pah and lung transplant fracp teaching 2007 tj mcwilliams respiratory physician
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PAH and Lung Transplant
FRACP Teaching 2007TJ McWilliamsRespiratory Physician
Pulmonary Hypertension
ClassificationDiagnosis and InvestigationTreatment
Pulmonary Circulation
BP 100-140/60-90Mean=70-105
LA (paw) =2-10
PA 15-30/2-8Mean=9-18
RA=2-8
RV 15-30/2-8
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*
1. PAH 2. Pulmonary Hypertension associated
with Left Heart Disease3. PH associated with Respiratory
Disease and/or Hypoxia4. PH Due to Chronic Thrombotic and/or
Embolic Disease5. Miscellaneous
* Venice 2003 – updated “Evian” Classification
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
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
Obesity, Kyphoscoliosis, Neuromuscular Disease
COPD, Pulmonary Fibrosis
Collagen Vascular DiseaseScleroderma (CREST), SLE
HIV, Drugs
Eisenmengers: PDA, VSD, ASD
CTEPH
Porto-pulmonaryHypertension
Pathology of PAHIntimal ThickeningIntimal ThickeningEndothelial Cell Endothelial Cell ProliferationProliferation
Medial HypertrophyMedial Hypertrophy ↑ ↑ Smooth Muscle FibersSmooth Muscle Fibers↑ ↑ CConnective Tissueonnective Tissue↑ ↑ Elastic FibersElastic Fibers
Complex Plexiform lesionsComplex Plexiform lesions::mass of disorganised vesselsmass of disorganised vesselsproliferating endothelial cells,proliferating endothelial cells, smooth muscle cells andsmooth muscle cells and myofibroblasts myofibroblasts arising from pre-existing PAarising from pre-existing PA
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*
I. Clinical Suspicion of PH• Sx/Physical Exam/Screening/Incidental
II. Detection of PH• ECG/CXR/TTE
III. PH Clinical Class Identification• LFT/ABG/VQ Scan/HRCT/CTPA
IV. 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 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) 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 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 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 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 ~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) 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 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
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
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
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
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
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
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 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
TJ McWilliamsRespiratory Medicine and NZ Heart and Lung Transplant UnitAuckland City Hospital
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 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
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 TRANSPLANTATIONKaplan-Meier Survival by Era (Transplants: January 1988 – June 2003)
0
25
50
75
100
0 1 2 3 4 5 6 7 8 9 10
Years
Su
rviv
al (
%)
.
1988-1994 (N=4,392)1995-1999 (N=6,726)2000-6/2003 (N=5,553)
1988-1994: 1/2-life = 3.9 Years; Conditional 1/2-life = 7.0 Years1995-1999: 1/2-life = 4.5 Years; Conditional 1/2-life = 7.0 Years
Survival comparisons by era1988-94 vs. 1995-99: p = 0.011988-94: vs. 2000-6/03: p <0.0001 1995-99 vs. 2000-6/03: p <0.0001
ISHLTJ Heart Lung Transplant 2005;24: 945-982
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
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 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
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
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
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
“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
< 55years ABO compatible < 20 pack smoking years Clear CXR PaO2 > 300mmHg < 48 hours intubation No significant chest trauma
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
Ischemia-Reperfusion Injury (PGF) Acute Rejection Infection (Donor and Recipient
Acquired) CMV Infection
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
BOS Infection Renal Impairment Malignancy Osteoporosis
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
Acute Rejection high grade/recurrent
CMV Infection CMV pneumonitis/DNAaemia
HLA mismatch Lymphocytic bronchiolitis
Mechanism of Action of immunosuppressive Agents
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
Everolimus and Sirolimus Not nephrotoxic but may potentiate
CNI nephrotoxicity Potent immunosuppressive agents Hyperlipidaemia
BOS Treatment
Augment Immunosuppression ATG TOR Inhibitors
Azithromycin Management of GERD
PPI Surgery
Retransplant
Other Options for End Stage Lung Disease
COPD – LVRS PAH – Medical Treatment
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
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
a) She has a good prognosis and should be started on calcium channel blockers because Reynaud’s is a vasoreactive disease
b) She has a poor prognosis and should be started on intravenous treatment and worked up for LT
c) She should be started on medical treatment with Bosentan or Sildenafil
d) She shouldn’t have warfarin because of a high risk of bleeding
Regarding RHC for PAH
a) It is a risky procedure and should only be considered for those who have early disease
b) A positive vasodilator test is when the mPAP falls by 10mmHg and the PVR returns to normal
c) A positive response to Iloprost means this is the best drug to use
d) RHC can help confirm the diagnosis, provide prognostic information and exclude significant L heart disease
Regarding BOS (or chronic Rejection) in LTR
a) It is diagnosed on transbronchial lung biopsies
b) It is a clinical diagnosis based on lung function
c) It is a rare complication as most LTR die of infection
d) It is easily treated by adding a TOR inhibitor such as Sirolimus or Everolimus
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%)
a) He is suitable for referral for LT but need to attend a pulmonary rehabilitation
b) He is unsuitable for LT because he may have asbestos related lung disease
c) He needs to be smoke free for 2 years before he can be referred for LT
d) He has an excellent 5 year prognosis after LT because he has CIOPD as his underlying disease