Pulmonary endarterectomy (PEA) is at present the only curative option for a subgroup of patients presenting with chronic thromboembolic pulmonary hypertension (CTPH).
Pulmonary thromboembolism is more common than usually thought [1,2]. Large emboli will often present dramatically, leading to hospital admission and possibly death. Survival is dependent on the dissolution of the clots, which will usually be complete after 8–14 days . In some patients, factors such as the accumulation of small emboli, the incomplete resolution of a large thrombus, or remodelling of the pulmonary vessels by the release of specific mediators, either alone or in combination, will lead to the insidious development of CTPH [3–6].
CTPH is a condition affecting many more patients that previously thought, and with increased awareness of the condition amongst physicians, the number of patients referred for surgery is steadily increasing. Since the initial successful intervention reported in 1973 , followed by the formal description of the operation by Daily in 1980 , and by the first successful human case series by Brown in 1984 , several thousands of patients have now been operated on successfully . The perioperative management of these patients is challenging but rewarding, and the procedure can now be performed in a number of specialized centres, with level of mortality lower than 10% [11–14].
The principles of management of CTPH will be of interest to all physicians, but it is paramount that the operation itself should only be offered in a small number of specialized centres receiving a high volume of referrals, as a steep learning curve has been observed in relation to operative success [11,14].
The World Health Organization (WHO) classically divides the causes of pulmonary hypertension in 5 generic categories with CTPH listed as WHO Group IV .
The name of the operation used to cure CTPH in some patients was reviewed at the third World symposium on pulmonary arterial hypertension in Venice in 2003, and was changed from pulmonary thromboendarterectomy (PTE) to PEA, as it is now recognized that there is no thrombus at the time CTPH has developed [15–17].
PEA is an intervention that can be also offered in some cases of chronic pulmonary obstruction caused by recurrent embolisms from renal cell carcinoma , right atrial myxoma , or also for various types of intrapulmonary sarcoma .
It is accepted that pulmonary embolism is the main causative factor for CTPH. In most patients surviving an embolic event, the thrombi will be dissolved by local fibrinolysis, but some of the patients will develop an organized mass inside the pulmonary artery . This mass will progressively transform or evolve and will ultimately obstruct the pulmonary artery. The end result is progressive right heart remodelling [21,22] and eventually right heart failure.
It is difficult to estimate the number of patients suffering from CTPH. It was initially thought that around 0.1% of patients surviving a pulmonary embolism will develop the disease (500–2500 patients per annum in the USA) . It is, however, likely that this number grossly underestimates the incidence; a prospective observational study reported that 3.8% of patients initially presenting with pulmonary embolism subsequently developed CTPH  suggesting that as many as six times more patients than previously thought will develop the disease each year.
It is striking that only 50% of patients diagnosed with this condition have a past history of deep venous thrombosis or pulmonary embolism and that the interval of time between the initial embolism and clinical CTPH can be many years.
Thrombotic tendencies as indicated by protein-C or factor V Leiden deficiency, the anti-phospholipid syndrome or other autoimmune disorders can be identified in a proportion of patients suffering from CTPH [25–29]. It is noteworthy that some patients have neither a past history of embolism nor identified thrombotic tendencies .
Common presenting symptoms include dyspnoea, reduced exercise tolerance, fatigue and syncope . It is not uncommon for a patient to have been diagnosed with asthma, chronic obstructive pulmonary disease (COPD), idiopathic pulmonary hypertension or other medical conditions before the diagnosis of CTPH is eventually recognized. For these reasons, patients will often present late and by that time have usually severe pulmonary hypertension. It is important to recognize the disease early as the 5-yr survival in the absence of surgery is directly related to the mean pulmonary arterial pressure (MPAP), and is only 10% for those patients with MPAP above 50 mmHg at diagnosis .
CTPH can affect individuals in any age group and of either sex and to our knowledge PEA has been offered to patients ranging from age 16 to 84 yr. These patients can present with a number of co-morbidities, including respiratory, which can adversely affect the outcome .
One could logically assume that CTPH is the result of in situ thrombogenesis in the pulmonary arteries but this has been ruled out . On histological examination, a thickening of the pulmonary vessel wall that can be seen protruding into the vascular lumen appears eccentric and contains septa and webs. Smooth muscle proliferation in the pulmonary vessel wall is observed most of the time.
The exact molecular mechanisms of the development are not yet known but various mediators including plasma monocytes, chemo-attractant protein-1, IL-6, IL-10 and TNF-α may play a role [4,34]. In addition, some patients will also present with additional in situ thrombus formation in CTPH and this may be facilitated by abnormalities in the clotting cascade, endothelial cells or platelets, all of which interact in the coagulation process.
Angiopoetin-1, a factor responsible for angiogenesis in the embryonic lung, is upregulated in the lung parenchyma of patients with pulmonary hypertension, and its messenger RNA might serve as a target for strategies to treat the disease .
The diagnosis is often delayed or unrecognized because signs are often subtle in the beginning . Clinical examination can reveal signs of right heart failure or tricuspid regurgitation such as high jugular pressure and hepatomegaly. Peripheral and central cyanosis is classical at later stages. Chest auscultation can reveal an accentuated second heart sound or, in approximately 1/3 of the patients, a characteristic murmur is heard over the lung fields . Some patients will rapidly become wheelchair bound.
Signs of pulmonary hypertension can be seen on ECG (right ventricular hypertrophy, axis deviated to the right).
Chest radiography will usually demonstrate clear lung fields with prominent hilar regions.
Ventilation/perfusion scanning can illustrate the mismatched lung segments and the location of perfusion defects, but usually underestimates the extent of the obstruction . Computed tomography scanning with pulmonary angiography is a useful tool in distinguishing between proximal and distal disease [39–41].
High-resolution spiral computed tomography with contrast medium is the most useful investigation, demonstrating a mosaic perfusion of both lung fields, and permitting visualization of the pulmonary vascular tree . In some centres, it has now replaced pulmonary angiography as the chosen investigation to diagnose CTPH and ascertain the location and extent of the disease.
Angioscopy can be performed preoperatively to confirm operability in patients with equivocal results of angiography , and will often be used intraoperatively to ensure good clearance .
Magnetic resonance imaging (MRI) can provide further three-dimensional anatomical information but is not as accurate as spiral CT or pulmonary angiography in assessing the distribution of the pulmonary vessel occlusion.
Right heart catheterization allows direct measurement of pulmonary artery and right ventricular pressures.
Transthoracic and transoesophageal echocardiography (TOE) typically show right ventricular hypertrophy and dilatation with abnormal ventricular septal motion. The pulmonary systolic pressure can be derived from the tricuspid regurgitation jet. Sometimes, the organized thrombotic material can be seen on TOE in the proximal pulmonary arteries.
It is important to test lung function to exclude concomitant pulmonary parenchymal disease that may share similar symptoms to CTPH and have an impact on perioperative management . Coronary angiography should be performed when there is a possibility or suspicion of coronary artery disease as coronary revascularization can be done during the course of the operation .
Blood coagulation tests should be performed and the presence of thrombotic diathesis investigated preoperatively.
Arterial blood gases are useful to define the impact of CTPH on gas exchange, and an increased alveolar–arterial oxygen gradient, which widens with exercise, is not unusual .
Finally, duplex scanning of the legs can reveal scarring from previous thrombosis.
To date, no medical therapy has proven curative in cases of CTPH  and only surgery can result in a complete clearance of the pulmonary vascular tree, subsequent remission of clinical symptoms with a dramatic improvement in quality and length of life. Lung transplantation has been offered for many years, but the scarcity of donor organs, the prospect of lifelong immuno-suppression and the lower survival at 5 yr, make it an unrealistic and uneconomical option for those patients amenable to conventional PEA. Angioplasty of the pulmonary artery with an inflatable balloon has been reported in 18 patients, 16 of whom survived at least 34 months .
Medical therapy may alleviate symptoms in some patients and will be used as a bridge to the operation, or will be used to accompany palliative therapy in those patients not amenable to surgery. It consists mainly of pulmonary vasodilators like prostacyclin and synthetic derivatives; the phosphodiesterase type-5 inhibitor sildenafil [48,49] or more recently non-selective endothelin-receptor antagonists such as bosentan [50,51]. Some of these substances can be administered intravenously (i.v.), others subcutaneously or by inhalation. Prostacyclin [52,53], and its new analogue treprostinil , or iloprost  have been recommended in the period preceding PEA as they improve the signs and symptoms of pulmonary hypertension. In addition of vasodilating effects, they also inhibit platelet aggregation and have anti-proliferative effects on the vascular wall smooth muscle cells .
The non-selective endothelin-receptor antagonist bosentan is used to antagonize the effect of increased circulatory concentrations of endothelin-1 observed in patients with CTPH  and has been shown to improve exercise capacity.
All patients will benefit from continuous anticoagulation, and it is advocated by some that an inferior vena cava filter should be inserted early, even in the absence of documented peripheral thrombi.
PEA, which involves removal of the organized embolic material from the pulmonary arteries, is the definitive treatment for CTPH and leads to haemodynamic recovery even in severely compromised patients .
PEA is only possible in patients with proximal disease, limited to the main, lobar and proximal segmental arteries.
Patients usually present with mean pulmonary vascular resistance of 800–1000 dyn s cm−5. The majority are in New York Heart Association (NYHA) functional class III or IV. The risk of perioperative death correlates with the degree of preoperative heart failure. Perioperative mortality is six times greater in patients with pulmonary vascular resistance of more than 1100 dyn s cm−5 and five times greater in those with MPAP greater than 50 mmHg .
The main prognostic criterion remains the surgical classification, obtained at the time of the operation. The material removed from the pulmonary artery can be divided into four categories: type 1 disease with fresh thrombus in main-lobar arteries; type 2 disease with organized thrombus and intimal thickening proximal to segmental arteries; type 3 disease with intimal thickening or fibrosis in distal segmental arteries with the surgical plane rising at each segmental level; type 4 disease with distal arteriolar vasculopathy with removal of normal intimal layer and no intraluminal disease .
Patient age and preoperative clinical deterioration are risk factors for hospital mortality, while severity of disease and female gender are associated with increased risk of inadequate postoperative haemodynamic improvement .
The surgical approach is always through a median sternotomy and requires the use of cardiopulmonary bypass. Other surgical approaches such as thoracotomy have been unsuccessful. Bicaval cannulation is advantageous as it offers unobstructed view of the pulmonary arteries and adequate drainage from the head.
An increased collateral blood flow to the lungs is observed in these patients, rendering visualization of the pulmonary arteries difficult even after aortic cross-clamping, and it is therefore advocated that deep hypothermic circulatory arrest (DHCA) be used in all patients. Alternative strategies such as using antegrade perfusion and balloon occlusion of the bronchial arteries  have been proposed, but so far none have proven superior in relation to surgical success and patient's outcome.
Each cardiac centre has its own specific technique for DHCA, which may include the administration of i.v. barbiturates, steroids, phenytoin, mannitol or other agents with alleged or demonstrated neuroprotective properties . Surface cooling the head with ice packs and heart cooling devices has been used . It is unknown if any of these agents affect reperfusion insult, in the brain, lungs or other organs.
The disease is always bilateral, and right and left endarterectomy is performed sequentially. The surgical planes are sometimes difficult to find and an inexperienced surgeon may fail to identify the dissection plane. Intraoperative use of an angioscope to assist the dissection and evaluate the vascular clearance has been advocated [44,64].
Additional surgery, such as atrial septal defect (ASD) closure, coronary grafting  or valve surgery is usually performed during rewarming, after completion of the endarterectomy . Some argue that a small ASD defect should not be repaired as it may act as a natural vent in case of elevated right-sided pressure.
Clamping of the aorta and cardioplegia are routinely required for cardiac protection, and topical cooling of the heart (with a cooling blanket) has proven useful. Division of the superior vena cava may help to achieve a better visualization of the surgical field, and the left heart is commonly vented through the superior pulmonary vein.
Throughout the intervention, the patients need vascular access for the administration of drugs, and invasive pressure monitoring, including pulmonary artery pressure. The surgeon usually repositions the pulmonary artery catheter after the dissection, and great care should be taken to avoid traumatic rupture of the fragile pulmonary vessels. The catheter should not be moved or wedged to measure capillary pressure (we usually use a default pulmonary capillary wedge pressure of 10 mmHg for haemodynamic calculations).
Patients normally continue their anticoagulation to the day of the operation, usually with a vitamin K inhibitor, and patients receive routinely 10 mg of vitamin K on induction of anaesthesia to attempt reversing the anticoagulant effect by the end of bypass. Anticoagulation management during cardiopulmonary bypass is traditionally with heparin, and protamine is used to reverse its effect after separation from cardio-pulmonary bypass (CPB). Recombinant-hirudin has been used in patients with heparin-induced thrombocytopenia (HIT) . Some centres administer aprotinin routinely in those patients.
A cell saver should be used throughout the procedure, and with the exception of concentrated red cells, it is uncommon for patients to require other blood products such as platelets concentrates or fresh frozen plasma at any stage.
Premedication is not indispensable but (oral) benzodiazepines alone or in combination with morphine and/or scopolamine (administered subcutaneously in case of high International Normalized Ratio (INR)) can be used.
In addition to the routine invasive arterial and venous invasive blood pressure monitoring, the pulmonary artery catheter is an essential monitoring tool to assess without delay the impact of surgery on pulmonary vascular reactivity. Both radial and femoral systemic blood pressures are monitored, since a large gradient between the two may develop in the period after cardiopulmonary bypass, for yet unknown reasons . TOE is a useful tool to assess RV and LV function before and after CPB, inspect the valvular apparatus and detect the presence of an ASD, patent foramen ovale or intracardiac thrombi. Accurate temperature monitoring is required. Electroencephalography is used routinely in some centres to indicate the absence of cerebral electrical activity before circulatory arrest, while others advocate the use of transcranial near-infrared spectroscopy (NIRS)  to monitor the adequacy of cerebral oxygenation during the different phases of cardiopulmonary bypass (cooling, circulatory arrest or low flow cerebral perfusion and rewarming).
Induction in anaesthesia should be controlled, aiming to avoid hypotensive episodes that are poorly tolerated by this group of patients. Most techniques used in cardiac anaesthesia for unstable patients are likely to be suitable. We usually administer a small dose of benzodiazepine (midazolam up to 0.10 mg kg−1) on induction, followed by the infusion of an i.v. anaesthetic agent (propofol at 3–4 mg kg−1 h−1) continued for the whole duration of the operation and on arrival in intensive care. We add a high dose opioid (fentanyl up to 15 μg kg−1) given in increment before sternotomy. Muscle relaxation is often achieved with a long acting drug such as pancuronium administered a few minutes before oro-tracheal intubation. Hypoxia, hypercarbia and hypotension will increase pulmonary vascular resistance and should be avoided. Hypotension may also jeopardize right ventricular perfusion and a small dose of alpha-agonists or/and dopamine may help to achieve haemodynamic stability. In the period preceding the endarterectomy, ino-vasodilators such as phosphodiesterase inhibitors or dobutamine will decrease systemic vascular resistances without affecting pulmonary vascular resistances, and should therefore be avoided. Systemic hypertension can easily be controlled by the administration of i.v. vasodilators such as sodium nitroprusside or glycerine trinitrate or, as commonly done during cardiac surgery, by the brief addition of inhaled agents in the anaesthetic circuit .
Intraoperative ventilation throughout the intervention is similar to other cases involving CPB, but it is intriguing to note that centres with extensive experience recommend the universal use of a positive end expiratory pressure (PEEP) greater than 6 cmH2O after separation from CPB and without interruption during transfer to the critical care area. While some have advocated the routine post-bypass administration of inhaled nitric oxide, its benefits in relation to outcome have not been demonstrated despite observed changes in oxygenation or pulmonary pressure [69–71].
Residual pulmonary hypertension can be the result of incomplete surgical clearance or may occur as a result of reperfusion injury or hypertensive changes in the small pulmonary arteries downstream from the diseased arteries .
Separation from CPB may require the use of inotropic agents to support either the right ventricle, left ventricle or both. The right ventricle is more likely to fail in case of incomplete clearance of the pulmonary circulation or poor myocardial preservation technique. The choice of inotropic agent is often guided by local preferences. In our centre, the combination of a phosphodiesterase inhibitor (enoximone) with a vasoconstrictor (noradrenaline), combined to the early use of intra-aortic balloon counterpulsation has proven useful in many occasions. The benefits of intra-aortic balloon counterpulsation as a mechanical assist device is well known  and has been described in case of acute right ventricular failure by others [74–76].
Severely disordered clotting laboratory results are relatively common postoperatively but do not always correlate with active bleeding. The transfusion of blood products is reserved for clinically haemorrhaging patients.
Perioperative antibiotic prophylaxis is important and should be in accordance with local antibiotic guidelines.
Intensive care management
The patients usually remain on the ventilator for several hours postoperatively to allow management of early lung reperfusion injury. Ventilatory support (FiO2 and PEEP) is progressively reduced and the trachea can usually be extubated within 18 hr of arrival.
Classical complications associated with cardiopulmonary bypass operations are observed at times (haemorrhage, cardiac or renal failure, stroke and multiple organ failure). Specific adverse events associated with PEA include haemoptysis, reperfusion injury, and right heart failure with or without residual pulmonary hypertension.
Residual pulmonary hypertension occurs in 10– 15% of the patients. It is likely to be caused by distal arteriopathy  and is a reliable predictor of death . It can be improved by the administration of inhaled iloprost [78,79] and justify the continued administration of an endothelin antagonist in the postoperative period.
Reperfusion injury  is a specific complication that usually appears within 48 h of the operation, resembles acute lung injury and is characterized by pulmonary hyperaemia in the revascularized pulmonary areas. It develops in the majority of the patients with a varying degree of severity [81,82]. It is characterized by increased vascular permeability, pulmonary hypertension, and leucocyte activation and sequestration . Inhaled nitric oxide can improve oxygenation in patients with hypoxaemia , but has not been shown to affect outcome. Steroids, prostaglandin E1 and prostacyclin have all been used. It has also been postulated that blocking neutrophil selectin-mediated adhesion on the day of surgery would reduce the incidence of reperfusion injury . It has been suggested that low tidal volumes (8 mL kg−1) coupled with low airway pressures (Paw < 18 cmH2O) would decrease the incidence of the reperfusion injury seen with higher tidal volumes (10–15 mL kg–1) and pulmonary airway pressure (up to 50 cmH2O) . Most patients benefit from a negative fluid balance in the first postoperative days. Extracorporeal membrane oxygenation can assist recovery in extreme situations, if the surgical clearance was satisfactory, but it will be of no use in cases of right heart failure with incomplete surgical clearance.
Postoperative delirium of varying severity can be observed in as many as 77% of patients with a peak at around 72 h postoperatively. This is strongly associated with long hypothermia and circulatory arrest times . Postoperative cognitive deficits after CPB are well described and the risk is no different for PEA patients. Neuroprotective strategies more specific to PEA include adequate drainage of the superior vena cava during CPB to avoid an uncontrolled rise in intracranial pressure, avoidance of hyperthermia during rewarming and the use of agents with putative neuroprotective properties.
It is known that TNF-α levels normalize rapidly in the postoperative period , while plasma thrombomodulin (a major anticoagulant proteoglycan) levels increase remarkably . Brain natriuretic peptide (BNP) is elevated prior to the intervention and decreases afterwards. BNP has been proposed as a non-invasive marker of the efficacy of the operation .
Massive pulmonary haemorrhage is a rare complication and usually fatal .
Perioperative mortality for this operation is usually quoted at 10%  but will be as low as 4% in those centres operating on a large number of patients . Survival at 6 yr has been reported to be as high as 75%, of which 62% of patients had returned to work and 93% had NYHA functional class I or II [92,93]. Adequate patient selection and experience of the hospital team are the most important factors for successful outcome.
The beneficial effects will be long lasting in most patients surviving the operation. Those patients must remain anticoagulated for life. Rarely, it may be necessary to repeat the operation several years later in some patients presenting with recurrence.
In the majority of patients, a marked reduction in the pulmonary arterial and right ventricular pressures is observed immediately, with return to normal of septal motion, left ventricular systolic function and diastolic filling patterns . A significant reduction in tricuspid regurgitation  and dramatic improvement in pulmonary gas exchange are usual [46,95,96]. The immediate improvement already observed in the operating room will usually continue. Cardiac output, gas exchange, clinical status and exercise tolerance will continue to improve for up to 2 yr after surgery .
Nevertheless, reduced diffusing capacity for carbon monoxide can persist for more than a year after PEA .
Successful PEA has been described in patients with various conditions precipitating recurrent thromboembolisms such as patients with cryoagglutinins , hereditary stomatocytosis  and sickle cell disease [101,102].
PEA is the curative treatment of choice for CTPH and is now offered throughout the world with a low morbidity and mortality. Management of these patients is challenging but rewarding to the skilled clinician.
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