Optimizing Oxygen Delivery in the Preterm Newborn

1
Mechanisms of Action and Use of Inotropes and
Vasopressors in the Neonate
Istvan Seri MD PhD USC Division of Neonatal
Medicine Womens and Childrens Hospital LAC/USC
Medical Center and Children Hospital Los
Angeles Keck School of Medicine University of
Southern California Los Angeles, CA
2
Hemodynamic Actions of Pressors, Lusitropes and
Inotropes in Neonates Blood Pressure Range Is
Gestational- and Postnatal-Age Dependent
Lower Limit of the 80 Confidence Interval of BP
in Neonates ( First 3 Postnatal Days)
37-43 weeks
33-36 weeks
Mean Blood Pressure (mm Hg)
27-32 weeks
23-26 weeks
0 12 24 36 48 60 72 Age (h)
90 of neonates will have a mean BP value at
or above the lower limit of the confidence
interval
Nuntnarumit et al, Clin Perinatol 1999
3
Hemodynamic Actions of Pressors, Lusitropes and
Inotropes in Neonates Clinical Presentations
Requiring Different Approach to Treatment

• Hypotensive ELBW neonate (lt28 weeks) during the
  first postnatal day
• Hypotensive ELBW/LBW neonate with a
  hemodynamically significant PDA (during the first
  week)
• Hypotensive preterm or term neonate with
  perinatal depression
• Hypotensive ELBW/LBW neonate with relative
  adrenal insufficiency and vasopressor/inotrope
  resistance
• Any hypotensive neonate with systemic
  inflammatory response (sepsis, NEC)

4
Hemodynamic Actions of Pressors, Lusitropes and
Inotropes in Neonates Pressors, Lusitropes,
Intorpes and Steroids Used in Neonates

1. Dopamine
2. Dobutamine
3. Epinephrine
4. Norepinephrine
5. Vasopressin
6. Isuprenaline
7. Phosphodiesterase III Inhibitors (Milrinone,
   Amrinone)
8. Hydrocortisone or Dexamethasone

5
Impaired Regulation of Vascular Tone (with or
without myocardial dysfunction)
Hemodynamic Actions of Pressors, Lusitropes and
Inotropes in Neonates Neonatal Shock
6
Hemodynamic Actions of Pressors, Lusitropes and
Inotropes in Neonates Dopamine
Cardiovascular Effects
7
Hemodynamic Actions of Pressors, Lusitropes and
Inotropes in Neonates Mechanisms of Action of
Dopamine

• DOBs efficacy is independent of affinity for
  ARs
• DA also has serotoninergic actions on the
  periphery

• Adrenergic, Dopaminergic and Vasopressin
  Receptors
• ?1/?2 ???? b2 ???????a1 ??????b1/?2 DA1/DA2
  V1a
• Vascular Vascular Cardiac
  Cardiac Vascular/Cardiac
  Vascular

Phenylephrine 0
0 0
0 Norepinephrine 0/
0
0 Epinephrine
0
0 Dopamine

0 Dobutamine /0
0
0 Isuprenaline 0
0
0 Vasopressin 0 0
0 0
0
PDE-III Inhibitors 0 0
0 0 0 0 PDE-V
Inhibitors 0 0 0
0 0 0

8
Hemodynamic Actions of Pressors, Lusitropes and
Inotropes in Neonates Effects of Dopamine
Infusion on Healthy Human Subjects
DA1 b1 a
Maximal Effect ()
DA1 receptor Renal blood flow b1 receptor
Cardiac index heart rate a receptor
Systemic vascular resistance index and arterial
pressure
Dopamine Dose (µg/kg/min)
DOrio et al, Arch Int Physiol Biochim 1986
9
Hemodynamic Actions of Pressors, Lusitropes and
Inotropes in Neonates Factors Affecting the
Hemodynamic Response to Dopamine and Other
Sympathomimetic Amins

1. Developmentally regulated level of expression of
   adrenergic receptors and intracellular signaling
   systems
2. Down-regulation of the adrenergic receptors and
   intracellular signaling systems in critical
   illness
3. Developmentally regulated maturity of the
   myocardium
4. Dysregulated release of local vasodilators
   (endogenous nitric oxide, vasodilatory
   prostaglandins, etc)

10
Hemodynamic Actions of Pressors, Lusitropes and
Inotropes in Neonates Dose-response Curves of
Dopamine on Heart Rate and Blood Pressure in
Preterm Neonates
Systolic and Diastolic Blood Pressure
Dose-response Curves in Hypotensive Preterm
Neonates
Heart Rate Dose-response Curve in Hypotensive
Preterm Neonates
0 2 4 8
(µg/kg/min)
0 2 4 8
(µg/kg/min)
Seri et al, Eur J Pediatr 1984
11
Hemodynamic Actions of Pressors, Lusitropes and
Inotropes in Neonates Effect of Dopamine on Blood
Pressure, Central Venous Pressure, Heart Rate and
TcpO2 in Preterm Neonates (2)
Seri et al, Eur J Pediatr, 1984
12
Hemodynamic Actions of Pressors, Lusitropes and
Inotropes in Neonates Effect of Dopamine on Blood
Pressure, Central Venous Pressure, Heart Rate and
TcpO2 in Preterm Neonates (2)
Seri et al, Eur J Pediatr, 1984
13
Hemodynamic Actions of Pressors, Lusitropes and
Inotropes in Neonates Estimation of Renal Blood
Flow in ELBW neonates
14
Dopamine-Induced Increase in Doppler Velocity
Profile in the Renal Artery in a Preterm Neonate
15
Hemodynamic Actions of Pressors, Lusitropes and
Inotropes in Neonates Pulsatility and
Resistance Indeces

1. Pulsatility Index Peak Systolic Velocity - End
   Diastolic Velocity / Mean Velocity (PI PSFV
   - EDFV / MFV)
2. Resistance Index (RI) Peak Systolic Velocity -
   End Diastolic Velocity / Peak Systolic Velocity
   PSFV - EDFV / PSFV x 100

16
Hemodynamic Actions of Pressors, Lusitropes and
Inotropes in Neonates Effect of dopamine (2.5-15
µg/kg/min) on systemic BP and MCA PI
Mean Blood Pressure Middle
Cerebral Artery (MCA) PI (mm Hg)
(PI
Pulsatility Index)

(23/23) (23/23)
Control Dopamine
Control Dopamine
Seri et al, J Pediatr, 1998
17
Hemodynamic Actions of Pressors, Lusitropes and
Inotropes in Neonates Effect of Dopamine on the
Resistance Index in the MCA in Hypotensive
Preterm and Term Neonates
Seri et al, Pediatr Res 1993
18
Hemodynamic Actions of Pressors, Lusitropes and
Inotropes in Neonates Effect of dopamine (2.5-15
µg/kg/min) on systemic BP and RA PI
Mean Blood Pressure Renal Artery (RA)
PI (mm Hg)
(PI Pulsatility Index)
(a)
(b)


(23/23) (23/23)
Control Dopamine
Control Dopamine
Seri et al, J Pediatr, 1998
19
Hemodynamic Actions of Pressors, Lusitropes and
Inotropes in Neonates Effect of dopamine (2.5-15
µg/kg/min) on renal artery PI in relation to the
drug-induced BP changes
Mean Blood Pressure
Renal Artery PI
(mm Hg)
(PI Pulsatility Index)
Plt0.05 vs Control



Plt0.05 vs lower panel Plt0.05 vs Control
(15/23)
(15/23)
Plt0.05 vs Control

(8/23)
(8/23)
Control
Dopamine Control
Dopamine
Seri et al, J Pediatr, 1998
20
The dopamine-induced increase in urine output (a)
and the percent change in the renal artery PI
versus baseline renal artery PI (b)

y 2.0511 - 13.453x R2 0.551
(a)
(b)
Urine Output (mL/kg/h)
Change in Renal Artery PI

23/23
20/23
Control Dopamine
Baseline Renal Artery PI
Study Periods
Seri et al, J Pediatr 133728 1998
21
Hemodynamic Actions of Pressors, Lusitropes and
Inotropes in Neonates Effect of dopamine (5
µg/kg/min) on systemic BP and right renal artery
PI(b) following indomethacin administration
Mean Blood Pressure Renal Artery PI
(mm Hg) (PI
Pulsatility Index)
(a)
(b)


(20/20) (20/20)
(23/23) (23/23)
Indo IndoDopamine
Indo IndoDopamine
Seri et al, J Perinatol, 2002
22
Hemodynamic Actions of Pressors, Lusitropes and
Inotropes in Neonates Effect of dopamine (2.5-15
µg/kg/min) on systemic BP and superior mesenteric
artery PI during 1st DOL (No Indo) and 2nd DOL
(Indo)
Superior Mesenteric Artery PI
Superior Mesenteric Artery PI No
Indomethacin
Indomethacin
(b)
(a)


(21/23) (18/20)
Control Dopamine
Indo Indo Dopamine
Seri et al, J Pediatr, 1998
23
Hemodynamic Actions of Pressors, Lusitropes and
Inotropes in Neonates Dose-dependent Effects of
Dopamine in Preterm Neonates
Vasodilation in kidneys, intestine, coronary
arteries Increase in GFR Direct renal tubular
effects Positive inotropy Endocrine effects
Dopamine Receptors
gt 0.5 µg/kg/min
Alpha Receptors
Vasoconstriction Positive
inotropy Metabolic effects
DOPAMINE
gt 2-4 µg/kg/min
Positive inotropy (direct and
indirect) Positive chronotropy
Peripheral vasodilation Metabolic effects
Beta Receptors
gt 4-8 µg/kg/min
Without adrenoreceptor down-regulation
24
Hemodynamic Actions of Pressors, Lusitropes and
Inotropes in Neonates Treatment of Low Systemic
Blood Flow (Dopamine versus Dobutamine)

34
35

2
-1
P lt 0.05 vs Dopamine
P lt 0.05 vs Dopamine
(Osborn et al J Pediatr 2002 140183)
25
Hemodynamic Actions of Sympathomimetic Agents and
Steroids in Neonates Blood Pressure and SVC flow
in ELBW/LBW neonates during the first 24 hours
SVC flow is used as surrogate of cerebral
blood flow
(Modified from Osborn et al Arch Dis Child 2004)
26
Hemodynamic Actions of Pressors, Lusitropes and
Inotropes in Neonates Relationship of Cerebral
FOE to BP and Left Ventricular Output in Preterm
Neonates during the First Three Postnatal Days
Kissack et al. Pediatr Res 2004 55400
Mean Blood Pressure (mm Hg)
Left Ventricular Output (mL/kg/min)
Cerebral Fractional Oxygen Extraction
Left Ventricular Output (mL/kg/min)
Mean Blood Pressure (mm Hg)
Left Ventricular Output (mL/kg/min)
Mean Blood Pressure (mm Hg)
Lower pCO2 values correlate with higher cerebral
FOE (i.e. decreased BF in the hemispheres)
27
Hemodynamic Actions of Pressors, Lusitropes and
Inotropes in Neonates Proposed BP Range for
Autoregulation of CBF in Neonates gt3 days old
Adults
Neonates
Cerebral Blood Flow
Cerebral Blood Flow
Mean Blood Pressure (mm Hg)
Mean Blood Pressure (mm Hg)
(Arch Dis Child 1996 74F63 Clin Perinatol
1997 24531 Ment Retard Dev Disab Res Rev 1997
33)
28
Hemodynamic Actions of Pressors, Lusitropes and
Inotropes in Neonates Dopamine
Renal Effects
29
Hemodynamic Actions of Pressors, Lusitropes and
Inotropes in Neonates Renal Effects of Dopamine
in Preterm InfantsEvidence for a Direct Tubular
Effect (1)
No significant changes in blood pressure in 30
normotensive preterm infants
Plt0.05 vs Control





Percent of Control
(0.5-2 mg/kg/min)
Tulassay, Seri et al, Int J Pediatr Nephrol 1983
30
Hemodynamic Actions of Pressors, Lusitropes and
Inotropes in Neonates Renal Effects of Dopamine
in Preterm InfantsEvidence for a Direct Tubular
Effect (2)

Plt0.05 vs Control




Percent of Control
Seri et al, Pediatr Res 1993
31
Hemodynamic Actions of Pressors, Lusitropes and
Inotropes in Neonates Renal Effects of Dopamine
in Preterm Infants Indirect Evidence for
Increased Medullary Blood Flow
No significant changes in blood pressure in 30
normotensive preterm infants

Plt0.05 vs Control




Percent of Control

(0.5-2 mg/kg/min)
Tulassay, Seri et al, Int J Pediatr Nephrol 1983
32
Hemodynamic Actions of Pressors, Lusitropes and
Inotropes in Neonates Changes in Renal and
Duodenal Blood Flow during Infusion of Dopamine,
LY (a DA2 Receptor Agonist) and DA S-SP (DA2
Receptor Blocker)
Duodenal Blood Flow
Renal Blood Flow
Plt0.05 vs Control
Plt0.05 vs Control




Duodenal Blood Flow (ml/g tissue/min)
Renal Blood Flow (ml/g tissue/min)
Seri et al, Acta Physiol Scand 1987
33
SFP - FFP PUFAA
SFP
FFP
CORTEX
PUFAA
AA
EA
Glomerulus
MEDULLA
SFP stop-flow pressure FFP free-flow
pressure PUFAA glomerular capillary
ultrafiltration pressure
Micropuncture Assessment of Single Nephron GFR
34
Hemodynamic Actions of Pressors, Lusitropes and
Inotropes in Neonates Effect of Dopamine on
Single Nephron GFR in Rats

Dopamine (1 µg/kg/min)
SNGFR ( Increase vs Control)
Time (minutes)
Seri et al, Am J Physiol 1989
35
Hemodynamic Actions of Pressors, Lusitropes and
Inotropes in Neonates Renal Effects of
DopamineMechanism of the Increase in Glomerular
Filtration Rate (1)
SFP - FFP PUFAA

Plt0.05 vs Control

Pressure (mm Hg)
Stop-Flow Free-Flow Glomerular
Pressure Pressure Ultrafiltration
Pressure
Control Dopamine
Seri et al, Am J Physiol 1989
36
Hemodynamic Actions of Pressors, Lusitropes and
Inotropes in Neonates Renal Effects of
DopamineMechanism of the Increase in Glomerular
Filtration Rate (2)
IN VITRO
Dopamine
Control
Afferent and efferent vasodilation
PT
PT
EA
AA
EA
AA
IN VIVO
Dopamine
Dopamine
PT
Afferent vasodilation
renin - angiotensin
efferent vasodilation
AA
EA
37
Hemodynamic Actions of Pressors, Lusitropes and
Inotropes in Neonates Effect of Dopamine on
Plasma Renin Activity and Aldosterone
Concentration in Preterm Neonates
Plasma Renin Activity Plasma
Aldosterone Concentration
(ng/mL/h)
(pg/mL)

Plt0.05 vs Control
Sulyok, Seri et al, Eur J Pediatr 1985
38
Hemodynamic Actions of Pressors, Lusitropes and
Inotropes in Neonates Renal Effects of Dopamine
in Preterm InfantsEvidence for Glomerular and
Direct Tubular Effects (1)


Plt0.05 vs Control



Percent of Control
(0.5-2 mg/kg/min)
Seri et al, Pediatr Res 1993
39
Hemodynamic Actions of Pressors, Lusitropes and
Inotropes in Neonates Renal Effects of Dopamine
in Preterm InfantsEvidence for Inhibition of the
Sodium Pump (1)
Effect of L-Dopa (10-4 M, ) and Vehicle ( )
on Ouabain-Sensitive O2-Consumption Rate (QO2) at
Different Sodium Concentrations in the Medium in
the Presence of Nystatin in Rat Renal Proximal
Tubule Cells
InsetLineweaver-Burk plot of data. L-Dopa
decreases Vmax and K0.5 to the same extent
indicating that dopamine acts as an uncompetitive
inhibitor of the Na, K-ATPase enzyme.
Seri et al, AJP, 1998
40
Hemodynamic Actions of Pressors, Lusitropes and
Inotropes in Neonates Renal Effects of Dopamine
in Preterm InfantsEvidence for Inhibition of the
Sodium Pump (2)
Effect of L-Dopa (10-4 M) and Ouabain (10-2 M) on
Net K Fluxes Rat Renal Proximal Tubule Cells
2
1
Seri et al, AJP, 1998
Rate of cellular K loss induced by dopamine (1)
and ouabain (2)
41
Hemodynamic Actions of Pressors, Lusitropes and
Inotropes in Neonates Renal Effects of Dopamine
in Preterm Infants Cellular Mechanisms of the
Dopamine-Induced Na-K,ATPase Inhibition
DOPAMINE

DA
Gp
1
PLC
AC
Gs
-
Gi
DA

2

DOPAMINE
PKC
AC Adenylate cyclase DA1 Dopamine1
receptor DA2 Dopamine2 receptor DARPP32
Dopamine and cAMP regulated
phosphoprotein Gi AC inhibitory G
protein Gp PLC stimulatory G
protein Gs AC stimulatory G protein PKA
Protein Kinase A PKC Protein Kinase C PLA2
Phospholipase A2 PLC Phospholipase C PP-1
Protein phosphatase-1

PKA

cAMP


DARPP
32
PLA 2
-
PP-1
3 Na


PK-A/C
-
-
-
?
?
P
i
Aperia, Bertorello Seri, 1987 Seri et al,
1988 Meister et al, 1989 Seri et al, 1990
Ibara et al, 1993
-
2 K
42
.
K
K
K
K
X
X
K
K
Na
Na
Na
Na
Na
Na
X
Na
H
X
K
X
K
Na
Pi
Na
X
K
Na
X
K
Na
Na
CORTEX
K
Na
H2O
ADH
K
Na
Dopamine Inhibits Na,K-ATPase, Na/H
exchanger, Na/Pi cotransporter, ADH-sensitive
H2O channel Dopamine Increases RBF, GFR The
net effect of dopamine ? Na, Pi , HCO-3 , H2O
excretion, ? concentrating capacitity
X
K
Na
MEDULLA
X
K
H2O
ADH
Na
43
Dose-dependent Effects of Dopamine in Preterm
Infants
Vasodilation in kidneys, intestine, coronary
arteries Increase in GFR Direct renal tubular
effects Positive inotropy Endocrine effects
Dopamine Receptors
gt 0.5 µg/kg/min
Alpha Receptors
Vasoconstriction Positive
inotropy Metabolic effects
DOPAMINE
gt 2-4 µg/kg/min
Positive inotropy (direct and
indirect) Positive chronotropy
Peripheral vasodilation Metabolic effects
Beta Receptors
gt 4-8 µg/kg/min
Without adrenoreceptor down-regulation
44
Neonatal Shock Blood Pressure
Decreased Sensitivity of the Cardiovascular
System to Catecholamines (1)
In critical illness, down-regulation of the
cardiovascular adrenergic receptors and signaling
pathways occurs
45
Neonatal Shock Blood Pressure
Down-Regulation of Adrenergic Receptors
Ligand
?
Minutes
Phosphorytlation Sequestration Minutes of
mM agonist exposure Rapidly reversible
(minutes) Down-Regulation Hours of agonist
exposure Decreased mRNA stability Decreased
transcription Reversal of down-regulation
requires new protein synthesis
G
s
AC
Hours
G
s
COOH
Ligand
P
P
Phosphorylation (PKA, bARK)
P
COOH
P
Lysosome
Sequestration
?
AC Adenylate Cyclase bAR b
Adrenoreceptor bARK b Adrenoreceptor Kinase Gs
Stimulatory G protein PKA Protein
Kinase A
Minutes
Down-Regulation
Hausdorff, Garon, Lefkowitz 1990
46
Primary Etiology C. Impaired Vascular Tone
Regulation Myocardial Dysfunction Treatment
Hydrocortisone
47
Neonatal Shock Blood Pressure
Effects of Steroids on Down-Regulation of
Adrenoreceptors and Signaling Pathways

• Genomic Effects of Steroids
• Increase in the rate of a- and b-adrenoreceptor
  and adenylate cyclase gene transcription
• Increased density of a- and b-adrenoreceptors
  and enhanced expression of adenylate
  cyclase
• Inhibition of iNOS gene activation and
  cytokine/ chemokine production
• (Ann Rev Physiol 53497 1991)

48
Neonatal Shock Blood Pressure
Decreased Sensitivity of the Cardiovascular
System to Catecholamines (2)
Relative or absolute adrenal insufficiency of the
critically ill preterm and term neonate
Watterberg et al Pediatrics 1999
49
Neonatal Shock Blood Pressure
Effect of hydrocortisone on mean blood pressure
at 2 and 4 hours after the first dose of the drug
Mean Blood Pressure
N23
Plt0.05 vs Control
mm Hg


Pre-HC HC 2 h HC 4 h
Seri et al Pediatrics 2001
50
Neonatal Shock Blood Pressure
Effects of Steroids on Cardiovascular Function
Non-Genomic Effects of Steroids
1. Inhibition of catechol-0-methyltransferase
(COMT) and norepinephrine reuptake (Circ Res
24383, 1969)

• 2. Increase in intracellular calcium
  availability
• physiologic concentrations of aldosterone and
  pharmacologic doses of
• cortisol via the PLC-PKC pathway (J
  Mol Med 73439,1995)
• glucocorticoid-induced calmodulin-dependent
  activation of calcium
• channels (J Steroid Bioch Mol Biol
  55185, 1995)

3. Improved capillary integrity due to decreased
cytokine/chemokine production (J Clin Invest
6813, 1981)
51
Neonatal Shock Blood Pressure
Changes in Blood Pressure and Pressor/Inotrope
Requirement in Preterm Neonates with Shock in
Response to Hydrocortisone
Dopamine Administration
Mean Blood Pressure
N23
N23




23
23

23
23
µg/kg/min
mm Hg
23

23

Pre-HC HC HC HC HC
HC (2h) (4h)
(6h) (12h) (24h)
Pre-HC HC HC HC HC
HC (2h) (4h)
(6h) (12h) (24h)
Plt0.05 vs Control
Plt0.05 vs Control N number of patients
treated
Seri et al Pediatrics 2001
52
Impaired Regulation of Vascular Tone (with or
without myocardial dysfunction)
Hemodynamic Actions of Pressors, Lusitropes and
Inotropes in Neonates Neonatal Shock
53
Hemodynamic Actions of Pressors, Lusitropes and
Inotropes in Neonates
Epinephrine
54
Hemodynamic Actions of Pressors, Lusitropes and
Inotropes in Neonates Mechanisms of Action of
Epinephrine

• DOBs efficacy is independent of affinity for
  ARs
• DA also has serotoninergic actions on the
  periphery

• Adrenergic, Dopaminergic and Vasopressin
  Receptors
• ?1/?2 ???? b2 ???????a1 ??????b1/?2 DA1/DA2
  V1a
• Vascular Vascular Cardiac
  Cardiac Vascular/Cardiac
  Vascular

Phenylephrine 0
0 0
0 Norepinephrine 0/
0
0 Epinephrine
0
0 Dopamine

0 Dobutamine /0
0
0 Isuprenaline 0
0
0 Vasopressin 0 0
0 0
0
PDE-III Inhibitors 0 0
0 0 0 0 PDE-V
Inhibitors 0 0 0
0 0 0

55
Hemodynamic Actions of Pressors, Lusitropes and
Inotropes in Neonates
Effect of the Addition of Epinephrine to
Dopamine/Dobutamine on BP and Urine Output in
Preterm Neonates with Shock
Mean Blood Pressure
Urine Output
N11
N11

Plt0.05 vs Control


mL/kg/hour
mm Hg
Plt0.05 vs Control
DA/DB EPI (6 h)
DA/DB EPI (1 h)
DA/DB EPI (6 h)
DA/DB
DA(DB)
Tan, Evans, Seri Pediatr Res 1999
56
Impaired Regulation of Vascular Tone (with or
without myocardial dysfunction)
Hemodynamic Actions of Pressors, Lusitropes and
Inotropes in Neonates Neonatal Shock
57
Hemodynamic Actions of Pressors, Lusitropes and
Inotropes in Neonates Neonatal Septic or
Vasodilatory Shock
Vasopressin
58
Hemodynamic Actions of Pressors, Lusitropes and
Inotropes in Neonates Mechanisms of Action of
Vasopressin

• DOBs efficacy is independent of affinity for
  ARs
• DA also has serotoninergic actions on the
  periphery

• Adrenergic, Dopaminergic and Vasopressin
  Receptors
• ?1/?2 ???? b2 ???????a1 ??????b1/?2 DA1/DA2
  V1a
• Vascular Vascular Cardiac
  Cardiac Vascular/Cardiac
  Vascular

Phenylephrine 0
0 0
0 Norepinephrine 0/
0
0 Epinephrine
0
0 Dopamine

0 Dobutamine /0
0
0 Isuprenaline 0
0
0 Vasopressin 0 0
0 0
0
PDE-III Inhibitors 0 0
0 0 0 0 PDE-V
Inhibitors 0 0 0
0 0 0

59
Hemodynamic Actions of Pressors, Lusitropes and
Inotropes in Neonates Regulation of Vascular
Smooth Muscle Tone
Landry Oliver 2001 N Eng J Med 345588
60
Hemodynamic Actions of Pressors, Lusitropes and
Inotropes in Neonates Septic ShockVasodilation
(low systemic vascular resistance)

1. Down-regulation of cardiovascular adrenergic
   receptors and signaling pathways (decreased
   sensitivity to catecholamines)
2. Relative or absolute adrenal insufficiency
   (decreased sensitivity to catecholamines)
3. Increased nitric oxide synthesis
4. Nitric oxide-independent activation of soluble
   guanylate cyclase (increased production of CO,
   OH- by bacterial endotoxin)
5. Vasopressin deficiency
6. Activation of KATP and KCa channels

61
Hemodynamic Actions of Pressors, Lusitropes and
Inotropes in Neonates Neonatal Septic or
Vasodilatory ShockVasopressin (1)

• Mechanisms of Action
• V1a receptor stimulation
• Baroreceptor inactivation in sepsis/autonomic
  failure enhances vasopressin-induced
  vasoconstriction
• Potentiation of vasopressor effects of
  catecholamines
• Direct inactivation of KATP channels in vascular
  smooth muscle
• AVP blunts NO- and ANP-induced increases in cGMP
• AVP inhibits the function of iNOS
• Organ-specific heterogeinity of vascular
  responsiveness at low doses, AVP stimulates
  oxytocin receptor-induced endothelial production
  of NO in the brain and coronary arteries

62
Hemodynamic Actions of Pressors, Lusitropes and
Inotropes in Neonates Neonatal Septic or
Vasodilatory ShockVasopressin (1)
Experience with vasopressin in critically ill
neonates Small number of newborns with
vasodilatory shock following cardiac
surgery (Rosenzweig et al. Intravenous
arginine-vasopressin in children with
vasodilatory shock after cardiac surgery.
Circulation 1999 100II-182)
63
Myocardial Dysfunction
Hemodynamic Actions of Pressors, Lusitropes and
Inotropes in Neonates Neonatal Shock
64
Hemodynamic Actions of Pressors, Lusitropes and
Inotropes in Neonates
Dobutamine
65
Hemodynamic Actions of Pressors, Lusitropes and
Inotropes in Neonates Mechanisms of Action of
Dobutamine

• DOBs efficacy is independent of affinity for
  ARs
• DA also has serotoninergic actions on the
  periphery

• Adrenergic, Dopaminergic and Vasopressin
  Receptors
• ?1/?2 ???? b2 ???????a1 ??????b1/?2 DA1/DA2
  V1a
• Vascular Vascular Cardiac
  Cardiac Vascular/Cardiac
  Vascular

Phenylephrine 0
0 0
0 Norepinephrine 0/
0
0 Epinephrine
0
0 Dopamine

0 Dobutamine /0
0
0 Isuprenaline 0
0
0 Vasopressin 0 0
0 0
0
PDE-III Inhibitors 0 0
0 0 0 0 PDE-V
Inhibitors 0 0 0
0 0 0

66
Hemodynamic Actions of Pressors, Lusitropes and
Inotropes in Neonates Treatment of Hypotension
(1)(Dopamine versus Dobutamine)
Gestational Age 27 (23-33) Weeks


Control Dopamine Dobutamine

Mean Blood Pressure (mm Hg)
n 20
n 20
Control Control
Dopamine Dobutamine
5 (5-10) µg/kg/min
10 (5-15) µg/kg/min

Plt0.05 vs Control Plt0.05 vs
Dobutamine
(Greenough and Emery, 1993)
67
Hemodynamic Actions of Pressors, Lusitropes and
Inotropes in Neonates Treatment of Hypotension
(2)(Dopamine versus Dobutamine)
Change in Mean Blood Pressure
Treatment Failure
Plt0.05 vs Dopamine
DA DOB Treatment
failure 0 5 Success with lt
10 µg/kg/min 30 22

(mm Hg)
n31
n32
Mean Gestational Age 28.5 Weeks Plt0.05 vs
Dopamine
Dobutamine Dopamine
(Klarr et al, 1994)
Rocourt 2004
68
Hemodynamic Actions of Pressors, Lusitropes and
Inotropes in Neonates Treatment of Hypotension
(3)(Dopamine versus Dobutamine - Meta-analysis)

• Four trials met inclusion criteria
• Randomized controlled trials comparing the
  effects of DA to DOB for the treatment of
  systemic arterial hypotension
• GA lt37 weeks and PA lt28 days
• Results
• No difference in neonatal mortality, incidence of
  PVL or severe P/IVH between the DA- and
  DOB-treated groups
• DA more successful in treating hypotension with
  less treatment failure
• No difference in left ventricular output or
  tachycardia between the DA and DOB groups
• None of the studies reported the incidence of
  adverse neurodevelopmental outcome
• Conclusions
• DA is more effective than DOB in the short-term
  treatment of neonatal hypotension
• In the absence of data confirming long-term
  benefit and safety of DA compared to DOB, no firm
  recommendations made regarding the choice of drug
  to treat neonatal hypotension

Subhedar N Cochrane Library Vol 2 2000
Rocourt 2004
69
Hemodynamic Actions of Pressors, Lusitropes and
Inotropes in Neonates Cardiovascular Effects of
Dobutamine in 13 Neonates with Gestational Age of
27-42 Weeks and Birth Weight of 850-4900 g


Percent Change from Baseline
Plt0.05 vs baseline
Dobutamine Infusion Rate (µg/kg/min)
Martinez et al, Pediatrics 8947 1993
Rocourt 2004
70
Hemodynamic Actions of Pressors, Lusitropes and
Inotropes in Neonates Cardiac Function,
Systemic Vascular Resistance and Mean Arterial
Blood Pressure in Preterm Neonates
Cardiac Output (mL/min/kg) Stroke
Volume (mL/kgx100) Heart Rate (Beats/min) SVR (m
m Hg/L/min/kg) Mean Arterial Blood Pressure (mm
Hg)

Plt0.05 vs No Inotropics Group Plt0.05
vs other groups



(Lopez et al. Pediatr Cardiol 1997 18292)
Measurements were made in 23 normotensive preterm
neonates with RDS on no inotropic support (No
Inotropics Group) 16 RDS patients receiving 9 1
µg/kg/min of dopamine (Dopamine Group) and 14
RDS patients receiving11 1 µg/kg/min of dopamine
and 9 1 µg/kg/min of dobutamine
(DopamineDobutamine Group).
Rocourt 2004
71
Hemodynamic Actions of Pressors, Lusitropes and
Inotropes in Neonates Cardiovascular Effects of
Dopamine and Dobutamine in Preterm Neonates with
Gestational Age lt 32 Weeks
Left Ventricular Output (ml/kg/min)
Mean Blood Pressure (mm Hg)
Systemic Vascular Resistance (dynes/sec/cm5/m2)







Plt0.05 vs Control Plt0.05 vs Dopamine
Plt0.05 vs Control Plt0.05 vs Dobutamine
Plt0.05 vs Control Plt0.05 vs Dobutamine
C DA DB
N20 Dopamine 12 µg/kg/min Dobutamine 17
µg/kg/min
Roze et al, Arch Dis Child 1993
72
Hemodynamic Actions of Pressors, Lusitropes and
Inotropes in Neonates Use of Lusitropes in
Neonatal Shock
Milrinone
73
Hemodynamic Actions of Pressors, Lusitropes and
Inotropes in Neonates Mechanisms of Action of
Milrinone

• DOBs efficacy is independent of affinity for
  ARs
• DA also has serotoninergic actions on the
  periphery

• Adrenergic, Dopaminergic and Vasopressin
  Receptors
• ?1/?2 ???? b2 ???????a1 ??????b1/?2 DA1/DA2
  V1a
• Vascular Vascular Cardiac
  Cardiac Vascular/Cardiac
  Vascular

Phenylephrine 0
0 0
0 Norepinephrine 0/
0
0 Epinephrine
0
0 Dopamine

0 Dobutamine /0
0
0 Isuprenaline 0
0
0 Vasopressin 0 0
0 0
0
PDE-III Inhibitors 0 0
0 0 0 0 PDE-V
Inhibitors 0 0 0
0 0 0

74
Hemodynamic Actions of Pressors, Lusitropes and
Inotropes in Neonates Use of Lusitropes in
Neonatal ShockMilrinone
Experience with milrinone in the critically ill
neonate Small number of newborns with
low-output cardiac syndrome following cardiac
surgery 1. Chang AC et al. Milrinone systemic
and pulmonary hemodynamic effects in neonates
after cardiac surgery. Crit Care Med 231907,
1995 2. Hoffman et al. Efficacy and safety of
milrinone in preventing low cardiac output
syndrome in infants and children after corrective
surgery for congenital heart disease. Circulation
107996, 2003
75
Hemodynamic Actions of Pressors, Lusitropes and
Inotropes in NeonatesMilrinone
Crit Care Med 231907, 1995
76
Hemodynamic Actions of Pressors, Lusitropes and
Inotropes in Neonates Decreased Sensitivity of
the Cardiovascular System to Catecholamines in
the Critically Ill Neonate
Hydrocortisone
77
Hemodynamic Actions of Pressors, Lusitropes and
Inotropes in Neonates Down-Regulation of
Adrenergic Receptors
Ligand
?
Minutes
Phosphorytlation Sequestration Minutes of
mM agonist exposure Rapidly reversible
(minutes) Down-Regulation Hours of agonist
exposure Decreased mRNA stability Decreased
transcription Reversal of down-regulation
requires new protein synthesis
G
s
AC
Hours
G
s
COOH
Ligand
P
P
Phosphorylation (PKA, bARK)
P
COOH
P
Lysosome
Sequestration
?
AC Adenylate Cyclase b AR b
Adrenoreceptor b ARK b Adrenoreceptor Kinase Gs
Stimulatory G protein PKA Protein
Kinase A
Minutes
Down-Regulation
Hausdorff, Garon, Lefkowitz 1990
78
Hemodynamic Actions of Pressors, Lusitropes and
Inotropes in Neonates
Effects of Steroids on Down-Regulation of
Adrenoreceptors and Signaling Pathways

• Increase in the rate of a- and b-adrenoreceptor
  and adenylate cyclase gene transcription
• Increased density of a- and b-adrenoreceptors
  and enhanced expression of adenylate cyclase
• Inhibition of iNOS gene activation and
  cytokine/chemokine production

Genomic Effects of Steroids
Ann Rev Physiol 53497 1991
79
Hemodynamic Actions of Pressors, Lusitropes and
Inotropes in Neonates
Relative or Absolute Adrenal Insufficiency and
Developmental Hypopituitarism in Preterm Neonates

1. Several studies have suggested the importance of
   adrenal function for survival and decreased
   morbidity in the ELBW neonate (Scott and
   Watterberg Pediatr Res 37112, 1995 Korte et al,
   J Pediatr 128 257, 1996 Watterberg et al,
   Pediatrics 1041258, 1999)
2. Indirect evidence also suggests the role of
   developmentally-regulated hypopituitarism in
   mortality and morbidity in the ELBW neonate
   (Scott and Cimino, J Perinatol 24429, 2004)

80
Hemodynamic Actions of Pressors, Lusitropes and
Inotropes in Neonates Effect of hydrocortisone
on mean blood pressure at 2 and 4 hours after the
first dose of the drug
Mean Blood Pressure
N23
Plt0.05 vs Control
mm Hg


Pre-HC HC 2 h HC 4 h
Seri et al Pediatrics 2001
81
Hemodynamic Actions of Pressors, Lusitropes and
Inotropes in Neonates Changes in Blood Pressure
and Pressor/Inotrope Requirement in Preterm
Neonates with Shock in Response to Hydrocortisone
Dopamine Administration
Mean Blood Pressure
N23
N23




23
23

23
23
µg/kg/min
mm Hg
23

23

Pre-HC HC HC HC HC
HC (2h) (4h)
(6h) (12h) (24h)
Pre-HC HC HC HC HC
HC (2h) (4h)
(6h) (12h) (24h)
Plt0.05 vs Control
Plt0.05 vs Control N number of patients
treated
Seri et al Pediatrics 2001
82
Hemodynamic Actions of Pressors, Lusitropes and
Inotropes in Neonates Effects of Steroids on
Cardiovascular Function
Non-Genomic Effects of Steroids
1. Inhibition of catechol-0-methyltransferase
(COMT) and norepinephrine reuptake (Circ Res
24383, 1969)

• 2. Increase in intracellular calcium
  availability
• physiologic concentrations of aldosterone and
  pharmacologic doses of
• cortisol via the PLC-PKC pathway (J
  Mol Med 73439,1995)
• glucocorticoid-induced calmodulin-dependent
  activation of calcium
• channels (J Steroid Bioch Mol Biol
  55185, 1995)

3. Improved capillary integrity due to decreased
cytokine/chemokine production (J Clin Invest
6813, 1981)
83
Hemodynamic Actions of Pressors, Lusitropes and
Inotropes in Neonates Changes in Blood
Pressure, Left Ventricular Output, Systemic
Vascular Resistance and Dopamine Requirement in
Preterm Neonates with Shock in Response to
Hydrocortisone (HC)
HC
HC
HC
HC
N12 no PDA Dopamine gt 15 µg/kg/min dobutamine
and/or epinephrine
84
Hemodynamic Actions of Pressors, Lusitropes and
Inotropes in Neonates Changes in Heart Rate,
Shortening Fraction, MCA and Renal Artery PI in
Preterm Neonates with Shock in Response to
Hydrocortisone (HC)
HC
HC
HC
HC
N12 no PDA Dopamine gt 15 µg/kg/min dobutamine
and/or epinephrine
85
Hemodynamic Actions of Pressors, Lusitropes and
Inotropes in Neonates
Questions?