2. The big picture …..
• 4 million neonatal deaths worldwide
• 36% due to sepsis .
• Worse in resource limited settings
• One half of VLBW babies die within first seven days of
life
• Exposure of the developing brain to infl mediators
secondary to sepsis leads to cerebral palsy
3. Definitions of the sepsis continuum
• Infection
• Sepsis
• Severe sepsis
• Septic shock
• SIRS
4. Definition contd…
Consensus definition Suggested modific for preterm
SIRS
The presence of at least 2 of the following
, one of which must be abnormal
temperature or leucocyte count
•Core temp > 38.5 ° c or < 36 °C
•Tachycardia – mean HR > 2SD above
normal for age or Bradycardia – HR < 10
th centile for age
•Mean resp rate > 2 SD above age or
mech ventilation for an acute process
•Leucocyte count elevated or depressed
for age or > 10 % immature neutrophils
SIRS
The presence of at least 2 of the following
, one of which must be abnormal
temperature or leucocyte count
•Core temp >38.0 ° c or < 36 °C
•Tachycardia – mean HR > 2SD above
normal for age or Bradycardia – HR < 10
th centile for age
•Mean resp rate > 2 SD above age or
mech ventilation for an acute process
•Leucocyte count elevated or depressed
for age or > 20 % immature to total
neutrophil ratio or CRP > 10mg/dl
Wynn et al , Clin Perinatol 2010 June
5. Definition contd………
Infection
A suspected or proven ( culture , tissue stain , PCR ) infection caused by any pathogen
OR A clinical syndrome associated with high probability of infection.
Sepsis
SIRS in the presence of or as a result of suspected or proven infection
Severe Sepsis
Sepsis plus one of the following : cardiovascular organ dysfunction or ARDS or 2 or
more other organ dysfunction
Septic shock
Sepsis and cardiovascular dysfunction
Wynn et al , Clin Perinatol 2010 June
6. Organ dysfunction
Consensus definitions of organ dysfunction25
Suggested modifications for premature infants
Cardiovascular dysfunction Cardiovascular dysfunction
Despite administration of isotonic intravenous fluid bolus >40 mL/kg
in 1 hr
Despite administration of isotonic intravenous fluid bolus >40 mL/kg in
1 hr (>10ml/kg in infants less than 32 weeks)1
• Decrease in BP (hypotension) <5th percentile for age or systolic BP
>2 SD below normal for age
• Decrease in BP (hypotension) <5th percentile for age or systolic BP
>2 SD below normal for age or MAP < 30mm Hg with poor capillary
refill time (>4 seconds)2
OR OR
• Need for vasoactive drug to maintain BP in normal range
(dopamine >5 mcg/kg/min or dobutamine, epinephrine, or
norepinephrine at any dose)
• Need for vasoactive drug to maintain BP in normal range (dopamine
>5 mcg/kg/min or dobutamine, or epinephrine at any dose)3
OR OR
• Two of the following: • Two of the following:
-Unexplained metabolic acidosis: base deficit >5.0 mEq/L -Unexplained metabolic acidosis: base deficit >5.0 mEq/L
-Increased arterial lactate >2 times upper limit of normal -Increased arterial lactate >2 times upper limit of normal
-Oliguria: urine output <0.5 mL/kg/hr -Oliguria: urine output <0.5 mL/kg/hr
-Prolonged capillary refill: >5 secs -Prolonged capillary refill: >4 sec4
-Core to peripheral temperature gap >3°C
-Simultaneous measurement of core and peripheral temperature not
common in premature neonates
7. Pathophysiology of Sepsis: A Disease
of The Microcirculation
• “Lethal Triad”
Systemic
Inflammation
Coagulation Impaired
Fibrinolysis
12. Septic shock – Hemodynamics and
other organ effects – Peculiarities in
newborn
• Hemodynamic responses are less well
characterized in neonates
• Factors that contribute to developmental
differences in hemodynamics include
1 Altered struc .& func. of cardiomyocytes
2 Transition from fetal to neonatal circ.
3. PDA
4. PPHN
• Wynn et al , Clin Perinatol 2010 June
13. Hemodynamics contd…
• Blood pressure = Q × PVR
• Low BP usually due to low Q , as PVR will be
high
• If Q normal and PVR is high there may
hypertension .
Silveria et al , Rev Bras Ter Intensiva 2010 ; 22(3):280-290
14. Vitals vary with day of life & gest. age
Silveria et al , Rev Bras Ter Intensiva 2010 ;
22(3):280-290
15. Silveria et al , Rev Bras Ter Intensiva 2010 ;
22(3):280-290
16. And BP fluctuation is not
permissible ..
Silveria et al , Rev Bras Ter Intensiva 2010 ;
22(3):280-290
17. Other peculiar contributaries in the
newborn
• Neonates are in a hypercoagulable state with
increased microcirculation endothelial
thrombomodulin receptors and reduced
anticoagulants – promotes DIC
• Prone to bleeding – reduced coag factors &
platelet function
• Limited innate immunity
• Diagnosis is primarily clinical
Silveria et al , Rev Bras Ter Intensiva 2010 ;
22(3):280-290
18. Multi organ dysfunction
• Poor cardiac output , microcirculatory failure
& microthrombi lead to compromised
perfusion of kidney , liver , gut , CNS
• Recent studies suggest – MODS is due to
decreases oxygen utilisation and
mitochondrial dysfunction rather than
impaired oxygen delivery
Silveria et al , Rev Bras Ter Intensiva 2010 ;
22(3):280-290
19. Other organs involved
• Pulmonary – ARDS , surfactant deficiency, pulmonary
edema , pneumonia , PPHN
• Endocrine – adrenal insufficiency , altered thyroid
function
• Hematologic – Lymphocte loss , thrombocytopenia ,
neutropenia
• Metabolic & nutrition - impaired growth & energy
failure
Silveria et al , Rev Bras Ter Intensiva 2010 ; 22(3):280-290
21. • A . Initial resuscitation
• B . Antibiotics & source control
• C Fluid resuscitation
• D . Inotropes /Vasopressors/ Vasodilators
• E . ECMO
• F . Corticosteroids
• G . Activated protein C
• H Blood products
• I Mechanical Ventilation
• J. Glycemic control
• K . Diuretics & RRT
• L. DVT / stress ulcer prophylaxis / nutrition
22. Initial resuscitation
• Established guidelines only for adults ,
children and term neonates
• No guidelines for preterms
• Airway – Initially high flow nasal oxygen ,
Nasopharyngeal CPAP or NIV
• Airway – intubation if apneic or severe
distress
• Timely restoration of adequate circulation
25. Therapeutic end points…. Within 1st
6
hours……….
• Term neonates
• CFT < 2 sec
• Normal pulses without differential between
central & peripheral pulses
• Warm extremities
• Urine output > 1ml/kghour
• Low lactate
• Mixed venous oxygen saturation > 70 %
• Cardiac index 3.3 – 6 L/min/m2
26. Other monitoring techniques
• Functional ECHO cardiography :
Cardiac output , Peripheral vascular resistance,
Organ flow in response to volume , colloid &
vasoactive medication
SVC flow > 40 ml/Kg/min
• NIRS – organ perfusion
27. Antibiotics & source control
• Empiric antibiotics – 1 hour of diagnosis.
• Choice depends on epidemic & endemic
ecologies ( H1N1, MRSA , Chloroquine
resistant malaria, penicillin resistant
pneumococci
• Clindamycin & anti toxin – TSS & refractory
hypotension
• Early & aggressive source control
28. Management of hypotension &
cardiovascular support
• Defn. of shock & hypotension is confounding
in preterms
• Inotrope use in hypotensive preterms no
shown to significantly improve outcome.
• Achieve MAP – 30 in preterms
29. Actions of B agonists
Circulation. 2008;118:1047-1056
30. Actions of a agonist
Circulation. 2008;118:1047-1056
33. Inotropic and Vasopressor Drugs –
action and adverse effects
Drug Clinical indication Dose
range
α1 β1 β2 DA Adverse effects
Dopamine Shock
(cardiogenic,
vasodilatory)
HF
Symptomatic
bradycardia
unresponsive to
atropine or
pacing
2 – 20
mcg/K
g/min
+++ ++++ ++ ++++ Severe hypertension
(especially in
patients taking
nonselective
-blockers)
Ventricular arrhythmias
Cardiac ischemia
Tissue
ischemia/gangrene
(high doses
or due to tissue
extravasation).
Severe systemic &
pulmonary
vasoconstriction
Circulation. 2008;118:1047-1056
34. Drug Clinical
indication
Dose
range
α1 β1 β2 DA Adverse effects
Dobutamine Low CO
(decompensa
ted HF,
cardiogenic
shock,
sepsis-
induced
myocardial
dysfunction)
Symptomatic
bradycardia
unresponsive
to atropine
or
pacing
2 – 20
mcg/K
g/min
+ +++++ +++ - Tachycardia
Increased ventricular
response rate in
patients with atrial
fibrillation
Ventricular
arrhythmias
Cardiac ischemia
Hypertension
(especially
nonselective
-blocker patients)
Hypotension
Circulation. 2008;118:1047-1056
35. Drug Clinical
indication
Dose
range
α1 β1 β2 DA Adverse effects
Nor-
epinephrine
Shock
(vasodilatory
,cardiogenic)
0.1-3
mcg/k
g/min
++++
+
+++ ++ - Arrhythmias
Bradycardia
Peripheral (digital)
ischemia
Hypertension
(especially
nonselective
-blocker patients
Epinephrine Shock
Cardiac
arrest
Bronchospas
m/anaphylax
is
Symptomatic
bradycardia
or
heart block
0.1-1
mcg/K
g/min
++++
+
++++ +++ - Ventricular
arrhythmias
Severe hypertension
resulting in
cerebrovascular
hemorrhage
Cardiac ischemia
Sudden cardiac
death
Circulation. 2008;118:1047-1056
36. Drug Clinical indication Dose range Action Adverse
effects
Milrinone Low CO
(decompensated
HF,
after cardiotomy
Bolus: 50
mcg/kg bolus
over
10 to 30 min
Infusion: 0.375
to 0.75
Mcg/ kg/ min
(dose
adjustment
necessary for
renal
impairment
PDE inh Ventricular
arrhythmias
Hypotension
Cardiac
ischemia
Torsade des
pointes
Circulation. 2008;118:1047-1056
37. Drug Clinical
indication
Dose range Action Adverse effects
Vasopressin Shock
(vasodilatory,
cardiogenic)
Cardiac arrest
Infusion: 0.01 to
0.1 U/min
(common fixed
dose 0.04
U/min)
Bolus: 40-U IV
bolus
V1 receptors
(vascular
smooth muscle)
V2 receptors
(renal collecting
duct system
Arrhythmias
Hypertension
Decreased CO
(at doses 0.4
U/min)
Cardiac ischemia
Severe
peripheral
vasoconstriction
causing
ischemia
(especially skin)
Splanchnic
vasoconstriction
Circulation. 2008;118:1047-1056
38. Drug Clinical
indication
Dose range Action Adverse
effects
Levosimendan Decompensate
d HF
Loading dose:
12 to 24
mcg/kg over 10
min
Infusion: 0.05
to 0.2
mcg / kg/ min
Calcium
sensitiser
Tachycardia,
enhanced AV
conduction
Hypotension
Circulation. 2008;118:1047-1056
41. • However no evidence for norepinephrine use
in newborns
• One study – Tourneux et al concluded that
“Noradrenaline was effective in increasing
systemic blood pressure. An increase in urine
output and a decrease in blood lactate
concentration suggest that noradrenaline may
have improved cardiac function and tissue
perfusion”.
43. Other drugs
• Hydrocortisone – Improves vessel wall
sensitivity , circulating catecholamines, inhibits
nitric oxide synthase expression and suppresses
immune response.
• Indic : fluid refractory shock , catecholamine
refractory shock , proven adrenal insuff.
• Immunomodulators – IVIG , Activated protein C –
no role
• Pentoxifylline – promising results in refractory
shock in prematures – 5mg/Kg/hour – 6 hours- 5
days
44. Supportive therapies
• Blood Products and plasma therapies
Hb levels of 10g/dl during phase of shock.
Plasma therapy for DIC , TTP.
Platelet –
<10,000 or <20,000 high risk of bleed-
prophylactic transfusion
If > 50,000 – transfuse if active bleeding.
45. Mechanical ventilation
1. Target a tidal volume of 6 mL/kg predicted body weight in patients with
sepsis-induced ARDS (grade 1A vs. 12 mL/kg).
2. Plateau pressures be measured in patients with ARDS and initial upper
limit goal ≤30 cm H2O (grade 1B).
3. Positive end-expiratory pressure (PEEP) be applied to avoid alveolar
collapse at end expiration (atelectotrauma) (grade 1B).
4. Strategies based on higher rather than lower levels of PEEP be used for
patients with sepsis- induced moderate or severe
ARDS (grade 2C).
5. Recruitment maneuvers be used in sepsis patients with severe refractory
hypoxemia (grade 2C).
46. 6. Prone positioning be used in sepsis-induced ARDS patients with a
Pao2/Fio2 ratio ≤ 100 mm Hg in facilities that have experience with such
practices (grade 2B).
•Maintain head of the bed elevated to 30-45 degrees to limit aspiration risk
and to prevent the development of ventilator-associated pneumonia (grade
1B).
• Noninvasive mask ventilation (NIV) be used in that minority of sepsis-
induced ARDS patients in whom the benefits of NIV have been carefully
considered and are thought to outweigh the risks (grade 2B).
47. 9. That a weaning protocol be in place and that mechanically
ventilated patients with severe sepsis undergo spontaneous breathing
trials regularly to evaluate the ability to discontinue mechanical
ventilation when they satisfy the following criteria:
a) arousable;
b) hemodynamically stable (without vasopressor agents);
c) no new potentially serious conditions
d) low ventilatory and end-expiratory pressure requirements; and
e) low Fio2 requirements which can be met safely delivered with a face
mask or nasal cannula.
• If the spontaneous breathing trial is successful, consideration should
be given for extubation (grade 1A).
