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  • Early Onset Neonatal Sepsis; Approach & Management

    Robert L. Schelonka MDCredit Union for Kids Endowed

    Professor of NeonatologyOregon Health and Sciences University

  • Newborn infections are responsible for one-third of the

    ~3.0 million neonatal deaths that occur globally every year

  • Newborn infections are responsible for one-third of the

    ~3.0 million neonatal deaths that occur globally every year

    2700 neonates die from infections every day

  • Infections in newborns

    Clinical syndrome of systemic illness accompanied by bacteremia occurring in the first month of age

    Mortality rate is 13-25%Higher rates in premature infants

    Sepsis Neonatorum

  • Incidence

    Varies regionally Overall incidence of 1-8/1000 live births

  • 0

    5

    10

    15

    20

    25

    30

    35

    40

    45

    501-600 701-800 901-1000 1101-1200 1301-1400

    21

    50

    64

    64

    42 45

    31 32 27 19

    Fanaroff, A.A. et al. Pediatr Infect Dis J 17(7):593, 1998

    Birth Weight Intervals (grams)

    Perc

    en

    t In

    fecti

    on

    Rates of Sepsis in VLBW Infants

  • Neonatal Sepsis Definitions

    Early onset Fulminant, multisystem infection acquired

    by vertical transmission from motherHigh case mortality rate

    Late onset Slowly progressive illness with focal infection,

    often meningitis

    Late late-onset Affects VLBW hospitalized neonates with

    commensal organisms such as fungi and coagulase negative staphylococcus

    Often associated with prolonged instrumentation

  • Neonatal Sepsis Definitions

    Early onset Fulminant, multisystem infection acquired by

    vertical transmission from mother High case mortality rate

    Late onsetSlowly progressive illness with focal

    infection, often meningitis Late late-onset

    Affects VLBW hospitalized neonates with commensal organisms such as fungi and coagulase negative staphylococcus

    Often associated with prolonged instrumentation

  • Early onset Fulminant, multisystem infection acquired by vertical

    transmission from mother High case mortality rate

    Late onset Slowly progressive illness with focal infection, often

    meningitis

    Late late-onset Affects VLBW hospitalized neonates with

    commensal organisms such as fungi and coagulase negative staphylococcus

    Often associated with prolonged instrumentation

    Neonatal Sepsis Definitions

  • Kaufman and Fairchild. Clin Microbiol Rev. 2004 Jul;17(3):638-80

    Timing of Sepsis in VLBW Infants

    http://cmr.asm.org/content/vol17/issue3/images/large/zcm0030420940001.jpeg

  • Transplacental: known to occur in viral, treponemal and listerial infections

    Ascending intra-amniotic infection and aspiration of amniotic fluid Higher risk if membranes ruptured >24 hrs

    1-4% of neonates born to mothers with intra-amniontic infection will become infected

    Bacterial colonization the mothers lower genital tract

    Nosocomial-fomites in the environment or from colonized caregivers

    EOS Transmission

  • EOS Transmission

    Transplacental: known to occur in viral, treponemal and listerialinfections

    Ascending intra-amniotic infection and aspiration of amniotic fluid Higher risk if membranes ruptured >24

    hrs 1-4% of neonates born to mothers with

    intra-amniontic infection will become infected

    Bacterial colonization the mothers lower genital tract Nosocomial-fomites in the environment or from colonized

    caregivers

  • EOS Transmission

    Transplacental: known to occur in viral, treponemal and listerial infections

    Ascending intra-amniotic infection and aspiration of amniotic fluid Higher risk if membranes ruptured >24 hrs

    1-4% of neonates born to mothers with intra-amniontic infection will become infected

    Bacterial colonization the mothers lower genital tract

    Nosocomial-fomites in the environment or from colonized caregivers

  • Transplacental: known to occur in viral, treponemal and listerial infections

    Ascending intra-amniotic infection and aspiration of amniotic fluid Higher risk if membranes ruptured >24 hrs

    1-4% of neonates born to mothers with intra-amniontic infection will become infected

    Bacterial colonization the mothers lower genital tract

    Nosocomial-fomites in the environment or from colonized caregivers

    EOS Transmission

  • EOS Predisposing Factors

    Maternal/Obstetrical Factors

    General socioeconomic status, poor prenatal care, maternal substance abuse, prematurity, twins

    Maternal infections chorioamnionitis (1-10% of pregnancies), fever (>38 C/100.4 F), venereal diseases, UTI/bacteriuria, GBS+

    Obstetrical manipulation amniocentesis, amnio-infusion, prolonged labor, fetal monitoring, digital exams

    Premature & Prolonged ROM, preterm labor

  • Infant/Host Factors

    Prematurity

    Race/Ethnicity GBS sepsis blacks>whites

    Male Sex sepsis & meningitis more common

    Birth asphyxia, meconium staining, stress

    Breaks in skin & mucosal integrity

    Environmental exposure

    Procedures (e.g. catheters, ET-tubes)

    EOS Predisposing Factors

  • InnateNeutrophilsComplementGI Mucosal BarrierSkin

    AdaptiveAntigen recognition

    T and B cell interaction

    Antigen-specific antibody

    Host Immunity

  • Segmented Neutrophil

    Newborn neutrophil storage pools

    Expanded precursor cell populations and basal proliferative rate is near maximal (Christensen 1984, 1989)

    storage pool size and may be exhausted in sepsis (Christensen 1980 and 1982)

    BandMetamyelocyteMyelocytePromyelocyteMyeloblast

    Neutrophil Proliferative Pool Neutrophil Storage Pool

    Adapted from Chandra et al NeoReviews2005

  • Capture/RollingAdhesion

    Spread/ Activation

    Transendothelial migration

    ENDOTHELIUM

    ROLLING ATTACHMENT MIGRATION

    Impaired chemotaxis: half speed

    expression and shedding of L-selectin

    reduced neutrophil-endothelial adherence and transmigration

    Adapted from Chandra et al NeoReviews2005

  • 18 weeks gestation

    Immune quiescence appears necessary for fetal survival

    Adaptive immunity

    Functional differences between neonatal and adult T and B cells

    Naivet

    Limitations in immune receptor

    repertoire

    22 weeks gestation

  • 0

    2

    4

    6

    8

    10

    12

    14

    16

  • Clinical Presentation

    Pneumonia, PPHN

    and respiratory failure

    Sepsis syndrome

    Meningitis Life-long morbidities

  • EOS Clinical Presentation

    Early Signs

    Generally nonspecific in neonates

    Temperature instability

    Respiratory-distress, cyanosis and apnea

    Feeding difficulties

    May be subtle or insidious and a high index of suspicion is needed to identify and evaluate at risk infants

  • Less common

    Seizures

    DIC

    Petechiae

    Hepatosplenomegaly

    Meningitis signs

    Irritability, lethargy, poorly responsive

    Changes in muscle tone

    EOS Clinical Presentation

  • EOS Evaluation

    Non-specific CBC/diff, platelets ANC, I/T ratio

    Radiographs

    C-reactive protein

    Fluid analysis Cerebrospinal, +/- urine

    Glucose, electrolytes, blood gases

    Specific Cultures, stains

    Other immunoassays, PCR

  • Blood culture definitive diagnosis of neonatal sepsis Sensitivity of a single blood culture ~ 90%

    Volume of blood A minimum blood volume of 1 mL is desirable for optimal detection of bacteremia

    Schelonka et al. J Pediatr. 1996 Aug;129(2):275-8.

    Time to positivity Automated systems for continuous monitoring of blood cultures become positive within 24 to 36 hours

    Garcia-Prats et al Pediatrics. 2000;105(3 Pt 1):523

    EOS Evaluation

    https://www.ncbi.nlm.nih.gov/pubmed?term=8765627

  • Biomarkers for Sepsis

  • CDC guidance

    2010 Centers for Diseases Control Guidelines on management for infants at risk for EOS: Well-appearing:

    GBS + mother with adequate prophylaxis (PCN, amp or cefazolin) >4h PTD: observe for 48h, no routine testing or antibiotics

    GBS+ with inadequate prophylaxis: If ROM >18h, and/or less than 37 weeks: CBC, blood culture,

    observe for 48h If not: Observe for 48h

    Mother with suspected chorioamnionitis: CBC, blood culture; antibiotics pending culture results

    No chorio and no indication for GBS prophylaxis: routine management

  • A recent case: practice change

    Called to attend a delivery of a 38 5/7 week infant Mother is Group B Streptococcus-negative Membranes rupture 4 hours Maternal fever to 38oC, 101oF

    Uterine tenderness Fetal tachycardia to 165 bpm Maternal tachycardia 115 bpm

    Diagnosis of chorioamnionitis Mother did not receive intrapartum ampicillin and

    gentamycin until after delivery

  • Case continues: baby is born

    APGAR Scores 8 and 9 at one and five minutes. Normal perfusion

    Normal respiratory rate

    Normal BP (58/38) and HR now 140

    Normal blood glucose

    Normal exam

    What to do for this newborn?

  • Admission to the NICU

    Evaluation for Sepsis

    Blood culture

    CBC

    Other tests as indicated, e.g. LP, urine cx

    Empirical antibiotic therapy

    48 hour NICU stay

    Case continues: baby treated

  • Magnitude of antibiot