7.14.08 Ford. Pulmonary HTN

8/3/2019 7.14.08 Ford. Pulmonary HTN

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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)



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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)



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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



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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

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7.14.08 Ford. Pulmonary HTN

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