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HIPERTENSIUNEA PULMONARA. CIRCULATIA PULMONARA NORMALA. PLAMANUL. - oxigenare Hb - filtru (particule, bacterii) - eliminarea CO2 – echilibru acido-bazic CIRCULATIA CIRCULATIA PULMONARABRONSICA Sange venossange arterial a. pulmonara a. b ronsice - PowerPoint PPT Presentation

Text of HIPERTENSIUNEA PULMONARA

  • - oxigenare Hb- filtru (particule, bacterii)- eliminarea CO2 echilibru acido-bazic

    CIRCULATIA CIRCULATIA PULMONARABRONSICASange venossange arteriala. pulmonaraa. bronsice CapilareCapilareVene pulmonare Vene sistemice

    CIRCULATIA PULMONARA NORMALA

    PLAMANUL

  • Sunt fiziologic dr-stg (pana la 30% din DC) - bronsiectazii - fibroza chistica - boli congenitale cardio-vasculareCIRCULATIA BRONSICA

  • NORMALA SISTEMICE media 20-25% din diam. vasuluiA. PULMONARE - media < 10- 5% din diam. vasuluiArteriolele pulmonare nu au tunica medie si nu contribuie la rezistenta vasculara

    VD fluxul coronarian cel mai mare in sistola - depinde de gradientul pres. pulm. aortaPres. VD creste gradientul scade fluxul coronar drept scade ischemie VD

    HIPERTENSIUNEA PULMONARA (HTP)

  • NORMALPRES. A. PULMONARA - sist. 18-25 mm Hg - diast. 6-10 mm Hg - medie 12-16 mm HgPRES V. PULMONARE 2-10 mm HgREZIST. VASC. PULM. = 1/10 din REZIST. SISTEMICA

    HIPERTENSIUNEA PULMONARA (HTP)PRES. A. PULMONARA - sist. > 30-35 mm Hg - medie > 20-25 mm Hg - diast. > 15 mm HgReducerea calibrului vaselor pulmonareCresterea fluxului

    HIPERTENSIUNEA PULMONARA (HTP)

  • HIPOXIA VASOCONSTRICTIE PULMONARA-histamina receptori H1 vasculari- endoteliu - echilibru NO endoteline- patrunderea Ca 2+ in celula musculara neteda

    HIPOXIA CRONICAExtensia musculaturii netede in peretele arterelor din periferia plamanilorIngrosarea peretilor arterelor musculareReducerea nr. arterelor cresterea raportului alveole/artere

    REACTIVITATEA VASCULARA PULMONARA

  • VASOCONSTRICTIEHipoxiaAcidozaProstaglandine F2 si A2HISTAMINA H1SEROTONINA ?ANGIOTENSINA A2ALTITUDINEVASODILATATIEAlcalozaPROSTAGLANDINE I2 si EBLOCANTI STIMULARE (ISOPROTERENOL)ACETILCOLINA (prin EDRF)HISTAMINA (prin H2 ?)INDOMETACIN creste rezistenta pulmonaraLa 10 000 m altitudineTA pulmonara medie = 25 mm Hg in repaus > 50 mm Hg in efort

  • HTP arteriala1.1. Idiopatica1.2. Ereditara1.3. Indusa de droguri si toxine1.4. Asociata cu:Boli de colagenHIVHipertensiune portalaBoli cardiace congenitaleSchistosomiazaAnemie hemolitica cronica1.5. HTP persistenta la nou nascut1 Boala venoocluziva pulmonara si/sau hemangiomatoza capilara pulmonara

    CLASIFICAREA HTPDana Point, 2008

  • 2. HTP prin suferinta ventriculului stang2.1. Disfunctie sistolica2.2. Disfunctie diastolica2.3. Boli valvulareCLASIFICAREA HTPDana Point, 2008

  • 3. HTP prin boli pulmonare sau hipoxie3.1. BPOC3.2. Boli interstitiale3.3. Alte boli cu restrictie si obstructie3.4. Apneea de somn3.5. Boli cu hipoventilatie alveolara3.6. Expunerea cronica la mare altitudine3.7. Anomalii de dezvoltare fizicaCLASIFICAREA HTPDana Point, 2008

  • 4. HTP prin tromboembolism

    5. HTP prin factori multipli neclari5.1. Boli hematologice: mieloproliferare, hipersplenism5.2. Boli sistemice: sarcoidoza, histiocitoza pulmonara cu celule Langerhans5.3. Boli metabolice: B. Gaucher, glicogenoze, disfunctii tiroidiene5.4. Altele: obstructii tumorale, mediastinita fibrozanta,, IRC sau dializaCLASIFICAREA HTPDana Point, 2008

  • In suferinta inimii stangiPRESIUNE ATRIU STG = 7 mm Hg scade rezistenta pulmonara (recrutare de vase)>7 mmHg creste presiunea in a. pulmonara (fluxul ramane constant; gradientul ramane constant)> 25 mmHg crestere disproportionata de presiune in a. pulmonara (gradientul creste; fluxul constant sau scade)CATEVA MECANISME FIZIOPATOLOGICE

  • Variabilitatea reactivitatii vasculare pulmonare:creste presiunea venoasa distrugere sau inchidere de cai aeriene hipoxie creste presiunea in a. pulmonaracreste presiunea venoasa edem interstitial rigidizarea vaselor HTP drenajul limfatic crestestarea VD normalhipertroficinsuficientmiopatic (+ VS)hipoperfuzat (infarct) Volumul sanguin pulmonar (depinde de debitul celor 2 ventriculi si de distensibilitatea vaselor pulmonare)CATEVA MECANISME FIZIOPATOLOGICE

  • Celule endoteliale capilare umflateMembrane bazale capilare ingrosateEdem interstitialRupturi de membrane bazale transudare de eritrocite hemosiderozaAlveole fibroaseDestindere de limfaticeMODIFICARI ANATOMICE

  • TABLE 73-2 --Clues for Interpretation of Diagnostic Tests for Pulmonary Hypertension

    TestNotable FindingsChest x-rayEnlargement of central pulmonary arteries reflects level of PA pressure and duration.ElectrocardiographyRight axis deviation and precordial T wave abnormalities are early signs.Pulmonary function testsElevated pulmonary artery pressure causes restrictive physiology.Perfusion lung scanNonsegmental perfusion abnormalities can occur from severe pulmonary vascular disease.Chest computed tomography scanMinor interstitial changes may reflect diffuse disease; mosaic perfusion pattern indicates thromboembolism and/or left heart failure.EchocardiographyRight ventricular enlargement will parallel the severity of the pulmonary hypertension.Contrast echocardiographyMinor right to left shunting rarely produces hypoxemia.Doppler echocardiographyThis is too unreliable for following serial measurements to monitor therapy.Exercise testingThis is very helpful to assess the efficacy of therapy. Severe exercise-induced hypoxemia should cause consideration of a right-to-left shunt.

  • Toate sunturile sistemico-pulmonare rezultand din mari defecte care duc la cresteri de presiune in VD si la inversarea suntului (pulmonar-sistemic) sau sunt bidirectional cu: cianoza, eritrocitoza si multiple suferinte de organSINDROM EISENMENGER

  • GR. I : hipertrofia mediei artereor mici musculareGR. II : + proliferarea intimeiGR. III: + fibroza concentrica cu obliterare de vaseGR. IV: leziuni plexiforme, dilatatii, trombiGR. V: complexe plexiforme, leziuni angiomatoase si cavernoase si hialinizaea fibrozei intimaleGR. VI: arterita necrozanta

    MODIFICARI ANATOMICE

  • Histopathology of endothelial cell lesions in IPAH. A. Pulmonary artery showing medial hypertrophy and lined by a single layer of endothelial cells, as outlined by Factor VIII related antigen immunostaining (arrow). Plexiform lesion (outlined by the rim of arrowheads) with the proximal vascular arterial segment with marked intimal and medial thickening by smooth muscle cells (arrow). Note the proliferation of endothelial cells with the outer edge (35 oclock) occupied by dilated blood vessel-like structures. C. Cross section of a plexiform lesion, outlined by arrowheads. Note perilesional inflammatory infiltrate (arrow). D. High magnification histology of plexiform lesions shown slit-like vascular channels lined by hyperchromatic and cuboidal endothelial cells. Cells in the core do not display distinct cytoplamic borders. E. Low magnification immunohistology with Factor VIII related antigen immunohistochemistry of different endothelial cell based vascular lesions. This area has re-vascularized lesions (possibly an organized thrombus), with well-formed and distinct small capillaries/vessels (arrowhead), a plexiform lesion (arrow), and dilated/angiomatoid lesions (between arrowheads). F. High magnification immunohistology of cellular plexiform lesion stained with Factor VIII related antigen (arrowheads). G and H. Histological identification of plexiform and dilation lesions (G) is markedly improved by Factor VIII related antigen immunohistochemistry (H) (arrowheads), while the parent vessel (arrow) shows mild medial remodeling. I. Highlight of vascular dilation/angiomatoid lesions with Factor VIII related antigen immunohistochemistry. J. Endothelial cells in plexiform lesion is highlighted by CD34 immunohisochemistry (arrowheads). Proximal pulmonary artery with marked intima and medial thickening is highlighted by the arrow. K and I. Endothelial cells are highlighted by CD31 immunohistochemistyr (arrowheads). Note that capillary endothelial cells express CD31 as well (arrow in I),

  • A. Fibrotic, relatively paucicellular intima thickening (outlined by arrowheads) in a pulmonary artery with the media highlighted with the arrow. B. Marked intima remodeling with almost complete obliteration by fibrous tissue with a marked intravascular and perivascular inflammatory infiltrate (arrows). C. Smooth muscle cell hypertrophy, with prominent thickening of medial layer (arrow). D. Highlight of medial hypertrophy with smooth muscle actin immunohistochemistry. E. Markedly remodeled pulmonary artery with endothelial cell layer highlighted by Factor VIII related antigen immunohistochemistry. Note that the intima and medial smooth muscle cells are negative for Factor VIII related antigen reactivity. F. Ingrowth of smooth muscle cells in a plexiform lesions, highlighted by smooth muscle cell actin immunohistochemistry (arrow).

  • Veno-occlusive PH. A. Low-power histological view of thickened pulmonary veins running into the lung parenchyma from the pleural surface (left edge) (arrows). Note marked vein wall thickening and decreased lumen. Adjacent alveoli are filled with blood and show septal thickening with engorged capillaries (arrowhead). B. Marked vein thickening with intimal projection probably representing organized thrombus (arrow). Alveolar hemorrhage and septal thickening are highlighted with arrowhead. C and D. Movat stained pulmonary vein showing arterialization pattern with internal and external elastic layers (arrow). The vein shows marked intima thickening with organized thrombus (arrowheads).

  • NormalFlux crescut in lobii inferioriGravitatiePresiuni diferite intra alveolareRaport A/B = 1,2 : 1CRESTEREA FLUXULUI PULMONARFLUX - VASE x 8 (rezerva) + vase - flux + presiune - presiuneCreste venosRx 1/3 ext. vascularizata - Circ. Inf = circ. sup.N a. pulm. desc. dr. = 10-15 mm la barbati si 9-14 mm la femei

    Rx n HTP

  • HTP arteriala- vasoconstrictie periferica- vasospasm- ingrosarea peretelui vascular

    Rxscade circulatia (creste transparenta) in 1/3 ext.vasele centrale elastice se largesccalcificari ale vaselor centraleRx n HTP

  • HTP de origine venoasa

    P venoasa > 8 12 mm Hg fluxul pulmonar este redistribuit spre lobii superioriRx inversare a aspectului normal (cefalizarea fluxului arterial si venos)P venoasa > 25 mm HgEdem pulmonar

    Rx n HTP

  • MecanismeSechestrarea de lichid interstitial in lobii inferiori Presiunea interstitiala Complianta pulmonara Fluxul spre lobii inferiori +Spasm arterial

    Fluxul este redistribuit spre lobii superiori

    Rx n HTP

  • ETIOLOGIEEmbolism pulmonar recurent, asimptomaticEmbolism amnioticTromboza in situ, tulburari de coagulare si fibrinoliza , contraceptiveVasoconstrictie cronica necroza fibrinoida leziuni plexiformeVasculita generala cu fenomen RaynaudHipersensibilitate la droguriIngestia de fumarat de aminorex (anorexigen)Hormoni feminini

    HTP IDIOPATICA

  • MODIFICARI HISTOLOGICEIngrosarea intimala a a. mici si arteriole cu fibroza in foi de ceapaIngrosarea mediei a. musculare si muscularizarea arteriolelorArterita necrozanta cu necroza fibrinoidaLeziuni plexiforme arteriopatie pulmonara plexogenica umbre vasculare reducerea patului vascular

    HTP IDIOPATICA

  • HIPOXIE raspuns anormal disfunctie endoteliala

    Modificarea raportului EDRF - endoteline

    Distrugeri de endoteliu

    Tromboza

    Vasoconstrictie necroza fibrinoida

    Leziuni plexiformeHTP IDIOPATICA

  • ASPECTE CLINICEFemei tinere4 simptome principaleDispnee de efortAccentuarea zgomotului IIModificari Rx cardiomegalie - a. pulmonara proeminentaModificari ECG : - HVD - deviatie axiala dr. - HADMai rar:- Ameteli si sincope de efort- Dureri toracice de efort- Edeme- Fenomene Raynaud- Ciroza hepatica- Istoric de tromboflebita superficialaHTP IDIOPATICA

  • PROGNOSTICProst (supravietuire peste 5 ani 21%)Anticoagulantele imbunatatesc prognosticulMOARTEAInsuficienta cardiaca congestivaPneumonieMoarte subitaMoarte la cateterismDisectie de a pulmonaraHEMOPTIZIA IN STADII TARDIVERuptura de leziuni plexiformeTromboze in situEmbolism pulmonarDUREREA TORACICAIschemia subendocardului VDDistensia a pulmonare

    HTP IDIOPATICA

  • SEMNE CLINICEZgomot II intarit la pulmonaraSuflu sistolic la pulmonaraSemne de insuficienta cardiaca dreaptaSemne de regurgitare triscuspidianaCianoza - tardiv prin deschidere de foramen ovaleParalizie de recurent (rara)

    HTP IDIOPATICA

  • LABORATOR - Uneori defecte de coagulare si fibrinoliza

    ECG: HVD, HAD Rx: largirea a pulmonare; marirea atriului si ventriculului dr

    CT a pulmonare

    TESTE FUNCTIONALE - Disfunctie restrictiva

    ECHOCARDIOGRAFIAMarirea atriului si ventriculului dreptCavitati stangi normaleIngrosarea septuluiRegurgitare tricuspidiana si prolaps de valva mitrala secundare dilatatiei de VDHTP IDIOPATICA

  • SCINTIGRAFIA PULMONARA - normala In stadii avansate poate fi daunatoare trasorul legat de albumina procoagulant

    CATETERISMUL CARDIAC SI ANGIOGRAFIARISCANTEPresiunea in VD egala sau chiar mai mare decit presiunea sistemicaRezistenta vasculara pulmonara depaseste uneori pe cea sistemicaUneori foramen ovale este patentPresiunile stg. sunt normale sau mici, dar uneori greu de determinat

    BIOPSIA PULMONARA

    HTP IDIOPATICA

  • HTP IDIOPATICADIAGNOSTIC DIFERENTIALHTP secundara (mai benigna si mai tratabila)

  • In sala de cateterism cardiacPAPm dupa administrarea de NO inhalator (sau adenozina iv, epoprostenol iv sau inhalator)

    Test + = reducerea cu 20% a PAPm sau a rezistentei vasculare pulmonare bolnavul va primi vasodilatator indelungatTESTUL VASODILATATOR

  • Supravietuirea medie in HTP netratata = 2,8 aniFactori de prognostic:Varsta < 14 ani sau 65 ani prognostic prostClasa NYHA: I II: supravietuire 6 ani in medie III: supravietuire 2,5 ani in medie IV: supravietuire 0,5 ani in medieScaderea capacitatii de efortSincopaHemoptizieSemne de insuficienta ventriculara dreaptaO2 in a pulmonara > 63 55% supravietuire la 5 ani < 63 17% supravietuire la 5 aniIndexul cardiac < 2,1 l/min/m2 supravietuire medie 17 luniPresiunea in AD < 10 mmHg - supravietuire 4 ani in medie > 20 mmHg - supravietuire medie o lunaTest de vasodilatatie negativ

    PROGNOSTICUL

  • 1. AnticoagulanteleWarfarina dubleaza supravietuirea in HPPIndicatiile anticoagularii permanente: toti pacientii cu HTPITromboembolismul pulmonar (INR = 2-3)HTP secundare, daca nu exista contraindicatii2. Oxigenoterapia Se recomanda monitorizarea Sat O2 nocturna, Sat O2 < 90% in aerul atmosferic corectabila la administrarea de O2, indica oxigenoterapia nocturna3. Tratamentul insuficientei ventriculare drepte:- Diuretice- Digoxinul creste DC in administrarea acuta in HTPI, efectul sau in administrarea cronica este discutabilTRATAMENTUL MEDICAL

  • 4. Tratamentul vasodilatatorAntagonistii de Ca (diltiazem sau nifedipina):HTP de tip arterial cu test vasodilatator pozitivCI in : HTP venoasa (precipita EPA) HTP hipoxica din bolile cronice pulmonare cu Sat O2 in sangele venos < 63% (agraveaza hipoxemia) PAD > 10 mm Hg Index cardiac < 2,1 l/min/m2

    TRATAMENTUL MEDICAL

  • Responders: Ca.-blockers(if bradicardic) Nifedipine :120 -240 mg(if tahicardic) Diltiazem 240-720 mg

    Begin low dosage , increase weeklyLess than of pts tolerate maximum dosage

  • 5. Prostaglandinele efectele pozitive ale tratamentului indelungat (min 3 luni)Reducerea rezistentei vasculare pulmonareCresterea indexului cardiacDublarea supravietuirii la 5 aniReducerea riscului si ameliorarea evolutiei dupa transplantul pulmonarTRATAMENTUL MEDICAL (PG)

  • IndicatiiBolnavii cu ICC cl III IV, index cardiac < 2,1 l/min/m2 si/sau Sat O2 in artera pulmonara < 63% si/sau PAD > 10 mmHg, indiferent de testul vasodilatatorToti bolnavii care nu raspund la tratamentul medical conventional, in asteptarea transplantului pulmonar

    TRATAMENTUL MEDICAL

  • Efecte adverse:Diaree, dureri abdominale, cefalee, flush, artralgii, dureri musculareAscita, edem pumonar (prin cresterea permeabilitatii vasculare)Toleranta ce necesita cresterea dozelorRebound al HTP la intreruperea brusca a tratamentuluiInfectii de cateter

    TRATAMENTUL MEDICAL (PG)

  • Preparate folosite:Epoprostenol = PGI2 iv. Se incepe cu 2 ng/kc/min in pev continua si se creste doza dupa o saptamana pana la doza maxima tolerata de pacientIloprost = analog al epoprostenolului, mai puternic iv (pev continua) sau in aerosoli, 6-9 inhalatii/zi (50 -200 g/zi)Trepostenil (UT 15) este analog de PGI2. Doza initiala este de 1,25 ng/kc/min si se creste cu 1,25 ng/kc/min la 7 zile pana la 9,3 ng/kc/min TRATAMENTUL MEDICAL (PG)

  • Beraprost: derivat stabil de PGI2, poate fi adminisrat p.o. 1 tb = 20g. Se incepe cu 1 tb/zi si dupa 6 saptamani de titrare, se ajunge la 6 tb/zi (studiul ALPHABET). Rezultate bune in HTPI, neconcludente in HTP sec. Se pare ca nu este eficient in stadiile avansate de boala.

    TRATAMENTUL MEDICAL (PG)

  • Prostanoid analogues

    CTD= boala de tesut conjunctiv

  • Epoprostenolshort HL, temp.-dependent , i- v (infusion pump ) , local facilities2-4ng/kg/min ..20-40 ( tolerance , rebound , adverse reactions: common)>100.000 $ /year

    Rubin LJ Ann. Intern.Med. 1990;112:485-92Barst RJ N.Engl. J Med 1996;334:296-304Badesch DB Ann. Intern.Med. 2000;132:425-343 month results: indic. surv/altern

    Conversion to oral agents ??Treprostenil sufficient chemical stability to be administered at ambient temperature allow iv / subcutaneous /oral ( bid ) and inhalatory adm.(6-9 d )

  • Beraprost

    Orally :40-80microg qid/zi efficacy does not appear to be sustainedwith extended duration of therapy

    Iloprost

    Inhalations 6-12 times/d (20-40 microg/d.)

    Advant: selective to pulm.circ.J Am CollCardiol. 2003 Jun 18;41(12): 211925

  • 6. Antagonistii receptorilor de endotelinaBosentan (ET1RA) po. Doze: 62,5 mg de 2 ori/zi, pana la 125 mg de 2 ori/zi, timp de 16 saptamani.TRATAMENTUL MEDICAL (ARE)

  • Endothelin receptor antagonists

    Type A receptor : vasoconstriction, proliferation, fibrosis. Type B receptor (endotelial): increases the synthesis of nitric oxide ( vasodilation )

    Type B receptor (SMC):activates aldosterone, thromboxane, norepinephrine.( vasoconstriction )

  • Bosentan ( Tracleer ) available in Romania dual ETA and ETB-receptor antagonist

    125 mg bid BREATHE-1 BREATHE-3 (children )10% liver enzimes > BREATHE -5 EARLY

    Sitaxsentan 6500 times greater affinity for the ETA STRIDE I and II Chest ,2008; 134(4): 775 - 782. 100-300 mg od 2004 : Level of evidence : BIncl .HTP in congenitals/CTD aproved in Europe Warfarine interference

    Ambrisentan ARIES-2 . Am J Respir Cirt Care Med. 2006;173: lower incidence of liver enzyme abnormality Ann. Pharmacother,2008; 42(11): 1653 absence of significant drug interactions - 2004 : Level of evidence : C

  • 7. Inhibitori de fosfodiesteraza (Sildenafil)

    TRATAMENTUL MEDICAL (IFD)

  • Phosphodiesterase inhibitorsSildenafil ( REVATIO ) 25 mg t.i.d.Available in RomaniaHumbert M N Engl J Med 2004;351: 142536.

  • Type 5 Phosphodiesterase inhibitorsVardenafil HCL ( Levitra ) Br J Pharmacol., 154(4):787-96. 2008 Apr 21 Tadalafil ( Cialis ) longer half-life (17.50 hours ) marketing approval began in late 2008

    J Am Coll Cardiol, 2004; 44:1488-1496 Circulation. 2004;110:3149-3155 The three PDE5 inhibitors differ markedly in :

    kinetics of pulmonary vasorelaxation (most rapid effect by vardenafil) selectivity for the pulmonary circulation (sildenafil and tadalafil, but not vardenafil), impact on arterial oxygenation (improvement with sildenafil only).

  • Septostomie atriala. Procedeu paleativ ce scade presiunea in inima dreapta. Indicatii:HTP severa, care nu raspunde la prostaglandineSe exclud pacientii cu Insuf Ventr dr severa, disfunctie de VS sau in stare criticaTrombendarterectomieTransplant pulmonar

    TRATAMENTE CHIRURGICALE

  • Indicatii transplant

    HTPI simptomatica, progresiva in ciuda tratamentului medical optim, cu test de mers de 6 min < 400 m, cu index cardiac < 2,1 l/min/m2 si/sau Sat O2 in artera pulmonara < 63% si/sau PAD > 10 mm Hg sau PAP m > 55 mmHg

    TRATAMENTE CHIRURGICALE

  • Test vasodilatator acut

    Raspuns +Sv O2>63%, IC > 2,1

    Raspuns -NYHA I/II, Sv O2>63%, IC > 2,1

    NYHA III/IV, Sv O2

  • Frequently asked questionsAt which level of pulm .pressure should we begin pharmacological treatment in sec. PHT ? Adapted to etiology ! Unknown borderline ! Is it harmful to use CCB in nonresponders ? Yes , at least for high doses ACCP Gd.: Level of evidence: expert opinion; benefit: substantial; grade of recommendation: E/A. Would it be better to use the more active drugs for responders also ? Probably yes , but economically unwise

  • Frequently asked questionsHow useful is multiple drug therapy Which order of introduction /doses ? BREATHE -2

    Is atrial septostomy an option ? Rarely (bridge to ) ; 5-15% mortality

  • CONCLUSIONSPPHT pts to be treated in dedicated centersNew therapies available ; debate on resultsCombination therapy in developpementRapid change of recomandations /guidelinesCost effectiveness analysis vital Hard end points-including mortality may be influenced

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