Pulmonary Embolism Treatment & Management

Immediate therapeutic anticoagulation is initiated for patients with suspected DVT or pulmonary embolism. Anticoagulation therapy with heparin reduces mortality rates from 30% to less than 10%.

The current eighth edition of the American College of Chest Physicians (ACCP) guidelines for antithrombotic and thrombolytic therapy are summarized as follows:

• All patients with pulmonary embolism require rapid risk stratification (grade 1C).
• Thrombolytic therapy should be used in patients with evidence of hemodynamic compromise, except in the face of major contraindications due to bleeding risks (grade 1B). Do not delay thrombolysis in this population, owing to the potential for the development of irreversible cardiogenic shock.
• Thrombolytic therapy is suggested in select high-risk patients who do not have hypotension and are at low risk for bleeding (grade 2B) .
• Assessment of pulmonary embolism severity, prognosis, and risk of bleeding dictate whether thrombolytic therapy should be started. Thrombolytic therapy is not recommended for most patients (grade 1B).

Immediate full anticoagulation is mandatory for all patients suspected of having have DVT or pulmonary embolism. Diagnostic investigations should not delay empirical anticoagulant therapy. Current guidelines recommend starting unfractionated heparin (UFH), low–molecular weight heparin (LMWH), or fondaparinux (all grade 1A) in addition to an oral anticoagulant (warfarin) at the time of diagnosis, and to discontinue UFH, LMWH, or fondaparinux only after the international normalized ratio (INR) is 2.0 for at least 24 hours, but no sooner than 5 days after warfarin therapy has been started (grade 1C recommendation).^[72] The recommended duration of UFH, LMWH, and fondaparinux is based on evidence suggesting that the relatively long half-life of factor II, along with the short half-lives of protein C and protein S, may provoke a paradoxical hypercoagulable state if these agents are discontinued prematurely.

Even in patients who are fully anticoagulated, however, DVT and pulmonary embolism can and often do recur. New pulmonary embolism in the hospital can occur in the following patients despite therapeutic anticoagulation:

• Patients who have nonfloating DVT without pulmonary embolism at presentation (3%)
• Patients who present with a floating thrombus but have no pulmonary embolism (13%)
• Patients who present with pulmonary embolism but have no floating thrombus (11%)
• Patients who present with pulmonary embolism who have a floating thrombus visible at venography (39%)

Deciding how to treat a venous thrombosis that may lead to a pulmonary embolism is difficult. A survey of Canadian pediatric intensivists reported 4 patient factors commonly used to determine if a venous thrombosis is clinically important^[21] :

• Clinical suspicion of a pulmonary embolism
• Symptoms
• Detection of thrombosis on clinical examination
• Presence of an acute or chronic cardiopulmonary comorbidity that affects the patient's ability to tolerate a pulmonary embolism

Anticoagulants are the treatment of choice in most children with pulmonary emboli. Thrombolytics are rarely used. To date, little data are available regarding the use of LMWH in children with thromboembolic disease.

The ACCP guidelines recommend that all patients with pulmonary embolism require rapid risk stratification (grade 1C). Thrombolytic therapy should be used in patients with evidence of hemodynamic compromise, except in the face of major contraindications due to bleeding risks (grade 1B). Do not delay thrombolysis in this population, owing to the potential for the development of irreversible cardiogenic shock. Thrombolytic therapy is suggested in select high-risk patients who do not have hypotension and are at low risk for bleeding (grade 2B). Assessment of pulmonary embolism severity, prognosis, and risk of bleeding dictate whether thrombolytic therapy should be started. Thrombolytic therapy is not recommended for most patients (grade 1B).

Although most studies demonstrate the superiority of thrombolytic therapy with respect to the resolution of radiographic and hemodynamic abnormalities within the first 24 hours, this advantage disappears 7 days after treatment. Controlled clinical trials have not demonstrated benefits in terms of reduced mortality rates or earlier resolution of symptoms when currently compared with heparin. A large, retrospective review suggests that the use of thrombolytic therapy in unstable patients with pulmonary embolism may lead to reduced mortality when compared to anticoagulation therapy alone. Concurrent use of thrombolytic therapy and vena cava filters in such patients may reduce mortality even further.^{[73, 74]}

Until randomized clinical trials demonstrate a clear morbidity or mortality benefit, the role of thrombolytic therapy in the management of acute pulmonary embolism will remain controversial. The currently accepted indications for thrombolytic therapy include hemodynamic instability or right ventricular dysfunction demonstrated on ECHO.

Unfractionated heparin therapy

In patients with massive pulmonary embolism, if concerns regarding subcutaneous absorption arise, severe renal failure exists, or if thrombolytic therapy is being considered, IV UFH is the recommended form of initial anticoagulation (grade 2C).^[72]

The efficacy of heparin therapy depends on achieving a critical therapeutic level of heparin within the first 24 hours of treatment. The critical therapeutic level of heparin is 1.5 times the baseline control value or the upper limit of normal range of the activated partial thromboplastin time (aPTT).

This level of anticoagulation is expected to correspond to a heparin blood level of 0.2-0.4 U/mL by the protamine sulfate titration assay and 0.3-0.6 by the antifactor X assay.

Each laboratory should establish the minimal therapeutic level for heparin, as measured by the aPTT, to coincide with a heparin blood level of at least 0.2 U/mL for each batch of thromboplastin reagent being used.

If IV UFH is chosen, an initial bolus of 80 U/kg or 5000 U followed by an infusion of 18 U/kg/h or 1300 U/h should be given, with the goal of rapidly achieving and maintaining the aPTT at levels that correspond to therapeutic heparin levels. Fixed-dose and monitored regimens of subcutaneous UFH are available and are acceptable alternatives.

Low-molecular-weight heparin therapy

Current guidelines for patients with acute nonmassive pulmonary embolism recommend LMWH over UFH (grade 1A).^[72]

LMWHs have many advantages over UFH. These agents have a greater bioavailability, can be administered by subcutaneous injections, and have a longer duration of anticoagulant effect. A fixed dose of LMWH can be used, and laboratory monitoring of aPTT is not necessary.

Trials comparing LMWH with UFH have shown that LMWH is at least as effective and as safe as UFH. The studies have not pointed to any significant differences in recurrent thromboembolic events, major bleeding, or mortality between the 2 types of heparin.

LMWH can be administered safely in an outpatient setting. This has lead to the development of programs in which clinically stable patients with pulmonary embolism are treated at home, at substantial cost savings.

An international, open-label, randomized trial compared outpatient and inpatient treatment (both using the LMWH enoxaparin as initial therapy) of low-risk patients with acute pulmonary embolism and concluded that outpatient treatment was noninferior to inpatient treatment.^[75]

Factor Xa Inhibitors

The results of the Einstein-PE study provide an important advance in the treatment of symptomatic pulmonary embolism. In a prospective, open-label study, 4832 patients were randomized to receive either rivaroxaban or enoxaparin followed by an adjusted-dose vitamin K antagonist for 3, 6, or 12 months. Treatment with a fixed-dose regimen of rivaroxaban was non-inferior to standard therapy and had a satisfactory safety profile. Confirmation and extension of these results may lead to the future use of factor Xa inhibitors as a substitute for vitamin K antagonists in the treatment of pulmonary embolism.^[76] This advance thus offers the prospect of a safe and effective regimen of anticoagulation for patients with the advantages of simplicity and cost-effectiveness in comparison to current management strategies.

Fondaparinux

Fondaparinux is a synthetic polysaccharide derived from the antithrombin binding region of heparin. Fondaparinux catalyzes factor Xa inactivation by antithrombin without inhibiting thrombin.

Fondaparinux has not been directly compared with subcutaneous UFH or LMWH. However, once-daily fondaparinux was found to have similar rates of recurrent pulmonary embolism, bleeding, and death as IV UFH, according to one randomized open-label study of 2213 patients with symptomatic pulmonary embolism.^[77]

With the exception of patients presenting with massive pulmonary embolism (defined by hemodynamic compromise), LMWH or fondaparinux is recommended over IV UFH. This is because of a more predictable bioavailability, more rapid onset of full anticoagulant effect, and the benefit of not typically needing to monitor anticoagulant effect. However, if uncertainty arises regarding the accuracy of dosing, factor Xa levels can be monitored to determine efficacy.

In cases in which an anticoagulant with a shorter half-life is more desirable (ie, patients at particularly high risk of bleeding) or in patients with impaired renal function, IV UFH may be preferred (grade 2C).^[72]

Warfarin therapy

The anticoagulant effect of warfarin is mediated by the inhibition of vitamin K–dependent factors, which are II, VII, IX, and X. The peak effect does not occur until 36-72 hours after drug administration, and the dosage is difficult to titrate.

A prothrombin time ratio is expressed as an INR and is monitored to assess the adequacy of warfarin therapy. The recommended therapeutic range for venous thromboembolism is an INR of 2-3. This level of anticoagulation markedly reduces the risk of bleeding without the loss of effectiveness. Initially, INR measurements are performed on a daily basis; once the patient is stabilized on a specific dose of warfarin, the INR determinations may be performed every 1-2 weeks or at longer intervals.

Duration of anticoagulation therapy

A patient with a first thromboembolic event occurring in the setting of reversible risk factors, such as immobilization, surgery, or trauma, should receive warfarin therapy for at least 3 months. No difference in the rate of recurrence was observed in either of 2 studies comparing 3 versus 6 months of anticoagulant therapy in patients with idiopathic (or unprovoked) first events.^{[78, 79]} The current recommendation is anticoagulation for at least 3 months in these patients; the need for extending the duration of anticoagulation should be reevaluated at that time.

The current ACCP guidelines recommend that all patients with unprovoked pulmonary embolism should undergo a risk-to-benefit evaluation to determine if long-term therapy is needed (grade 1C). Long-term treatment is recommended for these patients who do not have risk factors for bleeding and in whom accurate anticoagulant monitoring is possible (grade 1A).

Patients who have pulmonary embolism and preexisting irreversible risk factors, such as deficiency of antithrombin III, protein S and C, factor V Leiden mutation, or the presence of antiphospholipid antibodies, should be placed on long-term anticoagulation.

Heparin-induced thrombocytopenia

Heparin-induced thrombocytopenia (HIT) is a transient prothrombotic disorder initiated by heparin. The main features of HIT are (1) thrombocytopenia resulting from immunoglobulin G–mediated platelet activation and (2) in vivo thrombin generation and increased risk of venous and arterial thrombosis.

The highest frequency of HIT, 5%, has been reported in post–orthopedic surgery patients receiving up to 2 weeks of unfractionated heparin. HIT occurred in approximately 0.5% of post–orthopedic surgery patients receiving LMWH for up to 2 weeks.

HIT may manifest clinically as extension of the thrombus or formation of new arterial thrombosis. HIT should be suspected whenever the patient's platelet count falls to less than 100,000/µL or less than 50% of the baseline value, generally after 5-15 days of heparin therapy. The definitive diagnosis is made by performing a platelet activation factor assay.

The treatment of patients who develop HIT is to stop all heparin products, including catheter flushes and heparin-coated catheters, and to initiate an alternative, nonheparin anticoagulant, even when thrombosis is not clinically apparent. Preferred agents include direct thrombin inhibitors, such as lepirudin or argatroban. Start warfarin while the patient receives an alternative, nonheparin anticoagulant and only when the platelet count has recovered to at least 100,000/µL (preferably to 150,000/µL).

Resistance to heparin

Few patients with venous thromboembolism require large doses of heparin for achieving an optimal activated partial thromboplastin time (aPTT). Those patients who do require them have increased plasma concentrations of factor VIII and heparin-binding proteins. Increased factor VIII concentration causes dissociation between aPTT and plasma heparin values. The aPTT is suboptimal, but patients have adequate heparin levels upon protamine titration. This commonly occurs in patients with a concomitant inflammatory disease.

Monitoring the antifactor Xa assay results in this situation is safe and effective and results in less escalation of the heparin dose when compared with monitoring with aPTT. Whenever a therapeutic level of aPTT cannot be achieved with large doses of UFH, either determination of plasma heparin concentration or therapy with LMWH should be instituted.

Guidelines from the American Heart Association (AHA) advise that either catheter embolectomy and fragmentation or surgical embolectomy is reasonable for patients with massive pulmonary embolism who have contraindications to fibrinolysis or who remain unstable after receiving fibrinolysis.^[80] If these procedures are not available locally, it is reasonable to consider transferring the patient to an institution with experience in one of these procedures, providing the transfer can be accomplished safely.

In patients with submassive acute pulmonary embolism, either catheter embolectomy or surgical embolectomy may be considered if they have clinical evidence of an adverse prognosis (ie, new hemodynamic instability, worsening respiratory failure, severe right ventricular dysfunction, or major myocardial necrosis). These interventions are not recommended for patients with low-risk or submassive acute pulmonary embolism who have minor right ventricular dysfunction, minor myocardial necrosis, and no clinical worsening.^[80]

The current grade 1A recommendation is that patients with acute pulmonary embolism should not routinely receive vena cava filters in addition to anticoagulants.^[72] An ideal IVC filter should be easily and safely placed using a percutaneous technique, biocompatible and mechanically stable, and able to trap emboli without causing occlusion of the vena cava.^[81]

IVC interruption by the insertion of an IVC filter (Greenfield filter) is only indicated in the following settings:

• Patients with acute venous thromboembolism who have an absolute contraindication to anticoagulant therapy (eg, recent surgery, hemorrhagic stroke, significant active or recent bleeding)
• Patients with massive pulmonary embolism who survived but in whom recurrent embolism invariably will be fatal
• Patients who have objectively documented recurrent venous thromboembolism, adequate anticoagulant therapy notwithstanding
• • In patients with a time-limited indication for IVC filter placement (eg, a short-term contraindication to anticoagulation), it is reasonable to select a retrievable IVC filter and evaluate the patient periodically for filter retrieval. After placement of an IVC filter, AHA guidelines recommend that anticoagulation be resumed once contraindications to anticoagulation or active bleeding complications have resolved.^[80]

Compression stockings

For patients who have had a proximal DVT, the use of elastic compression stockings provides a safe and effective adjunctive treatment that can limit or prevent extension of the thrombus. Stockings with a pressure of 30-40 mm Hg at the ankle, worn for 2 years following diagnosis, are recommended (grade 1A) to reduce the risk of postphlebitic syndrome.

True gradient compression stockings are highly elastic, providing a gradient of compression that is highest at the toes and gradually decreases to the level of the thigh. This reduces capacitive venous volume by approximately 70% and increases the measured velocity of blood flow in the deep veins by a factor of 5 or more. Compression stockings of this type have been proven effective in the prophylaxis of thromboembolism and are also effective in preventing progression of thrombus in patients who already have DVT and pulmonary embolism.

A 1994 meta-analysis calculated a DVT risk odds ratio of 0.28 for gradient compression stockings (as compared to no prophylaxis) in patients undergoing abdominal surgery, gynecologic surgery, or neurosurgery.

Other studies found that gradient compression stockings and LMWH were the most effective modalities in reducing the incidence of DVT after hip surgery; they were more effective than subcutaneous UFH, oral warfarin, dextran, or aspirin.

The ubiquitous white stockings known as anti-embolic stockings or "Ted hose" produce a maximum compression of 18 mm Hg. Ted hose rarely are fitted in such a way as to provide even that inadequate gradient compression. Because they provide such limited compression, they have no efficacy in the treatment of DVT and pulmonary embolism, nor have they been proven effective as prophylaxis against a recurrence.

True 30-40 mm Hg gradient compression pantyhose are available in sizes for pregnant women. They are recommended by many specialists for all pregnant women because they not only prevent DVT, but they also reduce or prevent the development of varicose veins during pregnancy.

Additional support therapies

Activity is recommended as tolerated. Early ambulation is recommended over bed rest when feasible (grade 1A recommendation).

Pharmacologic support of the cardiovascular system may be necessary. Dopamine and dobutamine are the usual inotropic agents. Mechanical ventilation may be necessary 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.^[39] Transfusion with packed red blood cells (either simple or exchange) improves oxygenation immediately, helping to break the vicious cycle outlined above.

IV fluids may help or may hurt the patient who is hypotensive from pulmonary embolism, depending on which point on the Starling curve describes the patient's condition. A cautious trial of a small fluid bolus may be attempted, with careful surveillance of the systolic and diastolic blood pressures and immediate cessation if the situation worsens after the fluid bolus. Improvement or normalization of blood pressure after fluid loading does not mean the patient has become hemodynamically stable.

Individuals with acute, submassive pulmonary embolisms have low levels of endogenous activated protein C. A study by Dempfle et al determined that administering drotrecogin alfa (activated) along with therapeutic doses of enoxaparin enhanced the inhibition of fibrin formation in these patients.^[82]

Drotrecogin alfa was withdrawn from the worldwide market October 25, 2011 after analysis of the Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis (PROWESS)-SHOCK clinical trial. Drotrecogin alfa failed to demonstrate a statistically significant reduction in 28-day all-cause mortality in patients with severe sepsis and septic shock. Trial results observed a 28-day all-cause mortality rate of 26.4% in patients treated with activated drotrecogin alfa compared with 24.2% in the placebo group of the study.

The risk of venous thromboembolism is increased during pregnancy and the postpartum period. Pulmonary embolism is the leading cause of death in pregnancy. DVT and pulmonary embolism are common during all trimesters of pregnancy and for 6-12 weeks after delivery.

Diagnosis

The diagnostic approach to patients with pulmonary embolism should be exactly the same in a pregnant patient as in a nonpregnant one. A nuclear perfusion lung scan is safe in pregnancy, as is a chest CT scan.

Guidelines by the professional societies on the diagnosis of pulmonary embolism make this difficult assessment easier and reduce the risks of radiation to the fetus. If the patient has a low pretest probability for pulmonary embolism and a normal D-dimer test result, clinical exclusion from further investigations is recommended. When the suspicion is high, the patients should have bilateral leg Doppler assessment. If the results are positive, the patient should be treated for pulmonary embolism. If the results are negative, CT pulmonary angiography is the next step. To rule out contrast-induced hypothyroidism, all neonates exposed to the iodinated contrast in utero should have their serum thyrotropin level checked in the first week of life.

Treatment

Heparin and fibrinolysis are safe in pregnancy. Failure to treat the mother properly is the most common cause of fetal demise.

Pregnant patients diagnosed with DVT or pulmonary embolism may be treated with LMWH throughout their pregnancy. Warfarin is contraindicated, because it crosses the placental barrier and can cause fetal malformations. Unfractionated heparin is category C. Therefore, LMWH at full anticoagulation doses should be continued until delivery. Women experiencing a thromboembolic event during pregnancy should receive therapeutic treatment with unfractionated heparin or LMWH during pregnancy, with anticoagulation continuing for 4-6 weeks postpartum and for a total of at least 6 months.

In addition to the thrombotic risks in pregnancy, women of childbearing age who are prescribed warfarin should be advised of the teratogenic effects of this drug. Alteplase is a category C drug, and should only be given following a judicious assessment of the risk-to-benefit ratio.

Pregnant women who are in a hypercoagulable state or who have had previous venous thromboembolism should receive prophylactic anticoagulation during pregnancy.

Complications of pulmonary embolism include the following:

• Sudden cardiac death
• Obstructive shock
• Pulseless electrical activity
• Atrial or ventricular arrhythmias
• Secondary pulmonary arterial hypertension
• Cor pulmonale
• Severe hypoxemia
• Right-to-left intracardiac shunt
• Lung infarction
• Pleural effusion
• Paradoxical embolism
• Heparin-induced thrombocytopenia
• Thrombophlebitis

Preventing idiopathic outpatient pulmonary embolism is difficult, if not impossible. That said, the majority of pulmonary embolisms occur in hospitalized patients. The incidence in these cases can be reduced through appropriate prophylaxis, achieved mechanically or via the administration of heparin, LMWH, or warfarin.^[83]

The incidence of venous thrombosis, pulmonary embolism, and death can be significantly reduced by embracing a prophylactic strategy in high-risk patients. Prevention of DVT in the lower extremities inevitably reduces the frequency of pulmonary embolism; therefore, populations at risk must be identified, and safe and efficacious prophylactic modalities should be used.

The QThrombosis algorithm is intended to identify currently asymptomatic adults at greatest future risk of venous thrombosis based on established risk factors. According to the study in which it was developed and validated, QThrombosis estimates the absolute risk of venous thrombosis at 1 year and 5 years into the future, information that can be used to guide prophylaxis and medication decisions.^[84]

Pulmonary embolism is an extremely common disorder. It presents with nonspecific clinical features and requires specialized investigations for confirmation of diagnosis. Therefore, many patients die from unrecognized pulmonary embolism. The other common pitfalls are as follows:

• Disregarding patient's complaints of unexplained dyspnea as anxiety or hyperventilation
• Blaming complaints of unexplained chest pain on musculoskeletal pain
• Failing to recognize, diagnose, and treat DVT
• Failing to initiate an appropriate diagnostic workup in patients with symptoms consistent with pulmonary embolism
• Failing to initiate therapeutic anticoagulant therapy with heparin in patients suspected to have pulmonary embolism, before the V/Q scan or other investigations
• Failure to advise of risk factors, such as smoking, pregnancy, and use of the oral contraceptive pill
• Failure to diagnose predisposing or associated conditions

Advances over the past several decades have significantly improved physicians’ ability to diagnosis pulmonary embolism and have refined the treatment of this disorder. However, several areas need further research and properly conducted therapeutic trials. The role of LMWH and the optimal duration of anticoagulant therapy in different subgroups of patients with venous thromboembolism require further study.

Because warfarin therapy results in bleeding, future studies should determine whether less intense warfarin therapy is effective in preventing recurrences of pulmonary embolism.

Whether drugs that inhibit the action of thrombin (eg, hirudin) are useful in treating patients with venous thromboembolic disease also needs to be determined by future trials.

Fibrinolytic therapy should not be delayed while consultation is sought. The decision to treat pulmonary embolism by fibrinolysis is properly made by the responsible emergency physician alone, and fibrinolytic therapy is properly administered in the ED.

A pulmonologist is often consulted before the true diagnosis is made because of the nonspecific nature of the symptoms, and 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.

If embolectomy is considered, consultation with a cardiac surgeon is mandatory. 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. Thrombotic endarterectomy is another surgical treatment option for patients with hemodynamic compromise from large pulmonary emboli. Thrombotic endarterectomy is only performed at certain centers and has a high mortality rate, but it can be successful in certain populations.

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).

An interventional radiology consultation may be helpful for catheter-directed fibrinolysis in selected patients. In rare cases, arranging for placement of a venous filter may be appropriate if the patient is not a candidate for thrombolytic therapy.

PT should be measured on a regular basis; the goal is an INR of 2-3.

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.

Long-term anticoagulation is essential for patients who survive an initial DVT or pulmonary embolism. The optimum total duration of anticoagulation is controversial, but general consensus holds that at least 6 months of anticoagulation is associated with significant reduction in recurrences and a net positive benefit.^[85]

Patients may have treatment initiated using concomitant warfarin and unfractionated heparin for 5 days in the hospital, with discharge on warfarin alone when the international normalized ratio (INR) is 2. Alternatively, patients may be discharged on concomitant therapy with a LMWH and warfarin for at least 5 days. The LMWH is then discontinued in the outpatient setting when the INR reaches 2.