HIPERTENSIUNEA PULMONARA

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

CIRCULATIA CIRCULATIA PULMONARA BRONSICA

Sange venos sange arteriala. pulmonara a. bronsice

Capilare CapilareVene pulmonare Vene sistemice

CIRCULATIA PULMONARA NORMALA

PLAMANUL

Sunt fiziologic dr-stg (pana la 30%

din DC) - bronsiectazii - fibroza

chistica - boli

congenitale cardio-

vasculare

CIRCULATIA 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 Hg

PRES 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 Hg

Reducerea calibrului vaselor pulmonare Cresterea fluxului

HIPERTENSIUNEA PULMONARA (HTP)

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

HIPOXIA CRONICA1. Extensia musculaturii netede in peretele arterelor din

periferia plamanilor2. Ingrosarea peretilor arterelor musculare3. Reducerea nr. arterelor – cresterea raportului

alveole/artere

REACTIVITATEA VASCULARA PULMONARA

VASOCONSTRICTIEHipoxiaAcidozaProstaglandine F2α si A2HISTAMINA – H1

SEROTONINA ?ANGIOTENSINA A2

ALTITUDINE

VASODILATATIEAlcalozaPROSTAGLANDINE I2 si EBLOCANTI αSTIMULARE β (ISOPROTERENOL)ACETILCOLINA (prin EDRF)HISTAMINA (prin H2 ?)

INDOMETACIN – creste rezistenta pulmonara

La 10 000 m altitudine

TA pulmonara medie = 25 mm Hg in repaus

> 50 mm Hg in efort

1. HTP arteriala1.1. Idiopatica1.2. Ereditara1.3. Indusa de droguri si toxine1.4. Asociata cu:

Boli de colagenHIVHipertensiune portalaBoli cardiace congenitaleSchistosomiazaAnemie hemolitica cronica

1.5. 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 valvulare


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 fizica


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 dializa


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. pulmonara creste presiunea venoasa – edem interstitial –

rigidizarea vaselor – HTP drenajul limfatic creste starea VD

normal hipertrofic insuficient miopatic (+ VS) hipoperfuzat (infarct)

Volumul sanguin pulmonar (depinde de debitul celor 2 ventriculi si de distensibilitatea vaselor pulmonare)

CATEVA MECANISME FIZIOPATOLOGICE

- Celule endoteliale capilare umflate- Membrane bazale capilare ingrosate- Edem interstitial- Rupturi de membrane bazale – transudare de

eritrocite – hemosideroza- Alveole fibroase- Destindere de limfatice

MODIFICARI ANATOMICE

Test Notable FindingsChest x-ray Enlargement of central pulmonary arteries reflects level of PA

pressure and duration.

Electrocardiography Right axis deviation and precordial T wave abnormalities are early signs.

Pulmonary function tests Elevated pulmonary artery pressure causes restrictive physiology.

Perfusion lung scan Nonsegmental perfusion abnormalities can occur from severe pulmonary vascular disease.

Chest computed tomography scan Minor interstitial changes may reflect diffuse disease; mosaic perfusion pattern indicates thromboembolism and/or left heart failure.

Echocardiography Right ventricular enlargement will parallel the severity of the pulmonary hypertension.

Contrast echocardiography Minor right to left shunting rarely produces hypoxemia.

Doppler echocardiography This is too unreliable for following serial measurements to monitor therapy.

Exercise testing This is very helpful to assess the efficacy of therapy. Severe exercise-induced hypoxemia should cause consideration of a right-to-left shunt.

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

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 organ

SINDROM 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 (3–5 o’clock) 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 α 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 α 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).

Normal Flux crescut in lobii inferiori

GravitatiePresiuni diferite intra –alveolareRaport A/B = 1,2 : 1

CRESTEREA FLUXULUI PULMONARFLUX - Φ VASE x 8 (rezerva) + Φ vase - flux + presiune - presiune Creste Φ venosRx – 1/3 ext. vascularizata - Circ. Inf = circ. sup.N – Φ a. pulm. desc. dr. = 10-15 mm la barbati si 9-14 mm la

femei

Rx în HTP

HTP arteriala

- vasoconstrictie periferica- vasospasm- ingrosarea peretelui vascular

Rx- scade circulatia (creste transparenta) in 1/3 ext.- vasele centrale elastice se largesc- calcificari ale vaselor centrale

Rx în 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 Hg Edem pulmonar

Rx în HTP

Mecanisme Sechestrarea de lichid interstitial in lobii inferiori ↓ Presiunea interstitiala ↑ ↓ Complianta pulmonara ↓ ↓ Fluxul spre lobii inferiori ↓ + Spasm arterial

Fluxul este redistribuit spre lobii superiori

Rx în HTP

ETIOLOGIE Embolism pulmonar recurent, asimptomatic Embolism amniotic Tromboza in situ, tulburari de coagulare si fibrinoliza ,

contraceptive Vasoconstrictie cronica → necroza fibrinoida → leziuni

plexiforme Vasculita generala cu fenomen Raynaud Hipersensibilitate la droguri Ingestia de fumarat de aminorex (anorexigen) Hormoni feminini

HTP IDIOPATICA

MODIFICARI HISTOLOGICE Ingrosarea intimala a a. mici si arteriole cu

fibroza in “foi de ceapa” Ingrosarea mediei a. musculare si

muscularizarea arteriolelor Arterita necrozanta cu necroza fibrinoida Leziuni 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 plexiforme

HTP IDIOPATICA

ASPECTE CLINICE

Femei tinere4 simptome principale

Dispnee de efort Accentuarea zgomotului II Modificari Rx – cardiomegalie - a. pulmonara proeminenta Modificari ECG : - HVD - deviatie axiala dr. - HAD

Mai rar:- Ameteli si sincope de efort- Dureri toracice de efort- Edeme

- Fenomene Raynaud- Ciroza hepatica- Istoric de tromboflebita superficiala

HTP IDIOPATICA

PROGNOSTIC

Prost (supravietuire peste 5 ani – 21%) Anticoagulantele imbunatatesc prognosticul

MOARTEA Insuficienta cardiaca congestiva Pneumonie Moarte subita Moarte la cateterism Disectie de a pulmonara

HEMOPTIZIA IN STADII TARDIVE Ruptura de leziuni plexiforme Tromboze in situ Embolism pulmonar

DUREREA TORACICA Ischemia subendocardului VD Distensia a pulmonare

HTP IDIOPATICA

SEMNE CLINICE

Zgomot II intarit la pulmonara Suflu sistolic la pulmonara Semne de insuficienta cardiaca dreapta Semne de regurgitare triscuspidiana Cianoza - tardiv prin deschidere de foramen ovale Paralizie 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 – Φ a pulmonare

TESTE FUNCTIONALE - Disfunctie restrictiva

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

dilatatiei de VD

HTP IDIOPATICA

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

procoagulant

CATETERISMUL CARDIAC SI ANGIOGRAFIA RISCANTE Presiunea in VD egala sau chiar mai mare decit presiunea

sistemica Rezistenta vasculara pulmonara depaseste uneori pe cea sistemica Uneori foramen ovale este patent Presiunile stg. sunt normale sau mici, dar uneori greu de

determinat

BIOPSIA PULMONARA

HTP IDIOPATICA

HTP IDIOPATICA

DIAGNOSTIC DIFERENTIALHTP secundara (mai benigna si mai tratabila)

In sala de cateterism cardiac PAPm 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 indelungat

TESTUL 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. Anticoagulantele

Warfarina dubleaza supravietuirea in HPPIndicatiile anticoagularii permanente: toti pacientii cu HTPITromboembolismul pulmonar (INR = 2-3)HTP secundare, daca nu exista contraindicatii

2. Oxigenoterapia Se recomanda monitorizarea Sat O2 nocturna, Sat O2 < 90%

in aerul atmosferic corectabila la administrarea de O2, indica oxigenoterapia nocturna

3. Tratamentul insuficientei ventriculare drepte:- Diuretice- Digoxinul creste DC in administrarea acuta in HTPI, efectul

sau in administrarea cronica este discutabil

TRATAMENTUL MEDICAL

4. Tratamentul vasodilatatorAntagonistii de Ca (diltiazem sau nifedipina):

HTP de tip arterial cu test vasodilatator pozitiv CI 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 ½ 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

pulmonar

TRATAMENTUL MEDICAL (PG)

Indicatii Bolnavii 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 vasodilatator

Toti bolnavii care nu raspund la tratamentul medical conventional, in asteptarea transplantului pulmonar

TRATAMENTUL MEDICAL

Efecte adverse: Diaree, dureri abdominale, cefalee, flush,

artralgii, dureri musculare Ascita, edem pumonar (prin cresterea

permeabilitatii vasculare) Toleranta ce necesita cresterea dozelor Rebound al HTP la intreruperea brusca a

tratamentului Infectii de cateter


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 pacient

Iloprost = analog al epoprostenolului, mai puternic iv (pev continua) sau in aerosoli, 6-9 inhalatii/zi (50 -200 μg/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


Beraprost: derivat stabil de PGI2, poate fi

adminisrat p.o. 1 tb = 20μg. 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.


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;132:425-34

3 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): 2119–25

6. Antagonistii receptorilor de endotelina

Bosentan (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 inhibitors

Sildenafil ( REVATIO )

25 mg t.i.d.Available in Romania

Humbert M N Engl J Med 2004;351: 1425–36.

Type 5 Phosphodiesterase inhibitors

Vardenafil 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 prostaglandine Se exclud pacientii cu Insuf Ventr dr severa, disfunctie

de VS sau in stare critica

Trombendarterectomie Transplant 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<63%, IC < 2,1

Blocanti de CaNu raspund la tratament

Prostaglandine +/- transplant

Warfarina + diuretic + digoxin

Frequently asked questions

At 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 questions

How useful is multiple drug therapy Which order of introduction /doses ?

BREATHE -2

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

CONCLUSIONS

PPHT pts to be treated in dedicated centers New therapies available ; debate on results Combination therapy in developpement Rapid change of recomandations /guidelines Cost –effectiveness analysis vital Hard end points-including mortality may be

influenced

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HIPERTENSIUNEA PULMONARA