Incidence, Diagnosis and treatment of Neonatal Sepsis

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Incidence, Diagnosis and treatment of Neonatal
Sepsis

• Dr. Khalid N. Haque
• Reader in Neonatal Medicine
• University of London
• and Consultant Neonatologist
• Epsom St Helier NHS Trust

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NEONATAL SEPSIS

• Incidence or the burden of disease
• Diagnosis
• Treatment

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BURDEN OF NEONATAL SEPSIS

• 1.6 Million Deaths/ Year
• 2 Deaths/ Minute
• WHO 2000

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INCIDENCE OF NEONATAL SEPSIS
Incidence Overall 0.2 8 /1000 live births
In LBW 2 10 / 1000 births In VLBW 7 20 /
1000 births (VLBW babies given antibiotics
500/1000 EOS in VLBW 1.5 1.9 LOS in
VLBW 6.8 21 In Neonatal Intensive
Care EOS 10.4 - 33 LOS
43.2 - 70 Doyle 1999, Isaac 2000, Stoll
2002 Haque
2002
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Haque 2002
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Reasons for continuing high mortality and
morbidity in Neonatal Sepsis
Haque 1997

• Poor host defenses in the new-born.
• Our inability to diagnose sepsis early.
• Imprecise understanding of the patho-physiology
  of sepsis. Hence poorly directed therapy.
• Total reliance on killing the organism and
  inadequate attention to correcting the
  consequences of the inflammatory process.
• 
  

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REPORT CARDName New-Born
Class
Neonatal NurseryAge
Prem Term Remarks

• Anatomic Barriers B A
  Needs Attention
• Phagocytic Cells
• Polymorph - Neutrophils B -
  B Gets tired easily
• Macrophage/Monocyte C -
  B Often sleepy in class
• NK Cells C
  - A Needs constant
  stimulation
• T Cells
  D - B OK at multiplication
  and division.
• 
  Very weak at complex
  function
• Complement C
  B - Trouble getting started
• Antibody
  C - A Relies entirely on
  Mother
• Comments A sensitive child, often picked on by
  neighbourhood
• bullies. Needs support,
  constant attention and may
• need one to one tutoring.
• .

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EARLY DIAGNOSIS
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RISK FACTORS FOR NEONATAL SEPSIS

• CONDITION RELATIVE RISK
• 
  Gerdes 1991 Haque 2003
• 
  (n 400) (n 908)
• Prematurity 20
  lt 30 Wks 11.6
• 
  
  (CI 7.1-19.1)
• BW lt 1500 Grams
  
  9.7
• 
  
  (CI 5.8-16.0)
• PROM 8-11
  4.0
• Chorioamnionitis 3-5
  lt 1
• Maternal UTI 4
  lt 1
• Asphyxia (late infection)
  3 3-5
• Male gender 4
• Maternal GBS 0.5-1
  1
• PROM GBS 4-6
  1 - 3
• 
  
  

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THE LIKELIHOOD RATIOS OF CLINICAL FINDINGS FOR
NEONATAL INFECTION

• Clinical finding Likelihood Ratio

Pallor 14.4Poor feeding
8.7Tachycardia/arrhythmia 5.6 50
Decreased peripheral perfusion 5.4Unstable
BP 4.0Abdominal distention
3.5Apnoea 3.1 42 Lethargy
2.3 40 Temperature instability 0.7
68 Purpura 47.0Omphalitis 32.5
Rash 4.0Seizures 2.3
Radetsky 1995 Haque 2003
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LABORATORY INVESTIGATIONS FOR NEONATAL SEPSIS
Surface swabs Blood countDeep ear
swab Neutrophil countGastric
aspirate Platelet countUrine Coagulation
screenX-ray chest Blood cultureCRP CSF
cultureMini ESR C3Haptoglobin C3b1
Fibronectin CD 4 countNBT I-CAM
1Acradine Orange IL-1, IL-6,
IL-8PCR IL-10, TNFProcalcitonin Endotox
in
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VALUE OF SOME OF THE MOST FREQUENTLY DONE
INVESTIGATIONS IN NEONTAL SEPSIS

• 
  Sensitivity Specificity
  PPV NPV
• Blood Culture 11 38 68
  100 90-100 72-100
• WBC lt5000
• gt30,000 17 90
  31 100 50- 86 60-89
• I/T Ratio gt0.02 81
  45 23 92
• CRP gt 10mg/l 37
  95 63 87
• IL-8 gt70pg/ml 77
  76 42 94
• I/T Ratio gt0.02
• CRP gt 10 mg/l 89
  41 24 94
• IL-8 gt 70pg/ml
• CRP gt10 mg/l 91
  74 43 98
• Superficial Cultures 56
  8.2 7.5 4.1
• 
  
  
  
  Haque 96,
  Messer 96
• 
  
  Franz 97,
  Kuster 98, Evans 98

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Time course of IL-6, IL-8 and CRP in Neonatal
Sepsis
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lysis
THE SEPSIS CASCADE
Bacterium
Arachidonic acid metabolites
Cell wall fragments including LPS
Sepsis CCardiovascular Hypotension H
Haemopoetic DIC Anaemia
Neutropenia A Apoptosis Metabolic O
Organ dysfunction Renal failure
Heart failure Liver failure S Suppression
of Immune System
Septic shock
Septic syndrome Hypotension Acute RDS MOD
TREM-1 Cytokines e.g. TNF-a IL-1b, IL-6
LPS
Macrophage
Endothelial damage
Platelet activation
Death
LPS
Neutrophil activation
Activation of complement and coagulation cascades
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IMMUNOLOGICAL BALANCE IN SEPSIS
Late Phase
Early Phase
IL-10 IL-1RA IL-13 IL-14 sTNF-R sIL-2R TGF- ß
Endotoxin, Exotoxins (Super antigen) TNF-alpha
IFN-gamma IL-1 IL-2 IL-6 IL-8 C4b, C3b
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TREATMENT
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Main Objectives in the Treatment of Neonatal
Sepsis

• Kill the infecting organism (s). Antibiotics
• Correct/Reduce the sequelae of infection.
• Inhibit/Reduce Toxin levels.
• Boost Host Defences.
• Regain Immunological balance.

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ROUGES GALLERY Certain bacteria now defy all
antibiotics.
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MOST COMMON ORGANISMS CAUSING NEONATAL SEPSIS

• EOS
  LOS
• Group B Streptococcus 0.2 0.5 (0.8)
  18 20 (16)
• E. Coli 2.2 44
  (4) 18 (16)
• CONS 20 48
  (46) 42 70 (76)
• MRSA
  5 7 (lt1)
• Doyle
  1999, Brodie 2000, Mehr 2002, Stoll 2002
• 
  Brocklehurst 2003, Haque 2003 (unpublished)

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DURATION OF ANTIBIOTIC THERAPY IN NEONATAL
SEPSIS 173 NEONATAL UNITS IN UK
Condition Range (mean) in days
Suspected Sepsis (Culture Neg) 2 -
7 (2)Culture Proven Sepsis 5 - 21 (9)Staph
Epidermidis Sepsis 2 - 14 (7)Catheter/Line
related Sepsis 5 - 21 (11)PROM 5 - 7
(10) Meningitis 10 - 21 (14) NEC (Clinical
only) 2 - 10 (7)NEC (Radiological) 2 -
21 (14)
Haque KN 2000
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REFERENCES SUGGESTING SHORTER DURATION OF
ANTIBIOTIC THERAPY IN NEONATAL SEPSIS
Philip AGS J. Paed 1981 98(5)
795-799 Paed Infec Dis 1982 1
(2)85-90 J. Paed 1984 105 940-942 ONeil
P Lancet 1993 341 530 Pourcyrus M Paed
1993 92 431-435 Kawaura M Acta Paed 1995 84
10-13 Haque KN Arneil Forfar Textbook
of Paediatric 5th Edition 1998 Ehl S Paed
1997 99 216-221
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NEW WEAPONS AGAINST BACTERIA

• CONTACT KILLERS
• Blast holes in cell walls e.g. Meganin
• GENETIC TORPEDOES
• Chemicals which block DNA, RNA
• CRIPPLERS
• Chemicals stop microbes receiving vital
• stimuli. Block antibiotic clearance,
• Block cell wall, Prevent attachment to
• human cells, Stops cells breathing.
• VACCINES

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lysis
THE SEPSIS CASCADE
Bacterium
Sepsis CCardiovascular Hypotension H
Haemopoetic DIC Anaemia
Neutropenia A Apoptosis Metabolic O
Organ dysfunction Renal failure
Heart failure Liver failure S Suppression
of Immune System
Arachidonic acid metabolites
Cell wall fragments including LPS
Perfusion, Volume, Fluids, Early Inotropic
Support Transfusion Vit K Tissue
Oxygenation Correction of Acidosis,
Nutrition Symptomatic Nutrition Immune modulati
on
TREM-1 Cytokines e.g. TNF-a IL-1b, IL-6
LPS
Macrophage
Endothelial damage
Platelet activation
LPS
Neutrophil activation
Activation of complement and coagulation cascades
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RESTOREING THE IMMUNOLOGICAL BALANCE IN SEPSIS
Severe CARS
Severe SIRS
Death from excessive anti-inflammatory response
Death from overwhelming Infection
MARS
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Immunomodulatory Therapies in Neonatal Sepsis

• Exchange transfusion No benefit
• Granulocyte Transfusion Meta-analysis of five
  studies
• No reduction in mortality.
• Low dose steroid therapy No evidence of benefit
  in neonatal sepsis.
• Pentoxifylline Two RCTs showing up to
  30 reduction in mortality.
• Bacterial Permeability
• Increasing protein Little experience in
  new- borns.
• NO inhibitors No benefit
• Monoclonal anti-TNF Harmful

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Neonatal Sepsis
Colony Stimulating Factors G-CSF GM-CSF

• Correction of Neutropenia in sepsis (1,2,3,6,7,8)
• Protection of depletion of neutrophil storage
  pool (2,3)

Studies 1. Bedford Russell 1994
(G-CSF)2. Gillian 1994 (G-CSF)3. Cairo 1995
(G-CSF)4. Chirico 1996 (G-CSF)5. Barak 1997
(G-CSF)6. Carr 1997 (GM-CSF)7. Schibler 1998
(G-CSF) 8 Carr 2001
(GM-CSF) Cochrane Meta-analysis no effect on
Mortality (2/2003) Carr Modi
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SO WHERE DO WE GO FROM HERE IN THE TREATMENT OF
SEPSIS IN THE NEWBORN?
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The phagocytes wont eat the microbes unless the
microbes are nicely buttered for them. Well, the
patient manufactures the butter himself alright,
but my discovery is that the manufacture of that
butter, which I call OPSONIN, goes in the system
by ups and down.There is at the bottom only one
genuinely scientific treatment for all diseases,
and that is to stimulate phagocytosis.
The Doctors Dilemma G B Shaw
1909
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Increase opsonisation and increase phagocytosis
IVIG
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Neonatal Sepsis (1986-2003)

• What is the most important advance in neonatal
  sepsis
• Understanding the importance of the inflammatory
  process and host defense mechanisms.
• 2. What is the most important factor in reducing
  neonatal sepsis?
• 
  HAND WASHING
• 3. What is the most important therapy in neonatal
  sepsis?
• Equal attention to killing the organism,
  correcting sequlae of inflammatory process and
  up-modulating host defense mechanisms .
• 
  

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