Out-patient Management Out-patient Management of Pulmonary of Pulmonary HypertensionHypertension

Jameel A. Al-Ata, MDJameel A. Al-Ata, MD

KAAUH & KFSH&RC-JED.KAAUH & KFSH&RC-JED.

Taif 14th annual cardiovascular conference , march 2006.Taif 14th annual cardiovascular conference , march 2006.

ContentContent

Definition & TypesDefinition & Types

EpidemiologyEpidemiology

PathophysiologyPathophysiology

PHTN & CHDPHTN & CHD

Concepts & Goals of Concepts & Goals of managementmanagement

WorkupWorkup

Management StrategiesManagement Strategies

Conclusion. Conclusion.

Definition & TypesDefinition & Types

Pulmonary hypertension is Pulmonary hypertension is defined as a mean pulmonary defined as a mean pulmonary artery pressure greater than artery pressure greater than 25 25 mm Hgmm Hg at rest at rest , or greater than , or greater than 30 mm Hg during exercise. 30 mm Hg during exercise.

WHO classification WHO classification 1998 1998

Pulmonary arterial Pulmonary arterial hypertension;hypertension;

1.11.1 Idiopathic pulmonary Idiopathic pulmonary hypertensionhypertension

1.2 1.2 FamilialFamilial

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1.3 1.3 Associated withAssociated with: :

Collagen vascular diseaseCollagen vascular disease

Congenital systemic to pulmonary shuntsCongenital systemic to pulmonary shunts

Portal hypertensionPortal hypertension

HIV infectionHIV infection

Drugs (anorexigens)/toxinsDrugs (anorexigens)/toxins

Other thyroid disorders: Gaucher disease, hereditary Other thyroid disorders: Gaucher disease, hereditary haemorrhagic telangiectasia, haemoglobinopathieshaemorrhagic telangiectasia, haemoglobinopathies

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1.41.4 Persistent pulmonary Persistent pulmonary hypertension of the newbornhypertension of the newborn

1.51.5 Pulmonary veno-occlusive Pulmonary veno-occlusive diseasedisease

Pulmonary hypertension Pulmonary hypertension with left heart disease;with left heart disease;

2.12.1 Left sided atrial or ventricular Left sided atrial or ventricular heart diseaseheart disease

2.22.2 Left sided valvular disease Left sided valvular disease

Pulmonary hypertension associated Pulmonary hypertension associated with disorders of the respiratory with disorders of the respiratory system and/or hypoxaemia;system and/or hypoxaemia;

3.13.1 Chronic obstructive Chronic obstructive pulmonary diseasepulmonary disease

3.23.2 Interstitial lung disease Interstitial lung disease

3.33.3 Sleep disordered breathing Sleep disordered breathing

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3.43.4 Alveolar hypoventilation disorders Alveolar hypoventilation disorders

3.53.5 Chronic exposure to high altitude Chronic exposure to high altitude

3.63.6 Neonatal lung disease Neonatal lung disease

3.73.7 Alveolar-capillary dysplasia Alveolar-capillary dysplasia

3.8 3.8 OtherOther

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

4.14.1 Thromboembolic obstruction of Thromboembolic obstruction of proximal pulmonary arteries.proximal pulmonary arteries.

4.24.2 Obstruction of distal pulmonary Obstruction of distal pulmonary arteries arteries – – – Pulmonary embolism (thrombus, tumour, Pulmonary embolism (thrombus, tumour,

and/or parasites).and/or parasites).

– – – In situ thrombosis.In situ thrombosis.

Miscellaneous,Miscellaneous,

e.g. Sarcoidosise.g. Sarcoidosis

Genetics & Genetics & Epidemiology;Epidemiology; 6% of primary pulmonary hypertension cases 6% of primary pulmonary hypertension cases

are familialare familial. .

The disease is inherited as an autosomal The disease is inherited as an autosomal dominant with incomplete penetrance.dominant with incomplete penetrance.

The gene has been mapped to chromosome The gene has been mapped to chromosome 2q 2q 3333 and recently identified as a mutation of the and recently identified as a mutation of the BMPR2 geneBMPR2 gene (bone morphogenetic protein (bone morphogenetic protein receptor)receptor)

Mutations of the gene encoding BMPR-II are also Mutations of the gene encoding BMPR-II are also seen in at least 26% of sporadic cases of PPH. seen in at least 26% of sporadic cases of PPH.

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Primary pulmonary hypertension Primary pulmonary hypertension ((PPHPPH) ) has an incidence of 1-2 per has an incidence of 1-2 per million per annummillion per annum..

Other causes of pulmonary Other causes of pulmonary arterial hypertension may arterial hypertension may account for a further 1-2 cases account for a further 1-2 cases per million per annum. per million per annum.

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In a 1965 series of 35 patients with primary In a 1965 series of 35 patients with primary pulmonary hypertension 22 (63%) patients died pulmonary hypertension 22 (63%) patients died in the first year after the onset of symptoms.in the first year after the onset of symptoms.

In 1995, the median survival in a series of 18 In 1995, the median survival in a series of 18 children with primary pulmonary hypertension children with primary pulmonary hypertension was 4.12 years.was 4.12 years.

With new diverse medications 90% survival at 4 With new diverse medications 90% survival at 4 years in children with severe idiopathic years in children with severe idiopathic pulmonary hypertension was reported with pulmonary hypertension was reported with prostacyclin. prostacyclin.

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Without appropriate treatment, the Without appropriate treatment, the natural history of IPAH is progressive natural history of IPAH is progressive and fatal. and fatal.

In contrast, the natural history of In contrast, the natural history of pulmonary hypertension from pulmonary hypertension from congenital heart disease has a broad congenital heart disease has a broad range of survival, ranging from months range of survival, ranging from months to decades. to decades.

Pathophysiology;Pathophysiology;

The constituent cells of the vessel walls The constituent cells of the vessel walls appear to undergo changes in appear to undergo changes in phenotype which in turn alter their phenotype which in turn alter their structure and function. ( structure and function. ( proliferationproliferation ). ).

Pulmonary hypertension is associated Pulmonary hypertension is associated with pulmonary arterial thrombosis and with pulmonary arterial thrombosis and a hypercoaguable state associated with a hypercoaguable state associated with a fibrinolytic defect and haemostatic a fibrinolytic defect and haemostatic disturbance. ( disturbance. ( thrombosisthrombosis ). ).

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Vasoconstriction plays an important Vasoconstriction plays an important role in the pathogenesis of pulmonary role in the pathogenesis of pulmonary hypertension specially in hypoxemic hypertension specially in hypoxemic patients.patients.

In young children, pulmonary vascular In young children, pulmonary vascular disease can progress so rapidly due to disease can progress so rapidly due to severe obstructive intimal proliferation, severe obstructive intimal proliferation,

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Lung hypoplasia.Lung hypoplasia.

Lung fibrosis.Lung fibrosis.

Chronic thromboembolism.Chronic thromboembolism.

PHTN & CHDPHTN & CHD

The age at which these lesions cause The age at which these lesions cause irreversible pulmonary vascular disease irreversible pulmonary vascular disease varies from months to decades.varies from months to decades.

Patients with ventricular septal defect or Patients with ventricular septal defect or patent ductus arteriosus do not develop patent ductus arteriosus do not develop irreversible pulmonary vascular changes irreversible pulmonary vascular changes before 1 year of age. before 1 year of age.

Children with Down’s syndrome may have an Children with Down’s syndrome may have an increased risk of pulmonary hypertension.increased risk of pulmonary hypertension.

Cont”Cont”

Infants with an atrial septal defect or Infants with an atrial septal defect or ventricular septal defect with chronic ventricular septal defect with chronic lung disease have an increased risk for lung disease have an increased risk for the early development of severe the early development of severe pulmonary vascular disease. pulmonary vascular disease.

Patients with atrioventricular septal Patients with atrioventricular septal defect may develop irreversible defect may develop irreversible pulmonary vascular disease earlier than pulmonary vascular disease earlier than patients with other left-to-right shunt patients with other left-to-right shunt lesions. lesions.

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Hypoxaemia with increased shunting in Hypoxaemia with increased shunting in patients with cyanotic congenital cardiac patients with cyanotic congenital cardiac lesions are potent stimuli for the rapid lesions are potent stimuli for the rapid development of pulmonary vascular disease. development of pulmonary vascular disease.

Examples include;Examples include;1)1) Transposition of the great arteries, Transposition of the great arteries, 2)2) Truncus Truncus

arteriosus, and arteriosus, and 3)3) Univentricular heart with Univentricular heart with high flow. high flow.

Palliative shunting operations ( e.g. central Palliative shunting operations ( e.g. central aorto-pulmpnary shunts ) may lead to the aorto-pulmpnary shunts ) may lead to the development of pulmonary hypertension. development of pulmonary hypertension.

Eisenmenger syndrome;Eisenmenger syndrome;

Increased pulmonary vascular resistance.Increased pulmonary vascular resistance.

Bidirectional or right-to-left shunting Bidirectional or right-to-left shunting through a systemic-to-pulmonary through a systemic-to-pulmonary connection, such as a ventricular septal connection, such as a ventricular septal defect, patent ductus arteriosus, defect, patent ductus arteriosus, univentricular heart, or aortopulmonary univentricular heart, or aortopulmonary window characterises this syndrome. window characterises this syndrome.

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Prognosis of Eisenmenger Prognosis of Eisenmenger patients with syndrome is much patients with syndrome is much better than for patients with better than for patients with idiopathic pulmonary arterial idiopathic pulmonary arterial hypertension. hypertension.

Syncope, right heart failure, and Syncope, right heart failure, and severe hypoxemia have been severe hypoxemia have been associated with a poor prognosis. associated with a poor prognosis.

Concepts & Goals of Concepts & Goals of management;management;

Confirm the diagnosis of pulmonary Confirm the diagnosis of pulmonary hypertension.hypertension.

Treat the underlying cause.Treat the underlying cause.

Determine the type of disease Determine the type of disease according to the new classification, according to the new classification, assess the suitability of possible assess the suitability of possible treatments.( must include assessment treatments.( must include assessment of acute vasodilation response).of acute vasodilation response).

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Monitor response to therapy.Monitor response to therapy.

Reverse back to an operable state. Reverse back to an operable state.

Reduce the post operative risk of PHTN Reduce the post operative risk of PHTN crisis.crisis.

Improve survival & Estimate prognosis. Improve survival & Estimate prognosis.

Confirming the Confirming the diagnosis; diagnosis; History and examinationHistory and examination

Diet pill use; contraceptive pill; Diet pill use; contraceptive pill; methamphetamine use methamphetamine use

Onset and length of pulmonary hypertension Onset and length of pulmonary hypertension

Family history of pulmonary hypertension Family history of pulmonary hypertension

Prior cardiac and other surgeries Prior cardiac and other surgeries

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SymptomsSymptoms Chest pain; dyspnoea; shortness of breath; Chest pain; dyspnoea; shortness of breath;

syncope. syncope.

Physical examinationPhysical examination Loud second heart sound.Loud second heart sound. Systolic murmur of tricuspid regurgitation. Systolic murmur of tricuspid regurgitation. Diastolic murmur of pulmonary insufficiency. Diastolic murmur of pulmonary insufficiency. Palpable second heart sound. Palpable second heart sound. Peripheral oedema & jugular venous Peripheral oedema & jugular venous

distension distension

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Diagnostic evaluation of pulmonary Diagnostic evaluation of pulmonary hypertension;hypertension;

Chest radiograph (signs of cardiomegaly and Chest radiograph (signs of cardiomegaly and enlarged pulmonary arteries)enlarged pulmonary arteries)

ECG (right ventricular hypertrophy and ST-T ECG (right ventricular hypertrophy and ST-T changes)changes)

Echocardiogram Echocardiogram – – – (right ventricular hypertrophy, exclude congenital (right ventricular hypertrophy, exclude congenital

heart disease, left ventricular diastolic dysfunction, heart disease, left ventricular diastolic dysfunction, quantify right ventricular systolic pressure)quantify right ventricular systolic pressure)

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Cardiac catheterization with acute Cardiac catheterization with acute vasodilator testing; vasodilator testing; – – (evaluate pulmonary artery pressure (evaluate pulmonary artery pressure

and resistance and degree of and resistance and degree of pulmonary reactivity).pulmonary reactivity).

Positive response to Positive response to vasodilators;vasodilators;

Decrease in the mean pulmonary artery pressure and Decrease in the mean pulmonary artery pressure and resistance by 20%, or greater, with a fall to near resistance by 20%, or greater, with a fall to near normal levels (<40 mg Hg).normal levels (<40 mg Hg).

Experience no change or an increase in their cardiac Experience no change or an increase in their cardiac index.index.

Exhibit no change or a decrease in the ratio of Exhibit no change or a decrease in the ratio of pulmonary vascular resistance to systemic vascular pulmonary vascular resistance to systemic vascular resistance.resistance.

Normal right atrial pressure and cardiac output.Normal right atrial pressure and cardiac output.

Cont”Cont”

Liver evaluation;Liver evaluation; – – – Liver function tests with gamma Liver function tests with gamma

glutaryl transferaseglutaryl transferase

– – – Abdominal ultrasound (porto-Abdominal ultrasound (porto-pulmonary hypertension)pulmonary hypertension)

– – – Hepatitis profileHepatitis profile

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Complete blood Complete blood count, urinalysiscount, urinalysis

Hypercoagulable Hypercoagulable evaluation evaluation – – – DIC screenDIC screen

– – – Factor V LeidenFactor V Leiden

– – – Antithrombin IIIAntithrombin III

– Prothrombin Prothrombin mutation 22010mutation 22010

– – – Protein CProtein C

– – – Protein SProtein S

– – – Anticardiolipin Anticardiolipin IgG/IgMIgG/IgM

– – – Russel viper Russel viper venom testvenom test

Cont”Cont”

Collagen vascular workup—looking for Collagen vascular workup—looking for autoimmune disease; autoimmune disease; – – – Antinuclear antibody with profile (DNA, Antinuclear antibody with profile (DNA,

Smith, RNP, SSA, SSB, centromere, SCL-70)Smith, RNP, SSA, SSB, centromere, SCL-70)

– – – Rheumatoid factorRheumatoid factor

– – – Erythrocyte sedimentation rateErythrocyte sedimentation rate

– – – ComplementComplement

Cont”Cont”Lung evaluationLung evaluation

– Pulmonary function tests with DLCO/bronchodilators Pulmonary function tests with DLCO/bronchodilators (to exclude obstructive/restrictive disease)(to exclude obstructive/restrictive disease)

– Sleep study and pulse oximetry (degree of hypoxia or Sleep study and pulse oximetry (degree of hypoxia or diminished ventilatory drive)diminished ventilatory drive)

– CT/MRI scan of chest (evaluation of thromboembolic CT/MRI scan of chest (evaluation of thromboembolic disease or interstitial lung disease)disease or interstitial lung disease)

– Ventilation perfusion testVentilation perfusion test

– Lung biopsyLung biopsy

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Six minute walk testSix minute walk test//cycle ergometrycycle ergometry

HIV testHIV test

Thyroid function testsThyroid function tests

Toxicology screen Toxicology screen (cocaine/methamphetamine and HIV (cocaine/methamphetamine and HIV testing)testing)

Management Management strategies;strategies;

Vasodilator therapy;Vasodilator therapy;

Children who respond acutely to Children who respond acutely to vasodilator testing with nitric vasodilator testing with nitric oxide or epoprostenol should oxide or epoprostenol should initially be treated with calcium initially be treated with calcium channel blockers, such as channel blockers, such as nifedipine or diltiazem. nifedipine or diltiazem.

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Acute trial of calcium channel blocker Acute trial of calcium channel blocker therapy is reserved for those therapy is reserved for those

patients who are responsive to nitric patients who are responsive to nitric oxide or prostacyclin.oxide or prostacyclin.

At least 60% of children with severe At least 60% of children with severe pulmonary hypertension do not pulmonary hypertension do not respond calcium channel respond calcium channel antagonists. antagonists.

Cont”Cont”

These drugs can cause a These drugs can cause a decrease in cardiac output.decrease in cardiac output.

Consequently, increased right Consequently, increased right atrial pressure and low cardiac atrial pressure and low cardiac output are contraindications to output are contraindications to acute or chronic calcium channel acute or chronic calcium channel blockade. blockade.

Prostacyclin;Prostacyclin;

Imbalance in the biosynthesis of Imbalance in the biosynthesis of thromboxane A2 and prostacyclin thromboxane A2 and prostacyclin & diminished prostacyclin & diminished prostacyclin synthase expression in the lung synthase expression in the lung vasculature are seen in adults vasculature are seen in adults with IPAH & children with CHD. with IPAH & children with CHD.

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Intravenous epoprostenol made the Intravenous epoprostenol made the five year survival in patients with five year survival in patients with primary pulmonary hypertension who primary pulmonary hypertension who were not candidates for calcium were not candidates for calcium channel blocker therapy may be higher channel blocker therapy may be higher than 80%. And is promising in CHD. than 80%. And is promising in CHD.

Disadvantages of prostacyclin Disadvantages of prostacyclin analogues include :analogues include :

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Dose dependent side effects of the drug Dose dependent side effects of the drug (nausea, anorexia, jaw pain, diarrhoea, (nausea, anorexia, jaw pain, diarrhoea, musculoskeletal aches and pains)musculoskeletal aches and pains)

Side effects due to the method of Side effects due to the method of delivery. (through a central line) thus delivery. (through a central line) thus potential complications include clotting, potential complications include clotting, haemorrhage, cellulitis, and sepsis.haemorrhage, cellulitis, and sepsis.

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Abrupt cessation causing acute Abrupt cessation causing acute deterioration and in some cases deterioration and in some cases death.( rebound PHTN )death.( rebound PHTN )

In patients with residual In patients with residual shunting, continuous prostacylin shunting, continuous prostacylin may result in worsening cyanosis may result in worsening cyanosis and complications of and complications of cerebrovascular accidents. cerebrovascular accidents.

Alternative delivery routes Alternative delivery routes for prostacyclin analogues;for prostacyclin analogues;

TreprostinilTreprostinil, a subcutaneous , a subcutaneous prostacyclin has been tested in a prostacyclin has been tested in a multicentre international placebo multicentre international placebo controlled randomised study and was controlled randomised study and was found to have beneficial effects. found to have beneficial effects.

Can cause pain and erythema around Can cause pain and erythema around the infusion site, thus limiting its the infusion site, thus limiting its usefulness in young children. usefulness in young children.

Cont”Cont”

Iloprost Iloprost An inhaled prostacylin An inhaled prostacylin analogue, has undergone initial trials analogue, has undergone initial trials with significant beneficial effects on with significant beneficial effects on symptomatology and quality of life. symptomatology and quality of life.

IloprostIloprost has a half life of 20–25 minutes has a half life of 20–25 minutes and therefore 6–9 inhalations a day and therefore 6–9 inhalations a day are required to be clinically effective. are required to be clinically effective.

Cont”Cont”

Beraprost,Beraprost, An orally active prostacyclin analogue, An orally active prostacyclin analogue,

is fast acting and has a half life of 35–is fast acting and has a half life of 35–40 minutes; it has beneficial effects, 40 minutes; it has beneficial effects, which may be attenuated with which may be attenuated with increasing length of treatment. increasing length of treatment.

A recent study showed comparable if A recent study showed comparable if not superior PAP lowering effect to not superior PAP lowering effect to N.O.N.O.

Endothelins receptor Endothelins receptor antagonists;antagonists;

Bosentan,Bosentan,

a dual ET receptor antagonist, a dual ET receptor antagonist, which when used in children with which when used in children with pulmonary arterial hypertension pulmonary arterial hypertension related to congenital heart related to congenital heart disease or IPAH, it lowered disease or IPAH, it lowered pulmonary pressure and pulmonary pressure and resistance, and was well tolerated. resistance, and was well tolerated.

CONT”CONT”

Sitaxsentan,Sitaxsentan, An ET receptor antagonist with high oral An ET receptor antagonist with high oral

bioavailability, a long duration of action. bioavailability, a long duration of action.

When given orally for 12 weeks it had When given orally for 12 weeks it had beneficial effects on exercise capacity beneficial effects on exercise capacity and cardiopulmonary haemodynamics in and cardiopulmonary haemodynamics in patients with congenital heart disease.patients with congenital heart disease.

Phosphodiesterase-5 Phosphodiesterase-5 inhibitors;inhibitors;SildenafilSildenafil These drugs promote an increase in cGMP These drugs promote an increase in cGMP

levels and thus cause pulmonary levels and thus cause pulmonary vasodilatation.vasodilatation.

Useful in the setting of inhaled nitric Useful in the setting of inhaled nitric oxide therapy withdrawal, in oxide therapy withdrawal, in postoperative pulmonary hypertension, or postoperative pulmonary hypertension, or in the presence of pulmonary in the presence of pulmonary hypertension related to chronic lung hypertension related to chronic lung disease. disease.

Anticoagulation;Anticoagulation;

Required to prevent the Required to prevent the development of pulmonary thrombi.development of pulmonary thrombi.

Aspirin can be used instead in Aspirin can be used instead in children.children.

In adults with IPAH, use of warfarin In adults with IPAH, use of warfarin improves survival sgnificantly.improves survival sgnificantly.

Others;Others;

Prevent nocturnal hypoxemia by Prevent nocturnal hypoxemia by home O2 at least 15 hrs / day.home O2 at least 15 hrs / day.

Very good nutrition to help Very good nutrition to help increase the availability of cGMP.increase the availability of cGMP.

Conclusions;Conclusions;

Early surgical or interventional Early surgical or interventional treatment remains the corner stone treatment remains the corner stone in prevention of PHTN 2in prevention of PHTN 2ndnd CHD. CHD.

New anti-PHTN medications have New anti-PHTN medications have improved the quality of life and improved the quality of life and survival of pts. With 1ry & 2survival of pts. With 1ry & 2ndnd PHTN PHTN

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Perhaps inoperable CHD patients due Perhaps inoperable CHD patients due to severe PHTN can be reversed to to severe PHTN can be reversed to operable using combined aggressive operable using combined aggressive treatment protocols.treatment protocols.

Cost and availability of these new Cost and availability of these new medications is a serious obstacle in medications is a serious obstacle in our part of the world.our part of the world.

Specialized integrated services for Specialized integrated services for PHTN treatment are needed. PHTN treatment are needed.