CHAIR OF PAEDIATRICS WITH CHAIR OF PAEDIATRICS WITH

MEDICAL GENETICSMEDICAL GENETICS THEME OF LECTURETHEME OF LECTURE

““Neonatal sepsis”Neonatal sepsis”

Determination

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

Epidemiology Frequency of neonatal sepsis is 2-10 on 1000 live-Frequency of neonatal sepsis is 2-10 on 1000 live-

born;born; In hyperpremature – 1-2 on 100 live-born;In hyperpremature – 1-2 on 100 live-born; Lethality is 13-50%, maximal –among premature Lethality is 13-50%, maximal –among premature

children with the early symptoms of infection and at children with the early symptoms of infection and at its fulminant motion.its fulminant motion.

In the structure of neonatal death rate lethality from In the structure of neonatal death rate lethality from a sepsis occupies 3 places.a sepsis occupies 3 places.

For the last 20 years frequency of gram-negative For the last 20 years frequency of gram-negative neonatal sepsis grew in 10 times.neonatal sepsis grew in 10 times.

EtiologyEarly neonatal sepsisEarly neonatal sepsis: Streptococcus A and B, E.coli, Klebsiela spp., : Streptococcus A and B, E.coli, Klebsiela spp.,

Enterococcus, Listeria monocytogenes, Streptococcus pneumoniae, Enterococcus, Listeria monocytogenes, Streptococcus pneumoniae, Hem. Influenzae, Clostridium spp., Bacteroides spp.Hem. Influenzae, Clostridium spp., Bacteroides spp.

Late neonatal sepsis: Late neonatal sepsis: Staphilococcus aureus (in premature – 73%), Staphilococcus aureus (in premature – 73%), E.coli, Klebsiela spp., Streptococcus epidermidis, Candida albicans, E.coli, Klebsiela spp., Streptococcus epidermidis, Candida albicans, Pseudomonas spp., Serratia spp.Pseudomonas spp., Serratia spp.

At transplacental infection:At transplacental infection: viruses, treponema, listeria, candida. viruses, treponema, listeria, candida.

At the intranatal infecting: At the intranatal infecting: bacterial agents.bacterial agents.

For children with an immunodeficit: For children with an immunodeficit: nosocomial cultures gram+ and nosocomial cultures gram+ and грам- bacteria (Pseudomonas spp., Acinetobacter spp., Klebsiela грам- bacteria (Pseudomonas spp., Acinetobacter spp., Klebsiela spp., E.coli, Enterobacter spp., St. aureus).spp., E.coli, Enterobacter spp., St. aureus).

Main factors of risk1.Chorioamnionitis (ten-fold risk):1.Chorioamnionitis (ten-fold risk):

temperature of body > 37,8 0С plus two of list of symptoms:temperature of body > 37,8 0С plus two of list of symptoms:

pulse of mother > 100/min.pulse of mother > 100/min.

pulse of fetus > 160/min.pulse of fetus > 160/min.

pain at palpation of lower part of abdomen.pain at palpation of lower part of abdomen.

odor noisome of amniotic fluid.odor noisome of amniotic fluid.

leykocytosis > 15*109/л.leykocytosis > 15*109/л.

2.Prematurity (seven-fold risk).2.Prematurity (seven-fold risk).

3.Waterless interval >24 hours (seven-fold risk).3.Waterless interval >24 hours (seven-fold risk).

4.Men sex (six-fold risk compared with girls).4.Men sex (six-fold risk compared with girls).

5.Fever for a mother in births 38,3 0С and more (four-fold risk).5.Fever for a mother in births 38,3 0С and more (four-fold risk).

6.Meconium, stinking, dirty amniotic fluid.6.Meconium, stinking, dirty amniotic fluid.

7.Maternal infections, especially of urinary system (double risk).7.Maternal infections, especially of urinary system (double risk).

8.Colonization of cervix uteri by β-hemolytic streptococcus group B.8.Colonization of cervix uteri by β-hemolytic streptococcus group B.

Combination of 2 and more factors increase risk of arising of sepsis in Combination of 2 and more factors increase risk of arising of sepsis in 4-8 ones.4-8 ones.

PathogenesisBasic components

Entrance gate of infection.Entrance gate of infection. Overcoming of protective barriers of macroorganism by a Overcoming of protective barriers of macroorganism by a

microorganism.microorganism. Presence in the microorganism of factors of virulence Presence in the microorganism of factors of virulence

(lipopolysaccharides, peptidoglycan, exotoxine).(lipopolysaccharides, peptidoglycan, exotoxine). Inadequate immunological answer of “host”:Inadequate immunological answer of “host”:

surplus inflammatory reaction with septic shock and POI (mature surplus inflammatory reaction with septic shock and POI (mature and immunocompetent children) - phase of and immunocompetent children) - phase of “hyperinflammation”;“hyperinflammation”;

deficient inflammatory reaction with the secondary suppurative deficient inflammatory reaction with the secondary suppurative focus on background of septic katabolism (premature and focus on background of septic katabolism (premature and

immuneincompetent children) is phase “immuneparalysis”immuneincompetent children) is phase “immuneparalysis”

Pathogenesis Infectious hearthInfectious hearth

Penetration of microorganisms and toxinsPenetration of microorganisms and toxins    MicroorganismsMicroorganisms      Gram-Gram- Gramm- Gramm- FungusFungus Viral- Viral- negative negative positive positive bacterialbacterial bacteria bacteria bacteria bacteria association association       ToxinsToxins   

Endotoxin-Endotoxin- ExotoxinExotoxin Endotoxines-Endotoxines- lypopolysaccharide lypopolysaccharide hemolysines hemolysines

peptidoglycanepeptidoglycane   

Activating of the immune system and reactions of inflammationActivating of the immune system and reactions of inflammation Humoral system:Humoral system: Cellular system:Cellular system: system of complement system of complement macrophages, cells of endothelia, macrophages, cells of endothelia,

thrombocytesthrombocytes system of coagulation, bradykininsystem of coagulation, bradykinin granulocytes, microcytegranulocytes, microcyte T- and B-lymphocytes T- and B-lymphocytes   

Release of mediators:Release of mediators: cytokines (TNF, Il-1, Il-6) activating of granulocyte of freeing of mediators of ІІ cytokines (TNF, Il-1, Il-6) activating of granulocyte of freeing of mediators of ІІ degree degree (PG, leukotrien, NO, free radicals of (PG, leukotrien, NO, free radicals of

oxygen)oxygen)   

Damage of cells, violation of perfusion, death of cellsDamage of cells, violation of perfusion, death of cells

Shock and POI (acute Shock and POI (acute kidney and hepatic insufficiency kidney and hepatic insufficiency DIC, parafunction of CNS)DIC, parafunction of CNS)

ClassificationEtiologic factor of sepsis (gram+, gram- microorganisms, viral-Etiologic factor of sepsis (gram+, gram- microorganisms, viral-

bacterial associations, fungies).bacterial associations, fungies).Time of origin: intrauterine (antenatal, intranatal), postnatal (early, Time of origin: intrauterine (antenatal, intranatal), postnatal (early,

late), nosocomial.late), nosocomial.Entrance gate: umbilical, dermic, pulmonary, intestinal, urosepsis, Entrance gate: umbilical, dermic, pulmonary, intestinal, urosepsis,

otogenic, criptogenic (in 40% an entrance gate is impossible to otogenic, criptogenic (in 40% an entrance gate is impossible to be determined).be determined).

Clinical forms: septicemia (sepsis without purulent metastases), Clinical forms: septicemia (sepsis without purulent metastases), septicopyemia (sepsis with purulent metastases).septicopyemia (sepsis with purulent metastases).

Leading syndromes of sepsis: SIRS, bacteriemia, severe sepsis, septic Leading syndromes of sepsis: SIRS, bacteriemia, severe sepsis, septic shock, syndrome of POI.shock, syndrome of POI.

Leading syndromes of sepsisLeading syndromes of sepsisSIRS (systemic inflammatory response syndrome) which is SIRS (systemic inflammatory response syndrome) which is started by various reasons, including by infection. For started by various reasons, including by infection. For diagnosing of SIRS it is necessary 2 or more of the followings diagnosing of SIRS it is necessary 2 or more of the followings signs signs

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 .Clinical criteria of SIRS:Clinical criteria of SIRS:Disorders of temperature Disorders of temperature

homeostasis homeostasis (hyperthemia>38°C, (hyperthemia>38°C, hypothermia < 36°C)hypothermia < 36°C)

Tachypnoea >60/min.Tachypnoea >60/min.Tachycardia >160/min.Tachycardia >160/min.Oppression of CNS and/or cramps.Oppression of CNS and/or cramps.Oligouria (<1 ml/kg/hour. in the first Oligouria (<1 ml/kg/hour. in the first

3 days of life, <2 ml/kg/hour. in 3 days of life, <2 ml/kg/hour. in future) on background of future) on background of adequate infusion therapy. adequate infusion therapy.

Laboratory criteria of SIRSLaboratory criteria of SIRSMetabolic 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 sepsisBacteriemia - presence of viable bacteria in blood, which is

confirmed bacteriologically (positive result of bacterial

inoculation of blood). 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 sepsisSevere sepsis, septic shock

Severe sepsis is sepsis + one of Severe sepsis is sepsis + one of criteria of severity: criteria of severity:

disturbance of disturbance of consciousness;consciousness;

lactate-acidosis lactate-acidosis (concentration of lactate in (concentration of lactate in arterial blood >1,6 mmol/l or arterial blood >1,6 mmol/l or in venous >2,2 mmol/l);in venous >2,2 mmol/l);

oliguria (diuresis less than, oliguria (diuresis less than, 1 ml/kg in a hour during 2 1 ml/kg in a hour during 2 hours)hours)

Septic shock - sepsis + Septic shock - sepsis + arterial hypotension:arterial hypotension:

hypotension continues hypotension continues after entering of after entering of crystalloid or colloid crystalloid or colloid solutions in dose 20 solutions in dose 20 ml/kg;ml/kg;

combination of combination of hypotension with any of hypotension with any of criteria of severe sepsis.criteria of severe sepsis.

Leading syndromes of sepsisPolyorganic disorders- any combination of DIC,

SRD, acute kidney insufficiency, hepatobiliar disfunction, disfunction of CNS.

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 АТ та/або серцевого викиду (крім допаміну менше 5 мкг/кг/хв)

РаСО2 65 mm. mer. col.

РаО2 < 40 mm..mer..col

Nervous system < 5 of Glazgo scale or fixed extension pupil

Haematological readingHb < 50g/l, leukocytes < 3х109/l, thrombocytes < 20х109/l

Kidnees Креатинин плазми 40 micromol/l .

LiverGeneral bilirubin 60 micromol/l

Alimentary canal Gastroduodenal bleeding

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).

Criteria of early and late sepsisEarly sepsis – it is arisen up Early sepsis – it is arisen up

during 72 hours after birth.during 72 hours after birth. Transplacental or intranatal Transplacental or intranatal

way of infecting.way of infecting. Numerous hearths of infection Numerous hearths of infection

with predominance in clinical with predominance in clinical course of signs RI course of signs RI (pneumonia).(pneumonia).

Fulminant motion.Fulminant motion. Lethality 50% more.Lethality 50% more.

Late sepsis –is arisen up Late sepsis –is arisen up after the first 3 days life after the first 3 days life of child.of child.

Intranatal or contact way Intranatal or contact way of infecting.of infecting.

Symptoms of oppression Symptoms of oppression of CNS prevail in clinic of CNS prevail in clinic (meningitis).(meningitis).

Acute course.Acute course. Lethality 20%.Lethality 20%.

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.

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

concrete baby.concrete baby.

Clinical picture

Clinical picture

Infant

Badly breathes!

Badly uses feed!

Looks seedy!

Clinical picture

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

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.

Clinical picture

Cardiovascular system:

Tachycardia/bradycardia, arrhythmia;

Cyanosys;

disturbance of microcirculation (“white spot – symptom” > 3 sec.);

Arterial hypotension (late symptom);

Peripheral swelling;

Clinical picture

Alimentary canal:

Refuse of feeding

Regurgitation, vomiting;

Meteorism;

Liquid, watery stool, gastrointestinal bleeding;

Hepatosplenomegaly.

Clinical pictureNervous 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 . .

Diagnostics (plan of inspection): CBC.CBC. С-reactive protein (at entering and in 24 hours).С-reactive protein (at entering and in 24 hours). Biochemical analysis of blood+ionogramm+indexes of Biochemical analysis of blood+ionogramm+indexes of

ABB.ABB. Clinical uranalysis.Clinical uranalysis. Lumbar punction.Lumbar punction. Coagulogramm – at development of DIC.Coagulogramm – at development of DIC. NSG, US of abdominal region, chest x-ray.NSG, US of abdominal region, chest x-ray. Bacteriologic examination of placenta, blood, urine, Bacteriologic examination of placenta, blood, urine,

liquor, excrements, excretions from nasopharynx, eyes, liquor, excrements, excretions from nasopharynx, eyes, endotracheal tube.endotracheal tube.

On indications - specific virologic diagnostics (IFA and On indications - specific virologic diagnostics (IFA and PCR).PCR).

Laboratory signs of neonatal sepsis

LeukopeniaLeukopenia < 5 000*10< 5 000*1099 //ll

LeukocytosisLeukocytosis toto 4 4 days of lifedays of life

afterafter 4 4 days of lifedays of life

> 30 000 *10> 30 000 *1099 //ll

> 20 000 *10> 20 000 *1099 //ll

Absolute number of stab neutrophillsAbsolute number of stab neutrophills to to 4 4 days of lifedays of life

afterafter 4 4 days of lifedays of life

> > 500500//mmmm33

> > 10001000//mmmm33

Leukocyte index intoxicationLeukocyte index intoxication > > 0,20,2

C – reactive proteinC – reactive protein > > 20 20 mg/lmg/l

ThrombocytopeniaThrombocytopenia < < 115500 000*10 000*1099 //ll

ProcalcitoninProcalcitonin ( (afterafter 4 4 days of lifedays of life)) > > 0,5 0,5 ng/mlng/ml

TreatmentTherapeutic-protective regimen (adequate feeding and care).Therapeutic-protective regimen (adequate feeding and care).

Antibiotic therapy:Antibiotic therapy:

AB therapy is begun as earlier as possible at suspicion on a AB therapy is begun as earlier as possible at suspicion on a sepsis;sepsis;

Deescalation therapy is used – they prescribe the most powerful, Deescalation therapy is used – they prescribe the most powerful, effective antibiotic during 4-7 days with the subsequent effective antibiotic during 4-7 days with the subsequent passing to more simple drug, taking into account the results passing to more simple drug, taking into account the results of bacteriologic examination got on this time.of bacteriologic examination got on this time.

At suspicion on nosocomial sepsis choice of AB depends on the At suspicion on nosocomial sepsis choice of AB depends on the epidemiological situation of department.epidemiological situation of department.

AB are used i/vAB are used i/v

Duration and efficiency of treatment depends on duration of Duration and efficiency of treatment depends on duration of clinical-laboratory effect of drug.clinical-laboratory effect of drug.

TreatmentProtocols of empiric antibacterial therapy:Protocols of empiric antibacterial therapy: Cefuroxim (zinacef) 30-50 mg/kg + netromycin Cefuroxim (zinacef) 30-50 mg/kg + netromycin

7,5 mg/kg7,5 mg/kg Ceftriaxon 100 mg/kg + netromycin 7,5 mg/kgCeftriaxon 100 mg/kg + netromycin 7,5 mg/kg Cefazidim (fortum) 100 mg/kg + clindamycin 20 Cefazidim (fortum) 100 mg/kg + clindamycin 20

mg/kg + netromycin 7,5 mg/kgmg/kg + netromycin 7,5 mg/kgIn-hospital sepsisIn-hospital sepsis

Tsefepim (maxipim) 150 mg/kg + vancomycin 10 Tsefepim (maxipim) 150 mg/kg + vancomycin 10 mg/kg +amikacin 10 mg/kgmg/kg +amikacin 10 mg/kg

Vancomycin 10 mg/kg +amikacin 10 mg/kg + Vancomycin 10 mg/kg +amikacin 10 mg/kg + metronidazole 7,5 mg/kgmetronidazole 7,5 mg/kgAt duration of antibacterial therapy >5 days At duration of antibacterial therapy >5 days application of flukonasol 10 mg/kg is necessary.application of flukonasol 10 mg/kg is necessary.

Treatment3. Infusion therapy3. Infusion therapyConducted with the purpose of support of Conducted with the purpose of support of

hemodynamics, VCB, correction of plasma hemodynamics, VCB, correction of plasma osmolality and violations of metabolic processes, osmolality and violations of metabolic processes, providing of disintoxication.providing of disintoxication.

Standard solutions: 5 % glucose of 10 ml/kg, in the Standard solutions: 5 % glucose of 10 ml/kg, in the case of hypovolemia - fresh-frozen plasma 10 case of hypovolemia - fresh-frozen plasma 10 ml/kg each 6-12 hours.ml/kg each 6-12 hours.

At development of septic shock is an intravenous At development of septic shock is an intravenous reanimation of volume with addition of dopamine reanimation of volume with addition of dopamine or Dobutaminum.or Dobutaminum.

Treatment 4. Respiratory support4. Respiratory support

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

Treatment5. Immunotherapy5. ImmunotherapyI/v immunoproteins (Pentaglobin, Sandoglobulin, I/v immunoproteins (Pentaglobin, Sandoglobulin,

Gabriglobin, Polygam, Gammagard):Gabriglobin, Polygam, Gammagard):- Stimulate the process of opsonization;- Stimulate the process of opsonization;- Stimulate the processes of phagocytosis;- Stimulate the processes of phagocytosis;- Activating of complement system;- Activating of complement system;- Alleviate motion of neutrophils to the antigen;- Alleviate motion of neutrophils to the antigen;- Decrease toxicity of antigens;- Decrease toxicity of antigens;- Neutralize viruses.- Neutralize viruses.6. Local sanation of suppurative focus 6. Local sanation of suppurative focus 7. Syndromal therapy7. Syndromal therapy

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