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. 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)

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 ATP-

sensitive K-channels. Immune dysfunction: autoimmune etiology in

some cases

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!

Diagnosis – Physical Signs

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

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

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. 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

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.

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, 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.

Targets for Therapy

Humbert et al. New Engl J Med 2004

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®)

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

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 dose-dependent 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 arteriopathyM Chaudhari, M Vogel, C Wright, J Smith, S G HaworthArch 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

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

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 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)

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 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

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