1. Pulmonary Hypertension in Congenital Heart Disease
Greg Latham, MD
Associate Professor
Seattle Children’s Hospital
Updated 4/2017

2. Disclosures
No disclosures to report

3. Objectives
Review fetal circulation, simple intracardiac shunts, and causes of pulmonary over-circulation
Define and categorize pulmonary hypertension
Describe congenital heart disease-induced pulmonary hypertension

4. Fetal and Transitional Circulation
Understanding the shunts at birth are important for understanding the development of pulmonary hypertension and how reversal of shunts occurs in certain settings.

5. A graphic review of the fetal circulation
Trace the route of blood from the placenta and back again.
What are the 3 unique shunts of the fetal circulation? Answer: ductus venosus, PFO, and PDA
Children’s Hospital of Wisconsin.

6. Fetal Circulation Course of the oxygenated umbilical vein blood:
 bypasses liver via ductus venosus
 mixes with IVC
 eustachian valve shunts towards PFO  LA
 LA  LV
 aortic valve  head and neck arteries
Therefore, oxygenated blood from the umbilical vein perfuses the brain and coronary arteries by shunting across the liver (via the ductus venosus) and shunting across the right heart (via the foramen ovale)
See diagram on next slide
Two umbilical arteries originate from the internal iliac arteries and deliver fetal blood to the placenta where it is oxygenated. One umbilical vein carries oxygenated blood from the placenta to the fetus.
PVR is high in-utero, and SVR is very low because of the low resistance placenta. Therefore, shunting in utero is R  L. This reverses soon after birth.
IVC = inferior vena cava; RA = right atrium; PFO = patent foramen ovale; LA = left atrium; LV = left ventricle; SVC = superior vena cava

7. SVC Aorta PA PFO RA EuV LV RV Ductus venosus Liver Umbilical vein IVC
The eustachian valve directs the majority of oxygenated placental blood across the PFO and eventually across the aortic valve. Therefore, this higher oxygenated blood comprises most of the blood flow to the heart (via coronary arteries) and the brain (via the carotic arteries on the aortic arch).
SVC = superior vena cava; RA = right atrium; EuV = eustachian valve; PFO = patent foramen ovale; RV = right ventricle; PA = pulmonary artery; LV = left ventricle; IVC = inferior vena cava.
Ductus
venosus
Liver
Umbilical vein
IVC
Greg Latham, MD

8. Fetal Circulation
Desaturated SVC blood from the fetal brain takes a different course:
SVC RA  tricuspid valve (not to PFO)
 pulmonary valve
 ductus arteriosus
 descending aorta
 back to placenta for oxygenation
See diagram on next slide
Two umbilical arteries originate from the internal iliac arteries and deliver fetal blood to the placenta where it is oxygenated. One umbilical vein carries oxygenated blood from the placenta to the fetus.
PVR is high in-utero, and SVR is very low because of the low resistance placenta. Therefore, shunting in utero is R  L. This reverses soon after birth.
IVC = inferior vena cava; RA = right atrium; PFO = patent foramen ovale; LA = left atrium; LV = left ventricle; SVC = superior vena cava

9. PDA SVC Aorta PA RA TV LV RV Ductus venosus Liver Umbilical vein IVC
The more deoxygenated venous return to the heart is from the SVC, and it flows across the tricuspid valve, into the RV, and into the PA. Because PVR is high, very little goes to the lungs; most goes across the ductus arteriosus and into the descending aorta and towards the placenta for re-oxygenation.
SVC = superior vena cava; RA = right atrium; TV = tricuspid valve; RV = right ventricle; PA = pulmonary artery; LV = left ventricle; PDA = patent ductus arteriosus; IVC = inferior vena cava.
Ductus
venosus
Liver
Umbilical vein
IVC
Greg Latham, MD

10. Fetal Circulation Yellow arrow – eustachian valve
Red arrow – flow of umbilical blood
Blue arrow – flow of desaturated blood
Two umbilical arteries originate from the internal iliac arteries and deliver fetal blood to the placenta where it is oxygenated. One umbilical vein carries oxygenated blood from the placenta to the fetus.
PVR is high in-utero, and SVR is very low because of the low resistance placenta. Therefore, shunting in utero is R  L. This reverses soon after birth.
IVC = inferior vena cava; RA = right atrium; PFO = patent foramen ovale; LA = left atrium; LV = left ventricle; SVC = superior vena cava

11. Transitional Circulation - PFO
Transitional circulation begins when umbilical cord is clamped and lungs are inflated
Cord clamping removes the low resistance placenta from the circulation and raises SVR
Lung inflation and increased PaO2 lowers PVR dramatically, causing increased pulmonary blood flow and increased blood return to the left atrium
pLA > pRA  closes the flap of tissue covering the PFO
Functional closure occurs quickly but anatomic closure usually requires weeks. A PFO that is probe patent persists in approximately 25% of adults
Discussion of the closure of PFO sets the stage for re-opening of PFO and reversal of shunt in the setting of pulmonary hypertension.
The rise in SVR and drop in PVR causes a reversal of flow across the PDA, from R  L in utero to L  R soon after birth. This causes increased pulmonary blood flow compared to systemic blood flow, and thus venous return to the LA is > RA. This causes a greater left atrial pressure compared to the right atrial pressure, and the flap of the PFO effectively closes (unless distortion of the foramen ovale leads to a residual PFO).
pLA = left atrial pressure; pRA = right atrial pressure; SVR = systemic vascular resistance; PVR = pulmonary vascular resistance

12. Transitional Circulation - PDA
The ductus arteriosus remains patent in utero due to hypoxia, mild acidosis and placental prostaglandins. Removal of these factors after delivery causes functional closure with anatomic closure occurring weeks later
Persistent PDA often occurs in premature infants with lung disease. Indomethacin, via its anti-prostaglandin action can be used to try and close a PDA
Before anatomic closure of the PDA and PFO, pRA > pLA can cause reversion to fetal circulation (R  L shunt and cyanosis)
Hypothermia, hypercarbia, acidosis, hypoxia and sepsis can all cause a reversion to fetal circulation
Discussion of the closure of PDA sets the stage for re-opening of PDA and reversal of shunt in the setting of pulmonary hypertension.
Hypothermia, hypercarbia, acidosis, hypoxia and sepsis can all cause a reversion to fetal circulation.
pRA = right atrial pressure; pLA = left atrial pressure

13. Pulmonary Arterial Hypertension (PAH)

14. PAH Definition PVR = 80 (mPAP-PCWP)/CO
Normal PVR = 70 (range ) dyn.sec/cm5
Normal PVR = 1 (range ) Woods units
Woods unit is just another unit of resistance and is calculated as = 80 x dyn.sec/cm5

15. PAH Classification The classification of adult & peds PAH is big
In young children, persistent pulmonary hypertension of the newborn (PPHN) and CHD are the primary causes (>80%)
Idiopathic PAH, although less common, is an important cause in children
In 1998, at a World Symposium on PAH, the clinical classification was established. The most recent and 5th world symposium was held in 2013 and maintained the general scheme of 5 Groups or main classifications of PAH
The most common cause of PAH in children is congenital heart disease (CHD), followed by PPHN and idiopathic PAH
Simonneau, G., et al. (2013). Updated Clinical Classification of Pulmonary Hypertension. Journal of the American College of Cardiology, 62(25), D34–D41.

16. Why Does PAH Occur in Children?
 pLA
LV systolic/diastolic dysfunction
MV or AV stenosis/regurgitation
Pulmonary vein obstruction
 pulmonary blood flow
Congenital heart disease with L  R shunt
 PVR
Pulmonary parenchymal disease
Thromboembolic disease
This simply describes the most common mechanical principles behind the etiology of PAH in children.
pLA = left atrial pressure; LV = left ventricle; MV = mitral valve; AV = aortic valve; PVR = pulmonary vascular resistance

17. PAH Associated with Congenital Heart Disease (CHD)
Because this is the biggest cause of PAH in children, this will be discussed in further detail.

18. CHD-associated PAH
PAH is major acquired complication of CHD with L  R shunts
PAH causes increased morbidity and mortality
PAH may prevent complete repair in those with advanced pulmonary vascular disease
15%-30% of the CHD population is thought to develop at least transient PAH
Kidd L, Driscoll DJ, Gersony WM, et al. Second natural history study of congenital heart defects: results of treatment of patients with ventricular septal defects. Circulation 1993;87 (2, Suppl):I38–I51
Multiple forms of CHD have L  R (systemic-to-pulmonary) shunts, and the development of PAH represents a major complication in the child’s cardiopulmonary physiology.
Onset of PAH increases morbidity and mortality, and it can complicate or preclude the preferred medical and surgical management of these children.
Unfortunately, the incidence of PAH in the CHD population is quite high.

19. Cause of CHD-associated PAH
L  R shunt
Increases pulmonary blood flow, leading to pulmonary vascular injury and shear stress, then
Leads to progressive smooth muscle hypertrophy and hyperplasia, intimal proliferation, and pulmonary vasoconstriction
L  R shunt is the most common cause of CHD-associated PAH.
Akin to longstanding systemic hypertension, the chronic excessive pulmonary blood flow from L  R shunt leads to vascular changes of the pulmonary vasculature.
Although reversible in its early stages, prolonged and progressive smooth muscle hypertrophy and hyperplasia, intimal proliferation, and pulmonary vasoconstriction eventually leads to irreversible PAH
Open Access License: Tian X, Vroom C, Ghofrani HA, et al. Phosphodiesterase 10A Upregulation Contributes to Pulmonary Vascular Remodeling. El-Rifai W, ed. PLoS ONE. 2011;6(4):e (

20. Cause of CHD-associated PAH
Risk factors for PAH in children with CHD:
Type of defect:
High risk: truncus arteriosus, AV canal, TGA with VSD
Almost 100% risk if untreated
Moderate risk: VSD (risk of Eisenmenger’s syndrome if untreated: 3% when <1.5cm; 50% when >1.5cm), PDA
Low risk: ASD, PAPVR
Pressure and flow of LR shunt
Presence of associated noncardiac syndromes (especially Down syndrome)
1. Systemic-pulmonary (L  R) shunts PRIOR to the tricuspid valve have a lower risk of PAH compared to shunts AFTER the tricuspid valve. That is because shunts after the tricuspid valve tend to produce not just high pulmonary blood flow but also high (ventricular) pressures.
2. The larger the shunt (i.e., the higher the pressure and volume of LR shunt), the higher risk of developing PAH 3.
PAPVR = partial anomalous pulmonary venous return; TGA = transposition of the great arteries;

21. When Does CHD-PAH Develop?
The age at which congenital heart lesions cause irreversible pulmonary vascular disease varies
Endothelial changes occur as early as 2 months after birth in some children with increased pulmonary blood flow
The type of CHD matters; combination of high pressure and high flow causes more rapid and severe remodeling
Clinical onset ranges from as early as 4-6 months in CAVC or truncus arteriosus to never in small ASDs or VSDs
The pulmonary vascular remodeling process is reversible in the early stages of the disease
When PAH becomes irreversible in individual patients is difficult to predict. Cardiac catheterization can test vascular reactivity of the pulmonary bed by measuring hemodynamics on room air, 100% O2, and then 100% O2 with inhaled nitric oxide.
CAVC = complete atrioventricular canal defect

22. Eisenmenger Syndrome (ES)
The most severe form of CHD-associated PAH
Definition:
“CHD with an initial large systemic-to-pulmonary shunt that induces progressive pulmonary vascular disease and PAH, with resultant reversal of the shunt and central cyanosis”
When shunt reversal occurs, symptoms include:
Cyanosis, dyspnea, fatigue, dizziness, syncope, and arrhythmia
Poor exercise tolerance
Life expectancy is markedly reduced
In short, ES is progressive worsening of PAH to the point that “RV and PA pressures exceed LV and aortic pressures”, leading to a reversal of shunting from R  L.
Signs and symptoms as listed develop, and life expantancy is markedly reduced.
The CT angiography demonstrates a markedly dilated main and branch pulmonary arteries in an individual with Eisenmengers syndrome
Lee J, Kwon HM, Hong BK, et al. Total Occlusion of Left Main Coronary Artery by Dilated Main Pulmonary Artery in a Patient with Severe Pulmonary Hypertension. The Korean Journal of Internal Medicine. 2001;16(4):  

23. Conclusion CHD is a frequent and important cause of PAH in children.
Early repair of congenital cardiac lesions with intensive postoperative care is the best strategy to prevent the development of progressive PAH in CHD.
Once PAH develops, aggressive medical treatment ensues in the hopes of reversibility.
Chronic PAH increase morbidity and mortality, and anesthetic management must be carefully considered!

24. References Suggested Reading:
Kidd L, Driscoll DJ, Gersony WM, et al. Second natural history study of congenital heart defects: results of treatment of patients with ventricular septal defects. Circulation 1993;87 (2, Suppl):I38– I51
Simonneau, G., et al. (2013). Updated Clinical Classification of Pulmonary Hypertension. Journal of the American College of Cardiology, 62(25), D34–D41.
van Loon, R. L. E., Roofthooft, M. T. R., Hillege, H. L., Harkel, ten, A. D. J., van Osch-Gevers, M., Delhaas, T., et al. (2011). Pediatric pulmonary hypertension in the Netherlands: epidemiology and characterization during the period 1991 to Circulation, 124(16), 1755–1764.
Suggested Reading:
Friesen, R. H., & Williams, G. D. (2008). Anesthetic management of children with pulmonary arterial hypertension. Pediatric Anesthesia, 18(3), 208–216
Shukla, A. C., & Almodovar, M. C. (2010). Anesthesia considerations for children with pulmonary hypertension. Pediatric Critical Care Medicine, 11(2), S70–S73
Beghetti, M., & Tissot, C. (2009). Pulmonary Arterial Hypertension in Congenital Heart Diseases. Seminars in Respiratory and Critical Care Medicine, 30(04), 421–428
Taylor, K., Moulton, D., Zhao, X. Y., & Laussen, P. (2015). The impact of targeted therapies for pulmonary hypertension on pediatric intraoperative morbidity or mortality. Anesthesia & Analgesia, 120(2), 420– 426.
Chau, D. F., Gangadharan, M., Hartke, L. P., & Twite, M. D. (2016). The Post-Anesthetic Care of Pediatric Patients With Pulmonary Hypertension. Seminars in Cardiothoracic and Vascular Anesthesia, 20(1), 63– 73.