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PAH and Lung Transplant

PAH and Lung Transplant. FRACP Teaching 2007 TJ McWilliams Respiratory Physician. Pulmonary Hypertension. Classification Diagnosis and Investigation Treatment . Pulmonary Circulation. BP 100-140/60-90 Mean=70-105. PA 15-30/2-8 Mean=9-18. LA (paw) = 2-10. RA=2-8. RV 15-30/2-8.

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PAH and Lung Transplant

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  1. PAH and Lung Transplant FRACP Teaching 2007 TJ McWilliams Respiratory Physician

  2. Pulmonary Hypertension Classification Diagnosis and Investigation Treatment

  3. Pulmonary Circulation BP 100-140/60-90 Mean=70-105 PA 15-30/2-8 Mean=9-18 LA (paw) =2-10 RA=2-8 RV 15-30/2-8

  4. Diagnosis of PAH • Mean PAP ≥25 mm Hg (30mm Hg with exercise) • ↑Pulmonary Vascular Resistance = >3mmHg/l/min (Woods Units) or ≥120dyne.sec.cm-5 • Normal PACWP (≤15 mm Hg)

  5. Classification of Pulmonary Hypertension* • PAH • Pulmonary Hypertension associated with Left Heart Disease • PH associated with Respiratory Disease and/or Hypoxia • PH Due to Chronic Thrombotic and/or Embolic Disease • Miscellaneous * Venice 2003 – updated “Evian” Classification

  6. Pulmonary Arterial Hypertension* • Idiopathic (IPAH) • Familial (FPAH) – BMPR2 mutations • Associated with (APAH) • CTD • Congenital Systemic to Pulmonary Shunts • Portal hypertension • HIV • Drugs and Toxins • Other • Associated with Significant Venous or Capillary Involvement • PVOD • PCH • PPHN * Venice 2003 – updated “Evian” Classification

  7. Risk Factors and Associated Conditions • Drugs • Definite: Aminorex, Fenfluramine, Toxic Rapeseed Oil • Very likely: Amphetamines, • Demographic and Medical Conditions • Definite: Gender • Possible: Pregnancy, Systemic ↑BP • Diseases • Definite: HIV • Very Likely: Portal ↑BP/Liver Disease, CTD, CHD

  8. Causes of Secondary Pulmonary Hypertension Obesity, Kyphoscoliosis, Neuromuscular Disease Eisenmengers: PDA, VSD, ASD COPD, Pulmonary Fibrosis CTEPH Collagen Vascular Disease Scleroderma (CREST), SLE HIV, Drugs Porto-pulmonary Hypertension

  9. Pathology of PAH Intimal Thickening Endothelial Cell Proliferation Complex Plexiform lesions: • mass of disorganised vessels • proliferating endothelial cells, smooth muscle cells and myofibroblasts • arising from pre-existing PA Medial Hypertrophy ↑ Smooth Muscle Fibers ↑ Connective Tissue ↑ Elastic Fibers

  10. Diagnosing PAH • Difficult to diagnose and often presents late! (present when mean PAP = 30-40mmHg) • First symptoms may be non specific such as breathlessness, lethargy • May present with RVF: ankle oedema, weight increase, chest pain and syncope • Clinicians need to think of the diagnosis when seeing a patient with unexplained breathlessness

  11. Diagnostic Strategy* • Clinical Suspicion of PH • Sx/Physical Exam/Screening/Incidental • Detection of PH • ECG/CXR/TTE • PH Clinical Class Identification • LFT/ABG/VQ Scan/HRCT/CTPA • PAH Evaluation • Type (HIV, Auto Immune Screen, US Scan) • Functional Capacity (6MW , Peak VO2, NYHA) • Haemodynamics (R Heart Catheter +Vasodilator) *ESC Guidelines 2004 Elsevier Ltd

  12. Right Heart Catheter • HR, RAP, PAP, PWP, CO, PVR SVR, BP, ABG and mixed venous BG • Diagnostic in NYHA I and II • Prognostic in NYHA III and IV • ↑RAP, mPAP and ↓CO associated with the worst prognosis • Vasodilator Challenge: • ↓ mPAP ≥10mmHg to reach a mPAP ≤ 40mmHg with ↑ or stable CO • 10-15% IPAH only • Trial CCB

  13. Treatment PH(NYHA III and IV) • Ca Channel Blockers • PAH if vasodilator testing +ve • Anticoagulation • All PH except Eisenmengers • PGI Analogues • Epoprostenol IV and Iloprost nebulised • Endothelin Antagonists • Bosentan • Phosphodiesterase Inhibitors • Sildenafil

  14. Prostaglandin Analogues • IV Epoprostenol/Prostacycline® • 2-4ng/kg/min up to 10-15ng/kg/min • Side effects of hypotension, flushing, headache, jaw pain, diarrhoea, restlessness • Improved haemodynamics and functional improvement and mortality • Nebulised Iloprost/Ventavis® • Single inhalation reduces PAP by 100-20% for 1-2 hours • Short duration of action so need to use 6-12X/day • Aim for 150-300μg/day (15µ / X 6 doses))

  15. Oral Endothelin Antagonists • Bosentan (Tracleer® Actelion) • Vasodilator which antagonizes endothelin a potent vasoconstrictor in vascular endothelial cells • Improves exercise capacity haemodynamics and functional class • Dose: 62.5-125mg bd • ~15% dose dependent ↑ in LFT’s • Teratogenic and may reduce efficacy of OC • May see some peripheral oedema

  16. Phosphodiesterase Inhibitors • Enhance endogenous NO • Sildenafil (Viagara® Pfizer) selectively acts on PDE 5 predominant in human corpora cavernosa and pulmonary vessels compared with systemic blood vessels • Dose: 25-100mg tds • Side effects: headache, flushing, dizziness, visual changes, rhinitis, headache, dyspepsia

  17. PH associated with CTD • ~2% of connective tissue diseases • Occurs in: • Scleroderma and CREST* (prevalence 12%*) • SLE,MCTD, Rh Arthritis, Sjogrens, DM/PM • Similar presentation to PPH, may precede symptoms of CTD • Treatment • Medical • May not be suitable for LT

  18. Idiopathic Pulmonary Arterial Hypertension (IPAH) • Rare disease: Incidence of 2 per million • Median survival 2.8 years after diagnosis • Risk of death ≡ Haemodynamics and NYHA class • Mortality: R Heart Failure 47% and Sudden Cardiac Death 26% • Risk factors • Familial (6% of cases) • Drugs (fenfluramine, toxic rapeseed oil, amphetamines) • HIV • Female (pregnancy)

  19. Eisenmengers and PAH • CHD that initially causes a large L→R shunt with resultant PAH and reversal • May see haemoptisis and CVA (paradoxical emboli) • Slowly progressive compared with IPAH • 97% 1 year vs. 77% and 77% vs. 35% 3 year survival • Treatment • Medical and then LT

  20. CTEPHChronic Thromboembolic Pulmonary Hypertension • Caused by recurrent and/or unresolved (undiagnosed ) PE • May occur despite anti-coagulation • Suspect if signs and symptoms of pulmonary hypertension and a past history of blood clots • Diagnosis: CTPA • Can use prostaglandin analogue but ultimately need Lung Transplantation

  21. PVODPulmonary Veno-Occlusive Disease • Most devastating form of PH • Median survival after dx= 84 days • 71% dead in 6 months • Probably 10% of PH is in fact PVOD • Histology: luminal narrowing and occlusion of pulmonary veins • Difficult to distinguish from PH • Profound hypoxia at rest • CT Chest: septal thickening and ground glass • Vasodilators not used due to risk of pulmonary oedema • LUNG TRANSPLANTATION

  22. Porto Pulmonary Hypertension • Associated with liver disease and portal hypertension (2%) • May be a contra-indication to isolated Liver Transplant • mPAP ≥ 35mmHg or PVR ≥250dynes • Treatment • Vasodilators and then LiTx • ?Combined Li-LTx

  23. A Pragmatic Approach • Is this PH? • Is this IPAH or is there another cause? • How severe is it? • NYHA Class III or IV • Is the vasodilator response +ve • ?Ca channel blockers • Oral treatment ? Or nebulised or IV?

  24. Lung Transplantation • Number of LT for PH has declined in the last 10 years • Now indicated for PPH, CTEPH and PVOD who fail medical treatment • Highest early and late mortality • Haemodynamic Criteria: RAP>15mmHg, CI<2l/min/m2 , PAP>55mmHg • 6MW<350m, NYHA III and IV

  25. Outcomes in LT • 4% of LT (predominantly BSLT) • Worse one year mortality compared with other diagnosis • RR=3.16 (SLT) RR=2.01(BSLT) • Similar long term outcomes • 50% 5 year survival

  26. Summary • PH is a bad disease! • Difficult to diagnose and may present late • High mortality even with treatment • Treatment options • Costly • Variable funding • Lung Transplantation should be reserved for selected candidates where medical treatment has failed

  27. Update on Lung Transplantation TJ McWilliams Respiratory Medicine and NZ Heart and Lung Transplant Unit Auckland City Hospital

  28. History of Lung Transplantation • First LTx performed in 1963 • prisoner with Ca Lung • survived 18 days ( died of renal failure) • 36 LTx from 1963-1974 • 2 survived > 1 month • Cyclosporine developed in the 1970’s • First successful HLTx in 1981 • LTx is now an accepted option for end-stage lung disease

  29. Lung Transplant in this Millennium • Survival has improved in the first 3 years but there has been no significant change in long term mortality • 50-60% 5 year survival • Chronic rejection or BOS remains the greatest limitation on long term survival • Significant problems with immunosuppression toxicity in longer term survivors

  30. Indications • The main indications for LTx are: • COPD (38%) • IPF (17%) • CF (17%) • 1 ATD (8.6%) • PPH (4%) • Sarcoidosis (2.5%) • Bronchiectasis (2.7%)

  31. ADULT LUNG TRANSPLANTATIONKaplan-Meier Survival by Era (Transplants: January 1988 – June 2003) Survival comparisons by era 1988-94 vs. 1995-99: p = 0.01 1988-94: vs. 2000-6/03: p <0.0001 1995-99 vs. 2000-6/03: p <0.0001 ISHLT J Heart Lung Transplant 2005;24: 945-982

  32. Recipient Criteria • End stage pulmonary disease with debilitating symptoms • Age • HLTX ~ 55 years • SLTx ~ 65 years (non supparative lung disease) • BSLTx ~ 60 years

  33. Disease Specific Criteria • COPD • FEV1 <25%, pCO2 >7.3kPa/55mmHg • ↑PAP ± Cor pulmonale • CF and Bronchiectasis • FEV1 <30% rapid clinical deterioration, malnutrition, massive haemoptisis • pCO2 >6.7kPa (50mmHg) pO2 <7.3kPa (55mmHg)

  34. Disease Specific Criteria • IPF • Rapidly progressive disease and symptomatic desaturation with exercise or at rest • FVC <70% and DLCO <50-60% • PAH • Severe progressive symptoms and NYHA III-IV despite optimal medical treatment • CI <2l/min/m2, RAP >15mmHg, mean PAP >55mmHg

  35. Contraindications • Dysfunction of major organs other than the lung • Kidneys: CrCl<50mg/ml/min • Heart: consider CABGS/Angioplasty • Infection with HIV • Hepatitis B antigen positive • Hepatitis C (bx proven liver disease) • Pulmonary Fungal Infection

  36. Active malignancy within the last 2 years • except BCC and SCC of the skin • 5 years for extracapsular renal cell cancer, Ca Breast stage 2, Ca Colon > Dukes A, Melanoma  level 3 • BMI <70% or >130% ideal • Psychiatric disease affecting comprehension and compliance

  37. Relative Contraindications • Symptomatic osteoporosis • Severe musculoskeletal disease affecting the thorax • kyphoscoliosis • Corticosteroid use (aim <10mg/day) • Psychosocial problems • high likelihood of impacting negatively on outcome

  38. When to Transplant • “Window of opportunity” • Aim to transplant when benefit > risk • 2 year survival is < 50% • not so debilitated that benefit and improvement in quality of life is limited • Able to survive time on the waiting list

  39. Ideal Donor Criteria • < 55years • ABO compatible • < 20 pack smoking years • Clear CXR • PaO2 > 300mmHg • < 48 hours intubation • No significant chest trauma

  40. Updated LT Donor Acceptability Criteria* • Age > 55 if ischaemia time short and otherwise ideal • PaO2/FiO2 <300 ? Increased PGF • CXR: consider if unilateral infiltrate • G Stain +ve should not exclude a donor • Can extend graft ischaemia time beyond 6 hours • No adverse outcomes with donor smoking history > 20 pack years • Consider Asthmatic (mild) donors, Drowning (laryngospasm) and CO Poisoning (if otherwise ideal) *Orens, JB et al J Heart lung Transplant 2003;22:1183-1200

  41. Early Morbidity and Mortality • Ischemia-Reperfusion Injury (PGF) • Acute Rejection • Infection (Donor and Recipient Acquired) • CMV Infection

  42. Risk Factors for Early Mortality • Pre transplant diagnosis • Sarcoidosis OR=2.15, PPH OR=2.74, • IPF OR=1.91 • Repeat transplant OR=2.03 • Tx from a ventilator or ICU OR=2.42 • CMV mismatch OR=1.29

  43. Late Morbidity and Mortality • BOS • Infection • Renal Impairment • Malignancy • Osteoporosis

  44. Bronchiolitis Obliterans Syndrome (BOS) • Manifestation of chronic rejection • Still the most significant limitation to long term survival in LTR (Most common cause of death after 1 year) • About half of LTR have BOS by 5yrs • Unexplained irreversible decline in lung function • no evidence of reversible causes • fall in FEV1 and FEF25-75 compared to best post transplant

  45. Risk Factors for BOS • Acute Rejection • high grade/recurrent • CMV Infection • CMV pneumonitis/DNAaemia • HLA mismatch • Lymphocytic bronchiolitis

  46. Mechanism of Action of immunosuppressive Agents

  47. Immunosuppression in LT • Maintenance regimen typically CNI, antiproliferative agent and corticosteroid • CNI’s (Cyclosporin and Tacrolimus) • Renal impairment, ↑BP, • Hirsutism (CSA) • IGT (Tacrolimus) • Azathioprine and Mycophenolate Mofetil • Bone marrow suppression • Nausea, hepatic dysfunction

  48. TOR Inhibitors • Everolimus and Sirolimus • Not nephrotoxic but may potentiate CNI nephrotoxicity • Potent immunosuppressive agents • Hyperlipidaemia

  49. BOS Treatment • Augment Immunosuppression • ATG • TOR Inhibitors • Azithromycin • Management of GERD • PPI • Surgery • Retransplant

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