Selective Serotonin Reuptake Inhibitors (SSRI) (see Selective Serotonin Reuptake Inhibitors): no clear association between SSRI’s and the development adult pulmonary hypertension
Epidemiology
Maternal Use of SSRI’s Has Been Associated with Persistent Pulmonary Hypertension in the Neonate (JAMA, 2015) [MEDLINE]
Use of SSRI’s in Patients with Established Pulmonary Hypertension Has Been Associated with an Increased Mortality Rate (Chest, 2013) [MEDLINE]
Epidemiology: pulmonary hypertension occurs in 0.7-6% of patients with liver disease (rates may be as high as 16% in patients with end-stage liver disease)
Congenital Heart Disease in Adults
Eisenmenger Syndrome (see Eisenmenger Syndrome): includes all large intracardiac/extracardiac defects which begin as systemic-to-pulmonary shunts, progress to severe elevation of pulmonary vascular resistance, and progress to reverse shunting (pulmonary-to-systemic) or bidirectional shunting
Cyanosis, secondary erythrocytosis, and multiple organ involvement are usually present
Pulmonary vascular resistance is mildly to moderately increased
Systemic-to-pulmonary shunting is still prevalent
Cyanosis is not a feature
Pulmonary Hypertension with Small/Coincidental Congenital Heart Disease: includes conditions with marked elevation in pulmonary vascular resistance in the presence of small cardiac defects, which themselves do not account for the development of elevated pulmonary vascular resistance
Clinical picture is very similar to idiopathic pulmonary arterial hypertension
Closing the defect is contraindicated
Pulmonary Hypertension Occurring Post-Operatively Following Repair of Congenital Heart Disease: includes conditions where the congenital heart disease is repaired but pulmonary arterial hypertension either persists immediately after surgery or recurs months or years later after surgery (in the absence of significant post-operative hemodynamic lesions)
Clinical phenotype is often aggressive
Schistosomiasis (see Schistosomiasis): probably the most common worldwide etiology of pulmonary hypertension
Epidemiology: schistosomiasis is the most common cause of pulmonary hypertension worldwide
Physiology: schistosome ova embolize to the lung and induce a granulomatous reaction in the pulmonary arterioles
Persistent Pulmonary Hypertension of the Newborn (PPHN)
Group 2: Pulmonary Arterial Hypertension Due to Left Heart Disease
General Comments
Pulmonary hypertension due to left heart disease is the most frequent cause of pulmonary hypertension
Diagnostic Features: left atrial-mean pressure >14 mm Hg with associated pulmonary venous hypertension
Importantly, the degree of pulmonary hypertension that results from a given level of left atrial hypertension is highly variable due to individual differences in the vasoconstrictive and vascular remodeling responses in the pulmonary arterial circulation
Obesity-Associated Restrictive Cardiomyopathy: characterized by fatty infiltration of cardiac myocytes, restrictive physiology, and elevation in left and right heart filling pressure -> severe pulmonary hypertension secondary to occlusive vasculopathy of the small pulmonary arteries and arterioles may also occur
Epidemiology: 90% of COPD patients have mild-moderate pulmonary hypertension (while only 3-5% have severe pulmonary hypertension)
Severe pulmonary hypertension portends a worse prognosis: PA-mean pressure >45 mm Hg has a significantly worse 5–year survival (<10% versus >90%) [MEDLINE]
Patients with PA-Mean ≥35 mmHg or ≥25 mm Hg + Cardiac Index <2 L/min/m2: this subset of COPD/ILD/CPFE patients (at higher risk for mortality) is defined under the NICE classification as having severe pulmonary hypertension, meriting consideration of care at a specialized center or being enrolled in investigational therapy
Bronchiectasis (see Bronchiectasis): with severe, diffuse disease
Epidemiology: pulmonary hypertension occurs in 8-32% of ILD cases
Patients with PA-Mean ≥35 mmHg or ≥25 mm Hg + Cardiac Index <2 L/min/m2: this subset of COPD/ILD/CPFE patients (at higher risk for mortality) is defined under the NICE classification as having severe pulmonary hypertension, meriting consideration of care at a specialized center or being enrolled in investigational therapy
Idiopathic Pulmonary Fibrosis (IPF) (see Idiopathic Pulmonary Fibrosis): pulmonary hypertension is more common when hypoxemia and severe pulmonary dysfunction are present
Other Severe Interstitial Lung Disease of Any Etiology (see Interstitial Lung Disease): pulmonary hypertension is more common when hypoxemia and severe pulmonary dysfunction are present
3.3: Other Pulmonary Disease with Mixed Restriction-Obstruction
Combined Pulmonary Fibrosis and Emphysema (see Combined Pulmonary Fibrosis and Emphysema): pulmonary hypertension is a common complication (and pulmonary hypertension is more frequent and severe, as compared to COPD and ILD alone)
Patients with PA-Mean ≥35 mmHg or ≥25 mm Hg + Cardiac Index <2 L/min/m2: this subset of COPD/ILD/CPFE patients (at higher risk for mortality) is defined under the NICE classification as having severe pulmonary hypertension, meriting consideration of care at a specialized center or being enrolled in investigational therapy
Normal Pulmonary Arterial-Systolic Pressure: 15-30 mm Hg
Normal Pulmonary Artery-Diastolic Pressure: 4-12 mm Hg
Normal Pulmonary Artery-Mean Pressure: ≤20 mmHg
Hypoxic Pulmonary Vasoconstriction
Background
Hypoxic Pulmonary Vasoconstriction is a Normal Physiologic Mechanism Designed to Decrease Blood Flow to Hypoxic Alveoli and Optimize Ventilation/Perfusion Matching
Acute Hypoxic Pulmonary Vasoconstriction
Reversibility: completely reversible with oxygen therapy
Mechanisms of Acute Hypoxic Pulmonary Vasoconstriction
Immediate Pre-Capillary Arteriolar Vasoconstriction Mediated by Mitochrondrial Signaling and Smooth Muscle Ion Channels
Chronic Hypoxic Vasoconstriction
Reversibility: initially reversible with oxygen therapy, but eventually becomes only partially reversible (due to superimposed vascular remodeling)
The degree of vascular remodeling is individually variable, explaining the variable progression to pulmonary hypertension in diseases such as COPD
Mechanisms of Chronic Hypoxic Vasoconstriction (and Narrowing)
Decreased Endothelial Nitric Oxide Synthase (eNOS) with Resulting Decreased NO Synthesis and Increased Hemoglobin-Mediated Inactivation
Decreased Voltage-Gated Potassium Channel Alpha Subunits or Voltage-Gated Potassium Channel Activity with Resulting Change in Resting Membrane Potential: results in increased free calcium and pulmonary arterial smooth muscle contraction (vasoconstriction)
Increased Cytosolic Phospholipase A2 (cPLA2) Activity with Increased Arachidonic Acid Release from Membranes: arachidonic acid is metabolized by cyclooxygenases/lipoxygenases to eicosoanoids (prostaglandins, thomboxanes, and leukotrienes)
Increased Endothelin Expression
Neomuscularization, Intimal Thickening, and Medial Hypertrophy of Pulmonary Arterioles: later in course, collagen matrix is deposited in the adventitia
Pathophysiology of Pulmonary Hypertension by Group
Group 1: proliferative vasculopathy of small muscular pulmonary arterioles
Intimal Hyperplasia
Medial Hypertrophy
Plexiform Lesions
Group 2-5: pathophysiology is less well understood
Clinical Utility: PFT’s are useful to assess for underlying lung disease, but may demonstrate findings which are specific for the pulmonary hypertension itself
Findings
Mild-Moderate Restriction: may be seen (and is related to disease severity)
Decreased DLCO: variable
Normal DLCO does not rule out pulmonary hypertension
DLCO <45% pred is asscociated with a worse outcome
Echocardiogram is a screening test for the presence of pulmonary hypertension
However, due to its limitations (in terms of sensitivity/specificity), Swan-Ganz catheter measurement of pulmonary artery pressure is considered the gold standard
Clinical Findings
Tricuspid Regurgitation
Estimated PA-Systolic = TR Jet Peak Velocity (in m/sec) Squared x 4 + Central Venous Pressure
Right Ventricle/Left Ventricle Basal Diameter Ratio >1.0
Flattening of Intraventricular Septum*: left ventricular eccentricity index >1.1 in systole and/or diastole
Right Ventricular Outflow Doppler Acceleration Time <105 msec and/or Midsystolic Notching
Early Diastolic Pulmonary Regurgitation Velocity >2.2 m/sec
IVC Diameter >21 mm with Decreased Inspiratory Collapse (<50% with a Sniff or <20% with Quiet Inspiration)
Right Atrial Area (End-Systole) >18 cm2
Clinical Efficacy
Study of Echocardiogram in the Diagnosis of Pulmonary Hypertension (Eur Respir J, 2022) [MEDLINE]: n= 278 patients referred for pulmonary hypertension who underwent a comprehensive echocardiography followed by a right heart catheterization
With Pulmonary Hypertension Defined by a Mean PAP >20 mmHg, 23 patients Had No Pulmonary Hypertension, 146 Had Pre-Capillary Pulmonary Hypertension, and 94 Had Post-Capillary Pulmonary Hypertension
At univariate analysis, maximum velocity of tricuspid regurgitation (TRV) ≥2.9 and ≤3.4 m s-1, left ventricle (LV) eccentricity index >1.1, right ventricle (RV) outflow tract (OT) notching or acceleration time <105 ms, RV-LV basal diameter >1 and PA diameter predicted PH, whereas inferior vena cava diameter and right atrial area did not
At multivariable analysis, only TRV ≥2.9 m s-1 independently predicted Pulmonary Hypertension
Additional independent prediction of Pulmonary Vascular Resistance (PVR) >3 Wood Units was offered by LV eccentricity index >1.1 and RVOT acceleration time <105 ms and/or notching, but with no improvement of optimal combination of specificity and sensibility or positive prediction
V/Q scan has traditionally been considered the screening method of choice for chronic thromboembolic pulmonary hypertension because of its higher sensitivity than CT pulmonary angiogram (especially in inexperienced centers)
Normal CT Pulmonary Angiogram: 90-100% sensitivity/94-100% specificity for the diagnosis of chronic thromboembolic pulmonary hypertension (CTEPH)
However, many V/Q scans are not diagnostic
Idiopathic Pulmonary Arterial Hypertension (IPAH): normal or “mottled” appearance (small peripheral unmatched or non-segmental perfusion defects)
However, unmatched perfusion defects may also be seen in pulmonary veno-occlusive disease (PVOD) (see Pulmonary Veno-Occlusive Disease)
Chronic Thromboembolic Pulmonary Hypertension (CTEPH): 1 or more segmental or lobar defects
Clinical Utility: 3-dimensional magnetic resonance perfusion mapping has been demonstrated to be as sensitive as V/Q scanning in the diagnosis of chronic thromboembolic pulmonary hypertension (CTEPH)
Definition of Pulmonary Hypertension: defined as resting pulmonary arterial-mean pressure ≥25 mmHg at rest (confirmed by Swan-Ganz catheterization)
PA-Mean 21-24 mm Hg: borderline elevated -> unclear clinical significance
Definition of Exercise-Associated Pulmonary Hypertension: due to the lack of reliable data which defines this entity, standard diagnostic parameters (for pulmonary pressures and PVR) have not been defined
Swan-Ganz catheter Measurement of Pulmonary Artery Pressure is Considered the Gold Standard
Pulmonary Hypertension with Elevated Pulmonary Capillary Wedge Pressure (PCWP)
Approximately 10% of Patients with Idiopathic Pulmonary Arterial Hypertension are Vasoreactive: treatment with calcium channel blockers may result im a marked decrease in pulmonary hypertension and PVR
True Calcium Channel Blocker Responders are Uncommon in Other Types of Pulmonary Hypertension
Technique
Swan-Ganz Catheter Monitoring of Pulmonary Artery Pressure with Short-Acting Pulmonary Vasodilator Administration
Hypotension (see Hypotension): since vasoreactivity testing may precipitate hypotension
Low Cardiac Output
Presence of WHO Functional Class IV Symptoms
Interpretation
Vasoreactivity: defined as a >10 mm Hg decrease in PA-Mean and to a value <40 mm Hg with an increased or unchanged cardiac output (and a minimally decreased or unchanged systemic blood pressure)
Recommendations (Chest 2014 Guidelines for Pharmacologic Therapy of Pulmonary Hypertension in Adults) (Chest, 2014) [MEDLINE]
In the Absence of Contraindications, All Patients with Pulmonary Hypertension Should Undergo Acute Vasoreactivity Testing with a Short-Acting Pulmonary Vasodilator at a Center Experienced in Performing Such Testing (Grade CB Recommendation)
Hoarseness (see Hoarseness): due to compression of the left recurrent laryngeal nerve by dilated pulmonary artery
Pulmonary Manifestations
Hemoptysis (see Hemoptysis): may occur in some cases due to rupture of hypertrophied bronchial arteries
Hypoxemia with Hypocapnia (see Hypoxemia): due to hyperventilation
Nocturnal Hypoxemia (see Hypoxemia): common in pulmonary hypertension (occurs in 70-80% of cases) [MEDLINE]
Central Sleep Apnea (CSA) (see Central Sleep Apnea): common in pulmonary hypertension (occurs in 70-80% of cases) [MEDLINE]
Exertional Dyspnea (see Dyspnea): due to inability to increase cardiac output during exercise
Wheezing: may occur in some cases due to large airway compression by dilated pulmonary artery
Rheumatologic Manifestations
Anasarca/Peripheral Edema (see Peripheral Edema): due to RV failure
Cool Extremities
Reproductive Manifestations
Increased Risk of Death with Pregnancy (see Pregnancy)
General Comments
Diagnosis of Pulmonary Hypertension May Be Delayed/Missed During Pregnancy: due to the dyspnea that occurs in normal pregnancy (that is believed to be related to high levels of circulating progesterone)
Pregnancy Increases the Mortality Rate in Pulmonary Hypertension: due to the increased physiologic demands of pregnancy and childbirth
Parturition and the First Postpartum Week are the Most Vulnerable Period for Pregnant Patients with Pulmonary Hypertension
Physiology
During Pregnancy, Cardiac Output Increases by Up to 30-50% Above Pregestational Levels (Begin During First Trimester and Peak During 20-24 wks of Gestation): stroke volume increases with decrease in systemic vascular resistance and blood pressure
During Pregnancy, Plasma Volume Increases by Up to 30-50% Above Pregestational Levels (Begin During First Trimester and Peak During 20-24 wks of Gestation)
During Pregnancy, Heart Rate Increases 10-20 Beats/min (Begin During First Trimester and Peak During 20-24 wks of Gestation)
During Delivery, Valsalva Manuever and Pain Increase the Heart Rate and Vascular Resistances
In Hours-Days Post-Parturition, Autotransfusion of Blood from Contracting Uterus and Shifting of Peripheral Edema from the Extravascular Compartment Back into the Systemic Vascular Space Occur
Clinical Data
Systematic Review of Mortality of Pulmonary Hypertension in Pregnancy (Eur Heart J, 2009) [MEDLINE]
Mortality Rate of Pulmonary Hypertension in Pregnancy Has Decreased from 30-56% (Mean: 38%) in the Articles Published in the Period 1978-1996 to 17-33% (Mean: 25%) in the Articles Published in the Period 1997-2006
78% of Deaths Occurred Within the First Month After Delivery
Primigravidae and Parturients who Received General Anesthesia were at the Highest Risk of Death
Case Series of 18 Pregnant Patients with Pulmonary Hypertension (Chest, 2013) [MEDLINE]
33% (6/18) Patients Had the Pregnancy Terminated in the First Trimester
None of These Patients Experienced Maternal Complications
66% (12/18) Patients Received Care Consisting of Daily Fluid Restriction, Anticoagulation, Diuretics, and Supplemental Oxygen
Maternal Mortality Rate in This Group: 16.7% (this mortality rate is lower than previously reported and may be related to care early termination in a significant number of pregnant patients and for those who did not, care in a experienced pulmonary hypertension center)
75% of Patients Received Pulmonary Hypertension-Specific Therapy Several Weeks Prior to Delivery
Increased Risk of Small-for-Gestational Age Infants
Epidemiology: demonstrated in women with idiopathic pulmonary arterial hypertension
Increased Risk of Congenital Anomalies
Epidemiology: has been reported
Increased Risk of Death with Mechanical Ventilation, General Anesthesia, and Surgical Procedures
Rate of Major Complications in Patients with Pulmonary Hypertension Undergoing Surgery: 6% (Anaesth Intensive Care, 2009) [MEDLINE]
Rate of Perioperative Mortality in Patients with Pulmonary Hypertension Undergoing Surgery: 3.5% (Anaesth Intensive Care, 2009) [MEDLINE]
Risk Factors Predicting Major Complications
6-Minute Walk Test (6MWT) Distance ≤399 meters (see 6-Minute Walk Test): odd ratio 2.2
Supplemental Oxygen Should Be Used at Altitude to Maintain SaO2 >91% (Grade CB Recommendation) (see Oxygen) (Chest 2014 Guidelines for Pharmacologic Therapy of Pulmonary Hypertension in Adults) (Chest, 2014) [MEDLINE]
Avoidance of Non-Essential Surgery (Grade CB Recommendation) (Chest 2014 Guidelines for Pharmacologic Therapy of Pulmonary Hypertension in Adults) (Chest, 2014) [MEDLINE]
If Surgery is Necessary, Should Be Performed at a Center Specializing in Pulmonary Hypertension Care and with Cardiovascular Anesthesia Services (Grade CB Recommendation)
Avoidance of Pregnancy (with Adequate Contraception) (see Pregnancy) (Chest 2014 Guidelines for Pharmacologic Therapy of Pulmonary Hypertension in Adults) (Chest, 2014) [MEDLINE]
Estrogen-Containing Contraceptives Increase the Risk of Venous Thromboembolism and are Not Recommended for Women of Childbearing Age with Pulmonary Hypertension
Bosentan May Decrease the Efficacy of Hormonal Contraception
Termination of Pregnancy May Be Recommended in Specific High-Risk Cases
Influenza Vaccination (Grade CB Recommendation) (see Influenza Virus) (Chest 2014 Guidelines for Pharmacologic Therapy of Pulmonary Hypertension in Adults) (Chest, 2014) [MEDLINE]
Pneumocccal Vaccination (Grade CB Recommendation) (see Streptococcus Pneumoniae) (Chest 2014 Guidelines for Pharmacologic Therapy of Pulmonary Hypertension in Adults) (Chest, 2014) [MEDLINE]
Recommendations-General Recommendations (Chest 2014 Guidelines for Pharmacologic Therapy of Pulmonary Hypertension in Adults) (Chest, 2014) [MEDLINE]
Pulmonary Hypertension Should Be Evaluated Using a Combination of World Health Organization (WHO) Functional Class, Exercise Capacity, Echocardiogram, and Laboratory/Hemodynamic Variables (Grade CB Recommendation)
When Possible, All Pulmonary Hypertension Patients Should Be Evaluated at a Center with Expertise in the Diagnosis of Pulmonary Hypertension (Grade CB Recommendation)
Care of Pulmonary Hypertension Patients Should Be Coordinated Between Local Physicians and Those with Expertise in Pulmonary Hypertension Care (Grade CB Recommendation): may involve cardiologists, pulmonologists, rheumatologists, primary care, etc
Recommendations-Treatment Naive Patients without Symptoms (WHO Functional Class I) and Patients at Increased Risk for the Development of Pulmonary Hypertension (Chest 2014 Guidelines for Pharmacologic Therapy of Pulmonary Hypertension in Adults) (Chest, 2014) [MEDLINE]
For Treatment Naive Patients without Symptoms (WHO Functional Class I), Continued Monitoring is Recommended to Detect Symptoms that Would Merit the Initiation of Pharmacotherapy (Grade CB Recommendation)
For Patients at Risk of the Development of Pulmonary Hypertension (Scleroderma, Known Mutation Associated with Pulmonary Hypertension), Patient Should Be Monitored to Detect Symptoms Consistent with Pulmonary Hypertension (Grade CB Recommendation)
Contributing Causes of Pulmonary Hypertension (Obstructive Sleep Apnea, Systemic Hypertension) Should Be Treated Aggressively in Patients with Pulmonary Hypertension (Grade CB Recommendation)
Recommended Therapies by WHO Functional Class (Chest 2014 Guidelines for Pharmacologic Therapy of Pulmonary Hypertension in Adults) (Chest, 2014) [MEDLINE]
WHO Functional Class II
For WHO Functional Class II Patients Who are Not Candidates for (or Who Have Failed) Calcium Channel Blocker Therapy, Monotherapy with Endothelin Receptor Antagonist, Phosphodiesterase Type 5 Inhibitor, or Soluble Guanylate Cyclase Stimulator is Recommended
Ambrisentan is Recommended to Increase 6MWT Distance (Grade 1C Recommendation)
Bosentan is Recommended to Delay the Time to Clinical Worsening (Grade CB Recommendation)
Macitentan is Recommended to Delay the Time to Clinical Worsening (Grade CB Recommendation)
Sildenafil is Recommended to Increase 6MWT Distance (Grade 1C Recommendation)
Tadalafil is Recommended to Increase 6MWT Distance (Grade CB Recommendation)
Riociguat is Recommended to Increase 6MWT Distance (Grade CB Recommendation), Improve WHO Functional Class (Grade CB Recommendation), Delay the Time to Clinical Worsening (Grade CB Recommendation), and Improve Cardiopulmonary Hemodynamics
Inhaled/Parenteral Prostanoids Should Not Be Chosen as the Initial Therapy for Treatment Naive WHO Functional Class II Patients or as Second-Line Agents for WHO Functional Class II Patients Who Have Not Met Their Treatment Goals (Grade CB Recommendation)
WHO Functional Class III
For Treatment Naive WHO Functional Class III Patients, Who are Not Candidates for (or Who Have Failed) Calcium Channel Blocker Therapy, Monotherapy with Endothelin Receptor Antagonist, Phosphodiesterase Type 5 Inhibitor, or Soluble Guanylate Cyclase Stimulator is Recommended
Ambrisentan is Recommended to Increase 6MWT Distance (Grade 1C Recommendation)
Bosentan is Recommended to Increase 6MWT Distance (Grade 1B Recommendation)
Bosentan is Recommended to Decrease Hospitalizations Related to Pulmonary Hypertension in the Short-Term (Grade 2C Recommendation) and to Improve Cardiopulmonary Hemodynamics
Macitentan is Recommended to Improve WHO Functional Class (Grade CB Recommendation) and Delay the Time to Clinical Worsening (Grade CB Recommendation)
Sildenafil is Recommended to Increase 6MWT Distance (Grade 1C Recommendation), to Improve WHO Functional Class (Grade CB Recommendation), and to Improve Cardiopulmonary Hemodynamics
Tadalafil is Recommended to Increase 6MWT Distance (Grade CB Recommendation), to Improve WHO Functional Class (Grade CB Recommendation), to Delay the Time to Clinical Worsening (Grade CB Recommendation), and to Improve Cardiopulmonary Hemodynamics
Riociguat is Recommended to Increase 6MWT Distance (Grade CB Recommendation), Improve WHO Functional Class (Grade CB Recommendation), Delay the Time to Clinical Worsening (Grade CB Recommendation), and Improve Cardiopulmonary Hemodynamics
For Treatment Naive WHO Functional Class III Patients Who Have Evidence of Rapid Progression or Other Markers of Poor Clinical Prognosis, Parenteral Prostanoid Should Be Initially Considered
Eposprostenol (Continuous IV) is Recommended to Improve WHO Functional Class (Grade CB Recommendation), Increase 6MWT Distance (Grade CB Recommendation), and Improve Cardiopulmonary Hemodynamics
Treprostinil (Continuous IV) is Recommended to Increase 6MWT Distance (Grade CB Recommendation)
Treprostinil (Continuous SQ) is Recommended to Increase 6MWT Distance (Grade CB Recommendation) and Improve Cardiopulmonary Hemodynamics
For WHO Functional Class III Patients Who Have Evidence of Disease Progression and/or Other Markers of Poor Clinical Prognosis Despite Treatment with One of Two Classes of Oral Agents, Inhaled or Parenteral Prostanoid Should Be Considered
Eposprostenol (Continuous IV) is Recommended to Improve WHO Functional Class (Grade CB Recommendation), Increase 6MWT Distance (Grade CB Recommendation), and Improve Cardiopulmonary Hemodynamics
Treprostinil (Continuous IV) is Recommended to Increase 6MWT Distance (Grade CB Recommendation) and Improve Cardiopulmonary Hemodynamics
In Patients Who Remain Symptomatic on Stable and Appropriate Doses of an Endothelin Receptor Antagonist or Phosphodiesterase Type 5 Inhibitor, the Addition of Inhaled Treprostinil is Recommended to Increase 6MWT Distance (Grade 2C Recommendation
Usual Initial Dose of Inhaled Treprostinil is 3 Inhalations (18 mg) q6hrs: however, optimal effect of inhaled treprostinil may require titrating dose up to 9 inhalations (54 mg) q6hrs
In Patients Who Remain Symptomatic on Stable and Appropriate Doses of an Endothelin Receptor Antagonist or Phosphodiesterase Type 5 Inhibitor, the Addition of Inhaled Iloprost is Recommended to Improve WHO Functional Class (Grade CB Recommendation) and Delay the Time to Clinical Worsening (Grade CB Recommendation)
In Patients Initiating Eposprostenol (Continuous IV) Therapy, Routine Simultaneous Initiation of Bosentan is Not Recommended (Grade CB Recommendation)
WHO Functional Class IV
For Treatment Naive WHO Functional Class IV Patients, Monotherapy with a Parenteral Prostanoid is Recommended
Eposprostenol (Continuous IV) is Recommended to Improve WHO Functional Class (Grade CB Recommendation), Increase 6MWT Distance (Grade CB Recommendation), and Improve Cardiopulmonary Hemodynamics
Treprostinil (Continuous IV) is Recommended to Increase 6MWT Distance (Grade CB Recommendation)
Treprostinil (Continuous SQ) is Recommended to Increase 6MWT Distance (Grade CB Recommendation) and Improve Cardiopulmonary Hemodynamics
For Treatment Naive WHO Functional Class IV Patients Who are Unable or Do Not Desire to Manage Parenteral Prostanoid Therapy, Inhaled Prostanoid in Combination with an Endothelin Receptor Antagonist is Recommended
Bosentan is Recommended to Increase 6MWT Distance (Grade 2B Recommendation) and Improve Cardiopulmonary Hemodynamics
Inhaled Iloprost is Recommended to Increase 6MWT Distance (Grade CB Recommendation) and Improve WHO Functional Class (Grade CB Recommendation)
Inhaled Treprostinil (in Combination Only) is Recommended to Increase 6MWT Distance (Grade CB Recommendation)
In Patients Initiating Eposprostenol (Continuous IV) Therapy, Routine Simultaneous Initiation of Bosentan is Not Recommended (Grade CB Recommendation)
WHO Functional Class III or IV with Unacceptable Clinical Status Despite Established Pulmonary Hypertension-Specific Monotherapy
In Patients with WHO Functional Class III or IV with Unacceptable Clinical Status Despite Established Pulmonary Hypertension-Specific Monotherapy, Addition of a Second Class of Pulmonary Hypertension Therapy is Recommended to Improve Exercise Capacity: these patients are best evaluated at specialized pulmonary hypertension centers
In Patients Who Remain Symptomatic on Stable Doses of Endothelin Receptor Antagonist or Phosphodiesterase Type 5 Inhibitor, Addition of Inhaled Iloprost is Recommended to Increase 6MWT Distance (Grade CB Recommendation)
In Patients Who Remain Symptomatic on Stable Doses of Endothelin Receptor Antagonist or Phosphodiesterase Type 5 Inhibitor, Addition of Inhaled Treprostinil is Recommended to Increase 6MWT Distance (Grade 1C Recommendation)
Usual Initial Dose of Inhaled Treprostinil is 3 Inhalations (18 mg) q6hrs: however, optimal effect of inhaled treprostinil may require titrating dose up to 9 inhalations (54 mg) q6hrs
In Patients Who Remain Symptomatic on Stable Doses of Eposprostenol (Continuous IV), Addition of Sildenafil or Uptitration is Recommended to Increase 6MWT Distance (Grade CB Recommendation)
In Patients Who Remain Symptomatic on Stable Doses of Bosentan/Ambrisentan/Inhaled Prostanoid, Addition of Soluble Guanylate Cyclase Stimulator is Recommended to Increase 6MWT Distance (Grade CB Recommendation), Improve WHO Functional Class (Grade CB Recommendation), and Improve Cardiopulmonary Hemodynamics and Delay the Time to Clinical Worsening (Grade CB Recommendation)
In Patients Who Remain Symptomatic on Stable Doses of Phosphodiesterase Type 5 Inhibitor or Inhaled Prostanoid, Macitentan is Recommended to Increase 6MWT Distance (Grade CB Recommendation), Improve WHO Functional Class (Grade CB Recommendation), and Delay the Time to Clinical Worsening (Grade CB Recommendation)
In Patients with WHO Functional Class III or IV with Unacceptable or Deteriorating Clinical Status Despite Established Pulmonary Hypertension-Specific Therapy with Two Classes of Pharmacotherapy, Addition of a Third Class of Pulmonary Hypertension Therapy is Recommended (Grade CB Recommendation): these patients are best evaluated at specialized pulmonary hypertension centers
Approximately 10% of Patients with Idiopathic Pulmonary Arterial Hypertension are Vasoreactive: treatment with calcium channel blockers may result im a marked decrease in pulmonary hypertension and PVR within the first few months of treatment
True Calcium Channel Blocker Responders are Uncommon in Other Types of Pulmonary Hypertension
Calcium Channel Blockers are Not FDA-Approved for this Indication
Agents: high doses may be required
Amlodipine (Norvasc) (see Amlodipine): typical dose = 20-30 mg/day
Diltiazem (Cardizem) (see Diltiazem): typical dose = 720-960 mg/day
Nifedipine (Procardia, Adalat) (see Nifedipine): typical dose = 180-240 mg/day
Use in Pregnancy: may be used
Recommendations (Chest 2014 Guidelines for Pharmacologic Therapy of Pulmonary Hypertension in Adults) (Chest, 2014) [MEDLINE]
In the Absence of Contraindications, All Patients with Pulmonary Hypertension Should Undergo Acute Vasoreactivity Testing with a Short-Acting Pulmonary Vasodilator at a Center Experienced in Performing Such Testing (Grade CB Recommendation)
Patients with Vasoreactive Pulmonary Hypertension without Contraindications to Calcium Channel Blocker Should Be Considered for a Trial of Oral Calcium Channel Blocker Therapy (Grade CB Recommendation)
Calcium Channel Blockers Should Not Be Used Empirically to Treat Pulmonary Hypertension without Evidence of Pulmonary Vasoreactivity (Grade CB Recommendation)
Prostacyclin Analogues (Prostanoids)
General Comments
Clinical Efficacy: when used as monotherapy, prostanoids generally have more significant impact on pulmonary hypertension mortality than do other classes of agents
Meta-Analysis of Pulmonary Hypertension Therapies (Eur Heart J, 2009) [MEDLINE]
Treatment with Prostanoid, Endothelin Receptor Antagonist, or Phosphodiesterase Type 5 Inhibitor Improved mortality, as Compared to Control
Epoprostenol (PGI2, Prostacyclin, Flolan, Veletri) (see Epoprostenol)
Clinical Efficacy
When Used as Monotherapy, Prostacyclin Analogues Generally Have More Significant Impact on Pulmonary Hypertension Mortality Than Do Other Classes of Agents
Epoprostenol has been shown to decrease pulmonary hypertension mortality rates (J Am Coll Cardiol, 2002) [MEDLINE]
Inhaled Iloprost (Ilomedin, Ventavis) (see Iloprost)
Pharmacology: longer half life and has fewer systemic side effects than epoprostenol, because of local delivery to the lungs
Clinical Efficacy
When Used as Monotherapy, Prostacyclin Analogues Generally Have More Significant Impact on Pulmonary Hypertension Mortality Than Do Other Classes of Agents
Improves 6-Minute Walk Distance and Pulmonary Hemodynamics
Administration
INH: xxx
Adverse Effects
xxx
Treprostinil (Remodulin, Tyvaso) (see Treprostinil)
Clinical Efficacy
When Used as Monotherapy, Prostacyclin Analogues Generally Have More Significant Impact on Pulmonary Hypertension Mortality Than Do Other Classes of Agents
Improves 6-Minute Walk Distance and Pulmonary Hemodynamics
Administration
INH: initial dose of 3 inhalations (18 mg) q6hrs -> however, optimal effect of inhaled treprostinil may require titrating dose up to 9 inhalations (54 mg) q6hrs
Randomized Controlled Trial of Macitentan in Symptomatic Pulmonary Hypertension (NEJM, 2013) [MEDLINE]
Macitentan Improved Morbidity and Mortality in Pulmonary Hypertension: this is unique, as other non-prostacyclin analogue agents have not been demonstrated to have a mortality benefit in the treatment of pulmonary hypertension
Improves 6-Minute Walk Distance and Pulmonary Hemodynamics
AMBITION Trial (NEJM, 2015) [MEDLINE]: initial ambrisentan and tadalafil resulted in significantly decreased risk of clinical failure events than with J each agent alone
Although Vaginal Delivery is, in General, Associated with Fewer Bleeding Complications and Infections, C-Section in Pregnant Pulmonary Hypertension Patients Avoids Prolonged Labor, Allows Preparation of Anesthesia, Allows More Precise Optimization of Hemodynamics, and Allows Development of Contingency Plans (Should Problems Arise)
C-Section Does Not Appear to Negatively Impact Outcome in Pregnant Pulmonary Hypertension Patients
Regional Anesthesia is Preferred Over General Anesthesia: due to a lesser effect on systemic vascular tone and cardiac function
Endothelin Receptor Antagonists are Contraindicated in Pregnancy (see Endothelin Receptor Antagonists): due to teratogenicity
Riociguat (Adempas) is Contraindicated in Pregnancy (see Riociguat): due to teratogenicity
Fluid Restriction to 1.5-2.0L Per Day: especially during the 3rd trimester
Sodium Restriction
Management of Pregnancy in a Center Specializing in Pulmonary Hypertension Care and with High-Risk Obstetrical and Cardiovascular Anesthesia Services (Chest 2014 Guidelines for Pharmacologic Therapy of Pulmonary Hypertension in Adults) (Chest, 2014) [MEDLINE]
Specific Management of Hypotension Associated with Right Ventricular Failure
Strategies to Decrease Pulmonary Artery Pressures and/or Decrease RV Afterload
Hypercapnia Induces Pulmonary Vasoconstriction: this effect may be attenuated by nitric oxide
Hypercapnic Pulmonary Vasoconstriction with High PEEP in ARDS May Lead to RV Dilatation and Decreased Cardiac Output (see Acute Respiratory Distress Syndrome)
Avoidance of Compression of Pulmonary Vasculature at the Very Low Tidal Volumes (or in Areas of Atelectasis) (see Hemodynamics): at low lung volumes/with atelectasis, capillaries are compressed -> this increases PVR
Avoidance of Compromise of Pulmonary Vasculature at Very High Tidal Volumes or with High Plateau Pressure (see Hemodynamics): at high tidal volume/high plateau pressure, capillaries are stretched, decreasing their caliber -> this increases PVR
Systematic Review of Treatments of RV Dysfunction in the Critical Care Setting (Crit Care, 2010) [MEDLINE]
Monitoring of the RV is Advised as Volume Loading May Worsen RV Performance (Weak Recommendation, Very Low-Quality Evidence)
Low-Dose Norepinephrine is an Effective Pressor for Patients with RV Dysfunction (Weak Recommendation, Low-Quality Evidence)
Low-Dose Vasopressin May Be Useful to Manage Patients with Resistant Vasodilatory Shock
Low-Dose Dobutamine (<10 μg/kg/min) Improves RV Function in Pulmonary Vascular Dysfunction (Weak Recommendation, Low to Moderate-Quality Evidence)
Phosphodiesterase Type III Inhibitors (Enoximone, Milrinone, Amrinone) Decrease PVR and Improve RV Function (Although Hypotension is Frequent) (Strong Recommendation, Moderate-Quality Evidence)
Levosimendan May Be Useful for Short-term Improvement in RV Function (Weak Recommendation, Low-Quality Evidence)
Pulmonary Vasodilators Decrease PVR and Improve RV Function (Especially with Pulmonary Vascular Dysfunction Post-Cardiac Surgery (Strong Recommendation, Moderate-Quality Evidence)
Side Effects are Decreased by Using Inhaled Agents (Inhaled Nitric Oxide, Inhaled Iloprost, Inhaled Prostacyclin-Epoprostenol, Nebulized Milrinone), as Compared to Systemic Agents
Mechanical Therapies (Right Ventricular Assist Device, Venoarterial Extracorporeal Membrane Oxygenation, Intra-Aortic Balloon Pump) May Be Useful as Rescue Therapy in Some Settings of Pulmonary Vascular Dysfunction Awaiting Definitive Therapy (Weak Recommendation, Very Low-Quality Evidence)
Prognosis
Overall Mortality Rate for Pulmonary Hypertension
From 1980-2002: pulmonary hypertension mortality rate has increased from 5.2 -> 5.4 per 100,000 (MMWR Surveill Summ, 2005) [MEDLINE]
Greatest Rate of Increase Has Been Observed in African-Americans and Women
Group 1 Pulmonary Hypertension
Group 1 Patients Have Overall Worse Survival Than Groups 2-5: of note, group 4 (chronic thromboembolic pulmonary hypertension) survival is dependent on candidacy for pulmonary thromboendarterectomy (which may be curative)
There are variable survival rates across the group 1 etiologies: for example, mortality rates for scleroderma-associated pulmonary hypertension is worse than that for idiopathic pulmonary arterial hypertension (particularly when associated with co-existent interstitial lung disease)
Median Survival in Idiopathic Pulmonary Arterial Hypertension (Untreated): approximately 3 years
Prognosis Varies with That of the Underlying Disease
References
General
Pulmonary Arterial Hypertension: Screening, Management, and Treatment [Internet] [MEDLINE]
Role of hypoxia in the pulmonary hypertension of chronic bronchitis and emphysema. Scand J Respir Dis Suppl. 1971;77:61 [MEDLINE]
Primary pulmonary hypertension: a national prospective study. Ann Intern Med 1987;107:216–223 [MEDLINE]
Pulmonary hypertension predicts mortality and morbidity in patients with dilated cardiomyopathy. Ann Intern Med 1992 Jun 1;116(11):888-95 [MEDLINE]
Familial primary pulmonary hypertension (gene PPH1) is caused by mutations in the bone morphogenetic protein receptor-II gene. Am J Hum Genet 2000;67:737-744 [MEDLINE]
Nocturnal hypoxemia is common in primary pulmonary hypertension. Chest 2001;120:894-899 [MEDLINE]
Pulmonary function in primary pulmonary hypertension. J Am Coll Cardiol 2003;41:1028-1035
Clinical classification of pulmonary hypertension. J Am Coll Cardiol 2004;43(Suppl 1):S5–S12 [MEDLINE]
Pulmonary arterial hypertension. J Am Coll Cardiol. 2008;51:1527-1538 [MEDLINE]
Pulmonary hypertension: an increasingly recognized complication of hereditary hemolytic anemias and HIV infection. JAMA. 2008;299:324-331 [MEDLINE]
Updated Clinical Classification of Pulmonary Hypertension. J Am Coll Cardiol 2009; 54: S43-S45 [MEDLINE]
Role of obesity in cardiomyopathy and pulmonary hypertension. Clin Chest Med. 2009 Sep;30(3):509-23 [MEDLINE]
Guidelines for the diagnosis and treatment of pulmonary hypertension: the Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS), endorsed by the International Society of Heart and Lung Transplantation (ISHLT). Eur Heart J 2009;30:2493-2497 [MEDLINE]
Genetics and genomics of pulmonary arterial hypertension. J Am Coll Cardiol 2009;54(Suppl):S32-S42 [MEDLINE]
Anaesthesia and right ventricular failure. Anaesth Intensive Care. 2009 May;37(3):370-85 [MEDLINE]
Has there been any progress made on pregnancy outcomes among women with pulmonary arterial hypertension? Eur Heart J. 2009;30(3): 256-265 [MEDLINE]
Clinical outcomes of pulmonary arterial hypertension in patients carrying an ACVRL1 (ALK1) mutation. Am J Respir Crit Care Med 2010;181:851-861 [MEDLINE]
Molecular genetic characterization of SMAD signaling molecules in pulmonary arterial hypertension. Hum Mutat 2011; 32:1385-1389 [MEDLINE]
Obesity and pulmonary hypertension: a review of pathophysiologic mechanisms. J Obes. 2012;2012:505274. Epub 2012 Sep 3 [MEDLINE]
Whole exome sequencing to identify a novel gene (caveolin-1) associated with human pulmonary arterial hypertension. Circ Cardiovasc Genet 2012;5:336-343 [MEDLINE]
Use of selective serotonin reuptake inhibitors and outcomes in pulmonary arterial hypertension. Chest. 2013 Aug;144(2):531-41. doi: 10.1378/chest.12-2081 [MEDLINE]
Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol. 2013 Dec 24;62(25 Suppl):D34-41 [MEDLINE]
High occurrence of hypoxemic sleep respiratory disorders in precapillary pulmonary hypertension and mechanisms. Chest 2013;143:47-55 [MEDLINE]
Severely reduced diffusion capacity in idiopathic pulmonary arterial hypertension: patient characteristics and treatment responses. Eur Respir J 2013;42:1575–1585
A novel channelopathy in pulmonary arterial hypertension. N Engl J Med 2013;369:351-361 [MEDLINE]
Scope of problem of pulmonary arterial hypertension. Am J Med. 2015;128(8):844 [MEDLINE]
Antidepressant use late in pregnancy and risk of persistent pulmonary hypertension of the newborn. JAMA. 2015 Jun 2;313(21):2142-51. doi: 10.1001/jama.2015.5605 [MEDLINE]
2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT). Eur Heart J. 2016 Jan 1;37(1):67-119. doi: 10.1093/eurheartj/ehv317. Epub 2015 Aug 29 [MEDLINE]
SSRI and SNRI use during pregnancy and the risk of persistent pulmonary hypertension of the newborn. Br J Clin Pharmacol. 2016 Nov 22. doi: 10.1111/bcp.13194 [MEDLINE]
Diagnosis
Echocardiographic probability of pulmonary hypertension: a validation study. Eur Respir J. 2022 Jan 7;2102548. doi: 10.1183/13993003.02548-2021 [MEDLINE]
Treatment
General
Continuous or nocturnal oxygen therapy in hypoxemic chronic obstructive lung disease: a clinical trial. Nocturnal Oxygen Therapy Trial Group. Ann Intern Med. 1980 Sep;93(3):391-8 [MEDLINE]
Use of supplemental oxygen in patients with pulmonary arterial hypertension in REVEAL. J Heart Lung Transplant. 2018 Mar 17. pii: S1053-2498(18)31395-0 [MEDLINE]
Other
Long-term intravenous epoprostenol infusion in primary pulmonary hypertension: prognostic factors and survival. J Am Coll Cardiol. 2002;40(4):780 [MEDLINE]
Bosentan therapy for pulmonary arterial hypertension. N Engl J Med 2002;346:896 [MEDLINE]
A meta-analysis of randomized controlled trials in pulmonary arterial hypertension. Eur Heart J. 2009;30(4):394 [MEDLINE]
Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Heart J 2009;30:2493-2537 [MEDLINE]
Pulmonary vascular and right ventricular dysfunction in adult critical care: current and emerging options for management: a systematic literature review. Crit Care. 2010;14(5):R169 [MEDLINE]
Riociguat for chronic thomboembolic pulmonary hypertension and pulmonary arterial hypertension: a phase II study. Eur Respir J 2010;36:792-799 [MEDLINE]
Safety, tolerability, pharmacokinetics and pharmacodynamics of macitentan, an endothelin receptor antagonist, in an ascending multiple dose study in healthy subjects. J Clin Pharmacol 2013;53(11):1131-1138 [MEDLINE]
Macitentan and morbidity and mortality in pulmonary arterial hypertension. N Engl J Med. 2013 Aug 29;369(9):809-18. doi: 10.1056/NEJMoa1213917 [MEDLINE]
CHEST-1 Study Group. Riociguat for the treatment of chronic thromboembolic pulmonary hypertension. N Engl J Med. 2013 Jul 25;369(4):319-29. doi: 10.1056/NEJMoa1209657 [MEDLINE]
PATENT-1 Study Group. Riociguat for the treatment of pulmonary arterial hypertension. N Engl J Med. 2013 Jul 25;369(4):330-40. doi: 10.1056/NEJMoa1209655 [MEDLINE]
Management of pulmonary arterial hypertension during pregnancy. A retrospective, multicenter experience. Chest. 2013 May; 143(5): 1330–1336 [MEDLINE]
Pharmacologic Therapy for Pulmonary Arterial Hypertension in Adults. CHEST Guideline and Expert Panel Report. Chest. 2014 Aug; 146(2): 449–475 [MEDLINE]
Riociguat for pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension. Am J Health Syst Pharm. 2014 Nov 1;71(21):1839-44. doi: 10.2146/ajhp130777 [MEDLINE]
What’s new: the management of acute right ventricular decompensation of chronic pulmonary hypertension. Intensive Care Med. 2014;40:1930–1933 [MEDLINE]
Current treatment approaches to pulmonary arterial hypertension. Can J Cardiol. 2015;31:460–477 [MEDLINE]
Perspectives on oral pulmonary hypertension therapies recently approved by the U.S. Food and Drug Administration. Ann Am Thorac Soc. 2015;12:269–273 [MEDLINE]
Effects of oral treatments on clinical outcomes in pulmonary arterial hypertension: A systematic review and meta-analysis. Am Heart J. 2015 Jul;170(1):96-103, 103.e1-14. doi: 10.1016/j.ahj.2015.04.003. Epub 2015 Apr 9 [MEDLINE]
AMBITION Trial. Initial Use of Ambrisentan plus Tadalafil in Pulmonary Arterial Hypertension. N Engl J Med. 2015 Aug;373(9):834-844 [MEDLINE]