Final Mansoura April 2-4.2009

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

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Infections 32% Asphyxia 29% Complications of prematurity 24% 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 in newborns can be short.

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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  

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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  

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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 

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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)

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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 

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There are a number of well known hostrelated 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

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Hipothalamic-pituitary-adrenal axis

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Cardiac dysfunction Tissue oxygenation and perfusion

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SEPSIS-SEPTIC SHOCK CONSIDERATIONS Genetic polymorphisms    

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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

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Low monocyte count (CD13) IL-12 IL-8

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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, 7,50506 (Abs)2001

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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 : 

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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

5Immunosuppression 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

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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  

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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??? 

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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 J Evans et al, Clin Therapeutics, 2006 (6%)

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 shock

Cold or warm shock

Warm 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

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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

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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 ?  

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Some known effects Upregulation of betaadrenergic 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 hygiene

Gene therapy

Simple interventions that work 

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Hand washing and aseptic precautions Enteral nutrition Strict antibiotic policy Nursing training and involvement of nurses in decision making and administrative issues Agarwal et al. 2007 Involvement ofJ Perinatol mothers

REFERENCES 1-Wheeler DS,WongHR.The impact of molecular biology on the practice of pediatric critical care medicine. Pediatr Crit Care Med 2001;2: 299-310 2-Collins FS,Mckusick VA.Implications of the human genome project for medical science.JAMA 2001;285:540-544 3-Levin M,Qunit PA,Goldstein B.Recombinant bactericidal/permeability increasing protein(eBPI21) as adjunctive treatment for children with severe meningococcal sepsis :A randomized trial.Lancet 2000;356:961-967 4-SchmidtsSM,Murphy C,While R.APC inhibits TNF and MIF production in monocytes.Eur Cytokine Netw 2000;11:407-413. 5-Brett P.G.septic shock :beyond antibiotics.AAP meeting syllabus 1996

6- S.A.EL MENEZA,N A .Khodeir and SS Khattab 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 7-EL Meneza S,Khalil O.Aly E .Necrotizing enterocolitis, early detection and Prevention.Hot topics 98 In Neonatology,Washington DC,December 6-8.1998 Proceeding 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 perinatal asphyxia. 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 and thrombosis in newborn MD,thesis,AL Azhar University 1997 11-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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