7.14.08 ford. pulmonary htn
TRANSCRIPT
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Pulmonary
HypertensionJimmy Ford, MD
Pulmonary and Critical Care
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How Common is It?
Pulmonary HypertensionRelatively Common
PulmonaryArterial
Hypertension
RelativelyUncommon
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What is the Difference?
Pulmonary Hypertension = A general term used todescribe elevated pressure in the pulmonary vascularbed, not describing where the lesion is.
Pulmonary Arterial Hypertension = A term thatdescribes elevated pressure in the pulmonary
vasculature, limited to the arteries/arterioles, and due toan intrinsic abnormality in the pulmonary arterial bed.
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Definition of PAH by WHO
Required:
Mean PAP 25 mm Hg at rest or 35 mmHg
with exercise PCWP 15 mm Hg
Should be present:
PVR 3 Wood Units (240 dynes.sec.cm-5)
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A Word about Hemodynamics
The right heart catheterization is crucial.
Diagnosis and/or treatment choices shouldalmost never be made based uponechocardiography alone, it is a screening tool.
Useful calculations:
mPAP = 1/3 sPAP + 2/3 dPAP
PVR = mPAPPCWP / C.O.
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PAH The term PAH represents truepulmonary ateriopathy,
characterized by:In situ microthrombosisPlexiform lesion formation
Leads to progressive increase inpulmonary vascular resistance andculminates in right heart failure and
deathThree key pathogeneses:
Relative decrease inbioavailability of NORelative increase in serumendothelin-1
Relative deficieny ofPGI2/excess of thromboxaneA2
The term PH represents increasedPAP but not due to intrinsicvascular disease
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Classification of PH
The current classification system groupstogether forms of pulmonary hypertensionbased on similarities in their pathophysiologies
and responses to treatment.
Important to classify patients correctly to ensuretherapeutic choices are appropriate.
Current classification system revised in 2003,with recent update pending (2/2008).
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Group 1 -- PAH IPAH Familial Associated with PAH
Connective Tissue Disease (Scleroderma, SLE, MCTD, DM/PM, RA) Congenital Heart Disease Portal hypertension (5-7% of patients) HIV (0.5% of patients) Drugs/toxins (aminorex-, dexfenfluramine-, or fenfluramine-
containing products, cocaine, methamphetamine) Other: thyroid disorders, glycogen storage disease, Gauchers disease,hereditary hemorrhagic telangiectasia, hemoglobinopathies,
myeloproliferative disorders, splenectomy Associated with venous/capillary involvement
Pulmonary veno-occlusive disease (elevated mPAP, normal PCWP,evidence of pulmonary vascular congestion)
Pulmonary capillary hemangiomatosis
PPHN
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Groups 2-5 -- PH Group 2: Pulmonary hypertension with left heart disease
Left-sided ventricular or atrial disease Left-sided valvular disease
Group 3: Pulmonary hypertension associated with lung disease and/orhypoxemia Chronic obstructive lung disease Interstitial lung disease Sleep-disordered breathing Alveolar hypoventilation disorders Chronic exposure to high altitude Developmental abnormalities
Group 4: Pulmonary hypertension due to chronic thrombotic and/or embolic disease
Thromboembolic obstruction of proximal pulmonary arteries Thromboembolic obstruction of distal pulmonary arteries
Group 5: Miscellaneous Sarcoidosis, histiocytosis X, lymphangiomyomatosis, compression of
pulmonary vessels (adenopathy, tumor, fibrosing mediastinitis)
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Symptoms of PAH
Dyspnea 60%
Fatigue 19%
Near syncope/syncope 13%
Chest pain 7%
Palpitations 5%
LE edema 3%
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Reasons to Suspect PAH
Unexplained dyspnea despite multiplediagnostic tests
Typical symptoms (look for Raynauds) Comorbid conditons:
CREST, liver disease, HIV, sickle cell
Family history of PAH
History of stimulant/anorexigen use
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Why is it missed?
Young patients with non-specific sxs with nlCXR and EKGs often attributed to
somatization and treated with reassurance Lack of therapies in earlier era lead to attitude
of indifference with regard to aggressive
workup Comorbid conditions with similar sxs
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Physical exam clues
Telengectasias Calcinosis
Raynauds
Palmar erythema/stigmata of liver dz JVD
RV heave
Murmur TR, VSD/ASD
Loud P2 (can hear 2nd heart sound clearly atapex)
Clubbing
LE edema
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Diagnostic Work-up
Labs
Autoimmune serologies
Markers of liver synthetic function
HIV serologies when dictated by history EKG
Not sensitive enough to be a screen but can help guide dxworkup
RVH 87% of PH
RAD 79% of PH
RAE: p wave > 2.5 mm in II, III, aVF
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Diagnostic Work-up
Chest x-ray Not sensitive enough to screen
Attenuated motheaten peripheral vasculature
Enlarged PAs (especially right)
Echocardiogram Order for screening when clinical suspicion exists
Order for standard interval screening in selected groups:
Family of those with IPAH or with known BMPR2 mutation Scleroderma spectrum
CHD pts
Pre-liver transplant
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Echocardiogram Findings
Increased sPAP or TR jet Right atrial and ventricular hypertrophy
Flattening of interventricular septum
Small LV dimension
Dilated PA
Pericardial effusion
Poor prognostic sign
RA pressure so high it impedes normal drainage frompericardium
Do not drain, usually does not induce tamponade since RVunder high-pressure and non-collapsible
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Always Rule out CTEPH
Must be excluded in every case of PAH Potentially surgically remediable
1 center with most experience = UCSD
V/Q scan is preferred screening test, not PE protocolCT (this is best for acute emboli).
In chronic thromboembolic disease, at least one (andmore commonly, several) segmental or largermismatched ventilation-perfusion defects are present.
Formal angiography will be done before surgicalprocedure if V/Q positive
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Right Heart Cath
Essential for firm diagnosis: Helps to not dx people with PAH that do not have
it!
Vasoreactivity testing NO, Flolan, Adenosinedrop in mPAP by 10 mmHg tovalue < 40 mmHg
Predicts CCB response
Evaluate for septal defects Shed light on the issue of diastolic dysfunction
Interpret data in context of patients volume status
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How do we Treat Them?
General measures:
Avoid pregnancy
Contraception imperative
Maternal mortality 30%
Immunizations for respiratory illnessesInfluenza & pneumonia vaccinations
Minimize valsalva maneuversincrease risk ofsyncope
Cough, constipation, heavy lifting, etc
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Classes of therapy
Medical
Diuretics
Coumadin (IPAH, Anorexigen)
Oxygen
PAH specific therapy
Surgical therapy
Atrial septostomy
Lung transplantation
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Diuretics
Principally to treat edema from right heartfailure
Ventricular interdependenceensure LV outputpreserved.
May need to combine classes
-Thiazide and loop diuretics
Careful to avoid too much pre-load reduction
Patients often require large doses of diuretics
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Coumadin
Studies only show benefit in IPAH patients,based on improved survival.
Other PAH groups not as clear, use in themconsidered expert opinion.
Generally, keep INR 2.0-2.5.
Thought to lessen in-situ thrombosis
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Oxygen
Formal assessment of nocturnal and exertionaloxygenation needs.
Minimize added insult of hypoxic vasoconstriction
Keep oxygen saturation 90% May be impossible with large right to left shunt
Exclude nocturnal desaturation
Overnight oximetry Rule out concomitant obstructive sleep apnea and
hypoventilation syndromes
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WHO functional classification
PAH Class I: No limitation in physical activity. Ordinary
physical activity does not cause undue dyspnea or fatigue,chest pain or near syncope.
Class II: Slight limitation in physical activity. Ordinaryphysical activity causes undue dyspnea or fatigue, chestpain or near syncope.
Class III: Marked limitation in physical activity. Less than
ordinary physical activity causes undue dyspnea or fatigue,chest pain or near syncope. Class IV: Inability to perform any physical activity
without symptoms. Signs of right heart failure. Dyspneaand/or fatigue may be present at rest. Syncope.
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PAH-Specific Therapies
Calcium channel blockers
Endothelin receptor antagonists (ERAs)
bosentan, sitaxsentan, ambrisentan
Phosphodiesterase (type 5) inhibitors (PDE 5-I)--sildenafil
Prostanoidsepoprostenol, treprostinil,iloprost
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Calcium Channel Blockers
Use only when demonstrated vasoreactivity inRHC (about 10% or less of patients)
Diltiazem or nifedipine preferred.
Titrate up to maximum tolerated dose. Systemic hypotension may prohibit use
Only 50% of patients maintain response to
CCB. Not in FC IV patients or severe right heart
failure
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Endothelin Receptor Antagonists
(ETRA)
Targets relative excess of endothelin-1 by blockingreceptors on endothelium and vascular smooth muscle
Bosentan (Tracleer, 5 yrs) and ambrisentan (Letairis, 1
yr) Ambrisentan is ET-A selective.
Both show improvement in 6MWD and time to clinical
worsening. Monthly transaminase monitoring required for both
Annual cost about $40,000
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Bosentan (Tracleer)
215 patients
70% IPAH92% Class III
Week 16:36 meterImprovement44 meter
treatmenteffect
1Adapted from Rubin LJ et al. N Engl J Med2002;346:896-903
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Bosentan (Tracleer)
Improved Hemodynamics
Adapted from Channick, et al. Lancet 2001
Changefromb
aseline
(%)
TracleerPlacebo
-30%
-20%
-10%
0%
10%
20%
30%
40%
50%
PAP
- 6.7 mm Hg(p
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Bosentan (Tracleer)
Potential for serious liver injury(including very rare cases of unexplained hepatic
cirrhosis after prolonged treatment)
Tracleer causes at least a 3-fold increase in aminotransferases (ALT and AST) in
about 11% of patients and may be accompanied by an elevation of bilirubin in a
small number of cases
Teratogenic and lowers sperm Significant drug interactions Glyburide inhibits bosentan metabolism Bosentan induces metabolism of oral
contraceptives, warfarin, and statins Calcineurin inhibitors (cyclosporin A,tacrolimus), protease inhibitors, amiodarone, ketoconozole
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Bosentan (Tracleer)
Oral dosing
Initiate at 62.5 mg BID for first 4 weeks
Increase to maintenance dose of 125 mg BID thereafter
Initiation and maintenance dose of 62.5 mg BID
recommended for patients >12 years of age with bodyweight
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Ambrisentan (Letairis)
5 or 10 mg once daily
Much less risk of transaminase elevation (about
1%), but monthly monitoring still required
No dose adjustment of coumadin needed
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PDE-5 inhibitors
Adapted from Hill, N. NJ Fellows Conf in PAH 12/2/06
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Sildenafil (Revatio)
Adapted from Hill, N. NJ Fellows Conf in PAH 12/2/06
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Sildenafil (Revatio)
Adapted from Hill, N. NJ Fellows Conf in PAH 12/2/06
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Sildenafil (Revatio)
Safety
Side effects: headaches, epistaxis, and hypotension(transient)
Sudden hearing loss
Drug interaction with nitrates
FDA approved dose is 20 mg tid
Higher doses often used given hemodynamic findings.
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Prostacyclin analogues
Epoprostenol, treprostinil, iloprost
Benefits
Vasodilation
Platelet inhibition
Anti-proliferative effects
Inotropic effects
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Epoprostenol (Flolan)
Adapted from Hill, N. NJ Fellows Conf in PAH 12/2/06
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Epoprostenol (Flolan)
Adapted from Hill, N. NJ Fellows Conf in PAH 12/2/06
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Epoprostenol (Flolan)
Side effects: headache, jaw pain, flushing,diarrhea, nausea and vomiting, flu-likesymptoms, and anxiety/nervousness
Complex daily preparation
Individualized dosing Catheter complications
Dislodgement/malfunction
Catastrophic deterioration
Embolization
Infection (3% deaths)
1 Flolan Flolan[package [package insert]. Research Triangle Park, NC:GlaxoSmithKline;2002 insert].Research Triangle Park, NC:GlaxoSmithKline;20022Rich S et al. Rich S et al. J Am College J Am College Cardiol Cardiol1999;34:1184 1999;34:1184-87 87
McLaughlin V et al. McLaughlin V et al. Circulation Circulation2002;106:1477 2002;106:1477-82 82
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Treprostinil (Remodulin)
Continuous subcutaneousinfusion or IV infusion
Longer t1/2 than flolan = 4hours Less risk of rapid fatal
deterioriation if infusion stops
Significant site pain at infusionsite limits use
Adapted from Hill, N. NJ Fellows Conf in PAH 12/2/06
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Treprostinil (Remodulin)
Adapted from Hill, N. NJ Fellows Conf in PAH 12/2/06
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Treprostinil (Remodulin)
Intravenous treprostinil Hemodynamic improvements and 6MWD
improvements 1
No site pain Risk of catheter related bloodstream infection and
embolic phenomenon
Recent concerns about increased gram-negative
bloodstream infections (CDC MMWR March 2,2007 / 56(08);170-172)
1Tapson VF et al. Chest2006;129:683-88
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Iloprost (Ventavis)
Inhaled prostacyclin
Administered 6-9 timesdaily via special nebulizer
Reported risk ofmorning syncope
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Iloprost (Ventavis)
Improvements in 6MW, functional class and hemodynamicsobserved
Olschewski H et al.N Engl J Med2002;347:322-29
Safety and side effects Potential for increased hypotensive effectwith antihypertensives Increased risk of bleeding, especially withco-administration of anticoagulants Flushing, increased cough, headache, insomnia Nausea, vomiting, flu-like syndrome Increased liver enzymes
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ACCP 2007 Treatment Guidelines
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Following Response to Therapy
Six minute walk test
Echocardiogram
Right heart catheterization
BNP
Functional class
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Acute Decompensations
Patients with advanced PAH may present acutely withvolume overload, marginal blood pressure, and, attimes, elevated creatinine, related either to an acuteprocess or simply worsening RV failure.
In the decompensated patient, elevated RV volumeleads to septal shift, with reduced left ventricular end-diastolic volume and low cardiac output.
Treatment of the acutely ill patient with PAH shouldinclude careful evaluation for secondary causes ofdecompensation such as a low-grade line infection (forthose on an intravenous therapy) or pulmonarythromboembolism.
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Acute Decompensations
Many patients are volume overloaded at presentation,and diuresis, even in the setting of marginal cardiacoutput and low blood pressure, may be required.
In some cases, support with inotropes or pressors isnecessary: animal data suggest a better hemodynamicresponse with sympathomimetic agents such asdobutamine, norepinephrine, and dopamine rather than
vasopressin or phenylephrine; milrinone also hasfavorable effects on cardiac output but may lead toexcessive hypotension.
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Summary
Make sure to differentiate PAH from PH
Determine etiology of PAH as best as possible
Refer early to specialist if you find it
Dont treat without a RHC
Treat agressively, dont settle for stability