Optimizing Oxygen Delivery in the Preterm Newborn

1
Pathophysiology and Treatment of Neonatal Shock
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
Pathophysiology and Treatment of Neonatal Shock
Definition of Hypotension and Normal Blood
Pressure

• Hypotension is best defined by the absence of
  adequate perfusion pressure to vital organs
• Normal (autoregulatory) blood pressure range
• developmentally regulated (gestational- and
  postnatal-age dependent)
• may be affected by the underlying pathophysiology
• not known in the neonate

3
Pathophysiology and Treatment of Neonatal Shock
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
4
Pathophysiology and Treatment of Neonatal Shock
Phases of Neonatal Shock

• Compensated phase
• ? Heart rate ? Urine output but no change in
  blood pressure blood flow maldistributed to
  vital organs (brain, heart, adrenal glands)
• Uncompensated phase
• ? Heart rate ? Urine output ? Blood pressure
  blood flow decreases in all organs, tissue
  hypoperfusion and acidemia develop
• Irreversible phase
• Irreversible cellular damage

5
Pathophysiology and Treatment of Neonatal Shock
Neonatal Shock

1. Blood pressure (BP) is an acceptable measure of
   tissue perfusion in the neonate with
   uncompensated shock as long as the normal range
   of BP is known
2. By definition, BP is a poor measure of tissue
   perfusion in compensated shock
3. As vital organ assignment appears to be
   developmentally regulated, in the ELBW neonate
   during the first 24 hours of extrauterine life
   normal BP does not necessarily indicate normal
   brain blood flow

6
Pathophysiology and Treatment of Neonatal Shock
Factors Influencing Treatment

1. Gestational age
2. Postnatal age
3. Underlying pathophysiology and severity of
   illness
4. Etiology/type/phase of shock
5. Pharmacodynamics and pharmakokinetics of
   vasoactive agent(s)
6. Presence or absence of inflammatory response
   syndrome, adrenal insufficiency, state of
   adrenergic receptor expression

7
Pathophysiology and Treatment of Neonatal Shock
Etiology of Neonatal Shock

• Hypovolemic shock
• Inadequate circulating blood volume
• 2. Cardiogenic shock
• Myocardial dysfunction
• 3. Distributive shock
• Failure of vasoregulation with or without
  dysfunction of the immature myocardium

8
Pathophysiology and Treatment of Neonatal
Shock 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

9
Pathophysiology and Treatment of Neonatal Shock
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)

10
Pathophysiology and Treatment of Neonatal Shock
Estimation of Renal Blood Flow in ELBW neonates
11
Pathophysiology and Treatment of Neonatal Shock
Approaches to Organ Blood Flow measurements SVC
Blood Flow
Measurement of SVC Blood Flow in ELBW neonates
during the first DOL
Evans et al Arch Dis Child 2000 82 F182
12
Pathophysiology and Treatment of Neonatal Shock
Evaluating Blood Flow in the Fetus
13
Sensory-Motor Pathways Contra-lateral,
Bi-lateral Thalamus
Pathophysiology and Treatment of Neonatal Shock
Evaluating Brain Development by fMRI in the
Neonate
39/42w GA/PCA male
26/39w GA/PCA female
39/42w GA/PCA male
40/43w GA/PCA male
(a,b) Contra-lateral sensory-motor (c)
Bi-lateral deactivation, (d) Bilateral
deactivation in thalamus
14
Hypovolemia
Pathophysiology and Treatment of Neonatal Shock
Neonatal Shock
15
Pathophysiology and Treatment of Neonatal Shock
Primary Etiology HypovolemiaRelationship
Between BP and Blood Volume in Preterm Neonates
Mean BP
Mean BP
Systolic BP
Blood Pressure (mm Hg)
Blood Volume (mL/kg)
Blood Volume (mL/kg)
Blood Volume (mL/kg)
Wright et al, Arch Dis Child 1994
Bauer et al, Arch Dis Child 1993
Barr et al, J Pediatr 1977
16
Pathophysiology and Treatment of Neonatal Shock
Primary Etiology Hypovolemia Randomized
Controlled Trial of Colloid and Crystalloid
Infusions in Hypotensive Preterm Infants
5 Albumin (n32) ? 59 required pressor
support Normal Saline (n31) ? 58 required
pressor support
Mean Blood Pressure (mm Hg)
MAP x FiO2 (cm H2O)
Mean Blood Pressure (mm Hg)
MAP x FiO2 (cm H2O)
2 8 24 48
2 8 24 48
Time (hours)
Time (hours)
So et al, Arch Dis Child 1997
17
Pathophysiology and Treatment of Neonatal Shock
Primary Etiology Hypovolemia Randomized
Controlled Trial of Colloid and Crystalloid
Infusions in Hypotensive Neonates
Preterm Neonates Term Neonates


Blood Pressure


Oca et al, J Perinatol 23473 2003
18
Impaired Regulation of Vascular Tone (with or
without myocardial dysfunction)
Pathophysiology and Treatment of Neonatal Shock
Neonatal Shock
19
Pathophysiology and Treatment of Neonatal Shock
Dopamine
20
Pathophysiology and Treatment of Neonatal Shock
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

21
Pathophysiology and Treatment of Neonatal
Shock 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
22
Pathophysiology and Treatment of Neonatal Shock
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)

23
Pathophysiology and Treatment of Neonatal
Shock Effect of Dopamine on Blood Pressure,
Central Venous Pressure, Heart Rate and TcpO2 in
Preterm Neonates
Seri et al, Eur J Pediatr, 1984
24
Neonatal Shock Blood PressureDopamine Therapy
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
25
Pathophysiology and Treatment of Neonatal
Shock 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
26
Pathophysiology and Treatment of Neonatal Shock
Effect of Dopamine on the Resistance Index in
the MCA in Hypotensive Preterm and Term Neonates
Seri et al, Pediatr Res 1993
27
Pathophysiology and Treatment of Neonatal Shock
Changes in HbD (CBF), MAP and SaO2 in a 1-day-old
28-week GA preterm infant. Subsequent HU/S
remained normal
Changes in HbD (CBF), MAP and SaO2 in a 1-day-old
27-week GA preterm infant. Subsequent HU/S
revealed PVL
Changes in HbD (cerebral intravascular
oxygenation HbO2-Hb) correlate with changes in
CBF (Tsuji et al Pediatrics 2000 106625)
28
Pathophysiology and Treatment of Neonatal
Shock 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
29
Pathophysiology and Treatment of Neonatal
Shock 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
30
Pathophysiology and Treatment of Neonatal
Shock 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
31
Pathophysiology and Treatment of Neonatal Shock
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)
32
Pathophysiology and Treatment of Neonatal Shock
Mean 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)
33
Pathophysiology and Treatment of Neonatal Shock
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)
34
Pathophysiology and Treatment of Neonatal Shock
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)
35
Impaired Regulation of Vascular Tone (with or
without myocardial dysfunction)
Pathophysiology and Treatment of Neonatal Shock
Neonatal Shock
36
Pathophysiology and Treatment of Neonatal Shock
Epinephrine
37
Pathophysiology and Treatment of Neonatal Shock
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

38
Pathophysiology and Treatment of Neonatal Shock
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
39
Impaired Regulation of Vascular Tone (with or
without myocardial dysfunction)
Pathophysiology and Treatment of Neonatal Shock
Neonatal Shock
40
Pathophysiology and Treatment of Neonatal Shock
Neonatal Septic or Vasodilatory Shock
Vasopressin
41
Pathophysiology and Treatment of Neonatal Shock
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

42
Pathophysiology and Treatment of Neonatal Shock
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

43
Pathophysiology and Treatment of Neonatal Shock
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

44
Pathophysiology and Treatment of Neonatal Shock
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)
45
Myocardial Dysfunction
Pathophysiology and Treatment of Neonatal Shock
Neonatal Shock
46
Pathophysiology and Treatment of Neonatal Shock
Dobutamine
47
Pathophysiology and Treatment of Neonatal Shock
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

48
Pathophysiology and Treatment of Neonatal Shock
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)
49
Pathophysiology and Treatment of Neonatal
Shock 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
50
Pathophysiology and Treatment of Neonatal Shock
Use of Lusitropes in Neonatal Shock
Milrinone
51
Pathophysiology and Treatment of Neonatal Shock
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

52
Pathophysiology and Treatment of Neonatal Shock
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
53
Pathophysiology and Treatment of Neonatal Shock
Milrinone
Crit Care Med 231907, 1995
54
Pathophysiology and Treatment of Neonatal Shock
Decreased Sensitivity of the Cardiovascular
System to Catecholamines in the Critically Ill
Neonate
Hydrocortisone
55
Pathophysiology and Treatment of Neonatal Shock
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
56
Pathophysiology and Treatment of Neonatal Shock
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
57
Pathophysiology and Treatment of Neonatal Shock
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)

58
Pathophysiology and Treatment of Neonatal Shock
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
59
Pathophysiology and Treatment of Neonatal Shock
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)
60
Pathophysiology and Treatment of Neonatal Shock
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
61
Pathophysiology and Treatment of Neonatal Shock
Questions?