6/7/2012
CD
BL
Disclosure
Center for Developmental Biology of the Lung
Persistent Pulmonary Hypertension of the Newborn (PPHN)
Satyan Lakshminrusimha, MD
Associate Professor of Pediatrics
Chief, Division of Neonatology
University at Buffalo
Director, Center for Developmental Biology of the Lung (CDBL)
Pediatric Grand Rounds
June 8 2012
• Speaker’s Bureau – Ikaria
• Consultant – Ikaria
• Research support – Investigator initiated research grant through UB from Ikaria
– American Academy of Pediatrics, Neonatal Research Program
– National Institutes of Health – NHLBI (RHS), NICHD
• The use of sildenafil and milrinone for pulmonary hypertension are not currently approved in the newborn period.
Outline
Fetal Circulation
• Changing pattern of PPHN
• Pulmonary vascular transition at birth
– Normal fetal pulmonary circulation
– Transition to neonatal circulation
– Abnormal vascular transition and PPHN
Physiologic pulmonary hypertension
• Current pulmonary vasodilator management
–
–
–
–
Ventilator management
Surfactant
Optimal PO2
Nitric oxide
• PPHN resistant to iNO
• Future and potential pulmonary vasodilators
– Phosphodiesterase inhibitors
– Other agents
Placenta
Small Changes in PA Pressure Æ Significant Changes in Pulmonary Blood Flow
PAP < SBP
Normal Transition
Pulm hypertension resolved
Abnormal Transition
Persistent Pulmonary Hypertension/HRF
Pulmonary Blood Flow vs. Sys PA Pressure
PAP > SBP
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Critical Window
Etiology of HRF/ PPHN
• Transient tachypnea of Abnormal Transition
newborn (TTN)
PA Pressure
Irreversibility
• Aspiration syndromes ‐
Transitional
Zone from Normal
Transitional
Zone to Normal
Modified from Aschner JL et al Pediatric Pulmonary Hypertension: An Integrated View from Pediatric Subspecialists 2011
meconium or blood
• Congenital Diaphragmatic Hernia (CDH)
• HYaline membrane disease (RDS)
• PNEumonia / Sepsis
• Air leaks
Pneumothorax
Age
Case # 1 from 1998
• A 32 year old G4P3 mother is admitted in labor at 42 weeks gestation. Artificial rupture of membranes reveals thick meconium stained fluid. Post‐term Infant with “Pea‐soup Meconium)
• Baby’s mouth is suctioned at the perineum
• Noted to have some tachypnea but transferred to the nursery Variations in PVR and SVR During
Gestation - Human Fetus
Pulmonary Vascular Changes During Fetal and Postnatal Period
Post‐term
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Clinical Course
• An hour later, cyanosis and respiratory distress are noted. Pulse oximeter reading on the right foot is 79%.
Placed on an oscillator & 20 ppm
iNO
7.31/51/15/‐2.4
MHb – 0.8% 16 cm water MAP
Amp ‐ 45
11 Hz 100% O2
First ABG after intubation in the NICU 7.23/63/33/‐2.7
Infasurf & MAP increased to 25 cm water 20 ppm iNO
7.41/41/60/1.1 (MHb – 1.7%)
25 MAP
Amp ‐ 40
11 Hz 70% O2
#‡*ѭ҉
҈ᴓῷ
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Effect of Ventilation ‐Pulmonary Vascular Resistance (PVR) is Minimal at FRC
Surfactant and Pulmonary Hemodynamics
Low lung volume
High lung volume
Optimal lung volume at FRC
Keszler & Abubakar – Physiologic principles in Goldsmith & Karotkin –
Assisted ventilation of the neonate
Simmons DH et al, Circ. Res. 1961: 9, 465‐471
Kappa P et al, J Pediatrics 1993
Optimal PaO2 Level
Oxygen – Pulmonary Vasodilator
Women & Children’s Hospital of Buffalo – Intensive Care Nursery
Infant with PPHN
O2
82 140
O2.-
Atmospheric pO2 160 mmHg
Alveolar pO2 100 mmHg
Distributing Oxygen vs. Restricting Oxygen
Arterial pO2 90 mmHg
Intracellular pO2 1‐10 mmHg
Mitochondrial pO2 0.5 mmHg
Arteriolar pO2 70 mmHg
Capillary pO2 50 mmHg
Oxygen and PVR in Neonatal Lambs
3
Left Pulmonary Vascular Resistance (mmHg*ml‐1*kg*min‐1)
Purpose of the Circulatory System
2.5
Change point – 50 + 0.2 mmHg
2
1.5
1
0.5
0
0
50
100
150
200
250
300
350
Arterial PO2
400
450
500
550
600
Lakshminrusimha et al, Pediatric Research 2009
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Respiratory acidosis (pACO2) and metabolic acidosis worsen HPV
Normal pH and alkalosis –
metabolic or respiratory partially protect against HPV
2
Pulmonary Vascular Resistance (mmHg*mL1*kg*min)
Acidosis Exacerbates Hypoxic Vasoconstriction
Oxygen Saturation and PVR
PPHN _____________
1.8
Quartile range ------------
1.6
•
1.4
1.2
•
1
As oxygenation is labile in PPHN/ HRF, it is difficult to precisely maintain oxygen saturations in a specific range
Many clinicians “buffer” with higher PaO2
to avoid episodes of hypoxemia
0.8
0.6
0.4
0.2
0
Rudolph AM, Yuan S: Response of pulmonary vasculature to hypoxia and hydrogen ion changes, JCI 1966
Orchard CH et al, J Physiol 1983, 338 p 61‐74, Malik AB J Appl Physiol 1973
Methemoglobin
70-79 80-81 82-83 84-85 86-87 88-89 90-91 92-93 94-95 96-97 98-99 100
Oxygen Saturation (%)
Lakshminrusimha S et al, Pediatr Res. 2009 Nov;66(5):539‐44
Nitric Oxide Pathway
Interaction
Between Inhaled
Nitric Oxide &
Oxygen
Sheer stress, oxygen, ventilation & various
agonists
L-arginine
eNOS
L-citrulline
Endothelial Cell
NO
O2.-
GMP
cGMP
Peroxynitrite
OONO Reduced
Ca++
K+
OI at Initiation of NO (as a marker of prior oxygen exposure) and incidence of ECMO or 60
Death
50
% ECMO / death
Smooth
muscle cell
PDE5
sGC
Faraci and Didion, Vascular protection:
superoxide dismutase isoforms in the
vessel wall; Arterioscler Thromb Vasc
Biol. 2004
49.
Gupta
3
Pabalan
31
Cornfield
42.
6
NINOs 43
40
Roberts 43
30
Clark 36
Wessel 30
20
Davidson 24
10
Konduri (early iNO)
0
10
20
30
40
50
60
Oxygenation Index (at initiation of iNO)
Lakshminrusimha et al – Clinics in Perinatology (submitted)
Marriage made
in Heaven or
Hell?
Sarcoplasmic
Reticulum
19.
7Konduri (standard 25
iNO)
21
Finer ("high" dose)
Satyan
HRF Resistant to Inhaled NO
• Alveolar recruitment –
PEEP, HFV, Surfactant
• Avoid prolonged hyperoxic ventilation
• Remodeled pulmonary arteries – high pulsatility index
• ROS induced stimulation of PDE5 –
sildenafil
• ROS + NO induced stimulation of PDE3 and LV dysfunction with pulmonary venous hypertension –
milrinone
• Endothelin receptor antagonists
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Non-responder to Inhaled NO
Responder to Inhaled NO
Airway
obstruction
NO
NO
Responders – Higher Level of Methb/NO exposure Ratio
7
NO
NO
NO
Satyan
Poor delivery of NO to alveolus /
pulmonary circulation
Well
recruited
and
ventilated
alveoli
Adequate delivery of NO to
alveolus / pulmonary circulation
No contact with RBC
Contact with RBC
Low Methemoglobin / cumulative
NO exposure ratio
High Methemoglobin / cumulative
NO exposure ratio
Initial Methemoglobin(%) * 100/Cumulative NO exposure (ppm*h)
Diseased
alveoli
6
5
4
3
2
1
0
Responders
Non‐responders
Pabalan MJU, Nayak SP , Kumar VH, Ryan RM & Lakshminrusimha S ‐ J Perinatol 2009
Etiology of HRF
Avoid PEEP‐o‐phobia or MAP‐o‐phobia
• Transient tachypnea of newborn (TTN)
• Aspiration syndromes ‐
meconium or blood
• Congenital Diaphragmatic Hernia (CDH)
• HYaline membrane disease (RDS)
• PNEumonia / Sepsis
• Air leaks/ asphyxia
Pneumothorax
Case # 2 ‐ 2012
Preterm is less than 37 completed weeks gestation. Source: National Center for Health Statistics, final natality data. Retrieved June 6, 2012, from www.marchofdimes.com/peristats.
• 34 y old obese gestational diabetic mother
• C‐section delivery at 37 weeks gestation
• Niagara Falls
• Baby is grunting and tachypneic
• Requires 30% oxygen by hood but by 2 hours of age is on > 60% oxygen by hood and grunting with oxygen saturations – 90%
• Oxygen hood – increase to ~ 100% oxygen
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Guglani, Ryan, Lakshminrusimha, Transient tachypnea of newborn – Peds in Review
Normal Vaginal Delivery
Cesarean Delivery
Higher Proportion of PPHN Babies Delivered by C‐section
100
% of patients ‐ mode of delivery
90
80
70
C‐section with a trial of
labor
C‐section without
labor
Vaginal
60
50
40
30
20
10
0
Makihara et al Echocardiographic assessment of systolic time intervals in vaginal and cesarean delivered neonates, Am J Perinatology 1993 10 (1): 53‐57
100% Oxygen Hood – Without Positive Pressure
PPHN
Control
Hernandez‐Diaz – Risk factors for PPHN – Pediatrics 2007
Absorption Atelectasis
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Intubation and Surfactant
Mortality with ECMO by Gestational Age
Congenital Diaphragmatic Hernia (CDH)
• Incidence 1:2000 ‐ 3000 • 1500 babies born with CDH each year
• Mortality varies from 8‐80% depending on severity of lung hypoplasia
CDH Registry
Ramachandrappa A et al J Pediatrics 2011
Physiological Abnormalities
“Muscularization” of peripheral pulmonary arteries
Vascular hypoplasia
Alveolar hypoplasia
Pulmonary hypertension
Honeymoon Period
• The honeymoon period is the time after birth when the newborn with CDH seems to be in a good status primarily before (usually around 12 hours) oxygenation and circulation is breaking down. • An explanation for this is very likely exhausting pumping force of left ventricle, which is too small and not developed sufficiently
LV hypoplasia – direct compression vs. decreased inflow
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Inhaled NO in Infants with CDH: NINOS
Trial
RV‐dependent systemic circulation
Decreases with decreasing PVR
High LA pressure and pulmonary venous hypertension
100
% Death or Need for ECMO
End of Honeymoon
90
80
70
60
Control
50
iNO
40
30
20
10
0
Death
Reduced LV mass and function fails with increasing afterload
RV dependent systemic circulation – PGE1
Milrinone
Inhaled NO
ECMO
Death or ECMO
Courtesy: Dr. Steinhorn RH
Pediatrics 1997;99:838-845
Milrinone Pharmacokinetics
Cleared mainly by kidneys
Clogged drain (dysfunctional LV)
Inhaled NO with Left Ventricular Dysfunction
Dose in PPHN – 50 mcg/kg load followed by 0.33 to 1 mcg/kg/min
T ½ = 0.8h
T ½ = 3.7h
T ½ = 4.1h
T ½ = 10.3h
Kinsella JP et al Pulmonary vasodilator therapy in CDH Seminars in Perinatology 2005
Chest radiograph illustrating severe bronchopulmonary dysplasia (BPD) with pulmonary
hypertension
BPD and Pulmonary Hypertension
Exercise (bottling)
And sleep
Infection ‐ nosocomial
Mildly elevated PVR at baseline
Exaggerated hypoxic PVR response
25‐37% or infants with BPD
Oligohydramnios
and/or IUGR
Stress
Surgery e.g., hernia
Rule out airway abnormalities –
subglottic stenosis, tracheomalacia, vocal cord paralysis
Decreased angiogenesis and alveolar surface area
Abman, S. H. Neoreviews 2011;12:e645-e651
Copyright ©2011 American Academy of Pediatrics
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Critical Window
Candidates for Screening Echos
PA Pressure
Irreversibility
Abnormal Transition
Transitional
Zone from Normal
Transitional
Zone to Normal
Early echocardiograms
Modified from Aschner JL et al Pediatric Pulmonary Hypertension: An Integrated View from Pediatric Subspecialists 2011
Acquired PV stenosis
• History of oligohydramnios or IUGR
• Extreme prematurity < 26 weeks GA
• Persistent need for respiratory support
• Oxygen need disproportionate to lung disease
• Recurrent cyanotic episodes
• Elevated PaCO2
sPAP measured only in 61% and severity accurately assessed in 47%; Only 58% of patients with PH on cath had evidence of PH on echo
Age
Treatment options ‐ NO
PDE5 Inhibitors • Target SpO2 – 92 to 95% (higher than the range commonly used in premature infants)
• Sleep study – severity and type (obstructive, central, mixed) of hypoxemia
• Reflux and aspiration
• Inhaled NO
PDE 5 Inhibition
Endothelial Cell
100% Oxygen Ventilation
eNOS
O2.‐
NO
100% Oxygen Ventilation
sGC
GMP
cGMP
PDE5
O2.‐
Sildenafil
Relaxation
Smooth Muscle Cell
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Oxygenation Index Over Time
Sildenafil –
Pharmaco
kinetics in Neonates with HRF
35
Oxygenation Index
30
*
25
20
15
10
5
0
0
1
2
4
8
12
24
36
48
60
72
84
96
108
120 132
144
Time (Hours)
Based on Steinhorn RH, Kinsella JP et al Journal of Pediatrics 2009
Steinhorn RH, Kinsella JP et al Journal of Pediatrics 2009
Summary
• PPHN is associated with elevated PVR and V Q mismatch.
• Pulmonary vascular resistance is minimal at FRC and increases with both hypoinflation and hyperinflation. Provide adequate PEEP to maintain optimal lung inflation.
• Use of high concentrations of oxygen without positive pressure increases risk for absorption atelectasis and PPHN
• Milrinone and sildenafil are alternate agents with therapeutic potential in the management of PPHN.
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