pulmonary htn

8/13/2019 Pulmonary HTN

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Pulmonary

Hypertension


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How Common is It?

Pulmonary Hypertension Relatively CommonPulmonary Arterial

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 exercisePCWP 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 dPAPPVR = mPAP PCWP / 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

death Three key pathogeneses:Relative decrease inbioavailability of NORelative increase in serumendothelin-1

Relative deficieny ofPGI2/excess of thromboxane

A2 The term PH represents increasedPAP but not due to intrinsic

vascular disease


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Classification of PH

The current classification system groupstogether forms of pulmonary hypertensionbased on similarities in their pathophysiologiesand 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 -- PAHIPAHFamilial

Associated with PAHConnective Tissue Disease (Scleroderma, SLE, MCTD, DM/PM, RA)Congenital Heart DiseasePortal 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, Gaucher

s 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 -- PHGroup 2: Pulmonary hypertension with left heart disease

Left-sided ventricular or atrial diseaseLeft-sided valvular disease

Group 3: Pulmonary hypertension associated with lung disease and/orhypoxemia

Chronic obstructive lung diseaseInterstitial lung diseaseSleep-disordered breathing

Alveolar hypoventilation disordersChronic exposure to high altitudeDevelopmental abnormalities

Group 4: Pulmonary hypertension due to chronic thrombotic and/or embolicdisease

Thromboembolic obstruction of proximal pulmonary arteries Thromboembolic obstruction of distal pulmonary arteries

Group 5: MiscellaneousSarcoidosis, 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 Raynaud

s)Comorbid conditons:

CREST, liver disease, HIV, sickle cell

Family history of PAHHistory 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 reassuranceLack of therapies in earlier era lead to attitudeof indifference with regard to aggressive

workupComorbid conditions with similar sxs


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Physical exam clues TelengectasiasCalcinosisRaynaud

s

Palmar erythema/stigmata of liver dz JVDRV heaveMurmur TR, VSD/ASDLoud P2 (can hear 2nd heart sound clearly atapex)Clubbing

LE edema


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Diagnostic Work-up

Labs Autoimmune serologiesMarkers of liver synthetic function

HIV serologies when dictated by historyEKG

Not sensitive enough to be a screen but can help guide dx workup

RVH 87% of PHRAD 79% of PHRAE: p wave > 2.5 mm in II, III, aVF


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Diagnostic Work-up

Chest x-rayNot sensitive enough to screen

Attenuated

motheaten

peripheral vasculatureEnlarged PAs (especially right)

EchocardiogramOrder for screening when clinical suspicion existsOrder for standard interval screening in selected groups:

Family of those with IPAH or with known BMPR2 mutationScleroderma spectrumCHD ptsPre-liver transplant


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Always Rule out CTEPH

Must be excluded in every case of PAHPotentially 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 haveit!

Vasoreactivity testingNO, Flolan, Adenosine drop in mPAP by 10 mmHg to

value < 40 mmHgPredicts CCB response

Evaluate for septal defectsShed light on the issue of diastolic dysfunctionInterpret data in context of patient

s volume status


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How do we Treat Them?

General measures: Avoid pregnancy

Contraception imperativeMaternal mortality 30%

Immunizations for respiratory illnessesInfluenza & pneumonia vaccinations

Minimize valsalva maneuvers increase risk ofsyncopeCough, constipation, heavy lifting, etc


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Classes of therapyMedical

DiureticsCoumadin (IPAH, Anorexigen)OxygenPAH specific therapy

Surgical therapy Atrial septostomyLung transplantation


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Diuretics

Principally to treat edema from right heartfailure

Ventricular interdependence ensure LV outputpreserved.May need to combine classes-Thiazide and loop diuretics

Careful to avoid too much pre-load reductionPatients 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 oximetryRule out concomitant obstructive sleep apnea andhypoventilation syndromes


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WHO functional classification

PAHClass I: No limitation in physical activity. Ordinaryphysical 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 blockersEndothelin receptor antagonists (ERAs) bosentan , sitaxsentan, ambrisentanPhosphodiesterase (type 5) inhibitors (PDE 5-I)--sildenafilProstanoids epoprostenol , 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 useOnly 50% of patients maintain response toCCB.Not in FC IV patients or severe right heartfailure


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Endothelin Receptor Antagonists(ETRA)

Targets relative excess of endothelin-1 by blockingreceptors on endothelium and vascular smooth muscleBosentan (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 Med 2002;346:896-903


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Bosentan (Tracleer)Improved Hemodynamics

Adapted from Channick, et al. Lancet 2001

C h a n g

e f r o m

b a s e

l i n e

( % )

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 dosingInitiate at 62.5 mg BID for first 4 weeksIncrease to maintenance dose of 125 mg BID thereafterInitiation and maintenance dose of 62.5 mg BIDrecommended for patients >12 years of age with body

weight


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Ambrisentan (Letairis)

5 or 10 mg once dailyMuch less risk of transaminase elevation (about1%), but monthly monitoring still requiredNo 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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SafetySide effects: headaches, epistaxis, and hypotension(transient)

Sudden hearing lossDrug interaction with nitratesFDA approved dose is 20 mg tid

Higher doses often used given hemodynamic findings.


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Prostacyclin analogues

Epoprostenol, treprostinil, iloprostBenefits

VasodilationPlatelet inhibition

Anti-proliferative effectsInotropic effects


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Epoprostenol (Flolan)

First PAH specific therapy available in the mid1990

sLack of acute vasodilator response does notcorrelate well with epoprostenolunresponsiveness.

Very short half life = 2 minutesDelivered via continuous infusionCost about $100,000/year


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Side effects: headache, jaw pain, flushing,diarrhea, nausea and vomiting, flu-likesymptoms, and anxiety/nervousnessComplex daily preparation

Individualized dosingCatheter complications

Dislodgement/malfunctionCatastrophic deteriorationEmbolization

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 Cardiol 1999;34:1184 1999;34:1184-87 87McLaughlin V et al. McLaughlin V et al. Circulation Circulation 2002;106:1477 2002;106:1477-82 82


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Treprostinil (Remodulin)

Continuous subcutaneousinfusion or IV infusionLonger t1/2 than flolan = 4hours

Less risk of rapid fataldeterioriation if infusion stops

Significant site pain at infusionsite limits use



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Intravenous treprostinilHemodynamic improvements and 6MWDimprovements 1

No site painRisk of catheter related bloodstream infection andembolic phenomenonRecent concerns about increased gram-negativebloodstream infections (CDC MMWR March 2,2007 / 56(08);170-172)

1Tapson VF et al. Chest 2006;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 Med 2002;347:322-29

Safety and side effectsPotential for increased hypotensive effect

with antihypertensivesIncreased risk of bleeding, especially with

co-administration of anticoagulantsFlushing, increased cough, headache, insomniaNausea, vomiting, flu-like syndromeIncreased liver enzymes


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ACCP 2007 Treatment Guidelines


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Following Response to Therapy

Six minute walk testEchocardiogramRight heart catheterizationBNPFunctional class


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Acute Decompensations

Patients with advanced PAH may present acutely with volume 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 PHDetermine etiology of PAH as best as possibleRefer early to specialist if you find itDon

t treat without a RHC Treat agressively, don

t settle for

stability

pulmonary htn

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