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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


Neonatal sepsis the special case of group b strep sepsis

Neonatal Sepsis:the special case ofGroup B Strep Sepsis


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)


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


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


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


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


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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