Pulmonary hypertension and operability

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A talk given at the Dept of Pediatrics Lusaka University teaching Hospital. Basic and clinical approach to early operability to prevent pulmonary hypertension. Included is clinical management of Pulmonary Hypertension.

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Pulmonary hypertension and operability

  1. 1. PulmonaryHypertension
  2. 2. Best Method forMx of PHTN isPREVENTION
  3. 3. Conditions associated withPAH Acyanotic CHD  Increased Pulmonary Blood Flow Cyanotic CHD  Increased Pulm Blood Flow
  4. 4. CLASSIFICATION OF CHD ACYANOTIC  CYANOTIC Increased PBF  Decreased Flow  ATRIAL: ASD  TOF  VENTR: VSD  Pulm Atresia  ARTERIAL: PDA  Increased Flow  COMBINED:  TAPVD VSD+PDA  TGA No Shunts  Truncus  Pulm or Aortic  Tricuspid Atresia Stenosis
  5. 5. So what is theright time tooperate in theseconditions
  6. 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. 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. 8. ATRIAL SEPTAL DEFECTPRIMUM SINUS VENOSUS
  9. 9. ATRIAL SEPTAL DEFECT-II
  10. 10. ATRIAL SEPTAL DEFECT-II
  11. 11. ASD-DEVICE
  12. 12. 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
  13. 13. What is aLarge, Moderate, Small VSD Effects of VSD  PRESSURE EFFECT: Pulmonary Hypertension  VOLUME EFFECT: Cardiac enlargement
  14. 14. Pressure Effect: Types Flow Related PAH: Reversible Irreversible PAH due to permanent Changes
  15. 15. Flow Related PAH Increased Flow Increased Pressure When you remove the extra flow ie close the VSD, the Pulmonary Pressure comes back to normal
  16. 16. Flow related PAH (Pre/PostTricuspid 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
  17. 17. Increased Flow PAH All these indicatePatient is operable with good results without post-op PAH
  18. 18. Till when is this phase: Reversible PAH VSD-LARGE: UPTO 6 MONTHS PDA-LARGE: UPTO 6 MONTHS ASD: LARGE: UPTO LATER 4-8 YRS
  19. 19. So, What is a Large Shunt Post tricuspid Large VSD/PDA  Clinically PAH Present (Pressure Effect)  Clinically Volume Effect Present (Cardiac Enlargement)
  20. 20. Moderate Shunt No Pressure Effect But Volume Effect Present
  21. 21. Small Shunt No Pressure or Volume Effect No Symptoms or Signs of increased flow
  22. 22.  So if the surgery is done at the right time it is likely the patient will not get pulmonary hypertension
  23. 23. What Happens when Reversible PAH starts becoming Irreversible …the child shows some signs and these are signs of Post Op PAH
  24. 24. Signs of Reversible toIrreversible PAH Symptoms:  Start improving  Less FTT  Less Infectios  Less tachypnea Signs:  Murmur shorter, P2 Louder, Cardiac Enlargement less
  25. 25. When Reversible Changing toIrreversible Patient still operable Butthe post op risks are more and episode of life threatening PAH in immediate post op period is high
  26. 26. When Completely Irreversible Patient now has Eisenmanger’s Decreased Pulm Blood Flow Cyanosis starts Now risk of surgery more than living without surgery
  27. 27. Chest XraysIndicatingIncreased PBFw PAH ieoperability
  28. 28. VSD
  29. 29. ASD
  30. 30. MODERATE VSD
  31. 31. LARGE VSD LARGE SHUNT
  32. 32. AV CANAL
  33. 33. TGA
  34. 34. TRUNCUS
  35. 35. EISENMANGERS
  36. 36. PulmonaryHypertension
  37. 37. ClassificationGroup 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
  38. 38. 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
  39. 39. 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).
  40. 40. Histologically Speaking Theabove 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
  41. 41. PULMONARY VASODILATION HYPEROXIA HYPOCARBIA ALKALOSIS NON REM SLEEP SEDATED PARALYSED
  42. 42. 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
  43. 43. 3 types of abnormalities Maladaptation Maldevelopment Underdevelopment
  44. 44. Maladaptation Prototype: Meconium aspiration pneumonia Pneumonia, RDS Obstruction of the airways Chemical pneumonitis Release of endothelin,thromboxane vasoconstrictors
  45. 45. Maldevelopment Prototype: Idiopathic PPHN (―black lung‖ PPHN) Vessel wall thickening Smooth muscle hyperplasia Cause – intrauterine exposure to NSAID constriction of ductus arteriosus genetic
  46. 46. Maldevelopment Disruption of NO-cGMP pathway Disruption of PGI2-cAMP pathway Guanylate cyclase is less active Increased ROS (reactive oxygen species) vasoconstrictor Increased thromboxane, endothelin
  47. 47. 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
  48. 48. MEDIATORS OF PULMONARYHYPERTENSION Prostacycline Thromboxane A2 Endothelin-1 Nitric Oxide (NO) Serotonin Adrenomedullin Vasoactive Intestinal Peptide (VIP) Vascular Endothelial Growth Factor (VEGF)
  49. 49. 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
  50. 50. VASODILATORS Oxygen CCBs Endothelin-receptor antagonists BNP Calcitonin gene-related peptide
  51. 51. Bosentas
  52. 52. ENDOTHELIN RECEPTORANTAGONISTS Endothelin-1 overexpressed in PHT Improvepulmonary haemodynamics, exercise capacity, functional status, clinical outcomes Bosentas, sitaxentan and ambrisentan
  53. 53. BOSENTAS Sulphonamide-based ETA & ETB receptor blocker Inducer of  CYP2C9 - Vori/ fluconazole, warfarin, digoxin, simvastatin, t ac/ sirolimus, sildenafil, OCP  CYP3A4 – ketaconazole  t½ 5.6 +/- 1.6 hours
  54. 54. PHOSPHODIESTERASEINHIBITORS 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
  55. 55. PROSTACYCLINE ANALOGUES Vasodilators  Reduce R & L afterload & increase SV & CO Platelet aggregation inhibitors Main ADRs  H/A and dizziness (~80%)  Nausea and jaw pain
  56. 56. 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
  57. 57.  Epoprostenol  Continuous IV infusion  F 0.2/ t½ 2-6 mins  Spontaneous B/D to 6-oxo-prostaglandin F1α
  58. 58. WHERE TO NOW? PDE5 inhibitors & ERAs first line for 1oPHT Increasingevidence that combination therapies are more effective (theoretical)
  59. 59. 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
  60. 60. 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
  61. 61. Prostacyclins Potentpulm 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)
  62. 62. Endothelin receptorantagonists 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
  63. 63. BOSENTAS
  64. 64. BOSENTAS
  65. 65. BOSENTAS
  66. 66. BOSENTAS
  67. 67. BOSENTAS
  68. 68. BOSENTAS
  69. 69. BOSENTAS
  70. 70. BOSENTAS
  71. 71. BOSENTAS
  72. 72. BOSENTAS
  73. 73. BOSENTAS
  74. 74. DEFINITION Pulmonary hypertension is mean pulmonary artery pressure greater than 25mmHg at rest or greater than 30mmHg with exercise

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