AUTHOR INFORMATION

Section 1 of 11

Authored by Lennox H Huang, MD, Associate Chair (Clinical) of Pediatrics, Assistant Professor of Pediatrics, McMaster University, Deputy Chief, McMaster Children's Hospital, McMaster Children's Hospital

Coauthored by David J Vaughan, MBBCh, Consultant Pediatrician, Department of Pediatrics, Our Lady of Lourdes Hospital, Ireland; Jerry Zimmerman, MD, Professor, Department of Pediatrics/Anesthesia, University of Washington School of Medicine; Director, Division of Pediatric Critical Care Medicine, Children's Hospital of Seattle

Lennox H Huang, MD, is a member of the following medical societies: American Academy of Pediatrics, Canadian Medical Association, Ontario Medical Association, and Society of Critical Care Medicine

Edited by G Patricia Cantwell, MD, Associate Clinical Professor, Department of Pediatrics, Miller School of Medicine, University of Miami; Director of Pediatric Critical Care Medicine, Jackson Children's Hospital; Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine.com, Inc; Barry Evans, MD, Assistant Professor of Pediatrics, Temple University Medical School, Director of Pediatric Critical Care and Pulmonology, Associate Chair for Pediatric Education, Temple University Children's Medical Center; Mary E Cataletto, MD, Associate Director, Division of Pediatric Pulmonology, Winthrop University Hospital; Associate Professor, Department of Clinical Pediatrics, State University of New York at Stony Brook; and Michael R Bye, MD, Professor of Clinical Pediatrics, Columbia University College of Physicians and Surgeons; Acting Director, Department of Pediatric Pulmonary Medicine, Columbia University Medical Center

Author's Email:	Lennox H Huang, MD
Editor's Email:	G Patricia Cantwell, MD

eMedicine Journal, September 14 2006, VOLUME 7, Number 9

INTRODUCTION

Section 2 of 11

Background: Loschner first described pediatric pulmonary embolism (PE) in the 1860s. Deep venous thromboses (DVT) and pulmonary emboli are relatively rare phenomena in pediatric practice, but, when they do occur, they are associated with significant morbidity and mortality. Because of the rarity of PE in children, it is probably underdiagnosed. For the same reason, much of the information pertaining to diagnosis and management of PE has been derived from adult practice.

A specific diagnosis that should be mentioned because of its prevalence is sickle cell disease. Prompt recognition and management of pulmonary problems may lead to a decreased rate of pulmonary complications.

Pathophysiology: Most pulmonary emboli derive from a free-floating thrombus. In rare situations, extension of an existing pulmonary thrombus may result in pulmonary infarction. Many materials and substances may form emboli and move to the pulmonary circulation; these include fat, tumor, septic emboli, air, amniotic fluid, and injected foreign material.

The size of a PE determines at which points in the pulmonary vasculature it lodges. After the embolus lodges, it occludes the vessel, reducing distal blood flow to the area directly supplied by the vessel. The degree of obstruction of the pulmonary circulation directly affects the resulting pathophysiology.

In all cases of PE, ventilation/perfusion (V/Q) mismatch occurs to some degree, in which continued ventilation of lung units without circulation is present. Oxygenation is usually not affected by the V/Q mismatch, in contrast with V/Q mismatch that arises from obstruction of airways and lung parenchyma. Impaired oxygenation in the context of suspected PE implies a massive obstruction.

An increase in effective alveolar dead space is a direct result of the V/Q mismatch. Ventilation (carbon dioxide removal) is usually compensated for by tachypnea.

In cases in which the pulmonary embolus is large, a sudden increase in pulmonary artery pressure may lead to right ventricular strain and right heart failure. A sudden rise in the right ventricular pressure may cause a leftward shift of the intraventricular septum, which may impair left ventricular filling and output (classic obstructive shock).

Reflex bronchoconstriction is often associated with PE. This increases the work of breathing and decreases pulmonary compliance. Pulmonary infarction is also associated with diminished surfactant levels, which may contribute to the increased work of breathing and diminished oxygenation.

Children with PE often have a serious underlying condition that predisposes them to embolus development and may worsen their clinical outcome. Some of the more common underlying conditions include the following:

• Sickle cell disease

• Nephrotic syndrome

• Cancer

• Chemotherapy

• Inherited hypercoagulable state

• Vasculitis

In sickle cell disease, an initial trigger (often infection) exacerbated by dehydration (eg, due to fever, tachypnea, or decreased intake) leads to sickling of RBCs within small blood vessels of the lung and other organs. This precipitates a cycle of relative deoxygenation that further exacerbates the sickling tendency, leading to small vessel occlusion and, ultimately, infarction of areas of the pulmonary parenchyma. Allied to this sequence is the tendency of many patients with sickle cell disease to have a component of reactive airways disease, which further decreases oxygenation.

Frequency:

• In the US: PE is a rare disorder in pediatric practice. In 1993, David et al identified 308 children reported in the medical literature from 1975-1993 with DVT of an extremity, PE, or both. In 1986, Bernstein reported 78 episodes of PE per 100,000 hospitalized adolescents. Unselected autopsy studies in children estimate the incidence of PE from 0.05-3.7%.

• Internationally: Canadian data derived from 15 tertiary care centers show a frequency of 0.86 events per 10000 pediatric hospital admissions for patients aged 1 month to 1 year. Frequency of PE in developed countries has been increasing when compared with historical data. This increase in frequency is linked with the increased use of central venous lines in the pediatric population. The overall frequency is still considerably less than that seen in adults.

Mortality/Morbidity: Separating mortality attributable to PE from that due to conditions that may be associated with PE, such as trauma and surgery, is difficult.

• Various authors suggest that PE contributes to the death of affected children in approximately 30% of cases. Others, however, have reported PE as a cause of death in fewer than 5% of affected children.

• Morbidity may include pulmonary hypertension, right ventricular failure and cor pulmonale, paradoxical embolization to the systemic circulation in patients with intracardiac defects, and side effects of medications used to treat PE.

Race: No data exist outlining variations in PE prevalence by race.

Sex: Some authors have reported a female-to-male ratio of 2:1. Others have found that this ratio is reversed.

Age: Given the rarity of PE in childhood, no definitive data identify age as an independent risk factor for PE. The frequency of PE has a bimodal distribution, with peaks in the neonatal period and adolescence.

CLINICAL

Section 3 of 11

History: Classic symptoms of PE are rarely encountered. The frequency with which the diagnosis is missed in both adults and children is striking. Adding to the clinical dilemmas is the fact that few symptoms are sensitive or specific for PE. In adult series, clinical diagnosis has a sensitivity of 85% but a specificity of 38%, reflecting the vast differential diagnosis found in both adults and children. Symptoms vary according to the severity of the PE and the presence of underlying conditions. Pulmonary emboli of small-to-moderate size are generally asymptomatic.

• Respiratory symptoms


• • Pleuritic chest pain is reported to occur in up to 84% of children and adults with PE. Its presence suggests that the embolus is located more peripherally and, thus, may be smaller.
  
  
  
  • Tachypnea and dyspnea are observed in up to 60% of adult patients with PE but are generally less frequent in children.
  
  
  
  • Cough is present in approximately 50% of children with PE
  
  
  
  • Hemoptysis is a feature in a minority of children with PE, occurring in about 30% of cases.
  
  
  
• Other symptoms


• • A feeling of apprehension is a manifestation of arousal of the sympathetic system.
  
  
  
  • Sweating and syncope are rarely present.
  
  
  
• Medical history: Ask about recent pregnancy, termination of pregnancy, drug history, and family history.



• Sickle cell disease: Patients with sickle cell disease may present with manifestations of sickle cell anemia other than acute chest syndrome. These may include anemia, sequestration crisis, pain crisis, stroke, and priapism.

Physical: The use of physical findings as a diagnostic aid in suspected cases of PE brings the same problems as are outlined in History. Many physical findings are typically less marked than they are in adults, presumably because children have greater hemodynamic reserve and, thus, are better able to tolerate the significant hemodynamic and pulmonary changes.

• Pulmonary findings


• • Tachypnea is a feature in almost 50% of children with PE.
  
  
  
  • Crackles are heard in a minority of cases.
  
  
  
  • Cyanosis and hypoxemia are not prominent features of PE. If present, cyanosis suggests a massive embolism leading to a marked V/Q mismatch and systemic hypoxemia. Some case reports have described massive pediatric PE with normal saturation.
  
  
  
  • A pleural rub is often associated with pleuritic chest pain and indicates an embolism in a peripheral location in the pulmonary vasculature.
  
  
  
  • Signs that indicate pulmonary hypertension and right ventricular failure include a loud pulmonary component of the second heart sound, right ventricular lift, distended neck veins, and hypotension. An increase in pulmonary artery pressure is reportedly not evident until at least 60% of the vascular bed has been occluded.
  
  
  
• Cardiovascular findings


• • A gallop rhythm signifies ventricular failure.
  
  
  
  • Peripheral edema is a sign of CHF.
  
  
  
  • Various heart murmurs may be audible, including a tricuspid regurgitant murmur signifying pulmonary hypertension.
  
  
  
• Other signs


• • Fever is an unusual sign that is nonspecific.
  
  
  
  • Diaphoresis is a manifestation of sympathetic arousal.
  
  
  
  • Signs of other organ involvement in patients with sickle cell disease would be elicited, such as sequestration crisis, priapism, anemia, and stroke.
  
  
  

Causes: In contrast with adults, most children (98%) diagnosed with PE have an identifiable risk factor or a serious underlying disorder. DVT is associated with PE in 30-60% of cases. Thrombosis may also arise from intracardiac thrombi or intracerebral sinus thrombosis.

Acquired thrombosis has 3 broad etiological risk factors: (1) a relative stasis of blood flow due to either immobilization or the presence of a nidus on which a thrombus may form, (2) a prothrombogenic tendency (hypercoagulability), and (3) injury to a vascular wall. These 3 factors have been termed the Virchow triad. The following conditions predispose to some or all of these factors:

• Central venous catheters: In 1993, David et al reported that 21% of children with DVT, PE, or both had an indwelling central venous catheter. A clot may form as a fibrin sleeve that encases the catheter. When the catheter is removed, the fibrin sleeve is often dislodged, releasing a nidus for embolus formation. In another scenario, a thrombus may adhere to the vessel wall adjacent to the catheter.



• Surgery: Recent surgery and postsurgical immobilization are associated with approximately 15% of PE and DVT cases.



• Heart disease: Thrombi may be associated with dilated cardiomyopathy, a situation in which sluggish blood flow is combined with an enlarged cardiac chamber.



• Sickle cell disease: This condition often creates a diagnostic difficulty. A chest infection is often the presenting symptom. Hypoxemia, dehydration, and fever lead to intravascular sludging within pulmonary (among others) vasculature. This promotes a vicious cycle, further exacerbating local hypoxemia, ultimately leading to local tissue infarction. This process is further worsened by bone marrow infarction, which may cause release of fat emboli that lodge in the pulmonary circulation.



• Trauma: Whether the increased risk of PE in trauma patients is independent of the role of immobilization and surgery is unclear.



• Neoplasm: PEs have been reported to occur in association with solid tumors, leukemias, and lymphomas. This is probably independent of the indwelling catheters often used in such patients.



• Hyperalimentation: A recent study reported that major thrombosis or PE was present in more than 33% of children treated with long-term hyperalimentation and that PE was the major cause of death in 30% of these children. Fat embolization may exacerbate this clinical picture.



• Dehydration: Dehydration, especially hyperosmolar dehydration, is typically observed in younger infants with PE.



• Inherited disorders of coagulation: In 1993, David et al reported that 5-10% of children with venous thromboembolic disease have inherited disorders of coagulation, such as antithrombin III, protein C, or protein S deficiency. In 1997, Nuss et al reported that 70% of children with a diagnosis of PE have antiphospholipid antibodies or coagulation-regulatory protein abnormalities. However, this was a small study in a population with clinically recognized pulmonary emboli; hence, its applicability to the broader pediatric population is uncertain.



• Miscellaneous causes


• • Obesity
  
  
  
  • Estrogen use, including oral contraceptives
  
  
  
  • Pregnancy
  
  
  
  • Pregnancy termination
  
  
  
  • Nephrotic syndrome
  
  
  
  • Ventriculoatrial shunt: The tip of the atrial shunt may act as a nidus for thrombus formation.
  
  
  
  • Autoimmune disorders: These may be associated with antibodies that predispose to a hypercoagulable state.
  
  
  

DIFFERENTIALS

Section 4 of 11

Anxiety Disorder: Generalized Anxiety
Asthma
Myocardial Infarction in Childhood
Myocarditis, Nonviral
Myocarditis, Viral
Pericarditis, Viral
Pleural Effusion
Pneumonia
Pneumothorax
Thromboembolism
Vasculitis and Thrombophlebitis

Other Problems to be Considered:

Acute chest syndrome
Rib fracture
Musculoskeletal pain

WORKUP

Section 5 of 11

Lab Studies:

• Arterial or capillary blood gas


• • Blood gas findings are often normal. However, a calculated alveolar-arterial oxygen gradient may be elevated.
  
  
  
  • Abnormal findings are nonspecific and may include hypoxemia, hypocarbia or hypercarbia, and respiratory alkalosis that reflects dyspnea and anxiety or respiratory acidosis that reflects a V/Q mismatch.
  
  
  
  • Hypercarbia with hypoxemia is a poor prognostic sign and indicates a massive PE.
  
  
  
  • Metabolic acidosis is occasionally observed and is a sign of poor cardiac output. In the case of PE with obstructive shock, venous oxygen saturation is decreased.
  
  
  
• D-dimers


• • Two methods measure D-dimers, a qualitative assay and a quantitative enzyme-linked immunosorbent assay (ELISA). The ELISA is usually performed only if the result of the qualitative test is positive.
  
  
  
  • D-dimers are elevated (>500 ng/mL) in 90% of adults with PE. Although D-dimers measurement is a very sensitive test, its specificity is only on the order of 50%. Because of the poor specificity, positive D-dimers measurements are generally not helpful in diagnosis. In addition, the use of D-dimers in children is not well studied.
  
  
  
• Complete blood cell count: The WBC count may be slightly elevated. Hemoglobin and hematocrit are reduced in children with sickle cell disease who present with acute chest syndrome.

Imaging Studies:

• Chest radiography


• • Radiographic findings are abnormal in up to 70% of cases. Problems of sensitivity and specificity complicate its use as a diagnostic tool.
  
  
  
  • Chest radiography is useful to rule out other differential diagnoses; it is a necessary adjunct to the interpretation of the V/Q scan.
  
  
  
  • The most common radiographic changes include infiltrates, atelectasis, and pleural effusions. Effusions are bilateral in 10% of cases.
  
  
  
  • Signs that are said to be characteristic include Westermark sign, an area of focal hypoperfusion, and Hampton hump, a peripheral wedge-shaped density above the diaphragm. Evidence of a dilated pulmonary artery is occasionally observed.
  
  
  
• Ventilation/perfusion scanning


• • This noninvasive scan delineates both regional lung ventilation and perfusion. Note that a normal finding on V/Q scanning does not rule out PE. However, multiple V/Q scans with normal findings suggest that, if a PE is present, it is clinically unimportant. A problem that commonly arises is which test to perform first because confusion may stem from overlap of radioactive signals. Generally, if only one scan can be performed, the perfusion scan is thought to provide more useful information.
  
  
  
  • The test is undertaken in 2 steps. A sample of aggregated albumin labeled with radioactive technetium is administered intravenously and lodges in the pulmonary capillary bed. The patient is placed in a supine position to ensure optimal blood flow to the lung apices and thus reduce the risk of a false-positive test result. The gamma rays emitted by the technetium are revealed by a gamma camera. Areas of decreased perfusion, which suggest a PE, are observed as areas of decreased radiation emission. The ventilation scan is usually performed by having the patient inhale radiolabeled xenon (Xe) 133. Areas of decreased ventilation show up as areas of decreased radioactivity. The ventilation scan is then compared with the perfusion scan. An area with normal ventilation but decreased perfusion is consistent with a diagnosis of PE. An area of diminished ventilation is consistent with a large number of differential diagnoses.
  
  
  
  • A V/Q scan is usually reported in terms of probability of PE (ie, high, intermediate, moderate, low). A high-probability scan is defined as having 2 or more areas with segmental defects on a perfusion scan with a normal finding on a ventilation scan. V/Q scan reporting is based on adult risk stratification (Prospective Investigation of Pulmonary Embolus Diagnosis [PIOPED] study).
  
  
  
  • Forty percent of adults with a high clinical index of suspicion for PE and a low-probability V/Q scan are found to have a PE based on angiography findings. No similar data are available for children. Children generally have a more homogenous perfusion scan; thus, deficits in perfusion are more likely to represent real or significant PE compared with adults.
  
  
  
• MRI: Few data are available regarding the use of MRI in children suspected of having PE. Its use should be considered investigational at this time.



• DVT: The possibility of DVT should be considered. Most adults with a PE have a coexisting DVT; whether this holds true for children is unknown. The presence of a DVT may provide indirect evidence of a PE when the V/Q scan is a low-probability scan. Like PE, the reliability of clinical diagnosis of DVT is suboptimal. In a pediatric series, 18% of patients with clinically suspected DVT actually had a DVT confirmed radiologically. The 3 methods used for the diagnosis of DVT are as follows:


• • Doppler ultrasonography is based on the principle that ultrasonic waves reflected from blood traveling at different velocities vary in frequency. The change of frequency (ie, change in blood velocity) reflects the degree of obstruction.
  
  
  
  • Impedance plethysmography is based on the principle that the electrical impedance of a limb is related to the blood volume in that limb. A pneumatic cuff adjusts the pressure on the limb to be measured. An increase in blood volume within that limb signifies an obstruction (ie, DVT). No data are available regarding its use in children.
  
  
  
  • Venography is the criterion standard for diagnosing DVT. With the advent of noninvasive imaging, it has become less common in pediatric practice.
  
  
  
• Helical computerized tomography of the chest


• • Many diagnostic algorithms have been suggested to facilitate the evaluation of the patient with suspected PE. The widespread availability of CT has evoked much interest in the use of this modality to diagnose PE. Many centers now use helical CT scanning with intravenous contrast as an initial step in the workup of PE.
  
  
  
  • The embolism appears as a low-density filling defect within the pulmonary artery.

  • A recent study found that 1% of patients with PE had negative findings on helical CT scanning. As one would expect, small emboli are more likely to be missed, particularly if they are peripherally located. Hence, the negative predictive value is of the order of 99%, which does not substantially differ from that found with V/Q scanning or pulmonary angiography.

  • Radiopaque intravenous contrast should be used cautiously in patients with possible renal impairment.
  
  
  
• Echocardiography


• • Echocardiography (ECHO) provides useful information. It may allow diagnosis of other conditions that may be confused with PE, such as pericardial effusion.

  • ECHO allows visualization of the right ventricle and assessment of the pulmonary artery pressure.

  • ECHO serves a prognostic function; the mortality rate is almost 10% in the presence of right ventricular dysfunction and 0% in the absence of right ventricular dysfunction.

  • ECHO may be used to identify the presence of right-chamber emboli.
  
  
  

Other Tests:

• Electrocardiography


• • ECG findings may be normal. ECG is helpful to rule out other conditions in the differential diagnosis.
  
  
  
  • ECG changes found in PE include sinus tachycardia, T-wave inversion, S₁Q₃T₃ pattern, right axis deviation, right bundle branch block, and P pulmonale (ie, a tall P wave representing an enlarged right atrium).
  
  
  

Procedures:

• Pulmonary angiography


• • Angiography is the criterion standard for diagnosing PE. It detects emboli as small as 1 mm.
  
  
  
  • A positive test result is defined as an intraluminal filling defect that is visible in more than one radiographic view.
  
  
  
  • The usual indication for pulmonary angiography is an equivocal finding on a V/Q scan with a high index of suspicion for PE, especially in a patient at high risk for complications from therapy (ie, anticoagulation, thrombolysis); another indication are instances in which an embolectomy is considered.
  
  
  
  • Complications, apart from mortality, include hemorrhage, infection, arrhythmias, and great vessel or myocardial perforation. Patients at highest risk are those with right ventricular dysfunction or elevated pulmonary artery pressures. The mortality risk in adults is less than 0.5% in series from large centers. No similar data on children are available.
  
  
  

TREATMENT

Section 6 of 11

Medical Care: Medical therapy centers on providing initial cardiopulmonary support, anticoagulation to prevent clot extension, and thrombolysis in the rare event of PE that leads to massive cardiorespiratory failure. Much of the information regarding treatment of PE in children has been derived from that on adults.

• Anticoagulation
  • Anticoagulation should be started in patients without contraindications (active bleeding). Systemic anticoagulation should be started with unfractionated or low molecular weight heparin (LMWH) to achieve an antifactor Xa level of 0.5-1 U/mL or, in the case of unfractionated heparin, activated partial thromboplastin time (aPTT) levels of twice the control value. Therapy should continue for 5-10 days.

  • Long-term anticoagulation should continue with LMWH for up to 6 months to achieve a target antifactor Xa level of 0.5-1 U/mL. Alternatively, oral therapy with warfarin can be used to achieve an international normalized ratio (INR) of 2-3. If oral therapy is used, dosing should begin with initial systemic anticoagulation, with discontinuation of heparin on day 5.

  • Current studies suggest that attempts to achieve a higher INR with warfarin are associated with an increased risk of bleeding without commensurately reducing the risk of new clot formation; therefore, aiming for an INR of 2-3 is recommended. Levels of more than 3 are generally unnecessary. Patients with the antiphospholipid syndrome may require INRs of more than 3.



• Thrombolysis: This should be considered only if a large embolus is present in the pulmonary vasculature or in the setting of massive cardiac or pulmonary failure.



• Supportive care


• • Pharmacologic support of the cardiovascular system may be necessary. Dopamine and dobutamine are the usual inotropic agents. Mechanical ventilation may be necessary both to provide respiratory support and as adjunctive therapy for a failing circulatory system.
  
  
  
  • Children with sickle cell disease who present with pulmonary symptoms require treatment with a macrolide and cephalosporin antibiotic. Their clinical status should be closely monitored in order to anticipate those children who may develop acute chest syndrome.
  
  
  
  • Transfusion with packed RBCs (either simple or exchange) improves oxygenation immediately, helping to break the vicious cycle outlined above.
  
  
  

Surgical Care: Surgical interventions in the management of PE consist primarily of embolectomy. Inferior vena caval filters have been used to prevent recurrent emboli, but few data exist regarding their use in children.

• Embolectomy


• • Few data are available regarding the use of surgical embolectomy in children.
  
  
  
  • Consider embolectomy in the setting of massive cardiac failure when time is insufficient for natural or pharmacologic thrombolysis or if thrombolysis is contraindicated.
  
  
  
• Vena caval filters


• • Otherwise known as Greenfield filters, these are placed surgically in the inferior vena cava (IVC) and prevent further emboli from reaching the pulmonary circulation.
  
  
  
  • Indications for IVC filters include a contraindication to anticoagulation and recurrent PE despite adequate anticoagulation.
  
  
  
  • Complications include migration of the filter, sepsis, and misplacement of the filter.
  
  
  

Consultations:

• Pulmonology: A pulmonologist is often consulted before the true diagnosis is made because of the nonspecific nature of the symptoms.



• Cardiology: Consultation with a cardiologist is warranted to rule out a cardiac etiology for the presenting symptoms and signs and to perform ECHO and pulmonary angiography.



• Cardiothoracic surgery: If embolectomy is considered, consultation with a cardiac surgeon is mandatory.



• Hematology: A hematologist can suggest an appropriate workup for a procoagulant defect and can recommend an anticoagulation regimen. Consultation with a hematologist is essential in children with sickle cell disease. A free clinical consultation service for complex cases of thromboembolism in children is available for clinicians by calling 1-800-NO-CLOTS (1-800-662-5687).

Diet: No specific diet is contraindicated. However, excessive weight should be avoided in those with a history of PE.

Activity: Activity should not be limited. Mobilization should be encouraged in those with a history of PE or those at risk of having a PE. Patients taking anticoagulants should avoid high-impact sports.

MEDICATION

Section 7 of 11

Anticoagulants are the treatment of choice in most children with PE. Thrombolytics are rarely used. To date, little data exist regarding the use of LMWH in children with thromboembolic disease; however, a number of studies have described the efficacy of LMWH in thromboembolic disease.

A recent review examining the use of LMWH compared with standard unfractionated heparin (UFH) in the treatment of venous thromboembolic disease has concluded that therapy with LMWH is associated with a decreased risk of major hemorrhage, in addition to a decreased mortality rate compared with patients treated with UFH. Benefits of using LMWH include a lower overall cost, the convenience of twice-daily subcutaneous injections, decreased requirement for laboratory monitoring, and a more favorable antithrombotic-to-hemorrhagic ratio.

Duration of therapy must be individualized. A recent review recommends that in adult patients with transient risk factors (ie, surgery, immobilization, estrogen administration), therapy less than 3 months may be sufficient; however, no studies exist to validate this statement. Patients with slowly resolving or persistent risk factors should be treated for at least 3 months.

Previous studies have confirmed that longer duration of therapy is associated with decreased risk of disease recurrence. Adult patients with idiopathic thrombosis benefit most, although the relevance of comparing these patients with children (most of whom have identifiable risk factors) is uncertain. Patients with genetic thrombophilic states (factor V Leiden) may benefit from longer courses of therapy. Individuals with recurrent embolic disease should be treated for at least 12 months and possibly longer.

Drug Category: Anticoagulants -- Inhibition of thrombin prevents extension of the thrombus, thus allowing recanalization of the blood vessel over time, and reduces the risk of further embolization. Anticoagulation does not lyse the clot per se. It merely allows the body time to lyse the clot while reducing the risk of subsequent embolization.

Drug Name	Heparin, unfractionated -- Augments activity of antithrombin III and prevents conversion of fibrinogen to fibrin. Does not actively lyse but is able to inhibit further thrombogenesis. Prevents reaccumulation of clot after spontaneous fibrinolysis.
Adult Dose	Initial dose: 40-170 U/kg IV Maintenance infusion: 18 U/kg/h IV Alternatively, 50 U/kg/h IV initially, followed by continuous IV infusion of 15-25 U/kg/h and increase dose by 5 U/kg/h q4h prn using aPTT results
Pediatric Dose	Initial dose: <1 year: 50-75 U/kg IV over 10 min >1 year: 75 U/kg IV over 10 min Maintenance infusion: <1 year: 20-30 U/kg/h >1 year: 20 U/kg/h Adjust dose to keep aPTT at twice control value
Contraindications	Documented hypersensitivity; subacute bacterial endocarditis; active bleeding; history of heparin-induced thrombocytopenia
Interactions	Digoxin, nicotine, tetracycline, and antihistamines may decrease effects; NSAIDs, aspirin, dextran, dipyridamole, and hydroxychloroquine may increase heparin toxicity
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Avoid IM injections while on heparin; caution with peptic ulcer disease, menstruation, and renal and hepatic disease; may cause heparin resistance or heparin-induced thrombocytopenia

Drug Name	Warfarin (Coumadin) -- Reduces production of vitamin K–dependent clotting factors. Allows anticoagulation on an outpatient basis. Generally should be commenced shortly after initiating heparin, and their use should overlap by 5-10 d; adjust dosage to maintain INR of 2-3.
Adult Dose	5-15 mg/d PO; adjust dose to maintain INR at 2-3 after 2-5 d
Pediatric Dose	Administer weight-based dose of 0.05-0.34 mg/kg/d; adjust dose according to INR of 2-3
Contraindications	Documented hypersensitivity; severe liver or kidney disease; open wounds or GI ulcers
Interactions	Drugs that may decrease anticoagulant effects include griseofulvin, carbamazepine, glutethimide, estrogens, nafcillin, phenytoin, rifampin, barbiturates, cholestyramine, colestipol, vitamin K, spironolactone, PO contraceptives, and sucralfate; medications that may increase anticoagulant effects of warfarin include PO antibiotics, phenylbutazone, salicylates, sulfonamides, chloral hydrate, clofibrate, diazoxide, anabolic steroids, ketoconazole, ethacrynic acid, miconazole, nalidixic acid, sulfonylureas, allopurinol, chloramphenicol, cimetidine, disulfiram, metronidazole, phenylbutazone, phenytoin, propoxyphene, sulfonamides, gemfibrozil, acetaminophen, and sulindac
Pregnancy	D - Unsafe in pregnancy
Precautions	Do not switch brands after achieving therapeutic response; caution in active tuberculosis or diabetes; patients with protein C or S deficiency are at risk of developing skin necrosis; avoid IM injections while on warfarin

Drug Name	Enoxaparin (Lovenox) -- Has become first-line therapy in many patients with thromboembolism. Prevents DVT, which may lead to PE in patients undergoing surgery who are at risk for thromboembolic complications. Enhances inhibition of factor Xa and thrombin by increasing antithrombin III activity. In addition, preferentially increases inhibition of factor Xa. Average duration of treatment is 7-14 d.
Adult Dose	Prophylaxis: 30 mg SC q12h Treatment: 1 mg/kg/dose SC q12h; alternatively, 1.5 mg/kg SC qd
Pediatric Dose	Prophylaxis: <2 months: 0.75 mg/kg/dose SC bid >2 months: 0.5 mg/kg/dose SC bid Treatment: <2 months: 1.5 mg/kg/dose SC q12h >2 months: 1 mg/kg/dose SC q12h
Contraindications	Documented hypersensitivity; major bleeding; thrombocytopenia
Interactions	Platelet inhibitors or PO anticoagulants, such as dipyridamole, salicylates, aspirin, NSAIDs, sulfinpyrazone, and ticlopidine, may increase risk of bleeding
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	If thromboembolic event occurs despite LMW heparin prophylaxis, discontinue drug and initiate alternate therapy; elevation of hepatic transaminases may occur but is reversible; heparin-associated thrombocytopenia may occur with fractionated LMW heparins; 1 mg of protamine sulfate reverses effect of approximately 1 mg of enoxaparin if significant bleeding complications develop; avoid IM injections while on enoxaparin

Drug Category: Thrombolytic agents -- These convert plasminogen to plasmin, leading to clot lysis. Thrombolytic agents are rarely used in pediatric practice. Their use should be considered investigational and should be restricted to patients with severe pulmonary or cardiovascular compromise. If thrombolysis is being considered, the diagnosis of PE should first be confirmed by pulmonary angiography. Newborns may be relatively resistant to thrombolytics because of their lack of fibrinogen activity.

Drug Name	Streptokinase (Kabikinase, Streptase) -- Acts with plasminogen to convert plasminogen to plasmin. Plasmin degrades fibrin clots, as well as fibrinogen and other plasma proteins. Increase in fibrinolytic activity that degrades fibrinogen levels for 24-36 h takes place with IV infusion of streptokinase.
Adult Dose	Loading dose: 250,000 U IV over 30 min Maintenance dose: 100,000 U/h IV for 24-72 h
Pediatric Dose	Loading dose: 3500-4000 U/kg IV over 30 min Maintenance dose: 1000-1500 U/kg/h IV for 24-72 h
Contraindications	Documented hypersensitivity; active internal bleeding; intracranial neoplasm; aneurysm; diathesis; severe uncontrolled arterial hypertension
Interactions	Antifibrinolytic agents may decrease effects of streptokinase; heparin, warfarin, and aspirin may increase risk of bleeding
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Caution in severe hypertension, IM administration of medications, trauma, or surgery in the previous 10 d; measure hematocrit, platelet count, aPTT, TT, PT, or fibrinogen level before therapy is implemented; either TT or aPTT should be less than twice the reference range following infusion of streptokinase and before instituting or reinstituting heparin; do not take blood pressure in the lower extremities because it may dislodge a possible deep vein thrombi; PT, aPTT, TT, or fibrinogen should be monitored 4 h after the initiation of therapy

Drug Name	Alteplase (Activase) -- Also called tissue plasminogen activator (TPA). Produced naturally by vascular endothelium; however, the therapeutic agent is derived using recombinant technology. Binds tightly to fibrin, thus activating plasminogen, which results in clot lysis. With ongoing shortage of urokinase, more studies are emerging for use in pediatrics.
Adult Dose	Pulmonary embolus: 100 mg IV infused over 2 h
Pediatric Dose	Not established; limited data exist
Contraindications	Documented hypersensitivity; active internal bleeding; intracranial neoplasm; hemorrhage (including GI or GU hemorrhage within 21 d); head trauma within previous 3 mo; aneurysm; diathesis; severe uncontrolled arterial hypertension; stroke within previous 3 mo; recent MI; major surgery within 14 d; arterial puncture within 7 d (those unable to compress); platelets <100,000/mL
Interactions	Thrombolytic enzymes, alone or in combination with anticoagulants and antiplatelets, may increase risk of bleeding complications
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Dosage should be adjusted to maintain fibrinogen >100 mg/dL; bleeding is primary concern; avoid IM injections and nonessential handling of patient during alteplase systemic infusions; perform venipuncture carefully and only as required

FOLLOW-UP

Section 8 of 11

Further Outpatient Care:

• Monitoring prothrombin time (PT): PT should be measured on a regular basis; the goal is an INR of 2-3.



• Diagnostic workup: A hypercoagulation workup should be performed if no obvious cause for embolic disease is apparent. This may include screening for conditions such as antithrombin III deficiency, protein C or protein S deficiency, lupus anticoagulant, homocystinuria, occult neoplasm, and connective tissue disorders.



• Length of treatment: The length of treatment depends on the presence of risk factors. If no underlying risk factors are present, therapy can be stopped within 1-2 months. If risk factors are present, especially anticardiolipin antibodies, therapy should continue for at least 4-6 months.

Transfer:

• Transfer to an appropriate institution for further workup and therapy. Generally, this is a tertiary center in view of the rarity of embolic disease in children.

Deterrence/Prevention:

• Anticipate patients at risk.


• • Any child with a risk factor may develop a PE (see Causes). Methods to reduce risk include early mobilization, thromboembolic stockings, and prophylactic use of subcutaneous LMWH.
  
  
  
  • Females of childbearing age should be advised regarding the increased risk of thromboembolic disease during pregnancy. Women who are sexually active should be offered appropriate contraceptive advice. Those who wish to become pregnant should be referred to an obstetrician skilled in the management of hypercoagulable disorders during pregnancy.
  
  
  

Complications:

• Death



• Hemorrhage



• Heparin-induced thrombocytopenia



• Thrombophlebitis

Prognosis:

• Mortality: The data regarding death from PE in children are conflicting; various series report mortality rates from 5-30% of affected children. As in adults, the mortality rate is highest in the period immediately following embolization. If no major cardiovascular sequelae are present, a full recovery may be anticipated without complications.



• Recurrence: No data are available regarding the risk of recurrence of PE in children.

Patient Education:

• The importance of adherence to the treatment regimen should be repeatedly stressed. The patient should be instructed regarding what to do in the event of any bleeding complications. Because most patients are administered warfarin upon discharge from the hospital, they must be advised regarding potential interactions between warfarin and other medications.



• Risk factors for the development of PE should be discussed.


• • Pregnancy
  
  
  
  • Oral contraceptive pill use
  
  
  
  • Termination of pregnancy
  
  
  
  • Smoking
  
  
  
• For excellent patient education resources, visit eMedicine's Lung and Airway Center and Blood and Lymphatic System Center. Also, see eMedicine's patient education articles Pulmonary Embolism and Sickle Cell Crisis.

MISCELLANEOUS

Section 9 of 11

Medical/Legal Pitfalls:

• Potential medicolegal challenges may result from any of the following:


• • Failure to diagnose the condition promptly
  
  
  
  • Failure to treat appropriately
  
  
  
  • Failure to diagnose predisposing or associated conditions
  
  
  
  • Failure to advise of risk factors such as smoking, pregnancy, and use of the oral contraceptive pill
  
  
  

Special Concerns:

• In addition to the thrombotic risks imposed by pregnancy, women of childbearing age who are prescribed warfarin should be advised of the teratogenic effects of this drug.

TEST QUESTIONS

Section 10 of 11

CME Question 1: Which of the following risk factors is most commonly associated with the development of deep venous thrombosis (DVT) and pulmonary embolism (PE) in children?

A: Central venous catheters
B: Surgery
C: Neoplasm
D: Inherited disorders of coagulation
E: Nephrotic syndrome

The correct answer is A: In 1993, David et al reported that 21% of children with a diagnosis of DVT, PE, or both had an indwelling central venous catheter. Postoperative DVT and PE account for approximately 15% of cases. Inherited disorders of coagulation account for 5-10% of PE, and nephrotic syndrome is associated with fewer than 2% of cases.

CME Question 2: What diagnostic test is the criterion standard to confirm the diagnosis of pulmonary embolism (PE)?

A: Chest radiography
B: Ventilation/perfusion scanning
C: Magnetic resonance imaging
D: Echocardiography
E: Pulmonary angiography

The correct answer is E: Pulmonary angiography is the criterion standard for diagnosing PE. Emboli as small as 1 mm may be visualized with this technique. However, it is an invasive test requiring a skilled operator. For this reason, it is usually indicated when a finding on ventilation/perfusion (V/Q) scanning is equivocal and clinical suspicion for the presence of a PE is high, when a patient’s risk of complications from therapy (anticoagulation or thrombolysis) is high, or when surgical embolectomy is being considered. Hence, the usual diagnostic imaging algorithm suggests the initial use of chest radiography and V/Q scanning to diagnose PE. The role of MRI, although anecdotally very useful, remains to be fully defined in the workup of suspected PE.

Pearl Question 1 (T/F): Pulmonary embolism (PE) may be reliably diagnosed based on history and physical examination findings.

The correct answer is False: No reliable data exist on the clinical diagnosis of PE in children. Studies of adults indicate that a diagnosis of PE based on clinical findings has a sensitivity of 85% but a specificity of only 38%.

Pearl Question 2 (T/F): All children presenting with a pulmonary embolism should be treated immediately with warfarin.

The correct answer is False: Therapy should begin with heparin; warfarin therapy should commence shortly afterward, and therapy with the 2 agents should overlap by at least 5-10 days.

Pearl Question 3 (T/F): All children diagnosed with a pulmonary embolus should receive thrombolysis.

The correct answer is False: Only those children with severe cardiac or respiratory compromise should be considered candidates for thrombolysis. However, remember that experience with thrombolysis in children with PE is extremely limited.

Pearl Question 4 (T/F): Mortality associated with pulmonary embolism (PE) in children is well documented, revealing unequivocally that most children with PE die as a result of the PE or associated complications.

The correct answer is False: The data are conflicting. Various authors have reported death rates ranging from 5-30%. This variation is partly based on differing methods of case ascertainment, the confounding effects of comorbid conditions, and the relative paucity of large-center series.

BIBLIOGRAPHY

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• Babyn PS, Gahunia HK, Massicotte P: Pulmonary thromboembolism in children. Pediatr Radiol 2005 Mar; 35(3): 258-74[Medline].
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• Monagle P, Chan A, DeVeber G: Andrew's Pediatric Thromboembolism and Stroke. 3rd ed. Ontario, Canada; BC Decker: 2006.
• Nuss R, Hays T, Chudgar U, Manco-Johnson M: Antiphospholipid antibodies and coagulation regulatory protein abnormalities in children with pulmonary emboli. J Pediatr Hematol Oncol 1997 May-Jun; 19(3): 202-7[Medline].
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• Truitt AK, Sorrells DL, Halvorson E, et al: Pulmonary embolism: which pediatric trauma patients are at risk?. J Pediatr Surg 2005 Jan; 40(1): 124-7[Medline].
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• Vichinsky EP, Neumayr LD, Earles AN, et al: Causes and outcomes of the acute chest syndrome in sickle cell disease. National Acute Chest Syndrome Study Group. N Engl J Med 2000 Jun 22; 342(25): 1855-65[Medline].

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