neonatal sepsis forms an important topic ...as a major cause of newborn mortality...a brief account on its pathogenesis

1. NEONATAL SEPSIS
Chairperson - DR BALAJI M.D
Moderator - DR PAVAN
Speaker - DR G.HARSHAVARDHAN
DEPT OF PEDIATRICS –AIMS –SAH& RC

2. NEONATAL SEPSIS
 INTRODUCTION
 DEFINITION
 TYPES
 RISK FACTORS
 PATHOPHYSIOLOGY
 CLINICAL FEATURES
 DIAGNOSIS
 APPROACHTO A CASE OF SEPSIS
 SEPSIS SCREEN
 MANAGEMENT

3. INTRODUCTION
Definition -
 Neonatal septicemia is defined as syndrome of generalized
systemic infection of the newborn , accompanied by with or
without bacteremia occurring in 1st month of life.
 It is one of the most important causes of mortality and
morbidity in newborn.
 Neonatal sepsis is diagnosed when features of sepsis are
associated with growth of bacteria from one or more sites.

4. IMPORTANCE..
o Among the low birth weight & preterm babies, neonatal septicemia is
the most important cause of mortality, especially in developing
countries including India.
• Neonatal sepsis is the single most important cause of neonatal deaths
in the community, accounting for over half of them.
• If diagnosed early and treated aggressively with antibiotics and good
supportive care, it is possible to save most cases of neonatal sepsis

5. • When pathogenic bacteria gain access into the blood
stream,
 they may cause overwhelming infection without much localization
(septicemia),
 may get predominantly localized to the lung (pneumonia),the
meninges (meningitis).

6. CLASSIFICATION
• Neonatal sepsis can be classified into two sub-types depending upon
whether the onset of symptoms is before 72 hours of life (early
onset) or later (late onset).

7. CLASSIFICATION
• Neonatal sepsis can be classified into two
sub-types depending upon time of onset of
symptoms
Before 72
hours of life
(early onset
sepsis)
After 72
hours of life
(late onset
sepsis)

8. EARLY ONSET SEPSIS
 Early onset sepsis (EOS) often presents as a fulminant, multi-system
illness within 72 hours of delivery and is mainly due to bacteria
acquired before and during delivery.
 Early onset sepsis manifests frequently as pneumonia and less
commonly as septicemia or meningitis.

9. The associated factors for early-onset sepsis include
1 low birth weight,
2 prolonged rupture of membranes > 24 hours,
3 foul smelling liquor,
4 multiple per vaginum examinations,
5 maternal fever,
6 difficult or prolonged labour,
7 and aspiration of meconium.
Risk factors

10. Maternal factors:
- Fever,
- Urinary tract infection,diarrhea,
- Prolonged rupture of the membrane >24hrs,
- Foul smelling amniotic fluid,
- Maternal amnionitis,
- Maternal genital tract infection,& genital colonization,
- Socio economic factors: poor socio economic status,
poor nutrition and hygiene.

11. Neonatal factors:
- Preterm and low birth weight,
- Perinatal asphyxia,
- Vigorous resuscitation,
- Invasive procedures,
- Congenital malformations,e.g.meningomyelocele,
- Male child.

13. Prolonged rupture of membranes(PROM): the risk is reported to be
1% percent compared to a baseline incidence of 0.1 to 0.5 percent.
Chorioamnionitis: increases the risk of sepsis by 2 to 3 times.
 If PROM is associated with chorioamnionitis ,the risk of sepsis increases
by four fold.

14. • Prematurity & low birth weight: preterm babies are deficient in
immunoglobulin concentration,complement function &
phagocytic activity.
• They have 3 to 10 times higher risk of developing sepsis than term
infants.
• Chorioamnionitis may coexist & may trigger for preterm labor.
• Association of chorioamnionitis is and low birth weight increases
the risk of sepsis to 16 percent compared to association with
normal weight babies.

15. • Perinatal asphyxia: asphyxia is associated with depressed
immune function.in addition,several interventional procedures
increase the risk of infection.
• Presence of low apgar score (6 or less at 5 minutes)along with
prolonged rupture of membranes has shown to increase the risk of
infection by 4% & 27%.
• Male gender: boys have 2 to 6 times higher risk of development
of neonatal sepsis.
• Other factors: maternal fever, poor socio economic condition &
feeding artificial milk.

16. LATE ONSET SEPSIS
• Late onset sepsis (LOS) can present as either a fulminant or a
smoldering infection.
• The infection is often transmitted through the hands of the care-
providers.
• The onset of symptoms is usually delayed beyond 72 hours after
birth and the presentation is that of septicemia, pneumonia or
meningitis.

17. The associated factors of late-onset sepsis include:
 low birth weight,
 lack of breastfeeding,
 superficial infections (pyoderma, umbilical sepsis),
aspiration of feeds,
 disruption of skin integrity with needle pricks and use of intravenous
fluids.

18. • These factors enhance the chances of entry of organisms into the
blood stream of the neonates whose immune defences are poor as
compared to older children and adults.
• Proven sepsis: the baby presents with clinical picture of sepsis &
isolation of pathogens from blood, CSF, urine or other body fluids
or autopsy evidence of sepsis.

19. N a tional neonatology forum of India defines
neonatal sepsis as follows;
• Probable sepsis: newborn with clinical picture suggestive of sepsis
with one or more of the following criteria
• - Existence of predisposing factors,e.g.maternal fever foul smelling
liquor or prolonged rupture of the membrane (>12 hours) or gastric
polymorphs more than 6/high power field.
• - Positive sepsis screen(2 of the 4 parameters to be present).
• - Total leukocytes count<5,000/mm3,immature to total neutrophil
count ratio>0.2,c-reactive protein positive & micro ESR > 15 mm/1st
hour or >age in days + 3.
• Radiological evidence of pneumonia.

20.  Sepsis syndrome: when septicemia is associated with altered organ
perfusion ( hypoxia, increased blood lactate, oliguria & altered
mental state) it is termed as sepsis syndrome.
• If untreated, this condition leads to early septic shock with
decreased capillary refilling and low blood pressure, which can be
reversible with appropriate treatment.
• If untreated, this state progresses quickly into refractory shock &
leads to multi organ dysfunction

21. T
The common organisms reported by NNPD (
national neonatal & perinatal database) Survey
showed 3.8 percent incidence of neonatal sepsis
from pooled hospital data ..
Klebsiella,
Staph.aureus,
Esch.coli,
Pseudomonas,
Enterobacter,
Coagulase negative staphylococcus,
Acenatobacter and
Candida as the predominant organisms.

23.  The clinical presentations of EOS and LOS are different and the
risk factors are different, but the organisms causing the EOS
and LOS are similar and so are their antibiograms (Zaidi AK et
al, NNPD NETWORK).
 The early & efficient diagnosis of neonatal bacterial sepsis
remains a difficult task since most of the symptoms & signs of
sepsis in the neonatal period are of non specific nature.

26. CLINICAL FEATURES
• The manifestations of neonatal septicemia are often vague and
therefore demand a high index of suspicion for early diagnosis.
• The possibility of sepsis must be considered with any clinical
deterioration unless the event is readily explained by other causes.
• The most common and characteristic manifestation is
• An alteration in the established feeding behavior in late onset
sepsis,
• Respiratory distress in early onset sepsis.

27.  The baby, who had been active and sucking well, gradually or
suddenly, becomes lethargic, inactive or unresponsive and refuses
to suckle.
 hypothermia is a common manifestation of sepsis, whilst fever is
infrequent.
 Diarrhea, vomiting and abdominal distension may occur.

29.  Episodes of apneic spells or gasping may be the only
manifestation of septicemia.
 In sick neonates, the skin may become tight giving a hide-
bound feel (sclerema) and the perfusion becomes poor
(capillary refill time of over 3 seconds).
 Cyanosis may appear.
 The additional features of pneumonia or meningitis may be
present depending upon the localization of infection in
different systems and organs of the body

31. The evidence of pneumonia includes
tachypnea,
chest retractions,
grunting,
early cyanosis,
apneic spells in addition to inactivity and poor feeding.
Findings on auscultation of the chest are non-specific and non-
contributory.

32. Meningitis is often vague, the clinical picture being
dominated by manifestations of associated septicemia.
the appearance of excessive or high-pitched crying,
fever,
seizures,
staring look,
neck retraction,
bulging anterior fontanel are highly suggestive of meningitis.

33. Specific features related to various systems:
 Central nervous system (CNS): Bulging anterior fontanelle, vacant
stare, high-pitched cry, excess irritability, stupor/coma, seizures,
neck retraction. Presence of these features should raise a clinical
suspicion of meningitis
 Cardiac: Hypotension, poor perfusion, shock
 Gastrointestinal: Feed intolerance, vomiting, diarrhea, abdominal
distension, paralytic ileus, necrotizing enterocolitis (NEC)

34.  Hepatic: Hepatomegaly, direct hyperbilirubinemia (especially
with urinary tract infections)
 Renal: Acute renal failure
 Hematological: Bleeding, petechiae, purpura
 Skin changes: Multiple pustules, abscess, sclerema, mottling,
umbilical redness and discharge

35. Classification of sick young infants
for bacterial infection(WHO).
• Convulsion,
• Fast breathing,
• Severe chest indrawing,
• Nasal flaring,
• Grunting,
• Bulging fontanelle,
• Pus draining from ear,
• Umbilical redness extending to skin,
• Fever or hypothermia,
• Many or severe skin pustules,
possible
serious
bacterial
infection.
• Lethargic or unconscious,or less than normal movement.
• Red umbilicus or draining pus, local bacteria infection.

36. Diagnostic tests with maximal(100%)sensitivity & negative predictive
value are desirable for diagnosis of neonatal sepsis.
This indicates if infection were present,the result would always be
abnormal & if results were normal,infection would always be
absent.
a good specificity & positive predictive value is also acceptable.

37. DIAGNOSTIC TESTS.
 Definitive,specific
 Blood culture,
 Cerebrospinal fluid examination &
culture,
 Urine culture,
 Tracheal aspirates,
 Polymerase chainreaction,
 Latex particle agglutination test.
Nonspecific,diagnostic
CBC
C-reactive protein(CRP),
Erythrocyte sedimentation rate,
Other acute phase reactants,
Miscellaneous tests.

38. SEPSIS SCREEN.
Traditionally, the sepsis screen consists of 4
items:
- C-reactive protein (CRP),
- absolute neutrophil count (ANC),
- immature to total neutrophil ratio (ITR)
and micro-erythrocyte sedimentation rate
(μ-ESR).

39. ITR: Value above 27% in term babies is considered positive. For preterms,
it is considered to be 20%. ITR is defined as Immature neutrophils
(band forms, metamyelocytes, myelocytes) (Mature + immature
neutrophils).
μ-ESR:Value (in mm in first hour) of more than 3+ age in days in the
first week of life or more than 10 thereafter is considered positive.

40. If all the parameters of the sepsis screen are negative in a neonate
assessed to have low probability of LOS, antibiotics may not be
started and the neonate must be monitored clinically.
The screen must be repeated after 12-24 hours. Two consecutive
completely negative screens are suggestive of no sepsis.

43. DEFINITIVE, SPECIFIC DIAGNOSTIC TESTS
 Isolation of organism from blood or a central body fluid is the
standard & most specific method to confirm the diagnosis of
neonatal sepsis.
 The main draw back is that, the results are available after 48 to
72 hrs.
 Another dilemma often faced by the clinicians is the high
percentage of cases (up to 40%) where no bacteria can be isolated
from blood even in highly suspected cases of sepsis.

44. BLOOD CULTURE
- It is the gold standard for diagnosis of septicemia and should be
performed in all cases of suspected sepsis prior to starting
antibiotics. A positive blood culture with sensitivity of the isolated
organism is the best guide to antimicrobial therapy.
- Therefore it is very important to follow
the proper procedure for collecting a blood culture.

45. Cerebro-spinal fluid (CSF)
examination.
In an unstable neonate, the LP can be deferred, until stabilization
is achieved.
The cellular and biochemical abnormalities in the CSF of older
patients with bacterial meningitis persist for up to 3 days.
Gram positive bacteria clear in 36 hours of appropriate therapy
whereas gram negative bacteria may take up to 5 days.

46. TRADITIONALLY, THE FOLLOWING CUT-OFFS HAVE BEEN USED:
 30 cells,
 more than 60% of polymorphs,
 glucose less than 50% of blood glucose,
 protein more than 150 mg/dL in term babies and 180 mg/dL in preterm
babies.
 These cut-offs are no longer acceptable as they are based on old normative
data, and represent an over-simplified approach based on single cut-off
points derived from 2 standard deviation values.

47. Preterm infants: Treat if CSF WBC count ≥10 OR glucose <24
OR protein >170.
Do not treat if “CSF WBC count <10 AND glucose ≥25 AND protein
<170”.
For in-between results, clinical judgment will have to be used,
keeping in mind clinical features (seizures, degree of altered
sensorium, fullness of fontanelles) and prematurity (the lower the
gestation, lower should be the threshold for diagnosis).

48. TERM INFANTS: TREAT IF CSF WBC COUNT >8 OR GLUCOSE
<20 OR PROTEIN >120.
There is no safe cut-off at which one can recommend “do not
treat”. Clinical judgment as above would have to be
used.(The WHO Young Infant Study Group, Ahmed AS et
al, Smith PB et al, Garges HP et al)

49. In a neonate with meningitis not showing clinical recovery after
institution of antibiotics, LP should be repeated after 48 hours.
If the LP is traumatic, the CSF should be sent for gram stain and
culture.
The concentration of glucose is not significantly altered by a
traumatic lumbar puncture.
Therefore a low CSF glucose in the setting of a traumatic LP is
abnormal.

50. Ideally, the WBC cell count must be performed within
30 minutes of drawing the sample.
It must be noted that CSF WBC and glucose rapidly fall
with time, giving spurious results(Rajesh NT,et al).

51. Latex particle agglutination tests:a relatively simple test to
perform but is not very sensitive.
Polymerase chain reaction:a definitive advancement,but the
prohibitive cost & difficult technique precludes its use in the
routine evaluation of neonatal sepsis.

52. Nonspecific diagnostic septic
screening tests.
These tests indicate infection without identifying the
infecting micro organisms.
Because of the severity of the disease,it is essential for
these indirect tests not to miss any case(have 100%
sensitivity),

53. C-REACTIVE PROTEIN.
 CRP is a rapidly responsive acute phase reactant,synthesizd by the liver
within 6-8 hrs of stimulus of inflammatory process.
 A positive CRP latex agglutination test corresponds to plasma CRP
concentration of 0.8 to 1.0 mg/dl.
 A single value of negative CRP done at the outset may not be of much
significance.
 Therefore, in suspected cases,a repeat CRP test is done 12 hours later is more
significant.
 If the test is negative negative-it almost excludes sepsis.

54. Normalization of CRP is a helpful tool in determining the
response to antimicrobial therapy and duration of
treatment.
Failure to mount a CRP response is a poor prognostic sign.

55. Erythrocyte sedimentation
rate.
Micro ESR is an inexpensive & easy bedside screenig test
for neonatal sepsis.
Normal values increase with postnatal age & are equal to the
day of life plus 3mm/hour upto a maximum of 15
mm/hour.
ESR is less sensitive but more specific than CRP or I/T rato.

56. Other acute phase reactants
Haptoglobin & orosomucoid are acute phase reactants
that have been evaluated for diagnostic aids for neonatal
sepsis,are of limited utility because of their slower response
to infection.
A low plasma fibronectin concentration is
suggestive of neonatal sepsis,
It is also depressed by RDS & perinatal asphyxia,thus
limiting its use.

57. WHITE BLOOD CELL COUNT.
A total leukocyte count<5000/mm3
Total neutrophil count<1750/mm3,
An immature to total neutrophil count ratio(I/T)of
>0.2 are suggestive of sepsis.

58. MISCELLANEOUS TESTS.
Elastase-alpha-1-proteinase inhibitor complex:raises rapidly,100%
sensitive but not highly specific.
C3D,
Endotoxin,
Direct visualization of bacteria in neutrophils stained by
acridine orange,
NBT reduction by neutrophils,
Gastric aspirate of polymorph count & culture:has limited
value,indicative of high risk because of exposure to
chorioamnionitis.

59. NEWER DIAGNOSTIC MODALITIES.
Procalcitonin: a pro-peptide,released into the blood 3-6 hrs
after endotoxin injection & increses upto 24 hours.
Very high serum procalcitonin levels are present in neonates
with proven or clinically diagnosed bacterial infection;early
decrease of these concentrations reflects appropriate
antibiotic therapy.
Compared with CRP,proclcitonin has the advantage that it
increases more rapidly.
A recent meta analysis showed that procalcitonin showed
better accuracy than the CRP test for LOS.

60. CYTOKINES AND RECEPTORS.
 Interleukin-6(IL-6),
 Interleukin-1 receptor antagonist(IL-1ra)
 The level of these two markers increases two days before clinical
diagnosis of sepsis.
 IL-6 although a very early marker,the level becomes normal later even
if infection continues.
 The simultaneous determination of CRP can obviate this problem
because the rise in plasma CRP levels occurs 12 to 48 hours after the
onset of infection,at a time when IL-6 level would have fallen.

61. Specific leukocyte surface
antigens.
CD11b-promising marker for diagnosing early onset sepsis.
CD64-late onset sepsis.
Preterm express CD 64 to the same degree as those from
term infants,children & adults.
G-CSF;a higher level has been found to be associated with a
sensitivity of 95 percent for prediction of sepsis
& a specificity of 73 percent if the level is >200pg/ml.

62. Approach to a neonate with
suspected EOS.
There is no rationale for performing a “sepsis screen” (i.e.
CRP,hematological parameters, micro ESR) in suspected EOS.
The negative predictive value (NPV) of various sepsis screen
parameters is too low to confidently rule out EOS (Benitz WE et
al, Mahale R et al,).
Procalcitonin and IL-6 are more promising than the standard
screen for the diagnosis of EOS, but they are currently not easily
available on the bedside and are not considered standards of care.

63. Neonates who turn symptomatic within 72 hours must be clinically
assessed for probability of sepsis.
Twenty percent of symptomatic neonates in India suspected to have
EOS are blood culture positive
(Mahale R et al).
The following neonates need not be immediately started on
antibiotics but their clinical course must be carefully monitored:

64. THOSE WHO ARE BORN WITHOUT ANY OF THE KNOWN RISK FACTORS
OF SEPSIS
preterm,
premature rupture of membranes (pPROM),
prolonged rupture of membranes (PROM) >18 hrs,
spontaneous preterm onset of labor (SPTOL),
clinical chorioamnionitis,
foul smelling liquor,
unclean vaginal examinations,
maternal fever,

65. MATERNAL URINARY OR OTHER SYSTEMIC INFECTIONS,
frequent (>3) per vaginal examinations in labor,
perinatal asphyxia,
and maternal recto-vaginal group B
Streptococcus carriage],
AND
• Chest X ray is not suggestive of pneumonia,
• Have alternative reasons to explain the
symptoms.

66. • Those symptomatic neonates with any of the known risk factors or who
have a chest X-ray suggestive of pneumonia or do not have any alternate
explanation for the signs, must be immediately started on antibiotics
after drawing a blood culture.
• Lumbar puncture (LP) for CSF examination must be performed in all
symptomatic neonates, with the exception of premature neonates
presenting with respiratory distress at birth with no risk factors for sepsis
(Eldadah M et al, Weiss MG et al,)
The decision for performing LP should not be based on sepsis screen results
or blood culture results.

67. Approach to a neonate with
suspected LOS.
neonates who become symptomatic after 72 hours must be evaluated
for LOS.
30% neonates clinically suspected to have LOS in an NICU setting
have positive blood culture (Singh SA et al).
a single episode or transient presence of one of the above signs
may not warrant any action. The more persistent the sign the more
likely it is associated with LOS (Kudawla M et al,).

68. based on clinical assessment the neonate must be
categorized into those with low probability of sepsis or high
probability of sepsis.
The rule of thumb is “low probability” represents situations
where the clinician would be willing to withhold
antibiotics if the sepsis screen is negative.
Those assessed to have a low probability of sepsis (eg. single
episode of apnea or vomiting, but otherwise well)should
undergo a sepsis screen.

70. TREATMENT
No investigation is required as a prerequisite to start treatment in
a clinically obvious case
- early treatment is crucial.
-Institution of prompt treatment is essential for ensuring
optimum outcome of neonates with sepsis who often
reach the health care facilities late and in a critical
condition.

71. Supportive care and antibiotics are two equally
important components of the treatment.
It should be realized that antibiotics take at least 12 to 24
hours to show any effect and it is the supportive care that
makes the difference between life and death early in the
hospital course.

72. SUPPORTIVE CARE
The purpose of supportive care is to
- normalize the temperature,
- stabilize the cardiopulmonary status,
- correct hypoglycemia,
- prevent bleeding tendency.
- There is no role of intravenous immunoglobulin
therapy in neonatal sepsis.

74. Antibiotic therapy – empirical,
upgradation and modification.
There is generally no distinction in the choice of empirical
antibiotics, be it suspected EOS or LOS as the bacterial and
sensitivity profile in India seems to be is similar in both
situations(Sundaram V et al, Zaidi AK et al, NNPD network.).
Starting empirical antibiotics.
As the profile of organisms is similar for EOS and LOS, the
following policies can be used irrespective of whether it is EOS
or LOS.

75.  Antimicrobial therapy: There cannot be a single recommendation
for the antibiotic regimen of neonatal sepsis for all settings.The
choice of antibiotics depends on the prevailing flora in the given unit
and their antimicrobial sensitivity.
 This protocol does not aim to provide a universal recommendation
for all settings but lays down broad guidelines for the providers to
make a rational choice of antibiotic combination.
 Decision to start antibiotics is based upon clinical features and/ or a
positive septic screen. However duration of antibiotic therapy is
dependent upon the presence of a positive blood culture and
meningitis

76. Indications for starting antibiotics: The indications for starting
antibiotics in neonates at risk of EOS
 include any one of the following:
 (a) presence of >3 risk factors for early onset sepsis (see above)
 (b) presence of foul smelling liquor
 (c) presence of ≥2 antenatal risk factor(s) and a positive septic
screen and
 (d) strong clinical suspicion of sepsis.

77. The indications for starting antibiotics in LOS include:
 (a) positive septic screen and/or
 (b) strong clinical suspicion of sepsis.

78.  Prophylactic antibiotics: We do not use prophylactic antibiotics
in the following circumstances:
infants on IV fluids/TPN, meconium aspiration syndrome, and
after exchange transfusion(s).
An exchange transfusion conducted under strict asepsis (single
use catheter, sterile gloves, removal of catheter after the
procedure) does not increase the risk of sepsis and hence does
not merit antibiotics.

80.  Reserve antibiotics: Aztreonam has excellent activity against
gram-negative organisms while meropenem is effective against
most bacterial pathogens except methicillin resistant
staphylococcus aureus (MRSA) and enterococcus.
 Imipenem is generally avoided in neonates because of the
reported increase in the incidence of seizures following its use.
 Empirical use of these antibiotics should be avoided; they should
be reserved for situations where sensitivity of the isolated
organism warrants its use.

82. Adjunctive therapy
 Exchange transfusion (ET): Sadana et al have evaluated the
role of double volume exchange transfusion in septic neonates
with sclerema and demonstrated a 50% reduction in sepsis
related mortality in the treated group.
 Intravenous Immunoglobulin (IVIG): Non-specific pooled IVIG
has not been found to be useful.
 Granulocyte-Macrophage colony stimulating factor (GM-
CSF): This mode of treatment is still experimental

83. References-
 Care of newborn - meherban singh
 Neonatology - cloherty
 Neonatology – rennie & robertons
 Neonatology -Tricia lacy gomella

84. THANK YOU