Thrombolysis

for Pulmonary Samuel

Z. Goldhaber

EPIDEMIOLOGY

accounts for ENOUS thromboembolism approximately 300,000 hospitalizations and as many as 50,000 deaths per year in the United States, making it the third most common cardiovascular disease after acute ischemic syndromes and stroke. The number of hospital admissions is certainly an underestimate because pulmonary embolism (PE) and deep venous thrombosis (DVT) are notoriously difficult to diagnose. Approximately one-third of patients with PE or DVT are admitted with recurrent disease rather than with first episodes of venous thrombosis.’ The magnitude of the problem (Fig 1) mandates that we reconsider whether our conventional approach to management of PE has been sufficiently aggressive, particularly with respect to use of thrombolytic agents. Both in the United States’ and Canada3 there has been no decrease in the mortality rate from PE since the early 1960s (Fig 2). This distressing fact provides additional impetus to reexamine whether thrombolysis is being used sufficiently among patients with PE. In all American epidemiologic studies, men, nonwhites, and the elderly appear to be at highest risk of death from PE. Regardless of whether one examines data from the National Hospital Discharge Survey”*’ or more focused reports, such as Lilienfeld’s from Minneapolis-St PauJ6 it is striking to observe that the case fatality rate has not improved in two decades despite the advances that have been made in most areas of cardiovascular medicine (Fig 3). Biologically, it is logical that thrombolysis followed by anticoagulation will be more effective than anticoagulation alone for patients who are stricken with massive PE (Fig 4). Nevertheless, unfamiliarity with thrombolysis for PE makes the use of this strategy unwieldy for an individual physician when patients present with recognized massive PE at a particular hospital only several times per year. Current estimates are that no more than 10% of PEs are treated with thrombolysis in the United States. (In Europe, it appears that a higher proportion of patients receive thrombolytic therapy, particularly for DVT.) This article examines whether

V

Progressin

Cardiovascular

Diseases,

Vol XXXIV,

Embolism

No 2 (September/October).

the threshold for using thrombolysis lowered.

should be

CONTINUING PROBLEMS WITH ANTICOAGULATION ALONE

With anticoagulation alone, the rate of recurrent PE during the initial hospitalization is high (Table l), probably because of failure to lyse thrombus that embolizes from the pelvic and deep leg veins, Recurrent PE occurred in 23% of heparin-treated patients in Phase I of the Urokinase Pulmonary Embolism Trial (UPET)’ and in 18% of patients reported by Monreal et al.* Suspected or proven recurrent PE was observed in 17% of the heparin-treated patients of Wheeler and coinvestigators.9 The use of anticoagulation alone provides an opportunity for endogenous fibrinolytic processes to lyse PE. However, the endogenous system can be impaired by an excess of plasminogen activator inhibitor” or by deficiencies of antithrombin III,” protein C, or protein S.12*13 With anticoagulation as the sole treatment for PE, complete resolution of pulmonary artery clot may fail to occur in 75% of patients after 1 to 4 weeks14(Fig 5) and in 50% after 4 months of follow-up (Fig 6)” Expertise in PE is scattered through many specialties, including vascular medicine, vascular surgery, cardiology, pulmonary medicine, and hematology. Many physicians believe that PE treatment should remain entirely within their domain and that consultation is not warranted unless the patient becomes hemodynamically unstable. Therefore, progress in managing the cardiovascular aspects of PE has occurred more slowly than in other areas such as myocardial infarction where a sense of urgency is always paramount and the threshold for specialty consultation is low. The interdisciplinary From the Harvard Medical School, and the Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital, Boston, M-4. Address reprint requests to Samuel Z. Goldhaber, MD, Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital, Boston, MA 02115. Copyright @ 1991 by W. B. Saunders Company 0033.0620/91/3402-0003$5.00/O 1991:

pp 113-134

113

114

SAMUEL

2. GOLDHABER

171,178

200,000-

115,726

lOO,OOO55,452

O-

* Total

DWPE

nature of PE, which impacts on all areas of medicine, makes it difficult to organize trials that investigate the roIe of thrombolysis. Because of these special circumstances, the National Institutes of Health (NIH) consensus guidelines for PE thrombolysis, issued in 1980, appear to remain applicable today, even though more clinical research is required to define precisely the subsets of patients who can benefit the most. The NIH consensus recommended thrombolytic therapy for patients with obstruction of blood flow to a lobe or multiple pulmonary segments and for patients with hemodynamic compromise, regardless of the PE’s anatomic size.16 RATIONALE

FOR THROMBOLYSIS

The pathophysiological response to acute PE depends on the extent to which pulmonary

1962-M

lQ6!559

1970-74

1976-79

Fig 1. Estimated number of cases of venous thromboembolism in the United States in 1966, based on a XT-hospital survey in the Worcester, MA area.’

artery blood flow is obstructed, preexisting cardiopulmonary disease, and the release of vasoactive humoral factors from activated platelets that accumulate at the site of a new clot (Fig 7). In patients without prior cardiopulmonary disease, right ventricuIar afterload increases when pulmonary artery obstruction reduces the pulmonary vascular bed by 25% or more. To compensate for this impairment, right ventricular and pulmonary artery pressures increase. As right ventricular afterload increases acutely, this chamber dilates and becomes hypokinetic, leading in turn to tricuspid regurgitation. As the right ventricle fails, right atria1 pressure increases and cardiogenic shock ensues. When cardiac function has been compromised by previous cardiopulmonary illness, relatively smaller emboli obstructing only one or two pulmonary

iQSQ-64

Fig 2. Death rate from PE per 100,000 in the United States from 1962 through 1964, based on data from the National Hospital Discharge Survey. n , white men; q 3, white women; Cl, nonwhite men; 9% nonwhite women.2

Fig 3. the twin female!

The case fatality cities of Minneapolis

rate

from pulmonary embolism and St Paul, MN. l6, male;

in

n ,

PULMONARY

EMBOLISM

115

THROMBOLYSIS

Table

1. Recurrent

Phase Monreal Wheeler

Fig 4. This 67-year-old man collapsed suddenly and fered a cardiopulmonary arrest. Massive bilateral (right shown in figure) pulmonary emboli were documented autopsy.

suflung at

segments can exert a similar hemodynamic effect. Although preload, afterload, heart rate, and contractility have traditionally been considered

PE Among

Heparin-Treated In-Hospital

Study I UPET’ et ale et al9

PE Recurrence

Patients (%)

23 18 17

the determinants of Ieft ventricular systolic performance, acute increases in right ventricular pressure can adversely affect left ventricular function because of the anatomical juxtaposition of the two ventricles and “ventricular interdependency.” Moderate right ventricular hypertension can displace the inter-ventricular septum toward the left ventricle, resulting in decreased left ventricular diastolic filling and end-diastolic vo1ume.‘7 Among 14 patients with acute massive PE, echocardiography showed increased right ventricular end-systolic and enddiastolic areas, reduced right ventricular fractional area contraction, interventricular septal flattening at both end-systole and end-diastole, and markedly decreased left ventricular enddiastolic dimensions. Acute dilation of the right ventricle accounted for the leftward shift of the inter-ventricular septum and reduced left ventricular compliance. During recovery from PE, the interventricular septum returned progressively to a more normal configuration at both endsystole and end-diastole, and the left ventricular diastolic dimension steadily increased. Thus, it appeared that circulatory failure due to massive PE was mediated through a profound decrease in left ventricular preload.‘* After embolization, the release of neurohumoral factors can cause vasoconstriction and bronchospasm. The two most important humoral factors appear to be serotonin and thromboxane A, (TxA2).19 Serotonin, a potent neural and smooth muscle agonist, is stored primarily

116

SAMUEL

Fig 6. The were observed. patient was radioactivity. patient was intermediate

rate of recovery of the pulmonary circulation is expressed as a percentage of the total number of patients with PE who Numbers in parentheses indicate the number of patients observed at the time indicated after pulmonary embolism. A considered to have recovered completely when no region of the lung had a less than normal concentration of lf at least 60% of the regions of decreased radioactivity became normal, but the lung scan was still abnormal, the classified as improved. Results in this figure are among patients considered to have pulmonary embolism of size, defined as 16% to 30% of the lung involved. They were treated with anticoagulation alone. (Reprinted with

in the dense bodies of platelets and mediates bronchospasm in the small airways. Activated platelets also secrete TXA,, a potent vasoconstrictor and bronchoconstrictor. Increased dead space and reflex airway constriction from PE result in wasted ventilation. The surfactant concentration can decrease, with attendant alveolar collapse and atelectasis, especially during the first few days after embolization. The rationale for thrombolytic therapy of PE, followed by anticoagulation, is that thrombolysis actively dissolves the clot that has already formed, thereby returning cardiopulmonary function to baseline as quickly as possible. By relieving the obstruction to pulmonary artery blood flow, thrombolysis can quickly reduce the elevated pulmonary artery pressure and can reverse right ventricular hypertension. Because of interventricular dependency, improved right ventricular function leads to better left ventricul

Size of embolus.

l

Presence of coexistent

l

Neurohumoral

m I

2. GOLDHABER

lar function that helps reverse cardiogenic shock. Dissolution of the thrombus should normalize pulmonary arterial blood flow and improve pulmonary tissue perfusion which, in turn, should prevent chronic pulmonary hypertension as a late effect of PE and improve the quality of life. In addition, by lysing thrombus quickly, these agents can minimize the potentially adverse impact of the neurohumoral response to PE. These diverse beneficial effects of thrombolytic therapy should reduce the mortality rate from PE. PROVEN

ADVANTAGES

OF THROMBOLYSIS

The three thrombolytic agents that have been used most often to treat PE are urokinase (UK), streptokinase (SK), and recombinant human tissue-type plasminogen activator (rt-PA). UK, a direct plasminogen activator, is produced by human fetal kidney cell cultures. UK converts

cardiopulmonary

disease.

response.

I?RV *FTERLOADb (1 :;;;;.t;;;;;,;;; acute

I

tion

right

refer

ventricular

to text.

failure

PULMONARY

EMBOLISM

117

THROMBOLYSIS

Table

I of UK Pulmonary

Advantages

n

Study

Phase

2. Proven

Embolism

Trial’

of Thrombolysis

Thrombolytic Agent

160

Findings

UK

Accelerated reperfusion, nary

arterial

creased in lung Tibbutt

et al*’

LY et aP’

NOTE. improved

The proven pulmonary

advantages of thrombolysis capillary blood volume.

ADVANTAGES

Group

lysis, pulmonary and normalization pressure

bleeding. scans.

tissue of pulmo-

at 24 h, but inBy 7 days,

no difference

30

SK

Accelerated pulmonary

clot lysis and normalization arterial pressure.

20

SK

Accelerated bleeding.

clot

are (1) accelerated

plasminogen directly to plasmin through cleavage of a single peptide bond. For PE treatment, there is more published experience with UK than with SK or rt-PA, and UK is considered the standard thrombolytic agent for PE against which novel clot-dissolving agents must be compared. SK, a foreign protein produced commercially from ultrafiltrates of Streptococcus haemolyticus, combines with plasminogen in an equimolar ratio to form a SK-plasminogen activator complex. This activator complex converts other plasminogen molecules to plasmin. The major advantage of SK is that the cost of PE treatment is about one-fifth that of UK and rt-PA. However, SK often causes fever, chihs, and nausea, and the dose must often be increased to maintain a lytic state. Three published randomized controlled trials have compared thrombolysis with heparin7~20~21 and have demonstrated accelerated clot lysis, improved pulmonary tissue reperfusion, and reduced pulmonary artery pressures compared with heparin alone (Table 2). A subset of patients from the largest of these trials underwent follow-up investigation 2 weeks and 1 year after enrollment. A higher pulmonary capillary blood volume was observed in the group that received thrombolysis.” POSSIBLE

clot

in Thrombolytic

OF THROMBOLYSIS

Immediate clot lysis might salvage patients with massive PE who would otherwise die in cardiogenic shock. It is also possible that by lysing the source of the PE in situ, usually thrombus in the pelvic or deep leg veins, that the rate of recurrent PE might be lowered. In Phase I of the UPET, which compared UK and heparin, there was an indication that throm-

clot

lysis,

(2) accelerated

lysis

pulmonan/

of

but increased

tissue

reperfusion,

and

(3)

bolytic therapy fohowed by anticoaguIation might reduce both mortality and recurrent PE compared with anticoagulation alone. Of the 78 patients who received anticoagulation alone, 9% died, 23% had recurrent PE, and 31% died or had recurrent PE within the first 2 weeks of treatment. In contrast, among the 82 patients treated with UK followed by anticoagulation, 7% died, 17% had recurrent PE, and 23% died or had recurrent PE within 2 weeks after randomization. Thus, the rate of death or recurrent PE was lower among UK-treated patients than among those who received anticoagulation alone (23% v 31%), but the difference did not achieve statistica significance. Given the UPET sample size and event rate in the anticoagulation alone group, reductions in event rates would have had to have been approximately 60% to be detected with 80% power (Table 3). Thrombolysis in PE patients appears to rapidly reverse the frequently associated right heart failure.23 Come and coinvestigators performed Doppler echocardiography on 7 patients with PE before and after they received rt-PA. Within a day of treatment, the right ventricular enddiastolic diameter decreased from an average of 3.9 cm to 2.0 cm. Right ventricular wall motion normalized in five patients and improved to miId hypokinesis in two patients. Tricuspid regurgitation was present before lytic therapy in Table Reduced Reduced Accelerated

3. Possible

Advantages

mortality rate rate of recurrent PE reversal of right heart

of Thrombolysis

failure

Sustained improvement of pulmonary hemodynamics rest and during exercise24~25 and improved quality Reduced frequency of chronic pulmonary hypertension

at of life”

118

six patients but was detected after the completion of therapy in only two. Thus, the early reversal of right heart failure suggests a mechanism whereby thrombolysis might improve the survival rate from acute PE. Although sustained improvement in pulmonary capillary blood volume has been proven among PE patients treated with thrombolysis,” until recently, the clinical importance of this finding has been disputed. Fortunately, some of the patients in UPET who underwent pulmonary capillary blood volume testing 2 weeks and 1 year after enrollment were subsequently studied with a research right heart catheterization and supine bicycle exercise testing, an average of 7 years after the PE. Those assigned initially to thrombolysis had high pulmonary capillary blood volumes at 1 year and preservation of the normal pulmonary vascular response to exercise at 7 years.” In contrast, patients who had been treated with anticoagulation alone, on average 7 years previously, demonstrated a low pulmonary capillary blood volume at 1 year and a markedly abnormal increase in pulmonary artery pressure and pulmonary vascular resistance when undergoing supine bicycle exercise during right heart catheterization at 7 years after randomization. There was a close inverse correlation between low pulmonary capillary blood volume 1 year after treatment and high pulmonary vascular resistance 7 years after therapy. In addition, only one third as many PE patients randomly allocated to anticoagulation alone and followed for an average of 7 years were asymptomatic compared with those who had initially been assigned to receive UK or SK followed by anticoagulation? These preliminary data suggest that initial management with thrombolysis can confer an improved quality of life for many years after the original illness. In an observational study of seven patients with massive PE, all of whom received UK therapy, follow-up 15 months later demonstrated sustained improvement of pulmonary hemodynamics both at rest and during exercise. On average, pulmonary artery pressure decreased from 61/23 mm Hg before treatment to 25/8 mm Hg 6 days later and 2419 mm Hg 15 months later.” These findings are consistent

SAMUEL

2. GOLDHABER

with the long-term hemodynamic observations noted by Sharma and coinvestigators.” In my experience, patients with massive PE who continue to have a large clot burden (Fig 5) are at high risk for developing the uncommon but devastating complication of chronic pulmonary hypertension. The quality of life of these patients deteriorates, and they are often faced with the choice of a bed-to-chair existence with home oxygen or undergoing the highly risky and expensive operation known as pulmonary thromboendarterectomy. Even in the most experienced of centers, the mortality rate from this surgery is 13%.% The availability of this procedure is limited, and patients undergoing this operation must often travel thousands of miles for evaluation and treatment. It seems that initial thrombolysis in suitable patients would be more cost-effective than waiting until severe chronic pulmonary hypertension develops several years later. CONTRAINDICATIONS

AND COMPLICATIONS

No laboratory test is available to predict in advance which patients who receive thrombolysis will suffer bleeding complications.23 Therefore, a careful history and physical examination to screen for potential complications is of paramount importance. Our venous thromboembolism research group uses a checklist for every patient, regardless of the urgency of the clinical situation. Contraindications to the use of thrombolysis include intracranial or intraspinal disease, recent surgery, or trauma (Table 4). We always test the stool for occult blood and do not administer thrombolysis if the examination demonstrates more than a “trace” of blood. To Table Absolute Active History

4. Contraindications

to Thrombolytic

Therapy

contraindications or recent internal of hemorrhagic

bleeding stroke

Intracranial or intraspinal disease (eg. neoplasm) Recent cranial surgery or head trauma Relative contraindications Major surgery or trauma Biopsy or invasive procedure ble to external compression

in a location

Nonhemorrhagic stroke Uncontrolled severe hypertension Severe coagulation defects (thrombocytopenia platelets < 100,000 mm’] deficiency)

inaccessi-

[eg,

PULMONARY

EMBOLISM

119

THROMBOLYSIS

a multicentered European study of UK for PE had decreased to 4%.29 Of greatest concern is the risk of intracranial bleeding, which occurs in 2 to 6 of every 1,000 patients treated with thrombolytic therapy. Unfortunately, manifestations of a migraine headache may be virtually impossible to distinguish clinically from an intracranial bleed. Among patients with histories of migraine, a headache may be precipitated by radiographic contrast agent. The only way to differentiate reliably between an intracranial bleed and a migraine headache is with a head computed tomography (CT) scan. If intracranial bleeding is suspected, thrombolytic therapy or heparin (they are not given concomitantly in the United States) should be discontinued immediately and both neurological and neurosurgical consultation should be sought quickly. An emergent head CT (without contrast agent) should be obtained. The head CT is more sensitive to bleeding than magnetic resonance imaging (MRI) scanning. Keep in mind that the contrast agent from a recent pulmonary angiogram can be visualized on the head CT scan. To complicate matters further, the contrast agent mimics the appearance of blood. If the head CT is negative, thrombolysis or heparin can be resumed. The patient who suffers from a migraine headache should be medicated with acetaminophen, Percocet (Du Pont Pharmaceuticals, Wilmington, DE), or Esgic (Gilbert Laboratories, Chester, NJ). Retroperitoneal hemorrhage can also be life threatening because the bleeding is often sustained, brisk, and difficult to diagnose. This

maximize prevention of bleeding complications, we follow the five guidelines listed in Table 5. In some respects, our use of thrombolysis is more liberal than for patients with myocardial infarction. For example, we do not adhere to any upper age limit. Additionally, we do not consider the presence of cancer an exclusion criterion. Unlike patients with acute myocardial infarction, those with PE appear to have a much wider “window” for effective use of thrombolysis. We will administer this therapy to patients with any new symptoms or signs within the 2 weeks prior to presentation. Trivial superficial oozing at venipuncture or arterial catheter insertion sites may be considered an index of drug efficacy rather than a complication of thrombolytic therapy. Such bleeding can be controlled with manual compression followed by a pressure dressing (Table 6). In Phase I of UPET, severe bleeding, defined as the need for transfusion of more than 2 units of blood or a decrease in hematocrit of more than 10 points, occurred in 27% of the UK-treated patients. The large amount of blood drawn for research purposes during the first 24 hours of Phase I (about 200 mL) contributed to the decrease in hematocrit; during Phase II,28 fewer patients (12%) had severe bleeding. In many instances, bleeding occurred at the vascular puncture sites for pulmonary angiography. In the past decade, we have learned to minimize major bleeding complications by appropriate patient selection and by minimizing the “handling” of patients during the thrombolytic infusion. By 1987, the rate of severe bleeding in Table Take a careful

neurological

history.

For example,

ness and difficulty speaking rather Inquire about previous headaches. ciated visual changes excludes administration

though

obtaining

ABGs

to Minimize ask patients

than whether they have Determine the location,

or neurological of thrombolysis.

than during or after the therapy, Discourage arterial blood gases

5. Guidelines

abnormalities However,

whether

site for potential oozing. For patients undergoing pulmonary angiography, dividual) to perform the initial percutaneous

patients

Complications

they

have

had transient ischemic duration, and clinical

experienced

episodes

attacks. course of prior

of right

headaches

hand

along

with

weakasso-

that might have occurred. A history of migraine headaches in no way it is preferable to elicit this history prior to thrombolytic therapy rather

particularly if the patient does (ABGs) as a diagnostic screening

in no way excludes

Bleeding

from

arrange single-wall

develop a headache. test for PE. ABGs

receiving

thrombolysis,

are more

ABGs

misleading

do produce

for a senior staff angiographer puncture of the femoral vein.

hours before sheath removal on the day following the angiogram and at least 15 minutes plied after removing the venous sheath. Prior to initiating thrombolysis, send a “clot” to the blood bank (in a red top tube) for “type screen”).

(rather

than

an additional

than

helpful.

Al-

cutaneous

a less experienced

in-

Heparin should be held for several of manual pressure should be apand

hold”

(ie, “type

and

120

SAMUEL

Table Major

6. Management

of Complications

From

Thrombolytic

2. GOLDHABER

Therapy

bleeding

Intracranial

bleeding

Discontinue Obtain

Expanding

groin

despite

discontinuation

of therapy

or anticoagulation

Discontinue thrombolysis Order 10 U cryoprecipitate Thaw 2 U of FFP Reverse heparin with Transfuse Type and Obtain

Minor

or anticoagulation

CT scan

Consult neurology/neurosurgery Discontinue thrombolysis

hematoma

Gross hematuria If bleeding continues

thrombolysis head

or anticoagulation

protamine

platelet if bleeding time cross packed RBCs

consultation

prolongs

for endoscopicisurgical

control

of bleeding

bleeding

Superficial Gingival

skin

oozing

oozing

Apply manual pressure Determine if source is vascular Pack gingiva Dental

consult

with

puncture

site

gauze

if oozing

persists

Allergy Fever

Acetaminophen

650-1.000

Hydrocortisone

100 mg IV

Nausea

Diphenhydramine 25-50 Lorazepam 1-2 mg IV

Chills/rigors

Meperidine

Abbreviation:

50-100

mg mg IV

mg IV

IV. intravenous.

complication can occur during the femoral vein catheterization for pulmonary angiography if an artery is inadvertently punctured above the inguinal ligament. Gross hematuria and other internal bleeding can generallybe well managed by discontinuing therapy. If bleeding is brisk or potentially life threatening, 10 units of cryoprecipitate should be ordered from the blood bank. Each unit contains 200 to 500 mg of fibrinogen and 80 units of factor VIII in a volume of 10 to 15 mL. A dose of 10 units will increase the fibrinogen level by about 70 mg/dL and the factor VIII level by about 30% of normally circulating levels. Cryoprecipitate can be thawed rapidly and should be available within 10 minutes of a request. In addition, two units of fresh frozen plasma (FFP) should be ordered. FFP, which may take 45 minutes to thaw, is a source of factors V and VIII as well as cl,-antiplasmin, fibrinogen, and other active coagulation factors.30 Minor allergic reactions due to SK or, less often, UK occur occasionally and are manifested by fever and chills. In an attempt to suppress this reaction, steroids, diphenhydramine, and acetaminophen can be administered prophylactically. We have found that if rigors do occur, they can be effectively

treated with 50 to 100 mg of intravenous peridine. BOLUS

me-

THROMBOLYSIS

The concept of bolus thrombolysis for venous thromboembolism is not new (Table 7). In 1974, Dickie et al described the use of bolus urokinase to treat PET1 These investigators used bolus thrombolysis because of their concern that most of the deaths from PE occurred within the first few hours after arrival at the hospital. Ten years later, Pierre Duroux’s group3’ described 14 PE patients who received 15,000 III/kg of urokinase over 10 minutes, with a 34% decrease in pulmonary vascular obstruction 12 hours after treatment. Of particular importance is that no severe hemorrhagic complications were observed. Since the mid 198Os, laboratory work has attempted to refine the concept of bolus thrombolysis. In 1985, Agnelli and coinvestigators observed that the thrombolytic effect of r-t-PA persists beyond its clearance time from the circulation.33 In a rabbit model of jugular vein thrombosis, they found that wound bleeding in rabbits induced by a 4-hour infusion of t-PA is delayed for at least 1 hour after starting the

PULMONARY

EMBOLISM

121

THROMBOLYSIS

Table

7. Selected

Studies

of Bolus

Thrombolysis

Model/Investigation

Findings

Rabbit Agnelli Agnelli Agnelli Clozel

et al (1985Y’ et al (1985jy et al (1985)35 et al (1989)%

Lytic

effect

Wound 15-and

of rt-PA

bleeding 30-min

30,000 During with

is sustained

beyond

its plasma

clearance

time

during 4 h of t-PA is delayed for 60-90 min after starting the infusion t-PA infusions caused less bleeding than l-h and 4-h infusions

U/kg t-PA/4 h produced 36% lysis ~30,000 continuous t-PAfor 4 h, duration of action bolus and continuous infusion

U/kg t-PA/l was limited

5 min which produced 96% lysis to - 2 h; extent of lysis was similar

Canine Kanamasa Shiffman Prewitt Prewitt Clinical Dickie Petitpretz Levine

et al (1989)37 et al (1988)”

&PA Lysis

1 mg/kg/30 min is less likely rate is 56%/h with a 15-min

et al (1989)39

Total clot lysis thrombolytic

et al (1990)”

rt-PA

et al (1974)3’ et al (1984)‘* et al (1990)”

is greater with rate relation

2 mg/kg/l5

9 patients depended 14 patients

min did

receive

pulmonary

to lyse older thrombus than rt-PA 1 mg/kg/3 h r&PA bolus v 27%/h with a 90 min n-PA infusion

rt-PA/15

not cause arterial

min v rt-PA/5 more

lysis

injections

than

min. suggesting rt-PA

of bolus

on clinical response and fibrinogen receive right atrial injections of bolus

an upper

1 mg/kg/l5 UK over

levels UK 15,000

U/kg/l0

6-10

limit

min min;

repeated

t

daily

mean

hemody-

relative

t-PA

t-PA BOLUS (t-PA)

t-PA

XL-FDP PLASMINOGEN

im-

cross-linked fibrin degradation products (XLFDPs) when being lysed. Circulating XL-FDPs from a lysed PE can activate rt-PA when it is continuously present in the circulation due to a prolonged rt-PA infusion (Fig 8). This interaction of XL-FDPs with a prolonged rt-PA infusion could cause the undesirable activation of circulating (not fibrin bound) plasminogen to circulating plasmin and thus, in turn, could induce a systemic lytic state. The rationale supporting bolus rt-PA as potentially safer than a prolonged rt-PA infusion is that the bolus is cleared rapidly, thus preventing large amounts

PROLONGED t-PA Iff USION

Fig 8. Schematic repteaentation of the differences between a prolonged t-PA infusion versus a t-PA bolus. (Reprinted with permission.%)

boluses

min of UK; the greatest

namic improvement occurred during the first 3 h after the bolus 58 patients randomized: r&PA (0.6 mg/kg/2 min) v heparin; on lung scans, 37% provement in perfusion (IT-PA) v 19% (heparin) (P = .017); no major bleeding

infusion.” They also established, with t-PA infusions over periods ranging from 15 to 240 minutes, that 15 and 30 minute infusions of t-PA did not produce significantly more bleeding than saline infusions.” Ironically, a 4-hour infusion of 30,000 U/kg of t-PA produced 36% thrombolysis compared with 96% thrombolysis when the same dose of t-PA was administered over 15 minutes. Agnelli has proposed a schematic representation of the differences between a prolonged t-PA infusion and bolus t-PA.35” PEs are rich in fibrin and are likely to release large amounts of

to the dose-

-+PLASMlN

4 FIBRINOGEN +FDP

PLASMINOGEN

122

of continuously infused, circulating rt-PA from interacting with the XL-FDPs of the PE being lysed. Therefore, bolus rt-PA should be able to limit the potential of the circulating XL-FDPs to promote fibrinogenolysis. Clozel et a136found that the extent of thrombolysis was similar, in a rabbit jugular vein thrombosis model, regardless of whether the same dose of t-PA was administered as a bolus or as a continuous 4-hour infusion. Even during continuous infusion of t-PA, the rate of lysis decreased continuously with time. Therefore, t-PA infused as a bolus appears to be more efficient than t-PA infused for 4 hours. It is probably the concentration of active t-PA bound on the clot that determines the rate of lysis because fibrin binding sites for t-PA are not accessible to continuously infused t-PA after the initial t-PA binds to the clot. In a canine model using copper coils in the jugular and femoral veins, Kanamasa et aP7 demonstrated that rt-PA (1 mg/kg) administered over 30 minutes is less likely to lyse older thrombus than rt-PA administered over 3 hours. Hemostatic thrombi are likely to be older than thrombi causing acute PE. Therefore, the probability of serious bleeding may be diminished by bolus thrombolysis that allows lysis of fresh thrombus without dissolution of older hemostatic plugs. Prewitt’s group has used a canine model of pulmonary embolization with radioactive autologous clot. Prewitt’s group found that the rate of thrombolysis is markedly increased with a B-minute rt-PA infusion compared with a 90minute infusion, although the total clot lysis was similar in both groups of dogs (Fig 9).38 However, they found in a subsequent study that a 15minute rt-PA infusion caused more thrombolysis than a 5-minute infusion.39 This latter study suggests an upper limit to the dose-thrombolytic rate relation with rt-PA. In an even more recent study,40 Prewitt et al found that a Sminute infusion of 2 m&g of rt-PA did not cause significantly more clot lysis than a 15-minute infusion of 1 mg/kg of rt-PA. Thus, a bolus of rt-PA appears to be a very promising treatment strategy for patients with PE. However, its safety and efficacy has not been tested in a randomized controlled trial

SAMUEL

2. GOLOHABER

50-

40.B 3 5 u Ii g a

ao-

20.

lo-

-

I:1 HEPARIN

r’PA15

ft"Ago

Treatment Fig 9. The percent clot lysis achieved with heparin versus a 15-minute r&PA infusion (rtPA,,) versus a go-minute r&PA infusion (rt-PAJ in a canine model of PE. (Reprinted with permission.‘)

against a standard Food and Drug Administration (FDA) approved regimen for PE thrombolysis. Furthermore, use of bolus rt-PA does not confer a guarantee of protection against major bleeding complications. For example, in a trial of rt-PA administered as a 50-mg single bolus over 2 minutes to 20 patients with myocardial infarction, one patient died due to an intracranial hemorrhage 48 hours after the rt-PA bolus injection:’ Nevertheless, bolus thrombolysis for PE warrants intensive investigation with randomized clinical trials. Recently, Levine et al published a clinical study of PE patients” which suggests that weightadjusted bolus rt-PA can achieve comparable efficacy (assessed by pulmonary reperfusion on pre- and post-treatment perfusion lung scans) to the efficacy we achieved in our prior rt-PA versus UK trial” and to the pulmonary reperfusion observed in UPET.7 Fifty-eight patients with acute PE were randomized either to rt-PA (0.6 m&g ideal body weight) as a bolus over 2 minutes or to placebo. Continuous intravenous heparin therapy was interrupted only for the duration of the study drug infusion. At 24 hours, the mean relative improvement in the baseline perfusion lung scan defect was 37.0% in rt-PA treated patients compared with 18.8% in the placebo group (P = .017). There were no major bleeds in either group. For patients who re-

PULMONARY

EMBOLISM

123

THROMBOLYSIS

right ventricle. Dramatic clinical improvement was noted beginning 30 minutes after the start of the infusion. On the following day, the angiogram was repeated and marked radiological improvement was verified. There was no acute bleeding during or immediately after the rt-PA infusion. In a subsequent randomized controlled trial, peripheral intravenous and local pulmonary arterial infusion of rt-PA were compared among patients with angiographically documented PE.45 Both routes of administration caused similar rates of lysis, bleeding, and induction of a systemic lytic state. Therefore, locally delivered rt-PA appears to confer no advantage over peripheral administration of the drug. One published study has compared rt-PA plus heparin versus heparin alone, using preand post-treatment pulmonary angiograms as the primary end point. It4 was a pilot study at the six hospitals that had participated in PIOPED (Prospective Investigation of Pulmonary Embolism Diagnosis). The initial study design had planned for 50 patients but recruitment lagged and the trial was stopped after 13 patients were enrolled. Among these 13 patients, 9 received rt-PA (in two different dosing regi-

ceived rt-PA, there was an approximate onethird decrease from the baseline fibrinogen level at 30 minutes. THROMBOLYSIS

WITH TISSUE ACTIVATOR

PLASMINOGEN

Thrombolysis for PE is not routine, even though the FDA approved UK and SK for this purpose in 1977. Although many physicians continue to regard PE as a benign condition that rarely causes death or morbidity, the most important reason for circumventing thrombolysis has been its perceived inconvenience coupled with the fear of major bleeding complications. However, during the past decade, the successful use of rt-PA in myocardial infarction treatment reawakened interest in PE thrombolysis (Table 8). In 1985, Bounameaux and coinvestigators44 published the first case report of rt-PA therapy for PE. The patient was a 63-year-old man who had undergone a renal transplantation 5 weeks previously and who presented to the hospital 1 hour after the sudden onset of dyspnea. Pulmonary angiography showed massive saddle embolism. The patient received 30 mg of rt-PA over 90 minutes through a catheter placed in the Table

8. Selected

Trials

of t-t-PA Thrombolysis Findings

Investigation

Case

report

Bounameaux Case series Goldhaber

et al (1985)44 et al PE trial

rt-PA

no. 1

(1986)Randomized Verstraete

47 patients lysis

trial: Optimal et al (1988)‘”

route

30 mg190

to administer Local

receive

within

Trials: rt-PA v heparin investigators (1990)*

rt-PA

r-t-PA pulmonary

2 (1991)4’

Levine

et al (1990)“2

Randomized Goldhaber

trials: rt-PA v urokinase et al PE trial no. 2

(1988)”

European Group

50-90

arterial

mg/2-6

infusion

via a peripheral

40 mg/40

(N = 9); one PAIMS

r&PA

a patient

Study

h and

massive 94%

PE

have

angiographically

documented

clot

of rt-PA

min or 80 mg/90 rt-PA

treated

is neither

safer

nor more

effective

than

r&PA

min improves

patient

only

has major

slightly

GI bleeding;

the follow-up

angiogram

heparin-alone-treated

at 2 h patients

(N = 4) have no angiographic rt-PA 100 mg/2 h plus heparin

improvement v heparin-alone;

58 patients randomized: rt-PA tive improvement in perfusion

(0.6 mglkgl2 min) v heparin; on lung scans, 37% mean m-PA) v 19% (heparin) (P = .017); no major bleeding

45 patients

randomized

(N = 5), hematuria fibrinogen levels Results are known

ad-

vein

to &PA

100 mgi2

U/lb/h for up to 24 h; at 2 h, 82% 23 UK patients required premature

Cooperative for PE@

with

6h

ministered Randomized PIOPED

min resuscitates

results

h v UK 2,000

are known

U/lb

bolus

but not Yet published

followed

&PA and 48% UK patients had angiographic termination of infusion because of groin

(N = 2). or hematemesis or improvement in lung but not Yet published

(N = 1); there was no difference scans between the two treatment

rela-

by 2,000 lysis; bleeding in plasma groups

8 of

124

SAMUEL

mens--40 mg over 40 minutes or 80 mg over 90 minutes) and 4 received placebo. At 2 hours after initiation of therapy, only minor improvement was observed in the rt-PA-treated patients, one of whom suffered massive gastrointestinal bleeding that required transfusion with eight units of packed red blood cells. The four heparin-treated patients did not demonstrate angiographic improvement. The major bleeding complications described in this study underscore the necessity for careful patient selection. It is possible that shorter infusion times may lead to more effective and safer thrombolytic regimens. The second randomized trial is known as PAIMS 2 (Plasminogen Activator Italian Multicenter Study 2) and compared rt-PA plus heparin versus heparin alone for treatment of patients with massive PE.4’ The r&PA dose was 100 mg over 2 hours. Entry in this trial required baseline pulmonary angiography. The principal end point was improvement as judged by comparing the baseline angiogram with an angiogram obtained 2 hours after initiation of the Table Completed PE trial

9. PE Trials

assigned therapy. Secondary end points included comparisons of pre- and post-treatment perfusion lung scans, pulmonary hemodynamits, oxygenation, as well as evaluation of coagulation parameters. TRIALS CONDUCTED BY OUR VENOUS THROMBOEMBOLISM RESEARCH GROUP

For PE management our initial objective is to identify effective and safe thrombolytic regimens that can be used in subsequent trials to compare thrombolysis followed by heparin with heparin alone. To help achieve this objective, our multicenter Venous Thromboembolism Research Group has completed four clinical PE trials and has just started a fifth trial (Table 9). PE Trial No. 1 This was an open-label study of 47 patients with angiographically documented PE that showed that 50 to 90 mg of rt-PA administered over 2 to 6 hours caused clot lysis in 94% of cases (Fig 1O).“8-5”All patients received 50 mg of rt-PA over 2 hours, followed immediately by a

Undertaken

By Our Research

Group

Trials no. 1

An open-label study sary, 6 h angiograms additional

40 mg/4

of r&PA among patients with after the initiation of therapy. h. In all our trials,

angiographically proven The dose was 50 mg/2

the lytic agents

monary artery catheter. Two patients had and one patient had mediastinal tamponade discharged home uneventfully. PE trial

2. GOLDHABER

are administered

PE that assessed h and, if significant

through

major bleeding complications. 8 d after CABG. Both patients

efficacy with 2 h and, if necesclot lysis had not occurred, an

a peripheral

One patient had their

vein

rather

had bleeding from bleeding controlled

than

through

an ovarian surgically

no. 2

A randomized [if lysis occurred] were improvement bleeding-related PE trial no. 3

controlled trial of rt-PA (100 or 24 h) among PE patients on the 2 h angiogram complications. trial

of r&PA

mgJ2 h) v urokinase with baseline lung

and

(100

24 h lung

scan.

mg/2 h) v urokinase

(2,000 U/lb as a bolus scans end pulmonary

No patient

had intracranial

(l,OOO,OOO U as a botus

followed by 2,000 U/lb/h angiograms. The principal bleeding

over

and

no patient

A randomized

controlled

as a continuous pal end points

infusion over 110 min) among PE patients with baseline lung scans and pulmonary angiograms. of this study are improvement on the 2 h angiogram and 24 h lung scan. Results not yet published.

PE trial

a pulcancer and were

10 min followed

for either 2h end points died

of

by 2.000.000 The princi-

no. 4

A randomized controlled trial of t-t-PA (100 mg12 h) v heparin lation-perfusion lung scans or positive pulmonary angiograms. celerates improvement in right ventricular function compared sults are being Planned Trial PE trial no. 5 A randomized mg) among

among PE patients with either baseline high probabilityventiThe objective of the trial is to determine whether r&PA acwith heparin, as assessed by serial echocardiography. Re-

analyzed.

controlled PE patients

double-blinded trial of rt-PA (100 with either baseline high probability

grams. The objective of the trial is to determine the FDA-approved dose of 100 mg/2 h. Centers

mg12 h) v bolus ventilation-perfusion

r&PA

whether bolus rt-PA is associated from the United States, Canada,

(0.6 mg/kg/15 min-maximum dose 50 lung scens or positive pulmonary angiowith fewer and Italy will

bleeding participate.

complications

than

U

PULMONARY

EMBOLISM

50

125

THROMBOLYSIS

mg rt-PA

via

peripheral

IV

I 2 hours 4 PAgram repeated

Significant Study

clot

J lysis

I No

+ terminates.

significant

clot + 40

Additional

lysls

mg H-PA

I 4 hours pGiG+zq Study Fig 10. Study protocol we used rt-PA. (Reprinted

for our initial PE trial with permission.“)

terminates. no. 1 in which

research angiogram (Fig 11A and B). If clot lysis had not occurred, as judged by the investigator at the time of the angiogram, an additional 40 mg of rt-PA was administered over the subsequent 4 hours and was followed immediately by a third angiogram. Two thirds of the patients received more than 2 hours of rt-PA. However, during the third and subsequent hours of rt-PA therapy, an increased frequency of bleeding, particularly at the femoral vein puncture site used for pulmonary angiography, caused us to

Fig 11. (A) A large peripheral vein, there with permission.q)

shorten the duration and increase the &PA dose in our subsequent trials. Two of our 47 r&PA-treated patients had bleeding problems that required surgical intervention: mediastinal tamponade 8 days after coronary artery bypass grafting and pelvic hemorrhage from a newly diagnosed ovarian carcinoma. Both patients subsequently did well and were discharged home uneventfully. Clot lysis was graded as moderate or marked in 83% and slight in an additional 11%. Among patients with pulmonary artery hypertension, the pulmonary artery pressures decreased during the acute treatment period from 43/17 (27) to 311’13 (19) mm Hg, without any change in systemic arterial pressure. Hemodynamic and angiographic improvement was accompanied by recovery in pulmonary perf&ionsl and right ventricular function. One day after rt-PA, the perfusion defect score for the 19 patients who had follow-up lung scans improved from 0.37 at baseline to 0.16 (a 57% increase in perfusion), using a new semiquantitative scoring system that integrates data from all six views of the perfusion scan. We performed Doppler echocardiography on 7 patients with PE before and after they re-

embolus is present in the right pulmonary artery (arrowhead). is pronounced resolution with only a small amount of residual

(B) After thrombus

a Z-hour infusion of r&PA through in segmental branches. (Reprinted

a

126

SAMUEL

2. GOLDHABER

Fig 12. Subcostaltwo-dimensional images at end diastole in a PE patient from our PE trial no. 1 who presented with syncope and “heart failure.” Before r&PA (A), the right ventricle (RV) is markedly enlarged and the leftventricular (LV) diameter is reduced. After r&PA (E), a remarkable decrease in RV size and a corresponding increase in LV size are apparent. RA, right atrium; SEP. septum; PW. posterior wall. (Reprinted with permission from the American College of CardiolwY.5zl

ceived rt-PA.52 Within a day of treatment, the right ventricular end-diastolic diameter decreased from an average of 3.9 cm to 2.0 cm (Fig 12). Right ventricular wall motion (initially graded as mildly, moderately, or severely hypokinetic in 1, 2, and 4 patients, respectively) normalized in 5 and improved to mild hypokinesis in 2. Tricuspid regurgitation was present before lytic therapy in 6 patients, but was detected after the completion of lytic therapy in only 2 patients and had disappeared by restudy 5 days later in 1 of these 2 patients. The early reversal of the hallmarks of right heart failureright ventricular dysfunction, right ventricular dilatation, and tricuspid regurgitation-suggests that thrombolytic agents might reduce the mortality from acute PE. PE Trial No. 2 This was a randomized trial comparing 100 mg of rt-PA over 2 hours versus 2,000 U/lb of UK as a bolus followed by 2,000 U/lb/h for up to 24 hours.43 The principal end points were improvement on the 2-hour angiogram and 24hour lung scan compared with the baseline studies (Fig 13). All 45 patients received the full dose of rt-PA, but UK infusions were terminated prematurely in 9 of 23 patients because of allergy in 1 and uncontrollable bleeding in 8. By 2 hours, 82% of rt-PA-treated patients showed clot lysis compared with 48% of UK-treated patients (P = .OOOS) (Fig 14). Thrombolysis at angiography was associated with a return of elevated pulmonary arterial pressures toward

normal (Fig 15). Thus, in the dosing regimens used, rt-PA was more rapid and safer than UK. However, at 24 hours there was no difference in scintigraphic improvement between rt-PA and UK patients (Fig 16). Furthermore, at 2 and 24 hours after initiation of thrombolysis, the fibrinogen levels were similar in both treatment groups (Fig 17). PE Trial No. 3 PE trial no. 3 has compressed the 24-hour dose of UK to make it more comparable to the high concentration/short infusion period that was used for rt-PA. The novel UK dose being tested is 3,000,OOO U per 2 hours, with the first l,OOO,OOOU given as a bolus over 10 minutes. A dose of high molecular weight UK (not available in the United States) similar to the UK dose in PE trial no. 3 was found to be effective and safe in the German Activator Urokinase Study of acute myocardial infarction (MI) patients (Fig 1Qs3 PE Trial No. 4 Unlike the prior studies, PE trial no. 4 is a randomized trial that compares rt-PA followed by heparin versus heparin alone. The central hypothesis is that rt-PA followed by heparin accelerates improvement in right ventricular function compared with heparin alone. The rt-PA group receives 100 mg of rt-PA as a continuous infusion over 2 hours, followed by heparin when the thrombin time or partial thromboplastin time (PTT) is less than twice

PULMONARY

EMBOLISM

127

THROMBOLYSIS

Time 0 hours

2 hours

Fig 13.

Study

protocol

;;~;~th~e~~~S~S~

for the

me-

24 hours

the upper limit of normal. All patients undergo serial Doppler echocardiography at 0, 3, and 24 hours after initiation of treatment, in addition to pre- and post-treatment perfusion lung scans. PE Trial No. 5 PE trial no. 5 compares 100 mg of rt-PA as a continuous infusion over 2 hours with a weightadjusted bolus of rt-PA, 0.6 mg/kg with a maximum dose of 50 mg, administered over 15 minutes. The hypothesis is that a smaller bolus of rt-PA may be safer but equally effective compared with a larger dose administered over several hours.35a We have observed in our previous trials that shorter thrombolytic infusion

d-PA

times of both rt-PA and of UK have been accompanied by fewer bleeding complications. Our Venous Thromboembolism Research Group plans to continue to search for an optimal thrombolytic regimen. Eventually, we hope to compare this optimally safe and effective regimen followed by anticoagulation with anticoagulation alone for PE treatment. Our objective is to determine whether routine use of thrombolysis will reduce the frequency of adverse clinical outcomes. In this future trial, which might encompass as many as 400 patients, the principal end point might be a combination of death, recurrent PE, persistent DVT, major hemorrhage before hospital discharge, or failure to

UK

None 39% Fig 14. Angiographic lysis after 2 hours of therapy: r&PA Y UK IN = 45). Based on our PE trial no. 2. (Reprinted with permission.-)

126

SAMUEL

Z. GOLDHABER

50 40

PA Pressure

30 Fig 15. Among rt-PA patients, pulmonary artery pressures decreased from 50/20 (mean 31) mm Hg to 39/15 (mean 24) mm Hg after 2 hours of therapy. UK patients had no change in pulmonary artery pressures, and neither group had a significant change in systemic arterial pressure after 2 hours of treatment. n , r&PA; q , UK. (Reprinted with permission.‘)

20 10 0 PRE TREATMENT return to prehospitalization functional status within 1 month due to PE. We believe that expensive and potentially risky therapy for PE will not gain widespread application unless properly conducted clinical trials are carried out. Fortunately, the dedication and enthusiasm of investigators at the network of centers .50 .40

1

STATUS

participating in PE trial nos. l-5 make this future trial feasible. CURRENT

CLINICAL SETTING THROMBOLYSIS

FOR

For patients with high clinical suspicion for PE and high probability ventilation-perfusion lung scans, one can usually proceed with thrombolytic therapy even when the diagnosis has not been confirmed by angiography. However, scans may be misleading and falsely positive in the 500

.30 .20 .lO 0I

I

PRE TREATMENT

POST STATUS

Fig 16. Proportion of nonperfused lung tissue after 24 hours of therapy: rt-PA v UK. Based on our PE trial no. 2. There is no significant difference in perfusion lung scans before therapy or after 24 hours of therapy between the two drug treatment groups. The proportion of nonperfused lung among rt-PA patients decreased from 41% to 29% and among UK patients decreased from 42% to 30%. n , r-t-PA; 0, UK. (Reprinted with permissionw)

400

300 Fibrinogen 200

100

0

POST POST 2 hours 24 hours TREATMENT STATUS

Fig 17. Plasma fibrinogen levels after rt-PA v UK therapy in our PE trial no. 2. With the doses used, there was no difference in fibrin specificity between &PA and UK. The average plasma fibrinogen levels (mg/dL) wara as follows: pretreatment, rt-PA 409 Y UK 394; 2 hours, N-PA 226 v UK 239; 24 hours, rt-PA 269 v UK 236. n , rt-PA; 0, UK. (Reprinted with permission.?

PULMONARY

EMBOLISM

129

THROMBOLYSIS

[Lung IPE

Scan 1 + on PAgram 1

Time

Fig 18. Protocol PE trial. For more refer to text.

for our third information

0 hours

IRandomize

2 hours

1 Repeat

to rt-PA

PAgram

1

1

24 hours

presence of asthma, chronic pulmonary disease, lung cancer, or prior PE. In these circumstances, further confirmation of the diagnosis with angiography is often warranted. At our institution, angiography is readily available and frequently performed. In hemodynamically stable patients, we usually confirm the diagnosis of PE with angiography prior to administering thrombolytic therapy. If the patient has been admitted in the evening or at night, we defer angiography until the next morning and empirically initiate heparin. (For patients who are hemorrhaging, urgent angiography is required to place an inferior vena caval filter among those in whom the diagnosis of PE is confirmed.) If we feel a patient has suffered massive PE, we continue heparin until the angiogram begins. Otherwise, we hold heparin for several hours prior to angiography. We perform the procedure with a Cordis sheath and side arm (for blood sampling) that is usually placed in the right femoral vein with a single-wall (rather than double-wall) percutaneous puncture of the vessel. We always use a side-hole catheter with a pigtail configuration rather than one with a straight end, in order to prevent inadvertent perforation of the right ventricle.54 In addition, we use low osmolar contrasts5 rather than conventional angiographic

dye. Low-osmolar contrast agents cost more than conventional dye but virtually abolish the heat sensation and urge to cough, thereby enhancing patient safety and comfort. Therefore, angiographic views almost never have to be repeated because of patient coughing and consequent blurring of the images. The clinician can now choose from among three FDA-approved regimens for PE thrombolysis (Table 10). UK has been used in clinical trials for more than 20 years and is considered the “gold standard” against which newer thrombolytic agents must be compared. The rt-PA regimen appears to act most rapidly and is the simplest and most convenient regimen to administer due to the short 2-hour dosing regimen. It is also free of the fever, chills, and flushing that usually characterize a prolonged infusion of SK and, on rare occasions, accompany UK. We Table

10.

Streptokinase Urokinase

rt-PA

FDA-Approved 250,000

Thrombolytic

Regimens

IU as a loading

dose

over

for PE 30 min

followed by 100,000 U/h for 24 h 2,000 IU/lb as a loading dose over 10 min followed by 2.000 IU/lb/h for 12 to 24h 100 mg as a continuous peripheral venous infusion administered

over

intra2h

130

SAMUEL

await the publication of PE trial no. 3 which tests a new 2-hour dosing regimen of UK. None of the thrombolytic regimens use concomitant heparin therapy, an important difference from the usual approach to thrombolysis in myocardial infarction (Table 11). All three regimens use Iixed doses of thrombolytic agents. Therefore, there is no need to obtain laboratory tests during the thrombolytic infusion because no dosage adjustments are made. After establishing the diagnosis of PE, we administer thrombolysis through a peripheral vein. At the conclusion of the thrombolytic infusion, either a P’IT or thrombin time (not contaminated by heparin) should be obtained. This laboratory value is usually less than twice the upper limit of normal. Under these circumstances, heparin therapy can be initiated (or resumed) as a continuous intravenous infusion without a loading dose. If the post thrombolysis PTT or thrombin time exceeds twice the upper limit of normal, the test should be repeated every 4 hours until it declines into the range for which heparin therapy is safe. We leave the Cordis sheath in place until the next morning. The heparin infusion should be discontinued for several hours before removing the sheath, and heparin should be resumed without a bolus after adequate hemostasis is obtained at the vessel puncture site. Our target PTT for heparin is 1.5 to 2.5 times the upper limit of normal. That evening, after the patient has been adequately reheparinized, we initiate warfarin in a Table 1. Begin

heparin

therapy

if PE is strongly

2. Confirm the diagnosis with pulmonary tion/perfusion lung scan that is high ease, prior PE, or lung cancer. 3. Pulmonary patient exclude 4. Insert

angiography cannot tolerate patients from

the pulmonary

and or fails receiving angiography

initiation

11.

Practical

2. GOLDHABER

dose of 10 mg. Our target prothrombin time (PT) for warfarin is 16 to 20 seconds. Even if the PT increases quickly into the target range, we overlap heparin and warfarin for a minimum of 5 days. How often do patients have contraindications to PE thrombolysis? To address this question, we coordinated a group of 44 institutions across the United States that surveyed a l-year period of their hospitalized patients with PE confirmed by high probability lung scan or pulmonary angiography. Our study identified 2,539 patients with PE. Overall, 1,345 (53%) would have been acceptable for treatment with thrombolysis,55 even after excluding patients with the usual contraindications to this therapy (Table 12). Thus, thrombolysis appears to have potential widespread use as a therapeutic strategy among PE patients. A number of myths regarding thrombolytic therapy need to be addressed (Table 13). There is no evidence to support the contention that most patients with massive PE die before reaching the hospital. Emergency medical services transport many patients with massive PE to the emergency department. The challenge lies in prompt diagnosis and treatment. Sudden collapse or syncope is a hallmark of massive PE. Such patients, at times, are incorrectly triaged to receive either monitoring for heart block or a head CT scan for a possible seizure disorder. If a patient is believed to have massive PE that warrants emergency embolectomy, the alterna-

Aspects

of PE Thrombolysis

suspected. angiography unless there is both high clinical probability for PE. Scans may be falsely positive of thrombolytic

therapy

are most

safely

suspicion and a technically in the presence of asthma,

accomplished

during

“daylight

heparin. Remember that there is a 14-day “window” for administration thrombolytic therapy on the basis of “old age” alone. catheter

through

a Cordis

sheath

that

has a side

arm for obtaining

excellent chronic hours”

of PE thrombolysis. blood

samples.

ventilalung dis-

unless

the Do not

The right

femoral vein is usually the most convenient access route. Occasionally, in the presence of massive thrombus in the inferior vena cava (IVC) or presence of an IVC filter, cannulation of the brachial vein will be necessary. Remove the catheter after the angiogram confirms the presence of PE, but leave the sheath in place until the next day. 5. Choose an FDA-approved thrombolytic regimen (see Table 10). No coagulation tests are necessary during thrombolysis because the doses are fixed. Minimize physical handling of the patient and try not to draw any blood during the infusion of thrombolytic therapy. 6. Do not administer concomitant heparin therapy. After thrombolysis. resume partial thromboplastin time is less than twice the upper limit of normal. 7. Initiate warfarin on the day after the angiogram. Overlap heparin and warfarin

heparin

without

for a minimum

a bolus

when

of 5 days.

the thrombin

time

or

PULMONARY

Table

12.

EMBOLISM

Frequency Patients

131

THROMBOLYSIS

of Exclusion With PE-TIPE

Exclusion

Criteria Patient

for Thrombolysis Survey

Risk of blood loss Internal or significant

bleeding

within

surgery

or organ

biopsy

than 12 to 24 hours Easy to administer

10d

findings

on liver

or intraspinal endocarditis

Severe arterial Special risks Open heart Pregnancy Survival Expected

410 (16.2)

Intensive

178 (7.0)

tests

surgery

234 (9.2) 148 (5.8)

disease

226 (8.9)

within

6 (0.2) 63 (2.5)

2 wk

7 (0.3) < 1 mo CNS,

116 (4.6) central

nervous

accident; TIA, transient with permissions’

ischemic

system;

CVA.

cere-

attack.

tive of thrombolysis should at least be considered. When PE thrombolysis is administered infrequently, it tends to become a “big production” that overuses precious hospital resources. We have seen patients receive multiple serial tests of PT, PTT, thrombin time, fibrinogen and fibrin(ogen) degradation products. As pointed out earlier (Table 1l), such a vast overuse of the hospital laboratory is expensive and unjustified. Similarly, patients receiving PE thrombolysis do not require an intensive care unit bed unless they have some associated complication such as dependency on a mechanical respirator. At McMaster University, during their rt-PA trial:’ the 2-minute rt-PA bolus was administered on the general medical ward, without any special monitoring. We tend to put our PE thrombolysis patients in an intermediate care unit so that Table Most patients pital

13. with

Biggest massive

Myths

in PE Thrombolysis

PE die before

reaching

Thrombolytic therapy requires frequent laboratorY toring and an intensive care unit bed. Most patients with PE cannot tolerate thrombolytic

the hosmonitherapy.

tests care

are other ventilator) *See

9 (0.4) 7 (0.3)

retinopathy surgery

Abbreviations: brovascular Adapted

function

hypertension

Hemorrhagic

No laboratory doses)

283 (11.2) 165 (6.5)

CVA or TIA Intracranial or intraspinal Intracranial Infective

255 (10.1) within

Hematocrit of