Pulmonary Hypertension

Jimmy Ford, MD Pulmonary and Critical Care

How Common is It?

Hypertension Relatively Common Pulmonary Arterial Hypertension Relatively Uncommon

Pulmonary

What is the Difference?

Pulmonary Hypertension = A general term used to describe elevated pressure in the pulmonary vascular bed, not describing where the lesion is.

Pulmonary Arterial Hypertension = A term that describes elevated pressure in the pulmonary vasculature, limited to the arteries/arterioles, and due to an intrinsic abnormality in the pulmonary arterial bed.

Definition of PAH by WHO

Required:
Mean PAP 25 mm Hg at rest or 35 mmHg with exercise PCWP 15 mm Hg

Should be present:

PVR 3 Wood Units (240 dynes.sec.cm-5)

A Word about Hemodynamics

The right heart catheterization is crucial. Diagnosis and/or treatment choices should almost never be made based upon echocardiography alone, it is a screening tool. Useful calculations:
mPAP = 1/3 sPAP + 2/3 dPAP PVR = mPAP PCWP / C.O.

PAH

The term PAH represents true pulmonary ateriopathy, characterized by: In situ microthrombosis Plexiform lesion formation Leads to progressive increase in pulmonary vascular resistance and culminates in right heart failure and death Three key pathogeneses: Relative decrease in bioavailability of NO Relative increase in serum endothelin-1 Relative deficieny of PGI2/excess of thromboxane A2 The term PH represents increased PAP but not due to intrinsic vascular disease

Classification of PH

The current classification system groups together forms of pulmonary hypertension based on similarities in their pathophysiologies and responses to treatment. Important to classify patients correctly to ensure therapeutic choices are appropriate. Current classification system revised in 2003, with recent update pending (2/2008).

Group 1 -- PAH

IPAH Familial Associated with PAH Connective Tissue Disease (Scleroderma, SLE, MCTD, DM/PM, RA) Congenital Heart Disease Portal hypertension (5-7% of patients) HIV (0.5% of patients) Drugs/toxins (aminorex-, dexfenfluramine-, or fenfluraminecontaining products, cocaine, methamphetamine) Other: thyroid disorders, glycogen storage disease, Gauchers disease, hereditary hemorrhagic telangiectasia, hemoglobinopathies, myeloproliferative disorders, splenectomy Associated with venous/capillary involvement Pulmonary veno-occlusive disease (elevated mPAP, normal PCWP, evidence of pulmonary vascular congestion) Pulmonary capillary hemangiomatosis PPHN

Groups 2-5 -- PH

Group 2: Pulmonary hypertension with left heart disease Left-sided ventricular or atrial disease Left-sided valvular disease Group 3: Pulmonary hypertension associated with lung disease and/or hypoxemia Chronic obstructive lung disease Interstitial lung disease Sleep-disordered breathing Alveolar hypoventilation disorders Chronic exposure to high altitude Developmental abnormalities Group 4: Pulmonary hypertension due to chronic thrombotic and/or embolic disease Thromboembolic obstruction of proximal pulmonary arteries Thromboembolic obstruction of distal pulmonary arteries Group 5: Miscellaneous Sarcoidosis, histiocytosis X, lymphangiomyomatosis, compression of pulmonary vessels (adenopathy, tumor, fibrosing mediastinitis)

Symptoms of PAH

Dyspnea Fatigue Near syncope/syncope Chest pain Palpitations LE edema

60% 19% 13% 7% 5% 3%

Reasons to Suspect PAH

Unexplained dyspnea despite multiple diagnostic tests Typical symptoms (look for Raynauds) Comorbid conditons:
CREST, liver disease, HIV, sickle cell Family history of PAH History of stimulant/anorexigen use

Why is it missed?

Young patients with non-specific sxs with nl CXR and EKGs often attributed to somatization and treated with reassurance Lack of therapies in earlier era lead to attitude of indifference with regard to aggressive workup Comorbid conditions with similar sxs

Physical exam clues

Telengectasias Calcinosis Raynauds Palmar erythema/stigmata of liver dz JVD RV heave Murmur TR, VSD/ASD Loud P2 (can hear 2nd heart sound clearly at apex) Clubbing LE edema

Diagnostic Work-up

Labs

Autoimmune serologies Markers of liver synthetic function HIV serologies when dictated by history
Not sensitive enough to be a screen but can help guide dx workup

EKG

RVH 87% of PH RAD 79% of PH RAE: p wave > 2.5 mm in II, III, aVF

Diagnostic Work-up

Chest x-ray

Not sensitive enough to screen Attenuated motheaten peripheral vasculature Enlarged PAs (especially right)
Order for screening when clinical suspicion exists Order for standard interval screening in selected groups:

Echocardiogram

Family of those with IPAH or with known BMPR2 mutation Scleroderma spectrum CHD pts Pre-liver transplant

Echocardiogram Findings

Increased sPAP or TR jet Right atrial and ventricular hypertrophy Flattening of interventricular septum Small LV dimension Dilated PA Pericardial effusion Poor prognostic sign RA pressure so high it impedes normal drainage from pericardium Do not drain, usually does not induce tamponade since RV under high-pressure and non-collapsible

Always Rule out CTEPH

Must be excluded in every case of PAH Potentially surgically remediable 1 center with most experience = UCSD V/Q scan is preferred screening test, not PE protocol CT (this is best for acute emboli). In chronic thromboembolic disease, at least one (and more commonly, several) segmental or larger mismatched ventilation-perfusion defects are present. Formal angiography will be done before surgical procedure if V/Q positive

Right Heart Cath

Essential for firm diagnosis:

Helps to not dx people with PAH that do not have it! Vasoreactivity testing

NO, Flolan, Adenosinedrop in mPAP by 10 mmHg to value < 40 mmHg Predicts CCB response

Evaluate for septal defects Shed light on the issue of diastolic dysfunction Interpret data in context of patients volume status

How do we Treat Them?

General measures:

Avoid pregnancy
Contraception imperative Maternal mortality 30%

Immunizations for respiratory illnesses

Influenza & pneumonia vaccinations

Minimize valsalva maneuversincrease risk of syncope

Cough, constipation, heavy lifting, etc

Classes of therapy

Medical Diuretics Coumadin (IPAH, Anorexigen) Oxygen PAH specific therapy Surgical therapy Atrial septostomy Lung transplantation

Diuretics

Principally to treat edema from right heart failure Ventricular interdependenceensure LV output preserved. May need to combine classes
-Thiazide and loop diuretics

Careful to avoid too much pre-load reduction Patients often require large doses of diuretics

Coumadin

Studies only show benefit in IPAH patients, based on improved survival. Other PAH groups not as clear, use in them considered expert opinion. Generally, keep INR 2.0-2.5. Thought to lessen in-situ thrombosis

Oxygen

Formal assessment of nocturnal and exertional oxygenation needs. Minimize added insult of hypoxic vasoconstriction Keep oxygen saturation 90%

May be impossible with large right to left shunt

Overnight oximetry

Exclude nocturnal desaturation

Rule out concomitant obstructive sleep apnea and hypoventilation syndromes

WHO functional classification PAH

Class I: No limitation in physical activity. Ordinary physical activity does not cause undue dyspnea or fatigue, chest pain or near syncope. Class II: Slight limitation in physical activity. Ordinary physical activity causes undue dyspnea or fatigue, chest pain or near syncope. Class III: Marked limitation in physical activity. Less than ordinary physical activity causes undue dyspnea or fatigue, chest pain or near syncope. Class IV: Inability to perform any physical activity without symptoms. Signs of right heart failure. Dyspnea and/or fatigue may be present at rest. Syncope.

PAH-Specific Therapies

Calcium channel blockers Endothelin receptor antagonists (ERAs) bosentan, sitaxsentan, ambrisentan Phosphodiesterase (type 5) inhibitors (PDE 5-I)-sildenafil Prostanoidsepoprostenol, treprostinil, iloprost

Calcium Channel Blockers

Use only when demonstrated vasoreactivity in RHC (about 10% or less of patients) Diltiazem or nifedipine preferred. Titrate up to maximum tolerated dose. Systemic hypotension may prohibit use Only 50% of patients maintain response to CCB. Not in FC IV patients or severe right heart failure

Endothelin Receptor Antagonists (ETRA)

Targets relative excess of endothelin-1 by blocking receptors on endothelium and vascular smooth muscle Bosentan (Tracleer, 5 yrs) and ambrisentan (Letairis, 1 yr) Ambrisentan is ET-A selective. Both show improvement in 6MWD and time to clinical worsening. Monthly transaminase monitoring required for both Annual cost about $40,000

Bosentan (Tracleer)

215 patients 70% IPAH 92% Class III Week 16: 36 meter Improvement 44 meter treatment effect

1Adapted from Rubin LJ et al. N Engl J Med 2002;346:896-903

Bosentan (Tracleer)
Improved Hemodynamics
CI
+ 1.0 L/min/m2
(p=0.001 )
50%

mRAP
- 6.2 mm Hg (p=0.001)
+4.9 4.6

PVR
- 415dyn/sec/cm-5 (p=0.001)

PAP
- 6.7 mm Hg (p<0.02)

Change from baseline (%)

40% 30% 20% 10% 0% -10%

-1.6 5.1 +5.1 8.8 +0.5 0.5 +191 235

-20%
-30%

-1.3 4.1
-0.5 0.5 -223 245

Placebo

Tracleer

One patient in each treatment group had no valid week 12 assessment and was not included in the analysis. Adapted from Channick, et al. Lancet 2001

Bosentan (Tracleer)
Potential for serious liver injury (including very rare cases of unexplained hepatic

cirrhosis after prolonged treatment)

Tracleer causes at least a 3-fold increase in aminotransferases (ALT and AST) in about 11% of patients and may be accompanied by an elevation of bilirubin in a

small number of cases Teratogenic and lowers sperm Significant drug interactions Glyburide inhibits bosentan metabolism Bosentan induces metabolism of oral contraceptives, warfarin, and statins Calcineurin inhibitors (cyclosporin A, tacrolimus), protease inhibitors, amiodarone, ketoconozole

Bosentan (Tracleer)

Oral dosing Initiate at 62.5 mg BID for first 4 weeks Increase to maintenance dose of 125 mg BID thereafter Initiation and maintenance dose of 62.5 mg BID recommended for patients >12 years of age with body weight <40kg No dose adjustment required in patients with renal impairment No predetermined dose adjustments required for concomitant warfarin administration*

Ambrisentan (Letairis)

5 or 10 mg once daily Much less risk of transaminase elevation (about 1%), but monthly monitoring still required No dose adjustment of coumadin needed

PDE-5 inhibitors

Adapted from Hill, N. NJ Fellows Conf in PAH 12/2/06

Sildenafil (Revatio)

Adapted from Hill, N. NJ Fellows Conf in PAH 12/2/06

Sildenafil (Revatio)

Adapted from Hill, N. NJ Fellows Conf in PAH 12/2/06

Sildenafil (Revatio)

Safety
Side effects: headaches, epistaxis, and hypotension (transient) Sudden hearing loss Drug interaction with nitrates FDA approved dose is 20 mg tid

Higher doses often used given hemodynamic findings.

Prostacyclin analogues

Epoprostenol, treprostinil, iloprost Benefits

Vasodilation Platelet inhibition Anti-proliferative effects Inotropic effects

Epoprostenol (Flolan)

First PAH specific therapy available in the mid 1990s Lack of acute vasodilator response does not correlate well with epoprostenol unresponsiveness. Very short half life = 2 minutes Delivered via continuous infusion Cost about $100,000/year

Epoprostenol (Flolan)

Adapted from Hill, N. NJ Fellows Conf in PAH 12/2/06

Epoprostenol (Flolan)

Adapted from Hill, N. NJ Fellows Conf in PAH 12/2/06

Epoprostenol (Flolan)

Side effects: headache, jaw pain, flushing, diarrhea, nausea and vomiting, flu-like symptoms, and anxiety/nervousness Complex daily preparation Individualized dosing Catheter complications

Dislodgement/malfunction Catastrophic deterioration Embolization Infection (3% deaths)

1 Flolan Flolan[package [package insert]. Research Triangle Park, NC:GlaxoSmithKline;2002 insert]. Research Triangle Park, NC:GlaxoSmithKline;2002 2Rich S et al. Rich S et al. J Am College J Am College Cardiol Cardiol 1999;34:1184 1999;34:1184-87 87 McLaughlin V et al. McLaughlin V et al. Circulation Circulation 2002;106:1477 2002;106:1477-82 82

Treprostinil (Remodulin)

Continuous subcutaneous infusion or IV infusion Longer t1/2 than flolan = 4 hours

Less risk of rapid fatal deterioriation if infusion stops

Significant site pain at infusion site limits use

Adapted from Hill, N. NJ Fellows Conf in PAH 12/2/06

Treprostinil (Remodulin)

Adapted from Hill, N. NJ Fellows Conf in PAH 12/2/06

Treprostinil (Remodulin)

Intravenous treprostinil
Hemodynamic improvements and 6MWD improvements 1 No site pain Risk of catheter related bloodstream infection and embolic phenomenon Recent concerns about increased gram-negative bloodstream infections (CDC MMWR March 2, 2007 / 56(08);170-172)

1Tapson VF et al. Chest 2006;129:683-88

Iloprost (Ventavis)

Inhaled prostacyclin Administered 6-9 times daily via special nebulizer Reported risk of morning syncope

Iloprost (Ventavis)

Improvements in 6MW, functional class and hemodynamics observed

Olschewski H et al. N Engl J Med 2002;347:322-29

Safety and side effects

Potential for increased hypotensive effect with antihypertensives Increased risk of bleeding, especially with co-administration of anticoagulants Flushing, increased cough, headache, insomnia Nausea, vomiting, flu-like syndrome Increased liver enzymes

ACCP 2007 Treatment Guidelines

Following Response to Therapy

Six minute walk test Echocardiogram Right heart catheterization BNP Functional class

Acute Decompensations

Patients with advanced PAH may present acutely with volume overload, marginal blood pressure, and, at times, elevated creatinine, related either to an acute process or simply worsening RV failure. In the decompensated patient, elevated RV volume leads to septal shift, with reduced left ventricular enddiastolic volume and low cardiac output. Treatment of the acutely ill patient with PAH should include careful evaluation for secondary causes of decompensation such as a low-grade line infection (for those on an intravenous therapy) or pulmonary thromboembolism.

Acute Decompensations

Many patients are volume overloaded at presentation, and diuresis, even in the setting of marginal cardiac output and low blood pressure, may be required. In some cases, support with inotropes or pressors is necessary: animal data suggest a better hemodynamic response with sympathomimetic agents such as dobutamine, norepinephrine, and dopamine rather than vasopressin or phenylephrine; milrinone also has favorable effects on cardiac output but may lead to excessive hypotension.

Summary

Make sure to differentiate PAH from PH Determine etiology of PAH as best as possible Refer early to specialist if you find it Dont treat without a RHC Treat agressively, dont settle for stability