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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 ?

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Presentation on theme: "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 ?"— Presentation transcript:

1 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

2 What is PH ? What is PAH ?

3 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

4 1. Pulmonary arterial hypertension 1.1Idiopathic PAH 1.2 Heritable 1.3 Drugs and toxin related 1.4 Associated with (APAH) Connective tissue diseases HIV Portal hypertension Congenital heart diseases Schistosomiasis 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

5 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.

6 Definition of PAH by WHO  Mean PAP > 25mmHg at rest  PAWP < 15 mmHg

7 What do we face ?  Rare  Miss diagnosis  Rapid progress  Poor prognosis

8 Really rare ? Or Under diagnosis?

9 Prevalence of PAH

10 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 the USA, EU, Canada and Japan. - US 50,000 to 100, ,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: Gomberg-Maitland M. Chest 2011;139:

11 Prevalence of PAH in Associated Conditions Associated ConditionPrevalence of PAH Systemic sclerosis7-12 % HIV infection % Portal hypertension2-6 % Congenital heart disease per million in those with congenital systemic-to-pulmonary shunts → % affected by Eisenmenger syndrome Schistosomiasis4.6 % in those with hepatosplenic disease Chronic hemolytic anemiaHighly variable; currently being studied Simonneau, et al. J Am Coll Cardiol. 2009;54(1):S43-54.

12 NORMAL REVERSIBLE DISEASE IRREVERSIBLE DISEASE Pathogenesis of Pulmonary Arterial Hypertension

13 PAH: Pathophysiology Pulmonary vessel remodeling Pulmonary vascular resistance increase RV remodeling RV dysfunction

14 Do we have a luxury time ?

15 I Preclinical / no symptoms II Symptomatic / stable III Progression / declining Pulm. pressure Cardiac output Level Time Years Months Therapeutic window PAH: a rapidly evolving disease RV function

16 Severity of Pulmonary Hypertension  Degree of disease –Mild –Moderate –Severe  Mean PAP (mmHg) – – –>55

17 NYHA/WHO classification of functional status ClassDescription I Patients 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 II Patients 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 III Patients 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 ; 43 (12 Suppl S): 40S–47S

18 Brenot F. Chest 1994; 105: 33S–36S WHO class I – II (n = 30) WHO class III – IV (n = 75) Months Survival (%) Early diagnosis of PAH and early intervention improves survival prospects PAH progresses rapidly if left untreated... even in mildly symptomatic disease

19 Prognosis of Pulmonary Hypertension Survival years

20 Early diagnosis is important, but is it easy ?

21 24% 63% 12% 1% 0% 10% 20% 30% 40% 50% 60% 70% 80% Class IClass IIClass IIIClass 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

22 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 )

23 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

24  Progressive Dyspnea  Pedal edema  Non-productive Cough  Fatigue  Syncope  Chest Pain  85%  30%  19%  13%  12%  7% Suspect PAH: Clinical Presentation

25 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

26 How to I know the patient really got PAH?

27 Diagnosis of PAH: a four-stage process Galiè N et al Eur Heart J 2004; 25: 2243– 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 Doppler echocardiography 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 )

28 Case 2006/03/11  21 y/o female  Dyspnea and fatigue for about several months  Visited LMD for help but in vain  Condition get worse and worse----

29 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

30 Electrocardiography Sinus tachycardia RAD RVH

31 CXR  Cardiomegaly  C/T ratio: 0.59  Dilated pulmonary trunk

32 Echocardiography  Dilated RA,RV.  RV hypertrophy  Adequate LV performance.  Moderate to severe TR with Pul.HTN

33  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

34 Chest CT  Dilated pulmonary trunk and pulmonary artery  No evidence of pulmonary embolism  No evidence of lung disease

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

36 Diagnosis  Primary pulmonary hypertension was impressed. (WHO FC IV)

37 How long do I have ? How can I do ? Could you help me ?

38 How can your patient do ?

39 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)

40

41 Could we help patient ?

42 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

43 PAH: Traditional Therapy  Pharmacologic –Calcium channel blocker –Supplemental O 2 –Anticoagulation (INR≈ 2-3) –Diuretics (  excessive preload) –Digoxin –IV inotropes (low dose dobutamine, dopamine 1-2 mcg/kg/min ) Rx for RV failure }

44 Diuretics  Treat edema  May need combine therapy

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

46 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

47 Humbert M, et al. NEJM 2004; 351:

48 FDA-Approved Agents for the Treatment of PAH  Prostacyclin analogs (PA) –Epoprostenol –Iloprost –Treprostinil  Endothelin-receptor antagonists (ERA) –Bosentan –Ambrisentan  Phosphodiesterase-5 inhibitors (PDE-I) –Sildenafil –Tadalafil

49 Endothelin Receptor Antagonist (ERA)

50 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-PHPH P<0.001 Delta ET-LI (PV-RV) (pg/ml) IPAH IrET-1 (pg/ml) Non-PPHPPH Scleroderma Concentration of ET-1(pg/ml) LcSSc PAH LcSSc Non-PAH P<0.05 P<0.001

51 Endothelin is a Key Pathogenic Mediator* Clozel. Ann Med * 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

52 Bosentan for PAH  Endothelin receptor antagonist (ET A /ET B 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

53 62.5 mg bid 125 or 250 mg bid Bosentan Bosentan (N = 144) Placebo (N = 69) BaselineWeek 4Week 8Week 16 P = Change from Baseline (meters) Rubin, et al. N Engl J Med. 2002;346: Bosentan for PAH: BREATHE Clinical Trial Change in 6-MWD (from Baseline to Week 16)

54 Long-term outcomes on bosentan Event rate/year (exponential): 5.5% Time (Months ) Patients at risk Cumulative Survival (%) Predicted (NIH) Bosentan 69% 57% 48% 96% 89% 86% McLaughlin VV et al. Eur Respir J. 2005;25: % and 70% were on bosentan monotherapy at 12 and 24 mos, respectively

55 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 < ) 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 (9630): Valerio et al. Vasc Health Risk Manag. 2009;5:

56 Bosentan for PAH: EARLY Clinical Trial Change in PVR (from Baseline to Week 24) Galie, et al. Lancet (9630): Valerio et al. Vasc Health Risk Manag. 2009;5: % of Baseline PVR at Week 24 (geometric means) P < Decrease in PVR: Surrogate marker for delaying disease progression Treatment effect = %

57 Bosentan for PAH: EARLY Clinical Trial  10 5 weeks Placebo (N= 91) Bosentan (N= 86) P =  20 1515 Change in 6-MWD (from Baseline to Week 24) Treatment effect = meters Change in 6-MWD (meters) Galie, et al. Lancet (9630): Valerio et al. Vasc Health Risk Manag. 2009;5: weeks

58 Bosentan for PAH: EARLY Clinical Trial Event-Free Patients (%) Patients at risk (N) Placebo Bosentan P < 0.02 Time to Clinical Worsening (from Baseline to Week 32) weeks Galie, et al. Lancet (9630): Valerio et al. Vasc Health Risk Manag. 2009;5:

59 NTUH data  Bosentan have benefit effects on functional status, exercise capacity, right heart function and pulmonary function. Respiratory Medicine 2007

60 Ambrisentan for PAH  Endothelin receptor antagonist (ET A selective)  Indication – WHO group I - functional class II, III  Dosage – 5 mg and 10 mg oral daily

61 Ambrisentan for PAH Galie, et al. Circulation. 2008;117: weeks 10 mg: m 5 mg: m Placebo: -7.8 m N = weeks 5 mg: m 2.5 mg m Placebo: m N = 192 Change from Baseline (meters) 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 Change in 6-MWD (from Baseline to Week 12)

62 Endothelin Receptor Antagonists Comparison of Agents Source: FDA-approved product labeling for individual agents. BosentanAmbrisentan Use in pregnancy Pregnancy category X (non- hormonal birth control method required) LFT elevationMonthly 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

63 Endothelin Receptor Antagonists Comparison of Drug-Drug Interactions Source: FDA-approved product labeling for individual agents. 1) Barst, et al. J Am Coll Cardiol. 2009;54:S ) Galie, et al. Eur Heart J. 2009;30: ) Spence, et al. ATS. San Diego, CA. May 15-20, ) Harrison, et al. ATS. San Diego, CA. May 15-20, BosentanAmbrisentan Ritonavir Rifampin Cyclosporine A Hormonal contraceptives Sildenafil Tadalafil 1 Glyburide Simvastatin (+ other CYP3A-metabolized statins) CYP2C9 inhibitors (fluconazole, amiodarone) CYP3A inhibitors (ketoconazole, itraconazole, amprenavir, erythromycin, fluconazole, diltiazem) Tacrolimus Phenytoin 2 Warfarin 2 Ritonavir Rifampin Cyclosporine A Hormonal contraceptives 3 Omeprazole 4 Ketoconazole 2,4

64 Phosphodiesterase-5 inhibitors (PDE5-I)

65 Sildenafil (Viagra, Revatio) Hypertension 1985 Angina 1989 ED PAH

66 L-Arginine Nitric oxide cGMP Lowers PA pressure eNOS GMP PDE-5 PDE-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: Nitric Oxide/ PDE-5 Inhibitors Increase cGMP

67 SUPER-1 study

68 REV-EM

69

70 Phosphodiesterase-5 Inhibitors Comparison of Drug-Drug Interactions SildenafilTadalafil Nitrates Alpha blockers Amlodipine Ritonavir Bosentan 1 HMG CoA reductase inhibitors 1 Phenytoin 1 Erythromycin 1 Ketoconazole 1 Cimetidine 1 Rifampin 1 Phenobarbital 1 Carbamazepine 1 Nitrates Alpha blockers Antihypertensive agents Ketoconazole Rifampin Ritonavir Bosentan 1 Source: FDA-approved product labeling for individual agents. 1) Galie, et al. Eur Heart J. 2009;30:

71 PROSTENOIDS

72 SMC IP PGI2 Smooth Muscle Cell relaxation Inhibits SMC proliferation ? Apoptosis Anti-thrombotic GS Adenylate cyclase cATP cAMP Prostacyclins

73 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 PGI 2 (30-90 vs 15 min) Prostenoid Analogue

74 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

75 Iloprost for PAH Composite Primary Endpoint at Week 12 Olschewski, et al. N Engl J Med. 2002;347: Responders (% Patients) P = N = 203

76 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

77 CADD pumpCentral line Epoprostenol for PAH  Prostacyclin analog  Indication – WHO group I - functional class III, IV  Administration – continuous IV infusion via central venous catheter  Dosage – ng/kg/min  Storage – must keep medication cold with ice packs (stable for 8 hours at room temp)

78 Weeks Epoprostenol (N = 41) Conventional therapy (N = 40) Patient Survival (%) P = Barst, et al. N Engl J Med. 1996;334: Epoprostenol vs. Conventional Therapy for IPAH Patient Survival

79 Subcutaneous Treprostinil (Remodulin  ) SQ administration Longer half-life than epoprostenol Pre-mixed Stable at room temperature

80 Treprostinil SC for PAH Change in 6-MWD (from Baseline to Week 12 ) < 5.0 ng/kg/min ng/kg/min 8.2 – 13.8 ng/kg/min > 13.8 ng/kg/min Change from Baseline (meters) P = 0.03 Simonneau, et al. Am J Respir Crit Care Med. 2002;165:800-4.

81 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

82 Which treatment is better ?

83 Comparison of Agents Agent Route of AdministrationAdverse Events EpoprostenolContinuous IV infusion Headache, jaw pain, flushing, nausea, diarrhea, skin rash, musculoskeletal pain IloprostInhalationHeadache, 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 BosentanOralHepatotoxicity (LFT elevation ≥ 3x ULN ~ 11%), peripheral edema, anemia AmbrisentanOralHepatotoxicity (LFT elevation ≥ 3x ULN ~ 2.8%), peripheral edema SildenafilOralHeadache, flushing, dyspepsia, epistaxis TadalafilOralHeadache, dyspepsia, back pain, myalgia, flushing Adapted from McLaughlin, et al. J Am Coll Cardiol. 2009;53: *Benza, et al. ATS. San Diego, CA. May 15-20, 2009.

84 ESC guidelines for PAH, Eur Heart J 2009;30:

85 How do I evaluate the efficacy ?

86 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

87 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

88 2007/03/21  Dilated RA,RV.  RV hypertrophy  Adequate LV performance.  Moderate TR with Pul.HTN  Dilated PA with PR.

89 2009  Function Class: IV -> I  BNP: 52.9 pg/ml  Radionuclide ventriculography :Right ventricular Ejection Fraction: 72 % (normal range 45~70%)

90 CXR  C/T ratio: 53 %

91

92 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

93 Critical PAH Patient  Cardiac arrest occurs frequently in critically ill patients with severe PAH.  Survival 90 days post-cardiac arrest was only 6 percent.

94 PH and RV Failure: The Downward Spiral Adaptation of Price lC et al. Crit Care. 2010;14:R169 HYPOTENSION RVEDP

95 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

96 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

97 Mechanical Devices DevicesindicationComments RV-assist devicesUsed 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

98 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

99 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:160 0 BP:56/46 sPA:90 Urine:115 BP:97/55BP: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

100 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 Goal-Directed Therapy Adapted from: Hoeper, et al. Eur Respir J. 2005;26:

101 Improved Patient Survival With Goal-Directed Therapy Hoeper, et al. Eur Respir J. 2005;26: Cumulative Patient Survival Months Patients at risk (N) Treatment group Historical control group Treatment group ( ) Historical control group ( ) Expected survival P = Treatment Vs. historical P < Treatment Vs. expected

102 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

103 NCKUH

104 Bosentan + Sildenafil PatientsDosingResultsP Mathai et al.45B 125 mg bid + S mg tid 6 MWD + 46 m NYHA improved in 5 of NS Hoper et al.9B 125 mg bid +S 25-50mg tid 6MWD +115 m VO2 max +3.4 ml/min/kg < European4996Bosentan vs bosentan+sild enafil Safety reports were similar Early trial29S + B vs S + Placebo Lower PVR 20.4% 6MWD +17M <

105 Bosentan + Prostacyclin CombinationPatientsResultp Hoper et alBosentan+ilo prost/berapro st 206 MWD +45 M<0.05 Channick et al. Bosentan+tre prostinil ih 116MWD +67M PAP-10% PVR-26% Benza RL et al. SC remodulin + Bosentan 196 MWD Brog dyspnea PAP <0.001 BREATH-2Bosentan + Epo 33PVR: 36 % vs 23 % NS STEPBosentan+ iloprost 676MWD Delayed TCW

106 Prostacyclin+ PDE inhibitors CombinationPatientsResultp Ghofrani et alIloprost+silde nafil 146 MWD +90 M0.002 Goberg- Matiland M et al. Treprostinil sc + sildenafil TET time +42% Ruiz MJ et al.Prostanoids+ sildenafil 206 MWD+79m (1 year) MWD +105m (2years) NYHA improved <0.005 Simonneau G et al. Epo+sildenafi l 2676MWD+26M TCW delay

107 CASE 3  38 y/o male  IPAH was diagnosed at 2008/8  Bosentan used since 2008/8/19  Add Iloprost since 2010/4/16

108 6 minute walk test 2008/08/19 Bosentan 375m 378m 350m 2010/4/16 Iloprost 320m 270m

109  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

110  Application Remodulin (2011/10/8)  Discuss with patient about lung transplant evaluation

111 Remodulin daily record Dose Blood pressur e Site pain Jaw pain Diarrea Heada che BNPNT-pro BNP Day 1 2ng/kg/min 108/ Day 2 4ng/kg/min 108/ Day 3 6ng/kg/min 97/ Day 4 8ng/kg/min 104/ Day 5 10ng/kg/min 107/ Day 6 12ng/kg/min 99/ Day 7 14ng/kg/min 93/ Day 8 16ng/kg/min 94/ Day 9 16ng/kg/min 89/ Day 10 16ng/kg/min 97/ Day 11 16ng/kg/min 94/ Day 12 16ng/kg/min 95/ Day 13 16ng/kg/min 94/592-3mild-- Day 14 16ng/kg/min 96/805mild--

112 3 month later  NYHA Fc III =>II  6 minute walk distance: 347 m ( increase 28.5 %)

113 Surgical Therapy  Transplantation - lung / heart-lung Reserved for patients who continue to deteriorate with poor QOL despite aggressive pharmacologic therapy 1 year survival % 5 year survival %

114 Team work is necessary !!

115 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

116 Core member training Whole member training Multiple center education program

117 How about the next five year ?

118 Investigational Treatments for PAH Targeted MechanismInvestigational Agents Prostacyclin Pathway Iloprost Treprostinil Beraprost Selexipeg Endothelin PathwayMacisentan Nitric Oxide Pathway Riociguat Cicletanine Growth Factors Signaling Imatinib Sorafenib Aviptadil (Vasoactive intestinal peptide) Cell Therapy Progenitor cells combined with gene therapy

119 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 )

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


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