1. Pulmonary Hypertension

2. Best Method for Mx of PHTN is PREVENTION

3. Conditions associated with PAH  Acyanotic CHD  Increased Pulmonary Blood Flow  Cyanotic CHD  Increased Pulm Blood Flow

4. CLASSIFICATION OF CHD  ACYANOTIC  Increased PBF  ATRIAL: ASD  VENTR: VSD  ARTERIAL: PDA  COMBINED: VSD+PDA  No Shunts  Pulm or Aortic Stenosis  CYANOTIC  Decreased Flow  TOF  Pulm Atresia  Increased Flow  TAPVD  TGA  Truncus  Tricuspid Atresia

5. So what is the right time to operate in these conditions

6. Timing of surgery: Acyanotic  ASD: 2 years or later  VSD  Large: 3-6 months  Moderate: when there is FTT  Small: when there is AI or InfectiveEndocardiaits

7. Acyanotic, when to operate  PDA  Infancy  ALL PDA’S CAN BE CLOSED WITH DEVICE  Neonatal  Prematurity  Closure by surgical ligation  Full Term  Wait for child to grow if possible

8. ATRIAL SEPTAL DEFECT PRIMUM SINUS VENOSUS

9. ATRIAL SEPTAL DEFECT-II

11. ASD-DEVICE

13. Acyanotic CHD  Increased Pulmonary Blood Flow  PRETRICUSPID SHUNT: RA RV DILATATION  ATRIAL SEPTAL DEFECT  POST TRICUSPID SHUNT: LA V DILATATION  VENTRICULAR SEPTAL DEFECT PATENT DUCTUS ARTERIOSUS

14. What is a Large, Moderate, Small VSD  Effects of VSD  PRESSURE EFFECT: Pulmonary Hypertension  VOLUME EFFECT: Cardiac enlargement

15. Pressure Effect: Types  Flow Related PAH: Reversible  Irreversible PAH due to permanent Changes

16. Flow Related PAH  Increased Flow  Increased Pressure  When you remove the extra flow ie close the VSD, the Pulmonary Pressure comes back to normal

17. Flow related PAH (Pre/Post Tricuspid Shunt)  Symptoms of increased Flow  Tachypnea, Rec infections, failure to thrive  Signs  Tachycardia, Harrison’s sulcus, retractions  X-ray  Cardiac enlargement, Increased Pulmonary Blood Flow

18. Increased Flow PAH  All these indicate  Patient is operable with good results without post-op PAH

19. Till when is this phase:  Reversible PAH  VSD-LARGE: UPTO 6 MONTHS  PDA-LARGE: UPTO 6 MONTHS  ASD: LARGE: UPTO LATER 4-8 YRS

20. So, What is a Large Shunt  Post tricuspid Large VSD/PDA  Clinically PAH Present (Pressure Effect)  Clinically Volume Effect Present (Cardiac Enlargement)

21. Moderate Shunt  No Pressure Effect  But Volume Effect Present

22. Small Shunt  No Pressure or Volume Effect  No Symptoms or Signs of increased flow

23.  So if the surgery is done at the right time it is likely the patient will not get pulmonary hypertension

24. What Happens when  Reversible PAH starts becoming Irreversible  …the child shows some signs and these are signs of Post Op PAH

25. Signs of Reversible to Irreversible PAH  Symptoms:  Start improving  Less FTT  Less Infectios  Less tachypnea  Signs:  Murmur shorter, P2 Louder, Cardiac Enlargement less

26. When Reversible Changing to Irreversible  Patient still operable  But the post op risks are more and episode of life threatening PAH in immediate post op period is high

27. When Completely Irreversible  Patient now has Eisenmanger’s  Decreased Pulm Blood Flow  Cyanosis starts  Now risk of surgery more than living without surgery

28. Chest Xrays Indicating Increased PBF w PAH ie operability

29. VSD

30. ASD

31. MODERATE VSD

32. LARGE VSD LARGE SHUNT

33. AV CANAL

34. TGA

35. TRUNCUS

36. EISENMANGERS

37. Pulmonary Hypertension

38. Classification Group 1 PAH Examples: "Pulmonary arterial hypertension".  1. Idiopathic (IPAH)  2. Familial (FPAH)  3. Associated with (APAH):  Collagen vascular disease  Congenital systemic-to-pulmonary shunts  Portal hypertension  HIV infection  Drugs and toxins  Other (thyroid disorders, glycogen storage disease, Gaucher disease, hereditary hemorrhagic telangiectasia, hemoglobinopathies, myeloproliferative disorders, splenectomy)  4. Associated with significant venous or capillary involvement  Pulmonary veno-occlusive disease (PVOD)  Pulmonary capillary hemangiomatosis (PCH)  5. Persistent pulmonary hypertension of the newborn

39. Classification  Group 2 PH — "Pulmonary venous hypertension". Examples:  1. Left-sided atrial or ventricular heart disease  2. Left-sided valvular heart disease  Group 3 PH — "Pulmonary hypertension associated with disorders of the respiratory system or hypoxemia". Examples:  1. Chronic obstructive pulmonary disease  2. Interstitial lung disease  3. Sleep-disordered breathing  4. Alveolar hypoventilation disorders  5. Chronic exposure to high altitude  6. Development abnormalities

40. Classification  Group 4 PH — "Pulmonary hypertension caused by chronic thrombotic or embolic disease". Examples:  1. Thromboembolic obstruction of proximal pulmonary arteries  2. Thromboembolic obstruction of distal pulmonary arteries  3. Non-thrombotic pulmonary embolism (tumor, parasites, foreign material)  Group 5 PH — These patients have PH caused by inflammation, mechanical obstruction, or extrinsic compression of the pulmonary vasculature (eg, sarcoidosis, histiocytosis X, lymphangiomatosis, compression of pulmonary vessels by adenopathy, and fibrosing mediastinitis).

41. Histologically Speaking  The above mechanisms all cause small muscular arteries and arterioles to undergo intimal hyperplasia and medial hypertrophy 1   Narrowed lumen   Decreased cross-sectional area   Increased resistance 1 - Though again with PPH likely primary process, rather than reactive

46. PULMONARY VASODILATION  HYPEROXIA  HYPOCARBIA  ALKALOSIS  NON REM SLEEP  SEDATED  PARALYSED

47. Basic 3 Mechanisms  2º pulmonary arterial hypertension:  Reduced cross-sectional area of pulmonary vasculature, secondary to:  Occlusion of vessels (e.g. emboli)  Primary disease of pulmonary vasculature walls (e.g. 1º pulmonary hypertension, portal hypertension)  Primary parenchymal disease (e.g. interstitial lung disease, emphysema)  Vasoconstriction 2/2 hypoxia or acidosis  Increased flow through pulmonary vascular bed secondary to left to right shunts  Increased “back pressure” secondary to pulmonary venous hypertension

48. 3 types of abnormalities  Maladaptation  Maldevelopment  Underdevelopment

49. Maladaptation  Prototype: Meconium aspiration pneumonia  Pneumonia, RDS  Obstruction of the airways  Chemical pneumonitis  Release of endothelin,thromboxane  vasoconstrictors

50. Maldevelopment  Prototype: Idiopathic PPHN  (“black lung” PPHN)  Vessel wall thickening  Smooth muscle hyperplasia  Cause – intrauterine exposure to NSAID  constriction of ductus arteriosus  genetic

51.  Disruption of NO-cGMP pathway  Disruption of PGI2-cAMP pathway  Guanylate cyclase is less active  Increased ROS (reactive oxygen species)  vasoconstrictor  Increased thromboxane, endothelin Maldevelopment

52. Underdevelopment  Prototype: Congenital diaphragmatic hernia  Pulmonary hypoplasia  Decreased cross sectional area of pulmonary vasculature  Decreased pulmonary blood flow  Abnormal muscular hypertrophy of the pulm arterioles

53. MEDIATORS OF PULMONARY HYPERTENSION  Prostacycline  Thromboxane A2  Endothelin-1  Nitric Oxide (NO)  Serotonin  Adrenomedullin  Vasoactive Intestinal Peptide (VIP)  Vascular Endothelial Growth Factor (VEGF)

54. ENDOTHELIN-1  Potent vasoconstrictor  Stimulates proliferation of smooth muscle cells in PA  Plasma levels increased in PHT  Level inversely proportional to pulmonary blood flow & CO - ? Direct effect

55. VASODILATORS  Oxygen  CCBs  Endothelin-receptor antagonists  BNP  Calcitonin gene-related peptide

57. Bosentas

58. ENDOTHELIN RECEPTOR ANTAGONISTS  Endothelin-1 overexpressed in PHT  Improve pulmonary haemodynamics, exercise capacity, functional status, clinical outcomes  Bosentas, sitaxentan and ambrisentan

59. BOSENTAS  Sulphonamide-based ET A & ET B receptor blocker  Inducer of  CYP2C9 - Vori/ fluconazole, warfarin, digoxin, simvastatin, tac/ sirolimus, sildenafil, OCP  CYP3A4 – ketaconazole  t½ 5.6 +/- 1.6 hours

60. PHOSPHODIESTERASE INHIBITORS  Sildenafil  PDE type5 inhibitor  Reduce metabolism of cGMP  t½ 3-5 hours  CYP3A4 & 2C9 substrate  Concentration increased by concurrent bosentan – I/As nitrates  Tadalafil  t½ 17 hours  CYP 3A4

61. PROSTACYCLINE ANALOGUES  Vasodilators  Reduce R & L afterload & increase SV & CO  Platelet aggregation inhibitors  Main ADRs  H/A and dizziness (~80%)  Nausea and jaw pain

62. PROSTACYCLINE ANALOGUES  Iloprost  IV or Inhaled  I/As with CCBs, BBs and ACEIs (animal data)  NO PK STUDIES FOLLOWING INHALATION!!  t½ ~ 0.7 hours  Treprostinol  IV or s/c injection  No CYP inhibition - ? induction  t½ 2-4 hours

63.  Epoprostenol  Continuous IV infusion  F 0.2/ t½ 2-6 mins  Spontaneous B/D to 6-oxo-prostaglandin F 1α

64. WHERE TO NOW?  PDE5 inhibitors & ERAs first line for 1 o PHT  Increasing evidence that combination therapies are more effective (theoretical)

65. Nitric Oxide  Selective pulmonary vasodilation, improves oxygenation  ↑ cGMP  Used in ARDS, PPHN, cardiogenic shock, post CPB  Risks: methemoglobinemia and carboxyhemoglobinemia, rebound pulm HTN when stopped  Requires closed inhalational circuit

66. Phosphodiesterase inhibitors  Inhibition of nitric oxide degradation  Sildenafil (PDE-5 inhibitor): ↓ PAP/PVR  Min effects on systemic vasculature  Synergistic with NO  Reduction in RV mass: role in prevention or reversal of remodeling of RV  Milrinone (PDE-3 inhibitor): ↓ PVR/PAP/SVR in setting of CV shock  Nebulized minimizes systemic vasodilation

67. Prostacyclins  Potent pulm and systemic vasodilators with antiplatelet properties  Epoprostenol (IV): ↓ PVR, better CO/ex. Tolerance  s/e: ↓BP, need for central line (risk of infection)  Beraprost (PO): Longer duration  Iloprost (nebulized)

68. Endothelin receptor antagonists  Endothelin-1: neurohormone that causes pulm vasoconstriction, smooth muscle proliferation, fibrosis  Stimulates endothelin receptors A & B  A: vasconstriction  B: vasodilation  Nonselective: Bosentan  A selective: sitaxsentan, ambrisentan  Chronic pulm htn tx given long ½ life and no IV preparation  s/e: hepatic toxicity

69. BOSENTAS

81. DEFINITION  Pulmonary hypertension is mean pulmonary artery pressure greater than 25mmHg at rest or greater than 30mmHg with exercise