..

2556
ThaiGuidelineforDiagnosisandTreatmentofPulmonaryHypertension2013

-1

-2

(Pulmonary Hypertension: PH)

(mean pulmonary arterial pressure: mPAP) 25 mmHg
(Right Heart Catheterization, RHC)

20

8
.. 2552
1.
morbidity mortality

2.




..2555
23 ..2555
17 ..2556







-3

1. ..2556
sildenafil
1. pulmonary arterial hypertension (PAH)
(CHD) systemic-to-pulmonary shunt idiopathic pulmonary arterial
hypertension (IPAH) PAH associated with connective tissue disease (CNTD)

2. WHO functional classification of PAH II

3.
4. 3 2
2
4.1 progressive right heart failure
4.2 WHO functional classification
4.3 6MWT 25%
4.4 Echocardiography right atrium right
ventricle , right ventricular systolic pressure (RVSP)
, RV dysfunction, TAPSE < 1.5 cm, RAP > 15 mmHg, CI 2
L/min/m2, pericardial effusion

2. FDA Drug Safety Communication: FDA recommends against use of Revatio (sildenafil)
in children with pulmonary hypertension 30 .. 2555
(http://www.fda.gov/Drugs/DrugSafety/ucm317123.htm)

-4

US FDA recommended dose sildenafil 20 mg 3

Revatio recommended dose

Revatio (1-17 )
European Medicine Agency (EMA) (1-17 )
primary pulmonary hypertension associated pulmonary hypertension congenital
heart disease 20 10 mg 3
20 20 mg 3

18

3.
(Pulmonary Arterial
Hypertension) (HITAP)
website 7 ..2556
(http://www.hitap.net/research/12467) sildenafil
sildenafil
iloprost bosentan
sildenafil

4. The 5th World Symposium on Pulmonary Hypertension Nice

27-28 .. 2556 (www.wsph2013.com)

new classification
etiology
(Heart rate recovery : HRR)
-5

6 MWT 1
16 clinical worsening (
clinical worsening death, lung transplantation, hospitalization for worsening
pulmonary hypertension (PH), or escalation of PH therapy)
6MWT combination therapy
clinical trial multicentre Soluable Guanylate
cyclase (SGc) riociguat endothelin receptor antagonist macitentan
guideline

-6

:
..
Executive Summary: Thai guideline for diagnosis and treatment of pulmonary hypertension
2013

(pulmonary hypertension, PH)

(mean pulmonary arterial pressure;
mPAP) 25 . (right heart
catheterization; RHC)
(pulmonary arterial hypertension, PAH)
(mPAP) 25 . pulmonary
capillary wedge pressure (PCWP) 15 . pulmonary vascular resistance (PVR)
3 Wood units (right heart catheterization; RHC)

-7

1 PH
1.

1
2.

3.

4.
5.

Pulmonary arterial hypertension (PAH)

1.1 Idiopathic PAH
1.2 Heritable
1.2.1 Bone morphogenetic protein receptor type 2 (BMPR2)
1.2.2 Activin receptor like kinase 1 (ALK1), endoglin with or without hereditary hemorrhagic telangiectasia
1.2.3 Unknown
1.3 Drug and toxin induced
1.4 Associated
1.4.1 Connective tissue diseases
1.4.2 HIV infection
1.4.3 Portal hypertension
1.4.4 Congenital heart diseases
1.4.5 Schistosomiasis
1.4.6 Chronic hemolytic anemia
1.5 Persistent pulmonary hypertension of the newborn
Pulmonary veno-occlusive disease and/or pulmonary capillary hemangiomatosis
Pulmonary hypertension (PH) left ventricle
2.1 Systolic dysfunction
2.2 Diastolic dysfunction
2.3 Valvular disease
Pulmonary hypertension (PH) hypoxia
3.1 Chronic obstructive pulmonary disease
3.2 Interstitial lung disease
3.3 Other pulmonary diseases with mixed restrictive and obstructive pattern
3.4 Sleep disordered breathing
3.5 Alveolar hypoventilation disorders
3.6 Chronic exposure to high altitude
3.7 Developmental abnormalities
Chronic thromboembolic pulmonary hypertension (CTEPH)
Pulmonary hypertension (PH)
5.1 Hematologic disorders: myeloproliferative disorders, splenectomy
5.2 Systemic disorders: sarcoidosis, pulmonary Langerhans cell histiocytosis, lymphangioleiomyomatosis,
vasculitis
5.3 Metabolic disorders: glycogen storage disease, Gaucher disease, thyroid disorders
5.4 Others: tumoral obstruction, fibrosing mediastinitis, chronic renal failure on dialysis

-8

PH
1 PH
1(PHdiagnosis)

2(PHclassification)

Historytaking&PE

Bloodtest:antiHIV,Cr,LFT,CBC,ANA(1)
O2saturation/ABG
CTA V/Qscan

CXR
ECG
ECHO(4)
RHC (5)

PFT,DLCObronchodilators(2)
Polysomnography(3)
RHC(5)

( echocardiography) PH
echocardiography left sided heart disease, congenital heart disease, AV fistula,
thrombus atrium pulmonary artery RVSP

RVSP

RVSP 36-50 mmHg

RVSP < 36 mmHg

No PAH

Diagnosis PAH

mPAP > 25 mmHg

PVR 3 Wood unitm2
E/e < 8
LA Vol index 28
ml/m2

Complete right heart

catheterization
-9

RVSP > 50 mmHg

- E/e < 8
- LA Vol index 28 ml/m2

Diagnosis PAH

Cardiac Catheterization
echocardiography

acute vasoreactivity test

acute vasoreactivity test
IPAH, heritable PAH associated with anorexigen PAH PAHspecific drug
CCBs

heart transplantation lung transplantation

acute vasoreactivity test IPAH

responder
mPAP 10 mmHg mPAP 40 mmHg cardiac output

- 10

right ventricular failure

FC
6MWT ()*
Echo

Hemodynamic
BNP**

()
Good prognosis

II, III
400
Minimal RV dysfunction

mRAP 8 mmHg,
CI 2.5 L/min/m2
Minimally elevated

()
Bad prognosis

IV
300
Pericardial effusion, significant
RV enlargement/dysfunction,
RA enlargement
mRAP 15 mmHg
CI < 2.5 L/min/m2
Significantly elevated

FC = functional class, 6MWT = 6-minute walk test*, Echo = echocardiography, CI = cardiac index, mRAP = mean right atrial
pressure, RV = right ventricle, BNP = brain natriuretic peptide
* 6 - minute walk test
** BNP baseline > 150 pg/ml > 180 pg/ml 3

1.
(general treatment)
warfarin digoxin

2. () PAH

- 11

PAH specific treatment

Pulmonary arterial hypertension

No

Yes

General treatment

(3,++)
Influenza and pneumococcal
vaccination (3,++)
(2,+)
Psycho-social support (3,+)

Treatment of underlying

Diuretic (3,++)
Oxygen (3,++)
Oral anticoagulant CTEPH (3,++)
IPAH, heritable PAH, PAH due to anorexigens
(3,+), APAH (3,+/-)
Digoxin (3,+/-)

Acute vasoreactivity IPAH CCBs (3,++)

Vasoreactive*

Nonvasoreactive / WHO functional class II-III

acute vasoreactivity test

WHO functional class I-III

CCBs

**

CCBs

Sildenafil

3-6 ( 7)

***

Sequential or combination therapy 3

ERA, Prostanoid, PDE5 inhibitor

***

- 12 - Atrial septostomy (3,++)

Lung transplantation (3,++)

WHOfuctionalclassIV

PAH-specific drug WHO FC

++,1
+,1

WHO
functional class II
Sildenafil (38-42)

WHO
functional class III
Sildenafil (38-42)
Bosentan (33-37)*
Iloprost inhaled (29-31)*

WHO
functional class IV

Iloprost inhaled (29-31) or i.v.

or combination therapy
Bosentan* (33-37), Sildenafil (38-42)

+,2
+/-,3
* sildenafil

calcium channel blockers PAH-specific

therapy () sildenafil
Bosentan Iloprost ..2556
calcium channel blockers
Nifedipine 10 mg 20 mg
Dltiazem 60 mg 120 mg
Amlodipine 5 mg 10 mg

- 13

PAH-specific therapy

Beraprost
(20 mcg)
Sildenafil
(20,50,100 mg)

Bosentan*
(125 mg)

20-40 mcg
: 1 mcg/kg/day
20 mg
: 1-2 mg/kg/day*
(US FDA warning
)

10-20 kg :
31.25 mg od 31.25 mg bid
>20-40 kg:
31.25 mg bid 62.5 mg bid
40 kg :
62.5 mg bid 125 mg bid
Iloprost inhalation 5-10 mcg
( vial 0.5 ml-1
Ventavis
ml)
(20 mcg/2ml)
Iloprost IV
0.5-2.0 mcg/kg/min

Ilomedin
(20 mcg/1ml)

3-4

240 mcg

60 mg

250 mg

Flushing, diarrhea, jaw

pain
Headache, hypotension,
nasal congestion

Leg edema, elevated

ALT/AST

LFT

nitric oxide
donors nitrates

sildenafil
CYP3A4 ritonavir
sildenafil
300% (4 )

LFT

ALT > 3

(bile salt export pump; BSEP)
cyclosporine A, glibenclamide,
fluconazole

sildenafil
sildenafil

bosentan

ultrasonic
nebulizer MMAD 3-5
Omron, Prodose, i-neb

Coughing, flushing
facial rash, conjunctivitis
jaw pain

mg = milligram, mcg = microgram, ng = nanogram, = micron, MMAD = mass median aerodynamic diameter, LFT = liver function test, ALT = alanine aminotransferase,
AST = aspartate aminotransferase
* = bosentan 4

14

Drug interaction /

PAH

, FC, ECG
6MWT
BNP/NT-proBNP
cardiac catheterization
Echocardiography

3-6

X
X
X
X
X

X
X
X
-

3-4
X
X
X
X

X
X
X
X
X

1 PAH-specific
drug
2
(monotherapy)
combination therapy
3 functional class functional class IV
combination therapy surgical intervention
3 2
2
1. progressive right heart failure
2. WHO functional classification
3. 6MWT 25%
4. Echocardiography right atrium right
ventricle , right ventricular systolic pressure (RVSP) , RV
dysfunction, TAPSE < 1.5 cm, RAP > 15 mmHg, CI 2 L/min/m2, pericardial
effusion

- 15 -

ABG
ANA
ANP
AOP
APAH
BNP
CBC
CCBs
CI
CHD
CO
Cr
CTA
CTEPH
CXR
DLCO
E/e

ECHO
ECG
ERA
FC
HRCT
IH
IPAH
LA Vol index
LAP
LFT
MCTD

arterial blood gas analysis

anti-nuclear antibody
atrial natriuretic peptide
aortic pressure
associated pulmonary artery hypertension
brain natriuretic peptide
complete blood count
calcium channel blockers
cardiac index
congenital heart disease
cardiac output
Creatinine
computed tomography angiography of chest
chronic thromboembolic pulmonary hypertension
chest x-ray
diffusing capacity of the lung for carbon monoxide
mitral E wave velocity
Doppler echocardiography e
velocity mid interventricolar septum
tissue Doppler
transthoracic doppler echocardiography
electrocardiography
endothelin receptor antagonist
functional class (WHO)
high resolution computerized tomography
Inhalation
idiopathic pulmonary arterial hypertension
left atrial volume index
left atrial pressure
liver function test
mixed connective tissue disease

- 16 -

mPAP
mRAP
NT-proBNP
PAH
PASP
PCWP
PDE5 inhibitor
PE
PFT
PH
PVR, Rp
PVR:SVR (Rp:Rs)
Qp:Qs
RHC
RV
RVSP
SBP
SSc
. . ..
V/Q scan

mean pulmonary arterial pressure

mean right atrial pressure
N-terminal pro-brain natriuretic peptide
pulmonary arterial hypertension
pulmonary arterial systolic pressure
pulmonary capillary wedge pressure
phosphodiesterase inhibitor type 5
physical examination
pulmonary function test
pulmonary hypertension
pulmonary vascular resistance pulmonary arteriolar
resistance Wood units dynes/sec/cm-5
ratio of pulmonary vascular resistance
systemic vascular resistance
ratio of pulmonary blood systemic blood flow
( 1:1)
right heart catheterization
right ventricle
right ventricular systolic pressure
systolic blood pressure
Systemic sclerosis
ventilation perfusion scan

- 17 -

(Quality of Evidence)
(Strength of Recommendation)

(right heart catheterization, RHC)

References
1
2
3
4

echocardiography

PAH scleroderma

/ (Pulmonary
hypertension due to lung disease and/or hypoxemia)

(Pulmonary hypertension due to
chronic thrombotic and/or embolic disease; CTEPH)

(Pulmonary arterial hypertension
associated with congenital heart disease)

(Intervention and surgical modalities of treatment
in pulmonary hypertension)

(Perioperative management of patients with pulmonary
hypertension)

- 18 -

19
20
21
24
28
29
32
41
46
51
54

56

57

58

64

67

(pulmonary hypertension; PH)

(mean pulmonary arterial pressure: mPAP) 25
mmHg (right heart catheterization;
RHC)
20
The 4th World
Symposium on Pulmonary Hypertension Dana Point, California
..2551(1-5)

1.
morbidity mortality

2.

21
..2555

- 19 -

2. (Quality of Evidence) (Strength of
Recommendation)


(Quality of Evidence, Strength of Recommendation)
(1,++)
2.1 (Quality of Evidence) *
1

systematic review randomized

controlled clinical trials well designed randomized
controlled clinical trials
systematic review controlled
clinical trials well designed controlled clinical
trials

(cohort study, case-control study)
descriptive study controlled
clinical trials
(consensus)

- 20 -

2.2 (Strength of Recommendation)

++
+
+/-

- -

3.
(pulmonary hypertension, PH)
(mean pulmonary arterial
pressure; mPAP) 25 mmHg
(right heart catheterization; RHC) (1,++)
(pulmonary arterial hypertension, PAH)
(mPAP) 25 mmHg
pulmonary capillary wedge pressure (PCWP) 15 mmHg pulmonary vascular
resistance (PVR) 3 Wood units (right
heart catheterization; RHC) (1,++)
(PH)
1
(pulmonary arterial hypertension; PAH 1)
pulmonary hypertension PVR (pulmonary vascular resistance
pulmonary arteriolar resistance )
( 2) ( 3) chronic thromboembolism ( 4)
( 5)
- 21 -

(PAH
1) (6) 2

gene
PH

- 22 -

1
(PH) World Symposium pulmonary hypertension Dana Point
.. 2008(6)
2. Pulmonary arterial hypertension (PAH)
2.1 Idiopathic PAH
2.2 Heritable
1.2.1 Bone morphogenetic protein receptor type 2 (BMPR2)
1.2.2 Activin receptor like kinase 1 (ALK1), endoglin with or without hereditary hemorrhagic telangiectasia
1.2.3 Unknown
1.3 Drug and toxin induced
1.4 Associated
1.4.1 Connective tissue diseases
1.4.2 HIV infection
1.4.3 Portal hypertension
1.4.4 Congenital heart diseases
1.4.5 Schistosomiasis
1.4.6 Chronic hemolytic anemia
1.5 Persistent pulmonary hypertension of the newborn
1 Pulmonary veno-occlusive disease and/or pulmonary capillary hemangiomatosis
2. Pulmonary hypertension (PH) left ventricle
2.1 Systolic dysfunction
2.2 Diastolic dysfunction
2.3 Valvular disease
3. Pulmonary hypertension (PH) hypoxia
3.1 Chronic obstructive pulmonary disease
3.2 Interstitial lung disease
3.3 Other pulmonary diseases with mixed restrictive and obstructive pattern
3.4 Sleep disordered breathing
3.5 Alveolar hypoventilation disorders
3.6 Chronic exposure to high altitude
3.7 Developmental abnormalities
4. Chronic thromboembolic pulmonary hypertension (CTEPH)
5. Pulmonary hypertension (PH)
5.1 Hematologic disorders: myeloproliferative disorders, splenectomy
5.2 Systemic disorders: sarcoidosis, pulmonary Langerhans cell histiocytosis, lymphangioleiomyomatosis,
Vasculitis
5.3 Metabolic disorders: glycogen storage disease, Gaucher disease, thyroid disorders
5.4 Others: tumoral obstruction, fibrosing mediastinitis, chronic renal failure on dialysis

- 23 -

2
(PAH) (6)
Definite

Possible

Aminorex
Fenfluramine
Dexfenfluramine
Toxic rapeseed oil
Benfluorex

Likely

Unlikely

Amphetamines
L-tryptophan
Methamphetamines

Oral contraceptives
Estrogen
Cigarette smoking

Cocaine
Phenylpropanolamine
St. Johns Wort
Chemotherapeutic agents
Selective serotonin reuptake inhibitors
Pergolide

4. (pulmonary hypertension;
PH) (1) (7-8)

1. (pulmonary
hypertension; PH)
(chest radiography; CXR) (electrocardiogram; ECG)
(echocardiography)
(right heart catheterization; RHC)

2. PH (
1) (pulmonary function test)
(computer tomography of chest)
(polysomnography) ventilation-perfusion lung scan
antinuclear antibody, liver function test, anti-HIV antibody
1 pulmonary arterial hypertension
(PAH)

- 24 -

1. echocardiography

2. echocardiography
right heart catheterization, ventilation-perfusion scan pulmonary
function test
3.

functional class /

1 (PH diagnosis)

2 (PH classification)

History taking & PE (3,++)

CXR (3,++)
ECG (3,++)
ECHO (1,++)
RHC*

Blood test: anti-HIV, Cr, LFT, CBC, ANA (1)

(3,++)
O2 saturation/ABG (3,++)
CTA V/Q scan (3,++)
PFT, DLCO bronchodilators (2) (4,++)
Polysomnography (3) (4,+)
RHC*

1
PH
(pulmonary hypertension;
PH) (baseline diagnosis) PH
classification
(1) PAH
(2)
(3)
*RHC (right heart catheterization) PH
(PH classification) RHC
- 25 -

(ECG)
right axis deviation, right atrial
enlargement, right bundle branch block pattern amplitude R wave V1
PAH (Class I) (WHO functional class III IV)
PH class right ventricular enlargement ECG
ECG
(CXR)
CXR interstitial lung disease,
emphysema, bronchiectasis, pleural disease
PH

anti HIV test antinuclear

antibody (ANA) (connective tissue disease)
autoimmune
PAH
idiopathic pulmonary arterial hypertension; IPAH
(arterial blood gas analysis, ABG)
ABG
PH
..

Ventilation-perfusion lung scan (V/Q scan)

..
V/Q scan PH
(chronic thromboembolic pulmonary hypertension; CTEPH) ..
V/Q
scan CTEPH perfusion defect ventilation defect
ventilation-perfusion mismatch IPAH perfusion lung scan
perfusion scan
peripheral pruning perfusion defect CTEPH
- 26 -

CT angiography of chest (CTA)

CTA PH
(CTEPH)
mediastinum
high
resolution CT (HRCT)
High resolution CT (HRCT)
lung parenchyma / airways
connective tissue disease unexplained hypoxia
(pulmonary function test ; PFT)
PFT (obstructive lung disease)
(restrictive lung disease)
IPAH diffusion capacity
of carbon monoxide (DLCO)
(polysomnography)
(obstructive sleep apnea) PH

nocturnal desaturation (polysomnography)

- 27 -

(echocardiography) ( 1)
echocardiography pulmonary hypertension
left sided heart disease, congenital heart disease, AV
fistula, thrombus atrium pulmonary artery
right ventricular systolic pressure (RVSP)
(pressure gradient) right atrium right ventricle
tricuspid regurgitation velocity ( 1) mean pulmonary artery pressure
(mPAP) Abbas pulmonary
artery right ventricle pulmonary regurgitation velocity
PH
1. RVSP 37 mmHg **
2. Mean pulmonary artery pressure pulmonary regurgitation jet
Abbas 25 mmHg
3. Systolic flattening of ventricular septum
4. Right ventricular enlargement
5. Right atrial enlargement
** severe tricuspid regurgitation non coaptation tricuspid valve
RVSP mPAP pulmonary regurgitation jet
pulmonary hypertension
5.

(right heart catheterization; RHC)

(9)

(PAH) (3, ++)
hemodynamic stable functional class IV ( poor
prognosis 3) PAHspecific therapy empirical treatment

- 28 -

(4)

right ventricular failure

FC
6MWT ()*
Echo

Hemodynamic
BNP**

()
Good prognosis

***
()
Bad prognosis

II, III
400
Minimal RV dysfunction

IV
300
Pericardial effusion, significant
RV enlargement/dysfunction,
RA enlargement
mRAP 15 mmHg
CI < 2.5 L/min/m2
Significantly elevated

mRAP 8 mmHg,
CI 2.5 L/min/m2
Minimally elevated

FC = functional class, 6MWT = 6-minute walk test*, Echo = echocardiography, CI = cardiac index, mRAP = mean right
atrial pressure, RV = right ventricle, BNP = brain natriuretic peptide
* 6 - minute walk test
** BNP baseline > 150 pg/ml > 180 pg/ml 3

- 29 -

Acute Vasoreactivity Test(10-16)

Acute vasoreactivity test CCBs
IPAH, heritable PAH, PAH associated with anorexigen (3,++)
(responder) mPAP 10 mmHg mPAP 40 mmHg
cardiac output CCBs (non
responder) PAH-specific drug
acute vasoreactivity test

CCBs CCBs
acute vasoreactivity test
1.

( 6) (2, ++)
2.
associated pulmonary arterial hypertension
(3, +/-)
3.

heart transplantation lung
transplantation (3, ++)
Acute vasoreactivity test 4

- 30 -

Nitric oxide
(++, 1)

acute vasoreactivity test

Iloprost( 12)
(++, 2)
Sildenafil ***
Oxygen
(++, 2)

Beraprost(15)
(+, 3)

10 ppm

10 ppm
80 ppm
0.5 mcg/kg
5 mcg
20 mcg
20 mg

100%
non-rebreathing mask

1 mcg/kg

IH
5-10
IH
10-30
Oral
30
IH
15

Oral
30

15-30

20-30

rebound PH,
pulmonary edema pulmonary
venous hypertension

flushing

flushing

cardiac output

PVR
dissolved oxygen

(IV = intravenous, IH = inhaled, mcg = microgram, kg = kilogram, PVR = pulmonary vascular resistance) *** dose sildenafil
1) oral sildenafil 50 mg q 30 min (Leuchte HH, et al. Chest 2004;125:580-6); 2) incremental Oral sildenafil (equivalent dose) 25, 50, 100 mg q 20 min
( Mikhail GW, et al. Eur heart J 2004;25:431-6); 3)Oral sildenafil 100 mg q 1 h (Klinger JR, et al. Chest 2006;129:417-25)

adenosine
bronchospasm, chest pain, bradycardia (16)

- 31 -

6.



3
6.1
(general treatment)
PAH



warfarin
4 (chronic thromboembolic pulmonary hypertension) (3,++) idiopathic
pulmonary arterial hypertension (IPAH), heritable pulmonary arterial hypertension PAH
(3,+) INR 2.0-3.0
associated PAH (3,+/-)
right sided heart failure
(3, ++)

electrolyte

(17)
(chronic obstructive pulmonary disease; COPD)


(Partial pressure O2; PaO2) 60 mmHg
90 (O2 saturation)
(3, ++)
Digoxin (supraventricular
tachyarrhythmias) atrial fibrillation (3, +/-)
(18)

32

(3, +/-) (supervised

rehabilitation) COPD (2,+)
(19) (3, ++)
barrier methods


(WHO functional class III-IV)
PaO2 60 mmHg 90
2-3 L/min
90 (3, +)
(Influenza vaccine)
pneumococcal pneumonia (pneumococcal pneumonia vaccine) (3,++)
Lower abdomen
general anesthesia epidural anesthesia peripheral
nerve block (3, +/-)
intravenous nebulized
6.2 ( 3)

PAH (right heart catheterization)
calcium channel blockers (CCBs) acute
vasoreactivity test responder CCBs
1-3
PAH-specific drug
non-responder PAH-specific drug

33

3
right heart catheterization
pulmonary artery hypertension PAH specific treatment
Pulmonary arterial hypertension

No

Yes

Treatment of underlying

General treatment

(3,++)
Influenza and pneumococcal
vaccination (3,++)
(2,+)
Psycho-social support (3,+)

Diuretic (3,++)
Oxygen (3,++)
Oral anticoagulant CTEPH (3,++)
IPAH, heritable PAH, PAH due to anorexigens
(3,+), APAH (3,+/-)
Digoxin (3,+/-)

Acute vasoreactivity IPAH CCBs (3,++)

Vasoreactive*

Nonvasoreactive / WHO functional class II-III

acute vasoreactivity test

WHO functional class I-III

CCBs

**

CCBs
***

Sildenafil

3-6 ( 7)

***

Sequential or combination therapy 3

ERA, Prostanoid, PDE5 inhibitor

34

Atrial septostomy (3,++)

Lung transplantation (3,++)

WHOfuctionalclassIV

* vasoreactive mPAP 10 mmHg mPAP 40 mmHg

cardiac output
** (
good prognosis 4)
*** 7
PAH specific drug
4 ( 5 6)
1. calcium channel blockers (20, 28)
1.1 Nifedipine 10 mg 20 mg
1.2 Dltiazem 60 mg 120 mg
1.3 Amlodipine 5 mg 10 mg
2. prostacyclin 3
2.1 beraprost sodium ( 20 mcg ) 20-60 mcg
3-4
2.2 iloprost Ventavis ( 20 mcg 2 ml)
(ultrasonic nebulizer) 2.5-80 mcg 4

2.3 IV iloprost Ilomedin ( 20 mcg 1 ml)

0.5-2 mcg/kg/min IV drip
3. endothelin receptor antagonist bosentan (62.5 125
mg ) 62.5 mg 125 mg 2
4. phosphodiesterase-5 inhibitor sildenafil (20 mg, 50 mg,
100 mg ) 20 mg 3
( US FDA : http://www.fda.gov/Drugs/DrugSafety/ucm317123.htm)
.. 2556

pulmonary arterial hypertension (PAH)
(CHD) systemic-to-pulmonary shunt idiopathic pulmonary
arterial hypertension (IPAH) PAH associated with connective tissue disease
(CNTD)

35

WHO functional classification of PAH II

3 2

2
- progressive right heart failure
- WHO functional classification
- 6MWT 25%
- Echocardiography right atrium
right ventricle , right ventricular systolic pressure (RVSP)
, RV dysfunction, TAPSE < 1.5 cm, RAP > 15 mmHg,
CI 2 L/min/m2, pericardial effusion

1. PAH specific drug dose titration

2. PAH specific drug
sildenafil
drug utility evaluation form (DUE) bosentan
iloprost

3. calcium channel blockers (CCBs) acute
vasoreactivity test
4.
( 7)

36

5 PAH-specific therapy CCB*(21-27)

Beraprost
(20 mcg)
Sildenafil
(20,50,100 mg)

20-40 mcg
: 1 mcg/kg/day
20 mg
: 1-2 mg/kg/day
(US FDA warning )

3-4

240 mcg

60 mg

Bosentan*
(125 mg)

10-20 kg :
31.25 mg od 31.25 mg bid
>20-40 kg:
31.25 mg bid 62.5 mg bid
40 kg :
62.5 mg bid 125 mg bid

250 mg

Iloprost inhalation
Ventavis
(20 mcg/ 2ml)
Iloprost IV
Ilomedin
(20 mcg/ 1ml)

5-10 mcg
( vial
0.5 ml-1 ml)

Flushing, diarrhea,
jaw pain
Headache,
hypotension,
nasal congestion
Leg edema,
elevated ALT/ AST

Coughing, flushing
facial rash,
conjunctivitis jaw pain

0.5-2.0 mcg/kg/min

LFT

LFT

nitric oxide donors
nitrates
ALT > 3


(bile salt
export pump; BSEP)
cyclosporine A,
glibenclamide,
fluconazole

mg = milligram, mcg = microgram, ng = nanogram, = micron, MMAD = mass median aerodynamic diameter, LFT = liver function test, ALT = alanine aminotransferase,
AST = aspartate aminotransferase
* = bosentan 4

37

Drug interaction /

sildenafil
CYP3A4 ritonavir

sildenafil 300% (4 )
sildenafil

bosentan

ultrasonic
nebulizer MMAD 3-5
Omron, Prodose, i-neb

6 PAH-specific drug
WHO FC


drug interaction PAH-specific drug
WHO FC

++,1
+,1

WHO
functional class II
Sildenafil (38-42)

WHO
functional class III
Sildenafil (38-42)
Bosentan (33-37)*
Iloprost inhaled (29-31)*

WHO
functional class IV

Iloprost inhaled (29-31) or i.v.

or combination therapy
Bosentan* (33-37), Sildenafil (38-42)

+,2
+/-,3

*

Beraprost Bosentan Iloprost
..2556
calcium channel blockers
Nifedipine 10 mg 20 mg
Dltiazem 60 mg 120 mg
Amlodipine 5 mg 10 mg

38

7 PAH

3-6
, FC, ECG
6MWT
BNP/NT-proBNP
cardiac catheterization
Echocardiography

X
X
X*
X
X

X
X
X*

3-4
X
X
X*
X

X
X
X*
X*
X

4
1. ( 3) PAH
specific drug 5-7 3-6
2. ( 4)
(monotherapy)
combination therapy (2, +)
3. functional class functional class IV
(Counseling and end of life
plan)
sildenafil ..2556
3 2
2
1
progressive right heart failure
2
WHO functional classification
3
6MWT 25%
4
Echocardiography right atrium right
ventricle , right ventricular systolic pressure (RVSP) ,

39

RV dysfunction, TAPSE < 1.5 cm, RAP > 15 mmHg, CI 2 L/min/m2,

pericardial effusion

40

References
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American College of Cardiology Foundation Task Force on Expert Consensus Documents
and the American Heart Association: developed in collaboration with the American College
of Chest Physicians, American Thoracic Society, Inc., and the Pulmonary Hypertension
Association. J Am Coll Cardiol 2009;53:1573-619.
2. McLaughlin VV, Archer SL, Badesch DB, Barst RJ, Farber HW, Lindner JR, et al.
ACCF/AHA 2009 expert consensus document on pulmonary hypertension: a report of the
American College of Cardiology Foundation Task Force on Expert Consensus Documents
and the American Heart Association: developed in collaboration with the American College
of Chest Physicians, American Thoracic Society, Inc., and the Pulmonary Hypertension
Association. Circulation 2009;119:2250-94.
3. Humbert M, McLaughlin VV. The 4th World Symposium on Pulmonary Hypertension.
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4. Gali N, Hoeper MM, Humbert M, Torbicki A, Vachiery JL, Barbera JA, et al. Guidelines
for the diagnosis and treatment of pulmonary hypertension The Task Force for the
Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology
(ESC) and the European Respiratory Society (ERS), endorsed by the International Society
of Heart and Lung Transplantation (ISHLT). Eur Heart J 2009;30:2493-537.
5. Gali N, Hoeper MM, Humbert M, Torbicki A, Vachiery JL, Barbera JA, et al. Task Force
for Diagnosis and Treatment of Pulmonary Hypertension of European Society of Cardiology
(ESC); European Respiratory Society (ERS); International Society of Heart and Lung
Transplantation (ISHLT). Guidelines for the diagnosis and treatment of pulmonary
hypertension, Eur Respir J 2009;34:1219-63.
6. Simonneau G, Robbins IM, Beghetti M, Channick RN, Delcroix M, Denton CP, et al.
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Suppl):S43-54.
7. Hoeper MM, Barber JA, Channick RN, Hassoun PM, Lang IM, Manes A, et al. Diagnosis,
assessment, and treatment of non-pulmonary arterial hypertension pulmonary hypertension.
J Am Coll Cardiol 2009; 54(1 Suppl):S85-96.

41

8. Badesch DB, Champion HC, Sanchez MA, Hoeper MM, Loyd JE, Manes A, et al. Diagnosis
and assessment of pulmonary arterial hypertension. Am Coll Cardiol 2009;54(1 Suppl):S5566.
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13. Berner M, Beghetti M, Spahr-Schopfer I, Oberhansli I, Friedli B. Inhaled nitric oxide to test
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14. Durongpisitkul K, Laoprasitiporn D, Layangool T, Sittiwankul R, Panamonta M, Mokrapong
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16. Weitzenblum E, Sautegeau A, Ehrhart M, Mammosser M, Pelletier A. Long-term oxygen
therapy can reverse the progression of pulmonary hypertension in patients with chronic
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17. Mereles D, Ehlken N, Kreuscher S, Ghofrani S, Hoeper MM, Halank M, et al. Exercise and
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cardiovascular diseases during pregnancy. Eur Heart J 2003;24:76181.

42

19. Barst RJ, Gibbs JS, Ghofrani HA, Hoeper MM, McLaughlin VV, Rubin LJ, et al. Updated
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2009;54(1 Suppl):S78-84.
20. Sitbon O, Humbert M, Jas X, Ioos V, Hamid AM, Provencher S, Garcia G, et al. Long-term
response to calcium channel blockers in idiopathic pulmonary arterial hypertension.
Circulation. 2005 Jun 14;111(23):3105-11.
21. Gali N, Humbert M, Vachiry JL, Vizza CD, Kneussl M, Manes A, et al;Arterial Pulmonary
Hypertension and Beraprost European (ALPHABET) Study Group. Effects of beraprost
sodium, an oral prostacyclin analogue, in patients with pulmonary arterial hypertension: a
randomized, double-blind, placebo-controlled trial. J Am Coll Cardiol 2002;39:1496-502.
22. Durongpisitkul K, Jakrapanichakul D, Laohaprasitiporn D, Soongswang J, Chanthong P,
Nana A. Combination therapy of prostacyclin for pulmonary hypertension in congenital heart
disease. J Med Assoc Thai 2005;88 Suppl 8:S60-5
23. Durongpisitkul K, Jakrapanichakul D, Sompradikul S. A retrospective study of bosentan in
pulmonary arterial hypertension associated with congenital heart disease. J Med Assoc
Thai 2008;91:196-202.
24. Limsuwan A, Pienvichit P, Khowsathit P. Beraprost therapy in children with pulmonary
hypertension secondary to congenital heart disease. Pediatr Cardiol 2005;26:787-91
25. Limsuwan A, Wanitkul S, Khosithset A, Attanavanich S, Samankatiwat P. Aerosolized
iloprost for postoperative pulmonary hypertensive crisis in children with congenital heart
disease. Int J Cardiol 2008;129:333-8.
26. Archer SL, Michelakis ED. Phosphodiesterase type 5 inhibitors for pulmonary arterial
hypertension. N Engl J Med 2009;361:1864-71.
27. Kanjanawart S, Kongyingyoes B, Gaysornsiri D, Tangsucharit P, Puapairoj P,
Vannaprasaht S, et al. Bioequivalence and Pharmacokinetic Study of Sildenafil in Healthy
Thai Male Volunteers Srinagarind Med J 2008;23:38-44.
28. Rich S, Kaufmann E, Levy PS. The effect of high doses of calcium-channel blockers on
survival in primary pulmonary hypertension. N Engl J Med 1992; 327:76-81.
29. Olschewski H, Simonneau G, Galie N, Higenbottam T, Naeije R, Rubin LJ, Nikkho S,
Sitbon O, Speich R, Hoeper M, Behr J, Winkler J, Seeger W, for the AIR Study Group.
Inhaled iloprost in severe pulmonary hypertension. N Engl J Med 2002; 347: 322-329.

43

30. McLaughlin W, Oudiz RJ, Frost A, Tapson VF, Murali S, Channick RN, Badesch DB, Barst
RJ, Hsu HH, Rubin LJ. Randomized study of adding inhaled iloprost to existing bosentan in
pulmonary arterial hypertension. Am J Respir Crit Care Med 2006; 174: 1257-1263.
31. Higenbottam T, Butt AY, McMahon A, Westerbeck R, Sharples L. Long-term intravenous
prostaglandin (epoprostenol or iloprost) for treatment of severe pulmonary hypertension.
Heart 1998; 80: 151-155
32. Barst RJ, McGoon M, Mc Laughlin W, Tapson V, Rubin L, Wesserman K, Oudiz R, Shapiro
S, Robbins I, Channick R, Badesch BD, Rayburn BK, Flinchbaugh R, Sigman J, Arneson K,
Jeffs R, for Beraprost Study Group. Beraprost therapy for pulmonary arterial hypertension. J
Am Coll Cardiol 2003; 41: 2125.
33. Channick RN, Simonneau G, Sitbon O, Robbins IM, Frost A, Tepson VF, Badesch DB,
Roux S, Rainisio M, Bodin F, Rubin LJ. Effect of the dual endothelin-receptor antagonist
bosentan in patients with pulmonary hypertension: a randomized placebo-controlled study.
Lancet 2001; 358: 1119-1123.
34. Rubin LJ, Badesch DB, Barst RJ, Galie N, Black CM, Keogh A, Pulido T, Frost A, Roux S,
Leconte I, Landzberg M, Simonneau G. Bosentan therapy for pulmonary arterial
hypertension. N Engl J Med 2002; 346: 896-903.
35. Hambert M, Barst RJ, Robbins IM, Channick RN, Galie N, Boonstra A, Rubin LJ, Horn EM,
Manes A, Simonneau G, Combination of bosentan with epoprostenol in pulmonary arterial
hypertension: BREATHE-2. Eur Respir J 2004; 24: 353-359.
36. Galie N, Rubin LJ, Hoeper M, Jansa P, Al-Hiti H, Meyer GMB, Chiossi E, Kusic-Pajic A,
Simonneau G. Treatment of patients with mildly symptomatic pulmonary arterial
hypertension with bosentan (EARLY study): a double-blind, randomized controlled trial.
Lancet 2008; 371: 2093-2100.
37. Galie N, Beghetti M, Gatzoulis MA, Granton J, Berger RMF, Lauer A, Chiossi E, Landzberg
M, for the Bosentan Randomised Trial of Endothelin Antagonist Therapy. Bosentan therapy
in patients with Eisenmenger syndrome: a multicenter, double-blind, randomized, placebocontrolled study. Circulation 2006; 114:48-54.
38. Bhatia s, Frantz RP, Severson CJ, Durst LA, McGoon MD, Immediate and long-term
hemodynamic and clinical effects of sildenafil in patients with pulmonary arterial
hypertension receiving vasodilator therapy. Mayo Clin Proc 2003; 78: 1207-1213.

44

39. Michelakis ED, Tymchak W, Noga M, Webster L, Wu XC, Lien D, Wang SH, Modry D,
Archer SL. Long-term treatment with oral sildenafil is safe and improves functional capacity
and hemodynamics in patients with pulmonary arterial hypertension. Circulation 2003; 108:
2066-2069.
40. Ghofrani HA, Schermuly RT, Rose F, Wiedemann R, Kohstall MG, Kreckel A, Olschewski
H, Weissmann N, Enke B, Ghofrani S, Seeger W, Grimminger F. Sildenafil for long-term
treatment of nonoperable chronic thromboembolic pulmonary hypertension. Am J Respir Crit
Care Med 2003; 167: 1139-1141.
41. Galie N, Ghofrani HA, Torbicki A, Barst RJ, Rubin LJ, Badesch D, Fleming T, Parpia T,
Burgess G, Branzi A, Grimminger F, Kurzyna M, Simonneau G. the Sildenafil Use in
Pulmonary Arterial Hypertension (SUPER) Study Group. Sildenafil citrate therapy for
pulmonary arterial hypertension. New Engl Med 2005; 353:2148-2157.
42. Badesch DB, Hill NS, Burgess G, Rubin LJ, Barst RJ, Galie N, Simonneau G. Sildenafil for
pulmonary arterial hypertension associated with connective tissue disease. J Rheumatol
2007; 34: 2417-2422.

45

1 Echocardiographic evaluation in pulmonary hypertension

(pulmonary pressure)
pulmonary artery
pressure (PAP)


echocardiography

PAP echocardiography
(1-6)

Pulmonary artery pressure peak systolic

18-25 mmHg end-diastolic 6-10 mmHg mean 12-16
mmHg
pulmonary hypertension right heart catheterization

echocardiography right ventricular

mPAP 25 mmHg(7)
systolic pressure (RVSP) 50 mmHg ( mPAP 25 mmHg )
pulmonary hypertension RVSP < 36 mmHg exclude pulmonary hypertension
echocardiography pulmonary hypertension
(right heart pressure) pulmonary
hypertension pulmonary artery pressure

doppler echocardiography pulmonary artery pressure
gradient across the valve stroke volume

(intracardiac pressure)
(pressure gradient) conservation of energy (Bernoulli equation)
laminar flow orifice
(V1) (V2)
simplified Bernoulli equation
P 4V22

P : (pressure gradient)
V2 : orifice

46

Hemodynamic data right heart evaluation (right heart pressure)

1. Mean right atrial pressure (RAP) or central venous pressure (CVP)
2. Pulmonary artery pressure (PAP)
- PA systolic pressure
- PA diastolic pressure
- mPAP
3. Pulmonary vascular resistance (PVR)
mean pulmonary artery pressure (mPAP):
Abbas 17 mean pulmonary artery pressure
(mPAP) peak pulmonary regurgitant gradient
mPAP 4PRV 2 + RAP
mPAP: mean pulmonary artery pressure (mmHg)
PRV: peak pulmonary regurgitant velocity (mmHg)
RAP: right atrial pressure (mmHg)

mPAP > 25 mmHg pulmonary hypertension

diastolic heart failure
left sided valvular heart diseases mPAP hemodynamic study
routine echocardiogram

47

mean pulmonary artery

pressure (mPAP) Doppler
echocardiography peak
pulmonary regurgitant velocity

right heart pressure

left heart filling pressure left ventricular end diastolic pressure
(LVEDP) left atrial pressure (LAP) pulmonary hypertension
chronic pulmonary venous congestion LAP
pulmonary arterial hypertension subgroup pulmonary
hypertension LAP LAP
pulmonary hypertension pulmonary hypertension due to left heart disease
subgroup
LAP
1. mitral E velocity mitral annular e velocity > 15
2. Left atrial volume index > 32 ml/m2

48

References
1. Lee FA. Hemodynamics of the right ventricle in normal and disease states. Cardiol Clin
1992;10:59-67.
2. Barnard D, Alpert JS. Right ventricular function in health and disease. Curr Probl Cardiol
1987;12:417-49.
3. Yock PG, Popp RL. Noninvasive estimation of right ventricular systolic pressure by
Doppler ultrasound in patients with tricuspid regurgitation. Circulation 1984;70:657-62.
4. Currie PJ, Seward JB, Chan KL, Hagler DJ, Mair DD, Reeder GS, et al. Continuous
wave Doppler-catheterization study in 127 patients. J Am Coll Cardiol 1985;6:750-6.
5. Miyatake K, Okamoto M, Kinoshita N, Matsushita M, Nagata S, Beppu S, et al.
Pulmonary regurgitation studied with the ultrasonic pulsed Doppler technique.
Circulation 1982;65:969-76.
6. Berger M, Haimowitz A, Tosh AV, Berdoff RL, Goldberg E. Quantitative assessment of
pulmonary hypertension in patients with tricuspid regurgitation using continuous wave
Doppler ultrasound. J Am Coll Cardiol 1985;6:359-65.
7. Badesch DB, Champion HC, Sanchez MA, Hoeper MM, Loyd JE, Manes A, et al.
Diagnosis and assessment of pulmonary arterial hypertension. J Am Coll Cardiol
2009;54(1 Suppl):S55-66.
8. Kircher BJ, Himelman RB, Schiller NB. Noninvasive estimation of right atrial pressure
from inspiratory collapse of the inferior vena cava. Am J Cardiol 1990;66:483-96.
9. Simmonson JS, Schiller NB. Sonospirometry: a new method for noninvasive estimation
of mean right atrial pressure based on two-dimensional echocardiographic
measurements of inferior vena cava during measured inspiration. J Am Coll Cardiol
1988;11:557-64.
10. Mintz GS, Kotler MN, Parry WR, Iskandrian AS, Kane SA. Real-time inferior vena cava
ultrasonography normal and abnormal findings and its use in assessing right-heart
function. Circulation 1981;64:1018-24.
11. Cook DJ. Clinical assessment of central venous pressure in the critically ill. Am J Med
Sci 1990;299:175-8.
12. Cook DJ, Simel DL. Dose this patient have abnormal central venous pressure? JAMA
1996;275:630-4.

49

13. Connors AF, McCaffree DR, Gray BA. Evaluation of right heart catheterization in the
critically ill patient without acute myocardial infarction. N Engl J Med 1983;308:263-7.
14. Eisenberg PR, Jaffe AS, Schuster DP. Clinical evaluation compared to pulmonary artery
catheterization in the hemodynamic assessment of critically ill patients. Crit Care Med
1984;12:549-53.
15. Aramsareewong T, Jakrapanichakul D, Udol K. Right atrial pressure determination by
two-dimensional echocardiography. Thai Heart J 2002;15:137-42.
16. Currie PJ, Seward JB, Chan KL, Fyfe DA, Hagler DJ, Mair DD, et al. Continuous wave
Doppler determination of right ventricular pressure: a simultaneous Dopplercatheterization study in 127 patients. J Am Coll Cardiol 1985;6:750-6.
17. Abbas AE, Fortuin FD, Schiller NB, Appleton CP, Moreno CA, Lester SJ.
Echocardiographic determination of mean pulmonary artery pressure. Am J Cardiol
2003;92:1373-6.
18. Abbas AE, Fortuin FD, Schiller NB, Appleton CP, Moreno CA, Lester SJ. A simple
method for noninvasive estimation of pulmonary vascular resistance. J Am Coll Cardiol
2003;41:1021-7.
19. Ommen SR, Nishimura RA, Appleton CP, Miller FA, Oh JK, Redfield MM, Tajik AJ.
Clinical utility of Doppler echocardiography and tissue Doppler imaging in the estimation
of left ventricular filling pressures: A comparative simultaneous Doppler-cathetherization
study. Circulation 2000;102:1788-94.
20. Lang RM, Bierig M, Devereux RB, Flachskampf FA, Foster E, Pellikka PA, et al.
Recommendations for chamber quantification: a report from the American Society of
Echocardiography's Guidelines and Standards Committee and the Chamber
Quantification Writing Group, developed in conjunction with the European Association of
Echocardiography, a branch of the European Society of Cardiology. J Am Soc
Echocardiogr 2005;18:1440-63.

50

2
(pulmonary arterial hypertension; PAH)


comprehensive evaluation
Exercise capacity

(functional class; FC)
WHO functional classification 4

Class I:

Class II:

Class III:

Class IV:

right sided heart failure

51

6 (6 Minute Walk Test : 6 MWT)

- 6
-
- 10
2 2
- : (a mechanical lap counter)
2
(sphygmomanometer)
(defibrillator)


10 ( )

2 6
- 6

-

52

(Borg dyspnea index)

Borg scale 0 10

0
0.5
1
2
3
4
5
6
7
8
9
10

Perceived Breathlessness (Borg scale)

Biomarker
Natriuretic peptide hormone

cardiac myocardial wall stress natriuretic

peptide atrial natriuretic peptide (ANP) B-type natriuretic
peptide (BNP)

atrium ventricle BNP N-terminal probrain natriuretic peptide (NT-proBNP) right ventricular dysfunction
ANP, BNP NT-proBNP

53

3 PAH Scleroderma
, syncope, functional class
scleroderma PAH, interstitial lung disease, left heart disease,
myopathy, restriction of thoracic cage, anemia functional class II, III IV
echocardiography (2,++)
CBC, CXR, PFT, HRCT, arterial
blood gas, thyroid function test (2,++) PAH
right heart catheterization (4,+) PAH-specific drug
RHC exclude PH post capillary PH
(4,++) echocardiography

echocardiography (4,++)
PAH scleroderma vasculopathy
1.
IPAH (5)
2. Anticoagulation randomized prospective controlled trial pulmonary hypertension
secondary to connective tissue disease antiphospholipid syndrome
anticoagulant(1,2) ( ) (4,+/-)
microthrombotic lesion(4-)
thromboembolic event low cardiac output, dilated right sided heart in
situ thrombosis pulmonary vascular bed
3. corticosteroid / immunosuppressive therapy (3,+/-)
PAH SSc pulmonary
artery vasculopathy
PAH connective tissue disease lupus(2), mixed connective
tissue disease (MCTD), overlapping syndrome
active disease steroid
immunosuppressive therapy
6MWT scleroderma PAH
scleroderma 6MWT

54

6MWT scleroderma
6MWT
References
1. Varga J, Denton CP. Systemic Sclerosis and the Scleroderma-Spectrum Disorders. In
Firestein GS et al, editors. Kellys Textbook of Rheumatology 8thed. Philadelphia:Saunders
Elsevie 2009:p1311-51
2. Sanchez O et al. Treatment of pulmonary hypertension secondary to connective tissue
diseases. Thorax 1999;54:273-7.
3. Denton CP, Humbert M, Rubin L, Black CM. Bosentan treatment for pulmonary arterial
hypertension related to connective tissue disease: A subgroup analysis of the pivotal
clinical trials and their open-label extensions. Ann Rheum Dis 2006; 65:1336-40.
4. Naeye RL. Pulmonary vascular lesions in systemic sclerosis. Dis Chest 1963;44:374-80.
5. Bunch TW, Tancredi RG, Lie JT. Pulmonary hypertension in polymyositis. Chest
1981:79:105-7.
6. Balagopal VP, Da Costa P, Greenstone MA. Fatal pulmonarry hypertension and rheumatoid
vasculitis. Eur Respir J 1995;8:331-3.

55

4
/ (Pulmonary hypertension due to lung disease and/or hypoxia)
(chronic obstructive
pulmonary disease; COPD), interstitial lung disease
obstructive sleep apnea
(high altitude)

hypoxemia lung transplantation candidate
echocardiography (3, ++)

poor acoustic window
right heart catheterization (3, ++)
- echocardiography
- candidate organ transplantation

COPD long term oxygen therapy pulmonary hypertension
COPD (3, ++) hypoxia

PAH specific therapy
hypoxemia (3, -)

56

5
(Pulmonary hypertension due to chronic
thrombotic and/ or embolic disease; CTEPH)

pulmonary hypertension


multirow detector computerized tomographic pulmonary
angiography (CTPA) pulmonary angiography / ventilation-perfusion lung scan,
polysomnography, lung volume study,
DLCO pulmonary angiography
CTEPH
thromboendarterectomy
(3, +)

Surgical pulmonary thromboendarterectomy (treatment of choice)

(3, ++) organized thrombi
(proximal pulmonary artery)
hypoxemia inferior vena
caval filter (3, +/-) anticoagulant pulmonary
thromboendarterectomy PAH specific therapy CTEPH
(3, +/-)
- organized thrombi (distal pulmonary
artery)
- pulmonary thromboendarterectomy

- pulmonary
thromboendarterectomy

57

6
(Pulmonary arterial hypertension associated with congenital heart
disease)

PAH (1)
(pulmonary systolic artery pressure;
PSAP) (systolic blood pressure; SBP) PAH
PSAP 25 SBP echocardiography
/ (4, ++)
Mild PAH
PSAP 25-50 SBP
Moderate PAH
PSAP 50-75 SBP
Severe PAH
PSAP 75 SBP

(4,++)
(CXR) (ECG) (pulse oximetry)
4
echocardiography PAH PAH
high pulmonary blood flow high pulmonary vascular resistance(2)
right left heart catheterization

PAH acute pulmonary vasoreactivity testing balloon/device
occlusion(2,3)
(4, 5)
1. Evaluate PAH and severity
pulmonary artery pressure (PAP) hemodynamic
right atrium pressure (RAP), right ventricular pressure (RVP), pulmonary
artery pressure (PAP), pulmonary capillary wedge pressure (PCWP) left ventricular
end diastolic pressure (LVEDP) cardiac output (CO)

58

RV failure (end stage) CO

PAP PVR
PAP
2. Evaluate magnitude of the shunt
..

Qp:Qs > 1.5:1

PAH Eisenmenger physiology
3. Evaluate status of the pulmonary circulation
PVRi > 6-8 Wood unitsm2 Eisenmenger syndrome
acute
vasoreactivity test hemodynamic ( 1)
4. Trial of test occlusion
PVR pulmonary reactivity (device)

cardiac output / RV filling

pressure

4 (6) (1,++)
1. PAH associated with systemic-to-pulmonary shunt
Qp:Qs > 1.5:1 PVR PCWP

PVRi 6-8 Wood unitsm2 PVR:SVR < 0.3:1(7)
(reversibility)

2. Eisenmenger syndrome


PVR

Eisenmenger physiology
1)

59

2) 90
3) severe PAH (PSAP > 75 SBP), PCWP < 15 mmHg, PVRi > 6-8 Wood unitsm2
PVR:SVR > 0.5:1

PAH-specific drug PVR

3. PAH after corrective cardiac surgery
PAH

residual defect

PAH-specific drug PH class I
4. PAH with small defects
IPAH
(idiopathic like PAH) IPAH
PAHspecific drug PH class I
Acute vasoreactivity test
severe PAH
PVR (> 4 Wood unitsm2) PAH specific drug

(positive response)

- hemodynamic PAH specific drug
Aortic saturation, RAP, RVP, PAP, AOP, LVP, Qp:Qs, Rp, Rp:Rs, CO
- PSAP SBP PAH

60

-
severe PAH vasoreactivity
(++,4)
-
acute pulmonary vasoreactivity test room air
30 PAH specific drug 6-1
- vasoreactivity agent (
oxygen agent)
6-2

6-1 vasoreactivity agent (

oxygen agent) APAH/CHD

systemic-to-pulmonary shunt closure
(positive response)

Agent

Any

1,++

PVR:SVR < 0.42(9)

Oxygen

1,++

PVR:SVR < 0.3(7,11)

iNO or Iloprost

1,++

PVR:SVR < 0.27(9)

Oxygen + iNO

1,++

PVR

< 6-8 Wood unitsm2 (8-10)

PVR

10-20(7,11)

iNO or Iloprost

3,+/-

PVR:SVR

10-20(7,9)

iNO or Iloprost

3,+/-

61

6-2 Hemodynamic data systemic-to-pulmonary shunt

congenital heart disease

systemic-to-pulmonary shunt closure
PVR
< 6-8 Wood unitsm2 (7,8)
PVR:SVR < 0.3-0.33 (7-9)
PVR:SVR < 0.5
DBP (AOP-PAP) > 20 mmHg

1, ++
1, ++
4, +
4, +

DBP (AOP-PAP) diastolic pressure aorta pulmonary

artery

References
1. McLaughlin VV, Archer SL, Badesch DB, Barst RJ, Farber HW, Lindner JR, et al.
ACCF/AHA 2009 expert consensus document on pulmonary hypertension: a report of the
American College of Cardiology Foundation Task Force on Expert Consensus Documents
and the American Heart Association: developed in collaboration with the American College
of Chest Physicians, American Thoracic Society, Inc., and the Pulmonary Hypertension
Association. Circulation 2009;119:2250-2294.
2. Suesaowalak M, Cleary JP, Chang AC. Advances in diagnosis and treatment of pulmonary
arterial hypertension in neonates and children with congenital heart disease. World J
Pediatr 2010;6:13-31.
3. Limsuwan A and Khowsathit P. Assessment of pulmonary vasoreactivity in children with
pulmonary hypertension. Curr Opin Pediatr 2009;21:594-599.
4. . Getting more from right heart catheterization.
, , . Pulmonary hypertension 2009 Raising the bar
for the treatment of pulmonary arterial hypertension. , 2009: 95-110.

62

5. Berger RM. Possibilities and impossibilities in the evaluation of pulmonary vascular disease
in congenital heart defects. Eur Heart J 2000;21:17-27.
6. Gali N, Hoeper MM, Humbert M, Torbicki A, Vachiery JL, Barbera JA, et al. The task
force for the diagnosis and treatment of pulmonary hypertension of the European Society of
Cardiology (ESC); European Respiratory Society (ERS); International Society of Heart and
Lung Transplantation (ISHLT). Guidelines for the diagnosis and treatment of pulmonary
hypertension. Eur Heart J 2009;30:2493-537.
7. Limsuwan A, Khosithseth A, Wanichkul S, Khowsathit P. Aerosolized iloprost for pulmonary
vasoreactivity testing in children with long-standing pulmonary hypertension related to
congenital heart disease. Catheter Cardiovasc Interv 2009;73:98-104.
8. Dimopoulos K, Michael AP, Gatzoulis MA. Evaluating operability in adults with congenital
heart disease and the role of pre treatment with targeted pulmonary arterial hypertension
therapy. Int J Cardiol 2007;116:427-9.
9. Balzer DT, Kort HW, Day RW, Corneli HM, Kovalchin JP, Cannon BC, et al. Inhaled nitric
oxide as a pre-operative test (INOP test I): The INOP Test Study Group. Circulation 2002;
106: I76-I81.
10. Neutze JM, Ishikawa T, Clarkson PM, Calder AL, Barratt-Boyes BG, Kerr AR. Assessment
and follow-up of patients with ventricular septal defect and elevated pulmonary vascular
resistance. Am J Cardiol 1989; 63: 327-31.
11. Berner M, Beghetti M, Spahr-Schopfer I, Oberhansli I, Friedli B. Inhaled nitric oxide to test
the vasodilator capacity of the pulmonary vascular bed in children with long-standing
pulmonary hypertension and congenital heart disease. Am J Cardiol 1996;77:532-5.

63

7
(Intervention and surgical modalities of treatment in pulmonary
hypertension)(1)
Surgical management in congenital heart disease with pulmonary hypertension
severe
PAH

repair of the shunt pulmonary vascular disease

pulmonary vascular resistance < 6 Wood unitsm2
safe large systemicto-pulmonary shunts pulmonary vascular disease
pulmonary vascular resistance 6 8 Wood
unitsm2 grey zone
( (positive
response)
6)
end-stage disease (Eisenmenger syndrome)
anatomical defect
heart-lung transplantation lung transplantation
corrective cardiac surgery
pulmonary vascular disease Eisenmenger syndrome
PAH-specific drug heart-lung transplantation

64

Interventional and surgical modalities of treatment in pulmonary hypertension

5
1. Chronic thromboembolic pulmonary hypertension (CTEPH)
2. Atrial septostomy in severe PAH
3. Lung transplantation
4. Extracorporeal life support
5. Ventricular assist devices
Chronic thromboembolic pulmonary hypertension (CTEPH)
mPAP > 25 mmHg symptomatic PAH
pulmonary endarterectomy CTEPH

4 7
- center experience
- Concordance between PVR and anatomic disease
- Pre-operative PVR < 1,000 1,200 dynes/sec/cm-5
- Absence of select comorbidities ( splenectomy, ventriculoatrial shunts)
- Post-operative PVR < 500 dynes/sec/cm-5
6

hemodynamics 6 12
persistent pulmonary hypertension

hemodynamics
Atrial septostomy (AS) in severe PAH
AS decompress right ventricle AS IPAH
syncope, persistent RV failure AS bridge to
lung transplantation lung transplantation AS

65

AS step wise balloon dilatation

5 RAP > 20 mmHg
AS
-

Oxygen saturation < 90 % in room air

RAP > 20 mmHg
LVEDP > 18 mmHg

Lung transplantation
Bilateral lung transplantation heart-lung transplantation single lung
transplantation PAH-specific drug
transplantation WHO FC IV
transplantation 5 transplantation
45 50
Extracorporeal Life Support (ECLS)
ECLS conventional support for RV

Venovenous type ECLS carbon dioxide removal, improve oxygenation, RV afterload

reduction
Venoarterial type ECLS RV decompression and support lung
transplantation
ECLS

Ventricular Assist Devices
right ventricular assist device

References
1. Keogh AM, Mayer E, Benza RL, Corris P, Dartevelle PG, Frost AE, et al. Interventional
and surgical modalities of treatment in pulmonary hypertension. J Am Coll Cardiol
2009;54(1 Suppl):S67-77.

66

8 Perioperative management of patients with pulmonary hypertension

morbidity

14 (major)
shift

perioperative risk, , functional class

/

1.
pulmonary vascular resistance (PVR)
PVR systemic vascular resistance (SVR) Qp : Qs 1
2.

3.
/ ( preload)

4.
sinus rhythm
5.
(contractility)
PVR
1.
respiratory / metabolic alkalosis, pH 7.50-7.55
2.
hyperventilation hypocarbia (PaCO2 28-35 mmHg) tidal volume 8-10
ml/kg pH PaCO2

3.
PaO2 100 mmHg
functional residual capacity (FRC) (atelectasis)
airway PEEP
4.

5.
opioids
sympathetic

67

6.

(nitroglycerin, iloprost, milrinone),

nitric oxide inhaled iloprost

PVR
1. respiratory metabolic acidosis
2.
3.
4. tidal volume (hyperinflation ), PEEP

5. lung collapse
6.
7.
8. (hemoconcentration)
9. laryngospasm
10.
11. sympathetic
12.
13. protamine heparin -
(anesthetic management)
1. (preoperative evaluation)
ECG, echocardiography, right heart
catheterization , CBC, chemistry coagulogram

2. Premedication
ASA class sedation
midazolam chloral hydrate 1-2

3. Monitoring

68

- (minor surgery) noninvasive BP (NIBP), ECG, SpO2, Endtidal CO2 (PETCO2), airway
- (major surgery) CVP, Aline, (PAP)
blood gases
- atrium ,
hematocrit, activated clotting time (ACT)
4.
4.1 Local infiltration periphery,
4.2 Total intravenous anesthesia (TIVA)

4.3 Nerve block, plexus block

4.4 Regional anesthesia
continuous epidural block
spinal block
4.5 (general anesthesia)
oxygenation balanced technique opioids
fentanyl morphine midazolam sedate
nondepolarizing N2O PVR
hypoxemia

fluid shift
-

protamine 1.0 -1.3 mg heparin

heparin protamine pulmonary
hypertension crisis ranitidine 1 mg/kg ( 50 mg)
chlorpheniramine 0.2-0.4 mg/kg protamine
protamine (4,+/-)
5. /
5.1

69

5.2

5.3 monitoring /
crisis
5.4 12-72

5.5 nitric oxide 5-20 ppm iloprost

2-5 10 2-4
iloprost 1-5
ng/kg/min
5.6 inotrope milrinone, dobutamine adrenaline

5.7 opioid NSAIDs

5.8 maintain intravascular volume
/ Crisis perioperative
1.
2.
3.

4.
5.
6.
6.1

6.2
6.3
6.4

nondepolarizing
pH mild alkalosis (pH 7.50-7.55, PaCO2 28-35
mmHg) airway PEEP FiO2
PaO2 >100-150 mmHg suction
CVP 8-12 mmHg
furosemide 10-40 mg IV 0.5-1 mg/kg
metabolic acidosis ventilation (
) respiratory acidosis

nitric oxide 10-50 ppm iloprost 20-25 mcg/kg 10-20 2-3

Delphinus Obtineb Aeroneb Bennett ventilator

iloprost 2-5 mcg 10-20 mcg 10-20
IV nitroglycerin 0.1-5 mcg/kg/min IV iloprost 1-5 mcg/kg/min
Milrinone 0.2-0.75 mcg/kg/min inotrope
sildenafil 0.1-0.3

70

6.5
6.6
7.
7.1
7.2
7.3

mg/kg 10-30 ml nasograstric

Bosentan postoperative (+/E)
Milrinone inhalation (+/E)
inotrope
Dobutamine 1-10 mcg/kg/min
Isoproterenol 0.03-0.05 mcg/kg/min
Adrenaline 0.01-0.1 mcg/kg/min

References
1. Friesen RH, Williams GD. Anesthetic management of children with pulmonary arterial
hypertension. Paediatr Anaesth 2008;18:208-16.
2. Gordon C, Collard CD, Pan W. Intraoperative management of pulmonary hypertension and
associated right heart failure. Curr Opin Anesthesiol 2009;23:49-56.
3. Hill NS, Roberts KR, Preston IR. Postoperative pulmonary hypertension: etiology and
treatment of a dangerous complication. Respir Care 2009;54:958-68.
4. MacKnight B, Martinez EA, Simon BA. Anesthetic management of patients with pulmonary
hypertension. Semin Cardiothorac Vasc Anesth 2008; 12:91-6.
5. Pritts CD, Pearl RG. Anesthesia for patients with pulmonary hypertension. Curr Opin
Anesthsiol 2010; 23: 411-6.
6. Ramakrishna G, Sprung J, Ravi BS, Chandrasekaran K, McGoon MD. Impact of pulmonary
hypertension on the outcomes of noncardiac surgery: predictors of perioperative morbidity
and mortality. J Am Coll Cardiol 2005;45:1691-9.

71

9
..

( .52/2552 8 ..2552)

72

73

74

21 ..2555
5 .

1.
2.
3.
4.
5.
6.

..
.
..
..
..
.

7. ..

8. ..
9. .
10. .

11. .

12. .
13. .

14. () .

PAH

75