initiate RRT. The decision to start RRT should be made not only based on laboratory blood data, but to a greater extent based on a comprehensive analysis of the overall clinical situation and an assessment of laboratory trends [170].

RRT modalities used in children include continuous and intermittent renal replacement therapy, as well as peritoneal dialysis [151–155].

Currently, there is no consensus regarding the optimal dialysis therapy strategy for AKI in children. There are differences in approaches to using RRT across different countries. Unfortunately, there are no randomized controlled trials in children that would identify the advantages of any specific method. The choice of renal replacement therapy method for each patient is made individually, taking into account the pros and cons of each method, patient characteristics, the goals of dialysis therapy for a specific child, the physician's experience and skills, and the availability of appropriate equipment [171].

In children with sepsis / septic shock, plasma exchange is not recommended [168–178].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comment. Plasma exchange in sepsis and septic shock aims to normalize the patient's plasma environment, remove cytokines and endotoxins, and correct immunoglobulin deficiency [172, 173]. However, there are currently no large RCTs evaluating its efficacy in sepsis / septic shock in children [172–174]. Even in adult studies, there is no consensus regarding its efficacy in sepsis [175–178]. Therefore, plasma exchange cannot currently be recommended for routine use. The decision to perform it in children with sepsis must be made by a medical board (consilium) on a case-by-case basis.

The use of sorption methods of extracorporeal hemocorrection in children with sepsis / septic shock is currently not recommended [179–188].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comment: considering the leading role of endotoxin and cytokines in triggering the septic cascade, the therapeutic target for extracorporeal hemocorrection methods such as selective lipopolysaccharide hemisorption and hemoperfusion using highly selective cytokine sorbents is evident [179, 180]. There are a large number of sorbents from different manufacturers with varying characteristics, as well as dialysis membranes with high sorption activity. Even in adult studies, there is no consensus on the efficacy of extracorporeal hemocorrection [181]. According to many authors, extracorporeal therapy should be tailored to the individual patient's condition [182]. In addition, there are technical challenges (the need for vascular access, availability of appropriate equipment, large extracorporeal circuit volume, requirement for anticoagulation, etc.) that significantly limit the use of the aforementioned methods in pediatric practice. It should be noted that in recent years, manufacturers have released hemisorption columns with reduced priming volumes adapted for use in children.

Over the past few years, studies have been published on the potential for stabilizing hemodynamics in children with shock and reducing the severity of multiple organ dysfunction syndrome using lipopolysaccharide (LPS)-selective hemoperfusion [183]. LPS-selective hemoperfusion may have a positive effect on hemodynamics, the oxygenation index, and laboratory markers of sepsis in children after cardiac surgery [184]. Additionally, membranes with a high endo-toxin adsorption capacity have been used in the treatment of septic shock in children [184, 185]. Combined and early use of hemoperfusion and continuous renal replacement therapy (CRRT) may reduce mortality compared to isolated prolonged CRRT [186].

However, there are currently no large-scale RCTs and insufficient data to draw a definitive conclusion regarding the benefit of extracorporeal blood purification methods in pediatric sepsis [187, 188]. Therefore, the use of extracorporeal hemocorrection sorption methods in a child with sepsis should be considered, but the decision to use them must be made by a medical board (consilium) in each individual case.

3.1.6 Additional Treatment Methods

Systemic corticosteroids for septic shock in children are not recommended if fluid resuscitation and inotropic therapy successfully eliminate hemodynamic instability [17, 189].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

The administration of #hydrocortisone** is recommended only in refractory septic shock [17].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comment: Recent guidelines for the diagnosis and management of septic shock in children and neonates find no indications for the administration of systemic corticosteroids. The clinical guidelines of the Society of Critical Care Medicine (USA) also state that systemic corticosteroids should be avoided in children with septic shock, ARDS, and severe community-acquired pneumonia due to the lack of robust randomized controlled trials [189].

In children with sepsis and septic shock, it is recommended to maintain blood glucose levels at or below 7.8 mmol/L [17, 20, 190, 191].

GCR ALOE 2Grade of Recommendation A (Level of Evidence – 2)

The use of #insulin, soluble [human biosynthetic]** in children with sepsis and septic shock is recommended only when blood glucose levels exceed 10 mmol/L [17, 20, 190, 191].

GCR ALOE 2Grade of Recommendation A (Level of Evidence – 2)

Comment: Numerous studies have proven that hyperglycemia is associated with poor outcomes; however, 3 prospective multicenter RCTs failed to demonstrate clinical efficacy of tight glycemic control within a lower target range in children [190, 191].

In children with sepsis and septic shock who require vasoactive drug infusions (ATC C01C: cardiac stimulants, excluding cardiac glycosides) and fluid therapy, it is recommended to maintain a normal blood ionized calcium level [192, 193].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comment: Hypocalcemia frequently occurs in septic shock; however, a systematic literature review identified no evidence to support the treatment of hypocalcemia in critical illness [192]. At the same time, timely correction of calcium deficiency, especially in the early stages of septic shock treatment, helps reduce the need for adrenergic and dopaminergic agents (ATC C01CA) [193].

Red blood cell transfusion in children with sepsis and septic shock with a blood hemoglobin level above 70 g/L in the setting of stable hemodynamics is not recommended [194, 195].

GCR ALOE 2Grade of Recommendation A (Level of Evidence – 2)

In children with septic shock, it is recommended to maintain hemoglobin levels within the range of 70–90 g/L [194, 195].

GCR ALOE 2Grade of Recommendation A (Level of Evidence – 2)

Comment: This decision was made based on a re-analysis of the TRIPICU trial results. Among 137 hemodynamically stable children with sepsis and septic shock, no differences were found between the restrictive and liberal transfusion strategy groups [194].

Prophylactic transfusion of fresh frozen plasma (FFP) and platelet concentrate in children with sepsis and septic shock without hemorrhagic syndrome is not recommended [196, 197].

LeRR CLoE 4Level of recommendation confidence C (level of evidence – 4)

Comment: A meta-analysis published in 2012 demonstrated that there is no convincing evidence of benefit from prophylactic FFP transfusion [196]. Observational studies in critically ill children showed that FFP transfusion is associated with worse clinical outcomes [197]. However, prophylactic FFP transfusion may be justified in certain patient groups: patients with disseminated intravascular coagulation (DIC), significant comorbidities, cancer, or children with sepsis undergoing extracorporeal life support [17, 20]. Platelet transfusions in children with sepsis have been linked to worse treatment outcomes (longer ICU stay, progression of multiple organ dysfunction, increased mortality) [198].

In children with sepsis and septic shock, the use of normal human immunoglobulin [IgG + IgM + IgA]** (NHIG) is recommended in the early stages of the disease [199–213].

GCR ALEL 1Grade of Recommendation A (Level of Evidence – 1)

Comment: The results of recent trials and systematic meta-analyses appear more promising regarding the use of intravenous normal human immunoglobulin [IgG + IgM + IgA]** in patients with sepsis [199–201]. It is believed that while the use of immunoglobulins enhances passive immunity by neutralizing bacterial toxins, facilitating bacterial opsonization, and inhibiting immune cell proliferation, enrichment with immunoglobulin M (IgM) also increases the bactericidal activity of leukocytes and suppresses cytokine effects [202–204]. Furthermore, the enhanced opsonization induced by its administration may be beneficial in combating infections caused by multidrug-resistant pathogens [205]. A Cochrane review evaluating seven studies on the use of NHIG as adjuvant therapy in adult patients with sepsis and septic shock showed a significant reduction in mortality compared to placebo or control [206]. Several RCTs have investigated the effect of NHIG in children with sepsis. For instance, among 100 children with sepsis, a reduction in mortality, hospital stay duration, and the number of complications was observed [207]. N.V. Beloborodova et al. and D.A. Popov et al. found that in children with congenital heart disease who underwent systemic inflammation in the early postoperative period, the incidence of infectious complications was lower, and the duration of ICU and hospital stay was shorter in the NHIG group [208, 209]. Increased survival in children with sepsis receiving NHIG compared to the control group was demonstrated by Kola E. et al. [210]. In 2020, a retrospective study (the PIGMENT study) on the use of NHIG in children was published [211]. The authors observed 254 patients aged 1 month to 18 years (mean age 13 months), of whom 100 had sepsis, 95 had septic shock, and 59 had shock due to multiple organ dysfunction; 162 children (63.7%) received infusions of cardiotonic drugs (ATC C01C: Cardiac stimulants, excluding cardiac glycosides). All patients received NHIG, with 104 receiving it for 3 days and 150 for 5 days. The 28-day mortality rate was 40.3% in the 3-day therapy group and 20.6% in the 5-day group. Thus, a 5-day intravenous administration of IgM-enriched immunoglobulin was associated with reduced mortality in children with sepsis, with the effect being particularly pronounced in Gram-negative infections and in infants aged 1–24 months [211]. It should be noted that the efficacy of NHIG therapy significantly depends on the timing of initiation and should be administered in the early phase within 6 hours of sepsis identification, which can significantly reduce the risk of mortality [212, 213].

Colecalciferol**, ascorbic acid**, and thiamine are not recommended for the treatment of sepsis in children [214].

LoE CGoE 5Level of Evidence C (Level of Confidence of Data – 5)

Comment: A systematic review and meta-analysis of 17 studies demonstrated that approximately 50% of critically ill children have low 25-hydroxyvitamin D levels upon admission to pediatric ICUs [214]. Moreover, vitamin D deficiency was associated with more severe disease course, multiple organ dysfunction, and mortality across these studies. A greater need for vasoactive drugs has been reported in children with vitamin D deficiency, although mortality was not directly linked to it [214]. There are no RCTs proving the efficacy of ascorbic acid** and thiamine for the treatment of sepsis in children.

Stress ulcer prophylaxis in children with sepsis is not recommended [215–218].

GCR ALEL 1Grade of Recommendation A (Level of Evidence – 1)

Comment: Routine stress ulcer prophylaxis in children with septic shock or other sepsis-associated organ dysfunctions is not recommended due to a lack of robust evidence of efficacy [215], while the risk of adverse effects (pneumonia, C. difficile infection) may increase [216]. Instead of routine stress ulcer prophylaxis, patients should be assessed for risk factors (clinically significant gastrointestinal bleeding, multiple organ dysfunction, prolonged mechanical ventilation (> 48 h), coagulopathy, refractory septic shock, treatment with systemic corticosteroids and nonsteroidal anti-inflammatory and antirheumatic drugs) [217, 218]. The risk of gastrointestinal bleeding is also reduced by protecting the gastrointestinal mucosa via enteral nutrition. Early enteral nutrition is an effective alternative to pharmacological stress ulcer prophylaxis.

Deep vein thrombosis prophylaxis in children with sepsis is not recommended [219].

GRC BLEL 2Grade of Recommendation B (Level of Evidence – 2)

Comment: There are no randomized controlled trials demonstrating the efficacy of heparin products in preventing catheter-associated thrombosis in children with sepsis. A randomized controlled trial evaluating the efficacy of heparin group drugs for the prevention of central venous catheter-associated thrombosis in pediatric intensive care units was prematurely terminated due to the inability to enroll patients according to inclusion and exclusion criteria [219].

3.2 Surgical Treatment

In all children with sepsis / septic shock, it is recommended to debride / drain the focus (or foci) of infection as soon as possible after the diagnosis of sepsis to prevent further clinical deterioration [17, 20].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comment: Diagnostic evaluation is necessary to identify the source of infection. If necessary, specialist consultations should be sought (initial examination/consultation by a pediatric surgeon; initial examination/consultation by an infectious disease physician) to determine the priority and methods of interventions required to achieve source control [17, 20].

In all children with sepsis / septic shock, it is recommended to remove vascular access devices (vascular catheters) identified as a proven source of infection as soon as alternative vascular access has been established (if necessary). This decision is made based on the type of pathogen, as well as the risk associated with removing/replacing the vascular access device [220].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comment: Source control is defined as a set of measures aimed at the debridement/drainage of the infection focus or foci, which prevents the generalization of the process [220]. These measures may include drainage of an abscess, empyema, removal of infected intravascular devices, etc. Source control measures should be implemented as soon as possible after initial hemodynamic stabilization, ideally no later than 6–12 hours after diagnosis [17, 20]. The importance of source control in children has been demonstrated for skin and deep tissue abscesses, as well as necrotizing fasciitis [221, 222]. Despite the relative paucity of pediatric data, source control is an important aspect of sepsis management and should not be delayed. Undrained foci of infection often respond poorly to systemic antibiotics, promoting local and hematogenous spread of infection with a high risk of generalization. A common and potentially preventable cause of sepsis is bloodstream infection associated with vascular access devices. Delayed removal of central venous catheters in patients with bacteremia caused by P. aeruginosa, Enterobacteriaceae, S. aureus, or yeasts delays recovery and increases the risk of adverse outcomes [223, 224], therefore the catheter must be removed. In cases where the infection is caused by coagulase-negative staphylococci, catheter replacement presents technical difficulties, and the patient is stable, targeted antibiotic therapy through the existing catheter may be permissible as a temporary measure.

3.3 Other Treatment

Not applicable.

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 everyday activity [225].

Main objectives of rehabilitation for patients with sepsis:

prevention or reduction of the severity of organ and body system dysfunctions;
prevention or reduction of activity limitations, disease progression, and complication development;
elimination and correction of emotional and psychological disorders;
reduction of the severity of disabling consequences of the disease, adaptation to daily physical loads;
continuation of education.

Rehabilitation may begin concurrently with treatment, may be delayed, but cannot precede treatment. Medical rehabilitation is carried out regardless of the disease stage, provided the patient's clinical condition is stable and there is a prospect for functional recovery (rehabilitation potential), when the risk of complications does not outweigh the prospect of functional recovery, and in the absence of contraindications to specific medical rehabilitation methods based on an established rehabilitation diagnosis.

Stages of medical rehabilitation and levels of care

Depending on the severity of the patient's condition, medical rehabilitation is carried out in three stages. The first stage of medical rehabilitation is performed during the acute period of sepsis in the intensive care units of medical organizations, provided there is a prospect for functional recovery confirmed by examination results and no contraindications to rehabilitation methods.

The second stage of medical rehabilitation is performed in the early rehabilitation period in inpatient settings of medical organizations: rehabilitation centers and rehabilitation departments. In the inpatient setting, medical rehabilitation is carried out by a multidisciplinary rehabilitation team.

Rehabilitation measures can be carried out in the patient's room using mobile physical therapy equipment or in physical therapy, medical massage, psychotherapy, medical psychology, and physiotherapy rooms.

The attending physician of a specialized inpatient medical organization department must determine risk factors and limiting factors for conducting rehabilitation measures, perform dynamic monitoring of the patient's condition and the effectiveness of the rehabilitation measures performed, with data recording in the medical history.

The third stage of medical rehabilitation is carried out during the period of residual symptoms on an outpatient basis in rehabilitation, physiotherapy, physical therapy, psychotherapy, medical psychology departments (rooms), rooms of specialists in the profile of care provided by medical organizations providing medical care, and in some cases by mobile teams at home. Third-stage measures can be carried out in sanatorium-resort institutions.

At the second and third stages of rehabilitation, issues regarding the timing of follow-up dispensary observation (recommended at least once every 6 months), health groups, and, if necessary, disability status determination can be addressed.

During rehabilitation measures at all stages, it is necessary to carry out prevention of infectious process complications and prevent the chronization of pathology of certain organs and systems that developed in the acute period of sepsis.

Criteria for the effectiveness of rehabilitation in patients with sepsis

Criteria for the effectiveness of rehabilitation in patients with sepsis are formed depending on the complications that have developed and concomitant diseases:

Prevention of disabling consequences of sepsis.
Minimization of life activity limitations caused by sepsis complications: return to and resumption of attending school, preschool institutions, starting education in colleges and universities.
Restoration of impaired or lost social roles.
Reduction of disability severity.

5. Prevention and Dispensary Observation

Prevention

The effectiveness of certain relatively simple measures of primary and secondary prevention of sepsis has been established [17, 20, 226-227]:

▪ promotion of a healthy lifestyle as a basis for increasing immunoresistance;

▪ sanitization of the oral cavity and other foci of chronic infection;

▪ prevention of trauma to mucous membranes and other tissues;

▪ compliance with sanitary requirements to prevent contamination of the skin and mucous membranes with endogenous flora;

▪ prevention of burn surface infection;

▪ adequate perioperative antibiotic prophylaxis in surgical patients (for interventions on the periodontium, soft tissues, nasopharynx, in thoracic, abdominal surgery, cardiac surgery);

▪ compliance with the rules for insertion and care of catheters (vascular, urinary) with their earliest possible removal when the need for their further use disappears;

▪ compliance with hand hygiene principles by medical personnel and visitors;

▪ hospital isolation of patients colonized with extensively and pan-resistant microorganisms, with dedicated medical staff assigned to their care;

▪ vaccination of high-risk patients (e.g., patients with primary immunodeficiencies, asplenia, etc.);

▪ testing of selective oral decontamination methods based on the STREPTO-TEST data (in case of recurrent tonsillitis or exacerbations of chronic tonsillitis, high antistreptolysin O titers).

Dispensary monitoring (active follow-up)

Dispenserary observation (follow-up care) is a necessary examination of children and adolescents who have undergone sepsis, suffer from any complications or consequences of this disease that have transformed into chronic diseases or functional disorders, carried out with a certain periodicity for the purpose of timely detection, prevention of complications, exacerbations of diseases, their prevention and implementation of medical rehabilitation of these persons, carried out in the manner established by the relevant orders.

During the routine clinical examination (dispensary observation) of children and adolescents who are "sepsis convalescents", it is advisable to be guided by the Order of the Russian Ministry of Health No. 302n dated May 16, 2019 "On approval of the Procedure for minors undergoing dispensary observation, including during the period of education and upbringing in educational organizations"; Article 46 of Federal Law No. 323-FZ dated November 21, 2011 "On the fundamentals of protecting the health of citizens in the Russian Federation" (Collected Legislation of the Russian Federation, 2011, No. 48, Art. 6724; 2013, No. 48, Art. 6165; 2016, No. 27, Art. 4219).

Dispenserary observation of children and adolescents who have had sepsis is carried out by medical workers of a medical organization or a structural unit of another organization carrying out medical activities where the minor receives primary health care. The follow-up involves a pediatrician, district pediatrician, general practitioner (family doctor), specialist doctors (according to the profile of the disease / condition of the minor; a paramedic of a feldsher-midwife station or a feldsher health post, if the head of the medical organization has entrusted him with certain functions of the attending physician, including conducting dispensary observation of minors. (Clause 8, subclauses 1-3 of the "Procedure for minors undergoing dispensary observation, including during the period of education and upbringing in educational organizations", approved by the Order of the Russian Ministry of Health No. 302n dated May 16, 2019).

The presence of grounds for dispensary observation, the dispensary observation group, its duration, the frequency of dispensary visits (examinations, consultations), the scope of examination, preventive, therapeutic and rehabilitation measures are determined by a medical worker in accordance with the procedures for providing medical care for certain profiles, diseases or conditions (groups of diseases or conditions), based on clinical guidelines, taking into account standards of medical care for lesions of certain organs and systems, as well as the health status of the minor, the stage, degree of severity and individual characteristics of the course of sepsis in the acute period and its complications (condition), but at least once a year.

When conducting dispensary observation, the recommendations of a specialist doctor for the profile of the disease (condition) contained in his medical documentation are taken into account, including those made based on the results of treatment of patients in inpatient settings, as well as the conducted preventive medical examination (Clause 8, subclauses 1-3 of the "Procedure for minors undergoing dispensary observation, including during the period of education and upbringing in educational organizations", approved by the Order of the Russian Ministry of Health No. 302n dated May 16, 2019).

In case of the impossibility for a child or adolescent subject to dispensary observation for complications of past sepsis to visit a medical organization due to the severity of the condition or motor impairment, a dispensary examination and/or consultation at home is provided.

The purpose of dispensary observation of convalescents with sepsis is:

➣ achievement of target health status indicators in accordance with clinical guidelines;

➣ reduction in the number of visits and/or hospitalizations for sepsis recurrence, exacerbations or complications of the disease for which children and adolescents (minors) are under dispensary observation;

➣ monitoring the effectiveness of rehabilitation of children and adolescents who have had sepsis and are under dispensary observation.

6. Organization of Medical Care

Medical care for children with sepsis and septic shock, aimed at primary stabilization of the condition, must be carried out at all stages, starting from the pre-hospital stage, regardless of the profile and structural features of the medical organization.

When providing emergency, including specialized emergency, medical care outside a medical organization, emergency medical teams carry out medical evacuation of patients with suspected sepsis to medical organizations if the initial examination reveals: 1) signs of an infectious focus of any localization (pneumonia, purulent wound, etc.), 2) signs of organ dysfunction that occurred after the onset of symptoms of distress. In patients with suspected sepsis at the pre-hospital stage, laboratory and instrumental studies aimed at confirming or excluding the diagnosis are not recommended. The diagnosis of sepsis is clinical; any pre-hospital diagnostic measures that may delay hospitalization are unacceptable.

Indications for inpatient hospitalization:

All patients with confirmed or suspected sepsis require emergency hospital admission. Septic shock is an absolute indication for hospitalization.

Patients with suspected sepsis are recommended to be hospitalized preferably in a level III multi-profile pediatric hospital with capabilities for emergency diagnosis of the infection source and treatment of various pathologies. A patient hospitalized in a hospital lacking such capabilities should be transferred as quickly as possible to a medical organization that has all modern technologies used in the treatment of sepsis, including the sanitation of the infection focus. Medical evacuation of patients with sepsis to a medical organization capable of providing the necessary specialized medical care is carried out by specialized emergency anesthesiology-resuscitation teams, air medical emergency teams, or emergency consultative emergency teams. In each region, it is recommended to develop regional rules for emergency transfer and a regional routing protocol for children with sepsis, taking into account regional characteristics.

A patient with obvious signs of sepsis must be placed in the intensive care unit of the emergency inpatient department (if available) or directly in the ICU for intensive therapy in parallel with diagnostic measures.

When providing care to a child in the ICU of an adult multi-profile hospital, telemedicine consultations with specialists from national medical research centers are justified. If necessary, the possibility of an on-site face-person consultation with the necessary diagnostic and therapeutic interventions by staff of national medical research centers should be considered.

There are isolated observational studies demonstrating a high need for the transfer of children to level III hospitals, showing that children treated in lower-level hospitals had higher all-hospital mortality [228-230]. There is also evidence that delayed treatment significantly increases sepsis mortality [231, 232]. Several studies in high-income countries where timely intensive care measures were organized have demonstrated reduced mortality in children with sepsis and septic shock [229, 230, 233].

Indications for ICU transfer

Since the diagnosis of sepsis in children implies the mandatory presence of organ dysfunction, all patients must be admitted to the ICU, which leads to a decrease in in-hospital mortality [234-240].

For children with suspected sepsis, indications for transfer to the ICU are:

Hemodynamic disturbances;
Depression of consciousness to the level of sopor;
Progressive respiratory failure;
Need for respiratory support.

Indications for transferring the patient from the ICU and discharging from the hospital

Following condition stabilization and normalization of hemodynamic parameters during infusion therapy and continuous vasopressor infusion, the earliest possible transfer of the child to a specialized pediatric ICU with experience in treating this category of patients is indicated.

It is recommended to implement local protocols for the diagnosis and treatment of sepsis and septic shock in children, developed on the basis of federal clinical guidelines [5, 17, 20, 22].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comment: a number of studies have shown that the use of protocols increases the speed of diagnosis and the effectiveness of treatment for children with sepsis and septic shock, which consisted in a reduction in mortality [17, 20], as well as the duration of organ dysfunction, mechanical ventilation, the use of cardiotonic drugs (ATC C01C: Cardiac stimulants, excluding cardiac glycosides), and hospital stay [5, 17, 22]. The protocols must take into account the specifics of the medical facility where children with sepsis/septic shock are admitted.

7. Additional Information

Not applicable.

Criteria for Evaluating the Quality of Medical Care

No.	Quality criteria for specialized medical care in sepsis and septic shock (ICD-10 codes: A41; R57.2)	Evaluation of compliance
1.	Measurement of heart rate, respiratory rate, peripheral blood pressure, and hemoglobin oxygen saturation was performed upon admission and every 24 hours of ICU treatment	Yes/No
2.	Assessment of condition using the pSOFA scale upon suspected sepsis at the time of admission to the hospital/ICU and every 24 hours of ICU treatment	Yes/No
3.	Complete blood count performed no later than 1 h from the time of ICU admission	Yes/No
4.	Urinalysis performed no later than 1 h from the time of ICU admission	Yes/No
5.	Microbiological (cultural) blood test for sterility with antibiotic susceptibility testing performed before starting antimicrobial therapy or before administering the next dose of antibiotics (if antimicrobial therapy has already been initiated)	Yes/No
6.	Systemic antimicrobial therapy initiated no later than 3 h after sepsis diagnosis (depending on indications and in the absence of contraindications)	Yes/No
7.	Systemic antimicrobial therapy initiated no later than 1 h from the moment of septic shock diagnosis (depending on indications and in the absence of contraindications)	Yes/No
8.	Infusion therapy for septic shock performed with an initial volume of not more than 40 ml/kg of body weight	Yes/No
9.	Sanation of the infection focus amenable to surgical control performed	Yes/No
10.	Availability of results of microbiological (cultural) examination of biological material from the infection focus and/or blood with determination of pathogen susceptibility to systemic antimicrobial drugs	Yes/No
11.	Adjustment of antibacterial therapy (if necessary) performed taking into account bacteriological test results	Yes/No
12.	When multidrug-resistant bacteria and fungi are detected, antimicrobial therapy regimens are prescribed in accordance with these recommendations	Yes/No
13.	Daily evaluation of therapy effectiveness performed taking into account the severity of the inflammatory response and organ dysfunction using scales	Yes/No
14.	Medical evacuation to a specialized pediatric department of anesthesiology and intensive care performed (for Level I medical organizations)	Yes/No

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Appendix A1. Working Group Composition

Dmitry Kirillovich Azovsky – Doctor of Medical Sciences, Head of the Anesthesiology and Intensive Care Center No. 2, Moscow Multidisciplinary Clinical Center «Kommunarka» of the Moscow Healthcare Department.
Yuri Stanislavovich Alexandrovich − Chief Freelance Pediatric Specialist Anesthesiologist-Intensivist of the Northwestern Federal District of the Russian Ministry of Health, Head of the Department of Anesthesiology, Intensive Care and Emergency Pediatrics of the Faculty of Postgraduate and Additional Professional Education, Saint Petersburg State Pediatric Medical University of the Russian Ministry of Health, President of the NGO «Association of Pediatric Anesthesiologists and Intensivists» of Russia, Professor, Doctor of Medical Sciences.
Andrey Ustinovich Lekmanov − Doctor of Medical Sciences, Professor, Chief Researcher at the Research Institute of Pediatric Surgery, Pirogov Russian National Research Medical University of the Russian Ministry of Health, Moscow.
Mironov, Petr I. – Doctor of Medical Sciences, Professor, Department of Pediatric Surgery with the Course of the Institute of Additional Professional Education, Bashkir State Medical University of the Russian Ministry of Health, Ufa.
Muzurov, Alexander L. – Candidate of Medical Sciences, Head of the Center for Blood Gravitational Surgery and Hemodialysis, St. Vladimir Children's City Clinical Hospital of the Moscow Healthcare Department, Associate Professor, Department of Pediatric Anesthesiology, Reanimatology and Toxicology, Russian Medical Academy of Continuous Professional Education of the Russian Ministry of Health, Moscow.
Popov, Dmitry A. – Doctor of Medical Sciences, Head of the Laboratory of Clinical Microbiology and Antimicrobial Therapy, Professor, Department of Anesthesiology and Resuscitation with the Course of Clinical Laboratory Diagnostics, Institute of Postgraduate Clinical Training, A.N. Bakulev National Medical Research Center for Cardiovascular Surgery of the Russian Ministry of Health, Member of the Presidium of the Board of the Interregional Public Organization "Alliance of Clinical Chemotherapists and Microbiologists".
Pshenisnov, Konstantin V. – Doctor of Medical Sciences, Associate Professor, Professor, Department of Anesthesiology, Reanimatology and Emergency Pediatrics of the Faculty of Postgraduate and Additional Professional Education, Saint Petersburg State Pediatric Medical University of the Russian Ministry of Health, Saint Petersburg.

Conflict of interest: none.

Appendix A2. Methodology for Developing Clinical Guidelines

Methods used for evidence collection/selection: electronic database search.

Description of methods used for evidence collection/selection: The evidence base for the guidelines included publications from the Cochrane Library, PubMed, EMBASE and MEDLINE, Scopus, Web of Science, eLibrary, clinicaltrials.gov, electronic libraries, and clinical guidelines published on the resources of The National Institute for Health and Care Excellence, The European Association of Perinatal Medicine, and the European Society for Pediatric Research. The search depth was 5 years.

During the preparation of the clinical guidelines, key questions were formulated using the PIPOH formula:

– P (population) – patient population and disease characteristics (neonates with sepsis and septic shock);

– I (interventions) – interventions (intensive care measures);

– P (professionals) – target audience of the clinical guidelines (anaesthesiologists-intensivists, neonatologists, pediatricians, surgeons, infectious disease specialists);

– O (outcomes) – expected outcomes that can be improved (patient outcomes, healthcare system indicators, epidemiological indicators, etc.);

– H (health care setting) – healthcare setting (outpatient clinic, inpatient facility, ICU).

Methods used to assess the quality and strength of evidence:

expert consensus;
assessment of significance in accordance with the rating scheme.

Scales for assessing levels of evidence (LE) (Tables 1, 2) for diagnostic, preventive, therapeutic, and rehabilitation methods (diagnostic, preventive, therapeutic, rehabilitation interventions) with definitions, and the scale for assessing grades of recommendation (GR) (Table 3) for preventive, diagnostic, therapeutic, and rehabilitation methods (preventive, diagnostic, therapeutic, rehabilitation interventions).

Methods used for evidence analysis:

reviews of published meta-analyses;
systematic reviews with evidence tables.

Description of methods used for evidence analysis.

When selecting publications as potential sources of evidence, the methodology used in each study was examined to ensure its validity. Methodological review was based on questions focusing on study design features that significantly impact the validity of results and conclusions.

To minimize potential subjective errors, each study was evaluated independently by at least two members of the working group. Any discrepancies in assessments were discussed by the full working group. If consensus could not be reached, an independent expert was involved.

Economic analysis:

Cost analysis was not performed, and pharmacoeconomic publications were not reviewed.

Method of recommendation validation:

external expert review;
internal expert review.

Description of the guideline validation method:

The preliminary version of these guidelines was reviewed by independent experts who were asked to comment primarily on whether the interpretation of the evidence underlying the recommendations was accessible and understandable.

Comments were received from primary care physicians and district pediatricians regarding the clarity of the presentation of the guidelines and their assessment of the importance of the guidelines as a working tool in daily practice.

The draft version was also sent to a non-medically trained reviewer to obtain comments from a patient perspective.

Comments received from experts were carefully systematized and discussed by the chair and members of the working group. Each point was discussed, and resulting modifications to the guidelines were recorded. If no changes were made, the reasons for declining the changes were recorded.

Consultation and peer review:

The draft guidelines were reviewed by independent experts who were asked to comment primarily on the clarity and accuracy of the interpretation of the evidence base underlying the recommendations.

For the final revision and quality control, the recommendations were re-evaluated by the members of the working group, who concluded that all comments and feedback from the experts had been taken into account and the risk of bias in the development of the recommendations was minimized.

Target audience for these clinical guidelines:

Anesthesiologists-intensivists;
Neonatologists;
Pediatricians;
Infectious diseases physicians;
Clinical pharmacologists;
Medical students;
Residents and interns.

Table 1 – Scale for assessing the levels of evidence (LE) for diagnostic methods (diagnostic interventions)

LoE	Definition
1	Systematic reviews of studies with reference standard control or systematic reviews of randomized controlled trials with meta-analysis
2	Individual studies with reference standard control or individual randomized controlled trials and systematic reviews of studies of any design, except randomized controlled trials, with meta-analysis
3	Studies without consecutive reference standard control or studies with a reference standard not independent of the test method, or non-randomized comparative studies, including cohort studies
4	Non-comparative studies, case report
5	Only justification of mechanism of action or expert opinion is available

Table 2 – Scale for assessing the levels of evidence (LE) for prevention, treatment and rehabilitation methods (preventive, therapeutic, rehabilitation interventions)

LoE	Definition
1	Systematic review of RCTs with meta-analysis
2	Individual RCTs and systematic reviews of studies of any design except RCTs, with meta-analysis
3	Non-randomized comparative studies, including cohort studies
4	Non-comparative studies, case reports or case series, case-control studies
5	Only justification of the mechanism of action of the intervention (preclinical studies) or expert opinion is available

Table 3 – Scale for assessing the grades of recommendation (GR) for prevention, diagnostic, treatment and rehabilitation methods (preventive, diagnostic, therapeutic, rehabilitation interventions)

GoR	Definition
A	Strong recommendation (all considered efficacy criteria (outcomes) are important, all studies are of high or acceptable methodological quality, and their conclusions on the outcomes of interest are consistent)
B	Conditional recommendation (not all considered efficacy criteria (outcomes) are important, not all studies are of high or acceptable methodological quality, and/or their conclusions on the outcomes of interest are inconsistent)
C	Weak recommendation (lack of adequate quality evidence (all considered efficacy criteria (outcomes) are unimportant, all studies are of low methodological quality, and their conclusions on the outcomes of interest are inconsistent)

Procedure for updating clinical guidelines.

The mechanism for updating clinical guidelines provides for their systematic revision at least once every three years, as well as upon the emergence of new evidence-based medicine data on the diagnosis, treatment, prevention, and rehabilitation of specific diseases, or in the presence of justified additions/comments to previously approved clinical guidelines, but no more frequently than once every 6 months.

Appendix A3. Reference Materials

Appendix A3.1 Related Documents

Federal Law No. 323-FZ of November 21, 2011, "On the Fundamentals of Healthcare Protection in the Russian Federation".
Order of the Ministry of Health of the Russian Federation No. 909n of November 12, 2012, "On Approval of the Procedure for Providing Medical Care to Children in the Profile 'Anesthesiology and Reanimatology'".
Order of the Ministry of Health and Social Development of the Russian Federation No. 179 of November 1, 2004, "On Approval of the Procedure for Providing Emergency Medical Care" (as amended on August 2, 2010, March 15, 2011).
Order of the Ministry of Health of the Russian Federation No. 1170n of October 28, 2020, "On Approval of the Procedure for Providing Medical Care to the Population in the Profile 'Transfusiology'".
Order of the Ministry of Health of the Russian Federation No. 302n of May 16, 2019, "On Approval of the Procedure for Minors Undergoing Dispensary Observation, Including During Education and Upbringing in Educational Organizations".

Appendix A3.2 Antimicrobial Regimens for the Treatment of Sepsis in Children

(State Register of Medicines)

№	INN	Age	Recommended doses
1	Ampicillin**	From 0 months.	100–200 mg/kg/day in 3–6 doses, IV
2	Ampicillin + [Sulbactam]**	From 0 months.	100–200 mg/kg/day in 3–6 doses, IV
3	Amoxicillin + [Clavulanic acid]**	From 0 months.	0 – 3 months, weight < 4 kg: 50 mg/kg/day (calculated as amoxicillin), in 2 doses, IV 0 – 3 months, weight > 4 kg: 75 mg/kg/day (calculated as amoxicillin), in 3 doses, IV 3 months – 12 years: 75–100 mg/kg/day (calculated as amoxicillin), in 3–4 doses, IV
4	Piperacillin + [Tazobactam]**	From 2 years of age	100/12.5 mg/kg IV 3 times daily
5	Cefazolin**		50–100 mg/kg/day in 3 doses; IV
6	Ceftriaxone**	From 0 months.	150 mg/kg/day in 3–4 doses; IV Meningitis: 200 mg/kg/day in 3–4 doses; IV
7	Cefoperazone + [sulbactam]**	From 0 months.	40–80 mg/kg/day, in 2–4 doses; IV For severe, prolonged infections – 160 mg/kg/day. Maximum daily dose – 160 mg/kg/day!
8	Ceftazidime**	From 0 months.	150 mg/kg/day in 3 doses; IV Meningitis: 150 mg/kg/day, IV in 3 doses
9	#Ceftazidime + [Avibactam]**	From 3 months.	For infections caused by aerobic Gram-negative microorganisms in patients with limited antibiotic treatment options: 3 – 6 months: 120 mg/kg/day (calculated as ceftazidime), in 3 doses, IV over 2 hours 6 months – 18 years: 150 mg/kg/day (calculated as ceftazidime) in 3 doses, IV over 2 hours Maximum single dose calculated as ceftazidime must not exceed 2 g!
10	Cefepime**	From 2 months.	100–150 mg/kg/day in 2–3 doses; IV
11	Cefepime + [Sulbactam]**	From 2 months.	100 mg/kg/day, in 2 doses, IV
12	Ceftaroline fosamil**	From 2 months.	2 months – 2 years: 30 mg/kg/day, in 3 doses, IV 2 years – 18 years: 36 mg/kg/day, in 3 doses, IV
13	Amikacin**	From 0 months.	15–20 mg/kg IV once daily
14	Gentamicin**	From 1 month.	2.5 mg/kg/day in 2–3 doses, IV. May be administered IV once daily at a dose of 5–7.5 mg/kg over 30–60 min.
15	Netilmicin	From 0 months.	Neonates under 7 days of life: 6 mg/kg/day, in 2 doses, IV 1 week – 1 year: 7.5 – 9.0 mg/kg/day, in 3 doses, IV Over 1 year: 6.0 – 7.5 mg/kg/day, in 3 doses, IV
16	Ciprofloxacin**	From 18 years of age!	15–30 mg/kg/day in 2 divided doses, IV
17	Aztreonam	From 9 months of age.	90–120 mg/kg/day in 3–4 divided doses; IV
18	Meropenem**	From 3 months.	60 mg/kg/day in 3 divided doses, IV Maximum daily dose: 120 mg/kg
19	Imipenem + [Cilastatin]**	From 3 months.	60–100 mg/kg/day in 3–4 divided doses, IV
20	Ertapenem**	From 3 months.	3 months – 13 years: 30 mg/kg/day in 2 divided doses, IV Over 13 years: 1 g in 1 single dose, IV Maximum daily dose: 1 g!
21	Vancomycin**	From 0 months.	40–60 mg/kg/day in 3–4 divided IV doses
22	Linezolid**	From 0 months.	0 – 12 years: 30 mg/kg/day in 3 divided doses, IV 12 – 18 years: 20 mg/kg/day in 2 divided doses, IV
23	Daptomycin**	From 1 year of age	Complicated skin and soft tissue infections
			1 – 2 years	10 mg/kg/day in 1 single dose, IV over 60 minutes.
			2 – 6 years	9 mg/kg/day in 1 single dose, IV over 60 minutes.
			7 – 11 years	7 mg/kg/day in 1 single dose, IV over 30 minutes.
			12 – 17 years	5 mg/kg/day in 1 single dose, IV over 30 minutes.
			Bacteremia with isolation of Staphylococcus aureus (methicillin-susceptible and methicillin-resistant strains)
			1 – 6 years	12 mg/kg/day in 1 single dose, IV over 60 minutes.
			7 – 11 years	9 mg/kg/day in 1 single dose, IV over 30 minutes.
			12 – 17 years	7 mg/kg/day in 1 single dose, IV over 30 minutes.
24	Polymyxin B**	0 – 1 year	0 mos. – 1 year: 4 mg/kg/day in 2 divided doses, IV 1 year – 18 years: Loading dose: 2.0–2.5 mg/kg over 1 h Maintenance dose: 1.25–1.5 mg/kg/day in 2 divided doses, IV Maximum dose: 2.5 mg/kg/day!
24	Polymyxin B**	2 – 18 years
25	Colistimethate sodium	From 0 months.	2.5–5 mg/kg/day in 2–4 divided doses, IV
26	Fosfomycin**	From 0 months.	200–400 mg/kg/day in 3 divided doses, IV
27	Tigecycline**	From 8 years of age	8 – 18 years: 2.4 mg/kg/day in 2 divided doses, IV 12 – 18 years: 100 mg/day in 2 divided doses, IV
28	Sulfamethoxazole + Trimethoprim**	From 0 months.	0 mos. – 12 years: 36 mg/kg/day in 2 divided doses, IV 12 – 18 years: 960 mg, 2–3 times a day, IV
29	Metronidazole**	From 0 months.	30 mg/kg/day in 4–3 divided doses, IV over 30–60 minutes.
30	Fluconazole **	From 0 months.	Mucosal candidiasis: Loading dose (day ¹ of treatment): 6 mg/kg/day in 1 single dose, IV Maintenance dose: 3 mg/kg/day in 1 single dose, IV Invasive candidiasis, protococcal meningitis: 6 – 12 mg/kg/day in 1 single dose, IV
31	Voriconazole**	From 12 years of age	Loading dose: 12 mg/kg/day in 2 divided doses, IV Maintenance dose: 6–8 mg/kg/day in 2 divided doses, IV
32	Caspofungin**	From 3 months.	Loading dose: 70 mg/m² in 1 single dose, IV Maximum daily dose: 70 mg! Maintenance dose: 50 mg/m², single dose, IV Maximum daily dose: 70 mg!
33	Micafungin**	From 0 months.	0 – 4 months
			Candidiasis prophylaxis		2 mg/kg/day, single dose, IV
			Candidiasis treatment		4–10 mg/kg/day, single dose, IV For severe CNS infections, the prescribed dose is 10 mg/kg/day.
			4 months – 16 years
			Candidiasis prophylaxis		Body weight < 40 kg: 1 mg/kg/day Body weight > 40 kg: 50 mg/day; single dose, IV
			Candidiasis treatment		Body weight < 40 kg: 2 mg/kg/day (maximum daily dose: 4 mg/kg/day) Body weight > 40 kg: 100 mg/day; single dose, IV (maximum dose 200 mg/kg/day)
			16 – 18 years
			Candidiasis prophylaxis		Body weight < 40 kg: 1 mg/kg/day Body weight > 40 kg: 50 mg/day; single dose, IV
			Candidiasis treatment		Body weight < 40 kg: 2 mg/kg/day (maximum daily dose: 4 mg/kg/day) Body weight > 40 kg: 100 mg/day; single dose, IV (maximum dose 200 mg/kg/day)
34	Amphotericin B [lipid complex]	From 0 months.	Starting dose: 250 mcg/kg, then gradually increase by 125–250 mcg/kg up to the maximum. Maximum daily dose: 1 mg/kg!

Doses of drugs for inotropic support

(Jentzer JC, Coons JC, Link CB, Schmidhofer M. Pharmacotherapy update on the use of vasopressors and inotropes in the intensive care unit. J Cardiovasc Pharmacol Ther. 2015;20(3):249-60)

Drug	Starting dose, mcg/kg/min	Dose range, mcg/kg/min	Dose titration (5–15 minutes)	Discontinuation (5–15 minutes)
#Dobutamine**	2,5 – 5,0	2,5 – 10,0	2,5 – 5,0	2,5 – 5,0
Dopamine**	2,0 – 10,0	2,0 – 20,0	2,5 – 5,0	1,0
Epinephrine**	0,02 – 0,05	0,005 – 0,2	0,02 – 0,05	0,02 – 0,05
Norepinephrine**	0,01 – 0,04	0,04 – 1,0	0,02 – 0,04	0,02 – 0,04
Phenylephrine**	0,1 – 0,3	0.1 – 1,5	0,2 – 0,4	0,2 – 0,4
Desmopressin**	0.01 – 0.04 IU/min.	0.01 – 0.04 IU/min.	-	Discontinuation of infusion

Appendix B. Physician Action Algorithms

Appendix C. Patient Information

Sepsis is one of the most severe diseases in childhood, with numerous causes. Most commonly, sepsis develops in children with various risk factors (immunodeficiency states, severe organic CNS lesions, presence of implantable devices) who require prolonged treatment in an intensive care unit.

Sepsis is diagnosed if a child shows signs of a severe infection involving various organ systems, with the earliest symptoms most often being pronounced pallor, jaundice, gray or cyanotic skin coloration, refusal to eat, excessive lethargy, and grunting respiration.

The highest risk of severe sepsis is characteristic of children with oncological and hematological diseases.

If sepsis is diagnosed, your child will most likely require prolonged treatment in an intensive care unit, where they will be prescribed medications to target the infectious agent and correct existing organ function impairments.

In severe cases, mechanical ventilation may be required, whereby a special tube connected to a ventilator is inserted into the child's trachea.

If there are no gastrointestinal issues, the child will be able to receive breast milk or infant formula through a special tube (nasogastric tube) inserted into the stomach. Therefore, it is very important for the mother to maintain lactation for as long as possible, as this is the most essential and helpful thing a mother can do for her baby.

If this is not possible, all nutrition and vitamins will be administered to the infant as liquid medications given intravenously.

Until recently, the risk of mortality from sepsis in children was extremely high; today, pediatric ICU intensivists have a powerful arsenal of equipment and medications allowing them to save even the most hopeless patients. However, the prognosis for this condition remains extremely guarded, even with modern intensive care advances.

Following stabilization in the intensive care unit, prolonged treatment and rehabilitation may be required, both in the hospital and in the coming months after discharge home.

It is very important to understand that sepsis is an extremely serious illness that cannot be cured in a single day; it can be marked by periods of improvement and worsening. Therefore, it is vital to have patience and resilience, maintain calm, show love for your child, retain faith in their recovery, and trust the doctors who will do everything possible to restore their little patient's health.

Remember that your mood directly affects your baby's condition!

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

Appendix G1.

Russian title: Pediatric SOFA score.

Original title: Pediatric Sequential Organ Failure Assessment Score (pSOFA).

Source: Matics TJ, Sanchez-Pinto LN. Adaptation and Validation of a Pediatric Sequential Organ Failure Assessment Score and Evaluation of the Sepsis-3 Definitions in Critically Ill Children. JAMA Pediatr. 2017;171(10):e172352. doi:10.1001/jamapediatrics.2017.2352

Type: rating scale.

Purpose: assessment of the severity of multiorgan dysfunction in children with sepsis.

Content:

Dysfunction	Points
	0	1	2	3	4
Respiratory system
PaO₂/FiO₂	≥ 400	300 – 399	200 – 299	100 – 199	< 100
SpO₂/FiO₂	> 292	264 – 291	221 – 264	148 – 220	< 148
Cardiovascular system Mean arterial pressure (mmHg) or cardiotonic agents (ATC C01C: cardiac stimulants excluding cardiac glycosides), mcg·kg^-1·min^-1
0 – 30 days	≥ 46	< 46	Dopamine < 5 mcg·kg^-1·min^-1or #dobutamine at any dose	Dopamine > 5 mcg·kg^-1·min^-1 Epinephrine or norepinephrine** ≤ 0.1 mcg·kg^-1·min^-1	Dopamine > 5 mcg·kg^-1·min^-1 Epinephrine or norepinephrine** > 0.1 mcg·kg^-1·min^-1
1 – 11 months 30 days	≥ 55	< 55
1 year – 1 year 11 months 30 days	≥ 60	< 60
2 years – 4 years 11 months 30 days	≥ 62	< 62
5 years – 11 years 11 months 30 days	≥ 65	< 65
12 years – 18 years	≥ 67	< 67
≥ 18 years	≥ 70	< 70
Kidneys, creatinine (mg/dL)
0 – 30 days	< 0,8	0,8 – 0,9	1,0 – 1,1	1,2 – 1,5	≥ 1,6
1 – 11 months 30 days	< 0,3	0,3 – 0,4	0,5 – 0,7	0,8 – 1,1	≥ 1,2
1 year – 1 year 11 months 30 days	< 0,4	0,4 – 0,5	0,6 – 1,0	1,1 – 1,4	≥ 1,5
2 years – 4 years 11 months 30 days	< 0,6	0,6 – 0,8	0,9 – 1,5	1,6 – 2,2	≥ 2,3
5 years – 11 years 11 months 30 days	< 0,7	0,7 – 1,0	1,1 – 1,7	1,8 – 2,5	≥ 2,6
12 years – 18 years	< 1,0	1,0 – 1,6	1,7 – 2,8	2,9 – 4,1	≥ 4,2
≥ 18 years	< 1,2	1,2 – 1,9	2,0 – 3,4	3,5 – 4,9	≥ 5,0
Kidneys, creatinine (μmol/L)*
0 – 30 days	< 70,72	70,72 – 79,56	88,4 – 97,24	106,08 – 132,6	141,44
1 – 11 months 30 days	< 26,52	26,52 – 35,36	44,2 – 61,88	70,72 – 97,24	106,08
1 year – 1 year 11 months 30 days	< 35,36	35,36 – 44,2	53,04 – 88,4	97,24 – 123,76	132,6
2 years – 4 years 11 months 30 days	< 53,04	53,04 – 70,72	79,56 – 132,6	141,44 – 194,48	203,32
5 years – 11 years 11 months 30 days	< 61,88	61,88 – 88.4	97,24 – 150,28	159,12 – 221,0	229,84
12 years – 18 years	< 88,4	88,4 – 141,44	150,28 – 247,52	256,36 – 362,44	371,28
≥ 18 years	< 106,08	106,08 – 167,96	176,8 – 300,56	309,4 – 433,16	442,0
Blood system
Platelets ×10⁹/L	≥ 150	100 – 149	50 – 99	20 – 49	< 20
Liver
Bilirubin (mg/dL**)	< 1,2	1,2 – 1,9	2,0 – 5,9	6,0 – 11,9	≥ 12
Bilirubin (µmol/L)	< 20,52	20,52 – 32,49	34,2 – 100,89	102,6 – 203,49	≥ 205,2
Central nervous system
Pediatric Glasgow Coma Scale	15	13 – 14	10 – 12	6 – 9	< 6

* µmol/L = mg/dL × 88.4

** µmol/L = mg/dL × 17.1

Interpretation: the higher the score, the more severe the patient's condition and the higher the probability of an unfavorable outcome.

Comment:

The pSOFA score in patients admitted to the ICU is assessed daily.
Scoring is performed by summing the scores of seven organ systems (CNS, respiratory, cardiovascular, renal, hepatic, and hematologic).
For the evaluation of each system, the worst value recorded during the 24-hour period is selected.

Appendix G2.

Russian title: Phoenix Sepsis Score.

Original title: Phoenix Sepsis Score.

Source: Schlapbach L.J., Watson R.S., Sorce L.R., et al. Society of Critical Care Medicine Pediatric Sepsis Definition Task Force. International Consensus Criteria for Pediatric Sepsis and Septic Shock. JAMA. 2024; 331(8): 665–74. DOI: 10.1001/jama.2024.017914

Type: rating scale.

Purpose: assessment of the severity of multiorgan dysfunction in children with sepsis.

Content:

Indicator	0		1		2
*Respiratory system (maximum 3 points)*
Oxygenation	PaO₂/ FiO₂≥ 400 or SpO₂ / FiO₂ ≥ 292	PaO₂/ FiO₂ < 400 or SpO₂ / FiO₂ < 292 receiving any respiratory support		PaO₂/FiO₂100–200 or SpO₂/FiO₂ 148–220 on mechanical ventilation		PaO₂/FiO₂<100 or SpO₂/FiO₂ < 148 on mechanical ventilation
*Cardiovascular system (maximum 6 points)*
Indicator	0		1		2
Drug support	Absent		1 drug (1 point)		≥ 2 drugs (2 points)
Lactate, mmol/L	Less than 5		5 – 10,9 (1 point)		> 11 (2 points)
*Mean arterial pressure, mmHg*
Age	0 points		1 point		2 points
< 1 month	> 30		17 – 30		< 17
1–12 months	> 38		25 – 38		< 25
1 – 2 years	> 43		31 – 43		< 31
2–5 years	> 44		32 – 44		< 32
5 – 12 years	> 48		36 – 48		< 36
12 – 17 years	> 51		38 – 51		< 38
*Hemostasis system (maximum 2 points)*
Indicator	0				1
Platelets	≥ 100 × 10⁹/L				< 100 × 10⁹/L
International Normalized Ratio	≤ 1,3				> 1,3
D-dimer	≤ 2 mg/L				> 2 mg/L
Fibrinogen	≥ 100 mg/dL				< 100 mg/dL
*Central nervous system (maximum 2 points)*
Indicator	0		1		2
Assessment using the Glasgow Coma Scale	> 10 points		≤ 10 points		–
Pupillary light reflex	Preserved				Bilateral mydriasis

Interpretation:

Sepsis: suspected infection + Phoenix Sepsis Score greater than 2 points.

Septic shock: sepsis + cardiovascular dysfunction score greater than 1 point.

Note:

a) The Phoenix Sepsis Score can be calculated even in the absence of certain variables. The severity of cardiovascular dysfunction can be assessed in the absence of certain parameters. If the lactate level is unknown and vasoactive drugs are not used, the score should be based on blood pressure indicators. Laboratory studies and other measurements should be performed at the discretion of the medical team based on clinical judgment. Unmeasured variables are not scored. Age is not adjusted for prematurity, and the criteria do not apply to hospitalized newborns delivered at a postmenstrual age of less than 37 weeks, nor to individuals aged 18 years and older.

b) The SpO₂/FiO₂ ratio is calculated only if SpO₂ is less than 97%.

c) Respiratory dysfunction (1 point) can be diagnosed in any patient receiving oxygen, high-flow nasal cannula, non-invasive positive pressure ventilation, or mechanical ventilation, and includes a PaO₂/FiO₂ ratio of less than 200 and an SpO₂/FiO₂ ratio of less than 220 in children not requiring mechanical ventilation.

d) Inotropic agents, excluding cardiac glycosides (ATC C01C), include epinephrine**, norepinephrine**, dopamine**, dobutamine**, and/or desmopressin** (not approved in Russia for shock), prescribed at any dose.

e) The physiological lactate range is 0.5–2.2 mmol/L. Lactate can be assessed in an arterial or venous blood sample.

f) Age is not adjusted for prematurity; the scale is not used in children with a postmenstrual age of less than 37 weeks or in patients older than 18 years.

g) It is preferable to use mean arterial pressure (MAP) (invasive arterial, if available, or non-invasive oscillometric); if measured MAP is not available, calculated MAP (1/3 × systolic + 2/3 × diastolic) can be used as an alternative.

h) Reference ranges for hemostasis parameters: platelets from 150 to 450 × 103 /µL; D-dimer < 0.5 mg/L; D-dimer, fibrinogen from 1.80 to 4.1 g/L.

i) The severity of neurological dysfunction is assessed in all patients, regardless of the use of hypnotics and sedatives (ATC code N05C) and mechanical ventilation.

j) The Glasgow Coma Scale assesses the level of consciousness based on verbal response, eye opening, and motor activity (range from 3 to 15 points; a higher score indicates better CNS function).

Appendix G3. Modified Pediatric SOFA Score (mpSOFA)

Characteristics				Score, points
				Respiratory system (maximum score 4 points)
				0	1				2				3			4
PaO₂/FiO₂				≥ 400	300 – 399				200 – 299				100 – 199			< 100
SpO₂/FiO₂				> 292	264 – 291				221 – 264				148 – 220			< 148
Characteristics				Cardiovascular system (maximum score 6 points)
Pharmacological support^b				Absent		1 vasoactive agent (1 point)							2 or more vasoactive agents (2 points)			–
Lactate, mmol/L^c				< 5 mmol/L		5,0 – 9,0 (1 point)							5,0 – 9,0 (2 points)			–
Mean arterial pressure, mmHg^d
Age	0 points							1 point				2 points
< 1 month	> 30							17 – 30				< 17
1–12 months	> 38							25 – 38				< 25
1 – 2 years	> 43							31 – 43				< 31
2–5 years	> 44							32 – 44				< 32
5 – 12 years	> 48							36 – 48				< 36
12 – 17 years	> 51							38 – 51				< 38
Characteristics	Kidneys, creatinine (mg/dL) (maximum score 4 points)
Characteristics	0		1			2				3					4
0 – 30 days	< 0,8		0,8 – 0,9			1,0 – 1,1				1,2 – 1,5					≥ 1,6
1 – 11 months 30 days	< 0,3		0,3 – 0,4			0,5 – 0,7				0,8 – 1,1					≥ 1,2
1 year – 1 year 11 months 30 days	< 0,4		0,4 – 0,5			0,6 – 1,0				1,1 – 1,4					≥ 1,5
2 years – 4 years 11 months 30 days	< 0,6		0,6 – 0,8			0,9 – 1,5				1,6 – 2,2					≥ 2,3
5 years – 11 years 11 months 30 days	< 0,7		0,7 – 1,0			1,1 – 1,7				1,8 – 2,5					≥ 2,6
12 years – 18 years	< 1,0		1,0 – 1,6			1,7 – 2,8				2,9 – 4,1					≥ 4,2
≥ 18 years	< 1,2		1,2 – 1,9			2,0 – 3,4				3,5 – 4,9					≥ 5,0
1 – 11 months 30 days	< 26,52		26,52 – 35,36			44,2 – 61,88				70,72 – 97,24					106,08
1 year – 1 year 11 months 30 days	< 35,36		35,36 – 44,2			53,04 – 88,4				97,24 – 123,76					132,6
2 years – 4 years 11 months 30 days	< 53,04		53,04 – 70,72			79,56 – 132,6				141,44 – 194,48					203,32
5 years – 11 years 11 months 30 days	< 61,88		61,88 – 88.4			97,24 – 150,28				159,12 – 221,0					229,84
12 years – 18 years	< 88,4		88,4 – 141,44			150,28 – 247,52				256,36 – 362,44					371,28
≥ 18 years	< 106,08		106,08 – 167,96			176,8 – 300,56				309,4 – 433,16					442,0
Characteristics	Kidneys, creatinine (µmol/L*) (maximum score 4 points)
Characteristics	0		1			2				3					4
0 – 30 days	< 70,72		70,72 – 79,56			88,4 – 97,24				106,08 – 132,6					141,44
1 – 11 months 30 days	< 26,52		26,52 – 35,36			44,2 – 61,88				70,72 – 97,24					106,08
1 year – 1 year 11 months 30 days	< 35,36		35,36 – 44,2			53,04 – 88,4				97,24 – 123,76					132,6
2 years – 4 years 11 months 30 days	< 53,04		53,04 – 70,72			79,56 – 132,6				141,44 – 194,48					203,32
5 years – 11 years 11 months 30 days	< 61,88		61,88 – 88.4			97,24 – 150,28				159,12 – 221,0					229,84
12 years – 18 years	< 88,4		88,4 – 141,44			150,28 – 247,52				256,36 – 362,44					371,28
≥ 18 years	< 106,08		106,08 – 167,96			176,8 – 300,56				309,4 – 433,16					442,0
Characteristics	Hematologic system (maximum score 4 points)
Characteristics	0		1			2				3					4
Platelets × 10⁹/L	≥ 150		100 – 149			50 – 99				20 – 49					< 20
Characteristics	Liver (maximum score 4 points)
Characteristics	0		1			2				3					4
Bilirubin (mg/dL**)	< 1,2		1,2 – 1,9			2,0 – 5,9				6,0 – 11,9					≥ 12
Bilirubin (µmol/L)	< 20,52		20,52 – 32,49			34,2 – 100,89				102,6 – 203,49					≥ 205,2
Characteristics	Central nervous system
Characteristics	0	1					2				3			4
Pediatric Glasgow Coma Scale	15	13 – 14					10 – 12				6 – 9			< 6

* µmol/L = mg/dL × 88.4.

** µmol/L = mg/dL × 17.1.

Interpretation:

The diagnosis of sepsis is established in the presence of suspected infection and an mpSOFA score ≥ 2 points.
The diagnosis of septic shock is established in the presence of confirmed sepsis and a cardiovascular dysfunction severity score ≥ 1 point.
The higher the mpSOFA score, the more severe the patient's condition and the worse the outcome.

Comment:

a) The severity of cardiovascular dysfunction can be assessed even in the absence of certain parameters. If the lactate level is unknown and vasoactive agents are not used, the assessment must be based on blood pressure measurements.

b) Inotropic agents, excluding cardiac glycosides (ATC C01C), include any dose of epinephrine**, norepinephrine**, dopamine**, dobutamine**, and/or desmopressin** (not approved for shock in Russia).

c) The physiological range of lactate is 0.5–2.2 mmol/L. Lactate can be measured in arterial or venous blood samples.

d) Age is not adjusted for prematurity; the criteria are not used in children with a gestational age of less than 37 weeks and in patients older than 18 years.

e) The Glasgow Coma Scale assesses the level of consciousness based on verbal, visual, and motor responses (ranging from 3 to 15 points, with a higher score indicating improved neurological function).

mpSOFA scoring in ICU patients is performed daily.
Scoring is performed by summing the scores of seven organ systems (CNS, respiratory, cardiovascular, renal, hepatic, and hematologic).
For the assessment of each system, the worst value recorded during the 24-hour period is selected.

Scales and calculators from this guideline

Norepinephrine calculatorCalculation of norepinephrine infusion rate in ml/h based on dose in mcg/kg/min, weight Dopamine calculatorCalculation of dopamine infusion rate (mcg/kg/min → ml/h) with automatic Dobutamine calculatorCalculation of dobutamine infusion rate (mcg/kg/min → ml/h) with automatic Glasgow Coma Scale (GCS)Assessment of the level of consciousness SOFAAssessment of multiple organ dysfunction (sepsis, ICU)

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Nongonococcal (nonspecific) urethritis in men
A49.3, A56.0, A59.0, A60, A63.8, B37.4…adults2024full text
Viral meningitis in children
A87.0, A87.1, A87.2, A87.8, A87.9, B00.3…children2025full text
Meningococcal Infection in Children
A39, Z22.3children2023full text
Postpartum infectious complications
O08.0, O75.3, O85, O86.0, O86.1, O86.4…adults, children2024full text
Fungal otitis externa
B37.8, B44.8, B49, H60.8, H62.2, H66.3adults, children2024full text
Meningococcal infection
A39adults2026full text
Herpes simplex (HS) in adults
B00.1, B00.2, B00.3, B00.4, B00.7, B00.8…adults2025full text