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Pulmonary Embolism in Children
RESPIRATORY MEDICINE II
0031-3955/94 $0.00 + .20
PULMONARY EMBOLISM IN CHILDREN Daniel A. Evans, MD, and Robert W. Wilmott, MD
In children, the diagnosis of pulmonary embolism (PE) is seldom considered, and many PE remain undiagnosed until postmortem examinations are performed. The most recent estimate for the incidence of PE in children was by Buck and associates6 in a retrospective analysis of autopsies performed at the University of Michigan Medical Center from January 1955 through December 1979. They determined the total incidence of PE in the pediatric population to be 3.7%. The embolism contributed to the death of the patient 31% of the time in cases of PE diagnosed at autopsy.6 Deep vein thrombosis (DVT), which plays a significant role in PE in adults, is a rare diagnosis in the pediatric patient18 and is more frequently absent than present in pediatric patients with PE.26 In studies of adult patients with PE, it has been estimated that 10% of people with acute PE die within 1 hour of the eventY Of the remaining patients who survive the first hour, only one third are correctly diagnosed initially. Even with proper diagnosis and therapy initiated early, 8% die. Of the group of patients who have delayed diagnosis, the mortality rate is 30%.5 RISK FACTORS
A variety of characteristics predispose pediatric patients to PE. Buck and associates6 organized the risk factors for PE in pediatric age patients and ranked them by clinical importance (Table 1). Bergquist and Lindblad5 completed a retrospective study in adult From the Division of Pulmonary Medicine, Children's Hospital Medical Center, and the University of Cincinnati College of Medicine, Cincinnati, Ohio
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Table 1. RISK FACTORS FOR PULMONARY EMBOLISM IN CHILDREN IN ORDER OF CLINICAL IMPORTANCE
1. 2. 3. 4. 5. 6.
Presence of a central venous catheter Immobility Heart disease Ventriculoatrial shunt Trauma Neoplasia
7. 8. 9. 10. 11. 12.
Operation Infection Medical illness Dehydration Shock Obesity
Data from Buck JA. Connors RH. Coon WW. et al: Pulmonary embolism in children. J Ped Surg
16:385. 1981; with permission.
patients during the period 1951 to 1980 and found that the danger of PE postoperatively continues for more than a month. This postoperative danger seems not to be the case in children, but similar studies have not been performed in children. The incidence of PE associated with general surgical procedures is 20%; and in women taking estrogen-containing oral contraceptives, it is 0.03%.6 PE associated with deficiency states of antithrombin III, protein C, and protein 5 are usually recurrent with the first episode occurring in the second or third decade of life. 39 Neither age nor sex is a risk factor for PE in children.6
CLINICAL PRESENTATION
The prerequisite for diagnosis of PE is clinical suspicion. There is no one physical finding nor group of physical findings that yields a high positive predictive value for the diagnosis of PE. Hull and colleagues,23 in a prospective study of 173 consecutive patients presenting to the emergency room with pleuritic chest pain, found that signs and symptoms, when used alone to diagnose PE, had at best a sensitivity of 85% but a specificity of only 37%.28 In the Urokinase-Streptokinase Pulmonary Embolism Trial (USPET?8 in 1974, which evaluated 327 adult patients, the most common presenting symptom in PE was pleuritic chest pain (88%). Chest pain was followed by dyspnea (84%), apprehension (59%), cough (53%), hemoptysis (30%), sweats (27%), and syncope (13%). In this same study, the physical findings were as varied with tachypnea (92%) being the most frequent physical finding. Other physical findings found were crackles (58%), increased intensity of the pulmonic component of the second heart sound (53%), tachycardia (44%), fever (43%), diaphoresis (36%), gallop rhythm (34%), phlebitis (32%), edema (24%), murmur (23%), and cyanosis (19%). Other reported physical findings include altered mental status, pleural friction rub, wheezing, and arrhythmiasY Unfortunately for the clinician, the differential diagnosis encompassing these signs and symptoms is broad. Even in massive PE with cor pulmonale, distended neck veins, a prominent right ventricular lift, and hypotension, the differential diagnosis includes cardiac tamponade, con-
i
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strictive pericarditis, restrictive cardiomyopathy, and right ventricular infarct. 3 Even though clinical presentation does not provide the diagnosis of PE, it can provide information about the severity of the vascular obstruction. A patient's response to PE is the sum of his or her response to the liberated vasoactive amines and the degree of vascular obstruction, with the vascular obstruction being significantly more important. In normal individuals, occlusion of one pulmonary artery is accompanied by few cardiodynamic changes. An increase in pulmonary artery pressure is usually not evident until the pulmonary vascular bed is 60% occluded. Cyanosis and dyspnea generally occur when there is 65% obstruction; severe pulmonary hypertension and shock occur at 70% to 80% obstruction, and death occurs at greater than 85% occlusion of the pulmonary vascular bed.lO
PATHOPHYSIOLOGY
The degree of cardiopulmonary disturbance observed in PE depends on two fundamental elements: the previous functional status of the heart and lungs and the severity of the pulmonary vascular occlusion. PE can produce severe disturbances characterized by pulmonary artery hypertension, right ventricular failure, and hypoxemia. 13 A major pathophysiologic consequence of acute PE is increased alveolar dead space. This increase occurs because lung units continue to be ventilated despite diminished or absent perfusion. Complete vascular obstruction by an embolus causes an increase in absolute dead space. In contrast, incomplete obstruction of a pulmonary artery increases physiologic dead space by increasing ratios of ventilation relative to blood flow of involved lung units. These effects impair the efficient elimination of CO2 by the lung. IS Although CO2 elimination may be impaired in PE, hypercapnia rarely develops, presumably reflecting the compensatory hyperventilation that occurs. In cases in which the thromboembolism is sufficiently severe to result in hypercapnia, there is an association of significant hemodynamic sequelae of acute right ventricular failure often resulting in death. IS PE has been associated with both decreased Paco2 and increased alveolar-arterial oxygen tension gradient [P(A-a)o2]' as well as normal Paco2 and P(A-a)o2. Preexistent cardiopulmonary disease frequently produces arterial hypoxemia. When patients without prior cardiopulmonary disease are studied, an inverse relationship is demonstrated between the percentage of pulmonary vasculature obstructed and the measured Pao2. Other factors that may contribute to hypoxemia include reflex bronchoconstriction, atelectasis, infarction of lung tissue, and the presence of a patent foramen ovale. 3 Mismatching of ventilation and perfusion, intracardiac and/or intrapulmonary shunting of mixed venous blood, and alveolar hypoventila-
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tion may each contribute to a reduced Pao2 following pulmonary embolism. Reduction of mixed venous P02 consequent to low cardiac output further decreases Pao2 by presenting the pulmonary capillary with a lower Po2 • In rare circumstances, an increased Paco2 due to massive pulmonary embolism and ventilatory failure contributes to arterial hypoxemia. Hypoxemia results because the rising PAco2 lowers PAo2, thus decreasing the driving pressure for oxygen transport across the alveolarcapillary membrane. ls Normal ventilatory control depends on the interaction of sensors and respiratory muscles. The sensors include the following. ls Central chemoreceptors, located on the surface of the brain stem, responding to changes in CO2 and hydrogen ion concentration Peripheral chemoreceptors, located adjacent to the carotid arteries, responding to decreases in Pao2 Proprioceptors, located in the lung tissue and muscle spindles of diaphragm, intercostal, and abdominal muscle groups, responding to stretch and irritation Hyperventilation is a common sign of PE and had been thought to result from hypoxia. This increased minute ventilation usually leads to hypocapnea and respiratory alkalosis. The mechanisms that lead to alveolar hyperventilation are undefined; however, correction of hypoxemia with supplemental oxygen, removing the stimulus of chemoreceptors, seldom reverses the respiratory alkalosis, suggesting that proprioceptors are the major contributors to hyperventilation associated with PE. Limited data suggest that irritant and juxtacapillary sensors contribute to the reflex stimulation of ventilation by PEY A number of clinical and experimental observations suggest that PE results in an increase in airway resistance which is an important determinant of the work of breathing. Airways resistance is critically dependent on lung volume and the radius of the conducting airways. Despite the obvious role that atelectasis, pleural effusions, and pulmonary edema play in the alterations of airway resistance by decreasing lung volume, bronchoconstriction also has been found to accompany PE, which would explain the physical finding of wheezing in patients with PE. 1S This bronchoconstriction is limited to the small peripheral airways that are perfused by the pulmonary artery occluded by the embolus. 36 This bronchoconstriction seems to be mediated by neurohumoral factors, such as serotonin and histamine, that are released when there is interaction between circulating platelets and the thromboembolism. 14 Untreated, this peripheral airway bronchoconstriction persists for 24 to 48 hours, but it can be blocked or quickly reversed with heparin. 36 Pulmonary compliance is another important determinant of the work of breathing. The total compliance of lungs is decreased by pulmonary edema, fibrosis, and atelectasis. In experimental models of total pulmonary artery occlusion, loss of pulmonary surfactant develops within 24 hours in lung units distal to the site of occlusion, resulting in atelectasis and transudation of fluid into the alveolar space. 14
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Pulmonary infarction is an uncommon sequel of PE owing to the fact that the lung has three sources of oxygen: pulmonary arteries, the airways, and bronchial arteries. In addition, nutrients may reach lung tissue distal to a pulmonary artery obstruction by retrograde flow of oxygenated blood from the pulmonary veins. Infarction rarely accompanies occlusion (or ligation) of central pulmonary arteries because of the bronchial arterial blood supply. Infarction usually results when smaller pulmonary arteries are obstructed and hemorrhage into the airways persists. In this situation, the anastomotic channels that exist between distal bronchial and pulmonary arterioles allow blood from the bronchial arterial blood to enter the pulmonary capillary. This blood then extravasates into the alveolus. If clearance of alveolar blood is delayed for any reason, then pulmonary infarction results. Left ventricular failure results in impaired clearance of alveolar blood so that patients with advanced heart failure, requiring vasodilator therapy, have a much higher incidence of pulmonary infarction associated with PE.ls The main hemodynamic consequence of pulmonary embolism is the acute mechanical reduction of the pulmonary vascular cross-sectional area. This reduction results in a sudden increase in pulmonary vascular resistance and, if the cardiac output is to be maintained, an increase in pulmonary artery pressure and right ventricular work. The extent of hemodynamic changes in PE is determined by the size of the emboli and whether the patient has underlying cardiopulmonary disease. Although humoral factors and neural reflexes playa role in determining the severity of hemodynamic response to pulmonary embolism in experimental animal models, their role in humans is uncertain. 34 In patients free of preexisting cardiopulmonary disease, the extent of embolic obstruction can be related directly to the mean pulmonary artery pressure. Obstruction of 25% to 40% leads to an increase in mean pulmonary artery pressure (PAP) of 20 to 30 mm Hg; massive obstruction over 75% results in a PAP of 40 to 45 mm Hg. A previously normal right ventricle will dilate at a mean PAP of 40 to 45 mm Hg, which may result in acute tricuspid insufficiency. If the pressure load is sustained, the stroke output will be reduced, cardiac output will fall, and shock will ensue. In massive embolism, the acute dilatation of the right ventricle with the concomitant restraining action of the pericardium accounts for leftward shift of the interventricular septum and reduced left ventricular compliance, further decreasing the left ventricular volume and resulting in circulatory failure. A mean PAP greater than 45 mm Hg suggests the presence of previous emboli or another underlying cardiopulmonary disease that has caused the right ventricle to work against an elevated PAP resulting in right ventricular hypertrophy.34
SUPPORTIVE LABORATORY DATA
Chest radiographic abnormalities are seen in approximately 70% of patients with acute PE. 37 The usefulness of the chest radiograph in sup-
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porting the diagnosis of PE is in the exclusion of entities that may mimic the presentation of PE. The chest radiograph is also important for use in interpreting the ventilation perfusion scan.31 The most frequent findings observed on the chest radiographs of patients found to have PE are some combination of parenchymal infiltrate, atelectasis, and pleural effusion. The parenchymal infiltrates often are ascribed to pulmonary infarction; however, their usual rapid resolution suggests that these infiltrates are hemorrhagic edema and not the tissue necrosis expected in true infarction. Pleural effusions have been reported in as many as 33% of patients with PE. Other subtle radiographic findings observed in PE include hypovascularity in a lung zone (Westermark's sign) and a pyramidally shaped infiltrate with the peak directed toward the hilus (Hampton's hump). When present, the pleural effusions are usually unilateral with less than 10% being bilateral. Evaluation of the pleural fluid has provided no diagnostic or prognostic benefit. The fluid is most often an exudate (even though it can be a transudate) and usually has red blood cells present if an infarction has taken place, it is usually bloody. Occasionally, the pulmonary artery may be enlarged on a chest radiograph as a result of the PE, even when there is documentation of normal PAP.36 Electrocardiograms (ECG) likewise are useful in excluding other entities that present with a similar clinical picture to PE, such as pericarditis and acute myocardial infarction, but are of little value in proving PE. In most cases of PE, the electrocardiogram shows nonspecific changes, demonstrating only a sinus tachycardia or nonspecific ST-T segment changes.9 In patients with acute cor pulmonale as a consequence of PE, the electrocardiogram may demonstrate P-pulmonale, right axis deviation, right bundle branch block, or classic manifestations, such as the SlQ3T3 pattern (S wave in lead I, Q wave with T wave inversion in lead III).25 Arterial blood gas tensions are often abnormal in patients with PE. They can reveal respiratory alkalosis, arterial hypoxemia, or they may be normal. Of adults with acute PE, 80% will have Pao2 less than 80 mm Hg; however, there are studies reporting normal Pao2 in 50% of PE patients. The alveolar-arterial gradient may be more useful as a screening test than the Pao2 alone. In one study, a widened P(A-a)o2 gradient was detected in 95% of patients with PE, and a widened P(A-a)o2 gradient or a low Paeo2 was found in 98% of patients with PE in the same studyY Arterial blood gas analysis has a greater role in assessing the impact of the embolism on pulmonary gas exchange and in confirming or ruling out respiratory failure than in diagnosing PE but supports the suspicion of PE if a widened P(A - a)o2 gradient is present or if a reduced Peo2 is found in a previously healthy individuaJ.25 Echocardiography can aid in the gathering of data to support the suspicion of PE, especially because PE is associated with abnormalities of right ventricular size, interventricular septum position, right ventricular function, and tricuspid regurgitant flow velocity. Echocardiography is also very helpful in the evaluation of patients with hemodynamic compromise prior to the onset of cardiogenic shock allowing intervention
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to proceed before signs and symptoms of cardiovascular collapse develop.9 In conditions in which thrombus is formed, such as PE, plasminmediated proteolysis of fibrin releases D-dimeric fragments, which can be quantified. D-dimers have been elevated in 89% of patients with PE confirmed by ventilation and perfusion isotope lung scanning. The specificity is only 56%, however, and so a D-dimer concentration less than 500 ng/mL has been suggested to exclude PE. 2o Pulmonary function tests may give abnormal results, but they are again nonspecific, although they may be of some benefit in assessing functional recovery after PE.40 BurkF demonstrated an increase in physiologic dead space (VDphys) and in the ratio of dead space (V D) to tidal volume (VT ). This increase in VDphys has been supported by many other studies. Theoretic and experimental studies of the effects of PE on lung function indicate that there is an increase in the alveolar dead space (V Dalv) and hence in VDphys and VD/VT because of a reduction or blockage in perfusion of the affected lung areas which, consequently, are relatively overventilated. The increase in VDalv may be less than expected because there can be some shift of ventilation away from the embolized area due to a reflex, localized bronchoconstriction. A right-to-Ieft shunt, either intracardiac or through nonventilated alveoli, also may contribute to an increase in calculated VD/VT by raising the Paco2 through the mixing of venous and arterial blood. This mixing results in a Paco2 higher than the P Aco2, increasing the calculated VD/VT because the Enghoff modification of the Bohr equation for calculating VD/VT is based on the assumption that the arterial and alveolar Pco2 are equal. A low-to-moderate shunt, however, produces a relatively small effect on VD/VT • Burki's7 findings also imply that a measured VD/VT less than 40% in a patient suspected to have PE virtually excludes the diagnosis. No routine blood tests help in establishing the diagnosis of PE. At one time, the triad of elevated lactate dehydrogenase (LDH), bilirubin, and aspartate aminotransferase (AST) were thought to be specific, but further studies have proven this to be untrue. The white blood cell (WBC) count may be slightly elevated. 14
DIAGNOSIS
The introduction of perfusion lung scintigraphy in 1964 made it possible for the first time to assess objectively the pulmonary circulation in patients with clinically suspected PE. With the subsequent implementation of ventilation scanning in 1970, the accuracy of lung scintigraphy was further improved. 30 Ventilation-perfusion (\1 IQ) imaging displays regional blood flow and ventilation by noninvasive means. It is a safe, inexpensive, and reproducible screening test, but a normal perfusion scintigram does not absolutely exclude PE. Several follow-up studies of patients with PE and normal ventilation-perfusion scans, however, conclude that such emboli
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are unlikely to be of any clinical significance, and the patient can be safely left untreated.35 The labelled material used for the perfusion scan is technetium-labelled albumin microspheres, which impact in the capillary beds during their first pass through the pulmonary capillary circulation so their distribution is fixed according to the distribution of pulmonary blood flow at the time of injection. The supine position is preferable, because sitting or standing decreases blood flow to the apices and may result in a false-positive scan.33 Because it is possible to rule out clinically significant PE by the results of the perfusion scan alone, that scan could be performed first, but the ventilation scan is routinely performed first. If there are perfusion abnormalities, a ventilation scan must be performed. Ventilation scans are performed by inhaling a radioactive gas and recording its distribution with a gamma camera. The ventilation and perfusion scans are then compared. 14 Unlike the limited choice of contrast for perfusion scans, ventilation scanning has several options, each with its own properties. 133Xenon has the advantages of a relatively long shelf life, which makes it easily available at short notice and relatively inexpensive compared with other radioactive gases. Its disadvantage is that only a single view of the lungs is obtained. Residual technetium activity can contaminate the xenon image, so xenon ventilation scanning is best performed prior to the perfusion scan. 81mKrypton has two major advantages: its half-life is so short that multiple views can be carried out, and the gamma energy is sufficiently distinct from that of technetium to allow simultaneous or rapidly consecutive data acquisition. The major disadvantage of krypton is its relatively higher cost and limited availability. Technetium-labeled aerosols offer a third option, allowing multiple-view ventilation studies to be obtained at a fairly low cost. Because it uses the same radionuclide as the perfusion study, however, one is faced with the decision of which investigation to perform first. 32 The perfusion scan is compared with the ventilation scan, and areas that are poorly perfused but well ventilated or vice versa are referred to as mismatched, whereas those in which the perfusion and ventilation appear similar are called matched. The size and number of the defects are measured and counted and placed into a number of categories. Interpretation algorithms use three, four, or five categories. The Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED) studt2 uses five categories: high probability, intermediate probability, low probability, very low probability, and normal.16 The PIOPED study reported a positive predictive value of 88% for patients with high probability V10. scans demonstrating angiographic evidence of PE. The positive predictive values for intermediate probability, low probability, very low probability, and normal lung scans were 33%,16%, and 9%.16 The difficulty in basing the diagnosis of PE on the ventilation-perfusion scan is that there are many illnesses and abnormalities that can cause ventilation-perfusion mismatch, as listed in Table 2. To improve the positive predictive value of ventilation-perfusion scans, investigators began to factor in the "clinical probability" of PE,
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Table 2. ETIOLOGY OF VENTILATION-PERFUSION MISMATCH
1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13.
Pulmonary embolism Pneumonia Bronchogenic carcinoma Radiation therapy Tuberculosis/histoplasmosis Metastases Obstructive lung disease Collagen vascular disease/vasculitis Sarcoidosis Pulmonary sequestration Vascular compression Lymphangitic carcinomatosis Dog heart worm
14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24.
Air, fat, or foreign body embolism Pulmonary hypertension Mitral valve disease Sickle cell disease Congenital pulmonary vascular abnormalities Traumatic pulmonary artery pseudoaneu rysm Pulmonary artery sarcoma Pulmonary veno-occlusive disease Hemangioendotheliomatosis Hiatal hernia Wedged Swan-Ganz catheter
which raised the probability of PE with high-probability scans to 90% and lowered the probability of PE in low-probability scans to 4%, thus easily adjusting the groupings to high-probability, indeterminate, and low-probability scansP For further review of the role of V/Q scanning in the diagnosis of PE, readers are referred to the results of the PIOPED study.32 Of the diagnostic procedures available for the diagnosis of PE, pulmonary angiography has the greatest sensitivity and specificity. Pulmonary angiography is indicated for the following patients. Patients with an indeterminate lung scan Patients with a high-probability lung scan in whom confirmation is necessary because of a high risk of bleeding complications from anticoagulation Patients in whom embolism is massive and embolectomy is contemplated Patients in whom thrombolytic therapy or vena caval interruption is considered Patients in whom there is significant clinical evidence for an alternative diagnosis or who have low-probability scans with a high degree of clinical suspicion. Despite the many indications for pulmonary angiography, it is rarely used in children for fear of the complications of the procedure. The complication rates are dependent on the experience of the person doing the procedure, and the mortality in experienced centers should be around 0.3%. Patients with pulmonary hypertension and a right ventricular end diastolic pressure exceeding 20 mm Hg are at greater risk. Other complications include cardiac perforation (1.0%) and subendocardial injury «0.2%). With the recent development of lower osmolarity contrast and pigtail catheters, the incidence of complications in this procedure has been reduced and should be readily performed in children suspected of having a PE. 4,1O In light of the potential risks associated with pulmonary angiography, there have been many attempts to seek other radiographic means to determine the presence of PE. Because 80% to 90% of all PE are
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associated with DVT of the proximal leg or pelvis and the treatment of stable PE and DVT are the same, then a patient who is thought to have a PE but without a high-probability ventilation-perfusion scan can avoid angiography if a DVT is diagnosed by other less-invasive means. There are three methods used to evaluate the lower extremities for the presence of venous thrombosis (VT). Electrical impedance plethysmography is a useful test for the diagnosis of DVT with 95% sensitivity and 96% specificity. A pneumatic cuff is applied to the mid-thigh and electrical impedance is measured distally while the cuff is deflated and inflated. Change of electrical impedance reflects change in blood volume, which indicates whether venous obstruction is present. False-positive impedance findings can result from isometric muscle contraction, reduced arterial blood flow to the limb, pelvic cancer, retroperitoneal fibrosis, and congestive heart failure. Doppler ultrasonography examines venous blood flow by utilizing the principle of the Doppler shift. Ultrasound is directed at a vein and reflected back by blood cells. Venous blood causes the ultrasound to be reflected back at a changed frequency with the degree of change proportional to the velocity of flow. The Doppler test is sensitive to obstruction of the popliteal and more proximal veins; however, interpretation is subjective compared with the objective interpretation of the impedance plethysmogram. Doppler is more sensitive than impedance plethysmography in patients with increased central venous pressure or arterial insufficiency and in patients in casts or traction. Venography is the reference standard for the diagnosis of DVT. Patients with conditions known to produce false-positive plethysmography results or individuals with negative plethysmograms, despite a high clinical suspicion of DVT, should undergo venography. The complications of lower extremity venography include pain and a 3% to 4% incidence of DVT. Furthermore, venography is limited by inadequate visualization of the external and common iliac veins in up to 18% of patients. 5 Fibrinogen leg scanning is of historic interest only and is no longer used. Fibrinogen leg scanning is performed by injection of 1251_ fibrinogen with follow-up scanning of the legs for up to the next 7 days. The 1251-fibrinogen is incorporated into developing thrombus. This scan is good for detection of calf vein thrombi but is relatively insensitive for venous thrombi in the thigh and pelvis, making it a poor test for detection of significant DVT.5 The use of fibrinogen carries a small risk of transmitting viral diseases. Two cases of hepatitis are known from the early days of the test, but no case of transmission of HIV has been reported. Fear of HIV has resulted in the test being prohibited in some countries despite very strict regulations concerning fibrinogen donors. 33 With the risks of pulmonary angiography and the inexactness of lower extremity evaluation, many new techniques are being evaluated to diagnose PE. Digital subtraction angiography seems to be the most promising, with peripheral contrast injection and image enhancement techniques used to generate images of the pulmonary vasculature. This technique is simple, fast, and does not require pulmonary artery catheterization. Good quality images depend on the patient being able to
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hold his or her breath for 15 seconds. Magnetic resonance (MR) imaging is generally useful in evaluating abnormalities of the pulmonary vasculature; and, because of this, there are current studies into its potential use in the diagnosis of PE. As experience grows with MR imaging, the sensitivity may improve and MR imaging may establish itself as a useful noninvasive diagnostic modality. 50 far, the disadvantages of MR imaging are that the patient's heart rate must be less than 100 beats per minute and it requires a 30-minute stay in the scanner room with limited access to the patient for monitoring. 5
TREATMENT The treatment of PE goes beyond attempts to lyse the thrombus. With the understanding that 10% of patients with acute PE die within the first hour, swift hemodynamic stabilization and appropriate oxygenation and ventilation are imperative, even prior to the onset of anticoagulation or thrombolysis. The tried and true ABCs of resuscitation must be consistently applied in any patient suspected of PE. In patients with acute respiratory failure (ARF), endotracheal intubation and mechanical ventilation must be instituted to ensure adequate tissue oxygenation and CO2 removal. The difficulty in providing proper oxygenation and ventilation in PE is that there can be a significant increase in airway resistance and decrease in lung compliance, leading to the use of high positive end expiratory pressure (PEEP), which can in turn impair venous return to the heart in an already hemodynamically compromised patient. Prewitf33 reviewed the hemodynamic management of patients with PE. Dopamine (DA) has been extensively evaluated and is effective for supporting blood pressure, cardiac output, and stroke volume. Unfortunately, several studies of the hemodynamic effects of DA show that the pulmonary capillary wedge pressure (PCWP) increases by almost 50%. Molloy and coworkers27,28 investigated the effects of DA in patients with acute respiratory failure and later compared the acute hemodynamic effects of DA and dobutamine (DB) in patients with adult respiratory distress syndrome (ARD5) and found DA to increase the PCWP by 45% and 50%, respectively.33 With increased pulmonary permeability, even a small increase in PCWP may significantly increase water accumulation in the lungs. When dobutamine was evaluated, patients had improved cardiac output, stable blood pressure, and decreases in PCWP. Both DA and DB resulted in small decreases in pulmonary vascular resistance. In patients with low cardiac output, norepinephrine (NE) also has been shown to be beneficial, explained by a direct inotropic effect or increased ventricular contractility due to increased systemic blood pressure and improved right ventricular myocardial blood flow. A caveat in patients with PE and poor cardiac output is that the excessive use of volume expansion may result in a decompensation of right ventricular function. This decompensation is explained by an obligatory increase in right ventricular work, so that a critical decrease in the right
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ventricular oxygen supply demand ratio develops. Such a change could result in right ventricular ischemia and a deterioration in right ventricular function. 33 With the new considerations of thrombolytic therapy for PE, a constant reminder should be that, historically, patients treated with heparin for PE who survived beyond the first 2 hours of symptoms had a survival rate of 92%. Therefore, as soon as a diagnosis of pulmonary embolism is strongly suspected and the difficult decisions of thrombolytic therapy are being made, intravenous heparin should be started without delay.3s Heparin accelerates the action of antithrombin III and factor Xa and prevents further fibrin deposition, allowing the fibrinolytic system to lyse the existing clot. 20 Heparin should be given for 7 to 10 days, and it usually is initiated by bolus followed by continuous infusion. Bolus dosing in children is between 50 units/kg body weight followed by a continuous infusion of 10 to 25 units/kg body weight per hour. 24 Approximately 24 to 48 hours after heparin therapy is initiated, warfarin (Coumadin) is begun so that there is an overlap of at least 5 days. Coumadin suppresses production of the vitamin K-dependent factors of coagulation (factors II, VII, IX, and X), and it takes 5 days to reach its full effect. Coumadin therapy should be continued for 3 to 6 months.s Only one randomized trial has compared heparin with placebo in the management of PE, and it was halted after 35 patients had been enrolled because of a significantly higher mortality in the placebo group. IS In the late 1960s and early 1970s, the National Institutes of Health sponsored large clinical trials to compare the use of urokinase (UK) and streptokinase (SK) and, more recently, anisoylated streptokinase-plasminogen activator complex (APSAC) and recombinant tissue plasminogen activator (rt-PA) for thrombolytic therapy of PE. Streptokinase (SK) is a product of several strains of hemolytic streptococci. It has no intrinsic enzymatic activity and cannot convert plasminogen to plasmin directly. SK that escapes neutralization by antibodies forms a complex with plasminogen that results in structural changes in both the SK and the plasminogen molecules. The alteration of the plasminogen portion of the complex exposes its active site and allows it to convert other plasminogen molecules to plasmin but does not allow itself to efficiently degrade fibrin to fibrinogen. The SK-plasmin complex activates plasminogen both in the plasma and on the surface of the thrombus. Because a portion of the circulating plasminogen is used for formation of SK-plasminogen complexes, less plasminogen is available to be converted to plasmin to participate in thrombolysis. Because of this, plasminogen depletion, with loss of fibrinolytic potential, can occur with high doses or prolonged infusion of SK. 16 The half-life of SK in the blood is 15 minutes. 16 Antibodies are produced to SK as a result of streptococcal infections, and these antibodies are inhibitory. As with any immunogenic treatment, SK can result in allergic reactions, evidenced by wheezing, itching, flushing, nausea, headaches, myalgias, and fever, in 10% to 15% of patients treated with SK. 14 Urokinase (UK) is a naturally occurring human protein synthesized principally by renal and vascular endothelial cells. The most physiologically relevant inhibitor of UK is plasminogen activator inhibi-
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tor-type I (PAl-I), which is synthesized in the liver and vascular endothelial cells. Pharmacologic doses of UK easily overcome the activity of PAI-l to allow UK to interact with plasminogen in the plasma or on the surface of the thrombus. UK directly converts plasminogen to plasmin by the proteolytic cleavage of a single peptide bond. The half-life of urokinase in blood is also 15 minutes, and there are no allergic responses?l Anisoylated SK-plasminogen activator complex (APSAC) is a preformed complex of plasminogen and streptokinase, the active site of which has been reversibly inhibited by acylation. Once administered, the compound undergoes spontaneous deacylation, exposing the active site of the SK-plasminogen complex. The rate of deacylation determines the duration of the fibrinolytic activity of the compound, and APSAC's halflife is 90 minutes. Recombinant tissue plasminogen activator (rt-PA) is a recombinantly synthesized endogenous plasminogen activator that is physiologically synthesized and stored in soft tissues. Its activity is modulated by PAI-1. The PAI-l is easily overcome by the pharmacologic doses of rt-PA given. The binding affinity of rt-PA for both circulating plasminogen and fibrinogen is relatively low, but it binds avidly to fibrin. Once it is bound to fibrin, it undergoes a conformational change, allowing it to interact efficiently with plasminogen, facilitating its binding to the fibrin surface and converting it to plasmin. Tissue plasminogen activator can efficiently convert plasminogen to plasmin only in the presence of fibrin, thus maximizing fibrinolytic activity at the level of thrombi and minimizing degradation of circulating fibrinogen. 21 The half-life of rt-PA is approximately 3 to 6 minutes. 8 The decision of who should not receive thrombolytic therapy is easier to make than that of who should receive it. There is indirect evidence that thrombolytic therapy may be more beneficial in massive pulmonary embolism than heparin; and in patients with PE who are hemodynamically unstable, thrombolysis is considered the frontline therapy. In all other PE patients, the difference between thrombolytic therapy and anticoagulation therapy at I-year follow-up showed patients receiving thrombolytic agents had less significant pulmonary function abnormalities and a higher reserve capacity of the pulmonary vascular bed during exercise. The clinical relevance of this is yet to be determined. 8 Absolute contraindications to thrombolytic therapy include: active internal bleeding, cerebrovascular accident within 2 months, and other intracranial processes. Relative major contraindications are major surgery, obstetric delivery, organ biopsy or puncture of noncompressible vessels within 10 days, recent serious gastrointestinal bleeding, recent serious trauma, and severe arterial hypertension. Relative minor contraindications are recent minor trauma or cardiopulmonary arrest, high likelihood of left heart thrombus, bacterial endocarditis, hemostatic defect, pregnancy, diabetic hemorrhagic retinopathy, and age of more than 75 years. 8 Dosages of thrombolytic therapy in pediatric patients have been standardized as in Table 3. Monitoring of therapy is performed only for heparin, in which the target for the activated partial thromboplastin time (APTT) is 1.5 to 2.0
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Table 3. STANDARDIZED DOSAGES OF THROMBOLYTIC THERAPY Drug
Dosage
Streptokinase
3500-4000 IUlkg as a loading dose over 30 minutes, followed by 1000-1500 IUlkg body weight per hour" 4400 IUlkg as a loading dose over 10 minutes, followed by 4400 IU/kg body weight per hour 2 0.1-0.5 mg/kg body weight per hour (used for as long as 3 days)26
Urokinase rt-PA*
*Has not yet received approval from the Food and Drug Administration for use in children.
times normal. If heparin levels can be measured, heparin levels of 0.2 to 0.4 U /mL (if performed by protamine titration assay) or 0.3 to 0.7 U /mL (if measured using chromogenic antifactor Xa assay) are optimal,22 In adult patients, there is no monitoring necessary for thrombolytic therapy, because it will change neither the duration nor the dosage of therapy. In one case report of rt-PA use in neonates, the rate of infusion was titrated to keep the fibrinogen levels above 100 mg/dL.l Baseline coagulation studies should be performed prior to thrombolysis to evaluate for a hemostatic disorder. Also, 4 to 6 hours after completion of thrombolysis, an APTT level should be drawn to determine when heparin therapy should be initiated, for long-term anticoagulation therapy will still be required. Embolectomy usually is reserved for patients with hemodynamic compromise that persists for more than 1 hour after the acute event. This procedure is performed by open thoracotomy and, when successful, provides immediate relief. This procedure has a high rate of mortality, however, and with the advancement of thrombolytic agents, surgical intervention is declining in use. Inferior vena caval interruption by catheter-placed filters is indicated for patients with PE who have contraindications for anticoagulation or recurrent PE despite appropriate anticoagulation. Complications of inferior vena cava filters include malpositioning, migration, venous thrombosis proximal or distal to the filter, hemorrhage at the percutaneous site of insertion, and sepsis. There are multiple inferior vena cava filter devices available. The first on the market that was used in the United States from 1969 to 1977 was the Mobin-Uddin, but the incidence of inferior vena caval occlusion was high (60%-70%), and so in 1977 the KimrayGreenfield filter (Meditech, Watertown, MA) became available, and it is still the filter of choice. Newer filters are being developed but are yet to supplant the Kimray-Greenfield filter. These include: the Bird's nest or modified Bird's nest (Cook, Inc, Bloomington, IN), Amplatz filter (Cook, Inc, Bloomington, IN), Gunther filter (William Cook, Denmark), SimonNitinol filter, and the titanium Greenfield filter. The current goals for filters are that they filter thrombi without occluding the vessels, are easily placed without migration, and are easily withdrawn if needed. More recently, with the development of MR imaging, there is a desire for filters to be nonferromagnetic, such as the titanium Greenfield and the Simon Nitinol filters.19
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CONCLUSION
PE is infrequently diagnosed in the pediatric patient. Clinicians should always have a high index of suspicion, especially when treating a child with the acute onset of respiratory distress or cardiovascular shock. The more familiar the clinician is with the risk factors for PE and the clinical signs and symptoms commonly observed in patients with PE, the greater the likelihood of making a swift and accurate diagnosis. Because 10% of patients die within the first hour after the onset of symptoms, an understanding of the available diagnostic modalities and proper therapeutic interventions could be critical. ACKNOWLEDGMENT The authors thank Linda Dixon for typing the manuscript and appreciate the helpful advice given by Robert P. Baughman, MD.
References 1. Anderson BJ, Keeley SR, Johnson NO: Caval thrombolysis in neonates using low doses of recombinant human tissue-type plasminogen activator. Anaesthes Intensive Care 19:22,1991 2. Benitz WE, Tatro OS: Pediatric Drug Handbook, ed 2. St. Louis, Mosby-Year Book, 1988 3. Benotti JR: Pulmonary angiography in the diagnosis of pulmonary embolism. Herz 14:115, 1989 4. Bergquist 0, Bergentz SE: Diagnosis of deep vein thrombosis. World J Surg 14:679, 1990 5. Bergquist 0, Lindblad B: A 30-year survey of pulmonary embolism verified at autopsy: An analysis of 1274 surgical patients. Br J Surg 72:105, 1985 6. Buck JR, Connors RH, Coon WW, et al: Pulmonary embolism in children. J Ped Surg 16:385, 1981 7. Burki N: The dead space to tidal volume ratio in the diagnosis of PE. Am Rev Respir Dis 133:679, 1986 8. Charbonnier B, Meyer G, Stem M, et al: Thrombolytic treatment of acute pulmonary embolism. Herz 14:157, 1989 9. Come PC: Echocardiographic evaluation of pulmonary embolism and its response to therapeutic interventions. Chest 101:151S, 1992 10. Comerota AJ: Deep vein thrombosis and pulmonary embolism: Clinical presentation and pathophysiologic consquence. Cardiovasc Interven Radiol11:S9, 1988 11. Cvitanic 0, Marino P: Improved use of arterial blood gas analysis in suspected pulmonary embolism. Chest 95:48,1989 12. Dobkin J, Reichel J: Pulmonary embolism: Diagnosis and treatment. Cardiol Clin 5:577, 1987 13. D'Orio V, Mendes P, Saad G, et al: Pathogenesis and management of acute pulmonary embolism. Acta Clin Belg 44:396,1989 14. Dumire SM: Pulmonary embolism. Emerg Med Clin North Am 7:339, 1989 15. Elliot CG: Pulmonary phYSiology during pulmonary embolism. Chest 101:163S, 1992 16. Goldhaber SZ: Recent advances in the diagnosis and lytic therapy of pulmonary embolism. Chest 99:173S, 1991 17. Goldhaber SZ, Morpurgo M: Diagnosis, treatment, and prevention of pulmonary embolism: Report of the WHO/International Society and Federation of Cardiology Task Force. JAMA 8:1727, 1992 18. Gorstein A: Nontatrogenic deep vein thrombosis of lower extremities in children. Kinderchirugie 41:375, 1986
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19. Grassi CJ, Goldhaber SZ: Interruption of the inferior vena cava for prevention of pulmonary embolism: Transvenous filter devices. Herz 14:182, 1989 20. Gray HH, Firoozan S: Management of pulmonary embolism. Thorax 47:825, 1992 21. Haire WD: Pharmacology of fibrinolysis. Chest 101:91S, 1992 22. Hall R: Problems in the management of pulmonary embolism. Herz 14:148, 1989 23. Hull RD, Raskob GE, Carter CJ, et al: Pulmonary embolism in outpatients with pleuritic chest pain. Arch Intern Med 148:838, 1988 24. Johnson KB (ed): Harriet Lane Handbook, ed 12. St. Louis, Mosby-Year Book, 1991 25. Kutty K: Pulmonary embolism: How to nail down the diagnosis. Postgrad Med 88:72, 1990 26. Levy M, Benson LN, Burrows PE, et al: Tissue plasminogen activator for the treatment of thromboembolism in infants and children. J Pediatr 118:467, 1991 27. Molloy OW, Dobson K, Girling L, et al: Effects of dopamine in cardiopulmonary function and left ventricular volumes in patients with acute respiratory failure. Am Rev Resp Dis 130:396, 1984 28. Molloy OW, Ducas J, Dobson K, et al: Hemodynamic management in clinical acute hypoxemic respiratory failure: Dopamine versus dobutamine. Chest 89:636,1986 29. Nguyen LT, Laberge JM, Guttman FM, et al: Spontaneous deep vein thrombosis in childhood and adolescence. J Ped Surg 21:640,1986 30. Nyman U: DiagnostiC strategies in acute pulmonary embolism. Haemostasis 23:220, 1993 31. Palevsky HI: The problems of clinical care and laboratory diagnosis of pulmonary embolism. Semin Nucl Med 21:276, 1991 32. PIOPED investigators: Value of the ventilation/perfusion scan in acute pulmonary embolism: Results of the prospective investigation of pulmonary embolism diagnosis (PIOPED). JAMA 263:2753,1990 33. Prewitt R: Hemodynamic management in pulmonary embolism and acute hypoxemic respiratory failure. Crit Care Med 18:561, 1990 34. Reidel M, Rudolph W: Hamodynamik und gasaustausch bei akuter lungenambolie. Herz 14:109, 1989 35. Robinson PJ: Lung scintigraphy: Doubt and certainty in the diagnosis of pulmonary embolism. Clinical Radiology 40:557, 1989 36. Rosenow E, Osmundson P, Brown M: Pulmonary embolism. Mayo Clin Proc 56:161, 1981 37. Talbot S, Worthington BS, Roebuck ES: Radiographic signs of pulmonary embolism and pulmonary infarction. Thorax 28:198,1973 38. USPET investigators: Urokinase-streptokinase embolism trial. JAMA 229:1606,1974 39. Valenzuela TO: Pulmonary embolism. Emerg Med Clin North Am 6:253, 1988 40. van Beek EJR, Tiel-van Buul MMC, Buller HR, et al: The value of lung scintigraphy in the diagnosis of pulmonary embolism. Eur J Nucl Med 20:173, 1993
Address reprint requests to Daniel A. Evans, MD Division of Pulmonary Medicine Children's Hospital Medical Center 3333 Burnet Avenue Cincinnati, OH 45229-3039
0031-3955/94 $0.00 + .20
PULMONARY EMBOLISM IN CHILDREN Daniel A. Evans, MD, and Robert W. Wilmott, MD
In children, the diagnosis of pulmonary embolism (PE) is seldom considered, and many PE remain undiagnosed until postmortem examinations are performed. The most recent estimate for the incidence of PE in children was by Buck and associates6 in a retrospective analysis of autopsies performed at the University of Michigan Medical Center from January 1955 through December 1979. They determined the total incidence of PE in the pediatric population to be 3.7%. The embolism contributed to the death of the patient 31% of the time in cases of PE diagnosed at autopsy.6 Deep vein thrombosis (DVT), which plays a significant role in PE in adults, is a rare diagnosis in the pediatric patient18 and is more frequently absent than present in pediatric patients with PE.26 In studies of adult patients with PE, it has been estimated that 10% of people with acute PE die within 1 hour of the eventY Of the remaining patients who survive the first hour, only one third are correctly diagnosed initially. Even with proper diagnosis and therapy initiated early, 8% die. Of the group of patients who have delayed diagnosis, the mortality rate is 30%.5 RISK FACTORS
A variety of characteristics predispose pediatric patients to PE. Buck and associates6 organized the risk factors for PE in pediatric age patients and ranked them by clinical importance (Table 1). Bergquist and Lindblad5 completed a retrospective study in adult From the Division of Pulmonary Medicine, Children's Hospital Medical Center, and the University of Cincinnati College of Medicine, Cincinnati, Ohio
PEDIATRIC CLINICS OF NORTH AMERICA VOLUME 41 • NUMBER 3 • JUNE 1994
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Table 1. RISK FACTORS FOR PULMONARY EMBOLISM IN CHILDREN IN ORDER OF CLINICAL IMPORTANCE
1. 2. 3. 4. 5. 6.
Presence of a central venous catheter Immobility Heart disease Ventriculoatrial shunt Trauma Neoplasia
7. 8. 9. 10. 11. 12.
Operation Infection Medical illness Dehydration Shock Obesity
Data from Buck JA. Connors RH. Coon WW. et al: Pulmonary embolism in children. J Ped Surg
16:385. 1981; with permission.
patients during the period 1951 to 1980 and found that the danger of PE postoperatively continues for more than a month. This postoperative danger seems not to be the case in children, but similar studies have not been performed in children. The incidence of PE associated with general surgical procedures is 20%; and in women taking estrogen-containing oral contraceptives, it is 0.03%.6 PE associated with deficiency states of antithrombin III, protein C, and protein 5 are usually recurrent with the first episode occurring in the second or third decade of life. 39 Neither age nor sex is a risk factor for PE in children.6
CLINICAL PRESENTATION
The prerequisite for diagnosis of PE is clinical suspicion. There is no one physical finding nor group of physical findings that yields a high positive predictive value for the diagnosis of PE. Hull and colleagues,23 in a prospective study of 173 consecutive patients presenting to the emergency room with pleuritic chest pain, found that signs and symptoms, when used alone to diagnose PE, had at best a sensitivity of 85% but a specificity of only 37%.28 In the Urokinase-Streptokinase Pulmonary Embolism Trial (USPET?8 in 1974, which evaluated 327 adult patients, the most common presenting symptom in PE was pleuritic chest pain (88%). Chest pain was followed by dyspnea (84%), apprehension (59%), cough (53%), hemoptysis (30%), sweats (27%), and syncope (13%). In this same study, the physical findings were as varied with tachypnea (92%) being the most frequent physical finding. Other physical findings found were crackles (58%), increased intensity of the pulmonic component of the second heart sound (53%), tachycardia (44%), fever (43%), diaphoresis (36%), gallop rhythm (34%), phlebitis (32%), edema (24%), murmur (23%), and cyanosis (19%). Other reported physical findings include altered mental status, pleural friction rub, wheezing, and arrhythmiasY Unfortunately for the clinician, the differential diagnosis encompassing these signs and symptoms is broad. Even in massive PE with cor pulmonale, distended neck veins, a prominent right ventricular lift, and hypotension, the differential diagnosis includes cardiac tamponade, con-
i
\
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strictive pericarditis, restrictive cardiomyopathy, and right ventricular infarct. 3 Even though clinical presentation does not provide the diagnosis of PE, it can provide information about the severity of the vascular obstruction. A patient's response to PE is the sum of his or her response to the liberated vasoactive amines and the degree of vascular obstruction, with the vascular obstruction being significantly more important. In normal individuals, occlusion of one pulmonary artery is accompanied by few cardiodynamic changes. An increase in pulmonary artery pressure is usually not evident until the pulmonary vascular bed is 60% occluded. Cyanosis and dyspnea generally occur when there is 65% obstruction; severe pulmonary hypertension and shock occur at 70% to 80% obstruction, and death occurs at greater than 85% occlusion of the pulmonary vascular bed.lO
PATHOPHYSIOLOGY
The degree of cardiopulmonary disturbance observed in PE depends on two fundamental elements: the previous functional status of the heart and lungs and the severity of the pulmonary vascular occlusion. PE can produce severe disturbances characterized by pulmonary artery hypertension, right ventricular failure, and hypoxemia. 13 A major pathophysiologic consequence of acute PE is increased alveolar dead space. This increase occurs because lung units continue to be ventilated despite diminished or absent perfusion. Complete vascular obstruction by an embolus causes an increase in absolute dead space. In contrast, incomplete obstruction of a pulmonary artery increases physiologic dead space by increasing ratios of ventilation relative to blood flow of involved lung units. These effects impair the efficient elimination of CO2 by the lung. IS Although CO2 elimination may be impaired in PE, hypercapnia rarely develops, presumably reflecting the compensatory hyperventilation that occurs. In cases in which the thromboembolism is sufficiently severe to result in hypercapnia, there is an association of significant hemodynamic sequelae of acute right ventricular failure often resulting in death. IS PE has been associated with both decreased Paco2 and increased alveolar-arterial oxygen tension gradient [P(A-a)o2]' as well as normal Paco2 and P(A-a)o2. Preexistent cardiopulmonary disease frequently produces arterial hypoxemia. When patients without prior cardiopulmonary disease are studied, an inverse relationship is demonstrated between the percentage of pulmonary vasculature obstructed and the measured Pao2. Other factors that may contribute to hypoxemia include reflex bronchoconstriction, atelectasis, infarction of lung tissue, and the presence of a patent foramen ovale. 3 Mismatching of ventilation and perfusion, intracardiac and/or intrapulmonary shunting of mixed venous blood, and alveolar hypoventila-
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tion may each contribute to a reduced Pao2 following pulmonary embolism. Reduction of mixed venous P02 consequent to low cardiac output further decreases Pao2 by presenting the pulmonary capillary with a lower Po2 • In rare circumstances, an increased Paco2 due to massive pulmonary embolism and ventilatory failure contributes to arterial hypoxemia. Hypoxemia results because the rising PAco2 lowers PAo2, thus decreasing the driving pressure for oxygen transport across the alveolarcapillary membrane. ls Normal ventilatory control depends on the interaction of sensors and respiratory muscles. The sensors include the following. ls Central chemoreceptors, located on the surface of the brain stem, responding to changes in CO2 and hydrogen ion concentration Peripheral chemoreceptors, located adjacent to the carotid arteries, responding to decreases in Pao2 Proprioceptors, located in the lung tissue and muscle spindles of diaphragm, intercostal, and abdominal muscle groups, responding to stretch and irritation Hyperventilation is a common sign of PE and had been thought to result from hypoxia. This increased minute ventilation usually leads to hypocapnea and respiratory alkalosis. The mechanisms that lead to alveolar hyperventilation are undefined; however, correction of hypoxemia with supplemental oxygen, removing the stimulus of chemoreceptors, seldom reverses the respiratory alkalosis, suggesting that proprioceptors are the major contributors to hyperventilation associated with PE. Limited data suggest that irritant and juxtacapillary sensors contribute to the reflex stimulation of ventilation by PEY A number of clinical and experimental observations suggest that PE results in an increase in airway resistance which is an important determinant of the work of breathing. Airways resistance is critically dependent on lung volume and the radius of the conducting airways. Despite the obvious role that atelectasis, pleural effusions, and pulmonary edema play in the alterations of airway resistance by decreasing lung volume, bronchoconstriction also has been found to accompany PE, which would explain the physical finding of wheezing in patients with PE. 1S This bronchoconstriction is limited to the small peripheral airways that are perfused by the pulmonary artery occluded by the embolus. 36 This bronchoconstriction seems to be mediated by neurohumoral factors, such as serotonin and histamine, that are released when there is interaction between circulating platelets and the thromboembolism. 14 Untreated, this peripheral airway bronchoconstriction persists for 24 to 48 hours, but it can be blocked or quickly reversed with heparin. 36 Pulmonary compliance is another important determinant of the work of breathing. The total compliance of lungs is decreased by pulmonary edema, fibrosis, and atelectasis. In experimental models of total pulmonary artery occlusion, loss of pulmonary surfactant develops within 24 hours in lung units distal to the site of occlusion, resulting in atelectasis and transudation of fluid into the alveolar space. 14
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Pulmonary infarction is an uncommon sequel of PE owing to the fact that the lung has three sources of oxygen: pulmonary arteries, the airways, and bronchial arteries. In addition, nutrients may reach lung tissue distal to a pulmonary artery obstruction by retrograde flow of oxygenated blood from the pulmonary veins. Infarction rarely accompanies occlusion (or ligation) of central pulmonary arteries because of the bronchial arterial blood supply. Infarction usually results when smaller pulmonary arteries are obstructed and hemorrhage into the airways persists. In this situation, the anastomotic channels that exist between distal bronchial and pulmonary arterioles allow blood from the bronchial arterial blood to enter the pulmonary capillary. This blood then extravasates into the alveolus. If clearance of alveolar blood is delayed for any reason, then pulmonary infarction results. Left ventricular failure results in impaired clearance of alveolar blood so that patients with advanced heart failure, requiring vasodilator therapy, have a much higher incidence of pulmonary infarction associated with PE.ls The main hemodynamic consequence of pulmonary embolism is the acute mechanical reduction of the pulmonary vascular cross-sectional area. This reduction results in a sudden increase in pulmonary vascular resistance and, if the cardiac output is to be maintained, an increase in pulmonary artery pressure and right ventricular work. The extent of hemodynamic changes in PE is determined by the size of the emboli and whether the patient has underlying cardiopulmonary disease. Although humoral factors and neural reflexes playa role in determining the severity of hemodynamic response to pulmonary embolism in experimental animal models, their role in humans is uncertain. 34 In patients free of preexisting cardiopulmonary disease, the extent of embolic obstruction can be related directly to the mean pulmonary artery pressure. Obstruction of 25% to 40% leads to an increase in mean pulmonary artery pressure (PAP) of 20 to 30 mm Hg; massive obstruction over 75% results in a PAP of 40 to 45 mm Hg. A previously normal right ventricle will dilate at a mean PAP of 40 to 45 mm Hg, which may result in acute tricuspid insufficiency. If the pressure load is sustained, the stroke output will be reduced, cardiac output will fall, and shock will ensue. In massive embolism, the acute dilatation of the right ventricle with the concomitant restraining action of the pericardium accounts for leftward shift of the interventricular septum and reduced left ventricular compliance, further decreasing the left ventricular volume and resulting in circulatory failure. A mean PAP greater than 45 mm Hg suggests the presence of previous emboli or another underlying cardiopulmonary disease that has caused the right ventricle to work against an elevated PAP resulting in right ventricular hypertrophy.34
SUPPORTIVE LABORATORY DATA
Chest radiographic abnormalities are seen in approximately 70% of patients with acute PE. 37 The usefulness of the chest radiograph in sup-
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porting the diagnosis of PE is in the exclusion of entities that may mimic the presentation of PE. The chest radiograph is also important for use in interpreting the ventilation perfusion scan.31 The most frequent findings observed on the chest radiographs of patients found to have PE are some combination of parenchymal infiltrate, atelectasis, and pleural effusion. The parenchymal infiltrates often are ascribed to pulmonary infarction; however, their usual rapid resolution suggests that these infiltrates are hemorrhagic edema and not the tissue necrosis expected in true infarction. Pleural effusions have been reported in as many as 33% of patients with PE. Other subtle radiographic findings observed in PE include hypovascularity in a lung zone (Westermark's sign) and a pyramidally shaped infiltrate with the peak directed toward the hilus (Hampton's hump). When present, the pleural effusions are usually unilateral with less than 10% being bilateral. Evaluation of the pleural fluid has provided no diagnostic or prognostic benefit. The fluid is most often an exudate (even though it can be a transudate) and usually has red blood cells present if an infarction has taken place, it is usually bloody. Occasionally, the pulmonary artery may be enlarged on a chest radiograph as a result of the PE, even when there is documentation of normal PAP.36 Electrocardiograms (ECG) likewise are useful in excluding other entities that present with a similar clinical picture to PE, such as pericarditis and acute myocardial infarction, but are of little value in proving PE. In most cases of PE, the electrocardiogram shows nonspecific changes, demonstrating only a sinus tachycardia or nonspecific ST-T segment changes.9 In patients with acute cor pulmonale as a consequence of PE, the electrocardiogram may demonstrate P-pulmonale, right axis deviation, right bundle branch block, or classic manifestations, such as the SlQ3T3 pattern (S wave in lead I, Q wave with T wave inversion in lead III).25 Arterial blood gas tensions are often abnormal in patients with PE. They can reveal respiratory alkalosis, arterial hypoxemia, or they may be normal. Of adults with acute PE, 80% will have Pao2 less than 80 mm Hg; however, there are studies reporting normal Pao2 in 50% of PE patients. The alveolar-arterial gradient may be more useful as a screening test than the Pao2 alone. In one study, a widened P(A-a)o2 gradient was detected in 95% of patients with PE, and a widened P(A-a)o2 gradient or a low Paeo2 was found in 98% of patients with PE in the same studyY Arterial blood gas analysis has a greater role in assessing the impact of the embolism on pulmonary gas exchange and in confirming or ruling out respiratory failure than in diagnosing PE but supports the suspicion of PE if a widened P(A - a)o2 gradient is present or if a reduced Peo2 is found in a previously healthy individuaJ.25 Echocardiography can aid in the gathering of data to support the suspicion of PE, especially because PE is associated with abnormalities of right ventricular size, interventricular septum position, right ventricular function, and tricuspid regurgitant flow velocity. Echocardiography is also very helpful in the evaluation of patients with hemodynamic compromise prior to the onset of cardiogenic shock allowing intervention
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to proceed before signs and symptoms of cardiovascular collapse develop.9 In conditions in which thrombus is formed, such as PE, plasminmediated proteolysis of fibrin releases D-dimeric fragments, which can be quantified. D-dimers have been elevated in 89% of patients with PE confirmed by ventilation and perfusion isotope lung scanning. The specificity is only 56%, however, and so a D-dimer concentration less than 500 ng/mL has been suggested to exclude PE. 2o Pulmonary function tests may give abnormal results, but they are again nonspecific, although they may be of some benefit in assessing functional recovery after PE.40 BurkF demonstrated an increase in physiologic dead space (VDphys) and in the ratio of dead space (V D) to tidal volume (VT ). This increase in VDphys has been supported by many other studies. Theoretic and experimental studies of the effects of PE on lung function indicate that there is an increase in the alveolar dead space (V Dalv) and hence in VDphys and VD/VT because of a reduction or blockage in perfusion of the affected lung areas which, consequently, are relatively overventilated. The increase in VDalv may be less than expected because there can be some shift of ventilation away from the embolized area due to a reflex, localized bronchoconstriction. A right-to-Ieft shunt, either intracardiac or through nonventilated alveoli, also may contribute to an increase in calculated VD/VT by raising the Paco2 through the mixing of venous and arterial blood. This mixing results in a Paco2 higher than the P Aco2, increasing the calculated VD/VT because the Enghoff modification of the Bohr equation for calculating VD/VT is based on the assumption that the arterial and alveolar Pco2 are equal. A low-to-moderate shunt, however, produces a relatively small effect on VD/VT • Burki's7 findings also imply that a measured VD/VT less than 40% in a patient suspected to have PE virtually excludes the diagnosis. No routine blood tests help in establishing the diagnosis of PE. At one time, the triad of elevated lactate dehydrogenase (LDH), bilirubin, and aspartate aminotransferase (AST) were thought to be specific, but further studies have proven this to be untrue. The white blood cell (WBC) count may be slightly elevated. 14
DIAGNOSIS
The introduction of perfusion lung scintigraphy in 1964 made it possible for the first time to assess objectively the pulmonary circulation in patients with clinically suspected PE. With the subsequent implementation of ventilation scanning in 1970, the accuracy of lung scintigraphy was further improved. 30 Ventilation-perfusion (\1 IQ) imaging displays regional blood flow and ventilation by noninvasive means. It is a safe, inexpensive, and reproducible screening test, but a normal perfusion scintigram does not absolutely exclude PE. Several follow-up studies of patients with PE and normal ventilation-perfusion scans, however, conclude that such emboli
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are unlikely to be of any clinical significance, and the patient can be safely left untreated.35 The labelled material used for the perfusion scan is technetium-labelled albumin microspheres, which impact in the capillary beds during their first pass through the pulmonary capillary circulation so their distribution is fixed according to the distribution of pulmonary blood flow at the time of injection. The supine position is preferable, because sitting or standing decreases blood flow to the apices and may result in a false-positive scan.33 Because it is possible to rule out clinically significant PE by the results of the perfusion scan alone, that scan could be performed first, but the ventilation scan is routinely performed first. If there are perfusion abnormalities, a ventilation scan must be performed. Ventilation scans are performed by inhaling a radioactive gas and recording its distribution with a gamma camera. The ventilation and perfusion scans are then compared. 14 Unlike the limited choice of contrast for perfusion scans, ventilation scanning has several options, each with its own properties. 133Xenon has the advantages of a relatively long shelf life, which makes it easily available at short notice and relatively inexpensive compared with other radioactive gases. Its disadvantage is that only a single view of the lungs is obtained. Residual technetium activity can contaminate the xenon image, so xenon ventilation scanning is best performed prior to the perfusion scan. 81mKrypton has two major advantages: its half-life is so short that multiple views can be carried out, and the gamma energy is sufficiently distinct from that of technetium to allow simultaneous or rapidly consecutive data acquisition. The major disadvantage of krypton is its relatively higher cost and limited availability. Technetium-labeled aerosols offer a third option, allowing multiple-view ventilation studies to be obtained at a fairly low cost. Because it uses the same radionuclide as the perfusion study, however, one is faced with the decision of which investigation to perform first. 32 The perfusion scan is compared with the ventilation scan, and areas that are poorly perfused but well ventilated or vice versa are referred to as mismatched, whereas those in which the perfusion and ventilation appear similar are called matched. The size and number of the defects are measured and counted and placed into a number of categories. Interpretation algorithms use three, four, or five categories. The Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED) studt2 uses five categories: high probability, intermediate probability, low probability, very low probability, and normal.16 The PIOPED study reported a positive predictive value of 88% for patients with high probability V10. scans demonstrating angiographic evidence of PE. The positive predictive values for intermediate probability, low probability, very low probability, and normal lung scans were 33%,16%, and 9%.16 The difficulty in basing the diagnosis of PE on the ventilation-perfusion scan is that there are many illnesses and abnormalities that can cause ventilation-perfusion mismatch, as listed in Table 2. To improve the positive predictive value of ventilation-perfusion scans, investigators began to factor in the "clinical probability" of PE,
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Table 2. ETIOLOGY OF VENTILATION-PERFUSION MISMATCH
1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13.
Pulmonary embolism Pneumonia Bronchogenic carcinoma Radiation therapy Tuberculosis/histoplasmosis Metastases Obstructive lung disease Collagen vascular disease/vasculitis Sarcoidosis Pulmonary sequestration Vascular compression Lymphangitic carcinomatosis Dog heart worm
14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24.
Air, fat, or foreign body embolism Pulmonary hypertension Mitral valve disease Sickle cell disease Congenital pulmonary vascular abnormalities Traumatic pulmonary artery pseudoaneu rysm Pulmonary artery sarcoma Pulmonary veno-occlusive disease Hemangioendotheliomatosis Hiatal hernia Wedged Swan-Ganz catheter
which raised the probability of PE with high-probability scans to 90% and lowered the probability of PE in low-probability scans to 4%, thus easily adjusting the groupings to high-probability, indeterminate, and low-probability scansP For further review of the role of V/Q scanning in the diagnosis of PE, readers are referred to the results of the PIOPED study.32 Of the diagnostic procedures available for the diagnosis of PE, pulmonary angiography has the greatest sensitivity and specificity. Pulmonary angiography is indicated for the following patients. Patients with an indeterminate lung scan Patients with a high-probability lung scan in whom confirmation is necessary because of a high risk of bleeding complications from anticoagulation Patients in whom embolism is massive and embolectomy is contemplated Patients in whom thrombolytic therapy or vena caval interruption is considered Patients in whom there is significant clinical evidence for an alternative diagnosis or who have low-probability scans with a high degree of clinical suspicion. Despite the many indications for pulmonary angiography, it is rarely used in children for fear of the complications of the procedure. The complication rates are dependent on the experience of the person doing the procedure, and the mortality in experienced centers should be around 0.3%. Patients with pulmonary hypertension and a right ventricular end diastolic pressure exceeding 20 mm Hg are at greater risk. Other complications include cardiac perforation (1.0%) and subendocardial injury «0.2%). With the recent development of lower osmolarity contrast and pigtail catheters, the incidence of complications in this procedure has been reduced and should be readily performed in children suspected of having a PE. 4,1O In light of the potential risks associated with pulmonary angiography, there have been many attempts to seek other radiographic means to determine the presence of PE. Because 80% to 90% of all PE are
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associated with DVT of the proximal leg or pelvis and the treatment of stable PE and DVT are the same, then a patient who is thought to have a PE but without a high-probability ventilation-perfusion scan can avoid angiography if a DVT is diagnosed by other less-invasive means. There are three methods used to evaluate the lower extremities for the presence of venous thrombosis (VT). Electrical impedance plethysmography is a useful test for the diagnosis of DVT with 95% sensitivity and 96% specificity. A pneumatic cuff is applied to the mid-thigh and electrical impedance is measured distally while the cuff is deflated and inflated. Change of electrical impedance reflects change in blood volume, which indicates whether venous obstruction is present. False-positive impedance findings can result from isometric muscle contraction, reduced arterial blood flow to the limb, pelvic cancer, retroperitoneal fibrosis, and congestive heart failure. Doppler ultrasonography examines venous blood flow by utilizing the principle of the Doppler shift. Ultrasound is directed at a vein and reflected back by blood cells. Venous blood causes the ultrasound to be reflected back at a changed frequency with the degree of change proportional to the velocity of flow. The Doppler test is sensitive to obstruction of the popliteal and more proximal veins; however, interpretation is subjective compared with the objective interpretation of the impedance plethysmogram. Doppler is more sensitive than impedance plethysmography in patients with increased central venous pressure or arterial insufficiency and in patients in casts or traction. Venography is the reference standard for the diagnosis of DVT. Patients with conditions known to produce false-positive plethysmography results or individuals with negative plethysmograms, despite a high clinical suspicion of DVT, should undergo venography. The complications of lower extremity venography include pain and a 3% to 4% incidence of DVT. Furthermore, venography is limited by inadequate visualization of the external and common iliac veins in up to 18% of patients. 5 Fibrinogen leg scanning is of historic interest only and is no longer used. Fibrinogen leg scanning is performed by injection of 1251_ fibrinogen with follow-up scanning of the legs for up to the next 7 days. The 1251-fibrinogen is incorporated into developing thrombus. This scan is good for detection of calf vein thrombi but is relatively insensitive for venous thrombi in the thigh and pelvis, making it a poor test for detection of significant DVT.5 The use of fibrinogen carries a small risk of transmitting viral diseases. Two cases of hepatitis are known from the early days of the test, but no case of transmission of HIV has been reported. Fear of HIV has resulted in the test being prohibited in some countries despite very strict regulations concerning fibrinogen donors. 33 With the risks of pulmonary angiography and the inexactness of lower extremity evaluation, many new techniques are being evaluated to diagnose PE. Digital subtraction angiography seems to be the most promising, with peripheral contrast injection and image enhancement techniques used to generate images of the pulmonary vasculature. This technique is simple, fast, and does not require pulmonary artery catheterization. Good quality images depend on the patient being able to
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hold his or her breath for 15 seconds. Magnetic resonance (MR) imaging is generally useful in evaluating abnormalities of the pulmonary vasculature; and, because of this, there are current studies into its potential use in the diagnosis of PE. As experience grows with MR imaging, the sensitivity may improve and MR imaging may establish itself as a useful noninvasive diagnostic modality. 50 far, the disadvantages of MR imaging are that the patient's heart rate must be less than 100 beats per minute and it requires a 30-minute stay in the scanner room with limited access to the patient for monitoring. 5
TREATMENT The treatment of PE goes beyond attempts to lyse the thrombus. With the understanding that 10% of patients with acute PE die within the first hour, swift hemodynamic stabilization and appropriate oxygenation and ventilation are imperative, even prior to the onset of anticoagulation or thrombolysis. The tried and true ABCs of resuscitation must be consistently applied in any patient suspected of PE. In patients with acute respiratory failure (ARF), endotracheal intubation and mechanical ventilation must be instituted to ensure adequate tissue oxygenation and CO2 removal. The difficulty in providing proper oxygenation and ventilation in PE is that there can be a significant increase in airway resistance and decrease in lung compliance, leading to the use of high positive end expiratory pressure (PEEP), which can in turn impair venous return to the heart in an already hemodynamically compromised patient. Prewitf33 reviewed the hemodynamic management of patients with PE. Dopamine (DA) has been extensively evaluated and is effective for supporting blood pressure, cardiac output, and stroke volume. Unfortunately, several studies of the hemodynamic effects of DA show that the pulmonary capillary wedge pressure (PCWP) increases by almost 50%. Molloy and coworkers27,28 investigated the effects of DA in patients with acute respiratory failure and later compared the acute hemodynamic effects of DA and dobutamine (DB) in patients with adult respiratory distress syndrome (ARD5) and found DA to increase the PCWP by 45% and 50%, respectively.33 With increased pulmonary permeability, even a small increase in PCWP may significantly increase water accumulation in the lungs. When dobutamine was evaluated, patients had improved cardiac output, stable blood pressure, and decreases in PCWP. Both DA and DB resulted in small decreases in pulmonary vascular resistance. In patients with low cardiac output, norepinephrine (NE) also has been shown to be beneficial, explained by a direct inotropic effect or increased ventricular contractility due to increased systemic blood pressure and improved right ventricular myocardial blood flow. A caveat in patients with PE and poor cardiac output is that the excessive use of volume expansion may result in a decompensation of right ventricular function. This decompensation is explained by an obligatory increase in right ventricular work, so that a critical decrease in the right
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ventricular oxygen supply demand ratio develops. Such a change could result in right ventricular ischemia and a deterioration in right ventricular function. 33 With the new considerations of thrombolytic therapy for PE, a constant reminder should be that, historically, patients treated with heparin for PE who survived beyond the first 2 hours of symptoms had a survival rate of 92%. Therefore, as soon as a diagnosis of pulmonary embolism is strongly suspected and the difficult decisions of thrombolytic therapy are being made, intravenous heparin should be started without delay.3s Heparin accelerates the action of antithrombin III and factor Xa and prevents further fibrin deposition, allowing the fibrinolytic system to lyse the existing clot. 20 Heparin should be given for 7 to 10 days, and it usually is initiated by bolus followed by continuous infusion. Bolus dosing in children is between 50 units/kg body weight followed by a continuous infusion of 10 to 25 units/kg body weight per hour. 24 Approximately 24 to 48 hours after heparin therapy is initiated, warfarin (Coumadin) is begun so that there is an overlap of at least 5 days. Coumadin suppresses production of the vitamin K-dependent factors of coagulation (factors II, VII, IX, and X), and it takes 5 days to reach its full effect. Coumadin therapy should be continued for 3 to 6 months.s Only one randomized trial has compared heparin with placebo in the management of PE, and it was halted after 35 patients had been enrolled because of a significantly higher mortality in the placebo group. IS In the late 1960s and early 1970s, the National Institutes of Health sponsored large clinical trials to compare the use of urokinase (UK) and streptokinase (SK) and, more recently, anisoylated streptokinase-plasminogen activator complex (APSAC) and recombinant tissue plasminogen activator (rt-PA) for thrombolytic therapy of PE. Streptokinase (SK) is a product of several strains of hemolytic streptococci. It has no intrinsic enzymatic activity and cannot convert plasminogen to plasmin directly. SK that escapes neutralization by antibodies forms a complex with plasminogen that results in structural changes in both the SK and the plasminogen molecules. The alteration of the plasminogen portion of the complex exposes its active site and allows it to convert other plasminogen molecules to plasmin but does not allow itself to efficiently degrade fibrin to fibrinogen. The SK-plasmin complex activates plasminogen both in the plasma and on the surface of the thrombus. Because a portion of the circulating plasminogen is used for formation of SK-plasminogen complexes, less plasminogen is available to be converted to plasmin to participate in thrombolysis. Because of this, plasminogen depletion, with loss of fibrinolytic potential, can occur with high doses or prolonged infusion of SK. 16 The half-life of SK in the blood is 15 minutes. 16 Antibodies are produced to SK as a result of streptococcal infections, and these antibodies are inhibitory. As with any immunogenic treatment, SK can result in allergic reactions, evidenced by wheezing, itching, flushing, nausea, headaches, myalgias, and fever, in 10% to 15% of patients treated with SK. 14 Urokinase (UK) is a naturally occurring human protein synthesized principally by renal and vascular endothelial cells. The most physiologically relevant inhibitor of UK is plasminogen activator inhibi-
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tor-type I (PAl-I), which is synthesized in the liver and vascular endothelial cells. Pharmacologic doses of UK easily overcome the activity of PAI-l to allow UK to interact with plasminogen in the plasma or on the surface of the thrombus. UK directly converts plasminogen to plasmin by the proteolytic cleavage of a single peptide bond. The half-life of urokinase in blood is also 15 minutes, and there are no allergic responses?l Anisoylated SK-plasminogen activator complex (APSAC) is a preformed complex of plasminogen and streptokinase, the active site of which has been reversibly inhibited by acylation. Once administered, the compound undergoes spontaneous deacylation, exposing the active site of the SK-plasminogen complex. The rate of deacylation determines the duration of the fibrinolytic activity of the compound, and APSAC's halflife is 90 minutes. Recombinant tissue plasminogen activator (rt-PA) is a recombinantly synthesized endogenous plasminogen activator that is physiologically synthesized and stored in soft tissues. Its activity is modulated by PAI-1. The PAI-l is easily overcome by the pharmacologic doses of rt-PA given. The binding affinity of rt-PA for both circulating plasminogen and fibrinogen is relatively low, but it binds avidly to fibrin. Once it is bound to fibrin, it undergoes a conformational change, allowing it to interact efficiently with plasminogen, facilitating its binding to the fibrin surface and converting it to plasmin. Tissue plasminogen activator can efficiently convert plasminogen to plasmin only in the presence of fibrin, thus maximizing fibrinolytic activity at the level of thrombi and minimizing degradation of circulating fibrinogen. 21 The half-life of rt-PA is approximately 3 to 6 minutes. 8 The decision of who should not receive thrombolytic therapy is easier to make than that of who should receive it. There is indirect evidence that thrombolytic therapy may be more beneficial in massive pulmonary embolism than heparin; and in patients with PE who are hemodynamically unstable, thrombolysis is considered the frontline therapy. In all other PE patients, the difference between thrombolytic therapy and anticoagulation therapy at I-year follow-up showed patients receiving thrombolytic agents had less significant pulmonary function abnormalities and a higher reserve capacity of the pulmonary vascular bed during exercise. The clinical relevance of this is yet to be determined. 8 Absolute contraindications to thrombolytic therapy include: active internal bleeding, cerebrovascular accident within 2 months, and other intracranial processes. Relative major contraindications are major surgery, obstetric delivery, organ biopsy or puncture of noncompressible vessels within 10 days, recent serious gastrointestinal bleeding, recent serious trauma, and severe arterial hypertension. Relative minor contraindications are recent minor trauma or cardiopulmonary arrest, high likelihood of left heart thrombus, bacterial endocarditis, hemostatic defect, pregnancy, diabetic hemorrhagic retinopathy, and age of more than 75 years. 8 Dosages of thrombolytic therapy in pediatric patients have been standardized as in Table 3. Monitoring of therapy is performed only for heparin, in which the target for the activated partial thromboplastin time (APTT) is 1.5 to 2.0
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Table 3. STANDARDIZED DOSAGES OF THROMBOLYTIC THERAPY Drug
Dosage
Streptokinase
3500-4000 IUlkg as a loading dose over 30 minutes, followed by 1000-1500 IUlkg body weight per hour" 4400 IUlkg as a loading dose over 10 minutes, followed by 4400 IU/kg body weight per hour 2 0.1-0.5 mg/kg body weight per hour (used for as long as 3 days)26
Urokinase rt-PA*
*Has not yet received approval from the Food and Drug Administration for use in children.
times normal. If heparin levels can be measured, heparin levels of 0.2 to 0.4 U /mL (if performed by protamine titration assay) or 0.3 to 0.7 U /mL (if measured using chromogenic antifactor Xa assay) are optimal,22 In adult patients, there is no monitoring necessary for thrombolytic therapy, because it will change neither the duration nor the dosage of therapy. In one case report of rt-PA use in neonates, the rate of infusion was titrated to keep the fibrinogen levels above 100 mg/dL.l Baseline coagulation studies should be performed prior to thrombolysis to evaluate for a hemostatic disorder. Also, 4 to 6 hours after completion of thrombolysis, an APTT level should be drawn to determine when heparin therapy should be initiated, for long-term anticoagulation therapy will still be required. Embolectomy usually is reserved for patients with hemodynamic compromise that persists for more than 1 hour after the acute event. This procedure is performed by open thoracotomy and, when successful, provides immediate relief. This procedure has a high rate of mortality, however, and with the advancement of thrombolytic agents, surgical intervention is declining in use. Inferior vena caval interruption by catheter-placed filters is indicated for patients with PE who have contraindications for anticoagulation or recurrent PE despite appropriate anticoagulation. Complications of inferior vena cava filters include malpositioning, migration, venous thrombosis proximal or distal to the filter, hemorrhage at the percutaneous site of insertion, and sepsis. There are multiple inferior vena cava filter devices available. The first on the market that was used in the United States from 1969 to 1977 was the Mobin-Uddin, but the incidence of inferior vena caval occlusion was high (60%-70%), and so in 1977 the KimrayGreenfield filter (Meditech, Watertown, MA) became available, and it is still the filter of choice. Newer filters are being developed but are yet to supplant the Kimray-Greenfield filter. These include: the Bird's nest or modified Bird's nest (Cook, Inc, Bloomington, IN), Amplatz filter (Cook, Inc, Bloomington, IN), Gunther filter (William Cook, Denmark), SimonNitinol filter, and the titanium Greenfield filter. The current goals for filters are that they filter thrombi without occluding the vessels, are easily placed without migration, and are easily withdrawn if needed. More recently, with the development of MR imaging, there is a desire for filters to be nonferromagnetic, such as the titanium Greenfield and the Simon Nitinol filters.19
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CONCLUSION
PE is infrequently diagnosed in the pediatric patient. Clinicians should always have a high index of suspicion, especially when treating a child with the acute onset of respiratory distress or cardiovascular shock. The more familiar the clinician is with the risk factors for PE and the clinical signs and symptoms commonly observed in patients with PE, the greater the likelihood of making a swift and accurate diagnosis. Because 10% of patients die within the first hour after the onset of symptoms, an understanding of the available diagnostic modalities and proper therapeutic interventions could be critical. ACKNOWLEDGMENT The authors thank Linda Dixon for typing the manuscript and appreciate the helpful advice given by Robert P. Baughman, MD.
References 1. Anderson BJ, Keeley SR, Johnson NO: Caval thrombolysis in neonates using low doses of recombinant human tissue-type plasminogen activator. Anaesthes Intensive Care 19:22,1991 2. Benitz WE, Tatro OS: Pediatric Drug Handbook, ed 2. St. Louis, Mosby-Year Book, 1988 3. Benotti JR: Pulmonary angiography in the diagnosis of pulmonary embolism. Herz 14:115, 1989 4. Bergquist 0, Bergentz SE: Diagnosis of deep vein thrombosis. World J Surg 14:679, 1990 5. Bergquist 0, Lindblad B: A 30-year survey of pulmonary embolism verified at autopsy: An analysis of 1274 surgical patients. Br J Surg 72:105, 1985 6. Buck JR, Connors RH, Coon WW, et al: Pulmonary embolism in children. J Ped Surg 16:385, 1981 7. Burki N: The dead space to tidal volume ratio in the diagnosis of PE. Am Rev Respir Dis 133:679, 1986 8. Charbonnier B, Meyer G, Stem M, et al: Thrombolytic treatment of acute pulmonary embolism. Herz 14:157, 1989 9. Come PC: Echocardiographic evaluation of pulmonary embolism and its response to therapeutic interventions. Chest 101:151S, 1992 10. Comerota AJ: Deep vein thrombosis and pulmonary embolism: Clinical presentation and pathophysiologic consquence. Cardiovasc Interven Radiol11:S9, 1988 11. Cvitanic 0, Marino P: Improved use of arterial blood gas analysis in suspected pulmonary embolism. Chest 95:48,1989 12. Dobkin J, Reichel J: Pulmonary embolism: Diagnosis and treatment. Cardiol Clin 5:577, 1987 13. D'Orio V, Mendes P, Saad G, et al: Pathogenesis and management of acute pulmonary embolism. Acta Clin Belg 44:396,1989 14. Dumire SM: Pulmonary embolism. Emerg Med Clin North Am 7:339, 1989 15. Elliot CG: Pulmonary phYSiology during pulmonary embolism. Chest 101:163S, 1992 16. Goldhaber SZ: Recent advances in the diagnosis and lytic therapy of pulmonary embolism. Chest 99:173S, 1991 17. Goldhaber SZ, Morpurgo M: Diagnosis, treatment, and prevention of pulmonary embolism: Report of the WHO/International Society and Federation of Cardiology Task Force. JAMA 8:1727, 1992 18. Gorstein A: Nontatrogenic deep vein thrombosis of lower extremities in children. Kinderchirugie 41:375, 1986
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19. Grassi CJ, Goldhaber SZ: Interruption of the inferior vena cava for prevention of pulmonary embolism: Transvenous filter devices. Herz 14:182, 1989 20. Gray HH, Firoozan S: Management of pulmonary embolism. Thorax 47:825, 1992 21. Haire WD: Pharmacology of fibrinolysis. Chest 101:91S, 1992 22. Hall R: Problems in the management of pulmonary embolism. Herz 14:148, 1989 23. Hull RD, Raskob GE, Carter CJ, et al: Pulmonary embolism in outpatients with pleuritic chest pain. Arch Intern Med 148:838, 1988 24. Johnson KB (ed): Harriet Lane Handbook, ed 12. St. Louis, Mosby-Year Book, 1991 25. Kutty K: Pulmonary embolism: How to nail down the diagnosis. Postgrad Med 88:72, 1990 26. Levy M, Benson LN, Burrows PE, et al: Tissue plasminogen activator for the treatment of thromboembolism in infants and children. J Pediatr 118:467, 1991 27. Molloy OW, Dobson K, Girling L, et al: Effects of dopamine in cardiopulmonary function and left ventricular volumes in patients with acute respiratory failure. Am Rev Resp Dis 130:396, 1984 28. Molloy OW, Ducas J, Dobson K, et al: Hemodynamic management in clinical acute hypoxemic respiratory failure: Dopamine versus dobutamine. Chest 89:636,1986 29. Nguyen LT, Laberge JM, Guttman FM, et al: Spontaneous deep vein thrombosis in childhood and adolescence. J Ped Surg 21:640,1986 30. Nyman U: DiagnostiC strategies in acute pulmonary embolism. Haemostasis 23:220, 1993 31. Palevsky HI: The problems of clinical care and laboratory diagnosis of pulmonary embolism. Semin Nucl Med 21:276, 1991 32. PIOPED investigators: Value of the ventilation/perfusion scan in acute pulmonary embolism: Results of the prospective investigation of pulmonary embolism diagnosis (PIOPED). JAMA 263:2753,1990 33. Prewitt R: Hemodynamic management in pulmonary embolism and acute hypoxemic respiratory failure. Crit Care Med 18:561, 1990 34. Reidel M, Rudolph W: Hamodynamik und gasaustausch bei akuter lungenambolie. Herz 14:109, 1989 35. Robinson PJ: Lung scintigraphy: Doubt and certainty in the diagnosis of pulmonary embolism. Clinical Radiology 40:557, 1989 36. Rosenow E, Osmundson P, Brown M: Pulmonary embolism. Mayo Clin Proc 56:161, 1981 37. Talbot S, Worthington BS, Roebuck ES: Radiographic signs of pulmonary embolism and pulmonary infarction. Thorax 28:198,1973 38. USPET investigators: Urokinase-streptokinase embolism trial. JAMA 229:1606,1974 39. Valenzuela TO: Pulmonary embolism. Emerg Med Clin North Am 6:253, 1988 40. van Beek EJR, Tiel-van Buul MMC, Buller HR, et al: The value of lung scintigraphy in the diagnosis of pulmonary embolism. Eur J Nucl Med 20:173, 1993
Address reprint requests to Daniel A. Evans, MD Division of Pulmonary Medicine Children's Hospital Medical Center 3333 Burnet Avenue Cincinnati, OH 45229-3039