Cover

Alteplase Treatment of
Acute Pulmonary Embolism
in the Intensive Care Unit
PAMELA L. SMITHBURGER, PharmD, BCPS
SHAUNA CAMPBELL, MSN
SANDRA L. KANE-GILL, MS, PharmD, MSC

Acute pulmonary embolism accounts for 50 000 to 100 000 deaths each year in the United States. Because
of the wide spectrum of clinical manifestations, ranging from massive pulmonary embolism to small
peripheral emboli, stratifying and treating patients according to their signs and symptoms is important
when an acute embolism is suspected. Patients clinical findings can range from no signs or symptoms to
unstable 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 presents
an assessment of the literature evaluating alteplase for the treatment of acute peripheral emboli. Clinical
pearls for the administration, monitoring, and care of a patient receiving alteplase in an intensive care
unit also are discussed. (Critical Care Nurse. 2013;33[2]:17-27)

cute 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.7-12

CNE Continuing Nursing Education

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 suspected
2. Discuss the medical management of acute peripheral emboli
3. Differentiate the classifications of acute peripheral emboli
2013 American Association of Critical-Care Nurses doi: http://dx.doi.org/10.4037/ccn2013626

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Table 1

Definitions of an acute pulmonary embolisma

Category

Description

Massive

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 causes
Persistent or pulseless, bradycardia (heart rate
<40/min) with shock

Submassive

Acute pulmonary embolism with myocardial

necrosis or right ventricular dysfunction but no
systemic hypotension

Low risk

Acute pulmonary embolism with normal levels

of biomarkers, no systemic hypotension or
right ventricular dysfunction

Based on information from Jaff et al.4

Table 2

Selected risk factors for thromboembolisma

Component of the
Virchow triad

Risk factor

Stasis

Immobilization
Paralysis
Atrial fibrillation
Long-distance travel
Venous insufficiency

Endothelial injury

Recent central venous instrumentation

Hypertension
Atherosclerosis
Trauma or surgery
Indwelling catheter

Hypercoagulability

Malignant neoplasms
History of heavy smoking
Pregnancy
Obesity
Estrogen therapy
Sepsis
Trauma or surgery of a lower extremity

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

Thrombi 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.16
In 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

Authors
Pamela L. Smithburger is an assistant professor of pharmacy and therapeutics, University of Pittsburgh, School of Pharmacy, and a critical
care 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 Pittsburgh
Medical Center.
Corresponding author: Pamela Smithburger, PharmD, BCPS, University of Pittsburgh School of Pharmacy, University of Pittsburgh Medical Center, 200 Lothrop St, Pittsburgh
PA 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.

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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%.11
In 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 patients
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.20
Clinical 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.

Acute Pulmonary Embolism

Initial Treatment
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

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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-molecularweight 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.21
Although 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
In addition to signs and symptoms, the
College of
gold standard for diagnosis of a pulmonary
Chest Physi- embolism is pulmonary angiography.
cians3 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
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.23

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Contraindications and Interactions. Patients

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.3,4,23
Use With Heparin. The 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.24,26,28
Table 4 reviews the grading criteria for clinical trials.
Table 5available online only at www.ccnonline.org
summarizes clinical trials on the use of alteplase in
patients with massive pulmonary embolism.

Treatment of Submassive
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

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Table 3

Contraindications to use of alteplasea

Absolute contraindications Relative contraindications

Internal bleeding
Previous intracranial
hemorrhage
History of a cerebral vascular
accident within the past 3
months
Recent intracranial or
intraspinal surgery or trauma
Intracranial neoplasm
Arteriovenous malformation
or aneurysm
Known bleeding diathesis

a Based

Age >75 y
Current use of anticoagulation
Pregnancy
Noncompressible vascular
punctures
Traumatic or prolonged cardiopulmonary resuscitation
(<10 min)
Recent internal bleeding
(within 2-4 wk)
History of chronic, severe, and
poorly controlled hypertension
Severe uncontrolled hypertension on initial examination
(systolic blood pressure
>180 mm Hg or diastolic
blood pressure >110 mm Hg)
Dementia
Remote ischemic stroke (>3 mo)
Major surgery within preceding
3 weeks

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

the use of thrombolytic agents in these patients. Administration of a thrombolytic agent in addition to heparin
requires assessment of a patients 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

Table 4

Grading criteria for clinical trialsa

Assessment

Grade

Grade description

Risk vs benefit

1
2

Benefit > risk

Risk > benefit

Quality of the data available

A
B
C

Good
Fair
Poor

a Based

on information from Ansani et al.31

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did those who received heparin

alone.34-36 In addition, primary
PE is diagnosed
thrombolysis with alteplase
and treatment is necessary
decreased the need for treatment
escalation, such as emergently
administering a thrombolytic after
Massive PE
Submassive PE
Low-risk PE
heparin therapy alone was unsuccessful.35 Differences in bleeding
between patients who received
RV strain or a possibility
Hemodynamic compromise
No RV strain
heparin alone and patients who
of poor prognosis
(SBP <90 mm Hg
received heparin plus alteplase were
for >15 minutes or
need inotropic support)
not significant.34-36 Table 6available
online only at www.ccnonline.org
summarizes the use of alteplase in
patients with submassive pulAnticoagulation
Anticoagulation
Anticoagulation
monary embolism. The Figure is a
proposed treatment algorithm
based on a patients risk of bleeding
Consider thrombolytic agents if:
and severity of the pulmonary
1. Patient has shock or respiratory distress
2. RV dysfunction
embolism as reflected by hemody3. Elevated levels of biomarkers (troponin, BNP)
3,4
namic compromise.
In systemic thrombolytic therapy,
the drug is given through a peripheral intravenous catheter. When sysLow or acceptable bleeding risk and no
contraindications to thrombolytic therapy
temic thrombolytic therapy is
contraindicated because of increased
risk for bleeding or insufficient time
for systemic thrombolysis, other
1. Discontinue heparin infusion
2. Administer alteplase 100 mg IV for 2 hours
therapies, such as catheter-directed
3. Check aPTT
thrombolysis (CDT), may be neces4. Restart heparin infusion when aPTT 2 times normal
sary.3,39,40 In CDT, the thrombolytic
agent is administered directly into
the pulmonary artery via a pulFigure Treatment algorithm for acute pulmonary embolism. Based on information
from Kearon et al3 and Jaff et al.4
monary artery catheter23; the usual
Abbreviations: aPTT, activated partial thromboplastin time; BNP, brain natriuretic peptide; IV, intravenous;
thrombolytic agent is full-dose
PE, pulmonary embolism; RV, right ventricle; SBP, systolic blood pressure.
heparin. Table 7 is a summary of the
clinical trials and assessments of the
mechanical thrombectomy, which can involve either
efficacy of CDT with alteplase.31,39,41-46 Overall, CDT
spinning wires or jets of physiological saline aimed at the
appears safe and effective. With CDT, medications can
thrombus, to increase the rate of dissolution.47 Currently,
be delivered directly to the thrombus at a high concenCDT with alteplase is an off-label use of the drug. When
tration. Lower doses of a thrombolytic and shorter duraused in CDT, alteplase has been infused at 0.5 to 1 mg/h
tions of infusions are used to achieve complete
for up to 48 hours.39 No clinical trials have been done to
thrombolysis. In theory, compared with systemic thromcompare systemic thrombolysis with CDT. In a review of
bolysis, the use of lower doses and shorter infusions
several methods of catheter-directed approaches with or
times with alteplase reduces the risk of bleeding compli3,40,41
without local or systemic thrombolytic therapy in patients
cations.
Thrombolytic methods have also been comwith acute massive pulmonary embolism, Kuo et al39
bined with mechanical methods such as percutaneous

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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

Study design

Type of PE

Treatment

Chamsuddin et al, 2008

RE

10

Acute massive

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

Kuo et al,39 2009

RE

594

Acute massive,
treated with
modern CDT

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

Griffith et al,43 2009

CR

Massive

Catheter-directed infusion of alteplase 1 mg/h + VA-ECMO +

inhaled nitric oxide 20 ppm + mechanical thrombolysis

Bechtel et al,44 2005

CR

Massive bilateral

Catheter-directed alteplase initial infusion of 12 mg followed

by an infusion of 0.7 mg/h

Lin et al,45 2009

RE

25

Massive

Catheter-directed alteplase at dose 0.93 mg/h for a mean

total dose of 25.43 mg (range 16-45 mg)
Mean duration of the infusion was 26.7 hours (range 14-46
hours) vs catheter-directed therapy + EkoSonic Endovascular System

Kuo et al,46 2008

RE

12

Massive

Among the 12 patients, 7 received CDT thombolysis: 5

received alteplase (mean dose 20 mg) and 2 received
tenecteplase (mean dose 12 mg) with catheter-directed
fragmentation and suction embolectomy

41

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

Table 8

Guideline recommendations for the use of thrombolytic agents to treat massive

and submassive pulmonary embolism (PE) and in catheter-directed thrombolysis (CDT)

Guideline

Massive PE

Gradea
IIA,B

Gradea

Submassive PE

American Heart
Association4

The use of thrombolytic agents is

reasonable for patients with massive acute PE and an acceptable
risk for bleeding complications

The use of thrombolytics may be considered for patients with submassive PE judged to have clinical evidence of adverse prognosis (new unstable hemodynamic status, worsening respiratory
insufficiency, severe right ventricular dysfunction, or major
myocardial necrosis) and low risk for bleeding complications

American College
of Chest
Physicians3

For patients with evidence of hemodynamic compromise, use of thrombolytic therapy is recommended
unless patient has major contraindications because of risk for bleeding

1B

In selected high-risk patients without hypotension who are

judged to have a low risk for bleeding, administration of
thrombolytic therapy is suggested

2B

European Society
of Cardiology48

Thrombolytic therapy is the first-line

treatment in patients with high-risk
PE presenting with cardiogenic
shock and/or persistent arterial
hypotension, with very few absolute
contraindications.

NA

Routine use of thrombolysis in patients not at high risk for

bleeding is not recommended, but may be considered in
selected patients with intermediate-risk PE and after thorough
consideration of conditions increasing the risk for bleeding

NA

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

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IIB,C

Results

Gradea

Lysis of thrombus was 69%, with a mean lysis time of

23.4 hours
The treatment group had no major hemorrhagic events

1B

In 60% to 67% of patients, a local thrombolytic agent was

infused 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%)

1C

VA-ECMO was stopped and patient was extubated

1C

Patient recovered completely and was discharged taking

enoxaparin 1 mg/kg twice a day

1C

EkoSonic Endovascular System treatment was a success

compared with the CDT group (P < .02)
The alteplase dosage and infusion time were lower in the
EkoSonic group than in the CDT group (P < .001).

1B

Mean systolic pulmonary pressure improved from 57.6 to

44 mm Hg (P < .05); shock index improved (<0.9) in
83% of patients
Clinical success was achieved in 83% of patients

1C

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.

Use of Alteplase in Patients With

Acute Pulmonary Embolism

CDT

Gradea

Direct intra-arterial delivery of thrombolytics, such as alteplase

0.6 mg/kg (up to 50 mg), over 15 minutes, may be helpful
when mechanical thrombectomy strategies are ineffective

NA

Infusion of alteplase directly into a pulmonary artery rather than

via a peripheral vein does not accelerate thrombolysis but does
cause more frequent bleeding at the catheter insertion site
When a lytic agent is appropriate for PE, thrombolytic agents
should be infused into a peripheral vein over 2 hours or less

NA

Direct local infusion of tissue plasminogen activator via a

catheter in the pulmonary artery (at a reduced dosage) did
not have any advantages over systemic intravenous thrombolysis
This approach should generally be avoided, because it is associated with an increased risk for bleeding at the puncture site

NA

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.

Bedside Nursing Management

Patients receiving alteplase for the treatment of acute
pulmonary embolism require specific nursing monitoring

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Table 9

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

Study

No.

Type of PE

Treatments

Results

Any

A total of 241 patients (52.3%)

received thrombolytic therapy
with streptokinase (n = 31),
urokinase (n = 102 ), or
alteplase (n = 108)
A total of 220 patients received
heparin

A total of 11 deaths (4.6%) occurred in the thrombolysis group and 17 deaths (7.7%) occurred in
the heparin group (RR, 0.59; 95% CI, 0.27-1.25)
Five fatal bleeding episodes (2.1%) occurred in
the thrombolysis group; none occurred in the
heparin group

Agnelli et al,49
2002

461 patients,
9 clinical trials

Wan et al,50
2004

748 patients,
11 trials

Acute

Dong et al,51
2006

679 patients,
8 trials

Confirmed

Patients in the included trials

Thrombolytic therapy resulted in a nonsignificant
were randomized to receive a
reduction in recurrent PE or death (6.7% vs 9.6%;
systemic thrombolytic agent,
OR, 0.67, 95% CI, 0.40-1.12, P for heterogeneincluding urokinase, streptokiity = .48), a nonsignificant increase in major
nase, alteplase, or heparin
bleeding (9.1% vs 6.1%; OR, 1.42; 95% CI,
0.81-2.46), and a significant increase in nonmajor bleeding (22.7% vs 10.0%; OR, 2.63; 95% CI,
1.53-4.54)
When a thrombolytic agent was used in patients
with unstable hemodynamic status, a reduction
in recurrent PE or death occurred (9.4% vs
19.0%; OR, 0.45; 95% CI, 0.22-0.92)
Patients were included in trials Results were similar between the heparin and
that used a thrombolytic, includthrombolytic groups for the following: death
ing streptokinase, urokinase,
(OR, 0.89; 95% CI, 0.45-1.78), PE recurrence
recombinant tissue plasmino(OR, 0.63; 95% CI, 0.33-1.20), major hemorgen activator, and alteplase
rhagic events (OR, 1.61; 95% CI, 0.91-2.86),
Results were compared with
minor hemorrhagic events (OR, 1.98; 95% CI,
those of patients who had
0.68-5.75)
heparin alone or placebo or
surgical intervention

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

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
Patients should be monitored closely several minutes. Of note,
for bleeding and hypertension in a
critical care setting for at least 24
alteplase
hours after administration of alteplase should not be
because of the high risk for bleeding. 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

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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.26
In 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

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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.43
The 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 patients subjective symptoms should also occur, such as less chest pain, shortness
of breath, and wheezing or cough.23

Summary
Acute 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

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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. CCN
Financial Disclosures
None reported.

Now that youve read the article, create or contribute to an online discussion
about this topic using eLetters. Just visit www.ccnonline.org and click Submit a
response in either the full-text or PDF view of the article.

To learn more about caring for patients with pulmonary

embolism, read Massive Pulmonary Embolism by Shaughnessy
in Critical Care Nurse, February 2007;27(1):39-50. Available at
www.ccnonline.org.
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Ouellette DW, Patocka C. Pulmonary embolism. Emerg Med Clin North
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Activase [package insert]. South San Francisco, CA: Genentech Inc;2011.
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in massive pulmonary embolism: a randomized trial assessing right heart
haemodynamics and pulmonary vascular obstruction. Eur Heart J. 1997;
18(7):1141-1148.
Meneveau N, Schiele F, Metz D, et al. Comparative efficacy of a two-hour
regimen of streptokinase versus alteplase in acute massive pulmonary
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follow-up. J Am Coll Cardiol. 1998;31(5):1057-1063.
Konstantinides S, Tiede N, Geibel A, et al. Comparison of alteplase versus
heparin for resolution of major pulmonary embolism. Am J Cardiol. 1998;
82:966-970.
Wang C, Zhai Z, Yang Y, et al; China Venous Thromboembolism (VTE)
study group. Efficacy and safety of low dose recombinant tissue-type
plasminogen activator for the treatment of acute pulmonary embolism:
a randomized, multicenter, controlled trial. Chest. 2010;137(2):254-262.
Sors H, Pacouret G, Azarian R, Meyer G, Charbonnier B, Simonneau G.
Hemodynamic effects of bolus vs 2-h infusion of alteplase in acute massive
pulmonary embolism: a randomized controlled multicenter trial. Chest.
1994;106(3):712-717.
Dalla-Volta S, Palla A, Santolicandro A, et al. PAIMS 2: alteplase combined with heparin versus heparin in the treatment of acute pulmonary,
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Cardiol. 1992;20(3):520-526.
PIOPED Investigators. Tissue plasminogen activator for the treatment
of acute pulmonary embolism. Chest. 1990;97:528-533.
Ansani NT, Fedutes-Henderson BA, Skledar SJ, et al. Practical approach
to grading evidence for formulary recommendations. Am J Health Syst
Pharm. 2005;62:1498-1501.
Le Conte P, Huchet L, Trewick D, et al. Efficacy of alteplase thrombolysis
for ED treatment of pulmonary embolism with shock. Am J Emerg Med.
2003;21(5):438-440.
Kucher N, Rossi E, De Rosa M, et al. Prognostic role of echocardiography
among patients with acute pulmonary embolism and a systolic arterial
pressure of 90 mm Hg or higher. Arch Intern Med. 2005;165:1777-1781.
Berghaus TM, Thilo C, Bluethgen A, et al. Effectiveness of thrombolysis
in patients with intermediate-risk pulmonary embolism: influence in
length of hospital stay. Adv Ther. 2010;27(9):648-654.
Konstantinides S, Geibel A, Heusel G, Heinrich F, Kasper W; Management
Strategies and Prognosis of Pulmonary Embolism-3 Trial investigators.
Heparin plus alteplase compared with heparin alone in patients with
submassive pulmonary embolism. N Engl J Med. 2002;347(15):1143-1150.
Fasullo S, Scalzo S, Maringhini G, et al. Six-month echocardiographic
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Sci. 2011;341(1):33-39.

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37. Goldhaber SZ, Agnelli G, Levine MN. Reduced dose bolus alteplase vs
conventional alteplase infusion for pulmonary embolism thrombolysis:
an international multicenter randomized trial. The Bolus Alteplase Pulmonary Embolism Group. Chest. 1994;106(3):718-724.
38. Goldhaber SZ, Haire WD, Feldstein ML, et al. Alteplase versus heparin
in acute pulmonary embolism: randomized trial assessing right-ventricular function and pulmonary perfusion. Lancet. 1993;341(8844):507-511.
39. Kuo WT, Gould MK, Louie JD, Rosenberg JK, Sze DY, Hofmann LV.
Catheter-directed therapy for the treatment of massive pulmonary
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J Vasc Interv Radiol. 2009;20(11):1431-1440.
40. Krichavsky MZ, Rybicki FJ, Resnic FS. Catheter directed lysis and
thrombectomy of submassive pulmonary embolism. Catheter Cardiovasc
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with the endowave system in the treatment of acute massive pulmonary
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42. Skaf E, Beemath A, Siddiqui T, et al. Catherter-tip embolectomy in the
management of acute massive pulmonary embolism. Am J Cardiol. 2007;
99:415-420.
43. Griffith KE, Jenkins E, Haft J. Treatment of massive pulmonary embolism
utilizing a multidisciplinary approach. Perfusion. 2009;24:169-172.
44. Bechtel JJ, Mountford MC, Ellinwood WE. Massive pulmonary embolism
in pregnancy treated with catheter fragmentation and local thrombolysis.
Obstet Gynecol. 2005;106:1158-1160.
45. Lin PH, Annambhotla S, Bechara CF, et al. Comparison of percutaneous
ultrasound-accelerated thrombolysis versus catheter-directed thrombolysis
in patients with acute massive pulmonary embolism [published correction
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46. Kuo WT, van den Bosch MAAJ, Hofmann LV, et al. Catheter-directed
embolectomy, fragmentation, and thrombolysis for the treatment of
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Chest. 2008;134:250-254.
47. Hubbard J, Saad WEA, Sabri SS, et al. Rheolytic thrombectomy with or
without adjunctive indwelling pharmacolysis in patients presenting with
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48. Torbicki A, Perrier A, Konstantinides S, et al; ESC Committee for Practice
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50. Wan S, Quinlan DJ, Agnelli G, Eikelboom JW. Thrombolysis compared
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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
1. Acute pulmonary embolism was reported to account for how many deaths
each year in the United States?
a. 1000 to 10000
b. 50000 to 100000
c. 150000 to 200000
d. 250000 to 500000

8. What is the rationale for the use of anticoagulants when treating

pulmonary embolism?
a. To decrease the bloods 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.

2. What percentage of patients who have a pulmonary embolism was also

reported to have a confirmed deep vein thrombosis?
a. 24%
b. 34%
b. 34%
d. 54%

9. Alteplase was approved by the Food and Drug Administration for

management of acute pulmonary embolism in adults in what year?
a. 2000
b. 2002
c. 2004
d. 2006

3. The Virchow triad includes stasis, hypercoagulability, and which of the

following?
a. Advanced age
b. Endothelial injury
c. Heredity
d. Vasoconstriction
4. Which of the following is a risk factor for developing a pulmonary embolism?
a. Atherosclerosis
b. Atrial flutter
c. Benign neoplasms
d. Hypotension
5. Which vein is the most common source of thrombi that become a
pulmonary embolism?
a. Great saphenous
b. Iliofemoral
c. Popliteal
d. Posterior tibial

10. Which of the following is an absolute contraindication to the use of

alteplase?
a. Concurrent use of an anticoagulant
b. History of a stroke within the past 3 months
c. Severe or poorly controlled hypertension
d. Recent history of internal bleeding
11. Which of the following is a relative contraindication to the use of
alteplase?
a. Abdominal aortic aneurysm
b. Age greater than 65 years
c. Arteriovenous malformation
d. 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. Acetaminophen
b. Clopidogrel
c. Protamine
d. Vitamin K

6. What is the most common symptom reported by patients with acute

pulmonary embolism?
a. Chest pain
c. Dyspnea
b. Cough
d. Wheezing

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

7. What is the gold standard to diagnose a pulmonary embolism?

a. Computed tomography
b. Magnetic resonance imaging
c. Pulmonary angiography
d. Ventilation-perfusion scan

Test answers: Mark only one box for your answer to each question. You may photocopy this form.

1. q a
qb
qc
qd

2. q a
qb
qc
qd

3. q a
qb
qc
qd

4. q a
qb
qc
qd

5. q a
qb
qc
qd

6. q a
qb
qc
qd

7. q a
qb
qc
qd

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qb
qc
qd

9. q a
qb
qc
qd

10. q a
qb
qc
qd

11. q a
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qc
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12. q a
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qc
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13. q a
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qc
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Test ID: C1323 Form expires: April 1, 2016 Contact hours: 1.0 Pharma hours: 1.0 Fee: AACN members, $0; nonmembers, $10 Passing score: 10 correct (77%)
Synergy CERP Category A Test writer: Lori Williams Black, DNP, RN, RNC-NIC, CCRN, NNP-BC

Program evaluation

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