neonatal shock: management of blood pressure, and systemic...

19.09.2014

1

Istvan Seri MD, PhD, HonD

Sidra Center of Excellence in Neonatology, Sidra Medical and Research Center

Weill-Cornell Medical College-Q, Doha Qatar

Neonatal Shock: Management of Blood Pressure,

and Systemic and Organ Blood Flow

The BEST of IPOKRaTES: UPDATE in NEONATOLOGY

Leuven, Belgium, September 17 - 20, 2014

Istvan Seri, MD, PhD, HonD has disclosed the following financial

relationships. Any real or apparent conflicts of interest related to the

content of this presentation have been resolved.

Affiliation / Financial Interest Organization

Educational Grant to support the

Neonatal Hemodynamics Club,

2013, 2014

Covidien Inc.; Mansfield, MA

Co-editorship of “Cardiology and

Neonatal Hemodynamics”; Book Royalty

Elsevier, Inc.; Philadelphia, PA

Disclosure Statement

OBJECTIVES

1. To define neonatal shock

2. To describe the cardiovascular effects of

a) Volume

b) Dopamine

c) Epinephrine

d) Norepinephrine

e) Dobutamine

f) Milrinone

g) Sildenafil

h) Vasopressin

i) Hydrocortisone

Management of Blood Pressure, and Systemic and Organ Blood Flow

19.09.2014

2

OBJECTIVES

1. To define neonatal shock

2. To describe the cardiovascular effects of

a) Volume

b) Dopamine

c) Epinephrine

d) Norepinephrine

e) Dobutamine

f) Milrinone

g) Sildenafil

h) Vasopressin

i) Hydrocortisone


OBJECTIVE #1 DEFINITION OF SHOCK


1. Hypovolemic Shock:

Inadequate circulating blood volume (absolute and/or relative)

Might be more common in the immediate postnatal period in the very preterm neonate

2. Cardiogenic Shock:

Myocardial dysfunction

VLBW neonates during transition, in neonates with asphyxia, sepsis or in cases with PDA-

associated systemic hypoperfusion

3. Distributive Shock:

Failure of vasoregulation

VLBW neonates during transition or in neonates with sepsis and relative adrenal

insufficiency-associated vasopressor resistance

Etiology of Neonatal Shock

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3

Phases of Neonatal Shock

Compensated phase

< Heart rate; < Urine output; No change in blood pressure;

Blood flow distributed to vital organs (brain, heart, adrenal glands) at the

expense of non-vital organ perfusion

Uncompensated phase

< Heart rate; < Urine output; < Blood pressure

Blood flow < in all organs, tissue hypoperfusion and acidemia develop

Irreversible phase

Irreversible cellular damage

3. Uncompensated Shock:

↓↓↓↓ in Vital & Non-Vital Organ BF

NIRS – ↑↑↑↑ O2 extraction

Doppler US - abnormal flow pattern

2. Compensated Shock:

Normal Vital Organ BF

NIRS – normal Cerebral rSO2

Doppler – normal flow pattern


Normal Vital Organ BF

NIRS – normal Cerebral rSO2

Doppler – normal flow pattern

3. Uncompensated Shock:

Organ (Brain) Function

↓↓↓↓ Brain Activity (aEEG) in

BP = CO x SVR

Monitoring:Blood pressuremeasurements

Monitoring:

• Calculated (BP/CO);• Laser-Doppler;• Visible-light;

• NIRS

Monitoring:• Echocardiography;

• Impedance EC;

• Pressure wave-form analysis;

• MRI

1. Systemic

Blood PressureDependent Variable

1. Systemic ResistanceIndependent variable

(Vasopressors, Lusitropes)

1. Systemic FlowIndependent variable

(Inotropes)


↓↓↓↓ in Non-Vital Organ BF

NIRS – ↑↑↑↑ O2 extraction (kidneys, gut, muscle)Doppler – US (abnormal flow pattern)

O2 Delivery

O2 Demand

HEMODYNAMICS AND SHOCKBLOOD PRESSURE, BLOOD FLOW, BLOOD FLOW DISTRIBUTION

Modified from Soleymani et al, Expert Rev. Med. Devices 9, 501–511; 2012

↔


A in Non-Vital Organ BF

NIRS – ↑↑↑↑ O2 extraction (kidneys, gut, muscle)Doppler – US (abnormal flow pattern)

Decreased CO

(cardiac dysfunction

and/or

hypovolemia)

+

Adequate

compensatory A in

vasomotor tone

(SVR)

Decreased CO

(cardiac

dysfunction

and/or

hypovolemia)

+

Inadequate

compensatory A

in vasomotor

tone (SVR)

Decreased

vasomotor

tone

+

Adequate

compensatory A in

CO

Normotension NormotensionHypotension

Decreased

vasomotor

tone

+

Inadequate

compensatory A

in CO

CO = cardiac output; SVR = systemic vascular resistance

Neonatal Cardiovascular Compromise:

Primary Myocardial Dysfunction or Primary Abnormal Vascular Tone

with or without Compensation by the Unaffected Variable

Wu et al. Neonatal Hypotension; Workbook in Practical Neonatology; in press - 2014

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CASE PRESENTATION

SHOCK AND PHARMACOLOGIC MANAGEMENT

A preterm infant (twin A) was born at 31 1/7 weeks gestation (BW 1180g, 8 percentile) via C/S due to abnormal cord Doppler findings. No signs of chorioamnionitis. Apgar scores were 41 and 75.

The baby is on no respiratory support and blood gases are normal. However, the baby has been “hypotensive”, and, after a bolus of NS at 3 hours of age, mean and systolic/diastolic blood pressure is 21 and 34/14 mm Hg, respectively and capillary refill is 2-3 seconds.

What would be your choice to address the hypotension?

Noori S, unpublished data – shown with permission

HYPOTENSION DURING THE TRANSITIONAL PERIOD

CASE REPORT

1) Start dobutamine at 5 mcg/kg/min and titrate

2) Give another 10-20 ml/kg 0.9% saline bolus

3) No intervention and continue close monitoring

4) Start dopamine at 2.5 mcg/kg/min and titrate

5) Start epinephrine at 0.05 mcg/kg/min and titrate

SF 34%

LVO = 377 mL/kg/min

M-mode (LV)

Short axis view (LV)

Aorta Doppler

Middle Cerebral Artery Doppler

MV 23 cm/s

PDA flow was equally bidirectional


HYPOTENSION DURING THE TRANSITIONAL PERIOD - CASE REPORT

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5

SF 34%

LVO = 377 mL/kg/min

M-mode (LV)

Short axis view (LV)

Aorta Doppler

Middle Cerebral Artery Doppler

MV 23 cm/s

PDA flow was equally bidirectional



What would you do now?

1) Start dobutamine at 5 mcg/kg/min and titrate

2) Give another 10-20 ml/kg 0.9% saline bolus

3) No intervention and continue close monitoring

4) Start dopamine at 2.5 mcg/kg/min and titrate

5) Start epinephrine at 0.05 mcg/kg/min and titrate

15

20

25

30

35

40

3hr 9hr 33hr

MAP (mmHg)

-20

-100

1020

3040506070

80

3hr 9hr 33hr

LVO SVR MAP

% change



Patient presented with “hypotension” and without

indirect evidence of poor tissue perfusion.

U/S studies revealed increased cardiac output, low

SVR, and normal CBF pattern at 3 hours of age with

low SVR being the cause of cardiovascular compromise.

In this patient, cardiac compensatory mechanisms

ensured appropriate systemic and organ blood flow

despite low perfusion pressure

How fast to correct “hypotension” in ELBW neonates?

15

20

25

30

35

40

3hr 9hr 33hr

MAP (mmHg)

? ? ?

Seri I et al. Eur J Pediatr, 1984

19.09.2014

6


15

20

25

30

35

40

3hr 9hr 33hr

MAP (mmHg)

? ? ?



15

20

25

30

35

40

3hr 9hr 33hr

MAP (mmHg)

? ? ?



15

20

25

30

35

40

3hr 9hr 33hr

MAP (mmHg)

? ? ?

MBP = 42 mm Hg

MBP = 50 mm Hg


DA - 2 mcg/kg/min DA - 4 mcg/kg/min

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15

20

25

30

35

40

3hr 9hr 33hr

MAP (mmHg)

? ? ?

MBP = 42 mm Hg

MBP = 50 mm Hg


DA - 2 mcg/kg/min DA - 4 mcg/kg/minObservation is appropriate if comprehensive monitoring

of systemic and organ blood flow and tissue oxygenation

reveals no evidence of

• compromised tissue O2 delivery, or

• abnormal function


15

20

25

30

35

40

3hr 9hr 33hr

MAP (mmHg)

? ? ?

MBP = 42 mm Hg

MBP = 50 mm Hg


DA - 2 mcg/kg/min DA - 4 mcg/kg/minObservation is appropriate if comprehensive monitoring

of systemic and organ blood flow and tissue oxygenation

reveals no evidence of

• compromised tissue O2 delivery, or

• abnormal function

GETTING INFORMATION:

COMPREHENSIVE

MONITORING


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Sadaf Soleymani, MS

Hemodynamic Monitoring and Data Acquisition System

Patient

Monitoring

System #1

Computer

Data

Acquisition

System

Camera

Impedance

Electrical

Cardiometry

Modules for

Modules for

HR, BP,

SPO2, RR,

TCOM

Near Infrared

Spectroscopy

(NIRS)

Patient

Monitoring

System #2

(for additional

channels)

aEEG

Laser Doppler

(Peripheral BF)

Philips MP70:

Numeric: HR, BP, SPO2, TCOM, RR

Waveform: ECG wave, BP wave

ICON:

Cardiac

Output (CO)

INVOS:

Regional O2(rSO2)

Ventilators:

(AVEA/

Servo-i)

CPC Virtual ServerCPC Virtual Server

NICU Data Flow

Patient Monitor (MP70)Patient Monitor (MP70)

Bernoulli Multi Port BridgeBernoulli Multi Port Bridge

Bedside Monitors (Non-Routine )Bedside Monitors (Non-Routine )

1. It is suboptimal to start treatment when neonates become

symptomatic (increased mortality and morbidity)

2. Instead, we need to know, with reasonable certainty. what will

happen during the next 12 - 24 hours

3. Using genotypic and real-time phenotypic data for predictive

mathematical modeling, we hypothesize that we will be able to

• Understand developmental physiology and pathophysiology

• Characterize patient populations

• Design population-specific trials with the potential for improved

effectiveness and less toxicity

4. Challenges: Validity and quality of acquired data, large data

management, complexity of modeling, AI, machine learning

Our Approach Under Development:

Genotypic and Phenotypic Characterization of Patients

Genome Sequencing and Cardiorespiratory & Neurocritical Monitoring

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Our Approach Under Development:

Genotypic and Phenotypic Characterization of Patients

Genome Sequencing and Cardiorespiratory & Neurocritical Monitoring1. Hemodynamic Parameters: Heart rate, cardiac output and

stroke volume (EIV), blood pressure, calculated SVR, organ

blood flow (NIRS), peripheral blood flow (Laser Doppler),

oxygen saturation

2. Pulmonary Parameters: Respiratory rate,

transcutaneous CO2, tidal volume, PIP, PEEP, mean

airway pressure, FiO2 (additional parameters are being

considered)

3. Neurocritical Care Monitoring: aEEG, EEG, video

aEEGContinuously downloaded waveform and digital data format

OBJECTIVE #2 TREATMENT


Volume


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Dopamine2 mcg/kh/min

0.9% SalineBolus (15 min)

Mechanisms of Action of Vasoactive Medications: Volume

Effect of saline bolus in a 1-day old 36-week’s gestation neonate

Cardiovascular

Medications

Mechanisms of Action of Vasoactive

Medications

Receptor

TypeA1/A2^ A2 A1 A1/A2

DA1/DA

2

V1a

Location Vascular Vascular Cardiac Cardiac Vascular/Ca

rdiac Vascular

Vasoconstriction ++++ 0 0 0 0 ++++

Vasodilation 0 ++++ 0 0 ++++* 0

+ Inotropy 0 0 ++ ++++ +/++ 0

+ Chronotropy 0 0 0 ++++ 0 0

Cond. Velocity 0 0 0 ++++ 0 0

Cardiovascular Actions of Adrenergic and

Vascular Vasopressin Receptors

* = renal, mesenteric, coronary circulation > pulmonary circulation > extracranial vessels of head

^ = α2 receptors cause arterial vasodilation and venous vasoconstriction

Noori S, Seri, I. Clin Perinatol 39:221–238; 2012

19.09.2014

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Adrenergic, Dopaminergic and Vasopressin

Receptors

<1/<2 <<<< <2 <<<<<< <1 <<<<< <1/<2 DA1/DA2 V1aVascular Vascular Cardiac Cardiac Vascular/Cardiac Vascular

+ DOB’s efficacy is

independent of

affinity for ARs

++ DA also has

serotoninergic

actions

Mechanisms of Action of Vasopressors,

Inotropes, and Lusitropes

0

0/+

+++

++

++

+++

0

0

0

+

++

++

++

++

0

0

0

0

0

++++

++++

+++

++++

++++

0

0

0

0

0

0

++++

0

0

0

0

0

0

0

0

0

0

0

++++

0

0

++++

++++

++++

++++

+/0

0

0

0

0

* = milrinone, amrinone

**= sildenafil Noori S, Seri, I. Clin Perinatol 39:221–238; 2012

Phenylephrine

Norepinephrine

Epinephrine

Dopamine++

Dobutamine+

Isoprenaline

Vasopressin

PDE-III Inhibitors*

PDE-V Inhibitors**

1) Developmentally regulated differences in expression of

adrenergic receptors and intracellular signaling systems and

catecholamine metabolism

2) Down-regulation of adrenergic receptors and intracellular

signaling systems in critical illness

3) Developmentally regulated maturation of myocardium and

autonomic nervous system

4) Dysregulated release of local vasodilators (endogenous nitric

oxide, vasodilatory prostaglandins, etc.) and hormones

affecting vascular tone, adrenergic receptor recruitment and

coupling to effectors

Factors Affecting Hemodynamic Response to

Sympathomimetic Amines


1. There is evidence that treatment of hypotension and/or low

systemic perfusion improves blood pressure, systemic perfusion,

organ blood flow (CBF), urine output and lactic acidosis

2. However, there is very little evidence that treatment of

hypotension, systemic hypoperfusion or both improves clinically

relevant outcomes

3. Thus, we use vasopressor/inotropes, inotropes, lusitropes,

pulmonary vasodilators and steroids

• Based on blood pressure and indirect signs of perfusion and non-

continuously collected hemodynamic data;

• Without relevant clinical outcome data;

• Based on poorly understood principles of developmental

cardiovascular physiology of the transitional period, and

• Personal experience.

TREATMENT OF NEONATAL SHOCK

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Dopamine



Receptors



independent of

affinity for ARs

++ DA also has

serotoninergic

actions



0

0/+

+++

++

++

+++

0

0

0

+

++

++

++

++

0

0

0

0

0

++++

++++

+++

++++

++++

0

0

0

0

0

0

++++

0

0

0

0

0

0

0

0

0

0

0

++++

0

0

++++

++++

++++

++++

+/0

0

0

0

0



Phenylephrine

Norepinephrine

Epinephrine

Dopamine++

Dobutamine+

Isoprenaline

Vasopressin

PDE-III Inhibitors*

PDE-V Inhibitors**

0

10

20

30

40

50

60

70

80

90

100

0 0.5 1 3 4 5 8 10 12 15 18 20 22 25 30

Dopamine Dose (µg/kg/min)

Maxim

al Effect (%)

DA1 ββββ1 αααα

DA1 receptor = Renal blood flow

ββββ1 receptor = Cardiac index & heart rate

αααα receptor = Systemic vascular

resistance index and arterial pressure

D’Orio et al, Arch Int Physiol Biochim; 1986

Cardiovascular Effects of Escalating Doses of

Dopamine in Healthy Human Subjects

19.09.2014

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Dopamine Receptors

Renal, mesenteric & coronary

> pulmonary circulation, heart

• Vasodilation in kidneys#,intestine#, coronary arteries

• Increase in GFR#

• Direct renal tubular effects#

• Positive inotropy#

• Lung fluid clearance

• Endocrine effects#

≥ 2-4 µg/kg/min

* Without adrenoreceptor down-regulation; # Demonstrated effects in preterm neonates

Alpha Receptors

More homogenously distributed

• Vasoconstriction#


• Metabolic effects#


(direct and indirect)

• Positive chronotropy#

• Peripheral vasodilation


Dose-Dependent Cardiovascular, Renal and Endocrine

Effects of Dopamine in Neonates*

DOPAMINE

Beta Receptors


Seri I; J Pediatr 126:333-344, 1995; Seri I; J Perinatol 26:S8-S13, 2006; Noori S, Seri, I. Clin Perinatol 39:221–238; 2012

Dopamine Receptors

Renal, mesenteric & coronary

> pulmonary circulation, heart

• Vasodilation in kidneys#,intestine#, coronary arteries

• Increase in GFR#

• Direct renal tubular effects#


• Lung fluid clearance

• Endocrine effects#

≥ 2-4 µg/kg/min

* Without adrenoreceptor down-regulation# Demonstrated effects in preterm neonates

Alpha Receptors






(direct and indirect)




DOPAMINE

Beta Receptors


Seri I; J Pediatr 126:333-344, 1995; Seri I; J Perinatol 26:S8-S13, 2006

1. CARDIOVASCULAR EFFECTS OF DOPAMINE:

a. ↑ BP by increasing SVR and cardiac output (HR and SV)

b. Organ Blood Flow:

+ Cerebral: ↑ CBF only in “hypotensive” VLBW neonates+ SVC: No increase in SVC flow in one study using 2 doses without

titration to optimum effect

+ Mesenteric: Variable effect• Vasodilation in most patients after1st postnatal day• May cause vasoconstriction in some patients at higher doses

+ Renal: ↑ renal blood flow and GFR+ Pulmonary :

• No discernable effect with low or normal pulmonary flow

• ↓ pulmonary blood flow in neonates with a hsPDA• ↑ lung fluid clearance (not yet demonstrated in neonates)

+ Peripheral: ↑ lower leg blood flow and MABP

2. RENAL TUBULAR EFFECTS OF DOPAMINE:

↑ Na+, Pi , HCO-3 , H2O excretion, ↓ concentrating capacity

3. ENDOCRINE EFFECTS OF DOPAMINE:

↑ Renin-angiotensin without changing aldosterone↓ of TSH, prolactin and GH secretion and in TBG and seT4 levels

EpinephrineEpinephrine


19.09.2014

14


Receptors



independent of

affinity for ARs

++ DA also has

serotoninergic

actions



0

0/+

+++

++

++

+++

0

0

0

+

++

++

++

++

0

0

0

0

0

++++

++++

+++

++++

++++

0

0

0

0

0

0

++++

0

0

0

0

0

0

0

0

0

0

0

++++

0

0

++++

++++

++++

++++

+/0

0

0

0

0



Phenylephrine

Norepinephrine

Epinephrine

Dopamine++

Dobutamine+

Isoprenaline

Vasopressin

PDE-III Inhibitors*

PDE-V Inhibitors**




Cardiovascular Effects of Epinephrine

Neonates*

EPINEPHRINEEPINEPHRINE

• Positive inotropy# (direct)



(renal, mesenteric)


Alpha Receptors


Beta Receptors







EPINEPHRINE




(renal, mesenteric)


Alpha Receptors


Beta Receptors


1. Cardiovascular Effects:

a. ↑ BP by increasing SVR and cardiac output (heart rate and stroke volume)

b. Organ Blood Flow: ↑ CBF in “hypotensive” VLBW neonates

2. Metabolic Effects:

↑ lactate production due to ↑ glycogenolysis, and ↓ release and ↓ cellular actions of insulin

Cardiovascular Effects of Epinephrine Neonates*



19.09.2014

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Norepinephrine



Receptors



independent of

affinity for ARs

++ DA also has

serotoninergic

actions



0

0/+

+++

++

++

+++

0

0

0

+

++

++

++

++

0

0

0

0

0

++++

++++

+++

++++

++++

0

0

0

0

0

0

++++

0

0

0

0

0

0

0

0

0

0

0

++++

0

0

++++

++++

++++

++++

+/0

0

0

0

0



Phenylephrine

Norepinephrine

Epinephrine

Dopamine++

Dobutamine+

Isoprenaline

Vasopressin

PDE-III Inhibitors*

PDE-V Inhibitors**




NOREPINEPHRINENOREPINEPHRINE




(renal, mesenteric)


Alpha Receptors


Beta Receptors



a. ↑ BP by increasing SVR (↑↑↑) and cardiac output (↑↑) (heart rate and stroke volume)

b. Organ Blood Flow: ↑ pulmonary BF in neonates with PPHN

2. Metabolic Effects:

Usually clinicaly less significant

Cardiovascular Effects of Epinephrine Neonates*



19.09.2014

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Dobutamine



Receptors



independent of

affinity for ARs

++ DA also has

serotoninergic

actions



0

0/+

+++

++

++

+++

0

0

0

+

++

++

++

++

0

0

0

0

0

++++

++++

+++

++++

++++

0

0

0

0

0

0

++++

0

0

0

0

0

0

0

0

0

0

0

++++

0

0

++++

++++

++++

++++

+/0

0

0

0

0



Phenylephrine

Norepinephrine

Epinephrine

Dopamine++

Dobutamine+

Isoprenaline

Vasopressin

PDE-III Inhibitors*

PDE-V Inhibitors**

Mechanisms of Action of Dobutamine* Enantiomers


* Without adrenoreceptor down-regulation

19.09.2014

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• Decreased myocardial

compliance (diastolic)

• Vasoconstriction

DOBUTAMINE


• Decreased myocardial

compliance (diastolic)

• Improved myocardial QO2


• Peripheral vasodilation#

• Metabolic effects

Alpha Receptors


Beta Receptors



a. ↑ BP by increasing cardiac output (heart rate and stroke volume)

b. No change or a ↓ in SVR

c. Organ Blood Flow: ↑ CBF, renal and mesenteric BF in “hypotensive” preterm neonates

d. Might impair diastolic function (especially in

patients with myocardial hypertrophy

2. Metabolic Effects:Usually clinically insignificant

Cardiovascular Effects of Dobutamine Neonates*



Milrinone



Receptors



independent of

affinity for ARs

++ DA also has

serotoninergic

actions



0

0/+

+++

++

++

+++

0

0

0

+

++

++

++

++

0

0

0

0

0

++++

++++

+++

++++

++++

0

0

0

0

0

0

++++

0

0

0

0

0

0

0

0

0

0

0

++++

0

0

++++

++++

++++

++++

+/0

0

0

0

0



Phenylephrine

Norepinephrine

Epinephrine

Dopamine++

Dobutamine+

Isoprenaline

Vasopressin

PDE-III Inhibitors*

PDE-V Inhibitors**

19.09.2014

18

Modified from Chen et al. Pediatric Res 2009; 66:682-687

Crosstalk between Phosphodiesterase (PDE)-3 and PDE-5 in

Pulmonary Arteries

prostacyclinββββ-adrenoreceptor

stimulation

ATP

cAMP

cGMP

5’-AMP

5’-GMP

smooth muscle relaxationsmooth muscle relaxation vasodilation

NO

GTP

guanylate cyclase

adenylate cyclase

Ventilation with

iNO + 100% O2

↑↑↑↑↑↑↑↑↑↑↑↑↓↓↓↓↓↓↓↓↓↓↓↓

MilrinoneSildenafil

↑↑↑↑↑↑↑↑↑↑↑↑

↑↑↑↑↑↑↑↑↑↑↑↑PDE5

PDE3

PAST AND PRESENT COLLABORATORS

CHLA-USC faculty International Collaborations

Philipe Friedlich, MD, MEpi, MBA Barna Vasarhelyi, PhD

Shahab Noori, MD Tivadar Tulassay, MD, DSci

Rowena Cayabyab, MD Lola Stavroudis, MD

Mac Ebrahimi, MD Anita Aperia, MD

Pierre Wong, MD Ann-Christine Eklof, PhD

Bijan Siassi, MD Alejandro Bertorello, MD

Rangasamy Ramanathan, MD Gianni Celsi, MD

Frank van Bel

Petra Lemmers

Flora Wong

CHLA-USC fellows/residents National Collaborations

Shazia Bohmbal, MD Michael Wider, PhD (Somanetics)

Bonnie Tam, MD Sandra L Drake, PhD (Somanetics)

Amin Addie, MD Erin A Booth, PhD (Somanetics)

Karine Barzaghyen, MD Jackie Evans, MD

Soraya Abbasi, MD

CHLA-USC PhD students Jeffrey Gerdes, MD

Matt Borzage Barbara Ballermann, MD

Sadaf Soliemani Steven R Gullans, PhD

Barry Brenner

International FellowsRaul Nachar, MD

QUESTIONS?


19.09.2014

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Noori S, Seri I. Clin Perinatol

2012; 39:221-38;



2012; 39:221-38;


2012; 39:221-38;

19.09.2014

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2012; 39:221-38;


2012; 39:221-38;

neonatal shock: management of blood pressure, and systemic...

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