Alteplase Treatment of Acute Pulmonary Embolism in the Intensive Care Unit

Acute pulmonary embolism is a deadly event that occurs in 1 per 1000 persons and is responsible for 50 000 to 100 000 deaths each year in the United States.1–3 A pulmonary embolism is an obstruction of the pulmonary artery or one of its branches by a thrombus. The signs and symptoms range from massive pulmonary embolism that results in unstable hemodynamic status to a small peripheral embolus that can be asymptomatic. To aid in the delineation of the types of pulmonary embolism, the American Heart Association has proposed several definitions4 (Table 1). These definitions have been used in clinical trials and practice guidelines to help stratify patients and aid in treatment selection.Approximately 44% of patients who have pulmonary embolism have a confirmed deep vein thrombosis.5 The pathogenesis of venous thromboembolism can be explained on the basis of the Virchow triad6: stasis, endothelial injury, and hypercoagulability. Table 2 provides risk factors for pulmonary embolism.7–12Thrombi from the iliofemoral vein are the most commonly involved source of pulmonary embolism.13,14 After traveling to the lungs, large thrombi often lodge in the bifurcation of the main pulmonary artery or the lobar branches, obstructing perfusion in the artery or its branches. The thrombus causes a blockage in the lung, resulting in an increase in pulmonary pressure, which increases the resistance to blood flow in the right ventricle. The result is increased right ventricular workload and decreased perfusion to the lung. If the right ventricle cannot pump against the increased pressure, right-sided heart failure can occur, which is manifested as hypoxemia, hypotension, and shortness of breath.15 Impaired gas exchange is also commonly associated with pulmonary embolism. The impairment is not solely due to the mechanical obstruction of the vasculature. Numbers of neutrophils and levels of platelet-activating factor are increased, and functional intrapulmonary shunting (area in the lung where perfusion exceeds ventilation), atelectasis, and surfactant dysfunction may occur, which can contribute to impaired gas exchange.16In the United States, acute pulmonary embolism is the third leading cause of death in hospitalized patients.17 Unfortunately, the manifestations of an acute pulmonary embolism can be highly variable and nonspecific, ranging from no signs or symptoms to unstable hemodynamic status and shock. Patients with acute pulmonary embolism can have a wide range of signs and symptoms, including dyspnea at rest or with exertion (73%), sharp chest pain that may radiate to the shoulder (44%), calf or thigh pain (44%), calf or thigh swelling (41%), cough (34%), 2+ pillow orthopnea (28%), and wheezing (21%). Clinical manifestations of a deep vein thrombosis are apparent in 44% of patients.15,18 Approximately 8% of patients experience circulatory collapse, and among these patients, dyspnea has been reported in 82% and dyspnea or tachypnea in 92%.18 In adults, the rate of asymptomatic acute pulmonary embolisms ranges from 28% to 58%.11In addition to signs and symptoms, the gold standard for diagnosis of a pulmonary embolism is pulmonary angiography.19 This study is performed by injecting contrast material into a branch of the pulmonary artery. Normal findings on pulmonary angiograms exclude a diagnosis of pulmonary embolism. Pulmonary angiography and computed tomography of the lungs can reveal pulmonary abnormalities that may explain a patient’s signs and symptoms. According to Wolf et al,19 66% to 93% of pulmonary embolisms can be detected by using computed tomography or pulmonary angiography.A D-dimer test can aid in the diagnosis of pulmonary embolism. D-dimers are specific degradation products of cross-linked fibrin. In patients with an acute clot, the serum level of D-dimer is elevated because of the simultaneous increase in coagulation and fibrinolysis.20 The D-dimer level has a high negative predictive value for venous thromboembolism and pulmonary embolism and therefore can be used to rule out these conditions.2 However, the test has poor specificity and a low positive predictive value. Therefore, other means of diagnosing pulmonary embolism are necessary.20Clinical outcomes of pulmonary embolism vary greatly depending on patients’ characteristics and the type of pulmonary embolism. The estimated 3-month mortality rate after diagnosis is 10% to 15%.21 However, 5% to 10% of patients with pulmonary embolism have an unstable hemodynamic status and shock and compared with patients without these characteristics have a higher mortality rate of almost 60%.9,12 Therefore, stratifying patients on the basis of their clinical signs and symptoms when pulmonary embolism is suspected is important.Treatment of pulmonary embolism includes both initial stabilization and anticoagulation, with consideration given to the use of a thrombolytic agent. In patients with suspected pulmonary embolism, stabilization of hemodynamic status should be the primary focus.3,4 Patients with hypoxemia should be given supplemental oxygen. For patients with hypotension, fluid boluses are used initially to replace fluids; vasopressors are given if fluid replacement is inadequate. Anticoagulation is the mainstay of treatment for patients with a high probability of pulmonary embolism. Patients with objectively confirmed pulmonary embolism or strongly suspected pulmonary embolism and no contraindications should receive anticoagulation therapy with low-molecular-weight heparin, subcutaneous fondaparinux, or intravenous unfractionated heparin.3,4 Anticoagulants, such as heparin, prevent the thrombus that is already formed from increasing in size. These medications cannot decrease the size of a thrombus that has already formed, but they can be used to stop clot growth and the development of new clots.21Although anticoagulants prevent both growth of established thrombus and formation of new thrombus, thrombolytics actually decrease the size of the already formed thrombus by dissolving fibrin. The 2011 guidelines of the American Heart Association4 and the guidelines of the American College of Chest Physicians3 recommend that patients with massive pulmonary embolism, evidence of hemodynamic compromise, and acceptable bleeding risk receive a thrombolytic. Use of a thrombolytic not only accelerates the lysis of the thrombus in acute pulmonary embolisms but also improves physiological parameters such as pulmonary perfusion and right ventricular function via dissolution of the thrombus.Alteplase initiates local fibrinolysis by binding to the fibrin in a clot and converting the trapped plasminogen to plasmin.22 The result is dissolution of the thrombus.22,23 When alteplase is administered, more than 50% of the drug concentration in the plasma is cleared within 5 minutes after the infusion is stopped. Alteplase is primarily cleared hepatically.23 The Food and Drug Administration (FDA) has approved this thrombolytic agent for management of ST-elevation myocardial infarction (lysis of thrombi in coronary arteries), acute stroke, and acute pulmonary embolism.23 Alteplase was approved for management of acute pulmonary embolism in 2002, and it can be used for management of acute, massive pulmonary embolism in adults for the lysis of acute pulmonary emboli accompanied by unstable hemodynamic status, such as hypotension.23Patients treated with alteplase should be evaluated; bleeding, especially at the catheter puncture site; and hemorrhages, including gastrointestinal, intracranial, and retroperitoneal hemorrhages should be considered.4 Most of the absolute and relative contraindications for use of alteplase (Table 3) are characteristics that would predispose a patient to a bleeding event.23 Clinicians should also be mindful of possible drug interactions. Concurrent administration of alteplase with an anticoagulant, such as heparin and vitamin K antagonists, or other medications that alter platelet function, such as aspirin and clopidogrel, may increase the risk of bleeding if administered before, during, or after alteplase therapy. The length of time the bleeding risk is increased depends on the agent used in addition to alteplase and can range from 1 hour for heparin to up to 5 days for clopidogrel.3,4 Therefore, patients given these combinations of drugs should be carefully monitored if the drugs are administered together.3,4,23The FDA-approved regimen of alteplase for an acute, massive pulmonary embolism is 100 mg administered by intravenous infusion over 2 hours.22 Heparin therapy should be stopped during the alteplase infusion and reinstituted after the infusion when the activated partial thromboplastin time (aPTT) or thrombin time returns to twice normal or less.23–27 With thrombolysis, patients may have an increased risk for bleeding. However, in a comparison of the bleeding rates after the administration of alteplase in patients who received heparin only and patients who received alteplase plus heparin, the rates of bleeding in the 2 groups did not differ significantly.24–30 Overall, compared with heparin alone, alteplase decreased total peripheral resistance and ventricular dilatation and increased cardiac output, ejection fraction, and oxygen saturation.24,26,28Table 4 reviews the grading criteria for clinical trials. Table 5—available online only at www.ccnonline.org— summarizes clinical trials on the use of alteplase in patients with massive pulmonary embolism.Thrombolysis should be considered for patients with submassive pulmonary embolism if they have a poor prognosis and a low risk for bleeding.4 The guidelines3 of the American College of Chest Physicians recommend the use of thrombolytic agents in these patients. Administration of a thrombolytic agent in addition to heparin requires assessment of a patient’s characteristics and of the risks and benefits of thrombolytic use, such as right ventricular strain and predisposition for bleeding.Of note, use of alteplase for treatment of submassive pulmonary embolism has not been approved by the FDA and is a widely debated topic. In patients with acute right ventricular dysfunction, use of alteplase can result in a 2- to 3-fold increase in death due to the embolism.33 Among patients with submassive pulmonary embolism, those who received heparin plus alteplase had less deterioration in clinical status, shorter hospital stays, an increase in pulmonary perfusion, shorter time to improved right ventricular function, and lower hospital mortality than did those who received heparin alone.34–36 In addition, primary thrombo lysis with alteplase decreased the need for treatment escalation, such as emergently administering a thrombolytic after heparin therapy alone was unsuccessful.35 Differences in bleeding between patients who received heparin alone and patients who received heparin plus alteplase were not significant.34–36Table 6—available online only at www.ccnonline.org— summarizes the use of alteplase in patients with submassive pulmonary embolism. The Figure is a proposed treatment algorithm based on a patient’s risk of bleeding and severity of the pulmonary embolism as reflected by hemodynamic compromise.3,4In systemic thrombolytic therapy, the drug is given through a peripheral intravenous catheter. When systemic thrombolytic therapy is contraindicated because of increased risk for bleeding or insufficient time for systemic thrombolysis, other therapies, such as catheter-directed thrombolysis (CDT), may be necessary.3,39,40 In CDT, the thrombolytic agent is administered directly into the pulmonary artery via a pulmonary artery catheter23; the usual thrombolytic agent is full-dose heparin. Table 7 is a summary of the clinical trials and assessments of the efficacy of CDT with alteplase.31,39,41–46 Overall, CDT appears safe and effective. With CDT, medications can be delivered directly to the thrombus at a high concentration. Lower doses of a thrombolytic and shorter durations of infusions are used to achieve complete thrombolysis. In theory, compared with systemic thrombolysis, the use of lower doses and shorter infusions times with alteplase reduces the risk of bleeding complications.3,40,41 Thrombolytic methods have also been combined with mechanical methods such as percutaneous mechanical thrombectomy, which can involve either spinning wires or jets of physiological saline aimed at the thrombus, to increase the rate of dissolution.47 Currently, CDT with alteplase is an “off-label” use of the drug. When used in CDT, alteplase has been infused at 0.5 to 1 mg/h for up to 48 hours.39 No clinical trials have been done to compare systemic thrombolysis with CDT. In a review of several methods of catheter-directed approaches with or without local or systemic thrombolytic therapy in patients with acute massive pulmonary embolism, Kuo et al39 reported that clinical success was achieved in 71% to 100% of patients who underwent a catheter-directed embolectomy with either systemic or local thrombolysis. In patients who underwent catheter-directed embolectomy alone, the success rate was 67% to 88%. Therefore, local experience with CDT and the expertise of the physician performing the procedure should be taken into account when CDT is being considered for a patient.Table 8 provides a summary of the recommendations of the American Heart Association,4 the American College of Chest Physicians,3 and the European Society of Cardiology48 for use of a thrombolytic agent in patients with massive pulmonary embolism or submassive pulmonary embolism and in CDT. For patients with massive pulmonary embolism, all 3 guidelines recommend use of a thrombolytic agent when the patients have no risk for bleeding. In patients with submassive pulmonary embolism, the 3 guidelines recommend use of thrombolytic agents in patients at high risk for death who have a low risk for bleeding. Neither the American College of Chest Physicians nor the European Society of Cardiology recommends the use of CDT. The American Heart Association suggests that CDT may be helpful when other mechanical thrombectomy strategies are unsuccessful.Currently, 3 meta-analyses49–51 (Table 9) have been conducted to evaluate thrombolysis for the treatment of pulmonary embolism. Agnelli et al49 found a lower composite end point of death and recurrence of embolism with thrombolysis than with heparin therapy alone. Wan et al50 reported a possible benefit for the use of thrombolysis in patients with unstable hemodynamic status and the highest risk for death or recurrence of embolism. Therefore, these authors50 recommend use of a thrombolytic agent in patients with a major pulmonary embolism and hemodynamic compromise. Dong et al51 did not find any benefit of thrombolysis or any difference in hemorrhagic events between control and interventional groups. They concluded that evidence of any benefit from the use of thrombolytic agents rather than heparin in the treatment of acute pulmonary embolism is insufficient.Patients receiving alteplase for the treatment of acute pulmonary embolism require specific nursing monitoring and care. Because of the high risk for bleeding, these patients should be cared for in a critical care setting for at least 24 hours, depending on their clinical status.50 Close monitoring for bleeding and hypertension are required during this time.Alteplase should be diluted with sterile water to a final concentration of 1 mg/mL for injection.22 The manufacturer provides a transfer device that should be used to add the sterile water to the alteplase powder. Foaming may occur when the sterile water is added but will dissipate if the mixture is allowed to stand undisturbed for several minutes. Of note, alteplase should not be shaken during dilution and mixing. In order to thoroughly mix the medication, the vial should be gently swirled or inverted. Alteplase is stable at room temperature for 8 hours after it is reconstituted and contains no antibacterial preservatives. For these reasons, the drug should be reconstituted immediately before use and should be administered within 8 hours of dilution.26In most patients, a continuous heparin infusion will already have been started while the decision to use alteplase is being made or while the alteplase is being dispensed by the pharmacy. In these patients, in order to decrease the risk for bleeding, the heparin infusion should be stopped when the alteplase infusion is started. Alteplase should be administered as a continuous infusion over a 2-hour period. During the infusion, patients’ neurological status should be monitored frequently because of the increased risk for cerebral hemorrhage. Neurological checks should be completed every 15 minutes during administration of the drug, then every 30 minutes for 6 hours, and then hourly for 24 hours after initiation of treatment.3,4,52 Alert patients should be instructed to report any changes in headache, vision, and sensorium. Any change in neurological status is reason to discontinue the infusion to investigate the possibility of intracranial bleeding,22 and computed tomography of the head should be conducted immediately. Bleeding remains a risk for up to 36 hours after completion of the alteplase infusion.4 Heart rate and blood pressure should be monitored continually, because these physiological indicators could alert bedside nurses to the occurrence of bleeding.22,52 Monitoring of heart rate and blood pressure is recommended for 24 hours after the administration of alteplase.Upon completion of the alteplase infusion, continuous infusion of heparin should be reinitiated. Before the infusion is restarted, blood should be obtained for determination of aPTT. In order to reduce the risk for bleeding, the heparin should not be started until the aPTT is twice the normal level or less.23 As the heparin infusion is restarted, monitoring for signs and symptoms of bleeding should continue. The aPTT should be monitored per institutional protocol to ensure the attainment of therapeutic anticoagulation and to prevent overanticoagulation.Other important nursing considerations include refraining from venous or arterial punctures and placement of invasive tubes during the first 24 hours after administration of alteplase.50 Existing insertion sites of invasive catheters should be assessed hourly for bleeding.At times, alteplase may be administered via a CDT method. In these situations, a smaller dose of alteplase (0.5-1 mg/h) is infused into the pulmonary artery via a pulmonary artery catheter for an extended time (14–46 hours).39,41–46 As with systemic administration of alteplase, bedside nurses should monitor patients for any signs or symptoms of bleeding. Specific attention should be paid to the insertion site of the pulmonary catheter.43The efficacy of alteplase can be monitored by noting the resolution of signs and symptoms related to the pulmonary embolism. For example, a patient should begin to have improvement in hemodynamic parameters, including blood pressure, heart rate, and right end-diastolic function. Improvement in the patient’s subjective symptoms should also occur, such as less chest pain, shortness of breath, and wheezing or cough.23Acute pulmonary embolisms are life-threatening abnormalities with a wide range of signs and symptoms. Because of the wide spectrum, from no signs or symptoms to hypotension and shock, diagnosis can be difficult. Early diagnosis and treatment are necessary to provide the best care and improve patients’ outcomes.53 Alteplase is efficacious in the treatment of acute massive and submassive pulmonary embolisms, although it has not been approved by the FDA for treatment of submassive pulmonary embolism. The risk for and development of bleeding should always be taken into account when therapy is started.