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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?
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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?
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Initial Labs
Labs: electrolytes and CBCD wnl
CXR: mild cardiomegaly with decreased pulmonary markings
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Initial Labs
EKG
What study might be helpful next?
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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?
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Pulmonary Hypertension
The Basics
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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”
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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.
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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
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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.
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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
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What causes it?4th World Symposium - 2008 Classification
1. Pulmonary arterial hypertension (WHO group I)
a. idiopathicb. 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)
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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
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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
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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
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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
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Pathophysiology
Pulmonary vasomotor tone controlled by:
Vasoconstrictors Thromboxane ET-1 Leukotrienes Platelet activating factor
Vasodilators NO PGI2
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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 ATP-
sensitive K-channels. Immune dysfunction: autoimmune etiology in
some cases
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Diagnosis in Children 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!
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Diagnosis – Physical Signs
Cyanosis Low output Venous congestion Active right ventricular impulse Loud P2 High frequency TR murmur High frequency diastolic PR murmur
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Diagnosis - Testing Echo: Purely a screening tool
Identify TR. Add mean RAP to the peak tricuspid jet velocity to get an
estimate of peak pulmonary pressure Definitive dx needs direct measure of PAP
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
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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
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How do you treat it?
1. Improve alveolar oxygenation 2. Minimize pulmonary vasoconstriction 3. Maintain systemic blood pressure and
perfusion
4. …No therapy is perfect and none restores normal life expectancy
All treatment is palliative. Currently there is no cure
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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 agonistrelaxes airways and increases airflow.
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pH and PO2 Important for PVR
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PVR Increases at Lung Volumes Below and Above FRC
Lung Volume
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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”
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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, non-treated 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.
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Targets for Therapy
Humbert et al. New Engl J Med 2004
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How do you treat it?
Vasoactive medications Prostacyclins
Epoprostenol (synthetic prostacyclin (PGI2) aka Flolan®)
Treprostinil (Remodulin®), Iloprost (Ilomedin®, Ventavis®)
Endothelin receptor antagonists Bosentan (Tracleer®), Sitaxsentan (Thelin®),
Ambrisentan (Letairis®)
Phosphodiesterase type 5 inhibitors Sildenafil (Revatio®), Tadalafil (Cialis®)
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RCTs of Approved AgentsClass of DrugClass of Drug Study/Study/
DrugDrugNN
EtiolEtiolClass*Class*
Design Design PositiveResultsPositiveResults Dis-advantagesDis-advantages
ET-1Antagonist
BREATHE-1Oral Bosentan/placebo
213PAHIII,IV
Double-Blind16-wk
6 MWDSymptoms Clinical WorseningCPH
Hepatic toxicity (11%;transient, reversible)
PDE-5 Inhibitor SUPERSildenafil Citrate (20, 40 or 80 mg tid)
278IPAH,CTCHDII, III
Double-blind, placebo12 wks
6 MWDCPHSymptoms
Headache, flushing, dyspepsia
Prostacyclinanalogue
InhalationalIloprost/Placebo
203PHIII-IV
Double-blind12-week
Composite Endpoint6 MWD, sx
Administration6 to 9 times daily
Prostacyclinanalogue
SQ Treprostinil/SQ placebo
470PAHII-IV
Double-blind12-wk
6 MWDSymptomsCPH
Pain, erythemaat infusion siteSide effects
Prostacyclin IV Epoprostenol/Conventional Rx
81PPHIII,IV
Open-Label12-wk
6 MWDSymptomsCPHSurvival
Indwelling central linePump(infection,malf)Side effects
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Phosphodiesterase-5 Inhibitors
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cGMP Pathway
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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
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Sildenafil
In animal models of acute pulmonary hypertension sildenafil decreased pulmonary artery pressures in a dose-dependent manner
Several case reports now exist suggesting sildenafil is effective
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Sildenafil Trial
Galie, N, et al. Sildenafil Citrate Therapy for PAH. NEJM 2005;353:2148-57.
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Sildenafil Trial
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Sildenafil Study in Neonates
Sildenafil in neonatal PH due to impaired alveolarisation & plexiform pulmonary arteriopathyM Chaudhari, M Vogel, C Wright, J Smith, S G HaworthArch Dis Child Fetal Neonatal Ed 2005;90:F527–F528.
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Sildenafil
FDA approved dose is 20 mg tid
Higher doses often used given hemodynamic findings
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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 ………
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Endothelin Receptor Antagonists
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Endothelin
Clozel. Ann Med. 2003
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Endothelin is increased in IPAH and PAH associated with other Diseases
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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
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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
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BREATHE 1 Trial - Bosentan
Rubin LJ, et al. The New England Journal of Medicine; 2002; 346(12):896-903
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BREATHE 1 – 6min Walk Test
62.5 mg bid62.5 mg bid 125 or 250 mg bid125 or 250 mg bid
-40
-20
0
20
40
60 Bosentan (n = 144)Bosentan (n = 144)Placebo (n = 69)
BaselineBaseline Week 4Week 4 Week 8Week 8 Week 16Week 16
PP = 0.0002 = 0.0002
W
alk
Dis
tan
ceW
alk
Dis
tan
ce(m
eter
s)(m
eter
s)
Mean ± SEM
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BREATHE 1 – Time to Clinical Worsening
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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
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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
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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
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Bosentan – Lab MonitoringLiver function testing
Prior to initiation of treatment and monthly ↑ in ALT, AST or bilirubin. Dose-
dependent, 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)
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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
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Prostanoids
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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
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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
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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)
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Epoprostenol
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Epoprostenol
Improved exercise capacity and hemodynamics
Sitbon, O et al. J Am Cardiol 2002;40:780-88
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Epoprostenol/Treprostinil Pump
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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
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SQ Remodulin
6 minute walk distance compared
Simonneau G. et al. Am J Resp Crit Care Med 2002;165:800-804.
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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)
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Inhalational Iloprost
Olschewski et al, NEJM 2002, 347:322-9
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Outcomes
Some improve 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
Some die rapidly 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
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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%
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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
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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.
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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