Neonatal Septic

shock

Safaa A. EL Meneza
Professor of Pediatrics
Faculty of Medicine for
Girls
AL Azhar University
 Objectives

 Definitions
 Epidemiology

 Pathophysiology

 Management of septic

shock
 Prevention
 Direct Causes of Neonatal
Deaths

☛ Infections 32%
☛ Asphyxia 29%
☛ Complications of prematurity
24%
☛ Congenital anomalies 10%
World Health Organization.State of the World’s Newborns 2005
☛ Other 5%
 Septic shock
 Diagnosis and treatment
of neonatal septic shock
are quite difficult as :
 Septic shock
 The hyperdynamic phase
of septic shock in
newborns can be short.
 VLBW may have acute
hypotension ,bradycardia
without preceding
tachycardia
 Septic shock

2. Sepsis is a clinical
diagnosis and does not
rely on early isolation of
the causative infectious
organism .
Bacterial isolates in
neonatal sepsis in NICUs
in Egypt
 Bakr AF. J Trop Pediatrics 2003
 45 cases of neonatal sepsis
 Klebsiella 78%, E. coli 11%, Candida
6.6%, Pseudomonas 4.4%
 Moore KL, Kainer MA, Badrawi N,et
al.
Pediatr Inf Dis J. 2005
 33 infants with clinical sepsis
 21 (64%) blood cultures + < 24 hours after
birth
 Klebsiella 80%, Enterobacter 10%, E.coli
6%,
Acinetobacter 3%.
 Bacterial isolates in neonatal
sepsis in NICUs in Egypt
 In NICU of AL Zhraa University
hospital
we found that gram negative in
55% of cases ; K. pneumoniae , E
coli, enterobactr spp, citrobacter
spp and serratia m.
 K. pneumoniae phenotyping and
genotyping showed
macrorestriction profiles of
chromosomal DNA of 15 distinct
patterns.
Abd ELHalim N. MD thesis 2009 ,supervised by Aly G.,
ELMeneza S. and EL salakawy A. , FMG , AL Azhar University
What is septic shock

Not a single pathologic

entity!
DEFINITIONS
 Septic shock

Sepsis and cardiovascular

organ dysfunction

Goldstein et.al Pediatr crit care Med 2005 Vol.6 No.1

●Cardiovascular
dysfunction
Decrease in BP
< 5th percentile for age or
systolic BP < 2 SD below
normal for age
 No response to

administration of isotonic
intravenous fluid bolus ≥40
Goldistein et al Ped.cri.car.Med.6,1,2oo5
mL/kg in 1 hr OR
 ● Cardiovascular
dysfunction
Need for vasoactive drug to


maintain BP in normal range

(dopamine > 5 u/kg/min or
dobutamine, epinephrine, or
nor epinephrine at any dose)
Goldistein et al Ped.cri.car.Med.6,1,2oo5
Septic shock
 Septic shock is caused
by
an acute failure of
circulatory function and
is characterized by
inadequate tissue and
organ perfusion.
Septic shock
 There is inadequate
amounts of oxygen and
nutrient substrate
delivered to body
tissues.
 Removal of metabolic

waste products is
 Septic Shock
 Septic shock is a
subclass
of distributive shock
commonly associated
with bacterial and viral
infections in neonates.
 Septic Shock
 The hallmark of septic
shock is marked
progressive hypotension
frequently refractory to
therapy .
 SEPSIS-SEPTIC SHOCK
CONSIDERATIONS
 There are a number of well known host-
related risk factors for sepsis. They
include:
 Extremes of age
 A compromised immune system
 Malnourishment
 Asplenia
 Chronic antibiotic or steroid use
 Additionally, any insult (shock, trauma,
burn) that makes the gastrointestinal
tract permeable to gram negative
bacteria puts individuals at risk for gram
 SEPSIS-SEPTIC SHOCK
CONSIDERATIONS

 Genetic polymorphisms
 Inflammatory cell function
 Endothelial activation and injury
 Coagulation and fibrin deposition
 Vasodilatory shock
 Vasopresin
 Hipothalamic-pituitary-adrenal axis
 Cardiac dysfunction
 Tissue oxygenation and perfusion
SEPSIS-SEPTIC SHOCK
CONSIDERATIONS

Genetic polymorphisms

 TNF- polymorphism (hypersecretion)

 LPS-binding protein alleles
 IL-1
 Toll-like receptor 4

 Frequency and survival

 Variability in septic course
 Response to therapy
 Outcome
 SEPSIS-SEPTIC SHOCK
CONSIDERATIONS
 Inflammatory cell function
 Low monocyte count (CD13)
 IL-12
 IL-8

 Greater risk of death

SEPSIS-SEPTIC SHOCK CONSIDERATIONS

Vasodilatory shock
 Septic Shock
 Septic shock
characterized by
arteriolar and venous
vasodilatation
that results in low
systemic vascular
resistance despite initial
 SEPSIS-SEPTIC SHOCK
CONSIDERATIONS
Hypothalamic-pituitary-adrenal
axis
•Relative adrenal insufficiency
•Corticotrophin resistance +
•Reduced adrenal glucocorticoids
synthesis
Longer length of stay and more
organ dysfunction
 Cardiac dysfunction
▪Direct depressive effect
on CVS by organisms or their
endotoxins as TSST-1
▪ Release of vasoactive
agents.
Cardiac dysfunction
Cardiac dysfunction
There is significant
decrease in the
myocardial contractility
among the newborn infant
suffered from septic shock
EL Meneza S,et al . Perinatology,Vol 21,No 7
505-06(Abs)2001
 -Cardiac dysfunction
through uncoupling of
β adrenergeic receptors
&
by direct inhibition of
intracellular calcium
homeostasis
Cardiac dysfunction

 Newborn infants have also

dysfunction due to
immaturity of myocardium
 Abnormal peripheral

vasoregulation due to
“immaturity of autonomic
nervous system”
Cardiac dysfunction

Lopez preceedings ICP conference2007

Septic Shock

Lopez preceedings ICP conference2007

Septic Shock
 We found significant
increase in No in newborn
infants with sepsis shock
EL Meneza S,et. al. Perinatology. 21, 7,505-
06 (Abs)2001
 Cytokines TNFα, IL-1β, IL-6
released in a large scale
inflammatory response
results in massive
vasodilation, increased
capillary permeability,
decreased systemic
vascular resistance, and
hypotension.
Kumar, et al .. (2007). Robbins Basic Pathology (8th ed.). Saunders Elsevier. pp. 102-103
Inflammatory mediators and
capillary leak syndrome

Ware and Matthay NEJM 342 (18): 1334

Protein C Activated Protein C

In MD study,in our unit we

could found significant
decrease of APC, protein c
,antithrombin III among septic
newborn than the control
group
EL Gandy MD, MD thesis,Supervised by ELMeneza S.
ELMahdy M, FMG, AL Azhar University, 1997
SEPSIS-SEPTIC SHOCK CONSIDERATIONS
Endothelial activation
Coagulation and fibrin deposition
Micro thrombus
formation
Pseudomonas sepsis with
DIC

J Evans et al, Clin Therapeutics, 2006

Invasive Candidiasis

J Evans et al, Clin Therapeutics, 2006

Our plan of care should
consider that there are
:
 1-Maldistribution of circulatory
volume
 2-Depressed myocardial
function
 3-Hypoxic hypoxia
-Diminished oxygen delivery
-A decrease in the number of functional
capillaries causes an inability to extract oxygen
maximally
-There is inability of the erythrocytes to
 3-Direct cytotoxicity

This is called cytopathic

or histotoxic anoxia

an inability to utilize oxygen

even when it is present
4-Apoptosis

The proinflammatory
cytokines
may delay apoptosis in
activated
macrophages and neutrophils
but
other tissues such as gut
epithelium, may undergo
 5-
Immunosuppression
The interaction between
proinflammatory
and
anti-inflammatory mediators
may lead to an imbalance
It is currently believed that if
pro-inflammatory predominate
an inflammatory cascade
ensues ,and immediate
pathophysiologic
processes are initiated
 Septic shock
 Signs of early septic shock
may be subtle and there is a
danger of overlooking them in
a busy emergency department.
 The patient may not always

adhere to the classic stages of

shock described in textbooks.
Pallor
poor skin
perfusion
1-Pallor and poor skin
perfusion
2-Capillary refill >2 sec
2-Cool extremities
3-CNS dysfunction
4-Decreased urine output
 TREATMENT
The recommendations for
support of term newborns
and children are primarily
expert opinion rather than
irrefutable evidence due to
lack of RCT
 Thus -state –of- the art
management

1- Haemodynamic
resuscitation and organ
support
 Adequate blood flow
 Preserve organ perfusion and

regional distribution of total cardiac

output
 Preserve vascular beds:

integrity and vasomotor tone

 Thus -state –of- the art
management

2- Eradicate infection
 Early recognition
 Early and adequate antibiotic
therapy
 Source control
 Thus -state –of- the art
management

3- Sustained support
 Minimizing iatrogenic injury
 Ventilation,Haemoglobin,
Glucose
4- Modulation of
inflammatory response
 Coagulation, adrenal response
RESUSCITATION OF
PEDIATRIC SEPTIC SHOCK
First Hour of
Resuscitation
(Level III)
 - 0 min
Recognize
decrease perfusion,
cyanosis, RDS

- 5 min
Maintain airway and access
according to NRP guidelines
 -Push 10 cc/kg isotonic
crystalloid
or colloid boluses to 60cc/kg
-Correct hypoglycemia &
hypocalcaemia
-Begin prostaglandin infusion
until echocardiogram
shows no dependent
lesion
It is important to distinguish
newborn septic shock from
cardiogenic shock caused by
closure of the PDA in
newborns with ductal
dependent complex
congenital heart disease
 15 min
Fluid responsive

Observe in NICU
 15 min
Fluid refractory shock

-Establish central venous

and arterial access
-Titrate dopamine/ and
dobutamine
 Homodynamic Support
(Level II)
Although dopamine can be
used as the first-line agent
its effect on
pulmonary vascular resistance
should be taken into account
 Are Inotropes the problem???

 Pressor medication certainly play an important

role in shock, but
 Use of pressors such as dopamine could be worse
than mild hypotension itself, particularly when not
close monitoring and control of BP
 There may be place for permissive
hypotension, particularly when low BP is the
only symptom….may be better to watch and
wait than to jump in
Al-Aweel J Perinatology 2001
Are Inotropes the problem??
Abstract, PAS 2007

Infants who were still

received inotropes after
being normotensive, were
more likely to have a
severe IVH (18%) than
hypotensive infants who
did not receive inotropes
(6%)
J Evans et al, Clin Therapeutics, 2006
Fluid refractory- dopamine
resistant shock

-Titrate epinephrine
-Systemic-alkalinization if
PPHN and acidosis is
present
 Phenomenon of non
responding to
vasopressor during shock
is due to decrease sensitivity
to dopamine due to
1-Down regulation of β
adrenergic receptors
2-Decrease in expression
of adrenergenic receptors
in critically ill neonates
3-Immaturity as depleted
myocardial nor epinephrine stores
Zhang 1999
 60 min
Catecholamine - resistant
shock

Direct therapies using

echocardiogram, arterial
and CVP
monitoring
 60 min
Catecholamine - resistant
shock

Cold Cold or Warm

shock warm shock
shock
 60 min
Catecholamine - resistant shock

Cold shock
Normal blood pressure
Poor LV function
Central venous O2 sat < 70%

Titrate vasodilator or
type III PDE inhibitor with
volume loading
 60 min
Catecholamine - resistant shock

Cold or warm shock

Poor RV function
PPHN
Central venous O2 sat
<70%

Inhaled nitric oxide

 60 min
Catecholamine - resistant shock

Warm shock
Low blood pressure

Titrate volume and

epinephrine
Refractory shock

ECMO
 What drug should we use?
 In general when blood pressure is low in a sick
neonate, dopamine is more effective than
dobutamine* in raising blood pressure and increasing
systemic vascular resistance probably best to use if
low BP but normal cardiac function
 If myocardial performance is impaired, the addition
of dobutamine may be beneficial as it has more
effect on left ventricular output; Dobutamine, used
without an alpha- adrenergic medication, may well
cause worsened hypotension…but still can improve
organ perfusion
 Epinephrine increases both cardiac output and blood
pressure: best to use when blood pressure and
 Therapeutic End Points
(Level III)

Therapeutic end points include:

• Capillary refill of < 2 secs
• Normal pulses with no
differential between
peripheral and central pulses
• Warm extremities,
• Urine output of > 1 mL/kg/hr
 Therapeutic End Points
•Normal mental status
•Normal blood pressure for age
•Difference in preductal and
postductal oxygen saturation of
< 5%
and
• Oxygen saturation of > 95%
•Increase pH and decrease lactate
Activities
A. Initial Resuscitation
B. Diagnosis
C. Antibiotic Therapy
D. Source Control
F. Use Vasopressors
G. Inotropic Therapy
H. Steroids
J. Blood Product Administration
Activities

K. Mechanical Ventilation of sepsis

Induced Acute Lung Injury (ALI)/ARD
L. Sedation, Analgesia, and neuromusc
Blockade in sepsis
M. Glucose Control
N. Renal Replacement
Stabilization: Beyond the
First Hour
Level (III)
Goals

*Maintain threshold heart rate

*Maintain normal perfusion and
blood pressure
*Maintain neonatal circulation
Central venous oxygen
saturation > 70%
Steroids

When
Should be used
??????
SCHEMATIC SUMMARY OF GLUCOCORTICOID
PROPERTIES

Carcillo,task force.Shock,
20(3):197-207,2003
Is There a Role for
Glucocorticoids in Neonatal
Shock ?

 Some known effects

 Upregulation of beta-
adrenergic receptors
 Increased concentrations of
catecholamines
 Improvement in capillary
integrity
 Direct inotropic effect on
myocytes-increased
Carcillo,Task force.Shock,20(3):197-207,2003
 Current Immune therapy

1-Immunoglobulin
2-Granulocytes infusions
3-Double volume exchange
transfusions
4-rhu-GM-CSF
Granulocyte Macrophage
Colony Stimulating Factor
Break the chain of
inflammation /tissue
injury
 Emphasized that no
single therapy would be
beneficial for all patient
with sepsis
 Gene therapy

Some patient may benefit from

i.e. microbial challenge is more

effectively cleared
 Gene therapy
Other will benefit from

i.e. reduce the cascade of

inflammatory mediators
Immune Therapy

Recent research has

focused on modifying
the host response to sepsis
by
 Immune Therapy

 Monoclonal antibodies against

tumour necrosis factor
 Blockade of eicosanoid

production
 Blockade IL-1 activity
 Inhibition of nitric oxide

synthase
Exogenous surfactant
 High Mobility Group
Box Protein 1
•Nuclear protein bind DNA
stabilize nucleosomes
•Extracellular mediator in
systemic inflammation
•Could be therapeutic target in
management of sepsis
Triggering receptor expressed on
myeloid cells

•Activates neutrophils and

monocytes/macrophages
•Amplifies TLRs responses
against
microbial challenges
 Toll-Like receptors

•Modulate the inflammatory

response
Variable expression
(neutrophils, dendritic cells, etc.)
Controlling or modifying :
septic process
 The future strategy will
relay on
1-Immunophenotype of
patients
2-Prediction of host response
to disease and therapy
Wheeler et al Pediatr Crit Care Med 2001;2: 299-310
Dellinger RP, Levy MM, Carlet JM, et al: Surviving Sepsis
Campaign: Guidelines for management of severe sepsis and
septic shock. Intensive Care Medicine (2008).
Hand Gene
therapy

hygiene
Simple interventions
that work

 Hand washing and aseptic

precautions
 Enteral nutrition
 Strict antibiotic policy
 Nursing training and involvement
of nurses in decision making and
administrative issues
 Involvement ofJ Perinatol
Agarwal et al. mothers 2007
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biology on the practice of pediatric critical care
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2001;285:540-544
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meeting syllabus 1996
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Significance of platelet derived growth factor- AB and
nitric oxide in newborns Suffering from perinatal asphyxia
Study II:Relation to cerebral blood flow Perinatal Med
vol29, suppl 1 2001,122
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early detection and Prevention.Hot topics 98 In
Neonatology,Washington DC,December 6-8.1998
Proceeding Page 483 -485
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Significance platelet-derived growth factor-AB and nitric
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nosocomial infection on mortality and morbidity of
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Washington DC December 5-7,1999 .Proceeding,424-425
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Study of some risk factors for hypercoagulation and
thrombosis in newborn MD,thesis,AL Azhar University
1997
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Biochemical Study on ICAM among neonates with
PA,b.Sc Aim Shamas 1995
‫شكرا‬