Acute pulmonary embolism is a deadly event that occurs in 1 per 1000 persons and isresponsible for 50 000 to 100 000 deaths each year in the United States.1-3 A pulmonaryembolism is an obstruction of the pulmonary artery or one of its branches by a throm-bus. The signs and symptoms range from massive pulmonary embolism that resultsin unstable hemodynamic status to a small peripheral embolus that can be asympto-

matic. To aid in the delineation of the types of pulmonary embolism, the American Heart Associationhas proposed several definitions4 (Table 1). These definitions have been used in clinical trials andpractice guidelines to help stratify patients and aid in treatment selection.

Approximately 44% of patients who have pulmonary embolism have a confirmed deep vein throm-bosis.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.7-12

Alteplase Treatment of Acute Pulmonary Embolismin the Intensive Care UnitPAMELA L. SMITHBURGER, PharmD, BCPSSHAUNA CAMPBELL, MSNSANDRA L. KANE-GILL, MS, PharmD, MSC

This article has been designated for CNE credit. A closed-book, multiple-choice examination follows this article,which tests your knowledge of the following objectives:

1. Identify signs and symptoms when acute embolism is suspected2. Discuss the medical management of acute peripheral emboli3. Differentiate the classifications of acute peripheral emboli

©2013 American Association of Critical-Care Nurses doi: http://dx.doi.org/10.4037/ccn2013626

CNE Continuing Nursing Education

Cover

www.ccnonline.org CriticalCareNurse Vol 33, No. 2, APRIL 2013 17

Acute pulmonary embolism accounts for 50 000 to 100 000 deaths each year in the United States. Becauseof the wide spectrum of clinical manifestations, ranging from massive pulmonary embolism to smallperipheral emboli, stratifying and treating patients according to their signs and symptoms is importantwhen an acute embolism is suspected. Patients’ clinical findings can range from no signs or symptoms tounstable hemodynamic status and shock. The 3-month mortality is 10% to 15%, but can be as high as 60%in patients with hemodynamic shock. This article reviews the classifications of acute peripheral emboli,explains the treatment of acute peripheral emboli, reviews the pharmacology of alteplase, and presentsan assessment of the literature evaluating alteplase for the treatment of acute peripheral emboli. Clinicalpearls for the administration, monitoring, and care of a patient receiving alteplase in an intensive careunit also are discussed. (Critical Care Nurse. 2013;33[2]:17-27)

Thrombi from the iliofemoral vein are the most com-monly involved source of pulmonary embolism.13,14 Aftertraveling to the lungs, large thrombi often lodge in thebifurcation of the main pulmonary artery or the lobarbranches, obstructing perfusion in the artery or itsbranches. The thrombus causes a blockage in the lung,resulting in an increase in pulmonary pressure, whichincreases the resistance to blood flow in the right ventri-cle. The result is increased right ventricular workloadand decreased perfusion to the lung. If the right ventriclecannot pump against the increased pressure, right-sidedheart failure can occur, which is manifested as hypoxemia,hypotension, and shortness of breath.15 Impaired gasexchange is also commonly associated with pulmonaryembolism. The impairment is not solely due to themechanical obstruction of the vasculature. Numbers ofneutrophils and levels of platelet-activating factor areincreased, and functional intrapulmonary shunting (areain the lung where perfusion exceeds ventilation), atelec-tasis, and surfactant dysfunction may occur, which cancontribute to impaired gas exchange.16

In the United States, acute pulmonary embolism isthe third leading cause of death in hospitalized patients.17

Unfortunately, the manifestations of an acute pulmonaryembolism can be highly variable and nonspecific, rang-ing from no signs or symptoms to unstable hemodynamicstatus and shock. Patients with acute pulmonary embolismcan have a wide range of signs and symptoms, includingdyspnea at rest or with exertion (73%), sharp chest painthat may radiate to the shoulder (44%), calf or thigh pain(44%), calf or thigh swelling (41%), cough (34%), 2+ pilloworthopnea (28%), and wheezing (21%). Clinical manifes-tations of a deep vein thrombosis are apparent in 44% ofpatients.15,18 Approximately 8% of patients experience cir-culatory collapse, and among these patients, dyspnea

Pamela L. Smithburger is an assistant professor of pharmacy and therapeutics, University of Pittsburgh, School of Pharmacy, and a criticalcare clinical specialist in the medical ICU, University of Pittsburgh Medical Center Presbyterian Hospital, Pittsburgh, Pennsylvania.

Shauna Campbell is the director of the medical ICU, University of Pittsburgh Medical Center.

Sandra L. Kane-Gill is an associate professor of pharmacy and therapeutics, Center for Pharmacoinformatics and Outcomes Research,University of Pittsburgh, School of Pharmacy, and a critical care patient safety officer, Department of Pharmacy, University of PittsburghMedical Center.Corresponding author: Pamela Smithburger, PharmD, BCPS, University of Pittsburgh School of Pharmacy, University of Pittsburgh Medical Center, 200 Lothrop St, PittsburghPA 15213 (e-mail: smithburgerpl@upmc.edu).

To purchase electronic or print reprints, contact The InnoVision Group, 101 Columbia, Aliso Viejo, CA 92656. Phone, (800) 899-1712 or (949) 362-2050 (ext 532); fax, (949)362-2049; e-mail, reprints@aacn.org.

Authors

Table 1 Definitions of an acute pulmonary embolisma

Category

Massive

Submassive

Low risk

Description

Acute pulmonary embolism with Sustained hypotension (systolic blood pressure

<90 mm Hg for at least 15 min) Requirement for inotropic support, not

because of other causesPersistent or pulseless, bradycardia (heart rate

<40/min) with shock

Acute pulmonary embolism with myocardialnecrosis or right ventricular dysfunction but nosystemic hypotension

Acute pulmonary embolism with normal levelsof biomarkers, no systemic hypotension orright ventricular dysfunction

a Based on information from Jaff et al.4

Table 2 Selected risk factors for thromboembolisma

Component of the Virchow triad

Stasis

Endothelial injury

Hypercoagulability

Risk factor

ImmobilizationParalysisAtrial fibrillationLong-distance travelVenous insufficiency

Recent central venous instrumentation HypertensionAtherosclerosisTrauma or surgeryIndwelling catheter

Malignant neoplasms History of heavy smokingPregnancyObesityEstrogen therapySepsisTrauma or surgery of a lower extremity

a Based on information from Stein et al,7 PIOPED Investigators,8 Darze et al,9

Heit et al,10 Green et al,11 and Goldhaber et al.12

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has been reported in 82% and dyspnea or tachypnea in92%.18 In adults, the rate of asymptomatic acute pulmonaryembolisms ranges from 28% to 58%.11

In addition to signs and symptoms, the gold standardfor diagnosis of a pulmonary embolism is pulmonaryangiography.19 This study is performed by injecting con-trast material into a branch of the pulmonary artery.Normal findings on pulmonary angiograms exclude adiagnosis of pulmonary embolism. Pulmonary angiogra-phy and computed tomography of the lungs can revealpulmonary abnormalities that may explain a patient’ssigns and symptoms. According to Wolf et al,19 66% to93% of pulmonary embolisms can be detected by usingcomputed tomography or pulmonary angiography.

A D-dimer test can aid in the diagnosis of pulmonaryembolism. D-dimers are specific degradation products ofcross-linked fibrin. In patients with an acute clot, the serumlevel of D-dimer is elevated because of the simultaneousincrease in coagulation and fibrinolysis.20 The D-dimerlevel has a high negative predictive value for venousthromboembolism and pulmonary embolism and there-fore can be used to rule out these conditions.2 However,the test has poor specificity and a low positive predictivevalue. Therefore, other means of diagnosing pulmonaryembolism are necessary.20

Clinical outcomes of pulmonary embolism vary greatlydepending on patients’ characteristics and the type ofpulmonary embolism. The estimated 3-month mortalityrate after diagnosis is 10% to 15%.21 However, 5% to 10%of patients with pulmonary embolism have an unstablehemodynamic status and shock and compared withpatients without these characteristics have a higher mor-tality rate of almost 60%.9,12 Therefore, stratifying patientson the basis of their clinical signs and symptoms whenpulmonary embolism is suspected is important.

Acute Pulmonary EmbolismInitial Treatment

Treatment of pulmonary embolism includes bothinitial stabilization and anticoagulation, with considera-tion given to the use of a thrombolytic agent. In patientswith suspected pulmonary embolism, stabilization ofhemodynamic status should be the primary focus.3,4

Patients with hypoxemia should be given supplementaloxygen. For patients with hypotension, fluid boluses areused initially to replace fluids; vasopressors are given iffluid replacement is inadequate. Anticoagulation is the

mainstay of treatment for patients with a high probabil-ity of pulmonary embolism. Patients with objectivelyconfirmed pulmonary embolism or strongly suspectedpulmonary embolism and no contraindications shouldreceive anticoagulation therapy with low-molecular-weight heparin, subcutaneous fondaparinux, or intra-venous unfractionated heparin.3,4 Anticoagulants, suchas heparin, prevent the thrombus that is already formedfrom increasing in size. These medications cannot decreasethe size of a thrombus that has already formed, but theycan be used to stop clot growth and the development ofnew clots.21

Although anticoagulants prevent both growth ofestablished thrombus and formation of new thrombus,thrombolytics actually decrease the size of the alreadyformed thrombus by dissolving fibrin. The 2011 guide-lines of the American Heart Association4 and the guide-lines of theAmericanCollege ofChest Physi-cians3 recom-mend that patients with massive pulmonary embolism,evidence of hemodynamic compromise, and acceptablebleeding risk receive a thrombolytic. Use of a throm-bolytic not only accelerates the lysis of the thrombus inacute pulmonary embolisms but also improves physio-logical parameters such as pulmonary perfusion and rightventricular function via dissolution of the thrombus.

AlteplaseAlteplase initiates local fibrinolysis by binding to the

fibrin in a clot and converting the trapped plasminogento plasmin.22 The result is dissolution of the thrombus.22,23

When alteplase is administered, more than 50% of thedrug concentration in the plasma is cleared within 5 min-utes after the infusion is stopped. Alteplase is primarilycleared hepatically.23 The Food and Drug Administration(FDA) has approved this thrombolytic agent for manage-ment of ST-elevation myocardial infarction (lysis ofthrombi in coronary arteries), acute stroke, and acutepulmonary embolism.23 Alteplase was approved for man-agement of acute pulmonary embolism in 2002, and itcan be used for management of acute, massive pulmonaryembolism in adults for the lysis of acute pulmonaryemboli accompanied by unstable hemodynamic status,such as hypotension.23

In addition to signs and symptoms, thegold standard for diagnosis of a pulmonaryembolism is pulmonary angiography.

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Contraindications and Interactions. Patientstreated with alteplase should be evaluated; bleeding,especially at the catheter puncture site; and hemor-rhages, including gastrointestinal, intracranial, andretroperitoneal hemorrhages should be considered.4

Most of the absolute and relative contraindications foruse of alteplase (Table 3) are characteristics that wouldpredispose a patient to a bleeding event.23 Cliniciansshould also be mindful of possible drug interactions.Concurrent administration of alteplase with an antico-agulant, such as heparin and vitamin K antagonists, orother medications that alter platelet function, such asaspirin and clopidogrel, may increase the risk of bleed-ing if administered before, during, or after alteplasetherapy. The length of time the bleeding risk is increaseddepends on the agent used in addition to alteplase andcan range from 1 hour for heparin to up to 5 days forclopidogrel.3,4 Therefore, patients given these combina-tions of drugs should be carefully monitored if the drugsare administered together.3,4,23

Use With Heparin. The FDA-approved regimen ofalteplase for an acute, massive pulmonary embolism is100 mg administered by intravenous infusion over 2hours.22 Heparin therapy should be stopped during thealteplase infusion and reinstituted after the infusionwhen the activated partial thromboplastin time (aPTT)or thrombin time returns to twice normal or less.23-27

With thrombolysis, patients may have an increased riskfor bleeding. However, in a comparison of the bleedingrates after the administration of alteplase in patientswho received heparin only and patients who receivedalteplase plus heparin, the rates of bleeding in the 2groups did not differ significantly.24-30 Overall, comparedwith heparin alone, alteplase decreased total peripheralresistance and ventricular dilatation and increased car-diac output, ejection fraction, and oxygen saturation.24,26,28

Table 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 inpatients with massive pulmonary embolism.

Treatment of Submassive Pulmonary Embolism

Thrombolysis should be considered for patients withsubmassive pulmonary embolism if they have a poorprognosis 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. Admin-istration of a thrombolytic agent in addition to heparinrequires assessment of a patient’s characteristics and ofthe risks and benefits of thrombolytic use, such as rightventricular strain and predisposition for bleeding.

Of note, use of alteplase for treatment of submassivepulmonary embolism has not been approved by the FDAand is a widely debated topic. In patients with acuteright ventricular dysfunction, use of alteplase can resultin 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 deteri-oration in clinical status, shorter hospital stays, an increasein pulmonary perfusion, shorter time to improved rightventricular function, and lower hospital mortality than

Table 3 Contraindications to use of alteplasea

Absolute contraindications

Internal bleeding Previous intracranial

hemorrhageHistory of a cerebral vascular

accident within the past 3months

Recent intracranial orintraspinal surgery or trauma

Intracranial neoplasmArteriovenous malformation

or aneurysmKnown bleeding diathesis

Relative contraindications

Age >75 yCurrent use of anticoagulationPregnancyNoncompressible vascular

puncturesTraumatic or prolonged car-

diopulmonary resuscitation(<10 min)

Recent internal bleeding(within 2-4 wk)

History of chronic, severe, andpoorly controlled hypertension

Severe uncontrolled hyperten-sion on initial examination(systolic blood pressure>180 mm Hg or diastolicblood pressure >110 mm Hg)

DementiaRemote ischemic stroke (>3 mo)Major surgery within preceding

3 weeks

a Based on information from Jaff et al4 and Ouellette and Patocka.22

Table 4 Grading criteria for clinical trialsa

Assessment

Risk vs benefit

Quality of the data available

Grade

12

ABC

Grade description

Benefit > riskRisk > benefit

GoodFairPoor

a Based on information from Ansani et al.31

20 CriticalCareNurse Vol 33, No. 2, APRIL 2013 www.ccnonline.org

did those who received heparinalone.34-36 In addition, primarythrombo lysis with alteplasedecreased the need for treatmentescalation, such as emergentlyadministering a thrombolytic afterheparin therapy alone was unsuc-cessful.35 Differences in bleedingbetween patients who receivedheparin alone and patients whoreceived heparin plus alteplase werenot significant.34-36 Table 6—availableonline only at www.ccnonline.org—summarizes the use of alteplase inpatients with submassive pul-monary embolism. The Figure is aproposed treatment algorithmbased on a patient’s risk of bleedingand severity of the pulmonaryembolism as reflected by hemody-namic compromise.3,4

In systemic thrombolytic therapy,the drug is given through a periph-eral intravenous catheter. When sys-temic thrombolytic therapy iscontraindicated because of increasedrisk for bleeding or insufficient timefor systemic thrombolysis, othertherapies, such as catheter-directedthrombolysis (CDT), may be neces-sary.3,39,40 In CDT, the thrombolyticagent is administered directly intothe pulmonary artery via a pul-monary artery catheter23; the usualthrombolytic agent is full-doseheparin. Table 7 is a summary of theclinical trials and assessments of theefficacy of CDT with alteplase.31,39,41-46 Overall, CDTappears safe and effective. With CDT, medications canbe delivered directly to the thrombus at a high concen-tration. Lower doses of a thrombolytic and shorter dura-tions of infusions are used to achieve completethrombolysis. In theory, compared with systemic throm-bolysis, the use of lower doses and shorter infusionstimes with alteplase reduces the risk of bleeding compli-cations.3,40,41 Thrombolytic methods have also been com-bined with mechanical methods such as percutaneous

mechanical thrombectomy, which can involve eitherspinning wires or jets of physiological saline aimed at thethrombus, to increase the rate of dissolution.47 Currently,CDT with alteplase is an “off-label” use of the drug. Whenused in CDT, alteplase has been infused at 0.5 to 1 mg/hfor up to 48 hours.39 No clinical trials have been done tocompare systemic thrombolysis with CDT. In a review ofseveral methods of catheter-directed approaches with orwithout local or systemic thrombolytic therapy in patientswith acute massive pulmonary embolism, Kuo et al39

Figure Treatment algorithm for acute pulmonary embolism. Based on informationfrom Kearon et al3 and Jaff et al.4

Abbreviations: aPTT, activated partial thromboplastin time; BNP, brain natriuretic peptide; IV, intravenous;PE, pulmonary embolism; RV, right ventricle; SBP, systolic blood pressure.

PE is diagnosedand treatment is necessary

RV strain or a possibility of poor prognosis

Consider thrombolytic agents if:1. Patient has shock or respiratory distress2. RV dysfunction3. Elevated levels of biomarkers (troponin, BNP)

1. Discontinue heparin infusion2. Administer alteplase 100 mg IV for 2 hours3. Check aPTT 4. Restart heparin infusion when aPTT ≤2 times normal

Low or acceptable bleeding risk and no contraindications to thrombolytic therapy

Hemodynamic compromise(SBP <90 mm Hg

for >15 minutes or need inotropic support)

Low-risk PE

No RV strain

Massive PESubmassive PE

Anticoagulation AnticoagulationAnticoagulation

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Table 7 Summary of clinical trials and assessments of the efficacy of catheter-directed thrombolysis (CDT) in patients with pulmonary embolism (PE)

Study

Chamsuddin et al,41 2008

Kuo et al,39 2009

Griffith et al,43 2009

Bechtel et al,44 2005

Lin et al,45 2009

Kuo et al,46 2008

Study design

RE

RE

CR

CR

RE

RE

n

10

594

1

1

25

12

Type of PE

Acute massive

Acute massive, treated with modern CDT

Massive

Massive bilateral

Massive

Massive

Treatment

Catheter-directed infusion of urokinase 60 000 IU in 12 hours,then 90 000 IU/h (n = 1); alteplase mean dose 0.88 mg/h (n = 8); reteplase 0.5 mg/h then 0.25 mg/hr (n = 1)

Mean infusion time was 24.76 hours

Modern CDT included low-profile devices; mechanical fragmentation and/or aspiration of emboli, including rheolytic thrombectomy, and intraclot thrombolytic injection if a local drug was infused

Catheter-directed infusion of alteplase 1 mg/h + VA-ECMO +inhaled nitric oxide 20 ppm + mechanical thrombolysis

Catheter-directed alteplase initial infusion of 12 mg followedby an infusion of 0.7 mg/h

Catheter-directed alteplase at dose 0.93 mg/h for a meantotal dose of 25.43 mg (range 16-45 mg)

Mean duration of the infusion was 26.7 hours (range 14-46hours) vs catheter-directed therapy + EkoSonic Endovascu-lar System

Among the 12 patients, 7 received CDT thombolysis: 5received alteplase (mean dose 20 mg) and 2 receivedtenecteplase (mean dose 12 mg) with catheter-directedfragmentation and suction embolectomy

Table 8 Guideline recommendations for the use of thrombolytic agents to treat massive and submassive pulmonary embolism (PE) and in catheter-directed thrombolysis (CDT)

Abbreviations: NA, not applicable; VA-ECMO, venoarterial extracorporeal membrane oxygenation.a Grading is based on criteria of the Agency for Healthcare Research and Quality.31

Guideline

American HeartAssociation4

American Collegeof Chest Physicians3

European Societyof Cardiology48

Massive PE

The use of thrombolytic agents isreasonable for patients with mas-sive acute PE and an acceptablerisk for bleeding complications

For patients with evidence of hemody-namic compromise, use of throm-bolytic therapy is recommendedunless patient has major contraindi-cations because of risk for bleeding

Thrombolytic therapy is the first-linetreatment in patients with high-riskPE presenting with cardiogenicshock and/or persistent arterialhypotension, with very few absolutecontraindications.

Gradea

IIA,B

1B

NA

Submassive PE

The use of thrombolytics may be considered for patients with sub-massive PE judged to have clinical evidence of adverse progno-sis (new unstable hemodynamic status, worsening respiratoryinsufficiency, severe right ventricular dysfunction, or majormyocardial necrosis) and low risk for bleeding complications

In selected high-risk patients without hypotension who arejudged to have a low risk for bleeding, administration ofthrombolytic therapy is suggested

Routine use of thrombolysis in patients not at high risk forbleeding is not recommended, but may be considered inselected patients with intermediate-risk PE and after thoroughconsideration of conditions increasing the risk for bleeding

Gradea

IIB,C

2B

NA

Abbreviations: CR, case report; RE, retrospective; VA-ECMO, venoarterial extracorporeal membrane oxygenation.a Grading is based on criteria of the Agency for Healthcare Research and Quality.31

22 CriticalCareNurse Vol 33, No. 2, APRIL 2013 www.ccnonline.org

reported that clinical success was achieved in 71% to100% of patients who underwent a catheter-directedembolectomy with either systemic or local thrombolysis.In patients who underwent catheter-directed embolec-tomy alone, the success rate was 67% to 88%. Therefore,local experience with CDT and the expertise of thephysician performing the procedure should be takeninto account when CDT is being considered for a patient.

Use of Alteplase in Patients With Acute Pulmonary Embolism

Table 8 provides a summary of the recommendationsof the American Heart Association,4 the American Col-lege of Chest Physicians,3 and the European Society ofCardiology48 for use of a thrombolytic agent in patientswith massive pulmonary embolism or submassive pul-monary embolism and in CDT. For patients with massivepulmonary embolism, all 3 guidelines recommend useof a thrombolytic agent when the patients have no riskfor bleeding. In patients with submassive pulmonaryembolism, the 3 guidelines recommend use of throm-bolytic agents in patients at high risk for death who havea low risk for bleeding. Neither the American College ofChest Physicians nor the European Society of Cardiologyrecommends the use of CDT. The American Heart Asso-ciation suggests that CDT may be helpful when othermechanical thrombectomy strategies are unsuccessful.

Currently, 3 meta-analyses49-51 (Table 9) have beenconducted to evaluate thrombolysis for the treatment ofpulmonary embolism. Agnelli et al49 found a lower com-posite end point of death and recurrence of embolismwith thrombolysis than with heparin therapy alone.Wan et al50 reported a possible benefit for the use ofthrombolysis in patients with unstable hemodynamicstatus and the highest risk for death or recurrence ofembolism. Therefore, these authors50 recommend use ofa thrombolytic agent in patients with a major pulmonaryembolism and hemodynamic compromise. Dong et al51

did not find any benefit of thrombolysis or any differencein hemorrhagic events between control and interventionalgroups. They concluded that evidence of any benefit fromthe use of thrombolytic agents rather than heparin in thetreatment of acute pulmonary embolism is insufficient.

Bedside Nursing ManagementPatients receiving alteplase for the treatment of acute

pulmonary embolism require specific nursing monitoring

Results

Lysis of thrombus was 69%, with a mean lysis time of23.4 hours

The treatment group had no major hemorrhagic events

In 60% to 67% of patients, a local thrombolytic agent wasinfused during the mechanical maneuvers

The pooled success rate was 86.5% (95% CI, 82.2%-90.2%;q = 60.3, P = .004 for heterogeneity; I 2 = 40.3%)

VA-ECMO was stopped and patient was extubated

Patient recovered completely and was discharged takingenoxaparin 1 mg/kg twice a day

EkoSonic Endovascular System treatment was a successcompared with the CDT group (P < .02)

The alteplase dosage and infusion time were lower in theEkoSonic group than in the CDT group (P < .001).

Mean systolic pulmonary pressure improved from 57.6 to 44 mm Hg (P < .05); shock index improved (<0.9) in83% of patients

Clinical success was achieved in 83% of patients

Gradea

1B

1C

1C

1C

1B

1C

CDT

Direct intra-arterial delivery of thrombolytics, such as alteplase0.6 mg/kg (up to 50 mg), over 15 minutes, may be helpfulwhen mechanical thrombectomy strategies are ineffective

Infusion of alteplase directly into a pulmonary artery rather thanvia a peripheral vein does not accelerate thrombolysis but doescause more frequent bleeding at the catheter insertion site

When a lytic agent is appropriate for PE, thrombolytic agentsshould be infused into a peripheral vein over 2 hours or less

Direct local infusion of tissue plasminogen activator via acatheter in the pulmonary artery (at a reduced dosage) didnot have any advantages over systemic intravenous throm-bolysis

This approach should generally be avoided, because it is asso-ciated with an increased risk for bleeding at the puncture site

Gradea

NA

NA

NA

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and care. Because of the high risk for bleeding, thesepatients should be cared for in a critical care setting forat least 24 hours, depending on their clinical status.50

Close monitoring for bleeding and hypertension arerequired during this time.

Alteplase should be diluted with sterile water to afinal concentration of 1 mg/mL for injection.22 Themanufacturer provides a transfer device that should beused to add the sterile water to the alteplase powder.Foaming may occur when the sterile water is added butwill dissipate if the mixture is allowed to stand undis-

turbed forseveral min-utes. Of note,alteplaseshould not beshaken duringdilution and

mixing. In order to thoroughly mix the medication, thevial should be gently swirled or inverted. Alteplase isstable at room temperature for 8 hours after it is

reconstituted and contains no antibacterial preserva-tives. For these reasons, the drug should be reconsti-tuted immediately before use and should beadministered within 8 hours of dilution.26

In most patients, a continuous heparin infusion willalready have been started while the decision to usealteplase is being made or while the alteplase is beingdispensed by the pharmacy. In these patients, in order todecrease the risk for bleeding, the heparin infusionshould be stopped when the alteplase infusion is started.Alteplase should be administered as a continuous infu-sion over a 2-hour period. During the infusion, patients’neurological status should be monitored frequentlybecause of the increased risk for cerebral hemorrhage.Neurological checks should be completed every 15 min-utes during administration of the drug, then every 30minutes for 6 hours, and then hourly for 24 hours afterinitiation of treatment.3,4,52 Alert patients should beinstructed to report any changes in headache, vision,and sensorium. Any change in neurological status isreason to discontinue the infusion to investigate the

Table 9 Summary of 3 meta-analyses on the use of thrombolysis for the treatment of pulmonary embolism (PE)

Study

Agnelli et al,49

2002

Wan et al,50

2004

Dong et al,51

2006

No.

461 patients, 9 clinical trials

748 patients, 11 trials

679 patients, 8 trials

Type of PE

Any

Acute

Confirmed

Treatments

A total of 241 patients (52.3%)received thrombolytic therapywith streptokinase (n = 31),urokinase (n = 102 ), oralteplase (n = 108)

A total of 220 patients receivedheparin

Patients in the included trialswere randomized to receive asystemic thrombolytic agent,including urokinase, streptoki-nase, alteplase, or heparin

Patients were included in trialsthat used a thrombolytic, includ-ing streptokinase, urokinase,recombinant tissue plasmino-gen activator, and alteplase

Results were compared withthose of patients who hadheparin alone or placebo orsurgical intervention

Results

A total of 11 deaths (4.6%) occurred in the throm-bolysis group and 17 deaths (7.7%) occurred inthe heparin group (RR, 0.59; 95% CI, 0.27-1.25)

Five fatal bleeding episodes (2.1%) occurred inthe thrombolysis group; none occurred in theheparin group

Thrombolytic therapy resulted in a nonsignificantreduction in recurrent PE or death (6.7% vs 9.6%;OR, 0.67, 95% CI, 0.40-1.12, P for heterogene-ity = .48), a nonsignificant increase in majorbleeding (9.1% vs 6.1%; OR, 1.42; 95% CI,0.81-2.46), and a significant increase in nonma-jor bleeding (22.7% vs 10.0%; OR, 2.63; 95% CI,1.53-4.54)

When a thrombolytic agent was used in patientswith unstable hemodynamic status, a reductionin recurrent PE or death occurred (9.4% vs19.0%; OR, 0.45; 95% CI, 0.22-0.92)

Results were similar between the heparin andthrombolytic groups for the following: death(OR, 0.89; 95% CI, 0.45-1.78), PE recurrence(OR, 0.63; 95% CI, 0.33-1.20), major hemor-rhagic events (OR, 1.61; 95% CI, 0.91-2.86),minor hemorrhagic events (OR, 1.98; 95% CI,0.68-5.75)

Abbreviations: OR, odds ratio; RR, relative risk.

24 CriticalCareNurse Vol 33, No. 2, APRIL 2013 www.ccnonline.org

Patients should be monitored closelyfor bleeding and hypertension in acritical care setting for at least 24hours after administration of alteplasebecause of the high risk for bleeding.

possibility of intracranial bleeding,22 and computedtomography of the head should be conducted immedi-ately. Bleeding remains a risk for up to 36 hours aftercompletion of the alteplase infusion.4 Heart rate andblood pressure should be monitored continually, becausethese physiological indicators could alert bedside nursesto the occurrence of bleeding.22,52 Monitoring of heartrate and blood pressure is recommended for 24 hoursafter the administration of alteplase.

Upon completion of the alteplase infusion, continu-ous infusion of heparin should be reinitiated. Before theinfusion is restarted, blood should be obtained for deter-mination of aPTT. In order to reduce the risk for bleed-ing, the heparin should not be started until the aPTT istwice the normal level or less.23 As the heparin infusionis restarted, monitoring for signs and symptoms of bleed-ing should continue. The aPTT should be monitored perinstitutional protocol to ensure the attainment of thera-peutic anticoagulation and to prevent overanticoagulation.

Other important nursing considerations includerefraining from venous or arterial punctures and place-ment of invasive tubes during the first 24 hours afteradministration of alteplase.50 Existing insertion sites ofinvasive catheters should be assessed hourly for bleeding.

At times, alteplase may be administered via a CDTmethod. In these situations, a smaller dose of alteplase(0.5-1 mg/h) is infused into the pulmonary artery via apulmonary artery catheter for an extended time (14-46hours).39,41-46 As with systemic administration of alteplase,bedside nurses should monitor patients for any signs orsymptoms of bleeding. Specific attention should be paidto the insertion site of the pulmonary catheter.43

The efficacy of alteplase can be monitored by notingthe resolution of signs and symptoms related to the pul-monary embolism. For example, a patient should beginto have improvement in hemodynamic parameters, includ-ing blood pressure, heart rate, and right end-diastolicfunction. Improvement in the patient’s subjective symp-toms should also occur, such as less chest pain, shortnessof breath, and wheezing or cough.23

SummaryAcute pulmonary embolisms are life-threatening

abnormalities with a wide range of signs and symptoms.Because of the wide spectrum, from no signs or symptomsto hypotension and shock, diagnosis can be difficult.Early diagnosis and treatment are necessary to provide

the best care and improve patients’ outcomes.53 Alteplaseis efficacious in the treatment of acute massive and sub-massive pulmonary embolisms, although it has not beenapproved by the FDA for treatment of submassive pul-monary embolism. The risk for and development ofbleeding should always be taken into account whentherapy is started. CCN

Financial DisclosuresNone reported.

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To learn more about caring for patients with pulmonaryembolism, read “Massive Pulmonary Embolism” by Shaughnessyin Critical Care Nurse, February 2007;27(1):39-50. Available atwww.ccnonline.org.

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26. Konstantinides S, Tiede N, Geibel A, et al. Comparison of alteplase versusheparin for resolution of major pulmonary embolism. Am J Cardiol. 1998;82:966-970.

27. Wang C, Zhai Z, Yang Y, et al; China Venous Thromboembolism (VTE)study group. Efficacy and safety of low dose recombinant tissue-typeplasminogen activator for the treatment of acute pulmonary embolism:a randomized, multicenter, controlled trial. Chest. 2010;137(2):254-262.

28. Sors H, Pacouret G, Azarian R, Meyer G, Charbonnier B, Simonneau G.Hemodynamic effects of bolus vs 2-h infusion of alteplase in acute massivepulmonary embolism: a randomized controlled multicenter trial. Chest.1994;106(3):712-717.

29. Dalla-Volta S, Palla A, Santolicandro A, et al. PAIMS 2: alteplase com-bined with heparin versus heparin in the treatment of acute pulmonary,embolism. Plasminogen Activator Italian Multicenter Study 2. J Am CollCardiol. 1992;20(3):520-526.

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32. Le Conte P, Huchet L, Trewick D, et al. Efficacy of alteplase thrombolysisfor ED treatment of pulmonary embolism with shock. Am J Emerg Med.2003;21(5):438-440.

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34. Berghaus TM, Thilo C, Bluethgen A, et al. Effectiveness of thrombolysisin patients with intermediate-risk pulmonary embolism: influence inlength of hospital stay. Adv Ther. 2010;27(9):648-654.

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26 CriticalCareNurse Vol 33, No. 2, APRIL 2013 www.ccnonline.org

CNE Test Test ID C1323: Alteplase Treatment of Acute Pulmonary Embolism in the Intensive Care Unit Learning objectives: 1. Identify signs and symptoms when acute embolism is suspected 2. Discuss the medical management of acute peripheral emboli 3. Differentiate the classifications of acute peripheral emboli

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nursing practice q qMy expectations were met q qThis method of CNE is effective

for this content q qThe level of difficulty of this test was:

q easy q medium q difficultTo complete this program,

it took me hours/minutes.

1. Acute pulmonary embolism was reported to account for how many deathseach year in the United States?a. 1000 to 10 000b. 50 000 to 100 000c. 150 000 to 200 000d. 250 000 to 500 000

2. What percentage of patients who have a pulmonary embolism was alsoreported to have a confirmed deep vein thrombosis?a. 24% b. 34%b. 34% d. 54%

3. The Virchow triad includes stasis, hypercoagulability, and which of the following?a. Advanced ageb. Endothelial injuryc. Heredityd. Vasoconstriction

4. Which of the following is a risk factor for developing a pulmonary embolism?a. Atherosclerosisb. Atrial flutterc. Benign neoplasmsd. Hypotension

5. Which vein is the most common source of thrombi that become a pulmonary embolism?a. Great saphenousb. Iliofemoralc. Popliteald. Posterior tibial

6. What is the most common symptom reported by patients with acute pulmonary embolism?a. Chest pain c. Dyspneab. Cough d. Wheezing

7. What is the gold standard to diagnose a pulmonary embolism?a. Computed tomographyb. Magnetic resonance imagingc. Pulmonary angiographyd. Ventilation-perfusion scan

8. What is the rationale for the use of anticoagulants when treating pulmonary embolism?a. To decrease the blood’s coagulability.b. To decrease the size of thrombi that may form.c. To minimize migration of thrombi.d. To stop further growth of an established clot.

9. Alteplase was approved by the Food and Drug Administration for management of acute pulmonary embolism in adults in what year?a. 2000b. 2002c. 2004d. 2006

10. Which of the following is an absolute contraindication to the use ofalteplase?a. Concurrent use of an anticoagulantb. History of a stroke within the past 3 monthsc. Severe or poorly controlled hypertensiond. Recent history of internal bleeding

11. Which of the following is a relative contraindication to the use ofalteplase?a. Abdominal aortic aneurysmb. Age greater than 65 yearsc. Arteriovenous malformationd. Recent history of internal bleeding

12. Concurrent administration of alteplase and which of the following medications was reported to increase the risk of bleeding?a. Acetaminophenb. Clopidogrelc. Protamined. Vitamin K

13. What is the approved dosage of alteplase for the treatment of an acute,massive pulmonary embolism?a. 1 mg b. 10 mgc. 100 mgd. 1000 mg

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