PAH Lung Transplant FRACP 2007

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Published on November 2, 2007

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PAH and Lung Transplant:  PAH and Lung Transplant FRACP Teaching 2007 TJ McWilliams Respiratory Physician Pulmonary Hypertension:  Pulmonary Hypertension Classification Diagnosis and Investigation Treatment Pulmonary Circulation:  Pulmonary Circulation BP 100-140/60-90 Mean=70-105 LA (paw) =2-10 PA 15-30/2-8 Mean=9-18 RA=2-8 RV 15-30/2-8 Diagnosis of PAH:  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) Classification of Pulmonary Hypertension*:  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 Pulmonary Arterial Hypertension*:  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 Risk Factors and Associated Conditions:  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 Causes of Secondary Pulmonary Hypertension:  Causes of Secondary Pulmonary Hypertension Obesity, Kyphoscoliosis, Neuromuscular Disease COPD, Pulmonary Fibrosis Collagen Vascular Disease Scleroderma (CREST), SLE HIV, Drugs Eisenmengers: PDA, VSD, ASD CTEPH Porto-pulmonary Hypertension Pathology of PAH:  Pathology of PAH Intimal Thickening Endothelial Cell Proliferation Medial Hypertrophy ↑ Smooth Muscle Fibers ↑ Connective Tissue ↑ Elastic Fibers Complex Plexiform lesions: mass of disorganised vessels proliferating endothelial cells, smooth muscle cells and myofibroblasts arising from pre-existing PA Diagnosing PAH:  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 Diagnostic Strategy*:  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 Right Heart Catheter:  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 Treatment PH (NYHA III and IV):  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 Prostaglandin Analogues:  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)) Oral Endothelin Antagonists:  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 Phosphodiesterase Inhibitors:  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 PH associated with CTD:  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 Idiopathic Pulmonary Arterial Hypertension (IPAH):  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) Eisenmengers and PAH:  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 CTEPH Chronic Thromboembolic Pulmonary Hypertension:  CTEPH Chronic 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 PVOD Pulmonary Veno-Occlusive Disease:  PVOD Pulmonary 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 Porto Pulmonary Hypertension:  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 A Pragmatic Approach:  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? Lung Transplantation:  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 Outcomes in LT:  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 Summary:  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 Update on Lung Transplantation:  Update on Lung Transplantation TJ McWilliams Respiratory Medicine and NZ Heart and Lung Transplant Unit Auckland City Hospital History of Lung Transplantation:  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 Lung Transplant in this Millennium:  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 Indications:  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%) ADULT LUNG TRANSPLANTATION Kaplan-Meier Survival by Era (Transplants: January 1988 – June 2003):  ADULT LUNG TRANSPLANTATION Kaplan-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 Recipient Criteria:  Recipient Criteria End stage pulmonary disease with debilitating symptoms Age HLTX ~ 55 years SLTx ~ 65 years (non supparative lung disease) BSLTx ~ 60 years Disease Specific Criteria:  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) Disease Specific Criteria:  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 Contraindications:  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 Slide37:  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 Relative Contraindications:  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 When to Transplant:  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 Ideal Donor Criteria:  Ideal Donor Criteria < 55years ABO compatible < 20 pack smoking years Clear CXR PaO2 > 300mmHg < 48 hours intubation No significant chest trauma Updated LT Donor Acceptability Criteria*:  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 Early Morbidity and Mortality:  Early Morbidity and Mortality Ischemia-Reperfusion Injury (PGF) Acute Rejection Infection (Donor and Recipient Acquired) CMV Infection Risk Factors for Early Mortality:  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 Late Morbidity and Mortality:  Late Morbidity and Mortality BOS Infection Renal Impairment Malignancy Osteoporosis Bronchiolitis Obliterans Syndrome (BOS):  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 Risk Factors for BOS:  Risk Factors for BOS Acute Rejection high grade/recurrent CMV Infection CMV pneumonitis/DNAaemia HLA mismatch Lymphocytic bronchiolitis Mechanism of Action of immunosuppressive Agents:  Mechanism of Action of immunosuppressive Agents Immunosuppression in LT:  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 TOR Inhibitors:  TOR Inhibitors Everolimus and Sirolimus Not nephrotoxic but may potentiate CNI nephrotoxicity Potent immunosuppressive agents Hyperlipidaemia BOS Treatment:  BOS Treatment Augment Immunosuppression ATG TOR Inhibitors Azithromycin Management of GERD PPI Surgery Retransplant Other Options for End Stage Lung Disease:  Other Options for End Stage Lung Disease COPD – LVRS PAH – Medical Treatment Summary:  Summary Treatment option for end stage lung disease without any other organ dysfunction Improved quality of life (COPD) and length of life (CF, PAH, Bronchiectasis) Success limited by the development of BOS and the requirement for more immunosuppression than other organ transplants Slide53:  A 28 year old woman presents with SOBOE on minimal exertion which has been a problem for a year. Echo confirms pulmonary ↑BP. She had treatment for Reynaud’s disease as a student in Dunedin and has some GERD treated with Losec. RH catheter shows mPAP=64mmHg, PVR = 9,normal RAP and a negative vasodilator test. 6MW=420m Slide54:  She has a good prognosis and should be started on calcium channel blockers because Reynaud’s is a vasoreactive disease She has a poor prognosis and should be started on intravenous treatment and worked up for LT She should be started on medical treatment with Bosentan or Sildenafil She shouldn’t have warfarin because of a high risk of bleeding Regarding RHC for PAH:  Regarding RHC for PAH It is a risky procedure and should only be considered for those who have early disease A positive vasodilator test is when the mPAP falls by 10mmHg and the PVR returns to normal A positive response to Iloprost means this is the best drug to use RHC can help confirm the diagnosis, provide prognostic information and exclude significant L heart disease Regarding BOS (or chronic Rejection) in LTR:  Regarding BOS (or chronic Rejection) in LTR It is diagnosed on transbronchial lung biopsies It is a clinical diagnosis based on lung function It is a rare complication as most LTR die of infection It is easily treated by adding a TOR inhibitor such as Sirolimus or Everolimus Slide57:  A 55 year retired Electrician with severe COPD presents to your general clinic. He gave up smoking 1 year ago but is now very breathless on minimal exertion with signs of early RHF. He is on Ventolin, Seretide and Spiriva. FEV1/FVC = 0.85/2.15 (20%/75%) Slide58:  He is suitable for referral for LT but need to attend a pulmonary rehabilitation He is unsuitable for LT because he may have asbestos related lung disease He needs to be smoke free for 2 years before he can be referred for LT He has an excellent 5 year prognosis after LT because he has CIOPD as his underlying disease

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