fibrinolysis in peripheral

Transcription

1 Low-dose direct vascular disease fibrinolysis in peripheral Barry T. Katzen, M.D., Keith C. Edwards, M.D., Arthur S. Albert, M.D., and Arina van Breda, M.D., Alexandria, Va. One hundred thirty patients underwent low-dose, catheter-directed fibrinolytic therapy for arterial and graft occlusions present for various periods of time. In 65 consecutive patients the therapeutic parameters were identical, and a careful hematologic evaluation was performed. In the subsequent 65 patients, varying doses of fibrinolytic agents were employed. Fibrinolytic therapy was found to be beneficial in a diverse group of clinical situations and in patients whose occlusions had occurred at varying lengths of time. Early study demonstrated that effective fibrinolysis can be achieved at approximately onetwentieth of the systemic level and that systemic effects could be avoided in all patients during 24-hour infusions and in many patients infused up to 96 hours. Bleeding complications occurred only in patients in whom concomitant heparinization was employed, and this was thought to be the causative factor. Therapeutic success and avoiding complications are strongly dependent on close monitoring of patients and joint decision making by the vascular surgeon and radiologist. (J VASC SURG 1984; 1: ) Successful fibrinolysis employing direct infusion of fibrinolytic agents directly into the site of occlusion at varying doses substantially lower than that employed for systemic fibrinolysis was first demonstrated in 1973 by Dotter et al.1 Although it has been demonstrated that fibrinolysis can be achieved at extremely low dosages when infused at the site of occlusion, little further investigation with this technique has been reported, in large part because of the lack of availability of fibrinolytic agents in the United States. Subsequent availability and further reports of initial experience with similar techniques 2,3 have led to increasing application and reports from a variety of centers. 4"5 The initial success prompted us to study the success of"low-dose" direct infusion of fibrinolytic agents in thromboembolic disease and to determine whether local fibrinolysis could be achieved without the development of systemic effects. MATERIAL AND METHODS One hundred thirty patients underwent infusion of fibrinolytic agents directly into the site of arterial occlusion. The first 65 consecutive patients were treated via the technique and protocol described be- From the Department of Radiology, The Alexandria Hospital. Dr. Edwards is currently affiliated with Grossmont Hospital, La Mesa, Calif., and Dr. Albert with the Hackensack Medical Center, Hackensack, N.J. Reprint requests: B. T. Katzen, M.D., Department of Radiology, The Alexandria Hospital, Alexandria, VA low; the subsequent 65 patients underwent infusion with both urokinase and streptokinase at varying doses. The results presented below represent the analysis of the first group of patients in whom perfusion parameters were constant. An arbitrary dose of 5000 U/hr was selected, which is one-twentieth the systemic dose and the lowest dose successful according to Dotter's experience. Technique. A No. 5 French multipurpose polyethylene catheter was embedded at the site of the occlusion after placing the catheter from the most direct percutaneous approach possible. This meant ipsilateral antegrade puncture in the case of femoral occlusions after diagnostic angiography from the contralateral femoral artery. More recently a coaxial catheter system with a No. 5 French catheter for initial arterial puncture and a No. 2.5 or 3.0 French catheter for purposes of infusion has been employed. The No. 5 French catheter is left in the most proximal position possible to avoid inadvertent placement through an area of reduced flow, which might promote thrombus formation. The status o~ flow is carefully evaluated under fluoroscopic observation. Streptokinase was infused at 5000 U/hr in a volume of 50 ml of DsW or normal saline solution, depending on the patient's fluid requirements. Initial follow-up angiography was performed at 8 to 1K hours for evaluation of progress of clot lysis, and infusion was continued depending on the patient's clinical and radiographic status.

2 Volume 1 Number 5 September 1984 Low-dose fibrinolysis 719 At the time of first follow-up, if angiographic evaluation and clinical status were unchanged or improved and some evidence of clot lysis was present, infusion was continued. If the clinical status was unchanged or improved and no evidence of lysis was documented, infusion was continued after reevaluation of therapeutic alternatives. This process was repeated at approximate intervals of 10 hours or sooner if necessary, depending on the clinical status. If the clinical stares deteriorated, infusion was generally terminated. Patients were generally placed in an intensive care unit during the infusion for close monitoring of puncture site, and precautions similar to thosc recommended for systemic infusions were followed. 6 With further experience, we occasionally placed subsequent patients on the surgical floor for careful monitoring by nurses after appropriate education. Careful evaluation of puncture sites, status of me infused extremity, and vital signs was performed hourly or more frequently as clinically dictated. Bleeding parameters were reevaluated at 8- to 12- hour intervals and at termination of infusion prior to catheter removal. When complete lysis was documented, the underlying cause of thrombosis was treated via transluminal angioplasty or surgery, depending on the pathologic condition demonstrated. Catheters were removed at completion of the infusion by applying manual compression. Concomitant heparinization was employed in the first I0 patients but not in subsequent infusions. Postinfusion anticoagulation was employed in 10 patients with graft occlusions but otherwise was not used. Hepatin therapy is clearly contraindicated during systemic tibrinolysis. 7"8 Although there is some ratior~ale to its use during low-dose tibrinolytic therapy, hemorrhage occurred in our series only when heparin was used, even at doses of 100 to 200 U/hr. Catheter placement through areas of reduced flow or through unsuspected stenoses can be avoided if the coaxial technique is used with small-infusion catheters. If necessary, infusion can be split evenly between the two coaxial catheters. When tibrinogen levels fell below normal and continued infusion was necessary in two patients, fresh frozen plasma was administered to maintain normal levels of fibrinogen. Hematologic parameters. Prior to initiating therapy, complete blood count, prothrombin time, partial thromboplastin time, thr0mbin time, fibrinogen, and fibrin split products were measured. These were repeated at intervals of approximately 8 to 12 hours during the course of infusion and at the ter- Table I. Average change in coagulation parameters measured at 24 hours Parameters Avg. change Prothrombin time sec Partial thromboplastin time sec Thrombin time +3.0 sec Fibrinogen mg/dl Fibrin split products mg/dl Hematocrit - 2.0% Hemoglobin grn Table II. Overall success rates Result No. of patients % Complete fibrinolysis Partial fibrinolysis 6 9 No fibrinolysis mination of infusion. Fibrinogen and thrombin time best reflected the status of the fibrinolytic system and were relied on for decision making. The average changes in bleeding parameters measured at 24 hours are listed in Table I. No evidence of systemic fibrinolytic effect, as determined by fibrinogen and thrombin time, was noted at up to 24 hours of infusion. Reduction in fibrinogen and elevation of thrombin time occurred in 3 of 65 patients at infusion times of 30, 48, and 56 hours, respectively. Infusions were conducted for up to 96 hours without evidence of systemic fibrinolytic effect. RESULTS In 63 patients streptokinase was infused at the dosage and with the technique described previously. Successful fibrinolysis, clinical outcome, and effects of hematologic parameters were evaluated. Overall success rates are given in Table II, with results based on the type of occlusion listed in Table III. Infusions were conducted for periods of time ranging from 6 to 96 hours (average duration 26 hours). Success rates, based on the nature of the occlusion, are shown in Table III. In patients with chronic occlusions, successful lysis was surprisingly high considering the lack of clinical suspicion of a lysable thrombus. Because of previous experience with extravasation and even hemorrhage during infusion of synthetic aortoiliofemoral bypass bygrafts and the relative ease of thrombectomy, only two patients in this category were infused. Eight patients with occluded femoropopliteal bypass grafts were infused (Fig, 1).

3 Journal of 720 K a t z e n et al. Fig. 1. A, Peripheral arteriogram demonstrating occluded left femoral-popliteal bypass graft riagin.atingfrom midsuperficial femoral artery with proximal anastomotic stenosis. B, After tataon of the proxamal anastomosis, infusion of streptokinase at 5000 U/hr produces lysis of graft, which demonstrates distal anastomotic stenosis. C, Inflated angioplasty balloon demonstrates defect produced by anastomotic stenosis. D, Postflbrinolysis and angioplasty angiogram shows patent bypass graft with good outflow. VASCULAR SURGERY

4 Volume 1 Number 5 September 1984 Low-dose fibrinolysis 721 Sixty-five patients underwent low-dose fibrinolyric therapy with varying agents at different doses, including streptokinase infusions at 2000 U/min for 45 minutes, followed by 5000 U/hr as described previously. Urokinase was also used in doses of 20,000 to 40,000 U/hr. Accelerated doses did not seem to alter length of infusion. Successful lysis was achieved in 54 of 65 patients (83%). In patients with embolic disease, clinical urgency frequently precluded long-term infusion, producing lower success rates than expected. M1 occlusions following transluminal angioplasty were successfully lysed without additional therapy. Complications. Of 65 patients undergoing infusion, six (9.1%) developed significant hemorrhage requiring transfusion of 2 to 4 units of blood. This occurred in 6 of 10 patients in whom concomitant h parinization was employed. The cause of hemorrhage appeared to be related to hepatin, since in five of these six patients fibrinolytic therapy was ultimately successful after heparin was discontinued. In the sixth patient, both methods of therapy were discontinued. Low-grade febrile reactions (<100 F) were present in five patients and relieved by oral administration of acetaminophen (Tylenol). In patients with significant hemorrhage, bleeding occurred at or around the puncture site, generally expanding into soft tissues rather than presenting as frank external hemorrhage from the puncture site. No anaphylaxis or other adverse reaction to the fibrinolytic infusions was noted. DISCUSSION Experience with fibrinolytic agents reported in the literature has been primarily with systemic doses employed for acute deep venous thrombosis, massive pulmonary emboli, some aortic occlusions, and more recently acute myocardial infarction, s This study was initiated to determine (1) whether fibrinolysis could be achieved with extremely low doses infused directly into the obstruction and (2) if lowdose infusions could be effective without inducing a systemic effect. Theoretically, the latter concept seemed sound since the biologic half-life of streptokinase is approximately 18 and '78 minutes. Additionally, if low-dose infusions are effective, is the mechanism of action directly on the thrombus or the result of creating a local fibrinolytic milieu? Clinical experience indicates that embedding the catheter in the thrombus for infusion is an important part of this technique. Clinical experience since 1978 has answered some questions and raised others. The results de- Table III. Results of infusion in clinical categories N0.0f Type of occlusion patients Success Acute thrombosis (post-percuta- 7 7 neous transluminal angioplasty) Accelerating claudication with angiographic occlusions Poorly collateralized occlusions, chronic history Acute graft occlusion 10 7 Total extremity thrombosis 5 4 Embolus 6 3 Renal artery thrombosis scribed herein confirm that direct fibrinolysis can be achieved at extremely low doses without activating the systemic fibrinolytic system. Yet evaluation of bleeding parameters demonstrates that even at low doses prolonged infusions can induce a systemic effect, creating risks in some patients similar to those associated with systemic infusions. The cause of this systemic effect is not completely understood, but it is related to the length of infusion and, in the case of streptokinase, may be the result of streptokinase-forrning complexes with fibrin split products, which may in turn produce an additive fibrinolytic effect. It is generally accepted that a limiting factor in successful fibrinolysis is the age of the thrombus, since thrombi are considered to be nonlysable after 7 to 10 days? Clinical experience in achieving effective clot lysis in arterial occlusions of up to 4 months' duration as confirmed by angiography raises questions about this concept. The model for understanding the mechanism of fibrinolysis has been the venous system, as well as laboratory studies. Experience has led us to appreciate that the age of the thrombus is not necessarily equal to the age of the occlusion. Further evaluation of this discrepancy is necessary; however, this phenomenon may be the result of some delay in "aging" of the thrombus in the atherosclerotic vessel or possibly the result of ongoing active turnover of the thrombus. On the other hand, it is generally accepted that fresh thrombus is more likely to be successfully lysed, as confirmed in the arterial system by the instances in which acute thrombosis is well documented, such as in thrombosis related to transluminal angioplasty, where effective fibrinolysis was generally noted between 6 to 12 hours. Thrombosis in the arterial system is generally the result of reduced flow from a variety of causes, in-

5 722 Katzen et al. Journal of VASCULAR SURGERY eluding reduced inflow, outflow, or midvascular stenosis, reducing flow to the extent that thrombosis might develop. An underlying cause of thrombosis was demonstrated in all patients, including those with total extremity thrombosis. In these patients evidence of significant superficial femoral artery disease was associated with compromised runoff vessels. All patients in this group were 70 years of age or older and had a history of cardiac disease and congestive heart failure; it was postulated that thrombosis was precipitated by an episode of reduced cardiac output associated with underlying cardiac disease. In patients with acute thrombosis of bypass grafts, this type of therapy might seem ideal, and success has beenreported by several investigators. 4,5 Several limiting factors exist, however, which suggest a cautious approach. Reports of extravasation of contrast material following successful lysis of Dacron aortofemoral grafts are disturbing and suggest that significant hemorrhage in these patients could occur, n In addition, the duration and risks of infusion must be compared with thrombectomy, a relatively fast, safe, and definitive procedure. Thrombolytic therapy has several major limitations, including inability to predict the success of infusion and the duration of infusion necessary to restore perfusion. Therefore infusions can only be attempted in patients in whom significant clinical urgency does not exist. The procedure requires substantial radiologic commitment for proper monitoring. In addition, a potential for major complications exists, and these should be considered carefully prior to initiation of infusion. In spite of these drawbacks, the technique has proved to be an important method of adjunctive treatment for occlusive vascular disease at our institution, increasing our awareness of coexisting thrombus in the presence of atherosclerotic vascular disease. In conclusion, low-dose direct fibrinolysis is effective in selected patients without producing systemic effects and in a variety of clinical settings. Clinical factors should limit patient selection; infusion should not be considered if delay in alternative methods of therapy will jeopardize the clinical outcome. Predictors of success and length of infusion remain unclear. Systemic effects can occasionally occur even at low doses, and it is suggested that infusions be limited to 18 to 24 hours to reduce this risk. Application of this technique requires careful evaluation of the patient and close cooperation between the surgeon and angiographer. REFERENCES 1. Dotter CT, Rosch J, Seaman AJ. Selective clot lysis with low-dose streptokinase. Radiology 1974; 111: Katzen BT, van Breda A. Low dose streptokinase in the treatment of arterial occlusions. AJR 1981; 136: Totty WG, et al. Low dose intravascular tibrinolytic therapy. Radiology 1982; 143: Hallett JW, Yrizarry JM, Greenwood LH. Regional low dosage thrombolytic therapy for peripheral arterial occlusions. Surg Gynecol Obstet 1983; 156: Van Breda A, Robison JC, Feldman L, Waltman AC, Brewster DC, Abbott WM, Athanasoulis CA. Local thrombolysis in the treatment of arterial graft occlusions. J VASC SURG 1984; 1: Thrombolytic therapy in treatment. Summary of an NIH Consensus Conference. Br Med J 1980; 280: Urokinase-Streptokinase Pulmonary Embolism Trial Study Group. Urokinase-streptokinase pulmonary embolism trial phase II results. JAMA 1974; 229: Rutkowsky DM, Burkle WS. Advances in thrornbolytic therapy. Drug Intell Clin Pharm 1982; 916: Verstraete N, Dermylen J, Donatim B. The effect of streptokinase infusion on chronic arterial occlusions and stenoses. Ann Intern Med 1971; 74: Verstraete N. Biochemical and clinical aspects of thrombolysis. Semin Hematol 1978; 15: Rabe FE, Becker GJ, Richmond BD, Yune HY, Holden RW, Dilley RS, Klatte EC. Contrast extravasation through Dacron grafts: A sequela of low dose streptokinase therapy. AJR 1982; 138: