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10
PulmonaryDiseases
AdrianShifren,MuraliChakinala,AlexanderChen,GabrielSchroeder,Katherine Dittman,PaulKannarkat,NathanielMoulton,PraveenChenna,JamesG.Krings, TonyaD.Russell
PulmonaryHypertension
GENERALPRINCIPLES
Definition
Pulmonaryhypertension(PH)isdefinedbysustainedelevationofthemeanpulmonaryarterypressure (mPAP)to>20mmHg(atrest).
1
Classification
PHissubcategorizedintofivemajorgroups(Table10-1):
GroupI—Pulmonaryarterialhypertension(PAH) GroupII—PHduetoleftheartdisease GroupIII—PHduetolungdiseasesand/orhypoxia GroupIV—PHduetopulmonaryarteryobstructions GroupV—PHwithunclearmultifactorialmechanisms
PAHisaspecificgroupofdisorderswithsimilarpathologiesandclinicalpresentation,andahigh
propensityforrightheartfailureintheabsenceofelevatedleft-sidedpressures.
Hemodynamicdefinition=mPAP>20mmHg,pulmonaryarterywedgepressure(PAWP)≤15 mmHg,andpulmonaryvascularresistance(PVR)≥3Woodunits
1
TABLE10-1
CLINICALCLASSIFICATIONOFPULMONARYHYPERTENSION:DANAPOINT(2008) CLASSIFICATIONSYSTEMOFPULMONARYHYPERTENSION
GroupI:Pulmonaryarterialhypertension(PAH)
Idiopathic(IPAH)
Heritable(HPAH)
Drugsandtoxin-induced:methamphetamines,fenfluramine,dasatinib
Associated(APAH)
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Connectivetissuediseases
HIVinfection
Portalhypertension
Congenitalheartdisease(systemic-to-pulmonaryshunt)
Schistosomiasis
PAHlong-termresponderstocalciumchannelblockers
PAHwithovertfeaturesofvenous/capillaries(PVOD/PCH)involvement
GroupII:Pulmonaryhypertension(PH)duetoleftheartdisease
PHduetoheartfailurewithpreservedLVEF
PHduetoheartfailurewithreducedLVEF
Valvulardisease
GroupIII:PHduetolungdiseaseand/orhypoxia
Obstructivelungdisease
Restrictivelungdisease
Otherpulmonarydiseaseswithmixedrestrictiveandobstructivepattern
Hypoxiawithoutlungdisease
Developmentallungdisorders
GroupIV:PHduetopulmonaryarteryobstructions
ChronicthromboembolicPH
Otherpulmonaryarteryobstructions
GroupV:PHwithunclearand/ormultifactorialmechanisms
Hematologicdisorders:myeloproliferativedisorders,hemoglobinopathies
Systemicandmetabolicdisorders:sarcoidosis,PLCH,LAM,neurofibromatosis,glycogen storagedisease,Gaucherdisease
Others:tumoralobstruction,fibrosingmediastinitis,chronicrenalfailureondialysis
Complexcongenitalheartdisease
LAM,lymphangioleiomyomatosis;LVEF,leftventricularejectionfraction;PCH,pulmonarycapillaryhemangiomatosis;PLCH, pulmonaryLangerhanscellhistiocytosis;PVOD,pulmonaryveno-occlusivedisease.
Epidemiology
PHismostoftenduetoleftheartdisease(GroupII)orparenchymallungdisease(GroupIII). PrevalenceofidiopathicPAH(IPAH)(GroupI)is6–9casespermillioncomparedwithoverallPAH prevalenceof15–26casespermillion.2,
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AverageageofPAHpatientsis 50years.2–4IPAHpatientstendtobeevenyounger,withamean ageof 35years.
5
IPAHandPAHassociatedwithconnectivetissuediseases(CTD)arethemostcommonsubtypes.4,
6
Incidenceofchronicthromboembolicpulmonaryhypertension(CTEPH)(GroupIV)maybeashighas 4%amongsurvivorsofacutepulmonaryembolism.
7
Pathophysiology
PAH is suspected to develop in susceptible individuals who develop a comorbid condition (e.g., systemic sclerosis or portal hypertension), contract an infection (e.g., HIV), or get exposed to a culpabledrug/toxin(e.g.,fenfluramine,methamphetamines,ordasatinib).
MutationsinbonemorphogeneticproteinreceptorII(BMPR-II)geneaccountfor 70%ofheritable PAH(HPAH).
8
Mutationsintheeukaryotictranslationinitiationfactor2alphakinase4(EIF2AK4)genecausePAH with significant venous/capillary involvement (formerly known as pulmonary veno-occlusive disease).
9
Othersusceptibilityfactorsarespeculatedtoexistbuthavenotbeenidentified.
Comprehensivegenepanelsarecommerciallyavailable. PAH involves a complex interplay of factors resulting in progressive vascular remodeling with endothelial cell and smooth muscle proliferation, vasoconstriction, and in situ thrombosis at an arteriolar level. Vessel wall changes and luminal narrowing restrict the flow of blood and lead to higher-than-normalpressureas blood flowsthroughthevessels,whichisquantifiablebyanelevated PVR.
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ElevatedPVR results inincreasedafterloadfortherightventricle(RV), whichincreasesRV wall
tensionandwork,leading to reduced RV contractility, decreasing cardiac outputandprogressive
exerciseintolerance.
The RVhas limited ability to hypertrophyand tolerates high afterload poorly, causing “vascular–
ventricularuncoupling”andeventualRVfailureanddeath. MechanismsofPHinGroupsII–Vvaryandincludehighpostcapillarypressures,hypoxemia-mediated vasoconstriction, vascular remodeling, parenchymal destruction, thromboembolic narrowing or occlusionoflargearteries,compressionofproximalvasculature,andhyperdynamicstatesleading to increasedcirculatoryflow. Combinedpre-andpostcapillaryPHdescribessituationswhenmultipleconditionsleadtoelevated pressures in the left-sided heart chambers (postcapillary) and simultaneous abnormalities in the pulmonaryarterialside(precapillary).
Hemodynamicdefinition =meanPAP>20 mm Hg,PAWP> 15 mm Hg,andPVR≥3Wood
units
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Prevention
Yearlyscreeningtransthoracicechocardiogram(TTE)isindicatedforhigh-riskgroupsincluding individualswithknownBMPR-IImutation,scleroderma,portalhypertensionundergoingliver transplantationevaluation,andcongenitalsystemic-to-pulmonaryshunts(e.g.,ventricularseptaldefects, patentductusarteriosus).
MoreformalscreeningalgorithmforearlydetectionofPAHinsclerodermaisavailable.
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DIAGNOSIS
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ClinicalPresentation
Symptomsincludedyspnea(mostcommon),fatigue,palpitations,exertionaldizziness,syncope,chest pain,lowerextremityswelling,andincreasedabdominalgirth(ascites). Explore underlying exposures (i.e., methamphetamines, chemotherapeutic agents)1 or associated conditions(e.g.,CTDs,left-sidedcardiacdisease,parenchymallungdiseases,obstructivesleepapnea syndrome[OSAS],andvenousthromboembolism). AuscultatorysignsofPHincludeprominentsecondheartsound(loudS2)with loudP2 component, RVS3,tricuspidregurgitation,andpulmonaryinsufficiencymurmurs. Signsofrightheartfailurearejugularvenousdistention,pedaledema,hepatomegaly,pulsatileliver, andascites. Examination findings of underlying conditions linked to PH include skin changes of scleroderma, stigmata of liver disease, clubbing (congenital heart disease), aortic/mitral murmurs, and abnormal breathsounds(parenchymallungdisease).
DiagnosticTesting
Confirm clinical suspicion and determine etiology of PH, while gauging the severity of the condition.
Acuteillnessescancausemildelevationsofpulmonaryarterysystolicpressure(PASP)(<50mmHg). Evaluation of chronic PH is necessary if pressures remain elevated after resolution of acute conditions. TTEistheinitialtestwhenchronicPHissuspectedorifscreeningavulnerablepopulation.
TTEWITHDOPPLERANDAGITATEDSALINEINJECTION
EstimatePASPbyDopplerinterrogationoftricuspidvalveregurgitantjet.
SensitivityforPHis80%–100%,andcorrelationcoefficientwithinvasivemeasurementis0.6–0.9.
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AbsenceoftricuspidregurgitationdoesnotexcludeelevatedpressuresorPH. RVfindingsofsignificance:
RV hypertrophy and dilation, depressed systolic function (reduced tricuspid annular systolic
excursion [<1.8 cm associated with worse survival13 ], systolic velocity of the tricuspid valve
annulus,andfree wallstrain),intraventricularseptaldisplacement andparadoxicalmotionleading
toleftventricular(LV)compression,andpericardialeffusion. Identifycauses of PH(e.g., LVsystolic or diastolic dysfunction, left-sided valvular disease, left atrialstructuralanomalies,andcongenitalsystemic-to-pulmonaryshunts).
Left atrial enlargement is an important clue for diastolic dysfunction that frequently leads to PH,
especiallyintheelderly.
14
Transesophagealechocardiogram(TEE)isindicatedtoexcludeintracardiacshuntssuspectedbyTTE; patentforamenovaleismostcommonshuntanddoesnotrequirefurtherevaluation. Additional studies outlined in the following text and Figure 10-1 should be completed if PH is unexplainedbyTTE,iflungdiseaseissuspected,orifPAHisstillaconsideration.12,
15
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Figure 10-1  Algorithm for diagnostic workupof pulmonary hypertension.ABG, arterial blood gas; CTD, connective tissue
disease; CTEPH,chronic thromboembolic pulmonaryhypertension;HRCT, high-resolutionCT;HTN,hypertension;LFT, liver
functiontest;MCTD,mixedconnectivetissuedisease,PAH,pulmonaryarterialhypertension;PFT,pulmonaryfunctiontest;PH,
pulmonaryhypertension;RA,rheumatoidarthritis;SLE,systemiclupuserythematosus;V/Q,ventilation–perfusion.
LABORATORIES
Evaluateforassociatedconditionsandgaugedegreeofcardiacimpairment.
Complete blood counts (CBCs), blood urea nitrogen, serum creatinine, hepatic function tests,
natriuretic peptides, HIV serology, CTD serologies (antinuclear, antitopoisomerase antibody, and
anticentromereantibodies;extractable nuclear antigen[ENA];andotherpotentialserologies based
onclinicalpresentation). Other contingent laboratories include thyroid function studies, hepatitis B and C serologies, hemoglobinelectrophoresis,antiphospholipidantibody,andlupusanticoagulant.
ELECTROCARDIOGRAPHY
SignsofrightheartenlargementareRVhypertrophy,rightatrialenlargement,rightbundlebranchblock, andRVstrainpattern(SwaveinleadIwithQwaveandinvertedTwaveinleadIII),butthesefindings havelowsensitivityinmilderPH.
PULMONARYFUNCTIONTESTING
Spirometry and lung volumes to lookfor obstructive (e.g., chronicobstructive lung disease) or restrictive(e.g.,interstitiallungdisease[ILD])ventilatoryabnormalities.  Diffusing capacity for carbon monoxide (DLCO) is mildly reduced in PAH; but more severe reductioninDLCO(i.e., <40%predicted)isaclueforparenchymal lungdiseaseorPAHassociated withsignificantvenous/capillaryinvolvement.
https://t.me/med1917
Arterial blood gas (ABG): Elevated arterial partial pressure of carbondioxide (PaCO2) suggests hypoventilationsyndromeorsevereobstructiveventilatorydefect.
Six-minutewalk(6MW)orsimpleexercisetest:
DistancewalkedcorrelateswiththeWorldHealthOrganizationfunctionalclassificationandoverall
prognosis.
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Nocturnaloximetry:DesaturationscouldindicateOSAS.
NocturnaldesaturationsarecommoninPAH,eveninabsenceofOSAS,andshouldbetreatedwith
nocturnalsupplementaloxygen.
17
Symptoms of sleep-disordered breathing and daytime hypercarbia should be evaluated with polysomnography(PSG).
IMAGING
CXR:
CentralpulmonaryarteriesandRVenlargement
CluestospecificPHdiagnosisincludethefollowing:
Decreasedperipheralvascularmarkingsorpruning(PAH) Largepulmonaryvasculaturethroughoutlungfields(congenital-to-systemicshunt) Regionaloligemiaofpulmonaryvasculature(chronicthromboembolicdisease) Interstitialinfiltrates(ILD) Hyperinflatedlungs(chronicobstructivelungdisease)
Ventilation–perfusion(V/Q)lungscan:
Criticalforexcludingchronicthromboembolicdiseasebutcouldalso beabnormal inPAHwith
venous/capillaryinvolvementandfibrosingmediastinitis.
Presence of one or more segmental mismatches should warrant CT angiography or pulmonary
angiography.
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ChestCTscan:
Angiogram can confirm CTEPH, if initial screening V/Q scan is suspicious, and also helps
determinesurgicalfeasibility;CTshouldgenerallynotbeusedtoscreenforCTEPH.
High-resolutionimagestoassessforinterstitialorbronchiolardisease.  Pulmonary angiography can be done safely in severe PH and confirms CTEPH and determines surgicalfeasibility. CardiacMRI:
ProvidesRVanatomicandfunctional information,including ventricularvolumes, ejectionfraction,
andstrokevolumeindex,whichhaveprognosticvalue.
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IdentifiescardiacanomaliesassociatedwithPAH(ifTEEcontraindicated).
DIAGNOSTICPROCEDURES
LungbiopsyisusuallyprohibitedbyseverePHorRVdysfunctionifpresent;rarelyperformedwhen suspectingPAHassociatedwithvenous/capillaryinvolvement. Rightheartcatheterization:
EssentialwhenPAHsuspectedandpulmonaryvasodilatorsbeingconsidered.
ConfirmsPHbecauseTTEcanbeinaccurate.
19
Excludesleftheartdiseasebymeasuringend-expiratoryPAWPandsystemic-to-pulmonaryshunts
(bynoting“step-up”inoxygensaturations).
Measure direct LVend-diastolicpressure if PAWP not reliable, especiallyinpatients older than65years.
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Reduced cardiac output and elevated mean right atrial pressure (RAP) are important
predictorsofmortality.
5
Acutefluidchallenge(7mL/kgover5minutes)canunmaskLVdysfunctionthatcouldbeetiology
ofmildPH.
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Acutevasodilatortesting recommended when IPAH,HPAH,or drug/toxin-induced PAHsuspected, unlessextremerightheartfailurepresent(meanRAP>20mmHg).
Useshort-actingvasodilator,suchasIVadenosineorinhalednitricoxide.
21
Significantresponseisacute dropin mPAP ≥ 10 mmHgand concludingmPAP < 40 mmHg
withstableorimprovedcardiacoutput.
21
Onlyacuterespondersshouldreceivelong-termCCBs(see“Treatment”section).
TREATMENT
Supplemental oxygen to keep arterial saturations (>89%) to avoid hypoxic vasoconstriction. Normoxemiamaynotbepossiblewithsignificantright-to-leftintracardiacshunting. In-lineIVfilterstopreventparadoxicalairemboliinpatientswithlargeright-to-leftshunts.DeepValsalvamaneuversraiseintrathoracicpressureandreducecentralvenousreturn(e.g.,vigorous exercise, severe coughing, straining during defecation, or micturition) and highaltitudes (>5000 ft) becauseoflowinspiredconcentrationofoxygen. AvoidpregnancybecauseofhemodynamicalterationsthatfurtherstraintheRV. PulmonaryrehabilitationisrecommendedfortreatedPAHpatientswhoremainlimitedduetophysical deconditioning. ManagementofPHdependsonthespecificcategoryofPH.
GroupIIPHshouldreceiveappropriatetherapyforunderlyingcausativeconditionwiththegoalof
minimizingpostcapillarypressures.
Group III PH should receive treatment for specific condition, for example, bronchodilators for
obstructive lung disease, immunomodulators, or antifibrotics for ILD, noninvasive ventilation for
OSASorobesityhypoventilationsyndrome,andsupplementaloxygen.
SelectPH–ILDpatientscanbenefitfromtheinhaledpulmonaryvasodilator,treprostinil. CTEPH is usually treated by pulmonary thromboendarterectomy or percutaneous balloon angioplastyatspecializedcentersandrequirescarefulevaluationtodeterminebestintervention.22
,
23
InoperableorpersistentCTEPH(afterintervention)benefitfrommedicaltherapy.
Medications
PAHpatientsarecandidatesforvasomodulator/vasodilatortherapy(seeTable10-2).
FourcategoriesofPAH-specifictherapieswithuniquemechanismsofaction:
Endothelinreceptorantagonistsblockendothelin-1’seffectonpulmonaryarterysmoothmuscle
cells,thusabrogatingvasoconstrictionandcellulargrowth.
TABLE10-2
VASOMODULATOR/VASODILATORY THERAPY FOR PULMONARY ARTERIAL HYPERTENSION
Drug Therapeutic
Class
Route of Delivery
Dosing Range
Adverse Effects
Cautions
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Nifedipine, amlodipine, diltiazem
Calciumchannel blockers
PO Varies
by patient tolerance
Peripheral edema, hypotension, fatigue
Useonlyin patientswho are vasoresponsive duringacute vasodilator challenge;avoid
iflowcardiac outputor decompensated rightheartfailure
Sildenafil Tadalafil
Phosphodiesterase type5inhibitor
PO 20mg
TID 40mg/d
Headache, hypotension, dyspepsia, myalgias, visual disturbances
Avoidusingwith
nitratesor protease inhibitors
Riociguat Solubleguanylate
cyclasestimulator
PO 2.5mg
TID
Hypotension Avoidusingwith
nitrates; approvedfor PAHand CTEPH,i.e., inoperableor
persistentafter endarterectomy
Bosentan Endothelin
receptor antagonist
PO 125mg
BID
Hepatotoxic, teratogen, peripheral edema
Monthlyliver function monitoring;
avoidusingwith glyburideand glipizide
Ambrisentan Endothelin
receptor antagonist
PO 5–
10mg/d
Teratogen, peripheral edema
Fluidretention, particularlyin olderpatients
Macitentan Endothelin
receptor antagonist
PO 10mg/d Teratogen,
peripheral edema
Monitorfor anemia
Iloprost Treprostinil
Prostacyclin analogue
IH 2.5–5μg
6–8/d ≥9 breaths QID
Cough, flushing, headache, trismus
Suboptimal adherencedue todosing frequency;
overnightdrug holiday
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Selexipag Prostacyclin
receptoragonist
PO 200–
1600µg BID
Headache, jawpain, diarrhea, extremity pain
Hyperthyroidism
Treprostinil Prostacyclin
analogue
SC,IV, orPO
Varies by patient tolerance
Headache, jawpain, diarrhea, extremity pain
With continuous parenteraluse,
catheter-related complications (IV);site
pain/reaction (SC);GIdistress
withPOuse
Epoprostenol Prostacyclin
analogue
IV Varies
by patient tolerance
Headache, jawpain, diarrhea, extremity pain
Continuous parenteral agent;very shorthalf-life;
catheter-related complications (IV);high-
outputstateat higherdoses
CTEPH, chronic thromboembolic pulmonary hypertension; GI, gastrointestinal; IH, inhaled; PAH, pulmonary arterial
hypertension;PO,oral.
Phosphodiesterase 5 inhibitors block enzyme that shuts down nitric oxide–mediated
vasodilation.
Soluble guanylate cyclase stimulator activates the downstream signal of nitric oxide and
inducesvasodilation.
Prostacyclinpathwayactivators,includingprostacyclinanaloguesandprostacyclinreceptor
agonists,inducevasodilation,inhibitcellulargrowth,andinhibitplateletaggregation. Choice of PAH-specific therapy should be individualized by severity of condition based on establishedriskassessmenttoolsthatareavailableonline(seeFigure10-2andTable10-3).
REVEAL2.0andREVEALLitecalculateaweightedscorebasedonmultiplevariables(such
as PAH subtype, demographics, New York Heart Association [NYHA] functional class, 6MW
distance,natriureticpeptides,hemodynamics,vitalsigns)anddeterminelow,intermediate,orhigh
riskfordeath.24,
25
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Figure10-2  Algorithm for managementof pulmonary arterial hypertension.ERA,endothelin receptor antagonist;
PDE5-I, phosphodiesterase type 5 inhibitor; PH, pulmonary hypertension; sGC, soluble guanylate cyclase. *Risk
determinedbycompositeassesmentofpredictorsofsurvival(see“Treatment”section).
TABLE10-3
VALIDATEDRISKASSESSMENTTOOLSINPAH
FrenchPulmonary REVEAL2.0 REVEALLite
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