I. Pulmonary Hypertension: What every physician needs to know.

Pulmonary hypertension is defined as mean pulmonary arterial pressure of 25 mm Hg or greater. Pulmonary hypertension therefore is a description rather than a diagnosis. Once pulmonary hypertension is detected, careful diagnostic steps are necessary to ensure accurate diagnosis, followed by appropriate evidence-based treatment.

Elevation of pulmonary pressure can be caused by a wide range of conditions with very different prognoses and treatment implications. Despite the growth in the field of pulmonary hypertension, in particular with expansion of available medical therapeutics, we need to recognize that these therapeutics are only indicated for a specific subtype of pulmonary hypertension. Accordingly, detection of elevated pulmonary artery pressure should not immediately result in treatment, but instead lead to an additional and careful diagnostic workup, including confirmation of the presence of pulmonary hypertension.

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

Pulmonary hypertension is often first suspected or discovered by echocardiography. Despite advances in echocardiography, pulmonary hypertension still requires a right heart catheterization (RHC) demonstrating mean pulmonary arterial pressure ≥ 25 mm Hg at rest for confirmation. A second critical information from the RHC that is central to the diagnosis is the pulmonary arterial occlusion or wedge pressure (Pawp).

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For patients with World Health Organization (WHO) group I cause of pulmonary hypertension, also known as pulmonary arterial hypertension (PAH), the Pawp should be less than 15 mm Hg. This is primarily to rule out the more common secondary pulmonary hypertension related to various left heart conditions or pulmonary venous hypertension—PH classified under WHO group II. The currently available PH targeted medical therapies are only indicated for patients with WHO group I PH (PAH) and should not be prescribed for patients outside of WHO group I.

A. History Part I: Pattern Recognition:

The history of PAH can be traced back to the aminorex (diet pill) epidemic in Europe causing primary pulmonary hypertension (PPH, the prior term for what we now call idiopathic pulmonary arterial hypertension) back in the 1960s and 70s. In response, the National Institutes of Health (NIH) conducted a registry in the U.S. of PPH patients. The typical patient at that time was an otherwise healthy young woman in her 30s, with an average life expectancy after diagnosis of approximately two and a half years.

With introduction of modern PH therapies, the outlook has improved significantly. Fast forwarding to the current era, the typical PAH patient tends to be older and with other comorbidities either linking with pulmonary hypertension or challenging its timely diagnosis and treatment. The most common presenting symptom remains shortness of breath on exertion, which is present in just about every patient with PAH. Other common symptoms include fatigue, light-headedness with exertion, cough, chest pain, and palpitation. These symptoms are nonspecific and therefore contribute to delayed diagnosis of PAH.

B. History Part 2: Prevalence:

PAH remains a rare condition and infrequent cause of pulmonary hypertension detected by echocardiogram. Despite limitations on deriving estimates, we suspect the incidence of PAH to be under 10 cases per million people. Although this may represent perhaps an underdiagnosis, a key take home message is that PAH is uncommon.

Numerous prevalence reports have been published over the years. Although there is some variability among the reports, the prevalence figures also indicate PAH is not common among the general population. However, within specific populations such as at risk groups (e.g., patients with connective tissue disease), we urge increased awareness and adherence to consensus guidelines in terms of screening and diagnosis.

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

If we were to start with pulmonary hypertension detected by echocardiogram, then the most common causes of pulmonary hypertension at the end of our workup are also the common conditions we see on a regular basis. In other words, common things are common—with pulmonary hypertension related to left heart condition (WHO group II) or chronic lung disease/hypoxemia (WHO group III) being the two most common causes of pulmonary hypertension.

The various diagnostic algorithms for pulmonary hypertension have been designed with this important recognition. Another major and unique cause of pulmonary hypertension worthy of a separate classification group is chronic thromboembolic pulmonary hypertension (CTEPH, WHO group IV). CTEPH is associated with unresolved pulmonary embolism, causing large vessel scarring amenable to surgical treatment.

Patients with CTEPH can present with identical history and examination findings as patients with PAH. Up to 25% of CTEPH patients have no history of pulmonary embolism, and 50% have never had deep venous thrombosis. Accordingly, the absence of venous thromboembolism history does not rule out CTEPH—and why CTEPH needs to be considered and ruled out in every patient diagnosed with pulmonary arterial hypertension.

D. Physical Examination Findings.

Physical examination findings in pulmonary hypertension correlate with the specific type of PH, as well as disease severity. Patients with PAH typically have clear lungs upon examination and on a radiograph. An accentuated pulmonic component of the second heart sound and a holosystolic murmur at the left lower sternal border representing tricuspid regurgitation are common.

As the disease progresses, additional signs of right heart failure from PAH can be detected with jugular venous distention, right-sided S3, hepatomegaly, ascites, lower extremity edema, and peripheral cyanosis. The presence of significant wheezing, crackles, or chest wall deformities should raise suspicion for possible non-WHO group I cause of pulmonary hypertension. The presence of pulmonary flow murmur caused by turbulent flow across a proximal pulmonary artery narrowing should raise the suspicion for CTEPH.

E. What diagnostic tests should be performed?

Echocardiography represents the most common test leading to initial detection of pulmonary hypertension. As mentioned above, this PH recognition by echocardiography represents only the beginning but an important step in the diagnostic algorithm for pulmonary hypertension. Some obvious causes of left heart disease causing PH can be assessed by echocardiogram and electrocardiogram.

Patients with chronic dyspnea should also have a chest radiograph and pulmonary function tests. Typically at this point, one has significant and relevant data to assess if the cause of pulmonary hypertension could be related to a left heart condition or chronic lung disease/hypoxemia.

A critical test in differentiating PAH from CTEPH is a lung ventilation/perfusion scan (VQ scan). Despite advances in computer tomography technology, a CT angiogram can miss chronic thromboembolic disease. Accordingly, all major guidelines recommend a VQ scan over CT for screening for patients with pulmonary hypertension for CTEPH. Lastly and very importantly, right heart catheterization is necessary for pulmonary hypertension confirmation among other valuable information derived from hemodynamics. For PAH, we consider right heart catheterization mandatory prior to any treatment.

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

PAH can be associated with numerous medical conditions such as connective tissue diseases, liver disease, and HIV. Accordingly, metabolic panel, antinuclear antibody (ANA), and HIV serology should be ordered for newly diagnosed patients with PAH. NT-pro BNP or BNP can be useful biomarkers for the assessment of disease severity and management. Other laboratory parameters associated with disease severity and PAH have included serum sodium, uric acid level, and platelet count.

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

Patients suspected of having pulmonary hypertension should be evaluated with a chest radiograph and transthoracic echocardiogram. On a chest radiograph, typical findings in pulmonary arterial hypertension include cardiac silhouette and proximal pulmonary artery enlargement, without evidence of significant parenchymal lung disease or pleural effusion. Echocardiogram with estimate of right ventricular systolic pressure can detect pulmonary hypertension, which will then require further workup in order to identify the etiology.

The recommended imaging modality to differentiate pulmonary arterial hypertension from chronic thromboembolic pulmonary hypertension remains a lung ventilation/perfusion scan (VQ scan). Confirmation of chronic thromboembolic disease then requires pulmonary angiography—which is also necessary for operability assessment. Due to the subjective and challenging nature of pulmonary thromboendarterectomy (PTE) assessment, all cases of chronic thromboembolic pulmonary hypertension should be referred to a PTE center for evaluation and treatment.

Figure 1. Chest radiograph from a patient with suspected pulmonary hypertension; notable findings include cardiomegaly, and enlarged central pulmonary arteries, with clear lung fields.

Figure 1.

Chest radiograph from a patient with suspected pulmonary hypertension.

Figure 2. Echocardiogram with apical four chamber view from a patient with severe pulmonary hypertension—notable for severe impairment of the left chambers due to right sided dilation and failure.

Figure 3. VQ scan from a patient with CTEPH. Multiple bilateral segmental and subsegmental perfusion defects are present.

Figure 3.

VQ scan from a patient with CTEPH.

Figure 4. Pulmonary thromboendarterectomy surgery (specimen shown) resulted in normal postoperative hemodynamics.

Figure 4.

Pulmonary thromboendarterectomy surgery (specimen shown) resulted in normal postoperative hemodynamics.

III. Management.

The management of pulmonary hypertension depends on the specific etiology or type. Pulmonary arterial hypertension (PAH, WHO group I) is treated with specialized medical therapy. In a relatively short period of time, the field has advanced from no treatment to now 7 different drugs given 10 or more different ways for the treatment of PAH. Currently and importantly, these drugs are not approved for use in patients outside WHO group I pulmonary hypertension.

For chronic thromboembolic pulmonary hypertension (CTEPH), pulmonary thromboendarterectomy (a.k.a. pulmonary endarterectomy) surgery remains the treatment of choice. For all other secondary forms of pulmonary hypertension, the management should focus on optimizing or addressing the underlying disease.

A. Immediate management.

The priority and ongoing challenge with pulmonary hypertension remain in making the correct diagnosis. Reaching for therapy without carefully determining the type or cause of pulmonary hypertension can result in a serious adverse outcome, including preventable death. Severe cases of PAH, and all cases of CTEPH, are also best evaluated and managed by a team of experienced specialists. Accordingly, a close working relationship and partnership are necessary with specialized centers to provide the best and timely care for these unique patients.

B. Physical Examination Tips to Guide Management.

Many of the physical examination findings in PAH or CTEPH can be subtle, especially in milder cases. Any evidence of right heart failure such as the presence of jugular venous distention, right-sided S3, hepatosplenomegaly, ascites, or peripheral edema may indicate severe pulmonary hypertension and deserve more urgent attention.

Untreated, such high-risk PAH patients have been associated with poor survival measured in weeks. On the other hand, the presence of pulmonary crackles, poor air movement, wheezing, chest wall deformity, or other associated signs of left heart disease should alert practitioners to the possibility of secondary pulmonary hypertension rather than PAH (or CTEPH). The medical history in such cases will also be invaluable in assessing probability and with sorting the various potential causes of pulmonary hypertension. For example, an 80 year old with chronic atrial fibrillation and COPD with pulmonary hypertension by echocardiogram is less likely to have PAH, and more likely to have either WHO group II or III cause of PH (neither which have approved PH targeted treatments).

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

For PAH, we follow New York Hospital Association (NYHA) functional class, 6-minute (hallway) walk distance, and periodic hemodynamics with right heart catheterization. Biomarkers of interest include NT-pro BNP or BNP. Right atrial size, presence of pericardial effusion, and tricuspid annular plane systolic excursion (TAPSE) on transthoracic echocardiogram have all been reported to correlate with prognosis in PAH.

D. Long-term management.

Patients with PAH require long-term management and routine follow-up. Although the treatment options have expanded, we do not (yet) have a cure. The frequency of follow-up and the need for specific testing depend on the etiology of PAH, severity of disease, and other logistic factors (e.g., some patients travel from long distances to remain under the care of a PH specialist or group).

For patients who fail to respond to medical therapy, bilateral lung transplantation remains a potential treatment option. Accordingly, the PH specialist needs to be aware of the proper timing and role of lung transplantation for this subset of challenging patients in order to provide the best and most comprehensive care possible. For patients with CTEPH, pulmonary thromboendarterectomy surgery often means a chance of clinical cure for their pulmonary hypertension. With good surgical outcome, these patients often just require life-long anticoagulation without the need for PH targeted treatment.

E. Common Pitfalls and Side-Effects of Management

The biggest concern with pitfalls in PH management is whether a proper diagnosis has been established. Missing a case of CTEPH is depriving that patient from a potential safe and curative intervention. Treating a patient with left heart related PH with PAH targeted therapy risks an adverse outcome from medication side effects (e.g., original epoprostenol trial in patients with left heart failure was associated with increased deaths prompting an early termination of the trial) and delay in addressing the primary problem. In terms of side effects for PAH patients receiving approved therapy, that depends on numerous factors, including the type or class of medical therapy.

Approved therapies in the U.S. for PAH fall under three pathways. Prostacyclin analogue replacement can be given continuous-intravenously (epoprostenol, treprostinil), subcutaneous (treprostinil), or inhaled (iloprost, treprostinil). The complexity of the parenteral formulas result in these treatments often reserved for higher volume or experienced PH centers. Endothelin receptor antagonists are pills taken orally: bosentan (BID) and ambrisentan (QD). Lastly, phosphodiesterase-5 inhibitors are also given orally and are approved for PAH: sildenafil (TID) and tadalafil (QD). All these therapies are only approved for WHO group I, PAH. The use in other forms of PH is discouraged and should be reserved only for clinical trials. (See Table I)

Table I.
Generic Name Brand Name (s) Class Route Dose*
Epoprostenol Flolan, Veletri Prostacyclin IV Start 2 ng/kg/min
Iloprost Ventavis Prostacyclin Inhaled 2.5 to 5 mcg 6 to 9 times/day
Treprostinil Remodulin Prostacyclin SQ, IV Start 1.25 ng/kg/min
Treprostinil Tyvaso Prostacyclin Inhaled 9 puffs QID
Ambrisentan Letairis Endothelin receptor antagonist PO 5 to 10 mg QD
Bosentan Tracleer Endothelin receptor antagonist PO 125 mg BID
Sildenafil Revatio Phosphodiesterase-5 inhibitor PO 20 mg TID
Tadalafil Adcirca Phosphodiesterase-5 inhibitor PO 40 mg QD

* Refer to the respective prescribing information for more details on dosing, side effects, and other considerations.

IV. Management with Co-Morbidities

For idiopathic PAH, comorbidity issues seldom arise. However, the other major cause of PAH is that due to associated conditions—ranging from connective tissue diseases, liver disease, HIV, and congenital heart defects. This latter group of PAH has challenges unique to each associated cause.

The treatment response across all therapies and the level of evidence for each subgroup varies depending on the specific subtype of PAH—with the majority of data in support of idiopathic PAH. Accordingly, experience in managing each subtype of PAH is invaluable and represents another reason to refer such patients to a PH center.

The sickest PAH patients in NYHAC IV should be treated with intravenous prostanoid therapy with close follow-up and with the option of lung transplantation if necessary. The majority of newly diagnosed PAH patients fall in NYHAC III and may be successfully managed with oral therapy with early follow-up to assess response within 3 months. CTEPH patients regardless of NYHAC or disease severity should be referred for pulmonary thromboendarterectomy surgery evaluation. For experienced PTE centers, no degree of right heart failure or PH severity is a contraindication for PTE. Indeed, those patients may have the most to gain from PTE surgery.

Untreated PAH carries a poor prognosis, with average survival of little over two and a half years. Those PAH patients in NYHAC IV or with right heart failure may have in weeks to months of survival time without treatment. Accordingly, all PAH patients should have a complete and proper diagnosis followed by treatment without delay. Significant delay may also limit the available treatment options. With timely diagnosis and PAH targeted therapy, survival and other important outcomes can be significantly improved.

V. Patient Safety and Quality Measures

A. Appropriate Prophylaxis and Other Measures to Prevent Readmission.

PAH patients should not get pregnant as the risk to the mother’s health is prohibitive. Chronic anticoagulation is recommended for idiopathic PAH based on mostly retrospective reports showing a survival benefit with anticoagulation. Exercise is recommended and encouraged for PAH patients not in NYHAC IV. Patients who are hypoxic and respond to supplemental oxygen are encouraged to be on therapy. Similarly, patients who are hypoxemic or symptomatic due to significant altitude are encouraged to avoid such altitudes. CTEPH patients should remain on life-long anticoagulation therapy.

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

We just held our 5th World Symposium on Pulmonary Hypertension (WSPH). The proceedings of this week long international meeting will be once again published with guidelines for PH and PAH assessment and treatment. Numerous other consensus statements have been reported since the last and 4th WSPH held in 2008. Until the new proceedings are published, I recommend the following publications:

Barst, RJ. “Updated evidence-based treatment algorithm in pulmonary arterial hypertension”. J Am Coll Cardiol. vol. 54. 2009. pp. S78-84. (4th WSPH)

Galie, N. “Guidelines for the diagnosis and treatment of pulmonary hypertension”. Eur Respir J.. vol. 34. 2009. pp. 1219-63. (ESC, ERS, ISHLT)

McLauglin, VV. “ACCF/AHA 2009 expert consensus document on pulmonary hypertension”. J Am Coll Cardiol. vol. 53. 2009. pp. 1573-619. (ACCF, AHA, ACCP, ATS, PHA)

Fedullo, P. “Chronic thomboembolic pulmonary hypertension”. Am J Respir Crit Care Med. vol. 183. 2011. pp. 1605-13.

Madani, MM. “Pulmonary endarterectomy: recent changes in a single institution's experience of more than 2,700 patients”. Ann Thorac Surg. vol. 94. 2012. pp. 97-103.

C. DRG Codes and Expected Length of Stay.

PAH 416.0; CTEPH 416.8. For an experienced pulmonary thromboendarterectomy (PTE) center, the typical length of inpatient stay for PTE surgery is a total of 2 weeks.