final mansoura april 2-4.2009
TRANSCRIPT
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Neonatal Septic
shock
Safaa A. EL Meneza
Professor of Pediatrics
Faculty of Medicine for
GirlsAL Azhar University
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Objectives Definitions Epidemiology Pathophysiology
Management of septicshock
Prevention
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Direct Causes of NeonatalDeaths
Infections 32%
Asphyxia 29%
Complications of prematurity24% Congenital anomalies 10%
Other 5%
World Health Organization.State of the World’s Newborns 2005
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Septic shock Diagnosis and treatment
of neonatal septic shock are quite difficult as :
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Septic shock The hyperdynamic phase
of septic shock innewborns can be short. VLBW may have acute
hypotension ,bradycardiawithout precedingtachycardia
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Septic shock
2. Sepsis is a clinical
diagnosis and does notrely on early isolation of the causative infectiousorganism .
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ac er a so a es nneonatal 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%.
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Bacterial isolates in neonatal
sepsis in NICUs in Egypt In NICU of AL Zhraa University
hospitalwe found that gram negative in55% of cases ; K. pneumoniae , Ecoli, enterobactr spp, citrobacterspp and serratia m.
K. pneumoniae phenotyping and
genotyping showedmacrorestriction profiles of chromosomal DNA of 15 distinctpatterns.
Abd ELHalim N. MD thesis 2009 ,supervised by Aly G.,ELMeneza S. and EL salakawy A. , FMG , AL Azhar University
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Not a single pathologic
entity!
What is septic shock
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DEFINITIONS
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Septic shock
Sepsis andcardiovascular
organ dysfunction
Goldstein et.al Pediatr crit care Med 2005 Vol.6 No.1
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Decrease in BP
< 5th percentile for age or
systolic BP < 2 SD belownormal for age
No response toadministration of isotonicintravenous fluid bolus ≥40
mL/kg in 1 hr OR
● Cardiovasculardysfunction
Goldistein et al Ped.cri.car.Med.6,1,2oo5
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● Cardiovascular
dysfunction
Need for vasoactive drug to
maintain BP in normal range(dopamine > 5 u/kg/min ordobutamine, epinephrine, or
nor epinephrine at any dose)
Goldistein et al Ped.cri.car.Med.6,1,2oo5
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Septic shock Septic shock is caused
byan acute failure of circulatory function and
is characterized byinadequate tissue andorgan perfusion.
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Septic Shock Septic shock is a
subclassof distributive shock commonly associated
with bacterial and viralinfections in neonates.
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Septic Shock The hallmark of septic
shock is markedprogressive hypotension frequently refractory to
therapy .
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SEPSIS-SEPTIC SHOCK CONSIDERATIONS
There are a number of well known host-related risk factors for sepsis. Theyinclude:
Extremes of age A compromised immune system Malnourishment Asplenia Chronic antibiotic or steroid use Additionally, any insult (shock, trauma,
burn) that makes the gastrointestinaltract permeable to gram negative
bacteria puts individuals at risk for gramne ative se sis
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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
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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
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SEPSIS-SEPTIC SHOCK CONSIDERATIONS
Inflammatory cell function
Low monocyte count (CD13) IL-12 IL-8
Greater risk of death
SEPSIS SEPTIC SHOCK CONSIDERATIONS
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SEPSIS-SEPTIC SHOCK CONSIDERATIONS
Vasodilatory shock
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Septic Shock
Septic shock
characterized byarteriolar and venousvasodilatation
that results in lowsystemic vascularresistance despite initial
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Hypothalamic-pituitary-adrenalaxis
•Relative adrenal insufficiency•Corticotrophin resistance +
•Reduced adrenal glucocorticoids
synthesisLonger length of stay and more
organ dysfunction
SEPSIS-SEPTIC SHOCK
CONSIDERATIONS
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Cardiac dysfunction
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There is significant There is significant
decrease in thedecrease in themyocardial contractilitymyocardial contractilityamong the newborn infantamong the newborn infant
suffered from septic shocksuffered from septic shockEL Meneza S,et al . Perinatology,Vol 21,No 7
505-06(Abs)2001
Cardiac dysfunction
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-Cardiac dysfunctionthrough uncoupling of
β adrenergeic receptors&
by direct inhibition of intracellular calcium
homeostasis
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Newborn infants have alsodysfunction due toimmaturity of myocardium
Abnormal peripheral
vasoregulation due to“immaturity of autonomicnervous system”
Cardiac dysfunction
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Cardiac dysfunction
Lopez preceedings ICP conference2007
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Septic Shock
Lopez preceedings ICP conference2007
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Septic Shock
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We found significantincrease in No in newborninfants with sepsis shock
EL Meneza S,et. al. Perinatology. 21, 7,505-06 (Abs)2001
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Cytokines TNFα, IL-1β, IL-6released in a large scale
inflammatory responseresults in massivevasodilation, increasedcapillary permeability,decreased systemicvascular resistance, andhypotension.Kumar, et al .. (2007). Robbins Basic Pathology (8th ed.). Saunders Elsevier. pp. 102-103
Inflammatory mediators and
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Ware and Matthay NEJM 342 (18): 1334
Inflammatory mediators andcapillary leak syndrome
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In MD study,in our unit wecould found significant
decrease of APC, protein c,antithrombin III among septic
newborn than the controlgroup
EL GandyEL Gandy MD, MD thesis,Supervised by ELMeneza S.ELMahdy M, FMG, AL Azhar University, 1997
Protein C Activated Protein C
SEPSIS-SEPTIC SHOCK CONSIDERATIONS
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SEPSIS SEPTIC SHOCK CONSIDERATIONSEndothelial activation
Coagulation and fibrin deposition
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Micro thrombusformation
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Pseudomonas sepsis withDIC
J Evans et al, Clin Therapeutics, 2006
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Invasive Candidiasis
J Evans et al, Clin Therapeutics, 2006
id th t th
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consider that there are:
1-Maldistribution of circulatoryvolume
2-Depressed myocardialfunction
3-Hypoxic hypoxia -Diminished oxygen delivery
-A decrease in the number of functionalcapillaries causes an inability to extract oxygenmaximally
-There is inability of the erythrocytes to
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3-Direct cytotoxicity
This is called cytopathic
or histotoxic anoxia an inability to utilize oxygen
even when it is present
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4-Apoptosis
The proinflammatorycytokines
may delay apoptosis inactivated
macrophages and neutrophilsbutother tissues such as gut
epithelium, may undergo
5
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5-Immunosuppression
The interaction betweenproinflammatory
andanti-inflammatory mediators
may lead to an imbalance
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It is currently believed that if pro-inflammatory predominate
an inflammatory cascadeensues ,and immediate
pathophysiologicprocesses are initiated
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Septic shock
Signs of early septic shockmay be subtle and there is a
danger of overlooking them ina busy emergency department.
The patient may not always
adhere to the classic stages of shock described in textbooks.
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Pallor
poor skinperfusion
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1-Pallor and poor skinperfusion2-Capillary refill >2 sec2-Cool extremities
3-CNS dysfunction4-Decreased urine output
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TREATMENT
The recommendations for
support of term newbornsand children are primarilyexpert opinion rather than
irrefutable evidence due tolack of RCT
Thus -state –of- the art
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Thus -state –of- the art management
1- Haemodynamicresuscitation and organ
support Adequate blood flow Preserve organ perfusion and
regional distribution of total cardiacoutput
Preserve vascular beds:
integrity and vasomotor tone
Thus -state –of- the art
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Thus -state –of- the art management
2- Eradicate infection Early recognition Early and adequate antibiotic
therapy Source control
Thus -state –of- the art
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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
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RESUSCITATION OFPEDIATRIC SEPTIC SHOCK
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First Hour of Resuscitation
(Level III)
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Push 10 cc/kg isotonic
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-Push 10 cc/kg isotoniccrystalloid
or colloid boluses to 60cc/kg
-Correct hypoglycemia &
hypocalcaemia
-Begin prostaglandin infusion
until echocardiogramshows no dependentlesion
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It is important to distinguishnewborn septic shock from
cardiogenic shock caused byclosure of the PDA innewborns with ductal
dependent complexcongenital heart disease
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15 min
Fluid responsive
Observe in NICU
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15 minFluid refractory shock
-Establish central venousand arterial access
-Titrate dopamine/ anddobutamine
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Homodynamic Support
(Level II)Although dopamine can be
used as the first-line agentits effect on pulmonary vascular resistance
should be taken into account
A I t th bl ???
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Are Inotropes the problem???
Pressor medication certainly play an importantrole in shock, but
Use of pressors such as dopamine could be worse
than mild hypotension itself, particularly when notclose monitoring and control of BP
There may be place for permissivehypotension, particularly when low BP is the
only symptom….may be better to watch andwait than to jump inAl-Aweel J Perinatology 2001
Are Inotropes the problem??
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p pAbstract, PAS 2007
Infants who were stillreceived inotropes after
being normotensive, weremore likely to have asevere IVH (18%) than
hypotensive infants whodid not receive inotropes(6%)J Evans et al, Clin Therapeutics, 2006
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Fluid refractory- dopamineresistant shock
- Titrate epinephrine-Systemic-alkalinization if
PPHN and acidosis ispresent
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Phenomenon of non
responding tovasopressor during shock
is due to decrease sensitivity
to dopamine due to
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1-Down regulation of βadrenergic receptors
2-Decrease in expressionof adrenergenic receptorsin critically ill neonates
3-Immaturity as depletedmyocardial nor epinephrine stores
Zhang 1999
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60 min
Catecholamine - resistantshock
Direct therapies usingechocardiogram, arterial
and CVPmonitoring
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60 minCatecholamine resistant shock
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Cold shockNormal blood pressurePoor LV function
Central venous O2 sat < 70%
Titrate vasodilator or
type III PDE inhibitor withvolume loading
Catecholamine - resistant shock
60 minCatecholamine - resistant shock
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Cold or warm shockPoor RV functionPPHN
Central venous O2 sat<70%
Inhaled nitric oxide
60 min
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Warm shockLow blood pressure
Titrate volume and
epinephrine
60 minCatecholamine - resistant shock
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Refractory shock
ECMO
What drug should we use?
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What drug should we use?
In general when blood pressure is low in a sickneonate, dopamine is more effective thandobutamine* in raising blood pressure and increasingsystemic 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 moreeffect on left ventricular output; Dobutamine, used
without an alpha- adrenergic medication, may wellcause worsened hypotension…but still can improveorgan perfusion
Epinephrine increases both cardiac output and blood
pressure: best to use when blood pressure and
Therapeutic End Points
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Therapeutic End Points(Level III)
Therapeutic end points include:• Capillary refill of < 2 secs
•Normal pulses with nodifferential between
peripheral and central pulses•Warm extremities,•Urine output of > 1 mL/kg/hr
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Therapeutic End Points
•Normal mental status•Normal blood pressure for age
•Difference in preductal andpostductal oxygen saturation of
< 5%
and• Oxygen saturation of > 95%
•Increase pH and decrease lactate
Activities
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Activities
A. Initial Resuscitation
B. Diagnosis
C. Antibiotic TherapyD. Source Control
F. Use Vasopressors
G. Inotropic Therapy
H. Steroids
J. Blood Product Administration
Activities
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K. Mechanical Ventilation of sepsis
Induced Acute Lung Injury (ALI)/AR
L. Sedation, Analgesia, and neuromus
Blockade in sepsis
M. Glucose Control
N. Renal Replacement
Activities
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Stabilization: Beyond the
First HourLevel (III)
Goals
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Goals
*Maintain threshold heart rate*Maintain normal perfusion and
blood pressure*Maintain neonatal circulation
Central venous oxygensaturation > 70%
Steroids
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Steroids
When
Should be used??????
SCHEMATIC SUMMARY OF GLUCOCORTICOIDPROPERTIES
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PROPERTIES
Carcillo,task force.Shock,
20(3):197-207,2003
Glucocorticoids in Neonatal
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Shock ?
Some known effects Upregulation of beta-
adrenergic receptors Increased concentrations of
catecholamines
Improvement in capillaryintegrity
Direct inotropic effect on
myocytes-increased
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Carcillo,Task force.Shock,20(3):197-207,2003
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Current Immune therapyCurrent Immune therapy
1-Immunoglobulin1-Immunoglobulin
2-Granulocytes infusions2-Granulocytes infusions3-Double volume exchange3-Double volume exchange
transfusionstransfusions4-rhu-GM-CSF4-rhu-GM-CSF
Granulocyte MacrophageC l S i l i
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Colony Stimulating Factor
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Break the chain of
inflammation /tissueinjury
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Emphasized that nosingle therapy would bebeneficial for all patient
with sepsis
G hG th
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SomeSome patient may benefit frompatient may benefit from
i.e. microbial challenge is morei.e. microbial challenge is moreeffectively clearedeffectively cleared
Gene therapyGene therapy
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OtherOther will benefit fromwill benefit from
i.e. reduce the cascade of i.e. reduce the cascade of inflammatory mediatorsinflammatory mediators
Gene therapyGene therapy
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Immune TherapyImmune Therapy
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Monoclonal antibodies againsttumour necrosis factor
Blockade of eicosanoidproduction
Blockade IL-1 activity Inhibition of nitric oxide
synthaseExogenous surfactant
High Mobility Group
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g y pBox Protein 1
•Nuclear protein bind DNAstabilize nucleosomes
•Extracellular mediator insystemic inflammation
•Could be therapeutic target inmanagement of sepsis
Triggering receptor expressed on
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myeloid cells
•Activates neutrophils andmonocytes/macrophages
•Amplifies TLRs responsesagainst
microbial challenges
Toll-Like receptors
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Toll Like receptors
•Modulate the inflammatoryresponse
Variable expression(neutrophils, dendritic cells, etc.)
Controlling or modifying :
septic process
The future strategy will
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1-Immunophenotype of patients
2-Prediction of host responseto disease and therapy
Wheeler et al Pediatr Crit Care Med 2001;2: 299-310
gyrelay on
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Dellinger RP, Levy MM, Carlet JM, et al: Surviving SepsisCampaign: Guidelines for management of severe sepsis andseptic shock. Intensive Care Medicine (2008).
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Simple interventions
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Simple interventionsthat work
Hand washing and asepticprecautions
Enteral nutrition Strict antibiotic policy Nursing training and involvement
of nurses in decision making andadministrative issues
Involvement of mothersAgarwal et al. J Perinatol 2007
REFERENCES1-Wheeler DS,WongHR.The impact of molecular
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g pbiology on the practice of pediatric critical care
medicine. Pediatr Crit Care Med 2001;2: 299-3102-Collins FS,Mckusick VA.Implications of the human
genome project for medical science.JAMA2001;285:540-544
3-Levin M,Qunit PA,Goldstein B.Recombinant
bactericidal/permeability increasing protein(eBPI21)as adjunctive treatment for children with severemeningococcal sepsis :A randomized trial.Lancet
2000;356:961-967
4-SchmidtsSM,Murphy C,While R.APC inhibits TNF andMIF production in monocytes.Eur Cytokine Netw2000;11:407-413.
5-Brett P.G.septic shock :beyond antibiotics.AAPmeeting syllabus 1996
h d i d h b
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6- S.A.EL MENEZA,N A .Khodeir and SS KhattabSignificance of platelet derived growth factor- AB and
nitric oxide in newborns Suffering from perinatal asphyxiaStudy II:Relation to cerebral blood flow Perinatal Med
vol29, suppl 1 2001,1227-EL Meneza S,Khalil O.Aly E .Necrotizing enterocolitis,
early detection and Prevention.Hot topics 98 InNeonatology,Washington DC,December 6-8.1998Proceeding Page 483 -485
8-S.A.EL MENEZA,N A .Khodeir and SS Khattab.J.Significance platelet-derived growth factor-AB and nitric
oxide in newborn infants suffering from perinatalasphyxia. Perinatology,Vol 21,No 7,505-06(Abs)2001
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9-EL Meneza S,Khalil O .Study of the impact of
nosocomial infection on mortality and morbidity of ventilated newborn infants. Hot topic IN Neonatology,Washington DC December 5-7,1999 .Proceeding,424-425
10-EL Gandy M,EL Meneza S,EL Mahdy M and Nasef S.Study of some risk factors for hypercoagulation andthrombosis in newborn MD,thesis,AL Azhar University
199711-Sheata K,Refaie F,EL Meneza S and Esmat A.
Biochemical Study on ICAM among neonates with
PA,b.Sc Aim Shamas 1995
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