The natural history of pulmonary embolism is generally total embolic resolution or resolution leaving minimal residua, with restoration of normal hemodynamic status.⁸ However, for unknown reasons, embolic resolution is incomplete in a small subset of patients. If the acute pulmonary emboli are not lysed in 1 to 4 weeks, the embolic material becomes attached to the pulmonary arterial wall at the main, lobar, segmental, or subsequential levels.⁵⁵ With time, the initial embolic material progressively becomes converted into connective and elastic tissue. Often, visualization of the pulmonary arteries by angioscopy a few weeks after the finding of an unresolved pulmonary embolism reveals vessel narrowing at the site of embolic incorporation and vessel wall remodeling. In some patients, recanalization of some of the pulmonary arterial branches occurs, with the formation of fibrous tissue in the form of bands and webs.¹² By a mechanism that is poorly understood, chronic thromboembolic obstruction may also lead to a small vessel arteriolar vasculopathy characterized by excessive proliferation of smooth muscle cells around small arterioles in the pulmonary circulation.¹⁴ This small vessel vasculopathy is seen in the remaining open vessel beds, which are subjected to long exposure at high flow. Pulmonary hypertension results when the capacitance of the remaining open bed cannot absorb the cardiac output, either because of the degree of primary obstruction by embolus or the combination of a fixed obstructive lesion and secondary small vessel vasculopathy.

The incidence of pulmonary hypertension caused by chronic pulmonary emboli is even more difficult to determine than that of acute pulmonary embolism. In the United States, there are more than 500,000 survivors per year of acute symptomatic episodes.^5,45 The incidence of chronic thrombotic occlusion/stenosis in the population depends on the percentage of patients who fail to resolve acute embolic material. A multinational prospective long-term follow-up study recently demonstrated that chronic thromboembolic disease develops in 3.8% of patients within 2 years of an acute embolic event.⁵² If this figure is correct, and counting patients with symptomatic acute pulmonary emboli, approximately 19,000 individuals would progress to chronic thromboembolic pulmonary hypertension in the United States each year. However, because many (if not most) patients diagnosed with chronic thromboembolic disease have no antecedent history of acute embolism, the true incidence of this disorder is probably much higher.

Regardless of the true incidence, it is clear that acute embolism and its chronic relation, chronic thromboembolic occlusive disease, are both much more common than is generally appreciated and are seriously underdiagnosed. In 1963, Houk and colleagues²¹ reviewed the literature of 240 cases of chronic thromboembolic obstruction of major pulmonary arteries and
found that only 6 cases had been diagnosed correctly before death. Autopsy analysis of 13,216 patients in 1993 showed pulmonary thromboembolism in 5.5% of autopsies and in up to 31.3% in the elderly at the time of death.⁵¹

It is unclear why acute emboli fail to resolve in a subset of patients who subsequently develop pulmonary hypertension. Lupus anticoagulant may be detected in 10% of chronic thromboembolic patients;⁴ 20% of patients carry anticardiolipin antibodies, lupus anticoagulant, or both.²⁹ A recent study has demonstrated that the plasma level of factor VIII, protein that is associated with primary and recurrent venous thromboembolism, is elevated in 39% of patients with chronic thromboembolic pulmonary hypertension.⁷ Analyses of plasma proteins in patients with chronic thromboembolic pulmonary hypertension have shown that fibrin from these patients is resistant to thrombolysis in vitro.⁴⁴ In this study, the fibrin β chain’s N-terminus was particularly resistant to thrombolysis, suggesting that it could be responsible for failure of resolution of the thrombus. In addition, there are limited data on the role of thrombomodulin, an endothelial cell membrane protein that binds thrombin and acts as a cofactor for the conversion of protein C to activated protein C, a natural anticoagulant in this disease. One group has shown a negative correlation between thrombomodulin plasma concentrations with mean pulmonary arterial pressure and pulmonary vascular resistance in chronic thromboembolic surgical patients compared with acute venous thromboembolism and control patients.⁶³ In patients who underwent pulmonary endarterectomy, thrombomodulin concentration increased significantly, implying endothelial cell dysfunction in addition to a prothrombotic state in the prepulmonary endarterectomy patients.

Case reports and small series have suggested links between chronic thromboembolism and previous splenectomy, permanent intravenous catheters, and ventriculoatrial shunts for the treatment of hydrocephalus or chronic inflammatory conditions. In addition to these observations, associations with sickle cell disease, hereditary stomatocytosis, and the Klippel–Trenaunay syndrome have been described by Guillinta and colleagues.¹⁶ However, the vast majority of cases of chronic thromboembolic pulmonary hypertension are not linked with a specific coagulation defect or underlying medical condition.

Patients with chronic thromboembolic pulmonary hypertension usually present with subtle or nonspecific symptoms. The most common symptoms are progressive exertional dyspnea and exercise intolerance. Dyspnea experienced by patients with chronic thromboembolic pulmonary hypertension is usually out of proportion to any abnormalities found on clinical examination. These symptoms are due to elevated dead space ventilation and limited cardiac output from obstruction of the pulmonary vascular bed. As the disease progresses, additional symptoms such as edema, chest pain, light-headedness, and syncope may develop. Nonspecific chest pains occur in approximately 50% of patients with more severe pulmonary hypertension. Hemoptysis can occur in all forms of pulmonary hypertension and probably results from abnormally dilated vessels distended by increased intravascular pressures. Peripheral edema, early satiety, and epigastric fullness or pain may develop as the right heart fails and cor pulmonale develops.

There are no consistent physical signs in patients with chronic thromboembolism, and the physical examination may be unrevealing if right heart failure has not occurred. A jugular venous pulse that is characterized by a large A wave may be seen. As the right heart fails, the V wave becomes predominant. The right ventricle is usually palpable near the lower left sternal border, and pulmonary valve closure may be audible in the second intercostal space. Patients with advanced disease may be hypoxic and cyanotic. Clubbing is an uncommon finding. As the right heart fails, a right atrial gallop may be ausculated and tricuspid insufficiency develops. Because of the large pressure gradient across the tricuspid valve in pulmonary hypertension, the murmur is high-pitched and may not exhibit respiratory variation. These findings differ from those usually observed in tricuspid valvular disease. A murmur of pulmonic regurgitation may also be detected, and a specific auscultatory finding is a flow murmur over the lung fields, thought to be from stenosed pulmonary vessels.³

Pulmonary vascular disease must always be considered in the differential diagnosis of unexplained dyspnea. The diagnostic evaluation serves three purposes: to establish the presence and severity of pulmonary hypertension, to determine its etiology, and, if thromboembolic disease is present, to determine to what degree it will be surgically correctable.

The three major reasons for considering a patient for pulmonary endarterectomy are hemodynamic, respiratory, and prophylactic. The hemodynamic goal is to prevent or ameliorate right ventricular compromise caused by pulmonary hypertension. The respiratory objective is to improve function by the removal of a large ventilated but unperfused physiologic dead space. The prophylactic goals are to prevent progressive right ventricular failure, retrograde extension of clot, and secondary vasculopathic changes in the remaining patent vessels. Pulmonary endarterectomy is considered in patients who are symptomatic and have evidence of hemodynamic or ventilatory impairment at rest or with exercise. Patients undergoing surgery typically exhibit a preoperative pulmonary vascular resistance (PVR) more than 300 dynes · sec · cm^-5, typically in the range of 800 to 1,400 dynes · sec · cm^-5.²³ There is no upper limit of PVR or degree of right ventricular dysfunction or tricuspid regurgitation that excludes a patient from operation. Patients with suprasytemic pulmonary artery pressures can safely undergo pulmonary endarterectomy.⁶⁹ An inferior vena cava filter is routinely placed several days in advance of the operation. Patients are treated with warfarin until the time of surgery, and this is continued lifelong after surgery.

There are several guiding principles for the operation. It must be bilateral because both pulmonary arteries are usually substantially involved when pulmonary hypertension is present.
The approach used is a median sternotomy. Historically, there were reports of unilateral operation and occasionally this is still performed, through a thoracotomy.²⁸ However, the unilateral approach ignores disease on the contralateral side, subjects the patient to hemodynamic jeopardy during the clamping of the pulmonary artery, and does not allow good visibility because of the continued presence of bronchial blood flow. In addition, collateral channels develop in chronic thromboembolic pulmonary hypertension, not only through the bronchial arteries but also from diaphragmatic, intercostal, and pleural vessels. This makes the approach through a thoracotomy somewhat bloody, particularly when the lung is adherent to the chest wall. The dissection of the pulmonary arteries within the pericardium via a median sternotomy avoids entry into the pleural cavities and allows for the ready institution of cardiopulmonary bypass.

Cardiopulmonary bypass is essential to ensure cardiovascular stability when the operation is performed and to cool the patient for circulatory arrest. Good visibility is required, in a field without ongoing bleeding, to define an adequate endarterectomy plane and to then follow the endarterectomy specimen deep into the subsegmental vessels. Because of the copious bronchial blood flow usually present in these cases, periods of circulatory arrest are necessary to ensure perfect visibility.²⁵ There have been sporadic reports of the performance of this operation without circulatory arrest.¹⁷ However, it should be emphasized that although embolectomy is possible without circulatory arrest, a complete endarterectomy is not. The circulatory arrest parts of the case are confined to the most distal portion of the endarterectomy process, deep in the subsegmental vasculature and are usually limited to 20 minutes for each side with restoration of flow in between.

A true endarterectomy in the plane of the media must be accomplished. It is essential to appreciate that the removal of visible thrombus is largely incidental to this operation. Indeed, in most patients, no free thrombus is present; on initial direct examination, the pulmonary vascular bed may appear normal. The early literature on this procedure describes many cases where thrombectomy was performed without endarterectomy. In these cases, the pulmonary artery pressures remained high, often resulting in death.

The technique for pulmonary endarterectomy has largely been developed by Dr. Stuart Jamieson at the University of California, San Diego (UCSD).^22,35 After a median sternotomy incision is made, the pericardium is incised longitudinally and attached to the wound edges. Typically the right heart is enlarged, with a tense right atrium and a variable degree of tricuspid regurgitation. There is usually severe right ventricular hypertrophy, and the patient’s condition may become unstable with manipulation of the heart. Anticoagulation is achieved with the use of beef lung heparin sodium (400 U/kg administered intravenously) to prolong the activated clotting time beyond 400 seconds. Full cardiopulmonary bypass is instituted with high ascending aortic cannulation and two caval cannulas. These cannulas must be inserted into the superior and inferior vena cavae sufficiently to enable subsequent opening of the right atrium. The heart is emptied on bypass, and a temporary pulmonary artery vent is placed in the midline of the main pulmonary artery, 1 cm distal to the pulmonary valve. This will mark the beginning of the left pulmonary arteriotomy.

After cardiopulmonary bypass is initiated, surface cooling with both a head jacket and cooling blanket on the operating room table is begun. The blood is cooled with the pump-oxygenator. During cooling, a 10°C gradient between arterial blood and bladder or rectal temperature is maintained.⁷⁴ Cooling generally takes 45 minutes to an hour. When ventricular fibrillation occurs, an additional vent is placed in the left atrium through the right superior pulmonary vein. This prevents atrial and ventricular distention from the large amount of bronchial arterial blood flow that is common with these patients. It is most convenient for the primary surgeon to stand initially on the patient’s left side. During the cooling period, some preliminary dissection can be performed, with full mobilization of the right pulmonary artery from the ascending aorta. The superior vena cava is fully mobilized. All dissection of the pulmonary arteries takes place intrapericardially, and neither pleural cavity is entered. An incision is then made in the right pulmonary artery from beneath the ascending aorta out under the superior vena cava and entering the lower lobe branch of the pulmonary artery just after the takeoff of the middle lobe artery.

Any loose thrombus is removed. The endarterectomy cannot be performed in the presence of thrombus, as this obscures the plane and prevents collapse of the endarterectomized specimen, hindering distal exposure. It is important to recognize that first, an embolectomy without subsequent endarterectomy is ineffective and, second, in most patients with chronic thromboembolic pulmonary hypertension, direct examination of the pulmonary vascular bed at operation generally shows no obvious embolic material. Therefore, to the inexperienced or cursory glance, the pulmonary vascular bed may well appear normal even in patients with severe chronic embolic pulmonary hypertension. If the bronchial circulation is not excessive, the endarterectomy plane can be found during this early dissection. However, although a small amount of dissection can be performed before the initiation of circulatory arrest, it is unwise to proceed unless perfect visibility is obtained, because the development of a correct plane is essential.

When the patient’s temperature reaches 20°C, the aorta is cross-clamped and a single dose of cold cardioplegic solution administered. Additional myocardial protection is obtained by the use of a cooling jacket wrapped around the heart. The entire procedure is now performed with a single aortic cross-clamp period with no further administration of cardioplegic solution. A modified cerebellar retractor is placed between the aorta and superior vena cava. When back bleeding from bronchial collaterals obscures direct vision of the pulmonary vascular bed, thiopental is administered (500 mg–1 g) until the electroencephalogram becomes isoelectric.¹⁹ Circulatory arrest is then initiated, and the patient undergoes exsanguination. It is rare that one 20-minute period for each side is exceeded. Although retrograde cerebral perfusion has been advocated for total circulatory arrest in other procedures, it is not helpful in this operation because it does not allow a completely bloodless field; with the short arrest times that can be achieved, it is not necessary.

Any loose thrombotic debris is removed. Then, a microtome knife and ball-tipped suction cannula are used to develop the endarterectomy plane posteriorly within the media of the vessel.
Dissection in the correct plane is critical, because if the plane is too deep, the pulmonary artery may perforate, with fatal results; if the dissection plane is not deep enough, inadequate amounts of the partially resorbed thromboembolic material will be removed. Once the plane is correctly developed, a full-thickness layer is left in the region of the incision to ease subsequent repair. For the endarterectomy, gentle traction with forceps while sweeping the outer vessel wall layer away with the ball-tipped suction cannula manufactured expressly for this purpose²² will result in the progressive withdrawal of the endarterectomy specimen. As each lobar branch appears, it is grasped individually and the specimen withdrawn until each segmental vessel branches again. Each of these subsegmental specimens is then extracted. Removal of each lobar and then segmental branch makes subsequent distal dissection easier. If a large mass of endarterectomized tissue begins to obscure visibility, it is excised. The entire specimen can thus be removed for a length of approximately 20 cm. The distalmost portion endarterectomy is performed with an eversion technique. Perforation at the level of the subsegmental vessels will become completely inaccessible later, so care must be taken to remain in the plane of the media for endarterectomy. Clear visualization in a completely bloodless field provided by circulatory arrest is therefore essential during development of the distal surgical plane, and this operation cannot be done properly without circulatory arrest. It is important that each subsegmental branch is followed and freed individually until it ends in a “tail,” beyond which there is no further obstruction. Residual material should never be cut free; the entire specimen should “tail off” and come free spontaneously.