CHAIR OF PAEDIATRICS WITH MEDICAL GENETICS

1. CHAIR OF PAEDIATRICS WITH MEDICAL GENETICS THEME OF LECTURE “Neonatal sepsis”

2. Determination Sepsis – generalized infectious acyclic disease, basis of which is made by the system inflammatory response of organism (SIRS), bacterial infection, which is manifestated with generalized defeat of bloodstream, intoxication, disorders of hemostasis with DIC and development of POI.

3. Epidemiology • Frequency of neonatal sepsis is 2-10 on 1000 live-born; • In hyperpremature – 1-2 on 100 live-born; • Lethality is 13-50%, maximal –among premature children with the early symptoms of infection and at its fulminant motion. • In the structure of neonatal death rate lethality from a sepsis occupies 3 places. • For the last 20 years frequency of gram-negative neonatal sepsis grew in 10 times.

4. Etiology Early neonatal sepsis: Streptococcus A and B, E.coli, Klebsiela spp., Enterococcus, Listeria monocytogenes, Streptococcus pneumoniae, Hem. Influenzae, Clostridium spp., Bacteroides spp. Late neonatal sepsis: Staphilococcus aureus (in premature – 73%), E.coli, Klebsiela spp., Streptococcus epidermidis, Candida albicans, Pseudomonas spp., Serratia spp. At transplacental infection: viruses, treponema, listeria, candida. At the intranatal infecting: bacterial agents. For children with an immunodeficit: nosocomial cultures gram+ and грам- bacteria (Pseudomonas spp., Acinetobacter spp., Klebsiela spp., E.coli, Enterobacter spp., St. aureus).

5. Main factors of risk 1.Chorioamnionitis (ten-fold risk): temperature of body > 37,8 0С plus two of list of symptoms: pulse of mother > 100/min. pulse of fetus > 160/min. pain at palpation of lower part of abdomen. odor noisome of amniotic fluid. leykocytosis > 15*109/л. 2.Prematurity (seven-fold risk). 3.Waterless interval >24 hours (seven-fold risk). 4.Men sex (six-fold risk compared with girls). 5.Fever for a mother in births 38,3 0С and more (four-fold risk). 6.Meconium, stinking, dirty amniotic fluid. 7.Maternal infections, especially of urinary system (double risk). 8.Colonization of cervix uteri by β-hemolytic streptococcus group B. Combination of 2 and more factors increase risk of arising of sepsis in 4-8 ones.

6. PathogenesisBasic components • Entrance gate of infection. • Overcoming of protective barriers of macroorganism by a microorganism. • Presence in the microorganism of factors of virulence (lipopolysaccharides, peptidoglycan, exotoxine). • Inadequate immunological answer of “host”: surplus inflammatory reaction with septic shock and POI (mature and immunocompetent children) - phase of “hyperinflammation”; deficient inflammatory reaction with the secondary suppurative focus on background of septic katabolism (premature and immuneincompetent children) is phase “immuneparalysis”

7. Pathogenesis • Infectious hearth • Penetration of microorganisms and toxins • Microorganisms • Gram- Gramm- Fungus Viral- • negative positive bacterial • bacteria bacteria association • Toxins • Endotoxin- Exotoxin Endotoxines- • lypopolysaccharide hemolysines peptidoglycane • Activating of the immune system and reactions of inflammation • Humoral system: Cellular system: • system of complement macrophages, cells of endothelia, thrombocytes • system of coagulation, bradykinin granulocytes, microcyte • T- and B-lymphocytes • Release of mediators: • cytokines (TNF, Il-1, Il-6) activating of granulocyte of freeing of mediators of ІІ • degree • (PG, leukotrien, NO, free radicals of oxygen) • Damage of cells, violation of perfusion, death of cells • Shock and POI (acute kidney and hepatic insufficiency • DIC, parafunction of CNS)

8. Classification Etiologic factor of sepsis (gram+, gram- microorganisms, viral-bacterial associations, fungies). Time of origin: intrauterine (antenatal, intranatal), postnatal (early, late), nosocomial. Entrance gate: umbilical, dermic, pulmonary, intestinal, urosepsis, otogenic, criptogenic (in 40% an entrance gate is impossible to be determined). Clinical forms: septicemia (sepsis without purulent metastases), septicopyemia (sepsis with purulent metastases). Leading syndromes of sepsis: SIRS, bacteriemia, severe sepsis, septic shock, syndrome of POI. Leading syndromes of sepsisSIRS (systemic inflammatory response syndrome) which is started by various reasons, including by infection. For diagnosing of SIRS it is necessary 2 or more of the followings signs

9. Clinical criteria of SIRS: Disorders of temperature homeostasis (hyperthemia>38°C, hypothermia < 36°C) Tachypnoea >60/min. Tachycardia >160/min. Oppression of CNS and/or cramps. Oligouria (<1 ml/kg/hour. in the first 3 days of life, <2 ml/kg/hour. in future) on background of adequate infusion therapy. Laboratory criteria of SIRS Metabolic lactate-acidosis. Leukocytosis or leukopenia with a neutrophilia, or neutropenia. Regeneratory changes of leukocytar formula to the left, at the amount of immature forms >2*109/l. Toxic granulosity of neutrophyles. Thrombocytopenia. Anaemia. Increase of level of acute stage proteins. Bakteriemia. Leading syndromes of sepsisSIRS (systemic inflammatory response syndrome) which is started by various reasons, including by infection. For diagnosing of SIRS it is necessary 2 or more of the followings signs .

10. SIRS + bacteriemia = sepsis. SIRS + local hearth of infection (omphalitis) = sepsis. SIRS + clinic of infection = sepsis. SIRS and bacteriemia can exist for a child independently, it is unconnected with a sepsis: Local infection (pneumonia) + short-term bacteriemia ≠sepsis. Only in 2% children with clinical-laboratory signs of early sepsis there is the positive bacterial inoculation of blood or liquor is marked. Leading syndromes of sepsisBacteriemia - presence of viable bacteria in blood, which is confirmed bacteriologically (positive result of bacterial inoculation of blood).

11. Severe sepsis is sepsis + one of criteria of severity: disturbance of consciousness; lactate-acidosis (concentration of lactate in arterial blood >1,6 mmol/l or in venous >2,2 mmol/l); oliguria (diuresis less than, 1 ml/kg in a hour during 2 hours) Septic shock - sepsis + arterial hypotension: hypotension continues after entering of crystalloid or colloid solutions in dose 20 ml/kg; combination of hypotension with any of criteria of severe sepsis. Leading syndromes of sepsisSevere sepsis, septic shock

12. Factor Children< 1 years Children > 1 years Systolic AP <40 mm.mer. col. < 50 mm. mer .col Heart reat < 50 or  220 < 40 or  200 Breathing  90  70 рН плазми < 7,2 (with normal РаО2) AVL  24 hour (for babies after surgery) Інотропні препарати Необхідні для підтримки АТта/або серцевого викиду (крім допаміну менше 5 мкг/кг/хв) РаСО2  65 mm. mer. col. РаО2 < 40 mm..mer..col Nervous system < 5 of Glazgoscaleorfixed extension pupil Haematological reading Hb<50g/l, leukocytes<3х109/l, thrombocytes<20х109/l Kidnees Креатинин плазми 40 micromol/l . Liver General bilirubin 60 micromol/l Alimentary canal Gastroduodenal bleeding Leading syndromes of sepsisPolyorganic disorders- any combination of DIC, SRD, acute kidney insufficiency, hepatobiliar disfunction, disfunction of CNS.

13. Criteria of neonatal sepsis • Presence of factors risk development of neonatal sepsis. • Presence of respiratory dysfunctions (noisy breathing of child, intercostal retraction, RR>60/min. or apnoea >15 sec.), circulatory dyfunctions (HR >160/min. or < 100/min., oliguria, low perfusion of organs and tissues, hypotension – systolic AP < 35 mm. Hg ). • Presence of early nonspecific clinical signs of infection (microsymptoms of sepsis): flabbiness, refuse of feeding, disturbance of thermoregulation, abdominal distension , dyspepsia, icteritiousness, grayness of skin, hepatomegaly) in combination with one of laboratory criteria SIRS. • Combination of SIRS and pneumonias (lungs – main organ-target for causative agent).

14. Early sepsis – it is arisen up during 72 hours after birth. Transplacental or intranatal way of infecting. Numerous hearths of infection with predominance in clinical course of signs RI (pneumonia). Fulminant motion. Lethality 50% more. Late sepsis –is arisen up after the first 3 days life of child. Intranatal or contact way of infecting. Symptoms of oppression of CNS prevail in clinic (meningitis). Acute course. Lethality 20%. Criteria of early and late sepsis

15. Nosocomial sepsis - arises up in newborns of risk group at infecting of neonatal department by flora.. Ways of infecting: Contact- through the hands of medical staff, through catheters, medical equipment. Air-drop (at ALV). Alimentary-through maternal milk. Parenterally – through infusion solutions. Risk factors: Low weight at birth. Peripheral venous catheter > 3 days. Umbilical venous catheter > 7 days. Subclavian venous catheter > 10 days. RDS at entering of child into department. Presence of nasogastric catheter. Complete parenterally feeding. UNEC Localized infection of skin.

16. Clinical picture There are not characteristic clinical signs of neonatal sepsis. They are determined by etiology of causative agent, time infecting and by the features organism of concrete baby.

17. Clinical picture Infant Badly breathes! Badly uses feed! Looks seedy!

18. Clinical picture General appearance: pallor, mottled of skin, greyish or icteric tint. Abdominal distension, dilated venous network of front abdominal wall, hepatomegaly, areas of sclerema . The infant has suffering appearance, inhibition or excitement.

19. Clinical picture Respiratory system: Tachypnoea (especially for the mature infants); Disorders rhythm of breathing, apnoea; Moan on expiration; Increased requirement in oxygen; Diffuse changes on x-ray.

20. Clinical picture Cardiovascular system: Tachycardia/bradycardia, arrhythmia; Cyanosys; disturbance of microcirculation (“white spot – symptom” > 3 sec.); Arterial hypotension (late symptom); Peripheral swelling;

21. Clinical picture Alimentary canal: Refuse of feeding Regurgitation, vomiting; Meteorism; Liquid, watery stool, gastrointestinal bleeding; Hepatosplenomegaly.

22. Nervous system: Inhibition or excitability; Cramps or coma; Oppression of physiology reflexes; Tension of fontanel . Metabolism: Metabolic acidosis; Hyper- or hypoglycemia; Glucosuria; Hyperbilirubinemia (due to direct bilirubin). Thermoregulation: Fever over 37,70С; Hypothermia less than 36,50С; Difference of axilla (armpit) and rectal temperature more than 20С. Clinical picture

23. Diagnostics (plan of inspection): • CBC. • С-reactive protein (at entering and in 24 hours). • Biochemical analysis of blood+ionogramm+indexes of ABB. • Clinical uranalysis. • Lumbar punction. • Coagulogramm – at development of DIC. • NSG, US of abdominal region, chest x-ray. • Bacteriologic examination of placenta, blood, urine, liquor, excrements, excretions from nasopharynx, eyes, endotracheal tube. • On indications - specific virologic diagnostics (IFA and PCR).

24. Laboratory signs of neonatal sepsis

25. Treatment Therapeutic-protective regimen (adequate feeding and care). Antibiotic therapy: AB therapy is begun as earlier as possible at suspicion on a sepsis; Deescalation therapy is used – they prescribe the most powerful, effective antibiotic during 4-7 days with the subsequent passing to more simple drug, taking into account the results of bacteriologic examination got on this time. At suspicion on nosocomial sepsis choice of AB depends on the epidemiological situation of department. AB are used i/v Duration and efficiency of treatment depends on duration of clinical-laboratory effect of drug.

26. Treatment Protocols of empiric antibacterial therapy: • Cefuroxim (zinacef) 30-50 mg/kg + netromycin 7,5 mg/kg • Ceftriaxon 100 mg/kg + netromycin 7,5 mg/kg • Cefazidim (fortum) 100 mg/kg + clindamycin 20 mg/kg + netromycin 7,5 mg/kg In-hospital sepsis • Tsefepim (maxipim) 150 mg/kg + vancomycin 10 mg/kg +amikacin 10 mg/kg • Vancomycin 10 mg/kg +amikacin 10 mg/kg + metronidazole 7,5 mg/kg At duration of antibacterial therapy >5 days application of flukonasol 10 mg/kg is necessary.

27. Treatment 3. Infusion therapy Conducted with the purpose of support of hemodynamics, VCB, correction of plasma osmolality and violations of metabolic processes, providing of disintoxication. Standard solutions: 5 % glucose of 10 ml/kg, in the case of hypovolemia - fresh-frozen plasma 10 ml/kg each 6-12 hours. At development of septic shock is an intravenous reanimation of volume with addition of dopamine or Dobutaminum.

28. Treatment 4. Respiratory support Indications: Apnoe with bradycardia and cyanosys; RR over 70/min.; Cyanosys which conitinues after oxygenotherapy ; Gasping breathing; Arterial hypotension; Pallor and decreased peripheral perfusion; Severe lingering bradycardia ; P CO2 >60 mm. Hg, P O2<50 mm. Hg., рН<7,25; Mode of oxygenotherapy depends on the indexes of saturation of blood by oxygen, respiratory gases of blood and condition of child.

29. Treatment 5. Immunotherapy I/v immunoproteins (Pentaglobin, Sandoglobulin, Gabriglobin, Polygam, Gammagard): - Stimulate the process of opsonization; - Stimulate the processes of phagocytosis; - Activating of complement system; - Alleviate motion of neutrophils to the antigen; - Decrease toxicity of antigens; - Neutralize viruses. 6. Local sanation of suppurative focus 7. Syndromal therapy

30. Thank you for your attention!