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Management of Neonatal Sepsis. Niki Kosmetatos, MD Anthony Piazza, MD Ira Adams-Chapman, MD J. Devn Cornish, MD Emory University Department of Pediatrics. Note: Dr. Cornish does not have any financial relationships to disclose nor will he discuss any non-approved drug or device uses.

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management of neonatal sepsis

Management of Neonatal Sepsis

Niki Kosmetatos, MD

Anthony Piazza, MD

Ira Adams-Chapman, MD

J. Devn Cornish, MD

Emory University

Department of Pediatrics

Note: Dr. Cornish does not have any financial relationships to disclose nor will he discuss any non-approved drug or device uses.

babies and bacteria
Babies and Bacteria…

Gram positive bacteria

(anthrax)

Gram negative bacteria

(pseudomonas)

incidence
Incidence
  • Mortality
    • 13-69% world wide
    • 13-15% of all neonatal deaths (US) (8th cause)
  • Meningitis
    • 0.4-2.8/1000 live births (US 0.2-0.4/1000)
    • Mortality 13-59%; US 4% of all neonatal deaths
  • Sepsis
    • 1-21/1000 world wide; US,1-2/1000 live births
    • Culture proven 2/1000 (3-8% of infants evaluated for sepsis); 10-20/1000 VLBW
    • Prematures <1000 g 26/1000 1000 - 2000 g 8-9/1000
predisposing factors
Predisposing Factors

General Host Factors

Prematurity (OR 25 if < 1,000 gms)

Race – GBS sepsis blacks>whites (x4)

Sex – sepsis & meningitis more common in males, esp. gram negative infections

Birth asphyxia, meconium staining, stress

Breaks in skin & mucous membrane integrity (e.g. omphalocoele, meningomyelocoele)

Environmental exposure

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

predisposing factors1
Predisposing Factors
  • Maternal/Obstetrical Factors
    • General– socioeconomic status, poor prenatal care, vaginal flora, maternal substance abuse, known exposures, prematurity, twins
    • Maternal infections –chorioamnionitis (1-10% of pregnancies), fever (>38° C/100.4° F), sustained fetal tachycardia, venereal diseases, UTI/bacteriuria, foul smelling lochia, GBS+ (OR 204), other infections
    • Obstetrical manipulation – amniocentesis, amnioinfusion, prolonged labor, fetal monitoring, digital exams, previa/abruption?
    • Premature & Prolonged ROM, preterm labor
predisposing factors2
Predisposing Factors

Overall sepsis rate 2/1000

Maternal Fever 4/1000

PROM 10-13/1000

Fever & PROM 87/1000

preterm labor prom
Preterm Labor/PROM
  • Prematurity (~10%) 15-25% due to maternal infection
  • >18-24h term; >12-18h preterm
  • Bacterial infection
    •  synthesis of PG
    • Macrophage TNF/IL stimulate PG synthesis, cytokine release**
    • Release of collagenase & elastase ROM
  • + Amniotic fluid cultures 15% (with intact membranes)
s epsis
SEPSIS

ORGANISMS (all babies)

  • Group B strep (most common G+) 41%
  • Other strep 23%
  • Coliforms(E. coli most common G-) 17%
  • Staph aureus 4%
  • Listeria2%
  • Nosocomial infections
  • Candida
  • Note: 73% G+ and 27% G-
s epsis1
SEPSIS

ORGANISMS (VLBW)

  • Group B strep (most common G+) 12%
  • Other strep 9%
  • Coliforms(E. coli most common G-) 41%
  • CONS 15%
  • Listeria2%
  • Nosocomial infections
  • Candida 2%
  • Note: 45% G+ and 53% G-

Source: Stoll et al PedInfDis 2005, 24:635

routes of infection
Routes of Infection
  • Transplacental/Hematogenous
  • Ascending/Birth Canal
  • Aspiration
  • Device Associated Infection
  • Nosocomial
  • Epidemic
transplacental hematogenous
Transplacental/Hematogenous
  • Organisms (Not just “TORCHS”)

Toxoplasmosis Parvovirus

Rubella Gonorrhea

Cytomegalovirus Mumps

Herpes* TB

Syphilis Varicella

Acute Viruses HIV

Coxsackie Polio

Adenovirus GBS

Echo Malaria

Enterovirus Lyme

ascending birth canal
Ascending/Birth Canal
  • Organisms - GI/GU flora, Cervical/Blood

E. Coli Herpes

GBS Candida

Chlamydia HIV

UreaplasmaMycoplasma

Listeria Hepatitis

Enterococcus Anaerobes

Gonorrhea Syphilis

HPV

nosocomial
Nosocomial
  • Organisms –

Skin Flora, Equipment/Environment

Staphylococcus – Coagulaseneg & pos

MRSA

Klebsiella

Pseudomonas

Proteus

Enterobacter

Serratia

Rotavirus

Clostridium – C dificile

Fungi

infection
Infection

Timing

  • Onset
    • Early Onset 1st 24 hrs 85 %

24-48 hrs 5%

    • Late Onset 7-90 days
symptoms
Symptoms
  • Non-specific/Common
    • Respiratory distress (90%) - RR, apnea (55%), hypoxia/vent need (36%), flaring/grunting
    • Temperature instability, feeding problems
    • Lethargy-irritability (23%)
    • Gastrointestinal – poor feeding, vomiting, abdominal distention, ileus, diarrhea
    • Color—Jaundice, pallor, mottling
    • Hypo- or hyperglycemia
    • Cardiovascular – Hypotension(5%), hypoperfusion, tachycardia
    • Metabolic acidosis NICHD data
symptoms1
Symptoms
  • Less common
    • Seizures
    • DIC
    • Petechiae
    • Hepatosplenomegaly
    • Sclerema
  • Meningitis symptoms
    • Irritability, lethargy, poorly responsive
    • Changes in muscle tone, etc.
evaluation
Evaluation
  • Non-specific
    • CBC/diff, platelets – ANC, I/T ratio
    • Radiographs
    • CRP
    • Fluid analysis – LP, U/A
    • Glucose, lytes, gases
  • Specific – Cultures, stains
  • Other – immunoassays, PCR, DNA microarray
results trigger points
Results “Trigger Points”
  • CBC
    • WBC <5.0, abs neutro <1,750, bands >2.0
    • I/T ratio > 0.2*
    • Platelets < 100,000
  • CRP > 1.0 mg/dl
  • CSF > 20 WBC’s with few or no RBC’s
  • Radiographs: infiltrates on CXR, ileus on KUB, periosteal elevation, etc.
treatment
Treatment
  • Prevention – vaccines, GBS prophylaxis, HAND-WASHING
  • Supportive – respiratory, metabolic, thermal, nutrition, monitoring drug levels/toxicity
  • Specific – antimicrobials, immune globulins
  • Non-specific – IVIG, NO inhibitors & inflammatory mediators
mother to infant transmission
Mother to Infant Transmission

GBS colonized mother (20-30% in US)

50%

50%

Non-colonized newborn

Colonized newborn

98%

2%

Early-onset sepsis, pneumonia, meningitis

Asymptomatic

gbs s epsis
GBS SEPSIS

RISK FACTORS

  • Previous GBS-infected baby
  • Gestational age <37 wks
  • Maternal disease (esp. GBS UTI)
  • Ruptured membranes > 18 hours
  • Location of delivery (e.g., home)
  • Infant/Fetal symptommatology
  • Clinical suspicion

Note: incidence has fallen 80% since CDC prevention guidelines were published in 1996

mothers in labor or with rom should be treated if
Mothers in labor or with ROM should be treated if:
  • Chorioamnionitis
  • History of previous GBS+ baby
  • Mother GBS+ or GBS-UTI this preg.
  • Mother’s GBS status unknown and:
    • < 37 wks gestation
    • ROM ≥ 18 hrs
    • Maternal temp ≥ 38o (100.4oF)
slide25

Group B Strep Association formed

1st ACOG & AAP

statements

CDC draft

guidelines published

Rate of Early- and Late-onset GBS Disease in the 1990s, U.S.

Consensus

guidelines

Schrag, New Engl J Med 2000 342: 15-20

gbs s epsis1
GBS SEPSIS

INFANTS TO BE SCREENED

  • Maternal “chorioamnionitis”
  • Maternal illness (i.e. UTI, pneumonia)
  • Maternal peripartum fever > 38o(100.4oF)
  • Prolonged ROM ≥ 18 hrs (≥ 12 hrs preterm)
  • Mother GBS+ with inadequate treatment (< 4 hrs)
    • No screening necessary if C-section delivery with intact membranes
gbs s epsis2
GBS SEPSIS

INFANTS TO BE SCREENED

  • Prolonged labor (> 20 hrs)
  • Home or contaminated delivery
  • “Chocolate-colored”/foul smelling amniotic fluid
  • Persistent fetal tachycardia
  • SYMPTOMATIC INFANT
    • treat immediately (in DR if possible)
gbs s epsis3
GBS SEPSIS

SEPSIS SCREEN

  • CBC with differential
  • Platelet count
  • Blood culture x 1-2 (ideally 1 ml)
  • Chest X-ray &/or LP if symptommatic
  • Close observation and frequent clinical evaluation
  • Role of CRP
slide29

Algorithm for Neonate whose MotherReceivedIntrapartum Antibiotics

Maternal Rx for GBS?

Maternal antibiotics

for suspected

chorioamnionitis?

Signs of neonatal sepsis?

Full diagnostic evaluation *

Empiric therapy++

Gestational age

<35 weeks?

Limited evaluation$ &

Observe ≥ 48 hours

If sepsis is suspected, full

diagnostic evaluation and

empiric therapy ++

Duration of IAP

before delivery

< 4 hours #

No evaluation

No therapy

Observe ≥ 48 hours**

YES

YES

YES

NO

NO

* CBC, blood cx, & CXR if resp sx. If ill consider LP.

++ Duration of therapy may be 48 hrs if no sx.

$ CBC with differential and blood culture

# Applies only to penicillin, Ampicillin, or cefazolin.

** If healthy & ≥ 38 wks & mother got ≥ 4 hours IAP, may D/C at 24 hrs.

NO

slide30

Careful Observation

&

Immediate Antibiotics

Careful Observation pending review of screen

  • Symptomatic INFANT
  • Maternal intrapartum fever > 38.6o
  • “Chocolate” or foul smelling fluid
  • Ill mother
  • Fetal tachycardia
  • Home delivery
  • Maternal fever < 38.6o
  • PROM
  • Mat GBS with < 2 dose abx

(-) Screen(+) Screen(-) Screen(+) Screen

Cont abx until bld cx neg for 48o if asympt. Use clini-cal judgement for cessation of abx if pt is/was sympt

d/c abx; careful obs and monit bld cx until d/c

Careful obs and monit bld cx until d/c

Initiate abx & cont until bl cx (-) for 48o. Clinical judgement for cessation of abx if pt sympt

Blood Culture Positive

Initiate, resume or continue abx therapy and treat for 7-10 days for gram pos organism or longer if gram neg organism cultured. LP may be performed at the discretion of attending, especially in seriously symptomatic pt

s epsis2
SEPSIS

SIGNS and SYMPTOMS

  • temp instability • lethargy
  • poor feeding/residuals • resp distress
  • glucose instability • poor perfusion
  • hypotension • bloody stools
  • abdominal distention • bilious emesis
  • apnea • tachycardia
  • skin/joint findings
s epsis3
SEPSIS

LABORATORY EVALUATION

  • Provide added value when results are normal
    • high negative predictive value
    • low positive predictive value
      • abnl results could be due to other reasons and not infection
  • IT < 0.3, ANC > 1,500 (normal) do not start abx, or d/c abx if started, if pt remains clinically stable
  • IT > 0.3, ANC < 1,500 consider initiation of abx pending bldcx in “at-risk” pt who was not already begun on antibiotics for other factors
s epsis4
SEPSIS

LABORATORY EVALUATION

  • Positive screen
    • total WBC < 5,000 – I/T > 0.3
    • ANC < 1,500 – platelets < 100,000
  • Additional work-up
    • CXR, urine cx, and LP as clinically indicated
  • CRP
    • no added value for diagnosis of early onset sepsis
    • best for negativepredicativevalue or when used serially
    • not to be used to decide about rx, duration of rx or need for LP
    • positive results for a single value obtained at 24 hrs ranges > 4.0 - 10.0 mg/dL
s epsis5
SEPSIS

TREATMENT

  • Review protocol
  • Antibiotics
    • Ampicillin 100 mg/kg/dose IV q 12 hours
    • Gentamicin 4 mg/kg/dose IV q 24 hours
      • IM route may be used in asymptomatic pt on whom abx are initiated for maternal risk factors or to avoid delays when there is difficulty obtaining IV
    • For meningitis: Ampicillin 200-300 mg/kg/d
  • Symptomatic management
    • respiratory, cardiovascular, fluid support
prognosis
Prognosis
  • Fatality rate 2-4 times higher in LBW than in term neonates
  • Overall mortality rate 15-40%
  • Survival less likely if also granulocytopenic (I:T > 0.80 correlates with death and may justify granulocyte transfusion).
infection and outcome
Infection and Outcome
  • Leviton, et al, Ped Res 1999
  • 1078 infants <1500 grams and/or <32 wks
  • Infants with IUI were more likely to have PVL
  • Chorioamnionitis was associated with a 4-fold increased risk of CP (17% vs. 3%)
  • Nelson, et al reported increased cytokine response in population based study of term but not preterm infants
infection and nd outcome
Infection and ND Outcome
  • IUI and postnatal infection both appear to increase the risk for adverse ND outcome
  • Role of inflammatory mediators/SIRS in brain injury in the preterm infant
    • Pressure passive CNS circulation
    • Direct cytotoxicity to the developing brain
    • Inherent vulnerability of the oligodendrocyte precursor
slide38

Postnatal Infection and ND Outcome: PDI < 70

Infection Groups Compared to Uninfected by Logistic Regression

Clinical Infection (N=1415)

Sepsis Alone (N=1740)

Sepsis+NEC (N=252)

Sepsis+Meningitis (N=152)

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

Adjusted Odds Ratios and 95% CIs

Stoll, JAMA 2004

slide39

Postnatal Infection and ND Outcome: Cerebral Palsy

Infection Groups Compared to Uninfected by Logistic Regression

Clinical Infection (N=1415)

Sepsis Alone (N=1740)

Sepsis+NEC (N=252)

Sepsis+Meningitis (N=152)

0.0

1.5

2.5

3.0

3.5

0.5

1.0

2.0

Adjusted Odds Ratios and 95% CIs

Stoll, JAMA 2004

late onset infection
Late Onset Infection
  • Majority of ELBW infants will develop

late onset sepsis

  • Significant associated morbidity and mortality
  • CONS still the most common pathogen
  • Gram-negative pathogens increasing in prevelance and are associated with higher mortality rate
neonatal infection and outcome
Neonatal Infection and Outcome
  • Increased risk of adverse ND outcome in ELBW infants with LOS
  • Increased risk of poor growth at 18 months AA in ELBW with LOS
  • Poor outcome associated with NEC
  • ?Role of cytokines and inflammatory mediators in CNS
prevention of nosocomial infections
Prevention of Nosocomial Infections
  • HANDWASHING
  • HANDWASHING
  • Universal precautions
  • Limit use devices and catheters
  • Minimize catheter manipulation
  • Nursery design
  • Meticulous skin care
  • Education
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