Indications for Acute Pulmonary Embolism - Europe PMC

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thromboembolic pulmonary hypertension is unknown, there is anatomic and ... pulmonary embolism, but there is emerging evidence that treatment of acute.
Review of the Literature

John A. Dieck, MD James J. Ferguson III, MD

Key words: Pulmonary embolism; thrombolytic therapy; pulmonary hypertension; streptokinase; urokinase; tissue plasminogen activator; review From: The Division of Adult Cardiology, Texas Heart Institute and St. Luke's Episcopal Hospital, and Baylor College of Medicine, Houston, Texas Address for reprints: John A. Dieck, MD, Mail Code 1-102, Division of Adult Cardiology, Texas Heart Institute, 6720 Bertner, Houston, TX 77030

Texas Heart Instituteioumal

Indications for Thrombolytic Therapy in Acute Pulmonary Embolism Pulmonary thromboembolism is commonly misdiagnosed and is associated with significant morbidity and mortality both in the early and late stages. A major cause of late morbidity is chronic pulmonary hypertension. Although the incidence of chronic thromboembolic pulmonary hypertension is unknown, there is anatomic and physiologic evidence that it is responsible for a significant degree of the late morbidity and mortality following acute pulmonary embolism. In the absence of underlying cardiopulmonary disease, pulmonary artery pressure is a useful indicator of the severity of acute pulmonary embolism and of the patient's prognosis. Thrombolytic agents accelerate the lysis of the thromboemboli, offer an excellent alternative to emergency embolectomy, and are likely to decrease the incidence of chronic pulmonaryhypertension. All currently available agents have been shown to be effective and have similarbleeding-complication profiles. In this review, we discuss the natural history andpathophysiologyof pulmonary thromboembolic disease, as wellas applications of thrombolytic therapyin the treatment of acute pulmonary embolism. (Texas Heart Institute Journal 1989;16:19-26)

A cute pulmonary embolism is associated with both early and late morbidity and mortality from resultant cardiopulmonary disease. Traditionally, anticoagulants such as heparin have been used in the treatment of pulmonary embolism, but there is emerging evidence that treatment of acute pulmonary embolism with thrombolytic agents decreases both early and late sequelae. Increasing experience with thrombolytic therapy in acute myocardial infarction and the development of recombinant tissue plasminogen activator (tPA) has led to an increased interest in this subject.1-5 The precise role of thrombolytic therapy in the treatment of pulmonary embolism has not been well delineated. The presence of shock or severe hemodynamic embarrassment is generally well accepted as an indication for thrombolytic therapy,' although some believe embolectomy is the therapy of choice when these complications exist or when pharmacologic therapy cannot be applied.6 Our purpose in this review is to analyze the natural history and pathophysiology of pulmonary thromboembolism, to discuss the application of thrombolytic agents used in treatment of this condition, and to formulate rational indications for the use of such agents in acute pulmonary embolism.

Natural History The exact incidence of pulmonary embolic disease and its associated mortality are somewhat difficult to ascertain. A review of the world literature by Laissue and associates7 in 1984 revealed that pulmonary embolism was listed as the cause of death in one-third of cases wherein a massive pulmonary embolus was found at autopsy.8 Less critical pulmonary emboli were found at postmortem examination 3 times more frequently than was stated on death certificates. In 1975, Dalen and Alpert9 estimated the occurrence of 630,000 cases per year; of those patients, 11% died within the 1st hour. Of the remaining cases, they estimated that 30% would be appropriately diagnosed and that this group would carry an 8% mortality. The mortality for untreated pulmonary embolism was 30%. The most common sources of emboli to the pulmonary circulation are the pelvic or deep thigh veins.'0 Other possible sources of thromboemboli include congenital heart disease,""2 heart failure,'3 and in situ thrombosis.' Deep venous thrombosis Thrombolysis in Pulmonary Embolism

19

of the calf without proximal propagation leading to pulmonary embolism has been reported,j5 but is quite uncommon. 16-18 There are many causes of thrombogenesis, including conditions associated with venous stasis, endothelial damage, and hypercoagulability.19 Thrombogenesis may also be seen in patients recovering from certain surgical procedures and from acute myocardial infarction.20 Pulmonary embolism is followed by endogenous plasmin activation and clot lysis.1 The rate of recurrent embolism following an initial embolus is 30% to 50%, depending on the source of the emboli.92021 Patients who do not receive anticoagulants have a high risk of developing recurrent emboli, either clinical or subclinical, and progressive dyspnea with pulmonary hypertension. It is estimated that 17% of those will eventually develop right heart failure.22 Additional data show that intravenously administered heparin decreases the mortality of patients with acute pulmonary embolism.23 These patients are now routinely treated with anticoagulants because of their short- and long-term benefits. In some cases, however, anticoagulation is contraindicated. Conventional anticoagulant therapy (i.e., heparin) decreases the incidence of recurrent pulmonary emboli. Emboli that have already occurred, however, are not affected by heparin. Therefore, patients treated with anticoagulants alone do not always regain pulmonary blood flow.8 In 1 study, 65% of patients treated with heparin had complete restoration of blood flow, 23% had incomplete restoration, and 12% had minimal restoration. Postmortem studies of cases in which there was minimal restoration often showed recurrent or persistent emboli, and 1 patient apparently died of cor pulmonale.24 The size of the embolus,21'25'26 angiographic evidence of arterial obstruction versus filling defects,27 advanced patient age,28 and preexisting cardiopulmonary disease262930 are all factors associated with impaired normalization of pulmonary blood flow. Furthermore, angiographic and hemodynamic studies have revealed minimal improvements in heparin-treated patients 2 to 7 days after the acute event.3'32 After 3 to 4 weeks, heparin-treated patients may show clear improvement, but they are yet not normal.26 There is usually normalization of the lung scan at the end of the 6-month period following an acute episode.28 Young patients who have no underlying cardiopulmonary disease and submassive pulmonary emboli have a high rate of blood flow restoration. Patients with a previous history of heart or lung disease and those who are elderly (over 60 years of age) have a very low rate of restoration.28 The size of the embolus may also have an effect on subsequent restoration. Tow and Wagner25 studied 72 patients with varying degrees of pulmonary obstruction. They found a 67% rate of complete restoration by use of lung scanning 20

Thrombolysis in Pulmonary Embolism

in patients with less than 15% obstruction, whereas 20% of patients with a 30% to 50% obstruction of the pulmonary vasculature had complete restoration. The incidence and prevalence of pulmonary hypertension resulting from thromboembolism has not been precisely determined. Patients who are free of other cardiopulmonary disease and have a single, discrete embolic episode rarely develop chronic pulmonary hypertension. On the other hand, patients with subacute or recurrent clinical episodes of pulmonary embolism have a significant risk of developing persistent pulmonary hypertension. This risk is highest in patients with moderate pulmonary hypertension (mean pulmonary artery pressure of 25 mmHg) at initial presentation. These patients frequently develop some degree of right ventricular hypertrophy. 13 During exercise, patients who have persistently elevated pulmonary artery pressure will experience a further increase in pulmonary artery pressure that is disproportionate to the accompanying increase in cardiac output (i.e., pulmonary vascular resistance increases with exercise).23 Finally, patients with occult thromboembolic disease usually have severe pulmonary hypertension and frequently develop progressive right heart failure. Survival is usually inversely proportional to the level of pulmonary artery pressure;13 and at postmortem examination, fresh emboli are frequently documented.13 33 Therefore, it appears that cor pulmonale develops as a result of recurrent embolic episodes. The late mortality associated with pulmonary thromboembolic disease is also difficult to assess because of the frequency of underlying disease, such as neoplasia. Survival appears to be most accurately correlated with underlying cardiopulmonary status, particularly left ventricular function. Late mortality ranges from 40% to 80% in patients with congestive heart failure and from to 9% to 14% in patients with normal left ventricular function.24 3- Left ventricular failure alone may portend a poor prognosis; however, a mechanism such as impaired clot lysis may increase the morbidity and mortality associated with pulmonary embolism in patients with impaired left ventricular function.

Pathophysiology Hemodynamic compromise becomes greater with increasing degrees of pulmonary obstruction. With low levels of obstruction, there is impaired gas exchange. With greater degrees of obstruction, pulmonary hypertension and impairment of forward cardiac output may develop. Table I summarizes the physiologic abnormalities associated with various degrees of pulmonary vascular obstruction in patients with no underlying cardiopulmonary disease. V'olu me 16, Nu m ber 11, 1989

TABLE 1. Pathophysiologic Correlates of Right Ventricular Outflow Obstruction in Patients without Underlying Cardiopulmonary Disease Physiologic Abnormality

Percentage of Outflow Obstruction

Widened A-a gradient

10

Pulmonary hypertension

30

Compromised cardiac output.

50

Shock, cardiovascular collapse

75

A-a gradient = arterial alveolar oxygen tension gradient

Abnormalities in gas exchange are sensitive, but not specific, indicators of pulmonary embolism.35 Arterial hypoxemia, the most common clinical manifestation of pulmonary vascular obstruction, occurs in as many as 95% of patients with acute pulmonary embolism.36 Virtually all patients with pulmonary embolism will have impaired gas exchange with an alveolar-arterial oxygen gradient that is larger than expected.36&38 This is associated with at least a 10% to 15% vascular obstruction. The mechanisms for this impaired gas exchange include ventilation-perfusion inequality,39-44 vasoconstriction mediated by neurohumoral reflexes,84546 impaired gas diffusion,j and shunting.39 The shunting, in association with pulmonary embolism, may be extrapulmonary (i.e., right atrium to left atrium through a patent foramen ovale), or intrapulmonary (i.e., secondary to atelectasis or pulmonary edema).38394849 If pulmonary edema is present, it is usually the result of impaired microvascular permeabilityf or left ventricular failure. A decrease in the mixed venous oxygen tension together with ventilation-perfusion abnormalities leads to a lower end-capillary oxygen tension and a largerthan-expected alveolar-arterial gradient.44 Patients with chronic thromboembolic disease have also been shown to have a restrictive ventilatory pattern.505' Moderate pulmonary hypertension occurs with a 30% degree of right ventricular outflow obstruction. Patients without underlying cardiopulmonary disease will usually develop a maximum mean pulmonary arterial pressure of 40 mmHg. Patients with higher pressures are likely to have underlying cardiopulmonary or recurrent thromboembolic disease.36 Underlying cardiopulmonary diseases include ischemic and valvular heart disease; dilated, restrictive, and hypertrophic cardiomyopathy; obstructive lung disease; primary pulmonary hypertension; and chronic thromboembolic pulmonary hypertension: all ofwhich may contribute to elevated pulmonary arterial pressures. Furthermore, for a given degree of vascular obTexas Heail Instittitejourtial

struction, patients with underlying cardiopulmonary disease tend to develop disproportionately higher pressures than do patients without underlying disease.51'52 Pulmonary hypertension in thromboembolic disease results from hypoxemia and vasoconstriction mediated by neurohumoral reflexes and is the consequence of a mechanically decreased vascular crosssectional area.45465356 Elevated right atrial pressure and acute tricuspid regurgitation are less sensitivebut specific-indicators for right ventricular outflow obstruction, and correlate well with the degree of obstruction.36 The presence of either finding suggests impending right ventricular failure.5' Cardiac output, which usually rises as a response to hypoxemia5_58 and to autonomic discharge following acute pulmonary embolus,59 may be decreased in patients with a massive pulmonary embolus (i.e., vascular obstruction greater than 50%)36 or in those with underlying cardiopulmonary disease.5' Patients with circulatory collapse have evidence of right ventricular overload and failure such as elevated right atrial and right ventricular end-diastolic pressures, and increased right ventricular volumes.6' Sudden right ventricular dilatation itself can lead to decreased coronary perfusion of the right ventricle.62 Left ventricular failure (as a consequence of decreased preload) may also occur. In this setting, the septum is shifted leftward, causing a further decrease in right ventricular diastolic compliance. Acute right ventricular dilatation may also contribute to pericardial constraint6' and a pseudotamponade hemodynamic picture. Patients with vascular obstruction greater than 75% have an extremely high mortality.i63

Thrombolytic Therapy Four major randomized clinical trials have been conducted to compare the use of thrombolytic therapy with heparin in the treatment of pulmonary embolism.64-67 The largest was a national cooperative

multicenter study called the Urokinase Pulmonary Embolism Trial (UPET). This double-blinded heparin-controlled trial involved 160 patients and was carried out under the auspices of the National Heart, Lung, and Blood Institute. In UPET, as well as in the 3 smaller trials, there were marked improvements in treatment outcome when urokinase or streptokinase was used, as opposed to heparin. After 24 hours, there were improvements in vascular obstruction as noted by angiography, in pulmonary pressure, and in right ventricular end-diastolic pressure. After 1 year, normalization of pulmonary capillary blood volume was noted. In UPET, the most dramatic difference between urokinase- and heparin-treated patients (as noted by angiography at 24 hours) was seen in patients sufferThrombolysis in Pulmonary Embolism

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ing from shock. In this trial, patients were evaluated by serial lung scans. There was accelerated restoration of blood flow in all urokinase-treated patients except for those who had an embolus that was more than 48 hours old at the time of randomization. Specifically, urokinase accelerated restoration regardless of the size of the embolus, age of the patient, presence of previous cardiopulmonary disease, size of the preinfusion perfusion defect, preinfusion right atrial and pulmonary artery pressures, and preinfusion cardiac output and arterial oxygen tension.65 The 2nd phase of the national trial of thrombolytic therapy for pulmonary embolism involved a comparison of a 24-hr regimen of urokinase and a 24-hr regimen of streptokinase with the 12-hr regimen of urokinase studied in UPET. This study was entitled the Urokinase-Streptokinase Pulmonary Embolism Trial (USPET) and included 167 patients, who were randomized to the 3 treatment arms. The 12-hr regimen of urokinase produced results similar to those in Phase I of UPET, which were no different from the results obtained in the 24-hr regimen of urokinase. Although urokinase seemed to produce better results on angiography than did streptokinase, any difference between the drugs in terms of treatment outcome was small.68 Other studies have shown that streptokinase and urokinase accelerate the restoration of pulmonary blood flow (as assessed by angiography and lung scanning) in comparison with heparin.64M69-71 Leeper and colleagues72 studied 15 patients with bilateral pulmonary emboli. Full systemic heparinization was used and, in addition, streptokinase was infused selectively into 1 pulmonary artery. The streptokinase side showed marked improvement, and the side in which heparin only was infused showed minimal resolution on angiography.72 In angiographic studies, accelerated restoration of blood flow has also been shown by use of tPA.23 Intravenous and intraarterial administration of tPA are reported to be equally effective in terms of angiographic appearance.2 There is advanced improvement in pulmonary artery and right atrial pressures following thrombolytic therapy.3'20'65'69'71 In the study by Verstraete and coworkers,2 tPA reduced the mean pulmonary artery pressure from 31 mmHg to 12 mmHg 7 to 18 hours later. Pulmonary infarction may be less readily reversible as evidenced by the fact that the hemodynamic improvement following thrombolytic therapy is less dramatic if there is an infiltrate on chest radiography.65 The arterial partial pressure of oxygen and arterial alveolar oxygen gradient also respond more slowly following thrombolytic therapy.72 Sharma and associates73 studied pulmonary capillary blood volume in patients from both UPET and USPET, excluding patients with previous cardiopul22

Thrombolysis in Pulmonary Embolism

monary disease, in order to compare standard heparin therapy with thrombolytic therapy. All patients had received adequate long-term anticoagulation, and the thrombolytic-treated and heparin-treated groups were well matched for age, size of the embolus, pulmonary function, and hemoglobin. The pulmonary capillary blood volume in the heparin group (30 mL/m2 and 28 mL/m2 at 2 weeks and 1 year) was significantly lower than that of the thrombolytic group (45 mL/m2 and 49 mL/m2, respectively). (Normal capillary volume is 47 mL/m2 ± 5 mL/m2.) The difference between the 2-week and 1-year volumes in the thrombolytic group was also statistically significant. There are several possible explanations for these findings. After a pulmonary embolus, the distal pulmonary vasculature is likely to have more complete occlusion and less blood flow. Since arterial obstructions resolve more slowly than do filling defects,2 it is possible that endogenous thrombolysis is too slow to prevent pulmonary infarction at the capillary level. As the thrombus becomes organized and endothelialized,7'7' endogenous thrombolysis may be ineffective in lysing small clots in the distal pulmonary vasculature. Also, because recurrent occult thromboembolic events may result in distal obstruction and because thrombolytic therapy is more effective in clearing deep venous thromboses,758 thrombolytic therapy may decrease recurrent subclinical emboli. The importance of pulmonary capillary blood volume is not known, but it is intuitively obvious that in certain subsets of patients, the incidence of chronic pulmonary hypertension may be changed by thrombolytic agents.

Complications The major complication associated with the use of thrombolytic agents is bleeding. In UPET, bleeding was more frequent (45% vs. 27%) and more severe in the urokinase group than in the heparin group. The increased incidence of bleeding with the use of urokinase was primarily related to bleeding at the site of instrumentation; the incidence of bleeding from other sites was similar (see Table II). However, intracranial hemorrhage following thrombolytic therapy was seen in 1 patient who had suffered a stroke 1 month earlier and in another who had undergone a craniotomy 3 weeks earlier for an intracranial tumor.65 The overall incidence of intracranial hemorrhage with streptokinase or urokinase may be as high as 2%.79 Bleeding complications associated with the use of tPA have been similar to those noted with other agents.2'15 The incidence of intracranial hemorrhage in patients treated with 100 mg of tPA for acute myocardial infarction is about 0.4%. More serious probVolume 16, Number 1, 1989

TABLE Il. Combined Incidence of Bleeding Complications with the Use of Streptokinase, Urokinase, and Tissue Plasminogen Activator Site of Bleeding Instrumentation site

Percentage of Incidence 20 - 30

Gastrointestinal system

3-7

Retroperitoneal system

0.5 - 1

Urinary system

4- 7

Within cranium

0.4 - 2

lems with bleeding may be noted in post-surgical and cancer patients. Bleeding complications in postoperative patients treated with tPA range from 10% to 33%. In cancer cases, hemorrhage into large tumors has been described.4 The degree of fibrinogen depletion did not correlate directly with the risk and severity of bleeding in UPET.65 In USPET, with infusion of urokinase, fibrinogen dropped to 50% of baseline; with streptokinase, it decreased to 38% of baseline.Y0 After treatment with tPA for acute pulmonary embolism, fibrinogen levels may drop as low as 36% of baseline.2 There is some evidence that in patients treated with tPA, clinical response correlates with the degree of fibrinogenolysis.' Streptokinase use is associated with the additional risk of pyrogenicity and allergy.8' Serum sickness with leukocytoclastic vasculitis has also been reported.82.83

Indications for Thrombolytic Therapy Primarily, thrombolytic agents for treatment of pulmonary embolism should be used in patients who present in shock, in those who experience right heart failure, and in patients who have underlying cardiopulmonary disease, recurrent pulmonary emboli, or severe pulmonary hypertension. The patient who presents in shock should be treated with thrombolytic agents if satisfactory circulatory support can be established. Surgical embolectomy carries a high mortality,84 and is reserved for patients who have hypotension that is refractory to pharmacologic intervention or in whom there is a contraindication to thrombolysis. The assessment of pulmonary artery pressures is very helpful in determining the need for thrombolytic therapy. This can be measured invasively, or estimated by use of Doppler echocardiography. Patients Texas Hea?l Institutejournal

with right ventricular diastolic dysfunction and an elevated right ventricular end-diastolic pressure may develop shock, or they may die, if additional embolic episodes occur early in their hospital course. The mortality in this group of patients is high.85 They are also candidates for thrombolytic therapy if no contraindication is present. Patients with pulmonary hypertension, normal right ventricular end-diastolic pressure, and underlying cardiopulmonary disease are likely to have increased morbidity and mortality associated with pulmonary embolism and therefore are candidates for thrombolysis. In this group of patients, however, the anatomic severity of the embolus should be angiographically assessed since their symptoms and hemodynamic aberrations may be multifactorial in origin. It has been demonstrated that angiography (using either ionic or non-ionic contrast media) may be safely performed in patients with pulmonary hypertension.'6 In general, patients with greater than 25% to 30% vascular obstruction should be considered candidates for thrombolytic therapy. Patients with recurrent emboli, either clinical or occult, are at risk for subsequently developing pulmonary hypertension and should receive thrombolytic therapy. Determining appropriate treatment is difficult in a patient with an acute, single embolic episode associated with pulmonary hypertension, a normal right ventricular end-diastolic pressure, and no underlying cardiopulmonary disease. In such a case, the patient's age and the risk of recurrence must be considered. Some investigators suggest that since recurrence cannot be predicted, such patients should also be treated.87 Virtually all patients who develop sustained pulmonary hypertension have had severe pulmonary hypertension noted at presentation (mean pulmonary artery pressure of 25 to 30 mmHg). 13 Thus, these patients may be considered good candidates for thrombolysis. In cases wherein the pulmonary artery pressures are mildly to moderately elevated (mean pulmonary artery pressure of 15 to 24 mmHg), the indication for thrombolytic therapy remains controversial.

Choice of Thrombolytic Agents Thrombolytic agents currently available include urokinase, streptokinase, and tPA. Infusions of urokinase, streptokinase over 24 hours, and tPA have all been shown to be superior to heparin alone.688088 There are a limited number of studies comparing thrombolytic agents. In USPET, urokinase was shown to be slightly more effective than streptokinase, particularly in treatment of massive pulmonary emboli.68 One disadvantage of streptokinase is its association with allergic reactions; however, these are rarely fatal.f80""' Like urokinase, tPA does not cause allergic Thrombolysis in Pulmonary Embolism

23

reactions. Sufficient data are not available to compare tPA with conventional thrombolytic agents. Treatment regimens for urokinase and streptokinase are well established.65 68,80 -, The recommended regimen for urokinase is 4400 IU/kg intravenously delivered over a 10-minute period followed by 4400 IU/kg/hr for 12 hours. This infusion should be followed by anticoagulation therapy, 5 days of which should include intravenous infusion of heparin. Intrapulmonary arterial urokinase is not recommended. In a multicenter randomized trial, urokinase administered intravenously at 2000 IU/kg/hr plus heparin was no different with regard to efficacy and morbidity than was the regimen recommended above.8'9 The recommended dosage for streptokinase is 250,000 IU intravenously administered over 30 minutes followed by 100,000 IU/hr intravenously for 24 hours. The infusion may be extended to 72 hours if improvement is present but slow, or if deep venous thrombosis is present.550 Studies suggest that the regimen for tPA should be 90 to 100 mg over 6 to 7 hours.1 2'4

Future Investigations Future studies should be aimed at comparing tPA and single-chain urokinase-type plasminogen activator with the more traditional agents. Inasmuch as these are relatively fibrin-specific, they are more efficacious in older emboli and therefore may be more effective in pulmonary embolism. Furthermore, the 2 newer agents are fibrin-specific by 2 different mechanisms and may for that reason be synergistic.90 Combining streptokinase or urokinase with the newer agents also merits further investigation. Currently, there is interest in combining and comparing urokinase and tPA in treatment of acute myocardial infarction.91

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embolism. Circulation 1988;77:353-60. Come PC, Kim D, Parker JA, et al. Early reversal of right ventricular dysfunction in patients with acute pulmonary embolism after treatment with intravenous tissue plasminogen activator. J Am Coll Cardiol 1987;10:971-8. 4. Goldhaber SZ, Markis JE, Meyerovitz MF, et al. Acute pulmonary embolism treated with tissue plasminogen activator. Lancet 1986;2:886-8. 5. Bounameaux H, Vermylen J, Collen D. Thrombolytic treatment with recombinant tissue-type plasminogen activator in a patient with massive pulmonary embolism. Ann Intern Med 1985;103:64-5. 3.

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1962;33:738-52.

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16, Number 1, 1989