This document provides guidelines and recommendations for the diagnosis and management of pulmonary hypertension (PH) and pulmonary arterial hypertension (PAH) in children. It discusses: - Definitions and classifications of PH and PAH in children. - The need to establish specialized pediatric PAH programs and registries to better understand the conditions. - Recommendations for diagnostic testing including imaging, cardiac catheterization, and biomarkers to evaluate PH causes and severity. - Treatment guidelines for PH in newborns including inhaled nitric oxide and prostacyclin analogs. - Surgical and postoperative considerations for children with structural heart defects and PH. - Medical therapy options and guidelines for managing PAH in children.

1. AHA & ATS GUIDELINES
CIRCULATION. 2015; 132:00-00. DOI: 10.1161/CIR.0329
MURTAZA KAMAL
FELLOW PEDIATRIC CARDIOLOGY
DOP: 19/04/2018
1

2. 2

3. 3

4. • PH
mPAP ≥25 mm Hg in children >3 mo at sea level
(NO EVIDENCE OF INCREASED VALUE WITH
EXERCISE)
• PAH
• mPAP ≥25 mm Hg
• PAWP <15 mm Hg
• PVRI >3 WU × M2
4

5. • IPAH or isolated PAH:
• No underlying disease known to be associated
• Referred as HPAH with positive family/genetic
evaluation
• PHVD:
• Broad category
• Includes forms of PAH but includes subjects with
elevated TPG (mPAP−left atrial pressure or PAWP
>6 mm Hg) or high PVRI as observed in patients with
cavopulmonary anastomoses without high mPAP 5

6. • Many associated conditions fragmenting classification
of pediatric PH
• Relatively small numbers of patients at each center
• Scarcity of multidisciplinary pediatric PAH programs
• Lack of a national PH network
• Suboptimal communication between scientists and
clinicians
6

7. • To better define natural history and course of
paediatric PAH
• Develop new strategies to identify patients at risk for
development of PAH
• Establish novel approaches to diagnose, monitor
disease progression and treat
7

8. • Intrinsically linked to issues of lung growth and
development
• Prenatal and early postnatal influences
• Impaired functional and structural adaptation of pulmonary
circulation during transition from fetal to postnatal life
• Timing of pulmonary vascular injury: Critical determinant of
subsequent response of developing lung to adverse
stimuli:
• Hyperoxia
• Hypoxia
• Hemodynamic stress
• Inflammation
8

9. • Normal maturation of lung circulation: Critical
roles in lung organogenesis and development of
distal airspace
• Normal pulmonary vascular bed required for
maintenance of lung structure, metabolism, and
gas exchange: Confers ability to tolerate
increased workloads imposed by exercise
9

10. 10

11. 11

12. 12

13. 13

14. 14

15. 15

16. 16

17. 17

18. • Comprehensive history + physical
examination
• Diagnostic testing for assessment of PH
pathogenesis
• Classification + formal assessment of
cardiac function
• Should be performed before initiation of therapy
at experienced center
(Class I; Level of Evidence B)
18

19. • Imaging to diagnose:
• Pulmonary thromboembolic disease
• Peripheral pulmonary artery stenosis
• Pulmonary vein stenosis
• Pulmonary veno-occlusive disease (PVOD),
and
• Parenchymal lung disease
• Should be performed at time of diagnosis
(Class I; Level of Evidence B)
19

20. • After comprehensive initial evaluation: Serial
echocardiograms should be performed
• Frequent echocardiograms recommended in
setting of changes in therapy/ clinical condition
(Class I; Level of Evidence B)
20

21. • Cardiac catheterization: Recommended before
initiation of PAH-targeted therapy
(Class I; Level of Evidence B)
• Exception: Critically ill patients requiring
immediate initiation of empirical therapy
(Class I; Level of Evidence B)
21

22. • Cardiac catheterization should include acute
vasoreactivity testing (AVT) unless specific
contraindication
(Class I; Level of Evidence A)
22

23. • Minimal hemodynamic change that defines +ve
response to AVT for children :
≥20% decrease in PAP and PVR/SVR
without decrease in CO
(Class I; Level of Evidence B)
23

24. • Repeat cardiac catheterization:
Recommended within 3 -12 months after
initiation of therapy
To evaluate response or with clinical
worsening
(Class I; Level of Evidence B)
24

25. • Serial cardiac catheterizations with AVT
recommended as follows:
• a. To be done during follow-up to assess
prognosis and potential changes in therapy
(Class I; Level of Evidence B)
• b. Intervals for repeat catheterizations: To be
based on clinical judgment but include
worsening clinical course/ failure to improve
during treatment
(Class I; Level of Evidence B)
25

26. • MRI can be useful as part of diagnostic
evaluation and during follow-up:
• To assess changes in ventricular function
and
• Chamber dimensions
(Class IIa; Level of Evidence B)
26

27. • BNP or N-terminal (NT) proBNP: Should be
measured at diagnosis + during follow-up  To
supplement clinical decision
(Class I; Level of Evidence B)
27

28. • 6MWD test: Should be used to follow exercise
tolerance in pediatric PH patients of appropriate
age
(Class I; Level of Evidence A)
28

29. • Recommendations for sleep study:
• Should be part of diagnostic evaluation of
patients with PH at risk for sleep-disordered
breathing
(Class I; Level of Evidence B)
• Indicated in evaluation of patients with poor
responsiveness to PAH targeted therapies
(Class I; Level of Evidence B)
29

30. 30

31. 31

32. 32

33. 33

34. • Genetic testing with counselling: Can be useful
for children with IPAH/ families with HPAH
• To define pathogenesis
• Identify family members at risk
• Inform family planning
(Class IIa; Level of Evidence C)
34

35. Recommendations for genetic testing of 1st degree
relatives of patients with monogenic forms of
HPAH:
• Indicated for risk stratification
(Class I; Level of Evidence B)
• Reasonable to screen asymptomatic carriers
with serial echocardiograms/ other
noninvasive studies
(Class IIa; Level of Evidence B)
35

36. • Members of families afflicted with HPAH:
Developing new cardiorespiratory symptoms
Evaluate immediately for PAH
(Class I; Level of Evidence B)
36

37. • Families of patients with genetic syndromes
associated with PH: Educated about symptoms
of PH and counselled to seek evaluation of
affected child should symptoms arise
(Class I; Level of Evidence B)
37

38. 38

39. Indicated to reduce need for ECMO support in
term and near-term infants with PPHN or
hypoxemic respiratory failure who have an
oxygenation index > 25
(Class I; Level of Evidence A)
39

40. • Can improve efficacy of iNO therapy
• Should be performed in patients with PPHN
associated with parenchymal lung disease
(Class I; Level of Evidence B)
40

41. • Indicated for term and near term neonates with
severe PH or hypoxemia refractory to iNO and
optimization of respiratory and cardiac function
(Class I; Level of Evidence A)
41

42. • Evaluation for disorders of lung development:
• Alveolar capillary dysplasia (ACD)
• Genetic surfactant protein diseases
• Reasonable for infants with severe PPHN who
fail to improve after vasodilator, lung recruitment
or ECMO
(Class IIa; Level of Evidence B)
42

43. • Reasonable adjunctive therapy for infants with
PPHN who are refractory to iNO, especially with
an oxygenation index > 25
(Class IIa; Level of Evidence B)
43

44. • Inhaled prostacyclin (PGI2) analogs: May be
considered as adjunctive therapy for infants with
PPHN who are refractory to iNO and have an
oxygenation index > 25
(Class IIb; Level of Evidence B)
44

45. • Reasonable in infants with PPHN and signs of
LV dysfunction
(Class IIb; Level of Evidence B)
45

46. • Can be beneficial for preterm infants with severe
hypoxemia due primarily to PPHN physiology
rather than parenchymal lung disease
• Particularly if associated with PROM and
oligohydramnios
(Class IIa; Level of Evidence B)
46

47. 47

48. May be considered for children with PAH
suspected of having:
PVOD
Pulmonary capillary hemangiomatosis or
Vasculitis
(Class IIb; Level of Evidence C)
48

49. Referral to lung transplantation centers for
evaluation: Recommended for patients with
severe disease on optimized medical therapy
or
Have rapidly progressive disease
(Class I;Level of Evidence A)
49

50. Referral to a lung transplantation center for
evaluation: Recommended for patients who have
confirmed pulmonary capillary hemangiomatosis
or
PVOD
(Class I; Level of Evidence B)
50

51. 51

52. Children with significant structural heart disease(ie,
ASD, VSD, PDA) who have not undergone early
repair (as generally defined as by 1- 2 years of age,
depending on lesion and overall clinical status),
following are recommended:
a. Cardiac catheterization should be considered to
measure PVRI and to determine operability
(Class II; Level of Evidence B)
b. Repair should be considered if PVRI is <6 (WU)・
m2 or PVR/SVR <0.3 at baseline
(Class I; Level of Evidence B)
52

53. Children with evidence of RT LT shunting and
cardiac catheterization revealing PVRI ≥6 WU
m2 or PVR/SVR ≥0.3: Repair can be beneficial if
AVT reveals reversibility of PAH (absolute PVRI
<6 WU m2 and PVR/SVR <0.3)
(Class IIa; Level of Evidence C)
53

54. If cardiac catheterization reveals PVRI ≥6 WU・
m2
or PVR/SVR ≥0.3 and minimal responsiveness to
AVT:
Repair not indicated (Class III; Level of Evidence
A)
Reasonable to implement PAH-targeted therapy
followed by repeat catheterization with AVT after 4
to 6 months and to consider repair if the PVRI is
<6 WU (Class IIb; Level of Evidence C)
54

55. 55

56. 56

57. 57

58. General postoperative strategies for avoiding PH
crises (PHCs):
Avoidance of hypoxia
Acidosis and
Agitation
should be used in children at high risk for PHCs
(Class I; Level of Evidence B)
58

59. Can be useful for treatment
(Class IIa; Level of Evidence C)
59

60. Opiates
Sedatives and
Muscle relaxers
Recommended for reducing postoperative stress
response and risk for or severity of PHCs
(Class I; Level of Evidence B)
60

61. iNO and/or inhaled PGI2 should be used as initial
therapy for PHCs and failure of right side of
heart (Class I; Level of Evidence B)
61

62. Should be prescribed to prevent rebound PH in
patients who have evidence of sustained
increase in PAP on withdrawal of iNO and
require reinstitution of iNO despite gradual
weaning of iNO dose
(Class I; Level of Evidence B)
62

63. Patients with PHCs, inotropic/pressor therapy
should be used to avoid RV ischemia caused by
systemic hypotension
(Class I; Level of Evidence B)
Mechanical cardiopulmonary support should be
provided in refractory cases
(Class I; Level of Evidence B)
63

64. Recommended for patients with:
RV failure
Recurrent syncope or
PHCs that persist despite optimized medical
management
Must be performed in an experienced PH center
(Class I; Level of Evidence B)
64

65. 65

66. 66

67. Children with chronic diffuse lung disease: Should
be evaluated for concomitant cardiovascular
disease
or PH by echocardiogram, especially those with
advanced disease
(Class I; Level of Evidence B)
67

68. Recommended to assess PH and RV function in
patients with severe obstructive sleep apnea
(OSA)
(Class I; Level of Evidence B)
68

69. Exercise-limited patients with advanced lung
disease and evidence of PAH, recommended:
a. Trial of PAH-targeted therapy
(Class IIa; Level of Evidence C)
b. Catheterization of right side of heart may
be considered
(Class IIb; Level of Evidence B)
69

70. 70

71. Patients with symptomatic high altitude–related PH
may be encouraged to move to low altitude
(Class IIb; Level of Evidence C)
71

72. With (amlodipine/ nifedipine) may be reasonable
for high-altitude pulmonary edema (HAPE)
prophylaxis in children with previous history of
HAPE
(Class IIb; Level of Evidence C)
72

73. Therapy for symptomatic HAPE should include
supplemental O2 and immediate descent
(Class I; Level of Evidence B)
73

74. Children with HAPE: Undergo evaluation to rule
out abnormalities of:
Pulmonary arteries
Pulmonary veins
Lung disease or
Abnormal control of breathing
(Class I; Level of Evidence B)
74

75. 75

76. Early evaluation including Doppler echo,
reasonable for children with:
Hemolytic hemoglobinopathies
Hepatic
Renal
Metabolic diseases
who develop cardiorespiratory symptoms
(Class IIa; Level of Evidence C)
76

77. Children with chronic hepatic disease: Echo
performed to rule out:
Portopulmonary hypertension (PPHTN) and
Pulmonary arteriovenous shunt
Before liver transplantation
(Class I; Level of Evidence B)
77

78. Children with SCD undergo echo Screen for PH
and associated cardiac problems by 8 years of
age or earlier in patients with frequent
cardiorespiratory symptoms
(Class IIa; Level of Evidence C)
78

79. SCD who have evidence of PH by echo, recommended:
a. Undergo further cardiopulmonary evaluation,
including:
PFT
Polysomnography
Assessment of oxygenation and
Evaluation for thromboembolic disease
(Class I; Level of Evidence C)
b. Should undergo cardiac catheterization before
initiation of PAH-specific drug therapy 79

80. Can be useful in screening for PH in patients with
SCD (Class IIa;Level of Evidence C)
80

81. With diagnosis of PH in children with SCD,
optimization of SCD-related therapies
recommended:
Blood transfusions
Hydroxyurea
Iron chelation and
Supplemental oxygen
(Class I; Level of Evidence C) 81

82. Should not be used empirically in SCD-associated
PH: Potential adverse effects
(Class III; Level of Evidence C)
82

83. May be considered in patients with SCD in whom
there is confirmation of PH with marked elevation
of PVR without an elevated PCWP by cardiac
catheterization
(Class IIb; Level of Evidence C)
83

84. Trial of a PGI2 agonist or ERA preferred over
PDE5 inhibitors in patients with markedly elevated
PVR and SCD
(Class IIa; Level of Evidence B)
84

85. 85

86. • DIGOXIN:
• Limited data
• Now rarely used in peds PH
• Not effective for acute deterioration
• DIURETICS:
• Care needed: Over diuresis reduces preload of failing RV
• O2:
• IF SPO2<92% Daytime
• Polysomnography: For night o2 requirement
86

87. • Vit K antagonist (Warfarin):
• May be useful in PH with CV line
• Patients with hypercoagulable state
87

88. • Nifidipine, Diltiazem, Amlodipine
• Duration of benefit may be limited even with favorable
initial response
• Periodic repeat assessments for responsiveness
indicated
88

89. • Sildenafil :
• High dosing to be avoided in children
• Greated mortality noted in a multicentric study in IPAH
children treated with high doses
• FDA: 1-17 years age
• Teladafil (Safety and efficacy data limited in children)
89

90. • Bosentan:
• Data have been published on efficacy in eisenmenger’s
PH
• Hepatotoxic
• Decreases sildenafil efficacy
• Ambrisentan:
• Hepatotoxic
• Safety data limited in children
90

91. • Epoprostinol:
• Contineous IV infusion
• Interaction with sildenafil
Standard therapy for severe PH
• Triprostinil:
• IV or S/C or inhaled
• Iloprost:
• Intermittent inhalation
• In peds: Dosing frequency may limit usefulness
91

92. 92

93. 93

94. Supportive care with digitalis and diuretic therapy:
Reasonable with signs of right heart failure but
should be initiated cautiously
(Class IIb; Level ofEvidence C)
94

95. Recommendations for long-term anticoagulation
with warfarin:
a. 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
(Class IIb; Level of Evidence C)
b. INR 1.5 and 2.0 recommended
(Class I; Level of Evidence C)
95

96. Should not be used in young children with PAH
because of concerns about harm from
hemorrhagic complications
(Class III; Level of Evidence C)
96

97. Oxygen reasonable for hypoxemic PAH
patients with sPO2 <92%, especially with
associated respiratory disease
(Class IIa; Level of Evidence B)
97

98. To be given only to those who are reactive as
assessed by AVT and >1 year of age
(Class I; Level of Evidence C)
Contraindicated in children who have not
undergone or are nonresponsive to AVT and in
patients with right-sided heart dysfunction owing
to potential for negative inotropic effects of CCB
therapy
(Class III; Level of Evidence C)
98

99. Oral PAH-targeted therapy in children with lower
risk
PAH is recommended and should include either
a phosphodiesterase type 5 (PDE5) inhibitor or an
endothelin (ET) receptor antagonist (ERA)
(Class I; Level of Evidence B)
99

100. Goal-targeted therapy approach in which PAH
specific
drugs are added progressively to achieve
specified therapeutic targets can be useful
(Class IIa; Level of Evidence C)
100

101. Intravenous and subcutaneous PGI2 or its analogs
should be initiated without delay for patients with
higher-risk PAH
(Class I; Level of Evidence B)
101

102. Recommendations for transition from parenteral
to oral/ inhaled therapy:
a. May be considered in asymptomatic children
with PAH who have demonstrated sustained,
near-normal pulmonary hemodynamics
(Class IIb; Level of Evidence C)
b. The transition requires close monitoring in an
experienced pediatric PH center
(Class I; Level of Evidence B)
102

103. 103

104. Children with PH: Evaluated and treated in
comprehensive, multidisciplinary clinics at
specialized pediatric centers
(Class I; Level of Evidence C)
104

105. Outpatient follow-up visits at 3- to 6-month
intervals: Reasonable
More frequent visits for patients with advanced
disease or after initiation of or changes in
therapy
(Class IIa; Level of Evidence B)
105

106. Preventive care measures for health maintenance
recommended:
• Respiratory syncytial virus prophylaxis (if
eligible)
• Influenza and pneumococcal vaccination
• Rigorous monitoring of growth parameters
• Prompt recognition and treatment of infectious
respiratory illnesses
• Antibiotic prophylaxis for prevention of
subacute bacterial endocarditis in cyanotic
patients and those with indwelling central lines 106

107. Careful preoperative planning,
Consultation with cardiac anesthesia and
Plans for appropriate postprocedural
monitoring:
Recommended for pediatric patients with PH
undergoing surgery or other interventions
(Class I; Level of Evidence C)
107

108. Elective surgery: Performed at hospitals with
expertise in
PH and in consultation with pediatric PH service
and anesthesiologists with experience in
perioperative
management of children with PH
(Class I;Level of Evidence C)
108

109. Significant maternal and fetal mortality associated
with pregnancy in patients with PH
Recommended: Female adolescents with PH be
provided with age-appropriate counseling about
pregnancy risks and options for contraception
(Class I; Level of Evidence C)
109

110. Risks of syncope or sudden death with exertion
Recommended: Thorough evaluation, including
cardiopulmonary exercise testing (CPET) and
treatment, be performed before patient engages
in athletic activities
(Class I; Level of Evidence C)
110

111. Severe PH or recent history of syncope: Should
not participate in competitive sports
(Class III; Level of Evidence C)
111

112. During exercise, recommended: Engage in light to
moderate aerobic activity
Avoid strenuous and isometric exertion
Remain well hydrated, and
Be allowed to self-limit as required
(Class I; Level of Evidence C)
112

113. Airplane travel: Supplemental oxygen use is
Reasonable
(Class IIa; Level of Evidence B)
113

114. Given the impact of childhood PAH on entire
family, children, siblings, and caregivers should
be assessed for psychosocial stress
Readily provided support and referral as needed
(Class I; Level of Evidence C)
114

115. 115

116. 116

117. • Minimize PIP
• Avoid large TV
• To reduce ventilator-associated ALI in infants
with CDH
(Class I; Level of Evidence B)
117

118. • A reasonable alternative for subjects when:
• Poor lung compliance
• Low volumes
• Poor gas exchange
complicate clinical course
(Class IIa; Level of Evidence A)
118

119. • Can be used to improve oxygenation in infants
with CDH and severe PH
• Use cautiously in subjects with suspected LV
dysfunction
(Class IIa; Level of Evidence B)
119

120. • Recommended for patients with CDH with
severe PH who do not respond to medical
therapy
(Class I; Level of Evidence B)
120

121. • May be considered to maintain patency of ductus
arteriosus and
• Improve cardiac output in infants with CDH and
suprasystemic levels of PH or RV failure
(Class IIb; Level of Evidence C)
121

122. • Evaluation for long-term PAH-specific therapy for
PH in infants with CDH should follow
recommendations for all children with PH
including cardiac catheterization
(Class I; Level of Evidence B)
122

123. • Longitudinal care in interdisciplinary paediatric
PH program for infants with CDH who have PH
or are at risk of developing late PH
(Class I; Level of Evidence B)
123

124. 124

125. • Recommended in infants with established BPD
(Class I; Level of Evidence B)
125

126. • Evaluation and treatment of lung disease
• Assessments for:
• Hypoxemia
• Aspiration
• Structural airway disease
• Need for changes in respiratory support
• Recommended in infants with BPD and PH
before initiation of PAH-targeted therapy
(Class I; Level of Evidence B)
126

127. • Evaluation for long-term therapy for PH in infants
with BPD: Should follow recommendations for all
children with PH
• Include cardiac catheterization to diagnose
disease severity and potential contributing
factors such as:
LV diastolic dysfunction
Anatomic shunts
Pulmonary vein stenosis, and
Systemic collaterals
(Class I; Level of Evidence B)
127

128. Reasonable to avoid episodic or sustained
hypoxemia
Goal: Spo2 92% and 95% in patients with
established BPD and PH
(Class IIa; Level of Evidence C)
128

129. • Can be useful for infants with BPD and PH on
optimal treatment of underlying respiratory and
cardiac disease
(Class IIa; Level of Evidence C)
129

130. • Can be effective for infants with established BPD
and symptomatic PH
(Class IIa; Level of Evidence C)
130

131. • Serial echocardiograms are recommended
(Class I; Level of Evidence B)
131

132. 132

133. 133