Arthur A. Sasahara

A Comparison of Recombinant Urokinase with Vascular Surgery as Initial Treatment for Acute Arterial Occlusion of the Legs

BACKGROUND Recent controlled trials suggest that thrombolytic therapy may be an effective initial treatment for acute arterial occlusion of the legs. A major potential benefit of initial thrombolytic therapy is that limb ischemia can be managed with less invasive interventions. METHODS In this randomized, multicenter trial conducted at 113 North American and European sites, we compared vascular surgery (e.g., thrombectomy or bypass surgery) with thrombolysis by catheter-directed intraarterial recombinant urokinase; all patients (272 per group) had had acute arterial obstruction of the legs for 14 days or less. Infusions were limited to a period of 48 hours (mean [+/-SE], 24.4+/-0.86), after which lesions were corrected by surgery or angioplasty if needed. The primary end point was the amputation-free survival rate at six months. RESULTS Final angiograms, which were available for 246 patients treated with urokinase, revealed recanalization in 196 (79.7 percent) and complete dissolution of thrombus in 167 (67.9 percent). Both treatment groups had similar significant improvements in mean ankle-brachial blood-pressure index. Amputation-free survival rates in the urokinase group were 71.8 percent at six months and 65.0 percent at one year, as compared with respective rates of 74.8 percent and 69.9 percent in the surgery group; the 95 percent confidence intervals for the differences were -10.5 to 4.5 percentage points at six months (P=0.43) and -12.9 to 3.1 percentage points at one year (P=0.23). At six months the surgery group had undergone 551 open operative procedures (excluding amputations), as compared with 315 in the thrombolysis group. Major hemorrhage occurred in 32 patients in the urokinase group (12.5 percent) as compared with 14 patients in the surgery group (5.5 percent) (P= 0.005). There were four episodes of intracranial hemorrhage in the urokinase group (1.6 percent), one of which was fatal. By contrast, there were no episodes of intracranial hemorrhage in the surgery group. CONCLUSIONS Despite its association with a higher frequency of hemorrhagic complications, intraarterial infusion of urokinase reduced the need for open surgical procedures, with no significantly increased risk of amputation or death.

The Hemodynamic Response to Pulmonary Embolism in Patients Without Prior Cardiopulmonary Disease

The hemodynamic status of 20 patients free of prior cardiopulmonary disease was related to the degree of pulmonary embolic obstruction estimated by selective pulmonary angiography. Angiographic estimation of obstruction ranged from 13 to 68 percent. Systemic arterial hypoxemia occurred in virtually all patients (95 percent) including those with only 13 percent obstruction, thus suggesting that angiographically detectable emboli virtually do not occur without producing systemic hypoxemia. Mean pulmonary arterial pressure was increased in 14 patients (70 percent) and was consistently increased when obstruction exceeded 30 percent. Elevation of the level of mean right atrial pressure was found in 10 patients (50 percent) and was usually associated with obstruction in excess of 35 percent and mean pulmonary arterial pressure in excess of 30 mm Hg. Good correlation was observed between mean pulmonary arterial pressure and angiographic estimation of obstruction (P < 0.01), mean right atrial pressure and obstruction (P < 0.01), mean pulmonary and right atrial pressures (P < 0.01), and pO2 and obstruction (P < 0.05). Cardiac index was characteristically normal or mildly increased, being below the lower limit of normal in only 4 patients (20 percent). In patients who had not experienced cardiac failure, the cardiac index appeared to increase as systemic arterial pO2 decreased (P < 0.01) once hypoxemia was well established. Mean pulmonary arterial pressure never exceeded 40 mm Hg, despite massive obstruction in some patients, thereby suggesting that this level approximates the maximal pressure response of the previously normal right ventricle.

Thrombolysis or peripheral arterial surgery: Phase I results

PURPOSE Thrombolytic therapy is widely used in the treatment of peripheral arterial occlusion, but prospective, randomized comparisons with standard therapy remain few. A multicenter trial of thrombolysis or peripheral arterial surgery (TOPAS) was organized to compare critically the use of recombinant urokinase (rUK) or surgery for the initial treatment of acute lower-extremity ischemia. Phase I of the trial was designed as a dose-ranging trial to evaluate the safety and efficacy of three doses of rUK in comparison with surgery. METHODS In a multicenter, prospective, double-blind comparison, 213 patients who had acute lower-extremity ischemia for 14 days or fewer were randomized to one of two groups. The first group received one of three dosages of rUK (catheter-directed at 2000, 4000, or 6000 IU/min for 4 hours, then 2000 IU/min to a maximum of 48 hours). The second group underwent surgery. Successful thrombolysis was followed by surgical or endovascular interventions when anatomic lesions responsible for the occlusion were unmasked. Patients were followed-up for 1 year; data were evaluated on an intent-to-treat basis. RESULTS The 4000 IU/min rUK dosage was chosen as the most appropriate thrombolytic regimen because it maximized lytic efficacy against the risk of bleeding. Complete (> 95%) lysis of thrombus was achieved in 71% of the 49 patients who were randomized to the 4000 IU/min group, with a mean infusion time of 23 hours. In contrast, complete lysis was achieved in 67% of patients who received 2000 IU/min and in 60% of patients who received 6000 IU/min. Hemorrhagic complications occurred in 2% of the 4000 IU/min group versus 13% of the 2000 IU/min group (p = 0.05) and 16% of the 6000 IU/min group (p = 0.03). In a comparison of the 4000 IU/min group with the surgical group, the 1-year mortality rate (14% vs 16%) or amputation-free survival rate (75% vs 65%) did not differ significantly. The frequency and magnitude of surgery in the patients randomized to rUK were decreased (p < 0.001). CONCLUSION The preliminary results suggest that an initial rUK dose of 4000 IU/min is safe and efficacious in the treatment of acute lower-extremity ischemia. rUK therapy is associated with limb salvage and patient survival rates similar to those achieved with surgery, concurrent with a reduced requirement for complex surgery after thrombolytic intervention.

The electrocardiogram in acute pulmonary embolism

Electrocardiograms of 90 patients with arteriographically documented acute submassive or massive pulmonary embolism and no associated cardiac or pulmonary disease were studied. Patients were derived from the Urokinase-Pulmonary Embolism Trial National Cooperative Study. In massive embolism, the electrocardiogram was normal in 6 per cent (3 of 50) of patients. With submassive embolism, 23 per cent of patients (9 of 40) had a normal electrocardiogram. Since one or more of the traditional manifestations of acute cor pulmonale (S1Q3T3, right bundle branch block, P pulmonale, or right axis deviation) occurred in only 26 per cent of patients, one could not rely exclusively upon these electrocardiographic abnormalities for the diagnosis of pulmonary embolism. The most common electrocardiographic abnormalities were nonspecific T wave changes which occurred in 42 per cent of patients and nonspecific abnormalities (elevation or depression) of the RST segment which occurred in 41 per cent of patients. Left axis deviation occurring in 7 per cent of the patients was as frequent as right axis deviation. Low voltage QRS complexes, previously undescribed in pulmonary embolism, occurred in 6 per cent of patients. None of the patients had atrial flutter or atrial fibrillation, which appears to occur more typically in patients with pulmonary embolism who have preexistent cardiac disease. All of the varieties of electrocardiographic abnormalities disappeared in some of the patients by 2 wk. Inversion of the T wave was the most persistent abnormality. Larger defects on the lung scan or pulmonary arteriogram occurred in patients with various abnormalities on the electrocardiogram than in patients with normal electrocardiograms. The pulmonary arterial mean pressure and/or right ventricular end-diastolic pressure was significantly higher in patients with several varieties of abnormal electrocardiograms, although the partial pressure of oxygen in arterial blood, in general, did not differ from that in patients with normal electrocardiograms. These hemodynamic correlations, made for the first time in patients, suggest that acute ventricular dilatation, possibly in combination with hypoxemia, is a causative factor of the electrocardiographic changes in acute massive or submassive pulmonary embolism.

ACUTE PULMONARY EMBOLISM TREATED WITH TISSUE PLASMINOGEN ACTIVATOR

Recombinant human tissue-type plasminogen activator (rt-PA) was given via a peripheral vein to 36 patients with angiographically documented pulmonary embolism. The regimen was 50 mg/2 h followed by repeat angiography and, if necessary, an additional 40 mg/4 h. By 6 h, 34 of 36 patients had angiographic evidence of clot lysis, slight in 4, moderate in 6, and marked in 24. The quantitative score improved 21% by 2 h and 49% by 6 h. Fibrinogen decreased 30% from baseline at 2 h and 38% from baseline at 6 h. 2 patients had major complications: in one, bleeding from a pelvic tumour required surgery; in the other, who had had coronary artery bypass surgery eight days earlier, pericardial tamponade developed. These initial results in selected patients make a case for expanded investigational use of peripheral intravenous rt-PA in pulmonary embolism.

Thrombolytic Therapy in Thrombosis: A National Institutes of Health Consensus Development Conference

Excerpt For over three decades, the primary method of therapy used by almost all physicians for the management of acute deep-vein thrombosis and pulmonary embolism has been anticoagulation. This fo...

Effect of Thrombolytic Therapy on Pulmonary-Capillary Blood Volume in Patients with Pulmonary Embolism

To compare the effects of heparin thrombolytic agents in pulmonary thromboembolic disease, we randomly assigned 40 patients with pulmonary emboli but without other clinical cardiopulmonary disease either to heparin followed by oral anticoagulants (21 patients) or to urokinse or streptokinase followed by heparin and then by oral anticoagulants (19 patients). The effects on pulmonary-capillary blood volume and diffusing capacity were compared at two weeks and at one year. The pulmonary-capillary blood volume (in milliliters per square meter of body-surface area) was abnormally low (30 +/- 2.4) [+/- S.E.]; normal, 47 +/- 1.5) in the heparin-treated group at two weeks and remained unchanged at one year. In contrast, it was normal (45 +/- 2.5) in the group receiving thrombolytic agents, both at two weeks and at one year (P < 0.001). The pulmonary diffusing capacity was reduced to 69% of the predicted value in the heparin group at two weeks and 72% at one year, whereas it was 85% of the predicted value in the thrombolytic group at two weeks and 93% at one year (P < 0.001). These results indicate that thrombolytic agents allow more complete resolution of thromboemboli than do heparin and anticoagulants and that they improve capillary perfusion and diffusion.

History and physical examination in acute pulmonary embolism in patients without preexisting cardiac or pulmonary disease

The history and physical examination were assessed in 215 patients with acute pulmonary embolism uncomplicated by preexisting cardiac or pulmonary disease. The patients had been included in the Urokinase Pulmonary Embolism Trial or the Urokinase-Streptokinase Embolism Trial. Presenting syndromes were (1) circulatory collapse with shock (10 percent) or syncope (9 percent); (2) pulmonary infarction with hemoptysis (25 percent) or pleuritic pain and no hemoptysis (41 percent); (3) uncomplicated embolism characterized by dyspnea (12 percent) or nonpleuritic pain usually with tachypnea (3 percent) or deep venous thrombosis with tachypnea (0.5 percent). The most frequent symptoms were dyspnea (84 percent), pleuritic pain (74 percent), apprehension (63 percent) and cough (50 percent). Hemoptysis occurred in only 28 percent. Dyspnea, hemoptysis or pleuritic pain occurred separately or in combination in 94 percent. All three occurred in only 22 percent. The most frequent signs were tachypnea (respiration ate 20/min or more) (85 percent), tachycardia (heart rate 100 beats/min or more) (58 percent), accentuated pulmonary component of the second heart sound (57 percent) and rales (56 percent). Signs of deep venous thrombosis were present in only 41 percent and a pleural friction rub was present in only 18 percent. Either dyspnea or tachypnea occurred in 96 percent. Dyspnea, tachypnea or deep venous thrombosis occurred in 99 percent. As a group, the identified clinical manifestations, although nonspecific, are strongly suggestive of acute pulmonary embolism. Conversely, acute pulmonary embolism was rarely identified in the absence of dyspnea, tachypnea or deep venous thrombosis.

Clinical and physiologic studies in pulmonary thromboembolism

Abstract The clinical and physiologic studies of 72 patients with pulmonary thromboembolism were analyzed in detail. Pulmonary emboli occurred most frequently in the setting of some chronic condition, such as heart disease, previous pulmonary embolism, or chronic obstructive pulmonary disease. Coronary disease was most common, followed by mitral disease. The incidence of chronic bronchitis and emphysema can be expected to rise. The four most often encountered symptoms were: dyspnea in all patients, cough and pleural pain in about two thirds, and hemoptysis in slightly more than one third. Nonspecific physical findings were most frequent: loud P2, tachypnea, rales and tachycardia. More specific findings of embolism, such as pleural friction rub and chest splinting, occurred in less than a fifth of the patients. Phlebitis was present in only a third. No specific laboratory test is presently available, but determination of enzyme levels (LDH, SGOT) were useful in suggesting the presence of pulmonary embolism. Over half of the patients had the characteristic elevated level of serum lactic dehydrogenase (LDH) and a normal level of serum glutamic oxalacetic transaminase (SGOT). However, negative studies do not exclude embolism. The most frequent biochemical triad consisted of elevated LDH and normal SGOT and bilirubin. Bilirubin elevation generally signaled the presence of complicating congestive failure. The white cell count in uncomplicated embolism was less than 15,000/mm.3 Ventilatory derangements included hyperventilation, pulmonary restriction, bronchoconstriction and diminished diffusing capacity. Impairment of oxygenation was observed in almost all patients. Two thirds showed evidence of venous admixture, and other contributing factors responsible for hypoxemia were diffusion defects and diminished ventilation-perfusion ratios. Virtually all patients with pO2 levels less than 60 mm. Hg showed evidence of venous admixture. Pulmonary hypertension was observed in varying degrees in 80 per cent of the patients. Almost all patients with mean pulmonary artery pressures above 30 mm. Hg and all those with pressures above 40 had hemodynamic evidence of right heart failure. About two-thirds of the patients showed a diminished cardiac index, increased arteriovenous oxygen extraction, and elevated right ventricular end-diastolic pressure when these combined determinations were made. Fifty-eight per cent of the patients were initially correctly diagnosed. The others had various nonspecific symptoms and signs attributed to congestive failure, pneumonia, myocardial infarction or chronic pulmonary disease. In each instance, a diagnostic protocol was useful in heightening suspicion of pulmonary emboli. The final decision was based on the results of lung scanning, selective pulmonary angiography, or both.

Long-term benefit of thrombolytic therapy in patients with pulmonary embolism

A total of 23 of the 40 patients who had angiographically proven pulmonary embolism and who had initially been randomized to an IV infusion of heparin (n = 11) or a thrombolytic agent (urokinase or streptokinase, n = 12) were restudied after a mean follow-up of 7.4 years to measure the right-sided pressures and to evaluate their response to exercise during supine bicycle ergometry. Results showed that, at rest, the pulmonary artery (PA) mean pressure and the pulmonary vascular resistance (PVR) were significantly higher in the heparin group compared with the thrombolytic group (22 vs. 17 mmHg, p < 0.05, and 351 vs. 171 dynes s- 1 cm- 5, p < 0.02, respectively). During exercise both parameters rose to a significantly higher level in the heparin group (from rest to exercise, PA: 22-32 mmHg, p < 0.01; PVR: 351-437 dynes s- 1 cm- 5, p < 0.01, respectively), but not in the thrombolytic group (rest to exercise, PA: 17-19 mmHg, p = NS; PVR: 171-179 dynes s- 1 cm- 5, p = NS). It is concluded that thrombolytic therapy preserves the normal hemodynamic response to exercise in the long term and may prevent recurrences of venous thromboembolism and the development of pulmonary hypertension.