Management of Neonatal Sepsis

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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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Babies and Bacteria
Gram positive bacteria (anthrax)
Gram negative bacteria (pseudomonas)
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Dont mix!
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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 lt1000 g 26/1000 1000 - 2000
  g 8-9/1000

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Predisposing Factors

• General Host Factors
• Prematurity (OR 25 if lt 1,000 gms)
• Race GBS sepsis blacksgtwhites (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)

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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 (gt38 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

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Predisposing Factors

• Overall sepsis rate 2/1000
• Maternal Fever 4/1000
• PROM 10-13/1000
• Fever PROM 87/1000

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Preterm Labor/PROM

• Prematurity (10) 15-25 due to maternal
  infection
• gt18-24h term gt12-18h 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)

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SEPSIS

• ORGANISMS (all babies)
• Group B strep (most common G) 41
• Other strep 23
• Coliforms (E. coli most common G-) 17
• Staph aureus 4
• Listeria 2
• Nosocomial infections
• Candida
• Note 73 G and 27 G-

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SEPSIS

• ORGANISMS (VLBW)
• Group B strep (most common G) 12
• Other strep 9
• Coliforms (E. coli most common G-) 41
• CONS 15
• Listeria 2
• Nosocomial infections
• Candida 2
• Note 45 G and 53 G-
• Source Stoll et al Ped Inf Dis 2005, 24635

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Routes of Infection

• Transplacental/Hematogenous
• Ascending/Birth Canal
• Aspiration
• Device Associated Infection
• Nosocomial
• Epidemic

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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

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Ascending/Birth Canal

• Organisms - GI/GU flora, Cervical/Blood
• E. Coli Herpes
• GBS Candida
• Chlamydia HIV
• Ureaplasma Mycoplasma
• Listeria Hepatitis
• Enterococcus Anaerobes
• Gonorrhea Syphilis
• HPV

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Nosocomial

• Organisms
• Skin Flora, Equipment/Environment
• Staphylococcus Coagulase neg pos
• MRSA
• Klebsiella
• Pseudomonas
• Proteus
• Enterobacter
• Serratia
• Rotavirus
• Clostridium C dificile
• Fungi

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Infection

• Timing
• Onset
• Early Onset 1st 24 hrs 85
• 24-48 hrs 5
• Late Onset 7-90 days

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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
• ColorJaundice, pallor, mottling
• Hypo- or hyperglycemia
• Cardiovascular Hypotension (5), hypoperfusion,
  tachycardia
• Metabolic acidosis NICHD data

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Symptoms

• Less common
• Seizures
• DIC
• Petechiae
• Hepatosplenomegaly
• Sclerema
• Meningitis symptoms
• Irritability, lethargy, poorly responsive
• Changes in muscle tone, etc.

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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

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Results Trigger Points

• CBC
• WBC lt5.0, abs neutro lt1,750, bands gt2.0
• I/T ratio gt 0.2
• Platelets lt 100,000
• CRP gt 1.0 mg/dl
• CSF gt 20 WBCs with few or no RBCs
• Radiographs infiltrates on CXR, ileus on KUB,
  periosteal elevation, etc.

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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

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Neonatal Sepsisthe special case ofGroup B
Strep Sepsis

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Mother to Infant Transmission
GBS colonized mother (20-30 in US)
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50
Non-colonized newborn
Colonized newborn
98
2
Early-onset sepsis, pneumonia, meningitis
Asymptomatic
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GBS SEPSIS

• RISK FACTORS
• Previous GBS-infected baby
• Gestational age lt37 wks
• Maternal disease (esp. GBS UTI)
• Ruptured membranes gt 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

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Mothers in labor or with ROM should be treated if

• Chorioamnionitis
• History of previous GBS baby
• Mother GBS or GBS-UTI this preg.
• Mothers GBS status unknown and
• lt 37 wks gestation
• ROM 18 hrs
• Maternal temp 38o (100.4oF)

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

Group B Strep Association formed
1st ACOG AAP statements
CDC draft guidelines published
Consensus guidelines
Schrag, New Engl J Med 2000 342 15-20
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GBS SEPSIS

• INFANTS TO BE SCREENED
• Maternal chorioamnionitis
• Maternal illness (i.e. UTI, pneumonia)
• Maternal peripartum fever gt 38o (100.4oF)
• Prolonged ROM 18 hrs ( 12 hrs preterm)
• Mother GBS with inadequate treatment (lt 4 hrs)
• No screening necessary if C-section delivery with
  intact membranes

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GBS SEPSIS

• INFANTS TO BE SCREENED
• Prolonged labor (gt 20 hrs)
• Home or contaminated delivery
• Chocolate-colored/foul smelling amniotic fluid
• Persistent fetal tachycardia
• SYMPTOMATIC INFANT
• treat immediately (in DR if possible)

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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

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Algorithm for Neonate whose Mother Received
Intrapartum Antibiotics
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
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Careful Observation Immediate Antibiotics
Careful Observation pending review of screen

• Symptomatic INFANT
• Maternal intrapartum fever gt 38.6o
• Chocolate or foul smelling fluid
• Ill mother

• Fetal tachycardia
• Home delivery
• Maternal fever lt 38.6o
• PROM
• Mat GBS with lt 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
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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

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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 lt 0.3, ANC gt 1,500 (normal) do not start abx,
  or d/c abx if started, if pt remains clinically
  stable
• IT gt 0.3, ANC lt 1,500 consider initiation of abx
  pending bld cx in at-risk pt who was not
  already begun on antibiotics for other factors

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SEPSIS

• LABORATORY EVALUATION
• Positive screen
• total WBC lt 5,000 I/T gt 0.3
• ANC lt 1,500 platelets lt 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 negative predicative value 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 gt 4.0 - 10.0 mg/dL

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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

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Prognosis

• Fatality rate 2-4 times higher in LBW than in
  term neonates
• Overall mortality rate 15-40
• Survival less likely if also granulocytopenic
  (IT gt 0.80 correlates with death and may justify
  granulocyte transfusion).

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Infection and Outcome

• Leviton, et al, Ped Res 1999
• 1078 infants lt1500 grams and/or lt32 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

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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

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Postnatal Infection and ND Outcome PDI lt 70
Infection Groups Compared to Uninfected by
Logistic Regression
Clinical Infection (N1415)
Sepsis Alone (N1740)
SepsisNEC (N252)
SepsisMeningitis (N152)
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
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Postnatal Infection and ND Outcome Cerebral
Palsy
Infection Groups Compared to Uninfected by
Logistic Regression
Clinical Infection (N1415)
Sepsis Alone (N1740)
SepsisNEC (N252)
SepsisMeningitis (N152)
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
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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

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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

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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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Thank You!!