What every physician needs to know:
Prospective observational studies suggest that the cumulative incidence of chronic thromboembolic pulmonary hypertension (CTEPH) is in the range of 0.57-3.8 percent following an episode of acute pulmonary embolism. Survival without intervention is poor and, similar to other forms of pulmonary hypertension, is proportional to the degree of pulmonary hypertension and right ventricular dysfunction at the time of diagnosis.
Although acute pulmonary embolism and obstruction of the central pulmonary vasculature is the initiating event for CTEPH, the subsequent hemodynamic progression of the disease appears to involve secondary events in the pulmonary microvascular circulation. A major focus of the preoperative evaluation is attempting to partition the proximal component of the elevated vascular resistance from the distal arteriopathy and, by extension, estimating the anticipated hemodynamic outcome.
Are you sure your patient has chronic thromboembolic pulmonary hypertension? What should you expect to find?
Although most patients with CTEPH can provide a prior history of acute pulmonary embolism, approximately 20 percent cannot. The complaint common to patients with CTEPH is exertional dyspnea. With disease progression, exertion-related presyncope, frank syncope, and exertional chest pain may develop. Early in the course of the disease, physical examination findings may be subtle and limited to an accentuation of the pulmonic component of the second heart sound.
As the disease progresses, findings consistent with pulmonary hypertension or right ventricular failure appear (right ventricular lift, closely split second heart sound with further accentuation of its pulmonic component, right ventricular S4 or S3 gallop, varying degrees of tricuspid regurgitation, elevated jugular venous pressure, edema).
Beware: there are other diseases that can mimic chronic thromboembolic pulmonary hypertension:
Extrinsic pulmonary vascular compression from mediastinal adenopathy or fibrosis, primary pulmonary vascular tumors, large-vessel pulmonary arteritis, and pulmonary veno-occlusive disease may have a clinical presentation and imaging findings similar to that of CTEPH.
How and/or why did the patient develop chronic thromboembolic pulmonary hypertension?
The role of acquired and hereditary risk factors in the development of CTEPH has not been fully defined. The antiphospholipid antibody syndrome is the most common hypercoagulable state associated with CTEPH, occurring in up to 20 percent of patients. Increased levels of factor VIII have been reported in patients with CTEPH when compared to patients with non-thrombotic pulmonary hypertension. CTEPH has been associated with myeloproliferative syndromes as well as chronic inflammatory states, chronic ventriculoatrial shunts, splenectomy, recurrent episodes of venous thromboembolism, and chronic indwelling central venous catheters.
Which individuals are at greatest risk of developing chronic thromboembolic pulmonary hypertension?
Systolic pulmonary artery pressure (PAsP) greater than 50 mmHg at the time of diagnosis of acute embolism, systolic PAsP greater than 50 mmHg at the time of hospital discharge following acute embolism, previous pulmonary embolism or occult embolism, and an increased degree of pulmonary vascular obstruction at the time of acute pulmonary embolism diagnosis have been identified as risk factors for CTEPH.
What laboratory studies should you order to help make the diagnosis, and how should you interpret the results?
Transthoracic echocardiography – Echocardiography commonly provides the initial objective evidence that pulmonary hypertension is present and that it is not the result of primary left ventricular dysfunction, valvular disease, or, when performed with a contrast study, an intracardiac shunt.
Chest radiography – Pleural abnormalities or regions of avascularity on a chest radiograph can suggest a chronic thromboembolic basis for the pulmonary hypertension.
Pulmonary function testing – Approximately 20 percent of patients will demonstrate a mild restrictive ventilatory defect that appears to be related to parenchymal scarring associated with acute embolism. A reduced diffusion capacity for carbon monoxide is common and appears to be predominantly related to a reduction in pulmonary membrane diffusion capacity.
Arterial blood gas – Some degree of hypoxemia is common and is related to a moderate ventilation-perfusion inequality and a depressed mixed venous saturation resulting from limitation in cardiac output.
What imaging studies will be helpful in making or excluding the diagnosis of chronic thromboembolic pulmonary hypertension?
Ventilation-perfusion (V/Q) scanning represents an essential and noninvasive means of differentiating disorders of the peripheral pulmonary vascular bed from those of the central vasculature.
In chronic thromboembolic disease, at least one–and more commonly several–segmental or larger mismatched perfusion defects are present (Figure 1). In disorders of the distal pulmonary vascular bed, perfusion scans are either normal or they exhibit a “mottled” appearance characterized by subsegmental defects.
The magnitude of the perfusion defects in chronic thromboembolic disease often understates to a considerable extent the degree of pulmonary vascular obstruction determined angiographically or at surgery. The presence of even a single mismatched, segmental ventilation-perfusion scan defect in a patient with pulmonary hypertension should raise concerns regarding a potential thromboembolic basis.
Mismatched segmental or larger defects in patients with pulmonary hypertension may also arise from other processes that result in obstruction of the central pulmonary arteries or veins, such as pulmonary artery sarcoma, large-vessel pulmonary vasculitides, extrinsic vascular compression by mediastinal adenopathy or fibrosis, and pulmonary veno-occlusive disease.
What non-invasive pulmonary diagnostic studies will be helpful in making or excluding the diagnosis of chronic thromboembolic pulmonary hypertension?
Although a negative CT angiogram (CTA) cannot exclude the possibility of CTEPH, it may demonstrate a variety of parenchymal, vascular, or mediastinal abnormalities consistent with CTEPH. These abnormalities include a mosaic parenchymal perfusion pattern, parenchymal scars, enlargement of the right ventricle and/or central pulmonary arteries, asymmetry in the size and distribution of lobar and segmental vessels, intraluminal thrombus, organized thrombus lining the pulmonary vascular walls, arterial webs or bands, and mediastinal collateral vessels. CT scanning may also be useful in excluding potential differential possibilities, such as mediastinal fibrosis, extrinsic vascular compression, and pulmonary artery sarcoma (Figure 2).
What diagnostic procedures will be helpful in making or excluding the diagnosis of chronic thromboembolic pulmonary hypertension?
The reference standard for the diagnosis and determination of surgical accessibility remains combined right heart catheterization (to quantify the hemodynamic impairment) and conventional pulmonary angiography (to determine the extent and proximal location of the chronic thromboembolic obstruction).
Five angiographic patterns have been described in chronic thromboembolic disease that correlate with findings at the time of surgery. pouch defects; pulmonary artery webs or bands; intimal irregularities; abrupt, often angular narrowing of the major pulmonary arteries; and complete obstruction of main, lobar, or segmental vessels at their point of origin (Figure 3).
If you decide the patient has chronic thromboembolic pulmonary hypertension, how should the patient be managed?
Pulmonary thromboendarterectomy (PTE) represents the intervention of choice for patients with CTEPH. Criteria for PTE include:
A mean pulmonary artery pressure greater than 30 mmHG or a pulmonary vascular resistance greater than 300 dynes-sec-cm-5
Dyspnea related to high dead space and high minute ventilation demands in the absence of pulmonary hypertension
Surgical accessibility of the chronic thromboembolic obstruction (main, lobar or proximal segmental pulmonary arteries)
Consideration of the anticipated postoperative pulmonary vascular resistance and of comorbid conditions that may adversely affect perioperative mortality or morbidity and long-term survival
Pulmonary thromboendarterectomy involves median sternotomy, cardiopulmonary bypass, and periods of hypothermic circulatory arrest to avoid bronchial arterial back-bleeding. The organized material is fibrotic in nature, and the procedure is a true thromboendarterectomy, not an embolectomy (Figure 4).
Overall perioperative (30-day) mortality rates following PTE at centers experienced in the management of this disease process have dropped to the range of 4-7 percent. A mortality rate of 1.3 percent has been reported in patients at low risk based on their preoperative hemodynamic profile.
Attributable reported causes of death following PTE surgery are consistent with those associated with other high-risk, open-heart procedures: cardiac arrest, multi-organ failure, uncontrollable mediastinal bleeding, sepsis syndrome, and massive pulmonary hemorrhage. In recent series, the major causes of postoperative morality are right ventricular failure related to persistent pulmonary hypertension and acute lung injury.
Disease-modifying therapies developed for use in idiopathic pulmonary arterial hypertension (IPAH), including prostacyclin analogs, endothelin receptor antagonists, phosphodiesterase-5 inhibitors, and a soluble guanylate cyclase stimulator have been studied in patients with CTEPH. Of these, the soluble guanylate cyclase stimulator riociguat is the first to demonstrate both improved hemodynamic and functional status in patients with CTEPH. Potential indications for medical therapy in CTEPH include:
Surgically accessible CTEPH in patients who elect not to undergo surgery by personal choice or where co-morbidities are so substantial as to exclude the patient from considering PTE;
Distal chronic thromboembolic disease or limited central disease that is so disproportionate to the severity of the pulmonary hypertension that the surgical mortality risk of PTE is prohibitive;
Use as a preoperative therapeutic “bridge” to surgery in patients with severe right ventricular dysfunction;
Management of persistent pulmonary hypertension following PTE.
The hemodynamic and symptomatic benefits accrued from medical therapy, although often positive, are modest in comparison to those resulting from PTE. A decision to forego PTE and to utilize medical therapy should be made only after a comprehensive evaluation has been performed, only for defined indications, and only after consultation with a center experienced in the management of this disease process.
Percutaneous balloon pulmonary angioplasty may have a potential role in patients with inoperable CTEPH. Observational studies in selected patients have demonstrated a beneficial effect in hemodynamics, exercise tolerance, and biomarkers. Further study is necessary to determine its role in CTEPH management.
Lung transplantation remains a therapeutic alternative for patients not deemed candidates for PTE based on the location and/or extent of their thromboembolic disease and for patients who have undergone PTE with an inadequate hemodynamic outcome not responsive to medical therapy. There are currently no data on how CTEPH patients fare following lung transplantation compared to other categories of patients.
What is the prognosis for patients managed in the recommended ways?
The short-term and long-term hemodynamic outcomes are favorable following PTE. The pulmonary artery pressure and pulmonary vascular resistance are dramatically reduced and at times normalized. In published series, the mean reduction in pulmonary vascular resistance has approximated 70 percent, and a pulmonary vascular resistance in the range of 200 to 350 dyne·s·cm-5 can be achieved. A corresponding improvement in right ventricular function determined by echocardiography, gas exchange, exercise capacity, and quality of life has also been reported.
What other considerations exist for patients with chronic thromboembolic pulmonary hypertension?
In patients with persistent pulmonary hypertension following PTE, disease-modifying therapy appears beneficial although the threshold level of postoperative pulmonary hypertension requiring therapy remains to be defined.
Life-long anticoagulant therapy is strongly recommended after pulmonary thromboendarterectomy. Thromboembolic recurrence can occur when anticoagulation is discontinued or is maintained at a subtherapeutic level. Reoperative PTE is feasible with a perioperative risk that is comparable with primary PTE.
What’s the Evidence?
Klok, F. “Prospective cardiopulmonary screening program to detect chronic thromboembolic pulmonary hypertension in patients after acute pulmonary embolism”. Haematologica. vol. 95. 2010. pp. 970-975. (In a cohort screening study involving 866 survivors of acute pulmonary embolism, four patients were ultimately diagnosed with CTEPH (confirmed by right heart catheterization) for a cumulative incidence of CTEPH of 0.57%.)
Auger, WR, Fedullo, PF.. “Chronic thromboembolic pulmonary hypertension”. Semin Respir Crit Care Med. vol. 30. 2009. pp. 471-483. (Comprehensive review of the evaluation and management of chronic thromboembolic disease.)
Miniati, M, Monti, S, Bottai, M. “Survival and restoration of pulmonary perfusion in a long-term follow-up of patients after pulmonary embolism”. Medicine. vol. 85. 2006. pp. 253-262. (Lung perfusion scan continued to demonstrated abnormalities in 35 percent of patients one year after the acute event although the degree of pulmonary vascular obstruction was less than 15 percent in 90 percent of the patients.)
Riedel, M, Stanek, V, Widimsky, Prerovsky I.. “Long-term follow-up of patients with pulmonary thromboembolism: late prognosis and evolution of hemodynamic and respiratory data”. Chest.. vol. 81. 1982. pp. 151-158. (Pulmonary hypertension occurred most frequently in patients with occult embolism. Pulmonary hypertension progressed farther in patients with mean pulmonary artery pressure greater than 30 mm Hg.)
Wolf, M, Soyer-Neumann, C, Parent, F. “Thrombotic risk factors in pulmonary hypertension”. Eur Resp J.. vol. 15. 2000. pp. 395-399. (Prevalence of prothrombotic tendencies in patients with CTEPH.)
Bonderman, D, Turecek, PL, Jakowitsch, J. “High prevalence of elevated clotting factor VIII in chronic thromboembolic pulmonary hypertension”. Thromb Haemost. vol. 90. 2003. pp. 372-376. (CTEPH patients had significantly higher FVIII levels than controls did.)
Moser, KM, Bloor, CM.. “Pulmonary vascular lesions occurring in patients with chronic major vessel thromboembolic pulmonary hypertension”. Chest. vol. 103. 1993. pp. 685-692. (Original description of the distal vasculopathy that develops in patients with CTEPH.)
Morris, TA, Auger, WR, Ysrael, MZ. “Parenchymal scarring is associated with restrictive spirometric defects in patients with chronic thromboembolic pulmonary hypertension”. Chest. vol. 110. 1996. pp. 399-403. (Of patients referred for thromboendarterectomy, 22 percent had a restrictive ventilatory pattern. The presence of parenchymal scarring was highly associated with lung restriction.)
Ryan, KL, Fedullo, PF, Davis, GB. “Perfusion scan findings understate the severity of angiographic and hemodynamic compromise in chronic thromboembolic pulmonary hypertension”. Chest. vol. 93. 1988. pp. 1180-1185. (Perfusion scans consistently understated the degree of pulmonary artery obstruction as defined by pulmonary angiography.)
van der Plas, MN, Reesink, HJ, Roos, CM. “Pulmonary endarterectomy improves dyspnea by the relief of dead space ventilation”. Ann Thorac Surg. vol. 89. 2010. pp. 347-352. (Dead space ventilation increases in CTEPH and correlates with hemodynamic severity of disease and symptomatic dyspnea.)
Pitton, MB, Duber, C, Mayer, E. “Hemodynamic effects of nonionic contrast bolus injection and oxygen inhalation during pulmonary angiography in patients with chronic major-vessel thromboembolic pulmonary hypertension”. Circulation. vol. 94. 1996. pp. 2485-2491. (Pulmonary angiography can be performed safely in patients with severe pulmonary hypertension secondary to chronic thromboembolic disease.)
Auger, WR, Fedullo, PF, Moser, KM. “Chronic major-vessel thromboembolic pulmonary artery obstruction: appearance at angiography”. Radiology. vol. 182. 1992. pp. 393-398. (Original description of angiographic patterns encountered in CTEPH.)
Thistlethwaite, PA, Kaneko, K, Madani, MM, Jamieson, SW.. “Techniques and outcomes of pulmonary endarterectomy surgery”. Ann Thorac Cardiovasc Surg. vol. 14. 2008. pp. 274-282. (Discussion of the updated surgical approach and outcome in 1,100 patients undergoing thromboendarterectomy.)
Olman, MA, Auger, WR, Fedullo, PF. “Pulmonary vascular steal in chronic thromboembolic pulmonary hypertension”. Chest. vol. 98. 1990. pp. 1430-1434. (A description of the pulmonary artery steal phenomenon occurring after thromboendarterectomy.)
Levinson, R, Shure, D, Moser, KM.. “Reperfusion pulmonary edema after pulmonary artery thromboendarterectomy”. Am Rev Respir Dis. vol. 134. 1986. pp. 1241-1245. (Original description of reperfusion pulmonary edema occurring after thromboendarterectomy.)
Corsico, AG, D’Armini, AM, Cerveri, I. “Long-term outcome after pulmonary endarterectomy”. Am J Resp Crit Care Med. vol. 178. 2008. pp. 419-424. (Long-term survival and cardiopulmonary function recovery is excellent in most patients who undergo thromboendarterectomy.)
Archibald, CJ, Auger, WR, Fedullo, PF. “Long-term outcome after pulmonary thromboendarterectomy”. Am J Respir Crit Care Med. vol. 160. 1999. pp. 523-528. (Long-term symptomatic, quality-of-life, and functional follow-up in 308 patients who underwent thromboendarterectomy.)
Condliffe, R, Kiely, DG, Gibbs, JS. “Improved outcomes in medically and surgically treated chronic thromboembolic pulmonary hypertension”. Am J Respir Crit Care Med. vol. 177. 2008. pp. 1122-1127. (Long-term prognosis for patients with persistent pulmonary hypertension three months after thromboendarterectomy is good.)
Becattini, C, Manina, G, Busti, C. “Bosentan for chronic thromboembolic pulmonary hypertension: findings from a systematic review and meta-analysis”. Thromb Res. vol. 126. 2010. pp. e51-e56. (Bosentan therapy is associated with an improvement in hemodynamics and probably exercise capacity in patients with CTEPH.)
Bresser, P, Pepke-Zaba, J, Jais, X. “Medical therapies for chronic thromboembolic pulmonary hypertension”. Proc Am Thorac Soc. vol. 3. 2006. pp. 594-600. (Comprehensive review of medical therapies for chronic thromboembolic disease.)
Ogo, T.. “Balloon pulmonary angioplasty for inoperable chronic thromboembolic pulmonary hypertension”. Curr Opin Pulm Med. vol. 21. 2015. pp. 425-431. (Review of recent studies of balloon pulmonary angioplasty for inoperable CTEPH.)
Ghofrani, HA, D’Armini, AM, Grimminger, F. “Riociguat for the treatment of chronic thromboembolic pulmonary hypertension”. N Engl J Med. vol. 369. 2013. pp. 319-329. (Randomized trial demonstrating hemodynamic and functional improvement associated with riociguat in patients with inoperable CTEPH.)
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- What every physician needs to know:
- Are you sure your patient has chronic thromboembolic pulmonary hypertension? What should you expect to find?
- Beware: there are other diseases that can mimic chronic thromboembolic pulmonary hypertension:
- How and/or why did the patient develop chronic thromboembolic pulmonary hypertension?
- Which individuals are at greatest risk of developing chronic thromboembolic pulmonary hypertension?
- What laboratory studies should you order to help make the diagnosis, and how should you interpret the results?
- What imaging studies will be helpful in making or excluding the diagnosis of chronic thromboembolic pulmonary hypertension?
- What non-invasive pulmonary diagnostic studies will be helpful in making or excluding the diagnosis of chronic thromboembolic pulmonary hypertension?
- What diagnostic procedures will be helpful in making or excluding the diagnosis of chronic thromboembolic pulmonary hypertension?
- If you decide the patient has chronic thromboembolic pulmonary hypertension, how should the patient be managed?
- What is the prognosis for patients managed in the recommended ways?
- What other considerations exist for patients with chronic thromboembolic pulmonary hypertension?