肺高壓的診斷與治療國立成功大學附設醫院許志新醫師 2012/05/26, tainan. what...

肺高壓的診斷與治療

國立成功大學附設醫院許志新　醫師

2012/05/26, Tainan

What is PH ? What is PAH ?

Pulmonary Hypertension

Pulmonary hypertension is defined as an increase in mean pulmonary artery pressure 25 mmHg at rest≧

Pulmonary hypertension is a hemodynamic and pathophysiological state that can be found in multiple clinical condition

1. Pulmonary arterial hypertension

• 1.1Idiopathic PAH

• 1.2 Heritable

• 1.3 Drugs and toxin related

• 1.4 Associated with (APAH) 1.4.1 Connective tissue diseases

1.4.2 HIV 1.4.3 Portal hypertension 1.4.4 Congenital heart diseases 1.4.5 Schistosomiasis

1.4.6 Chronic haemolytic anaemia

• 1.5 Persist PH of the newborn

1’ Pulmonary veno-occlusive disease

3. PH with Lung Diseases/Hypoxemia

• 3.1 COPD

• 3.2 Interstitial lung diseases

3.3 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 thromboembolicPH • TE obstruction of proximal PA • TE obstruction of distal PA • Non thrombotic P embolism

5. PH with unclear and /or

multifactorial mechanisms

Dana Point 2008

Pulmonary Arterial Hypertension Diagnostic Classification

2. PH with left heart disease • 2.1 Systolic dysfunction • 2.2 Diastolic dysfunction 2.3 Valvular disease

Pulmonary Arterial Hypertension

Pulmonary hypertension Elevated pressure in the pulmonary vascular bed,

without specify the location of the pathology

Pulmonary arterial hypertension Elevated pressure in the pulmonary vascular bed,

specially ascribed to pathology in the pulmonary arterial tree.

Definition of PAH by WHO

Mean PAP > 25mmHg at rest

PAWP < 15 mmHg

What do we face ?

Rare Miss diagnosis Rapid progress Poor prognosis

Really rare ? Or Under diagnosis?

Prevalence of PAH

PAH is a rare disease: Prevalence of PAH

France: – 15 cases/million

England and Wales:– Severe PAH: 30–50 cases/million

Estimated prevalence of 120,000 pts with PAH in theUSA, EU, Canada and Japan.- US 50,000 to 100,000- 15,000 to 25,000 diagnosed and treated

Estimated 260,000 pts hospitalized/year with all cause PH in USA (medicare database)

Humbert, et al. Am J Resp Crit Care Med 2006; 173: 1023–30 Peacock. BMJ 2003; 326: 835–6 Link J. Chest 2011; 139:497-504.Gomberg-Maitland M. Chest 2011;139:482-483

Prevalence of PAH in Associated Conditions

Associated Condition Prevalence of PAHSystemic sclerosis 7-12 %

HIV infection 0.46-0.5 %

Portal hypertension 2-6 %

Congenital heart disease 1.6-12.5 per million in those with congenital systemic-to-pulmonary shunts → 25-50 % affected by Eisenmenger syndrome

Schistosomiasis 4.6 % in those with hepatosplenic disease

Chronic hemolytic anemia Highly variable; currently being studied

Simonneau, et al. J Am Coll Cardiol. 2009;54(1):S43-54.Simonneau, et al. J Am Coll Cardiol. 2009;54(1):S43-54.

NORMAL REVERSIBLE DISEASE IRREVERSIBLE DISEASE

Pathogenesis of Pulmonary ArterialPathogenesis of Pulmonary ArterialHypertensionHypertension

PAH: Pathophysiology

Pulmonary vessel

remodeling

Pulmonary vascular

resistance increase

RV remodeling

RV dysfunction

Do we have a luxury time ?

IPreclinical /

no symptoms

IISymptomatic /

stable

IIIProgression /

declining

Pulm. pressure

Cardiac outputLev

el

Time

Years Months

Therapeutic window

PAH: a rapidly evolving disease

RV function

Severity of Pulmonary Hypertension

Degree of disease

– Mild

– Moderate

– Severe

Mean PAP (mmHg)

– 25 - 40

– 41 - 55

– >55

NYHA/WHO classification of functional status

Class Description

IPatients with pulmonary hypertension in whom there is no limitation of usual physical activity: ordinary physical activity does not cause increased dyspnoea, fatigue, chest pain or pre-syncope

IIPatients with pulmonary hypertension who have mild limitation of physical activity. There is no discomfort at rest but normal physical activity causes increased dyspnoea, fatigue, chest pain or pre-syncope

IIIPatients with pulmonary hypertension who have a marked limitation of physical activity. There is no discomfort at rest but less than ordinary activity causes increased dyspnoea, fatigue, chest pain or pre-syncope

IV

Patients with pulmonary hypertension who are unable to perform any physical activity and who may have signs of right ventricular failure at rest. Dyspnoea and/or fatigue may be present at rest and symptoms are increased by almost any physical activity

1. Barst RJ et al. J Am Coll Cardiol 2004 16; 43 (12 Suppl S): 40S–47S

Brenot F. Chest 1994; 105: 33S–36S

0 12 24 36 48 60 72 84 960

25

50

75

100

WHO class I – II (n = 30)

WHO class III – IV (n = 75)

Months

Su

rviv

al (

%)

Early diagnosis of PAH and early intervention improves survival prospects

PAH progresses rapidly if left untreated... even in mildly symptomatic disease

Prognosis of Pulmonary Hypertension

Survival years

Early diagnosis is important, but is it easy ?

24%

63%

12%

1%0%

10%

20%

30%

40%

50%

60%

70%

80%

Class I Class II Class III Class IV

n = 674

Humbert M, et al. Am J Resp Crit Care Med 2006; 173: 1023–30

PAH is still often diagnosed late:French National Registry 2002–2003

Symptoms

– Symptoms may include:• Dyspnea ● Fatigue• Syncope ● Edema• Dizziness ● Chest Pain

– Non-specific nature of complaint can lead to:• Misdiagnosis • Delayed diagnosis ( It takes an average of 3 years from

first symptoms to diagnosis )

Why is missed?

Young patient with non specific symptom with “normal” CXR and EKG

Lack of practical therapy in the earlier era lead to therapeutic nihilism

Co-mobid condition have similar symptoms

Progressive Dyspnea Pedal edema Non-productive

Cough Fatigue Syncope Chest Pain

85%

30% 19% 13% 12% 7%

SuspectPAH: Clinical Presentation

Reason to suspect PAH

Unexplained dyspnea Typical symptom with signs “At risk“ condition CREST, liver disease, HIV, sickle cell Family history of PAH History of stimulant/anorexigen drug use

How to I know the patient really got PAH?

Diagnosis of PAH: a four-stage process

Galiè N et al Eur Heart J 2004; 25: 2243–2278

1. Suspicion of pulmonary

hypertension 2. Detection of pulmonary

hypertension

3. Pulmonary hypertension

class identification

4. Pulmonary arterial

hypertension evaluation

•Symptoms and physical examination

•Screening procedures

•Incidental findings

•Electrocardiogram

•Chest radiograph

•Transthoracic Dopplerechocardiography

•Pulmonary function tests and arterial blood gases

•Ventilation/perfusion lung scan

•High-resolution CT

•Spiral CT

•Pulmonary angiography

•Type (blood tests and immunology, HIV test, abdominal ultrasound)

•Exercise capacity (6MWD, peak oxygen consumption)

•Haemodynamics (right- heart catheterisation)

Case2006/03/11

21 y/o female Dyspnea and fatigue for about several

months Visited LMD for help but in vain Condition get worse and worse----

NCKUH ER

Physical examination BP: 150/80 mmHg, HR: 120 bpm, RR: 24/min, SaO2:

90% Lip: mild cyanotic change Jugular vein enlargement Breathing sound: clear Heart : tachycardia, fix split S2 , increased P2, systolic

murmur GrIV/VI over LLSB, RV heave (+) Extremities: warm, mild edema. ABG: PaO2: 52mmHg

Electrocardiography

Sinus tachycardia

RAD

RVH

CXR

Cardiomegaly C/T ratio: 0.59 Dilated pulmonary trunk

Echocardiography

Dilated RA,RV. RV hypertrophy Adequate LV performance. Moderate to severe TR with

Pul.HTN <systolic PAP= 140mmHg>

Pulmonary hypertension with right heart failure was suspected, R/O pulmonary embolism, R/O congenital heart disease, R/O primary pulmonary hypertension

Admitted to CCU for further care

Chest CT

Dilated pulmonary trunk and pulmonary artery

No evidence of pulmonary embolism

No evidence of lung disease

TEE: No congenital heart disease Autoimmune screen: Normal HIV: Negative Pregnancy test : Negative

Diagnosis

Primary pulmonary hypertension was impressed. (WHO FC IV)

How long do I have ? How can I do ?

Could you help me ?

How can your patient do ?

PAH Therapy: Life style considerations

Sodium restriction

Abstinence from smoking

Avoid high altitude

• <4,000 feet above sea level

Avoid physical exertion in setting of pre- or frank

syncope

Avoid pregnancy

Immunization for illnesses (Influenza and

pneumococcal vaccination)

Could we help patient ?

Goals of Therapy

Alleviate symptoms, improve exercise capacity and quality of life

Improve cardiopulmonary hemodynamics and prevent right heart failure

Delay time to clinical worsening Reduce morbidity and mortality

PAH: Traditional Therapy

Pharmacologic

– Calcium channel blocker

– Supplemental O2

– Anticoagulation (INR≈ 2-3)

– Diuretics (excessive preload)

– Digoxin

– IV inotropes (low dose dobutamine,

dopamine 1-2 mcg/kg/min)Rx for RV

failure}

Diuretics

Treat edema May need combine therapy

Anticoagulation

Studies only show benefit in iPAH patients Other PAH groups not as clear Aim for INR 2-2.5 Benefit thought to be Reduction of in-situ thrombosis Reduction DVT risk in low CO status

Oxygen

Formal assessment of nocturnal and exertion oxygen levels

Minimal added insult of hypoxic vasocontriction

Aim to keep oxygen saturation > 90% Often impossible in large right to left shunt

patients

Humbert M, et al. NEJM 2004; 351:1425-36.

FDA-Approved Agents for theTreatment of PAH

Prostacyclin analogs (PA)– Epoprostenol– Iloprost– Treprostinil

Endothelin-receptor antagonists (ERA)– Bosentan– Ambrisentan

Phosphodiesterase-5 inhibitors (PDE-I)– Sildenafil– Tadalafil

Endothelin Receptor Antagonist(ERA)

Endothelin is increased in IPAH and PAH associated with other Diseases

Stewart et al., Ann Inter Med,1991 Vancheeswaran et al., J. Rheum, 1994 Yoshibayashi et al., Circulation, 1991

Congenital Heart Disease

Non-PH PH0

1

2

3

4

5 P<0.001

Del

ta E

T-L

I (P

V-R

V)

(pg/

ml)

IPAH

IrE

T-1

(pg

/ml)

Non-PPH PPH0

2

4

6

8

10

Scleroderma

Con

cent

ratio

n of

ET

-1(p

g/m

l)

4

6

8

10

LcSSc PAH

LcSSc Non-PAH

P<0.05P<0.001

Endothelin is a Key Pathogenic Mediator*

Clozel. Ann Med. 2003

*Based on observations reported from in-vitro, in-vivo, or animal models. The clinical significance in humans is unknown.

Proliferation Vascular Smooth Muscle

Fibroblasts

Fibrosis Fibroblast Proliferation

Extracellular Matrix Proteins Collagenase Production

Inflammation Vascular Permeability

Neutrophil / Mast Cell Activation Promotes Cellular Adhesion

Cytokine Production

Hypertrophy Cardiac/Vascular

Vasoconstriction Direct Or Via Facilitation Of

Other Vasoconstrictor Systems (Renin

Angiotensin System, Sympathetic)ET

Bosentan for PAH

Endothelin receptor antagonist (ETA/ETB non selective)

Indication – WHO group I - functional class II, III, IV

Dosage – 62.5 mg oral twice daily for 4 weeks then 125 mg oral twice daily

62.5 mg bid 125 or 250 mg bid Bosentan

-40

-20

0

20

40

60

80

Bosentan (N = 144)

Placebo (N = 69)

Baseline Week 4 Week 8 Week 16

P = 0.0002

Cha

nge

from

Bas

elin

e (m

eter

s)

Rubin, et al. N Engl J Med. 2002;346:896-903.

Bosentan for PAH:BREATHE Clinical Trial

Change in 6-MWD (from Baseline to Week 16)

Long-term outcomes on bosentan

Event rate/year (exponential): 5.5%

0 6 12 18 24 30 36 Time (Months ）

169 167 163 153 113 23 16 Patients at risk

0

10

20

30

40

50

60

70

80

90

100

Cu

mu

lati

ve S

urv

ival

(%

)

Predicted (NIH)

Bosentan

69%57%

48%

96% 89% 86%

McLaughlin VV et al. Eur Respir J. 2005;25:244-249.

85% and 70% were on bosentan monotherapy at 12 and 24 mos, respectively

Bosentan for PAH:EARLY Clinical Trial

Study design– Randomized, double-blind, placebo-controlled, six-month study

Patients– N = 177– Mildly-symptomatic PAH (WHO group II)

Study results– Primary study endpoints

• Decreased PVR (P < 0.0001)• No significant change in 6-MWD (P = 0.076)

– Secondary study endpoints• Delayed time to clinical worsening (P = 0.018; 70% reduction in risk)

– Safety• Consistent with previous studies

Galie, et al. Lancet. 2008.371(9630):2093-100.Valerio et al. Vasc Health Risk Manag. 2009;5:607-19.


Change in PVR (from Baseline to Week 24)


% o

f B

asel

ine

PV

R a

t W

eek

24(g

eom

etric

me

ans)

P < 0.0001

Decrease in PVR:Surrogate marker for

delaying disease progression

Treatment effect =- 22.6%

Treatment effect =- 22.6%


10

5

0

5

10

15

20

12 24 weeks

Placebo (N= 91)

Bosentan (N= 86)P = 0.076

25

20

15


Treatment effect =+ 19.1 meters

Treatment effect =+ 19.1 meters

Cha

nge

in 6

-MW

D (

met

ers)


11.2

- 7.9

weeks


100

80

60

40

20

00 4 8 12 16 20 2824 32

92 90 89 86 84 83 1877 993 92 87 85 84 83 2780 15

Eve

nt-

Fre

e P

atie

nts

(%

)

Patients at risk (N)

Placebo

Bosentan

P < 0.02

Time to Clinical Worsening (from Baseline to Week 32)

weeksweeks


NTUH data

Bosentan have benefit effects on functional status, exercise capacity, right heart function and pulmonary function.

Respiratory Medicine 2007

Ambrisentan for PAH

Endothelin receptor antagonist (ETA selective)

Indication – WHO group I - functional class II, III

Dosage – 5 mg and 10 mg oral daily

Ambrisentan for PAH

Galie, et al. Circulation. 2008;117:3010-9.

-25

0

25

50

4 8 12 weeks

10 mg:+43.6 m

5 mg:+22.8 m

Placebo:-7.8 m

N = 202

4 8 12 weeks

5 mg:+49.4 m

2.5 mg+22.2 m

Placebo:-10.1 m

-20

0

20

40

60N = 192

Cha

nge

from

Bas

elin

e (m

eter

s)

ARIES 1 ARIES 2

Placebo-adjusted change at week 12:Ambrisentan 5 mg = 31 m; 10 mg = 51 m

Placebo-adjusted change at week 12:Ambrisentan 2.5 mg = 32 m; 5 mg = 59 m


Endothelin Receptor AntagonistsComparison of Agents

Source: FDA-approved product labeling for individual agents. Source: FDA-approved product labeling for individual agents.

Bosentan Ambrisentan

Use in pregnancy

Pregnancy category X (non-hormonal birth control method required)

Pregnancy category X (non-hormonal birth control method required)

LFT elevation Monthly LFT monitoring required; ≥ 3x ULN in ~ 11% patients (pooled data from 16-week studies)

≥ 3x ULN in 0.8% patients in 12-week studies, 2.8% patients in 1-year studies

Peripheral edema

1.7% patients (placebo-adjusted; fluid retention/edema)

6% patients (placebo-adjusted)

Additional adverse events

Respiratory tract infections, headache, fainting, flushing, low blood pressure, sinusitis, joint pain, irregular heartbeat

Nasal congestion, sinusitis, flushing, palpitations, nasopharyngitis, abdominal pain, constipation

Endothelin Receptor AntagonistsComparison of Drug-Drug Interactions

Source: FDA-approved product labeling for individual agents. 1) Barst, et al. J Am Coll Cardiol. 2009;54:S78-84. 2) Galie, et al. Eur Heart J. 2009;30:2493-2537. 3) Spence, et al. ATS. San Diego, CA.

May 15-20, 2009. 4) Harrison, et al. ATS. San Diego, CA. May 15-20, 2009.

Source: FDA-approved product labeling for individual agents. 1) Barst, et al. J Am Coll Cardiol. 2009;54:S78-84. 2) Galie, et al. Eur Heart J. 2009;30:2493-2537. 3) Spence, et al. ATS. San Diego, CA.

May 15-20, 2009. 4) Harrison, et al. ATS. San Diego, CA. May 15-20, 2009.

Bosentan Ambrisentan

Ritonavir

Rifampin

Cyclosporine A

Hormonal contraceptives

Sildenafil

Tadalafil1

Glyburide

Simvastatin (+ other CYP3A-metabolized statins)

CYP2C9 inhibitors (fluconazole, amiodarone)

CYP3A inhibitors (ketoconazole, itraconazole, amprenavir, erythromycin, fluconazole, diltiazem)

Tacrolimus

Phenytoin2

Warfarin2

Ritonavir

Rifampin

Cyclosporine A

Hormonal contraceptives3

Omeprazole4

Ketoconazole2,4

Phosphodiesterase-5 inhibitors (PDE5-I)

Sildenafil (Viagra, Revatio)

HypertensionHypertension

19819855 AnginaAngina

19891989

EEDD

19921992 19981998

PAHPAH

L-Arginine Nitricoxide

cGMP Lowers PA

pressure

eNOS

GMP

PDE-5PDE-5I

PDE-5 located in pulmonary circulation PDE-5 responsible for cGMP hydrolysis in the lung cGMP appears to regulate pulmonary vascular tone and

growth PDE-5 inhibitor raises cGMP levels

Wharton J et al. Am J Respir Crit Care Med. 2005;172:105-113.

Nitric Oxide/ PDE-5 Inhibitors Increase cGMP

SUPER-1 study

REV-EM-0807001

Phosphodiesterase-5 InhibitorsComparison of Drug-Drug Interactions

Sildenafil TadalafilNitrates

Alpha blockers

Amlodipine

Ritonavir

Bosentan1

HMG CoA reductase inhibitors1

Phenytoin1

Erythromycin1

Ketoconazole1

Cimetidine1

Rifampin1

Phenobarbital1

Carbamazepine1

Nitrates

Alpha blockers

Antihypertensive agents

Ketoconazole

Rifampin

Ritonavir

Bosentan1

Source: FDA-approved product labeling for individual agents. 1) Galie, et al. Eur Heart J. 2009;30:2493-2537.Source: FDA-approved product labeling for individual agents. 1) Galie, et al. Eur Heart J. 2009;30:2493-2537.

PROSTENOIDS

SMC IP

PGI2PGI2

Smooth Muscle Cell relaxation

Inhibits SMC proliferation

? Apoptosis

Anti-thrombotic

GSGS

Adenylate cyclaseAdenylate cyclasecATPcATP

cAMPcAMP

Prostacyclins

Inhalational Iloprost (Ventavis®) Approved for WHO Class III, IV patients with PAH

Properties: Selective pulmonary vasodilator Vasodilatory potency similar to PGI2 Exerts preferential vasodilation in well- ventilated lung

regions Longer duration of vasodilation than PGI2 (30-90 vs 15

min)

Prostenoid Analogue

Ventavis® (iloprost) Inhalation Solution:

Dosage and Administration Indicated for inhalation via the Prodose® AAD® system only 2.5 mcg initial dose

– increase to 5 mcg if 2.5 mcg dose is tolerated

– maintain at maximum tolerable dose (2.5 mcg or 5 mcg) 6-9 inhalations daily during waking hours; 8-10 minutes each

Iloprost for PAHComposite Primary Endpoint at Week 12

Olschewski, et al. N Engl J Med. 2002;347:322-9.

Res

pond

ers

(% P

atie

nts)

P = 0.0033

N = 203

FLOLAN ® (epoprostenol): Synthetic prostenoid

Sodium epoprostenol (Flolan)--short-lived relatively locally acting vasodilator, t1/2 3-5 minutes.

Most potent effect -- cardiac output in patients with PAH

Resting heart rate, mean right atrial pressure, and a marked improvement in survival.

Abrupt cessation can be fatal Contraindicated in veno-occlusive disease

CADD pump Central line

Epoprostenol for PAH

Prostacyclin analog Indication – WHO group I

- functional class III, IV Administration –

continuous IV infusion via central venous catheter

Dosage – 20-40 ng/kg/min

Storage – must keep medication cold with ice packs (stable for 8 hours at room temp)

100

80

60

40

20

0Weeks

Epoprostenol (N = 41)

0 2 4 6 8 1210

Conventional therapy (N = 40)

Pat

ient

Sur

viva

l (%

)

P = 0.003P = 0.003

Barst, et al. N Engl J Med. 1996;334:296-301.

Epoprostenol vs. Conventional Therapy for IPAHPatient Survival

Subcutaneous Treprostinil(Remodulin )

•SQ administration•Longer half-life than epoprostenol•Pre-mixed•Stable at room temperature

Treprostinil SC for PAH


0

5

10

15

20

25

30

35

40

< 5.0ng/kg/min

5.0 - 8.1ng/kg/min

8.2 – 13.8ng/kg/min

> 13.8 ng/kg/min

3.31.4

20

36.1

Cha

nge

from

Bas

elin

e (m

eter

s)

P = 0.03

Simonneau, et al. Am J Respir Crit Care Med. 2002;165:800-4.

Administration of Treprostinil

Subcutaneous Administration Continuous infusion using ambulatory

pump designed for SC infusions Self-inserted SC catheter Store at room temperature Change medication every 48 hours

(half-life > 4 hours)

Limitations Requires capable patient Possible pain (~ 85% of patients),

erythema, and induration at infusion site Mixed results with treatments for pain

(ice or heat, capsaicin, lidocaine patches, collagenase, NSAIDs, gabapentin, pregabalin, transdermal gels, low-dose narcotics)

Mini-Med

CADDms3

Infusion site reaction

Which treatment is better ?

Comparison of Agents

AgentRoute of

Administration Adverse Events

Epoprostenol Continuous IV infusion

Headache, jaw pain, flushing, nausea, diarrhea, skin rash, musculoskeletal pain

Iloprost Inhalation Headache, cough, flushing, jaw pain

Treprostinil » Subcutaneous

» IV

» Inhalation*

» Pain and erythema at injection site, headache, nausea, diarrhea, rash

» Headache, jaw pain, flushing, nausea, diarrhea, skin rash, musculoskeletal pain

» Cough, headache, flushing, throat irritation, nausea

Bosentan Oral Hepatotoxicity (LFT elevation ≥ 3x ULN ~ 11%), peripheral edema, anemia

Ambrisentan Oral Hepatotoxicity (LFT elevation ≥ 3x ULN ~ 2.8%), peripheral edema

Sildenafil Oral Headache, flushing, dyspepsia, epistaxis

Tadalafil Oral Headache, dyspepsia, back pain, myalgia, flushing

Adapted from McLaughlin, et al. J Am Coll Cardiol. 2009;53:1573-1619. *Benza, et al. ATS. San Diego, CA. May 15-20, 2009.

Adapted from McLaughlin, et al. J Am Coll Cardiol. 2009;53:1573-1619. *Benza, et al. ATS. San Diego, CA. May 15-20, 2009.

ESC guidelines for PAH , Eur Heart J 2009;30: 2498-2537

How do I evaluate the efficacy ?

Parameters using in evaluation for treatment efficacy

• 6 minute-walking distance (MWD)• Cardiopulmonary exercising testing

– Peak oxygen uptake (V’O2)

• Hemodynamics– Cardiac index– Right atrial pressure

• Biomarkers– B-type natriuretic peptide (BNP)– N-terminal pro-BNP

2006/04/10

Bosentan 62.5mg bid Symptom improved post 2 dose Keep treatment and F/U liver function one month later

(GOT/GPT: 48/55) Bosentan 125 mg bid 1 month later

2007/03/21

Dilated RA,RV. RV hypertrophy Adequate LV performance. Moderate TR with

Pul.HTN<systolic PAP= 81mmHg>

Dilated PA with PR.

2009

Function Class: IV -> I BNP: 52.9 pg/ml Radionuclide ventriculography :Right ventricular

Ejection Fraction: 72 % (normal range 45~70%)

CXR

C/T ratio: 53 %

But……….

The patient suffered from progressive dyspnea since 2010/06

Syncope (+) Screening cardiac echo

– Estimated PAP > 200 mmHg

Admitted to ICU on 2010/07/02

Critical PAH Patient

Cardiac arrest occurs frequently in critically ill patients with severe PAH.

Survival 90 days post-cardiac arrest was only 6 percent.

PH and RV Failure: The Downward Spiral

Adaptation of Price lC et al. Crit Care. 2010;14:R169

HYPOTENSION

RVEDP

Management Principles

Optimal volume status: avoid filling if RV volume overload, diuretics if necessary

Augment CO

Reduce PVR :

a) use pulmonary vasodilators

b)treat reversible factors that may increase PVR

Maintain adequate systemic pressure: Keep PVR well below SVR; use pressors if necessary

Course of hospitalization

• ICU– Milrinone infusion– Diuretics for symptom– Bosentan 125mg bid po– Iloprost 5 mg q4h inhalation– Sildenafil 25mg tid po

• Symptom improved gradually• Shift iloprost to prn use• Discharge on 2010/07/13

– Bosentan 125mg bid + Sildenafil 25 mg tid + iloprost 5mg inhalation prn

Mechanical Devices

Devices indication CommentsRV-assist devices Used in primary RV

dysfunction and have been used with coexisting

PH

Pulsatile devices may cause pulmonary

microcirculatory damage in PH . A pumpless "lung assist" device has been used in patients bridging

to transplant.

Extracorporeal membrane oxygenation

Used in severe PH as a bridge to lung transplant and after endarterectomy

or massive PE.

Intraaortic balloon counterpulsation

Used for RV failure after CPB and transplantation

Improves CO by augmenting left coronary flow rather than by direct

RV effects

Adaptation of Price lC et al. Crit Care. 2010;14:R169

Case

55 y/o male Progressive dyspnea, leg edema and

hypotension Pulmonary hypertension was noted Transfer to CCU under the impression of

PAH with right heart failure complicated with shock and multiple organ failure

Case 2se

11/21

Levophd

Primacor

11/25

illoprast

11/27

ECMO

CVVHD

11/30

Revatio

12/07

Remove ECMO

12/12

Stop CVVHD

1/25

Discharge

BP:89/65

sPA:90

BNP:721

Urine:1600

BP:56/46

sPA:90

Urine:115

BP:97/55 BP:127/73

Crea:1.21

ALT:33

Urine:345

BP:122/65

sPA:55

BNP:183

Crea:0.96

Urine:2935

BP:110/70

BNP:152

Crea:0.5

Urine:2060

Diagnosis of PAH vasoreactivity test negative

Baseline exam and 3-6 monthly re-evaluation to assess treatment goals(Clinically stable, functional class II, 6-MWD > 400 meters, RAP/CI normal)

Treatment goals NOT met Treatment goals met

Start ERA or PDE-I

Add ERA or PDE-I

Parenteral PA and/or enrollment in clinical trials

Urgent lung transplantation

Continue treatment

Continue treatment

Continue treatment

Goal-Directed Therapy

Adapted from: Hoeper, et al. Eur Respir J. 2005;26:858-63.

Improved Patient Survival With Goal-Directed Therapy

Hoeper, et al. Eur Respir J. 2005;26:858-63.

Cum

ulat

ive

Pat

ient

Sur

viva

l

1.0

0.8

0.6

0.4

0.2

0 6 12 18 24 30 36 Months

Patients at risk (N)

Treatment group

Historical control group

Treatment group(2002 -2004)

Historical control group(1999 -2001)

Expected survival

89

67

83

64

69

47

61

38

46

31

43

23

37

20

P = 0.011 Treatment Vs. historicalP < 0.001 Treatment Vs. expected

Combination therapy: frequently utilised strategy in PAH treatment

Monotherapy (47%):• 13% bosentan\ambrisenten• 13% sildenafil• 8% epoprostenol• 2% sitaxentan• 4% calcium channel blocker

Dual combination (36%):

Background therapy only (8%)

Triple combination (9%)

McGoon, et al. Chest 2007; 132: 631S

Patients with PAH

n=1226

Bosentan + Sildenafil

Patients Dosing Results P

Mathai et al. 45 B 125 mg bid + S 20-100mg tid

6 MWD + 46 m NYHA improved in 5 of 13

0.05NS

Hoper et al. 9 B 125 mg bid +S 25-50mg tid

6MWD +115 mVO2 max +3.4 ml/min/kg

<0.0070.006

European 4996 Bosentan vs bosentan+sildenafil

Safety reports were similar

Early trial 29 S + B vs S + Placebo

Lower PVR 20.4%6MWD +17M

<0.05

0.855

Bosentan + Prostacyclin

Combination Patients Result p

Hoper et al Bosentan+iloprost/beraprost

20 6 MWD +45 M <0.05

Channick et al.

Bosentan+treprostinil ih

11 6MWD +67MPAP-10%PVR-26%

0.010.0410.052

Benza RL et al.

SC remodulin + Bosentan

19 6 MWDBrog dyspneaPAP

0.0010.02<0.001

BREATH-2 Bosentan + Epo

33 PVR: 36 % vs 23 %

NS

STEP Bosentan+ iloprost

67 6MWDDelayed TCW

0.0510.022

Prostacyclin+ PDE inhibitors

Combination Patients Result p

Ghofrani et al Iloprost+sildenafil

14 6 MWD +90 M 0.002

Goberg-Matiland M et al.

Treprostinil sc + sildenafil

TET time +42%

0.049

Ruiz MJ et al. Prostanoids+ sildenafil

20 6 MWD+79m (1 year)MWD +105m (2years)NYHA improved

<0.005

Simonneau G et al.

Epo+sildenafil

267 6MWD+26M TCW delay

0.00880.012

CASE 3

38 y/o maleIPAH was diagnosed at 2008/8Bosentan used since

2008/8/19Add Iloprost since 2010/4/16

6 minute walk test 6 minute walk test

2008/08/19 Bosentan375m 378m

350m

2010/4/16 Iloprost

320m

270m

2011 RA ： 18 RV ： 52/24 PA ： 54/46/39 PCWP ： 9 Cardiac output:

2.46 L/min PVR ： 15

woods

2008 RA:22 RV:55/32 PA:60/56/53 PCW: 15 Cardiac output:

6.7 L/min PVR: 6.1 woods

Application Remodulin (2011/10/8) Discuss with patient about lung

transplant evaluation

Remodulin daily recordRemodulin daily record

DoseBlood pressure

Site pain

Jaw pain

DiarreaHeadache

BNP NT-pro BNP

Day 1 2ng/kg/min 108/66 0 - - - 320 1890

Day 2 4ng/kg/min 108/64 2 - - -

Day 3 6ng/kg/min 97/58 3-4 - - - 256 1124

Day 4 8ng/kg/min 104/59 5 - - -

Day 5 10ng/kg/min 107/67 5 - - -

Day 6 12ng/kg/min 99/57 5-7 - - -

Day 7 14ng/kg/min 93/57 6 - - - 197 1214

Day 8 16ng/kg/min 94/63 6 - - -

Day 9 16ng/kg/min 89/54 6 - - -

Day 10 16ng/kg/min 97/56 6 - - -

Day 11 16ng/kg/min 94/58 6-8 - - -

Day 12 16ng/kg/min 95/59 6 - - - 191

Day 13 16ng/kg/min 94/59 2-3 mild - -

Day 14 16ng/kg/min 96/80 5 mild - -

3 month later

NYHA Fc III =>II 6 minute walk distance: 347 m ( increase

28.5 %)

Surgical Therapy

Transplantation - lung / heart-lung

• Reserved for patients who continue to

deteriorate with poor QOL despite

aggressive pharmacologic therapy

• 1 year survival - 65-70%

• 5 year survival - 40-50%

Team work is necessary !!

NCKUH Team Members

PAH- specific Cardiologist (PAH clinic, 24 hr on call)

Special nurse (24 hr on call) Radiologist Pharmacist Dietician Critical care team (24 hr on call) ECMO team (24 hr on call) Lung transplant team Lab

Core member training

Whole member training

Multiple centereducation program

How about the next five

year ?

Investigational Treatments for PAH

Targeted Mechanism Investigational Agents

Prostacyclin Pathway

Iloprost

Treprostinil

Beraprost

Selexipeg

Endothelin Pathway Macisentan

Nitric Oxide Pathway Riociguat

Cicletanine

Growth Factors Signaling

Imatinib

Sorafenib

Aviptadil (Vasoactive intestinal peptide)

Cell Therapy Progenitor cells combined with gene

therapy

Future Directions in PAH:Potential New Therapeutic Targets

Tyrosine kinase/growth factor receptor inhibitors (imatinib,sorafenib, nilotinib)

Vasoactive intestinal peptide (VIP) (aviptadil) Serotonin transporter agonists Tissue-targeting ERA (macitentan) Non-prostanoid IP receptor antagonist (selexipag) Adrenomedullin Rho-kinase inhibitors Nitric oxide enhancement (cicletanine) Soluble guanylate cyclase stimulator (riociguat) ECE/NEP inhibitor (daglutril) Monoclonal antibody to CD20 (rituximab) Endothelial progenitor cells Gene therapy (vectors expressing prostacyclin synthase, endothelial

NOS, or vascular endothelial growth factor )

A cure for PAH ---is only a matter of time

肺高壓的診斷與治療 國立成功大學附設醫院 許志新 醫師 2012/05/26, tainan. what...

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