Pulmonary Embolism in Children

Paediatric Respiratory Reviews 13 (2012) 112–122

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Paediatric Respiratory Reviews

CME Review

Pulmonary Embolism in Children F. Nicole Dijk 1,y, Julie Curtin 2, David Lord 3, Dominic A. Fitzgerald 1,4,* 1

Department of Respiratory Medicine, The Children’s Hospital at Westmead, Locked Bag 4001, Westmead, NSW, Australia, 2145 Department of Haematology, The Children’s Hospital at Westmead, Locked Bag 4001, Westmead, NSW, Australia, 2145 3 Department of Radiology, The Children’s Hospital at Westmead, Locked Bag 4001, Westmead, NSW, Australia, 2145 4 Sydney Medical School, University of Sydney, Australia 2

EDUCATIONAL AIMS In reading the article the reader will be able: 1. 2. 3. 4.

Describe the incidence patterns of pulmonary embolism [PE] in children. Present the predisposing risk factors for PE in children. Discuss the differences in PE assessment between adults and children. Provide guidance in the anticoagulant treatment of PE in children.

A R T I C L E I N F O

S U M M A R Y

Keywords: Pulmonary embolism Children Incidence Epidemiology Diagnostic methods Treatment

Unlike in adults, pulmonary embolism (PE) is an infrequent event in children. It has a marked bimodal distribution during the paediatric years, occurring predominantly in neonates and adolescents. The most important predisposing factors to PE in children are the presence of a central venous line (CVL), infection, and congenital heart disease. Clinical signs of PE are non-specific in children or can be masked by underlying conditions. Diagnostic testing is necessary in children, especially with the lack of clinical prediction rules. Recommendations for tests are derived from adult studies with ventilation/perfusion (V/Q) scintigraphy being well established. There exists an increasing role for computerised tomography pulmonary angiography (CTPA) and magnetic resonance pulmonary angiography (MRPA). Thrombotic events in children are initially treated with unfractionated heparin (UFH) or low molecular weight heparin (LMWH). For the extended anticoagulant therapy LMWH or vitamin K antagonists can be used with duration of treatment recommendations extrapolated from adult data. Mortality rates for PE in children are reported to be around 10%, with death usually related to the underlying disease processes. Exact data about recurrence risk in children is unknown. Because of the difference in aetiology, presentation, diagnostic methods and treatment between adults and children further research is necessary to assess the validity of recommendations for children. Crown Copyright ß 2011 Published by Elsevier Ltd. All rights reserved.

INTRODUCTION Pulmonary embolism (PE) is an uncommon and rarely fatal event in children. Over the last two decades there has been an increase in its recognition which has been attributed to an improved survival of previously lethal childhood diseases, an increase in use of central venous catheters and the increased availability of relatively non-invasive methods of diagnosing PE.1

* Corresponding author. Dept of Respiratory Medicine, The Children’s Hospital at Westmead, Locked Bag 4001, Westmead, Sydney, Australia, 2145. Tel.: +61 2 9845 3397; fax: +61 2 9845 3396. E-mail address: [email protected] (D.A. Fitzgerald). y Medical student, University of Groningen, Groningen, The Netherlands.

In adults, PE is the third most common acute cardiovascular disease.2 However, PE in neonates and children is not directly comparable to that in adults because of different risk factors and less specific clinical signs. Interestingly, the current recommendations for the assessment of PE in children remain based up on adult studies. This article reviews the published data on incidence (Figure 1), pathophysiology and management of pulmonary embolism in children, highlighting the similarities and differences with the assessment and management of PE in adults. EPIDEMIOLOGY The overall average age and sex adjusted annual incidence of venous thromboembolism is around 1-2:1000.3,4 The incidence is

1526-0542/$ – see front matter . Crown Copyright ß 2011 Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.prrv.2011.09.002

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40 35

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Age distribuon Number of events from pooled data, three studies

Incidence %

30 25 20 15 10 5 0

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18

Age Figure 1. Incidence in different studies of pulmonary embolism when diagnosed using V/Q scans in children with a variety of predisposing factors. Studies included range form 1986 to 2003.

strongly correlated with age and increases exponentially, with an incidence of almost 1% in people aged >75 yrs. PE is estimated to have an overall average age and sex adjusted annual incidence of 69:100,000.3 In children, PE is characteristically seen in combination with serious underlying medical disorders and the incidence is much lower. Studies report an incidence of 8.6–57:100,000 in hospitalized children,5,6 whereas the incidence in all children in the community is estimated to be 0.14–0.9:100,000.7,8 Because PE is often clinically silent and masked by symptoms of underlying diseases these numbers are probably an underestimate. Consistent with the under-diagnosis of PE in children are autopsy studies which report an incidence of 0.05–4.2%.9–12 (Figure 2) Buck et al. found in their autopsy study that only 50% of the children with PE had clinical signs and symptoms usually associated with PE, whereas the diagnosis was only considered in 15% of patients.11 The discrepancy in incidence number can be explained by other diagnostic criteria, the index of suspicion, difference in diagnostic methods and the inclusion of symptomatic or asymptomatic patients. Certain innate protective mechanisms in children might explain the difference in presentation and recognition of PE between adults and children. In children, these include a decreased capacity to generate thrombin caused by decreased plasma concentrations of prothrombin, an enhanced capacity to inhibit thrombin reflecting increased plasma concentrations of alpha-2 macroglobulin and differences in platelet/vessel-wall interaction.13,14 The age distribution of children with PE shows a bimodal pattern, with an initial peak in infants <1 year of age and a second peak during adolescence.5–7,11 In infants <1 year of age most cases are actually in neonates as shown in a Dutch report7 which

Incidence %

5

Figure 3. Age distribution in pediatric patients with a thrombotic event. Numbers are acquired from combined data from Andrew et al. (1994), van Ommen et al. (2001) and Gibson et al. (2003). Only one study included subjects over the age of 16 years which may influence the results.

highlighted that 47% of the PE cases in infancy occurred in neonates. (Figure 3) The Canadian and Dutch registries of thromboembolism found an equal sex distribution, which is similar to earlier studies in children7,11 and in adults when adjusted for age.15 PATHOPHYSIOLOGY In 1845, Virchow hypothesized that the pathological process underlying the development of thromboembolism consisted of stasis of blood flow, hypercoagulability or endothelial injury.16 Stasis is the main reason in adults.17 However, in children, injury to veins and hypercoagulability are the most important predisposing factors.18 PREDISPOSING FACTORS An important characteristic in children is the uncommon occurrence of idiopathic thrombosis, a traditional risk factor for PE. (Figure 4) Spontaneous thrombosis is suggested to occur in 0–4% of children with clots,5,19 whereas in adult studies idiopathic events represent 30% of the cases of thrombosis.20 At present, the greatest risk factors for the development of PE in children are the presence of a CVL, infection, and congenital heart disease. This is in contrast with adults, where PE is mostly caused by prolonged immobility, coronary heart disease, surgery, obesity, pregnancy and oral contraceptive use. However, in the last twenty

Incidence of PE in autopsy studies

4 3 2 1 0 Emery et al. 1962

Jones et al. 1966

Buck et al. 1981

Byard et al. 1990

Year of study Figure 2. Incidence of Pulmonary embolism in autopsy studies from 1962–1990.

Figure 4. Predisposing factors for pulmonary embolism in children. Data are extracted from Andrew et al (1994), van Ommen et al. (2001) and Biss et al. (2008).

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years oral contraceptive use has become a significant risk factor for thrombosis and PE in adolescents.21 To date, obesity as a risk factor for PE does not seem to contribute greatly in children.6,7 The presence of multiple co-existing risk factors is another marked finding in children.7,11,19,22 Data from a Canadian study showed 12.4% children with only one associated condition, 39.4% with two conditions, 35% with three conditions and 9.6% with four conditions predisposing to thrombosis.5 Pulmonary embolism is highly associated with DVT. In children, Biss et al identified DVT in 72.1% of their patients with PE,6 whereas in other studies the incidence is closer to 60%.23 In adults approximately 95% of the cases of venous thromboembolism are attributed to a lower extremity DVT, whereas in children upper extremity DVT is seen in up to 20% of the cases.5–7,11,19,24 This distribution is largely explained by the use of upper extremity and jugular/subclavian CVLs placed in small bore vessels in children. Currently, the most important predisposing factor for PE in childhood is the presence of a central venous line, which is increasingly being used in paediatric care for drug administration, parenteral nutrition and chemotherapy. Several studies have demonstrated a thrombotic event occurrence of 33% to 64% in children with a CVL, which increases further to 89%-94% in neonates alone.5–7 When a CVL becomes infected the chance of a thrombotic event increases even further.25,26 Indwelling CVLs may cause thrombotic complications from fibrin sleeves that are not adherent to vessel walls which can occlude the catheter tips. Furthermore, there can be altered blood flow and damage to the vessel wall, caused by the CVL itself or by the infused substances (eg. TPN, chemotherapy).27,28 Recent studies have also discussed the site of catheter placement and the insertion technique used as contributing factors for venous thrombosis.29 Some authors report a preferred placement of CVLs on the right side and in the brachial or jugular veins, contributing to lesser thrombus formation, whereas CVLs placed on the left side, in the subclavian or femoral vein and placed via the subcutaneous route are at a greater risk of developing a thrombotic event.29 Thrombophilia leads to an increased risk for a thrombotic event because of an inherited or acquired abnormality of the blood. Studies report an incidence of 9-35% in patients with a thrombotic event having either a congenital prothrombotic disorder and/or an acquired prothrombotic disease.5–7 In adolescents this number increases to 52%.6 However, these percentages may well be biased because of the low number of patients that have been tested. Furthermore, clinicians should be aware of the risks of thromboembolism and PE in children with vascular malformations, particularly of the lower limb, and syndromes that are associated with these such as the Klippel-Trenaunay syndrome, CLOVES (Congenital lipomatous overgrowth, vascular malformations and epidermal naevi syndrome) and Proteus syndrome. This is especially relevant if these patients are undergoing surgery, are pregnant, have a neoplasm or have suffered trauma.30,31 In adults, sickle cell disease leads to a fourfold increased risk of developing PE. Despite the fact this risk is not clearly known in children, studies suggest asymptomatic and symptomatic PE diagnoses in children are common in sickle cell disease. It should be highlighted that pulmonary infarcts in sickle cell disease are often due to fat embolism from infarcted bone marrow rather than from venous thromboembolism.32,33 The aetiology of PE in children with malignancy is multifactorial. There is the frequent use of central venous catheters for medications and blood product administration. Furthermore, coagulation abnormalities resulting from the disease itself or the treatment, and damage to the vessel walls or alterations in a number of haemostatic proteins due to the use of particular chemotherapeutic agents such as l-asparaginase predispose to

thrombosis.34 Data from a study in children with a haematological malignancy showed that 2.9% of the patients were diagnosed with symptomatic PE.35 In patients with nephrotic syndrome there is an increased occurrence of PE caused by the development of a hypercoagulable state. This has been attributed to urinary losses of antithrombin and free protein S, elevated FVIII levels, elevated fibrinogen and lipoprotein A, reduction in antithrombin and a hyperaggregability of platelets.36.37 PE was demonstrated in 28%–40% asymptomatic screened patients with nephrotic syndrome.37,38 This makes a high index of suspicion necessary, although raises questions about whether these findings warrant treatment. Adult patients suffering traumatic injuries have a higher risk of venous thrombosis, whereas in young children this is not proven, with an incidence of PE in paediatric trauma patients of only 7:100,000.39 CLINICAL SIGNS The diagnosis of PE on clinical signs is difficult, because the presentation can be non-specific and young children cannot accurately describe their symptoms. Further, PE can be hidden by underlying conditions. If there are symptoms consistent with a PE, the differential diagnosis includes pneumonia, atelectasis, intrathoracic malignancies and trauma. Clinical symptoms and signs of PE can include shortness of breath, pleuritic chest pain, cough, hypoxemia, haemoptysis, tachycardia, fever and syncope. Severe cases may present with pulmonary hypertension, evidence of right heart failure and cardiopulmonary arrest.6,23,40 Rarely, PE can present with abdominal pain, resulting from diaphragmatic irritation/pleurisy or hepatic congestion.41 In one study of adolescents diagnosed with PE, the most common presenting sign reported was pleuritic pain, seen in 84% of the patients.21 Dyspnoea (58%), cough (47%) and haemoptysis (32%) were other frequent complaints. Compared with adults there was less dyspnoea reported by adolescents.21 Physical findings included hypoxaemia, fever, deep-vein thrombosis of the lower extremity, tachypnoea, increased second heart sound and abnormal breathing sounds. The last three also occurred less in adolescents when compared with adults.21 The diagnosis of PE may be missed in children, as seen in autopsy studies,11 or delayed with Rajpurkar et al. reporting diagnoses made on average 7 days (range 1–21 days) after the onset of symptoms.19 In adults, clinical prediction rules for PE have been validated, such as the Well’s clinical probability score42 and the Geneva score43 which combine clinical signs and the presence of risk factors to assess the pre-test probability of PE. In children, such prediction rules have not been validated. Therefore, it is important to explore the presence of one or more risk factors which may give cause to start a diagnostic evaluation for PE. DIAGNOSTIC TESTING Because of the variability and the non-specificity of the clinical signs of PE, diagnostic imaging is necessary to either confirm or exclude the diagnosis. Even without any abnormal findings in laboratory results, blood gas or ECG, further investigation is implicated if PE is suspected. While organizing imaging for suspected PE, initial tests should be performed. Laboratory testing should include a full blood count with a differential white cell count and platelet count, prothrombin time (PT), partial thromboplastin time (PTT), and International Normalized Ratio (INR), thrombin time, fibrinogen level and D-dimer.44 During the plasmin-mediated fibrinolysis of fibrin, D-dimers are released and therefore elevated in a thrombotic event. D-dimer testing has a high negative predictive value and is an excellent triage test in

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adult patients.45 However, the test is not validated for use in children. Recent studies reported that a negative d-dimer was found in 13% to 40% of the children diagnosed with PE.6,19,46,47 Arterial blood gas (ABG) measurements and pulse oximetry (SpO2) have a limited role in diagnosing PE.48 The classic findings are hypoxaemia, hypocapnia and respiratory alkalosis on an ABG, but they are not always seen and therefore not that useful in making the diagnosis.48 Electrocardiography can show right axis deviation, right bundle branch block, a sinus tachycardia or, most often ST segment and T wave abnormalities in adult patients with PE. However, these findings are non-specific and not reliable in children.49 A pregnancy test may be considered in adolescent females. Imaging Diagnostic imaging for PE includes pulmonary angiography, ventilation / perfusion (V/Q) scanning, computed tomography (CT), magnetic resonance imaging (MRI) and echocardiography. As there are no reports about the sensitivity and specificity of these tests in children, recommendations about the usage and the interpretation of these tests are obtained from adult studies. Chest X-ray The chest X-ray is not particularly useful for diagnosing PE, but can be helpful in excluding other conditions, such as pneumothorax or pneumonia.50 Non-specific signs seen in patients with PE include parenchymal infiltrates, atelectasis and an ipsilateral pleural effusion. More specific signs that are difficult to compute include Westermark’s-sign (oligaemia in parts of the lung affected by the emboli) and Hampton’s hump (a peripheral wedge-shaped density with the peak directed to the hilum).23,49,51

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Table 1 Genetic and Acquired conditions of thrombophilia High probability 2 large (>75% of a segment) segmental perfusion defects without corresponding ventilation or radiographic abnormalities 1 large segmental perfusion defect and z2 moderate (25–75% of a segment) segmental perfusion defects without matching ventilation or chest radiographic abnormalities 4 moderate segmental perfusion defects without corresponding ventilation or chest radiographic abnormalities Intermediate probability 1 moderate >2 large segmental perfusion defects without corresponding ventilation or radiographic abnormalities Corresponding V/Q defects and radiographic parenchymal opacity in lower lung zone Single moderate matched V/Q defects with normal radiographic ndings Corresponding V/Q defects and small pleural effusion Difficult to categorize as normal, low or high probability Low probability Multiple matched V/Q defects, regardless of size, with normal radiographic ndings Corresponding V/Q defects and radiographic parenchymal opacity in upper or middle lung zone Corresponding V/Q defects and large pleural effusion Any perfusion defect with substantially larger chest radiographic abnormality Defects surrounded by normally perfused lung (stripe sign) >3 small segmental perfusion defects (<25% of a segment) with a normal chest radiograph Non-segmental perfusion defects (cardiomegaly, aortic impression, enlarged hila) Very low probability 3 small segmental perfusion defects (<25% of a segment) with a normal chest radiograph Normal No perfusion defects and perfusion outlines the shape of the lung seen on chest radiographs Data is extracted from Heit et al. (2000), Johnson et al. (2010) and Goldhaber et al. (2010). PIOPED interpretation criteria of ventilation-perfusion (V/Q) in adults. (Worsley).

Pulmonary angiography The gold standard for diagnosing PE is pulmonary angiography. Contrast is injected into a pulmonary artery branch after percutaneous catheterization, usually via the femoral or jugular vein. Filling defects or an abrupt ending of a vessel suggests an embolus.52 The Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED) study reported a low morbidity and mortality of the procedure, 5% and 0.5% respectively, and definitive diagnosis was obtained in up to 96% of the patients with PE.53 It is however, an invasive method and not available in every centre. This test in children requires general anaesthesia. Inter-observer variation has been noted in the interpretation of pulmonary angiography because of the complexity of the images.54 Therefore, the test is, in both children and adults, increasingly being replaced by less invasive methods.55 Radionuclide scintigraphy Historically, ventilation/perfusion (V/Q) scintigraphy, has been the primary diagnostic test in adults and in children.5,19,56 It is considered to be a safe and sensitive procedure without needing iodinated contrast agents. Also, it is easy to perform, which is an important consideration for the use in children. There is however the risk of causing hypoxemia.57 V/Q mismatches can also been seen in several other diseases, namely congenital and acquired arterial stenosis, tuberculosis, air, fat and foreign body embolism, pneumonia and sickle cell disease.58,59 Interpretation can also be difficult because of underlying diseases, such as congenital heart disease, especially those with right-to-left shunts and high haematocrits.23

It should be pointed out that the validity of the PIOPED interpretation criteria used for the classification of V/Q scans has not been established in children. (Table 1) In adults the PIOPED study reported a clinically useful diagnostic value of a high-probability scan with a chance of more than 85% that the patient has PE. However, as the specificity is low, there is still a 20% chance of having PE when a patient has a low probability V/Q scan. Furthermore, there are often non-diagnostic scans, almost 75% of patients with clinically suspected PE having a low or intermediate probability scan.56 These patients are in need of further diagnostic investigations. CT angiography The helical CT pulmonary angiography (CT-PA) has become the diagnostic method of choice in adults who are suspected of PE.60 Two recent paediatric studies reported a high diagnostic performance of CTPA for diagnosing PE in children, using multislice spiral CT technology.61,62 CTPA reports visualization to sixth-order pulmonary artery branches with additional evaluation of mediastinal and parenchymal structures and direct thrombus visualization.63,64 An advantage is the identification of other disorders when no embolism is found.64 Other putative advantages are the cost-effectiveness and the quick performance, which makes it a useful test in the acute or critically ill patient.65 Even though, with current multidetector technology, the scan is quick (1-6 seconds depending on machine type and patient size) the child must be as immobile as possible for a diagnostic study and general anaesthesia may be needed. The child requires a secure 20G (possibly 22G) intravenous cannula for rapid pump injection of iodinated contrast. Furthermore, infrequent use of the test in

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Figure 5. Algorithm for diagnostic testing when pulmonary embolism is suspected in children.

paediatric hospitals means interpreting radiologists may not be as nuanced to diagnostic interpretation of CTPA as adult colleagues. However, the principle concern with the use of CTPA in children is radiation dose.66 In children there is an increased radiosensitivity in certain tissues, such as the thyroid gland, breast tissue and the gonads.67 The chance of developing cancer from exposure as a child is also raised, a term described as latency: the longer lifetime of cells after being exposed to radiation. Recommended dose reduction methods are reduced milliamperes per second (mAs), use of automatic exposure control and the use of reduced irradiation.68,69 CTPA was included in PIOPED II but again, these are adult data. This study showed a CTPA sensitivity of 83%, which increased to 95% when a combination of CT venography and CT angiography was used. The specificity was 95%, which stayed almost the same (96%) with CT angiography and CT venography used together. However, sensitivity varies among different lung regions, with positive predictive value of only 25% in the subsegmental branches.70 There has been no multicentre trial in children. Kritsaneepalboon et al. pooled available paediatric data on CTPA and found a false positive rate of 9.3% and 2.4% false negative.60 The clinical signicance of these isolated subsegmental emboli is still unclear. Thus a normal helical CT scan does not totally exclude the diagnosis of PE.

Oudkerk et al reporting a sensitivity of 100%, 84% and 40% in respectively the lobar, segmental and subsegmental vessels.73 Other disadvantages are the general lack of access, long examination time, and difficulty monitoring critically ill patients in the MR suite.23 Also, in younger children, there is the need for general anaesthesia. However, the continuing technologic advances offer promise for an expanded role of MRA in the future; for instance with the use of real-time MR imaging.74,75 Echocardiography Echocardiography, either transoesophageal or transthoracic views, makes it possible to visualise thrombi directly within the heart and central pulmonary arteries. Signs that are indirectly associated with pulmonary embolism may also be seen. These include right ventricular dilatation and hypokinesis, abnormal motion of the interventricular septum, tricuspid regurgitation, and lack of collapse of the inferior vena cava during inspiration.76 Although not classified as a routine diagnostic test for PE, echocardiography can contribute to differentiating between massive pulmonary embolism and other causes of haemodynamic instability. This is useful in the critically ill patient when additional and more-invasive testing is not possible.77,78 Deep Venous Thrombosis

Magnetic resonance angiography Magnetic resonance pulmonary angiography (MRPA), enables evaluation of the pulmonary arteries without using radiation. The use of gadolinium as a contrast agent makes it also a useful test for patients who are allergic to iodinated contrast material.71 Furthermore, with MRPA it is possible to image the upper body and central venous system, together with the pulmonary arteries in the same investigation. This is useful for children with central venous lines. The sensitivity of MRPA ranges from 77-100% with a specificity 95%.72 Like CTPA it is also difficult to correctly evaluate the subsegmental arterial branches with MRPA, with data from

Recently, venography, which is the historical gold standard method for evaluating DVT, has been replaced by non-invasive or minimally invasive radiologic imaging modalities.78 Ultrasonography is typically being used to diagnose DVT, as it also defines the extent and the degree of occlusion of the thrombosis79 However, it is less sensitive for detecting thrombi in the pelvic or abdominal veins and the central upper venous system and additional testing may be necessary in those veins.80 There is no widely accepted algorithm for children, so we include a proposed one for the assessment of children with a suspected PE. (Figure 5)

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TREATMENT There are different management options for children with PE, including supportive care, anticoagulant therapy with unfractionated heparin (UFH), low molecular weight heparin (LMWH), vitamin K antagonist, thrombolysis, IVC filters and thrombectomy. It depends on the individual condition of the patient as to which treatment is preferred. Because of the lack of large studies in children, therapy recommendations are obtained from adult clinical trials and a few smaller paediatric studies. Before starting treatment laboratory investigation for the evaluation of genetic or acquired conditions causing thrombophilia should be considered. (Table 2) Unfractionated Heparin Unfractionated heparin (UFH) is the most frequently used anticoagulant agent in paediatric care for treating a thrombotic event.5,7,19 Its action depends on catalysing the ability of antithrombin to inactivate specific coagulation enzymes, in particular thrombin and Factor Xa.81,82 The activity of heparin is measured against the prolongation of the activated partial thromboplastin time (aPTT), and the goal is to maintain aPTT in the range of 1.5-2.5 times the patient’s baseline value. Corresponding therapeutic ranges of heparin blood concentration, by protamine titration, are 0.2–0.4 U/mL.83 The aPTT is influenced by many factors and data from paediatric patients report an inaccurate aPTT approximately 30% of the time.84 Anti-factor Xa levels may also be used in the monitoring, with therapeutic ranges of 0.3–0.7 U/ml.83 Initial heparin dosing begins with an intravenous 75–100 units/kg bolus over 10 minutes. The following maintenance doses are age dependent. (Table 3) Advantages of UFH are its rapid onset of action, short half-life and the fact that it can be neutralised by protamine sulphate given intravenously.83 Disadvantages are that a continuous intravenous infusion is necessary and that the clinical dose response can be unpredictable because of the binding properties of heparin to plasma proteins.82 The most common complication to occur is bleeding, with one study reporting an incidence of 2% in paediatric patients.84 However, many children were treated with suboptimal amounts of heparin. The relationship between heparin and osteoporosis is being further explored in adult studies.85 Although the complication is rarely reported in children current practice is to avoid long term administration of heparin. Heparin-induced thrombocytopenia (HIT) can be a life-threatening complication, caused by heparin-dependent antiplatelet antibodies.86 It seems to be relatively uncommon in childhood, with a higher incidence reported in the paediatric ICU.87 If HIT is present, all forms of heparin (including LMWH) should be discontinued and an alternative anticoagulation (danaparoid, hirudin, or argatroban) strategy should be considered.88 Low-molecular-weight heparin Low-molecular-weight heparins are fragments of heparin obtained by chemical or enzymatic polymerization. The anticoagulant action depends on catalysis of antithrombin. Although this is the same mechanism as heparin, LWMHs have only a high specific activity against Factor Xa and less activity against thrombin.89 As a consequence, monitoring of LMWH is not possible by using aPTT values, but should be done by using the anti-factor Xa assay. The therapeutic range is 0.5–1.0 U/mL, whereas prophylactic levels are 0.1–0.3 U/mL.90 Dosing guidelines have been established for enoxaparin, dalteparin, reviparin and tinzaparinm, which are age dependent, with neonates requiring an increased dose per body weight, in

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Table 2 Genetic and Acquired conditions of thrombophilia Genetic and Acquired conditions of thrombophilia Genetic

Acquired

Protein C deficiency

Antiphospholipid syndrome, with lupus anticoagulant as seen in SLE, anticardiolipin antibodies or anti-b2-glycoprotein1antibodies Acquired antithrombin, protein C, protein S abnormalities Elevated plasma factor VIII activity Exogenous oestrogen therapy (oral contraceptive use) Nephrotic syndrome Inflammatory Bowel Disease Pregnancy Diabetes mellitus Hyperlipidaemia Diffuse intravascular coagulation Heparin induced thrombocytopenia Paroxysmal nocturnal haemoglobinuria

Protein S deficiency Factor V Leiden Prothrombin G20210A polymorphism Lipoprotein (a) elevation Antithrombin III deficiency Hyperhomocysteinemia Thalassemia Sickle cell disease Plasminogen deficiency Fibrinolysis impairment Elevated plasma factor VIII activity

Data is extracted from Heit et al. (2000), Johnson et al. (2010) and Goldhaber et al. (2010).

contrast with older children. This might be due to a larger volume of distribution. Peak anti-FXa levels occur 2-6 h following a subcutaneous LMWH injection.91,92 LMWH is becoming the anticoagulant agent of choice in in children because of several advantages over UFH.83 LMWH has a greater bioavailability, longer half-life and a more predictable anticoagulant response. Furthermore there is minimal laboratory monitoring and it can be administrated subcutaneously, which is important in children with poor venous access.81,82 Bleeding is the most common complication with reported bleeding risk rates of up to 5% with LMWH treatment.93–95 LMWH is not as easily reversed with protamine sulphate as UFH, because there is only partial neutralisation of the anti-FXa activity.83 Compared with UFH, there is a reduced risk of HIT, and probably a reduced risk of osteoporosis development with long-term use of LMWH.96 Recommendations for the duration of the initial heparinization therapy are extrapolated from adult data and begin at 5 days.97 When there is extensive PE this should be extended to 710 days.83 Extended anticoagulant therapy can be either by the use of LMWH or oral anticoagulant therapy (vitamin K antagonist).78 Vitamin K antagonists Vitamin K antagonists (warfarin, acenocoumarol, phenprocoumon) function as anticoagulants by inhibiting the production of vitamin K-dependent coagulation proteins (factors II, VII, IX, and X).98 The production of anti-coagulant proteins C and S are also inhibited by vitamin K antagonists, which can lead to an increase in procoagulant effects.90 Activity is monitored via the prothrombin time (PT), reported as an international normalized ratio (INR).This is validated in laboratory and home settings in children.99 The INR therapeutic range is 2.0–3.0.83 However, monitoring children is difficult and they require more frequent measurements and dose adjustment when compared with adults. This is because of vitamin K levels may vary with dietary intake, medication use and underlying clinical conditions (eg malabsorption).100,101 Furthermore, underlying diseases and the use of medications are very common in children with a thrombotic event, thus complicating the dose requirements for vitamin K antagonists.100

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Table 3 Treatment recommendations of conventional antithrombotic agents in children with Pulmonary Embolism Drug

Loading dose

Maintenance dose

Monitoring

Therapeutic range

Duration of therapy

Unfractionated Heparin

75 U/kg iv. over 10 min

Infants < 1 yr 28 U/kg iv Children > 1 year 20 U/kg iv

Determine APTT after 4 hours of initial bolus dose, and 4 hours after every change in the infusion rate. When therapeutic check daily.

0.2–0.4 U/l Heparin level or 0.3–0.7 U/ml anti-factor Xa level

5 to 10 days

Weight < 5 kg 150 U/kg/ dose each 12 h sc Weight > 5 kg 100 U/kg/ dose each 12h sc

Determine anti-factor Xa level 4-6 hours after subcutaneous injection.

0.5-1.0 U/mL anti factor Xa level

5-10 days for initial heparinization therapy For extended treatment:

LMWH Reviparin Enoxaparin

First episode With reversible risk factor: 3-6 months Idiopathic: 6-12 months With chronic clinical risk factor: 12 months-lifelong Recurrent episode With reversible risk factor: 6-12 months Idiopathic: 12 months-life long With chronic clinical risk factor: life long

Dalteparin Age < 2 months 1.5mg/kg/ dose each 12h sc Age >2 months 1.0 mg/kg/ dose each 12h sc

Tinzaparin

All age 126  43 U/kg/ dose each 12h sc

Vitamin K antagonists Warfarin Acenocoumarol Phenprocoumon

Thrombolytic therapy tPA

0.2 mg/kg

Age 0–2 months 275 U/kg 2–12 months 250 U/kg 1–5 yr months 240 U/kg 5–10 yr months 200 U/kg 10–16 yr months 275 U/kg Subsequent dose adjustments based on INR

0.1-0.6 mg/kg/h iv for 6 hour

Frequent monitoring with close supervision

INR 2.0-3.0

Clinical monitoring important. INR, aPTT, fibrinogen determines need for cryoprecipitate and/or plasma replacement. D-dimer or brin degradation products determines presence of fibrinolysis.

Fibrinogen concentration < 1 g/L Platelet count > 50-100 x 109/L.

Firs episode: with reversible risk factor: 3-6 months idiopathic: 6-12 months with chronic clinical risk factor: 12 months-lifelong Recurrent episode: with reversible risk factor: 6-12 months idiopathic: 12 months-life long with chronic clinical risk factor: life long

Data extracted from Monagle et al. (1994), Goldenberg et al. (2010) and Long et al. (2011).

Bleeding is the main complication of vitamin K antagonist treatment, with data reporting an incidence of 1% per year in children requiring warfarin.100 An increase in INR by 0.5 can multiply the risk of major bleeding by 1.43.102 For reversing the effects of excess anticoagulation or when there is significant bleeding, vitamin K and/or fresh-frozen plasma (FFP), prothrombin complex concentrates, or recombinant factor VIIa can be administrated effectively.83 Non-haemorrhagic complications are uncommon and include alopecia, rash, and tracheal calcification.103 A reduced bone density, which can lead to osteoporosis, was reported in two cohort studies looking at children who have received warfarin for >1 year.104,105 The administration of vitamin K should initially be combined with heparin for at least 5 days. If the INR is in his therapeutic range for two consecutive days the heparin can be stopped. Recommendations about the duration of the anticoagulant therapy in venous thromboembolism are derived from the results in adult studies. It is important to balance the risk of bleeding against the risk of recurrence. The administration of oral anticoagulant can be difficult. It does not dissolve in water and because of the attachment to plastic it

can’t be given through a plastic syringe or tube. Our practice is to administrate it crushed under the child’s tongue. For the recommended duration of antithrombotic therapy see Table 3. Thrombolytic agents The activity of thrombolytic therapy is mediated by converting endogenous plasminogen to plasmin, which is active in fibrin breakdown. Thrombolytic agents commonly used in paediatric care are urokinase (UK), streptokinase (SK) and tissue plasminogen activator (tPA). tPa has become the agent of choice.106 A further consideration exists when using tPa in neonates because newborns have decreased levels of plasminogen and there is slow generation of plasmin and therefore a reduced effect of the thrombolytic agents. Supplementation of fresh frozen plasma as a plasminogen source before or during treatment with thrombolytic agents might also be helpful.107 Studies have demonstrated the efcacy and safety of thrombolytic agents in adults, but the results in children are variable and it is advised not to use thrombolytic agents routinely for the treatment

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of venous thrombo-embolism.83 However, it is recommended as a first line therapy for hemodynamically significant PE, without the presence of contraindications.36 There is no consensus about the route of administration. It seems that local therapy, compared with systemic, may be more appropriate for the treatment of catheter-related thrombotic events when the catheter is already in situ.83 Major bleeding complications are significant in thrombolytic therapy, with bleeding occurring in 68% of patients in the Gupta study; which included 39% of subjects who required transfusion.106

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effective. Successful data are reported from studies with neonates and infants undergoing surgical embolectomy.111 However, it is a complicated technique, and the mortality rate is as high as 64%.112 Catheter thrombectomy techniques include: aspiration thrombectomy, fragmentation thrombectomy, rheolytic thrombectomy and mechanical thrombectomy.113 Although there is no evidence that one strategy is better than the others, catheter fragmentation seems to be the most commonly used method. Although there are significant risk factors such as vessel perforation or damage, worsening of hemodynamic parameters due to distal embolization and bradycardia, data suggests that catheter thrombectomy is a viable alternative to surgical therapy.113

New anticoagulants Vena cava filter New anticoagulant agents being studied are factor Xa inhibitors, such as fondaparinux and direct thrombin inhibitors, which include bivalirudin and argatroban. Recently, the only validated reason for the use of one of these anticoagulants is in patients with HIT, because heparin and LMWH need to be withdrawn and for the acute treatment vitamin K antagonists are not suitable.107–109 It has been suggested that Bivalirudin might also be in indicated for children undergoing percutaneous interventions, where it would replace heparin.108 Fondaparinux has been used for both prophylaxis and treatment in thrombotic events in adults. Reports suggest that it is safe to use and, because it has a longer half-life when compared to LMW, only once-daily dosing is necessary with less frequent monitoring. There is no risk of HIT and it has no effect on bone metabolism.108–110 Before these new medicines are routinely used, it is important that they are studied further in children to determine efficiency, safety and optimal dosage.

Inferior vena cava (IVC) filters may be indicated in children who have contraindications to anticoagulation or have recurrent PE despite anticoagulation, with the required condition of having large enough vessels (more than 10 kg in weight).114 IVC filters have been successfully placed and retrieved in children with IVC of 1 cm in maximal diameter.115 The placement of a device in the IVC can be used temporarily at times of increased risk of thromboembolism or for the longer term with a retrievable rather than permanently placed device, when there is an ongoing risk for PE. Both seem to be successful. Implementation time can be prolonged safely by serial repositioning of the filter.115 Permanent placement of an IVC device is not recommended, because the lack of experience with surgical removal and the chance of complications, such as incorporation of the filter into to vessel wall.116–118 General complications of IVC devices include thrombosis at the distal and proximal filter sites, malpositioning, migration and potentially pneumothorax.116

Thrombectomy OUTCOME Thrombectomy, which can either be surgical or via a transvenous catheter, is reserved for massive PE or in haemodynamically unstable patients when thrombolysis is contraindicated and there is insufficient time for anticoagulation therapy to be

Studies report a mortality rate of PE in children is around 10%., but the number of children tested for PE in those studies was low.6,7 In adults, the mortality rate within 3 months of PE ranges

Table 4 Pulmonary Embolism differences between children and adults123–128

Incidence Pathophysiology Origin of thrombus

Cause of thrombosis Predominant Risk factors

Children

Adults

Uncommon, incidence 0.14-4.6:100.000 Injury to veins main reason Besides lower extremity veins origin (30%), also role for upper extremity veins, right heart, pelvis, or renal veins Rarely spontaneous event (0-4%) CVL Infection Immobility Congenital heart disease Surgery

Third most common acute cardiovascular disease, incidence 1-2:1000 Stasis of blood important factor Most from deep venous system lower extremity (95%)

Traumatic injury Presenting signs

No risk factor Pleuritic pain most presenting complaint

Physical findings

Hypoxemia, fever, ECG abnormalities not reliable Not valid CTPA choice of diagnostic test, but with radiation doses reduction and strategies to minimize the radiation exposure Dose adjustments for UFH, LMWH and vit. K antagonists Thrombolysis not advised aPTT not valid for monitoring UFH Better outcome, mortality 10%, recurrence rate 7%-18,5%,

Prediction rules Diagnostic methods

Treatment

Outcome

Often idiopathic (30%) Immobility Coronary heart disease Surgery Obesity Pregnancy Oral contraceptive use Traumatic patients more at risk Dyspnoea and pleuritic pain most common Tachypnea, hypoxemia, abnormal breathing sounds, increased second heart sound, ECG abnormalities Well’s score and Geneva score useful to assess PE probability CTPA

UFH, LMWH, vit. K antagonist and thrombolysis

Mortality 8.9%-17.4%. Recurrence rate 7-9%-30.7% (heit, goldhaber)

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from 8.9%-17.4%. (For a summary with PE differences between children and adults see Table 4).119–121 The cause of death in paediatric patients with PE is usually related to the underlying disease processes. Biss et al.6 reported in a high mortality rate (21.4%) in children with PE, but only 8.9% of the deaths were directly related to thromboembolism. The most common underlying diagnoses in the children that died, were congenital heart disease and malignancy, assuming that these may attribute to a poorer prognosis.6 Similar results are reported by the Canadian Childhood Thrombophilia Registry of catheter-related venous thrombosis.122 The reported recurrence rates for PE ranges from 7%-18.5%,6,7,107,122 but these numbers were associated with VTE of all types, and do not reflect the recurrence risk of PE alone. However, identifying patients who have an increased risk of a recurrent thrombotic event is important, because of the possibility of continuous anticoagulation treatment.6 CONCLUSION In children pulmonary embolism is a rare condition, but its incidence is likely to be underestimated. Because of an increasing number of risk factors, such as central venous lines and an increase in survival of children with chronic disease, it is becoming an important consideration in children with complex conditions. More knowledge about the true incidence and the aetiology are important. Recommendations about diagnostic measures and therapeutic management are generally derived from results in adult trials and therefore it is necessary that they become evidence based for children as well. This is especially the case with the recent development of new antithrombotic strategies. Finally, uncertainty remains about the mortality rate, recurrence risk and the chance of complications in paediatric pulmonary embolism. Multicentre randomised controlled trials are essential to further investigate and discover the characteristics of pulmonary embolism to improve care and clinical outcomes in children. FUTURE RESEARCH Future research for PE in children should address:     

Investigating the true incidence of PE. The creation of valid prediction rules. Specific diagnostic methods of identifying PE Evidence based treatment recommendations for management. The investigation of mortality rate, recurrence risk and complications.

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MEDICAL EDUCATION QUESTIONS 1. Which, if any, of the following are important predisposing factors in the development of PE in children? a. Obesity b. Central venous lines c. Traumatic injury d. Prolonged immobility e. Malignancy 2. With regards of diagnostic testing, which of the following is true? a. The gold standard test for diagnosing PE in children is V/Q scintigraphy. b. The reported mortality rate in pulmonary angiography is around 5%. c. An advantage of CTPA over MRPA is the possible finding of other disorders when no embolism is found. d. CTPA and MRPA are both unreliable tests in the visualization of the subsegemantal arterial branches. e. Echocardiography can be a useful test in the critically ill child suspected of having PE

119. Carson JL, Kelley MA, Duff A, et al. The clinical course of pulmonary embolism. N Engl J Med 1992;326:1240. 120. Goldhaber SZ, Visani L, De Rosa M. Acute pulmonary embolism: clinical outcomes in the International Cooperative Pulmonary Embolism Registry (ICOPER). Lancet 1999;353:1386. 121. Nijkeuter M, So¨hne M, Tick LW, et al. The natural course of hemodynamically stable pulmonary embolism: Clinical outcome and risk factors in a large prospective cohort study. Chest 2007;131:517. 122. Monagle P, Adams M, Mahoney M, et al. Outcome of pediatric thromboembolic disease: a report from the Canadian Childhood Thrombophilia Registry. Pediatr Res 2000;47:763–6. 123. Nuss R, Hays T, Manco-Johnson M. Childhood thrombosis. Pediatrics 1995;96(2 Pt 1):291–4. 124. Massicotte MP, Dix D, Monagle P, Adams M, Andrew M. Central venous catheter related thrombosis in children:analysis of the Canadian Registry of Venous Thromboembolic Complications. J Pediatr 1998;133:770–6. 125. Levy DM, Massicotte MP, Harvey E, Hebert D i, editors. Thromboembolism in paediatric lupus patients. Lupus 2003;12:741–6. 126. Goldhaber SZ. Risk factors for venous thromboembolism. J Am Coll Cardiol 2010;56:1–7. 127. Heit JA, Mohr DN, Silverstein MD, Petterson TM, O’Fallon WM, Melton 3rd LJ. Predictors of recurrence after deep vein thrombosis and pulmonary embolism: a population-based cohort study. Arch Intern Med 2000 Mar 27;160: 761–8. 128. Worsley DF, Alavi A. Comprehensive analysis of the results of the PIOPED study. Prospective investigation of pulmonary embolism diagnosis study. J Nucl Med 1995;36:2380–7.

3. Please mark true or false with regarding heparin treatment for PE a. Therapeutic anti factor Xa levels for UFH are 0.3-0.7 U/ml. b. Osteoporosis is a significant complication of heparin use in children. c. The risk of developing HIT is comparable by using either UFH or LMWH. d. Actions of UFH and LMW can be (partly) reversed with oral protamine sulphate. e. The initial treatment of vitamin K should be combined with the administration of heparin for at least 5 days. 4. Which of the following is true regarding PE treatment in general? a. The INR therapeutic range when using a vitamin K antagonist is 2.0-3.0. b. The recommended duration of antithrombotic therapy when there is recurrent PE should be a period of 3-6 months. c. The first agent of choice in thrombolytic therapy is streptokinase. d. Catheter thrombectomy is an acceptable alternative to surgical therapy e. IVC filters can be safely used as a permanently placed device. 5. With regard to of the pulmonary embolism differences between adults and children, which of the following is true? a. Stasis in blood flow in both adults and children is the main pathophysiological hallmark of developing PE. b. Spontaneous thrombosis is more common in children than in adults. c. Venous emboli originate in adults in 95% of the cases in the lower extremity, an equal number is reported in children. d. Determination of D-dimer levels when PE is suspected is a validated test for both adults and children. e. As a clinical sign of PE, dyspnoea is more often seen in adults than in children.