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IntroductionIntroduction
Septicemia is a state of microbial invasion Septicemia is a state of microbial invasion
from a portal of entry to blood stream whichfrom a portal of entry to blood stream whichcauses sign of illness *causes sign of illness *
Important changes in function of every organImportant changes in function of every organ
y yy y
B/P + PerfusionB/P + Perfusion
Septic shockSeptic shock
**By Schottmuller in 1914By Schottmuller in 1914
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DefinitionsDefinitions
Sepsis:Sepsis:
Systemic inflammatory response to aSystemic inflammatory response to a
documenteddocumented infection.infection.SIRS manifestations + at least 1 of inadequateSIRS manifestations + at least 1 of inadequate
1/ Alteration in mental state1/ Alteration in mental state
2/ Hypoxemia (PaO2 < 72 mmHg)2/ Hypoxemia (PaO2 < 72 mmHg)
3/ Elevated plasma lactate level3/ Elevated plasma lactate level
4/ Oliguria (
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DefinitionsDefinitionsSeptic shockSeptic shock
A subset of patient with severe sepsisA subset of patient with severe sepsis
resuscitation, along with presence of allresuscitation, along with presence of all
manifestations of inadequate organmanifestations of inadequate organ
function/perfusionfunction/perfusion
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CausesCauses
Immature immune defense system:Immature immune defense system:
Underlying major cause for sepsis & septic shock inUnderlying major cause for sepsis & septic shock inneonatesneonates
Any microorganism (Bacterial/ Viral/ Fungal)Any microorganism (Bacterial/ Viral/ Fungal)
Major:Major:
-- Staphylococcus AureusStaphylococcus Aureus-- GroupGroup bb--Hemolytic Strep.Hemolytic Strep.
-- Gram negative bacilli (EGram negative bacilli (E--coli)coli)
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PathophysiologyPathophysiology
Hemodynamics in neonatal septic shock haveHemodynamics in neonatal septic shock have
not been systematically studiednot been systematically studied
Warm shock =loss of vascular tone,Warm shock =loss of vascular tone, systemicsystemic
blood flow andblood flow and B/PB/P
Cold shock =Cold shock = vascular tone,vascular tone, systemic bloodsystemic bloodflow and eventuallyflow and eventuallyB/PB/P
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PathophysiologyPathophysiology
MediatorMediator--induced cellular injuryinduced cellular injury
Inflammatory mediators are key players inInflammatory mediators are key players in
pathogenesispathogenesis
gram + and gramgram + and gram -- bacteria induce abacteria induce a
variety of proinflammatory mediators,variety of proinflammatory mediators,
including cytokinesincluding cytokines sepsis and shocksepsis and shock
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PathophysiologyPathophysiology
MediatorMediator--induced cellular injuryinduced cellular injury(1) The bacterial cell wall components:(1) The bacterial cell wall components:
-- li o ol saccharide ramli o ol saccharide ram Li id ALi id A
moietymoiety
-- Peptidoglycan (gram + &gramPeptidoglycan (gram + &gram --))
-- Lipoteichoic acid (gram+)Lipoteichoic acid (gram+)
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PathophysiologyPathophysiology
-- ILIL--8 : Important regulator of neutrophil8 : Important regulator of neutrophilfunctionfunction
Contributes to lung injury &Contributes to lung injury &dysfunction of other organsdysfunction of other organs
-- Other cytokines: ILOther cytokines: IL--1010
InterferonInterferon--gammagammaILIL--1212GG--CSF and GMCSF and GM--CSFCSF
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PathophysiologyPathophysiology
Activation complement systemActivation complement system Clearance ofClearance of
infecting microorganisms + enhances tissue damageinfecting microorganisms + enhances tissue damage
, ,, ,
occurs via induction of nitric oxideoccurs via induction of nitric oxide
Neutrophils dual role:Neutrophils dual role:Defense against microorganismsDefense against microorganisms
Become toxic inflammatory mediatorsBecome toxic inflammatory mediators
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TypeType MediatorMediator ActivityActivity
CellularCellular
mediatorsmediators
LipopolysaccharidLipopolysaccharidee
Lipoteichoic acidLipoteichoic acid
PeptidoglycanPeptidoglycan
SuperantigensSuperantigens
EndotoxinEndotoxin
Activation of macrophages, neutrophils, platelets,Activation of macrophages, neutrophils, platelets,
and endothelium releases various cytokines andand endothelium releases various cytokines and
other mediatorsother mediators
CytokinesCytokines
Potent proinflammatory effectPotent proinflammatory effect
HumoralHumoral
mediatorsmediators
ILIL--1b1b
ILIL--88
ILIL--66
ILIL--1010
MIF &GMIF &G--CSFCSF
Nitric oxideNitric oxide
ComplementComplement
Acts as pyrogen, stimulates B and TActs as pyrogen, stimulates B and T
lymphocyte proliferation, inhibits cytokinelymphocyte proliferation, inhibits cytokine
production, induces immunosuppressionproduction, induces immunosuppression
Activation and degranulation of neutrophilsActivation and degranulation of neutrophils
Cytotoxic, augments vascular permeability,Cytotoxic, augments vascular permeability,
contributes to shockcontributes to shock
Involved in hemodynamic alterations of septicInvolved in hemodynamic alterations of septic
shockshock
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PathophysiologyPathophysiology
Abnormalities of coagulation and fibrinolysisAbnormalities of coagulation and fibrinolysishomeostasis in sepsishomeostasis in sepsis
(1) Inflammatory mediators(1) Inflammatory mediators direct injury todirect injury tovascular endotheliumvascular endothelium endothelial cellsendothelial cells
release tissue factor (TF)release tissue factor (TF)
Extrinsic coagulation cascade & production ofExtrinsic coagulation cascade & production ofthrombinthrombin
Intravascular clotsIntravascular clots
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PathophysiologyPathophysiology
Abnormalities of coagulation and fibrinolysisAbnormalities of coagulation and fibrinolysishomeostasis in sepsishomeostasis in sepsis
(2) Endotoxins(2) Endotoxins activity of fibrinolysisactivity of fibrinolysisinhibitors lasmino en activator inhibitor &inhibitors lasmino en activator inhibitor &
thrombin)thrombin)
Imbalance among inflammation, coagulation,Imbalance among inflammation, coagulation,and fibrinolysisand fibrinolysis Multiple organMultiple organdysfunction and deathdysfunction and death
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PathogenesisPathogenesis
Predominant hemodynamic feature of septic shockPredominant hemodynamic feature of septic shock
is arterial vasodilationis arterial vasodilation
Dependency of blood pressure on C.ODependency of blood pressure on C.O
So if insufficient compensation with rise in C.OSo if insufficient compensation with rise in C.O
Vasodilation result inVasodilation result in hypotensionhypotension
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PathogenesisPathogenesis
Early: The rise in C.O is limited byEarly: The rise in C.O is limited by
hypovolemia and fall in preload because ofhypovolemia and fall in preload because of
cardiac filling pressurescardiac filling pressures
Later: Even though C.O elevatesLater: Even though C.O elevates
(Hyperdynamic phase of sepsis and shock),(Hyperdynamic phase of sepsis and shock),
performance of heartperformance of heart
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PathogenesisPathogenesis
Maldistribution of blood flowMaldistribution of blood flow
Disparity between the uptake and oxygenDisparity between the uptake and oxygen
demand in the tissuesdemand in the tissues
Resultant defect in capacity to extract oxygenResultant defect in capacity to extract oxygen
locallylocally++
Elevated arterial blood lactate levelsElevated arterial blood lactate levels
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PathogenesisPathogenesisMultiorgan dysfunction syndromeMultiorgan dysfunction syndrome
Described as auto destructive process that permitsDescribed as auto destructive process that permitsextension of normal pathophysiologic response toextension of normal pathophysiologic response toinfection, resulting in multiple organ dysfunctioninfection, resulting in multiple organ dysfunctionsyndrome. Organ dysfunction or failure may be the firstsyndrome. Organ dysfunction or failure may be the first
clinical sign of sepsis, and no organ system is immune toclinical sign of sepsis, and no organ system is immune tothe consequences of the inflammatory excesses of sepsis.the consequences of the inflammatory excesses of sepsis.
-- HypoxiaHypoxia
-- Direct cytotoxicityDirect cytotoxicity-- ApoptosisApoptosis
-- ImmunosuppressionImmunosuppression
-- CoagulopathyCoagulopathy
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Diagnosis of circulatoryDiagnosis of circulatory
compromisecompromise
Gold standard for diagnosis of circulatoryGold standard for diagnosis of circulatory
compromisecompromise unknownunknownBlood pressureBlood pressure
Skin capillary refill timeSkin capillary refill time
CoreCore--peripheral temperature differenceperipheral temperature difference
Urine output and hyperkalemiaUrine output and hyperkalemiaAcidosisAcidosis
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Diagnosis of circulatory compromiseDiagnosis of circulatory compromise
Blood pressure:Blood pressure:
In preterm, mean B/P indicator valuesIn preterm, mean B/P indicator values
20 mmHg 40 mmHg20 mmHg 40 mmHg? In between? In between
Skin capillary refill time:Skin capillary refill time:
-- Traditionally acceptable < 3 secondsTraditionally acceptable < 3 seconds
-- Little relationship between Cap. Refill time andLittle relationship between Cap. Refill time andmeasures of systemic blood flowmeasures of systemic blood flow
-- Also in PT < 30 weeks only when > 5 secondsAlso in PT < 30 weeks only when > 5 seconds
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Diagnosis of circulatoryDiagnosis of circulatory
compromisecompromise
CoreCore--peripheral temperature difference:peripheral temperature difference:
In termIn term-- Little data to support accuracy ofLittle data to support accuracy of
corecore--peripheral temperature differenceperipheral temperature difference
In pretermIn preterm-- No relat onsh p ound betweenNo relat onsh p ound betweenthis measure and systemic blood flowthis measure and systemic blood flow
Low urine output & hyperkalemia:Low urine output & hyperkalemia:
Strong relationshipStrong relationship DelayDelay
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Diagnosis of circulatoryDiagnosis of circulatory
compromisecompromise
Lactic acid, PH, and base excess:Lactic acid, PH, and base excess:PH and BE: Little relationship with lowPH and BE: Little relationship with low
Lactic acid: No relationLactic acid: No relation
Organ blood flow:Organ blood flow:
Doppler velocity measurements (Small BVDoppler velocity measurements (Small BV
Limited )Limited )
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TreatmentTreatment
Treatment Strategy should relay on causativeTreatment Strategy should relay on causativefactors leading to cardiovascular compromise:factors leading to cardiovascular compromise:
1/ Inappropriate peripheral vasoregulation1/ Inappropriate peripheral vasoregulation
2/ Dysfunction of immature myocardium2/ Dysfunction of immature myocardium
Generally, absolute hypovolumia is a muchGenerally, absolute hypovolumia is a muchless frequent cause of neonatal hypotension,less frequent cause of neonatal hypotension,
especially in PT (regardless shock type)especially in PT (regardless shock type)
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TreatmentTreatment
(1)(1) Volume administrationVolume administration
Evidence that absolute hypovolumia isEvidence that absolute hypovolumia isuncommon cause of neonatal hypotension:uncommon cause of neonatal hypotension:
1.1.B/P usually associated with N / or evenB/P usually associated with N / or evenCOCO2. Dopamine better than volume adm in2. Dopamine better than volume adm in
normalizing B/Pnormalizing B/P
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TreatmentTreatment
(1)(1) Volume administrationVolume administration
3. Most important: Myocardial dysfunction3. Most important: Myocardial dysfunctionfrequently contributes to the development offrequently contributes to the development of
4. Aggressive volume administration, esp. in PT4. Aggressive volume administration, esp. in PT
is associated with higher pulmonary, CV, GIis associated with higher pulmonary, CV, GIand CNS morbidity & mortalityand CNS morbidity & mortality
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TreatmentTreatment
-- Therefore, esp. in PT, fluid resuscitationTherefore, esp. in PT, fluid resuscitation
should be minimizedshould be minimized
-- Another concern: Type of fluidAnother concern: Type of fluid
BestBest Isotonic saline 10Isotonic saline 10--20ml/kg20ml/kgButBut Unbalanced nature of N/SUnbalanced nature of N/S
I.e.: Its adm. in large amount over a short periodI.e.: Its adm. in large amount over a short periodof time may worsen metabolic acidosis !of time may worsen metabolic acidosis !
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TreatmentTreatment
(2)(2) Pharmacologic TherapyPharmacologic Therapy(A) Dopamine(A) Dopamine
-- Most commonly used Tx of hypotension in PTMost commonly used Tx of hypotension in PT-- DoseDose--dependent dopaminergic,dependent dopaminergic, . and. and ..
adrener ic and serotonin rece tor CVadrener ic and serotonin rece tor CV
stimulantstimulant-- Basically affects all 3 major determinants ofBasically affects all 3 major determinants of
CVS function mainly after load and MC effectCVS function mainly after load and MC effect
-- Dosage: 2 to 20 ug /kg/min (adult dataDosage: 2 to 20 ug /kg/min (adult data
pharmacodynamics)pharmacodynamics)
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TreatmentTreatment
(A) Dopamine(A) Dopamine
-- Severe illnessSevere illnessCV sensitivity to dopamineCV sensitivity to dopamine
so with disease advancement, larger doses mayso with disease advancement, larger doses may
be neededbe needed
i.e.: Dosage adm. should be tailored toi.e.: Dosage adm. should be tailored to
pharmacodynamic effect in pt. at bedsidepharmacodynamic effect in pt. at bedside
(rather than following conventional dose(rather than following conventional doserecommendations based on adult data)recommendations based on adult data)
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TreatmentTreatment
Practical TipPractical Tip
In Extreme PTIn Extreme PT
--11-- Weak relationship between BP and systemicWeak relationship between BP and systemic
blood flow (blood flow ( BP does not necessarilyBP does not necessarily
guarantee good tissue perfusion)guarantee good tissue perfusion)
--22-- Immature myocardium struggle to maintainImmature myocardium struggle to maintain
appropriate systemic blood flow againstappropriate systemic blood flow against
suddensudden in peripheral VRin peripheral VR
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TreatmentTreatment
Practical TipPractical Tip
So,So, dopamine doses willdopamine doses will after loadafter load improveimprove
BP but, without effective myocardial functionBP but, without effective myocardial functionimprovement, the systemic blood flow may notimprovement, the systemic blood flow may not
im rove and ma even worsenim rove and ma even worsen
So neonatologists must accept lower end BPSo neonatologists must accept lower end BP
values with Dopamine dosages below 10values with Dopamine dosages below 10ug/kg/min ( unless measures to monitor systemicug/kg/min ( unless measures to monitor systemic
blood flow are available)blood flow are available)
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TreatmentTreatment
Practical TipPractical Tip
Recommendation: Combination of DobutamineRecommendation: Combination of Dobutamineand lowand low-- medium dose of Dopamine to maintainmedium dose of Dopamine to maintain
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TreatmentTreatment
(3)(3) CorticosteroidsCorticosteroids
Evidence of benefit in vasopressor resistantEvidence of benefit in vasopressor resistant
hypotension:hypotension:
11-- Regulates the expression of CV adrenergicRegulates the expression of CV adrenergic
recep orsrecep ors reverse vasopressor res s ancereverse vasopressor res s ance
22-- Inhibit catecholamine metabolism and theInhibit catecholamine metabolism and the
production of vasoactive factors( nitric oxide)production of vasoactive factors( nitric oxide)
33-- Improve intracellular Calcium levelImprove intracellular Calcium level
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TreatmentTreatment
(3)(3) CorticosteroidsCorticosteroids
Concerns:Concerns:
11-- Potential short & long term side effectPotential short & long term side effect22 If adrenal function intactIf adrenal function intact Reactive toReactive to
I.e.: Steroids administration benefit mayI.e.: Steroids administration benefit may
become equivocal ( always analyze steroidsbecome equivocal ( always analyze steroidslevel prior to adm.)level prior to adm.)
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TreatmentTreatment
(4) Other :(4) Other :
-- Antibiotics !Antibiotics !-- Supportive measures:Supportive measures:
zz
calcium levelscalcium levels
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ConclusionConclusion
Hemodynamics in neonatal septic shock haveHemodynamics in neonatal septic shock havenot been systematically studiednot been systematically studied
None of the parameters used to diagnoseNone of the parameters used to diagnoseneonatal circulatory compromise has sufficientneonatal circulatory compromise has sufficientaccuracy to be used on its ownaccuracy to be used on its own
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ConclusionConclusion
Sustained stabilization of CV status withSustained stabilization of CV status with
rovision of a ro riate BP, CO, tissuerovision of a ro riate BP, CO, tissue
perfusion and oxygenation remains aperfusion and oxygenation remains adifficult task in most critically illdifficult task in most critically ill
hypotensive newbornshypotensive newborns
C l iC l i
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ConclusionConclusion
The addition of echocardiographic hemodynamicThe addition of echocardiographic hemodynamicassessment to BP monitoring to clinicalassessment to BP monitoring to clinical
evaluation of neonates are necessar to betterevaluation of neonates are necessar to better
understand changes in organ blood flow andunderstand changes in organ blood flow andtissue perfusiontissue perfusion
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ReferencesReferences
Cardiovascular Compromise In The Newborn Infant. AverysCardiovascular Compromise In The Newborn Infant. AverysDiseases of the newborn by Taeusch /Ballard /Gleason. 8thDiseases of the newborn by Taeusch /Ballard /Gleason. 8thedition Chapter 31edition Chapter 31
Towards The Early Diagnosis Of Neonatal Sepsis And SepsisTowards The Early Diagnosis Of Neonatal Sepsis And Sepsis--like Illness Using Novel Heart Rate Analysis. Pamela Griffin,like Illness Using Novel Heart Rate Analysis. Pamela Griffin,MD. Pediatrics VOL.107 No.1 January 2001, pp.97MD. Pediatrics VOL.107 No.1 January 2001, pp.97--104104
Septic Shock . Sat Sharma, MD, FRCPC, FACP, FCCP,Septic Shock . Sat Sharma, MD, FRCPC, FACP, FCCP,DABSM. Medline.DABSM. Medline.
Shock, Septic. Michael R filbin,MD. Medline.Shock, Septic. Michael R filbin,MD. Medline.
Heart Rate Characteristics In Neonatal Sepsis: A PromisingHeart Rate Characteristics In Neonatal Sepsis: A Promising
Test That Is Still Premature. Braham Goldstein. PediatricsTest That Is Still Premature. Braham Goldstein. Pediatrics2005;115:10702005;115:1070--10721072
Historical Perspectives: Group B Streptococcus In NeonatalHistorical Perspectives: Group B Streptococcus In NeonatalSepsis: Emergence As An Important Pathogen. Alistair G.SSepsis: Emergence As An Important Pathogen. Alistair G.S
Philip. Neoreviews 2004;5;ePhilip. Neoreviews 2004;5;e--467467--e470e470