Case



2 year old ex 30 week premie
discharged home on oxygen until 6
months of age
presents with decreased energy,
distended abdomen, decreased
appetite
Thoughts?
Exam
PE: no dysmorphic features, PERRL,
mmm, some coarse breath sounds but
moving air well, RRR with no murmur,
right ventricular heave, liver edge 4
cm below RCM, no splenomegaly.
Thoughts?
Initial Labs


Labs: electrolytes and CBCD wnl
CXR: mild cardiomegaly with
decreased pulmonary markings
Initial Labs

EKG

What study might be helpful next?
Echo




flat septal wall
mild TR with RVPE 55 mmHg above the
atrial v wave (systolic BP at time of study =
90)
no MR
good function
Diagnosis?
Pulmonary Hypertension
The Basics
What is it?
Normally, pulmonary blood flow occurs in a
low pressure, high compliance system



High blood pressure in the lungs
The walls of the pulmonary arteries constrict
The heart has to work harder to pump blood
to the lungs
“High resistance and low capacity”
What defines Vascular Resistance?



Ohm’s Law:

Voltage (V) = Current (I) x Resistance (R)

Pressure (P) = Flow (Q) x Resistance (R)
Only at flows > 4x resting flow or pressures > 2x nml does Ohm’s law
predict changes in total pulmonary resistance
Because of recruitment, PVR decreases with increased pulmonary
arterial pressure or flow.
Why is it bad?



Remodeling of the pulmonary vascular bed
 Intimal and medial hypertrophy with proliferation of
smooth muscle cells and eventual obliteration
 Pulmonary arteries constrict
 Right heart must pump against resistance
 Right heart becomes dilated and less efficient  TR
Less blood gets out to the lungs and to the body
Adaptation to stress, increased activity or growth become
impossible
Incidence



Incidence of PH of various etiologies ~
2/1000 newborns in the NICU with
associated mortality of 10-20%.
PH affects 2% of infants following
cardiac surgery.
Idiopathic PH has a yearly incidence in
the range of 1-2/106.
History

First reported case: 1891


Dr. Romberg in Germany published a
description of an autopsy case in which
significant thickening of the pulmonary artery
was noted in the absence of clearly evident
cardiac or lung disease.
Formally named: 1951

Dr. Dresdale reported on 39 cases in United
States
What causes it?
4th World Symposium - 2008
Classification

1. Pulmonary arterial hypertension (WHO
group I)
a. idiopathic
b. familial (10%): AD w/variable penetrance, 2:1 F
to M, but M more symptomatic and die younger
c. secondary to toxins (fenfluramine (fen-phen),
HIV, liver disease (portal HTN), heart disease with
shunting to the lungs (PDA, VSD), other diseases
(sickle cell, lupus, sarcoidosis)
What causes it?

2. Pulmonary venous hypertension
(WHO group II)


Caused by disease of the left side of the
heart (mitral valve disease, pulmonary
vein stenosis)
3. PHTN associated with hypoxia and
other resp disease (WHO group III)

Chronic lung disease, sleep apnea
What causes it?

4. PHTN associated with chronic
thrombotic disease (WHO group IV)


Blood clots in the pulmonary arteries, PE
5. PHTN associated with
miscellaneous things (WHO group V)

pulmonary capillary disease
Heath-Edwards Classification






I – Medial hypertrophy
II – Intimal hyperplasia
III – Occlusive changes (by fibroelastic
tissue)
IV – Dilation, medial thinning, occlusion
V – Plexiform lesions
VI – Necrotizing arteritis
WHO Classification of Severity




Class I: No limitation of usual physical activity; Activity
doesn’t cause dyspnea, fatigue, chest pain, or presyncope
Class II: Mild limitation of physical activity; no discomfort
at rest; but activity causes dyspnea, fatigue, chest pain
Class III: Marked limitation of activity; no discomfort at rest
but less than normal physical activity causes increased
dyspnea, fatigue, chest pain, or presyncope
Class IV: Unable to perform physical activity at rest; may
have signs of RV failure; symptoms increased by almost
any physical activity
Pathophysiology
Pulmonary vasomotor tone controlled by:

Vasoconstrictors





Thromboxane
ET-1
Leukotrienes
Platelet activating factor
Vasodilators


NO
PGI2
Pathogenesis


BMPR2 abnormal: vascular hyperplasia and
abnormal neovascularization.
Three key pathogeneses:
•
•
•


Relative decrease in bioavailability of NO
Relative increase in serum endothelin-1
Relative deficieny of PGI2/excess of thromboxane
A2  platelet dysfxn
Intense vasoconstriction: abnormal ATPsensitive K-channels.
Immune dysfunction: autoimmune etiology in
some cases
Diagnosis in Children






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Dyspnea (60%)
Failure to thrive in infancy
Fatigue; excessive napping (19%)
Diaphoresis
Palpitations
Syncope
Chest pain
Occasional hemoptysis
All exacerbated by exertion –
Doom is impending!
Diagnosis – Physical Signs



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Cyanosis
Low output
Venous congestion
Active right ventricular impulse
Loud P2
High frequency TR murmur
High frequency diastolic PR murmur
Diagnosis - Testing

Echo: Purely a screening tool



Definitive dx needs direct measure of PAP



Identify TR.
Add mean RAP to the peak tricuspid jet velocity to get an
estimate of peak pulmonary pressure
Normal mean PAP at sea level at rest = 12–16 mm Hg
PHTN = mean PAP > 25 mmHg at rest and >30 mmHg with
exercise
Diagnosis requires the presence of above + 2 other
conditions:


Pulmonary artery occlusion pressure (PAOP or PCWP) < 15 mm Hg
Pulmonary vascular resistance (PVR) > 3 Wood units
Cath Lab Testing






Pulmonary resistance = (PAPmean - LAmean)/ CI
 expressed as Woods Units and is indexed to BSA
 Normal < 2, “inoperable” >6
Vasoreactivity testing
 NO, Flolan, Adenosine—drop in mPAP by 10 mmHg to
value < 40 mmHg
 Predicts CCB response
 Flolan testing for aortic pressure sensitivity
100% O2 helpful in evaluating lung function
Evaluate for septal defects
Shed light on the issue of diastolic dysfunction
Interpret data in context of patient’s volume status
How do you treat it?
1.
2.
3.
4.
Improve alveolar oxygenation
Minimize pulmonary vasoconstriction
Maintain systemic blood pressure and
perfusion
…No therapy is perfect and none
restores normal life expectancy


All treatment is palliative.
Currently there is no cure
Acute Treatments




Avoid acidosis and
hypercarbia
Avoid under or over
inflation
Avoid preload
depletion
Avoid inadequate
sedation




O2 (hypoxia is a potent
vasoconstrictor)
Hyperventilation
(hypocapnia blunts hypoxic
vasoconstriction)
iNO (FDA approved 12/99). ↑
levels of cGMP in vascular
smooth muscle  relaxation
and inhibition of vascular
smooth muscle growth
Isoproterenol: beta
adrenergic receptor
agonistrelaxes airways and
increases airflow.
pH and PO2 Important for PVR
PVR Increases at Lung Volumes
Below and Above FRC
Lung Volume
Goals of Therapy
Alleviate symptoms and improve
quality of life (exercise tolerance)
 Improve cardiopulmonary
hemodynamics and prevent right
heart failure
 Delay time to clinical worsening
 Reduce morbidity and mortality
“It is not possible to vasodilate vessels
that do not exist”

The Role of CCBs


Primary PHTN
Treatment with CCBs in those who respond to
acute testing associated with improved 5 yr
survival (97% vs 29% non-responding, nontreated patients).
(Rich, et al, 1992; Barst, 1999)


+ responses in 10-25% include decreased
PAP & PVR, and increased CI.
- responses include increased CHF,
decreased CI, and death.
Targets for Therapy
Humbert et al. New Engl J Med 2004
How do you treat it?

Vasoactive medications

Prostacyclins



Endothelin receptor antagonists


Epoprostenol (synthetic prostacyclin (PGI2) aka
Flolan®)
Treprostinil (Remodulin®), Iloprost (Ilomedin®,
Ventavis®)
Bosentan (Tracleer®), Sitaxsentan (Thelin®),
Ambrisentan (Letairis®)
Phosphodiesterase type 5 inhibitors

Sildenafil (Revatio®), Tadalafil (Cialis®)
RCTs of Approved Agents
Class of Drug
Study/
Drug
N
Etiol
Class*
Design
PositiveResults
6 MWD
Symptoms
Clinical
Worsening
CPH
6 MWD
CPH
Symptoms
Hepatic toxicity (11%;
transient, reversible)
Composite
Endpoint
6 MWD, sx
6 MWD
Symptoms
CPH
6 MWD
Symptoms
CPH
Survival
Administration
6 to 9 times daily
ET-1
Antagonist
BREATHE-1
Oral Bosentan/
placebo
213
PAH
III,IV
DoubleBlind
16-wk
PDE-5 Inhibitor
SUPER
Sildenafil Citrate
(20, 40 or 80 mg tid)
Doubleblind,
placebo
12 wks
Prostacyclin
analogue
Inhalational
Iloprost/
Placebo
SQ Treprostinil/
SQ placebo
278
IPAH,CT
CHD
II, III
203
PH
III-IV
470
PAH
II-IV
81
PPH
III,IV
Prostacyclin
analogue
Prostacyclin
IV Epoprostenol/
Conventional Rx
Doubleblind
12-week
Doubleblind
12-wk
OpenLabel
12-wk
Dis-advantages
Headache, flushing,
dyspepsia
Pain, erythema
at infusion site
Side effects
Indwelling central line
Pump
(infection,malf)
Side effects
Phosphodiesterase-5 Inhibitors
cGMP Pathway
Sildenafil





Sildenafil citrate is a selective and potent inhibitor of
cGMP-specific phosphodiesterase type 5 (PDE 5)
PDE5 is the major subtype in the pulmonary
vasculature and is more abundant in the lung than in
other tissues
Pulmonary vascular cGMP levels can be ↑ by inhibiting
phosphodiesterases responsible for cGMP hydrolysis
Relatively selective pulmonary vasodilation with little
systemic hypotension
Recommended for WHO Class II and III
Sildenafil


In animal models of acute pulmonary
hypertension sildenafil decreased
pulmonary artery pressures in a dosedependent manner
Several case reports now exist
suggesting sildenafil is effective
Sildenafil Trial
Galie, N, et al. Sildenafil Citrate Therapy for PAH. NEJM 2005;353:2148-57.
Sildenafil Trial
Sildenafil Study in Neonates
Sildenafil in neonatal PH due to impaired alveolarisation & plexiform pulmonary arteriopathy
M Chaudhari, M Vogel, C Wright, J Smith, S G Haworth
Arch Dis Child Fetal Neonatal Ed 2005;90:F527–F528.
Sildenafil
FDA approved dose is 20 mg tid
Higher doses often used given hemodynamic
findings
Sildenafil – Adverse Effects







Abdominal pain, nausea, diarrhea
Hypotension, vasodilation, hot flushes
Dry mouth, arthralgia, myalgia
HA, abnormal dreams, vertigo
Dyspnea, abnormal vision, deafness
Penile erection, UTI, vaginal
hemorrhage
Retinitis of prematurity ………
Endothelin Receptor
Antagonists
Endothelin
Clozel. Ann Med. 2003
Endothelin is increased in IPAH and PAH
associated with other Diseases
Bosentan



Specific and competitive antagonist at
endothelin receptor types ETA and ETB
Blocks the action of ET-1, a
neurohormone with potent
vasoconstrictor activity in the
endothelium and vascular smooth
muscle
FDA approved 11/2001
Study 351 - Bosentan
Channick R, et al. Effects of the dual endothelin-receptor antagonist
bosentan in patients with pulmonary hypertension: a randomised
placebo-controlled study. Lancet 2001;358:1119-23
BREATHE 1 Trial - Bosentan
Rubin LJ, et al. The New England Journal of Medicine; 2002;
346(12):896-903
 Walk Distance
(meters)
BREATHE 1 – 6min Walk Test
60
Placebo (n = 69)
Bosentan (n = 144)
40
20
P = 0.0002
Mean ± SEM
0
-20
-40
Baseline
Week 4
62.5 mg bid
Week 8
125 or 250 mg bid
Week 16
BREATHE 1 – Time to Clinical
Worsening
BREATHE-3 – Bosentan in Kids


Inclusion Criteria
 Age: 2–17 yrs, WHO class II–III
 PPH or CHD
 Oxygen sats > 88%
 Concomitant epoprostenol (Flolan®) (at least
3 months)
Exclusion Criteria
 Liver Disease (ALT/AST > 2 X ULN)
 Poor Cardiac Fxn (CI < 2 l/min /m2 )
 Low BP (Systolic < 80 mm Hg)
Dunbar Ivy, UCHS
BREATHE-3 - Conclusions

Significant hemodynamic
improvements were observed after 12
weeks of bosentan

Bosentan was well tolerated in children
with PAH, either alone or in
combination with epoprostenol
Bosentan – Who Qualifies?

Indication: Treatment of pulmonary
arterial hypertension in patients with
WHO Class III or IV symptoms, to
improve exercise ability and decrease
the rate of clinical worsening
Bosentan – Lab Monitoring
Liver function testing

Prior to initiation of treatment and monthly

↑ in ALT, AST or bilirubin. Dosedependent, typically asymptomatic, and
reversible after treatment cessation
 Hemoglobin


Prior to initiation of treatment
After 1 month, then every 3 months
 HCG

Prior to initiation of treatment and monthly
(teratogen)
Bosentan – Adverse Effects






Cardiovascular: edema (lower limb),
flushing, hypotension, palpitations
CNS: fatigue, headache
Dermatologic: pruritus
GI: dyspepsia
Hematologic: decrease in H/H
Respiratory: nasopharyngitis
~$40,000 per year
Prostanoids
Prostacyclins





Promote vasodilation
Inhibit platelet aggregation
Inhibit vascular smooth muscle proliferation
On treatment algorithm for WHO Class III or
IV
Only Flolan and Remodulin approved in US
Epoprostenol (Flolan )







Actions: relatively locally acting
vasodilatation and platelet inhibition
Most potent effect -- cardiac output in
patients with PAH
Resting HR, mean right atrial pressure,
and a marked improvement in survival
t½ = 3-5 mins
Abrupt cessation can be fatal
May worsen intrapulmonary shunt initially
Contraindicated in veno-occlusive disease
Epoprostenol


Adverse effects 2˚ delivery system

Pump malfunction

Catheter related infections

Thrombosis
Drug-induced side effects

Flushing, HA, dizziness, anxiety, hypotension, chest pain

N/V, abd pain, diarrhea

Myalgias, arthralgias, jaw pain, cramps, dyspnea

Thrombocytopenia, rash

Tolerance

Unstable (Reconstituted daily in alkaline buffer and refrigerated)

Cost

Outpatient cost up to $100,000 per year (adult)
Epoprostenol
Epoprostenol
Improved exercise capacity and hemodynamics
Sitbon, O et al. J Am Cardiol 2002;40:780-88
Epoprostenol/Treprostinil
Pump
Treprostinil (Remodulin)






IV or SQ administration
Longer half-life than epoprostenol (4 hrs)
Pre-mixed
Stable at room temperature
BUT
Need to change site /pump q3 days
Site pain major problem
SQ Remodulin
6 minute walk distance compared
Simonneau G. et al. Am J Resp Crit Care Med 2002;165:800-804.
Iloprost (Ventavis®)Inhalation
Solution
Indicated for inhalation via the Prodose® AAD® system only
 2.5 mcg initial dose

increase to 5 mcg if 2.5 mcg dose is tolerated

maintain at maximum tolerable dose (2.5 mcg or 5 mcg)
 6-9 inhalations daily during waking hours; 8-10 minutes each
Properties:
 Exerts preferential vasodilation in well- ventilated lung regions
 Longer duration of vasodilation than PGI2 (t ½ = 40 min)

Inhalational Iloprost
Olschewski et al, NEJM 2002, 347:322-9
Outcomes

Some improve




Some die rapidly




PPHN
Lung dx—as the dx improves, so does the PHTN
In the absence of a correctable anatomic lesion, reports of
spontaneous remission are very rare
Pulmonary veno-occlusive disease and CHD leading to
cardiovascular collapse within one year
Alveolar capillary dysplasia
Congenital pulmonary vein stenosis
Some get worse slowly


Seems to be most common and may need lung transplant
Must stay on top of associated OSA, RAD, chronic aspiration
and other triggers
Who is a Candidate for Lung Tx?




PHTN associated with rapid death
All previous medical therapy has failed, and
the probability of survival for another 2 yrs
predicted to be <50%.
Nutritional and psychological issues
important
Time to listing is a function of:



Predicted duration of survival
Predicted waiting time on transplant list
Survival rates: 1 yr = 65-70%, 5 yr = 40-50%
Outcome of Children with PHN
referred for Lung Tx



8/24 children with PHN referred for LTX
died prior to transplant
Retrospective application of predictive
score (RA x PVR) showed that death
prior to tx was predictable (p<0.009)
1/3 of children with PHN are referred for
LTX too late to be expected to survive
until organs become available.
Bridges, et al., 1996
Looking to the Future

Better therapies and prevention
require a better understanding of the
mechanisms which trigger and
perpetuate PHN:



The genetic basis of the disease
The role of proliferation and
neovascularization.
Better delivery methods for better
drugs.
Summary





Pulmonary arterial hypertension is a progressive
disease with significant morbidity and mortality
Right heart failure is an important development
which clearly prognosticates and marks disease
progression
Treatment of right heart failure is essential
Therapies with proven benefit in transpulmonary
hemodynamics, functional class and exercise
tolerance include ET-1 receptor antagonism
(bosentan), prostanoids, and oral sildenafil.
Continuous IV Flolan is reserved for advanced
(class IV) disease where there is a proven survival
benefit