Post on 29-Dec-2015
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
CLASIFICAREA 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 fizica
CLASIFICAREA 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 dializa
CLASIFICAREA 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. 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
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 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
TRATAMENTUL MEDICAL (PG)
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.
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;132:425-34
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