I. Pulmonary Arterial Hypertension: What Every Physician Needs To Know.

Pulmonary arterial hypertension (PAH) is a disorder specific to the pulmonary arteries, resulting in an increase in pulmonary artery pressure (PAP), and pulmonary vascular resistance (PVR), leading to right ventricular (RV) dysfunction, right heart failure, and death. Pulmonary hypertension (PH) refers to elevated pressure in the pulmonary vasculature that can result from a wide range of conditions.

It is critical to go through the appropriate diagnostic tests to determine whether your patient has PAH versus PH related to other underlying systemic disorders since treatment approaches are vastly different. Right heart catheterization (RHC) is the only method of diagnosing PAH (see section II: Right Heart Catheterization: Necessary to Diagnose PAH).

II. Diagnostic Confirmation: are you sure your patient has Pulmonary Arterial Hypertension?

If PH is suspected (based on history, risk factor assessment, and physical examination), an echocardiogram is the next step. The Doppler echocardiogram provides the following:

Estimation of RV systolic pressure

Done by using the modified Bernoulli equation 4v²

v is the velocity of the tricuspid regurgitation (TR) jet in m/s.

Right ventricular systolic pressure (RVSP) is derived by adding the right atrial pressure (RAP) to the gradient (RVSP = 4v² + RAP).

The RAP is either a standardized value or an estimated value based on the echocardiographic characteristics of the inferior vena cava, or the vertical height of the jugular venous pulse on physical examination.

Degree of correlation between RVSP derived from TR jet and hemodynamics from RHCs with marked various results from poor to significant correlations. Several factors attribute to the various results:

Spectral Doppler profile of TR is too weak or insufficient to measure the RV to RA pressure gradient in about 10% to 25% patients referred for PH evaluation. The signal can be enhanced by intravenous bolus administration of a small amount of agitated saline contrast or with commercially available encapsulated microbubble contrast agents which are used to enhance imaging quality. Very small amounts are needed to define TR jet, but the encapsulated agents need to be used with caution in patients with significant pulmonary vascular disease/pulmonary disorder.

Patients with comorbidities (obesity, pulmonary disorder) have demonstrated worse correlation, mostly related to difficulty in obtaining adequate acoustic windows. Thus it is important to note the technical quality of the study to determine how reliable the echo is to indicate possible presence of PAH.

Lack of accuracy of RAP estimation can significantly influence the RVSP result, especially in “borderline” elevated pressure.

Doppler echocardiography may underestimate RVSP in patients with severe PH due to inadequate jet visualization and overestimate in patients with near normal pressures usually as a result of inaccurate RAP estimation.

Evaluation of RV size and function to assess functional and morphologic cardiac consequences due to PAH

Size and function of the RV have been shown to be critical determinants in the outcome of patients with PAH.

Presence of enlarged right atrium and RV, septal flattening, and reduced RV systolic function highly correlate with significant PH and are well recognized markers of poor prognosis.

Methods of assessing quantitative measures of RV function:

Visual estimation – most often used but highly subjective.

RV fractional area change done in apical four chamber view. Though this method incorporates both longitudinal and transverse RV shortening into a single measurement, it can be limited by incomplete endocardial definition leading to high variability.

TAPSE (tricuspid annular plane systolic excursion) – simple to perform and has shown to be reproducible in PAH. This measures the total longitudinal systolic displacement of the RV base toward the RV apex, performed using the 2-D echocardiography or M-mode. Normal TAPSE is 2.4-2.7 cm. Ranges of RV dysfunctions are: mild (1.9-2.2 cm), moderate (1.5-1.8 cm), and severe (<1.5 cm).

Presence any pericardial effusion (even trivial) has been found to be associated with worse prognosis.
To rule out left heart disease (LHD) as a cause of PH since diagnosis of PAH mandates the absence of clinically significant LHD.

Assessment of LV size, structure and function is important to exclude significant LV systolic and diastolic dysfunction, enlargement, and hypertrophy. Close scrutiny for diastolic abnormalities is becoming more relevant since older patients with multiple cardiac risk factors are being diagnosed with elevated pulmonary pressure (see Competing Diagnoses That Can Mimic Pulmonary Hypertension section).

Presence of left atrial enlargement, even in the absence of obvious LV dysfunction, should raise the suspicion of elevated left-sided pressure and a diagnosis of pulmonary venous hypertension (PVH) rather than PAH. In these patients, it is critical to obtain a reliable pulmonary capillary wedge pressure (PCWP) during right heart catheterization; if a satisfactory PCWP cannot be obtained, left heart catheterization may need to be performed to accurately measure the left ventricular end diastolic pressure to definitively rule out PVH. PAH-specific therapies can worsen PVH by precipitating pulmonary edema.

It has been suggested that LA size can be viewed for PH as HgbA1c for DM. It is a marker of duration, chronicity, and severity of left-sided pressure elevation

Assess for valvular abnormality and congenital heart disease, which can precede or coincide with the diagnosis of PH. An echocardiographic contrast (“bubble”) study using agitated saline solution can screen for presence of intracardiac shunting. Transesophageal echocardiography (TEE) can add more refined structural information in these cases and may better define atypically situated atrial septal defects of the sinus venosus type (Table 2).

Table 2.n

Echocardiographic Findings to Differentiate PAH vs. PVH

Right Heart Catheterization: Necessary To Diagnose PAH

Right heart catheterization is needed in PAH to:

Establish the diagnosis of PAH by confirming that pulmonary artery pressures are elevated with normal left sided filling pressure.
Perform acute vasodilator testing for patients with a new diagnosis of PAH of idiopathic, hereditary, or anorexigen-associated conditions.
Assess prognosis of PAH based on RAP and cardiac output measurements.
Guide treatment of the patient

Normal Parameters

The normal PAP is systolic 15-30 mm Hg, diastolic 4-12 mm Hg, and mean 9-18 mm Hg. The normal PA pulse pressure is approximately 15 mm Hg.

The upstroke of the PAP waveform marks the onset of RV ejection followed by systolic peak and pressure decay. The dicrotic notch is due to pulmonic valve closure. The peak of the PAP wave occurs within the T wave of surface electrocardiography.

A gradient should not exist between the RV and PA systolic measurements, unless there is pulmonary valvular or pulmonary artery stenosis (Table 3). PAP waveform is affected by respiratory changes similar to other right-sided pressure.

The pressure changes upon cardiac chambers due to respiration are negligible under normal physiology. Important exceptions to this are seen for patients on mechanical ventilatory support, respiratory distress, marked pulmonary disease, or morbid obesity, where a significant variation in intrathoracic pressure can be seen resulting in marked differences in PAPs with the respiratory cycle. A reading at the end-expiration should be obtained since this is the phase where intrathoracic pressure is closest to zero.

Table 3.n

Range of Normal Pressure Obtained with Invasive Hemodynamic Assessment

Pulmonary Artery Pressure Measurements in PAH

The PA diastolic pressure is close (within 2-4 mm Hg) to both the mean PCWP and left ventricular end-diastolic pressure (LVEDP) in normal individuals (normal pulmonary vascular resistance and in the absence of mitral valve disease). The PA diastolic pressure does not correlate well with the mean PCWP in the presence of pulmonary vascular disease where the PA diastolic pressure overestimates the mean PCWP. The lack of correlation is also seen in mitral regurgitation with large v wave where the PA diastolic pressure underestimates the mean PCWP.

The normal mean PCWP is 2-12 mm Hg. The PCWP is used as a measurement of left-sided filling pressure and under normal physiology, a close correlation exists between the PCWP, left atrial pressure, and LVEDP.
Conditions where the PCWP does not correlate with LVEDP include in the presence of following conditions:

Severe mitral regurgitation or aortic regurgitation

Mitral stenosis

Pulmonary venous obstruction

Significant LV noncompliance
Accurate measurement of left heart filling pressure is critical for the correct diagnosis of PAH:

Definition of PAH requires both elevation of mPAP (≥ 25 mm Hg) and normal PCWP or LVEDP (≤ 15 mm Hg).

The difference between these two measurements calculates the transpulmonary gradient (TPG = mPAP – PCWP in mm Hg).

Accurate PCWP is critical in calculating PVR (PVR = TPG/CO in Wood units).

Elevated PCWP is characteristic of PH in the setting of chronically elevated left-sided cardiac filling pressure, termed pulmonary venous hypertension (PVH), and is classified as WHO Group 2 PH (see Clinical Classification section). PVH usually results from systolic and/or diastolic cardiac dysfunction or valvular heart diseases.

Therefore, therapeutic decisions can be significantly different based on the left-sided filling pressure measurement.

PAH is characterized by elevated PAPs, normal PCWP, and elevated TPG.

PVH is characterized by elevated PAPs, elevated PCWP, and normal TPG.

Common Pitfalls in Obtaining Accurate PCWP: Underwedging or Hybrid Waveform

“Underwedging” typically occurs with incomplete advancement of the PA catheter resulting in a hybrid tracing of PAP and PCWP. This usually results in a falsely elevated PCWP, leading to misdiagnosing a patient as PVH.
If an operator is suspicious that the PCWP being measured is greater than expected based on clinical assessment, an oxygen saturation measurement can be done from the distal port with the catheter in the wedge position. It should be equal or close to the systemic arterial oxygen saturation (usually >90%) done by pulse oximetry. If lower, the catheter is most likely underwedged.
Placing the catheter in the correct PCWP position can be very difficult in a patient with significantly elevated PAPs, especially if PA is markedly dilated. One helpful maneuver is deflating the balloon, allowing the catheter to migrate distally, and carefully reinflating the balloon following the pressure tracings closely. Usually with this approach, optimal placement is obtained with balloon partially inflated. An intraluminal guide wire can also aid in advancing the catheter to a more distal position. All these maneuvers must be performed very cautiously and under direct fluoroscopic visualization; it must be remembered that patients with PAH are at increased risk of PA rupture, a likely fatal event.

Common Pitfalls in Obtaining Accurate PCWP: Overwedged Waveform

“Overwedged” tracing occurs due to excessive inflation of the balloon relative to the size of the vessel. The result is a characteristic pressure tracing, which is usually easily detected.
This should be avoided not only due to inaccurate pressure measurement but due to the increase in risk of vessel rupture.
In bedside catheter measurements, the potential for PA catheter migration also needs to be kept in mind. The balloon should be slowly inflated at every measurement with close monitoring of the pressure tracings, with inflation stopped when a PCWP tracing is obtained.

Common Pitfalls in Obtaining Accurate PCWP: The “V” Wave

The v wave is a normal finding on the wedge tracing and normally higher than the a wave so as to what measurement constitutes a “large” v wave can be subjective.
Common causes of a large v wave include mitral regurgitation (MR), though the height of the v wave is neither sensitive nor a specific indicator of the degree of MR.
Other causes include any situations that increase the volume or flow into a noncompliant left atrium, such as ventricular septal defect, mitral stenosis, cardiomyopathy of any etiology, or postoperative surgical conditions.
The presence of a large v wave distorts the correlation between the PA diastolic pressure and PCWP so PA diastolic pressure now underestimates the mean PCWP.

A large v wave causes the PCWP to overestimate the LVEDP. The best point to estimate the LV filling pressure in the presence of a large v wave is to measure the wedge pressure at end diastole, which coincides with end of a wedge pressure a wave.

In PAH where determination of an accurate wedge pressure is critical to guide therapy, if there is any question regarding accuracy or reliability of the measurement, obtaining LVEDP is recommended.

Characteristics of a Physiologically Reliable PCWP

Distinct a and v waves should be present. An exception is noted in atrial fibrillation where an a wave will be absent.
Need to wait for steady state in PCWP tracing to occur (not immediately after the balloon is inflated) and record at end-expiratory phase.
A distinct immediate rise in pressure when balloon is deflated out of the wedge position.
Catheter tip should be stable in PA when viewed under fluoroscopy with the balloon inflated (not moving back and forth).
An oxygen saturation measured in PCWP >90%.
Multiple measurements of PCWP with similar results.
If these maneuvers fail to obtain a reliable PCWP, a left heart catheterization should be performed to measure LVEDP.

Normal Parameters

Normal cardiac output (CO) at rest is 5-8 L/min and the normal cardiac index is 2.6-4.2 L/min/m² (see Table 3).
Accurate cardiac output measurement is critical in calculating PVR and assessing prognosis in PAH.
The total pulmonary resistance (TPR) calculates the relationship between the mPAP and CO:

TPR = mPAP × 80/CO; the normal TRP is 100-300 dynes-sec-cm^-5.
The PVR measures the resistance to flow imposed by the pulmonary vasculature without the influence of the left-sided filling pressure:

PVR = (mPAP – PCWP) × 80/CO or PVR = TPG × 80/CO; the normal PVR is 20-130 dynes-sec-cm^-5

(PVR = TPG/CO in Wood units)
CO assessment is a critical measure of RV performance in the presence of elevated PAPs and decreased cardiac index (<2.2 or 2.5 L/min/m², pending sources) is a marker of poor prognosis.

Fick Cardiac Output

The Fick output equation is based upon the principle that in the absence of a significant intracardiac shunt, the pulmonary blood flow and the systemic blood flow are equal.
Fick equation:

CO = oxygen consumption/arteriovenous oxygen difference, or

CO = oxygen consumption/(arterial saturation – mixed venous saturation) × (Hgb) × 13.6.

The measurement of the arteriovenous oxygen (AV O₂) difference provides an estimate of the cardiac output.

The arterial oxygen saturation is the constant factor for most individuals. Thus changes in AV O₂ difference reflect the increase or decrease in the mixed venous oxygen saturation.

A decrease in the CO is compensated by an increase in tissue oxygen extraction, which results in the decrease in the mixed venous saturation. The correlation between cardiac output and changes in mixed venous oxygen saturation applies in the setting of constant hemoglobin, arterial oxygen saturation, and oxygen consumption.
In most hemodynamic laboratories, due to the impracticality of obtaining the exact oxygen consumption which requires collecting the patient’s exhaled air over several minutes, “assumed Fick” is used, which is derived from oxygen consumption based on the patient’s age, gender, and body surface area.

Potential sources of error include incorrect measurement of venous or arterial blood samples, presence of mitral or aortic regurgitation, and intracardiac shunting or peripheral shunting at the tissue level, such as in septic shock.

Thermodilution Cardiac Output

Thermodilution cardiac output is derived by injecting a 10-ml bolus of saline over 2-4 seconds into the RA via the proximal port. This is done with the distal catheter tip in a stable position in the PA and not in a “wedge” position.
The cardiac output measurements are obtained in triplicates, and the variances between the measurements should be less than 10%.
Thermodilution method can potentially overestimate CO in low flow states when compared with Fick method. The thermodilution method is known to be inaccurate in the presence of severe TR, intracardiac shunts, low output states, and marked respiratory variation. With significant TR, a portion of the indicator warms during its prolonged stay within the RA and RV, which produces a characteristic curve with a slow decay to baseline temperature. Although the Fick method is used often in the presence of TR, studies have demonstrated conflicting results regarding the accuracy of both techniques.

Evaluation for Intracardiac Shunting

Chronic left-to-right intracardiac shunting can produce PAH. Echocardiogram with agitated saline contrast can detect right-to-left shunt but can fail to detect left-to-right shunts. Multiple measurements of oxygen saturations from superior and inferior vena cava, right atrium, and PA can detect and quantify shunts. This step is a crucial part of right heart catheterization in a patient with clinical or echocardiographic suspicion of intracardiac shunting.

The risks associated with RHC in PAH has been studied. A recent multicenter study, which included 15 PAH centers over a 5-year period with more than 7,000 procedures evaluated the safety and risks of performing RHC in the PAH population. The overall incidence of serious adverse events was 1.1%.
The most frequent complications were related to obtaining venous access; others included arrhythmia and hypotension due to vagal reactions or pulmonary vasoreactivity testing.
When performed in experienced centers, RHC in PAH patients are safe and associated with low morbidity rates.

Maneuvers To Enhance Safety

RHC can be performed via femoral or jugular approach and is often determined by operator’s preference. Accessing from an internal jugular approach allows use of an ultrasound device to visualize the size and depth of the vein, which can enhance safety.
PAH patients often have dilated right-sided chambers, which can make maneuvering the catheter difficult, especially under high pressure systems and under significant tricuspid valvular regurgitation. Performing the procedure under fluoroscopy reduces the risks of catheter “coiling” and inducing arrhythmia. Direct visualization also assists in placing the catheter in the safe and optimal “wedge” position to avoid PA rupture, “overwedging” and migration of the catheter. Fluoroscopy is also necessary in patients with intracardiac devices.
Obtaining peripheral IV access in patients prior to starting the procedure is recommended to promptly deliver treatment in the event of vagal episodes, which can lead to significant clinical deterioration in PAH patients.

The purpose of evaluating PAH patients with a short-acting vasodilator is to determine the degree in which the pulmonary vasoconstriction is contributing to the elevated PAPs. Vasodilator responsiveness identifies patients with a better prognosis and those who are more likely to have a sustained beneficial response to calcium channel blockers (CCB).

Before PAH-directed therapies were available, initial reports of improved outcome upon treatment with high doses of oral nifedipine or diltiazem led to a flurry of treatment with CCBs. However, only a small number of patients (approximately 6%) were found to be “responders” in large series retrospective analysis.

For the majority of patients who are not responders, treatment with high dose CCBs can result in clinical deterioration (hypotension, arrhythmia, syncope, or death), which can be worsened by the long half-life of the agents. Reports of adverse outcomes associated with vasodilator testing with CCBs led to the use of short-acting agents to assess responsiveness to identify those patient who may be considered treating with CCBs.
Intravenous epoprostenol and IV adenosine have both been studied as acute vasodilators. Both are short-acting, potent vasodilators and investigators have reported different degrees of responsiveness depending on the criteria used. However, because both agents have the potential to cause systemic hypotension and side effects, using inhaled nitric oxide (NO) has emerged as the vasodilator of choice due to its pulmonary selectivity, short half-life, and lack of systemic side effects. However, it is expensive and requires trained respiratory personnel to administer (Table 4).

The definition of what constitutes acute vasodilator “responder” has undergone changes over the years. Initial studies used a composite decrease in mPAP and PVR of 20%-30% to define responsiveness. A recent analysis by the European group has demonstrated that the number of patients who remained stable long term (>1 year) on CCB monotherapy (initially placed using the previous definition of 20% reduction in PAP and PVR) was smaller than previously reported (6.8%).

A comparison of the initial vasoreactivity hemodynamics between patients who remained stable on CCB alone versus those who decompensated on CCBs led the European Society of Cardiology to define a positive acute vasodilator responder in an IPAH patient as:

A fall in mPAP of at least 10 mm Hg to less than or equal to 40 mm Hg and

Increased or unchanged CO

For the small number of patients who demonstrate significant hemodynamic response and meet the criteria, initiation of treatment with CCBs can be considered. Such treatment requires very close vigilant follow-up to monitor for both efficacy and safety.

For patients who fail to improve by clinical and objective criteria (reach FC II symptoms, exercise, and hemodynamic parameters) within the initial 3 months, treatment with PAH-directed therapies need to be implemented. The majority of patients who fail to achieve this acute response are not likely to respond to CCBs.

Contraindications for CCB treatment (and acute vasodilator testing) include patients with advanced disease defined as:

Functional class IV symptoms

Overt clinical right heart failure

Hemodynamic markers of advanced process (high RAP and/or reduced CO, systemic hypotension)

Agents Used in Acute Vasodilator Testing

Patients with such an advanced state should not undergo acute vasodilator testing since these patients need prompt treatment with PAH-approved therapies.

It needs to be emphasized that all the CCB testing and treatments were performed in IPAH patients. For patients with PAH associated with other underlying processes (i.e., scleroderma), the number of patients who had acute vasodilatory response is even less, and the net benefit of vasodilator testing is at best weak if used for the sole purpose of determining candidates for CCB therapies.

The development of acute pulmonary edema during vasodilator testing should raise the suspicion of veno-occlusive disease or pulmonary capillary hemangiomatosis, in which therapy with pulmonary vasodilator is contraindicated.

Assessment of Prognosis

Since PAH is a disease manifested by an increase in afterload of pulmonary arteries leading to progressive right ventricular dysfunction and failure, hemodynamic markers are considered to be the gold standard for indicating prognosis. This was first demonstrated in the NIH PPH Registry in the 1980s where the investigators concluded that “mortality was most closely associated with right ventricular hemodynamic function and can be characterized by means of an equation using three variables: mean pulmonary artery pressure, mean right atrial pressure, and cardiac index.”

Specifically, RAP greater than or equal to 20 mm Hg, mPAP greater than or equal to 85 mm Hg, and CI less than 2 L/min/m² were shown to be associated with an increased risk of death. The data obtained were the basis of formulating the regression equation to calculate survival based on hemodynamics, which was validated in a prospective study.

Subsequent studies have corroborated the importance of elevated RAP (>12 or 15 mm Hg, pending sources) and low cardiac index (<2.2 or 2.5 L/min/m², pending sources) as determinants of poor outcome. The relevance of mPAP on prognosis has been variable.

In the retrospective study among patients treated with epoprostenol, patients with lower mPAP correlated with poor outcome, which may indicate that mPAP per se is not a reliable surrogate for RV function but needs to be assessed as part of pulmonary vascular resistance.

A. History Part 1: Pattern Recognition

Diagnosing PAH can be challenging primarily due to the nonspecific nature of the presenting symptoms. Here is a list of common baseline demographics and presenting symptoms of PAH patients:

From the REVEAL Registry, which reports current PAH patient population from U.S. centers, the mean age is reported to be 53 ± 14 years and majority (80%) to be females.
From the NIH PPH Registry, the most common presenting symptoms were the following:

Dyspnea (98%), fatigue (73%), chest pain (47%), near syncope (41%), syncope (36%), leg edema (37%), and palpitations (33%).

The quality of dyspnea has been described as progressive and “relentless,” different from seasonal or allergic-related phenomena.

Dyspnea is usually exacerbated by activity, particularly going up an incline or climbing steps are usually reported to be difficult.

Other activities patients describe being problematic include bending down (to pick up objects off the floor), squatting (such as to tie shoes), vacuuming, carrying any weight up the stairs, and lifting any objects overhead. It is not uncommon for these activities to produce dizziness and/or chest pain; in patients with severe PAH, they can provoke syncope. The difficulties faced in performing these activities reflect hemodynamic changes that increase pulmonary vascular flow and/or resistance.

Young patient presenting with syncope: need to at least consider PAH.

Although PAH is a rare disorder, it should be considered in the differential for a young patient presenting with syncope associated with exertion (i.e., related to sports activity). PAH in a young patient can be difficult to recognize because young individuals can compensate well during initial stages of PAH and the condition can progress rapidly (especially if related to a genetic mutation).

B. History Part 2: Prevalence:

These are updated risk factors for PAH as outlined from the Dana Point World Symposium in 2008. Risk factors for PAH include “any factor or condition that is suspected to play a predisposing or facilitating role in the development of the disease.”

Definite association – defined as an epidemic or from a large, multicenter epidemiologic study

aminorex, fenfluramine, dexfenfluramine, toxic rapeseed oil
Possible association – defined as drugs with similar mechanisms of action as those in the “definite” or “likely” categories but which have not been studied

cocaine, phenylpropanolamine, St. John’s Wort, chemotherapeutic agents, SSRI
Likely association – defined as a single-center, case-control study demonstrating an association or a multiple-case series

amphetamines, L-tryptophan, methamphetamines

Recent observational studies have reported methamphetamine abuse significantly increases the risk of developing PAH
Unlikely association – defined as one in which a drug has been studied in epidemiologic studies and an association with PAH has not been demonstrated

Oral contraceptives, estrogen, cigarette smoking

A. Idiopathic PAH (IPAH) – corresponds to sporadic disease in which there is neither a family history of PAH nor an identified risk factor.

Recent epidemiologic studies show that the prevalence for PAH is 15 cases per million; for IPAH, 5.9 cases per million.
A trend for older age range of patients being diagnosed has shown to be increasing (patients >70 years of age).
REVEAL registry has shown that the majority are females (80%).

B. Heritable PAH – when PAH occurs with a family history. Mutations in the BMPR2 gene can be detected in approximately 70% of the cases that are transmitted in autosomal dominant pattern.

U.S. Registries among PH centers report prevalence of PAH associated with positive family history ranging from 10% to 13%.
Characteristics of genetic transmission include:

Variable penetrance – there can be “skipped” generations as far as phenotypic manifestations.

Genetic anticipation – the disease can manifest at an earlier age with more aggressive features in subsequent generations.
Recent studies have suggested that patients with PAH associated with BMPR2 mutations most likely represent a subgroup of patients with more severe disease and are less likely to demonstrate vasoreactivity than those with IPAH without BMPR2 mutations. This stresses the need to understand the indications for performing acute vasoreactivity testing during right heart catheterization (see Right Heart Catheterization, Acute Vasodilator Testing).
It should be noted that all patients with BMPR2 mutations have heritable disease, regardless of family history. BMPR2 mutations have been identified in 11% to 40% of IPAH patients with no family history.

C. Drug and toxin-induced PAH – the most recent update of identified drugs and toxins associated with PAH are listed above in Risk Factors in PAH. A few recent findings include:

Serotonin produces vasoconstriction, promotes PA smooth muscle cell hypertrophy and hyperplasia, and has been implicated in PAH. However, serotonin level alone per se is probably not likely a determinant of PAH since serotonin-reuptake inhibitors have not been associated with an increased incidence of PAH.

However, a recent case control study that brought this line of thought into question regarding the use of selective serotonin reuptake inhibitors in pregnant women after 20 weeks of gestation was found to have a possible association with an increased risk in offspring developing persistent PH of the newborn. The role of serotonin with PAH in the setting of pregnancy needs further evaluation.

A significant association between methamphetamine use, whether inhaled, smoked, taken orally or intravenously, and the development of IPAH has been reported.

D. PAH associated with connective tissue disease (CTD) – among all CTDs, scleroderma patients represent the largest subset of patients at risk for developing PAH.

The prevalence of PAH has been well studied only for the systemic sclerosis population. Recent studies using echocardiography as screening and RHC for confirmation found a prevalence of PAH between 7% and 12%.
The most recent analysis from the REVEAL Registry demonstrates that patients with CTD-associated PAH had a worse overall outcome compared with IPAH patients (1-year survival rate and freedom from hospitalization, 85% for IPAH and 67% for CTD-associated PAH ). This is particularly true for patients with PAH associated with scleroderma. Thus CTD patients represent the largest group at risk and for those who develop PAH and the worst prognosis (even with PAH-specific therapies).

It is recommended for scleroderma patients to have a baseline echocardiogram and PFTs [International and European guidelines recommend annual Doppler echocardiography].

Obtain a follow-up test with development of any symptoms. It is most challenging to detect if any pulmonary vascular disease is progressing since dyspnea and/or fatigue can occur due to the underlying disease or treatments. It is recommended that if patients have these symptoms, which cannot be explained by other reasons, PAH should be considered and an echocardiogram evaluated. With findings consistent with PAH, RHC needs to be performed.

A recently published report suggests that improved outcome can be seen with patients diagnosed due to active screening, though the effects of lead time bias need to be considered.
Patients with systemic sclerosis can have other processes that can cause elevated PAPs other than PAH, such as lung fibrosis, diastolic dysfunction, and primary cardiac involvement due to scleroderma. This stresses the critical importance of RHC to confirm the elevated PAPs and to classify its etiology, whether PAH or pulmonary venous hypertension, to determine appropriate therapy.

E. PAH associated with HIV infection – shown to have clinical, hemodynamic, and histologic characteristics similar to those seen in IPAH

Recent prevalence reported to be 0.46%.
Mechanism remains unclear. Indirect action of the virus through secondary messengers (cytokines, growth factors, endothelin, and viral proteins) suspected.
Small studies have shown a benefit of PAH-directed therapy in patients with HIV (bosentan, epoprostenol). Current recommendations include monitoring and optimal treatment with both antiretroviral and PAH-specific therapies.

F. PAH associated with liver disease – portopulmonary hypertension is development of PAH in association with elevated pressure in the portal circulation. It is the presence of portal hypertension, rather than underlying liver disease, that is the main risk factor.

All candidates for liver transplantation need to undergo echocardiography to screen for portopulmonary hypertension. If the echocardiogram shows elevated pulmonary pressure, RHC must be performed to confirm the diagnosis and assess risk/candidacy for liver transplant.
Overall about 8% of candidates for liver transplantation have portopulmonary hypertension and are at risk of its complications.
A recent study identified female sex and autoimmune hepatitis as risk factors for development of portopulmonary hypertension (hepatitis C associated with decreased risk in this study).
Pathologic changes in the small arteries in patients with portopulmonary hypertension appear identical to those seen in IPAH.

RHC is absolutely critical for diagnosis of portopulmonary hypertension because there are several other factors that can elevate PAPs with advanced liver disease, such as high CO associated with the hyperdynamic circulatory state and elevated PCWP due to fluid overload and/or diastolic dysfunction.

G. PAH associated with congenital heart disease (CHD) – with the number of patients with adult CHD increasing, long-term complications, which include PH and right heart failure, pose serious risks for this group of patients.

Patients with hemodynamically significant systemic-to-pulmonary shunts will develop PAH if left untreated.
This can result in Eisenmenger syndrome, which is defined as CHD with an initial large systemic-to-pulmonary shunt that initiates and propagates pulmonary vascular changes due to the persistent presence of increased blood flow and pressure, which over time increases PVR that results in a reversal of the shunt and cyanosis. Eisenmenger syndrome represents the most advanced form of PAH associated with CHD.
Prevalence of PAH associated with congenital systemic-to-pulmonary shunts in Europe and North America has been estimated to range between 1.6 and 12.5 cases per million adults; 25% to 50% of this population have been shown to be affected by Eisenmenger syndrome.

H. PAH associated with schistosomiasis – most likely due to multifactorial mechanisms, including portopulmonary hypertension (which is a common complication of schistosomiasis) and vascular inflammation (as a result of impacted Schistosoma eggs). This entity has been shown to have a similar clinical presentation to IPAH and histologic findings, including plexiform lesions.

It is estimated that more than 200 million people are infected with Schistosoma and that 4% to 8% will develop hepatosplenic disease. Recent hemodynamic data demonstrate prevalence of PAH to be 4.6% of those individuals with hepatosplenic disease.
Pulmonary venous hypertension is also common (3%), which addresses the need for invasive hemodynamic studies.

I. PAH associated with chronic hemolytic anemia – PH has been most well described in patients with sickle cell disease (SCD).

Prevalence of PAH in SCD is not clearly established. The largest study reported 32% of patients had PH; however, PH was defined echocardiographically. There is very limited data with hemodynamic confirmation and a large proportion of patients with SCD have pulmonary venous hypertension. Furthermore, a hyperdynamic state leading to high CO can also result in moderate elevation of PAPs with normal PVR.
The mechanism of PAH in SCD remains unclear. It has been proposed that chronic hemolysis results in high rates of nitric oxide consumption and produces a state of resistance of nitric oxide bioactivity.

A. Patients with hereditary PAH – genetic mutations predisposing to PAH (i.e., BMPR2) identified

Echocardiogram yearly; RHC if echo demonstrates evidence of PAH (high RVSP or right heart chamber enlargement)

B. First degree relative of a patient with BMPR2 mutation (or within pedigree of two or more patients with a diagnosis of PAH)

Genetic counseling regarding BMPR2 genotyping
Echocardiogram yearly; RHC if echo demonstrates evidence of PAH (high RVSP or right heart chamber enlargement)

C. Patients with systemic sclerosis

Response to approved PAH treatment not as favorable compared to IPAH
Early detection, accurate diagnosis, and appropriate therapy imperative
Baseline echocardiogram and yearly thereafter; RHC if echo demonstrates evidence of PAH (high RVSP or right heart chamber enlargement)

D. HIV infection

Echocardiogram if symptoms or signs are suggestive of PAH; RHC if echo demonstrates evidence of PAH (high RVSP or right heart chamber enlargement)

E. Patients with portal hypertension prior to liver transplantation

All candidates for liver transplantation need to undergo echocardiogram
RHC is necessary for full hemodynamic measurements; increased PAP associated with significant risk of perioperative mortality and contraindication to transplantation

F. Prior appetite suppressant use

Echocardiogram only if symptomatic

G. Patients with congenital systemic to pulmonary shunts

Echocardiogram and RHC at the time of diagnosis
Consider repair of defect if significant L-R shunt present (need to consider RV function, degree of hypoxia, and PVR)
High probability of PAH developing if unrepaired shunts (Eisenmenger syndrome)

H. Recent acute pulmonary embolism

VQ scan 3 months after event if symptomatic, and echocardiogram pending clinical course
Pulmonary angiogram if results positive

G. Sickle cell disease

Echocardiogram yearly; RHC if echo demonstrates evidence of PAH

C. History Part 3: Competing diagnoses that can mimic Pulmonary Arterial Hypertension

Diastolic dysfunction leading to diastolic heart failure (DHF; aka HFpEF: heart failure with preserved ejection fraction) refers to a clinical syndrome in which patients present with heart failure symptoms with preserved left ventricular (LV) systolic function. Epidemiologic studies have shown high prevalence of DHF (approximately 40%-70%) among symptomatic patients and the risk factors have been well elucidated (age >65 years, hypertension, elevated pulse pressure, obesity, coronary artery disease, diabetes mellitus, and atrial fibrillation).

The predominant underlying structural abnormalities in diastolic heart failure are concentric remodeling and hypertrophy of the LV caused by chronic pressure overload, usually due to systemic hypertension. These alterations produce abnormalities in both relaxation and filling, which can be a precursor to LV systolic dysfunction or the main structural abnormality, producing symptoms and signs of heart failure.

Patients presenting with diastolic dysfunction and PH is a common clinical dilemma and can be very challenging to distinguish from PAH. Up to 70% of patients with LV diastolic dysfunction may develop PH, the presence of which is associated with a poor prognosis.

The presentations are similar to PAH and include dyspnea, fatigue, and/or signs and symptoms of heart failure. An echocardiogram can be misleading, for at “first glance” it typically shows normal LV systolic function with some degree of elevated pulmonary pressure, which can be misinterpreted as a presentation representing pulmonary vascular disease.

It is crucial to carefully scrutinize the echocardiogram to specifically focus on findings suggestive of LV diastolic dysfunction in all patients (left atrial enlargement, LV hypertrophy, and elevated LV filling pressure [grade II to IV diastolic dysfunction]), but especially those with risk factors for diastolic dysfunction. Conversely, it is imperative to have a reliable assessment of RV size and systolic function as well, because in a patient with hemodynamically significant PAH, the RV will be enlarged and/or dysfunctional, whereas in cases of DHF, RV usually demonstrates normal size and function (see Table 2).

At this juncture, it is critical to perform RHC to measure the left-sided filling pressure and calculate the TPG and PVR. It needs to be emphasized that attention must be paid to the quality of the PCWP tracing in order for the correct diagnosis to be made.

Misinterpretation of either “underwedged” or hybrid tracing as true PCWP (thereby misdiagnosing as diastolic dysfunction due to falsely elevated PCWP) or recorded measurements from improper placement of the catheter can lead to a wrong diagnosis (see Diagnostic Confirmation section)

The hemodynamic assessment can possibly fall into one of the following three categories:

1. The PCWP is normal (<15 mm Hg) and the TPG and PVR are elevated (≥ 3 Wood units); the patient has PAH and treatment needs to be considered after full evaluation. The diagnosis cannot be fully dependent on the single measurement of PCWP alone, because if the patient has just undergone diuresis, the PCWP can be “normal.”

If the patient has clinical risk factors and/or echo findings suggestive of diastolic dysfunction, additional hemodynamic maneuvers including fluid challenge or an exercise RHC may be needed to assess response as a measure of the LV compliance. Although there are no definite standardizations, the recently published ACCF/AHA Expert Consensus Document on Pulmonary Hypertension and reports from the 4th World Symposium on Pulmonary Hypertension outline consensus-based recommendations for evaluation of patients presenting with Group II PH.

2. The PCWP is elevated (>15 mm Hg), the PVR is less than 3 Wood Units, and the TPG is normal; the patient has diastolic dysfunction, and therapy should be aimed at optimizing volume status, heart rate, and systemic blood pressure.

3. The PCWP and the PVR are both elevated (the TPG can be normal or elevated); careful evaluation and intervention need to be made to determine if the elevated PVR is passive (due to elevated filling pressure and thus responsive to diuretics and/or a systemic vasodilator) or fixed (remains elevated despite normalizing the PCWP and systemic blood pressure).

If the PCWP and PVR both decrease (TPG normal) with optimal heart failure therapy, then the patient needs to be treated aggressively with these regimens. If the PCWP is normalized but the PVR remains elevated (elevated TPG with variable CO), this may be indicative of pulmonary arteriopathy being the dominant disorder with structural changes in pulmonary vasculature along with diastolic dysfunction.

No PAH-specific therapies have been shown to be beneficial in heart failure to date; recent small studies with phosphodiesterase-5 inhibitor (PDE-5 inhibitor) sildenafil have shown promise in a few small studies. Treatment with epoprostenol and endothelin receptor antagonists (ERAs) have failed to show beneficial effects, though these trials did not specifically target patients with heart failure and PH.

Studies using sildenafil have shown improvement in LV systolic and diastolic function, as well as systemic vasoreactivity in animal models of heart failure. Recent short-term studies evaluating patients with chronic systolic heart failure and PH using sildenafil have demonstrated improvement in exercise capacity and quality of life. However, data from a well-designed trial studying long-term benefits is necessary before any recommendations can be made in regards to use of sildenafil in patients with heart failure and PH.

D. Physical Examination Findings.

Accentuated P2 – high pulmonary pressure increases the force of pulmonic valve closure; heard best at apex
Left parasternal heave and right-sided S4 – presence of high right ventricular pressure and hypertrophy
Holosystolic murmur increasing with inspiration and increased jugular v waves – tricuspid regurgitation
Diastolic murmur – pulmonary regurgitation
RV lift – due to enlargement and/or hypertrophy of RV

Right ventricular S3 – right ventricular dysfunction
Marked distended jugular veins, hepatojugular reflux, hepatomegaly, peripheral edema, and ascites – right ventricular dysfunction and tricuspid regurgitation
Low blood pressure, diminished pulse pressure, and cool extremities – low CO due to right ventricular failure

Central cyanosis – intrapulmonary shunt, hypoxemia, pulmonary to systemic shunt
Clubbing – congenital heart disease
Rales and decreased breath sounds – pulmonary congestion (left heart failure), effusion
Fine rales or crackles, accessory muscle use, wheezing, and productive cough – pulmonary parenchymal disorder
Sclerodactyly, arthritis, telangiectasia, Raynaud phenomenon, and rash – connective tissue disease
Peripheral venous insufficiency or obstruction – venous thrombosis
Splenomegaly, spider angiomata, palmar erythema, icterus, caput medusae, and ascites – portal hypertension

E. What diagnostic tests should be performed?

Diagnosing PAH and determining etiology of disease requires the following steps:

1. The recognition of predisposing conditions and genetic susceptibilities placing certain patients at greater risk (see History Part B: Prevalence – Risk Factors for PAH).

2. Knowing the nonspecific nature of clinical presentation and having a high index of suspicion to screen for PAH.

3. Understanding the usefulness and pitfalls of echocardiography as a screening modality.

4. Undergoing the complete evaluation to classify the type of PH.

5. Performing the invasive hemodynamic assessment and acute vasodilator challenge, when indicated, to confirm a PAH diagnosis.

6. Obtaining risk stratification to determine therapy, including assessment for exercise capacity.

List of tests to perform to diagnose PAH (see Figure 2. ).

Evaluation Approach for Diagnosis of Pulmonary Arterial Hypertension

1. Screening evaluations – history and physical, CXR, ECG, and echocardiogram

2. Determine associated conditions for PAH – serologies (HIV, ANA [and other CTD labs, such as RF, Scl-70], and LFTs [hepatitis serologies])

3. To evaluate for significant LHD pathology – echocardiogram (TEE and coronary angiography as indicated)

4. To evaluate for significant pulmonary pathology – PFTs and sleep study (CT of chest as indicated)

5. To evaluate for thromboembolic disease – VQ scan (CT angiography and/or pulmonary angiogram as indicated)

6. To assess exercise capacity/functional status – 6 MWT (CPET in some centers)

7. For diagnosis – right heart catheterization

1. What laboratory studies (if any) should be ordered to help establish the diagnosis?

Diagnostic Tests A: Laboratory Evaluations in the Diagnosis for PAH

There is no one laboratory marker of value that indicates presence of, or diagnostic for, PAH. The laboratory tests listed below are necessary to assess for presence of associated systemic diseases and to determine degree of right heart failure.

Laboratory assessments to determine the etiology of PH

Connective tissue disease evaluation

ANA, rheumatoid factor

Rheumatologist referral for further characterization of any positive CTD screening or high clinical suspicion of CTD
Hepatic dysfunction

LFTs

Hepatitis B and C
HIV test

Other laboratory evaluations

Routine comprehensive laboratory evaluations (CBC, BMP, LFTs)
BNP (baseline and periodic evaluations with treatment recommended)
TSH (as clinically indicated)

The measurement of distance walked in 6 minutes has become the test most frequently used to assess baseline exercise capacity and response to therapy in PAH. Indeed, the difference in the 6-minute walk distance (6MWD) has been used as the primary objective for almost all clinical trials for PAH treatments.

The advantage of 6MWD is that it is noninvasive, has been reasonably validated and standardized among patients with PAH, and is simple to perform, inexpensive, and well tolerated in most patients with PAH. The disadvantage of this modality includes a learning effect after repeated testing, comorbid conditions affecting test performance, and other activities of the day influencing results.

Increases in 6MWD have been shown to correlate with hemodynamics, quality of life, and survival. While there is no “set” distance that determines outcome, most experts agree that 6MWD is a useful tool to follow patients on therapy.

From risk standpoint, 380 m is considered one marker that has been shown to correlate with improved clinical outcome. In interpreting 6MWD, there is varied opinion as to which parameter is most indicative of RV function (i.e., absolute distance, % predicted based on age and gender, heart rate recovery, Borg score).

Most consider that achieving 15%-20% improvement in 6MWD in the first 3-4 months of initiating a PAH-specific therapy should be a goal.

2. What imaging studies (if any) should be ordered to help establish the diagnosis?

Diagnostic Tests B: Radiographic Studies for Evaluation of PAH

Usually performed as initial evaluation for complaints of dyspnea. Findings on chest radiograph are neither sensitive nor specific for PAH (i.e., normal chest radiograph is a common finding)
Findings indicative of PH (usually seen in advanced stages) include:

Prominent hilar pulmonary arteries

Peripheral hypovascularity (pruning)

RV enlargement (seen in lateral view)

Electrocardiograms are usually neither sensitive nor specific for PH in the initial nonadvanced stage
Changes consistent with PAH (usually indicative of advanced PAH with right-sided chamber dilatation) include:

Right axis deviation

Right atrial enlargement

RV hypertrophy

Thorough pulmonary evaluation is needed to determine if PH is associated with a significant degree of parenchymal and/or airway related disorders. Full pulmonary function test (PFT) with diffusion capacity (DLCo) is required.
Chest CT – to determine parenchymal lung disease
Sleep study – as clinically indicated

Full evaluation for chronic thromboembolic disease is essential. It has been reported that about 3%-4% of patients who survive acute pulmonary embolus (PE) do not fully resolve the thrombus burden despite anticoagulation and can develop chronic thromboembolic pulmonary hypertension (CTEPH). Furthermore, it can be present in the absence of a clear history of PE in up to 50% of the patients. CTEPH is associated with poor prognosis (30% probability of survival at 5 years with mPAP >40 mmHg).
Screening using a ventilation perfusion (VQ) scan is the test of choice:

A normal or very low probability scan essentially excludes CTEPH, whereas a high probability scan warrants further evaluation with a pulmonary angiogram. It is necessary to rule out CTEPH even in those patients with an identifiable underlying risk factor or cause of PAH, such as scleroderma, for therapeutic implications of the diagnosis is significant.

Clinical judgment is required for those with nondiagnostic or intermediate scans; need to account for suspicion of underlying parenchymal lung disease.

CT angiogram, while excellent for excluding acute PE, is less sensitive than the perfusion scan to exclude CTEPH.

In patients with parenchymal lung disease where a perfusion scan may be difficult to interpret, a CT angiogram may be useful.

Pulmonary angiography is the “gold standard” to fully assess location and extent of thrombus burden and to determine if a patient is a candidate for thromboendarterectomy

Surgical intervention (thromboendarterectomy) can reverse pulmonary hypertension and potentially cure the patient.

cMRI is being explored as a potential tool in PAH since RV function is the ultimate determinant regarding outcome and prognosis.

Possible utilities of cMRI in PAH include:

Anatomic evaluation (RV volume and mass)

Noninvasive hemodynamics (curvature ratio, delayed contrast enhancement, and PA flow velocity and area)

Marker of RV response and remodeling (prognostic information, response to treatment). Studies have shown that baseline cMRI RV size and function serve to predict long-term survival while conventional prognostic markers (FC and 6MWT) do not.
Clinically, there are barriers in using cMRI in the PAH population which include:

Test and interpretation not widely available

Difficulty for unstable patients to tolerate the test (length of the study, need to lie supine, claustrophobia, need to time with respiratory cycle and breathholding, and/or the need for contrast agent)

For patients on intravenous epoprostenol, need to arrange for long tubing (the cassette must be kept out of the cMRI area)

Cost of the study and insurance coverage

III. Management

Significant advances in developing PAH targeted therapies have been accomplished in the past two decades. There are currently nine FDA approved treatments for PAH (Table 5).

Table 5.n

Current Approved Pharmacologic Therapies for Pulmonary Arterial Hypertension

These treatments aim to restore the imbalances in the endothelial system that are present in PAH patients: augmenting prostacyclin and nitric oxide pathways and blocking the endothelin pathways (see Section I: Pulmonary Arterial Hypertension – Pathobiology).

Clinical Research Highlights

Intravenous epoprostenol, the first PAH-specific therapy to be approved by the FDA in 1995, was shown to improve functional class (FC), exercise capacity, hemodynamics, and survival in IPAH. The landmark pivotal trial enrolled 81 functional class III and IV IPAH patients in a 1:1 randomization comparing IV epoprostenol to a conventional treatment (diuretics, digoxin, warfarin, calcium channel blockers). There were eight deaths during the 12-week trial period, all which occurred among patients who were randomized to conventional therapy that resulted in a survival benefit (P = .003).

This was soon followed by a clinical trial evaluating epoprostenol in PAH associated with connective tissue disease that demonstrated marked improvements in 6MWD and hemodynamics but no effect on mortality in a 12-week, open-label randomized trial. Two longer-term observational studies have confirmed the chronic benefits of IV epoprostenol in PAH patients, specifically improvements in survival compared with historical controls, FC, 6MWD, and hemodynamics.

Clinical Considerations

Intravenous epoprostenol is a challenging treatment to implement due to its short half-life (<6 min) and the need for continuous IV infusion via a tunneled catheter. Each patient must learn the techniques of sterile preparation of the medication, operation of the ambulatory infusion pump, and care of the central venous catheter.

Incidences of sepsis and catheter-related infections are not negligible (0.1 to 0.6 case per patient-year) and can cause significant morbidity. Mastering the sterile techniques required to take care of the indwelling catheter is essential. Any interruption of the drug infusion can be potentially life threatening due to the short half-life of epoprostenol and potential for rebound pulmonary hypertension.

Intravenous epoprostenol is commonly started in the hospital at a dose of 1-2 ng/kg/min and titrated on the basis of PAH symptoms and side effects. Most experts consider an optimal dose of chronic therapy to be between 25 to 40 ng/kg/min.

Chronic overdose can lead to high CO failure and worsening of heart failure symptoms. Periodic follow-up RHC is recommended to obtain full hemodynamics, including CO measurements, for patients on chronic intravenous epoprostenol treatment.

Common side effects include headache, jaw pain, diarrhea, nausea, flushing, rash, musculoskeletal pain, and thrombocytopenia.

Jaw pain (usually with first bite) rarely completely resolves.
Over-the-counter prophylaxes are used for diarrhea, which is usually a chronic problem.
Nausea and flushing usually subsides and resolves after a period of time (usually days to weeks).
A “Flolan” rash can appear in some people (on face, trunk, or limbs).
Thrombocytopenia can occur with long-term use so there is a need to follow platelet counts. This can be dose dependent.

Intravenous epoprostenol is also unstable at room temperature so the cassette needs to be kept cold (usually with ice packs). Recently, temperature-stable epoprostenol (Veletri®) has been approved by the FDA. Its properties are reported to be generally similar except for the difference in the temperature-related stability.

A registry of patients being treated is being collected. Due to the complexity of administering this therapy, epoprostenol use should be limited to experienced centers.

Authors’ Preferred Method of Treatment/Recommendation

Intravenous epoprostenol is recommended as the therapy of choice for the following:

Young patients presenting with IPAH/advanced and/or worrisome clinical features/possible family history of PAH

Syncope, symptoms or signs indicating advanced disease/RV dysfunction

Echocardiogram showing enlarged right-sided chambers, RV dysfunction, pericardial effusion

Hemodynamics showing elevated RAP (>12 mm Hg) and/or decreased CI (<2.5 L/min)
Patients progressing/not improving on other therapies (usually in combination treatments)
As a “bridge” to lung transplant

Generally recommended for patients who are rapidly progressing, advanced stage upon initial diagnosis, high risk markers

Initiate on intravenous epoprostenol as lung transplant evaluation takes place

If patient responds well and improves, listing for transplant can be delayed and patient followed on therapy
For patients with portopulmonary hypertension

Initiate therapy to assess response on intravenous epoprostenol as “bridge to candidacy” for liver transplant
Epoprostenol is considered the “gold standard” in PAH-specific therapy and recommended for advanced PAH (especially patients presenting in FC IV) and PAH with right heart failure, cardiogenic shock from RV failure, and/or requiring rescue therapy.

Clinical Research Highlights

Treprostinil is a prostacyclin analogue with a half-life of 4 hours, which was studied as a continuous subcutaneous infusion in a 12-week, placebo-controlled, randomized trial of four hundred seventy patients with FC II, III, or IV PAH. There was a modest but statistically significant median increase of 16 meters in 6MWD; the improvement was dose related and patients in the highest dose quartile reported close to a 40-m improvement. However, the major obstacle of using subcutaneous treprostinil is the pain and erythema at the infusion site, which was reported by 85% of the patients, and curtailed titration of the infusion. It is now recognized that site pain is not dose related, and that for most patients the initial site pain diminishes after proper dose escalation, which helps them improve their PAH symptoms.

Due to the limitations imposed by the subcutaneous route of delivery, IV treprostinil was studied in a 12-week open-label trial of 16 patients. It demonstrated improvements in 6MWD (82 m) and hemodynamics.

In another open-label trial, 31 FC II and III PAH patients on IV epoprostenol were transitioned to IV treprostinil. Twenty-seven patients completed the transition, but four needed to be transitioned back to epoprostenol.

6MWD measurements were maintained among patients who completed the transition; however, there was a modest increase in mPAP and decrease in cardiac index. Noteworthy is that the dose of IV treprostinil at the end of the study period was more than twice the dose of epoprostenol at the start of the study.

Clinical Considerations

Pain at the site of administration (site pain) is the most commonly encountered difficulty in using subcutaneous (SC) treprostinil. Usually the pain is most troublesome at the beginning of the therapy.

It is not dose related; rather, the discomfort tends to get less as the dose is increased and PAH symptoms improve. Most patients, with adequate support can tolerate this treatment and gain benefit.

Patients need to be told what can be expected at the onset and be educated as to what can be done. Several remedies are available ranging from topical ointments, creams, antiinflammatory agents, or different techniques that can help with the site pain.

The advantage is that patients can receive the benefit of continuous prostacyclin treatment without the risk of tunneled catheter. For those patients who cannot tolerate the site pain, treprostinil can be given intravenously.

The need for a tunneled intravenous catheter and managing the pump for patients receiving intravenous treprostinil are the same as intravenous epoprostenol. The side effect profile is also similar.

The major difference lies in that treprostinil’s longer half-life (4-5 minutes for epoprostenol versus 4-5 hours for treprostinil), potentially renders it “safer” in the event of line malfunction and/or therapy interruption. Transition from intravenous epoprostenol to intravenous treprostinil has been shown to be overall safe and well tolerated, though the dose of treprostinil is typically higher, ranging from 1.5 to 2x the original epoprostenol dose.

Another major difference is regarding management of line-related infections. A Centers for Disease Control and Prevention report has raised concerns regarding possible increased incidence of blood stream infections, particularly with gram-negative organisms, in patients receiving intravenous treprostinil. It is unclear if the rates of infections are truly different, but the increased incidence of gram-negative organisms needs to be noted.

If there is concern for line infection or bacteremia, initiate appropriate antibiotics to cover both gram-positive and gram-negative organisms after appropriate cultures have been drawn.

Authors’ Preferred Method of Treatment/Recommendation

For patients who understand the benefits of the SC method, starting with this approach is recommended. Intravenous treprostinil may be used instead of epoprostenol for added safety related to longer half-life and convenience (cassette change every other day instead of every day with epoprostenol; also room temperature stable).

For patients with family support concerns, or for those who live at a farther distance from the PH center where accessing emergent treatment may be a concern, treprostinil provides a safer approach of providing intravenous prostacyclin infusion. Given the complexity of administering and following patients receiving these treatments, administration should be limited to centers with experience.

Clinical Research Highlights and Clinical Considerations

Iloprost is a stable prostacyclin analogue that is delivered via an aerosolized device for 6 to 9 treatments per day. It was studied in a 12-week, multicenter, placebo-controlled, randomized trial of 207 FC III and IV patients.

The unique aspect of this study was that patients enrolled were comprised not only of PAH patients but also of patients with PH related to inoperable chronic thromboembolic disease. This study also used a novel composite end point (improvement in FC by at least 1 level and increase in 6MWD by at least 10% in the absence of clinical deterioration), which demonstrated treatment benefit (16.8% vs. 4.9%, treated vs. placebo, P = .007).

It is available in a 2.5 mcg test dose followed by 5.0 mcg and 20 mcg doses. The average inhalation times on the 20 mcg dose ranges from 5-8 minutes per session.

It is generally well tolerated with coughing, headache, and flushing occurring as the most common side effects. Assessing for compliance is important when prescribing inhaled iloprost. When combined with oral therapies, some prescribers have recommended four to five treatments a day.

Clinical Research Highlights and Clinical Considerations

Inhaled treprostinil was studied in a 12-week, placebo, randomized study in patients with PAH added to background therapies of bosentan or sildenafil as assessed by improvements in the 6WMT (median placebo-corrected treatment effect of 20 m). Treprostinil is taken four times a day via inhalation using a specialized nebulizer.

The initial therapy is started with three breaths four times a day, with increased breaths as tolerated. The maximal dose is nine breaths four times a day. It is generally well tolerated with cough and hypotension as the most common side effects. The usual practice is to use as combination treatment with oral therapies.

Clinical Research Highlights and Clinical Considerations

Bosentan is a nonselective endothelin receptor blocker (ET_A and ET_B). It is the first orally available therapy approved for PAH.

The pivotal study, named BREATHE-1, was conducted in a 12-week placebo-controlled study among 213 patients with group I PAH. Treatment with bosentan improved the primary end point of 6MWD by 36 m, whereas placebo patients deteriorated by 8 m (P = .0002).

Bosentan also improved the composite end point of time to clinical worsening (defined as death, initiation of IV epoprostenol, hospitalization for worsening PAH, lung transplantation, or atrial septostomy).

Long-term observational findings in survival of patients treated with bosentan as first line therapy have shown improved survival compared with expected outcome based on the NIH registry equation. Bosentan was shown to be effective in mildly symptomatic patients in a landmark trial called the EARLY study.

This was a placebo controlled trial of 6 months duration that enrolled 168 FC II PAH patients. The baseline 6MWD of this cohort was 438 m, which is higher than all the other studies in PAH (approximately 330-350 m). The results demonstrated a significant decrease in PVR, which was the primary end point to evaluate treatment effects on vascular remodeling, and a significant delay in clinical worsening.

Bosentan is available in 62.5 mg and 125 mg. It is recommended to be started with 62.5 mg twice a day for 4 weeks; if LFTs are stable, increase to 125 mg twice a day.

Bosentan is mainly metabolized through the hepatic P450 enzymes, and an increase in hepatic transaminases greater than 3 times the upper limit of normal has been reported in 10%-12% of the clinical trial population. It is dose related and transaminase abnormalities resolve upon dose reduction or discontinuation of the treatment.

Bosentan is teratogenic and may decrease the efficacy of hormonal contraception, so women of childbearing age must be counseled to use dual contraception for birth control. Other side effects include headache, flushing, lower-extremity edema, and anemia.

Treatment with bosentan requires monitoring of liver function tests on a monthly basis, and pregnancy tests on women of childbearing potential on a monthly basis, and hemoglobin/hematocrit on a quarterly basis. Patients should be counseled regarding potential for lower extremity edema, especially in the initial weeks of therapy, and the possible need for diuretic adjustments. Glyburide and cyclosporine A are contraindicated with bosentan due to significant drug-drug interactions.

Authors’ Preferred Method of Treatment/Recommendation

Bosentan is most effective among PAH patients who are diagnosed early (as shown by the EARLY trial). PAH patients that are FC II or early III (IIIA), and those with CTD-associated PAH (ERAs demonstrate antifibrotic properties). Patients who respond to bosentan tend to do well and the efficacy tends to remain long term.

Patients for whom bosentan would not be recommended include: patients who are diagnosed late in the course of disease (i.e., FC IV or right heart failure) and patients with hepatic dysfunction. It must be stressed that ERAs are not effective as rescue therapy.

Special attention must be paid to those patients who present with overt right heart failure, because ERAs can make the heart failure worse. One approach is to diurese and stabilize the patient with other PAH-directed therapy and use bosentan after right heart failure has been fully treated.

Clinical Research Highlights and Clinical Considerations

Ambrisentan is a selective ET_A receptor antagonist studied in two placebo-controlled, randomized, 12-week studies of WHO Group I patients (ARIES-1 and ARIES-2), which were conducted in the U.S. and Europe/South America, respectively, in approximately 400 patients. The treatment resulted in a significant improvement in 6MWD and delay in time to clinical worsening in all treatment groups. The 2-year open label extension results from the ARIES clinical studies was recently published, showing that improvements in exercise capacity and functional class were sustained with a low risk of clinical worsening.

Ambrisentan is available in 5 mg and 10 mg oral tablets taken once a day. The incidence of hepatic transaminase elevation greater than 3 times the upper limit of normal was low at 0.8% in clinical trials. After reviewing the post marketing safety data, the FDA has removed the monthly LFT monitoring requirement. It is agreed upon by most experts that LFT monitoring is recommended on a scheduled periodic basis with other laboratory evaluations.

Peripheral edema, a known side effect of the ERA-class, was reported as mild to moderate in the clinical trials. Reports of significant edema during post marketing use followed.

Analysis of reported events showed clinically significant fluid retention to be most notable among elderly patients and has prompted the FDA to issue a warning to be placed in the package insert. Though the precise mechanisms behind the fluid retention is not clear, retention occurs most commonly in patients with clinical diastolic features (i.e., elderly, hypertensive, diabetic, obese, and those with echocardiographic findings to support diastolic dysfunction).

Ambrisentan is also teratogenic, so a monthly pregnancy test is required for women of childbearing age. Ambrisentan also can decrease hemoglobin so periodic monitoring of laboratory checks are required.

Authors’ Preferred Method of Treatment/Recommendation

Ambrisentan is also best used for patients who are diagnosed early in the course of the disease (FC II and early III PAH), including CTD-associated PAH. It is best to not initiate in patients who are in right heart failure, FC IV, or with evidence of advanced disease.

A special note for elderly patients who are diagnosed with PAH: if the patient has clinical evidence of right heart failure, peripheral edema, or echocardiogram findings of diastolic dysfunction (especially enlarged left atrium), it is recommended not to use ambrisentan (or at least ensure euvolemic state), for heart failure can significantly worsen.

Clinical Research Highlights and Clinical Considerations

Sildenafil was studied in a 12-week randomized placebo-controlled study of 278 symptomatic PAH patients. The primary end point of 6MWD improved by 45, 46, and 50 m in the 20, 40, and 80 mg groups, respectively (P <.001).

There was no change in the time to clinical worsening at week 12. The result of 222 patients who completed 1 year of treatment demonstrated that the 6MWD improvement was maintained; however, nearly all patients were titrated up to a dose of 80 mg three times a day.

Side effects included headache, flushing, dyspepsia, and epistaxis. Visual and hearing impairments have been reported; patients at risk (i.e., elderly or diabetics) should be counseled and evaluations performed as clinically indicated. Sildenafil is contraindicated with nitrates for risk of inducing hypotension.

Authors’ Preferred Method of Treatment/Recommendation

Considerable variation in the use of sildenafil exists regarding dose and type of patients. Some studies have shown a higher dose to be more effective (used as titration) and clinicians have advocated using higher doses off-label. However, obtaining financial approval can, for higher doses, can be difficult. Some patients have further improvement with a higher dose but this is not seen in all patients.

Use of sildenafil for “secondary” PH (i.e., those with predominant PH but with some features of left heart disease and lung disease) has gained considerable interest. Among all PAH therapies available, sildenafil seems to be most well suited for this group of patients.

However, it must be emphasized that consideration for treating these patients needs to be done with complete evaluation, including a RHC that demonstrates PAH (or PH “out of proportion” of the underlying condition).

The primary underlying pathology must be in the pulmonary vascular component for this therapy to have a chance to be effective. To date, there are no large randomized trials, though one trial studying patients with diastolic dysfunction and PH is underway.

Sildenafil is most likely the agent of choice for patients who are mildly symptomatic. Note, this treatment is not effective as a “rescue” per se, but can be used along with diuretics for moderately symptomatic patients and features of right heart failure.

Hypotension can be an issue, so it needs to be monitored carefully. The benefit of sildenafil can be seen fairly quickly upon initiation of treatment; however, it can also “wane” with chronic use (patient variability). It is imperative to follow patients closely for maintenance of efficacy.

Clinical Research Highlights and Clinical Considerations

Tadalafil, a PDE-5 inhibitor with a longer half-life than sildenafil, was recently studied in a 16-week, double-blind, placebo-controlled trial among 405 PAH patients using 2.5, 10, 20, and 40 mg tablets once a day.

The highest dose of tadalafil demonstrated a 41 m increase in 6MWD compared with 9 m for a placebo (P <.001). There was also a delay in the time to clinical worsening (defined as death, hospitalization, initiation of new PAH therapy, and worsening WHO FC). Side effects include headache, diarrhea, nausea, back pain, dizziness, dyspepsia, and flushing.

Authors Preferred Method of Treatment/Recommendation

The above comments regarding sildenafil also applies to tadalafil. The notable difference would be since tadalafil has a longer half-life, it may not be the agent of choice for unstable patients, for effects of hypotension can last longer.

CCBs are recommended for patients who demonstrate responsiveness during an acute vasodilator testing (see Diagnostic Confirmation section). Patients with IPAH who meet the criteria may be considered for treatment with CCBs.

Long-acting nifedipine, diltiazem, or amlodipine is suggested. Verapamil should be avoided due to its potential negative inotropic effects. Patients need to be followed closely for efficacy and safety on CCBs. If a patient does not improve to FC I or II with CCBs, the patient should not be considered a chronic responder and PAH-specific treatment should be initiated.

Anticoagulation has been studied in two small uncontrolled trials in IPAH patients. Based on these studies, most experts recommend warfarin anticoagulation.

The recommended targeted to international normalized ratio for PAH is 1.5-2.0. In patients with APAH, anticoagulation is controversial with few data to support its use.

In CTD, CHD, and portopulmonary patients, the risk of gastrointestinal bleeding may be increased. Most experts recommend warfarin anticoagulation in APAH patients to be considered in patients with advanced disease on intravenous prostanoids after careful assessment for any contraindicating factors.

Hypoxemia is a potent pulmonary vasoconstrictor and thus can contribute to the progression of PAH. It is recommended that patients with PAH maintain oxygen saturation greater than 90% at all times; the exception would be CHD patients and those with Eisenmenger physiology, which need to be assessed case by case.

Diuretics are used to treat volume overload due to right heart failure. For diuretic naïve patients, slow initiation and monitoring of renal function are recommended with a goal of attaining near-normal intravascular volume. In acute decompensated right heart failure and/or in presence of diuretic resistance, IV diuretics are needed. Although digoxin has not been well studied in patients with PAH, it is used with careful monitoring in low doses in the setting of refractory right heart failure and/or atrial arrhythmia.

With the approval of therapies targeting different pathways, combining treatments to attain improved outcome has been the natural progression in the treatment approach. The potential to increase efficacy by using combination therapy must be measured against possible toxicity and drug-drug interactions.

Most studies are an add-on combination approach. One study used an upfront combination using bosentan versus a placebo in FC III or IV patients receiving intravenous epoprostenol (BREATHE-2). The study failed to show benefit, though the study was underpowered.

Two studies evaluated adding inhaled iloprost to bosentan therapy in a randomized, double-blind, placebo-controlled design. The STEP study enrolled 67 patients in a 12 week study that demonstrated safety as well as improvement in 6MWD (26 m, placebo corrected, P = .051); the COMBI study, which evaluated 40 patients, failed to demonstrate benefit and the study was terminated.

The largest completed combination trial in PAH to date is the PACES study, which added sildenafil as an add-on therapy to intravenous epoprostenol. This 16-week, multinational, double-blind, placebo-controlled study enrolled 267 patients who were stable on epoprostenol therapy.

Patients were randomized to receive 20 mg three times a day, titrated to 40 mg and 80 mg tid, at 4-week intervals, or a corresponding placebo. At the end of 16 weeks, more than 80% of patients had reached the 80 mg tid dosing level.

The primary endpoint was changed in 6MWD and there was a placebo-adjusted increase of 26 m in the subjects who received sildenafil. There were 7 deaths in the placebo group and none in patients receiving sildenafil.

Clinical worsening events, defined as death, transplant, hospitalization, or an increase in epoprostenol dose, were significantly different in favor or the treated group.

Several large studies are currently underway evaluating the effect of combining different classes of oral regimen, including the COMPASS-2 trial (Effects of combination of bosentan and sildenafil versus sildenafil monotherapy on morbidity and mortality in symptomatic patients with pulmonary arterial hypertension), which is the first morbidity/mortality driven trial focusing on combination therapy in PAH.

Lung transplantation as a potential therapeutic option needs to be considered and discussed at the time of diagnosis. Optimal timing of referral can be challenging; local practices and organ availability need to be considered:

Patients who are good candidates with suboptimal response/progression on treatment need to be referred without delay
Note that under the current prioritizing system used by the United Network of Organ Sharing (UNOS), PAH patients may be assigned lung allocation score below that of patients with other common diagnosis (i.e., pulmonary fibrosis, COPD).

The thoracic committee is working on the system and is reviewing exceptions based on hemodynamic criteria to elevate the score to be more consistent with the degree of the patients’ clinical status
Although no “absolute” indications for lung transplant referral exists, it is recommended that for patients who are on optimal medical therapy (which usually includes a systemic prostacyclin) and have evidence of hemodynamic instability (elevated right atrial pressure and/or decreased cardiac output), proceeding with completing lung transplant evaluation needs to take place.

With an increasing number of options available, the decision regarding when and how to use such treatments have become more complex. It is important to realize that head-to-head comparative trials of agents have not been performed.

A useful tool to guide clinicians in making therapeutic decisions is outlined in the ACCF/AHA recommendations for PAH, which uses a list of clinically relevant parameters to make a risk assessment of patients (Table 6). Patients with more advanced and symptomatic diseases are recommended to receive continuous infusion prostacyclins (Figure 3). Additionally, for those patients who are assessed as functional class II or III, either class of oral drugs can be initiated, but frequent reassessment is critical (Table 1). (See section on Long-term Management.)

Table 1.n

Longitudinal Evaluation of the PAH Patient

Table 6.n

Assessing Risk in PAH Patients

A. Immediate management.

Pulmonary arterial hypertension usually manifests itself as a gradual, progressive development of dyspnea, therefore generally an outpatient presentation and evaluation. There are cases in which PAH can present acutely:

Young patients presenting with syncope: Although PAH is a rare disorder, it should be considered in the differential for a young patient presenting with syncope associated with exertion (i.e., related to sports activity, acute onset). PAH in a young patient can be difficult to recognize for they can compensate well during initial stages and the condition can progress rapidly (especially if related to a genetic disorder
Patients with PAH (not diagnosed or on therapy): Presenting with systemic disorder (most common presentations include upper respiratory infection/pneumonia, atrial arrhythmias, dietary indiscretion leading to right heart failure)

As discussed above, the consequences of pulmonary vascular remodeling are an increase in pulmonary vascular resistance (PVR) and impedance of flow. These changes cause RV strain that impairs filling and causes RV volume and pressure overload.

The RV then either hypertrophies and/or dilates, encroaching on the LV. Due to ventricular interdependence (note that two ventricles share the same shared bundle of fibers and that they move in “series”), RV hypertrophy and dilatation results in decreasing LV preload, cardiac output, and coronary perfusion. Increased RV wall stress results in RV ischemia.

Tricuspic regurgitation develops as a result of RV dilatation resulting in chronic elevation of central venous pressure (CVP), which increases renal vein pressure leading to renal dysfunction; peripheral edema; visceral organ edema, resulting in hepatic dysfunction; and gut edema, causing decreased absorption of medications and nutrients. Another consequence of RV failure is the opening of the foramen ovale and development of right to left shunting that can augment cardiac output at the expense of oxygenation, causing or worsening hypoxemia.

Definition of RV Failure

Essentially, it is the inability of the RV to maintain adequate circulation through the pulmonary vascular bed at normal central venous pressure

Goals for Management of RV Failure

1. Optimize RV preload

2. Maintain systemic blood pressure (keep PVR less than SVR) to avoid RV ischemia

3. Augment cardiac output

4. Reduce PVR

A. Optimal Preload Critical in RV Failure

Within physiologic limits, RV preload does improve contractility (approximately CVP 12-15 mm Hg)
Excessive RV preload has the potential to overdistend the RV and cause impaired LV filling and decrease cardiac output via ventricular interdependence. Essential to avoid fluid bolus without careful assessment
Diuretic use in RV failure

Consider effects of ineffective GI absorption in RV failure

Intravenous diuretics are more effective to “unload” the gut edema and initiate diuresis process

If inadequate response, consider continuous intravenous diuretic drip

Use combination treatments with

Spironolactone (relatively preserved renal function and electrolytes; effective in aiding treatment of ascites)

Intravenous Diuril in conjunction with loop diuretics

Ultrafiltration when diuretics are not sufficient to unload the RV

B. Use of Pressors in the Management of Acute RV Failure

Essential goal of treating decompensated RV failure is to maintain systemic blood pressure above pulmonary artery pressure to preserve right coronary blood flow

Perfusion of RCA occurs throughout the cardiac cycle, dominating in systole. As PVR approaches SVR, coronary perfusion decreases.

Judicious use of vasopressors can ameliorate RV ischemia. Need to balance with direct effects on pulmonary circulation (effect on PVR and HR)
Key points regarding pressors (Table 7)

Table 7.

Use of Pressors in Pulmonary Hypertension and Right Heart Failure

Norepinephrine (Equipotent ß₁ and α₁ receptor agonist)

Low doses decrease PVR/SVR ratio

Probably the best first-line agent for PH/RHF with hypotension

Improves RV function by improving SVR and increasing cardiac output

Potential to increase PVR at higher doses

Phenylephrine (Direct α₁ agonist)

Increases PAP and PVR, decreases cardiac output, and worsens RV function

In PH and RVF, should be avoided

Epinephrine (Potent ß₁ and α₁ agonists)

Often agent of last resort

Not much data in PH and RVF

Isoproterenol (ß₁ and ß₂ adrenergic agonist)

Use limited by tachyarrhythmia

Arginine vasopressin (V₁ receptor agonist)

Decreases PVR/SVR ratio

Less tachyarrhythmias than norepinephrine

Useful in PH/RVF and hypotension refractory to/or as first-line agent

Used as rescue therapy in PH crisis, RV failure with hypotension after cardiac surgery, sepsis with PH and RV failure

C. Optimizing Cardiac Output

Dobutamine

Animal models of PH

Doses up to 5 mcg/kg/min, reduce PVR while increasing CO

Doses 5-10 mcg/kg/min, significant tachycardia without improving PVR

Canine model of acute RVF

Dobutamine superior to NE in promoting RV/PA coupling

Clinical uses for both acute and chronic PH

Doses should be maintained <5 mcg/kg/min

Combine with pulmonary vasodilator when feasible

May cause systemic hypotension due to peripheral -adrenergic effects and may need NE or vasopressin for BP support
Milrinone

Animal models of PH

Significantly reduce PVR and improve RV function

In pediatric population, demonstrated additive pulmonary vasodilatation when combined with inhaled nitric oxide

One comparison study with PDE-5 inhibitor demonstrated inferior pulmonary selectivity and more systemic hypotension

Clinical use in PH patients

Systemic hypotension is the most common limiting factor. In a patient with stable BP, milrinone can augment cardiac output and provide both arterial and venous dilatation .

Low dose recommended and better tolerated (0.25-0.375 mcg/kg/min)

Dose adjustment needed for renal impairment (relatively contraindicated for clinically relevant renal insufficiency)
Dopamine

Unclear benefit due to tachyarrhythmia effects, which is commonly seen with dopamine. A major drawback since increase in heart rate can worsen demand ischemia. Increase in heart rate can be seen in low doses (so called “renal dose”).

Shown to increase PVR/SVR ratio
Levosimendan (available in Europe)

Acts as a vasodilator and has been shown to improve diastolic function and myocardial contractility without increasing oxygen consumption.

It has been shown to reduce PVR and improve PA-RV coupling in experimental acute RV failure

D. Optimizing PVR – Pulmonary Vasodilators

Pulmonary vasodilators in acute RVF setting – desirable characteristics

Selective for pulmonary vascular bed with little or no systemic effects

Administered via intravenous or inhaled route

Easily titratable and short half-life

No toxic metabolites/side effects

Cost benefit ratio favorable
Inhaled Nitric Oxide

Highly selective for pulmonary vascular bed with no systemic BP effects, thus ideal agent for PH/RV crisis

Can be given via facemask or endotracheal tubing for a ventilated patient

Not widely available in all institutions; high cost associated with use
Inhaled Epoprostenol

Intravenous epoprostenol can be challenging to initiate in the setting of acute RVF due to systemic hypotensive effects

Inhaled epoprostenol has been shown to decrease PAPs, and improve cardiac output without effect on systemic BP after CT surgery. Also shown to improve oxygenation.

Significant cost savings reported compared with inhaled nitric oxide

Refractory PAH to medical therapy is characterized by

Progression of RV failure and end-organ damage

Worsening hypoxia and oxygenation requirement

Hemodynamic instability
Spectrum of mechanical circulatory support for the failing RV include the following

Right ventricular assist device (RVAD), which can be surgically or percutaneously implanted

For PAH patients, complications associated with increased PVR makes this not an ideal supportive device

Extracorporeal Membrane Oxygenation (ECMO)

Novalung
ECMO – routinely used to completely bypass the failing heart and provide gas exchange

VA ECMO (Veno-Arterial) – used when both circulatory and pulmonary support required, as in decompensated PAH

VV ECMO (Veno-veno) – used for respiratory support
Novalung – pumpless device serving as parallel circuit to the lung

This can unload the RV by providing right to left shunt and provide oxygenation without centrifugal pump

Most experiences reported from group in Toronto, as well as a few in Europe

Patients presenting with line related problems with intravenous prostacyclin infusions

For patients receiving intravenous prostacyclins (epoprostenol or treprostinil) with complaints of irritation/discomfort, drainage, fever, malaise, complications of line infection need to be managed immediately which include:

Full evaluation including comprehensive laboratory evaluations, cultures

Prompt initiation of intravenous antibiotics

Gram-positive coverage (i.e., Vancomycin) for patients on epoprostenol

Gram-positive and negative coverage (i.e., Vancomycin and Piperacillin) for patients on treprostinil

Critical points to remember for emergent treatments:

PROSTACYCLIN INFUSIONS CANNOT BE INTERRUPTED

If the tunneled line cannot be used (purulent drains, dislodged, line malfunction, etc), epoprostenol and treprostinil can be given via peripheral catheter temporarily

For epoprostenol, this diluent is not compatible with any other drugs/infusions. There must be a dedicated line solely for the epoprostenol infusion

In the case of sepsis with hemodynamic instability (hypotension), a dose decrease may be necessary. This is best done with the PH specialist managing the patient. Vasopressor support may also be needed (see Immediate Management – Pressors in the Management of RV Failure)

A. Physical Examination Tips to Guide Management.

Signs of Refractory / Worsening RV Failure

Blood pressure – decreasing/low blood pressure ominous sign for further progression of RV failure (see section: Immediate Management)
Heart rate – maintaining optimal heart rate essential to optimize cardiac output (CO = SV × HR).

Insufficient heart rate – with clinical evidence of low output state, may need to adjust therapies to assist achieving optimal rate. If patient is on AV nodal blocking medications or beta blockers, decrease the dose. If in context with systemic hypotension, initiation of vasopressors and/or inotropes would be of clinical benefit.

Tachycardia – usually a sign of decompensated state and best not to slow it down pharmacologically but to treat underlying problem (i.e., optimize volume status and cardiac output).

Atrial arrhythmia – atrial fibrillation uncommon in PAH. If present, should carefully scrutinize for evidence of LHD. Atrial flutter can be seen as well as atrial tachycardia. All these arrhythmias poorly tolerated in PAH. Need to assess to restore sinus rhythm whenever possible.
Oxygenation – maintaining stable and adequate oxygenation is critical in the treatment of PAH for hypoxemia/acidosis further aggravates vasoconstriction and pulmonary vascular dysfunction. Support with appropriate modalities (facemask, BIPAP, CPAP, Vapotherm) need to be done as expediently as possible.

Mechanical Ventilatory Support – patients with advanced PAH generally do not tolerate the measures associated with intubation well. The effects of anesthesia used for intubation can result in hemodynamic/circulatory compromise. Furthermore, weaning the patient off the ventilatory support usually becomes very difficult process.

Due to high morbidity (as well as mortality) associated with mechanical ventilatory support in these patients, every effort should be placed to use pharmacologic and respiratory support, as well as treating underlying conditions (sepsis, pneumonia, acid/base imbalance). However, patients with PAH do not tolerate hypoxemia well either. These are very challenging patients to manage. A referral to a PAH center is highly advisable.
Signs of volume overload due to RVF – increase in JVP, hepatomegaly, ascites, hepatojugular reflux, peripheral edema.
Signs of inadequate perfusion – low systolic pressure, low pulse pressure, decreased mentation (especially in elderly), cool extremities, unintentional weight loss, loss of appetite, nausea with oral intake, presyncope, and syncope.

B. Laboratory Tests to Monitor Response To, and Adjustments in, Management

Renal function assessment

BUN, creatinine, urine output – essential to follow renal function parameters and response to diuretic treatments. If there is an inadequate urine output response, then consider providing more inotropic support and/or intensify diuretic regimen.
Ultrafiltration or renal replacement therapy (continuous versus intermittent) may need to be considered.

Markers of RV Function / Perfusion

Total bilirubin (T. bili) – elevated T. bili can be a marker of hepatic congestion due to RV failure.
BNP – marker of cardiac “stretch and stress.” Useful to compare with a baseline (if available) to determine the extent and follow with treatment.

C. Long-term management.

It is critical to have scheduled close follow-up of PAH patients on treatment(s). Three major reasons include:

Patients usually have variable responses to PAH treatments. It is imperative to reassess patients within 1-3 months (depending on severity/therapy used) to assess for clinical changes.
The effects of therapy can wane and change over the course of time. Even patients who did well initially can have recurrence of symptoms and worsen precipitously
Side effects of PAH medications are diverse and varied. Close follow-up of these parameters are needed to ensure safety and optimal care of patients.

In order to assess patient’s prognosis and progress on treatment, several surrogate markers have been studied as discussed below. A risk based approach has been recommended to determine appropriate treatments (see Medical Treatment).

A list of surrogate markers and associated risk parameters are listed in Table 6. On treatment goals for PAH patients are as follows:

To reach functional Class I or II
Achieve 6MWD greater than 380 m (there is considerable amount of debate and controversy regarding use of 6MWD in PAH. While the set distance “number” is not agreed upon, it is accepted that a walk distance of greater than 400 m is associated with a better outcome.
To improve hemodynamics with normalization of cardiac index (>2.2 L/min/m²) and RAP (<8 mm Hg)
On echo, to normalize RV size and function and absence of any pericardial effusion
In following BNP as a surrogate for RV function, for BNP to decrease (studies have shown that a decrease in BNP by 33-50% in the initial 3 months of starting a therapy is associated with favorable 1-year survival) and normalize.

Functional Class

Functional class (FC) assessment has proven to be a reliable indicator of severity of disease at baseline and as a marker to determine response to therapy. Functional assessment classification modified from New York Heart Association (NYHA) functional classification has been adopted for PAH (Table 8). The most notable difference between the two systems is in its definition of class IV, which included patients with signs of right heart failure and syncope, highlighting the importance of right ventricular dysfunction as a significant clinical marker of poor outcome.

Table 8.n

World Health Organization Classification of Functional Status of Patients with PAH

Extensive studies have explored correlation between FC at baseline and outcome. Patients with IPAH in the NIH study, the risk of death was higher for patients in NYHA-FC III or IV than among those in NYHA-FC I or II. For patients in NYHA-FC I or II, the median survival was almost 6 years, while it was 2.5 years for patients in NYHA-FC III and 6 months for NYHA-FC IV.

Baseline functional assessment was also shown to be highly predictive of outcome among patients treated with long-term epoprostenol. In one large retrospective study among IPAH patients treated with epoprostenol, survival after 3 and 5 years was 81% and 70%, respectively, for those patients who were in NYHA-FC III at presentation whereas for patients who were in functional class IV at baseline, the survival rates at the same time points were 47% and 27%. These earlier studies highlighted the importance of initiating treatments early in the course of PAH.

Assessments to determine correlation between FC on therapy and outcome have been done as well. In the same retrospective study as above among IPAH patients treated with epoprostenol, patients who improved to FC I or II by first follow-up period (17 ± 15 months) had 3- and 5-year survival rates of 89% and 73%, respectively, compared with 62% and 35% for patients who were FC III. Patients who were FC IV at the same time period suffered the worst outcome with 42% survival at 2 years and 0% at 3 years.

Current recommendations states that FC assessment is recommended to be made early after initiation of therapy with the goal of attaining FC I to II. For patients who demonstrate clinical improvement achieving FC I or II within the initial months after therapy, they should be carefully followed. For patients who deteriorate or remain in functional class IV, evaluation for lung transplantation should be pursued.

Six-Minute Walk Test

The distance covered during a 6 minute hall walk test (6MWD) has been the primary end point for almost all the major pivotal clinical trials in PAH. However, significant debates and studies are ongoing that explore which parameter(s) best serves as a surrogate of RV function with activity in PAH patients (i.e., absolute distance covered, % predicted achieved, heart rate recovery, or combination of these factors). It is generally agreed that patients who can achieve greater than 400 m have a favorable clinical outcome.

Right Heart Catheterization

Follow-up RHC is necessary in patients who are on continuous systemic prostanoid therapy, who demonstrate clinical deterioration, or a suboptimal response to treatment(s). Specifically, RHC is needed to ensure that continuous prostanoid dose is optimal by adjusting based on the cardiac index rather than increasing as clinically, which can result in high CO failure. Repeat RHC is highly variable among PH centers.

Echocardiography

Echocardiographic changes have been noted following therapies. In the prospective randomized trial with epoprostenol, the 12-week infusion of prostacyclin had beneficial effects on right ventricular size, curvature of the interventricular septum, and maximal tricuspid regurgitant jet velocity. Similarly, comparison of patients receiving treatment with the nonselective endothelin-1 antagonist bosentan demonstrated significant differences in changes in ventricular morphology, the minimum diameter of the inferior vena cava, and Doppler measurements, including right ventricular ejection time and mitral valve peak velocity.

The echocardiographic finding that tends to be the focus by most physicians when evaluating for PAH—the estimation of PA systolic pressure measurement—has not been found to be predictive of outcome. Furthermore, studies performed to assess correlation between echocardiographic assessment of PASP and right heart measurement have demonstrated variable findings, depending on the population studied, the time interval between the two measurements, and the method of estimating the right atrial pressure, among others.

Biomarker: B-type Natriuretic Peptide

Brain natriuretic peptide (BNP) is produced mainly in the ventricles in response to myocyte stretch and stress. Considering the effect PAH has on the right ventricle, measuring BNP level has biologic plausibility.

BNP levels have been shown to correlate with hemodynamics and survival in following patients on therapy. Furthermore, follow-up measurements after 3 months of epoprostenol therapy indicated that changes in plasma BNP levels correlated closely with changes in hemodynamics and demonstrated to be an independent predictor of survival. NT-proBNP among PAH patients of various etiology demonstrated good correlation between plasma levels of NT-proBNP and hemodynamics and survival.

Using plasma BNP measurements as surrogate markers appears attractive since it is relatively easy to obtain, and provides an objective data that lends to serial comparative evaluations over time. The weakness lies in its variability, both in defining a range for the disease state and intrasubject variability.

Furthermore, the potential for comorbidities and concurrent therapies, which can affect BNP levels makes it difficult to interpret findings. However, it provides yet another way of assessing the state of the right ventricle and studies are being conducted to further elucidate potential use of BNP as a marker of disease severity in PAH.

Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL) is a U.S. database of over 3,000 patients used to assess outcomes in those receiving PAH-directed therapy. It is the largest database being collected for PAH. The clinical risk factors for mortality are as follows:

PVR more than 32 Wood units
PAH associated with portal hypertension
Functional Class IV
Men older than 60 years of age
Family history of PAH
Other factors predictive of mortality

Renal insufficiency

PAH associated with connective tissue disease

Functional Class III

Mean RAP more than 20 mm Hg

Resting systolic BP less than 100 mm Hg and HR more than 92 bpm

6MWD less than 165 ms

BNP greater than 180 pg/ml

Percent predicted carbon monoxide diffusing capacity less than or equal to 32%

Pericardial effusion on echocardiogram

Functional Class I
6MWD more than or equal to 440 ms
BNP less than 50 pg/ml
Percent predicted carbon monoxide diffusion capacity more than or equal to 80%

E. Common Pitfalls and Side-Effects of Management

Patients on Intravenous Prostacyclins

Tunneled catheter care

Patient and at least one family member must be fully knowledgeable on the management of the catheter and the pump.

Patient must be educated to call if any discomfort is felt around the line, drains, any elevation in temps, or alarms from the pump.

Patient should have the number to their specialty pharmacy that provides the intravenous medications since they provide 24/7 nursing support.

Patients are best advised to alert their local hospital ED department about their diagnosis, treatment, and potential need for emergency care.

Patients on Endothelin receptor antagonists

The development of edema and increasing symptoms can be seen. Patients must be counseled to monitor their weight and to call if they see increase in peripheral edema, weight gain, or worsening dyspnea. It is not unusual to need increase in diuretics during the initiation of ERA treatments. For most individuals, after the appropriate adjustment period, their symptoms improve and the need for diuretics resolve. If this period goes untreated, patients can present with marked exacerbation of right heart failure, hypoxia, and decline in renal function.

Patients on PDE-5 Inhibitors

Patients need to be followed closely to see if their clinical improvement is maintaining. Similar to other therapies in this class (i.e., nitrates), the initial efficacy can diminish.
Patients need to be educated regarding contraindication with all forms of nitrates and to let their emergency health care providers know that they are on “Viagra” (Revatio not known to most physicians).

IV. Management with Co-Morbidities

Portopulmonary hypertension is one of several pulmonary complications of liver disease, where PAPs are due to increased resistance to blood flow in patients with portal hypertension.
ALL candidates for liver transplantation must undergo echocardiography to screen for portopulmonary hypertension. If elevated PAPs are detected, RHC must be performed.

The definition of portopulmonary hypertension by RHC is as follows (same as PAH hemodynamic definition):

Elevated mPAP more than 25 mm Hg

Increased PVR more than 240 dynes.s.cm^-5 (>3 Wood units)

Normal PCWP less than 15 mm Hg or an elevated transpulmonary gradient (TPG) (mPAP-PCWP; abnormal is >12 mm Hg)

In portopulmonary hypertension, it is critical to determine what is causing the PAPs to be elevated:

High CO state – in general, patients with liver disease have high CO, which can elevate PAPs

Increased blood volume due to fluid shifts (elevated PCWP)

In portopulmonary hypertension, the PAPs and PVR are elevated. Thus in a patient with mPAP of 45 mm Hg, PCWP 14 mm Hg (TPG = 31 mm Hg) and CO of 6 L/min, the PVR (TPG/CO) is 5.2 Wood units, this patient has portopulmonary hypertension. However, if the patient has mPAP of 45 mm Hg and PCWP 18 (TPG 27) and CO 6 L/min, though the PCWP is above the defined limit of 15 mm Hg the PVR is elevated at 4.5 Wood units so you would not exclude the diagnosis. If the same patient had CO 9 L/min, then the PVR would be 3 Wood units, which would suggest that elevated PAPs are due to a high output state.

Acute vasodilator studies are not very helpful in portopulmonary hypertension. These patients generally do not tolerate calcium channel blockers since they can exacerbate edema and portal hypertension. Also a positive vasodilator response does not predict survival with or without liver transplantation.
General recommendations regarding portopulmonary hypertension and liver transplantation:

mPAP less than 35 mm Hg: usual risk; no treatment for PH needed

mPAP 35-50 mm Hg: increased risk; consider PAH-directed therapy to determine response

Risk during induction of anesthesia, during and after graft reperfusion, and in the immediate post op period

Hemodynamic perturbations are due to an increase in blood flow following reperfusion or due to fluid boluses needed, which can exacerbate pulmonary hypertension and RV failure

Mortality rates reported range from 36% to 92% for patients who underwent liver transplant with an mPAP greater than 35 mm Hg

mPAP greater than 50 mm Hg: high risk; most likely not eligible for liver transplant; consider medical therapy

Scleroderma population represents the largest group of patients potentially at risk for developing PAH

The most at-risk are patients with limited scleroderma (especially after several years of diagnosis).

Patients with scleroderma complicated by PAH do not respond well to PAH treatments compared to IPAH patients.
Scleroderma, the diffuse form in particular, is associated with other organ involvements, which can cause significant complications:

Digital ulcerations

Renal complications

GI complications – this is common with scleroderma and can be problematic since many of the PAH therapies can exacerbate these problems (i.e., reflux and diarrhea). Other GI problems include difficulty swallowing, malabsorption, bleeding, and weight loss.

Pulmonary disease – most common and deadly manifestation. The most often seen are pulmonary fibrosis or interstitial lung disease.

V. Patient Safety and Quality Measures A. Appropriate Prophylaxis and Other Measures to Prevent Readmission.

It needs to be stressed that the outcome of patients with PAH have improved significantly with advances in medical therapy. PAH has evolved from a fatal disease to a chronically managed condition.
Prognosis is dependent on the following:

Functional Class upon presentation – worse for those who present at FC IV

Associated conditions – scleroderma-associated PAH have worse prognosis

Demographics – male gender, older population

Presence of other organ dysfunction – renal insufficiency

Salt and Fluid Management

Sodium restricted diet (<2,000 mg/day) is advised and is especially critical for patients with RV dysfunction in order to manage volume status.

For advanced disease state with RV failure, fluid restriction (<2 L/day) is recommended.

Monitoring daily weights should be encouraged.
Immunizations

Yearly influenza vaccinations are advised, as well as being up to date with pneumococcal vaccinations.
Pregnancy

Hemodynamic fluctuations of pregnancy, labor, delivery, and postpartum period are poorly tolerated in PAH patients and can result with devastating consequences. Though not much data is present, some series report up to a 50% maternal mortality rate. Current guidelines recommend that pregnancy be avoided or terminated early in women with PAH.

It is imperative to have discussions regarding methods of birth control with patients. There is a great deal of controversy as to what is the preferred method. Estrogen-containing contraceptives may increase the risk of venous thromboembolism; however, currently available lower-dose preparations with concurrent warfarin anticoagulation may be an option. Some have advocated surgical sterilization and barrier methods.

Low-level graded aerobic exercise (i.e., walking) recommended as tolerated. A study among 30 PAH patients who were stable on PAH treatments demonstrated improvements in 6-minute walk distance (6MWD), quality of life, functional class, and peak oxygen consumption.
It is best to avoid heavy physical exertion or isometric exercise (i.e., straining against a fixed resistance) as this can cause exertional syncope.

Exposure to high altitudes may contribute to hypoxic pulmonary vasoconstriction and is not well tolerated.
For air travel, it is recommended that for patients with preflight pulse oximetry less than 92% to receive supplemental oxygen.

Sodium restricted diet (<2,000 mg/day) is advised and is especially critical for patients with RV dysfunction to manage volume status.
For advanced disease state with RV failure, fluid restriction (<2 L/day) is recommended.
Monitoring daily weights should be encouraged.

Yearly influenza vaccinations are advised as well as being up to date with pneumococcal vaccinations.

Hemodynamic fluctuations of pregnancy, labor, delivery and postpartum period are poorly tolerated in PAH patients and can result with devastating consequences. Though not much data is present, some series report up to 50% maternal mortality rate. Current guidelines recommend that pregnancy be avoided or terminated early in women with PAH.

It is imperative to have discussions regarding methods of birth control with patients. There is a great deal of controversy as to what is the preferred method. Estrogen-containing contraceptives may increase risk of venous thromboembolism; however, currently available lower-dose preparations with concurrent warfarin anticoagulation may be an option. Some have advocated surgical sterilization and barrier methods.

B. What's the Evidence for specific management and treatment recommendations?

McLaughlin, VV, Archer, SL, Badesch, DB. “ACCF/AHA 2009 expert consensus document on pulmonary hypertension: a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents”. J Am Coll Cardiol. vol. 53. 2009. pp. 1573-1619. (Comprehensive up-to-date recommendations on background, evaluation, and management of PAH.)

D’Alonzo, GE, Barst, RJ, Ayres, SM. “Survival in patients with primary pulmonary hypertension: results from a national prospective registry”. Ann Intern Med. vol. 115. 1991. pp. 343-9. (Epidemiology and risk assessments from the first NIH PPH Registry data from 1980s, prior to PAH-specific treatments were available. Only publications with natural history and outcome of PAH.)

Simonneau, G, Robbins, IM, Beghetti, M. “Updated clinical classification of pulmonary hypertension”. J Am Coll Cardiol. vol. 54. 2009. pp. S43-54. (Lists clinical classification for PH from the 5th Dana Point World Symposium Meeting)

Barst, RJ, Gibbs, SR, Hossein, A. ” Updated evidence-based treatment algorithm in pulmonary arterial hypertension”. J Am Coll Cardiol. vol. 54. 2009. pp. S78-84. (Discusses updated treatment recommendations from the 5th Dana Point World Symposium Meeting)

Badesch, DB, Champion, HC, Sanchez, MA. “Diagnosis and assessment of pulmonary arterial hypertension”. J Am Coll Cardiol. vol. 54. 2009. pp. S55-66. (Discusses the evaluation recommendations from the 5th Dana Point World Symposium Meeting)

de Perrot, M. J Heart Lung Transplantation. vol. 30. 2011. pp. 997(Study demonstrating Novalung experience from the Toronto Group)

C. DRG Codes and Expected Length of Stay.

DRG Codes

Despite changes in nomenclature in medical research and in published literature, billing codes still use the old terminologies “Primary Pulmonary Hypertension” (PPH) and “Secondary Pulmonary Hypertension” (SPH).

Primary Pulmonary Hypertension (416.0)
Secondary Pulmonary Hypertension (416.8)

Other relevant DRGs

Dyspnea/shortness of breath (786.05)
Syncope (780.2)
Fatigue (780.7)
Edema (782.2)
Palpitations (785.1)
Scleroderma (710.1, 701.0)
Diastolic heart failure, unspecified (428.30)
Diastolic heart failure, acute (428.31)
Diastolic heart failure, chronic (428.32)
Diastolic heart failure, acute on chronic (428.33)
Right heart failure (428.0)

Length of Stay (LOS)

This varies depending on clinical situation

1. Initial admission for evaluation; full workup, including RHC; and possible initiation of treatment.

LOS can vary mostly depending on how unstable patient is upon presentation.

Key workups include echocardiogram (with bubble if not done), VQ scan, PFTs, 6MWT (if able), serologies, and RHC.

2. For patients with advanced PAH (FC IIIB or IV, or decompensated RHF) and require intravenous therapy, usually LOS 3-5 days. Recommend transfer to PH Center.

3. For decompensated right heart failure admission requiring intravenous diuretics with or without inotropes, usually 3-5 days but can vary pending other underlying comorbidities and conditions.

4. For central access-related admissions, 1-3 days (or longer) depending if related to malfunction or infectious or both.

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Jump to Section

Management of Pulmonary Hypertension

I. Pulmonary Arterial Hypertension: What Every Physician Needs To Know.

Figure 1.

II. Diagnostic Confirmation: are you sure your patient has Pulmonary Arterial Hypertension?

Right Heart Catheterization: Necessary To Diagnose PAH

Table 4.

Assessment of Prognosis

A. History Part 1: Pattern Recognition

B. History Part 2: Prevalence:

C. History Part 3: Competing diagnoses that can mimic Pulmonary Arterial Hypertension

D. Physical Examination Findings.

E. What diagnostic tests should be performed?

Figure 2.

1. What laboratory studies (if any) should be ordered to help establish the diagnosis?

Diagnostic Tests A: Laboratory Evaluations in the Diagnosis for PAH

2. What imaging studies (if any) should be ordered to help establish the diagnosis?

Diagnostic Tests B: Radiographic Studies for Evaluation of PAH

III. Management

Figure 3.

A. Immediate management.

A. Physical Examination Tips to Guide Management.

B. Laboratory Tests to Monitor Response To, and Adjustments in, Management

C. Long-term management.

E. Common Pitfalls and Side-Effects of Management

Patients on Intravenous Prostacyclins

Patients on Endothelin receptor antagonists

Patients on PDE-5 Inhibitors

IV. Management with Co-Morbidities

V. Patient Safety and Quality Measures A. Appropriate Prophylaxis and Other Measures to Prevent Readmission.

B. What's the Evidence for specific management and treatment recommendations?

C. DRG Codes and Expected Length of Stay.

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