Pulmonary Hypertension and its management

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Seminar on Pulmonary Hypertension and its management by Mohit Goyal on 21-08-2013

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Pulmonary Hypertension and its management

  1. 1. Pulmonary Hypertension and its management Presented by: Mohit Goyal Under the guidance of: Dr. V. K. Goyal Sir
  2. 2. Pulmonary hypertension (PH) is an abnormal elevation in pulmonary artery pressure, as a result of left heart failure, pulmonary parenchymal or vascular disease, thromboembolism, or a combination of these factors. Pulmonary Hypertension and its management
  3. 3. Pulmonary Hypertension and its management
  4. 4. Salient features of Pulmonary circulation:-  It is a low resistance circuit  Pulmonary BP is about 1/8th of systemic blood pressure  PH occurs when Pulmonary BP reaches 1/4th of systemic levels Pulmonary Hypertension and its management
  5. 5. Genesis of PH:-  Increased pulmonary blood flow  Increased pulmonary vascular resistance  Increased left heart resistance to blood flow Pulmonary Hypertension and its management
  6. 6. Right Ventricular Output ᾳ Right Ventricular Systolic Pressure Pulmonary Vascular Resistance Pulmonary Hypertension and its management
  7. 7. Adaptability of Right Ventricle to increased vascular resistance depends upon:-  Age of the patient  Rapidity of development of Pulmonary Hypertension Pulmonary Hypertension and its management
  8. 8. Conditions leading to PH (Secondary PH):-  Those with elevated PAP and normal PCWP E.g. Idiopathic, Familial, in Collagen disorders, in L to R shunts, drugs, toxins, persistent PH of newborn  Those with elevated PAP and PCWP E.g. Left side valve disease, Pulmonary venoocclusion  Those associated with chronic hypoxia E.g. COLD, ILD, Sleep apnoea  Elevated PAP with Pulmonary arterial obstruction > 3 months E.g. Pulmonary embolism, Chronic thromboembolism Pulmonary Hypertension and its management
  9. 9. Connective tissue diseases e.g. Systemic sclerosis Intimal fibrosis, Medial hypertrophy Reduced functional cross sectional area Increased pulmonary vascular resistance Increased pulmonary arterial pressure Pulmonary Hypertension and its management
  10. 10. Heart Diseases Mitral stenosis Increased left atrial pressure Increased pulmonary venous pressure Increased pulmonary arterial pressure Pulmonary Hypertension and its management
  11. 11. COLD/ILD Destruction of lung parenchyma Fewer alveolar capillaries Increased pulmonary arterial resistance Increased pulmonary arterial pressure Pulmonary Hypertension and its management
  12. 12. Pulmonary thromboembolism Pulmonary emboli Reduced functional cross sectional area Increased pulmonary vascular resistance Increased pulmonary arterial pressure Pulmonary Hypertension and its management
  13. 13. Pulmonary Hypertension and its management Pulmonary embolism Chronic thromboembolism
  14. 14. Miscellaneous substances found to cause PH  Crotolaria spectabilis – tropical leguminous plant  Aminorex – Appetite depressant  Adulterated olive oil  Fenfluramine, Phentermine – anti-obesity drugs They are postulated to act through effects on serotonin transporter expression or activity. Pulmonary Hypertension and its management
  15. 15. Underlying mechanisms in Secondary PH  Shear and mechanical injury in left to right shunts  Biochemical injury by fibrin in thromboembolism  Pulmonary vasoconstriction by decreased prostacyclin, decreased nitric oxide and increased endothelin  Promotion of platelet activation and adhesion by decreased prostacyclin and nitric oxide Pulmonary Hypertension and its management
  16. 16. Idiopathic Pulmonary Hypertension Uncommon form encountered sporadically in patients whom all known causes of Pulmonary hypertension are excluded. Pulmonary Hypertension and its management
  17. 17. Familial Pulmonary Hypertension Least common form having autosomal dominant inheritance with incomplete penetrance, consequently only 10-20% family members developing overt disease. Pulmonary Hypertension and its management
  18. 18. BMPR2 is a cell surface protein belonging to the TGF-β receptor superfamily, which binds a variety of cytokines, including TGF-β, bone morphogenetic protein (BMP), activin, and inhibin. Apart from its role in bone growth, BMP-BMPR2 signalling is now known to be important for embryogenesis, apoptosis, and cell proliferation and differentiation. Pulmonary Hypertension and its management
  19. 19. Inactivating germline mutations in the BMPR2 gene are found in 50% of the familial cases of pulmonary arterial hypertension and 25% of sporadic cases. In many families, even without mutations in the coding regions of the BMPR2 gene, linkage to the BMPR2 locus on chromosome 2q33 can be established, thus indicating that other possible lesions such as gene rearrangements, large deletions, or insertions could be involved. Pulmonary Hypertension and its management
  20. 20. Unanswered questions Topics of researches First, how does loss of a single allele of the BMPR2 gene lead to complete loss of signalling?  Either the mutation might act as a dominant negative or  A secondary loss of the normal allele might occur in the vascular wall via e.g. microsatellite instability, thus leading to a homozygous loss of BMPR2. Pulmonary Hypertension and its management
  21. 21. Why the phenotypic disease occurs only in 10% to 20% of individuals with BMPR2 mutations?  Existence of modifier genes like endothelin, prostacyclin synthetase, and angiotensin converting enzymes.  Environmental triggers which affect vascular tone. Pulmonary Hypertension and its management
  22. 22. Thus, a two-hit model has been proposed whereby a genetically susceptible individual with a BMPR2 mutation requires additional genetic or environmental insults to develop the disease. Pulmonary Hypertension and its management
  23. 23. Vasospastic component in PH Some individuals with PH have a vasospastic component; in such patients, pulmonary vascular resistance can be rapidly decreased with vasodilators. Exact mechanism is not known. “It appears that even in cases with very advanced primary pulmonary hypertension there is a vasospastic component which can be influenced by vasodilators e.g. Phentolamine.” Heinrich U, Angehrn W, Steinbrunn W. (1983). Therapy of primary pulmonary hypertension with phentolamine, 113(4):145-8. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/6828847 Pulmonary Hypertension and its management
  24. 24. Morphology  All forms of PH have some common pathologic features  Medial hypertrophy of muscular and elastic arteries  Atheromas of pulmonary artery and its major branches  Right ventricular hypertrophy  Pulmonary embolism - organizing or recanalized  Coexistence of diffuse pulmonary fibrosis, or severe emphysema and chronic bronchitis, points to chronic hypoxia as the initiating event Pulmonary Hypertension and its management
  25. 25. Pulmonary Hypertension and its management Gross appearance of atheroma formation Marked medial hypertrophy Plexiform lesions in PH due to drugs, HIV
  26. 26. Symptoms  Exertional dyspnoea  Fatigue  Angina pectoris  Syncope, near syncope  Peripheral oedema Pulmonary Hypertension and its management
  27. 27. Signs  Raised JVP  Reduced carotid pulse  Increased component of P2 in S2  Right Sided S4  Tricuspid regurgitation  Peripheral cyanosis and oedema in late stage Pulmonary Hypertension and its management
  28. 28. Pulmonary Hypertension and its management Class NYHA WHO 1/I No symptoms with ordinary physical activity. Patients with PH but without resulting limitation of physical activity. Ordinary physical activity does not cause undue dyspnoea or fatigue, chest pain, or near syncope. 2/II Symptoms with ordinary activity. Slight limitation of activity. Patients with PH resulting in slight limitation of physical activity. They are comfortable at rest. Ordinary physical activity causes undue dyspnoea or fatigue, chest pain, or near syncope. 3/III Symptoms with less than ordinary activity. Marked limitation of activity. Patients with PH resulting in marked limitation of physical activity. They are comfortable at rest. Less than ordinary activity causes undue dyspnoea or fatigue, chest pain, or near syncope. 4/IV Symptoms with any activity or even at rest. Patients with PH with inability to carry out any physical activity without symptoms. These patients manifest signs of right-heart failure. Dyspnoea and/or fatigue may even be present at rest.
  29. 29. Investigations  Chest Radiography  Electrocardiogram  Echocardiography  Lung function testing  Ventilation-perfusion scanning  HRCT scanning  Pulmonary angiography  Cardiac catheterization  Exercise testing Pulmonary Hypertension and its management
  30. 30. Chest Radiograph  Enlargement of pulmonary trunk  Pruning of peripheral pulmonary arterial tree  Right ventricular enlargement  Findings corresponding to condition leading to PH Pulmonary Hypertension and its management
  31. 31. Pulmonary Hypertension and its management
  32. 32. Electrocardiogram  RAD  Right Ventricular Enlargement Pulmonary Hypertension and its management
  33. 33. Echocardiogram and Continuous Wave Colour Doppler  Thickened right ventricle  Regurgitant flow across the tricuspid valve  Regurgitant flow across the pulmonic valve Pulmonary Hypertension and its management
  34. 34. Pulmonary Hypertension and its management
  35. 35. Pulmonary Hypertension and its management
  36. 36. Pulmonary Hypertension and its management Cardiac catheterization
  37. 37. Cardiac catheterization Determination of:-  Right atrial pressure  Right ventricular pressure  PAP  PCWP  Pulmonary blood flow (cardiac output)  Vasoreactivity Pulmonary Hypertension and its management
  38. 38. Pulmonary Hypertension and its management
  39. 39. Other Investigations  Lung function testing  Ventilation-perfusion scanning  HRCT scanning  Lung biopsy  Pulmonary angiography  Exercise testing Pulmonary Hypertension and its management
  40. 40. Pulmonary Hypertension and its management Echocardiogram Dilated RV PFT Obstructive Restrictive Left heart disease Valvular heart disease Congenital anomaly Cardiac Catheterization COLD HRCT Normal or enlarged pulmonary arteries ILD Pulmonary thromboembolism Lab tests: CBC, ANA, HIV, TSH, LFTs Exercise testing, Catheterization, Vasodilator testing
  41. 41. Pulmonary Hypertension and its management Management options  Drug therapy  Atrial septostomy  Lung transplantation
  42. 42. Pulmonary Hypertension and its management Drug options  Calcium channel blockers  Endothelin receptor antagonists  Phosphodiesterase-5 inhibitors  Prostacyclin analogues
  43. 43. Pulmonary Hypertension and its management
  44. 44. Pulmonary Hypertension and its management Principles of drug treatment  Patients should undergo cardiac catheterization before initiating therapy.  Obtain baseline assessments of the disease to know whether treatments are effective.  Test Vasoreactivity.  Reactive patients should be treated with calcium channel blockers.  Nonreactive patients should be offered other therapies.  Reassess at 8 weeks; patients who don’t respond are unlikely to respond with longer exposure.  Ineffective treatments should be substituted rather than new added.  Patients who fail all treatments should be considered for lung transplantation.  Only the addition of sildenafil to epoprostenol has been shown to be efficacious.
  45. 45. Pulmonary Hypertension and its management Calcium channel blockers  Indicated in patients who respond to vasodilators during catheterization  Mean PAP<40 mm of Hg and fall > or = 10 mm of Hg  High doses required e.g. nifedipine 240 mg/d, or amlodipine, 20 mg/d  Dramatic reductions in PAP, resistance associated with improved symptoms  Regression of RV hypertrophy  Improved survival now documented to exceed 20 years  However <20% patients respond to calcium channel blockers in the long term  Not approved for the treatment of PAH by the U.S. FDA
  46. 46. Pulmonary Hypertension and its management Endothelin receptor antagonists  Bosentan and ambrisentan are approved treatments of PAH  Both improved exercise tolerance in RCTs  Bosentan initiated at 62.5 mg BD for first month and increased to 125 mg BD  Ambrisentan initiated as 5 mg OD and can be increased to 10 mg daily  Liver function be monitored monthly throughout the duration of use  Contraindicated in patients on cyclosporine or glyburide concurrently
  47. 47. Pulmonary Hypertension and its management Phosphodiesterase-5 inhibitors  Approved for the treatment of PAH  Phosphodiesterase-5 is responsible for the hydrolysis of cyclic GMP  Sildenafil and tadalafil improve exercise tolerance  Effective dose for sildenafil is 20–80 mg TID  The effective dose for tadalafil is 40 mg OD  The most common side effect is headache  Neither drug should be given to patients who are taking nitrovasodilators
  48. 48. Pulmonary Hypertension and its management Prostacyclin analogues Iloprost  Approved via inhalation for PAH  Improves a composite measure of symptoms and exercise tolerance by 10%  Given at either 2.5 or 5 µg per inhalation treatment via a dedicated nebulizer  Most common side effects are flushing and cough  Very short half-life of <30 min  Recommended to be administered as often as every 2 h
  49. 49. Pulmonary Hypertension and its management Prostacyclin analogues Epoprostenol  Approved as a chronic IV treatment of PAH  Improvement in symptoms, exercise tolerance, and survival  Administration requires placement of a permanent central venous catheter  Infusion done through an ambulatory infusion pump system  Cause vasodilation and platelet inhibition  Also inhibition of vascular smooth muscle growth and inotropic effects  Side effects include flushing, jaw pain, and diarrhoea  Doses of epoprostenol range from 25 to 40 ng/kg per min
  50. 50. Pulmonary Hypertension and its management Prostacyclin analogues Treprostinil  Analogue of epoprostenol, approved for PAH  May be given intravenously, subcutaneously, or via inhalation  Clinical trials have demonstrated an improvement in symptoms with exercise  Local pain at the infusion site with subcutaneous administration  Doses of treprostinil range from 75 to 150 ng/kg per min
  51. 51. Pulmonary Hypertension and its management Atrial Septostomy  Blade-balloon atrial septostomy is performed  In patients with severe refractory RV pressure and volume overload  Decompresses overloaded right heart  Improves systemic output of the underfilled left ventricle  Increased venous admixture  Worsening hypoxaemia is expected over time
  52. 52. Pulmonary Hypertension and its management Lung transplantation  Only 1/3rd patients of primary PH are responsive to oral vasodilators  Indicated in patients on IV prostacyclin, who continue to manifest right heart failure  Handicapped by shortage of lung donors  Single/double lung transplantation has largely replaced heart-lung transplantation  Median survival after transplantation is 3 years  Rejection phenomena e.g. Bronchiolitis obliterans are limiting factors  Recurrence not reported after transplantation
  53. 53. Pulmonary Hypertension and its management What we can do…  High index of suspicion  Electrocardiography, Radiography, Echocardiography, Lung function testing, HRCT, Angiography, Exercise testing  Easily available – CCBs, Sildenafil  Educate suitable candidates about catheterization
  54. 54. Pulmonary Hypertension and its management THANK YOU HAVE A GOOD DAY Bibliography  Rich, S., 2012. Pulmonary Hypertension. In: D. Longo, A. Fauci, D. Kasper, S. Hauser, J. Jameson, J. Loscalzo, ed. 2012 Harrison’s Principles of Internal Medicine. USA: McGraw-Hill. pp.2076-2082.  Rubin, L.J., 2001. Pulmonary Hypertension. In: R.A. O’Rourke, V. Fuster, R.W. Alexander, R. Roberts, S.B. King III, H.J.J. Wellens, eds. 2001. Hurst's The Heart : Manual of Cardiology. USA: McGraw-Hill. Ch.19.  Husain, A.N., 2010. The Lung. In: V. Kumar, A.K. Abbas, N. Fausto, J.C. Aster, eds. 2010. Robbins and Cotran Pathologic Basis of Disease. USA: Saunders. Ch.15.

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