Cor Pulmonale and Pulmonary Embolism

Cor Pulmonale and Pulmonary Embolism

 

 

Chronic Cor Pulmonale

The term “cor pulmonale” is still very popular in the medical literature, but its definition varies and there is presently no consensual definition. Forty years ago an expert committee of the World Health Organization¹ defined cor pulmonale as “hypertrophy of the right ventricle resulting from diseases affecting the function and/or structure of the lungs . . .”. This pathological definition is in fact of limited value in clinical practice. It has been proposed to replace the term “hypertrophy” by “alteration in the structure and function of the right ventricle”. It has also been proposed to define clinically cor pulmonale by the presence of oedema in patients with respiratory failure. Finally, as pulmonary arterial hypertension is “the sine qua non” of cor pulmonale, we believe that the best definition of cor pulmonale is : pulmonary arterial hypertension resulting from diseases affecting the structure and/or the function of the lungs; pulmonary arterial hypertension results in right ventricular enlargement (hypertrophy and/or dilatation) and may lead with time to right heart failure.

A new diagnostic classification of pulmonary hypertension was developed by a group of experts in 1998 and is presented on table. In our opinion cor pulmonale corresponds to the third part of this classification (pulmonary hypertension associated with disorders of the respiratory system and/or hypoxaemia) and must be distinguished from pulmonary venous hypertension (part 2), and also from primary pulmonary hypertension (part 1) and from thromboembolic pulmonary hypertension (part 4).

 

DEFINITIONS AND EPIDEMIOLOGY

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Pulmonary hypertension complicating chronic respiratory disease is generally defined by the presence of a resting mean pulmonary artery pressure (PAP) > 20 mm Hg. This is slightly different from the definition of primary pulmonary hypertension (PAP > 25 mmHg). In young (< 50 years) healthy subjects PAP is most often between 10–15 mm Hg. With aging there is a slight increase in PAP, by about 1 mm Hg/10 years. A resting PAP > 20 mm Hg is always abnormal. In the “natural history” of COPD, pulmonary hypertension is often preceded by an abnormally large increase in PAP during exercise, defined by a pressure > 30 mm Hg for a mild level of steady state exercise. The term “exercising” pulmonary hypertension has been used by some authors, but the term “pulmonary hypertension” should be reserved for resting pulmonary hypertension.

Cor pulmonale is a common type of heart disease, as a result of its close association with COPD which has emerged, in recent years, as a leading cause of disability and death. But there are in fact very few data about the incidence and prevalence of cor pulmonale. The main reason is that right heart catheterisation cannot be performed on a large scale in patients at risk. An alternative approach is the use of non-invasive methods, particularly Doppler echocardiography. It should be possible to investigate large groups of respiratory patients with echo Doppler within the next few years.

A UK study performed in Sheffield has tried to determine the prevalence of patients at risk of developing pulmonary hypertension and cor pulmonale—that is, patients with hypoxaemic lung disease. In the study population, aged 45 years, an estimated 0.3% had both an arterial oxygen tension (PaO₂) < 7.3 kPa (55 mm Hg) and a forced expiratory volume in one second (FEV₁) < 50% of the predicted value. For England and Wales this could represent 60 000 subjects at risk of pulmonary hypertension and eligible for long term oxygen therapy.

The mortality related to cor pulmonale is also difficult to assess. There are data about the mortality resulting from chronic lung disease (100 000/year in the USA) but we do not know precisely the role of secondary pulmonary hypertension in this mortality. Pulmonary hypertension is a complication, among others, of advanced COPD and it is not possible to separate it from its causative diseases.

AETIOLOGY: WHICH CHRONIC LUNG DISEASE MAY LEAD TO COR PULMONALE?

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Table below lists the chronic respiratory diseases which may lead to cor pulmonale. Primary pulmonary hypertension, pulmonary thromboembolic disease, and diseases of the pulmonary vascular bed have been excluded from this list which is far from exhaustive. There are three major groups of diseases:

·        those characterised by a limitation to airflow (COPD and other causes of chronic bronchial obstruction)

·        those characterised by a restriction of pulmonary volumes from extrinsic or parenchymatous origin (restrictive lung diseases)

·        those where the relatively well preserved mechanical properties of the lungs and chest wall contrast with pronounced gas exchange abnormalities which are partially explained by poor ventilatory drive (respiratory insufficiency of “central” origin).

 

COPD is the major cause of chronic respiratory insufficiency and cor pulmonale, and it probably accounts for 80–90% of the cases. COPD includes chronic obstructive bronchitis and emphysema which are often associated. Among the restrictive lung diseases kyphoscoliosis, idiopathic pulmonary fibrosis, and pneumoconiosis are the main causes of cor pulmonale. Among the aetiologies of respiratory insufficiency of “central” origin the obesity–hypoventilation syndrome (formerly “Pickwickian syndrome”) is a relatively frequent cause of cor pulmonale.

MECHANISMS OF COR PULMONALE

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As stated above pulmonary hypertension is the “sine qua non” of cor pulmonale. Accordingly, the mechanisms of cor pulmonale are first those of pulmonary hypertension. In chronic respiratory diseases pulmonary hypertension results from increased pulmonary vascular resistance (PVR) whereas cardiac output and pulmonary “capillary” wedge pressure are normal; pulmonary hypertension is said to be precapillary.

The factors leading to an increased PVR in chronic respiratory disease are numerous but alveolar hypoxia is by far the most predominant, at least in COPD, kyphoscoliosis, and the obesity–hypoventilation syndrome. Two distinct mechanisms of action of alveolar hypoxia must be considered: acute hypoxia causes pulmonary vasoconstriction, and chronic longstanding hypoxia induces structural changes in the pulmonary vascular bed (pulmonary vascular remodelling).

Hypoxic pulmonary vasoconstriction (HPV) has been known since the studies in 1946 of Von Euler and Liljestrand on the cat. HPV explains the rise of PVR and PAP observed in humans, and in almost all species of mammals, during acute hypoxia. This vasoconstriction is localised in the small precapillary arteries. Its precise mechanism is not fully understood. The clinical situations which bear the closest analogy with acute hypoxic challenges are probably exacerbations of COPD leading to acute respiratory failure, and the sleep related episodes of worsening hypoxaemia.

Pulmonary hypertension is generally observed in respiratory patients exhibiting pronounced chronic hypoxaemia (PaO₂ < 55–60 mm Hg). It is accepted that chronic alveolar hypoxia leads to remodelling of the pulmonary vascular bed (hypertrophy of the muscular media of the small pulmonary arteries, muscularisation of pulmonary arterioles, and intimal fibrosis) comparable to that observed iatives living at high altitude. This remodelling leads to elevation of PVR and to pulmonary hypertension. In fact the remodelling of the pulmonary vessels may be observed early ion-hypoxaemic COPD patients with mild disease severity.

Furthermore, other functional factors must be considered, namely hypercapnic acidosis and hyperviscosity caused by polycythaemia, but their role seems small when compared to that of alveolar hypoxia. In idiopathic pulmonary fibrosis the increase of PVR is caused by anatomical factors: loss of pulmonary vascular bed or compression of arterioles and capillaries by the fibrosing process.

Pulmonary hypertension increases the work of the right ventricle, which leads more or less rapidly to right ventricular enlargement (associating hypertrophy and dilatation) which can result in ventricular dysfunction (systolic, diastolic). Later, right heart failure (RHF) characterised by the presence of peripheral oedema can be observed, at least in some respiratory patients. The interval between the onset of pulmonary hypertension and the appearance of RHF is not known and may vary from one patient to another. There is a relation between the severity of pulmonary hypertension and the development of RHF.

 

CLINICAL ASSESSMENT OF COR PULMONALE: PLACE OF NON-INVASIVE METHODS

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The clinical signs of cor pulmonale are relatively insensitive and some of them (signs related to an increased jugular venous pressure) are often obscured by hyperinflation of the chest which is present in a number of COPD patients. Furthermore, the clinical signs occur late, being observed at an advanced stage of the disease far after the development of pulmonary hypertension. Peripheral (ankle) oedema is the best sign of RHF but it is not specific and can arise from other causes; in some patients with pulmonary hypertension, it does not occur at all. A murmur of tricuspid regurgitation, suggesting right ventricular dilatation, is a very late sign in respiratory patients. Accentuation of the pulmonary component of the second heart sound is only observed in patients with severe pulmonary hypertension.

The detection of right ventricular hypertrophy by electrocardiography has a high specificity but a very low sensitivity. A normal ECG does not exclude the presence of pulmonary hypertension, particularly in COPD patients. Similarly, the radiological signs of pulmonary hypertension (increased width of the right descending pulmonary artery) are poorly sensitive and the radiological appearance of a dilated right ventricle is a very late (and inconsistent) sign.

The non-invasive diagnosis of pulmonary hypertension is presently based on echocardiography. Continuous wave Doppler echocardiography allows the calculation of the transtricuspid pressure gradient from the peak velocity of the tricuspid regurgitant jet, by applying the Bernouilli equation. Assuming a right atrial pressure of 5 mm Hg, it is thus possible to calculate right ventricular systolic pressure (right atrial pressure + transtricuspid pressure gradient) which is identical to pulmonary artery systolic pressure. It is also possible to estimate the diastolic pulmonary artery pressure by summing the right atrial pressure and the end diastolic pressure gradient between the pulmonary artery and the right ventricle. Pulsed wave Doppler echocardiography, also based on the measurement of flow velocity, allows an indirect estimation of pulmonary artery systolic pressure. However, hyperinflation makes echocardiography difficult in many COPD patients and a reliable examination cannot be obtained in more than 60–80% of the cases. The good correlations that have been observed in cardiac patients between PAP estimated from echo data and pressures measured invasively have not always been confirmed in COPD patients and a mean error of the estimate, for PAP, of about 10 mm Hg has been reported.

Two dimensional echocardiography is used to measure right ventricular dimensions and the right ventricular wall thickness, making it possible to assess the presence of right ventricular hypertrophy and/or dilatation. However, magnetic resonance imaging (MRI) is probably the best method for measuring right ventricular dimensions because it produces the best images of the right ventricle. In COPD patients good correlations have beeoted between right ventricular free wall volume measured by MRI and PAP. MRI is also a good method for detecting changes in right ventricular function, but it is expensive and available only in specialised centres.

Radionuclide ventriculography allows the measurement of right ventricular ejection fraction (RVEF). An RVEF < 40–45% is considered abnormal, but RVEF is not a good index of right ventricular function; it gives only an estimate of the systolic function and is afterload dependent, decreasing when PAP and PVR increase. Accordingly, the decreased RVEF observed in many COPD patients is caused primarily by increased afterload conditions and is not an indicator of “true” right ventricular dysfunction.

MAIN FEATURES OF PULMONARY HYPERTENSION IN CHRONIC RESPIRATORY DISEASE

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The main characteristic of pulmonary hypertension in chronic respiratory disease is probably its mild to moderate degree of hypertension, with resting PAP in a stable state of the disease ranging usually between 20–35 mm Hg. This modest degree of pulmonary hypertension, well recognised in COPD, is very different from left heart disease, congenital heart disease, pulmonary thromboembolic disease, and particularly primary pulmonary hypertension, where PAP is usually > 40–50 mm Hg. Table below compares the pulmonary haemodynamic data of COPD patients with a large series of patients with primary pulmonary hypertension (US National Institutes of Health Registry). It can be seen that pulmonary hypertension is severe in primary pulmonary hypertension (mean (SD) PAP 60 (15) mm Hg) but is rather modest in COPD (PAP 26 (6) mm Hg). A PAP 40 mm Hg is unusual in COPD patients except when they are investigated during an acute exacerbation or when there is an associated cardiopulmonary disease. The consequences of this modest level of pulmonary hypertension include the absence or late occurrence of RHF and the frequent inability of non-invasive methods to achieve a diagnosis of pulmonary hypertension. However, pulmonary hypertension, even if mild at baseline, may worsen during exercise and sleep and during acute exacerbations of the disease.

 

 

Abbreviations

·         COPD: chronic obstructive pulmonary disease

·         FEV₁: forced expiratory volume in one second

·         HPV: hypoxic pulmonary vasoconstriction

·         LTOT: long term oxygen therapy

·         MRI: magnetic resonance imaging

·         PaO₂: arterial oxygen tension

·         PaCO₂: arterial carbon dioxide tension

·         PAP: pulmonary artery pressure

·         PVR: pulmonary vascular resistance

·         RHF: right heart failure

·         RVEF: right ventricular ejection fraction

 

 

THROMBOTIC PULMONARY EMBOLISM

Definitions

Pulmonary embolism (PE) refers to exogenous or endogenous material that travels to the lungs through the pulmonary circulation, causing a potential spectrum of consequences. Thrombus from the deep veins of the lower extremities is by far the most common material to embolize to the lungs; deep venous thrombosis (DVT) and PE must be recognized as parts of the continuum of one disease entity, venous thromboembolism (VTE). Tumor cells, air bubbles , carbon dioxide, intravenous catheters, fat droplets, and talc in intravenous drug abusers are also potential sources of emboli. However, unless otherwise specified, in this chapter, PE refers to thromboemboli arising from the deep leg veins or, less frequently, from the axillarysubclavian system.

The diagnostic approach to suspected acute DVT or PE generally depends on which of the two is the initial cause of symptoms. VTE is usually but not always associated with specific risk factors that help guide prophylaxis and together with compatible symptoms and signs also help the clinician suspect the diagnosis of DVT or PE. Both DVT and PE are frequently unsuspected clinically, thereby resulting in significant diagnostic and therapeutic delays that account for substantial morbidity and mortality. Even though VTE is diagnosed and treated in as many as 260,000 patients in the United States each year, more than half of the cases that actually occur are never diagnosed, and as many as 600,000 cases may therefore occur. Many patients who die of acute PE have coexisting terminal illnesses, but this disease entity appears to be responsible each year in the United States for the deaths of at least 100,000 to 200,000 patients who have an otherwise good prognosis and whose deaths are otherwise preventable. Autopsy studies have repeatedly documented the high frequency with which PE has gone unsuspected and undetected; furthermore, prophylaxis continues to be underused. The incidence of VTE is especially high in hospitalized patients, whether on a medical service or in the postoperative setting.

Pathobiology

Venous thrombi develop most commonly in the leg veins. One or more components of Virchow’s triad (stasis, hypercoagulability, and intimal injury) are present in the majority of patients. The risk increases with age. Calf vein thrombi often propagate into the proximal veins, including and above the popliteal veins, from which they are more likely to embolize. More than 95% of these emboli arise from the deep veins of the legs. Emboli from axillary-subclavian vein thromboses often develop in patients with central vein catheters, particularly those with malignant neoplasms, but may also result from effort-induced upper extremity thrombosis (Paget von Schroetter syndrome).

In acute PE, minute ventilation acutely increases with resulting tachypnea, and hypoxemia develops in most patients. The obstruction of blood flow creates alveolar dead space with regions of high ventilationperfusion ratios as well as shunting due to perfusion of atelectatic areas. This imbalance appears to be the principal explanation for hypoxemia in acute PE.

When emboli obstruct a substantial portion of the pulmonary arterial bed, profound hemodynamic alterations occur. The impact of the embolic event depends on the extent of reduction of the cross-sectional area of the pulmonary vasculature as well as on the presence or absence of underlying cardiopulmonary disease. Hypoxemia stimulates an increase in sympathetic tone, with resulting systemic vasoconstriction, increased venous return, and increase in stroke volume. With more massive emboli, the increase in pulmonary vascular resistance impedes right ventricular outflow and reduces left ventricular preload. In the absence of underlying cardiopulmonary disease, occlusion of 25 to 30% of the vascular bed by emboli is associated with a significant increase in pulmonary artery pressure. With increasing vascular obstruction, hypoxemia worsens, stimulating vasoconstriction and a further increase in pulmonary artery pressure. More than 50% obstruction of the pulmonary arterial bed is usually present before there is substantial elevation of the mean pulmonary artery pressure. When the extent of obstruction of the pulmonary circulation approaches 75%, the right ventricle must generate a systolic pressure in excess of 50 mm Hg to preserve pulmonary perfusion. A normal right ventricle is rarely able to achieve this pressure acutely and thus may fail. Patients with underlying cardiopulmonary disease often experience a more substantial deterioration in cardiac output than do normal individuals in the setting of massive embolism. Although supportive measures may sustain a patient with massive PE, any additional increment in embolic burden may be fatal.

The pathologic findings of PE vary according to the age and extent of the emboli. In general, both lungs are involved, and the lower lobes are involved more often than the upper lobes. An embolus generally has blunt, nontapering ends and may be folded over on itself. When unfolded, emboli often appear as casts of the originating venous segment and may have imprints of venous valve cusps. In cases of massive embolism with rapid deterioration and death, the autopsy may reveal large emboli obstructing the right ventricular outflow tract, the main pulmonary artery, or the pulmonary artery bifurcation. Smaller, more peripheral emboli of various ages and in various stages of organization usually indicate emboli predating the terminal event. Pulmonary infarction is characterized histologically by intra-alveolar hemorrhage and necrosis of alveolar walls and is usually evident in peripheral lung supplied by smaller vessels. Because of the dual pulmonary circulation arising from the pulmonary and bronchial arteries, infarction is not present in most cases.

Clinical Manifestations

The history and physical examination are notoriously insensitive and nonspecific for both DVT and PE. Patients with lower extremity venous thrombosis often do not exhibit erythema, warmth, pain, swelling, or tenderness. When these signs are present, they are nonspecific but still may merit further evaluation. Homans’ sign (pain with dorsiflexion of the foot) may be present in the setting of DVT, but this finding is neither sufficiently sensitive nor specific enough to be relied on. The most common symptom of acute PE is dyspnea (Table 1), which is often sudden in onset. Pleuritic chest pain and hemoptysis occur more commonly with pulmonary infarction. Palpitations, cough, anxiety, and lightheadedness may all be associated with acute PE but may also result from a number of other entities, thereby contributing to difficulty in making the diagnosis. Syncope or sudden death may occur with massive PE. PE should be considered whenever unexplained symptoms including dyspnea, syncope, hypotension, and hypoxemia are present. Tachypnea and tachycardia are the most common signs of PE but are also nonspecific. Other physical findings may include fever, wheezing, crackles, pleural rub, loud pulmonic component of the second heart sound, right-sided third or fourth heart sound, and right ventricular lift. Both the cardiac and pulmonary physical examinations are nonspecific in patients with PE. Findings such as dyspnea, cough, tachypnea, crackles, and hypoxemia in patients with concomitant cardiopulmonary disease (such as heart failure, pneumonia, or chronic obstructive pulmonary disease) may be caused by the underlying disease or by superimposed acute PE. Symptoms and signs consistent with PE should be particularly heeded in the setting of significant risk factors for VTE, such as concomitant malignant disease, immobility, and the postoperative state.

TABLE 1   —  SYMPTOMS AND SIGNS IN PATIENTS WITH ACUTE PULMONARY EMBOLISM WITHOUT PREEXISTING CARDIAC OR PULMONARY DISEASE

Modified from Stein PD, Terrin ML, Hales CA, et al: Clinical, laboratory, roentgenographic and electrocardiographic findings in patients with acute pulmonary embolism and no pre-existing cardiac or pulmonary disease. Chest 1991;100:598–603.

*

Whereas these symptoms and signs have been documented in the setting of acute pulmonary embolism, their presence does not necessarily imply that the symptom is due to acute pulmonary embolism. Dyspnea and chest pain, for example, may be due to underlying pneumonia, which places the patient at risk for acute pulmonary embolism.

 

 

Diagnosis

The differential diagnosis of acute PE (Table 2) depends on the clinical presentation and concomitant disease. When patients present with dyspnea or chest pain, the differential diagnosis may include pneumonia, a flare of asthma or chronic obstructive lung disease, anxiety with hyperventilation, pneumothorax , heart failure, angina or myocardial infarction, musculoskeletal pain, pericarditis, pleuritis from infection or connective tissue disease, herpes zoster, rib fracture, intrathoracic cancer, and, occasionally, intra-abdominal processes such as acute cholecystitis. Acute PE can be superimposed on another underlying cardiopulmonary disease, on which new or worsening symptoms are sometimes blamed.

TABLE 2   —  DIFFERENTIAL DIAGNOSIS OF ACUTE PULMONARY EMBOLISM^[*]

 

*	Diagnoses that commonly present with chest pain or dyspnea and, in a few cases, hemoptysis and that might be considered along with acute pulmonary embolism, depending on the clinical setting.

 

Blood Tests

Hypoxemia on respiration of ambient air is common in acute PE. Some individuals, particularly young patients without underlying lung disease, may have a normal arterial oxygen tension (Pao₂) and, rarely, a normal alveolar-arterial difference. A sudden decrease in the Pao₂ or in the oxygen saturation in a patient unable to communicate an accurate history (e.g., a mechanically ventilated patient) may be evidence of acute PE.

A circulating D-dimer (a specific derivative of cross-linked fibrin) positive test result (i.e., above a designated threshold value) by enzyme-linked immunosorbent assay (ELISA) is 96 to 98% sensitive for acute PE, but its positive predictive value is much lower. In one prospective study, for example, only 1 of 437 patients presenting to the emergency department with suspected PE and with a negative result of the D-dimer test (SimpliRED assay, a non-ELISA, qualitative test) and low clinical probability (score < 2) by the Wells clinical decision rule (Table 3) developed PE during follow-up; thus, the negative predictive value for this strategy was 99.5%. A number of D-dimer assays are available, and the sensitivity and specificity of these assays vary. A positive D-dimer test result means that DVT or PE is possible, but it is by no means proof of VTE. Similarly, although a negative D-dimer test result may strongly suggest that VTE is absent, D-dimer testing should not be ordered in the setting of a high clinical suspicion for acute VTE; one should instead proceed straight to imaging. Troponin levels may be elevated in acute PE, especially in more massive embolism, when myocyte injury due to right ventricular strain might be expected. Troponin levels cannot, however, be used like D-dimer testing; that is, they are not sensitive enough to exclude PE, even when the clinical suspicion is relatively low, without additional diagnostic testing.

TABLE 3   —  DICHOTOMIZED CLINICAL DECISION RULE FOR SUSPECTED ACUTE PULMONARY EMBOLISM^[*]

From van Belle A, Buller HR, Huisman MV, et al: Christopher Study Investigators: Effectiveness of managing suspected pulmonary embolism using an algorithm combining clinical probability, D-dimer testing, and computed tomography. JAMA 2006;295:172–179.

 

†	Minimum of leg swelling and pain with palpation of the deep veins.

 

‡	Pulmonary embolism as likely as or more likely than an alternative diagnosis. Physicians were told to use clinical information along with chest radiography, electrocardiography, and laboratory tests.

 

 

Imaging

Electrocardiography

Electrocardiographic findings, which are present in the majority of patients with acute PE, include ST segment abnormalities, T wave changes, and left or right axis deviation. Only one third of patients with massive or submassive emboli have manifestations of acute cor pulmonale, such as an S₁-Q₃-T₃ pattern, right bundle branch block, P wave pulmonale, or right axis deviation. All of these findings are also nonspecific. Thus, the utility of electrocardiography in suspected acute PE arises more from its ability to establish or to exclude alternative diagnoses, such as acute myocardial infarction (Chapter 72) or pericarditis (Chapter 77), rather than from diagnosis or exclusion of PE.

Chest Radiography

The chest radiograph is often abnormal in patients with acute PE, but it is nearly always nonspecific. Common findings include pleural effusion, atelectasis, pulmonary infiltrates, and mild elevation of a hemidiaphragm. Classic findings of pulmonary infarction, such as Hampton‘s hump and decreased vascularity (Westermark’s sign), are suggestive of the diagnosis but are infrequent. PE should be considered in patients who have dyspnea and hypoxemia with a normal chest radiograph in the absence of bronchospasm or anatomic cardiac shunt. Under most circumstances, however, the chest radiograph cannot be used for conclusive diagnosis or exclusion. Although the radiograph may exclude other processes, such as pneumonia, pneumothorax, or rib fracture, which may cause similar symptoms, acute PE may frequently coexist with other underlying heart or lung diseases.

Spiral Computed Tomography

Spiral (helical) computed tomography (CT) can be used for diagnosis of both acute and chronic PE and has replaced ventilation-perfusion (VQ) scanning at many centers (Fig. 1). This technique involves continuous movement of the patient through the CT scanner and allows concurrent scanning by a constantly rotating gantry and detector system. Rapid scanning is performed with continuous acquisitions obtained during a single breath. Retrospective reconstructions can be performed. An intravenous injection of contrast material is required for imaging of the pulmonary vasculature.

FIGURE 1  Spiral computed tomographic image of acute pulmonary emboli in both main pulmonary arteries in a postoperative patient with the sudden onset of dyspnea, hypoxemia, and hypotension.

 

Increased experience and advances in multislice scanning provide rapid images with a sensitivity in the 80 to 90% range and specificity to consistently above 90%. By also including images of the legs without additional contrast material, the sensitivity for VTE was increased from about 83% to about 90% in one large study, in which the specificity was 95%. The imperfect results should not be surprising because even the “gold standard” test, pulmonary arteriography, is not perfect for smaller, peripheral emboli. Spiral CT is most sensitive for detecting emboli in the main, lobar, or segmental pulmonary arteries; its specificity for clot in these vessels is also excellent. For subsegmental emboli, spiral CT appears to be less accurate, but the importance of emboli of this size has been questioned. An advantage of spiral CT over VQ scanning and arteriography is the ability of CT to define nonvascular conditions such as lymphadenopathy, lung tumors, emphysema, and other parenchymal abnormalities as well as pleural and pericardial disease. A second advantage of spiral CT over other diagnostic methods is the rapidity with which the scan can be performed. Conversely, disadvantages of CT include its poor sensitivity for detecting clots in small vessels, the fact that it is not portable at present, and the fact that patients with significant renal insufficiency cannot be scanned without risk of renal failure.

Stable patients with suspected acute PE, nondiagnostic CT scans, and adequate cardiopulmonary reserve (absence of hypotension or severe hypoxemia) may undergo noninvasive lower extremity testing in an attempt to diagnose DVT. An abnormal compression ultrasound finding (in the absence of prior DVT) presents the opportunity to treat without further testing.

Data suggest that the outcome after a normal spiral CT scan is excellent, with the risk of recurrence (development of acute VTE) being exceedingly low. For example, a strategy using a dichotomized version of the Wells score (see Table 3), D-dimer testing, and CT imaging can reduce the need for expensive testing and provide good outcomes at 3 months (Fig. 2).

FIGURE 2  A CT scan–based algorithm for the diagnostic approach to suspected acute pulmonary embolism. CT = computed tomography; DVT = deep venous thrombosis; PE = pulmonary embolism; VQ = ventilation-perfusion.*The evidence base for the use of this decision rule score with D-dimer testing and CT scanning is derived from a large multicenter clinical trial (Christopher Study; JAMA 2006;295:172-179). In the study, not all patients with inconclusive CT scans underwent further testing or received treatment, but only 20 such patients were studied. Thus, additional testing in these individuals is recommended in the algorithm, pending confirmatory data.†See Table 3.‡Rapid enzyme-linked immunosorbent assays provide excellent sensitivity and are favored.§Contrast-enhanced spiral CT of the chest with timed contrast including leg imaging could be considered, but more limited data are available. A VQ scan-based algorithm could be considered instead of CT, but the VQ scan is much more frequently nondiagnostic. The VQ scan may be particularly useful when the chest radiograph is clear and wheo underlying cardiopulmonary disease is present. When PE is deemed clinically likely but findings on CT are normal, compression ultrasonography could also be considered.¶Pulmonary arteriography could be considered instead. Although it is invasive, arteriography remains the gold standard test for suspected acute PE. Because CT offers the advantage of potentially identifying alternative disease processes, it should be performed before arteriography is considered.

Ventilation-Perfusion Scanning

A normal perfusion scan (Fig. 3) excludes PE with a high enough degree of certainty that further diagnostic evaluation is almost never necessary. Although large, central, nonocclusive emboli might transiently permit tracer to perfuse the lungs normally, this phenomenon is exceedingly unusual, and PE should be pursued only when the clinical suspicion is exceptionally high. Matching areas of decreased ventilation and perfusion in the presence of a normal chest radiograph generally represent a process other than PE. However, low- or intermediate-probability (nondiagnostic) VQ scans are commonly found with PE, and further evaluation with pulmonary arteriography or leg studies is often appropriate in such situations.

FIGURE 3  High-probability ventilation-perfusion scan.

The specificity of high-probability scans is 97%, but the sensitivity is only 41%. When the clinical suspicion of PE is considered very high, PE is present in 96% of patients with high-probability VQ scans, 66% of patients with intermediate scans, and 40% of patients with lowprobability scans. Thus, the diagnosis of PE should be rigorously pursued even when the lung scan is of low or intermediate probability if the clinical setting strongly suggests the diagnosis. Although the VQ scan either may be diagnostic of PE in higher risk patients or may exclude the possibility with sufficient certainty in low-risk patients, it is ofteondiagnostic. Even in the latter circumstance, however, it may serve as a guide for the interventional radiologist by directing selective dye injection to minimize the contrast load and to limit the duration of pulmonary arteriography.

Pulmonary Arteriography

Pulmonary arteriography, which remains the gold standard for the diagnosis of acute PE, is an extremely sensitive and specific test. Major nonfatal complications occur with 1% of angiograms, and death occurs in 0.5%. Its clinical role has been for patients in whom PE must be diagnosed or excluded, but preliminary testing has beeondiagnostic. However, with the advent of CT, pulmonary angiography is now used infrequently.

Magnetic Resonance Imaging

Magnetic resonance imaging can be used in suspected PE, but the main advantage of magnetic resonance imaging at present is its excellent sensitivity and specificity for the diagnosis of DVT (Chapter 81). Disadvantages include the potential difficulty in transporting and studying more critically ill patients.

Echocardiography

Echocardiography, which can often be obtained more rapidly than either lung scanning or pulmonary arteriography, may reveal abnormalities of right ventricular size or function that strongly support the diagnosis of hemodynamically significant PE. However, because these patients often have underlying cardiopulmonary disease such as chronic obstructive lung disease, neither right ventricular dilatioor hypokinesis can be reliably used even as indirect evidence of PE. In the setting of documented PE, echocardiographic evidence of right ventricular dysfunction can identify patients who may benefit from thrombolytic therapy (see Treatment).

Treatment

Therapy for acute PE overlaps substantially with treatment of DVT (Chapter 81). Parenteral anticoagulation with low-molecular-weight heparin (LMWH) or with standard, unfractionated heparin is initiated unless it is contraindicated. Depending on the clinical setting, thrombolytic therapy, inferior vena cava filter placement, or surgical embolectomy may be considered. Each approach has specific indications as well as advantages and disadvantages. The unstable patient requires a rapid evaluation and integration of data to optimize therapeutic decisions and outcome. Bedrest is not generally helpful, except when substantial pain and swelling are present. Otherwise, outpatient therapy is often appropriate. Heparin, Low-Molecular-Weight Heparin, and Warfarin Recommendations for treatment of acute PE with LMWH, unfractionated heparin, and warfarin are based largely on clinical trials in patients presenting with acute DVT (Chapter 81) because DVT and PE are manifestations of a single clinical entity, and a significant minority of patients presenting with proximal DVT also have symptomatic or asymptomatic PE. However, therapy may differ in certain specific settings, including massive PE, in which thrombolytic therapy may be considered. Although heparins do not directly dissolve thrombus or emboli, they allow the fibrinolytic system to proceed unopposed and more readily reduce the size of the thromboembolic burden. Nevertheless, early recurrence can sometimes develop, even in the setting of therapeutic anticoagulation. When DVT or PE is diagnosed, anticoagulation should be instituted immediately unless contraindications are present.[1] It is also appropriate to initiate therapy in patients in whom there is a high index of suspicion for acute PE even while diagnostic testing is under way, as long as the risk of anticoagulation is not excessive. If possible, warfarin therapy should be initiated within the first 24 hours, but premature initiation of warfarin without LMWH or heparin may intensify hypercoagulability and increase the clot burden because of the short half-life of anticoagulation factors that are inhibited by warfarin. At least 5 days of subcutaneous LMWH or intravenous unfractionated heparin is generally recommended because definitive anticoagulation requires the depletion of factor II (thrombin), a process that takes approximately 5 days. Ideally, the parenteral anticoagulant should be maintained until the international normalized ratio (INR) is stable at 2.0 to 3.0. LMWH preparations have greater bioavailability, more predictable dosing, fewer side effects, and the advantage of being administered subcutaneously once or twice per day; they do not require monitoring of the activated partial thromboplastin time (aPTT) and are less likely to cause heparin-induced thrombocytopenia (Chapters 35 and 179). As a result, they are preferred to unfractionated heparin (Tables 4 and 5). Anti–factor Xa levels performed approximately 4 hours after the subcutaneous administration of a weight-adjusted dose of LMWH may be used to monitor LMWH in certain settings, such as in morbidly obese patients, very small patients (<40 kg), pregnant patients, and patients with renal insufficiency. For twice-daily administration, a conservative therapeutic range for the assay is 0.6 to 1.0 IU/mL. The target range is less clear in patients treated with LMWH once daily, but a level between 1.0 and 2.0 IU/mL appears reasonable. Because LMWHs are renally metabolized, they should be used with caution when the creatinine clearance is significantly reduced; enoxaparin can be administered at a lower therapeutic dose (1 mg/kg once daily, instead of the usual 1 mg/kg every 12 hours) when the creatinine clearance is less than 30 mL/min. Although outpatient therapy for acute DVT  is proved to be safe, outpatient therapy for acute, symptomatic PE is not routinely recommended. However, patients with mild PE who are minimally symptomatic can be treated successfully in the outpatient setting or after a brief hospitalization. No data strongly support a search for asymptomatic PE in patients who present with acute symptomatic DVT. In the United States, three LMWH preparations are currently approved by the Food and Drug Administration (FDA) for treatment of patients with proven DVT with or without acute PE. Enoxaparin is approved for both inpatients and outpatients at a dose of 1 mg/kg subcutaneously every 12 hours or as a once-daily dose of 1.5 mg/kg for inpatient use (see Table 3). Both doses have proved as effective and safe as unfractionated heparin. The second preparation, tinzaparin, is administered as 175 units once daily, with the FDA approval being based on therapy for inpatients with DVT. The third drug, a pentasaccharide or “ultra-LMWH” called fondaparinux, is approved for treatment of DVT and PE. The only advantage of standard heparin over LMWH is when the short half-life of intravenous unfractionated heparin is beneficial and when its complete reversibility with protamine is potentially advantageous. When continuous intravenous unfractionated heparin is initiated, the aPTT should be observed at 6-hour intervals until it is consistently in the therapeutic range of 1.5 to 2.5 times control values. This range corresponds to a heparin level of 0.2 to 0.4 U/mL as measured by protamine sulfate titration. Achieving a therapeutic aPTT within 24 hours after PE has been documented to reduce recurrences. Heparin dosing should be weight based; one approach is an intravenous bolus of 80 IU/kg followed by a maintenance dose of 18 IU/kg/hr by continuous infusion (see Table 4). Further adjustment of the heparin dose should also be based on weight. Patients with acute PE require long-term anticoagulant treatment to prevent a high frequency (as high as 50%) of symptomatic extension of thrombosis or recurrent VTE. The recommendations about long-term anticoagulation for PE are the same as for DVT; documented PE in the setting of transient risk factors should be treated for 3 to 6 months, but more extended treatment is appropriate when significant risk factors persist, when thromboembolism is idiopathic, or when previous episodes of VTE have been documented. For idiopathic VTE, standard-dose warfarin (INR goal of 2.0–3.0) is recommended. Bleeding related to warfarin increases with the intensity and duration of therapy. Warfarin-induced skiecrosis is a rare but serious complication mandating immediate cessation of the drug. Warfarin crosses the placenta and may cause fetal malformations if it is used during pregnancy. Unlike heparin and LMWH, which work indirectly and require antithrombin III as a cofactor, newer antithrombotic agents are effective against clot-bound thrombin. Like heparin, these direct thrombin inhibitors have narrow therapeutic indices. Ximelagatran, an oral direct thrombin inhibitor, is efficacious for the treatment of acute VTE; however, because of potential hepatic toxicity and rebound thrombosis, it was not approved by the FDA. Bleeding is the major complication of anticoagulation. Heparin-induced thrombocytopenia typically develops 5 days or more after the initiation of heparin therapy. The primary problem is not bleeding but rather venous or arterial thrombosis as a result of platelet and thrombin activation by heparin-dependent immunoglobulin G antibodies that activate the platelets through their Fc receptors. If a patient is prescribed heparin for acute PE and the platelet count progressively decreases to 100,000/mm3 or less, or to 50% of the initial value, all heparin therapy (including LMWH) should be discontinued, and heparin-induced thrombocytopenia should be considered. Both argatroban and lepirudin have been FDA approved for use in the setting of VTE with heparin-induced thrombocytopenia. These drugs are not reversible but have relatively short half-lives. Warfarin should not be initiated until the heparin-induced thrombocytopenia is clearly controlled because of the potential for further thrombotic complications, including venous limb gangrene and warfarin-induced skiecrosis. Argatroban should be initiated at a dose of 2 μg/kg/min. The aPTT should be rechecked 2 hours after initiation and adjusted until a target aPTT value of 1.5 to 3.0 times baseline is attained (not to exceed 100 seconds). Doses above 10 μg/kg/min should not be administered. No adjustment is necessary in renal failure. Lepirudin is administered as an intravenous bolus of 0.4 mg/kg up to a maximum of 44 mg during 15 to 20 seconds; no bolus is necessary if the aPTT is 1.5 to 2 times baseline. A continuous intravenous infusion at 0.15 mg/kg/hr up to a maximum of 16.5 mg for 2 to 10 days is used with an aPTT goal of 1.5 to 2.5 above baseline. Lepirudin is excreted by the kidneys, so the dose must be reduced in renal insufficiency (creatinine clearance of less than 60 mL/min or a serum creatinine concentration above 1.5 mg/dL). The circulating half-life is only 1.3 hours in patients with normal renal function but may be as long as 2 days in patients with advanced renal failure, so patients on dialysis should receive lepirudin with caution and at a reduced dose. Vena Cava Interruption When a patient cannot be anticoagulated in the setting of proven DVT or PE, inferior vena cava filter placement is indicated to prevent lower extremity thrombi from embolizing. The primary indications for filter placement include contraindications to anticoagulation, significant bleeding complications during anticoagulation, and recurrent embolism with adequate therapy. Inferior vena cava filters are sometimes placed in the setting of massive PE when it is believed that any further emboli might be lethal, particularly if thrombolytic therapy is contraindicated; however, this indication is not based on firm clinical trial data. Although filters are effective in reducing PE, they increase DVT and have not been shown to increase overall survival.[3] Filters inserted through the jugular or femoral vein are effective, and complications including insertion-related problems and migration of the filter are unusual. Retrievable filters can be used when the risk of bleeding appears to be short term; such devices can be removed up to 2 weeks later, and some can be removed as late as 90 days after placement. Thrombolytic Therapy Because anticoagulants do not actively lyse emboli, thrombolytic therapy is indicated when PE causes hemodynamic instability with hypotension. Other settings in which thrombolytic therapy might be considered include echocardiographic right ventricular dysfunction without hypotension, severely compromised oxygenation, massive radiographic embolic burden even without clear hemodynamic instability, and extensive DVT accompanying nonmassive embolism. In the United States, currently approved drugs for thrombolysis in acute PE include streptokinase (administered as a 250,000-unit bolus during 30 minutes followed by 100,000 units per hour for 12 to 24 hours) and recombinant tissue-type plasminogen activator (100 mg administered intravenously during a 2-hour period) (Table 6). When thrombolytics appear reasonable but are contraindicated (Table 7), low-dose direct intraembolic infusion of tissue-type plasminogen activator or mechanical fragmentation appears reasonable. Heparin is generally withheld until the thrombolytic infusion is completed, but several large clinical trials have continued heparin during the thrombolytic infusion without adverse consequences. The most devastating complication associated with thrombolytics is intracranial hemorrhage, which occurs in approximately 1 to 3% of patients. In the setting of imminent death due to massive PE, a clinician may elect to use thrombolytic therapy even in the setting of a relative contraindication such as recent surgery or bleeding. Pulmonary embolectomy is appropriate in patients who have massive embolism with hypotension and cannot receive thrombolytic therapy. Hemodynamic Management of Massive Pulmonary Embolism Massive PE should always be considered in the setting of the sudden onset of hypotension, extreme hypoxemia, electromechanical dissociation, or cardiac arrest. Once massive PE associated with hypotension or severe hypoxemia is suspected, supportive treatment is immediately initiated (Fig. 4). Intravenous saline should be infused rapidly but cautiously because right ventricular function is often markedly compromised. Dopamine (initial dose of 1 μg/kg/min, titrated to 10 to 20 μg/kg/min) or norepinephrine (initial dose of 0.05 μg/kg/min and increased as tolerated) appears appropriate in massive PE and should be administered if the blood pressure is not rapidly restored. In general, upper dose limits for these pressor agents are not set in the presence of severe hypotension due to acute PE, but cautious monitoring is required. Because death due to PE results from right ventricular failure, dobutamine (5 to 20 μg/kg/min) can be considered to augment right ventricular output; however, this drug may also worsen hypotension. Oxygen therapy is administered, and thrombolytic therapy is considered as described before. Intubation and mechanical ventilation are instituted wheecessary to support respiratory failure.

TABLE 4   —  A COMPARISON OF LOW-MOLECULAR-WEIGHT HEPARIN WITH UNFRACTIONATED HEPARIN

 

 

 

TABLE 5   —  POTENTIAL ADVANTAGES OF LOW-MOLECULAR-WEIGHT HEPARIN OVER UNFRACTIONATED HEPARIN

 

*

No monitoring needed for either prophylaxis or treatment. With body weight below 40 kg or above 150 kg or with unstable renal insufficiency, anti–factor Xa levels can be measured to aid in dosing. With stable, abnormal renal function (creatinine clearance of less than 30 mL/min), a lower dose of enoxaparin (1 mg/kg once daily for treatment, or 30 mg subcutaneously once daily) can be used. In the therapeutic setting, when the creatinine is changing signifi-cantly over time, unfractionated heparin should be considered.

 

†	For both prophylaxis and treatment.

 

TABLE 6   —  THROMBOLYTIC THERAPY FOR ACUTE PULMONARY EMBOLISM: REGIMENS APPROVED FOR USE IN THE UNITED STATES

 

*	Streptokinase administered during 24 to 72 hours (at this loading dose and rate) has also been approved for use in patients with extensive deep venous thrombosis.

 

†	The American College of Chest Physicians has recommended that agents with shorter infusion times (i.e., tissue-type plasminogen activator) be used. This is not, however, based on conclusive evidence (see Buller HR, Agnelli G, Hull RD , et al: Chest 2004;126;401S–428S).

 

TABLE 7   —  CONTRAINDICATIONS TO THROMBOLYTIC THERAPY IN PULMONARY EMBOLISM^[*]

 

*

The use of thrombolytic therapy depends on the severity of pulmonary embolism; resultant hypotension is the clearest indication. There should be a lower threshold to administer thrombolytic therapy in the setting of a contraindication when a patient is extremely unstable from life-threatening pulmonary embolism.

 

†	The waiting time after surgery needed to permit safe administration of thrombolytic therapy depends on the type of surgery performed and its associated bleeding risk.

 

 

FIGURE 4  An algorithm for the approach to the patient with massive acute pulmonary embolism. Contraindications to thrombolytic therapy include intracranial abnormality, gastrointestinal or other bleeding, bleeding diathesis, surgery within the previous 10 days, and pregnancy (see text). ICU = intensive care unit; IV = intravenous; IVC = inferior vena cava; PTT = partial thromboplastin time; SK = streptokinase; tPA = tissue-type plasminogen activator; UK = urokinase.

Prognosis

Most patients with PE who receive adequate anticoagulation survive. However, patients who are treated for PE are almost four times more likely (1.5% vs. 0.4%) to die of recurrent VTE in the next year than are those treated only for DVT. The 3-month mortality rate is about 15 to 18%. In some series, PE itself has been the principal cause of death, whereas other series report that only 10% of deaths during the first year are attributable to PE. The presence of shock defines a three-fold to seven-fold increase in mortality; a majority of deaths appear to occur within the first hour of presentation. A potential long-term sequela from acute DVT is chronic leg pain and swelling (postphlebitic syndrome), which may result in significant morbidity.

Chronic Thromboembolic Pulmonary Hypertension

Although most cases of acute PE resolve with therapy, a substantial residual thromboembolic burden occasionally persists or develops over time. The risk of pulmonary hypertension from chronic PE may be as high as 3 to 4% during 2 to 3 years after an acute PE. However, at least 50% of patients who develop chronic thromboembolic pulmonary hypertension have no documented history of previous thromboembolic disease.

Clinical Manifestations and Diagnosis

If the obstruction becomes extensive, pulmonary hypertension develops. Fatigue and dyspnea with exertion are the most common complaints. The nonspecific nature of these findings may substantially delay the correct diagnosis. The physical examination generally reveals a right ventricular heave, a loud P₂, and tricuspid regurgitation consistent with pulmonary hypertension. In 20% of patients, murmurs due to partially occluded and remodeled vessels may be auscultated over the lung fields. The chest radiograph usually shows right ventricular enlargement and enlarged main pulmonary arteries. The electrocardiogram often reveals changes consistent with pulmonary hypertension. Arterial blood gas analysis generally reveals hypoxemia with a widened alveolar-arterial difference, although some patients may demonstrate hypoxemia only with exercise. Echocardiography documents pulmonary hypertension and enlargement of the right ventricle. Spiral CT scanning may reveal evidence of chronic thromboembolism but occasionally may be normal. At present, it is not believed that chronic thromboembolic pulmonary hypertension can be definitively excluded by CT; a VQ scan should always be considered. The VQ scan is usually high probability for PE but occasionally is less impressive. Pulmonary arteriography should be performed to establish the diagnosis with certainty, to aid in characterizing severity, and to determine operability. Pulmonary angioscopy frequently has proved complementary to arteriography in assessing these patients.

Treatment

When chronic thromboembolic pulmonary hypertension is diagnosed, anticoagulation should be instituted and an inferior vena cava filter placed. Pulmonary thromboendarterectomy through median sternotomy on cardiopulmonary bypass should be considered in selected cases; the overall mortality rate is less than 5% at centers with considerable experience. Treatment of nonoperable chronic thromboembolic pulmonary hypertension with medications such as the oral endothelin antagonist bosentan (initial dose of 62.5 mg twice daily, increased to 125 mg twice daily after 1 month) may effectively address small vessel vasculopathy associated with this disease. In more severely ill patients, epoprostenol (initial dose inglkglmin increasing to 30–40 ng/kg/min by continuous intravenous) infusion should be considered. Lung transplantation can be considered in selected patients with severe pulmonary hypertension in whom thrombi are too distal to be extracted, if appropriate criteria are met (Chapter 67).

Prevention

The risk of DVT and subsequent PE is substantial in hospitalized patients, but the risk can be reduced significantly when patients receive appropriate prophylaxis. Such preventive measures appear to be grossly underused. Anticoagulant prophylaxis appears more effective than mechanical prophylaxis, but the risk of both thrombosis and bleeding must be considered.

After total hip or knee replacement, the risk of DVT is 50% or greater without prophylaxis. The superiority of LMWH over standard, unfractionated heparin has been clearly demonstrated in these settings as well as in trauma (Chapter 113) and spinal cord injury (Chapter 422). In other settings, low-dose standard heparin appears adequate. In general medical patients, the risk of DVT without prophylaxis may be as high as 15%, and LMWH (enoxaparin, at 40 mg subcutaneously once daily, or dalteparin or fondaparinux) is superior to placebo in preventing acute DVT. These drugs appear to be at least as effective and as safe as standard heparin prophylaxis with 5000 units every 8 hours in the general medical patient.^[5]

Three LMWH preparations (enoxaparin, dalteparin, and fondaparinux) are available for specific prophylactic indications. At present, enoxaparin has the most FDA-approved prophylactic indications, including patients undergoing total hip replacement, total knee replacement, and general abdominal surgery as well as general medical patients. Fondaparinux, a pentasaccharide (an ultra-LMWH), is approved for abdominal surgery and several orthopedic prophylactic settings, including total hip and knee replacement and hip fracture surgery. It is a pure anti–factor Xa inhibitor with a longer half-life than that of other larger LMWH preparations, but at present, there is not a way to reverse this drug. Other LMWHs, although not as easily reversed as standard heparin, are approximately 70% reversible with protamine sulfate. The appropriate dosage for all surgical and medical prophylactic indications for enoxaparin is 40 mg subcutaneously once daily except in the setting of total knee replacement (30 mg every 12 hours). When the creatinine clearance is less than 30 mL/min, the dose is reduced to 30 mg once daily. In the setting of surgical prophylaxis, the drug is initiated 12 to 24 hours after surgery. The prophylactic dose of dalteparin is 2500 units once daily for moderate-risk surgical patients and medical patients. For high-risk patients (e.g., orthopedic surgery or patients with a malignant neoplasm undergoing abdominal or gynecologic surgery), 5000 units is recommended. Finally, the recommended dose for prophylaxis with fondaparinux is 2.5 mg once daily, initiated no sooner than 6 hours after surgery.

Intermittent pneumatic compression devices should be used when prophylactic doses of LMWH or heparin are contraindicated. Both methods combined are reasonable in patients deemed at exceptionally high risk, but combination regimens have not been studied in large populations of such individuals.

Every hospitalized patient should be assessed for the need for prophylactic measures. All hospitals should formulate their own written guidelines for each particular clinical setting based on the available medical literature.

 

NONTHROMBOTIC PULMONARY EMBOLISM

Because of venous blood return to the lungs, the pulmonary vascular bed is exposed to a wide variety of potentially obstructing and detrimental substances. These substances, which may be exogenous or endogenous in origin, may result in a number of consequences, including dyspnea, chest pain, hypoxemia, and sometimes death.

   Fat Embolism

Epidemiology

Fat embolism generally occurs in the setting of traumatic fracture of long bones and is usually a more impressive clinical syndrome when larger bones and multiple fractures are involved. However, orthopedic procedures and trauma to other fat-rich tissues such as the liver or subcutaneous tissue can occasionally result in similar consequences.

Pathobiology

The physiologic consequences of fat embolism derive from both the obstruction of multiple vessels by neutral fat particles and the deleterious effects of free fatty acids released from neutral fat by lipases. These free fatty acids appear to cause diffuse vasculitis with capillary leak from cerebral, pulmonary, and other vascular beds.

Clinical Manifestations

After the traumatic event, there is generally a delay of 24 to 48 hours before symptoms develop. As neutral fat enters the vascular system, a characteristic syndrome of dyspnea, petechiae, and mental confusion often develops. It is not clear why the syndrome develops in some patients and not in others, even when the extent of injury is comparable, but it is possible that the presence of a patent foramen ovale could render patients more susceptible to the sequelae.

Diagnosis

The diagnosis is made from the clinical and radiographic findings in the setting of risk factors such as surgery and trauma. Although fat droplets (by oil red O stain) in bronchoalveolar lavage fluid may be suggestive of fat embolism, this finding does not appear to be sensitive or specific. The diagnosis of fat embolism syndrome remains a diagnosis of exclusion and is based on clinical criteria. Whereas clinically apparent fat embolism syndrome is uncommon, it also may be masked by the effects of concomitant injuries in more severely injured patients.

Treatment

Treatment is supportive, including oxygen and mechanical ventilation, and the prognosis is generally good. Corticosteroid therapy remains controversial and is generally not recommended.

   Amniotic Fluid Embolism

Epidemiology and Pathobiology

Amniotic fluid embolism is an uncommon syndrome but still represents one of the leading causes of maternal death in the United States. It occurs during or after delivery when amniotic fluid gains access to uterine venous channels and then to the pulmonary and general circulations. The delivery may be either spontaneous or by cesarean section and usually has been without complication. There are no identifiable risk factors in either the mother or the baby. The primary mechanism of injury appears to involve the thromboplastic activity of amniotic fluid, which leads to extensive fibrin deposition in the pulmonary vasculature and sometimes in other organs.

Clinical Manifestations

The syndrome is heralded by the sudden onset of severe respiratory distress; hypotension and death frequently result. A severe consumptive coagulopathy develops, with marked hypofibrinogenemia. After the acute event, an enhanced fibrinolytic state often is present. Left ventricular dysfunction may occur, possibly due to the myocardial depressant effect of amniotic fluid. The resulting pulmonary edema may be both hydrostatic and noncardiogenic.

Diagnosis

The diagnosis may be suspected on the basis of the clinical picture. The differential diagnosis includes PE, septic and hemorrhagic shock, venous air embolism, aspiration pneumonia, heart failure (from acute myocardial infarction or other causes), abruptio placentae, and ruptured uterus. Examination of the pulmonary arterial blood may or may not reveal the amorphous fragments of vernix caseosa, squamous cells, or mucin. Although administration of heparin, antifibrinolytic agents such as &epsiv;-aminocaproic acid, and cryoprecipitate has been suggested, the primary treatment is supportive, with oxygen, mechanical ventilation, and any necessary hemodynamic support.

   Air Embolism

Epidemiology and Pathobiology

The incidence of this entity reflects the variety of invasive surgical and medical procedures now available, the frequent use of indwelling venous and arterial catheters, and the frequency of thoracic and other forms of trauma. With venous embolism in the setting of a patent foramen ovale, embolization to the coronary or cerebral circulation is of most concern. In the absence of a patent foramen ovale, the lungs can filter modest amounts of air, but large single or continuous episodes of air embolism can still gain access to the systemic arterial circulation.

Clinical Manifestations and Diagnosis

Symptoms and signs are dependent on the severity of the episode, and the consequences of venous air embolism range from none to death. Air in the systemic circulation may be difficult to recognize because only small quantities may cause significant symptoms, yet intravascular air clears quickly. Dyspnea, wheezing, chest pain, cough, agitation, confusion, tachycardia, and hypotension may be evident. A “mill wheel murmur” from air in the right ventricle may sometimes be auscultated. Hypoxemia and hypercapnia are present in severe cases, and the chest radiograph may reveal pulmonary edema or air-fluid levels.

Treatment

The treatment of venous air embolism includes immediate placement of the patient in the Trendelenburg–left lateral decubitus position and administration of 100% oxygen. If a central venous catheter is in place near the right atrium, air aspiration should be attempted. Hyperbaric oxygen should be considered. Anticonvulsants are administered in the presence of seizures.

  

 Schistosomiasis

Schistosomiasis causes severe pulmonary vascular obstruction and pulmonary hypertension from both anatomic obstruction by the organism itself and an inflammatory vasculitic response. In endemic areas such as Egypt, schistosomal disease is a common cause of cor pulmonale. The liver is always involved, usually extensively, before pulmonary involvement occurs. The disease is refractory to treatment unless it is detected before extensive hepatic and pulmonary inflammation occurs.

   Septic Embolism

Septic embolism was first noted as a complication of septic pelvic thrombophlebitis due to septic abortion or postpartum uterine infection. In recent years, however, intravenous drug abuse, infections caused by indwelling intravenous catheters, and right-sided infective endocarditis are the most common causes.

   Other Emboli

A variety of other substances can also embolize to the lungs. Cancer cells may enter and adhere to pulmonary vessels, occasionally mimicking PE. Brain tissue has been discovered in the lungs after head trauma, and liver cells have been found after abdominal trauma. Bone marrow has been reported in lung tissue after cardiopulmonary resuscitation.

Noninfectious vasculitic-thrombotic complications also occur in intravenous drug users. Materials such as talc, used to “cut” heroin or cocaine, and occasionally the drugs themselves may provoke vascular inflammation and secondary thrombosis. Perfusion scans occasionally demonstrate segmental or smaller defects. Distinguishing these from VTE can be difficult.

Overview of keypoints

 

COR PULMONALE

 

 

Definition

 

Cor pulmonale is a right-sided heart failure caused by arterial pulmonary hypertension.  Pulmonary hypertension is defined as an elevated mean pulmonary artery pressure of  ≥25 mm Hg at rest as assessed by right heart catheterization (Table 1).

 

Classification and terminology

 

Cor pulmonale is classified as acute and chronic. 

 

Acute cor pulmonale is a form of acute right heart failure produced by a sudden increase in resistance to blood flow in the pulmonary circulation: it is observed in pulmonary embolism (PE) and acute respiratory distress syndrome.

 

Chronic cor pulmonale is a right heart failure caused by chronic pulmonary arterial hypertension resulting from chronic lung disease, pulmonary vascular disorders, or neuromuscular and skeletal diseases causes.

 

Right-sided ventricular disease caused by a primary abnormality of the left side of the heart or congenital heart disease is not considered cor pulmonale.

 

Pulmonary embolism and chronic cor pulmonale will be discussed in this chapter.

 

 

 

 

 

 

 

Table 1. Clinical classification of pulmonary hypertension (Dana Point, 2008)

 

1. Pulmonary arterial hypertension (PAH) 1.1. Idiopathic 1.2. Heritable 1.2.1. BMPR2 (bone morphogenic protein receptor, type 2) 1.2.2. ALK1 (activin receptor-like kinase 1 gene), endoglin, with or without hereditary hemorrhagic teleangiectasia) 1.2.3. Unknown 1.3. Drugs and toxins induced 1.4. Associated pulmonary arterial hypertension 1.4.1. Connective tissue diseases 1.4.2. Human immunodeficiency virus (HIV) infection 1.4.3. Portal hypertension 1.4.4. Congenital heart disease 1.4.5. Schistosomiasis 1.4.6. Chronic hemolytic anemia 1.5. Persistent pulmonary hypertension of the newborn

1′. Pulmonary veno-occlusive disease and/or pulmonary hereditary capillary hemangiomas

2. Pulmonary hypertension due to left heart disease 2.1. Systolic dysfunction 2.2. Diastolic dysfunction 2.3. Valvular disease

3. Pulmonary hypertension due to lung diseases and/or hypoxia 3.1. Chronic obstructive pulmonary disease 3.2. Interstitial lung disease 3.3. Other pulmonary diseases with mixed restrictive and obstructive pattern 3.4. Sleep-disordered breathing 3.5. Alveolar hypoventilation disorders 3.6. Chronic exposure to high altitude 3.7. Developmental abnormalities

4. Chronic thromboembolic pulmonary hypertension

5. Pulmonary hypertension with unclear and/or multifactorial mechanisms 5.1. Hematological disorders: myeloproliferative disorders, splenectomy 5.2. Systemic disorders: sarcoidosis, pulmonary Langerhans cell histiocytosis, lymphangioleiomyomatosis, neurofibromatosis, vasculitis 5.3. Metabolic disorders: glycogen storage disease, Gaucher disease, thyroid disorders 5.4. Other: tumoural obstruction, fibrosing mediastinitis, chronic renal failure on dialysis

From Simonneau G. et al. J Am Coll Cardiol 2009;54:S43-S54

 

 

 

 

 

 

 

 

 

PULMONARY EMBOLISM

 

Definition

 

Pulmonary embolism (PE) is a spectrum of consequences resulting from obstruction of the pulmonary artery or of one of its braches by a blood clot or other substances (fat, amniotic fluid, air, tumor cells or a foreign body) travelling to the lungs through the pulmonary circulation.

 

Terminology and classification

 

Deep venous thrombosis (DVT) of extremities and pelvic veins, and the embolic events arising from them (PE, chronic thromboembolic disease, chronic thromboembolic pulmonary hypertension) are recognized as parts of the continuum of one disease entity, venous thromboembolism (VTE).  

 

High-risk PE (previously classified as “massive PE”) is associated with shock and/or hypotension (defined as systolic blood pressure <90 mmHg); the risk of in-hospital death is high (>15%), particularily during the first few hours after admission.

Intermediate-risk PE (previously classified as “submassive PE”) defines patients who appear hemodynamically stable on admission but have evidence of right ventricular (RV) dysfunction and/or myocardial injury. The risk of in-hospital death is 3-15%.

Low-risk PE defines patients with normal hemodynamics and normal RV size and function. The risk of in-hospital death is <1%.

 

 

Epidemiology

The true incidence of  PE is difficult to assess in view of its nonspecific clinical presentation. According to estimates from both Europe and the USA, PE accounts for approximately 100 admissions to hospital per 100,000 population per year. This corresponds to 50 diagnosed cases of PE per year, or 1% of all admissions, in a general hospital serving a population of 200,000.

Etiology and pathogenesis

 

Thrombus from the deep veins of the lower extremities is by far the most common material to embolize to the lungs; in this chapter, unless otherwise specified, PE refers to thromboemboli arising from the deep leg veins or, less frequently, from the axillary-subclavian system. DVT can be found in about 70% of patients with PE. Among patients with DVT, about 50% have an associated, usually clinically asymptomatic PE at lung scan. In around 30% of cases PE occurs in the absence of any predisposing factors (unprovoked or idiopathic PE).

 

A variety of acquired and hereditary disorders have been implicated in the pathogenesis of VTE. Their prothrombotic effect involves one or more of the mechanisms that make up the classic Virchow’s triad: venous stasis, increased blood coagulability, and injury to the vessel wall (Fig. 1).

 

Figure 1. The pathogenesis of venous thromboembolism.

Modified from Konstantinides S. and Kasper W. Pulmonary embolism. In: Crawford M.H., Di Marco J.P., Paulus W.J., eds. Cardiology . 2nd edition. Philadelphia, Elsevier Ltd; 2004: chap. 18, P. 1028.

 

Hereditary thrombophilias caow be identified in 30% of unselected patients who have VTE, and at least in 50% of those with familial thrombosis. Most of them include activated protein C resistance caused by mutation of the factor V gene (factor V Leiden mutation). Prothrombin 20210A mutation, deficiences of anthithrombin, protein C or protein S, hyperhomocystinemia are also associated with a high incidence of thrombosis.

 

Clinical presentation

 

In 90% of cases clinical suspicion of PE is raised by dyspnea (70%), pleuritic or atypical chest pain (65%) and syncope, either singly or in combination. Pleuritic chest pain and hemoptysis (10%) occur more commonly with pulmonary infarction. Palpitations (10%), cough (40%), anxiety, and lightheadedness may all be associated with acute PE but may also result from a number of other entities, thereby contributing to difficulty in making the diagnosis. Despite the limited sensitivity and specificity of individual symptoms and signs, the use of prediction rules permits to assess the clinical probability of PE (Table 2).

 

Table 2. Clinical prediction rules for pulmonary embolism

 

Revised Geneva score1		Wells score2
Variable	Points	Variable	Points
Predisposing factors		Predisposing factors
Age >65 years	+1
Previous DVT or PE	+3	Previous DVT or PE	+1,5
Surgery or fracture within 1 month	+2	Recent surgery or immobilization	+1,5
Active malignancy	+2	Cancer	+1
Symptoms		Symptoms
Unilateral lower limb pain	+3
Haemoptysis	+2	Haemoptysis	+1
Clinical signs		Clinical signs
Heart rate		Heart rate
75-94 beats/min	+3	≥95 beats/min	+1,5
≥95 beats/min	+5
Pain on lower limb deep vein at palpation and unilateral oedema	+4	Clinical signs of DVT	+3
		Clinical judgement
		Alternative diagnosis less likely than PE	+3
Clinical probability	Total	Clinical probability (3 levels)	Total
Low	0-3	Low	0-1
Intermediate	4-10	Intermediate	2-6
High	≥11	High	≥7
		Clinical probability (2 levels)
		PE unlikely	0-4
		PE likely	>4
From 1Le Gal G et al. Ann Intern Med 2006;144:165-171 2Wells PS et al. Thromb Hemost 2000;83:416-420

 

Pulmonary infarction. Pulmonary infarction is characterized by pleuritic chest pain and is occasionally accompanied by hemoptysis. It usually occurs 3 to 7 days after embolism. this syndrome often includes fever, leukocytosis, elevated erythrocyte sedimentation rate, and radiologic evidence of infarction. The embolus usually lodges in the peripheral pulmonary arterial tree, near the pleura.

 

 

Diagnostic tests

 

Laboratory tests

 

D-dimer is a degradation product released into circulation when crosslinked fibrin undergoes endogenous fibrinolysis. It is almost invariably present in PE.

 

– D-dimer levels have a high negative predictive value: a D-dimer concentration of <500 mcg/L assessed by enzyme-linked immunosorbent assay (ELISA) renders PE or DVT very unlikely and permits to exclude PE in patients with “PE unlikely” clinical probability score.

– Normal D-dimer levels do not exclude PE in patients in whom PE is “likely” according to clinical probability score, and necessitate  the use of diagnostic algorithm with imaging studies in these patients. 

– Elevated D-dimer concentration yields no diagnostic information and does not permit to confirm PE (low positive predictive value): increased levels of D-dimer may be also detected in acute myocardial infarction, pneumonia, pregnancy, trauma, cancer, sepsis, as well as in the aged and hospitalized patients.

 

Elevated cardiac troponin and braiatriuretic peptide (BNP or NT-proBNP) concentrations predict in-hospital mortality and, therefore, may be useful for risk stratification of patients with PE.

 

Arterial blood gases are not part of the contemporary diagnostic algorithm for PE. Noninvasive oximetry meters placed on the finger or earlobe are now usually used to determine oxygen saturation.

 

Electrocardiography

Although patients with PE may have normal ECGs, abnormalities are noted in 80% of cases. The most common abnormalities include sinus tachycardia (90%), ST-T abnormalities (65%), incomplete or complete right bundle branch block (12%), right axis deviation (12%), P pulmonale (10%), S_IS_IIS_III pattern,  atrial fibrillation or flutter. The classic pattern of S wave in lead I and Q wave in lead III and T wave inversion in lead III (S₁Q₃T₃ or McGinn-White syndrome) is seen only in 15% of patients. T wave inversion in leads V₁ to V₄ has the greatest accuracy for prediction of severity of RV dysfunction in PE.

 

Chest radiography

The main value of chest radiography is to exclude diagnoses that clinically mimic PE, such as pneumonia, pneumothorax, or rib fracture, although acute PE may frequently coexist with other underlying heart or lung diseases. Chest radiographs are normal in 30% of patients. Chest radiographic abnormalities in PE may be associated, and include:

1) loss of lung volume with elevation of ipsilateral hemidiaphragm (60%);

2) enlarged cardiac shadow (45%);

3) “sausage-like” enlargement of the descending right pulmonary artery (40%): the vessel often tapers rapidly after the enlarged portion;

4) pulmonary infiltrates: solitary or multiple homogeneous consolidations abutting the pleural surface (30%). Peripheral pleural-based wedge-shaped opacity above the diaphragm (Hampton hump) is rare; resolution occurs through a gradual decrease in size (“melting ice cube sign”);

5) oligemia resulting in increased radiolucency of affected lung areas (Westermark sign) indicating massive central embolic occlusion (10-50%);

6) prominent central pulmonary artery or Fleischner sign (20%);

7) pleural effusion (20-50%).

 

Echocardiography

In a patient with hemodynamically significant PE, transthoracic echocardiography (TTE) can reveal pathophysiological responses to increased pulmonary artery pressure:

 1) right heart dilatation (25%);

2) RV free wall hypokinesis with sparing of the apex (McConnell sign): this sign is nonspecific may be mimicked by RV free wall hypo/akinesis due to RV infarction;

3) flattening and paradoxical motion of interventricular septum;

4) tricuspid regurgitation with pressure gradient ≤60 mmHg + acceleration time of RV ejection flow <60 ms (the 60/60 sign);

5) dilated inferior vena cava without inspiratory collapse;

6) direct visualization of thrombus in the right heart and/or pulmonary artery (4%).

 

Negative TTE does not exclude PE. Only patients with significant embolization and >30% lung involvement have evidence of RV dysfunction. However, in suspected high-risk PE presenting with shock and hypotension, the absence of echocardiographic signs of RV overload/dysfunction excludes PE as a cause of hemodynamic compromise.

 

Computed tomographic angiography

 

A pulmonary computed tomography angiogram (CTA) is considered positive for PE when it detects an artery that is completely or partially occluded, has mural defects at vessel wall or central thrombus surrounded by contrast.

 

In chronic thromboembolic pulmonary hypertension, findings on pulmonary angiogram include mosaic perfusion of lung parenchyma, central pulmonary artery enlargement, the presence of collateral vessels arising from systemic pulmonary circulation, eccentric and calcified thrombus, abrupt cutoff of segmental or lobar arteries, and irregularities of PA diameter.

 

When interpreting the results, the type of CT scanner used (single-detector versus multidetector) be considered: while single-detector CT is excellent for the diagnosis of central or lobar PE, multidetector CT scanners can image thrombi in segmental and subsegmental arteries. Therefore, in patients with non-high clinical probability, a negative single-detector CT must be combined with compression ultrasound (CUS) to exclude PE, while multidetector CT may be used alone.

 

Compression venous ultrasonography

 

Compression venous ultrasonography (CUS) has a sensitivity of 90% and a specifity of  95% for proximal DVT. Normally, the vein collapses completely when gentle pressure is applied to the skin overlying it. lack of compressibility is the most characteristic finding of acute DVT. Doppler flow is absent if the vein occlusion is complete. if there is a subtotal occlusion or recanalization of the thrombus, the pulse Doppler would be continuous, but not phasic, with minimal or no response to Valsalva maneuver or distal compression.

 

Recently CT venography has been proposed as a single method to diagnose DVT in patients with suspected PE as it can be combined as a single procedure using only one intravenous injection of contrast dye.

 

Other diagnostic tests

 

Nuclear ventilation-perfusion imaging (V/Q scan) is designed to detect lung areas that are ventilated, but not perfused, a mismatch that suggests PE. The basic principle of the test is based on an intravenous injection of technetium-99m (^99mTc) labeled macroaggregated albumin particles, which block a small fraction of pulmonary capillaries and thereby enable scintigraphic assessment of lung perfusion at the tissue level. Where there is occlusion of pulmonary arterial branches, the peripheral capillary bed will not receive particles, resulting in “cold” area on subsequent images.  perfusion scans are combined with ventilation studies for which xenon (¹³³Xe), ^99mTc-labeled aerosols or ^99mTc-labeled carbon microparticles can be used. Normal V/Q scan excludes PE iearly 100%. However, V/Q scan is rarely used due to limited availability.

 

The role of magnetic resonance imaging (real time MRI, MR perfusion imaging, and MR angiography) in DVT and PE is still undergoing validation and continues to evolve.

 

Pulmonary angiography, although considered the gold standard for diagnosis of PE, is an invasive test and its use is currently limited. The diagnostic criteria for acute PE include direct evidence of a thrombus, either a filling defect or amputation of a pulmonary arterial branch. Currently it is used to assist in direct visualization of thrombosis and catheter-directed thrombolytic infusion or in preoperative evaluation prior to surgical embolectomy.

 

Differetial approach to management

Suspected high-risk and non-high-risk PE are two distinct situations because the management strategies differ (Fig. 2-3).

 

Differential diagnosis

The differential diagnosis of acute PE depends on the clinical presentation and concomitant disease. When patients present with dyspnea or chest pain, the differential diagnosis may include pneumonia, a flare of asthma or chronic obstructive lung disease, anxiety with hyperventilation, pneumothorax, heart failure, angina or myocardial infarction, musculoskeletal pain, pericarditis, pleuritis from infection or connective tissue disease, herpes zoster, rib fracture, intrathoracic cancer, and, occasionally, intra-abdominal processes such as acute cholecystitis. Acute PE can be superimposed on another underlying cardiopulmonary disease, on which new or worsening symptoms are sometimes blamed.

Figure 2. Management algorithm for patients with suspected high-risk PE APTT = activated partial thromboplastin time;  CT = computed tomography; INR = international normalozed ratio; i.v. = intravenously; UFH = unfractionated heparin Modified from Pruszczyk P., Torbicki A. Zatorowość płucna. W: Szczeklik A., Gajewski P (red.) Choroby Wewnętrzne. Kompendium Medycyny Praktycznej. Wydawnictwo Medycyna Praktyczna, Kraków, 2011, 319-326

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Non-high-risk PE,  i.e., without shock or hypotension

Figure 3. Management algorithm for patients with suspected non-high-risk PE CT = computed tomography Modified from Pruszczyk P., Torbicki A. Zatorowość płucna. W: Szczeklik A., Gajewski P (red.) Choroby Wewnętrzne. Kompendium Medycyny Praktycznej. Wydawnictwo Medycyna Praktyczna, Kraków, 2011, 319-326

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Treatment strategies

1. Hemodynamic and respiratory support is necessary in patients with suspected or confirmed PE presenting with shock or hypotension (Table 3).

 

Table 3. Recommendations for acute and long-term treatment of PE

 

 

 

2. Anticoagulation

2.1. Unfractionated heparin (UFH). Begin with UFH bolus of 80 units/kg, followed by a continuous infusion at 18 units/kg per hour. Target activated partial thromboplasin time (ATTP) between 1,5 and 2,5 times the control value (commonly the therapeutic range is 60 to 80 s). A nomogram may be helpful for heparin dose adjustment (Table 4).

 

Table 4. Adjustment of intravenous UFH dose (Raschke nomogram)

 

 

2.2. Low molecular weight heparins (LMWH) and selective factor Xa antagonist fondaparinux may be considered for initial treatment of PE. Although not recommended for high-risk PE with hemodynamic instability (due to lack of studies), LMWH and fondaparinux , given subcutaneously in weight-adjusted doses are the treatment of choice ion-high-risk PE (Table 5). 

 

Table 5. Subcutaneous regimens of LMWH and fondaparinux

 

 

2.3. Warfarin is a vitamin K antagonist used for long-term anticoagulation and secondary prevention of PE at doses adjusted to maintain a target INR of 2,5 (2,0-3,0).

3. Thrombolytic therapy is the first line treatment in patients presenting with cardiogenic shock and/or persistent arterial hypotension. The approved thrombolytic regimens of streptokinase, urokinase and recombinant tissue plasminogen activator (rtPA) are shown in Table 6.

 

Table 6. Thrombolytic regimens for pulmonary embolism

 

 

Heparin should not be infused concurrently with streptokinase or urokinase, but it can be gived during alteplase administration.

4. Other methods (surgical pulmonary embolectomy, percutaneous catheter embolectomy or fragmentation, venous filters) – see Table 3 for indications.

 

Prognosis

 

If unntreated, mortality in PE reaches 30%. Aggressive therapy reduces mortality to 3-8%. Importantly, the majority of preventable deaths due to PE (up to 68% in various autopsy series) can be attributed to missed diagnosis rather than therapeutic failure.

 

CHRONIC COR PULMONALE

 

Definition

 

Cor pulmonale is defined as a condition that affects the structure and function of the right ventricle (RV), which is the result of a disease that affects the function and/or structure of the lungs.

 

Etiology

 

Chronic obstructive pulmonary disease (COPD) accounts for 80-90% of cases of cor pulmonale. Among the restrictive lung diseases kyphoskoliosis, idiopathic pulmonary fibrosis, and pneumoconiosis are the main caused of cor pulmonale. Among the etiologies of respiratory insufficiency of central orogin the obesity-hypoventilation syndrome (formerly “Pickwickian syndrome”) is a relatively frequent cause of cor pulmonale (Table 7).

 

Table 7. Respiratory diseases associated with cor pulmonale associated with pulmonary hypertension (excluding primary pulmonary hypertension, pulmonary thromboembolic disease, and diseases of the pulmonary vascular bed)

 

 

 

Pathophysiology

Several different pathophysiologic mechanisms can lead to pulmonary hypertension and, subsequently, to cor pulmonale. The main pathogenetic mechanisms include the following:

1) Acute hypoxic pulmonary vasoconstriction.

2) Pulmonary vascular remodeling resulting from chronic alveolar hypoxia.

3) Hypercapnic acidosis and hyperviscosity secondary to polycythemia.

4) Loss of pulmonary vascular bed and compression of alveolar vessels by fibrosing process (in idiopathic pulmonary fibrosis).

 

Clinical presentation

 

Clinical signs develop relatively late and are not sensitive indicators of pulmonary hypertension or right ventricular hypertrophy. Peripheral (ankle) edema is the best sign of right heart failure, but it is not specific and can arise from other causes. it may also indicate the presence of secondary hyperaldosteronism secondary to respiratory failure. Accentuation of the pulmonary component of the second heart sound is in patients with severe pulmonary hypertension. A systolic left parasternal heave and a murmur of tricuspid regurgitation suggest right ventricular dilatation. All these signs are often obscured by hyperinflation of the chest in COPD patients. Many patients with COPD never develop right-sided heart failure, other patients experience episodes of right heart failure during exacerbations of the disease and worsening of pulmonary hypertension.

Diagnosis

Chest radiography

RV hypertrophy is not easily discernible on a plain chest X-ray, although dilatation of the RV gives the heart a globular appearance. Also, the width of the right descending pulmonary artery has been shown to relate with the presence of pulmonary arterial hypertension: levels of >16 mm have been shown to discriminate between those with and without pulmonary arterial hypertension.

 

Electrocardiography

Electrocardiographic criteria for detection of RV hypertrophy include:

1. Right axis deviation (>100° without right bundle branch block);

2. R or R’ > S in V₁;

3. R in V1 + S in V5 or V6 ≥ 10 mm;

4. R in V1 ≥ 7 mm;

5. R in V1 ≥ 15 mm with right bundle branch block;

6. Right atrial enlargement

 

Echocardiography is used to measure right ventricular dimensions as well as to assess pulmonary hypertension. Pulmonary hypertension in COPD is usually mild to moderate in contrast pulmonary thromboembolic disease and primary pulmonary arterial hypertension in which pulmonary artery pressure is usually high.

 

Magnetic resonance imaging (MRI) produces the best images of the right ventricle and, therefore, may be used for measuring RV dimensions. Its use is limited by high cost and limited availability.

 

Radionuclide ventriculography using ^99mTc-labeled erythrocytes or human serum albumin can be used to assess RV ejection fraction (RVEF). A RVEF <40-45% is considered abnormal, but this index is afterload dependent, decreasing when pulmonary artery pressure and pulmonary vascular resistance increase. Moreover, RVEF may be overestimated in the presence of significant tricuspid regurgitation.

 

Treatment

 

1. Treatment of the underlying cause, e.g., COPD

2. Long-term oxygen therapy (LTOT). In patients with COPD, LTOT is recommended when the PaO₂ is less than 55 mm Hg or the O₂ saturation is less than 88% (class I, level B). However, in the presence of impaired mental or cognitive function, LTOT can be considered even if the PaO₂ is greater than 55 mm Hg or the O₂ saturation is greater than 88%.

3. Treatment of heart failure with diuretics (e.g., furosemide 40-160 mg/d), particularly in the management of associated peripheral edema. Potassium supplements should be added if needed.

4. Phlebotomy is indicated in patients with chronic cor pulmonale and chronic hypoxia causing severe polycythemia, defined as hematocrit of 65% or more. It should be reserved as an adjunctive therapy for patients with acute decompensation of cor pulmonale and patients who remain significantly polycythemic despite appropriate LTOT.

 

Prognosis

 

Patients COPD who develop cor pulmonale have a 50% 5-year survival if the degree of pulmonary hypertension is mild . The prognosis is psrticularly poor fpr those with severe pulmonary hypertension. LTOT significantly improves survival of patients with COPD.

 

References

A – Basic:

1.                  Davidson’s Principles and practice of medicine (21^st revised ed.) / by Colledge N.R., Walker B.R., and Ralston S.H., eds. – Churchill Livingstone, 2010. – 1376 p.

2.                  Harrison’s principles of internal medicine (18^th edition) / by Longo D.L., Kasper D.L., Jameson J.L. et al. (eds.). – McGraw-Hill Professional, 2012. – 4012 p.

3.                  The Merck Manual of Diagnosis and Therapy (nineteenth Edition)/ Robert Berkow, Andrew J. Fletcher and others. – published by Merck Research Laboratories, 2011.

4.                  Web -sites:

a.      http://emedicine.medscape.com/

b.     http://meded.ucsd.edu/clinicalmed/introduction.htm

 

B – Additional:

1.      Lawrence M. Tierney, Jr. et al: Current Medical Diagnosis and treatment 2000, Lange Medical Books, McGraw-Hill, Health Professions Division, 2000.

2. Braunwald’s Heart Disease: a textbook of cardiovascular medicine (9^th ed.) / by Bonow R.O., Mann D.L., and Zipes D.P., and Libby P. eds. – Saunders, 2012. – 2048 p.

3. Braunwald’s Heart Disease: review and assessment (9^th ed.) / Lilly L.S., editor. – Saunders, 2012. – 320 p.

4. Cardiology Intensive Board Review. Question Book (2^nd ed.) / by Cho L., Griffin B.P., Topol E.J., eds. – Lippincott Williams & Wilkins, 2009. – 385 p.

5. Cleveland Clinic Cardiology Board Review / Griffin B.P., Kapadia S.R., Rimmerman C.M., eds. – Lippincott Williams & Wilkins, 2012. – 952 p.

6. Hurst’s the Heart (13^th ed.) / by Fuster V., Walsh R.A., Harrington R., eds. – McGraw-Hill, 2010. – 2500 p.

7. Oxford Handbook of Cardiology (2^nd ed.) / by Ramrakha P., Hill J., eds. – Oxford University Press, 2012. – 851 p.