1. Pulmonary Hypertension Allison K. Cabalka, MD Associate Professor of Pediatrics Consultant, Pediatric Cardiology Mayo Clinic Allison K. Cabalka, MD Associate Professor of Pediatrics Consultant, Pediatric Cardiology Mayo Clinic

2. CHD and PHTN: Issues What is Pulmonary HTN? What is Pulmonary HTN?  How does one define elevated pulmonary artery pressure  Classification scheme How do we assess PHTN in those with CHD? How do we assess PHTN in those with CHD?  Non-invasive: clinical, echo  Invasive: cath evaluation Treatment of PHTN? Treatment of PHTN? What is Pulmonary HTN? What is Pulmonary HTN?  How does one define elevated pulmonary artery pressure  Classification scheme How do we assess PHTN in those with CHD? How do we assess PHTN in those with CHD?  Non-invasive: clinical, echo  Invasive: cath evaluation Treatment of PHTN? Treatment of PHTN?

3. What is Pulmonary HTN? Simple Description Simple Description Elevated PA pressure (   pulm vein pressure) Definition (mm Hg) Definition (mm Hg) PA pressure>30/15 PA (mean) >25 Mild 26-35 Moderate 36-50 Severe >50 Simple Description Simple Description Elevated PA pressure (   pulm vein pressure) Definition (mm Hg) Definition (mm Hg) PA pressure>30/15 PA (mean) >25 Mild 26-35 Moderate 36-50 Severe >50

4. Why is PTHN Important? It is a disease of the entire pulmonary circulation It is a disease of the entire pulmonary circulation It is a critical determinant of outcome It is a critical determinant of outcome  Morbidity, mortality in pediatric lung, cardiac, pulmonary, hematologic, and other diseases It is a disease of the entire pulmonary circulation It is a disease of the entire pulmonary circulation It is a critical determinant of outcome It is a critical determinant of outcome  Morbidity, mortality in pediatric lung, cardiac, pulmonary, hematologic, and other diseases

5. Evian-Venice Classification PHTN in the setting of CHD with systemic to PA shunts PHTN in the setting of CHD with systemic to PA shunts  Classified as Pulmonary Arterial Hypertension Considering the following: Considering the following:  Type of CHD  Prognosis/evolution of pulmonary vascular disease  Circulatory physiology PHTN in the setting of CHD with systemic to PA shunts PHTN in the setting of CHD with systemic to PA shunts  Classified as Pulmonary Arterial Hypertension Considering the following: Considering the following:  Type of CHD  Prognosis/evolution of pulmonary vascular disease  Circulatory physiology World Symposiums on PHTN; Evian 1998 and Venice 2003

6. Characterizing PHTN in CHD Presence of systemic-to- pulmonary shunt Presence of systemic-to- pulmonary shunt  Location of shunt  Direction of shunt  Size of defect State of repair State of repair Associated cardiac anomalies Associated cardiac anomalies Presence of systemic-to- pulmonary shunt Presence of systemic-to- pulmonary shunt  Location of shunt  Direction of shunt  Size of defect State of repair State of repair Associated cardiac anomalies Associated cardiac anomalies Evian/Venice Classification

7. Systemic-to-Pulmonary Shunt Yes/No Yes/No Previously present by history? Previously present by history?  If not, consider another classification system (such as WHO) For purposes of this discussion, we will assume all pts have a shunt lesion (CHD) For purposes of this discussion, we will assume all pts have a shunt lesion (CHD) Yes/No Yes/No Previously present by history? Previously present by history?  If not, consider another classification system (such as WHO) For purposes of this discussion, we will assume all pts have a shunt lesion (CHD) For purposes of this discussion, we will assume all pts have a shunt lesion (CHD) Evian/Venice Classification

8. Location of Shunt? Pre-tricuspid level Pre-tricuspid level  Inter-atrial communication (ASD)  Anomalous pulmonary venous drainage/connection Post-tricuspid level Post-tricuspid level  Ventricular septal defect (VSD)  Patent ductus arteriosus/AP window  Functionally univentricular hearts Pre-tricuspid level Pre-tricuspid level  Inter-atrial communication (ASD)  Anomalous pulmonary venous drainage/connection Post-tricuspid level Post-tricuspid level  Ventricular septal defect (VSD)  Patent ductus arteriosus/AP window  Functionally univentricular hearts Evian/Venice Classification

9. Where is the Shunt?

10. Direction of Shunt? Systemic to pulmonary Systemic to pulmonary  Left-to-right Pulmonary to systemic Pulmonary to systemic  Right-to-left Bidirectional Bidirectional Systemic to pulmonary Systemic to pulmonary  Left-to-right Pulmonary to systemic Pulmonary to systemic  Right-to-left Bidirectional Bidirectional Evian/Venice Classification

11. Size of Defect? Anatomic and functional Anatomic and functional Consider size at presentation and current size Consider size at presentation and current size Quantification of shunt Quantification of shunt  Ratio of pulmonary and systemic flows Restriction? Restriction?  Is there any pressure gradient through the post-tricuspid defect? Anatomic and functional Anatomic and functional Consider size at presentation and current size Consider size at presentation and current size Quantification of shunt Quantification of shunt  Ratio of pulmonary and systemic flows Restriction? Restriction?  Is there any pressure gradient through the post-tricuspid defect? Evian/Venice Classification

12. State of Repair? Unoperated Unoperated Palliated Palliated  Age at repair  Type of surgery Repaired Repaired  Age at repair  Type of surgery Unoperated Unoperated Palliated Palliated  Age at repair  Type of surgery Repaired Repaired  Age at repair  Type of surgery Modified from Venice 2003

13. IF Postoperative Patient? Correction of shunt and age at correction Correction of shunt and age at correction Pulmonary arterial banding Pulmonary arterial banding  Age at PAB, duration of banding Presence and type of surgical shunts Presence and type of surgical shunts  Blalock-Taussig, Pott’s, Waterston Residual shunting Residual shunting  Quantification and direction Correction of shunt and age at correction Correction of shunt and age at correction Pulmonary arterial banding Pulmonary arterial banding  Age at PAB, duration of banding Presence and type of surgical shunts Presence and type of surgical shunts  Blalock-Taussig, Pott’s, Waterston Residual shunting Residual shunting  Quantification and direction Evian/Venice Classification

14. Associated Cardiac Anomalies Especially those that affect pulmonary hemodynamics: Pulmonary valve stenosis Pulmonary valve stenosis Defects affecting pulmonary venous “outflow” Defects affecting pulmonary venous “outflow”  Cor triatriatum, mitral stenosis, LV dysfunction Ventricular function Ventricular function  Systolic, diastolic  Overall cardiac output Especially those that affect pulmonary hemodynamics: Pulmonary valve stenosis Pulmonary valve stenosis Defects affecting pulmonary venous “outflow” Defects affecting pulmonary venous “outflow”  Cor triatriatum, mitral stenosis, LV dysfunction Ventricular function Ventricular function  Systolic, diastolic  Overall cardiac output Evian/Venice Classification

15. Considering CHD and PHTN Basic issues at presentation: Is the patient still repairable? Is the patient still repairable?  Is the shunt lesion recognized in a timely fashion? Is the pulmonary hypertension reversible? Is the pulmonary hypertension reversible?  There may be a point of “no return” but the time course varies widely from patient to patient… Basic issues at presentation: Is the patient still repairable? Is the patient still repairable?  Is the shunt lesion recognized in a timely fashion? Is the pulmonary hypertension reversible? Is the pulmonary hypertension reversible?  There may be a point of “no return” but the time course varies widely from patient to patient…

16. Pulmonary Arterial HTN In patients with CHD: Pulmonary artery is exposed to systemic pressure when VSD or PDA is unrestrictive Pulmonary artery is exposed to systemic pressure when VSD or PDA is unrestrictive Pulmonary HTN is present from birth Pulmonary HTN is present from birth Pulmonary vascular resistance determines outcome Pulmonary vascular resistance determines outcome In patients with CHD: Pulmonary artery is exposed to systemic pressure when VSD or PDA is unrestrictive Pulmonary artery is exposed to systemic pressure when VSD or PDA is unrestrictive Pulmonary HTN is present from birth Pulmonary HTN is present from birth Pulmonary vascular resistance determines outcome Pulmonary vascular resistance determines outcome

17. What is the Point of No Return? Eisenmenger syndrome: Pulmonary vascular resistance is elevated Pulmonary vascular resistance is elevated Shunt reverses and becomes right-to-left Shunt reverses and becomes right-to-left Eisenmenger syndrome: Pulmonary vascular resistance is elevated Pulmonary vascular resistance is elevated Shunt reverses and becomes right-to-left Shunt reverses and becomes right-to-left

18. PVD: Who is at Risk? PulmonaryVascularDiseasePulmonaryVascularDisease Shunt + Pulmonary Hypertension Hypertension Particularly if there is Cyanosis

19. Two Ventricles… Large VSD, Large PDA Large VSD, Large PDA Combined intracardiac shunts Combined intracardiac shunts  i.e. d-TGA with VSD; DORV  Cyanosis and mixing is a BAD combination What about large ASD? What about large ASD?  This may be a separate issue i.e. Primary pulmonary HTN Other factors: Other factors:  Pulmonary venous obstruction, arch obstruction (Shone’s syndrome), AV valve regurgitation Large VSD, Large PDA Large VSD, Large PDA Combined intracardiac shunts Combined intracardiac shunts  i.e. d-TGA with VSD; DORV  Cyanosis and mixing is a BAD combination What about large ASD? What about large ASD?  This may be a separate issue i.e. Primary pulmonary HTN Other factors: Other factors:  Pulmonary venous obstruction, arch obstruction (Shone’s syndrome), AV valve regurgitation

20. One Ventricle… Basically anyone with an unprotected PA bed (no PS) Basically anyone with an unprotected PA bed (no PS)  Tricuspid atresia with unrestrictive VSD, no PS  DILV without pulmonary stenosis  DORV with small LV, no PS  Ductal-dependent, complex CHD with persistently large PDA Basically anyone with an unprotected PA bed (no PS) Basically anyone with an unprotected PA bed (no PS)  Tricuspid atresia with unrestrictive VSD, no PS  DILV without pulmonary stenosis  DORV with small LV, no PS  Ductal-dependent, complex CHD with persistently large PDA

21. Assessment of PHTN In the Setting of CHD

22. Assessment in CHD Early recognition and referral of CHD is critical Early recognition and referral of CHD is critical  This is extremely important!  Natural history may vary; timing or presentation may also vary Clinical evaluation Clinical evaluation  Symptoms, growth pattern, other illnesses and hospitalizations?  Physical examination  Laboratory evaluation Early recognition and referral of CHD is critical Early recognition and referral of CHD is critical  This is extremely important!  Natural history may vary; timing or presentation may also vary Clinical evaluation Clinical evaluation  Symptoms, growth pattern, other illnesses and hospitalizations?  Physical examination  Laboratory evaluation

23. Clinical Assessment in CHD Clinical exam: Does the patient have evidence of large L-to-R shunt? Does the patient have evidence of large L-to-R shunt?  S2, P2 component  Continuous PDA murmur  Systolic murmur with diastolic flow rumble through mitral valve Or not? Or not?  Loud, single S2 (P2), minimal murmur  Very short systolic murmur  No flow rumble or continuous murmur Clinical exam: Does the patient have evidence of large L-to-R shunt? Does the patient have evidence of large L-to-R shunt?  S2, P2 component  Continuous PDA murmur  Systolic murmur with diastolic flow rumble through mitral valve Or not? Or not?  Loud, single S2 (P2), minimal murmur  Very short systolic murmur  No flow rumble or continuous murmur Is the patient PINK or cyanotic?

24. CXR in Shunt Physiology This should be reassuring…

25. CXR in Shunt Physiology This is more reassuring…

26. CXR in Shunt Physiology This is NOT reassuring…

27. Echo Assessment Careful evaluation of anatomy and physiology: Confirmation of location, size and associated defects Confirmation of location, size and associated defects  Doppler profile (velocity)  Shunt direction, left-to-right; bidirectional; right-to-left  Left-sided structural enlargement  Associated valve pathology  Ventricular function Careful evaluation of anatomy and physiology: Confirmation of location, size and associated defects Confirmation of location, size and associated defects  Doppler profile (velocity)  Shunt direction, left-to-right; bidirectional; right-to-left  Left-sided structural enlargement  Associated valve pathology  Ventricular function

28. Echo Assessment Need to be very careful in the patient with a large post-tricuspid defect (i.e. VSD) to NOT miss other defects Need to be very careful in the patient with a large post-tricuspid defect (i.e. VSD) to NOT miss other defects  Always evaluate the aortic arch and ductus very carefully  Sometimes the PDA with bidirectional shunt is very easy to “miss” Be careful in the patient with bidirectional or right-to-left shunt Be careful in the patient with bidirectional or right-to-left shunt  Suspicions of elevated pulmonary resistance?  The patient needs hemodynamic cath study Need to be very careful in the patient with a large post-tricuspid defect (i.e. VSD) to NOT miss other defects Need to be very careful in the patient with a large post-tricuspid defect (i.e. VSD) to NOT miss other defects  Always evaluate the aortic arch and ductus very carefully  Sometimes the PDA with bidirectional shunt is very easy to “miss” Be careful in the patient with bidirectional or right-to-left shunt Be careful in the patient with bidirectional or right-to-left shunt  Suspicions of elevated pulmonary resistance?  The patient needs hemodynamic cath study

29. Pulmonary Artery Pressure TR = 5.8 m/sec 135 mmHg PR end diastolic = 3.6 51 mmHg 51 mmHg Estimated PA = 145/61 mmHg

30. Shunts and Resistance Resistance determination is the MAIN reason to cath a child/adult with CHD Resistance determination is the MAIN reason to cath a child/adult with CHD Meticulous collection of data! Meticulous collection of data! Resistance is related to pressure divided by flow: Resistance is related to pressure divided by flow: Resistance determination is the MAIN reason to cath a child/adult with CHD Resistance determination is the MAIN reason to cath a child/adult with CHD Meticulous collection of data! Meticulous collection of data! Resistance is related to pressure divided by flow: Resistance is related to pressure divided by flow: Rpa = Pressure drop across PA bed Flow

31. Looking at Resistance Another Way Relationship of pressure to flow and resistance Relationship of pressure to flow and resistance PAP = Flow (Qp) Resistance IMPT point: Increased pressure can have either or both as possible sources IMPT point: Increased pressure can have either or both as possible sources Relationship of pressure to flow and resistance Relationship of pressure to flow and resistance PAP = Flow (Qp) Resistance IMPT point: Increased pressure can have either or both as possible sources IMPT point: Increased pressure can have either or both as possible sources

32. The “Basic” Cath Study Hemodynamics needed: Hemodynamics needed:  RA and LA (PCWP), MPA mean, and systemic artery mean pressures Blood samples needed: Blood samples needed:  Mixed venous (SVC), pulmonary artery, pulmonary vein, aorta Typically done first in room air Typically done first in room air  Calculate the Qp, Qs and Resistance Perform 100% O2 study Perform 100% O2 study Hemodynamics needed: Hemodynamics needed:  RA and LA (PCWP), MPA mean, and systemic artery mean pressures Blood samples needed: Blood samples needed:  Mixed venous (SVC), pulmonary artery, pulmonary vein, aorta Typically done first in room air Typically done first in room air  Calculate the Qp, Qs and Resistance Perform 100% O2 study Perform 100% O2 study

33. Cath: Basic Formulas Shunts from O2 saturation data Shunts from O2 saturation data Qp = Pulmonary blood flow (index) Qp = VO2 / (PV sat-PA sat) (O2 capacity) Qs = Systemic blood flow (index) Qs = VO2 / (SA sat- MV sat) (O2 capacity)  VO2 = Oxygen consumption (ml/min/m2)  O2 Capacity = 13.6 x Hgb (gm/dL) Shunts from O2 saturation data Shunts from O2 saturation data Qp = Pulmonary blood flow (index) Qp = VO2 / (PV sat-PA sat) (O2 capacity) Qs = Systemic blood flow (index) Qs = VO2 / (SA sat- MV sat) (O2 capacity)  VO2 = Oxygen consumption (ml/min/m2)  O2 Capacity = 13.6 x Hgb (gm/dL)

34. Dissolved Oxygen ? O2 content = O2 capacity x O2 saturation + PaO2 x.03ml/mmHg O2 content = O2 capacity x O2 saturation + PaO2 x.03ml/mmHg  Hgb 11.5 gm/dl  Room air; PV pO2 = 106 Oxygen content =(11.5x13.6x0.99)+ (106x0.03) = 155 + 3.3 = 158  100% Oxygen; PV pO2 = 566, sat 100% Oxygen content = (11.5x13.6x1.0) + (566x0.03) = 156 + 17 = 173 O2 content = O2 capacity x O2 saturation + PaO2 x.03ml/mmHg O2 content = O2 capacity x O2 saturation + PaO2 x.03ml/mmHg  Hgb 11.5 gm/dl  Room air; PV pO2 = 106 Oxygen content =(11.5x13.6x0.99)+ (106x0.03) = 155 + 3.3 = 158  100% Oxygen; PV pO2 = 566, sat 100% Oxygen content = (11.5x13.6x1.0) + (566x0.03) = 156 + 17 = 173

35. Dissolved Oxygen? Remember that Qp = VO2 / (PV sat-PA sat) x (O 2 capacity) Remember that Qp = VO2 / (PV sat-PA sat) x (O 2 capacity) If we ignore dissolved O2 then we have a smaller number in denominator, and a “higher” Qp If we ignore dissolved O2 then we have a smaller number in denominator, and a “higher” Qp This will falsely reduce the Rpa in calculations… This will falsely reduce the Rpa in calculations… Remember that Qp = VO2 / (PV sat-PA sat) x (O 2 capacity) Remember that Qp = VO2 / (PV sat-PA sat) x (O 2 capacity) If we ignore dissolved O2 then we have a smaller number in denominator, and a “higher” Qp If we ignore dissolved O2 then we have a smaller number in denominator, and a “higher” Qp This will falsely reduce the Rpa in calculations… This will falsely reduce the Rpa in calculations… * Resistance = PAP/ Flow (Qp)

36. Rpa: Pulmonary Resistance Normal ≤ 3 wood unitsm 2 Normal ≤ 3 wood unitsm 2 Borderline between 3-6 wood unitsm 2 Borderline between 3-6 wood unitsm 2 Over 6 wood unitsm 2 Over 6 wood unitsm 2  Questionable  PHTN may persist or progress  May treat for reversibility over time Eisenmenger physiology pts usually live longer than those with repair! Eisenmenger physiology pts usually live longer than those with repair! Normal ≤ 3 wood unitsm 2 Normal ≤ 3 wood unitsm 2 Borderline between 3-6 wood unitsm 2 Borderline between 3-6 wood unitsm 2 Over 6 wood unitsm 2 Over 6 wood unitsm 2  Questionable  PHTN may persist or progress  May treat for reversibility over time Eisenmenger physiology pts usually live longer than those with repair! Eisenmenger physiology pts usually live longer than those with repair!

37. What about Altitude?

38. Altitude Physiology Potential contribution of altitude Potential contribution of altitude  Delayed transition of decline in pulmonary vascular resistance Delayed remodeling of vascular bed Increased muscularization of arteries  Persistence of the PDA High altitude High altitude  Living above 4000 meters  These changes are even more accentuated Potential contribution of altitude Potential contribution of altitude  Delayed transition of decline in pulmonary vascular resistance Delayed remodeling of vascular bed Increased muscularization of arteries  Persistence of the PDA High altitude High altitude  Living above 4000 meters  These changes are even more accentuated

39. Treatment Options?

40. Treatment of Elevated Rpa Once you’ve demonstrated that Rpa is elevated… Treatment with pulmonary vasodilator therapy Treatment with pulmonary vasodilator therapy  Sildenafil  Bosentan  Other more complex regimens are not usually practical Once you’ve demonstrated that Rpa is elevated… Treatment with pulmonary vasodilator therapy Treatment with pulmonary vasodilator therapy  Sildenafil  Bosentan  Other more complex regimens are not usually practical

41. SildenafilSildenafil Cyclic GMP Phosphodiesterase type 5 inhibitor Cyclic GMP Phosphodiesterase type 5 inhibitor  Prolongs vasodilatory effect of nitric oxide Cyclic GMP Phosphodiesterase type 5 inhibitor Cyclic GMP Phosphodiesterase type 5 inhibitor  Prolongs vasodilatory effect of nitric oxide

42. SildenafilSildenafil Typical adult dose = 20 mg TID Typical adult dose = 20 mg TID Pediatric dosing Pediatric dosing  Initial dose: 0.5 mg/kg/dose every 8 hours  Increased if needed and if tolerated  Typical maximum: 2 mg/kg/dose every 6-8 hours Typical adult dose = 20 mg TID Typical adult dose = 20 mg TID Pediatric dosing Pediatric dosing  Initial dose: 0.5 mg/kg/dose every 8 hours  Increased if needed and if tolerated  Typical maximum: 2 mg/kg/dose every 6-8 hours

43. BosentanBosentan Endothelin receptor antagonist Endothelin receptor antagonist  Endothelin-1 receptors are potent vasoconstrictors; found in higher concentration in lungs of PTHN pts BREATHE – 5 BREATHE – 5  Reduced Rpa  Improved 6 min walk distance  With Rx effects may be maintained for 2 yrs (may improve PHTN mortality) Endothelin receptor antagonist Endothelin receptor antagonist  Endothelin-1 receptors are potent vasoconstrictors; found in higher concentration in lungs of PTHN pts BREATHE – 5 BREATHE – 5  Reduced Rpa  Improved 6 min walk distance  With Rx effects may be maintained for 2 yrs (may improve PHTN mortality)

44. BosentanBosentan Dosage Dosage  10-20 kg: Initial: 31.25 mg daily for 4 weeks; increase to maintenance dose of 31.25 mg twice daily  >20-40 kg: Initial: 31.25 mg twice daily for 4 weeks; increase to maintenance dose of 62.5 mg twice daily  >40 kg: Initial: 62.5 mg twice daily for 4 weeks; increase to maintenance dose of 125 mg twice daily Must monitor liver enzymes Must monitor liver enzymes Dosage Dosage  10-20 kg: Initial: 31.25 mg daily for 4 weeks; increase to maintenance dose of 31.25 mg twice daily  >20-40 kg: Initial: 31.25 mg twice daily for 4 weeks; increase to maintenance dose of 62.5 mg twice daily  >40 kg: Initial: 62.5 mg twice daily for 4 weeks; increase to maintenance dose of 125 mg twice daily Must monitor liver enzymes Must monitor liver enzymes

45. Take Home Points Patient with shunt lesion and obvious increased PBF on clinical/echo evaluation should be repairable Patient with shunt lesion and obvious increased PBF on clinical/echo evaluation should be repairable Elevated Rpa on clinical evaluation warrants further study Elevated Rpa on clinical evaluation warrants further study  Cardiac cath and O 2 study  Evaluate shunt and reactivity of the pulmonary vascular bed Patient with shunt lesion and obvious increased PBF on clinical/echo evaluation should be repairable Patient with shunt lesion and obvious increased PBF on clinical/echo evaluation should be repairable Elevated Rpa on clinical evaluation warrants further study Elevated Rpa on clinical evaluation warrants further study  Cardiac cath and O 2 study  Evaluate shunt and reactivity of the pulmonary vascular bed

46. Take Home Points Early recognition is critical Early recognition is critical  If evidence of increased pulmonary resistance consider treatment with pulmonary vasodilator therapy In patients with obvious Eisenmenger physiology it is better to leave them alone In patients with obvious Eisenmenger physiology it is better to leave them alone  They will survive longer!!! Early recognition is critical Early recognition is critical  If evidence of increased pulmonary resistance consider treatment with pulmonary vasodilator therapy In patients with obvious Eisenmenger physiology it is better to leave them alone In patients with obvious Eisenmenger physiology it is better to leave them alone  They will survive longer!!!