Out-patient Management of Pulmonary Hypertension

1. Out-patient Management of Pulmonary Hypertension Jameel A. Al-Ata, MD KAAUH & KFSH&RC-JED. Taif 14th annual cardiovascular conference , march 2006.

2. Definition & Types Epidemiology Pathophysiology PHTN & CHD Concepts & Goals of management Workup Management Strategies Conclusion. Content

3. Definition & Types • Pulmonary hypertension is defined as a mean pulmonary artery pressure greater than 25 mm Hgat rest , or greater than 30 mm Hg during exercise.

4. WHO classification 1998

5. Pulmonary arterial hypertension; • 1.1 Idiopathic pulmonary hypertension • 1.2 Familial

6. Cont” • 1.3 Associated with: • Collagen vascular disease • Congenital systemic to pulmonary shunts • Portal hypertension • HIV infection • Drugs (anorexigens)/toxins • Other thyroid disorders: Gaucher disease, hereditary haemorrhagic telangiectasia, haemoglobinopathies

7. Cont” • 1.4 Persistent pulmonary hypertension of the newborn • 1.5 Pulmonary veno-occlusive disease

8. Pulmonary hypertension with left heart disease; • 2.1 Left sided atrial or ventricular heart disease • 2.2 Left sided valvular disease

9. Pulmonary hypertension associated with disorders of the respiratory system and/or hypoxaemia; • 3.1 Chronic obstructive pulmonary disease • 3.2 Interstitial lung disease • 3.3 Sleep disordered breathing

10. Cont” • 3.4 Alveolar hypoventilation disorders • 3.5 Chronic exposure to high altitude • 3.6 Neonatal lung disease • 3.7 Alveolar-capillary dysplasia • 3.8 Other

11. Pulmonary hypertension due to chronic thrombotic and/or embolic disease; • 4.1 Thromboembolic obstruction of proximal pulmonary arteries. • 4.2 Obstruction of distal pulmonary arteries • – Pulmonary embolism (thrombus, tumour, and/or parasites). • – In situ thrombosis.

12. Miscellaneous, e.g. Sarcoidosis

13. Genetics & Epidemiology; • 6% of primary pulmonary hypertension cases are familial. • The disease is inherited as an autosomal dominant with incomplete penetrance. • The gene has been mapped to chromosome 2q 33 and recently identified as a mutation of the BMPR2 gene (bone morphogenetic protein receptor) • Mutations of the gene encoding BMPR-II are also seen in at least 26% of sporadic cases of PPH.

14. CONT” • Primary pulmonary hypertension (PPH) has an incidence of 1-2 per million per annum. • Other causes of pulmonary arterial hypertension may account for a further 1-2 cases per million per annum.

15. Cont” • In a 1965 series of 35 patients with primary pulmonary hypertension 22 (63%) patients died in the first year after the onset of symptoms. • In 1995, the median survival in a series of 18 children with primary pulmonary hypertension was 4.12 years. • With new diverse medications 90% survival at 4 years in children with severe idiopathic pulmonary hypertension was reported with prostacyclin.

16. Cont” • Without appropriate treatment, the natural history of IPAH is progressive and fatal. • In contrast, the natural history of pulmonary hypertension from congenital heart disease has a broad range of survival, ranging from months to decades.

17. Pathophysiology; • The constituent cells of the vessel walls appear to undergo changes in phenotype which in turn alter their structure and function. ( proliferation ). • Pulmonary hypertension is associated with pulmonary arterial thrombosis and a hypercoaguable state associated with a fibrinolytic defect and haemostatic disturbance. ( thrombosis ).

18. Cont” • Vasoconstriction plays an important role in the pathogenesis of pulmonary hypertension specially in hypoxemic patients. • In young children, pulmonary vascular disease can progress so rapidly due to severe obstructive intimal proliferation,

19. Cont” • Lung hypoplasia. • Lung fibrosis. • Chronic thromboembolism.

20. PHTN & CHD • The age at which these lesions cause irreversible pulmonary vascular disease varies from months to decades. • Patients with ventricular septal defect or patent ductus arteriosus do not develop irreversible pulmonary vascular changes before 1 year of age. • Children with Down’s syndrome may have an increased risk of pulmonary hypertension.

21. Cont” • Infants with an atrial septal defect or ventricular septal defect with chronic lung disease have an increased risk for the early development of severe pulmonary vascular disease. • Patients with atrioventricular septal defect may develop irreversible pulmonary vascular disease earlier than patients with other left-to-right shunt lesions.

22. Cont” • Hypoxaemia with increased shunting in patients with cyanotic congenital cardiac lesions are potent stimuli for the rapid development of pulmonary vascular disease. Examples include; 1) Transposition of the great arteries, 2) Truncus arteriosus, and 3) Univentricular heart with high flow. • Palliative shunting operations ( e.g. central aorto-pulmpnary shunts ) may lead to the development of pulmonary hypertension.

23. Eisenmenger syndrome; • Increased pulmonary vascular resistance. • Bidirectional or right-to-left shunting through a systemic-to-pulmonary connection, such as a ventricular septal defect, patent ductus arteriosus, univentricular heart, or aortopulmonary window characterises this syndrome.

24. Cont” • Prognosis of Eisenmenger patients with syndrome is much better than for patients with idiopathic pulmonary arterial hypertension. • Syncope, right heart failure, and severe hypoxemia have been associated with a poor prognosis.

25. Concepts & Goals of management; • Confirm the diagnosis of pulmonary hypertension. • Treat the underlying cause. • Determine the type of disease according to the new classification, assess the suitability of possible treatments.( must include assessment of acute vasodilation response).

26. Cont” • Monitor response to therapy. • Reverse back to an operable state. • Reduce the post operative risk of PHTN crisis. • Improve survival & Estimate prognosis.

27. Confirming the diagnosis; History and examination • Diet pill use; contraceptive pill; methamphetamine use • Onset and length of pulmonary hypertension • Family history of pulmonary hypertension • Prior cardiac and other surgeries

28. Cont” Symptoms • Chest pain; dyspnoea; shortness of breath; syncope. Physical examination • Loud second heart sound. • Systolic murmur of tricuspid regurgitation. • Diastolic murmur of pulmonary insufficiency. • Palpable second heart sound. • Peripheral oedema & jugular venous distension

29. Cont” Diagnostic evaluation of pulmonary hypertension; • Chest radiograph (signs of cardiomegaly and enlarged pulmonary arteries) • ECG (right ventricular hypertrophy and ST-T changes) • Echocardiogram • – (right ventricular hypertrophy, exclude congenital heart disease, left ventricular diastolic dysfunction, quantify right ventricular systolic pressure)

31. Cont” Cardiac catheterization with acute vasodilator testing; – (evaluate pulmonary artery pressure and resistance and degree of pulmonary reactivity).

32. Positive response to vasodilators; • Decrease in the mean pulmonary artery pressure and resistance by 20%, or greater, with a fall to near normal levels (<40 mg Hg). • Experience no change or an increase in their cardiac index. • Exhibit no change or a decrease in the ratio of pulmonary vascular resistance to systemic vascular resistance. • Normal right atrial pressure and cardiac output.

33. Cont” Liver evaluation; • – Liver function tests with gamma glutaryl transferase • – Abdominal ultrasound (porto-pulmonary hypertension) • – Hepatitis profile

34. Complete blood count, urinalysis Hypercoagulable evaluation – DIC screen – Factor V Leiden – Antithrombin III Prothrombin mutation 22010 – Protein C – Protein S – Anticardiolipin IgG/IgM – Russel viper venom test Cont”

35. Cont” Collagen vascular workup—looking for autoimmune disease; • – Antinuclear antibody with profile (DNA, Smith, RNP, SSA, SSB, centromere, SCL-70) • – Rheumatoid factor • – Erythrocyte sedimentation rate • – Complement

36. Cont” Lung evaluation • Pulmonary function tests with DLCO/bronchodilators (to exclude obstructive/restrictive disease) • Sleep study and pulse oximetry (degree of hypoxia or diminished ventilatory drive) • CT/MRI scan of chest (evaluation of thromboembolic disease or interstitial lung disease) • Ventilation perfusion test • Lung biopsy

37. Cont” • Six minute walk test/cycle ergometry • HIV test • Thyroid function tests • Toxicology screen (cocaine/methamphetamine and HIV testing)

38. Management strategies; Vasodilator therapy; • Children who respond acutely to vasodilator testing with nitric oxide or epoprostenol should initially be treated with calcium channel blockers, such as nifedipine or diltiazem.

39. Cont” • Acute trial of calcium channel blocker therapy is reserved for those patients who are responsive to nitric oxide or prostacyclin. • At least 60% of children with severe pulmonary hypertension do not respond calcium channel antagonists.

40. Cont” • These drugs can cause a decrease in cardiac output. • Consequently, increased right atrial pressure and low cardiac output are contraindications to acute or chronic calcium channel blockade.

41. Prostacyclin; Imbalance in the biosynthesis of thromboxane A2 and prostacyclin & diminished prostacyclin synthase expression in the lung vasculature are seen in adults with IPAH & children with CHD.

42. Cont” • Intravenous epoprostenol made the five year survival in patients with primary pulmonary hypertension who were not candidates for calcium channel blocker therapy may be higher than 80%. And is promising in CHD. • Disadvantages of prostacyclin analogues include :

43. Cont” • Dose dependent side effects of the drug (nausea, anorexia, jaw pain, diarrhoea, musculoskeletal aches and pains) • Side effects due to the method of delivery. (through a central line) thus potential complications include clotting, haemorrhage, cellulitis, and sepsis.

44. Cont” • Abrupt cessation causing acute deterioration and in some cases death.( rebound PHTN ) • In patients with residual shunting, continuous prostacylin may result in worsening cyanosis and complications of cerebrovascular accidents.

45. Alternative delivery routes for prostacyclin analogues; • Treprostinil, a subcutaneous prostacyclin has been tested in a multicentre international placebo controlled randomised study and was found to have beneficial effects. • Can cause pain and erythema around the infusion site, thus limiting its usefulness in young children.

46. Cont” Iloprost An inhaled prostacylin analogue, has undergone initial trials with significant beneficial effects on symptomatology and quality of life. Iloprost has a half life of 20–25 minutes and therefore 6–9 inhalations a day are required to be clinically effective.

47. Cont” Beraprost, • An orally active prostacyclin analogue, is fast acting and has a half life of 35–40 minutes; it has beneficial effects, which may be attenuated with increasing length of treatment. • A recent study showed comparable if not superior PAP lowering effect to N.O.

48. Endothelins receptor antagonists; Bosentan, a dual ET receptor antagonist, which when used in children with pulmonary arterial hypertension related to congenital heart disease or IPAH, it lowered pulmonary pressure and resistance, and was well tolerated.

49. CONT” Sitaxsentan, • An ET receptor antagonist with high oral bioavailability, a long duration of action. • When given orally for 12 weeks it had beneficial effects on exercise capacity and cardiopulmonary haemodynamics in patients with congenital heart disease.

50. Phosphodiesterase-5 inhibitors;Sildenafil • These drugs promote an increase in cGMP levels and thus cause pulmonary vasodilatation. • Useful in the setting of inhaled nitric oxide therapy withdrawal, in postoperative pulmonary hypertension, or in the presence of pulmonary hypertension related to chronic lung disease.