Treatment of ILD and Pulmonary Hypertension

Levent Tabak, M.D.

Istanbul Medical Faculty

DEFINITION• Mean pulmonary artery pressure ~14 mmHg)• Pulmonary hypertension;

– During resting > 25 mm Hg

– During exercise > 30 mm Hg

Pulmonary Hypertension(PH)

PH severity

Mild 26 - 35 mmHg Moderate 36 - 45 mmHg Severe > 45 mmHg

PULMONARY HYPERTENSIONVenice 2003

1.Pulmonary arterial hypertension1.Idıopathic

2.Familial 3.Secondarya)Collagen vascular diseaseb)Congenital systemic to pulmonary shuntc)Portal hypertensiond)HIV infectione)Drugs and toxinsf) Other(Thyroid, glycogen storage disease

splenectomy, nyeloproliferative disor) 4.Venous or capillary involvementa)Pulmonary veno-oclusive diseaseb)Pulmonary capillary hemangiomatozis2. Pulmonary venous hypertension 1.Left sided atrial/ventricular heart dise 2.Left sided valvular heart disease

3.PH associated with hypoxemia 1. COPD 2. Interstitial lung diseases 3. Sleep disorders 4. Alveolar hypoventilation 5. High altitude 6. Developmental abnormalities4.PH due to chronic thrombotic/embolic disease 1.Obstruction of proximal pulmonary arteries 2.Obstruction of distal pulmonary arteries 3.Non-thrombotic pulmonary embolism5.Miscellaneous a)Sarcoidosis b)Histiocytosis XSarkoidoz c)Lymphangiomatosis d)Compression of pulmonary vessels

• Fatique

• Dyspnea

• Chest pain

• Syncop

• Hemoptysis The interval between disease onset and symptoms

is around 3 years

Clinics

Diagnosis of PH

PH Detection Chest Radiography ECGTT Echocardiography

PH Class Identification Pulmonary Function TestV/Q scanHRCTSpiral CTPulmonary Angiography

PAH evaluation Blood Tests&ImmunologyHIV testAbdominal USG6 min Walk Test, Max VO2Right Heart

Cath+Vasoreactivity

• May helpfull only in 30-40% of patients!• Dilated central pulmonary arteries• Reduced peripheral vascularization (Tree in bud)

Chest X-ray

• Right atrial dilatation• Right ventricular hypertrophy• RBBB (55% sensitivity, 70% specifity)

ECG

Best non-invasive diagnostic test.

• Right ventricular and atrial

dilation

• Tricuspid/pulmonary valve

regurgitation• Non-invasive measurement of

pulmonary arterial pressure

ECHOCARDIOGRAPHY

Diagnosis of PH

PH Detection Chest Radiography ECGTT Echocardiography

PH Class Identification Pulmonary Function TestV/Q scanHRCTSpiral CTPulmonary Angiography

PAH evaluation Blood Tests&ImmunologyHIV testAbdominal USG6 min Walk Test, Max VO2Right Heart

Cath+Vasoreactivity

Pulmonary Function tests & Blood Gases

• PAH patients usually have mild to moderate reduced lung volumes and decreased DLCO

• PaO2 is normal or slightly low and PaCO2 is decreased due to alveolar hyperventilaton

• PaCO2 is increased in COPD as a cause of hypoxic PH together with obstruction

• A decrease in lung volumes and DLCO indicate ILD

V/Q Lung Scan

• In PAH V/Q scans may be entirely normal

• V/Q scanning showed sensitivity of 90-100% with spesifity of 94-100% for distinguishing between IPAH and CTEPH

• V/Q scans are similar in veno-occlusive disease and CTEPH, HRCT is reguired for differentiation

Chest CT/MRI

• Right ventricular morphology

• Right atrial morphology

• Pulmonary artery morphology

• Right ventricular function

*The value of serial CT/MRI scans in following

the course of patients is not established

*CT; evaluate the lung parenchyma

Pulmanary angiography

Diagnosis of PH

PH Detection Chest Radiography ECGTT Echocardiography

PH Class Identification Pulmonary Function TestV/Q scanHRCTSpiral CTPulmonary Angiography

PAH evaluation Blood Tests&ImmunologyHIV testAbdominal USG6 min Walk Test, Max VO2Right Heart

Cath+Vasoreactivity

Exercise testing

• A six-minute walk test or a cardiopulmonary exercise test is recommended

• Exercise test best characterise the functional impairment of patients with PPH and their response to therapy

Right Cath+Vasodilator Testing

• Patients with idiopathic pulmonary arterial hypertension (IPAH) should undergo acute vasoreactivity testing using a short-acting agent such as intravenous (IV) epoprostenol, adenosine, or inhaled nitric oxide (NO).

• Level of evidence: fair; benefit: substantial; grade of recommendation: A.

• Patients with pulmonary arterial hypertension (PAH) associated with underlying processes, such as scleroderma or congenital heart disease, should undergo acute vasoreactivity testing.

• Level of evidence: expert opinion; benefit: small/weak; grade of recommendation: E/C.

PAH Treatment• General

– Oral anticoagulant– Diuretics-venesection– Oxygen– Digoksin

• VAZODİLATÖR TEDAVİ– Calciun Channel Blockers– Endothelin antagonists

• Bosentan…Sitaxsenten/Ambrisentan– Prostacyclins

• Epoprostenol, Treprostinil, Iloprost, Oral beraprost– PDE-5 inhibitors (c-GMP elevators)

• Sildenafil

• SURGICAL INTERVENTIONS– Atrial septostomY– Lung transplantation

Anticoagulation

• Microthrombosis of the small vessels is often seen in PPH• Fibrin degradation products have a proliferative effect on the

vessels• Patients treated with coumadin have a better prognosis• Targed INR value in IPAH patients;

– North America 1.5-2.5– Europe; 2-3

*Patients with IPAH should receive anticoagulation with warfarin. Level of evidence: fair; benefit: intermediate; grade of recommendation: B. **In patients with PAH occurring in association with other underlying processes, such as scleroderma or congenital heart disease, anticoagulation should be considered. Level of evidence: expert opinion; benefit: small/weak; recommendation: E/C.

*Patients with IPAH should receive anticoagulation with warfarin. Level of evidence: fair; benefit: intermediate; grade of recommendation: B. **In patients with PAH occurring in association with other underlying processes, such as scleroderma or congenital heart disease, anticoagulation should be considered. Level of evidence: expert opinion; benefit: small/weak; recommendation: E/C.

Diuretics

• Prevent sodium and water retension

• Great impact on physical capacity and quality of life in many patients with right heart failure

• Drug and dose;……….expertise

• Follow up;……………. Electrolits, renal

function

Venesection

• Polycytemia increases the viscosity of the blood and therefore increases vascular resistance (HCT>60%)

• Benefial in COPD patients

• Decompensation in Eisenmenger

Oxygen Therapy

• Oxygen treatment decreases pulmonary artery pressure

• Recommended when PaO2< 65 mmHg, or oxygen saturation < 85%

• It does rarely work in IPAH patients

• O2 therapy is beneficial for right ventricle and respiratory muscles

In patients with PAH, supplemental oxygen should be used as necessaryto maintain oxygen saturations at >90% at all times.Level of evidence: expert opinion; benefit: substantial; recommendation: E/A.

In patients with PAH, supplemental oxygen should be used as necessaryto maintain oxygen saturations at >90% at all times.Level of evidence: expert opinion; benefit: substantial; recommendation: E/A.

Digitalis&Dobutamine

• Depression of myocardial contractility is the primary event in the progression of right heart failure, inotropic agents have been used.

• Short-term IV administration of digoxin produces increase in cardiac output and a significant reduction in circulating norepinephrine levels

• End stage PAH patients treated with dobutamine in most centres

• Long-term treatment?

Calcium Channel Blockers Smooth muscle hyperthrophy Vasoconstriction Voltage-dependent potassium channels

• Rich ve ark.NEJM,1992

Only in patients with vasodilator testing (+) Side effects should be followed closely

– Nifedipin (in case of bradicardia)– Diltizem (in case of tachycardia)– ***Verapamil : negative inotropic effects!!! A/F!

Follw-up 1 earl 3 yearl 5 year

Vasodilator testing (-) %68 %47 %38

Vaso-testing(+) & yüksek doz KKB %94 %94 %94

Calcium Channel Blockers

• Beginning with low doses are recommende;– Nifedipine 30 mg 2x1– Diltiazem 60 mg 3x1

• Doses increased gradually in weeks up to maxium tolerated level;– Nifedipine…> 120-240 mg/day– Diltiazem….-> 240-720 mg/day

*Systemic hypotension and peripheral edema of lower extremities are dose limiting factors.

NOProstacyclin

C-GMP

EndothelinHypoxia

Pulmonary Arterial Hypertension(New treatments)

Vasoconstruction Vasodilation

New Agents

• Prostacyclins– Epoprostenol– Treprostinil– Iloprost– Beraprost

• Endothelin Receptor Antagonists– Nonselective Endothelin Receptor Blockade:

(Bosentan)– Specific A-receptor Blockers. (Sitaxentan,

Ambrisentan)• Phosphodiesterase 5 Inhibitors;

– Sildenafil

PAH and IPF survival

• The median length of survival has been estimated to be between 2.5 and 5 years after the onset of respiratory symptoms or diagnosis

• 1-year survival rate;– 45% in patients with IPF and PAP> 50 mmH– 83% in patients with IPF and PAP< 50 mm Hg

• Therefore, there is often a short window to enable the study of pulmonary hypertension in this population

Chest X-ray

• Patients with a suggestion of pulmonary hypertension on chest radiography have a poorer prognosis than those without pulmonary artery enlargement

Echocardiography

• Echocardiography is the most common noninvasive test used to screen for pulmonary hypertension. Unfortunately, in patients with advanced lung disease, the sensitivity and specificity of echo-cardiography are imperfect:

• sensitivity; 85%• specificity; 55%• positive predictive; 52%• Negative predictive; 87%

V/Q Lung Scan

• In PAH V/Q scans may be entirely normal• V/Q scanning showed sensitivity of 90-100% with

spesifity of 94-100% for distinguishing between IPAH and CTEPH

• V/Q scans are similar in veno-occlusive disease and CTEPH, HRCT is reguired for differentiation

• In parenchymal lung disease the perfusion defects are matched by ventilation defects

PAH-PFT relationship

• FVC is 50 to 80% of that predicted; – pulmonary hypertension may occur with exercise

• FVC < 50% or DLCO < 45% :– pulmonary hypertension may occur at rest

ILD-PH Treatment

• Limited data suggest that the treatment of pulmonary hypertension in ILD is beneficial.

• There are some theoretic risks to vasodilation in patients with ILD. – pulmonary artery vasodilation leads to improved blood flow into

areas of fibrotic lung, then worsening of ventilation perfusion mismatch may result

• Patients receiving intravenous prostacyclin experienced decreased arterial oxygen tension, largely because of an increase in shunt fraction. By contrast, inhaled nitric oxide and sildenafil maintained ventilation perfusion matching and decreased pulmonary vascular resistance without a decrease in arterial oxygen tension.– Ghofrani HA, Wiedemann R, Rose F, et al. Sildenafil for treatment of lung

fibrosis and pulmonary hypertension: a randomised controlled trial. Lancet 2002; 360:895-900

Therapy for PH in ILD

• Pulmonary hypertension is common in advanced ILD and correlates with poor outcome.

• Therapy that targets pulmonary hypertension has been initiated in small clinical trials.

• Larger randomized controlled trials will be needed to establish that therapy of pulmonary hypertension is both efficacious and safe for patients with ILD

PAH Treatment-summary• General

– Oral anticoagulant– Diuretics-venesection + Physiotherapy– Oxygen Control of infection– Digoksin

• VAZODİLATÖR TEDAVİ– Calciun Channel Blockers– Endothelin antagonists

• Bosentan…Sitaxsenten/Ambrisentan– Prostacyclins

• Epoprostenol, Treprostinil, Iloprost, Oral beraprost– PDE-5 inhibitors (c-GMP elevators)

• Sildenafil

• SURGICAL INTERVENTIONS– Atrial septostomY– Lung transplantation

?

References

• Medical Therapy For Pulmonary Arterial Hypertension

ACCP Evidence-Based Clinical Practice Guidelines

David B. Badesch, Steve H. Abman, Gregory S. Ahearn, Robyn J. Barst, Douglas C. McCrory, MHSc; Gerald Simonneau,Vallerie V. McLaughlin

Chest 2004;126;35-62• Guidelines on diagnosis and treatment of pulmonary

arterial hypertension Nazzarone Galie, Adam Torbicki, Robyn Barst, Philippe Dartevelle, Shelia Haworth,

Tim Higenbottam, Horst olschewki, Andrew Peacock, Guiseppe Pietra, Lewis J Rubin

European Heart Journal 2004; 25: 2243-2278