Primary Pulmonary Hypertension

Nurul Rahayu Ningrum

Introduction

Primary pulmonary hypertension:

SPP > 35 mmHg, DPP > 15 mmHg, mPAP > 25 mmHg1
Its rare disease, and the true incidence of PPH is unknown,2
The first reported case in 1891, E. Romberg, a German
doctor, published a description of a patient who, at autopsy,
showed thickening of the pulmonary artery but no heart or
lung disease that might have caused the condition.2
In 1951, when Dresdale and colleagues in the United States
reported 39 cases, the illness received its name.2,3
Its associated with fenfluramine (appetite suppressant) 2

1.
2.
3.

Oh JK, Seward JB, Tajik AJ. The echo manual. Lippincott Williams & Wilkins. 1999. pp215
NHLBI. Facts about primary pulmonary hypertension. 1996
Oudiz RJ. Primary pulmonary hypertension. www.emedicine.com.

PENDAHULUAN
Pulmonary arterial hypertension (PAH) :
meningkatnya tekanan arteri pulmoner 25 mmHg
(istirahat) dan lebih dari 30 mmHg saat latihan
PAH ( WHO tahun 1998 ) :
kelompok penyakit yang mempunyai karakteristik suatu
perubahan patologis identik pada mikrosirkulasi
pulmoner dan berespons terhadap prostasiklin jangka
panjang.
PAH : - Primary Pulmonary Hypertension (PPH)
- Secondary Pulmonary Hypertension

Revised Nomenclature and Classification of

PH (2003)

Next

CHEST 2004; 126:7S10S

Functional Classification of Pulmonary Arterial Hypertension.*

Class Description

Class I

Pulmonary arterial hypertension without a resulting limitation of physical activity.

Ordinary physical activity does not cause undue dyspnea or fatigue, chest pain, or near
syncope

Class II

Pulmonary arterial hypertension resulting in a slight limitation of physical activity. The

patient is comfortable at rest, but ordinary physical activity causes undue dyspnea or
fatigue, chest pain, or near-syncope.

Class III

Pulmonary arterial hypertension resulting in a marked limitation of physical activity. The

patient is comfortable at rest, but less than ordinary activity causes undue dyspnea or
fatigue, chest pain, or near-syncope.

Class IV

Pulmonary arterial hypertension resulting in an inability to carry out any physical activity
without symptoms. The patient has signs of right heart failure. Dyspnea, fatigue, or both
may be present even at rest, and discomfort is increased by any physical activity.

Functional Assessment

Next
CHEST 2004; 126:7S10S

TIGA PROSES PADA PAH :

- VASOKONTRIKSI
- REMODELING
- TROMBOSIS IN SITU
ENDOTEL VASODILATOR (PGI2 & NO )
VASOKONSTRIKTOR ( TX A2 & ET 1 )
SEL OTOT POLOS REMODELING VASKULER ,
KANAL ION ( Ca , K dan Cl)

Patophysiology

http://www.chestnet.org/images/education/online/

Diagnostic

http://www.chestnet.org
/images/education/online/

Summary of Recommendations

1. Genetic testing and professional genetic counseling should be offered to relatives of patients with
FPAH.
2. Patients with IPAH should be advised about the availability of genetic testing (for their relatives).
3. In patients with a suspicion of PAH, ECG should be performed to screen for a spectrum of cardiac
anatomic and arrhythmic problems; it lacks sufficient sensitivity to serve as an effective screening tool
for PAH, but contributes prognostic information in patients with known PAH.
4. In patients with a suspicion of PAH, a CXR should be obtained to reveal features supportive of a
diagnosis of PAH and to lead to diagnoses of underlying diseases. Quality of evidence: low; benefit:
intermediate; strength of recommendation: C.
5. In patients with a clinical suspicion of PAH, Doppler echocardiography should be performed as a
noninvasive screening test that can detect PH, though it may be imprecise in determining actual
pressures compared to invasive evaluation in a portion of patients. 6. In patients with a clinical suspicion
of PAH, Doppler echocardiography should be performed to evaluate the level of right ventricular systolic
pressure and toassess the presence of associated anatomic abnormalities such as right atrial
enlargement, right ventricular enlargement, and pericardial effusion.
7. In asymptomatic patients at high risk, Doppler echocardiography should be performed to detect
elevated pulmonary arterial pressure..
8. In patients with suspected or documented PH, Doppler echocardiography should be performed to look
for left ventricular systolic and diastolic dysfunction, left-sided chamber enlargement, or valvular heart
disease.
9. In patients with suspected or documented PH, Doppler echocardiography with contrast should be
obtained to look for evidence of intracardiac shunting.
10. In patients with unexplained PAH, testing for connective tissue disease and HIV infection should be
performed.
11. In patients with PAH, V /Q scanning should be performed to rule out CTEPH; a normal scan result
effectively excludes a diagnosis of CTEPH.
12. In patients with PAH, contrast-enhanced CT or MRI should not be used to exclude the diagnosis of
CTEPH.
13. In patients with PAH and a V /Q scan suggestive of CTEPH, pulmonary angiography is required for
accurate diagnosis and best anatomic definition to assess operability.
14. In patients with PAH, testing of pulmonary function and arterial blood oxygenation should be
performed to evaluate for the presence of lung disease.
15. In patients with systemic sclerosis, pulmonary function testing with DLCO should be performed
periodically (every 6 to 12 months) to improve detection of pulmonary vascular or interstitial disease.
16. In patients with PAH, lung biopsy is not routinely recommended because of the risk, except under
circumstances in which a specific question can only be answered by tissue examination.
17. In patients with suspected PH, rightheart catheterization is required to confirm the presence of PH,
establish the specific diagnosis, and determine the severity of PH.
18. In patients with suspected PH, rightheart catheterization is required to guide therapy.
19. In patients with PAH, serial determinations of functional class and exercise capacity assessed by the
6-min walk test provide benchmarks for disease severity, response to therapy, and progression.

Echocardiographic Findings

Diminished or absent a wave of the pulmonary

valve
Midsystolic closure or notching of the pulmonary
valve
Enlarged chambers on the right side of the heart
D-shaped LV cavity
Findings of possible underlying cause (Eg: left
sided abnormality, LR shunt, cor pulmonale,
pulmonary embolism

Anderson B. Echocardiography, the normal examination and echocardiographic measurement. 2 nd ed 2002.

Asmi MH, Walsh MJ. A practical guide to echocardiography. Chapman & Medical. 2000
Oh JK, Seward JB, Tajik AJ. The echo manual. Lippincott Williams & Wilkins. 1999.

Medical Therapy

PERJALANAN PENYAKIT PAH

(PPH ATAU SECONDARY PH)
BERAT
IRREVERSIBLE
GAGAL JANTUNG KANAN
KEMATIAN

MODALITAS TERAPI : - ERA SEBELUM 90 AN KONVENSIONAL

- ERA SETELAH 90 AN VASODILATOR BARU

SURVIVAL

Prognosis of PH

Without PTE: Poor

5 year survival rate of 30%

Chest 2001;119: 818-23

Sitaxsentan

EPOPROSTENOL
(PROSTASIKLIN)

EPOPROSTENOL : -PERTAMA DIPAKAI PADA PPH TAHUN 1980

- INTRAVENA , KONTINYU
-

VASODILATOR JANGKA PENDEK DAN PENGHAMBAT AGREGASI

PLATELET
WAKTU PARUH 3 5 MENIT AKSES VENA SENTRAL
PEMAKAIANNYA :- PERANTARA TRANSPLANTASI PARU PADA PPH
- PILIHAN UTAMA
- ALTERNATIF TRANPLANTASI PADA PPH
RUBIN DKK STUDI TERANDOMISASI PERTAMA PD 25 PASIEN
PPH
PENINGKATAN TOLERANSI LATIHAN & HEMODINAMIK

Survival 178 pasien PPH selama 5 tahun terapi epoprostenol , studi oleh Sitbon dkk

N
Kelas NYHA
Etiologi
6MWT (mean), m
Efek terapi
Mean perubahan 6MWT
keseluruhan
PPH
Parameter
hemodinamik
Kondisi Klinis

EPOPROSTENOL
PPH 1

EPOPROSTENOL
PPH2

EPOPROSTENOL
SKLERODERMA2

23
III IV
PPH
226

81
III IV
PPH
293

111
III IV
CTD
255

45
45
PERBAIKAN
PERBAIKAN

47
47
PERBAIKAN
PERBAIKAN

94
PERBAIKAN
TETAP

DIKUTIP DARI PROGRESS IN CARDIOVASCULAR DISEASES VOL.45 ,2002

1. Rubin dkk
2. Rubin & Barst

KETERBATASAN EPOPROSTENOL :
- PEMAKAIANNYA TIDAK NYAMAN
- INFEKSI DAN TROMBOSIS PADA AKSES VENA
- HARGA YANG MAHAL
- BAHAYA AKIBAT PENGHENTIAN MENDADAK
KOMPLIKASI :
EDEMA PARU
ASITES
TETAP BUKAN TERAPI YANG IDEAL

PENGHAMBAT KANAL
KALSIUM

PEMAKAIAN TERBANYAK : NIFEDIPINE DAN DILTIAZEM

DIBERIKAN PADA PASIEN RESPONS THD UJI VASODILATASI
HANYA 10 15 % PASIEN PAH YANG RESPONS DNG TERAPI
JANGKA PANJANG
UJI VASODILATASI :
KATETERISASI JANTUNG KANAN
ADENOSINE , EPOPROSTENOL DAN INHALASI NO
RESPONS BILA MPAP SAMPAI 20% NILAI AWAL
RESPONS BILA PVR 30% DARI NILAI AWAL

DOSIS : - DILTIAZEM : 360 S/D 720 MG/HARI

- NIFEDIPINE : 90 180 MG/HARI

BERAPROST

BERAPROST SODIUM: ANALOG PROSTASIKLIN ORAL

- DOSIS PUNCAK : 30 MENIT
- WAKTU PARUH : 35 40 MENIT

STUDI ALPHABET (ARTERIAL,PULMONARY, HYPERTENSION

AND BERAPROST EUROPEAN TRIAL)
- 130 PASIEN PAH DNG KELAS NYHA II & III
- PPH & SEKUNDER PH
- BERAPROST 4 X PER HARI SAMPAI 80 MG /KALI
- PERUBAHAN HEMODINAMIK SIGNIFIKAN (-)
- KAPASITI LATIHAN PADA PPH MENURUN
- ANGKA MORTALITI 1,5% , TIDAK ADA PERBEDAAN
ANTARA KELOMPOK

ILOPROST

ILOPROST ADALAH ANALOG PROSTASIKLIN TERSEDIA

DALAM SEDIAAN : INTRAVENA, INHALASI DAN ORAL
INHALASI : OLSCHEWSKI DKK
- PENURUNAN MPAP 10 20% SELAMA 60 MENIT
- FREKUENSI PEMBERIAN 6 12 KALI/ HARI
STUDI AIR (AEROSOLIZED ILOPOROST RANDOMIZED STUDY)
- 204 PASIEN PAH DNG KELAS NYHA III & IV 12
MINGGU
- 2,5 5 g/HARI 6 9 KALI PEMBERIAN
- PERBAIKAN KLINIS VS PLASEBO (p= 0,007)
- PERBAIKAN 6MWT VS PLASEBO (p= 0,024)
- PERBAIAKAN KELAS NYHA (p=0,032)

TERBOGREL

TERBOGREL : ANTAGONIS RESEPTOR TROMBOXAN DAN

SINTETASE TROMBOXAN

STUDI TERANDOMISASI PADA 71 PASIEN PPH

KELAS NYHA II DAN III
DIHENTIKAN LEBIH AWAL NYERI TUNGKAI BAWAH ?
- KENAIKAN INR

FARMAKOLOGIS : EFEKTIF MENURUNKAN METABOLIT

TROMBOXAN SAMPAI 98%

TREPROSTINIL

TREPROSTINIL : ANALOG BENZIDINE TRISIKLIK EPOPROSTENOL

SEDIAAN : INTRAVENA DAN SUBKUTAN
WAKTU PARUH : 27 MENIT (IV) DAN 58 83 MENIT (SK)
EFIKASI : 2 STUDI TERANDOMISASI
- 470 PASIEN PAH , KELAS NYHA II IV 12 MINGGU
- PERBAIKAN KAPASITI LATIHAN, PARAMETER HEMODINAMIK
- EVENT FREE SURVIVAL VS PLASEBO : 94% VS 88 (p=0,05)
- MORTALITI 3% , TIDAK ADA PERBEDAAN BERMAKNA

BOSENTAN

BOSENTAN : ANTAGONIS DUAL RESEPTOR ENDOTHELIN 1

STUDI TERANDOMISASI PERTAMA :

33 PASIEN BOSENTAN 125 MG 2X/HARI
PERBAIKAN 6MWT DAN HEMODINAMIK
KARDIOPULMONER

BREATHE-1 (BOSENTAN RANDOMIZED TRIAL OF

ENDOTHELIN ANTAGONIST THERAPY FOR PAH) :
- 213 PASIEN PAH, KELAS NYHA III & IV
- BOSENTAN 62,5 MG 2X/HARI SELAMA 4 MINGGU 125
MG ATAU 250 MG 12 MINGGU
- PERBAIKAN 6MWT , INDEKS BORG DAN KELAS NYHA
- PENURUNAN FUNGSI HEPAR YG TERGANTUNG DOSIS

TERBOGREL

TREPROSTINI
L

BOSENTA
NPILOT

BREATHE1

ALPHABET

AIR

N
Rute
Kelas NYHA
Etiologi

71
ORAL
II III
PPH

469
SUBKUTAN
II-IV
PPH,CHD,
CTD

33
ORAL
III
PPH,
CTD

213
ORAL
III-IV
PPH,
CTD

130
ORAL
II-III
PPH,CTD,
CHD,HIV

6MWT (mean),
m
Efek terapi
Mean
perubahan
6MWT
Keseluruhan
PPH
Parameter
Hemodinamik
Kondisi klinis

393

327

358

335

372

203
INHL
III-IV
PPH,C
TD,TE
PH
324

0
0
+/-

16
19
+

76
76
+

44
52
+

25
45
+/-

35
57
+

+/-

DIKUTIP DARI PROGRESS IN CARDIOVASCULAR DISEASES VOL.45 ,2002

SILDENAFIL

SILDENAFIL

SILDENAFIL : INHIBITOR PDE 5 SELEKTIF

ZHAO DKK : 100 MG SILDENAFIL ORAL DAPAT MENURUNKAN
PAP

MICHELAKIS DKK : STUDI TAK TERANDOMISASI 3 BULAN

- 5 PASIEN PAH , KELAS NYHA II III 50 MG/8JAM
- PENINGKATAN KELAS NYHA, HEMODINAMIK,6MWT

SHEKERDEMIAN DKK : STUDI PADA PIGLET MODEL PPHN

- SILDENAFIL IV DIBANDINGKAN DNG INHALASI NO
- MPAP = SILDENAFIL (26%) VS NO (21%)

SITAXSENTAN

SITAXSENTAN: ANTAGONIS RESEPTOR ETA (SELEKTIF)

SEDIAAN ORAL, WAKTU PARUH 5 7 JAM
STUDI STRIDE-1 (SITAXSENTAN TO RELIEVE IMPAIRED
EXERCISE IN PULMONARY ARTERIAL HYPERTENSION):
- 178 PASIEN PAH SEKUNDER DAN PPH, 12 MINGGU
- SITAXSENTAN 100 DAN 300 MG VS PLASEBO
- 6MWT MENINGKAT PADA KEDUA KELOMPOK SITAXSENTAN
- pVO2 MENINGKAT PADA KELOMPOK 300 MG
- GGN FUNGSI HEPAR DIDAPAT SAMPAI 21% PADA
KELOMPOK SITAXSENTAN 300 MG.

Medical Therapy
Limitations

Anderson SL, Heberlig RM, Koons K. The

Pharmacologic Management of Primary
Pulmonary Hypertension.
http//:www.vapbm.org

Terimakasih