Out-patient Management of Pulmonary Hypertension Jameel A. Al-Ata, MD KAAUH & KFSH&RC-JED. Taif 14th annual cardiovascular conference, march 2006.

Content Definition & Types Definition & Types Epidemiology Epidemiology Pathophysiology Pathophysiology PHTN & CHD PHTN & CHD Concepts & Goals of management Concepts & Goals of management Workup Workup Management Strategies Management Strategies Conclusion. Conclusion.

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

WHO classification 1998

Pulmonary arterial hypertension; 1.1 Idiopathic pulmonary hypertension 1.1 Idiopathic pulmonary hypertension 1.2 Familial 1.2 Familial

Cont” 1.3 Associated with: 1.3 Associated with: Collagen vascular disease Collagen vascular disease Congenital systemic to pulmonary shunts Congenital systemic to pulmonary shunts Portal hypertension Portal hypertension HIV infection HIV infection Drugs (anorexigens)/toxins Drugs (anorexigens)/toxins Other thyroid disorders: Gaucher disease, hereditary haemorrhagic telangiectasia, haemoglobinopathies Other thyroid disorders: Gaucher disease, hereditary haemorrhagic telangiectasia, haemoglobinopathies

Cont” 1.4 Persistent pulmonary hypertension of the newborn 1.4 Persistent pulmonary hypertension of the newborn 1.5 Pulmonary veno-occlusive disease 1.5 Pulmonary veno-occlusive disease

Pulmonary hypertension with left heart disease; 2.1 Left sided atrial or ventricular heart disease 2.1 Left sided atrial or ventricular heart disease 2.2 Left sided valvular disease 2.2 Left sided valvular disease

Pulmonary hypertension associated with disorders of the respiratory system and/or hypoxaemia; 3.1 Chronic obstructive pulmonary disease 3.1 Chronic obstructive pulmonary disease 3.2 Interstitial lung disease 3.2 Interstitial lung disease 3.3 Sleep disordered breathing 3.3 Sleep disordered breathing

Cont” 3.4 Alveolar hypoventilation disorders 3.4 Alveolar hypoventilation disorders 3.5 Chronic exposure to high altitude 3.5 Chronic exposure to high altitude 3.6 Neonatal lung disease 3.6 Neonatal lung disease 3.7 Alveolar-capillary dysplasia 3.7 Alveolar-capillary dysplasia 3.8 Other 3.8 Other

Pulmonary hypertension due to chronic thrombotic and/or embolic disease; 4.1 Thromboembolic obstruction of proximal pulmonary arteries. 4.1 Thromboembolic obstruction of proximal pulmonary arteries. 4.2 Obstruction of distal pulmonary arteries 4.2 Obstruction of distal pulmonary arteries –– Pulmonary embolism (thrombus, tumour, and/or parasites). –– In situ thrombosis.

Miscellaneous, e.g. Sarcoidosis

Genetics & Epidemiology; 6% of primary pulmonary hypertension cases are familial. 6% of primary pulmonary hypertension cases are familial. The disease is inherited as an autosomal dominant with incomplete penetrance. The disease is inherited as an autosomal dominant with incomplete penetrance. The gene has been mapped to chromosome 2q 33 and recently identified as a mutation of the BMPR2 gene (bone morphogenetic protein receptor) The gene has been mapped to chromosome 2q 33 and recently identified as a mutation of the BMPR2 gene (bone morphogenetic protein receptor) Mutations of the gene encoding BMPR-II are also seen in at least 26% of sporadic cases of PPH. Mutations of the gene encoding BMPR-II are also seen in at least 26% of sporadic cases of PPH.

CONT” Primary pulmonary hypertension (PPH) has an incidence of 1-2 per million per annum. Primary pulmonary hypertension (PPH) has an incidence of 1-2 per million per annum. Other causes of pulmonary arterial hypertension may account for a further 1-2 cases per million per annum. Other causes of pulmonary arterial hypertension may account for a further 1-2 cases per million per annum.

Cont” In a 1965 series of 35 patients with primary pulmonary hypertension 22 (63%) patients died in the first year after the onset of symptoms. In a 1965 series of 35 patients with primary pulmonary hypertension 22 (63%) patients died in the first year after the onset of symptoms. In 1995, the median survival in a series of 18 children with primary pulmonary hypertension was 4.12 years. In 1995, the median survival in a series of 18 children with primary pulmonary hypertension was 4.12 years. With new diverse medications 90% survival at 4 years in children with severe idiopathic pulmonary hypertension was reported with prostacyclin. With new diverse medications 90% survival at 4 years in children with severe idiopathic pulmonary hypertension was reported with prostacyclin.

Cont” Without appropriate treatment, the natural history of IPAH is progressive and fatal. Without appropriate treatment, the natural history of IPAH is progressive and fatal. In contrast, the natural history of pulmonary hypertension from congenital heart disease has a broad range of survival, ranging from months to decades. In contrast, the natural history of pulmonary hypertension from congenital heart disease has a broad range of survival, ranging from months to decades.

Pathophysiology; The constituent cells of the vessel walls appear to undergo changes in phenotype which in turn alter their structure and function. ( proliferation ). The constituent cells of the vessel walls appear to undergo changes in phenotype which in turn alter their structure and function. ( proliferation ). Pulmonary hypertension is associated with pulmonary arterial thrombosis and a hypercoaguable state associated with a fibrinolytic defect and haemostatic disturbance. ( thrombosis ). Pulmonary hypertension is associated with pulmonary arterial thrombosis and a hypercoaguable state associated with a fibrinolytic defect and haemostatic disturbance. ( thrombosis ).

Cont” Vasoconstriction plays an important role in the pathogenesis of pulmonary hypertension specially in hypoxemic patients. Vasoconstriction plays an important role in the pathogenesis of pulmonary hypertension specially in hypoxemic patients. In young children, pulmonary vascular disease can progress so rapidly due to severe obstructive intimal proliferation, In young children, pulmonary vascular disease can progress so rapidly due to severe obstructive intimal proliferation,

Cont” Lung hypoplasia. Lung hypoplasia. Lung fibrosis. Lung fibrosis. Chronic thromboembolism. Chronic thromboembolism.

PHTN & CHD The age at which these lesions cause irreversible pulmonary vascular disease varies from months to decades. The age at which these lesions cause irreversible pulmonary vascular disease varies from months to decades. Patients with ventricular septal defect or patent ductus arteriosus do not develop irreversible pulmonary vascular changes before 1 year of age. Patients with ventricular septal defect or patent ductus arteriosus do not develop irreversible pulmonary vascular changes before 1 year of age. Children with Down’s syndrome may have an increased risk of pulmonary hypertension. Children with Down’s syndrome may have an increased risk of pulmonary hypertension.

Cont” Infants with an atrial septal defect or ventricular septal defect with chronic lung disease have an increased risk for the early development of severe pulmonary vascular disease. Infants with an atrial septal defect or ventricular septal defect with chronic lung disease have an increased risk for the early development of severe pulmonary vascular disease. Patients with atrioventricular septal defect may develop irreversible pulmonary vascular disease earlier than patients with other left- to-right shunt lesions. Patients with atrioventricular septal defect may develop irreversible pulmonary vascular disease earlier than patients with other left- to-right shunt lesions.

Cont” Hypoxaemia with increased shunting in patients with cyanotic congenital cardiac lesions are potent stimuli for the rapid development of pulmonary vascular disease. Hypoxaemia with increased shunting in patients with cyanotic congenital cardiac lesions are potent stimuli for the rapid development of pulmonary vascular disease. Examples include; Examples include; 1) Transposition of the great arteries, 2) Truncus arteriosus, and 3) Univentricular heart with high flow. Palliative shunting operations ( e.g. central aorto- pulmpnary shunts ) may lead to the development of pulmonary hypertension. Palliative shunting operations ( e.g. central aorto- pulmpnary shunts ) may lead to the development of pulmonary hypertension.

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

Cont” Prognosis of Eisenmenger patients with syndrome is much better than for patients with idiopathic pulmonary arterial hypertension. Prognosis of Eisenmenger patients with syndrome is much better than for patients with idiopathic pulmonary arterial hypertension. Syncope, right heart failure, and severe hypoxemia have been associated with a poor prognosis. Syncope, right heart failure, and severe hypoxemia have been associated with a poor prognosis.

Concepts & Goals of management; Confirm the diagnosis of pulmonary hypertension. Confirm the diagnosis of pulmonary hypertension. Treat the underlying cause. Treat the underlying cause. Determine the type of disease according to the new classification, assess the suitability of possible treatments.( must include assessment of acute vasodilation response). Determine the type of disease according to the new classification, assess the suitability of possible treatments.( must include assessment of acute vasodilation response).

Cont” 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 crisis. Reduce the post operative risk of PHTN crisis. Improve survival & Estimate prognosis. Improve survival & Estimate prognosis.

Confirming the diagnosis; History and examination Diet pill use; contraceptive pill; methamphetamine use Diet pill use; contraceptive pill; 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

Cont” Symptoms Chest pain; dyspnoea; shortness of breath; syncope. Chest pain; dyspnoea; shortness of breath; syncope. Physical 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 distension Peripheral oedema & jugular venous distension

Cont” Diagnostic evaluation of pulmonary hypertension; Chest radiograph (signs of cardiomegaly and enlarged pulmonary arteries) Chest radiograph (signs of cardiomegaly and enlarged pulmonary arteries) ECG (right ventricular hypertrophy and ST-T changes) ECG (right ventricular hypertrophy and ST-T changes) Echocardiogram Echocardiogram –– (right ventricular hypertrophy, exclude congenital heart disease, left ventricular diastolic dysfunction, quantify right ventricular systolic pressure)

Cont” Cardiac catheterization with acute vasodilator testing; – (evaluate pulmonary artery pressure and resistance and degree of pulmonary reactivity).

Positive response to vasodilators; Decrease in the mean pulmonary artery pressure and resistance by 20%, or greater, with a fall to near normal levels (<40 mg Hg). Decrease in the mean pulmonary artery pressure and resistance by 20%, or greater, with a fall to near normal levels (<40 mg Hg). Experience no change or an increase in their cardiac index. Experience no change or an increase in their cardiac index. Exhibit no change or a decrease in the ratio of pulmonary vascular resistance to systemic vascular resistance. Exhibit no change or a decrease in the ratio of pulmonary vascular resistance to systemic vascular resistance. Normal right atrial pressure and cardiac output. Normal right atrial pressure and cardiac output.

Cont” Liver evaluation; –– Liver function tests with gamma glutaryl transferase –– Abdominal ultrasound (porto-pulmonary hypertension) –– Hepatitis profile

Cont” Complete blood count, urinalysis Complete blood count, urinalysis Hypercoagulable evaluation Hypercoagulable evaluation –– DIC screen –– Factor V Leiden –– Antithrombin III –Prothrombin mutation –– Protein C –– Protein S –– Anticardiolipin IgG/IgM –– Russel viper venom test

Cont” Collagen vascular workup—looking for autoimmune disease; –– Antinuclear antibody with profile (DNA, Smith, RNP, SSA, SSB, centromere, SCL-70) –– Rheumatoid factor –– Erythrocyte sedimentation rate –– Complement

Cont” Lung evaluation – Pulmonary function tests with DLCO/bronchodilators (to exclude obstructive/restrictive disease) –Sleep study and pulse oximetry (degree of hypoxia or diminished ventilatory drive) –CT/MRI scan of chest (evaluation of thromboembolic disease or interstitial lung disease) –Ventilation perfusion test – Lung biopsy

Cont” Six minute walk test/cycle ergometry Six minute walk test/cycle ergometry HIV test HIV test Thyroid function tests Thyroid function tests Toxicology screen (cocaine/methamphetamine and HIV testing) Toxicology screen (cocaine/methamphetamine and HIV testing)

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

Cont” Acute trial of calcium channel blocker Acute trial of calcium channel blocker therapy is reserved for those patients who are responsive to nitric oxide or prostacyclin. therapy is reserved for those patients who are responsive to nitric oxide or prostacyclin. At least 60% of children with severe pulmonary hypertension do not respond calcium channel antagonists. At least 60% of children with severe pulmonary hypertension do not respond calcium channel antagonists.

Cont” These drugs can cause a decrease in cardiac output. These drugs can cause a decrease in cardiac output. Consequently, increased right atrial pressure and low cardiac output are contraindications to acute or chronic calcium channel blockade. Consequently, increased right atrial pressure and low cardiac output are contraindications to acute or chronic calcium channel blockade.

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

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

Cont” Dose dependent side effects of the drug (nausea, anorexia, jaw pain, diarrhoea, musculoskeletal aches and pains) Dose dependent side effects of the drug (nausea, anorexia, jaw pain, diarrhoea, musculoskeletal aches and pains) Side effects due to the method of delivery. (through a central line) thus potential complications include clotting, haemorrhage, cellulitis, and sepsis. Side effects due to the method of delivery. (through a central line) thus potential complications include clotting, haemorrhage, cellulitis, and sepsis.

Cont” Abrupt cessation causing acute deterioration and in some cases death.( rebound PHTN ) Abrupt cessation causing acute deterioration and in some cases death.( rebound PHTN ) In patients with residual shunting, continuous prostacylin may result in worsening cyanosis and complications of cerebrovascular accidents. In patients with residual shunting, continuous prostacylin may result in worsening cyanosis and complications of cerebrovascular accidents.

Alternative delivery routes for prostacyclin analogues; Treprostinil, a subcutaneous prostacyclin has been tested in a multicentre international placebo controlled randomised study and was found to have beneficial effects. Treprostinil, a subcutaneous prostacyclin has been tested in a multicentre international placebo controlled randomised study and was found to have beneficial effects. Can cause pain and erythema around the infusion site, thus limiting its usefulness in young children. Can cause pain and erythema around the infusion site, thus limiting its usefulness in young children.

Cont” Iloprost An inhaled prostacylin analogue, has undergone initial trials with significant beneficial effects on symptomatology and quality of life. Iloprost has a half life of 20–25 minutes and therefore 6–9 inhalations a day are required to be clinically effective.

Cont” Beraprost, An orally active prostacyclin analogue, is fast acting and has a half life of 35–40 minutes; it has beneficial effects, which may be attenuated with increasing length of treatment. An orally active prostacyclin analogue, is fast acting and has a half life of 35–40 minutes; it has beneficial effects, which may be attenuated with increasing length of treatment. A recent study showed comparable if not superior PAP lowering effect to N.O. A recent study showed comparable if not superior PAP lowering effect to N.O.

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

CONT” Sitaxsentan, An ET receptor antagonist with high oral bioavailability, a long duration of action. An ET receptor antagonist with high oral bioavailability, a long duration of action. When given orally for 12 weeks it had beneficial effects on exercise capacity and cardiopulmonary haemodynamics in patients with congenital heart disease. When given orally for 12 weeks it had beneficial effects on exercise capacity and cardiopulmonary haemodynamics in patients with congenital heart disease.

Phosphodiesterase-5 inhibitors; Sildenafil These drugs promote an increase in cGMP levels and thus cause pulmonary vasodilatation. These drugs promote an increase in cGMP levels and thus cause pulmonary vasodilatation. Useful in the setting of inhaled nitric oxide therapy withdrawal, in postoperative pulmonary hypertension, or in the presence of pulmonary hypertension related to chronic lung disease. Useful in the setting of inhaled nitric oxide therapy withdrawal, in postoperative pulmonary hypertension, or in the presence of pulmonary hypertension related to chronic lung disease.

Anticoagulation; Required to prevent the development of pulmonary thrombi. Required to prevent the development of pulmonary thrombi. Aspirin can be used instead in children. Aspirin can be used instead in children. In adults with IPAH, use of warfarin improves survival sgnificantly. In adults with IPAH, use of warfarin improves survival sgnificantly.

Others; Prevent nocturnal hypoxemia by home O2 at least 15 hrs / day. Prevent nocturnal hypoxemia by home O2 at least 15 hrs / day. Very good nutrition to help increase the availability of cGMP. Very good nutrition to help increase the availability of cGMP.

Conclusions; Early surgical or interventional treatment remains the corner stone in prevention of PHTN 2 nd CHD. Early surgical or interventional treatment remains the corner stone in prevention of PHTN 2 nd CHD. New anti-PHTN medications have improved the quality of life and survival of pts. With 1ry & 2 nd PHTN New anti-PHTN medications have improved the quality of life and survival of pts. With 1ry & 2 nd PHTN

Cont” Perhaps inoperable CHD patients due to severe PHTN can be reversed to operable using combined aggressive treatment protocols. Perhaps inoperable CHD patients due to severe PHTN can be reversed to operable using combined aggressive treatment protocols. Cost and availability of these new medications is a serious obstacle in our part of the world. Cost and availability of these new medications is a serious obstacle in our part of the world. Specialized integrated services for PHTN treatment are needed. Specialized integrated services for PHTN treatment are needed.