Sepsis in children

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

Over the past 10 years, children have been using the definition of sepsis adopted in adults, with different critical thresholds for SSER. Meanwhile, it is known that the proportion of children with concomitant diseases (including those with impaired immunity) among sick children with severe sepsis exceeds that of adults.

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

[1], [2], [3], [4], [5]

Severe sepsis ranks fourth among all causes of death of children under 1 year and the second among causes of death of children from 1 year to 14 years. In 1995, there were more than 42,000 cases of bacterial or fungal sepsis in children in the United States with a lethality of 10.3% (ie, about 4,300 patients, or 7% of all child mortality). The cost of treating sepsis in children in the United States is $ 1.97 billion per year.

[6], [7], [8], [9], [10], [11],

Classification of sepsis

The syndrome of a systemic inflammatory reaction is the presence of at least two of the following four criteria, one of which is necessarily an abnormal temperature or the number of leukocytes.

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

Infection - presumed or proven (excising agent, histological confirmation of infection or positive PCR data) caused by any pathogenic microorganism, or clinical syndromes associated with a high probability of infection. Evidence of infection includes positive findings or clinical explanations of imaging or laboratory tests (leukocytes in sterile liquids and body cavities, petechial or purple rash or acute purpura, pulmonary infiltrates on radiographs, intestinal perforation).

Sepsis - SSRM in the presence or as a result of an alleged or proven infection.

Severe sepsis - sepsis plus one of the listed cardiovascular organ dysfunction or ARDS, or two or more dysfunctions of other organs and systems (respiratory, renal, neurologic, hematological, hepatobiliary).

Septic shock - sepsis and cardiovascular organ dysfunction.

The basis for the definition and classification of pediatric sepsis was the SSVR criteria used in the clinical trial of recombinant human activated protein C in the treatment of severe sepsis in children (ENHANCE). Experts have taken into account that in children tachycardia and tachypnea are nonspecific symptoms of many pathological processes. In this regard, the main differences in the definition of SSRM between adults and children are that in order to diagnose SSRS in children, either changes in body temperature or changes in the number of leukocytes are necessary (the SSC of the child can not be diagnosed only on the basis of dyspnoea and tachycardia). In addition, some criteria should be modified to take into account the child's age. In particular, bradycardia can be a sign of SSRM in newborns and infants, whereas in older children, a rare heart rhythm is a sign of a preterminal condition. Hypothermia (body temperature below 36 ° C) may also indicate a serious infection, especially in infants.

Body temperature above 38.5 ° C increases the specificity and affects the nature of intensive therapy. The temperature measured on the toe by temporal or axillary access is not sufficiently accurate. The central temperature should be measured with a rectal, a urinary or central catheter (in the pulmonary artery).

In adults and young children, diagnostic criteria for septic shock differ significantly. In pediatric practice, a shock is defined as a tachycardia (may be absent in hypothermia) with symptoms of decreased perfusion (weakening of the peripheral pulse as compared to the central one, changing its filling, increasing the time of capillary filling to 2 s or more, marble and cold extremities, diuresis decrease). It must be remembered that in children arterial hypotension is a late sign of shock, a manifestation of decompensation of the circulatory system, that 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, therefore the information presented is based on the opinion of experts and the data of the medical literature.

It is necessary to take into account the age features of patients, since the clinical differences between SSRM and organ failure largely depend on the physiological changes occurring in the child's body as it grows up. For this reason, the definition of sepsis in a child depends both on the biological, and on the actual age and laboratory data. Taking into account the peculiarities of the course of sepsis, 6 clinically and physiologically significant age groups were proposed, as well as threshold diagnostic values of the signs of SSER.

Age groups of children with reference to the definition of severe sepsis

Newborns	0-7 days of life
Newborns	1 week - 1 month
Infants	1 month - 1 year
Preschoolers	2-5 years
Pupils	6-12 years old
Teens	13-18 years old

These age groups were determined taking into account the characteristics 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.

[12]

Criteria for diagnosing organ dysfunction in children with severe sepsis

Cardiovascular dysfunction - arterial hypotension, despite the intravenous fluid injection of 40 ml / kg for 2 hours (systolic blood pressure is reduced by two quadratic deviations from the age norm), or the need for vasopressors to maintain blood pressure within the norm (dopamine or dobutamine more than 5 μg / kg per minute or any dose of epinephrine or norepinephrine), or two of the following five symptoms:

1. metabolic acidosis (deficiency of bases 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. lengthening the time of capillary filling more than 5 s,
5. skin-rectal temperature gradient exceeding 3 ° C.

Respiratory dysfunction of pO2 / FiO2 <300 in the absence of congenital heart disease of blue type or concomitant pulmonary pathology, or pACO2> 60 mm. Gt; st, or 20 mm. Gt; Art. More than usual pACO2, or the need for FiO2> 0.5 to maintain Sa2> 92%, or the need for mechanical ventilation.

Neurological dysfunction assessment according to coma scale Glasgow <11 points or acute change in mental status with a decrease in Glasgow coma score by 3 points.

Hematologic dysfunction - the number of platelets <80х10 ⁹ / l or their decrease by 50% of the greatest number in the last 3 days (for chronic oncohematological patients).

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

Hepatic dysfunction:

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

Microbiological diagnosis of sepsis involves the investigation of a probable focus of infection and peripheral blood. When the same pathogenic microorganism is isolated from both loci, its etiological role is considered proven. When distinguishing various pathogens from the focus of infection and peripheral blood, it is necessary to evaluate the etiological significance of each of them. At the same time, it must be remembered that bacteremia (the presence of a microorganism in the systemic blood flow) is not a pathognomonic sign of sepsis. Detection of microorganisms without clinical and laboratory evidence of SSRS should be regarded not as a sepsis, but as transient bacteremia.

When isolating typical pathogenic microorganisms (S. Aureus, Kl. Pneumoniae, Ps. Aeruginosa, fungi), one positive result is sufficient for the diagnosis. When allocating skin saprophytes to confirm the true bacteremia, two hemocultures are needed.

Some experts recommend the tactics of early aggressive management of children with severe sepsis and septic shock to reduce mortality by 25% within the next 5 years. In complex intensive therapy of sepsis in children, it is necessary to include control of the source of infection (together with surgeons), adequate antibiotic therapy, multicomponent accompanying intensive therapy and prevention of associated organ disorders.

[13],

Treatment of sepsia in children

Antibiotic therapy

The most important component of intensive sepsis therapy is antibiotics, since early adequate empirical antibiotic therapy of sepsis helps to reduce the lethality and frequency of its complications. Accordingly, antibiotics for sepsis should be prescribed urgently when establishing a nosological diagnosis and until the results of a bacteriological study are obtained. After receiving the results of bacteriological examination, the antibiotic therapy regimen can be changed taking into account the sensitivity of the isolated microflora.

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

Doses of antibiotics (single) for the treatment of sepsis in children

Penicillins

Amoxicillin / clavulanate	30 mg / kg for amoxicillin 2 times / day	30-40 mg / kg for 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 anti-synergic activity

Cefazaline	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 I-III generation with antisognegnoy activity
Cefepim	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 for cefoperazone 2 times / day	20 mg / kg for 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
Nethylmycin	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

Preparations 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
Fuzidine	20 mg / kg 3 times / day	20 mg / kg 3 times / day

Preparations with antifungal activity

Amphotericin B	0.25-1 mg / kg 1 p / d	0.25-1 mg / kg 1 p / d
Voriconazole	No data	8 mg / kg 2 p / the first day, then 4 μg 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 study of blood, the following rules must be observed:

• Blood for research needs to be recruited before the appointment of antibiotics. If antibiotic therapy is already performed, the blood should be collected before the drug is administered. Blood sampling at fever height does not increase the sensitivity of the method.
• The blood for examination should be recruited from the peripheral vein.
• From a venous catheter, blood should be recruited for microbiological examination only if a catheter-associated sepsis is suspected. In this case, a simultaneous quantitative bacteriological study of blood obtained from an intact peripheral vein and from a suspicious catheter should be carried out. If the same microorganism is isolated from both samples, and the quantitative ratio of the sampling of the samples from the catheter and vein is equal to or greater than 5, then the catheter is most likely a source of sepsis and must be removed.

Thorough skin treatment at the point of peripheral vein puncture, the vial cap with medium, and the use of commercial blood collection systems with an adapter allow to reduce the degree of contamination of samples to 3% or less.

The empirical choice of antibacterial drugs already at the first stage of treatment causes the use of antibiotics with a sufficiently high activity spectrum, sometimes in combination, given the extensive list of potential pathogens with different sensitivities. When localizing the primary focus in the abdominal cavity and the oropharynx, one should also suspect involvement in the infectious process of anaerobic microorganisms. Another parameter that determines the program of starting empirical therapy for sepsis is the severity of the disease. Severe septicemia with PON has a higher percentage of mortality and terminal septic shock, so the application of maximum antibiotic therapy in a child with severe sepsis should be performed at the earliest stage of treatment. Due to the fact that early application of adequate antibiotic therapy reduces the risk of death, the antibiotic effectiveness factor should dominate the factor of its cost.

In addition, the rational choice of the initial antibacterial therapy for sepsis depends not only on the localization of the source (focus) of the infection, but also on the conditions of infection (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 (so-called problem microorganisms). They include many gram-positive (methicillin-resistant staphylococci, penicillin-resistant pneumococci, multiresistant enterococci) and Gram-negative (Kl pneumoniae, E. Coli, Serratia marcesens, Ps. Aeruginosa, Stenotrophomonas maltophilia, Acinetobacter spp) bacteria. In this regard, the optimal mode of empirical therapy for severe nosocomial sepsis is the use of carbapenems (meropenem, imipenem) as drugs with the widest spectrum of activity and the lowest resistance level among the "problem" strains of gram-negative bacteria. When prescribing imipenem, the child should remember that the prepared solution must be used within 1 hour, later it becomes unusable (i.e., it is unacceptable to administer the drug to a patient from one bottle within 24 hours). In addition, meropenem penetrates better into the brain tissue and therefore serves as a drug of choice for sepsis against the background of meningitis, imipenem also with impaired permeability of the BBB can cause seizures as a result of the action of the cilastatin component.

Antibiotic therapy of sepsis with an unidentified primary focus

Conditions of occurrence	Means of the 1st row	Alternative drugs
Sepsis developed in out-of-hospital settings	Amoxicillin / clavulanate (sulbactam) ± aminoglycoside	Ciprofloxacin + metronidazole
	Ampicillin / sulbactam + aminoglycoside
	Ceftriaxone ± metronidazole
	Cefotaxime ± metronidazole
Sepsis, developed in a hospital, without SPON	Cefepime ± metronidazole	Meropenem
	Cefoperazone / sulbactam	Imipenem
		Ceftazidime ± metronidazole
		Ciprofloxacin + metronidazole
Sepsis developed in a hospital, the presence of SPON	Meropenem	Cefepime + metronidazole
	Imipenem	Cefoperazone / sulbactam
		Ciprofloxacin ± metronidazole

In the case of ineffectiveness of these regimens, the expediency of additional administration of vancomycin or linezolid, as well as systemic antimycotics (fluconazole, caspofungin, voriconazole) should be assessed.

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

Recommendations for etiotropic therapy for sepsis

Gram-positive organisms
Staphilococcus aureus, Staphilococcus epidermidis	Oxacillin	Amoxicillin / clavulanate
	Cefazolin	Cefuroxime
OH
Staphilococcus aureus, Staphilococcus epidermidis	Vancomycin	Rifampicin + co-trimoxazole (ciprofloxacin)
	Linezolid
OP		Fuzidine + co-trimoxazole (ciprofloxacin)
Streptococcus viridans	Ampicillin	Vancomycin
	Benzylpenicillin	Cefotaxime
		Ceftriaxone
Streptococcus pneumoniae	Cefotaxime	Ampicillin
	Ceftriaxone	Benzylpenicillin
	Cefepim	Vancomycin
		Meropenem
		Imipenem
Enterococcus faecalis	Ampicillin + gentamicin	Vancomycin ± gentamicin
		Linezolid
Enterococcus faecium	Linezolid	Vancomycin + gentamicin
Gram-negative organisms
E coli,	Amoxicillin / clavulanate	Meropenem
P mirabilis	Cefotaxime	Imipenem
	Ceftriaxone	Cefepim
		Ciprofloxacin
K. Pneumoniae	Meropenem	Amikacin
P vulgaris	Imipenem	Cefepim
		Cefoperazone / sulbactam
		Cefotaxime
		Ceftriaxone
		Ciprofloxacin
Enterobacter spp	Meropenem	Amikacin
Citrobacter spp	Imipenem	Cefotaxime
Serratia spp	Cefepim	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
Burcholdena cepacica	Meropenem	Ceftazidime
	Ciprofloxacin	Cefoperazone
		Co-trimoxazole
Stenotrophomonas maltophilia	Co-trimoxazole	Ticarcillin / Clavulanate
Candida spp	Fluconazole	Voriconazole
	Caspofungin	Amphotericin B

Anaerobic microorganisms are of clinical importance not for all forms of sepsis, but mainly in the localization of the primary focus in the abdominal cavity (more often Bacteroides spp.) Or soft tissues (Clostridium spp, etc.). In these cases, it is advisable to prescribe antibiotic regimens with antianaerobic activity. Protected ß-lactams and carbapenems are highly active against anaerobic microorganisms and can be used in monotherapy. Cephalosporins, aminoglycosides and fluoroquinolones (except moxifloxacin) have no clinically significant activity against anaerobes, so they should be combined with metronidazole.

Fungal sepsis is classified as the most severe form of the disease with a mortality rate exceeding 50%. In the practice of intensive therapy, fungal sepsis is most often referred to as candidemia and acute disseminated candidiasis. Candidemia refers to a single discharge of Candida spp. When sowing blood collected during a rise in body temperature above 38 ° C or in the presence of other signs of SSER. Acute disseminated candidiasis is understood as the combination of candidemia with mycological or histological signs of the defeat of deep tissues or the isolation of Candida spp from two or more sterile normal loci of the body.

Unfortunately, the possibility of treating fungal sepsis is currently limited to four drugs amphotericin B, caspofungin, fluconazole and voriconazole. When choosing an antimycotic, it is important to have an idea of the generic candidiasis, since some of them (C. Glabrata, C. Krusei, C parAPSilosis) are most often resistant to azoles, but remain sensitive to amphotericin B and a much less toxic to the macroorganism caspofungin. In addition, it should be remembered that the unjustifiably frequent administration of fluconazole to prevent fungal superinfection leads to the selection of strains of C albicans, also resistant to azoles, but usually sensitive to caspofungin.

It should be remembered that the use of antibacterial therapy does not mean the necessity of simultaneous administration of antimycotic drugs for the purpose of preventing fungal superinfection. The use of antimycotics for primary prevention of invasive candidiasis is recommended only for patients at high risk of this complication (prematurity, immunosuppression, repeated intestinal perforation).

When choosing a scheme of antibiotic therapy should also consider the function of the liver and kidneys. In ARI, aminoglycosides, vancomycin are contraindicated, fluconazole dose adjustment is necessary, in acute PN, neonatal hyperbilirubinemia, ceftriaxone, metronidazole, amphotericin B.

Criteria for sufficiency of antibacterial therapy for sepsis:

• Positive dynamics of the main organ symptoms of infection.
• Absence of signs of SSER.
• Normalization of the function of the digestive tract.
• Normalization of the number of blood leukocytes and leukocyte formula.
• Negative blood culture.

Preservation of only one sign of bacterial infection (fever or leukocytosis) is not considered an absolute indication for the continuation of antibiotic therapy. Isolated subfebrile fever (maximum daily temperature within 37.9 ° C) without chills and changes in the blood test usually does not serve as an indication for the continuation of antibiotic therapy, as is the maintenance of moderate leukocytosis (9-12x10 ⁹ / L) in the absence of a left shift and other symptoms bacterial infection.

In the absence of a persistent clinico-laboratory response to adequate antibiotic therapy for 5-7 days, an additional study (ultrasound, CT, MRI, etc.) is needed to find complications or an infectious focus of other localization. In addition, it should be remembered that in sepsis against osteomyelitis, endocarditis, purulent meningitis, a long duration of antibiotic therapy is required in connection with the difficult achievement of effective drug concentrations in the above-mentioned organs. In 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 refers to the initial treatment measures for sepsis. Its goals are to fill the deficit of bcc and restore adequate tissue perfusion, reduce the plasma concentration of toxic metabolites and pro-inflammatory cytokines, normalize homeostatic disorders.

With systemic hypotension, it is necessary to intravenously inject liquid in a volume of 40 ml / kg for 2 hours. Subsequently, the child must receive the maximum allowable daily amount of fluid for his age, if necessary - against a background of diuretic therapy.

Unambiguous recommendations for the choice of the type of infusion medium for sepsis in children are not currently available. It can be used as crystalloids (balanced saline solutions, isotonic sodium chloride solution, 5% glucose solution), and colloids (albumin, hydroxyethyl starch solutions). Crystalloid solutions do not negatively affect haemostasis, do not cause anaphylactoid reactions, the colloids also circulate longer in the vascular bed against the background of the circular leakage syndrome and increase the number of VCPs 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 in the presence of hypovolemia, the drugs of choice are considered crystalloids in combination with solutions of albumin (10-20 ml / kg). 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 ICE, the presence of peripheral edema and the concentration of albumin. Solutions of soda or trometamol (trisamine) should not be administered at pH> 7.25.

It should be remembered that with severe degrees of ARDS, intravenous albumin penetrates into the pulmonary interstitium and can worsen gas exchange. For this reason, for severe ODN, a test dose of 5 ml / kg albumin should be administered and the infusion should be interrupted to assess gas exchange if no deterioration of oxygenation occurs within 30 min, the remaining amount of albumin can be administered. Transfusion of FFP, cryoprecipitate is indicated only in the presence of clinical signs of ICE. As for the transfusion of erythrocytes, there are no unambiguous recommendations for their use in pediatric sepsis. Most experts recommend maintaining hemoglobin for sepsis at 100 g / l. An obligatory condition for transfusion of FFP and donor red blood cells is the use of leukocyte filters, as donor leukocytes play a leading role in aggravating the manifestations of SSRM and ARDS.

Inotropic and vasoactive act of sepsis

If after intravenous administration of 40 ml / kg of liquid for 2 hours or achieve CVP of 10-12 mm. Gt; Art. BP remains below the age norm, it is necessary to begin infusion of catecholamines (dopamine, dobutamine, epinephrine, norepinephrine). In connection with the inability to use the Swan-Ganz catheter and the thermodilution method for measuring CB in children, when selecting catecholamine, it is necessary to focus on the EchoCG data. If there is a decrease in LVEF by up to 40% or less, infusion of dopamine or dobutamine in a dose of 5-10 μg / (kg × min) should be started. A combination of dopamine and dobutamine infusion is possible, if monotherapy with one of them at a dose of 10 μg / (kg × min) does not result in stabilization of hemodynamics. If systemic hypotension is observed against the background of normal LVEF (more than 40%), norepinephrine or epinephrine (at a dose of 0.02 μg / kg per minute and higher, until an acceptable blood pressure value is reached) is considered the drug of choice. Infusion of epinephrine is also indicated with a decrease in LVEF, if the administration of a combination of dopamine and dobutamine [at a dose of at least 10 μg / (kg × min) each] is not sufficient to maintain stable blood circulation.

It must be remembered that in young children the Frank-Starling law does not work, and the only way to compensate for a decreased CB is high heart rate. In this regard, with tachycardia the child can not be fought, and any antiarrhythmic drugs in conditions of low CB are contraindicated.

Nutritional support

The development of PNS in sepsis is usually accompanied by hypermetabolism. Autokannibalism (the covering of energy needs due to the material of its own cells) leads to aggravation of the manifestations of PON. In this regard, the conduct of adequate nutritional support plays the same important role in sepsis as antibiotic therapy. The choice of the method of nutritional support depends on the severity of nutritional insufficiency and gastrointestinal disorders - oral enteral nutrition, probing, parenteral nutrition, mixed nutrition.

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

Parenteral nutrition in sepsis is indicated when it is impossible to enter enteric feeding in full, it does not differ from that in other conditions. The only thing to remember about - in the acute phase, it is necessary to introduce the minimum amount of energy for a given age, while the phase of stable hypermetabolism is introduced the maximum amount of energy. There was evidence that enrichment of both enteral and parenteral nutrition with glutamine (dipeptide) in sepsis helps to reduce hospital mortality and morbidity.

Contraindications to any nutritional support:

• Refractory shock (hypotension against infusion of epinephrine or norepinephrine in a dose of more than 0.1 μg / kg per minute).
• Uncapsulated arterial hypoxemia.
• Decompensated metabolic acidosis.
• Uncurved hypovolemia.

Activated Protein C

The appearance of activated protein C (zigris), judging from the data obtained during 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) at the time of writing this guide was not completed. Nevertheless, the preliminary data obtained make it possible to recommend its administration in severe sepsis with PON and in children.

Indications for the use of activated protein C in children - the presence of sepsis OCH or ODN. Cardiovascular dysfunction with regard to the administration of activated protein C is understood to mean a need for infusion of> 5 μg / kg per minute of dopamine or dobutamine or epinephrine / norepinephrine / phenylephrine at any dose, despite the introduction of a liquid in an amount of 40 ml / kg for 2 hours. By respiratory dysfunction is understood the need for a background of sepsis in invasive mechanical ventilation. The peculiarity of the use of activated protein C is its use in the first 24 hours after the appearance of the above indications. According to the ENHANCE study, mortality in the group of patients who received activated protein C infusion was started in the first 24 hours after the onset of organ dysfunction was less than in the group with the later onset of infusion. Enter the drug intravenously drip for 24 hours at a dose of 24 mcg / kg per hour.

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

Interruptions in the infusion of activated protein C for the period of invasive procedures are 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 in the absence of bleeding
Catheterization of the femoral vein
Intubation or change of tracheostomy tube (if not emergency)
More invasive procedures
The installation of a central venous catheter or Svan-Ganz catheter (in the subclavian or jugular vein)	Stop the infusion 2 hours before the procedure and resume 2 hours after the execution in the absence of bleeding
Lumbar puncture
Drainage of the thoracic cavity or thoracocentesis Paracentesis Percutaneous drainage Nephrostomy Gastroscopy (possible biopsy) Surgical treatment of the wound (decubital ulcer, infected wound, change of bandage on the open abdominal cavity, etc.)
"Large" procedures
Operation (laparotomy, thoracotomy, dilated surgical treatment of the wound, etc.)	Stop the infusion 2 hours before the procedure and resume 12 hours after the end
Epidural catheter	Do not use drtrekogin alpha (activated) with epidural catheterization or initiate infusion of the drug 12 hours after removal of the catheter

Contraindications and precautions when using aPS

Contraindications

Precautions

Active internal bleeding A recent (within 3 months) hemorrhagic stroke A recent (within 2 months) operation on the brain or spinal cord or a severe head injury requiring hospitalization Injury with an increased risk of life-threatening bleeding (eg, liver injury, spleen or complicated pelvic fracture) Patients with an epidural catheter Patients with intracranial tumor or brain destruction, confirmed by cerebral hernia

Heparin in a dose> 15 U / kg per hour International Normalized Ratio (INR)> 3 Platelet count <30000 / mm 3 even if their number rises after platelet transfusions (USA) According to the criteria of the European Agency for the Evaluation of Medicinal Products this is a contraindication Recent gastrointestinal bleeding (within 6 weeks) A recent (within 3 days) appointment of thrombolytic therapy The recent (<7 days) administration of oral anticoagulants or glycoprotein IIb / IIIa inhibitors The recent (<7 days) appointment of aspirin at a dose of> 650 mg / day or other platelet inhibitors Recent (<3 months) ischemic stroke Intracranial arteriovenous malformation Hemorrhagic diathesis in anamnesis Chronic hepatic impairment Any other condition in which bleeding poses a significant risk or bleeding, which will be particularly difficult to treat due to its localization

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

Glucocorticoids

Current evidence suggests that the use of high doses of glucocorticoids (particularly methylprednisolone, betamethasone) in septic shock does not lead to a reduction in mortality, but is accompanied by an increase in the frequency of purulent-septic complications. The only glucocorticoid, recommended today for inclusion in the complex therapy of sepsis, is hydrocortisone in a dose of 3 mg / kg per day (in 3-4 injections). Indications for him are quite narrow:

• refractory to catecholamines septic shock,
• severe sepsis against adrenal insufficiency (plasma concentration of cortisol is less than 55 nmol / L in newborns and less than 83 nmol / L in older children).

Immunoglobulins

The use of intravenous immunoglobulins in the framework of immunosuppressive therapy for severe sepsis is the only proven method of immunocorrection at the present time. At the same time, the best results were achieved with the administration of the combination and (pentaglobin). The drug is administered at 5 ml / kg for 3 days. With septic shock, the administration of 10 ml / kg on the first day and 5 ml / kg on the following day is permissible.

Anticoagulants

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

As in adult patients, in older children (over 1 year) it is necessary to prevent the formation of stress ulcers of 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 (not more than 40 mg) once during the day.

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

Control of glycemia

The data obtained in the cohort of adult patients that lethality from sepsis decreases when insulin monitoring of glycemia is controlled (maintenance of plasma glucose concentration at the level of 4.4-6.1 mmol / l) can not be extrapolated to young children (and, accordingly, having low body weight). The reason for this is the technical difficulties in the precise dosing and administration of insulin in children weighing less than 10 kg. In these patients, the risk of hyperglycemia transition to hypoglycemia is extremely high.

Based on the foregoing, glycemic control (maintenance of plasma glucose concentration with insulin within the range of 4.5-6.1 mmol / L) should probably be performed in children weighing 15 kg and above.

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