Key Points

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  Pulmonary embolism (PE) carries a high risk of mortality and is underdiagnosed in children.

  
  
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  PE is a complication of venous thromboembolism (VTE).

  
  
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  The highest risk for VTE is the use of a central venous line, but congenital heart disease is also a significant, independent risk factor.

  
  
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  The symptoms of PE in children are variable but unlikely if tachypnea and hypoxia are absent. Timely diagnosis requires a high degree of suspicion.

  
  
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  Adult diagnostic algorithms for PE do not apply to children.

  
  
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  Computed tomography pulmonary angiography is the most sensitive and specific diagnostic modality for PE in children.

  
  
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  The treatment of PE requires anticoagulation at the minimum.

  
  
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  If assays for anti-factor X _a are immediately available and surgery is not imminent, low-molecular-weight heparin is the first-line drug of choice in the treatment of PE.

  
  
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  Systemic thrombolysis may be considered in an unstable child with an imminent risk to life, but bleeding complications are significant.

  
  
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  When systemic thrombolysis is contraindicated, surgical or catheter-based embolectomy may be considered on a case-by-case basis in experienced centers.

Pathophysiology

Physiologic factors promoting the formation of venous thromboembolism (VTE) are well defined ( Box 74.1 ). Virchow first described his famous “triad” over 100 years ago. His work suggested that a hypercoagulable state, venous stasis, and endothelial injury promoted both thrombus formation and clot growth. Although the quantitative degree to which each of Virchow’s points contributes to thrombus formation will never be known, there is no denying that each increases the risk of VTE and therefore pulmonary embolism (PE).

The body’s natural coagulation pathway begins with the exposure of tissue factor (TF) on the cell surface. Even the most insignificant cellular damage exposes TF and initiates the coagulation cascade. When TF is uncovered, factors VII, V, and X are then activated locally. Their activation triggers a burst of thrombin activity and massive factor IX activation. Clot amplification then proceeds rapidly as thrombin and factor V _a activate platelets and factor VIII. At the terminal end of the cascade, fibrinogen is cleaved into fibrin, and the clot is stabilized by activated factor XIII.

Unchecked, thrombus formation would be catastrophic. Fortunately, fibrinolysis begins in concert with coagulation. Fibrinolysis slows thrombus formation and keeps it localized. Protein C, protein S, antithrombin (AT), and TF pathway inhibitor activation promote degradation of fibrin to fibrin degradation products simultaneously with clot formation. It is the balance of fibrinolysis and coagulation that determines the actual rate of clot formation as well as its terminal vascular extent.

The repair of any congenital heart disease (CHD) creates the perfect conditions for clinically significant clot formation. The abnormal anatomy of the heart with CHD, by definition, decreases cardiac output and promotes abnormal flow dynamics even before repair. Cardiopulmonary bypass increases this low-flow status, dilutes both the procoagulation and anticoagulation factors, activates platelets, and initiates massive systemic inflammation. Even myocardial and neurologic protective strategies, such as hypothermia and hypothermic arrest, promote a hypercoagulable state. The Virchow triad is completed by the cardiac surgery itself. By definition, cardiothoracic surgery causes direct vascular damage that exposes TF in both major vessels and the heart itself.

Following cardiac surgery, inflammation, myocardial stunning, and imperfect hemostasis further predispose the postoperative patient to thrombus formation in an unpredictable fashion. The postbypass low cardiac state increases venous stasis. Medical management using platelets, fresh frozen plasma, cryoprecipitate, and polycythemia further increase the hypercoagulable physiologic status to variable degrees. Combined with multiple central venous lines (CVLs) and direct atrial and/or ventricular access, the cardiac patient’s postoperative physiologic state creates a perfect storm for VTE and therefore VTE complications.

Venous Thromboembolism

Because PE is considered a complication of VTE, clinicians should suspect a venous thrombus in any patient presenting with PE. Unlike adults, deep venous thrombosis (DVT) in children is rarely idiopathic (<4%) and, more often than not, is associated with CVL usage. CHD, surgery, immobility, and hypovolemia are also significant risk factors for DVT formation. In the absence of a CVL, especially in patients with recurrent VTE, thrombophilia should also be considered. The most common thrombophilic disorders in children include protein S deficiency, protein C deficiency, factor V Leiden mutation, prothrombin G20210A mutation, hyperhomocysteinemia, and elevated lipoprotein A.

Venography is still considered the gold standard for locating DVTs, but ultrasonography (US) is not only rapid, but less invasive and quite sensitive. In proximal DVTs, US has a sensitivity of 97% and a specificity of 94%. In contrast to the lower extremities, US detection of clot in the upper limbs is difficult, especially when the clot occurs in the subclavian or deeper central veins. Upper extremity thrombus detection may still require venography for complete assessment. Similarly, US may not allow visualization of the pelvic veins at all. Echocardiography remains the modality of choice for visualization of intracardiac, central inferior vena cava, superior vena cava, and central pulmonary artery thrombi. Because CVLs pose the greatest risk for VTE, any search for venous thrombus should initially focus in and around sites of CVL placement.

Incidence of Pulmonary Embolism

PE is a complication of VTE. Studies examining the incidence of PE in children report an incidence of 8.6 to 57 in 100,000 in hospitalized children. This wide-ranging incidence in hospitalized children may be a manifestation of the “often clinically silent nature of PE, misdiagnosis, more comprehensive reporting, or a function of the biased population of a tertiary care center.” There appears to be a predilection for pediatric PE in infants and toddlers, with a second peak seen in teenagers. Black children are estimated to have an incidence 2.38 times higher than white children. However, it is likely that these numbers are underestimated due to the frequent asymptomatic presentation of PE in children as noted earlier. Autopsy data show discordance in the rate of actual PE presence in comparison with a clinical suspicion of PE. In one study the diagnosis of PE was considered in only 15% of patients with pathologically detected PE. In contrast to adults, the time to diagnosis of PE in children is often longer, with a mean time to diagnosis as high as 7 days in some studies. Therefore it is paramount that the clinician have a high index of suspicion for timely and effective care for children with PE.

Almost 60% of pediatric patients with PE have a significant clot at another location. In contrast to adults, most pediatric VTEs are found in an upper extremity rather than the lower. When all pediatric hospital admissions are considered, the incidence of VTE is approximately 5 per 10,000 admissions. The incidence is higher in the neonatal intensive care setting. One study found 24 individual thrombi in 10,000 admissions.

Although any critical illness can promote VTE formation, only 3.6% of pediatric patients hospitalized for PE lacked identifiable risk factors for VTE. In nearly every study of pediatric inpatients to date, the presence of a CVL posed the single greatest risk for thrombus development. Not unexpectedly, bed rest for 3 or more days and recent surgery with general anesthesia also promote clot formation. VTE risks in adults are similar to those of children, but, in that population, mechanical ventilation and hospital length of stay are also important. Interestingly, for outpatient pediatric patients presenting with PE as their primary diagnosis, obesity appears to be the most significant risk factor.

The incidence of PE in pediatric patients is unclear. In children with a high clinical suspicion of PE, a PE was present in only 15% of those patients. A Canadian data registry study of children with VTE demonstrated PE in 0.86 children per 10,000 hospital admissions (0.14 to 0.9 events per 100,000 children). When autopsy studies are considered, almost 4% of pediatric patients dying from any cause had gross or microscopic evidence of PE.

Symptomatic PE in childhood is extremely rare and is underdiagnosed in pediatric patients for a number of reasons. First of all, because the symptoms of PE are extremely variable, without a high index of suspicion the diagnosis of PE will not be pursued. Following the development of rapid high-resolution computed tomography (CT) scans, diagnosis of PE in both adult and pediatric patients has become easier. The incidence of PE has risen concomitantly. Unexpectedly, as the use of CT in the diagnosis of PE rises, mortality from PE in the adult population has been on the decline. Although pediatric data are not available, a similar decrease in mortality in children would not be surprising. The decreased mortality likely stems from the fact that CT has made the diagnosis of asymptomatic PE possible. This allows for more intensive surveillance and, potentially, treatment in those children before they become symptomatic. In addition, the practice of earlier removal of CVLs and mandates for DVT prophylaxis in hospitalized adults has likely had a significant effect on the incidence of PE.

Children with CHD have an extremely high risk of thromboembolic complications, including PE. In infants presenting with strokes, nearly half of those children have some form of CHD. After 6 months of age, children with CHD still account for one-third of patients with new-onset cerebral infarction. Because children with right-to-left shunting at the cardiac level by definition have an elevated stroke risk compared with the general pediatric population, this finding is not unexpected. However, although the stroke studies mentioned previously did not examine the incidence of PE in their cohort, the extremely high incidence suggests these children may also be predisposed to other VTE-associated morbidities. In support of this supposition, bypass surgery for right heart defects is known to carry a high incidence of acute pulmonary artery obstruction.

Signs and Symptoms of Pulmonary Embolism

The symptoms of PE are variable. In adults the majority of patients with PE have pleuritis and difficulty breathing. Only approximately one-third of adults have cough, wheezing, or orthopnea with PE. Very few patients (13%) present with hemoptysis. Not surprisingly, nearly half of those with PE have signs of deep venous thrombus such as calf or thigh pain. Cardiovascular collapse, arrhythmia, and syncope are extremely rare presentations.

The risk of PE in pediatric patients without rapid heart rate and hypoxia is very low (<1.5%). In a single-center study of adolescents with PE, the most frequent presenting symptoms were chest pain, difficulty breathing, cough, and hemoptysis, but signs of DVT were also common. Importantly, the incidence of PE in pediatric patients with documented VTE may be as high as 30% to 60%.

Because younger children are unable to vocalize their symptoms, a high degree of clinical suspicion is required in any patient with risk factors for PE formation. As in older children, rapid respiratory rates, pleuritic chest pain, cough, shortness of breath, and tachycardia are common but nonspecific symptoms. Sudden cardiac collapse in any pediatric patient requires immediate consideration of PE even though, as in adults, it is an extremely rare presentation.

Diagnostic Workup for Pulmonary Embolism

In adults, specific, validated diagnostic prediction tools, such as the Wells criteria, the Geneva score, and the pulmonary embolism rule-out criteria, exist for diagnosis of PE. These models combine patient clinical signs and additional risk factors to assess pretest probability for the diagnosis of PE in adults. Similar models have not been validated in children.

Diagnostic algorithms for PE in adults immediately bifurcate based on the hemodynamic status of the patient at presentation. If there is suspicion of PE in an unstable patient, the patient should be immediately stabilized, anticoagulated, and then sent for CT pulmonary angiography (CTPA). However, most patients are stable at presentation. Hemodynamically stable patients undergo a tiered diagnostic strategy based on clinical probability of PE. Based on symptoms, the risk of PE in adults can be determined by several different validated models. Patients with a high probability of PE undergo immediate CTPA. If the study is inconclusive, magnetic resonance pulmonary angiography or contrast pulmonary angiography may be required. In patients with a low probability of PE, an initial screening by quantitative D-dimer is initiated. If D-dimer is elevated, the patient again follows the high-probability algorithm (discussed previously). If the D-dimer level is low in patients with a low probability of PE, the diagnosis is excluded.

Diagnosis of PE in children is more difficult than in adults. Plain film chest x-ray findings are abnormal in the majority of children with PE, with cardiomegaly and pleural effusion being the most common findings. The Westermark sign (oligemia), Hampton hump (pleura-based area of increased opacification), and Fleischner sign (a prominent central pulmonary artery) are rarely seen. Because risk models for clinical probability of PE have not been validated in children, nondefinitive test results are difficult to interpret regardless of the study used. For instance, a low D-dimer in children does not rule out PE, but a high value lends support to the diagnosis. Similarly, although a positive ventilation/perfusion (V/Q) scan may provide supportive evidence for PE, a negative scan will not rule it out because no probability model is available to guide interpretation. In addition, because participation in the youngest children is unreliable or impossible, needed radiographic V/Q views may not even be adequate. More importantly for this discussion, CHD patients with left-to-right shunts have variable scan results due to uneven distribution of isotope. Therefore, although V/Q scans have historically been used to test for diagnosis of PE in children, they are not guaranteed to provide a definitive diagnosis.

Due to its speed and reliability, CTPA has rapidly overtaken V/Q scans as a primary imaging technique for diagnosis of PE. The most significant disadvantages to this modality are the exposure to ionizing radiation and its insensitivity to small, subsegmental emboli. Pulmonary angiography has been the traditional gold standard for diagnosis of PE; it is both invasive and expensive, which limits its use in the pediatric population. When used in patients with CHD as part of a catheter-based evaluation and intervention, pulmonary angiography remains the modality of choice for diagnosis of PE.

Magnetic resonance imaging and magnetic resonance pulmonary angiography (MRI/MRPA) eliminates the effects of ionizing radiation and may be used in patients in whom CT is contraindicated. Although MRI/MRPA has become important in the diagnosis of childhood PE, the requirement for patient immobility during MRI and scan duration make it unlikely these will become the imaging modality of choice in unstable patients. Most importantly, due to the absence of tests validating MRI in the detection of PE, a positive result may support the diagnosis of PE, but a negative MRI does not rule it out.

Extrapolating from current algorithms for diagnosis of PE in adults, hemodynamically unstable pediatric patients with suspected PE should undergo immediate CTPA. Unfortunately, although CTPA has a 96% specificity, as noted previously, it may not reliably detect peripheral emboli in very small children. CTPA with three-dimensional reconstruction appears to improve diagnostic resolution, but it has not yet been validated in children.

Probability and prediction models for adults with PE stratify all patients into high risk (presentation with cardiovascular collapse), intermediate risk (patients who are normotensive but show evidence of right heart strain either on electrocardiogram (ECG) or echocardiography or by biomarkers), or low risk (symptomatic but absence of preceding features) categories. Unfortunately, similar risk categorization is not validated in children. Therefore adjunctive testing, including ECG (right ventricular strain pattern), echocardiography, and biomarkers (brain natriuretic peptide, troponin), may aid in the diagnosis of pediatric PE.

When a substantial amount of pulmonary flow has been occluded, right ventricular heart strain invariably occurs. Right axis deviation, ST segment elevation, and right bundle branch block on ECG can be useful in the verification of increased right heart work, but the findings are not specific for PE. Similarly, echocardiographic data showing dyskinetic right ventricular motion compared with the apex has low sensitivity for PE but a positive predictive value and specificity of nearly 100%.