Final Mansoura April 2-4.2009

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Neonatal Septic

shock

Safaa A. EL Meneza

Professor of Pediatrics

Faculty of Medicine for

GirlsAL Azhar University



Objectives Definitions Epidemiology Pathophysiology

Management of septicshock

Prevention



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



Septic shock Diagnosis and treatment

of neonatal septic shock are quite difficult as :



Septic shock The hyperdynamic phase

of septic shock innewborns can be short. VLBW may have acute

hypotension ,bradycardiawithout precedingtachycardia



Septic shock

2. Sepsis is a clinical

diagnosis and does notrely on early isolation of the causative infectiousorganism .



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%.



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



Not a single pathologic

entity!

What is septic shock



DEFINITIONS





Septic shock

Sepsis andcardiovascular

organ dysfunction

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



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



● 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



Septic shock Septic shock is caused

byan acute failure of circulatory function and

is characterized byinadequate tissue andorgan perfusion.





Septic Shock Septic shock is a

subclassof distributive shock commonly associated

with bacterial and viralinfections in neonates.



Septic Shock The hallmark of septic

shock is markedprogressive hypotension frequently refractory to

therapy .







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




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




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




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 byarteriolar and venousvasodilatation

that results in lowsystemic vascularresistance despite initial



Hypothalamic-pituitary-adrenalaxis

•Relative adrenal insufficiency•Corticotrophin resistance +

•Reduced adrenal glucocorticoids

synthesisLonger length of stay and more

organ dysfunction

SEPSIS-SEPTIC SHOCK

CONSIDERATIONS





Cardiac dysfunction



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





-Cardiac dysfunctionthrough uncoupling of

β adrenergeic receptors&

by direct inhibition of intracellular calcium

homeostasis



Newborn infants have alsodysfunction due toimmaturity of myocardium

Abnormal peripheral

vasoregulation due to“immaturity of autonomicnervous system”

Cardiac dysfunction



Cardiac dysfunction

Lopez preceedings ICP conference2007



Septic Shock

Lopez preceedings ICP conference2007





Septic Shock













We found significantincrease in No in newborninfants with sepsis shock

EL Meneza S,et. al. Perinatology. 21, 7,505-06 (Abs)2001





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



Ware and Matthay NEJM 342 (18): 1334

Inflammatory mediators andcapillary leak syndrome





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 CONSIDERATIONSEndothelial activation

Coagulation and fibrin deposition



Micro thrombusformation









Pseudomonas sepsis withDIC

J Evans et al, Clin Therapeutics, 2006



Invasive Candidiasis

J Evans et al, Clin Therapeutics, 2006

id th t th



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



3-Direct cytotoxicity

This is called cytopathic

or histotoxic anoxia an inability to utilize oxygen

even when it is present



4-Apoptosis

The proinflammatorycytokines

may delay apoptosis inactivated

macrophages and neutrophilsbutother tissues such as gut

epithelium, may undergo

5



5-Immunosuppression

The interaction betweenproinflammatory

andanti-inflammatory mediators

may lead to an imbalance



It is currently believed that if pro-inflammatory predominate

an inflammatory cascadeensues ,and immediate

pathophysiologicprocesses are initiated







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.



Pallor

poor skinperfusion



1-Pallor and poor skinperfusion2-Capillary refill >2 sec2-Cool extremities

3-CNS dysfunction4-Decreased urine output





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



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





2- Eradicate infection Early recognition Early and adequate antibiotic

therapy Source control





3- Sustained support Minimizing iatrogenic injury Ventilation,Haemoglobin,

Glucose

4- Modulation of inflammatory response Coagulation, adrenal response

RESUSCITATION OF



RESUSCITATION OFPEDIATRIC SEPTIC SHOCK







First Hour of Resuscitation

(Level III)



Push 10 cc/kg isotonic



-Push 10 cc/kg isotoniccrystalloid

or colloid boluses to 60cc/kg

-Correct hypoglycemia &

hypocalcaemia

-Begin prostaglandin infusion

until echocardiogramshows no dependentlesion



It is important to distinguishnewborn septic shock from

cardiogenic shock caused byclosure of the PDA innewborns with ductal

dependent complexcongenital heart disease



15 min

Fluid responsive

Observe in NICU



15 minFluid refractory shock

-Establish central venousand arterial access

-Titrate dopamine/ anddobutamine



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 ???



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??



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





Fluid refractory- dopamineresistant shock

- Titrate epinephrine-Systemic-alkalinization if

PPHN and acidosis ispresent



Phenomenon of non

responding tovasopressor during shock

is due to decrease sensitivity

to dopamine due to



1-Down regulation of βadrenergic receptors

2-Decrease in expressionof adrenergenic receptorsin critically ill neonates

3-Immaturity as depletedmyocardial nor epinephrine stores

Zhang 1999



60 min

Catecholamine - resistantshock

Direct therapies usingechocardiogram, arterial

and CVPmonitoring



60 minCatecholamine resistant shock



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



Cold or warm shockPoor RV functionPPHN

Central venous O2 sat<70%

Inhaled nitric oxide

60 min



Warm shockLow blood pressure

Titrate volume and

epinephrine

60 minCatecholamine - resistant shock



Refractory shock

ECMO

What drug should we use?



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



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



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



Activities

A. Initial Resuscitation

B. Diagnosis

C. Antibiotic TherapyD. 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)/AR

L. Sedation, Analgesia, and neuromus

Blockade in sepsis

M. Glucose Control

N. Renal Replacement

Activities



Stabilization: Beyond the

First HourLevel (III)

Goals



Goals

*Maintain threshold heart rate*Maintain normal perfusion and

blood pressure*Maintain neonatal circulation

Central venous oxygensaturation > 70%

Steroids



Steroids

When

Should be used??????

SCHEMATIC SUMMARY OF GLUCOCORTICOIDPROPERTIES



PROPERTIES

Carcillo,task force.Shock,

20(3):197-207,2003

Glucocorticoids in Neonatal



Shock ?

Some known effects Upregulation of beta-

adrenergic receptors Increased concentrations of

catecholamines

Improvement in capillaryintegrity

Direct inotropic effect on

myocytes-increased



Carcillo,Task force.Shock,20(3):197-207,2003





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



Colony Stimulating Factor





Break the chain of

inflammation /tissueinjury



Emphasized that nosingle therapy would bebeneficial for all patient

with sepsis

G hG th



SomeSome patient may benefit frompatient may benefit from

i.e. microbial challenge is morei.e. microbial challenge is moreeffectively clearedeffectively cleared

Gene therapyGene therapy



OtherOther will benefit fromwill benefit from

i.e. reduce the cascade of i.e. reduce the cascade of inflammatory mediatorsinflammatory mediators

Gene therapyGene therapy



Immune TherapyImmune Therapy



Monoclonal antibodies againsttumour necrosis factor

Blockade of eicosanoidproduction

Blockade IL-1 activity Inhibition of nitric oxide

synthaseExogenous surfactant

High Mobility Group



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



myeloid cells

•Activates neutrophils andmonocytes/macrophages

•Amplifies TLRs responsesagainst

microbial challenges

Toll-Like receptors



Toll Like receptors

•Modulate the inflammatoryresponse

Variable expression(neutrophils, dendritic cells, etc.)

Controlling or modifying :

septic process

The future strategy will



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



Dellinger RP, Levy MM, Carlet JM, et al: Surviving SepsisCampaign: Guidelines for management of severe sepsis andseptic shock. Intensive Care Medicine (2008).



Simple interventions



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



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



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



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

شكرا



Final Mansoura April 2-4.2009

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