Systemic Thrombolysis for

Pulmonary Embolism
Evidence, Patient Selection, and
Protocols for Management
Hafeez Ul Hassan Virk, MDa,1, Sanjay Chatterjee, MDb,2,
Partha Sardar, MDc,3, Chirag Bavishi, MD, MPHa,4,
Jay Giri, MD, MPHd, Saurav Chatterjee, MDe,*,5

KEYWORDS
 Pulmonary embolism  Systemic thrombolysis  Selection of patients  Risk stratification
 Management protocol

KEY POINTS
 Acute pulmonary embolism is associated with significant morbidity and mortality.
 Treatment options include anticoagulation, systemic thrombolysis, catheter-based
interventions, and surgical embolectomy.
 Selecting candidates who derive maximal benefit with thrombolysis, while being exposed to
the least possible risks of bleeding is difficult.
 Optimal and pragmatic selection of patients should involve a multidisciplinary approach.

INTRODUCTION 39% in the elderly.3 It affects hospitalized pa-

tients as well as outpatients, with an in-hospital
Pulmonary embolism (PE) affects 23 per 100,000 fatality rate of 12%.1 In spite of recent advances
people annually,1 causing morbidity including in diagnostic tools, PE remains underdiagnosed
prolonged hospital stay, recurrence, postthrom- and is still considered a diagnostic dilemma, pre-
botic syndrome, and even mortality. Annual US senting with a wide range of symptoms from
mortality rates associated with PE are 4 to 5 mild dyspnea to sudden death. Depending on
times greater than those associated with breast the likelihood of PE, initial diagnostic tests
cancer or human immunodeficiency virus.1,2 include D-Dimer, electrocardiogram, cardiac
The incidence of PE rises with increasing age biomarkers, transthoracic echocardiography,
with an associated 1-year mortality approaching computed tomography (CT) scans, and

Disclosure: None (for all authors).

a
Mount Sinai St Luke’s-Roosevelt Hospitals, 1111 Amsterdam Avenue, 3rd Floor, Clark Building, New York, NY
10025, USA; b Apollo Gleneagles Hospital, 58, Canal Circular Road, Kolkata, West Bengal 700054, India;
c
Division of Cardiovascular Medicine, University of Utah, 30 North 1900 East, Room 4A100, Salt Lake City, UT
84132, USA; d Penn Cardiovascular Outcomes, Quality and Evaluative Research Center, 3400 Civic Center Boule-
vard, Philadelphia, PA 19104, USA; e Hoffman Heart Institute, Saint Francis Hospital, University of Connecticut
School of Medicine, 110 Woodland Street, Hartford, CT 06106, USA
1
Present address: #9 to 210 Apartment, Chestnut Hill Village Apartments, 7800 Stenton Avenue, Philadelphia,
PA 19118.
2
Present address: 1010 Arch Street Apartment 604, Philadelphia, PA 19107.
3
Present address: 66 South Main Street Apartment 480, Salt Lake City, UT 84101.
4
Present address: 515 West, 59th Street Apartment 27F, New York, NY 10019.
5
Present address: 1010 Arch Street Apartment 604, Philadelphia, PA 19107.
* Corresponding author.
E-mail address: sauravchatterjeemd@gmail.com

Intervent Cardiol Clin 7 (2018) 71–80

http://dx.doi.org/10.1016/j.iccl.2017.08.001
2211-7458/18/ª 2017 Elsevier Inc. All rights reserved.
72 Virk et al

ventilation perfusion scans. Based on the results cardiac biomarkers) were called submassive
of these tests and hemodynamics of the patient, PE, which labeled a patient as intermediate
PE can be categorized into varying grades of risk in terms of adverse clinical outcomes.
clinical severity, each requiring different ap- This was defined as “acute PE without
proaches to management to optimize outcomes. systemic hypotension (systolic blood pressure
A major goal of therapy in the management 90 mm Hg) but with either RV [right ventricu-
of PE is improvement of hemodynamics by lar] dysfunction or myocardial necrosis.”4 Pa-
reducing strain on the right ventricle. This can tients without hemodynamic instability or
lead to symptom improvement, restoration of evidence of right heart strain were considered
pulmonary arterial flow, decreased risk of recur- low risk.
rent PE, and prevention of the development of
chronic thromboembolic pulmonary hyperten- SELECTION OF PATIENTS FOR
sion (CTEPH). Anticoagulation is the cornerstone SYSTEMIC THROMBOLYSIS
of therapy for most patients with PE.4 Patients
with high-risk PE or those judged to have a Selecting the correct patient for systemic
high likelihood of decompensation can be thrombolysis necessitates a thorough assess-
considered for systemic thrombolysis or ment of the patient’s preexisting comorbidities,
catheter-based thrombolysis. These therapies mode of presentation, and focused clinical ex-
may improve symptoms and mortality4 but place amination to assess the immediate risk of he-
patients at elevated risks of bleeding from their modynamic collapse, the risk of long-term
systemic effects. Thrombolytic agents target complications, and the risk of major bleeding
fibrin via converting plasminogen to plasmin, associated with the thrombolytic agent. As
which breaks down the fibrin,5 resulting in described previously, high-risk PE patients war-
partial or complete dissolution of clot, rapidly rant strong consideration of aggressive treat-
increasing the pulmonary vasculature perfusion. ment options including systemic thrombolysis
Advances in pharmacotherapy have led to with a high incidence of adverse outcomes if
fibrin-specific thrombolytic agents that, unlike not instituted expediently.8 In patients who
first-generation agents (eg, streptokinase), present with acute high-risk PE, the risk of
cleave fibrin only by activating plasminogen on mortality is high, which makes the decision
the surface of the clot, thus reducing its systemic for systemic thrombolysis relatively easier as
effects. compared with patients who are hemodynami-
cally stable. The case fatality of these hemody-
RISK STRATIFICATION OF namically unstable patients ranges from 35% to
PULMONARY EMBOLISM 58%.6,9 Therefore, benefits clearly outweigh
the risk of adverse outcomes in most patients
Historically, high-risk PE was identified through with high-risk PE who are not experiencing se-
assessment of embolus burden via invasive vere active bleeding.10
angiography using the Miller index,6 but its On the contrary, decision making in patients
use has declined due to its invasive nature. In with intermediate-risk PE is more complex,
different studies and registries, hemodynamic with controversy surrounding the population-
instability (hypotension/circulatory shock) has based risk of decompensation.11 Although an
been shown to be the most important determi- analysis of the International Cooperative Pulmo-
nant of short-term morbidity and mortality,7 nary Embolism Registry in 1999 demonstrated
therefore this clinical marker helps to risk- that 15% of hemodynamically stable patients
stratify patients with PE. In an American Heart died in first 90 days of diagnosis,7 a meta-
Association (AHA) scientific statement, massive analysis of randomized trials demonstrated
PE was defined as “acute PE with sustained hy- only 3% short-term mortality rates in
potension (systolic blood pressure <90 mm Hg intermediate-risk patients treated with isolated
for at least 15 minutes or requiring inotropic anticoagulation.10 Close monitoring of these pa-
support, not due to a cause other than PE, tients is necessary with early administration of
such as arrhythmia, hypovolemia, sepsis, or thrombolytic agent for “rescue reperfusion” if
left ventricular [LV] dysfunction), pulselessness, worsening hemodynamics develop. Thrombo-
or persistent profound bradycardia (heart rate lytic therapy is not advisable in patients
<40 bpm with signs, or symptoms of shock).”4 with low-risk PE due to a clearly unfavorable bal-
These patients were considered high-risk. Pa- ance between improving hemodynamics and
tients with normal hemodynamics but objective the elevated risk of intracranial and major
evidence of right heart strain (via imaging or bleeding.12
 Systemic Thrombolysis for Pulmonary Embolism 73

CLINICAL ASSESSMENT precision but simpler to use. It includes age, his-

tory of heart failure or cancer, and blood pres-
Ideally, a prognostic model should be able sure, pulse rate, and oxygen saturation.14 Both
to precisely identify the risk of mortality and prognostic models can be used to risk-stratify
recurrent PE in patients so that escalation of patients under consideration for thrombolytic
treatment can be performed when necessary. therapy, but these models fail to predict the
Also useful would be a risk model that predicts risk of adverse outcomes in these patients. In
risks of various therapies beyond anticoagula- fact, there is no well-validated prediction model
tion. Various risk prediction tools have been to assess the risk of bleeding in patients
described in the literature with the Pulmonary receiving thrombolysis for PE. Therefore, abso-
Embolism Severity Index (PESI) (Table 1) being lute and relative contraindications for thrombo-
the best validated to determine short-term mor- lytic therapy along with clinical judgment are
tality (30-day) in patients with PE.13 This prog- the only tools available to risk-stratify for
nostic model classifies patients from risk class I bleeding.4,15
(very low risk) to class V (very high risk) based
on demographics (age and sex), comorbidities BIOMARKERS AND IMAGING
(history of cancer, heart failure, chronic lung dis- ASSESSMENT
ease), and clinical findings (mentation, oxygena-
tion, blood pressure, pulse and respiratory rate). Rise in cardiac biomarkers, including troponin
Mortality risk range from 1% in class I patients to and brain-type natriuretic peptide may repre-
24.5% in class V patients. With most patients fall- sent right heart dysfunction and have been asso-
ing in class II and class III, the negative predictive ciated with an increased risk of PE-related
value for mortality reaches higher than 90% in deaths.16–18 Chest CT scan is the gold standard
low-risk patients (class I–III). Simplified PESI was imaging modality for patients who come to the
also introduced, which is a modified version of emergency department with suspicion of PE.
previously described PESI with similar predictive In a previous study, left and right ventricular

Table 1
Original and simplified Pulmonary Embolism Severity Index (prognostic model to predict 30-day
outcomes in patients with acute pulmonary embolism)
Simplified Pulmonary Embolism
Pulmonary Embolism Severity Index (PESI) Severity Index (sPESI)
Demographics Demographics
Age >80 y Age >80 y
Male sex
Comorbidities Comorbidities
History of heart failure History of cancer
History of cancer History of chronic lung disease
History of chronic lung disease
Clinical findings Clinical findings
Tachycardia >110 beats/min Heart rate >110/min
Systolic blood pressure <100 mm Hg Systolic blood pressure <100 mm Hg
Respiratory rate >30/min Arterial oxygenation saturation <90% (with
or without supplemental oxygenation)
Temperature <36 C
Altered mental status (lethargy, stupor, coma)
Arterial oxygen saturation <90% (with or without
supplemental oxygenation)
Adapted from Aujesky D, Roy PM, Le Manach CP, et al. Validation of a model to predict adverse outcomes in patients with
pulmonary embolism. Eur Heart J 2006;27(4):476–81, with permission; and Jimenez D, Aujesky D, Moores L, et al. Simpli-
fication of the pulmonary embolism severity index for prognostication in patients with acute symptomatic pulmonary em-
bolism. Arch Intern Med 2010;170(15):1383–9; with permission.
74 Virk et al

dimensions of 431 patients with confirmed with intravenous heparin therapy in patients
acute PE were analyzed.19 RV enlargement, with PE, although promising results were
defined as RVD/LVD >0.9 was associated with seen with regard to clot resolution and
15.6% 30-day mortality as compared with 7.7% improving the hemodynamics of patients. The
30-day mortality in patients with no RV enlarge- role of thrombolytic therapy in patients with
ment. Similarly, in another study in which 120 high-risk PE resulting in hemodynamic instability
consecutive patients with acute PE were retro- and cardiogenic shock has not been well studied
spectively studied, both the RV/LV ratio and in randomized clinical trials (RCTs) due to a
the obstruction (Miller index) index were found perceived lack of equipoise for randomization
to be significant risk factors for mortality at in this population given the high rates of short-
3-month follow-up.20 These easy-to-measure di- term mortality with conservative therapies. In
mensions can be prognostically important in the early 1990s, Jerjes-Sanchez and colleagues24
selecting patients who are at elevated risk of randomized 8 patients with high-risk PE to
early deterioration. receive either heparin with streptokinase or iso-
Bedside transthoracic echocardiography can lated heparin. All 4 patients who received strep-
be used to detect RV dysfunction in the setting tokinase improved quickly and survived without
of acute PE. It can detect a wide range of imag- any major side effects at 2 years of follow-up.
ing indicators form very nonspecific RV dilata- On the contrary, all 4 patients died in the hepa-
tion and hypokinesis to the very specific rin group from RV failure due to massive PE
McConnell sign, in which the RV has a charac- (confirmed on autopsy). This is the main pub-
teristic appearance of significant enlargement lished data that has led to the consensus in
with free wall dysfunction and relative apical guidelines that reperfusion with systemic throm-
sparing.15 In a study by Kasper and col- bolysis (in the absence of absolute contraindica-
leagues,21 317 patients were prospectively tions) is indicated in patients who present with
evaluated for right ventricular strain by echo- high-risk PE.4,15 In patients with relative and ab-
cardiography and it was found that 1-year mor- solute contraindications to the use of systemic
tality was approximately 13% in patients with thrombolysis (Table 2), other therapies,
RV dysfunction as compared with 1.3% in including catheter-based therapies, should be
patients with no RV dysfunction. Echocardiog- considered.25
raphy should be performed to further risk-
stratify patients with clinical evidence of RV EVIDENCE OF BENEFITS IN PATIENTS
failure, elevated cardiac enzymes, or in clinical WITH INTERMEDIATE-RISK
decompensation. All these modalities can be PULMONARY EMBOLISM
helpful in not only classifying these patients as
intermediate or high risk, but also to segregate Evidence of beneficial effects of systemic throm-
patients with high likelihood of early deteriora- bolysis in patient with intermediate-risk PE has
tion so that systemic thrombolysis can be been a topic rife with controversy. Conflicting re-
used.22 sults from RCTs, registries, and meta-analyses
Summarizing the patient selection criteria for have led to less robust guidelines to manage
systemic thrombolysis, it is clear that the clinical these apparently stable patients. Traditionally,
judgment to use a thrombolytic agent in addi- intravenous anticoagulation with heparin has
tion to anticoagulation in a patient with acute been considered sufficient to resolve the clot
PE necessitates an individualized assessment of and prevent further morbidity, but some studies
the benefits23 of improving morbidity and mor- raise concerns that a portion of these patients
tality versus the risk of major bleeding. with RV dysfunction may be at intermediate
risk for early decompensation.15,26 As
EVIDENCE OF IMPROVEMENT IN mentioned previously, prognostic models can
CLINICAL OUTCOMES WITH be useful for supplementing clinical judgment
THROMBOLYSIS IN PATIENTS WITH in the management of patients with PE
HIGH-RISK PULMONARY EMBOLISM with different risks of decompensation.27–29
Importantly, unlike in the setting of high-risk
It has been more than 4 decades since the first PE, there is also a fairly robust evidence base
use of systemic thrombolysis by Miller and col- to assist in our decision making.
leagues6 in 1971 in patients with acute PE. Early In 2002, Konstantinides and colleagues9 pub-
randomized controlled trials failed to show lished data from an RCT that randomized 256 pa-
any evidence of mortality benefit with tients to alteplase versus conservative therapy
the use of thrombolytic agents in comparison for intermediate-risk PE. The group receiving
 Systemic Thrombolysis for Pulmonary Embolism 75

Table 2 often than in the group receiving heparin alone,

Contraindications to systemic thrombolysis in a concerning trend toward increased intracranial
patients with acute pulmonary embolism bleeding and major nonintracranial bleeding
was seen.30 Over the past decade, many addi-
Absolute Relative
Contraindications Contraindications tional smaller RCTs have been performed with
variable results. A systematic review and meta-
 Prior intracranial  History of chronic analysis by Chatterjee and colleagues10 attemp-
hemorrhage severe uncontrolled
ted to reconcile these data through analysis of
hypertension
the mortality, major bleeding, and intracranial
 Known structural  Severe uncontrolled hemorrhage (ICH) rates in the 8 RCTs that have
cerebral lesion hypertension studied intermediate-risk PE. The investigators
(systolic >180 mm Hg
concluded that although there was potential mor-
or diastolic
>110 mm Hg tality benefit with thrombolytic therapy among
the population of patients with intermediate-risk
 Known malignant  History of ischemic
PE in contemporary clinical practice, this comes
intracranial cerebrovascular
at the expense of increased major bleeding
neoplasm accident >3 mo
events and ICH. Specifically the number needed
 Ischemic stroke  Trauma or prolonged to treat (NNT) to prevent 1 death was 59, and
within 3 mo cardiopulmonary
the NNT to prevent a recurrent PE event was 54.
resuscitation >10 min
The benefit was offset by the risk of major bleeds
 Suspected aortic  Major surgery within (number needed to harm [NNH]) of 18, with an
dissection 3 wk NNH for ICH of 78. Although varying doses and
 Active bleeding  Recent internal bleed types of thrombolytic agents were used in
(excluding menses) (2–4 wk) different studies, this was the first meta-analysis
 Significant closed-  Pregnancy, active with sufficient statistical power to show mortality
head or face peptic ulcer, benefit. Also of significance is that the short-
trauma within 3 mo pericarditis, age >75 y, term mortality rate of patients treated only with
diabetic retinopathy, anticoagulation in this pooled analysis was
recent invasive 3.89% (41 deaths of 1054 patients with PE treated
procedure, current with anticoagulation), with the rate in
anticoagulant use intermediate-risk patients less than 3%. Although
Up to two-thirds of patients with acute PE do not receive clinical trial populations are not totally represen-
thrombolytic therapy due to contraindications. tative of those treated in general clinical care,
Adapted from Konstantinides SV, Torbicki A, Agnelli G,
this calls into question the mortality range of 3%
et al. 2014 ESC guidelines on the diagnosis and manage-
ment of acute pulmonary embolism. Eur Heart J to 15% range specified for patients with
2014;35(43):3033–69, 3069a–k; with permission. intermediate-risk PE in the current AHA guide-
lines26 (Table 3). The low baseline mortality rate
alteplase, with a background of anticoagulation makes the threshold high for escalating therapy
therapy, as initial therapy for submassive PE beyond anticoagulants for the prevention of
showed improved 30-day event-free survival as acute mortality. Another postulated reason for
compared with heparin plus placebo. This was administering thrombolytic therapy is the preven-
largely driven by a reduction in need for escala- tion of CTEPH. However, longer-term follow-up
tion of therapy (ie, initiation of pressors or resusci- from the PEITHO trial suggested therapeutic
tation from cardiac arrest) in the thrombolytic equivalence with thrombolytics compared with
arm. This study opened the discussion for the anticoagulation alone for the prevention of subse-
intermediate-risk PE which at that time was rec- quent CTEPH after acute PE.31
ommended only for high-risk PE. Subsequently, In view of these equivocal data, it is prudent
the international PEITHO (Pulmonary Embolism to risk-stratify these patients before deciding
Thrombolysis) trial30 randomized 1006 patients to give thrombolytic agents in these stable pa-
with a similar design. Single intravenous bolus of tients. Rigorously examining the benefits versus
tenecteplase plus heparin showed benefits in pre- risks using clinical judgment, prognostic models
vention of hemodynamic decompensation when and consideration of other possible treatment
compared with placebo plus heparin in patients options should be performed in patients who
with intermediate-risk PE. In the tenecteplase are intermediate risk. The evidence base at pre-
group, although the primary outcome of all- sent does not support thrombolytic therapy in all
cause death or hemodynamic decompensation/ patients with intermediate-risk PE. However,
collapse within 7 days occurred significantly less acknowledging the possibility of benefit in
76 Virk et al

Table 3
Latest recommendations for systemic thrombolysis in patients with acute massive and submassive
pulmonary embolism (PE)
Society Entity Recommendations
American College Massive PE with low bleeding risk Grade 2B
of Chest Submassive PE Grade 1B
Physicians,25
2016 Patients with submassive PE who deteriorate Grade 2C
(not developed hypotension yet) and low
bleeding risk
American Heart Massive PE Class IIa, Level of Evidence B
Association,26 Submassive PE with evidence of adverse Class IIb, Level of Evidence C
2011 prognosis and low bleeding risk
Submassive PE Class III; Level of Evidence B
European Society Massive PE Class I; Level of Evidence B
of Cardiology,15 Submassive PE Class III, Level of Evidence B
2014

some patients,10 ongoing research efforts increasing age. Observational data have
should try to identify those most likely to benefit demonstrated significantly increased risks with
with minimal trade-off of risk. age older than 65, whereas the PEITHO trial
identified most ICH events occurring in patients
EVIDENCE OF BENEFITS OF SYSTEMIC older than 75.30,33
THROMBOLYSIS IN LOW-RISK
PULMONARY EMBOLISM NEW CATHETER-BASED
TREATMENT OPTIONS
Patients with neither hemodynamic compromise
nor any evidence of RV dysfunction or myocar- Interestingly, the concept of using catheter-
dial injury are considered low risk, and use of based techniques to manage patients with PE
systemic thrombolysis is not recommended has roots that predate the initial consideration
(Grade III, level of evidence B).26 These patients of systemic thrombolysis in these patients. The
have short-term mortality rates of 1% or less Food and Drug Administration approved
from the acute PE, so any potential benefits deployment of Greenfield suction catheters in
are outweighed by the bleeding risks of throm- 1969 to remove thrombus from the pulmonary
bolysis. Isolated anticoagulation remains the vasculature. Currently, many catheter-mediated
mainstay of treatment in these patients. techniques have been used in the pulmonary ar-
teries.34–41 Extensive details regarding these
ASSESSMENT OF BLEEDING RISK techniques are available in Bedros Taslakian
and Akhilesh K. Sista’s article, “Catheter
One of the determinants of outcomes with Directed Therapy for Pulmonary Embolism:
thrombolytic use especially in patients with Patient Selection and Technical Considerations”
intermediate-risk PE is a judicious assessment and Wissam A Jaber and colleagues’ article,
of bleeding risk, especially of intracranial “Catheter-Based Embolectomy for Acute
bleeds. Conventional risk scores used to assess Pulmonary Embolism: Devices, Technical
bleeding risk with use of anticoagulants in Considerations, Risks & Benefits,” elsewhere in
different populations like HASBLED and ATRIA this issue.
have poor predictive ability to identify potential
for major bleeding with PE.32 Ongoing research MANAGEMENT PROTOCOLS
efforts are directed toward developing risk
assessment tools for predicting the risk of ma- In the recent PEITHO trial,30 the patients ran-
jor bleeding and intracranial hemorrhage,33 domized to receive fibrinolytics received a single
although these efforts have been hindered weight-based intravenous bolus (given over a
by the inadequacy of currently available period of 5–10 seconds) of the fibrinolytic agent
population-based datasets for PE. The most tenecteplase. The dose ranged from 30 mg to
consistent marker of risk for bleeding with sys- 50 mg, depending on body weight. Another
temic thrombolysis among patients with PE is trial23 assessed low-dose thrombolytics for
 Systemic Thrombolysis for Pulmonary Embolism 77

reduction of recurrent PE or subsequent devel- 1.5 million IU over 2 hours; urokinase 4400 IU/kg
opment of pulmonary hypertension. Alteplase as a loading dose over 10 minutes, followed by
0.5 mg/kg (maximum 50 mg), given as a 10-mg 4400 IU/kg per hour over 12 to 24 hours, accel-
bolus followed by the remainder over 2 hours, erated regimen 3 million IU over 2 hours; alte-
was associated with a reduction in pulmonary hy- plase 100 mg over 2 hours or 0.6 mg/kg over
pertension (16% vs 57%) as well as the compos- 15 minutes (maximum dose 50 mg). A definitive
ite outcome of pulmonary hypertension or trial looking at comparisons of different dosing
recurrent PE (16% vs 63%). European Society regimens for intravenous (IV) thrombolysis in
of Cardiology (ESC) has published “approved” acute PE has not been performed to date.
thrombolytic regimens for pulmonary embo- The following is a “real-life” protocol for
lism15: streptokinase 250,000 IU as a loading systemic thrombolysis followed by the PE
dose over 30 minutes, followed by 100,000 IU/ response team at the Hospital of the University
h over 12 to 24 hours, accelerated regimen: of Pennsylvania:

Procedures before/  If possible and indicated, place nasogastric tubes, indwelling bladder
after alteplase catheters, intra-arterial lines, or intravenous lines before administration of
systemic alteplase.
 If unable to perform before therapy, delay placement of nasogastric tubes,
indwelling bladder catheters, intra-arterial pressure catheters, or intravenous
lines for 24 hours if possible.
Alteplase dosing Massive (or submassive) PE:
 100-mg IV infusion over 2 h for most patients.
 In patients at high risk of bleeding, relative contraindications (see Table 1),
age >65 y, weight <65 kg, body mass index <25 kg/m2, a dose of 50-mg IV
infusion over 1 h may be considered (or recommended by the PERT
attending).
Cardiac arrest:
 Registered nurse (RN) may administer (physician/advanced practitioner can
give if they prefer).
 50-mg IV over 2–5 min.
 Once alteplase is given for cardiac arrest, high-quality cardiopulmonary
resuscitation (CPR) should be continued at least 15 min after the dose to
allow drug to circulate. CPR should be continued while alteplase is being
administered.
 If no return of spontaneous circulation 15 min after alteplase bolus: can
consider a second 50 mg IV over 2–5 min.
 If return of spontaneous circulation after alteplase 50-mg bolus: give
remaining 50-mg IV infusion over 1 h.
Concomitant  IV unfractionated heparin (UFH) in full therapeutic doses is the preferred
anticoagulation anticoagulant for those receiving alteplase for PE before alteplase infusion.
 While considering/preparing alteplase, initiate UFH treatment with a bolus as
endorsed by the Recommended Protocols for Initiation and Maintenance for
Heparin Therapy and Prophylaxis for Non-Neonates on the PennMedicine
Formulary.
 Once the decision to give alteplase is made, alteplase should be given as
soon as possible. Suspend IV UFH treatment immediately before the
initiation of alteplase infusion and throughout infusion.
 When the alteplase infusion is complete, check an aPTT immediately and
restart UFH without a bolus at the previous infusion rate if aPTT <80 s.
 If a patient received a therapeutic dose of enoxaparin before alteplase, start
the UFH infusion 12 h after the last dose of low-molecular weight heparin
(LMWH) (24 h if given dalteparin/fondaparinux), provided the patient does
not have new renal dysfunction, and did not receive a 1.5-mg/kg enoxaparin
dose. If either of the latter two occur, please contact a critical care clinical
pharmacy specialist for guidance.
 After 48–72 h of stability, the patient may be transitioned to a LMWH,
warfarin, or a novel oral anticoagulant as clinically indicated.
(continued on next page)
78 Virk et al

(continued )
Administration A dedicated IV line is required; may be given peripherally
100-mg or 50-mg alteplase dose slow infusion (RN):
 Must be given via IV infusion pump.
 Can be found in library under alteplase / pulmonary embolism.
 VTBI entered should be 100 mL (or 50 mL for 50-mg dose).
 Rate of infusion will be 50 mL/h.
 When there is no alteplase left in the vial but drug left in the drip chamber,
a 0.9% sodium chloride IV bag (100 mL or 250 mL as available on the unit)
should be spiked and attached to the IV tubing where the empty vial was
to continue to run at the same rate (50 mL/h) to complete the 2 (or 1 as
stated based on dose above) -hour infusion time. No need for further
modifications to IV.
Administration Infusion pump, when pump is finished infusing, discard the remainder of the
(continued) sodium chloride bag. This will ensure patient receives the entire dose
ordered at correct rate (approximate IV tubing space is approximately
25–28 mL).
50-mg bolus–cardiac arrest dose (RN or physician/advanced practitioner):
 RN may administer (physician/advanced practitioner may give if they prefer)
IV over 2–5 min (rate of administration may be prolonged in patients with
smaller-gauge IV catheters).
 When RN administers medication, ordering provider must remain at bedside
during administration.
Monitoring/ Alteplase therapy can be initiated on all floors. If alteplase is initiated on the
intensive care floor, patients should be transferred to an ICU as soon as possible, as critical
unit (ICU) care care nursing and an ICU bed are required. Patients should remain in the ICU
until 24 h after for the duration of the alteplase infusion and for at least 24 h after
alteplase completion of the alteplase infusion.
administration Obtain baseline assessment of hemodynamics and laboratory data.
Perform neurologic assessments (add neuro parameter to the vital signs
flowsheet)
 Every 15 min during the infusion, then
 Every 30 min thereafter for the next 6 h, then
 Hourly until 24 h after treatment
Blood pressure (BP) monitoring
 Every 15 min for the first 2 h, then
 Every 30 min for the next 6 h, then
 Hourly until 24 h after treatment
 BP must be maintained at or below 180/105 mm Hg for 24 h
 Increase the frequency (per primary team) if a systolic BP is >180 mm Hg or
if a diastolic BP is >105 mm Hg; administer antihypertensive medications
to maintain BP at or below these levels.
Bleeding precautions
 Check puncture sites for hematomas.
 Apply digital pressure or pressure dressing to active compressible
bleeding sites.
 Visual inspection of urine, stool, and emesis for blood.
 Monitor patient for evidence of gingival bleeding.
Management Bleeding
of common  If serious bleeding occurs during or after the alteplase infusion, alteplase
adverse events should be discontinued immediately with a consideration of suspending UFH
as well. If RN discovers, immediately notify covering provider.
Allergic reactions
 Orolingual angioedema has been observed in up to 5% of patients who
receive alteplase. If angioedema develops, stop infusion and treat with
supportive therapy (airway management, histamine antagonists, steroids).
Abbreviations: aPTT, activated partial thromboplastin time; PERT, pulmonary embolism response team; VTBI, volume to
be infused.
 Systemic Thrombolysis for Pulmonary Embolism 79

LATEST GUIDELINES 4. Kearon C, Akl EA, Comerota AJ, et al. Antithrom-

botic therapy for VTE disease: Antithrombotic
Summary recommendations: Available data sug- Therapy and Prevention of Thrombosis, 9th ed:
gest that the following patients may derive American College of Chest Physicians Evidence-
significant benefits with thrombolytic administra- Based Clinical Practice Guidelines. Chest 2012;
tion potentially justifying the substantial risks of 141(2 Suppl):e419S–496.
bleeding: 5. Weinberg I, Jaff MR. Accelerated thrombolysis for
pulmonary embolism: will clinical benefit be ULTI-
1. Patients with high-risk PE who are not
experiencing acute cardiovascular collapse MAtely realized? Circulation 2014;129(4):420–1.
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