Management of Management of Neonatal SepsisNeonatal Sepsis

Niki Kosmetatos, MDNiki Kosmetatos, MD

Anthony Piazza, MDAnthony Piazza, MD

J. Devn Cornish, MDJ. Devn Cornish, MD

Emory UniversityEmory University

Department of PediatricsDepartment of Pediatrics

IncidenceIncidence MortalityMortality

– 13-69% world wide13-69% world wide– 13-15% of all neonatal deaths (US)13-15% of all neonatal deaths (US)

MeningitisMeningitis– 0.4-2.8/1000 live births (US 0.2-0.4/1000)0.4-2.8/1000 live births (US 0.2-0.4/1000)– Mortality 13-59%; US 4% of all neonatal Mortality 13-59%; US 4% of all neonatal

deathsdeaths SepsisSepsis

– 1-21/1000 world wide; US1-8/1000 live 1-21/1000 world wide; US1-8/1000 live birthsbirths

– Culture proven 2/1000 (3-8% of infants Culture proven 2/1000 (3-8% of infants evaluated for sepsis)evaluated for sepsis)

– Prematures Prematures <1000 g <1000 g 26/1000 26/1000 1000 - 2000 g 1000 - 2000 g 8-8-

9/10009/1000

Predisposing FactorsPredisposing FactorsGeneral Host FactorsGeneral Host Factors PrematurityPrematurity Race – GBS sepsis blacks>whitesRace – GBS sepsis blacks>whites Sex – sepsis & meningitis more common Sex – sepsis & meningitis more common

in males, esp. gram negative infectionsin males, esp. gram negative infections Birth asphyxia, meconium staining, stressBirth asphyxia, meconium staining, stress Breaks in skin & mucous membrane Breaks in skin & mucous membrane

integrity integrity (e.g. omphalocoele, meningomyelocoele)(e.g. omphalocoele, meningomyelocoele)

Environmental exposureEnvironmental exposure Procedures Procedures (e.g. lines, ET-tubes)(e.g. lines, ET-tubes)

Predisposing FactorsPredisposing Factors Maternal/Obstetrical FactorsMaternal/Obstetrical Factors

GeneralGeneral – – socioeconomic status, poor prenatal socioeconomic status, poor prenatal care, vaginal flora, maternal substance abuse, care, vaginal flora, maternal substance abuse, known exposures, known exposures, prematurityprematurity, twins, twins

Maternal infectionsMaternal infections – –chorioamnionitis (1-10% of chorioamnionitis (1-10% of pregnancies), fever (>38° C/100.4° F), sustained pregnancies), fever (>38° C/100.4° F), sustained fetal tachycardia, venereal diseases, fetal tachycardia, venereal diseases, UTI/bacteriuria, foul smelling lochia, GBS+, other UTI/bacteriuria, foul smelling lochia, GBS+, other infectionsinfections

Obstetrical manipulationObstetrical manipulation – – amniocentesis, amniocentesis, amnioinfusion, prolonged labor, fetal monitoring, amnioinfusion, prolonged labor, fetal monitoring, digital exams, previa/abruption?digital exams, previa/abruption?

Premature & Prolonged ROM, preterm laborPremature & Prolonged ROM, preterm labor

Predisposing FactorsPredisposing Factors

Overall sepsis rateOverall sepsis rate 8/10008/1000

Maternal FeverMaternal Fever 4/10004/1000

PROMPROM 10-13/100010-13/1000

Fever & PROMFever & PROM 87/100087/1000

Preterm Labor/PROMPreterm Labor/PROM

Prematurity Prematurity (~10%) 15-25% due to (~10%) 15-25% due to maternal infectionmaternal infection

>18-24h term; >12-18h preterm>18-24h term; >12-18h preterm Bacterial infectionBacterial infection

synthesis of PGsynthesis of PG– Macrophage TNF/IL stimulate PG Macrophage TNF/IL stimulate PG

synthesis, cytokine releasesynthesis, cytokine release****– Release of collagenase & elastase Release of collagenase & elastase

ROMROM + Amniotic fluid cultures 15% + Amniotic fluid cultures 15% (with (with

intact membranes)intact membranes)

SSEPSISEPSIS

ORGANISMSORGANISMS Group B strep Group B strep (most common G+)(most common G+)

Coliforms Coliforms (E. coli most common G-)(E. coli most common G-)

ListeriaListeria Nosocomial infectionsNosocomial infections Staph epidermidisStaph epidermidis CandidaCandida Note: 50% G+ and 50% G-Note: 50% G+ and 50% G-

Routes of InfectionRoutes of Infection

Transplacental/HematogenousTransplacental/Hematogenous Ascending/Birth CanalAscending/Birth Canal NosocomialNosocomial

Transplacental/Transplacental/HematogenousHematogenous Organisms (Not just “TORCHS”)Organisms (Not just “TORCHS”)

SyphilisSyphilis Herpes*Herpes*ToxoplasmosisToxoplasmosis GonorrheaGonorrheaRubellaRubella MumpsMumpsCytomegalovirusCytomegalovirus TBTBAcute VirusesAcute Viruses HIVHIV

CoxsackieCoxsackie PolioPolioAdenovirusAdenovirus GBSGBSEchoEcho MalariaMalariaEnterovirusEnterovirus LymeLyme

VaricellaVaricellaParvovirus*Parvovirus*

Ascending/Birth CanalAscending/Birth Canal

Organisms - GI/GU flora, Organisms - GI/GU flora, Cervical/BloodCervical/Blood

E. Coli E. Coli HerpesHerpes

GBSGBS CandidaCandida

ChlamydiaChlamydia HIVHIV

UreaplasmaUreaplasma MycoplasmaMycoplasma

ListeriaListeria HepatitisHepatitis

EnterococcusEnterococcus AnaerobesAnaerobes

GonorrheaGonorrhea SyphilisSyphilis

HPVHPV

NosocomialNosocomial Organisms – Organisms –

Skin Flora, Equipment/Environment Skin Flora, Equipment/Environment Staphylococcus – Coagulase neg & posStaphylococcus – Coagulase neg & posMRSAMRSAKlebsiellaKlebsiellaPseudomonas/ProteusPseudomonas/ProteusEnterobacterEnterobacterSerratiaSerratiaRotavirusRotavirusClostridia – C dificileClostridia – C dificileFungiFungi

InfectionInfection

TimingTiming

OnsetOnset– Early OnsetEarly Onset 1 1stst 24 hrs 24 hrs 85 %85 %

24-48 hrs24-48 hrs5%5%

– Late OnsetLate Onset 7-90 days 7-90 days

SymptomsSymptoms Non-specific/Common Non-specific/Common

– Respiratory distress Respiratory distress (90%)(90%) - - RR, apnea RR, apnea (55%), (55%),

hypoxia/vent need hypoxia/vent need (36%), (36%), flaring/gruntingflaring/grunting

– Temperature instability, feeding problemsTemperature instability, feeding problems– Lethargy-irritability Lethargy-irritability (23%)(23%)

– Gastrointestinal – Gastrointestinal – poor feeding, vomiting, poor feeding, vomiting, abdominal distention, ileus, diarrheaabdominal distention, ileus, diarrhea

– Color—Color—Jaundice, pallor, mottlingJaundice, pallor, mottling

– Hypo- or hyperglycemiaHypo- or hyperglycemia– Cardiovascular – Cardiovascular – HypotensionHypotension (5%), (5%),

hypoperfusion, tachycardiahypoperfusion, tachycardia– Metabolic acidosisMetabolic acidosis NICHD dataNICHD data

SymptomsSymptoms Less commonLess common

– SeizuresSeizures– DICDIC– PetechiaePetechiae– HepatosplenomegalyHepatosplenomegaly– ScleremaSclerema

Meningitis symptomsMeningitis symptoms– Irritability, lethargy, poorly responsiveIrritability, lethargy, poorly responsive– Changes in muscle tone, etc.Changes in muscle tone, etc.

EvaluationEvaluation Non-specific Non-specific

– CBC/diff, platelets – ANC, I/T ratioCBC/diff, platelets – ANC, I/T ratio– RadiographsRadiographs– CRPCRP– Fluid analysis – LP, Fluid analysis – LP, U/A U/A – Glucose, lytes, gasesGlucose, lytes, gases

Specific – Cultures, stainsSpecific – Cultures, stains Other – immunoassays, PCR, DNA Other – immunoassays, PCR, DNA

microarraymicroarray

Results “Trigger Results “Trigger Points” Points” CBCCBC

– WBC <5.0, abs neutro <WBC <5.0, abs neutro <1,7501,750, bands >2.0, bands >2.0– I/T ratio > I/T ratio > 0.2*0.2*– Platelets < 100,000Platelets < 100,000

CRP > 1.0 mg/dlCRP > 1.0 mg/dl CSF > 20 WBC’s with few or no RBC’s CSF > 20 WBC’s with few or no RBC’s Radiographs: infiltrates on CXR, ileus Radiographs: infiltrates on CXR, ileus

on KUB, periosteal elevation, etc.on KUB, periosteal elevation, etc.

TreatmentTreatment PreventionPrevention – vaccines, GBS – vaccines, GBS

prophylaxis, HAND-WASHINGprophylaxis, HAND-WASHING SupportiveSupportive – respiratory, metabolic, – respiratory, metabolic,

thermal, nutrition, monitoring drug thermal, nutrition, monitoring drug levels/toxicitylevels/toxicity

SpecificSpecific – antimicrobials, immune – antimicrobials, immune globulinsglobulins

Non-specificNon-specific – IVIG, NO inhibitors & – IVIG, NO inhibitors & inflammatory mediatorsinflammatory mediators

Neonatal Sepsis:Neonatal Sepsis:the special case ofthe special case of

Group B Strep Group B Strep SepsisSepsis

RISK FACTORSRISK FACTORS Gestational ageGestational age Maternal well-beingMaternal well-being Ruptured membranes > 18 hoursRuptured membranes > 18 hours Location of deliveryLocation of delivery Infant/Fetal symptomatologyInfant/Fetal symptomatology Clinical suspicionClinical suspicion

GBS SGBS SEPSISEPSIS

Mothers in labor or Mothers in labor or with ROM with ROM should be should be treated treated if:if: ChorioamnionitisChorioamnionitis History of previous GBS+ baby History of previous GBS+ baby Mother GBS+ or GBS-UTI this preg.Mother GBS+ or GBS-UTI this preg. Mother’s GBS status unknown and:Mother’s GBS status unknown and:

– < 37 wks gestation< 37 wks gestation– ROM ROM ≥≥ 18 hrs 18 hrs– Maternal temp Maternal temp ≥≥ 38 38o o (100.4(100.4ooF)F)

INFANTS TO BE SCREENEDINFANTS TO BE SCREENED Maternal “chorioamnionitis”Maternal “chorioamnionitis” Maternal illness Maternal illness (i.e. UTI, pneumonia)(i.e. UTI, pneumonia) Maternal peripartum fever > 38Maternal peripartum fever > 38oo

(100.4(100.4ooF)F) Prolonged ROM Prolonged ROM ≥≥ 18 hrs ( 18 hrs (≥≥ 12 hrs 12 hrs

preterm)preterm) Mother GBS+ with inadequate Mother GBS+ with inadequate

treatment (treatment (< 4 hrs< 4 hrs))– No screening necessary if C-section delivery No screening necessary if C-section delivery

with intact membraneswith intact membranes

GBS SGBS SEPSISEPSIS

INFANTS TO BE SCREENEDINFANTS TO BE SCREENED Prolonged labor (> 20 hrs)Prolonged labor (> 20 hrs) Home or contaminated deliveryHome or contaminated delivery ““Chocolate-colored”/foul smelling Chocolate-colored”/foul smelling

amniotic fluidamniotic fluid Persistent fetal tachycardiaPersistent fetal tachycardia SYMPTOMATIC INFANTSYMPTOMATIC INFANT

– treat immediately (in DR if possible)treat immediately (in DR if possible)

GBS SGBS SEPSISEPSIS

SEPSIS SCREENSEPSIS SCREEN CBC with differentialCBC with differential Platelet countPlatelet count Blood culture x 1 (ideally 1 ml)Blood culture x 1 (ideally 1 ml) Chest X-ray &/or LP if Chest X-ray &/or LP if

symptomaticsymptomatic Close observation and frequent Close observation and frequent

clinical evaluationclinical evaluation Role of CRPRole of CRP

GBS SGBS SEPSISEPSIS

* 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.

Maternal antibiotics for suspectedchorioamnionitis?

Duration of IAPbefore delivery

< 4 hours #

Full diagnostic evaluation *Empiric therapy++

Limited evaluation$ & Observe ≥ 48 hoursIf sepsis is suspected, full diagnostic evaluation and empiric therapy ++

Gestational age

<35 weeks?

No evaluation No therapyObserve ≥ 48 hours**

Maternal Rx for GBS?

Signs of neonatal sepsis?

Algorithm for Neonate whose Mother Received Intrapartum Antibiotics

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 (+) Screend/c abx; careful obs and monit bld cx until d/c

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

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

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

Blood Culture Positive

SSEPSISEPSIS

SIGNS and SYMPTOMSSIGNS and SYMPTOMS temp instabilitytemp instability • lethargy • lethargy poor feeding/residualspoor feeding/residuals • resp distress • resp distress glucose instabilityglucose instability • poor • poor

perfusionperfusion hypotensionhypotension • bloody stools • bloody stools abdominal distentionabdominal distention • bilious • bilious

emesisemesis apneaapnea • tachycardia • tachycardia skin/joint findingsskin/joint findings

LABORATORY EVALUATIONLABORATORY EVALUATION Provide added value when results are Provide added value when results are

normalnormal– high negative predictive valuehigh negative predictive value– low positive predictive valuelow positive predictive value

abnl results could be due to other reasons and not abnl results could be due to other reasons and not infectioninfection

IT < 0.3, ANC > 1,500 (normal) do not start IT < 0.3, ANC > 1,500 (normal) do not start abx, or d/c abx if started, if pt remains abx, or d/c abx if started, if pt remains clinically stableclinically stable

IT IT >> 0.3, ANC < 1,500 consider initiation of 0.3, ANC < 1,500 consider initiation of abx pending bld cx in “at-risk” pt who was abx pending bld cx in “at-risk” pt who was not already begun on antibiotics for other not already begun on antibiotics for other factorsfactors

SSEPSISEPSIS

LABORATORY EVALUATIONLABORATORY EVALUATION Positive screenPositive screen

– total WBC total WBC << 5,000 5,000 – – I/T I/T >> 0.3 0.3– ANC ANC << 1,500 1,500 – platelets < 100,000– platelets < 100,000

Additional work-upAdditional work-up– CXR, urine cx, and LP as clinically indicatedCXR, urine cx, and LP as clinically indicated

CRPCRP– no added value for diagnosis of early onset no added value for diagnosis of early onset

sepsissepsis– best for best for negativenegative predicativepredicative valuevalue or when or when

used seriallyused serially– notnot to be used to decide about rx, duration of to be used to decide about rx, duration of

rx or need for LPrx or need for LP– positive results for a single value obtained at positive results for a single value obtained at

24 hrs ranges > 4.0 - 10.0 mg/dL24 hrs ranges > 4.0 - 10.0 mg/dL

SSEPSISEPSIS

SSEPSISEPSISTREATMENTTREATMENT Review protocolReview protocol AntibioticsAntibiotics

– Ampicillin 100 mg/kg/dose IV q 12 hoursAmpicillin 100 mg/kg/dose IV q 12 hours– Gentamicin 3.5 mg/kg/dose IV q 24 hoursGentamicin 3.5 mg/kg/dose IV q 24 hours

IM route may be used in asymptomatic pt on IM route may be used in asymptomatic pt on whom abx are initiated for maternal risk factors whom abx are initiated for maternal risk factors or or to avoid delays to avoid delays when there is difficulty when there is difficulty obtaining IVobtaining IV

– For meningitis: Ampicillin 200-300 mg/kg/dFor meningitis: Ampicillin 200-300 mg/kg/d Symptomatic managementSymptomatic management

– respiratory, cardiovascular, fluid supportrespiratory, cardiovascular, fluid support

PrognosisPrognosis

Fatality rate 2-4 times higher in Fatality rate 2-4 times higher in LBW than in term neonatesLBW than in term neonates

Overall mortality rate 15-40%Overall mortality rate 15-40% Survival less likely if also Survival less likely if also

granulocytopenic (I:T > 0.80 granulocytopenic (I:T > 0.80 correlates with death and may correlates with death and may justify granulocyte transfusion).justify granulocyte transfusion).