Transcript 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
RA=2-8
RV 15-30/2-8
PA 15-30/2-8
Mean=9-18
LA (paw) =2-10
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 Disease
3. PH associated with Respiratory
Disease and/or Hypoxia
4. PH Due to Chronic Thrombotic
and/or Embolic Disease
5. Miscellaneous
* Venice 2003 – updated “Evian” Classification
Pulmonary Arterial Hypertension*
 Idiopathic (IPAH)
 Familial (FPAH) – BMPR2 mutations
 Associated with (APAH)
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CTD
Congenital Systemic to Pulmonary Shunts
Portal hypertension
HIV
Drugs and Toxins
Other
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PVOD
PCH
 Associated with Significant Venous or Capillary
Involvement
 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
CTEPH
Porto-pulmonary
Hypertension
Eisenmengers:
PDA, VSD, ASD
COPD,
Pulmonary Fibrosis
Collagen Vascular Disease
Scleroderma (CREST), SLE
HIV, Drugs
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
Diagnosing PAH
 Difficult to diagnose and often presents
late! (present when mean PAP = 3040mmHg)
 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
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II.
Sx/Physical Exam/Screening/Incidental
Detection of PH
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ECG/CXR/TTE
III. PH Clinical Class Identification
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LFT/ABG/VQ Scan/HRCT/CTPA
IV. PAH Evaluation
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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 612X/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
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
 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 McWilliams
Respiratory Medicine and NZ Heart and
Lung Transplant Unit
Auckland 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:
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COPD (38%)
IPF (17%)
CF (17%)
1 ATD (8.6%)
PPH (4%)
Sarcoidosis (2.5%)
Bronchiectasis (2.7%)
ADULT LUNG TRANSPLANTATION
Survival (%)
.
Kaplan-Meier Survival by Era
100
(Transplants: January 1988 – June 2003)
1988-1994
1995-1999
2000-6/2003
75
(N=4,392)
(N=6,726)
(N=5,553)
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
50
25
1988-1994: 1/2-life = 3.9 Years; Conditional 1/2-life = 7.0 Years
1995-1999: 1/2-life = 4.5 Years; Conditional 1/2-life = 7.0 Years
0
0
1
2
3
4
5
6
7
Years
ISHLT
J Heart Lung Transplant 2005;24: 945-982
8
9
10
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
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< 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)
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*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
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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