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Pediatric Pulmonary Artery Hypertension: An Update for Respiratory Therapists

Alphonso Quinones, DHA, MA, RT, RRT-NPS, RPFT, RPSGT, CCT, AE-C, FACHE President, Quinones Healthcare Seminars, LLC Director Respiratory Therapy, North Shore University Hospital Past Chairman, New York State Licensure Board for Respiratory Therapy and Polysomnography

Pulmonary Artery Hypertension Objectives

•  Review epidemiology •  Discuss hemodynamic fundamentals •  Provide an overview of related

pharmacology

Pulmonary Arterial Hypertension in Pediatrics

•  PAH has no cure

•  Life-threatening disease, the prognosis of which has changed dramatically in the past decade

•  Introduction of new therapeutic agents

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Pulmonary Vascular Pressures and Hemodynamics

(8 mmHg) 15/4

4

2 15/2

15 50/15

10

(30mmHg) 50/20

Normal Pulmonary HTN

Pulmonary Hypertension

•  Definition: –  Mean PA pressure >25 mm Hg at rest –  Mean PA pressure >30 mm Hg with exercise –  Normal PCWP

–  Some definitions have also included the pulmonary vascular resistance, requiring the pulmonary vascular resistance index to be ≥3 Woods units x m2

Pulmonary Vascular resistance

(MPAP- PCWP) / C0

(15-10) / 5 = 1 WU

(25-10) / 5 = 3 WU

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RA

RV

LA

LV

LUNGS

PV

ORGAN SYSTEMS

AORTA

IVC/SVC

Hypoxemia Related PH

PA

Pulm Veno- Occlusive Dz

PPHTN

Thrombo- Embolic Dz

Cardiac Dysfn SPHTN

Changing Prevalence of PAH Over Time •  Although diagnosis of PAH remains

challenging, greater disease recognition and diagnosis may increase observed incidence

•  Improved survival will lead to higher prevalence –  Improving medical and surgical

options1

•  Prevalence may increase because of demographic trends in associated conditions –  ↑ incidence of connective tissue

disease2

–  ↑ prevalence of HIV infection/AIDS3

–  Trends in drug use (eg, methamphetamine)4

–  ↑ complexity of heart disease

1. McLaughlin and McGoon. Circulation. 2006;114:1417-1431. 2. Krishnan and Furst. Eur J Epidemiol. 2005;20:855-861. 3. Bokazhanova and Rutherford. Coll Antropol. 2006;30(suppl 2):3-10. 4. Chin et al. Chest. 2006;130:1657-1663.

*HIV infection is a significant risk factor for PAH.

Survival Diagnosis

Awareness

PAH

pre

vale

nce

Simonneau G, et al. J Am Coll Cardiol 2004;43:5S-12S

WHO Classification of PH (Venice, 2003)

Group 1. Pulmonary arterial hypertension [PAH] Group 2. Pulmonary hypertension with left heart failure Group 3. PH with lung diseases and/or hypoxemia Group 4. PH due to chronic thrombotic and/or embolic diseases Group 5. Miscellaneous

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WHO Functional Classification* of PAH: Predictor of Prognosis

Rich S ed. Executive summary of the World Congress on PPH 1998. http://www.who.int/ncd/cvd/pph.html

* New York Heart Assoc./World Health Org. modification

Class I No limitation of physical activity.

Ordinary physical activity does not cause undue dyspnea or fatigue, chest pain or near syncope.

Class II Slight limitation of physical activity.

Ordinary physical activity causes undue dyspnea or fatigue, chest pain or near syncope.

Class III Marked limitation of physical activity.

Less than ordinary physical activity causes undue dyspnea or fatigue, chest pain or near syncope.

Class IV Inability to perform any physical activity without symptoms.

Signs of right heart failure. Dyspnea and/or fatigue may be present at rest, and discomfort is increased by any physical activity.

Risk Factors for PH

•  Drugs: –  Fenfluramine – Aminorex –  Dexfenfluramine – Rapeseed oil

•  Female gender •  HIV infection •  Portal HTN/Liver Disease •  Collagen Vascular Disease •  Systemic-to-pulmonary cardiac shunts

PAH: Survival Based on Etiology1

1 2 3 4 5 Years

0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0

0

1. Adapted from McLaughlin VV et al. Chest. 2004;126:78-92.

Survival in PAH

CHD CVD HIV IPAH Portopulm

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Pathogenesis of PAH

Gaine S. J Am Med Assoc 2000;284:3160-68

Aventitia

Media

Intima

Smooth Muscle Hypertrophy

Early Intimal Proliferation

Collagen Vascular Disease Congenital Heart Disease Portal Hypertension HIV Infection Drugs and Toxins Pregnancy

Abnormal BMPR2 Gene Other Genetic Factors

Endothelial Dysfunction ↓Nitric Oxide Synthase ↓Prostacyclin Production ↑Thromboxane Production ↑Endothelin 1 Production

Vascular Smooth Muscle Dysfunction Impaired Voltage-Gated Potassium Channel (Kv1.5)

Smooth Muscle Hypertrophy

Adventitial and Intimal Proliferation

In situ Thrombosis

Plexiform Lesion

Loss of Response to Short-Acting Vasodilator Trial

Vasoconstriction Advanced Vascular Lesion

IRREVERSIBLE DISEASE

Pulmonary HTN Questions

Respond with true or false. 1. Pulmonary HTN can be cured with appropriate treatment.

- False 2. Diagnostic criteria for pulmonary artery HTN include:

–  Mean PA pressure >25 mm Hg at rest –  Mean PA pressure >30 mm Hg with exercise –  Normal PCWP

- True

Pathogenesis of PH •  Unclear, but at least 3 processes believed to

contribute to arterial narrowing

–  Vasoconstriction

–  Vascular remodeling

–  Thrombosis in situ

Frost A, 2002

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Pathogenesis of PAH

Vasoconstriction

Mutation of

BMPR-2

Thrombosis Proliferation

Symptoms of PAH in Children Symptoms of PAH in children are frequently misleading, should be suspected in any child with: -  undue shortness of breath -  tiredness -  syncopal episodes.

PAH rare in children, except for PH related to congenital heart disease PAH must be confirmed with catheterization, and pulmonary vasoreactivity testing should be performed, usually with inhaled nitric oxide (NO)

Diagnosis Signs & Symptoms

•  HISTORY –  Dyspnea (>95% long term) – Fatigue (25%) –  Syncope (10%) – Hemoptysis –  Raynaud’s (10%) – Angina (20%) –  Medication use

•  PHYSICAL EXAM –  JVD – ↑ Pulm S2 –  ↑ a wave – RV S3 (50%) –  Hepatomegaly – Cyanosis –  TR murmur (70%) – Edema

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CXR

•  Enlarged central PA

•  Enlarged RV •  Sequelae of

underlying dx (COPD)

CXR

EKG

•  RV hypertrophy •  Tall precordial R waves •  R axis deviation

•  RV Strain •  Inc RBBB

The 6 Minute Walk

Miyamoto Am J Respir Crit Care Med 2000; 161:487

•  Timed walk at submaximal pace measuring distance, O2 saturation, BP and HR

•  Can stop if needed •  Strong independent association with

mortality in PPH

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6MWD sources of variability [Factors reducing the 6MWD]

•  Shorter height •  Older age •  Higher body weight •  Female sex •  Impaired cognition •  A shorter corridor (more turns) •  Pulmonary disease (COPD, asthma, cystic fibrosis, interstitial lung

disease) •  Cardiovascular disease (angina, MI, CHF, stroke, TIA, PVD, AAI) •  Musculoskeletal disorders (arthritis, ankle, knee, or hip injuries,

muscle wasting, etc.) •  Factors increasing the 6MWD •  Taller height (longer legs) •  Male sex •  High motivation •  A patient who has previously performed the test •  Medication for a disabling disease taken just before the test •  Oxygen supplementation in patients with exercise-induced hypoxemia

Pressure = Flow X Resistance

PVR = Mean PAP – Mean PCWP Cardiac Output

Vascular resistance relates to the radius of the vessel to the fourth power – therefore small changes in vessel caliber (or lumen size) will have a substantial effect on the resistance to flow within that vessel

Vasodilator Challenge (Inhaled Iloprost, NO)

•  Does the patient have reversible vasoconstriction? [Responder] –  (defined as a fall in mPAP of at least 10

mm Hg to ≤40 mm Hg, with an increased or unchanged CO)

–  [ PVR = mean PA-PCWP/CO] – “Responders” to NO → CCB – Non Responders → epoprostenol , bosentan,

Treprostinil , Inhaled Iloprost

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Questions

Respond with true or false. 1. CXR finding of enlarged central PA and enlarged RV are consistent with PHTN.

- True 2. Calcium Channel Blockers are the treatment of choice when the PHTN patient “responds” to Nitric Oxide or Inhaled Iloprost.

- True

PAH Pharmacology •  Chronic Calcium Channel Blockers Chronic calcium channel blockade is efficacious in patients who

demonstrate an acute response to vasodilator testing. Approximately 7% to 40% of children with chronic PAH are ‘‘responders’’ and can be effectively treated with oral calcium channel blockers

•  Prostacyclin Metabolite of arachidonic acid endogenously produced by the

vascular endothelium. It is a potent pulmonary and systemic vasodilator with anti-platelet activity.

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Prostacyclin Epoprostenol ( Flolan)

•  A synthetic prostacyclin used via intravenous infusion

•  Epoprostenol is known to lower PAP, increase cardiac output and increase oxygen transport.

•  Barst et al have shown improved survival rate in children treated with long-term intravenous epoprostenol, with a 4-year survival rate for treated children of 94%, compared with 38% in untreated patients

Epoprostenol ( Flolan)

Administer continuous chronic infusion of Flolan through a central venous catheter. Temporary peripheral intravenous infusion may be used until central access is established.

Prostacyclin

Iloprost • Is an inhaled prostacyclin, a longer half-life of 20 to 30 minutes. In children treated with iloprost, World Health Organization (WHO) functional class has been shown to: 1. Be improved in 35% 2. Remained unchanged in 50%, and 3. Decreased in 15%. Lower-airway reactivity is a problem in some children, as is poor compliance with the need for frequent aerosol administrations (6–8 times daily).

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Iloprost

Prostacyclin Treprostinil ( Remodulin)

•  A prostacyclin usually administered with continuous subcutaneous infusion and also is approved by the US Food and Drug Administration (FDA) for intravenous and inhaled delivery.

•  Subcutaneous treprostinil has been shown to improve exercise tolerance, clinical signs, symptoms, and hemodynamics in adult patients with PAH, but discomfort at the infusion site is common and represents the most limiting factor in children.

Treprostinil ( Remodulin)

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Endothelin Endothelin-1 (ET-1) is a potent vasoactive peptide produced in the vascular endothelial cell and smooth muscle cells. •  Two receptor sub-types, ETA and ETB, mediate

the activity of ET-1. •  ETA and ETB receptors on vascular smooth

muscle mediate vasoconstriction, whereas ETB receptors on endothelial cells cause release of NO and prostacyclin

Endothelin •  Bosentan •  Is an oral dual endothelin receptor antagonist acting on both

ETA and ETB receptors.

•  Bosentan has been shown to lower mean PAP and PVR and improve WHO functional status and survival estimates at 1 and 2 years (98% and 91%, respectively).

•  However, in a study including both children and adults with PAH and systemic-to-pulmonary shunt, bosentan therapy has been shown to produce only short-term improvement

Endothelin Sitaxsentan and ambrisentan •  Oral selective ETA receptor antagonists with a long

half life. •  They block the vasoconstrictor effect of ETA

receptors while maintaining the vasodilator effect. •  Sitaxsentan and ambrisentan have shown beneficial

effects on exercise capacity and New York Heart Association functional class in adult patients, but little data are available for children.

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Phosphodiesterase type 5 inhibitors

•  Phosphodiesterase type 5 inhibitors prevent the breakdown of cyclic guanosine monphosphate, resulting in pulmonary vasodilation.

•  Phosphodiesterase type 5 inhibitors are acute pulmonary

vasodilators as efficient as inhaled NO and potentiate pulmonary vasodilation with NO.

Phosphodiesterase type 5 inhibitors

Sildenafil •  Can be used orally, and recently the intravenous

formulation has been approved by the FDA. •  Sildenafil has been approved for the treatment of WHO

functional class II to IV PAH in adults •  In a pilot study of 14 children with PAH, oral sildenafil

decreased PAP and PVR significantly and improved the mean 6-MWD

Phosphodiesterase type 5 inhibitors

Sildenafil •  A recent study of intravenous sildenafil has shown

improvement in oxygenation index in persistent pulmonary hypertension of the newborn in patients treated with or without inhaled NO

Tadalafil •  A selective phosphodiesterase type 5 inhibitor with a

longer duration of action (half life, 17 hours). Tadalafil was recently approved by the FDA in 2009 for adults with PAH, but no data are available in children.

• 

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Creation of a Right-to-Left Shunt and Transplantation Children not responding to conventional medical therapy may

be candidates for - atrioseptostomy, or -  transplantation Right-to-left shunting through an Atrioseptostomy allows maintenance of cardiac output at the expense of increased hypoxemia and alleviates signs of right heart failure by decompression of the right heart. Transplantation reserved for children when their probability of 2-year survival without transplantation is ≤50%.

Therapeutic Approach •  There are no evidence-based treatment

recommendations for children with PAH

•  The aim of medical treatment is to dilate and reverse the abnormal remodeling of the pulmonary vascular bed and to restore endothelial function

•  Prostacyclin, Endothelin, and NO pathways In practice, a therapeutic algorithm similar to PAH in

adults appears to guide treatment of children with PAH.

Is there a reason to suspect PAH? Clinical history, Exam, CXR, ECG

No further evaluation necessary

Is PAH Likely? Echocardiogram

No

Is PAH due to LH Disease? Echo

Measure RVSP, RVE, RAE, RV dysfunction

Dx LV systolic; diastolic dysfunction; valvular dysfunction. Appropriate treatment and further evaluation if necessary

Yes

Is PAH due to CHD? Echo with contrast

Rationale

Dx abnormal morphology; shunt surgery; medical treatment of PAH or evaluation for further definition or contributing causes

Yes

ACCP Diagnostic Guidelines

McGoon, et al. Chest 2004

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ACCP Diagnostic Guidelines

Is PAH due to CTD, HIV? Serologies

Is chronic PE suspected? V/Q scan

Dx scleroderma, SLE, other CTD, HIV. Medical treatment for PAH and further evaluation for contributing causes

Is chronic PE confirmed and operable? Pulmonary angiogram

Yes

Is PAH due to lung disease or hypoxemia? PFT’s, arterial saturation

Yes

Thromboendarterectomy if appropriate or medical treatment

No

Yes

Dx parenchymal lung disease, hypoxemia or sleep disorder. Medical treatment, oxygen, positive pressure breathing, and further evaluation for other contributing causes

Yes

McGoon, et al. Chest 2004

ACCP Diagnostic Guidelines (cont.)

McGoon, et al. Chest 2004

What limitations are caused by the PAH?

FC, 6 MWT

What are the precise hemodynamics?

RHC

Document PA and RA pressures, PCWP (LV or LA pressure if PCWP unobtainable or uncertain), transpulmonary gradient, CO,PVR,SvO2,response to vasodilators: Confirm PAH , or IPAH if no other cause identified. Discuss genetic testing and counseling of IPAH family

Document exercise capacity regardless of cause of PH: Establish baseline, prognosis and document progression/response to treatment with serial re-assessment

Pulmonary Arterial Hypertension: Goals of Therapy

•  Improve hemodynamics

•  Improve exercise capacity

•  Improve functional class

•  Prevent clinical worsening

•  Improve survival

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Conclusion •  Advances in the understanding of pulmonary vasculature

has led to new therapeutic options and improved survival rates in children with PAH.

•  Timely diagnosis is crucial because earlier treatment

leads to improved outcome. •  Initial evaluation includes acute vasodilator testing at

cardiac catheterization, which determines initial therapy.

•  RTs have an evolving role in the care of children with PAH.

Any Questions?

References •  1. McLaughlin VV, Archer SL, Badesch DB, Barst RJ, Farber HW, Lindner JR, et al. ACCF/AHA 2009 expert consensus

document on pulmonary hypertension: a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association: developed in collaboration with the American College of Chest Physicians, American Thoracic Society, Inc. and the Pulmonary Hypertension Association. Circulation. 2009;119:2250–94. [PubMed]

•  2. Barst RJ, Maislin G, Fishman AP. Vasodilator therapy for primary pulmonary hypertension in children. Circulation. 1999;99:1197–208. [PubMed]

•  3. Ivy DD, Feinstein JA, Humpl T, Rosenzweig EB. Non-congenital heart disease associated pediatric pulmonary arterial hypertension. Prog Pediatr Cardiol. 2009;27:13–23. [PMC free article] [PubMed]

•  4. Badesch DB, Champion HC, Sanchez MA, Hoeper MM, Loyd JE, Manes A, et al. Diagnosis and assessment of pulmonary arterial hypertension. J Am Coll Cardiol. 2009;54(1 Suppl):S55–66. [PubMed]

•  5. Simonneau G, Robbins IM, Beghetti M, Channick RN, Delcroix M, Denton CP, et al. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol. 2009;54(1 Suppl):S43–54. [PubMed]

•  6. van Loon RL, Roofthooft MT, van Osch-Gevers M, Delhaas T, Strengers JL, Blom NA, et al. Clinical characterization of pediatric pulmonary hypertension: complex presentation and diagnosis. J Pediatr. 2009;155:176–82. e1. [PubMed]

•  7. Fraisse A, Jais X, Schleich JM, di Filippo S, Maragnes P, Beghetti M, et al. Characteristics and prospective 2-year follow-up of children with pulmonary arterial hypertension in France. Arch Cardiovasc Dis. 2010;103:66–74. [PubMed]

•  8. Beghetti M, Hoeper MM, Kiely DG, Carlsen J, Schwierin B, Segal ES, et al. Safety experience with bosentan in 146 children 2–11 years old with pulmonary arterial hypertension: results from the European Post-marketing Surveillance program. Pediatr Res. 2008;64:200–4. [PubMed]

•  9. Haworth SG, Hislop AA. Treatment and survival in children with pulmonary arterial hypertension: the UK Pulmonary Hypertension Service for Children 2001–2006. Heart. 2009;95:312–7. [PubMed]

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