Neonatal Sepsis Outcome

DR. Tetty Yuniaty, dr., Sp.A(K), M.Kes

Ayu Alya, dr SpA
 Neonatal Sepsis

Still represents an important cause mortality and

morbidity of infants
Incidence is increasing in verylow-birth-weight
(VLBW, birth weight < 1500 g) preterm infants

Stoll BJ, et al. Term and Preterm develop infection

3080% : neurodevelopmental impairement
30100%: Poor head growth
a good predictor of longterm morbidity
Cortese F,, et al. Early and late infections in newborns: where do we stand? a review. Pediatrics Neonat. 2016;57:26573
Shah AB et al. Neonatal sepsis and old problem with new insights. Virulence. 2014;5(1):17078
 Perinatal and Neonatal Infection
Poor neurodevelopmental outcome

OUTCOME

Neuro-developmental impairment, cerebral

palsy, motoric and cognitive impairment,
neonatal death

Haque KN. Understanding and optimizing outcome in Neonates with sepsis and septic Shock. 2014
Neonatal Sepsis
Clinical syndrome systemic disease + bacteremia
occurs in the first month of life
Immunity immaturity

Susceptible to Infection

Morbidity Mortality

Incidence ranging from 1-5/1000 live births to 49-170/1000

live births
The leading cause of infant deaths in developing countries
(42%)
Cortese F, et al. Early and late infections in newborns: where do we stand? a review. Pediatrics Neonat. 2016;57:26573.
 Neonatal Sepsis Classification
Early Onset Neonatal Sepsis, (EOS)

Late Onset Neonatal Sepsis, (LOS)

<72 hours
Transmission during labor or in utero
>72 hours
Easily become severe
caused by a postnatal acquisition (nosocomial or
Etiology: Grup B Streptococcus, E. coli, H. influenzae, & L.
community sources) of the pathogen
monocytogenes (developed countries); Gram Negative
Insidence 5 25%, mortality 10 20%
Bacteria (developing countries)
Etiology: CoNS, C. albicans (developed countries); Negative Gram
Bacteria (developing countries)

CoNS: Coagulase-Negative Staphilococci

Shah AB, Padbury FJ. Neonatal sepsis and old problem with new insights. Virulence. 2014;5(1):17078.
Haque KN. Understanding and optimizing outcome in Neonates with sepsis and septic Shock. 2014.
 Neonatal Sepsis Microorganism Risk Factors
EOS Group B streptococci (GBS) Maternal GBS colonization
ETIOLOGY E. coli Chorioamnionitis
Streptococcus viridans PROM > 18 hours
Enterococci Prematurity
S. aureus Multiple Gestation
P. aeruginosa
Other Gram Negative Bacteria

LOS Gram Negative Staphylococcus Prematurity

S. aureus Low Birth Weight
Candida albicans long term use of catheters
E. coli Invasive Procedure
Klebsiella pneumonia Ventilator associated pneumonia
Enterococci Long term use of Antibiotics
P. aeruginosa
GBS
Shane LA, Sanchez P, Stoll JB. Neonatal sepsis. Journal Of Inf. 2017;(17):111
 Patophysiology
The existence of complex interactions between
bacterial toxins (antigen) & innate immune response
Failure to regulate host response mechanisms between pro-
inflammatory (early phase) & anti-inflammatory (late phase)

Pro-inflammatory(late
Anti-inflammatory (early phase):
phase) :
PRRs detected
Occurs after an PAMPs & DAMPs
inflammatory response (negative feedback effect)
Strengthen the pro-inflammatory response through TLR
Mediator anti-inflammatory IL-4, IL-10, IL-13, & Transforming GF-B
Excessive inflammation occurs after uncontrolled stimulation
Apoptosis Immune Disfunction
Machado JR, Soave FG, Silva da VM, Menezes LB, Etchebehere MR,
Monteiro RD, et al. Neonatal sepsis and inflammatory mediators. Mediators PRRs : Pattern-recognition receptors, PAMPs : Pathogen-associated molecular patterns,
Of Inflama. 2014. 110 DAMPs: Danger-associated molecular pattern, TLR : Toll-like receptor
 Bacteria
PAMPs DAMPs 1. PAMPs & DAMPs
bonds to PRRs
PRRs

NF-k 2. Induction of
Inflammatory
Response
PMN Activations,
Lymphocyte,
Dendritic cell
Release of NO
Complement
Coagulopathy Activations
Cytokines
Release

Mitochondrial Apoptosis, 3. Clinical Sepsis

Dysfunction Immunoparalysis
Syndrome

SEPSIS SYNDROME Sepsis Pathophysiology

 Clinical Manifestations
o Not specific
o Related to micro-organism characteristic and body response
o Includes:
Temperature instability Bradicardia or tachycardia
Lethargic Respiratory Distress / apnea
Poor feeding Hypo / hyperglicemia
Prolonged CRT Metabolic Acidosis
Hypotonia Seizure
Diminished neonatal reflexes Shock

Gonzalez CA, et al. Neonatal infectious diseases: Evaluation of neonatal sepsis. Pediatr Clin North Am. 2013;60(2):36789
 Clinical Manifestations
o Other manifestations associated with interference body systems
CNS Bulging Anterior Fontanel, blank stares, high pitched cry, seizure, consciousness

Cardiac Hypotension, Poor Perfussion, Shock

Feeding intolerance, Vomit, Diarrhae, Abd distention, Ileus paralytic, Necr.

G.I Tract enterocolitis

Liver Hepatomegaly, direct bilirubin

Renal Acute renal failure

Hematology Bleeding, Petechiae, Purpura

Skin Pustula, Abses, Sclerema, Papulae eritema

 Laboratory Findings
Hematology
Neutropenia PMN < 1800/ml
Trombocytopenia < 150.000/ml
Immature Neutrophyl > 1500/ml
Immature Neutrophyl : Total ratio > 0,2
Occurrence of acute phase reactants : CRP, GCSF, Sitokin IL-1, IL-6, & TNF

Blood Culture/ body fluids, resistancy test, lumbar puncture Controversial

Fecal culture/ Urine, Gram Smears, Bilirubiin, Blood Glucose, Electrolyte, &
radiology based on indication
 Laboratory
Evaluation in assessing the association of early onset
sepsis and impaired brain function assessment of NEONATAL
level of interleukin-6, interleukin-8, and alpha tumor SEPSIS
necrosis factor
 Outcome Neonatal Sepsis
Neonatal sepsis can account of:

MDI < 70 (Bayley) Neurodevelopmental Impairment

Not progressive with abnormal tonus (Stoll et al.) Cerebral Palsy
Unilateral or bilateral blindness, visus disruption (Haller S) Visual Impairment
Unilateral or bilateral deafness (mild,moderate,severe) Hearing Impairment

Neonatal sepsis was an independent risk factor for Death

neuromotor development impairment at 12 months
of corrected age, but not for mental development
impairment
(Ferreira, et al.) Haller S, et al. Neurological sequelae of healthcare-associated sepsis in very-low-birthweight
infants: Umbrella review and evidence-based outcome tree. Euro Surveill. 2016;21(8)

Ferreira CR et al. Neonatal sepsis as risk factor for neurodevelopmental changes in

preterm infants with very low birth weight. 2014;90(3);29399
 Outcome Neonatal Sepsis
Brain Blood Brain
Damaged
Neonatal Sepsis

Cerebrovascular
Disfunction

Oxygenation &
Neurotransmitter
dysfunction
Pro-inflammatory Cytokine (TNF-,
Neuronal IL-1, IL-1, & IL-6) can penetrate
Degeneration the blood brain barrier
With lipopolysaccharide (LPS)
Cerebral Schlapbach JL, et al. Impact of sepsis on
bacteria can induce CNS
neurodevelopmental outcome in a Swiss national
inflammation
Edema cohort of extremelly premature infants. American
academy of pediatric. 2011;128(2). 34856
 Many studies have linked the incidence of
brain damage (ie. PVL, Neurodevelopmental
impairment, CP) to
perinatal infection

The association of both is often found with

many factors, ie : prematurity, and other
comorbids

These factors will cause an inflammatory

reaction & exotoxicity in the white matter of
the brain through the formation of
astrocytosis, microglial reactivity, & excitatory
amino acids

The end result is the necrosis of

oligodendrocyte precursor & axon
destruction
Brain damage
The increased odds of developing visual
impairments in neonatal sepsis survivors
Increased susceptibility of
oligodendrocytes in the Apoptosis
developing optic nerve

Subplate neurons Affected in

required for normal visual sepsis
cortical development

Spasojevi I, Obradovi B and Spasi S. Bench-to-bedside review: Neonatal sepsis redox processes in pathogenesis. Critical Care 2012, 16:221
The use of ototoxic drugs, including loop diuretics and
aminoglycosides, has been associated with increased
vulnerability of the cochlear to damage

Pourarian S, Khademi B, Pishva N, Jamali A. Prevalence of Hearing Loss in Newborns Admitted to Neonatal Intensive Care Unit. Iranian
Journal of Otorhinolaryngology. 2012
Outcome Neonatal Sepsis
Mortality
Prematurity Risk of death increases
Immaturity of the immune system
VLBW with sepsis : Mortality 3x
Premature with EOS mortality > premature with LOS
Term Infant at higher risk of infection if they have comorbidities (such
as impaired immune function, meconium aspiration, galactosemia, and
underlying cardiac or pulmonary abnormalities )
Term Infant mortality < premature

Simonsen AK, et al. Early-onset neonatal sepsis. Clin. Microbiol Rev. 2014;27(1):2147.
Outcome Neonatal Sepsis
Morbidity
Infection on Premature Poor neurodevelopmental outcome

Long term morbidity in premature infants with infections : risk

incidence of bronchopulmonary dysplasia (BPD)
Term Infants with GBS 50% have neurologic sequelae (seizure,
blindness, hearing impairment, cognitive delays in speech and
language)
Other very rare complications develop from sepsis-associated endocarditis
and thrombosis and can include valvular damage, pulmonary embolism,
and secondary infectious thromboembolism
Simonsen AK, et al. Early-onset neonatal sepsis. Clin. Microbiol Rev. 2014;27(1):2147.
 BPD
EOS associated with an increased
chronic lung disease in
risk of bronchopulmonary dysplasia
(BPD) preterm infants up to
36 weeks of correction
age, birth weight
<1.500 gram, still need
oxygen supplements
Adams-Chapman, et al. release of cytokines
results in progressive damage to the lung at risk
for BPD

Stoll JB, Hansen IN, Chapman AI, Fanaroff AA, Hintz RS, Vohr B et al. Neurodevelopmental and growth impairment among extremely low birth weight infants
with neonatal infection. American Med associ. 2004
FOLLOW UP

Rates of infection increase with decreasing

birth weight and gestational age
increased risk of poor neurodevelopmental
and growth outcomes

Growth monitoring and development are

required routinely
Follow Up
Monitoring Growth Tools

Screening to identify high-risk children

The principle of tool selection:
Reliability, Validity, Sensitivity, & Spesifity
 Follow Up
Fenton 2013 curves is used to monitor
the growth and development of the
Body Length Measurement baby

Growth Monitoring with Bayley infant

neurodevelopment screening (BINS)
Body Weight Measurement or Denver development screening
test II (DDST II)
Head Circumference
Measurement
ROP Screening

AAP. Screening Examination of Premature Infants for Retinopathy of Prematurity. 2013

 Hearing Screening
The currently acceptable methods for physiologic hearing
screening in newborns are auditory brainstem response (ABR) and evoked
optoacoustic emissions (EOAE)
ABR is reliable after 34 weeks postnatal age
All infants should have access to hearing screening using a physiologic
measure no later than 1 month of age

All infants who do not pass the initial hearing screening and the subsequent
rescreening should have appropriate audiologic and medical evaluations to
confirm the presence of hearing loss no later than 3 months of age

All infants with confirmed permanent hearing loss should receive early
intervention services as soon as possible after diagnosis but no later than 6
months of age

American Academy of Pediatrics, Joint Committee on Infant Hearing. Year 2007 position statement: principles and guidelines for early hearing detection and
intervention programs. Pediatrics 2007;120(4):898921
 HEAD ULTRASOUNDS

Shankar et al,2014,Head
Ultrasound Screening: are
important for high-risk babies
morphology of brain damage

Shankar, Poornima, and S.L. Nithya. "Role of cranial ultrasound in high risk neonates in NICU."Journal
of Evolution of Medical and Dental Sciences, vol. 3, no. 15, 2014
Head Ultrasound

Hynes RA, Andrews TM. Discharge planning. Dalam: Cloherty JP, Eichenwald EC, Hansen AR, Stark AR, penyunting. Manual of neonatal care. 2012
Conclusion

v Neonatal sepsis can provide poor outcomes in

infants, especially in premature infant

v Good management and evaluation are necessary

to minimize the occurrence of poor outcomes