PAH-CHD related

PAH-CHD related

Ming-Chih Lin M.D.

Division of Pediatric Cardiology Department of Pediatrics

Taichung Veterans General Hospital

Circulation. 1978 Dec;58(6):1107-22.

Pathophysiology

Cardiol Young. 2003;13(3):219-27.

Pathophysiology

P = F x r P = f x R

Lab Invest. 1986 Dec;55(6):632-53.

Pathology

Cardiol Young. 2003;13(3):219-27.

Pathology

Cardiol Young. 2003;13(3):219-27

Time frame of PAH

Survival of PAH in Children

J Am Coll Cardiol. 1997 Aug;30(2):554-60. Circulation. 2011;124(16):1755-64.

Definition of PAH in Children

• Mean PA pressure ≧ 25 mmHg

• For children

– PVR / SVR > 0.5

– PVRI > 3 Woods*m² – With PWP < 15 mmHg

JACC 2009; 54: S55~66 (The 4^th world symposium on pul. Hypertension) Heart 2001; 86 supple 1:1~13

Classification (Dana Point 2008)

• 1 PAH

– 1.4 Associated with (aPAH)

• 1.4.4 Congenital heart diseases

JACC 2009; 54: S43~54 (The 4^th world symposium on pul. hypertension)_

Clinical classification

• Eisenmenger syndrome

• PAH associated with systemic-to- pulmonary shunt

• PAH with small defect

• PAH with corrective cardiac surgery

J Am Coll Cardiol. 2009 ;54(1 Suppl):S43-54.

Functional Assessment

• 6-minute walk test not always feasible

• WHO function classification (1998) not suitable for infants

• Alternate indexes:

– Feeding

– Respiratory

– Abnormal respiratory pattern – diastolic filling sounds

– hepatomegaly

Pediatr Cardiol. 1992 Apr;13(2):72-5.

Epidemiology (REVEAL Registry, USA)

Chest. 2010;137(2):376-87.

Epidemiology (USA)

• 200 pediatric patients enrolled

• age at diagnosis <= 18 years, mean 8.0

• mean age at enrollment of 15.1 years

• Female (67%)

• At the time of enrollment,

– 38 (21%) functional class I, – 93 (52%) functional class II,

– 43 (24%) were in functional class III, – 5 (3%) were in functional class IV.

Chest. 2010;137(2):376-87. (REVEAL Registry, USA)

Epidemiology (Netherlands)

• Female predominating (2:1)

• Prevalence

– 15.6 cases/million APAH-CHD – 4.4 cases/million iPAH

Circulation. 2011;124(16):1755-64.

Nature course of iPAH in Children (USA)

Circulation. 1999;99(9):1197-208.

Nature course of iPAH in Children (USA)

Circulation. 1999;99(9):1197-208.

Prognosis (UK)

Heart. 2009 ;95(4):312-7.

Prognosis (UK)

Heart. 2009 ;95(4):312-7.

Improving in Prognosis after 2

^nd

G. medication (UK)

Heart. 2009 ;95(4):312-7.

Improving in Prognosis after 2

^nd

G. medication (Netherland)

Am J Cardiol. 2010;106(1):117-24.

Clinical Presentation

• Fatigue upon exertion

• Angina

• Syncope (not in Eisenmenger)

• Chest pain, hemoptysis

• Loud P2

• Hemoptysis, cyanosis (neonates)

• Cyanosis and polycythemia

• CVA

Diagnosis Evaluation

• ECG

• CXR

• Echocardiography

• Ventilation-Perfusion Scintigraphy

• Pulmonary Angiography

• Radionuclide Angiography

• MRI or CT

• Pulmonary function test

• Cardiopulmonary exercise tests

• Connective tissue disease and coagulation studies

• Lung biopsy

• Cardiac catheterization

Moss and Adams' Heart Disease in Infants, Children, and Adolescents.

Lippincott Williams & Wilkins, 2007/10/16

Treatment for PAH-CHD related

• Correct underlying disease

• But can it be done?

Operable or irreversible?

• Criteria

– PCRI < 6 Woods*m² ; Rp/Rs < 0.3

• 100% oxygen test

• iNO

• Prostacyclin iv or inh

• Considerations

– Polycythemia and increased PVR

• Fenestration on the patch

Pediatric Treatment Considerations

• Needing multiple-discipline specialists, and community-based family support

• Limitation of high-quality evidence

– Extrapolation from adult trial

– Validity compromised by disease entity APAH-CHD V.S. IPAH

General Measures

• Avoiding competitive team sports

• Cautious use of decongestant and NSAID

• Phlebotomy

• Avoiding pregnancy

• Oxygen

• Cardiac glycosides and diuretics

• Anticoagulation (INR 1.5 ~ 2.0)

Moss and Adams' Heart Disease in Infants, Children, and Adolescents.

Lippincott Williams & Wilkins, 2007/10/16

Specific Therapy

Circulation. 1999 Mar 9;99(9):1197-208.

Moss and Adams' Heart Disease in Infants, Children, and Adolescents. Lippincott Williams & Wilkins, 2007/10/16

Specific therapy

• iNO

• Silendafil

• Prostacycline analogues

• Endothelin antagonists

Nitric Oxide

Pediatr Cardiol. 2012 Feb 2.

Acute decompensation after surgery

One Day After iNO

Sildenafil

• PDE-Vi, NO-augmentation strategy

• US-FDA approved fro pediatric and adult patients (Revatio)

• Advantage: low cost and low toxicity

• Dose 1-5 mg/kg/day, divided 6~8 hours

• Disadvantages

– Needing P450

– Abd discomfort, dizziness, flushing, headached and nausea

Sildenafil for children of PAH

Circulation. 2005 Jun 21;111(24):3274-80.

For children under 2 years

J Pediatr. 2009 ;154:379-84

Medium dose favored

• Oxygen consumption, no difference between groups

• Improved in oxygen consumption, functional class and hemodynamic

suggesting efficacy with median and high doses (STARTS-1)

• Higher mortality in STARTS-2 data

• Medium dose favored (0.5~1 mg/kg/day)

Circulation. 2012 ;125(2):324-34.

Baby of CLD, frequent cyanotic spell

Sildenafil 0.25~0.375 mg/kg/dose

q6h, 1 weeks later

Prostacyclin Analogues

• cAMP pathway

• S.E.: headache, jaw pain, rashes, thrombocytopenia and flushing

• Epoprostenol (i.v.)

• Others

– Trerostinil (i.v.) – Beraprost (p.o.) – Iloprost (inh.)

• Needing more pediatric evidence

Iloprost for post-operative crisis

Clin Res Cardiol. 2011 Jul;100(7):595-602.

Endothelin antagonists

• Bosentan (ET_A + ET_B); selective (Ambrisentan)

• Shown efficacy both in adult and pediatric PAH patients

Bosentan in children of iPAH

Heart. 2006 ;92:664-70.

Bosentan in L-to-R shunt

Am Heart J. 2007 Oct;154(4):776-82.

Bosentan in PPHN

Acta Paediatr. 2009 Oct;98(10):1683-5. J Perinatol. 2011 Nov 10. doi:10.1038/jp.2011.157.

BREATH-5 trial

• Eisenmenger’s syndrome patient, Fc III, 16 weeks;

• RCT, double-blind

– Bosentan (37); placebo(17)

• Outcome

– PVRi -472 dyn*sec/cm⁵ – 6MWD + 53 m

– No increased in shunting

Circulation 2006; 114: 48~54

PAH Case Round:

An Unproportionate Case

林明志 傅雲慶 徐宗正

Division of Pediatric Cardiology Department of Pediatrics

Taichung Veterans General Hospital

History Brief

• 30-year-old female

• Chief complaint of chest pain

• GR 2-3 SM LUSB, fixed splitting S2

• Cardiomegaly by CXR

2005 2010

CXR, 2011

Hemodynamic Measurement

• SVC 53%, RA 69%, LPA 69%, RUPV 97%

– Qp/Qs = 1.57

• Pressure

– LPA 51/27/36 – PA 50/27/36 – RV 47/9

– RA11/11/9 – LA 12/10/9,

– LV 90/14; AO 82/58/69 – PUL WEDGE: N/A

• PVR/SVR=20%

Post Cath

• LPA 45/24/32

• PA 50/27/36

• RV 47/9

• RA11/11/9

• AO 82/54/63

6 months after ASOD

• C.C.

–Occasional chest pain

–Dizziness during postural change

Cath: 9 months after ASOD

• PCW 16/20/15 , LPA 74/32/51, MPA 74/34/52, RV 73/8, RA 16/15/13

• LV 84/10, AO 83/53/68, DAO 89/53/70

• PVR= 3.42 Wood Units,

• SVR= 20.32 Wood Units,

• PVR/SVR = 0.17

Work-up

• Autoimmune profile

– All negative

• SMA: non-significant findings

• D-dimer: WNL

• Thyroid profile: WNL

• Pulmonary function test: WNL

• Lung Scan: negative

• Lung CT: negative

Treatment

• Bosentan (62.5 mg) BID PO, self paid

• Warfarin 2.5 mg QD

• 6-min walk at last visit: 620 m

3 months later

Others

• Atrial septostomy

• Transplantation