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
Management of Blood Pressure, and Systemic and Organ Blood Flow
OBJECTIVE #1 DEFINITION OF SHOCK
Management of Blood Pressure, and Systemic and Organ Blood Flow
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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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
2. Compensated Shock:
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)
2. Compensated Shock:
↓↓↓↓ 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
↔
2. Compensated Shock:
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
Noori S, unpublished data – shown with permission
HYPOTENSION DURING THE TRANSITIONAL PERIOD - CASE REPORT
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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
Noori S, unpublished data – shown with permission
HYPOTENSION DURING THE TRANSITIONAL PERIOD - CASE REPORT
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
Noori S, unpublished data – shown with permission
HYPOTENSION DURING THE TRANSITIONAL PERIOD - CASE REPORT
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
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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
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
How fast to correct “hypotension” in ELBW neonates?
15
20
25
30
35
40
3hr 9hr 33hr
MAP (mmHg)
? ? ?
MBP = 42 mm Hg
MBP = 50 mm Hg
Seri I et al. Eur J Pediatr, 1984
DA - 2 mcg/kg/min DA - 4 mcg/kg/min
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How fast to correct “hypotension” in ELBW neonates?
15
20
25
30
35
40
3hr 9hr 33hr
MAP (mmHg)
? ? ?
MBP = 42 mm Hg
MBP = 50 mm Hg
Seri I et al. Eur J Pediatr, 1984
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
How fast to correct “hypotension” in ELBW neonates?
15
20
25
30
35
40
3hr 9hr 33hr
MAP (mmHg)
? ? ?
MBP = 42 mm Hg
MBP = 50 mm Hg
Seri I et al. Eur J Pediatr, 1984
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
Management of Blood Pressure, and Systemic and Organ Blood Flow
19.09.2014
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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
Management of Blood Pressure, and Systemic and Organ Blood Flow
Volume
Management of Blood Pressure, and Systemic and Organ Blood Flow
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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
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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
Noori S, Seri, I. Clin Perinatol 39:221–238; 2012
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
Management of Blood Pressure, and Systemic and Organ Blood Flow
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**
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
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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#
• Positive inotropy#
• Metabolic effects#
• Positive inotropy#
(direct and indirect)
• Positive chronotropy#
• Peripheral vasodilation
• Metabolic effects#
Dose-Dependent Cardiovascular, Renal and Endocrine
Effects of Dopamine in Neonates*
DOPAMINE
Beta Receptors
More homogenously distributed
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#
• 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#
• Positive inotropy#
• Metabolic effects#
• Positive inotropy#
(direct and indirect)
• Positive chronotropy#
• Peripheral vasodilation
• Metabolic effects#
DOPAMINE
Beta Receptors
More homogenously distributed
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
Management of Blood Pressure, and Systemic and Organ Blood Flow
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**
• Vasoconstriction#
• Positive inotropy#
• Metabolic effects#
Cardiovascular Effects of Epinephrine
Neonates*
EPINEPHRINEEPINEPHRINE
• Positive inotropy# (direct)
• Positive chronotropy#
• Peripheral vasodilation
(renal, mesenteric)
• Metabolic effects#
Alpha Receptors
More homogenously distributed
Beta Receptors
More homogenously distributed
* Without adrenoreceptor down-regulation; # Demonstrated effects in preterm neonates
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
• Vasoconstriction#
• Positive inotropy#
• Metabolic effects#
EPINEPHRINE
• Positive inotropy# (direct)
• Positive chronotropy#
• Peripheral vasodilation
(renal, mesenteric)
• Metabolic effects#
Alpha Receptors
More homogenously distributed
Beta Receptors
More homogenously distributed
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*
* Without adrenoreceptor down-regulation; # Demonstrated effects in preterm neonates
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
19.09.2014
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Norepinephrine
Management of Blood Pressure, and Systemic and Organ Blood Flow
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**
• Vasoconstriction#
• Positive inotropy#
• Metabolic effects#
NOREPINEPHRINENOREPINEPHRINE
• Positive inotropy# (direct)
• Positive chronotropy#
• Peripheral vasodilation
(renal, mesenteric)
• Metabolic effects#
Alpha Receptors
More homogenously distributed
Beta Receptors
More homogenously distributed
1. Cardiovascular Effects:
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*
* Without adrenoreceptor down-regulation; # Demonstrated effects in preterm neonates
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
19.09.2014
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Dobutamine
Management of Blood Pressure, and Systemic and Organ Blood Flow
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**
Mechanisms of Action of Dobutamine* Enantiomers
Noori S, Seri, I. Clin Perinatol 39:221–238; 2012
* Without adrenoreceptor down-regulation
19.09.2014
17
• Positive inotropy#
• Decreased myocardial
compliance (diastolic)
• Vasoconstriction
DOBUTAMINE
• Positive inotropy# (direct)
• Decreased myocardial
compliance (diastolic)
• Improved myocardial QO2
• Positive chronotropy#
• Peripheral vasodilation#
• Metabolic effects
Alpha Receptors
More homogenously distributed
Beta Receptors
More homogenously distributed
1. Cardiovascular Effects:
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*
* Without adrenoreceptor down-regulation; # Demonstrated effects in preterm neonates
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
Milrinone
Management of Blood Pressure, and Systemic and Organ Blood Flow
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**
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?
Management of Blood Pressure, and Systemic and Organ Blood Flow
19.09.2014
19
Noori S, Seri I. Clin Perinatol
2012; 39:221-38;
Management of Blood Pressure, and Systemic and Organ Blood Flow
Noori S, Seri I. Clin Perinatol
2012; 39:221-38;
Noori S, Seri I. Clin Perinatol
2012; 39:221-38;
19.09.2014
20
Noori S, Seri I. Clin Perinatol
2012; 39:221-38;
Noori S, Seri I. Clin Perinatol
2012; 39:221-38;