Pulmonary Hypertension:

Recognize the Signs

Denise A. Gonzales, MD, MS

Pulmonary and Critical Care Medicine

Presbyterian Medical Group

Albuquerque, NM

What is Pulmonary Arterial Hypertension?

Normal Cardiac Chamber Pressures

PAH is an abnormal increase in the blood pressure in the pulmonary arteries

Normal mean pressure 8-20 mmHg at rest

Normal Oxygenation by Chamber Desaturated blood

enters RA The RV delivers

blood to lungs Fully saturated

blood returns to LA The LV delivers

oxygenated blood to body

Chamber Pressures in PAH

55

>30>30

Mean >24 at rest, >30 with exercise PCWP <15 mmHg

Pathophysiology of PHTN Hypoxemia causes vasoconstriction Decreased perfusion worsens

hypoxemia Hypoxic alveoli cause arterioles to

vasocontrict further to preserve VQ matching

Pulmonary pressures increase and become sustained

Right ventricle works harder, develops hypertrophy and overload

Physiologic Effects of PAH

Old Classification Idiopathic pulmonary arterial

hypertension (IPAH) Or primary pulmonary hypertension

(PPH)

Secondary pulmonary hypertension

Current WHO Classification

Group 1 PAH Connective tissue diseases

12% SSc have PAH HIV infection

0.5% have PAH Portal hypertension

2-6% have PAH Congenital heart disease Chronic hemolytic anemia Pulmonary veno-occlusive disease Pulmonary capillary hemangiomatosis Idiopathic (BMPR2 gene abnormality)

Pathologic Vascular Changes1. Walls of small pulmonary

arteries thicken. 2. Fibrous, or scarred, tissue

appears on inner wall of small pulmonary artery.

3. Bands of scarred tissue build up on inner wall of small pulmonary artery, substantially narrowing the blood vessel.

1

2

3

Normal

Group 1 PAH Drug- and Toxin-Induced

Aminorex Fenfluramine/Dexfenfluramine Toxic rapeseed oil Amphetamines

methamphetamines, cocaine L-tryptophan Phenylpropanolamine St. John’s Wort Chemotherapeutic agents Selective serotonin reuptake

inhibitors

Group 2 Pulmonary Hypertension (PH)

Group 2 Due to left

heart disease systolic

dysfunction diastolic

dysfunction valvular heart

disease

Group 3 PHLung Diseases or Hypoxemia

COPD interstitial lung

disease (ILD) sleep-disordered

breathing (OSA 15% have PAH)

alveolar hypoventilation disorders (OHV)

other causes of hypoxemia

Central OHV

COPD/ILDCHF

OSA

Group 3 PH COPD 5-year survival

< 10% if mean PAP > 45 mmHg

> 90% if mean PAP < 25 mmHg

PH more strongly associated with hypoxemia than lung function

Group 4 PHChronicThromboembolic Disease

Group 5 PH Secondary to unclear

multifactorial causes hematologic

(myeloproliferative disease)

systemic disorders (sarcoidosis)

metabolic disorders (glycogen storage disease)

What Are the

Signs of PHTN?

What should prompt an evaluation?

Diagnostic Tests: Bloodwork Complete metabolic panel

liver and kidney function Autoantibody tests (ANA, ESR, etc)

collagen vascular diseases Thyroid stimulating hormone HIV Arterial blood gases Complete blood count

infection, elevated hemoglobin, and anemia

B-type natriuretic peptide (BNP) heart failure

Diagnostic Tests: CXR Enlarged right

ventricle and pulmonary arteries.

Diagnostic Testing: EKG Right-axis

deviation

R/S>1 in V1

Deep S-wave in V5, V6

Tall P-wave in lead II

Right bundle branch block

Diagnostic Tests

Doppler echocardiogram

Diagnostic Tests: CT Scan Pulmonary

emboli Interstitial lung

disease PA/Ao > 2/3 can

indicate PHTN

Diagnostic Testing Ventilation perfusion scan (V/Q)

Q: Perfusion V: Ventilation

Diagnostic Testing: Right Heart Catheterization

Heart pressures RA, RV, PA, LVEDP

Cardiac output Valve competence Septal defects

Diagnostic Testing Pulmonary Angiography

Diagnostic Tests: Physiology 6 minute walk test

track effects of therapy Pulmonary function tests

Diagnose COPD, ILD, hypoventilation PSG or overnight oximetry

Diagnose hypoxemia due to sleep disordered breathing

Functional Assessment Class I

Patients with PHTN without limitation of physical activity

Ordinary physical activity does not cause undue dyspnea or fatigue, chest pain or near syncope

Class II Slight limitation of physical activity,

comfortable at rest Ordinary physical activity causes undue

dyspnea or fatigue, chest pain or near syncope

Functional Assessment Class III

Marked limitation of physical activity, comfortable at rest

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 Dyspnea and/or fatigue may be present at

rest, and discomfort is increased by any physical activity

*Modified from the New York Heart Association classification of patients with cardiac disease

PAH/PH Natural History Group 1 symptomatic patients who do

not receive treatment Median survival ~3 years If mean RAP ≥20 mmHg, median survival ~1 month!

Groups 2-5 symptomatic patients have a

worse prognosis If severe PHTN or RHF, death within one year

Patients with cardiac arrest rarely survive 3000 patients with PAH who required CPR had a 6%

90-day survival (180 people lived to 90 days)

Risk Factors for Poor Prognosis Age at presentation > 45 years Functional class III or IV Pericardial effusion Large right atrial size Elevated right atrial pressure Septal shift during diastole Increased BNP level Failure to improve to a lower

functional class during treatment

Routine Medical Treatments Continuous oxygen

Pulmonary artery vasodilator Anticoagulants

Treat and prevent thrombosis Diuretics / Low Salt Diet

Decrease RA pressures Treat right heart failure

Digoxin Increases cardiac output

Routine Medical Treatments Calcium channel blockers

Lowers pulmonary artery pressure May improve right heart cardiac

output Exercise Immunization

Prevent pulmonary infections Opportunistic Infection Prophylaxis

Patients on immunosuppression (ILD)

Surgical Therapies Pulmonary thromboendarterectomy Correct mitral stenosis Repair left to right shunt (ASD, VSD) Atrial septosotomy to relieve RHF

when PA pressure exceeds systemic pressure

Lung transplantation for advanced PHTN not responsive to medical

therapy ~1,000 lung transplants/year in US

Heart / lung transplantation

Who Should Receive Advanced Medical Therapy?

Group 1 (PAH) rarely respond to primary therapies

Group 2 (cardiac abnormalities) usually worsen with advanced therapies

Group 3 (COPD) respond to oxygen therapy

Group 4 (thromboembolic) respond to thrombectomy and anticoagulation

Group 5 unknown effects of advanced therapies, primary therapy indicated

Before Starting Advanced Therapies

Vasoreactivity test IV adenosine or epoprostenol inhaled nitric oxide  patients with Type 1 PAH are most likely to

respond Vasoreactivity test is positive if

mean PAP decreases at least 10 mmHg and to a value < 40 mmHg

increased or unchanged cardiac output minimally reduced or unchanged systemic

blood pressure

Step-up Therapy CCB therapy is the first-line treatment

for patients with +vasoreactivity test

Prostanoids IV epoprostenol (Prostacyclin), treprostinil

(Remodulin) Subcutaneous treprostinil (Ventavis) Inhaled treprostinil, iloprost

Prostacyclin delivered continuously through a central venous catheter initiated at doses of 1 to 2 ng/kg /min increase by 1-2 ng/kg/min every 1-2 days doses ~150-200 ng/kg/min side effects: jaw pain, diarrhea, arthralgias

Iloprost (Ventavis) Inhaled but administered 6-9 times daily

Endothelin Receptor Antagonists Endothelin-1

potent vasoconstrictor and smooth muscle mitogen high concentrations found in group 1 PAH

Bosentan (Tracleer) orally administered

nonselective endothelin receptor antagonist

Ambrisentan (Letaris) and sitaxsentan (Thelin) selective type A endothelin-1 receptor antagonist

Phosphodiesterase Inhibitors Sildenafil (Viagra, Revatio) Tadalafil (Cialis, Adcirca) Vardenafil (Levitra)

orally administered cyclic GMP phosphodiesterase type 5 (PDE5)

inhibitors prolong vasodilatory effect of nitric oxide

Substantial treatment effect differences in PDE5 inhibitors rate of onset pulmonary vascular selectivity only sildenafil associated with improved oxygenation

Combination Medical Therapy Bosentan added to epoprostenol or treprostinil

BREATHE-2 trial randomized 22 patients Treprostinil added to bosentan or sildenafil

TRIUMPH trial randomized 235 patients improved 6 minute walk

Sildenafil added to epoprostenol 267 patients with group 1 PAH improved hemodynamics, exercise capacity, quality of life,

and time to worsening Sildenafil added to bosentan

25 patients with group 1 PAH clinical improvement of symptoms, exercise capacity, and

WHO functional class Sildenafil added to iloprost

73 patients with group 1 PAH improvement in exercise capacity, WHO functional class,

and hemodynamics

Nitric Oxide (NO) Endogenous NO

endothelium-derived relaxing factor (EDRF) naturally occurring vasodilator produced from L-arginine in endothelial cells by endothelial

nitric oxide synthase (eNOS) induces increased cGMP which causes smooth muscle

relaxation T1/2 0.1 to 5 seconds

Pharmacology threshold for pulmonary vasodilation ~10 ppm No clear dose-effect curve suppresses smooth muscle proliferation Decreases platelet aggregation T1/2 15 to 30 seconds at a dose of 5 to 80 ppm rapidly inactivated to nitrosylmethemoglobin

NO Vasoreactivity Test Start at 5 ppm Titrate up by 10 ppm

every 10 minutes +Vasoreactivity test at

80 ppm predicts response to nifedipine with 94% predictive

accuracy

Other Uses for NO PAH worsened due to

acute illness PH after lung transplant PH after MVR in chronic

PH patients Acute right heart

syndrome causing systemic hypotension pulmonary embolism ARDS

Mechanism of Action: NO in VQ Mismatched States

Adapted from Up to Date

Will My Patient Respond to NO? Less likely with septic shock (33

vs 64%) Yes if high pulmonary vascular

resistance Maybe if responsive to PEEP

Dosing 1.25 -40 ppm continuously for days to weeks interruptions result in desaturation patients may become sensitized and

require lower doses

Potential Harm of NO Inhaled NO may produce toxic radicals

But so does high FiO2!

Methemoglobin and NO2 may increase both should be monitored only sustained doses of

80ppm cause increases Immunosuppressant

properties could increase risk of infection

NO for ARDS-Induced PHThe Studies

Multicenter trial (n=385), P/F ratio ≤ 250 mmHg NO at 5 ppm short-term improvement of oxygenation no improvement in mechanical ventilation or

mortality Multicenter RCT (n=177) with ARDS

modestly improved oxygenation no difference in 28-day mortality

Meta-analysis of 10 RCTs (n=1237 patients) NO versus conventional management no improvement in mortality or ventilator-free days increased P/F ratio without effect on mean PA

pressure

Why Use NO in ARDS? Hypothetical

antiinflammatory properties antiplatelet activity Improved vascular permeability

Treatment effects comparable to proning oscillation surfactant ECMO antioxidants including nutritionals when standard treatment is limited tidal

volume ventilation

Summary The signs and symptoms of

PAH/PH you can see as a respiratory therapist Dyspnea, fatigue, extremity

edema ILD by CXR or PFTs COPD by CXR of PFTs Hypoventilation by PFTs,

PSG Typical EKG changes

Summary The tests and therapies

you provide as a respiratory therapist for patients with PAH/PH PFTs, PSG, 6-minute walk NO vasoreactivity test NO therapy in the ICU