Chapter 55. Pulmonary Embolism and Pulmonary Thromboendarterectomy

Pulmonary embolism results in at least 630,000 symptomatic episodes in the United States yearly, making it about half as common as acute myocardial infarction, and three times as common as cerebrovascular accidents.1 Acute pulmonary embolism is the third most common cause of death (after heart disease and cancer). These estimates are probably low because approximately 75% of autopsy-proved PE are not detected clinically2 and in 70 to 80% of the patients in whom the primary cause of death was PE, premortem diagnosis was completely unsuspected.3,4 Of all hospitalized patients who develop PE, 12 to 21% die in the hospital, and another 24 to 39% die within 12 months.5–7 Thus approximately 36 to 60% of patients who survive the initial episode live beyond 12 months, and may present later in life with a wide variety of symptoms.

Approximately 2.5 million Americans develop deep vein thrombosis (DVT) each year, and more than 90% of clinically detected pulmonary emboli are associated with lower extremity DVT. However, in two-thirds of patients with DVT and PE, the DVT is asymptomatic.8–10

For the most part, DVT and acute pulmonary embolism are managed medically. Cardiac surgeons rarely become involved in management of acute pulmonary embolism, unless it is in a hospitalized patient who survives a massive embolus that causes life-threatening acute right heart failure with low cardiac output, with a large clot burden. On the other hand, the mainstay of treatment for patients with chronic pulmonary thromboembolic disease11 is the surgical removal of the disease by means of pulmonary thromboendarterectomy. Medical management is only palliative, and surgery by means of transplantation is an inappropriate use of resources with less than satisfactory results.

Deep vein thrombosis primarily affects the veins of the lower extremity or pelvis. The process may involve superficial as well as deep veins, but superficial venous thrombosis does not generally propagate beyond the saphenofemoral junction and therefore very rarely causes PE.9,12 Venous thrombosis of the upper extremity is almost always associated with trauma, indwelling catheters, or other pathologic states and is an uncommon cause of PE, but can be fatal. Pulmonary emboli that do not originate from the deep venous system of the legs and pelvis are thought to come from a diseased right atrium or ventricle or retroperitoneal and hepatic systems.12,13 DVT is most common in hospitalized patients but may occur in ambulatory patients outside the hospital.14,15

Pathogenesis

In 1856, Rudolf Virchow made the association between DVT and PE and suggested that the causes of DVT were related to venous stasis, vein wall injury, and hypercoagulopathy. This triad of etiologic factors remains relevant today and is supported by an ever-growing body of evidence.

Immobilization is by far the most important cause of venous stasis in hospitalized patients. Injections of contrast material in foot veins require up to 1 hour to clear from venous valves in the soleus muscle of immobilized patients.16 Venous stasis may also be produced by mechanical obstruction of proximal veins, by low cardiac output, by venous dilatation, and by increased blood viscosity.17 Some pelvic tumors, bulky inguinal adenopathy, the gravid uterus, previous caval or iliac venous disease, and elevated central venous pressures from cardiac causes also enhance venous stasis.

The role of vein wall injury is less clear because DVT often begins in the absence of mechanical trauma. Recent work shows that subtle vein wall injuries may occur during operation in veins remote from the operative field.18,19 In animals, endothelial cell tears have been found at junctions of small veins with larger veins at remote sites during hip replacement (Fig. 55-1).

Three uncommon familial deficiencies associated with venous thrombosis are seen in antithrombin, protein C, and protein S. Antithrombin is a natural plasma protease that inhibits thrombin after it is formed, and to a lesser extent before it is formed. Antithrombin is also the cofactor that is accelerated 1000-fold by heparin. Protein C is a potent inhibitor of factor V and platelet-bound factor VII and requires protein S as a cofactor for anticoagulant activity. Both protein C and S are vitamin-K–dependent zymogens that are activated by thrombin and accelerated by thrombomodulin produced by endothelial cells.20,21

A much more common coagulation deficiency, resulting from a mutation of factor V (factor V Leiden) that prevents its degradation by protein C, has been described and is present in approximately 6 to 7% of study populations of Swedes and North American males.22–24 Both the homozygous and heterozygous mutants are strongly associated with venous thrombosis and pulmonary embolism but are not associated with manifestations of arterial thrombosis.24,25

The presence of the lupus anticoagulant, which is an acquired IgG or IgM antibody against prothrombinase, increases the likelihood of venous thrombosis by poorly understood mechanisms.25 The disease may be associated with lupuslike syndromes, immunosuppression, or intake of specific drugs, such as procainamide.

Risk Factors for Deep Vein Thrombosis

Table 55-1 presents a list of major risk factors for the development of DVT or PE. Previous thromboembolism, older age, immobilization for more than 1 week, orthopedic surgery of the hip or knee, recent surgery, multiple trauma, and cancer are strong risk factors. In patients with a history of venous thromboembolism the risk of developing a new episode during hospitalization is nearly eight times that of someone without a history.9,26–29 Up to 10% of patients with a first episode of DVT or PE and up to 20% of those with a recurrent event develop a new episode of venous thromboembolism within 6 months.30

The incidence of DVT and PE increases exponentially with age (Fig. 55-2). Males are at greater risk than females. Immobility from any cause and prolonged bed rest are major risk factors. Although usually other risk factors are present, the incidence of autopsy-proved venous thrombosis rises from 15 to 80% in patients at bed rest for more than 1 week.30,31

The incidence of venous thromboembolism increases threefold in patients who have operations for cancer.9 Of particular interest to cardiac surgeons and cardiologists is the recent observation that clinically silent DVT develops during hospitalization in nearly 50% of patients after myocardial revascularization.32

A follow-up study33 found that the incidence of PE in hospital after coronary arterial bypass operations was 3.2% and hospital mortality in patients with PE was 18.7%. Interestingly, valvular surgery was not associated with the development of PE. In a retrospective study of 5694 patients who had open heart surgery, Gillinov and colleagues found the risk of PE proved by V/Q scan (20 patients), angiography (four patients), or autopsy (eight patients) was 0.56% within 60 days. However, the mortality was 34% in patients with PE.34

Diagnosis

Approximately two-thirds of patients with DVT do not have clinical symptoms;9 thus, the diagnosis depends on a high degree of clinical suspicion and a variety of objective diagnostic tests. Venography remains the most reliable test for detecting thrombus in calf veins, but is invasive, not suitable for serial studies, and the contrast material may be thrombogenic if allowed to remain within the deep venous system.10

The most popular noninvasive test, which can be done at the bedside, is a combination of ultrasound and color flow Doppler mapping, widely referred to as duplex scanning. The method does not detect fresh thrombi directly but infers the presence of clot by flow patterns and the inability to compress the vessel in specific locations.10 In the hands of skilled examiners duplex scanning is highly accurate for the detection of thrombus in popliteal, deep femoral, and superficial femoral veins and has a sensitivity between 89 and 100% against venography in symptomatic patients. Against magnetic resonance imaging (MRI) duplex scanning has a sensitivity of 70% for pelvic veins and a specificity of nearly 100%.35 Magnetic resonance imaging is a noninvasive method that can image the entire venous system, including upper extremity veins and mediastinum.36

Impedance plethysmography assesses volume changes in the leg after occlusion of the vein with calf electrodes and a thigh cuff. It is clinically useful in symptomatic patients but has relatively low sensitivity and specificity in asymptomatic patients and calf thrombosis.35 Injection of iodine 125–labeled fibrinogen with subsequent leg scanning is a sensitive test for detecting calf vein thrombus but does not detect iliofemoral vein thrombosis. The combination of these two tests improves sensitivity and specificity, but in most hospitals duplex scanning, venography, and MRI have superseded both tests.

Prophylaxis

The prevalence of DVT, its strong association with PE, and the identification of risk factors in the pathogenesis of the disease provide the basis and rationale for prophylactic measures that are recommended in patients with two or more major risk factors, such as age over 40 years and major surgery.9 Innocuous measures such as compression stockings probably should be prescribed more often and be used in most nonambulating patients in the hospital. Intermittent pneumatic compression is more expensive and more cumbersome but is effective. Both methods reduce the incidence of DVT after general surgery to approximately 40% of control patients.9 Low-dose subcutaneous heparin and low-molecular-weight heparin given once per day reduce the incidence of DVT to approximately 35 and 18% of controls, respectively.9,31,37 The reduction in PE with subcutaneous standard heparin or low-molecular-weight heparin is similar.31,37

Calf vein DVT that does not propagate has a low risk of PE, and controversy exists as to whether or not these patients should be anticoagulated.13 Of patients who have DVT diagnosed in hospital without PE, the probability of clinically diagnosed PE within the next 12 months is 1.7%.5 If PE occurs, the probability of recurrent PE is 8.0%.5 Six months of warfarin anticoagulation are recommended for patients who have DVT with or without PE as prophylaxis against recurrent disease.38

Pathology and Pathogenesis

The only firm attachment of leg thrombus is at the site of origin, usually a venous saccule or venous valve pocket.26 The degree of organization within the thrombus varies, but recent clots are more likely to migrate than older thrombi that are more firmly attached to the vessel wall.

Detached venous thrombi are carried in the bloodstream through the right heart into the pulmonary circulation. In autopsy series the percentage of emboli that obstruct two or more lobar arteries (major) ranges between 25 and 67% of all emboli;39 but this figure varies with the thoroughness of the examination. In clinical trials based on angiographic data the percentage of major emboli is similar and ranges from 30 to 64%.40 The majority of pulmonary emboli lodge in the lower lobes,12 and are slightly more common in the right lung than the left. Soon after reaching the lungs emboli become coated with a layer of platelets and fibrin.12

Simple mechanical obstruction of one or more pulmonary arteries does not entirely explain the often-devastating hemodynamic consequences of major or massive emboli. Humoral factors, specifically serotonin, adenosine diphosphate (ADP), platelet-derived growth factor (PDGF), thromboxane from platelets coating the thrombus, platelet-activating factor (PAF), and leukotrienes from neutrophils are also involved.41,42 Anoxia and tissue ischemia downstream to emboli inhibit endothelium-derived relaxing factor (EDRF) production and enhance release of superoxide anions by activated neutrophils. The combination of these effects contributes to enhanced pulmonary vasoconstriction.41

Natural History

The mortality of untreated PE is 18 to 33%, but can be reduced to about 8% if diagnosed and treated.7,43,44 Seventy-five to ninety percent of patients who die of pulmonary emboli do so within the first few hours of the primary event.45 In patients who have sufficient cardiopulmonary reserve and right ventricular strength to survive the initial few hours, autolysis of emboli occurs over the next few days and weeks.46 On average, approximately 20% of the clot disappears by 7 days, and complete resolution may occur by 14 days.44,46,47 For many patients, up to 30 days are needed to dissolve small emboli and up to 60 days for massive clots.48 As the natural fibrinolytic system dissolves the embolic mass, the available cross-sectional area of the pulmonary arterial tree progressively increases, and pulmonary vascular resistance and right ventricular afterload decrease. In the vast majority of patients, pulmonary emboli continue to resolve and thus an immediate interventional therapy, particularly surgical embolectomy, is not necessary for survival except in a minority of patients.

In an unknown but small percentage of patients with acute pulmonary embolism the clot will not lyse, and chronic thromboembolic obstruction of the pulmonary vasculature develops. The reasons for failure of emboli to dissolve are unknown. Patients often are asymptomatic until symptoms of dyspnea, exercise intolerance, or right heart failure develop, mostly secondary to the pulmonary hypertension that ensues. Asymptomatic patients may have partial or complete chronic thrombotic occlusion of one or more segmental or lobar arteries. Symptomatic patients usually have more than 40% of their pulmonary vasculature obstructed by organized and fresh thrombi; however, significant pulmonary hypertension can develop in patients despite lesser degrees of vascular obstruction.

Clinical Presentation

Acute pulmonary embolism usually presents suddenly. Symptoms and signs vary with the extent of blockage, the magnitude of the humoral response, and the pre-embolus reserve of the cardiac and pulmonary systems of the patient.49 Symptoms and signs vary widely, and in autopsy series of proven emboli only 16 to 38% of patients were diagnosed during life.39

The acute disease is conveniently stratified into minor, major (submassive), or massive embolism on the basis of hemodynamic stability, arterial blood gases, and lung scan or angiographic assessment of the blocked pulmonary arteries.40,49,50 Most pulmonary emboli are minor. These patients present with sudden, unexplained anxiety, tachypnea or dyspnea, pleuritic chest pain, cough, and occasionally streak hemoptysis.39,45,50 Examination may reveal tachycardia, rales, low-grade fever, and sometimes a pleural rub. Heart sounds and systemic blood pressure are often normal; sometimes the pulmonary second sound is increased. Interestingly less than one-third of the patients will have evidence of clinical DVT.39 Room air arterial blood gases indicate a Pao2 between 65 and 80 torr and a normal Paco2 around 35 torr.45 Pulmonary angiograms show less than 30% occlusion of the pulmonary arterial vasculature.

Major pulmonary embolism is associated with dyspnea, tachypnea, dull chest pain, and some degree of hemodynamic instability manifested by tachycardia, mild to moderate hypotension, and elevation of the central venous pressure.45,50 Some patients may present with syncope rather than dyspnea or chest pain. In contrast to massive pulmonary embolism, patients with major embolism (at least two lobar pulmonary arteries obstructed) are hemodynamically stable and have adequate cardiac output.40 Room air blood gases reveal moderate hypoxia (Pao2 <65, >50 torr) and mild hypocarbia (Paco2 <30 torr).50 Echocardiograms may show right ventricular dilatation. Pulmonary angiograms indicate that 30 to 50% of the pulmonary vasculature is blocked.

Massive pulmonary embolism is truly life threatening and is defined as a PE that causes hemodynamic instability.40 It is usually associated with occlusion of more than 50% of the pulmonary vasculature, but may occur with much smaller occlusions, particularly in patients with preexisting cardiac or pulmonary disease. The diagnosis is clinical, not anatomical. Patients develop acute dyspnea, tachypnea, tachycardia, and diaphoresis; and sometimes may lose consciousness. Both hypotension and low cardiac output (<1.8 L/m2/min) are present. Cardiac arrest may occur. Neck veins are distended; central venous pressure is elevated, and a right ventricular impulse may be present. Room air blood gases show severe hypoxia (Pao2 <50 torr), hypocarbia (Paco2 <30 torr), and sometimes acidosis.40,45,50 Urine output falls; peripheral pulses are decreased and perfusion is poor.

Diagnosis

The clinical diagnosis of acute major or massive pulmonary embolism is wrong in 70 to 80% of patients who have angiography subsequently.49,51 Even in postoperative patients and those with additional major risk factors for DVT, differentiation of major or massive pulmonary embolism from acute myocardial infarction, aortic dissection, septic shock, and other catastrophic states is difficult and uncertain.

The chest film may be normal but usually shows some combination of parenchymal infiltrate, atelectasis, and pleural effusion. A zone of hypovascularity or a wedged-shaped pleural-based density raises the possibility of PE. Usually, the ECG shows nonspecific T-wave or RS-T segment changes with PE. A minority of patients with massive embolism (26%) may show evidence of cor pulmonale, right axis deviation, or right bundle branch block.49 An echocardiogram showing right heart dilatation raises the possibility of major or massive PE. A Swan-Ganz catheter generally shows pulmonary arterial desaturation (Pao2 <25 torr), but usually does not show pulmonary hypertension over 40 mm Hg because of low cardiac output and cor pulmonale (the unprepared right ventricle cannot generate pulmonary hypertension).

Ventilation-perfusion (V/Q) scans will provide confirmatory evidence, but these studies may be unreliable, because pneumonia, atelectasis, previous pulmonary emboli, and other conditions may cause a mismatch in ventilation and perfusion and mimic positive results. In general, negative V/Q scans essentially exclude the diagnosis of clinically significant PE. V/Q scans usually are interpreted as high, intermediate, or low probability of PE to emphasize the lack of specificity but high sensitivity of the test (Fig. 55-3). Pulmonary angiograms provide the most definitive diagnosis, but collapse of the circulation may not allow time for this procedure, and pulmonary angiograms should not be performed if the patient's circulation cannot be stabilized by pharmacologic or mechanical means.52,53

Magnetic resonance imaging (MRI) and CT angiographies are better noninvasive methods for the diagnosis of pulmonary emboli and provide specific information regarding flow within the pulmonary vasculature.54 Unfortunately, these methods are expensive, somewhat time consuming, and not widely available. Furthermore, they are not generally suitable for hemodynamically unstable patients. Transthoracic (TTE) or transesophageal (TEE) echocardiography with color flow Doppler mapping can provide reliable information about the presence or absence of major thrombi obstructing right-sided chambers or the main pulmonary artery. More than 80% of patients with clinically significant PE have abnormalities of right ventricular volume or contractility, or acute tricuspid regurgitation by TTE (Fig. 55-4).55 In some patients, abnormal flow patterns can be discerned in major pulmonary arteries during TEE.

Management of Acute Major Pulmonary Embolism

For the purposes of this chapter, major or submassive pulmonary embolism is defined as an acute episode that causes hypoxia and mild hypotension (systolic arterial pressure >90 mm Hg), but does not cause cardiac arrest or sustained low cardiac output and cardiogenic shock. By definition there is sufficient time in these patients to definitely establish the diagnosis and to attempt pharmacologic therapy and possibly remove the embolic material by catheter suction.

The first priority after sudden collapse of any patient is to establish adequate ventilation and circulation. The first may require intubation and mechanical ventilation. Pharmacologic agents, including cardiovascular pressors and vasoactive agents, are then used to help stabilize the patient's hemodynamics. If the patient's circulation can be stabilized, intravenous heparin is started with an initial bolus dose of 70 U/kg followed by 18 to 20 U/kg/h if there are no contraindications. Heparin will prevent propagation and formation of new thromboemboli, but does not dissolve the existing clot. In most instances the patient's own fibrinolytic system lyses fresh thrombi over a period of days or weeks.46

The addition of lytic therapy, ie, streptokinase, urokinase, or recombinant tissue plasminogen activator (rt-PA), increases the rate of lysis of fresh thrombi and is recommended in patients with a stable circulation and no contraindications. This increases the rate of lysis of fresh pulmonary clots over that of heparin alone during treatment,56 but there is little difference in the amount of residual thrombus between the two treatments at 5 days or thereafter.57–60 There is also no statistical difference in mortality or in the incidence of recurrent PE, but more recent experience shows a trend toward better results with thrombolytic therapy because of a more rapid reduction in right ventricular afterload and dysfunction.56 Furthermore, there are no data that indicate that thrombolysis reduces the subsequent development of chronic pulmonary thromboembolism and pulmonary hypertension. Compared with Heparin therapy alone, thrombolytic agents carry a higher risk of bleeding complications, and despite precautions, bleeding complications occur in approximately 20% of patients.56,61,62

Mechanical removal of pulmonary thrombi is possible by a catheter device inserted under local anesthesia into the femoral (preferred) or jugular vein.50,63,64,67,69 Successful extraction of clot with meaningful reduction in pulmonary arterial pressure varies between 61 and 84%.64,69

Management of Acute Massive Pulmonary Embolism

If the circulation cannot be stabilized at survival levels within several minutes or if cardiac arrest occurs after a massive PE, time becomes of paramount importance. Eleven percent of patients with fatal PE die within the first hour, 43 to 80% within 2 hours, and 85% within 6 hours.65 To a great extent, circumstances and the timely availability of necessary equipment and personnel determine therapeutic options. A decision to treat medically in an effort to stabilize the circulation at a survival level may preempt life-saving surgery, but also may make surgery unnecessary. The relative infrequency of treatment opportunities in massive pulmonary embolism, mitigating factors, and the lack of clear criteria for prescribing medical or surgical therapy leave the management of massive PE unsettled.

When surgery is not immediately available, in patients who may not be surgical candidates, or in whom an alternate diagnosis seems more likely, emergency extracorporeal life support (ECLS) using peripheral cannulation is an attractive alternative.72,73 In prepared institutions ECLS can be instituted rapidly outside the operating room. ECLS compensates for acute cor pulmonale and hypoxia and sustains the circulation until the clot partially lyses, pulmonary vascular resistance falls, and pulmonary blood flow becomes adequate.

Emergency Pulmonary Thromboembolectomy

Emergency pulmonary thromboembolectomy is indicated for suitable patients with life-threatening circulatory insufficiency, but should not be done without a definitive diagnosis because a clinical diagnosis of PE is often wrong.47,58,66,67 If a patient has been taken directly to the operating room without a definitive diagnosis, transesophageal echocardiography and color Doppler mapping can confirm or refute the diagnosis in the operating room. Transesophageal echocardiography will indicate increased right ventricular volume, poor right ventricular contractility, and tricuspid regurgitation, which are strongly associated with massive pulmonary embolism and acute cor pulmonale.68 Echocardiographic detection of a large clot trapped within the right atrium or ventricle in a hemodynamically compromised patient with massive acute PE is another indication for emergency pulmonary thromboembolectomy.74,75,77

A midline sternotomy incision is used and cardiopulmonary bypass is initiated. The heart may be electrically fibrillated or arrested with cold cardioplegic solution. The main pulmonary artery is then opened 1 to 2 cm downstream to the valve, and the incision is extended into the proximal left pulmonary artery. Forceps and suction catheters remove the clot from the left pulmonary artery and behind the aorta to the right pulmonary artery. The right pulmonary artery can also be exposed and opened between the aorta and superior vena cava to allow better exposure in the distal segments, if necessary. If a sterile pediatric bronchoscope is available, the surgeon can use this instrument to locate and remove thrombi in tertiary and quaternary pulmonary vessels. Alternatively, the pleural spaces are entered, and each lung is gently compressed to dislodge small clots into larger vessels and suctioned out. Greenfield recommends placement of an inferior vena caval filter before closing the chest.10,69,70,79 European surgeons generally clip the intrapericardial vena cava at the end of pulmonary thromboembolectomy to prevent migration of large clots into the pulmonary circulation.77 However, this clip increases venous pressure and stagnant flow in the lower half of the body and causes considerable morbidity in more than 60% of patients.70,74,77

Anticoagulation for 6 months is recommended for most patients with PE, but an inferior vena caval filter is recommended for patients with contraindications to anticoagulation or with recurrent PE, or those who will require pulmonary thromboendarterectomy. The cone-shaped Greenfield filter is most widely used and is associated with a lifetime recurrent embolism rate of 5% and has a 97% patency rate.71

Extracorporeal Life Support

The wider availability of long-term extracorporeal perfusion (termed extracorporeal life support, ELS) using peripheral vessel cannulation to stabilize the circulation offers a compromise position because most massive pulmonary emboli will dissolve in time. ELS can be implemented outside the operating room within 15 to 30 minutes by an equipped team of trained personnel.72,73

ELS should not be needed beyond a few hours or 1 to 2 days because clot lysis proceeds rapidly. Once pulmonary vascular resistance is adequately reduced, ELS should be discontinued in the operating room as the femoral vessels will need to be sutured closed because of the need for heparin and long-term anticoagulation.

Results

Mortality rates for emergency pulmonary thromboembolectomy vary widely between 40 and 92%.66,70,74–77 Results are best if cardiopulmonary bypass is used to support the circulation during pulmonary arteriotomy.75 The eventual outcome depends largely upon the preoperative condition and circulatory status of the patient. If cardiac arrest occurs and external massage cannot be stopped without ELS, mortality ranges between 45 and 75%. Without cardiac arrest mortality ranges between 8 and 36%.74,70,77 ELS instituted during cardiac resuscitation is associated with survival rates between 43 and 56%.74,66 Recurrent embolism is uncommon,70,78 and approximately 80% of survivors maintain normal pulmonary arterial pressures and exercise tolerance. In these patients postoperative angiograms are normal or show less than 10% obstructed vessels. A minority of patients have 40 to 50% of pulmonary vessels obstructed and have significantly reduced exercise tolerance and pulmonary function.78

Incidence

The incidence of pulmonary hypertension caused by chronic pulmonary embolism is even more difficult to determine than that of acute pulmonary embolism. Twenty-five years ago it was estimated that there were more than 500,000 survivors per year of acute symptomatic episodes of acute pulmonary embolization in the United States alone.11,79,80 The population has increased since then, and of course many cases of pulmonary embolism are asymptomatic. The incidence of chronic thrombotic occlusion in the population depends on what percentage of patients fails to resolve acute embolic material. One estimate is that chronic thromboembolic disease develops in only 0.5% of patients with a clinically recognized acute pulmonary embolism.79 If these figures are correct and counting only patients with symptomatic acute pulmonary emboli, approximately 2500 individuals would progress to chronic thromboembolic pulmonary hypertension in the United States each year. However, because most patients diagnosed with chronic thromboembolic disease have no antecedent history of acute embolism, the true incidence of this disorder is probably much higher; we estimate on the order of five to ten times this number.

Regardless of the exact incidence or the circumstances, it is clear that acute embolism and its chronic relation, fixed chronic thromboembolic occlusive disease, are both much more common than generally appreciated and are seriously underdiagnosed. Houk and colleagues81 in 1963 reviewed the literature of 240 reported cases of chronic thromboembolic obstruction of major pulmonary arteries but found that only six cases had been diagnosed correctly before death. Calculations extrapolated from mortality rates and the random incidence of major thrombotic occlusion found at autopsy would support a postulate that more than 100,000 people in the United States currently have pulmonary hypertension that could be relieved by operation.

Pathology and Pathogenesis

Although most individuals with chronic pulmonary thromboembolic disease are unaware of a past thromboembolic event and give no history of deep vein thrombosis, the origin of most cases of unresolved pulmonary emboli are from acute embolic episodes. Why some patients have unresolved emboli is not certain, but a variety of factors must play a role, alone or in combination.

The volume of acute embolic material may simply overwhelm the lytic mechanisms. Total occlusion of a major arterial branch may prevent lytic material from reaching, and therefore dissolving, the embolus completely. Repetitive emboli may not be able to be resolved. The emboli may be made of substances that cannot be resolved by normal mechanisms (already well-organized fibrous thrombus, fat, or tumor). The lytic mechanisms themselves may be abnormal, or some patients may actually have a propensity for thrombus or a hypercoagulable state. In addition, there are other special circumstances. Chronic indwelling central venous catheters and pacemaker leads are sometimes associated with pulmonary emboli. More rare causes include tumor emboli; tumor fragments from stomach, breast, and kidney malignancies have been demonstrated to cause chronic pulmonary arterial occlusion. Right atrial myxomas may also fragment and embolize.

After the clot becomes wedged in the pulmonary artery, one of two processes occurs:82

1. Organization of the clot proceeds to canalization, producing multiple small endothelialized channels separated by fibrous septa (ie, bands and webs) or

2. Complete fibrous organization of the fibrin clot without canalization may result, leading to a solid mass of dense fibrous connective tissue totally obstructing the arterial lumen.

As previously described and discussed, in addition to the embolic material, a propensity for thrombosis or a hypercoagulable state may be present in a few patients. This abnormality may result in spontaneous thrombosis within the pulmonary vascular bed, encourage embolization, or be responsible for proximal propagation of thrombus after an embolus. But, whatever the predisposing factors to residual thrombus within the vessels, the final genesis of the resultant pulmonary vascular hypertension may be complex. With the passage of time, the increased pressure and flow as a result of redirected pulmonary blood flow in the previously normal pulmonary vascular bed can create a vasculopathy in the small precapillary blood vessels similar to the Eisenmenger's syndrome.

Factors other than the simple hemodynamic consequences of redirected blood flow are probably also involved in this process. For example, after a pneumonectomy, 100% of the right ventricular output flows to one lung, yet little increase in pulmonary pressure occurs, even with follow-up to 11 years.83 In patients with thromboembolic disease, however, we frequently detect pulmonary hypertension even when less than 50% of the vascular bed is occluded by thrombus. It thus appears that sympathetic neural connections, hormonal changes or both might initiate pulmonary hypertension in the initially unaffected pulmonary vascular bed. This process can occur with the initial occlusion either being in the same or the contralateral lung.

Regardless of the cause, the evolution of pulmonary hypertension as a result of changes in the previously unobstructed bed is serious, because this process may lead to an inoperable situation. Consequently, with our accumulating experience in patients with thrombotic pulmonary hypertension, we have increasingly been inclined toward early operation so as to avoid these changes.

Clinical Presentation

Chronic thromboembolic pulmonary hypertension is a frequently under-recognized but treatable cause of pulmonary hypertension. There are no signs or symptoms specific for chronic thromboembolism. The most common symptom associated with thromboembolic pulmonary hypertension, as with all other causes of pulmonary hypertension, is exertional dyspnea. This dyspnea is characteristically out of proportion to any abnormalities found on clinical examination.

Nonspecific chest pains or tightness 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 or right upper quadrant fullness or discomfort may develop as the right heart fails (cor pulmonale). Some patients with chronic pulmonary thromboembolic disease present after a small acute pulmonary embolus that may produce acute symptoms of right heart failure.

The physical signs of pulmonary hypertension are the same no matter what the underlying pathophysiology. Initially the jugular venous pulse is characterized by a large A-wave. 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. Occasional patients with advanced disease are hypoxic and slightly cyanotic. Clubbing is an uncommon finding.

The second heart sound is often narrowly split and varies normally with respiration; P2 is accentuated. A sharp systolic ejection click may be heard over the pulmonary artery. As the right heart fails, a right atrial gallop usually is present, 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 are quite different from those usually observed in tricuspid valvular disease. A murmur of pulmonic regurgitation may also be detected.

Pulmonary function tests reveal minimal changes in lung volume and ventilation; patients generally have normal or slightly restricted pulmonary mechanics. Diffusing capacity (DLco) is often reduced and may be the only abnormality on pulmonary function testing. Pulmonary arterial pressures are elevated and suprasystemic pulmonary pressures are not uncommon. Resting cardiac outputs are lower than the normal range, and pulmonary arterial oxygen saturations are reduced. Most patients are hypoxic; room air arterial oxygen tension ranges between 50 and 83 torr, the average being 65 torr.84 CO2 tension is slightly reduced and is compensated by reduced bicarbonate. Dead space ventilation is increased. Ventilation-perfusion studies show moderate mismatch with some heterogeneity among various respirator units within the lung and correlate poorly with the degree of pulmonary obstruction.85

Diagnosis

To ensure accurate diagnosis in patients with chronic pulmonary thromboembolism, a standardized evaluation is recommended for all patients who present with unexplained pulmonary hypertension. This workup includes a chest radiograph, which may show either apparent vessel cutoffs of the lobar or segmental pulmonary arteries or regions, or oligemia suggesting vascular occlusion. The central pulmonary arteries are enlarged, and the right ventricle may also be enlarged without enlargement of the left atrium or ventricle (Fig. 55-5). Despite these classic findings, many patients present with a relatively normal chest radiograph, even in the setting of high degrees of pulmonary hypertension. The electrocardiogram demonstrates findings of right ventricular hypertrophy (right axis deviation, dominant R-wave in V1). Pulmonary function tests are necessary to exclude obstructive or restrictive intrinsic pulmonary parenchymal disease as the cause of pulmonary hypertension.

The ventilation-perfusion lung scan is the essential test for establishing the diagnosis of unresolved pulmonary thromboembolism. An entirely normal lung scan excludes the diagnosis of both acute or chronic, unresolved thromboembolism. The usual lung scan pattern in most patients with pulmonary hypertension either is relatively normal or shows a diffuse nonuniform perfusion.84,85–87 When subsegmental or larger perfusion defects are noted on the scan, even when matched with ventilatory defects, pulmonary angiography is appropriate to confirm or rule out thromboembolic disease.

Currently, pulmonary angiography still remains the gold standard for the diagnosis of CTEPH. Organized thromboembolic lesions do not have the appearance of the intravascular filling defects seen with acute pulmonary emboli, and experience is essential for the proper interpretation of pulmonary angiograms in patients with unresolved, chronic embolic disease. Organized thrombi appear as unusual filling defects, webs, or bands, or completely thrombosed vessels that may resemble congenital absence of the vessel87 (Fig. 55-6). Organized material along the wall of a re-canalized vessel produces a scalloped or serrated luminal edge. Because of both vessel-wall thickening and dilatation of proximal vessels, the contrast-filled lumen may appear relatively normal in diameter. Distal vessels demonstrate the rapid tapering and pruning characteristic of pulmonary hypertension (see Fig. 55-6).

Pulmonary angiography should be performed whenever there is a possibility that chronic thromboembolism is the etiology of pulmonary hypertension. Several thousand angiograms in pulmonary hypertensive patients have now been performed at our institution without mortality.

In addition to pulmonary angiography, patients over 40 undergo coronary arteriography and other cardiac investigation as necessary. If significant disease is found, additional cardiac surgery is performed at the time of pulmonary thromboendarterectomy.

In approximately 15% of cases, the differential diagnosis between primary pulmonary hypertension and distal and small vessel pulmonary thromboembolic disease remains unclear and hard to establish. In these patients, pulmonary angioscopy may be helpful. The pulmonary angioscope is a fiberoptic telescope that is placed through a central line into the pulmonary artery. The tip contains a balloon that is then filled with saline and pushed against the vessel wall. A bloodless field can thus be obtained to view the pulmonary artery wall. The classic appearance of chronic pulmonary thromboembolic disease by angioscopy consists of intimal thickening, with intimal irregularity and scarring, and webs across small vessels. These webs are thought to be the residue of resolved occluding thrombi of small vessels, but are important diagnostic findings. The presence of embolic disease as seen by occlusion of vessels, or the presence of thrombotic material is also diagnostic.

Medical Treatment

Chronic anticoagulation represents the mainstay of a medical regimen. This is primarily used to prevent future embolic episodes, but also serves to limit the development of thrombus in regions of low flow within the pulmonary vasculature. Inferior vena caval filters are used routinely to prevent recurrent embolization. If caval filtration and anticoagulation fail to prevent recurrent emboli, immediate thrombolysis may be beneficial, but lytic agents are incapable of altering the chronic component of the disease.

Right ventricular failure is treated with diuretics and vasodilators, and although some improvement may result, the effect is generally transient because the failure is owing to a mechanical obstruction and will not resolve until the obstruction is removed. Similarly, the prognosis is unaffected by medical therapy,88,89 which should be regarded as only supportive. Because of the bronchial circulation, pulmonary embolization seldom results in tissue necrosis. Surgical endarterectomy therefore will allow distal pulmonary tissue to be used once more in gas exchange.

The only other surgical option for these patients is transplantation. However, we consider transplantation not to be appropriate for this disease because of the mortality and morbidity rates of patients on the waiting list, the higher risk of the operation, and the contrasted survival rate (approximately 80% at 1 year at experienced centers for transplantation versus 95% for pulmonary endarterectomy). Furthermore, pulmonary endarterectomy appears to be permanently curative, and the issues of a continuing risk of rejection and immunosuppression are not present.

Natural History

The natural history of chronic thromboembolic pulmonary hypertension is dismal, and nearly all patients die of progressive right heart failure.11 Because of the insidious onset, the diagnosis is usually made relatively late in the progression of the disease when dyspnea and/or early symptoms of right heart failure develop and pulmonary hypertension is severe (>40 mm Hg mean). In Riedel's series of 13 patients, nine died a mean of 28 months after the diagnosis of right heart failure.11 Seven of the 13 had recurrent episodes of fresh emboli demonstrated by new perfusion defects or by autopsy. The severity of pulmonary hypertension at the time of diagnosis inversely correlates with duration of survival.11

Pulmonary Thromboendarterectomy

Although there were previous attempts, Allison90 did the first successful pulmonary "thromboendarterectomy" through a sternotomy using surface hypothermia, but only fresh clots were removed. Since then, there have been many occasional surgical reports of the surgical treatment of chronic pulmonary thromboembolism,91–94 but most of the surgical experience in pulmonary endarterectomy has been reported from the UCSD Medical Center. Braunwald commenced the UCSD experience with this operation in 1970, which now totals more than 2500 cases. The operation described in the following, using deep hypothermia and circulatory arrest, is the standard procedure.

Indications

When the diagnosis of thromboembolic pulmonary hypertension has been firmly established, the decision for operation is based on the severity of symptoms and the general condition of the patient. Early in the pulmonary endarterectomy experience, Moser and colleagues92 pointed out that there were three major reasons for considering thromboendarterectomy: hemodynamic, alveolo-respiratory, and prophylactic. The hemodynamic goal is to prevent or ameliorate right ventricular compromise caused by pulmonary hypertension. The respiratory objective is to improve respiratory function by the removal of a large ventilated but unperfused physiologic dead space, regardless of the severity of pulmonary hypertension. The prophylactic goal is to prevent progressive right ventricular dysfunction or retrograde extension of the obstruction, which might result in further cardiorespiratory deterioration or death.92 Our subsequent experience has added another prophylactic goal: the prevention of secondary arteriopathic changes in the remaining patent vessels.87

Most patients who undergo operation are within New York Heart Association (NYHA) class III or class IV. The ages of the patients in our series have ranged from 7 to 85 years. A typical patient will have a severely elevated PVR level at rest, the absence of significant comorbid disease unrelated to right heart failure, and the appearances of chronic thrombi on angiogram that appear to be relatively in balance with the measured PVR level. Exceptions to this general rule, of course, occur.

Although most patients have a PVR level in the range of 800 dynes/sec/cm-5 and pulmonary artery pressures less than systemic, the hypertrophy of the right ventricle that occurs over time makes pulmonary hypertension to suprasystemic levels possible. Therefore many patients (approximately 20% in our practice) have a level of PVR in excess of 1000 dynes/sec/cm–5 and suprasystemic pulmonary artery pressures. There is no upper limit of PVR level, pulmonary artery pressure, or degree of right ventricular dysfunction that excludes patients from operation.

We have become increasingly aware of the changes that can occur in the remaining patent (unaffected by clot) pulmonary vascular bed subjected to the higher pressures and flow that result from obstruction in other areas. Therefore, with the increasing experience and safety of the operation, we are tending to offer surgery to symptomatic patients whenever the angiogram demonstrates thromboembolic disease. A rare patient might have a PVR level that is normal at rest, although elevated with minimal exercise. This is usually a young patient with total unilateral pulmonary artery occlusion and unacceptable exertional dyspnea because of an elevation in dead space ventilation. Operation in this circumstance is performed not only to reperfuse lung tissue, but to re-establish a more normal ventilation perfusion relationship (thereby reducing minute ventilatory requirements during rest and exercise), and also to preserve the integrity of the contralateral circulation and prevent the chronic arterial changes associated with long-term exposure to pulmonary hypertension.

If not previously implanted, an inferior vena caval filter is routinely placed several days in advance of the operation.

Operation

Principles

There are several guiding principles for the operation. Surgical treatment and endarterectomy must be bilateral because this is a bilateral disease in the vast majority of our patients, and for pulmonary hypertension to be a major factor, both pulmonary vasculatures must be substantially involved. The only reasonable approach to both pulmonary arteries is therefore through a median sternotomy incision. Historically, there were many reports of unilateral operation, and occasionally this is still performed, in inexperienced centers, through a thoracotomy. However, the unilateral approach ignores the disease on the contralateral side, subjects the patient to hemodynamic jeopardy during the clamping of the pulmonary artery, does not allow good visibility because of the continued presence of bronchial blood flow, and exposes the patient to a repeat operation on the contralateral side. In addition, collateral channels develop in chronic thrombotic hypertension not only through the bronchial arteries but also from diaphragmatic, intercostal, and pleural vessels. The dissection of the lung in the pleural space via a thoracotomy incision can therefore be extremely bloody. The median sternotomy incision, apart from providing bilateral access, avoids entry into the pleural cavities, and allows the ready institution of cardiopulmonary bypass.

Cardiopulmonary bypass is essential to ensure cardiovascular stability when the operation is performed and cool the patient to allow circulatory arrest. Excellent visibility is required, in a bloodless field, to define an adequate endarterectomy plane and then follow the pulmonary 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. Again, there have been sporadic reports of the performance of this operation without circulatory arrest. However, it should be emphasized that although endarterectomy is possible without circulatory arrest, a complete endarterectomy is not. We always initiate the procedure without circulatory arrest, and a variable amount of dissection is possible before the circulation is stopped, but never complete dissection. The circulatory arrest periods are limited to 20 minutes, with restoration of flow between each arrest. With experience, the endarterectomy usually can be performed with a single period of circulatory arrest on each side.

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; and on initial direct examination, the pulmonary vascular bed may appear normal. The early literature on this procedure indicates that thrombectomy was often performed without endarterectomy, and in these cases the pulmonary artery pressures did not improve, often with the resultant death of the patient.

Preparation and Anesthetic Considerations

Much of the preoperative preparation is common to any open-heart procedure. Routine monitoring for anesthetic induction includes a surface electrocardiogram, cutaneous oximetry, and radial and pulmonary artery pressures. After anesthetic induction a femoral artery catheter, in addition to a radial arterial line, is also placed. This provides more accurate measurements during rewarming and on discontinuation of cardiopulmonary bypass because of the peripheral vasoconstriction that occurs after hypothermic circulatory arrest. It is generally removed in the intensive care unit when the two readings correlate.

Electroencephalographic recording is performed to ensure the absence of cerebral activity before circulatory arrest is induced. The patient's head is enveloped in a cooling jacket, and cerebral cooling is begun after the initiation of bypass. Temperature measurements are made of the esophagus, tympanic membrane, urinary catheter, rectum, and blood (through the Swan-Ganz catheter). If the patient's condition is stable after the induction of anesthesia, up to 500 mL of autologous whole blood is withdrawn for later use, and the volume deficit is replaced with crystalloid solution.

Surgical Technique

After a median sternotomy incision, 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 with critical degrees of obstruction, the patient's condition may become unstable with the manipulation of the heart.

Anticoagulation with heparin (400 U/kg, intravenously) is administered to prolong the activated clotting time beyond 400 seconds. Full cardiopulmonary bypass is instituted with high ascending aortic cannulation and two caval cannulae. These cannulae must be inserted into the superior and inferior vena cavae sufficiently to enable subsequent opening of the right atrium if necessary. 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 the head jacket and the cooling blanket 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.93 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 to prevent 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 also fully mobilized. The approach to the right pulmonary artery is made medial, not lateral, to the superior vena cava. All dissection of the pulmonary arteries takes place intrapericardially, and neither pleural cavity should be 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 take-off of the middle lobe artery (Fig. 55-7). The incision stays in the center of the vessel and continues into the lower rather than the middle lobe artery.

Any loose thrombus, if present, is now removed, to obtain good visualization. It is most important to recognize, however, that first, an embolectomy without subsequent endarterectomy is quite ineffective and, second, that in most patients with chronic thromboembolic 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.

There are four broad types of pulmonary occlusive disease related to thrombus that can be appreciated, and we use the following classification87,94: Type I disease (approximately 10% of cases of thromboembolic pulmonary hypertension) (Fig. 55-8) refers to the situation in which major vessel clot is present and readily visible on the opening of the pulmonary arteries. All central thrombotic material has to be completely removed before the endarterectomy. In type II disease (approximately 70% of cases; Fig. 55-9), no major vessel thrombus can be appreciated. In these cases only thickened intima can be seen, occasionally with webs, and the endarterectomy plane is raised in the main, lobar, or segmental vessels. Type III disease (approximately 20% of cases; Fig. 55-10) presents the most challenging surgical situation. The disease is very distal and confined to the segmental and subsegmental branches. No occlusion of vessels can be seen initially. The endarterectomy plane must be carefully and painstakingly raised in each segmental and subsegmental branch. Type III disease is most often associated with presumed repetitive thrombi from indwelling catheters (such as pacemaker wires) or ventriculo-atrial shunts. Type IV disease (Fig. 55-11) does not represent primary thromboembolic pulmonary hypertension and is inoperable. In this entity there is intrinsic small vessel disease, although secondary thrombus may occur as a result of stasis. Small-vessel disease may be unrelated to thromboembolic events ("primary" pulmonary hypertension) or occur in relation to thromboembolic hypertension as a result of a high flow or high pressure state in previously unaffected vessels similar to the generation of Eisenmenger's syndrome. We believe that there may also be sympathetic "cross-talk" from an affected contralateral side or stenotic areas in the same lung.

When the patient's temperature reaches 20°C, the aorta is cross-clamped and a single dose of cold cardioplegic solution (I L) is administered. Additional myocardial protection is obtained by the use of a cooling jacket. 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 blood obscures direct vision of the pulmonary vascular bed, thiopental is administered (500 mg to 1 g) until the electroencephalogram becomes isoelectric. Circulatory arrest is then initiated, and the patient is exsanguinated. All monitoring lines to the patient are turned off to prevent the aspiration of air. Snares are tightened around the cannulae in the superior and inferior vena cavae. 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, and with the short arrest times that can be achieved with experience, it is not necessary.

Any residual loose, thrombotic debris encountered is removed. Then, a microtome knife is used to develop the endarterectomy plane posteriorly, because any inadvertent egress in this site could be repaired readily, or simply left alone. Dissection in the correct plane is critical because if the plane is too deep the pulmonary artery may perforate, with fatal results, and if the dissection plane is not deep enough, inadequate amounts of the chronically thromboembolic material will be removed. The plane should only be sought in the diseased parts of the artery; this often requires the initial dissection to begin quite distally.

The ideal layer is marked with a pearly white plane, which strips easily. There should be no residual yellow plaque. If the dissection is too deep, a reddish or pinkish color indicates the adventitia has been reached. A more superficial plane should be sought immediately.

Once the plane is correctly developed, a full-thickness layer is left in the region of the incision to ease subsequent repair. The endarterectomy is then performed with an eversion technique, using a specially developed dissection instrument (Jamieson aspirator, Fehling Corp.). Because the vessel is partly everted and subsegmental branches are being worked on, a perforation here will become completely inaccessible and invisible later. This is why absolute visualization in a completely bloodless field provided by circulatory arrest is essential. 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.

Once the right-sided endarterectomy is completed, circulation is restarted, and the arteriotomy is repaired with a continuous 6-0 polypropylene suture. The hemostatic nature of this closure is aided by the nature of the initial dissection, with the full thickness of the pulmonary artery being preserved immediately adjacent to the incision.

The surgeon now moves to the patient's right side. The pulmonary vent catheter is withdrawn, and an arteriotomy is made from the site of the pulmonary vent hole laterally beneath the pericardial reflection, and again into the lower lobe, but avoiding entry into the left pleural space. Additional lateral dissection does not enhance intraluminal visibility, may endanger the left phrenic nerve, and makes subsequent repair of the left pulmonary artery more difficult (Fig. 55-12). There is often a lymphatic vessel encountered on the left pulmonary artery at the level of the pericardial reflection, and it is wise to clip this before it being divided with the pulmonary artery incision.

The left-sided dissection is virtually analogous in all respects to that accomplished on the right. By the time the circulation is arrested once more it will have been reinitiated for at least 10 minutes, by which time the venous oxygen saturations are in excess of 90%. The duration of circulatory arrest intervals are again limited to 20 minutes.

After the completion of the endarterectomy, cardiopulmonary bypass is reinstituted and warming is commenced. Methylprednisolone (500 mg, intravenously) and mannitol (12.5 g, intravenously) are administered, and during warming a 10°C temperature gradient is maintained between the perfusate and body temperature, with a maximum perfusate temperature of 37°C. If the systemic vascular resistance level is high, nitroprusside is administered to promote vasodilatation and warming. The rewarming period generally takes approximately 90 to 120 minutes but varies according to the body mass of the patient.

When the left pulmonary arteriotomy has been repaired, the pulmonary artery vent is replaced at the top of the incision. The right atrium is then opened and examined. Any intra-atrial communication is closed. Although tricuspid valve regurgitation is invariable in these patients and is often severe, tricuspid valve repair is not performed unless there is independent structural damage to the tricuspid valve itself. Right ventricular remodeling occurs within a few days, with the return of tricuspid competence. If other cardiac procedures are required, such as coronary artery or mitral or aortic valve surgery, these are conveniently performed during the systemic rewarming period. Myocardial cooling is discontinued once all cardiac procedures have been concluded. The left atrial vent is removed, and the vent site is repaired. All air is removed from the heart, and the aortic cross-clamp is removed.

When the patient has rewarmed, cardiopulmonary bypass is discontinued. Dopamine hydrochloride is routinely administered at renal doses, and other inotropic agents and vasodilators are titrated as necessary to sustain acceptable hemodynamics. The cardiac output is generally high, with a low systemic vascular resistance. Temporary pacing wires are placed.

Despite the duration of extracorporeal circulation, hemostasis is readily achieved, and blood products are generally unnecessary. Wound closure is routine. A vigorous diuresis is usual for the next few hours, also a result of the previous systemic hypothermia.

Postoperative Care

Meticulous postoperative management is essential to the success of this operation. All patients are mechanically ventilated overnight, and subjected to a maintained diuresis with the goal of reaching the patient's preoperative weight within 24 hours. Although much of the postoperative care is common to more ordinary open-heart surgery patients, there are some important differences.

A higher minute ventilation is often required early after the operation to compensate for the temporary metabolic acidosis that develops after the long period of circulatory arrest, hypothermia, and cardiopulmonary bypass. Tidal volumes higher than those normally recommended after cardiac surgery are therefore generally used to obtain optimal gas exchange. The maximum inspiratory pressure is maintained below 30 cm of water if possible. Extubation should be performed on the first postoperative day, whenever possible.

Diuresis

Patients have considerable positive fluid balance after operation. After hypothermic circulatory arrest, patients initiate an early spontaneous aggressive diuresis for unknown reasons, but this may in part be related to the increased cardiac output related to a now lower PVR level, and improved RV function. This diuresis should be augmented with diuretics, however, with the aim of returning the patient to the preoperative fluid balance within 24 hours of operation. Because of the increased cardiac output, some degree of systemic hypotension is readily tolerated. Fluid administration is minimized, and the patient's hematocrit level should be maintained above 30% to increase oxygen-carrying capacity and to reduce the likelihood of the pulmonary reperfusion phenomenon.

Arrhythmias

The development of atrial arrhythmias, at approximately 10%, is no more common than that encountered in patients who undergo other types of non–valvular heart surgery. When a small atrial septal defect or persistent foramen ovale is closed this is done with a small inferior atrial incision directly over the fossa ovalis, away from the conduction system of the atrium or its blood supply. The siting and size of this incision may be helpful in the reduction of the incidence of these arrhythmias.

Transfusion

Despite the requirement for the maintenance of an adequate hematocrit level, with careful blood conservation techniques used during operation, transfusion is required in a minority of patients.

Inferior Vena Caval Filter and Anticoagulation

A Greenfield filter is usually inserted before operation, to minimize recurrent pulmonary embolism after pulmonary endarterectomy. However, if this is not possible, it can also be inserted at the time of operation. If the device is to be placed at operation, radiopaque markers should be placed over the level of the spine corresponding to the location of the renal veins to allow correct positioning. Postoperative venous thrombosis prophylaxis with intermittent pneumatic compression devices is used, and the use of subcutaneous heparin is begun on the evening of surgery. Anticoagulation with warfarin is begun as soon as the pacing wires and mediastinal drainage tubes are removed, with a target international normalized ratio of 2.5 to 3.

Complications

Aside from complications that are associated with open heart and major lung surgery (arrhythmias, atelectasis, wound infection, pneumonia, mediastinal bleeding, etc.), there are complications specific to this operation. These include persistent pulmonary hypertension, reperfusion pulmonary response, and neurologic disorders related to deep hypothermia.

Persistent Pulmonary Hypertension

The decrease in PVR level usually results in an immediate and sustained restoration of pulmonary artery pressures to normal levels, with a marked increase in cardiac output. In a few patients, an immediately normal pulmonary vascular tone is not achieved, but an additional substantial reduction may occur over the next few days because of the subsequent relaxation of small vessels and the resolution of intraoperative factors such as pulmonary edema. In such patients, it is usual to see a large pulmonary artery pulse pressure, the low diastolic pressure indicating good runoff, yet persistent pulmonary arterial inflexibility still resulting in a high systolic pressure.

There are a few patients in whom the pulmonary artery pressures do not resolve substantially. If the operation has been performed as described in the preceding, using circulatory arrest, and ensuring that all distal disease is removed, this will be the result of type IV disease. We do operate on some patients with severe pulmonary hypertension but equivocal embolic disease. Despite the considerable risk of attempted endarterectomy in these patients, because transplantation is the only other avenue of therapy, there may be a point when it is unlikely that a patient will survive until a donor is found. In our most recent 500 patients, the majority of perioperative deaths were directly attributable to the problem of inadequate relief of pulmonary artery hypertension. This was a diagnostic rather than an operative technical problem. Attempts at pharmacologic manipulation of high residual PVR levels with sodium nitroprusside, epoprostenol sodium, or inhaled nitric oxide are generally not effective. Because the residual hypertensive defect is fixed, it is not appropriate to use mechanical circulatory support or extracorporeal membrane oxygenation in these patients if they deteriorate subsequently.

The "Reperfusion Response"

A specific complication that occurs in most patients to some degree is localized pulmonary edema, or the "reperfusion response." Reperfusion response or reperfusion injury is defined as a radiologic opacity seen in the lungs within 72 hours of pulmonary endarterectomy. This unfortunately loose definition may therefore encompass many causes, such as fluid overload and infection.

True reperfusion injury that directly adversely impacts the clinical course of the patient now occurs in approximately 10% of patients. In its most dramatic form, it occurs soon after operation (within a few hours) and is associated with profound desaturation. Edema-like fluid, sometimes with a bloody tinge, is suctioned from the endotracheal tube.95 Frank blood from the endotracheal tube, however, signifies a mechanical violation of the blood airway barrier that has occurred at operation and generally stems from a technical error, though we have seen two cases where significant blood in the airway was the result of a technically good operation, but reperfusion of a known infarcted area of the lung. This complication should be managed, if possible, by identification of the affected area by bronchoscopy and balloon occlusion of the affected lobe until coagulation can be normalized.

One common cause of reperfusion pulmonary edema is persistent high pulmonary artery pressures after operation when a thorough endarterectomy has been performed in certain areas, but there remains a large part of the pulmonary vascular bed affected by type IV change. However, the reperfusion phenomenon is often encountered in patients after a seemingly technically perfect operation with complete resolution of high pulmonary artery pressures. In these cases the response may be one of reactive hyperemia, after the revascularization of segments of the pulmonary arterial bed that have long experienced no flow. Other contributing factors may include perioperative pulmonary ischemia and conditions associated with high permeability lung injury in the area of the now denuded endothelium. Fortunately, the incidence of this complication is much less common now in our series, probably as a result of the more complete and expeditious removal of the endarterectomy specimen that has come with the large experience over the last decade.

Management of the "Reperfusion Response"

Early measures should be taken to minimize the development of pulmonary edema with diuresis, maintenance of hematocrit levels, and the early use of peak end-expiratory pressure. Once the capillary leak has been established, treatment is supportive because reperfusion pulmonary edema will eventually resolve if satisfactory hemodynamics and oxygenation can be maintained. Careful management of ventilation and fluid balance is required. The hematocrit is kept high (32 to 36%), and the patient undergoes aggressive diuresis, even if this requires ultrafiltration. The patient's ventilatory status may be dramatically position sensitive. The Fio2 level is kept as low as is compatible with an oxygen saturation of 90%. A careful titration of positive end-expiratory pressure is carried out, with a progressive transition from volume- to pressure-limited inverse ratio ventilation and the acceptance of moderate hypercapnia.95 The use of steroids is discouraged because they are generally ineffective and may lead to infection. Infrequently, inhaled nitric oxide at 20 to 40 parts per million can improve the gas exchange. On occasion we have used extracorporeal perfusion support (extracorporeal membrane oxygenator or extracorporeal carbon dioxide removal) until ventilation can be resumed satisfactorily, usually after 7 to 10 days. However the use of this support is limited to patients who have benefited from hemodynamic improvement, but are suffering from significant reperfusion response. Extracorporeal devices should not be used if there is no evidence or hope of subsequent hemodynamic improvement, because it will not play a role in improving irreversible pulmonary pressures and carries mortality close to 100%.

Delirium

Early in the pulmonary endarterectomy experience (before 1990), there was a substantial incidence of postoperative delirium. A study of 28 patients who underwent pulmonary endarterectomy showed that 77% experienced the development of this complication.96,97 Delirium appeared to be related to an accumulated duration of circulatory arrest time of more than 55 minutes; the incidence fell to 11% with significantly shorter periods of arrest time.96–98 With the more expeditious operation that has come with our increased experience, postoperative confusion is now encountered no more commonly than with ordinary open heart surgery.

Results

More than 2700 pulmonary thromboendarterectomy have been performed at UCSD Medical Center since 1970. Most of these cases (more than 2600) have been completed since 1990, when the surgical procedure was modified as described earlier in this chapter. The mean patient age in our group is about 52 years, with a range of 7 to 85 years. There is a very slight male predominance. In nearly one-third of the cases, at least one additional cardiac procedure was performed at the time of operation. Most commonly, the adjunct procedure was closure of a persistent foramen ovale or atrial septal defect (26%) or coronary artery bypass grafting (8%).87

Hemodynamic Results

A reduction in pulmonary pressures and resistance to normal levels and a corresponding improvement in pulmonary blood flow and cardiac output are generally immediate and sustained.98,99 In general, these changes can be assumed to be permanent. Whereas before the operation, more than 95% of the patients are in NYHA functional class III or IV; at 1 year after the operation, 95% of patients remain in NYHA functional class I or II.99,100 In addition, echocardiographic studies have demonstrated that, with the elimination of chronic pressure overload, right ventricular geometry rapidly reverts toward normal. Right atrial and right ventricular enlargement regresses. Tricuspid valve function returns to normal within a few days as a result of restoration of tricuspid annular geometry after the remodeling of the right ventricle, and tricuspid repair is not therefore part of the operation.

Operative Morbidity

Severe reperfusion injury was the single most frequent complication in the UCSD series, occurring in 10% of patients. Some of these patients did not survive, and other patients required prolonged mechanical ventilatory support. A few patients were salvaged only by the use of extracorporeal support and blood carbon dioxide removal. Neurologic complications from circulatory arrest appear to have been eliminated, probably as a result of the shorter circulatory arrest periods now experienced, and perioperative confusion and stroke are now no more frequent than with conventional open heart surgery. Early postoperative hemorrhage required re-exploration in 2.5% of patients, and less than half of patients required intraoperative or postoperative blood transfusion. Despite the prolonged operation, wound infections are relatively infrequent. Only 1.8% experienced the development of sternal wound complications, including sterile dehiscence or mediastinitis.

Deaths

In our experience, the overall mortality rate (30 days or in-hospital if the hospital course is prolonged) is about 7% for the entire patient group, which encompasses a time span of over 35 years. The mortality rate was 9.4% in 1989 and has been less than 6% for the more than 2400 patients who have undergone the operation since 1990. In our most recent experience over the last 5 years, the mortality rate has been less than 4%. With our increasing experience and many referrals, we continue to accept some patients who, in retrospect, were unsuitable candidates for the procedure (type IV disease). We also accept patients in whom we know that the entire degree of pulmonary hypertension cannot be explained by the occlusive disease detected by angiography but feel that they will be benefited by operation, albeit at higher risk. Residual causes of death are operation on patients in whom thromboembolic disease was not the cause of the pulmonary hypertension (50%) and the rare case of reperfusion pulmonary edema that progresses to a respiratory distress syndrome of long standing, which is not reversible (25%).

Late Follow-Up

A survey of the surviving patients who underwent pulmonary endarterectomy surgery at UCSD between 1970 and 1995 formally evaluated the long-term outcome.100 Questionnaires were mailed to 420 patients who were more than 1 year after operation. Responses were obtained from 308 patients. Survival, functional status, quality of life, and the subsequent use of medical help were assessed. Survival after pulmonary thromboendarterectomy was 75% at 6 years or more. Ninety-three percent of the patients were found to be in NYHA Class I or II, compared with about 95% of the patients being in NYHA Class III or IV preoperatively. Of the working population, 62% of patients who were unemployed before operation returned to work. Patients who had undergone pulmonary endarterectomy scored several quality-of-life components just slightly lower than normal individuals, but significantly higher than the patients before endarterectomy. Only 10% of patients used oxygen, and in response to the question, "How do you feel about the quality of your life since your surgery?" Seventy-seven percent replied much improved, and twenty percent replied improved. These data appear to confirm that pulmonary endarterectomy offers substantial improvement in survival, function, and quality of life, with minimal later health-care requirements.100

It is increasingly apparent that pulmonary hypertension caused by chronic pulmonary embolism is a condition which is under-recognized, and carries a poor prognosis. Medical therapy is ineffective in prolonging life and only transiently improves the symptoms. The only therapeutic alternative to pulmonary thromboendarterectomy is lung transplantation. The advantages of thromboendarterectomy include a lower operative mortality and excellent long-term results without the risks associated with chronic immunosuppression and chronic allograft rejection. The mortality for thromboendarterectomy at our institution is now less than 4%, with sustained benefit. These results are clearly superior to those for transplantation both in the short and long term.

Although PTE is technically demanding for the surgeon, and requires careful dissection of the pulmonary artery planes and the use of circulatory arrest, excellent short- and long-term results can be achieved. It is the successive improvements in operative technique developed over the last four decades, which now allow pulmonary endarterectomy to be offered to patients with an acceptable mortality rate and excellent anticipation of clinical improvement. With this growing experience, it has also become clear that unilateral operation is obsolete and that circulatory arrest is essential.

The primary problem remains that this is an under-recognized condition. Increased awareness of both the prevalence of this condition and the possibility of a surgical cure should avail more patients of the opportunity for relief from this debilitating and ultimately fatal disease.