Neonatal sepsis A Diagnostic dilemma

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Neonatal sepsis A Diagnostic dilemma

• Dr. ASHISH MEHTA.
• Consultant Neonatologist
• Arpan Newborn Care Centre.
• AHMEDABAD

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• 130 million babies born worldwide, 26 million
  born in INDIA
• 4 million babies die in first 30 days 98 in
  developing country
• Major causes of Neonatal Deaths (GLOBALLY )
• Preterm birth (28)
• Sepsis(26)- Developing Country(30-50)
• Birth Asphyxia(23)

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Importance related to morbidity

• Incidence
• 3 of intramural deaths and 40 of extramural
  admissions
• Mortality
• 19 of intramural deaths and 38 of extramural
  mortality

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Definitions

• Septicemia
• Systemic symptoms and signs associated with
  growth of bacteria from one or more sterile body
  sites
• Probable Sepsis
• Clinical features but negative blood cultures
  usually positive rapid diagnostic tests like
  CRP,ANC ,Micro ESR.

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Archives of diseases 201297F-182-185
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Archives of diseases 201297F-182-185
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Risk Factors

• EONS
• Chorioamnionitis ,maternal fever, unclean
  vaginal examination, pPROM, unexplained pre term
  labor, prematurity, PROMgt18 hrs.
• LONS
• Presence of central venous catheters, Delayed
  enteral feeding, parenteral nutrition, mechanical
  ventilation.

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• 24 year old primi gravida
• H/O fever for 2 days
• Spontaneous Vaginal delivery at Full term
• No resuscitation required
• 3.4 kg birth weight

? SEPSIS
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• Clinician
• Antibiotic required/not?
• Prophylactic AB no role
• Normal flora becoming resistant
• Do not want to miss sepsis

• Pathologist
• First Blood test before 12 hrs reflects maternal
  picture
• Markers may not help

Difficult to justify sepsis for both
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• 660 gm baby
• Delivered at 26 weeks of maturity
• 16 day of life
• On TPN thro CVL and gradual grading of RT feeds
• 2 episodes of apnea with color change

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• Normal CBC, Negative CRP
• No antibiotic started
• After 18 hrs becomes off color, poor pulses,
  Extremities cold
• Intubated and ventilated
• Repeat samples s/o sepsis.
• Too late to start AB

who is at Fault ?
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• Always a diagnostic dilemma
• No symptoms and signs to begin with e.g. early
  onset sepsis
• Symptoms and signs are many but not specific to
  sepsis

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Symptoms

• CNS
• Lethargy, Difficult to arouse, Limp, Refusal
  to suck, poor or high pitched cry, irritable
  ,seizures.
• CVS
• Pallor, Cyanosis, Cold Clammy Skin
• Respiratory
• Tachypnea ,Apnea, Grunt, Retractions

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Symptoms of Neonatal Sepsis

• GIT
• Diarrhea, Vomiting, Abdominal Distension
• Hematologic
• Bleeding, Jaundice
• Skin
• Rashes, Purpura, Pustules
• Renal
• Oliguria

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Signs of Neonatal Sepsis

• Cold to touch (hypothermia)
• Poor perfusion ( Prolonged CRT)
• Hypotension
• Sclerema
• Bulging Fontanels, Neck Retraction
• Poor Weight Gain ( Low grade Sepsis)
• Prolonged Jaundice
• Hypoglycemia/Hyperglycemia
• Increased prefeed aspirates
• Metabolic Acidosis

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Diagnosis of Neonatal Sepsis

• Direct
• Isolation of organism from Blood, Urine or CSF
• Indirect
• Screening Tests

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Inflammatory cascade
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Revising some jargon

• If baby has definite sepsis, in what proportion
  is the test ve? sensitivity
• If baby does not have sepsis, in what proportion
  is the test ve? specificity
• If babys test is ve, what proportion actually
  have definite sepsis? PPV
• If babys test is ve, what proportion actually
  do not have definite sepsis? NPV

Maximum Sensitivity and High NPV
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Heamatological parameters

• Total leucocyte count
• Absolute neutrophil count
• I/T ratio
• CRP
• Morphology of neutrophil
• Micro ESR

Decision to start AB ????
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Reality is
Test Abn value Sensitivity Specificity
CRP gt10mg/L 47-100 83-94
TLC lt5000, gt15000 17-89 81-98
ANC lt1750/cumm 38-96 61-92
ITR gt20 (preterm) gt 27 (term) 90-100 50-78
mESR Age in d3mm 27-50 83-99
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TLC

• Wide range of sensitivity (17-89) and
  specificity (31-100)
• Use standard reference chart Monroes or
  Mouzinhos
• Arterial / venous sample
• Comfortable / crying
• Morphology vacuolation, toxic granulation
  (degenerative changes in cells)

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I/T ratio

• 90-100 of sensitivity 98 of negative
  predictive value
• Problem is manual identification of immature
  neutrophil i.e. Band form
• Band cell immature neutrophil where, width of
  isthmus is gt 0.3 of width of the lobe of
  neutrophil

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• Micro ESR
• Normal value changes significantly during first
  few weeks of life
• Good specificity but sensitivity is low because
  of delay in rise long time required for
  normalization after clinical recovery
• Increased / Decreased Neutrophils
• Thrombocytopenia close association with sepsis
  but is a late marker

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CRP

• Acute phase substance produced by liver in
  response to inflammation
• Rises to detectable level within 6-8 hours of
  stimuli peaks at 48- 72 hours
• Falls after stimuli is over
• There is generally 24 hr delay between rise in
  CRP onset of clinical symptoms

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CRP methods of measurements

• Latex agglutination
• Immunocapillary
• Immune turbidometry
• Nephalometric
• Chemilumnascence
• Dry Chemistry Principle

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CRP ref. range

• Recent longitudinal study
• At birth 5 mg/dl (95th percentile)
• At 24 hour 14 mg/dl (95th percentile)
• At 48 hours 9.7 mg/dl (95th percentile)
• (included neonates not necessarily free of H/O
  maternal intra partum complications but had
  unremarkable post natal course from birth to 4
  weeks)

Value of gt 1 mg/dl at any age is considered
positive
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Qualitative assay does not offer any
significant advantage over leucocytic indices
Quantitative assay particularly When repeated
after 12 hours Have high specificity
sensitivity
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Remember . . .

• CRP has good sensitive / negative predictive
  value but positive predictive value is poor so a
  positive CRP is poor predictor of sepsis. False
  positive results from IVH, MAS, NEC, Surgery and
  immunization (Any active inflammatory process)

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Literature search

• (Two recent reviews of hematological indices for
  diagnosis of sepsis)
• Tests are of limited value in early diagnosis of
  infection, Clinician can not rely on either CRP /
  Leucocyte indices alone as result vary
  significantly depending on method of measurement
  population targeted

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Available hematological indices are not vary
reliable
CRP good but still cant accept as sole
investigation
Micro ESR less sensitivity
Blood C/S not available everywhere
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Combination of readings

• Sensitivity 100
• Specificity 83.5
• Negative predictive value 97.4

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Tests in proven sepsis Sensitivity Negative predictive value
CRP gt 6mg/dl 85.7 95.9
TLC lt 5000 or gt20000 /cmm 39.3 84.4
ANC 71.4 91.7
IT Ratio 25 81.2
Thrombocytopenia 64.3 90
GAC for polymorphs 71.4 92.2
Toxic granulations 14.3 78.9
Dohle bodies 0.6 78.7
Cytoplasmic vacuolation 60.7 90.1
CRP ANC 100 100
CRP Thronbocytopenia 96.4 98.9
CRP GAC 100 100
CRP ANC Cytoplasmic vacuolation 100 100
CRP ANC Thronbocytopenia 100 100
CRP GAC Cytolasmic vacuolation 100 100
JCPSP 2005, Vol. 15(3)
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Tests in probable sepsis Sensitivity Negative predictive value
CRP gt 6mg/dl 80.5 87.1
TLC lt 5000 or gt20000 /cmm 27.8 63.9
ANC 63.9 77.2
IT Ratio 20.8 61.5
Thrombocytopenia 40.3 67.7
GAC for polymorphs 50 72.5
Toxic granulations 16.7 60
Dohle bodies 4.2 59.2
Cytoplasmic vacuolation 72 70.4
CRP ANC 94.4 95.6
CRP Thronbocytopenia 87.5 86.6
CRP GAC 91.6 93.9
CRP ANC Cytoplasmic vacuolation 94.4 95.6
CRP ANC Thronbocytopenia 95.8 96
CRP GAC Cytolasmic vacuolation 91.7 93.9
JCPSP 2005, Vol. 15(3)
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Blood C/S

• Gold standard confirmation of neonatal sepsis
• Result available after at least 24-48 hours
• Still not available every where
• With best technique yield is not 100
• 30 C/S still fails to grow bacteria in spite of
  clinical florid sepsis

Reliability , Turn around time
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Wanted

• A test that
• Has well-defined cut-off
• Sensitivity, NPV approaching 100
• Specificity, PPV gt85
• Detects sepsis early (lt24 hrs)
• Adequate sampling window
• Small blood volume
• Quick turn-around-time
• Easy method
• Low cost

Ng, ADC, 2004
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Time line
4
8
12
16
20
24 48 72
Hours after bacterial invasion
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Diagnostic markers

• Pro-inflammatory cytokines
• IL-6 many studies
• Chemokines
• IL-8 many studies
• IP-10 one large study
• Acute phase reactants
• PCT many studies
• SAA few studies
• LBP few studies
• I?IP one huge study
• Neutrophil surface antigens
• CD11b few studies
• CD64 few but large studies
• PCR many studies

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IL-6

• IL-6 vs. CRP at onset of nosocomial sepsis
• Sensitivity 89 vs 60
• NPV 91 vs 75
• Cord blood IL-6
• Sn 87-100, NPV 93-100
• Very short t1/2 narrow sampling window
• Serial IL-6 vs CRP _at_ 24 h, 48 h
• 67, 58 vs 82, 84
• Affected by underlying illness severity

IL-6 gt CRP, but for shorter duration
Ng, ADC, 1997 Ng , COP, 2006 D-Alquen, Ped Res
2005
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Diagnostic sensitivity Diagnostic sensitivity Diagnostic sensitivity Specificity
Day -1 Day 0
IL - Ira 64 93 92
IL - 6 37 86 83
CRP 43 18 93
In contrast to CRP, IL-6 is an early marker But
become normal even if Infection continues
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IL-6 CRP Combination
Sensitivity 100

• Day 0 CRP, IL-6, Hematologiocal indices
• Day 1 CRP serial

Negative predictive value increases
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Procalcitonin
Interpreting PCT for EOS is tricky

• Pros
• Substantial rise within 2 hrs of infection
• t1/2 longer than IL longer sampling window
• Unaffected by underlying disease severity
• Cons
• PCT physiological elevation in 1st 2 days
• IVH, asphyxia, pre-ecclampsia ? PCT
• Perinatal history nomogram essential

Turner, ADC, 2006 van Rossum, Lancet, 2004
Chiesa, Clin Chem, 2003, Verboon-Maciolek, Ped
Res, 2006
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Procalcitonin

• PCT vs. CRP in cord blood
• Sensitivity 87.5 vs. 50
• Specificity 98.7 vs. 97
• PCT vs. IL-6 vs. CRP for EOS
• Sensitivity in 1st 12 hrs 77 vs. 54 vs. 69
• Specificity 91 vs. 100 vs. 96
• PCT vs. IL-6 vs. IL-8 vs. CRP for LOS
• Sensitivity 69 vs. 68 vs. 84 vs. 65
• Specificity 89 vs. 76 vs. 52 vs. 52

PCT gtgt CRP for cord blood, gt IL-6 CRP for EOS
Joram ADC, 2006 Resch, Acta Paed, 2003
Verboon-Maciolek, Ped Res, 2006
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Approach to Sepsis..

• Do you need to start Antibiotic(s)?
• If you want to start which Investigation will
  you like to ask for?
• Once started How long will you like to give?

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• Always A Diagnostic dilemma
• Extreme Situations
• Overuse of Antibiotics and
• related microbial resistances
• V/S
• Neonatal morbidies if
• missed/not treated in time

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A real Case Scenario..

• 29 year , primi gravida
• Normal Vaginal delivery- prolonged labor
• No resuscitation Required
• With mother on breast feeding
• Developed High grade fever on DAY 2

Medical college
Corporate set up
PHC
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Primary Health Centre

• Limited Resources
• Many Training programs for Basic Newborn Care
• Danger Signs
• NOT many possess required infrastructure,
  manpower, money to support diagnostic
  microbiology services!!!!!!!!!

Blood C/S not possible
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Presence of any of 7 signs sensitivity
85 and Specificity75
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• 28 yr old, Primi, Sever PIH, Maternal Fever low
  grade
• Normal Vaginal delivery at 32 wks.
• No resuscitation required
• No oxygen requirement minimal grunt

Will you start antibiotics? Which Investigation
will you ask for?
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Do you need to start Antibiotic(s)?

• EOS
• Asymptomatic
• symptomatic

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Time line
Test becomes positive before baby becomes
symptomatic
4
8
12
16
20
24 48 72
Hours after bacterial invasion
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Risk Factor Based score
Mainly for asymptomatic EOS
Risk Factor Score
IP vaginal Examination gt 3 6
Clinical Chorioamnionitis 6
BWlt1.5 Kg. 3
Male Gender 3
No intrapartum antibiotics 2
Gestation lt30 wks. 2
0-6 No antibiotics, Monitor carefully /gt 7
Prophylactic empirical antibiotic
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• 32 yr old, G2P0, Normal ANC, Normal scan
• Elective LSCS at 37 wks for preterm labor
• Resuscitation in form of bag and mask
• Grunting and oxygen requirement
• Chest Xray good lung volume, ? Haziness on right
  lower zone
• On CPAP of 6 cm of H20, 30 Fio2

Will you start antibiotics? Which Investigation
will you ask for?
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• Symptomatic EOS
• Any of risk factor
• Preterm. pPROM, PROMgt18 hrs, Spont. onset of
  labor, Clinical chorioamnionitis, Foul smelling
  liquor, Unclean P/V, Maternal fever, Maternal
  UTI, perinatal asphyxia
• Do not have alternate explanation for S/S
• Chest X ray s/o pneumonia

Start antibiotic IF
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Late Onset Sepsis..

• Single episode OR transient presence of sign may
  NOT warrant any action.
• Low / High probability
• Low probability RULE OUT SEPSIS
• High probability ? ROLE OF SEPTIC
  SCREEN

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Choice of Antibiotics

• Coverage for both Gram negative and
  positive-choose based on local bacterial cultures
  and sensitivities
• Avoid reserve drugs like Vancomycin,
  Teicoplanin,Ciprofloxacin , Avoid Cephalosporins
• Route- Oral and IM routes unreliable, so always
  intravenous
• Dose/Frequency-As per body weight, gestation and
  post natal age
• Adjust dose/frequency in presence of
  renal/hepatic impairment

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• Pencillin Aminoglycoside
• For meningitis, CephalosporinAminoglycoside
• First line antibiotic according to C/S in your
  set up
• Empirical up gradation if expected clinical
  improvement does not occur give 48 72 hrs
  before failing given AB
• If extreme sick MAY bypass first line AB

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Antibiotics-Good Practices

• Downgrade antibiotics as per culture sensitivity
  report
• Do not treat colonization with antibiotics
• Do not use prophylactic antibiotics
• Universal precautions cheaper than an antibiotic
  course

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Antibiotics-Practical issues

• Correct techniques of dilution, storage and
  administration
• Note shelf life
• Take care of incompatibilities

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C/S Available

• Organism sensitive to narrow spectrum
  antibiotic.
• If antibiotics sensitive but Pt has worsen.
• If antibiotics Resistant but Pt improved .

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Meningitis

• 10- 15 of infants with sepsis have Meningitis
• Specific Symptoms and Signs uncommon

Lumbar Puncture Must be done in ALL
neonates with symptomatic sepsis
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Diagnosis of Meningitis

• Cells gt 32/cu.mm
• gt 60 Polymorphs
• Protein gt 150 mg/dl (term), gt170 mg/dl (preterm)
• Glucose lt 50 of Blood Glucose or absolute value
  lt 30 mg/dl

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CSF values
Suspected Sepsis Blood C/S proven sepsis
PRETERM
WBC gt 25 AND Protein gt 170 mg OR Glucose lt 25 mg OR WBC gt 100 WBC gt 10 OR Glucose lt 25 mg OR Protein gt 170 mg
TERM
WBC gt 21 OR Glucose lt 20 WBC gt 8 OR Glucose lt 20 OR Protein gt 120
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Management-Supportive Care

• Multi organ Dysfunction in Sepsis
• Hypoxia, Hypothermia, Poor Perfusion,
  Hypoglycemia, Coagulation disturbances

Key to success Anticipation and
early diagnosis by systematic and
frequent monitoring
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Supportive Care-Monitoring

• Clinical
• Activity, Anterior fontanels, feeding
  behavior, colour,CFT,HR,RR,BP,SPO2,abdomen,Urine
  output
• Laboratory
• Blood Glucose, Ca, Na,K,Bu,Cr,Blood Gas,
  Platelets and Coagulation profile, Urine exam

Monitor frequently and serially
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Management-Supportive care

• Provide Warmth
• Provide oxygen if tachypneic, cyanosed, grunting
  or chest indrawing
• Maintain fluid electrolyte balance
• Maintain tissue perfusion. If CRT prolonged,
  infuse 10ml/kg normal saline over 30-60 minutes
• Maintain normoglycemia
• Withhold feeds if aspiration( Convulsions,
  respiratory distress or abdominal distension)

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Adjunctive therapies

• Blood Exchange Transfusions
• IVIG
• G-CSF, GM-CSF

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Conclusion.

• Sepsis is directly responsible for a quarter of
  neonatal mortality
• There are no pathognomic symptoms and signs
• Early diagnosis of sepsis should be possible
  within 24 hrs
• No test can be firmly recommended yet
• Blood culture is the gold standard

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Conclusions

• Appropriate and timely antibiotic therapy is
  crucial
• Supportive therapy is as important as antibiotics
  to prevent mortality