TREATMENT OF ACUTE PULMONARY EMBOLISM

INTRODUCTION
Acute pulmonary embolism (PE) is common and often fatal, with a mortality rate of approximately 30 percent without treatment. Most deaths are due to recurrent PE within the first few hours of the initial event. Therapy with anticoagulants decreases the mortality rate to 3 to 8 percent, making it imperative that effective therapy be instituted as quickly as possible. The clinical severity of acute PE can be highly variable, ranging from asymptomatic to severe hypoxemia, right ventricular failure, shock, and death. As a result, therapy varies from patient to patient and requires considerable clinical judgment. Common questions asked by clinicians when a patient presents with PE include:

Which anticoagulant should I administer? How much? How long? Should I administer thrombolytic therapy? Should an inferior vena caval filter be placed? Is embolectomy indicated? Can the patient be treated as an outpatient?

Treatment of patients with acute PE is reviewed here. More detailed discussions regarding anticoagulation and thrombolysis in acute PE are presented separately. The epidemiology, prognosis, pathophysiology, risk factors, symptoms, signs, and diagnosis of acute PE are discussed separately.

RESUSCITATION
When a patient presents with suspected acute PE, the initial focus is on stabilizing the patient. This may require respiratory support, hemodynamic support, and/or empiric anticoagulation. Respiratory support Supplemental oxygen should be administered if hypoxemia exists. Severe hypoxemia or respiratory failure should prompt consideration of intubation and mechanical ventilation. Of note, patients with coexistent RV failure are prone to hypotension following intubation. The initiation of mechanical ventilation is discussed separately.

Hemodynamic support Hemodynamic support should be instituted when a patient presents with acute PE and hypotension. Hypotension may be roughly defined as a systolic blood pressure <90 mmHg or a drop in systolic blood pressure of 40 mmHg from baseline, but the precise thresholds that warrant hemodynamic support depend to some degree upon the patients baseline blood pressure and whether there is clinical evidence of hypoperfusion (eg, change in mental status, diminished urine output). Intravenous fluid administration is first-line therapy. It may improve hemodynamic performance, as illustrated by a series of 13 patients with acute PE and a cardiac index <2.5 L/min/m2. Administration of 500 mL of dextran significantly increased the cardiac index from a mean of 1.6 to 2.0 L/min/m2. Intravenous fluid (usually normal saline) should be administered cautiously because increased right ventricular (RV) wall stress can decrease the ratio of RV oxygen supply to demand. This may result in ischemia, deterioration of RV function, and worsening RV failure. Clinicians should be wary of administering more than 500 to 1000 mL of normal saline during the initial resuscitation period. If the patient's blood pressure and hemodynamic status do not improve with intravenous fluids, then intravenous vasopressor therapy should promptly follow. There are no randomized trials that definitively determine the optimal vasopressor for patients with shock due to acute PE:

Norepinephrine, dopamine, or epinefrine may be effective. Norepinephrine is the least likely to cause tachycardia. Dobutamine increases myocardial contractility and causes vasodilation (ie, decreases afterload), which is ideal for cardiogenic shock. However, the effects of vasodilation can exceed those of increased myocardial contractility and worsen the hypotension, particularly at low doses. Using a combination of dobutamine plus norepinephrine initially may increase myocardial contractility, while minimizing vasodilation and the risk of hypotension. As the dose of dobutamine is increased, the effects of the increased myocardial contractility may exceed those of the vasodilation, allowing the norepinephrine to be weaned off and the dobutamine to be used alone. Isoprotenero, amrinone, and milrinone have been investigated in animal models, but are not indicated for hypotension due to acute PE.

Physiologic properties and practical issues regarding the use of vasopressors are discussed separately. Empiric anticoagulation PE-directed therapy should be considered during the resuscitative period. Empiric anticoagulation is indicated when there is no excess risk for bleeding and there is a high

clinical suspicion of acute PE, a moderate clinical suspicion for acute PE and the diagnostic evaluation is expected to take longer than four hours, or a low clinical suspicion for acute PE and the diagnostic evaluation is expected to take longer than 24 hours [9]. Stratification of clinical suspicion and the initiation of empiric anticoagulant therapy for suspected acute PE are discussed separately. Once it has been determined that empiric anticoagulant therapy is indicated, it should be initiated as soon as possible because its efficacy may be related to achieving therapeutic levels of anticoagulation within the initial 24 hours. A pooled analysis of three anticoagulation trials demonstrated that the risk of recurrent PE was 25 percent if the activated partial thromboplastin time (aPTT) was not therapeutic within the first 24 hours after initiation of heparin. In contrast to the approach for patients with no excess risk for bleeding, empiric anticoagulant therapy should be considered on a case-by-case basis if there is a moderate or high risk of bleeding, or if there are conditions in the differential diagnosis that are contraindications to anticoagulation (eg, pericardial tamponade, aortic dissection). If anticoagulant therapy is judged to be contraindicated, the diagnostic evaluation must be expedited so that therapies that do not require anticoagulation (eg, inferior vena caval filter, embolectomy) can be initiated if acute PE is confirmed. Stratification of the risk of bleeding as low, moderate, or high is described separately.

POST-RESUSCITATION
The diagnostic evaluation should be performed as quickly as possible once the patient has been stabilized. For patients in whom the diagnostic evaluation EXCLUDES an acute PE, anticoagulant therapy should be discontinued if it was initiated empirically during the resuscitative period. Alternative causes of the patients symptoms and signs should be sought. For patients in whom the diagnostic evaluation CONFIRMS an acute PE:

Anticoagulant therapy should be initiated or continued if it was begun empirically. Placement of an inferior vena caval filter is an appropriate alternative to anticoagulant therapy for patients who have failed anticoagulant therapy, developed complications of anticoagulation, or have an unacceptable bleeding risk. It should be determined whether the clinical presentation is severe enough to warrant thrombolysis. Embolectomy is appropriate for patients whose presentation is severe enough to warrant thrombolysis, but in whom thrombolysis is either contraindicated or unsuccessful.

This approach is depicted in an algorithm for the management of suspected acute PE.

Anticoagulant therapy Anticoagulant therapy is considered primary therapy for acute PE. It is discussed in detail separately, including indications for empiric therapy, assessment of the risk for bleeding, anticoagulant agents, dosing, monitoring, outcomes, and duration of therapy. Thrombolytic therapy Thrombolytic therapy is generally considered for patients with severe clinical manifestations. Thrombolytic therapy for acute PE is reviewed in detail separately, including the indications, contraindications, agents, administration, and outcomes. IVC filters Inferior vena caval (IVC) filters provide a screen in the inferior vena cava, allowing blood to pass through while large emboli from the pelvis or lower extremities are blocked or fragmented before reaching the lung. Placement of an IVC filter is generally considered in patients who have contraindications to anticoagulation, failed anticoagulation, or developed a complication due to anticoagulation. In addition, IVC filter placement is often considered when the hemodynamic or respiratory compromise is severe enough that another PE may be lethal. IVC filter indications, types, outcomes, and complications are reviewed separately. Embolectomy Embolectomy (ie, removal of the emboli) can be performed using catheters or surgically. It should be considered when a patient's presentation is severe enough to warrant thrombolysis (eg, persistent hypotension due to acute PE), but thrombolytic therapy either fails or is contraindicated. Whether surgical or catheter embolectomy is chosen depends upon the availability of resources and expertise of the institution, since a direct comparison has never been performed and data regarding the effectiveness of each therapy are limited. Catheter embolectomy Rheolytic embolectomy, rotational embolectomy, suction embolectomy, thrombus fragmentation, and ultrasound plus low-dose thrombolytic therapy are techniques that have been utilized to reduce the embolic burden in patients with acute PE. Case series using these techniques are small and none of the techniques has been compared with other forms of therapy in randomized trials. Larger studies are needed to determine which, if any, catheter technique is most effective compared to alternative treatment modalities.

Rheolytic embolectomy Using a rheolytic embolectomy catheter (ie, the AngioJet embolectomy system), embolectomy is accomplished by injecting pressurized saline through the catheter's distal tip, which macerates the emboli. The saline and fragments of clot are then sucked back into an exhaust lumen of the catheter for disposal. The major disadvantage of this system is that a large venous sheath or a

venous cut-down is required to insert the large catheter, which increases the risk of bleeding at the insertion site. In a case series of 12 patients with acute PE who underwent rheolytic embolectomy with or without catheter-directed thrombolysis, technical success was achieved in all 12 patients. Ten patients survived (83 percent) and were discharged from the hospital, but two patients died (17 percent) due to cardiac arrest within 24 hours of the procedure. Rotational embolectomy Rotational catheter fragmentation of emboli has been performed using conventional cardiac catheters that do not require venotomy at the insertion site. Newer catheters also exist that use a rotating device to fragment the thrombus, while continuously aspirating the fragments. A case series of 20 patients treated with rotational embolectomy reported that approximately one-third of the procedures achieved recanalization, but mortality was high (20 percent). In a more recent case series, 18 patients with acute PE complicated by shock underwent catheter-directed rotational embolectomy, most with continuous aspiration of thrombotic fragments. Clinical success was achieved in 16 cases (89 percent), defined as improvement in oxygenation and blood pressure without a major complication. One patient died from refractory shock. Suction embolectomy Suction embolectomy involves suctioning thrombus through a large-lumen catheter by manually applying negative pressure with an aspiration syringe. This technique requires an aspiration sheath with a detachable hemostatic valve; it cannot be performed with a conventional vascular access sheath because the fragments of thrombus get trapped within the sheath due to the hemostatic valve. Thrombus fragmentation Mechanical disruption of the thrombus (to reduce pulmonary vascular resistance by breaking the thrombus into small fragments) can be achieved by manually rotating a standard pigtail catheter or peripheral balloon angioplasty catheter. Ultrasound plus low-dose thrombolytic therapy Catheter-directed ultrasound combined with low-dose thrombolytic therapy has been studied and may offer benefit. This was suggested by a case report in which a patient presented with shock due to massive bilateral pulmonary emboli. The patient was given a partial dose of standard systemic thrombolytic therapy and then managed with catheter-directed ultrasound plus a continuous infusion of low-dose thrombolytic therapy. The pulmonary emboli resolved in less than 24 hours.

Surgical embolectomy Surgical embolectomy is typically limited to large medical centers because an experienced surgeon and cardiopulmonary bypass are required. Although the usual indication for surgical embolectomy is systemic hypotension due to acute PE in a patient in whom thrombolysis is contraindicated, surgery has also been prompted by echocardiographic evidence of an embolus trapped within a patent foramen ovale, the right atrium, or the right ventricle. Surgical embolectomy has been compared to repeat thrombolysis in patients who failed initial thrombolysis. In a small observational cohort study, patients who underwent

surgical embolectomy had fewer recurrent PE. In addition, there were fewer deaths and fewer major bleeding complications among the surgical embolectomy group, although these differences did not achieve statistical significance. Surgical embolectomy has not been compared to catheter embolectomy or primary thrombolytic therapy. Transesophageal echocardiography (TEE) should be performed before or during pulmonary embolectomy to look for extrapulmonary thrombi (ie, thrombi in the right atrium, right ventricle, or vena cava). In a series of 50 patients with PE, intraoperative TEE detected extrapulmonary thrombi in 13 patients (26 percent), which altered the surgical management of five patients (10 percent). Cardiac arrest predicts mortality during surgical embolectomy. In one study of 36 patients with profound hypotension due to acute PE (but without cardiac arrest) who underwent surgical embolectomy, 35 patients survived (97 percent). In contrast, operative mortality among patients with acute PE who were resuscitated from a cardiac arrest, then underwent surgical embolectomy was approximately 75 percent. Mortality after cardiac arrest due to acute PE is high in the nonsurgical setting as well.

INPATIENT OR OUTPATIENT THERAPY

Not all patients who have symptomatic acute PE need to be admitted to the hospital for initial therapy. Patients who do not require supplemental oxygen and have a normal pulse, normal blood pressure, and no recent history of bleeding, may reasonably be considered for outpatient management if they do not have serious comorbid conditions (eg, ischemic heart disease, liver or renal failure, thrombocytopenia). Additional considerations include the amount of support from family and friends, access to a telephone, and the ability to return to the hospital quickly if there is clinical deterioration. This is supported by several observational studies and a randomized trial that showed no significant differences in outcomes when patients treated as outpatients were compared with patients treated as inpatients. In the trial, 344 patients with symptomatic acute PE and a low risk of death were randomly assigned to receive either inpatient or outpatient therapy with low molecular weight heparin followed by oral anticoagulation. Within 90 days, recurrent venous thromboembolism occurred in one outpatient (0.6 percent) and no inpatients, death occurred in one outpatient and one inpatient, and major bleeding occurred in three outpatients (1.8 percent) and no inpatients. The mean length of stay was 0.5 days for outpatients and 3.9 days for inpatients. The trial defined a low risk of death as falling within pulmonary embolism severity index (PESI) class I or II. The PESI is described separately. In stable patients being considered for outpatient therapy or early discharge, it is logical that an important risk factor for poor outcome would be residual clot burden in the legs. In fact, in patients with a first episode of acute symptomatic PE, the presence of concomitant deep vein thrombosis (DVT) has been shown to be an independent predictor of death in the ensuing three months after diagnosis. Thus, when outpatient therapy of acute PE is considered, the

clinician may wish to evaluate the legs prior to discharge (ie, assessment of the thrombotic burden may assist with risk stratification of these patients).

INFORMATION FOR PATIENTS

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Basics topics Beyond the Basics topics

1. When a patient presents with suspected acute pulmonary embolism (PE), initial care should focus on stabilizing the patient. Patients with significant hypoxemia or hemodynamic compromise should be admitted to the intensive care unit. 2. Supplemental oxygen should be administered if hypoxemia exists. Severe hypoxemia or respiratory failure should prompt intubation and mechanical ventilation. 3. If the patient presents with systemic hypotension, prompt hemodynamic support should be instituted. Intravenous fluid administration may be beneficial; however, clinicians should be wary of administering more than 500 to 1000 mL during the initial resuscitation period. 4. For patients whose hypotension does not resolve with intravenous fluids, we recommend prompt vasopressor therapy (Grade 1B). We suggest using norepinephrine as the initial agent (Grade 2C). Dopamine, epinephrine, or a combination of dobutamine plus norepinephrine may also be effective. 5. The decision about whether or not to initiate empiric anticoagulant therapy during resuscitation and the diagnostic evaluation depends upon both the degree of clinical suspicion for acute PE and the risk for bleeding.

6. When the diagnostic evaluation EXCLUDES acute PE, anticoagulant therapy is discontinued if it was initiated empirically during the resuscitative period and alternative causes of the patients symptoms and signs are sought. 7. When the diagnostic evaluation CONFIRMS acute PE, anticoagulant therapy is initiated (or continued if it was begun empirically) and it is determined whether the clinical presentation is severe enough to warrant thrombolysis. Anticoagulant and thrombolytic therapy for acute PE are reviewed separately. 8. An inferior vena cava filter is an appropriate alternative for patients with confirmed acute PE who have a high risk for bleeding, complications of anticoagulation, recurrent PE despite therapeutic anticoagulation, or hemodynamic or respiratory compromise that is severe enough that another PE may be lethal. 9. For patients with acute PE in whom thrombolysis is indicated, but who fail thrombolysis or have contraindications to thrombolysis, we suggest catheter or surgical embolectomy if the necessary resources and expertise are available (grade 2C). The decision of whether to pursue one of these approaches should be based upon local expertise. 10. Outpatient management is reasonable for selected patients with acute PE who do not require supplemental oxygen and have a normal pulse, normal blood pressure, and no recent history of bleeding, assuming that they do not have serious comorbid conditions (eg, ischemic heart disease, liver or renal failure, thrombocytopenia). Additional considerations include the amount of support from family and friends, access to a telephone, and the ability to return to the hospital quickly if there is clinical deterioration.