child with pulmonary hypertension

1. Dr. K.Nagendra prasad

2. TOPIC OUTLINE
 INTRODUCTION
 ANATOMY OF PULMONARY CIRCULATION
 DEFINITION & CLASSIFICATION of PAH
 PATHOPHYSIOLOGY
 EPIDEMIOLOGY & SURVIVAL
 CLINICAL PRESENTATION
 EVALUATION
 PHORMOCOLOGICAL THERAPY
 OTHER METHODS

3. INTRODUCTION
 Pulmonary hypertension (PH) is a rare disease in newborns, infants,
and children that is associated with significant morbidity and
mortality.
 The distribution of etiologies in children is quite different than that of
adults, with a predominance of idiopathic pulmonary arterial
hypertension (IPAH) and PAH associated with congenital heart disease
(APAH-CHD).
 In pediatric populations, IPAH is usually diagnosed in its later stages
due to nonspecific symptoms.

4.  Without appropriate treatments, median survival rate after diagnosis
of children with IPAH appears worse when compared with that of
adults.
 Therapeutic strategies for adult PAH have not been sufficiently studied
in children, especially regarding potential toxicities, formulation, or
optimal dosing, and appropriate treatment targets for goal-oriented
therapy in children are lacking.

5. Normal Anatomy of the Pulmonary Circulation
 The lung has a unique double arterial blood supply from the pulmonary
and bronchial arteries, as well as double venous drainage into the
pulmonary and azygos veins.
 Pulmonary arteries:
 Elastic: conducting vessel, ≥ 500 μm, highly distensible
 Muscular: 100-500 μm, no elastin, non distensible
 Arterioles: ≤ 100 μm, thin intima and single elastic lamina
 Bronchial arteries: nutrition to the airways
 The pulmonary circulation is characterized by high flow (the entire right
ventricular output) and by low pressure and low resistance due to Its wide
and thin-walled vessels.
 The normal pulmonary vascular bed offers less than one-tenth the
resistance to flow offered by the systemic bed.

7. CHANGES AFTER BIRTH
 The pulmonary circulation undergoes important physiologic and
anatomic changes in the first hours, weeks, and months of life.
 In utero, the pulmonary arteries are relatively thick walled, and
pulmonary vascular resistance is very high, limiting pulmonary blood
flow to less than 10% of combined right and left ventricular output.
 At birth PBF increases 8-10 times with a fall in pulmonary pressure to
a level less than 50% of systemic pressure.
 Reason - the combined effects of mechanical expansion of the lung,
increased oxygen tension, and shear stress lead to an increase in
prostacyclin and nitric oxide (NO) synthesis and to the release of
humoral substances such as bradykinin and adenosine.
 By 6 to 8 weeks, pulmonary vascular resistance usually has reached a
normal adult level of 1 to 3 Wood units

8. GROWTH AND REMODELLING OF NORMAL PUMONARY
VASCULAR BED WITH AGE

9. DEFINITION
 Pulmonary hypertention is defined as a mean pulmonary artery
pressure (PAP) greater than 25 mm Hg at rest.
 A mean PAP of 8 to 20 mm Hg at rest is considered normal.

11. CLASSIFICATION OF PULMONARY
HYPERTENSION
 Dana Point classification(2008) is modified by Pediatric
Task Force of the 5th World Symposium on Pulmonary
Hypertension (WSPH) in Nice, France (2013).

15. 10 basic categories of Pediatric Pulmonary Hypertensive Vascular Disease

18. Eisenmenger Syndrome - Underlying Basic Lesions
Type of lesion Somerville’98(n=132) Daliento
’98(182)
Ventricular Septal Defect 45 71
Atrial Septal Defect 6 21
Patent ductus arteriosus 12 36
Atrio ventricular septal defect 16 23
Truncus arteriosus 15 11
Single ventricle 13 9
Transposition of great
arteries
5 8
Others 20 9

19.  The task force also recognized lesions in which pulmonary vascular
disease is likely, but the specific criteria for PH are not met, and thus
are not included in the Nice clinical classification.
 This includes patients with single ventricle physiology who have
undergone bidirectional Glenn or Fontan-type procedures.
 In this setting of nonpulsatile flow to the pulmonary arteries, PAP may
not be >25 mm Hg; however, significant pulmonary vascular disease
can lead to a poor outcome.
 PH in the setting of single ventricle physiology is defined as a
pulmonary vascular resistance index >3.0 Wood units × m2 or a
transpulmonary gradient >6 mm Hg.
 segmental PAH include pulmonary atresia with ventricular septal
defect and major aortopulmonary collateral arteries and branch
pulmonary arterial stenosis of variable severity.

20. ETIOLOGY
 In children, idiopathic PAH, heritable PAH, and APAH-CHD constitute
the majority of cases, whereas cases of PAH associated with connective
tissue disease are relatively rare.
 Largest registries of PH – TOPP & REVEAL

21. TOPP Netherlands PH Service
 88% - group 1
1. 57 % - IPAH /HPAH
2. 36% - APAH
 12% - respiratory disease or
hypoxemia, with BPD the
most frequent.
 3 patients out of 366 – CTPE
 BPD is the most frequent
chronic lung disease
associated with PH
 Down s syndrome – 13%
 86% - group 1 - (transient -81%,
progressive – 5%)
 5% - group 2
 8% - group 3
 < 1% - group 4
 Downs syn – 12%
 The most common causes of
transient pulmonary
hypertension were PPHN (58%)
and APAHCHD (42%).
 In the progressive PAH cases,
APAH-CHD (72%) and IPAH
(23%) were common causes.

23. Survival rates
 Without appropriate treatments, median survival rate after diagnosis
of children with IPAH might be worse compared to adults, and was 10
months for children in the NIH registry.
 With the usage of targeted pulmonary vasodilators, the survival rate
has continued to improve in pediatric patients with PAH.
 Patients with childhood-onset PAH in the combined adult and
pediatric U.S. REVEAL registry demonstrated 1-, 3-,and 5-year
estimated survival rates from diagnostic catheterization of 96 ± 4%, 84
± 5%, and 74 ± 6%, respectively.
 Another study from UK showed that The survival rates of IPAH were
85.6%, 79.9%, and 71.9% at 1, 3, and 5 years, respectively, whereas
APAH-CHD survival rates were 92.3%, 83.8%, and 56.9% at 1, 3, and 5
years, respectively.

25. Second Congenital Heart Disease Natural History
Study (1993)
 Demontrated that patients with ES can survive for several decades
following diagnosis.
 In this study, 54% of 98 unoperated patients with ventricular septal
defects and ES were alive 20 years after diagnosis
Survival rates in ES :
 30 years of age: 75%
 40 years of age: 70%
 55 years of age: 55%

27. WHY GOOD PROGNOSIS?
1. RV appears to adapt to the rise in pressure through hypertrophy and
preservation of a fetal-like phenotype.
1. Regression of the physiologic right ventricular hypertrophy does not
occur and the right-to-left shunt serves as an excess flow valve.
1. Ability of Eisenmenger patients to maintain their systemic CO at the
expense of cyanosis

29. PATHOPHYSIOLOGY of PAH
 Panvasculopathy predominantly affecting small PA
 Exact mechanism is unknown, abnormalities in pulmonary
artery endothelial & smooth muscle cells (PASMCs) with
varying degrees of
I. Vasoconstriction, [PASMCs, K+ &Ca2+ channels]
II. Vascular proliferation, [PASMCs, ECM syn.] SERT ON
PASMCs: apoptosis , proliferation
III. Thrombosis, and
IV. Inflammation
contribute to the development of pulmonary hypertension

30. Endothelial cell dysfunction plays
major role in pathogenesis of PAH.

31. Probable pathways causing changes in pulmonary
endothelial and smooth muscle cells

34. Factors predisposing for in situ thrombosis during the
development of pulmonary arterial hypertension

35. PATHOGENISIS OF PAH IN EISENMENGER SYNDROME

36. PAH associated with heart Defects with Decreased
Pulmonary Blood Flow
 Condition like
 PA with intact IVS
 TOF
 Reasons for development of pulmonary hypertension:
 Hypoplasia of pulmonary arteries.
 Intra-acinar pulmonary arteries are small and few in number.
 Alveolar development is impaired (mostly reduction in alveolar number)
 ↑ Hematocrit resulting in in-situ thrombus.

37. PERSISTENT PULMONARY HYPERTENSION OF NEWBORN
 PPHN occurs primarily in term or late preterm infants ≥34 weeks
gestation.
 Three types of abnormalities: underdevelopment, maldevelopment,
and maladaptation of pulmonary vasculature.
 Experimental and clinical evidence suggests that injury to the
developing pulmonary circulation may disrupt vascular endothelial
growth factor (VEGF) signaling and contribute to these abnormalities.

39.  Stage I - Medial hypertrophy (reversible)
 Stage II - Cellular Intimal hyperplasia in a abnormally
muscular artery (reversible)
 Stage III - Lumen occlusion from intimal hyperplasia of
fibroelastic tissue (partially reversible)
 Stage IV - Arteriolar dilation and medial thinning
(irreversible)
 Stage V - Plexiform lesion, which is an angiomatoid
formation (terminal and irreversible)
 Stage VI - Fibrinoid/necrotizing arteritis (terminal and
irreversible
Heath-Edwards Classification
Rever
sible
Irre
vers
ible

42. Lung biospy
Grade Peripheral arteries Medial
thickness(muscular
arteries)
Arterial
concerntration
Grade A Muscle extened
into peripheral
arteries
<1.5 times N
NormalGrade B ( mild ) Increased
extension
1.5 to 2 times
Grade B (severe) > 2 times N
Grade C Arterial
concerntration
and size reduced

43.  Patients surgically corrected between 9 months and 2 years of life with
grade C and Heath–Edwards II or III structural changes may have
persistent elevation in pulmonary vascular resistance; this appears
inevitable in patients operated after the age of 2 years.
 A biopsy showing severe grade C and grade III or greater changes in
20% of vessels indicative of severe vascular disease that is unlikely to
regress postoperatively.
 Severe grade B, or grade II changes in any vessel may preclude a
favorable result from a Fontan procedure.

44. Right Ventricular Changes

46. Symptoms - frequently misleading
or subtle in children
1. Exertional dyspnea,
2. Lethargy, and
3. Fatigue,
In ability to
increase cardiac
output
1. Exertional chest pain (ie, angina),
2. Exertional syncope, and
3. Peripheral edema
The PH progresses
and right
ventricular failure
develops.

47. Right ventricular wall stress & Myocardial oxygen demand
Subendocardial hypoperfusion
Angina
Dynamic compression of the left main
coronary artery by an enlarged
pulmonary artery(if PA > 40mm)

49.  Other clinical symptoms may include hemoptysis, chest pain,
dizziness, arrhythmias, or in advanced disease, symptoms of right
heart failure.
 Passive hepatic congestion may cause anorexia and abdominal pain in
the right upper quadrant.
 In infants, symptoms are less specific and may involve poor appetite,
failure to thrive, lethargy, diaphoresis, tachypnea, tachycardia, and
irritability.

50. SIGNs
 Single and loud second heart sound without respiratory variation, right
ventricular lift, and hepatomegaly with peripheral edema in the case of
heart failure.
 In cases of severe disease, the second heart sound may be palpable.
 A diastolic murmur of pulmonary insufficiency, a holosystolic murmur
of tricuspid regurgitation, or gallop rhythm may be audible.

51. IPAH EISENMENGER
DURATION of
SYMPTOMS
SHORT
Development of HF RAPID
CENTRAL CYANOSIS LATE EARLY
HEMOPTYSIS RARE COMMON
SYNCOPE COMMON RARE
CLUBBING RARE PROMINENT
JVP - a wave prominent Less
Left parasternal heave prominent Less
Left 2nd ICS pulsation less more
S2 Single / narrow
P2 – not loud
1. ASD –wide fixed
2.VSD–single(55%),wide varying(12%)
3.PDA–narrow/wide varying(50%),
single(6%)
TR / PR murmur More common Less common

54. ECG
 RVH – tall R in v1 , R/S >1 , a qR complex in lead V1 or V3R regardless of
voltage.
 An upright T wave in V1 is indicative of right ventricular hypertrophy
from 7 days to 7 years.
 Right atrial abnormality – tall peaked P in lead 2
 RIGHT axis deviation
 Secondary ST- T Changes in V1- V4.
 RBBB – uncommon manifestation
 RVH ± RAD is present nearly 90% of patients.
 A normal ECG is reported in <5% cases.

55. CXR - Pulmonary artery hypertension
 Central pulmonary arterial
dilatation;
 Pruning of the peripheral arteries;
 Increased diameter (14 mm in
women and 16 mm in men) of the
right descending pulmonary artery,
measured from its lateral aspect to
the interlobar bronchus; and

56.  Lateral chest radiograph shows filling
of the retrosternal airspace, a result of
right ventricular dilatation.
 The right ventricle is in contact with
more than one-third of the distance
from the sternodiaphragmatic angle
to the point where the trachea meets
the sternum.

57.  Pulmonary venous hypertension – dilated upper lobe veins ,
perivascular cuffing , ground glass appearance of lung fields , kerly B
lines, thickened minor fissure.
 Shunt lesions – shunt at atrial and ventricular level may results in
inconspicuous aorta , shunt at arterial level leads to dilated ascending
aorta.
 Lund parenchymal diseases – ILD , COPD.
 Chronic thromboembolic PH- focal hypovascularity

58.  Chest radiography findings may be useful to uncover secondary causes
of PH.
 Pulmonary venous congestion may suggest PVOD or PCH;
 hyperinflation or kyphosis are signs of restrictive lung disease;
 asymmetry of the enlarged central pulmonary arteries may warrant
investigation of chronic thromboembolic disease or PPHTN.
 Asymmetric lung volumes may suggest either pulmonary arterial or
pulmonary venous abnormalities.

59. Echocardiographic Assessment
 Echocardiography with Doppler studies is the most useful first line
investigation in a patient presenting with clinical features suggestive of
pulmonary hypertension.
 It facilitates:
1) Estimation of pulmonary artery systolic pressure to determine if PH is
present.
2) Assessment of cardiac cause of PH
3) Assessment of severity of RV dysfunction
4) Assessment of prognostic variables

60.  Pulmonary valve M-Mode
1. Diminished or absent a
2. Presence of mid-systolic closure or
notching
3. Fluttering of the posterior
pulmonic leaflet

61. Estimating Pulmonary Artery Systolic Pressure
 Echocardiographic evaluation of pulmonary artery systolic pressure
(PASP) relies on the fact that PASP approximates right ventricular
systolic pressure (RVSP) in the absence of right ventricular outflow
obstruction.
 The most accurate echocardiographic method for estimating (PASP)
uses the simplified Bernoulli equation to obtain a systolic trans-
valvular pressure gradient.
 DPRV-RA = 4(VTR)2
 PASP » RVSP = 4(VTR)2 + RAP

63. ESTIMATION OF RAP
 Qualitative Features that suggest elevated RAP in ECHO –
1. RA enlargement
2. Persistent bowing of atrial septum toward left atrium
3. Dilated coronary sinus
4. Dilated IVC and hepatic veins.

65. Other methods to asses RAP
 Ratio between Tricuspid valve E velocity and tricuspid annulus tissue
doppler velocity E’ .
 If the ratio is >6 , RAP of >10 mmhg is predicted with a sensitivity of
79% and specificity of 87.7%.

66. Hepatic vein (HV) flow velocities
 The HV flow velocity profile consists of 4 components, 2 in forward
flow and 2 in flow reversal, each with a systolic and diastolic
component (S, D and SR, SD).
 Normally, there should be no prominent reversal of velocities and S is
higher than D.

68.  As RV filling pressure increases, flow reversal in systole and
diastole becomes prominent and is augmented by inspiration.
 HV diastolic flow reversal is seen in PH and constrictive pericarditis.
Respiratory variation helps differentiate between them.
 It is augmented with expiration in constriction, whilst in PH it remains
constant.

69.  Hepatic venous systolic filling fraction -
VTI of systolic flow/ systolic +diastolic flow VTI
 A Value of<55% is suggestive of RAP being heigher than 8mmhg with a
sensitivity of 86% and specificity of 90%.

70.  ESTIMATION of PAP in pts without PR /TR
 RV IVRT/HR >65 ms identifies those with PASP >40 mmhg.
 But if RA pressure is high ,IVRT may be shorter despite pumonary
hypertension.

71. PUMONARY ARTERY ACCELERATION TIME
 In normal individuals, AcT exceeds 140 milliseconds and progressively
shortens with increasing degrees of pulmonary hypertension.
 The shorter the acceleration time, the higher the pulmonary artery
pressure.

73. MEAN PAP
 Mpap = 0.61 × spap + 2mmhg
 Mpap = 4 × early diastolic PR velocity
 MPAP= 4× mean velocity of TR +RAP
 MILD PAH : 25 to 40 mmhg
 MODERATE : 40 – 55 mmhg
 SEVERE : >55 mmhg

74.  Mpap = 79-(0.45×acceleration time)
 If AT <120 ms ; Mpap = 90-(0.62×AT )
 This method is relatively easy to perform, highly reproducible, and
unlike pressure estimates based on tricuspid regurgitation velocity,
Doppler recordings from the RVOT are available in virtually all
patients.

75. DIASTOLIC PAP
 Dpap =( 4×end diastolic velocity of PR jet)+ RA pressure
 Dpap = 0.49 × SPAP
 In cases where PR jet is not available , RV pressure at the time of pulmonary
valve opening from TR velocity spectrum can be used.

76. PVR
 Pressures are flow dependent, so assessment of disease severity cannot
be reliably done from systolic pressure alone.
 Ex – pts with advanced PH , decreased RV function RVSP is lower than
expected.
 In these situations calculation of PVR is more dependable.

77.  PVR= ( TR velocity/RVOT VTI) 10₊0.16
 A TRV/RVO VTI cutoff value of 0.175 had a sensitivity of 77% and
specificity of 81% to determine PVR >2 WU.
 If >0.275 ,PVR of >6wu is very likely.
 But this equation performed poorly(underestimation) when PVR >8

78.  PVR = (RVSP – E/e’ )RVOT VTI
 This equation performed better than the previous one
when compared to invasively measured PVR.

79.  LINDQVIST method-
PVR= mPAP – PAWP / CO
Mpap= PASP × 0.61+ 2 mmhg
PAWP is assumed to be 10 mmhg
CO = LVO VTI × CSA of LVOT × heart rate

80. Assessing Severity of RV Dysfunction
 Assessment of right ventricular function is the single most important
aspect of the DE examination in patients with known or suspected
PVD
 As the morbidity and mortality associated with this condition is
heavily dependent on the degree of adaptation of the right ventricle to
its excessive pulmonary vascular load.

81.  The right ventricle is better suited for volume work.
 When there is afterload mismatch RV dilatation is seen.
 When RV dilates it assumes a bullet shape in A4C view and circular in
SAX view.
 The ratio of right ventricle to left ventricle size at end systole is a strong
predictor of outcome.

82.  SYSTOLIC FLATTENING OF IVS
 Degree septal bowing is quantified by measuring LV ECCENTRICITY
INDEX.
 Normally LV is circular in both systole and diatole ,with both vertical
and horizontal dimensions of the cavity is equal.
 Normal index is 1.
 Mild septal flattening – 1.1 to 1.4
 Moderate – 1.5 to 1.8
 Severe - >1.8

84. TAPSE
 TAPSE can be derived from 2D echo or M-Mode , is simple to perform
and has been shown to be highly reproducible, owed in part to the lack
of reliance on RV endocardial definition or geometric assumptions.

85. TDI
 Tissue Doppler imaging (TDI) can also be used to measure the velocity
of RV contraction in the longitudinal axis (denoted S’ or Sa), correlates
with TAPSE (r=0.90), and is another simple and reproducible method
of RV function assessment.
 An S’ <10 cm/sec predicts a cardiac index <2.0 l/min/m2 with 89%
sensitivity and 87% specificity.

86. TEI index
 The formula IVRT+IVCT/RVET

 The time intervals are typically derived from tissue Doppler signals.
 Increasing values represent worsening function, with an increased RV
MPI associated with decreased survival in PAH.

87. Doppler Echocardiography

88.  Normal value is 0.28 ± 0.004
 It is prolonged in RV dysfunction.
 The upper reference limit is 0.40 by pulsed doppler and 0.55 is by tissue
doppler.
 Limitation – it is load dependent and may get pseudonormalized if
RA pressure are high.

89. RV SIZE
 The normal RV measures approximately 2.5–3.5 cm at end-diastole, with
a planimetered area of 15–18 cm2.
 Typically, the RV dimension and area are two-thirds that of the LV.
 The normal RV:LV ratio is approximately 0.6–0.8, with increasing RV:LV
ratios in patients with mild (0.8–1.0), moderate (1.1–1.4), and severe
(≥1.5) RV dilatation.

90. RVFAC
 A more quantitative approach is to measure the total systolic area
change of the RV, referred to as the RV fractional area of change
(RVFAC).
 This measure is derived from the planimetered areas of the RV at end-
diastole and end-systole ([RVFAC=RV Area ED-RV areaES/RV AreaED] ×
100) from the apical four-chamber view.

91.  Normal value is 56 ± 13.
 A value of <40% implies RV dysfunction.
 The RVFAC does not require geometric assumptions and correlates
with the RV ejection fraction.
 However, incomplete visualization of the RV cavity (more common in
the setting of RV enlargement) as well as suboptimal endocardial
definition lead to relatively high inter- and intra-observer variablility.

92. STRAIN and STRAIN RATE
 2D strain using speckle tracking method is likely to be more sensitive
to detect early RV dysfunction.
 Normal value for strain : 25% -33%
 Through ventricular interdependence, PH induces left ventricular
dysfunction; reduced LV global longitudinal strain is reduced
predominantly because of reduced basal and mid septal strain.
 The right ventricle contracts primarily in a longitudinal fashion, thus
RV longitudinal strain measurement may play an important role in
evaluation of RV function.
 RV longitudinal strain is a powerful tool to predict clinical outcome in
adults with PH.

93. Echocardiographic Assessment of Cardiac
Causes of Pulmonary Hypertension
 The most common cause of pulmonary hypertension is left sided heart
disease resulting in venous pulmonary hypertension.
 Echocardiography allows for assessment of left ventricular systolic and
diastolic dysfunction as well as left sided valvular disease and
congenital heart disease.

94. PERICARDIAL EFFUSION
 In the setting of PAH, a mild to moderate circumferential pericardial
effusion is seen in up to half of patients.
 In general, a pericardial effusion typically indicates longstanding right
atrial hypertension and impaired myocardial lymphatic drainage.
 The presence of a pericardial effusion has been one of the most
consistent echocardiographic findings indicative of a poor prognosis in
PAH.
 The presence of a pericardial effusion is rare in children.

95. PROGNOSTIC FACTORS
Best predictors of poor outlook
1.RA size- RA area index change of 5 cm2/m
2. Pericardial effusion
3. Degree of interventricuar septal shift

96. CT CHEST
 Plays an important role in diagnosis of certain causes
of PH.
 CT findings in PH –
1. diameter of MPA > 29mm
2. MPA/ ascending thoracic aorta >1
3. A segmental artery to bronchus diameter ratio > 1 in three or four lobes.
4. distensibility of PA <16.5%

97. the pulmonary artery measures 41 mm in
diameter

98.  Cardiac changes –
1. RVH – wall thickness >4 mm
2. RV dilatation – RV/LV diameter ratio >1 at midventricular level on axial
images.
3.straightening or leftward bowing of IVS
4. reduced RV EF
5.dilated IVC / HEPATIC VEINS.

99.  MOSAIC pattern of lung attenuation :
 Regions of hyperemic lung and adjacent regions of oligemic lung.
 77% of pts with CTPH and 12% of IPAH patients.
 Other diseases – small airway diseases and infiltrative lung diseases.

100. CT PULMONARY ANGIOGRAM
 Useful in imaging the vascular changes that typically
occur in CTPH.
 The central Pas are dilated , luminal irregularities by organized
thrombus, rat tail appearance of PA branches ,bands ,pouches, webs or
flaps, stenosis, post stenotic dilatation and tortuosity.

101. eccentrically located thrombus that forms obtuse angles
with the vessel wall

102. Cardiac MRI
 Cardiac MRI provides exact measurements of heart function and blood
flow .
 Cardiac MRI provides valuable information without radiation on right
ventricular volumes, mass, left ventricular septal bowing, cardiac
index, and the presence of delayed contrast enhancement.
 Septal curvature measured by cardiac MRI correlates strongly with
mean PAP at baseline and during vasodilator testing.

103.  Ventilation–Perfusion Scintigraphy
 Ventilation–perfusion lung scanning is important in patients in whom
IPAH is suspected to exclude chronic thromboembolic disease as a
cause of the elevated PAP.
 Pulmonary Function Testing –
 A mild restrictive lung defect is seen in 20% to 50% of patients with
IPAH. The presence of moderate or severe restrictive or obstructive
physiologic defects should suggest another diagnosis.
 Mild reduction in the diffusion capacity is seen in most patients with
IPAH.

104. EXERCISE CAPACITY
 Cardiopulmonary exercise testing (CPET) using cycle ergometry or 6-
minute walk testing (6MWT) has been shown to correlate with disease
severity and prognosis, and is helpful in assessing responses to clinical
treatments.
 Exercise testing O2 consumption-<10.4ml/min/m2 associated with
poor prognosis
 The 6MWT reflected maximal exercise capacity in children with a
6MWT distance below 300 m, but correlation was poor above 300 m.
 However baseline 6MWD is not a predictor of survival.

105. (1) to confirm the diagnosis and assess the severity of disease;
(2) to assess the response to pulmonary vasodilators (AVT) before starting
therapy;
(3) to evaluate the response to or the need for changes in therapy;
(4) to exclude other, potentially treatable, diagnoses;
(5) to assess operability as part of the assessment of patients with systemic
to pulmonary artery shunts; and
(6) to assist in the determination of suitability for heart or heart-lung
transplantation.
Cardiac Catheterization

106. PRECAUTIONS WHILE DOING CATH
 Polycythemia
 PCV of >65% =Phlebotomy (O-D/O x wt x70)
 Anaemia
 Appropriate Hb =38 –(0.25 xSaO2)
 Contrast use
 Less than 4ml/kg

107. PITFALLS
 Hemodynamic evaluation of these patients is a “snapshot” that may not
represent the usual state of the patient.
 These studies are frequently performed under general anesthesia which
frequently leads to a lower systemic blood pressure than exists in the
pre-catheterization condition
 The LaFarge equation introduces significant overestimation of oxygen
consumption in ventilated patients with CHD of all ages, particularly
in children younger than 3 years.
 Estimation rather than measurement of PaO2 in the pulmonary veins
leads to overestimation of pulmonary blood flow, and subsequently
underestimation of the PVR.

108.  In patients with single ventricle anatomy and physiology additional
problems arise. In patients with a bidirectional cavopulmonary
anastomosis, the PAP is measured with less than a full cardiac output,
thus the pressure after Fontan completion may not be similar.
 Aortopulmonary collaterals are frequent in the single ventricle patient
leading to underestimation of pulmonary blood flow by
catheterization.
 Patients with CHD may also have various degrees of pulmonary vein
disease leading to inability to accurately measure PVR.

109. Assessing Operability of Patients with PAH Associated
with Congenital Heart Defects
As per Lopes and O’Leary operability is likely if all the
following criteria are met:
 A decrease of 20% in the PVR index
 A decrease of about 20% in the ratio of PVR:SVR
 A final PVR index <6 Wood units ¥ m2
 A final ratio of PVR:SVR <0.3.

111.  The algorithm is not applicable to complex conditions
such as the absence of a subpulmonary ventricle
(candidates to cavopulmonary anastomoses).

112. Acute vasodilator testing (AVT)
 AVT is critical for determining possible treatment with calcium
channel blockers (CCBs) in patients with IPAH.
 AVT may be helpful in the assessment of operability in children with
CHD.
 AVT may aid in assessing long-term prognosis.

114.  Adenosine and epoprostenol possess potent inotropic properties
leading to An increase in cardiac output with no change in PAP which
result in a reduction in calculated PVR and may be erroneously
interpreted as a vasodilator response.
 NO has little effect on cardiac output.

115.  MODIFIED BARST CRITERIA which is defined as a 20% decrease in
mean pulmonary artery pressure (PAPm) with normal or sustained
cardiac output and no change or decrease in the ratio of pulmonary to
systemic vascular resistance (PVR/SVR) has been associated with a
sustained response to CCBs.
 SITBON CRITERIA (e.g., a decrease in PAPm by 10 mm Hg to a value
<40 mm Hg with sustained cardiac output) has not been studied
adequately in children with PAH.
 These criteria are not suitable for patients with a post-tricuspid valve
shunt.

116.  7% to 30% of children with IPAH and 6% of those with APAH are
responders to acute vasodilator testing.
 The development of pulmonary edema in response to pulmonary
vasodilators suggests diseases such as PCH, PVOD, or in infants,
nonketotic hyperglycinemia.
 A rising capillary wedge pressure secondary to increased cardiac output
may be the first sign of impending left ventricular failure.
 An increase in RA pressure in the face of rising cardiac output suggests
RV diastolic dysfunction.

117. PIT FALLS
 Reversibility seen in <10%.
 Hemodynamic guidelines to ensure postoperative success and long-
term survival without pulmonary hypertension are still not precise.
 Technical difficulties leading to calculation errors and other medical
conditions need to be considered .

118.  Controversy whether testing at maximal stimulation (90% O2 and 80
parts per million of iNO) or a conservative intermediate protocols (O2
21–30%, iNO 40 PPM) or gradual increases in vasodilator challenge
would be better predictors.
 Advanced therapies for PAH have a combined vasodilative and
antiproliferative effect.
 Thus, there is also evidence to suggest that the pulmonary
hemodynamics and the clinical status may improve irrespective of the
response to acute vasodilator testing.

119. Repeat cardiac catheterization
 It is recommended within 3 to 12 months after initiation of
therapy to evaluate response or with clinical worsening.
 Indications for repeat cardiac catheterization in
children with PH include :
1. clinical deterioration,
2. Assessment of treatment effect,
3. detection of early disease progression,
4. listing for lung transplant, and
5. prediction of prognosis.

120. Pulmonary wedge angiography
 For the right-sided angiogram, a
5F or 6F pulmonary wedge
catheter was placed in the lower
lobe to a level one rib space
below the takeoff of the right
pulmonary artery.

121.  For the left-sided studies, the catheter was placed two rib spaces below
the takeoff of the left pulmonary artery.
 After the catheter was positioned, the balloon was inflated and contrast
material was injected at a dose of 0.3 ml/kg (minimum 2 ml).
 Injections were by hand as this was thought to be safer and simpler.
 Changes that can be evaluated quantitatively are –
 1. Sparsity of arborization of the pulmonary tree,
 2. Abrupt termination, tortuosity and narrowing of small arteries, and
 3. Reduced background capillary filling.

122. Analysis of the Angiogram
 AP view
 Maximum expiration
 The rate of tapering of the arteries is assessed by measuring the length
of a segment over which the lumen diameter narrows from 2.5 mm to
1.5 mm.

123. Rate of Tapering

124.  Background Haze :
 The degree of filling of small peripheral arteries that determines the
background haze.
 The degree of background haze was assessed as being normal, mildly,
moderately or markedly reduced by comparing the angiogram with
standard normal angiograms.
 Reduced background haze in patients with PAH.

125.  Pulmonary Circulation Time:
 Pulmonary circulation time as the transit time of the contrast material
through the capillaries and veins.
 Measured by counting the number of frames between the time the
balloon was deflated and the time contrast material was seen in the
pulmonary veins at their site of entry into the left atrium.
 This is divided by the frame rate of the cine film.
 Longer the circulation time severe the pulmonary vascular disease.
 Assessment of the circulation time depends on the exclusion of
pulmonary vein stenosis and intrapulmonary shunting.

126. LIMITATIONS
 Pulmonary stenosis or previous placement of a pulmonary artery band,
will give the impression of rapid tapering.
 With advanced vascular disease, there is sometimes such extensive
intimal hyperplasia that the vessel appears narrowed all the way from
the hilum so that abrupt tapering is no longer apparent.

127. LUNG BIOPSY
 Lung biopsy is not used as part of the routine workup of PH given the
relatively high risk of the procedure in children with PH.
 Lung biopsy may be considered for children with PAH suspected of
having PVOD, pulmonary capillary hemangiomatosis, or vasculitis.

128.  Recommendations for a sleep study :
a. A sleep study should be part of the diagnostic evaluation of patients
with PH at risk for sleep-disordered breathing.
b. A sleep study is indicated in the evaluation of patients with poor
responsiveness to PAH targeted therapies.

129. Laboratory Analyses for PAH Workup
 CBC, urinalysis, Chem-20
including liver function profile,
BNP/NT-proBNP
 Coagulation studies:
▪ AT III
▪ Protein C
▪ Protein S
▪ Factor V Leiden
▪ Prothrombin mutation
▪ Anticardiolipin antibodies
▪ Lupus anticoagulant
 HIV test
 Thyroid function tests
 Connective tissue disease
workup:
▪ ESR/CRP
▪ ANA
▪ Special ANAs
▪ CH50 complement and
components
▪ Anticentromere
▪ Rheumatoid factor
 Consider genetic testing

130. Biomarkers
 BNP correlates positively with functional status in children with PAH
and values above 130 pg/mL are associated with increased risk of death
or need for transplantation.
 NT-proBNP, uric acid, or norepinephrine levels have also been shown
to correlate with outcome in children with PAH.

131. NOVEL BIOMARKERS
 Serum amyloid A-4 was fourfold higher in those with poor outcome
compared to those with good outcome.
 Interleukin-6, a proinflammatory cytokine, is associated with the
occurrence of an adverse event in pediatric PH.
 Circulating fibrocytes and MDSCs were increased in children with
PAH compared to non-PAH controls.
 High levels of tissue inhibitors of metalloproteinases- 1 (TIMP-1), and
low levels of apolipoprotein-A1 (140), are strongly associated with
outcome in pediatric PH.

132. TREATMENT
 Pediatric PAH treatment goals may be divided into
those that are for patients at lower risk or higher risk
for death.

136. TARGETS for THERAPY

137. PAH-Specific Treatment Options for patients with
Failing Acute Vasoreactivity Testing

139. Conventional Therapy
 Conventional therapy in patients used to treat right ventricular failure
is frequently used in children who have PAH.
 Digoxin is used in the presence of right ventricular failure, although
there are no clear-cut data regarding its effectiveness in children .
 Diuretics
 Careful attention to respiratory tract infections is required as they may
worsen alveolar hypoxia, and routine influenza vaccination is
recommended.
 Oxygen therapy is reasonable for hypoxemic PAH patients who have
oxygen saturations <92%, especially with associated respiratory
disease.

140. Anticoagulation
 Recommendations for long-term anticoagulation with warfarin
include the following:
a. Warfarin may be considered in patients with IPAH/HPAH, patients
with low cardiac output, those with a long-term indwelling catheter,
and those with hypercoagulable states .
b. Targeting the therapeutic range for an international normalized ratio
between 1.5 and 2.0 is recommended for young children with PAH.
c. Anticoagulation should not be used in young children with PAH
because of concerns about harm of hemorrhagic complications.
 In retrospective trials in adults with IPAH, the use of warfarin has been
associated with improved survival .
 The use of anticoagulation in patients with Eisenmenger syndrome is
controversial and the potential risks and benefits of anticoagulation in
this setting must be carefully weighed.

141. Calcium Channel Blockers
 Treatment with CCBs in those who respond to acute testing associated
with improved 5 yr survival (97% vs 29% non-responding, non-treated
patients).
 CCBs are contraindicated in those who have not undergone AVT,
nonresponders, or have RV failure, children <1 year of age due to
prominent negative inotropic effect.
 Amlodipine, nifedipine, and diltiazem are the preferred agents

142. Prostacyclins
 Intravenous PGI2 - gold standard for treatment of severe disease with
right heart failure. Epoprostenol was FDA approved in 1995.
 Improve survival and quality of life.
 IV epoprostenol must be infused 24 hours/day via a central venous
catheter and kept cold with ice packs ; the half-life of the drug is 2 to 5
minutes placing the patient at risk for an acute pulmonary
hypertensive crisis if there is an accidental discontinuation of the
medication.
 Side effects - nausea, diarrhea, jaw pain, bone pain, and headaches.
 Complications - line sepsis, local infection, and catheter dislodgement
are not unusual and can be responsible for life-threatening rebound
PH.
 Inhaled PGI2 has been used in the critical care setting.

143. Epoprostenol/Treprostinil Pump

144.  The prostacyclin analog, treprostinil, was approved by the FDA.
 Subcutaneous treprostinil allows patients to remain free of central
venous catheters, and recent data have shown long-term efficacy in
adults with PAH .
 Intravenous treprostinil requires central line access and continuous
infusion, but is easier for families to mix, and has a halflife of 4 hours.
 It has fewer side effects than intravenous epoprostenol, but there are no
studies comparing efficacy.
 In its subcutaneous form, discomfort at the infusion site is common
and represents a limiting factor.
 Oral treprostinil was shown to effective as initial monotherapy
treatment in adult PAH, but not as add-on therapy .

145.  An inhaled prostacyclin analog, ILOPROST, received approval for the
treatment of PAH in the United States in 2004.
 This medication is administered by nebulization six to nine times a day.
 The advantage of an inhaled PGI2 is that it can cause selective
pulmonary vasodilation without affecting systemic blood pressure.
 Additionally, inhaled PGI2 analogs can improve gas exchange and
intrapulmonary shunt in cases of impaired ventilation/perfusion by
redistributing pulmonary blood flow from nonventilated to ventilated,
aerosolaccessible lung regions.
 In children with CHD and PAH, inhaled iloprost may be as effective in
lowering PAP and resistance as iNO, and thus may be useful in
evaluation of acute vasoreactivity.
 BERAPROST is an orally active PGI2 analog with a half-life of 35 to 40
minutes.
 Long-acting beraprost has recently been approved for adult PAH in
Japan .

146.  SELEXIPAG is an orally available and selective prostacyclin receptor (IP
receptor) agonist .
 Stimulation of the IP receptor alone may decrease systemic side effects
caused by the EP receptor.
 GRIPHON study showed Selexipag decreased the risk of a
morbidity/mortality event versus placebo by 40% ( p<0.0001).
 Selexipag was approved by the FDA in December 2015 for the treatment
of adult WSPH Group 1 PAH.

147. ENDOTHELIN
 The endothelins are a family of isopeptides consisting of ET-1, ET-2,
and ET-3.
 ET-1 is a potent vasoactive peptide produced primarily in the vascular
endothelial cell.
 ETA and ETB receptors on vascular smooth muscle mediate
vasoconstriction, whereas ETB receptors on endothelial cells cause
release of NO and prostacyclin (PGI2), and act as clearance receptors
for circulating ET-1.

148.  BOSENTAN, a dual Etreceptor antagonist, lowers pulmonary artery
pressure and resistance, and improves exercise tolerance in pts with
PAH
 Elevated hepatic aminotransferase levels occur in approximately 11% of
adults and 3% of children treated with bosentan.
 MACITENTAN, a new dual ET-receptor antagonist, was studied in
symptomatic PAH adults showed significantly reduced morbidity and
mortality.

149.  Selective ETA receptor blocker - AMBRISENTAN, high oral
bioavailability and a long duration of action, and high specificity for
the ETA receptor.
 Selective ETA receptor blockade may benefit patients with PAH by
blocking the vasoconstrictor effects of ETA receptors while maintaining
the vasodilator/clearance functions of ETB receptors
 Adults showed significant improvements in 6MWD and significant
delay in clinical worsening on ambrisentan.
 The incidence of elevated hepatic aminotransferase levels was 2.8%
and was similar to the placebo group.

150. Phosphodiesterase-5 Inhibitors
 SILDENAFIL , promote an increase in cGMP levels and thus promote
pulmonary vasodilation and remodeling. Sildenafil has been used
extensively in children with PAH
 Sildenafil may also be useful in the setting of iNO therapy withdrawal
in postoperative PH, or in the presence of PH related to chronic lung
disease.
 PDE-5 inhibitors have been associated with transient visual and
hearing abnormalities.
 In August 2012, the FDA released a strong warning against the
(chronic) use of sildenafil for pediatric patients (ages 1 through 17) with
PAH.

151.  TADALAFIL is also a selective PDE-5 inhibitor with a longer duration of
action. In adults with severe PAH, tadalafil has been used in addition
to PGI2 with some improvement.
 VARDENAFIL is not approved by FDA.
 RIOCIGUAT, a direct oral soluble guanylate cyclase (sGC) stimulator,
increases cGMP directly in a non-NO dependent manner but also
increases the sensitivity of sGC to NO .
 Riociguat was approved by the FDA in 2013 for the treatment of adult
PAH and is the first FDA-approved drug for the treatment of chronic
thromboembolic PH.

152. Atrial Septostomy
 Atrial septostomy may benefit patients with severe PAH with recurrent
syncope and intractable right heart failure.
 Right-to-left shunting through an interatrial defect allows to maintain
the cardiac output to the expense of increased hypoxemia, and
alleviates signs of right heart failure by decompression of the right
heart.
 Improvement of symptoms and increased survival have been reported,
but this remains controversial.
 Patients with severe PAH, right heart failure and markedly elevated
PVR may not tolerate atrial septostomy because of a massive
intracardiac right-to-left shunting and secondary severe hypoxemia.

153.  Potts Shunt
 Creation of a Potts shunt (anastomosis between the left pulmonary
artery and the descending aorta) may allow a decrease in right
ventricular afterload with subsequent improvement in right ventricular
function
 The Potts shunt allows a “systolic” pop-off whereas atrial septostomy
offers a “diastolic” pop-off.
 A potential advantage of the Potts shunt is maintenance of upper body
saturation with lower extremity desaturation.
 The high risk of the procedure should be reserved for the treatment of
children with right heart failure resistant to other forms of therapy.

154. Transplantation
 Referral to lung transplantation centers is recommended for patients
who are in World Health Organization (WHO) functional class III or
IV on optimized medical therapy or who have rapidly progressive
disease or patients who have confirmed pulmonary capillary
hemangiomatosis or PVOD.
 Limitations to transplantations are the shortage of donors and the high
incidence of bronchiolitis obliterans syndrome which limits the long-
term survival after lung transplantation.
 The median survival for those transplanted was 5.8 years, with 1- and 5-
year survival rates of 95% and 61%, respectively.

155.  Avoidance of hypoxia, acidosis, and agitation, at high risk for PHCs .
 Induction of alkalosis can be useful for the treatment of PHCs .
 Administration of opiates, sedatives, and muscle relaxers is
recommended for reducing postoperative stress response .
 iNO and/or inhaled PGI2 should be used as the initial therapy for PHCs
and failure of the right side of the heart.
 Sildenafil should be prescribed to prevent rebound PH on withdrawal of
iNO and require reinstitution of iNO .
 Inotropic/pressor therapy should be used to avoid RV ischemia caused
by systemic hypotension .
 Mechanical cardiopulmonary support should be provided in refractory
cases .
 Atrial septostomy (AS) is recommended for patients with RV failure,
recurrent syncope, or PHCs that persist despite optimized medical
management.
PH Crises/Acute RV Failure