Download Approaches to the Management of Pulmonary Hypertension

Persistent Pulmonary Hypertension of
the Newborn
Arthur E. D’Harlingue, M.D.
Director of Neonatology
Children’s Hospital & Research Center Oakland
[email protected]
Educational Objectives
• Discuss the initial evaluation and diagnosis of
pulmonary artery hypertension.
• Describe some of the underlying causes and
pathophysiology of pulmonary hypertension.
• Discuss the management of pulmonary artery
hypertension including the use of iNO and other
therapies.
Disclosures
• No conflicts of interests to report
• Will discuss some non-FDA approved uses
of medications/treatments
Incidence and mortality from neonatal
pulmonary hypertension
• 6.8/1000 live births
• Most common cause is meconium aspiration
• ~10-20% mortality despite high-frequency
ventilation, surfactant, nitric oxide, and ECMO
• ~ 40% non-responder rate with nitric oxide
• Higher mortality when these therapies are
unavailable
Related terminology……
• Pulmonary hypertension
• Persistence of the fetal circulation
• Persistent pulmonary hypertension of the
newborn (PPHN)
Critical signals in transition at birth
• Mechanical distention of the lung
• Decrease in PCO2
• Increase in PO2
– Associated increase in endothelial NOS and COX-1
• Above factors result in increase in pulmonary
blood flow and improvement in oxygenation
• Failure of this transition can results in pulmonary
artery hypertension and right to left shunting
Transitional Circulation
Fetus
• PA pressure
• Pulm blood flow
• Oxygen tension
• PDA
Newborn
Transitional Circulation
• PA pressure
Fetus
High
Newborn
LOW
• Pulm blood flow
Low
HIGH
• Oxygen tension
Low
HIGH
• PDA
Open
CLOSES
Transitional Circulation-PPHN
• PA pressure
Fetus
High
• Pulm blood flow
Low
• Oxygen tension
Low
• PDA
Open
PPHN
Transitional Circulation-PPHN
• PA pressure
Fetus
High
PPHN
HIGH
• Pulm blood flow
Low
LOW
• Oxygen tension
Low
LOW
• PDA
Open
OPEN
Persistent Fetal Circulation
Normal Heart
Pulmonary Hypertension
PA
Ao
Pulmonary Hypertension
Preductal Sp02
HIGH
Postductal Sp02
PA
Ao
LOW
Pathophysiology of neonatal
pulmonary hypertension
• Parenchymal lung disease
– Primary disease process contributes to pulmonary
hypertension, maladaptation of the lung to a disease
process
• Meconium aspiration syndrome
• Lung hypoplasia
– Smaller surface area for gas exchange
– Associated vascular abnormalities
• Congenital diaphragmatic hernia
Pathophysiology of neonatal
pulmonary hypertension
• Maldevelopment of the lung
– Abnormal pulmonary vasculature and anatomy
• Alveolar capillary dysplasia
– Remodeling of the pulmonary vasculature
• Premature closure of PDA
• Obstruction to pulmonary venous return
– Secondary changes to pulmonary vasculature
• TAPVR
Histologic Changes in PPHN
Abnormal Muscularization in PPHN
Nitric oxide (NO) and prostacyclin (PG) signaling pathways in regulation of vascular tone
Steinhorn, R. H et al. Neoreviews 2007;8:e14-e21
Copyright ©2007 American Academy of Pediatrics
Regulation of the Relaxation of Vascular Smooth Muscle by Nitric Oxide
Griffiths M and Evans T. N Engl J Med 2005;353:2683-2695
Disorders associated with
pulmonary hypertension
• Meconium aspiration syndrome
• Persistent pulmonary hypertension of the
newborn
– Absent or mild parenchymal disease
– Trisomy 21, infants of diabetic mother
• Bacterial pneumonia - group B strep
• Viral pneumonitis - enteroviruses
Disorders associated with
pulmonary hypertension
• Alveolar capillary dysplasia
• Pulmonary venous obstruction
– Total anomalous pulmonary venous return
• Premature closure of fetal ductus arteriosus
– Maternal prostaglandin synthesis inhibitors:
ibuprofen, indomethacin, naproxen
• Hyperviscosity syndrome
Pulmonary hypoplasia: etiologies
•
•
•
•
Congenital diaphragmatic hernia
Cystic adenomatoid malformation
Prolonged premature rupture of membranes
Renal dysplasia and fetal compression
(Potter’s syndrome)
• Fetal hydrops
Maternal (SSRI) and neonatal pulmonary
artery hypertension
• Excess of pulmonary hypertension cases
among mothers on SSRI (selective
serotonin reuptake inhibitors)
– Serotonin: pulmonary vasoconstrictor
– Pulmonary smooth muscle proliferation
– Decrease in NO production
N Engl J Med 2006;354:579-87
Late causes of pulmonary hypertension
• Post-op cardiac patients
– L to R shunt lesions (reactive post-op PA hypertension)
– TAPVR (PA hypertension may persist post-op)
• Bronchopulmonary dysplasia
– Tends to occur with the most severe BPD
– May lead to right heart failure
– Tends to improve as the BPD improves
• Chronic hypercarbia
• Superimposed infections
• Bordatella pertussis pneumonia
Diagnosis of pulmonary hypertension
• Clinical
– Hypoxemia despite respiratory support
– Pre/post ductal saturation difference
– May be associated with poor cardiac output
• Echocardiogram:
–
–
–
–
–
Elevated PA pressures
R to L shunting at PFO and/or PDA
Tricuspid regurgitation
Septal flattening
RV +/- LV dysfunction
Initial management of the newborn
with pulmonary hypertension
• Correct hypovolemia and support BP
– Critical role of cardiac output and systemic BP
• Correct metabolic acidosis
– Metabolic acidosis contributes to pulmonary
vasoconstriction
• Correct any electrolyte imbalances,
hypocalcemia, or hypoglycemia
Initial management of the newborn
with pulmonary hypertension
• Correct anemia
– Improve oxygen carrying capacity
• Correct polycythemia, if present
• Intubation and ventilation
– Adequate lung volume
– Role for high frequency ventilation
• Oxygen to reverse hypoxia
– Avoid prolonged hyperoxia
Disease Components
•
•
•
•
Airway
Alveolar
Pulmonary Vascular
Myocardial
Treatment of Pulmonary Hypertension:
Rationale for Old Approach
• Hypoxia causes pulmonary vasoconstriction
• Alkalosis/hypocarbia prevent pulmonary
vasoconstriction
• Therefore:
– Keep PO2 high (> 100)
– Keep pH high (> 7.45)
– Keep PCO2 low (20s)
Risks of Hyperventilation
•
•
•
•
Air leak
Alveolar damage, capillary leak
Decreased cardiac output
Decreased cerebral blood flow
Effects of Alkalosis
Alkalosis:
Sustained vs. Acute Effects
• Newborn piglets with hypoxia-induced pulmonary
hypertension
• Acute (20 min) resp alkalosis (25 torr) decreased
hypoxia-induced increase in PVR
• Sustained (70 min) respiratory alkalosis did not
attenuate subsequent hypoxia-induced pulmonary
hypertension
• After stopping sustained (70 min) resp alkalosis,
there was an increased PVR response to hypoxia
Gordon, Pediatr Research 46:735, 1999
CV Effects of Hypocarbia
• Normal 5-10 day old dogs
– 2 hrs of hypo-CO2 (22+2) vs nl-CO2
•
•
•
•
40% decrease in cerebral blood flow
25% decrease in myocardial blood flow
Variable decrease in SVR and BP
Trend to decreased cardiac output, esp in
2nd hour
Cartwright, Pediatr Research 18:685, 1984
Hypocapnea and PVL
• Review of 799 babies born < 28 wks
• Factors predisposing to periventricular
leukomalacia
• Hypocapnea in first day was a major risk
factor
– Odds Ratio 1.7
– Highest in babies without other predisposing
factors
Dammann, Pediatr Res 49:388, 2001
Pulmonary Vascular Resistance
Lung Volume and Vascular
Resistance
Lung Volume
Effects of over-distention of the lungs
• Alveolar and airway damage
• Increased PVR
– Increased shunt, decreased PaO2
– May be interpreted as need for more pressure
• Decreased pulmonary venous return to heart
– Decreased cardiac output
• Capillary stretch injury
– Capillary leak, inflammation
Ventilator Strategy Summary
• Optimize lung volume
– avoid atelectasis
– avoid overdistension
• Maintain “normal” blood gases
– Tolerate mildly low SpO2, high PCO2
Past therapies which were inadequate or
worked only transiently
• Intentional hyperoxia
• Intentional hyperventilation
• Metabolic alkalosis
– Sodium bicarbonate infusion
Surfactant and hypoxemic
pulmonary failure
• Meconium aspiration syndrome
• Congenital diaphragmatic hernia
• Randomized study in hypoxemic lung failure in
term and near term infants
– Lotze A et al. J Pediatr 1998;132:40-47
– 44 centers, 328 infants randomized to placebo or up to
4 doses of surfactant (4 additional if placed on ECMO)
– No difference in mortality between groups
– Primary outcome, need for ECMO
Reduction in need for ECMO with surfactant
Reduction in need for ECMO with surfactant
Need for selective pulmonary
vasodilator…..
• …and along came inhaled nitric oxide
Nitric oxide (NO) and prostacyclin (PG) signaling pathways in regulation of vascular tone
Steinhorn, R. H et al. Neoreviews 2007;8:e14-e21
Copyright ©2007 American Academy of Pediatrics
Biochemical Fates of Inhaled Nitric Oxide at the Alveolar-Capillary Membrane
Griffiths M and Evans T. N Engl J Med 2005;353:2683-2695
Mechanism of Action and Inaction of Inhaled Nitric Oxide
Griffiths M and Evans T. N Engl J Med 2005;353:2683-2695
Nitric oxide, term and near term infants
with hypoxemic respiratory failure
• Cochrane review
– 12 randomized controlled studies
– Reduced incidence of the combined endpoint of death
or need for ECMO. Reduction primarily from reduction
in need for ECMO; mortality is not reduced
– OI improved by (weighted) mean of 15.1 within 30 to
60 minutes after start of iNO
– PaO2 increased by mean of 53 mmHg.
– Response to iNO does not depend on clear
echocardiographic evidence pulmonary hypertension
– Diaphragmatic hernia group had no benefit from iNo
Nitric oxide for treatment of
pulmonary hypertension
•
•
•
•
•
•
•
Starting dose 20 ppm
Decrease to 5 ppm after positive response
Slower wean, decreasing by 1-2 ppm
Discontinue when stable on 1-2 ppm
Monitor methemoglobin
Monitor concentration of NO and NO2
iNO suppresses endogenous NO synthesis
Indications for iNO
• Term or near term infants with hypoxic respiratory
failure
• Documented pulmonary hypertension by echo
• OI = Paw x FIO2 x 100/ PaO2
• Oxygen index (OI) >25
• Early initiation of iNO with OI 15-25 improves
oxygenation, but does not reduce death or need for
ECMO
Possible mechanisms for iNO
non-responsiveness
• iNO delivery
– Poor lung inflation (decreased iNO delivery)
– Low dose of iNO (limited vasodilator response)
– High dose of iNO (increases V/Q mismatching)
• Abnormal pulmonary vasculature
structure/function
– Pulmonary hypoplasia, alveolar capillary dysplasia,
severe muscular hypertrophy of pulmonary vessels
Contraindications of iNO
• Congenital heart disease dependent on right
to shunt
– Hypoplastic left heart syndrome
– Critical aortic stenosis
– Interrupted aortic arch
• TAPVR (may increase pulmonary edema)
• Significant methemoglobinemia
Severe pulmonary hypertension with
hypoxemia despite iNO: what next?
• Other supportive measures optimal?
– Volume status
– Systemic blood pressure
– Lung volume appropriate?
• Is the patient an ECMO candidate?
• Is there a role for other pulmonary
vasodilators?
Role of ECMO in pulmonary
hypertension
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•
•
•
•
•
•
Oxygenation index (OI) >=40
OI = Paw x %O2/PaO2
Gestational age >=35 weeks
Weight >= 2 kg
Ventilation < 10 (14) days
Absence of significant CNS bleed
Reversible lung disease
HFV
Gentle Ventilation
Surfactant
iNO
ELSO database:
Neonatal Respiratory Cases
Cumulative Survival in Neonatal
Respiratory Support
Neonatal Diagnoses and Survival
Systemic vs. inhaled pulmonary
vasodilators
Possible adjuncts and/or alternatives
for pulmonary hypertension
• Sildenafil: phosphodiesterase inhibitor (PDE5)
• Dipyridamole: PDE inhibitor – anecdotal reports
of augmentation of the effect of NO
• Prostacyclin (PGI2): increases cAMP
• PGE1: pulmonary and systemic dilator, PDA
• Nitroprusside
• Adenosine
• Arginine
• Milrinone: PDE3 inhibitor (cAMP), systemic
effects
Sildenafil
• Phosphodiesterase (converts cGMP to
GMP) inhibitor type 5
• Causes pulmonary vasodilation
– Neonatal animal models, limited human data
– iNO with sildenafil cause systemic vasodilation
and worse oxygenation in animal model
– Human adults with primary and secondary
pulmonary hypertension
Sildenafil pilot randomized trial
• Inclusion criteria: oxygenation index (OI) >= 40
• 7 treatment and 6 control
• Starting dose 1 mg/kg q 6 hr, increase to 2 mg/kg
if no response
• Results: Sildenafil group showed a significant and
sustained drop in OI and increase in SPO2 from
baseline and as compared to placebo.
• 6/7 treatment vs. 1/7 placebo patients survived
(p<0.02)
• Baquero H, Sola A, et al. Pediatrics 2006;117:1077-1083
FIGURE 1 Oral sildenafil produced significant changes in OI
Baquero, H. et al. Pediatrics 2006;117:1077-1083
Copyright ©2006 American Academy of Pediatrics
FIGURE 2 SpO2 improved after oral sildenafil
Baquero, H. et al. Pediatrics 2006;117:1077-1083
Copyright ©2006 American Academy of Pediatrics
Cautions regarding sildenafil
• Large randomized study needed to prove safety
and efficacy
• Unlike iNO, sildenafil’s effects are not localized:
– Uncertain effects in the developing animal or human,
especially CNS
– Uncertain risk re: ROP in prematures
– Potential to slow gastric emptying
– Risk of systemic hypotension
FDA warning on sildenafil (8/30/12)
• FDA notified healthcare professionals…Revatio
(sildenafil) should not be prescribed to children
(ages 1 through 17) for pulmonary arterial
hypertension… based on a recent long-term
clinical pediatric trial showing that: (1) children
taking a high dose of Revatio had a higher risk of
death than children taking a low dose and (2) the
low doses of Revatio are not effective in
improving exercise ability.
Implications of FDA warning on
pediatric use of sildenafil
• Sildenafil should be used in
neonates/infants only with fully informed
consent (documented in writing) and/or as
part of a study
• Patients on long term sildenafil should be
closely monitored by a cardiologist
• Need for short/long term efficacy and safety
studies of sildenafil
Prostacyclin (PGI2)
• Stimulates adenylyl cyclase in smooth muscle,
increases cAMP, smooth muscle relaxation
• T½ 2-3 minutes, IV infusion vs. aerosol
• Pediatric and adult patients with pulmonary
hypertension by IV continuous infusion, home
therapy programs for chronic use
• Neonates: case reports only
– IV and aerosolized, alone and in combination with iNO
• Caution: can cause systemic hypotension
Iloprost
• Stable synthetic analog of prostacyclin (PGI2)
– Increases cAMP
– Aerosolized, IV
• Case reports and small series
– Limited experience in neonates
– Aerosolized iloprost improves oxygenation in
pulmonary hypertension in prematures, term, CHD
• May have a role as adjunct therapy or to wean off
of iNO
Milrinone
• Increases cAMP, causing pulmonary and
systemic vasodilation
• Reports in adults, pediatric and neonatal
patients, post op cardiac
• May be useful as adjunct therapy or to help
wean off iNO
References: milrinone
• Milrinone improves oxygenation in
neonates with severe persistent pulmonary
hypertension of the newborn. Journal of
critical care 2006; 21:217-233
• Neonatal persistent pulmonary hypertension
treated with milrinone: Four case reports.
Biology of the neonate 2006;89:1-5
Arginine: precursor to endogenous
nitric oxide
• Conversion of arginine to citrulline results
in release of NO
• Little or no neonatal data for its use in
pulmonary hypertension
• Probably not a limiting factor in NO
production in vivo
Enzymes and Intermediates in the Urea Cycle and Nitric Oxide Pathway
Pearson D et al. N Engl J Med 2001;344:1832-1838
Old discarded therapies
• Acetylcholine:
– used to test pulmonary vascular reactivity
• Tolazoline: (no longer available)
– Alpha blocker, histamine effects
– Associated with significant side effects
• Fentanyl
– Block hypoxia induced pulmonary
vasoconstriction
Potential future therapies of
pulmonary hypertension
• Modulation of endothelin-1 (ET-1) receptors
– ETA: ET-1 binding causes vasoconstriction
– ETB: activation causes ET-1 clearance and induces production of
NO and prostacyclin
• Combined ETA and ETB receptor antagonists:
– Bosentan: human adult studies showed benefit
– Tezosentan: decreases pulmonary artery pressure in pig meconium
aspiration model
• O-nitrosoethanol (ENO):
– increases endogenous S-nitrosothiols
Potential future therapies of
pulmonary hypertension
• Superoxide dismutase:
– scavenger of reactive oxygen species
– may augment responsiveness to inhaled nitric oxide
• Platelet derived growth factor inhibitor: imatinib
– Anecdotal reports in adults with PA HTN
– Report of one patient with congenital diaphragmatic hernia
– Adult phase III trial in progress
• Magnesium sulfate, non-randomized clinical reports
Management of the patient with
congenital diaphragmatic hernia
• Supportive ventilation: HFOV, avoid overdistention and pneumothorax
• Timing of surgical repair should be
individualized: delayed repair typical
• Unclear role for nitric oxide
– No reduction in ECMO or mortality with iNO
– iNO may play role in stabilization prior to
ECMO
Management of the patient with HIE
and pulmonary hypertension
• Common underlying pathophysiology:
– Placental insufficiency
– In utero hypoxia, ischemia
• Therapeutic hypothermia for HIE
– May exacerbate pulmonary hypertension
– Hypothermia may cause hypotension,
dysrhythmias, coagulopathy
Underlying etiologies for severe
long-term pulmonary hypertension
• Lung hypoplasia
– Congenital diaphragmatic hernia
• Pulmonary vascular anomalies
– Alveolar capillary dysplasia
• Pulmonary vascular remodeling
– Smooth muscle hyperplasia: chronic in utero
hypoxia, chronic pulmonary vascular overload
due to L to R shunt, multiple pulmonary emboli
Diagnostic approaches to severe
persistent pulmonary hypertension
• Cardiac catheterization
• Lung biopsy: open vs. percutaneous
• (autopsy)
References:
• Abman SH. Pulmonary Vascular Disease and
Bronchopulmonary Dysplasia: Evaluation and Treatment
of Pulmonary Hypertension. NeoReviews 2011;12;e645
• Baquero H, Sola A, et al. Oral sildenafil in infants with
persistent pulmonary hypertension of the newborn: a pilot
randomized blinded study. Pediatrics 2006;117:1077-1083
• Clark RH, et al for the Clinical Inhaled Nitric Oxide
Research Group. Low-dose nitric oxide therapy for
persistent pulmonary hypertension of the newborn. N Engl
J Med 2000;342:469-74
References:
• Steinhorn RH, Farrow KN. Pulmonary hypertension in the
neonate. NeoReviews 2007;8;e14
• The Neonatal Inhaled Nitric Oxide Study Group (NINOS).
Inhaled nitric oxide and hypoxic respiratory failure in
infants with congenital diaphragmatic hernia. Pediatrics
1997;99:838-845
• The Neonatal Inhaled Nitric Oxide Study Group (NINOS).
Inhaled nitric oxide in full-term and nearly full-term
infants with hypoxic respiratory failure. N Engl J Med
1997;336:597-604