Sepsis in children

To date, sepsis in children remains the leading cause of hospital mortality among pediatric patients.

Over the past 10 years, the definition of sepsis in children has been used as in adults, with different critical threshold values of SIRS. Meanwhile, it is known that the proportion of children with concomitant diseases (including immune disorders) among sick children with severe sepsis exceeds that in adults.

Currently, sepsis is understood as a systemic inflammatory reaction with a suspected or proven infection (bacterial, viral, fungal or rickettsial origin).

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Severe sepsis is the fourth leading cause of death in children under 1 year of age and the second leading cause of death in children aged 1 to 14 years. In 1995, more than 42,000 cases of bacterial or fungal sepsis in children were reported in the United States, with a mortality rate of 10.3% (i.e., about 4,300 patients, which is 7% of all child mortality). The cost of treating sepsis in children in the United States is $1.97 billion per year.

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Classification of sepsis

Systemic inflammatory response syndrome - the presence of at least two of the following four criteria, one of which must be an abnormal temperature or white blood cell count.

1. central temperature >38.5 °C or <36.0 °C,
2. tachycardia, defined as an average heart rate exceeding two square deviations from the age norm (in the absence of external and painful stimuli, long-term medication use) for more than 30 minutes, for children under 1 year - bradycardia, defined as an average heart rate less than the 10th age percentile (in the absence of an external vagal stimulus, the use of beta-blockers or congenital heart defects) lasting more than 30 minutes,
3. mean respiratory rate exceeding two square deviations from the age norm, or the need for mechanical ventilation in acute illness not associated with general anesthesia or neuromuscular diseases,
4. the number of leukocytes is greater or less than the age norm (not secondary leukopenia caused by chemotherapy) or more than 10% immature neutrophils.

Infection - presumed or proven (bacterial culture, histologic confirmation of infection, or positive PCR) caused by any pathogenic microorganism, or clinical syndromes associated with a high probability of infection. Evidence of infection includes positive findings or clinical explanation on imaging or laboratory tests (leukocytes in sterile body fluids and cavities, petechial or purpuric rash or acute purpura, pulmonary infiltrates on radiographs, intestinal perforation).

Sepsis - SIRS in the presence of or as a result of suspected or proven infection.

Severe sepsis is sepsis plus one of the following: cardiovascular organ dysfunction or ARDS, or two or more dysfunctions of other organs and systems (respiratory, renal, neurological, hematological, hepatobiliary).

Septic shock - sepsis and cardiovascular organ dysfunction.

The definition and classification of pediatric sepsis were based on the SIRS criteria used in the ENHANCE clinical trial of recombinant human activated protein C in severe sepsis in children. The experts took into account that in children, tachycardia and tachypnea are non-specific symptoms of many pathological processes. In this regard, the main differences in the definition of SIRS between adults and children are that either changes in body temperature or changes in the white blood cell count are necessary to diagnose SIRS in children (SIRS in a child cannot be diagnosed based on dyspnea and tachycardia alone). In addition, some criteria should be modified taking into account the child's age. In particular, bradycardia may be a sign of SIRS in neonates and infants, whereas in older children, a rare heart rate is a sign of a pre-terminal state. Hypothermia (body temperature below 36 °C) may also indicate a serious infection, especially in infants.

Body temperature above 38.5 °C increases specificity and influences the nature of intensive care. Temperature measured on the toe by temporal or axillary access cannot be considered sufficiently accurate. Central temperature should be measured by rectal, bladder or central catheter (in the pulmonary artery).

In adults and young children, diagnostic criteria for septic shock differ significantly. In pediatric practice, shock is defined as tachycardia (may be absent in hypothermia) with symptoms of decreased perfusion (weakening of the peripheral pulse compared to the central one, changes in its filling, an increase in the capillary filling time to 2 s or more, marbled and cold extremities, decreased diuresis). It should be remembered that in children, arterial hypotension is a late sign of shock, a manifestation of decompensation of the circulatory system, i.e. shock in a child can occur long before the onset of arterial hypotension.

It should be noted that there is no evidence base for the above points, so the information provided is based on expert opinions and medical literature data.

It is necessary to take into account the age characteristics of patients, since the clinical differences between SIRS and organ failure largely depend on the physiological changes that occur in the child's body as he or she grows up. For this reason, the definition of sepsis in a child depends on both biological and actual age and laboratory data. Taking into account the characteristics of the course of sepsis, 6 clinically and physiologically significant age groups, as well as threshold diagnostic values of SIRS signs, are proposed.

Age groups of children in relation to the definition of severe sepsis

Newborns	0-7 days of life
Newborns	1 week - 1 month
Babies	1 month - 1 year
Preschoolers	2-5 years
Schoolchildren	6-12 years
Teenagers	13-18 years old

These age groups were determined taking into account the features of the possible risk of invasive infections, age specificity, antibiotic therapy and age-related cardiorespiratory physiological changes. An important feature of the age gradation is the division of newborns into two groups up to 7 days and from 7 days to 1 month.

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Diagnostic criteria for organ dysfunction in children with severe sepsis

Cardiovascular dysfunction - arterial hypotension despite intravenous fluid administration of 40 ml/kg for 2 hours (systolic BP decreased by two square deviations from the age-specific normal value), or the need for vasopressors to maintain BP within the normal range (dopamine or dobutamine more than 5 mcg/kg per minute or any dose of epinephrine or norepinephrine), or two of the following five symptoms:

1. metabolic acidosis (base deficit over 5 mmol/l),
2. lactacidemia over 4 mmol/l,
3. oliguria (diuresis <0.5 ml/kg per hour, in newborns <1 ml/kg per hour),
4. extension of capillary filling time by more than 5 s,
5. skin-rectal temperature gradient exceeding 3°C.

Respiratory dysfunction paO2/FiO2 <300 in the absence of cyanotic congenital heart disease or associated pulmonary pathology, or paCO2 >60 mmHg, or 20 mmHg above normal paCO2, or the need for FiO2 >0.5 to maintain SaO2 >92%, or the need for mechanical ventilation.

Neurological dysfunction Glasgow Coma Scale score <11 points or acute change in mental status with a decrease in Glasgow Coma Scale score by 3 points.

Hematological dysfunction - platelet count <80x10 ⁹ /l or a decrease of 50% of the highest count over the last 3 days (for chronic oncohematological patients).

Renal dysfunction - plasma creatinine is 2 times higher than the age norm or has increased 2 times from the baseline value.

Liver dysfunction:

• total bilirubin concentration >68.4 μmol/l (except newborns),
• ALT activity is 2 times higher than the age norm

Microbiological diagnostics of sepsis involves examination of the probable source of infection and peripheral blood. When the same pathogenic microorganism is isolated from both loci, its etiological role is considered proven. When different pathogens are isolated from the source of infection and peripheral blood, the etiological significance of each of them must be assessed. It should be remembered that bacteremia (the presence of a microorganism in the systemic bloodstream) is not a pathognomonic sign of sepsis. Detection of microorganisms without clinical and laboratory confirmation of SIRS should be regarded not as sepsis, but as transient bacteremia.

When isolating typical pathogenic microorganisms (S. aureus, Kl. pneumoniae, Ps. aeruginosa, fungi), one positive result is sufficient to establish a diagnosis. When isolating skin saprophytes, two blood cultures are necessary to confirm true bacteremia.

Some experts recommend early aggressive management of pediatric patients with severe sepsis and septic shock to reduce mortality by 25% over the next 5 years. Comprehensive intensive care for pediatric sepsis should include source control (in collaboration with surgeons), adequate antibacterial therapy, multicomponent concomitant intensive care, and prevention of associated organ dysfunction.

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Treatment of sepsis in children

Antibacterial therapy

The most important component of intensive care for sepsis is antibiotics, since early adequate empirical antibacterial therapy for sepsis helps reduce mortality and the frequency of its complications. Accordingly, antibiotics for sepsis should be prescribed immediately upon establishing a nosological diagnosis and before receiving the results of a bacteriological study. After receiving the results of a bacteriological study, the antibiotic therapy regimen can be changed taking into account the sensitivity of the isolated microflora.

[ 14 ], [ 15 ], [ 16 ], [ 17 ]

Antibiotic Doses (Single) for Sepsis Treatment in Children

Penicillins

Amoxicillin/clavulanate	30 mg/kg amoxicillin 2 times/day	30-40 mg/kg amoxicillin 3 times/day
Ampicillin	50 mg/kg 3 times/day	50 mg/kg 4 times/day
Oxacillin	50 mg/kg 3 times/day	50 mg/kg 4 times/day
Ticarcillin/clavulanate	80 mg/kg 2 times/day	80 mg/kg 3 times/day

Cefazolines of the I-III generation without antipseudomonal activity

Cefazalin	20 mg/kg 2-3 times/day	30 mg/kg 3 times/day
Cefotaxime	50 mg/kg 3 times/day	30-50 mg/kg 3 times/day
Ceftriaxone	50 mg/kg 1 time/day	50-75 mg/kg 1 time/day
Cefuroxime	50 mg/kg 3 times/day	50 mg/kg 3 times/day
Cefazolines of the I-III generation with antipseudomonal activity
Cefepime	30 mg/kg 3 times/day	30 mg/kg 3 times/day
Cefoperazone	30 mg/kg 2 times/day	30 mg/kg 3 times/day
Ceftazidime	50 mg/kg 2-3 times/day	50 mg/kg 3 times/day
Cefoperazone/sulbactam	20 mg/kg cefoperazone 2 times/day	20 mg/kg cefoperazone 2 times/day

Carbapenems

Meropenem	20 mg/kg 3 times/day	20 mg/kg 3 times/day
Imipenem/cilastatin	| 15 mg/kg 4 times/day |	15 mg/kg 4 times/day

Aminoglycosides

Amikacin	7.5-10 mg/kg 1 time/day	10-15 mg/kg 1 time/day
Gentamicin	2-4 mg/kg 2 times/day	4 mg/kg 2 times/day
Netilmicin	4-6 mg/kg 1 time/day	5-7 mg/kg 1 time/day

Fluoroquinolones

Ciprofloxacin

Not applicable

5-10 mg/kg 2 times/day

Drugs with antianaerobic activity

Metronidazole

3.5 mg/kg 2 times/day

7.5 mg/kg 2 times/day

Drugs with antistaphylococcal activity

Vancomycin	20 mg/kg 2 times/day	20-30 mg/kg 2 times/day
Linezolid	10 mg/kg 2 times/day	10 mg/kg 2 times/day
Rifampicin	5 mg/kg 2 times/day	5 mg/kg 2 times/day
Fusidin	20 mg/kg 3 times/day	20 mg/kg 3 times/day

Drugs with antifungal activity

Amphotericin B	0.25-1 mg/kg 1 time per day	0.25-1 mg/kg 1 time per day
Voriconazole	No data	8 mg/kg 2 times/first day, then 4 mcg 2 times/day
Caspofungin	50 mg/m2 1 time/day	50 mg/m2 1 time/day
Fluconazole	10-15 mg/kg 1 time/day	10-15 mg/kg 1 time/day

To conduct an adequate microbiological blood test, the following rules must be observed:

• Blood for testing should be collected before antibiotics are prescribed. If antibacterial therapy is already being administered, blood should be collected before the drug is administered. Taking blood at the height of the fever does not increase the sensitivity of the method.
• Blood for testing must be collected from a peripheral vein.
• Blood should be collected from a venous catheter for microbiological testing only if catheter-associated sepsis is suspected. In this case, a simultaneous quantitative bacteriological study of blood obtained from an intact peripheral vein and from a suspect catheter should be performed. If the same microorganism is isolated from both samples and the quantitative ratio of the bacterial counts of the catheter and vein samples is equal to or greater than 5, the catheter is most likely the source of sepsis and should be removed.

Careful preparation of the skin at the site of puncture of the peripheral vein, the cap of the bottle with the medium, and the use of commercial blood collection systems with an adapter can reduce the degree of contamination of samples to 3% or less.

The empirical choice of antibacterial drugs already at the first stage of treatment determines the use of antibiotics with a sufficiently wide spectrum of activity, sometimes in combination, given the extensive list of potential pathogens with different sensitivities. When the primary lesion is localized in the abdominal cavity and oropharynx, the participation of anaerobic microorganisms in the infectious process should also be suspected. Another parameter that determines the initial empirical therapy program for sepsis is the severity of the disease. Severe sepsis with MOF has a higher mortality rate and terminal septic shock, therefore, the use of the maximum antibacterial therapy regimen in a child with severe sepsis should be carried out at the earliest stage of treatment. Due to the fact that early use of adequate antibacterial therapy reduces the risk of death, the antibiotic effectiveness factor should dominate over its cost.

In addition, the rational choice of the initial antibacterial therapy regimen for sepsis depends not only on the localization of the source (focus) of infection, but also on the conditions of infection occurrence (community-acquired or nosocomial). It is also necessary to plan not only the coverage of all potential pathogens, but also the possibility of participation in the infectious process of multidrug-resistant hospital strains of microorganisms (the so-called problem microorganisms). These include many gram-positive (methicillin-resistant staphylococci, penicillin-resistant pneumococci, multidrug-resistant enterococci) and gram-negative (Kl. pneumoniae, E. coli, Serratia marcesens, Ps. aeruginosa, Stenotrophomonas maltophilia, Acinetobacter spp) bacteria. In this regard, the optimal regimen of empirical therapy for severe nosocomial sepsis is the use of carbapenems (meropenem, imipenem) as drugs with the broadest spectrum of activity and the lowest level of resistance among the "problem" strains of gram-negative bacteria. When prescribing imipenem to a child, it should be remembered that the prepared solution must be used within 1 hour, otherwise it becomes unusable (i.e., it is unacceptable to administer the drug from one bottle to the patient within 24 hours). In addition, meropenem penetrates the brain tissue better and therefore serves as the drug of choice for sepsis against the background of meningitis, while imipenem, with impaired BBB permeability, can cause seizures as a result of the action of the cilastatin component.

Antibacterial therapy for sepsis with an unknown primary focus

Conditions of occurrence	1st line remedies	Alternative drugs
Sepsis developed in the community setting	Amoxicillin/clavulanate (sulbactam) ± aminoglycoside	Ciprofloxacin + metronidazole
	Ampicillin/sulbactam + aminoglycoside
	Ceftriaxone ± metronidazole
	Cefotaxime ± metronidazole
Hospital-acquired sepsis without MODS	Cefepime ± metronidazole	Meropenem
	Cefoperazone/sulbactam	Imipenem
		Ceftazidime ± metronidazole
		Ciprofloxacin + metronidazole
Sepsis developed in a hospital setting, presence of MODS	Meropenem	Cefepime + metronidazole
	Imipenem	Cefoperazone/sulbactam
		Ciprofloxacin ± metronidazole

If the indicated treatment regimens are ineffective, the advisability of additional administration of vancomycin or linezolid, as well as systemic antifungals (fluconazole, caspofungin, voriconazole) should be assessed.

When an etiologically significant microorganism is detected from the blood or primary source of infection, it becomes possible to carry out etiotropic therapy taking into account sensitivity, which significantly increases the effectiveness of treatment.

Recommendations for etiotropic therapy of sepsis

Streptococcus viridans

Streptococcus pneumoniae

Enterococcus faecalis

Burcholdena cepacica

Gram-positive organisms
Staphylococcus aureus, Staphylococcus epidermidis	Oxacillin	Amoxicillin/clavulanate
	Cefazolin	Cefuroxime
OH
Staphylococcus aureus, Staphylococcus epidermidis	Vancomycin	Rifampicin + co-trimoxazole (ciprofloxacin)
	Linezolid
OP		Fusidine + co-trimoxazole (ciprofloxacin)
Ampicillin	Vancomycin
Benzylpenicillin	Cefotaxime
	Ceftriaxone
Cefotaxime	Ampicillin
Ceftriaxone	Benzylpenicillin
Cefepime	Vancomycin
	Meropenem
	Imipenem
Ampicillin + gentamicin	Vancomycin ± gentamicin
	Linezolid
Enterococcus faecium	Linezolid	Vancomycin + gentamicin
Gram-negative organisms
E coli,	Amoxicillin/clavulanate	Meropenem
P mirabilis	Cefotaxime	Imipenem
	Ceftriaxone	Cefepime
		Ciprofloxacin
K. pneumoniae	Meropenem	Amikacin
P vulgaris	Imipenem	Cefepime
		Cefoperazone/sulbactam
		Cefotaxime
		Ceftriaxone
		Ciprofloxacin
Enterobacter spp	Meropenem	Amikacin
Citrobacter spp	Imipenem	Cefotaxime
Serratia spp	Cefepime	Ceftriaxone
		Ciprofloxacin
Acinetobacter spp	Meropenem	Ampicillin/sulbactam
	Imipenem	Ceftazidime + amikacin
	Cefoperazone/sulbactam	Ciprofloxacin + amikacin
P. aeruginosa	Meropenem	Cefoperazone/sulbactam + amikacin
	Ceftazidime + amikacin	Ciprofloxacin ± amikacin
	Cefepime + amikacin	Imipenem
Meropenem	Ceftazidime
Ciprofloxacin	Cefoperazone
	Co-trimoxazole
Stenotrophomonas maltophilia	Co-trimoxazole	Ticarcillin/clavulanate
Candida spp	Fluconazole	Voriconazole
	Caspofungin	Amphotericin B

Anaerobic microorganisms are not clinically significant in all forms of sepsis, but mainly when the primary focus is localized in the abdominal cavity (usually Bacteroides spp.) or soft tissues (Clostridium spp, etc.). In these cases, it is advisable to prescribe antibacterial therapy regimens with antianaerobic activity. Protected ß-lactams and carbapenems exhibit high activity against anaerobic microorganisms and can be used in monotherapy. Cephalosporins, aminoglycosides, and fluoroquinolones (except moxifloxacin) do not have clinically significant activity against anaerobes, so they should be combined with metronidazole.

Fungal sepsis is considered to be the most severe form of the disease with a mortality rate exceeding 50%. In intensive care practice, fungal sepsis most often refers to candidemia and acute disseminated candidiasis. Candidemia is a single isolation of Candida spp. during blood culture, taken during a period of body temperature rise above 38 °C or in the presence of other signs of SIRS. Acute disseminated candidiasis is understood as a combination of candidemia with mycological or histological signs of deep tissue damage or the isolation of Candida spp from two or more normally sterile loci of the body.

Unfortunately, the treatment options for fungal sepsis are currently limited to four drugs: amphotericin B, caspofungin, fluconazole, and voriconazole. When choosing an antifungal drug, it is important to know the genus of Candida, since some of them (C. glabrata, C. krusei, C parAPSilosis) are most often resistant to azoles, but remain sensitive to amphotericin B and caspofungin, which is much less toxic to the macroorganism. In addition, it should be remembered that the unjustifiably frequent use of fluconazole for the prevention of fungal superinfection leads to the selection of C albicans strains that are also resistant to azoles, but are usually sensitive to caspofungin.

It should be remembered that the use of antibacterial therapy does not mean the need for the simultaneous administration of antifungal drugs to prevent fungal superinfection. The use of antifungal drugs for the primary prevention of invasive candidiasis is recommended only for patients with a high risk of developing this complication (prematurity, immunosuppression, repeated intestinal perforation).

When choosing an antibacterial therapy regimen, liver and kidney function should also be taken into account. In acute renal failure, aminoglycosides and vancomycin are contraindicated, fluconazole dose adjustment is necessary, and in acute renal failure and hyperbilirubinemia of newborns, ceftriaxone, metronidazole, and amphotericin B are not used.

Criteria for the adequacy of antibacterial therapy for sepsis:

• Positive dynamics of the main organ symptoms of infection.
• No signs of SIRS.
• Normalization of gastrointestinal function.
• Normalization of the number of leukocytes in the blood and the leukocyte formula.
• Negative blood culture.

The persistence of only one sign of bacterial infection (fever or leukocytosis) is not considered an absolute indication for continuing antibacterial therapy. Isolated subfebrile fever (maximum daytime temperature within 37.9 °C) without chills and changes in the blood test is usually not an indication for continuing antibiotic therapy, as is the persistence of moderate leukocytosis (9-12x10 ⁹ /l) in the absence of a left shift and other signs of bacterial infection.

In the absence of a stable clinical and laboratory response to adequate antibacterial therapy within 5-7 days, additional examination (ultrasound, CT, MRI, etc.) is necessary to search for complications or an infectious focus of another localization. In addition, it should be remembered that in sepsis against the background of osteomyelitis, endocarditis, purulent meningitis, a longer duration of antibacterial therapy is necessary due to the difficulty of achieving effective concentrations of drugs in the above organs. For infections caused by S. aureus, longer courses of antibiotic therapy (2-3 weeks) are usually recommended.

[ 18 ], [ 19 ], [ 20 ], [ 21 ], [ 22 ], [ 23 ]

Infusion-transfusion therapy of sepsis

Intensive infusion therapy is considered to be the initial treatment for sepsis. Its goals are to replenish the deficit of circulating blood volume and restore adequate tissue perfusion, reduce the plasma concentration of toxic metabolites and proinflammatory cytokines, and normalize homeostatic disorders.

In case of systemic hypotension, it is necessary to administer intravenous fluid in a volume of 40 ml/kg for 2 hours. Subsequently, the child should receive the maximum daily amount of fluid permissible for his age, if necessary - against the background of diuretic therapy.

There are currently no clear recommendations on the choice of the type of infusion medium for sepsis in children. Both crystalloids (balanced salt solutions, isotonic sodium chloride solution, 5% glucose solution) and colloids (albumin, hydroxyethyl starch solutions) can be used. Crystalloid solutions do not negatively affect hemostasis, do not cause anaphylactoid reactions, while colloids circulate in the vascular bed longer against the background of circular leak syndrome and increase the CCP to a greater extent. In general, the experience of using synthetic colloids in children (especially newborns) is significantly less than in adult patients. In this regard, in newborns and children of the first year of life with hypovolemia, crystalloids in combination with albumin solutions (10-20 ml / kg) are considered the drugs of choice. In older children, the composition of the infusion therapy program does not differ from that in adults and depends on the degree of hypovolemia, the presence and phase of DIC, the presence of peripheral edema and the concentration of blood albumin. Soda or trometamol (trisamine) solutions should not be administered at pH values > 7.25.

It should be remembered that in severe ARDS, intravenously administered albumin penetrates the pulmonary interstitium and can worsen gas exchange. For this reason, in severe ARF, it is necessary to administer a test dose of 5 ml/kg of albumin and interrupt the infusion to assess gas exchange; if there is no deterioration in oxygenation within 30 minutes, the remaining amount of albumin can be administered. Transfusion of FFP and cryoprecipitate is indicated only in the presence of clinical signs of DIC. As for the transfusion of erythrocytes, there are no unambiguous recommendations for their use in pediatric sepsis. Most experts recommend maintaining hemoglobin at 100 g/l in sepsis. A mandatory condition for the transfusion of FFP and donor erythrocytes is the use of leukocyte filters, since donor leukocytes play a leading role in worsening the manifestations of SIRS and ARDS.

Inotropic and vasoactive therapy of sepsis

If after intravenous administration of 40 ml/kg of fluid for 2 hours or reaching a central venous pressure of 10-12 mm Hg, blood pressure remains below the age norm, it is necessary to begin an infusion of catecholamines (dopamine, dobutamine, epinephrine, norepinephrine). Due to the impossibility of using a Swan-Ganz catheter and the thermodilution method for measuring CO in children, when choosing a catecholamine, it is necessary to be guided by echocardiography data. If there is a decrease in LVEF to 40% or less, it is necessary to begin an infusion of dopamine or dobutamine at a dose of 5-10 mcg/(kg × min). A combination of dopamine and dobutamine infusion is possible if monotherapy with one of them at a dose of 10 mcg/(kg × min) does not lead to hemodynamic stabilization. If systemic hypotension is observed against the background of normal LVEF (more than 40%), the drugs of choice are norepinephrine or epinephrine (at a dose of 0.02 mcg/kg per minute and higher - until an acceptable blood pressure value is achieved). Epinephrine infusion is also indicated when LVEF decreases, if the administration of a combination of dopamine and dobutamine [at a dose of at least 10 mcg/(kg × min) each] is insufficient to maintain stable blood circulation.

It is important to remember that the Frank-Starling law does not work in young children, and the only way to compensate for decreased cardiac output is a high heart rate. In this regard, it is impossible to fight tachycardia in a child, and any antiarrhythmic drugs are contraindicated in conditions of low cardiac output.

Nutritional support

The development of multiple sclerosis in sepsis is usually accompanied by hypermetabolism. Autocannibalism (covering energy needs at the expense of the material of one's own cells) leads to aggravation of manifestations of multiple sclerosis. In this regard, adequate nutritional support plays the same important role in sepsis as antibiotic therapy. The choice of the method of nutritional support depends on the degree of nutritional deficiency and gastrointestinal dysfunction - oral enteral nutrition, tube nutrition, parenteral nutrition, mixed nutrition.

Enteral nutrition should be started as early as possible, if possible - within the first 24-36 hours after the child is admitted to the intensive care unit. As a starting mixture for enteral nutrition, it is necessary to use semi-elemental children's enteral formulas, followed by (against the background of normalization of the gastrointestinal tract function) a transition to standard adapted milk formulas. The starting volume of a single feeding is 3-4 ml/kg, followed by a stepwise increase to the age norm within 2-3 days.

Parenteral nutrition in sepsis is indicated when it is impossible to carry out enteral feeding in full, it is no different from that in other conditions. The only thing to remember is that in the acute phase it is necessary to introduce the minimum amount of energy for a given age, and in the phase of stable hypermetabolism the maximum amount of energy is introduced. There is evidence that enrichment of both enteral and parenteral nutrition with glutamine (dipeptiven) in sepsis helps to reduce hospital mortality and morbidity.

Contraindications to any nutritional support:

• Refractory shock (hypotension due to infusion of epinephrine or norepinephrine at a dose of more than 0.1 mcg/kg per minute).
• Uncontrolled arterial hypoxemia.
• Decompensated metabolic acidosis.
• Uncorrected hypovolemia.

Activated Protein C

The advent of activated protein C (Zigris), based on data obtained in multicenter studies (PROWESS, ENHANCE), has become a significant breakthrough in the treatment of severe sepsis in adults. Meanwhile, the study on the effectiveness of activated protein C in children (RESOLVE) has not been completed at the time of writing this guideline. Nevertheless, the obtained preliminary data allow us to recommend its administration in severe sepsis with MOF and in children.

Indications for the use of activated protein C in children include the presence of acute respiratory failure or acute respiratory failure against the background of sepsis. Cardiovascular dysfunction, as applied to the administration of activated protein C, is understood as the need for an infusion of >5 mcg/kg per minute of dopamine or dobutamine, or epinephrine / norepinephrine / phenylephrine in any dose, despite the administration of 40 ml/kg of fluid over 2 hours. Respiratory dysfunction is understood as the need for invasive mechanical ventilation against the background of sepsis. A special feature of the use of activated protein C is its administration in the first 24 hours from the onset of the above indications. According to the ENHANCE study, mortality in the group of patients who began infusion of activated protein C in the first 24 hours after the onset of organ dysfunction was lower than in the group with a later start of infusion. The drug is administered intravenously by drip over 24 hours at a dose of 24 mcg/kg per hour.

During diagnostic and therapeutic invasive interventions, a break in drug infusion is required. Monitoring of coagulation parameters can help identify patients with a higher risk of bleeding, but its results do not serve as a basis for adjusting the drug dose. OPN and HD are not considered a contraindication to treatment with activated protein C, while dose adjustment against the background of extracorporeal detoxification methods under systemic heparinization is not indicated.

Interruptions in activated protein C infusion during invasive procedures recommended actions

"Small" procedures
Catheterization of the radial or femoral artery	Stop the infusion 2 hours before the procedure and resume immediately after the procedure if there is no bleeding.
Femoral vein catheterization
Intubation or tracheostomy tube change (if not emergency)
More invasive procedures
Insertion of a central venous catheter or Swan-Ganz catheter (into the subclavian or jugular vein)	Stop the infusion 2 hours before the procedure and resume 2 hours after the procedure if there is no bleeding.
Lumbar puncture
Chest drainage or thoracentesis Paracentesis Percutaneous drainage Nephrostomy Gastroscopy (biopsy is possible) Surgical treatment of the wound (decubital ulcer, infected wound, change of dressing on the open abdominal cavity, etc.)
"Big" procedures
Operation (laparotomy, thoracotomy, extended surgical treatment of the wound, etc.)	Stop the infusion 2 hours before the procedure and resume 12 hours after its completion.
Epidural catheter	Do not use drotrecogin alfa (activated) during epidural catheterization or start the infusion of the drug 12 hours after catheter removal

Contraindications and precautions when using aRS

Contraindications

Precautions

Active internal bleeding Recent (within 3 months) hemorrhagic stroke Recent (within 2 months) brain or spinal cord surgery or severe head injury requiring hospitalization Trauma with an increased risk of life-threatening bleeding (eg, liver injury, spleen injury, or complicated pelvic fracture) Patients with epidural catheter Patients with intracranial tumor or brain destruction confirmed by cerebral herniation

Heparin at a dose of >15 U/kg per hour International Normalized Ratio (INR) >3 Platelet count <30,000/ mm3 even if the count increases after platelet transfusions (USA) This is a contraindication according to the criteria of the European Medicines Evaluation Agency Recent gastrointestinal bleeding (within 6 weeks) Recent (within 3 days) administration of thrombolytic therapy Recent (<7 days) administration of oral anticoagulants or glycoprotein IIb/IIIa inhibitors Recent (<7 days) use of aspirin >650 mg/day or other platelet inhibitors Recent (<3 months) ischemic stroke Intracranial arteriovenous malformation History of hemorrhagic diathesis Chronic severe liver failure Any other condition in which bleeding poses a significant risk or bleeding that would be particularly difficult to treat due to its location

[ 24 ], [ 25 ], [ 26 ], [ 27 ], [ 28 ], [ 29 ], [ 30 ], [ 31 ], [ 32 ]

Glucocorticoids

Current data indicate that the use of high doses of glucocorticoids (in particular, methylprednisolone, betamethasone) in septic shock does not reduce mortality, but is accompanied by an increase in the incidence of purulent-septic complications. The only glucocorticoid recommended today for inclusion in the complex therapy of sepsis is hydrocortisone at a dose of 3 mg/kg per day (in 3-4 injections). The indications for it are quite narrow:

• catecholamine-refractory septic shock,
• severe sepsis due to adrenal insufficiency (plasma cortisol concentration less than 55 nmol/l in newborns and less than 83 nmol/l in older children).

Immunoglobulins

The use of intravenous immunoglobulins in the context of immunoreplacement therapy for severe sepsis is the only proven method of immunocorrection at present. The best results have been achieved with the introduction of a combination of and (pentaglobin). The drug is administered at 5 ml/kg for 3 days. In septic shock, it is permissible to administer 10 ml/kg on the first day and 5 ml/kg on the following day.

Anticoagulants

In order to prevent thromboembolic complications in patients with sepsis, it is necessary to administer sodium heparin (200 U/kg per day). In the presence of thrombocytopenia, preference should be given to low-molecular heparins. Prevention of the formation of stress ulcers of the gastrointestinal tract.

As in adult patients, in older children (over 1 year old) it is necessary to prevent the formation of stress ulcers in the gastroduodenal zone. The drug of choice is the proton pump inhibitor omeprazole. In severe sepsis or septic shock, it is administered intravenously at a dose of 1 mg/kg (no more than 40 mg) once per day.

[ 33 ], [ 34 ], [ 35 ], [ 36 ], [ 37 ]

Glycemic control

The data obtained in a cohort of adult patients that mortality from sepsis is reduced by glycemic control with insulin (maintaining plasma glucose concentration at a level of 4.4-6.1 mmol/l) cannot be extrapolated to young children (and, accordingly, those with low body weight). The reason for this is the technical difficulties in accurately dosing and administering insulin in children weighing less than 10 kg. In these patients, the risk of hyperglycemia turning into hypoglycemia is extremely high.

Based on the above, glycemic control (maintaining plasma glucose concentrations with insulin within 4.5–6.1 mmol/L) should probably be performed in children weighing 15 kg or more.

[ 38 ], [ 39 ], [ 40 ], [ 41 ], [ 42 ], [ 43 ], [ 44 ], [ 45 ]