Download Treatment of Pulmonary Hypertension

10/22/2012
Treatment of Pulmonary
Hypertension in the
Pediatric Patient
Robin Kingston, CRNP
Pediatric Home Ventilator Program
Definition
 Abnormal pulmonary vascular proliferation and remodeling,
vasoconstriction, and thrombosis, leading to elevated
pulmonary arterial pressure, increases in peripheral vascular
resistance, and ultimately to right heart failure and death.
 Raised pulmonary artery pressure
 > 25mm Hg at rest
 > 30mm Hg during exercise
 What we also look at
 Percentage of the child’s systolic blood pressure
 May be 1/3-1/2 systemic, systemic, or suprasystemic
Definition
 Idiopathic or primary
 No underlying cause
 Secondary
 To a specific disease process
 Without treatment it can be progressive and fatal.
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Definition
 PPHN / D- hernia / ARDS
 Rapid onset / Rapid Deterioration
 Life threatening at Onset
 All Other Forms
 Gradual Onset of Symptoms
 Limitation of Exercise Capacity
Definition

Primary Pulmonary Hypertension


Sporadic
- Familial
Secondary Pulmonary Hypertension







Collagen Vascular Disease
- Drugs/toxins
Portal Hypertension / Liver Dx
- HIV
Congenital systemic to pulmonary shunt
-chronic lung disease
Cystic Fibrosis
- chronic thrombotic
High Altitude
and/or embolic disease
ARDS
Chronic obstructive sleep apnea
Natural History
 All forms of PH
 Progressive deterioration
 Increased right heart afterload
 Right ventricular failure and progressive decline in cardiac
index
 Symptoms at rest
 Progressive elevation of pulmonary artery pressure and
vascular resistance
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Pathophysiology
 PH starts when the small vessels that supply blood to
the lungs tighten up
 It becomes more difficult for the blood to get to the
lungs
 Heart has to pump harder to overcome resistance
 This stress causes the heart to enlarge and weaken
Abnormally high blood pressures in pulmonary arteries
Increased pressures damages large and small pulmonary arteries
Blood vessel walls thicken
Cannot transfer oxygen and carbon dioxide normally
Levels of oxygen in blood fall
Constriction of pulmonary arteries
Further increase in pressure in pulmonary circulation
Right side of heart must work harder
Cor pulmonale
Push blood through
The pulmonary arteries
To the lungs
Right ventricle thickens
And enlarges
Heart Failure
In some people the bone marrow will produce more red blood cells to
compensate for less oxygen in the blood leading
Polycythemia
Extra RBCs cause the blood to be thicker and stickier, further
increasing the load on the heart
pulmonary embolism
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High BP in
PA’s
PA’s
constrict
Further
increase
in Pressure
in PA’s
O2 levels
fall
Pressure
Damages
Large/ Small
PA’s
Transfer
O2/ CO2
abnormally
Vessel Walls
Thicken
Develop
Polycythemia
Biventricular
Heart
Failure
PH
Pulmonary
Embolism
Increased
Right Heart
Work
Cor
Pulmonale
Right
Ventricle
Thickens
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Diagnosis
 Workup involves
 Complete history and examination
 Diet pill use, contraceptive use, methamphetamine use,
onset and length of duration, family history, prior cardiac or
other surgeries
 Symptoms: chest pain, dsypnea, shortness of breath
 Extensive evaluation
 Aiming to exclude all known etiologies
 Second heart sound, murmur, palpable second heart sound,
peripheral edema, jugular venous distention
Diagnostic Studies
 Chest x-ray
 Looking for cardiomegaly
 EKG
 Signs of right ventricular hypertrophy
 Echocardiogram
 Right ventricular hypertrophy
 Exclude congenital heart disease
 Quantify right ventricular systolic pressure
Diagnostic studies
 Cardiac catheterization
 Gold standard
 Evaluate pulmonary artery pressure and resistance and
degree of pulmonary reactivity
 Swan Ganz pulmonary artery catheter
 To do the same thing as cath but can leave in for days
 Look at patient when awake, not just sedated
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Diagnostic Studies
 Liver evaluation
 Hypercoagulable evaluation
 Collagen Vascular work up
 Lung evaluation
 PFTs, pulse-oximetry, CT/MRI – look for interstitial lung
disease
 Six minute walk test
What do we see?
 Pulmonary hypertension secondary to:
 Chronic lung disease of infancy
 Congenital heart disease
 Primary pulmonary hypertension is usually seen in
young adult women
Treatment Options
 Most children with mild pulmonary hypertension do not
require treatment
 Treat the underlying cause
 Children with congenital heart disease
 Surgical treatment depends on several factors
 Age
 Lesion
 Vasoreactivity at cardiac cath
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Vasodilators
 Vasoconstriction important component in development
of medial hypertrophy
 Vasodilators frequently used to:
 Decrease pulmonary artery pressures
 Improve cardiac output
 Potentially reverse some of the pulmonary vascular
changes in the lung
Vasodilator Therapy
 Oxygen
 Nitric Oxide (NO)
 Calcium channel blockers
 Prostacyclin
 Endothelins
 Phospodiesterase-5 inhibitors
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Oxygen
 Alveolar hypoxia causes vasoconstriction of the pulmonary
vascular bed
 Results in increased pressure and resistance
 Good ventilation and oxygen therapy has been shown to be
of benefit acutely for both hypoxic and nonhypoxic patients
with PAH.
 Some patients may benefit from use of nocturnal oxygen
therapy both acutely and alongside maintenance therapy
Inhaled Nitric Oxide
 Currently among the first line treatments for acute PAH
 Reduces PA pressures rapidly
 Improves gas exchange and selectively lowers
pulmonary vascular resistance
Nitric Oxide Pathway
 NO molecules activate an enzyme, guanylyl cyclase (GC).
 GC converts guanosine triphosphate (GTP) to cyclic
guanosine monophosphate (cGMP).
 cGMP causes calcium ions to enter storage areas of the
cell. The lowered concentrations of calcium ions (Ca++) set
off a cascade of cellular reactions that cause the cell's
contractile filaments (myosin and actin) to slide apart.
 Smooth muscle cells relax.
 Blood vessel dilates.
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Inhaled Nitric Oxide
 Effective for short term treatment of critically ill patients
with PAH
 A low molecular weight lipophilic molecule in gaseous
form
 Rapid onset of action and short intravascular half-life
(seconds)
 Dosed in parts per million (ppm) from 20 ppm up to 80
ppm
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Calcium Channel Blockers
 Inhibit calcium influx though slow channel into cardiac
and smooth muscle
 In blood vessels, a decrease in calcium results in less
contraction of the vascular smooth muscle and
therefore an increase in arterial diameter - vasodilation
 Vasodilation decreases total peripheral resistance
Calcium Channel Blockers
 Nifedipine, Amlodipine, Diltiazem
 With Amlodipine dosing is only once daily
 Only efficacious in 5-10% of children and adults
 Some may switch from being “responders” to CCBs to
nonresponders
 Barst et al demonstrated nearly 50% of children on
conventional CCB therapy deteriorated clinically and
hemodynamically during long term treatment despite initial
acute vasodilator responsiveness.
 Continued monitoring
 Cath vs. ECHO
Prostacyclins
 Prostacyclin is an endogenous vasodilatory mediator in
the pulmonary vasculature
 Prostacyclin agonists act via cyclic AMP-dependent
pathways in smooth muscle cells
 Effects include:
 Reducing PVR
 Inhibiting platelet aggregation
 Reducing smooth muscle cell proliferation
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Prostacyclin
Prostacyclins
 Epoprostenol
 Trepostinil
 Iloprost
 Beraprost
Eproprostenol (flolan)
 Potent nonselective vasodilator
 Became available for treatment of PAH late 80s and
was clinically approved for treatment in 1995
 Administered intravenously via continuous infusion
 Has been shown to improve the survival of patients
with PAH in the long-term
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Epoprostenol (flolan)
 Has very short half-life
 < 6 minutes
 Interruption of infusion can lead to rapid increases in PVR,
hemodynamic collapse and death
 We require double lumen catheter or 2 access sites
 Dosed in nanograms (ng)/kg/min




Average dose in children is 50-80ng/kg/min (Rosenzqeig, et al)
Significant variability of “optimal dose”
Dosing depends on whether patient using combination therapy
Usually start low (2ng/kg/min) and titrate up for desired effects
Epoprostenol (flolan)
 Chemically unstable at room temperature/neutral ph
 Must be mixed daily and kept cold with ice packs
around the cassette
 5-year survival in children with idiopathic PAH shown to
be >80%
Epoprostenol (flolan)
 Side effects include:







Catheter related complications
Thrombocytopenia
Headache
Flushing
Rash
Gastrointestinal symptoms
Lower jaw pain
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Epoprostenol (flolan)
 CADD Legacy pump
 Used for continuous infusion
via central venous catheter
 Has carry case that ice
packs fit into to keep flolan
cold
 Infuses as xxml per 24 hour
period.
 Parents must always carry
back-up cassette with mixed
med
Treprostinil (remodulin)
 Analog of prostacyclin
 Initially approved for subcutaneous infusion
 Approved for intravenous infusion in 2004
 Similar in action to epoprostenol but with important
differences:
 Longer half-life - ~ 4hours
 Stable at room temperature for 48 hours
 Similar side effects as epoprostenol
Treprostinil (remodulin)
 Dosage comparison to epoprostenol
 Estimated to be 1.5-2ng/kg/min vs 1ng/kg/min of flolan
 Recommendations are to start at 1.25ng/kg/min and
titrate dose up based on resolution of symptoms
 In adults can have doses of up to 100ng/kg/min
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Treprostinil (remodulin)
 Uses same CADD Legacy
Pump for IV infusion
 Does not need to be kept
cool
 Parents should still carry
back-up cassette
Inhaled prostacyclin
 Iloprost (ventavis)





Prostacyclin analog
First inhaled formulation to be approved
Half-life 20-25minutes
Requires 6-9 inhalations/day to be clinically effective
Administered by the I-neb ADD (Adaptive Aerosol
Delivery) system or Prodose ADD system
 Dosing (adults) is recommended at 2.5 or 5 micrograms
per inhalation (single dose vials of 10mcg/ml)
 Start at 2.5mcg then titrate up to 5 mcg
 Generally takes 5-10 minutes to nebulize
Iloprost (ventavis)
 Selective for the pulmonary vasculature
 Induces a decrease in PVP with no or minor effects on
systemic circulation.
 Can be delivered to only ventilated regions avoiding
portiential increase of intrapulmonaary shunts by dilating
vessels in nonventilated areas
 Thus improves ventilation perfusion mismatch
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Iloprost (ventavis)
 Pediatric Use
 Ivy et al studied the acute and chronic effects of inhaled
iloprost in 23 children
 Results:
 Acute pulmonary vasodilator response to inhaled iloprost is
equivalent to the effects of inhaled nitric oxide as measured
during cardiac cath
 Acute inhalation can induce bronchoconstriction in some
children
 The addition of inhaled iloprost therapy can reduce the need
for intravenous prostanoid therapy in some patients
Iloprost (ventavis)
 Ivey et al results cont:
 Most children tolerated the combination of inhaled iloprost
and endothelin receptor antagonists
 Several patients had clinical deterioration during chronic
inhaled iloprost therapy and required rescue therapy with
intravenous prostanoids.
 Dose applied ranged from 2.5mcg-10mcg with 4-9
inhalations per day for a total daily dose of 3.75-50mcg
depending on age and wt of patients
 No real good dosing guidelines
Iloprost (ventavis)
 Advantage in acute pulmonary hypertensive crisis with
hemodynamic compromise
 Minor effect on systemic blood pressure
 Intrapulmonary selectivity may improve
ventilation/perfusion mismatch and potentially
oxygenation
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Iloprost (ventavis)
 Side effects:







Headache
Cough
Dizziness
Flushing
Jaw pain
Lower extremity pain
Diarrhea
Inhaled prostacyclin
 Treprostinil (tyvaso)
 Prostacyclin analog
 Longer half-life than Iloprost
 Less frequent administration
 Dosed 4 x daily
 18mcg (3 breaths) increase by 18mcg if tolerated to target dose
of 54mcg (Adults – no pediatric data).
 Less systemic side effects than Iloprost
 Must use Tyvaso Inhalation System to administer
 Still gaps in overnight coverage
Beraprost
 Oral formulation of Prostacyclin
 Used for treatment of early-stage PH and early-stage peripheral vascular
disease
 Currently in Phase III clinical trials
 Dilates blood vessels, prevents platelet aggregation and prevents proliferation
of smooth muscle cells surrounding blood vessels.
 Intermittent oral doses of beraprost do not seem to provide consistent levels
of the drug in the blood necessary to treat the advanced stages of PH.
 Reportedly proven to be safe and effective for the treatment of PVD in clinical
studies conducted outside the United States and has been approved for
treatment of PVD in Japan since 1994. It may soon be available for PH use in
the United States.
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Phosphodiesterase Inhibitors
 PDE5 (phosphodiesterase type 5) is found in
pulmonary smooth muscle
 NO activates guanylate cyclase which increases levels
of cyclein guanosine monophosphae (cGMP)
 cGMP produces relaxation of smooth muscle
 PDE5 breaks down cGMP
 Inhibition of PDE5 increases cGMP – thus causing
vasodilation.
Phosphodiesterase Inhibitors
 Sildenafil
 Viagra
 Revatio
 Tadalafil (adcirca)
 Vardenafil (levitra, staxyn)
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Sildenafil
 Potent and selective pulmonary vasodilator
 Small scale pilot study (published 2005) suggested it
improves hemodynamics and exercise capacity in children.
 Other studies have shown improvement in 6 minute walk
test
 Improves mean PA pressure, PVR, and exercise tolerance
 Also shown to work synergistically w/ NO to further increase
vasodilation.
Sildenafil
 Revatio
 Brand that is FDA approved for PAH (for adults)
 Available as 20mg tablet
 Suspension can be made 2.5mg/ml
 Dosing starts at 0.5mg/kg/day
 Can be increased as high as 4mg/kg/day in 3-4 divided doses
 See next slide
 Side effects:




Nausea, abdominal discomfort
Headache, blurred vision, dizziness
Flushing, hypotension
Prolonged erection
Sildenafil
 Drug warning issued October 2011
 Long-term study looking at sildenafil treatment in pediatric
patients
 Compared sildenafil to placebo
 Compared low, medium, and high dose sildenafil
Body wt (kg)
Low Dose
Medium Dose
High Dose
>8-20
NA
10mg
20mg
>20-45
10mg
20mg
40mg
>45
10mg
40mg
80mg
 When looking at mortality trends, high dose sildenafil was
associated with harmful effect on survival when compared to
low dose.
 Recommended immediate discontinuation of 40, 80mg doses as
well as 20mg dose for wt < 20kg
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Sildenafil

Revatio (sildenafil): Drug Safety Communication - Recommendation Against Use in Children

AUDIENCE: Pediatrics, Cardiology, Pulmonology

ISSUE: FDA notified healthcare professionals and their medical care organizations that Revatio (sildenafil) should not be
prescribed to children (ages 1 through 17) for pulmonary arterial hypertension (PAH).This recommendation against use is
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. Treatment of PAH in children with this drug is an off-label use (not approved by FDA) and a new warning, stating
the use of Revatio is not recommended in pediatric patients has been added to the Revatio labeling.

BACKGROUND: Revatio is a phosphodiesterase-5 inhibitor used to treat pulmonary arterial hypertension by relaxing the
blood vessels in the lungs to reduce blood pressure and is approved to improve exercise ability and delay clinical
worsening of PAH in adult patients (WHO Group I).

RECOMMENDATION: Patients and caregivers are advised to not change the Revatio dose or stop taking Revatio without
talking to a health care professional. Healthcare professionals were reminded that use of this product, particularly chronic
use, in children is an off-label indication, not approved by FDA, and is not recommended. See the Drug Safety
Communication for the Data Summary from the randomized, double-blind, placebo-controlled clinical trial of 234 patients
with PAH, 1 to 17 years of age with mild to moderate symptoms at baseline.

Read the MedWatch safety alert, including a link to the FDA Drug Safety Communication, at:

http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm317743.htm
Tadalafil
 Approved for patients > 40kg
 Dosed 40mg once daily
 Available in 20mg tablets
Verdenafil
 Research has suggested this may be more effective
than sildenafil
 Acts directly to reduce calcium influx in the pulmonary
artery in addition to vasodilatory effects via cGMP.
 The studies have looked at dosing at 5mg once daily
and twice daily.
 Not FDA approved for treatment of pulmonary
hypertension
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Endothelin Receptor
Antagonists
 Bosentan (tracleer)
 Ambrisentan (letairis)
Endothelin receptor
antagonists
 Endothelins (ET) are a family of isopeptides consisting
of ET-1, ET-2, ET-3
 ET-1 – a potent vasoactive peptide produced primarily in
vascular endothelial cell
 Also maybe produced in smooth muscle cells
 2 receptor types:
 ETa, ETb
 Both of these mediate vasoconstriction on smooth muscle cells
 ETb receptors on endothelial cells cause release of NO or prostacyclin (PGI2) and
act as clearance receptors for circulating ET-1.
ETb
ET-1
Endothelin
cell
ET-1
NO, PGI2
ETa
ETb
Smooth
muscle cell
Vasoconstriction
Vasodilation
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Bosentan (tracleer)
 Nonselective (ETa and ETb) antagonist
 Has been shown to reduce mean PA pressure and PVR, and
increase quality of life in patients with IPAH (adults)
 Found to be effective in reducing PA pressure and improving
exercise capacity without reducing oxygen saturations
 In children with PAH related to congenital heart disease or
IPAH it lowered pulmonary pressure and resistance and was
well tolerated.
 Shown to cause hepatic dysfunction in some patients
 Check monthly liver studies
Bosentan (tracleer)
 Side effects (in addition to liver dysfunction)
 Most common include: respiratory tract infection,
headache, fainting, flushing, low blood pressure, inflamed
nose passages (sinusitis), joint pain and irregular
heartbeats.
 Birth defects
 Fluid retention
 Anemia
Bosentan (tracleer)
 Available as a 62.5mg tablet and 125mg tablet
(31.25mg tablet available for pediatric use in Europe)
 No suspension available that is stable for more than 24
hours.
 Dosing in 6 clinical studies in children
 31.25mg bid -10-20kg
 62.5mg bid - 20-40kg
 125mg bid - > 40kg
 FUTURE-1 –multicenter phase III trial
 Started at 2mg/kg twice daily and then advanced to 4mg/kg
twice daily (<30kg)
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Bosentan (tracleer)
 1-2mg/kg orally BID x 4weeks, increase to
maintenance dose of 2-4mg/kg twice daily (<10kg)
 31.25mg daily x 4 weeks, increase to maintenance
does of 31.25mg BID (10-20kg)
 31.25mg BID x 4 weeks, increase to maintenance dose
of 62.5mg BID (20-40kg)
 62.5mg twice daily x 4 week, increase to maintenance
dose of 125mg BID (>40kg)
Ambrisentan (letairis)
 Selective endothelin receptor antagonist (ETa)
 Approved by FDA 2007
 Dosing 5mg daily but can be increased to 10mg daily
 No data for children
 2 Clinical Trials sponsored by GlaxoSmithKline looking at
abrisentan in children 8-18years old.
 University of Colorado Denver School of Medicine and
Columbia University Medical Center
 Children 3-18 years currently on ambrisentan
 Doses included 2.5mg, 5mg, 10mg daily
Anticoagulation
 Rationale:
 Patients with chronic PH undergo occlusion of small pulmonary
vessels thus reducing the pulmonary vascular bed area
 Endothelin cell abnormalities present in many forms of PH lead
to platelet activation and thrombosis
 Many children with PH will not be treated with
anticoagulation
 Recommended for those at high risk of thromboembolism
 IPAH with reduced cardiac output
 Indwelling venoatrial shunt
 Severe polycythemia
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Anticoagulation
 Warfarin
 Enoxaparin
 Aspirin
How do you know what to do?
Positive response to
vasodilators
 Patients responding positively to acute vasodilator
testing are defined as those who show all of the
following:
 Decrease in mean pulmonary artery pressure and
resistance by 20% or greater with a fall to near normal
levels
 Experience no change or an increase in their cardiac
index
 Exhibit no change or a decrease in the ratio of pulmonary
vascular resistance to systemic vascular resistance
 Normal right atrial pressure and cardiac output
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What do we do?
 Swan ganz catheter or heart catherization
 Look at vasoreactivity – if looks good may try CCB
 With data that CCBs may not be good for long term
therapy we often start with sildenafil
 If sildenafil not working well may add bosentan if no
liver issues
 If persistant pulm htn with using these then go to IV
epoprostenol or treprostinil (1st choice due to longer
half life)
Outcomes
 We have been able to successfully wean our patients
from mechanical ventilation as well as IV
epoprostenolo or treprostinil.
 They get transitioned to oral sildenafil or bosentan
 With new FDA warnings not sure about use of sildenafil
 Most of our patients have been able to wean from oral
meds as well
 They are still followed by cardiology on a yearly basis
Questions?
Thank You!
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