ENDOVASCULARSURGERY
0039-6109/92 $0.00 + .20
THROMBOLYTIC THERAPY Peter F. Lawrence, MO, and Greg R. Goodman, MO
Thrombolytic agents have been known to exist for longer than 100 years, although clinical applications have been reported only since 1949. The first large prospective clinical trials of thrombolysis for venous thrombosis and pulmonary embolism 36, 37 resulted in approval of both streptokinase and urokinase for pulmonary embolism in 1978. Since that time, both of these agents, as well as the recently approved tissue plasminogen activator (tPA), have been used to treat patients with acute myocardial infarction, thrombosed venous catheters, acute thrombosis of the deep veins of the legs and arms, and acute and chronic peripheral arterial occlusions, These agents are particularly indicated for peripheral vascular applications either when the clot is surgically inaccessible or in patients with a high operative risk. In addition, these agents provide a minimally invasive alternative to surgical extraction of the clot, even when the two approaches, surgery and clot lysis, might be equally effective. Most surgeons, however, have found that thrombolytic therapy is a useful adjunct to surgical therapy of peripheral arterial and venous occlusions, often with results superior to those achieved by thrombolytic therapy or surgery alone. THROMBOLYTIC AGENTS
Streptokinase Streptokinase is a single-chain polypeptide with a molecular weight of 47,000 that is produced by hemolytiC streptococci. It was the first thrombolytic agent used clinically: in 1949, Tillett and Sherry injected cultures of hemolytic streptococcus in the pleural space to lyse fibrin. Since that time, streptokinase has been, and continues to be, used clinically for deep vein thrombosis, pulmonary emboli, arterial thrombosis, and acute myocardial infarction. The mechanism of action of streptokinase is through indirect activation of From the Department of Surgery, University of Utah School of Medicine, Salt Lake City, Utah
SURGICAL CLINICS OF NORTH AMERICA VOLUME 72 • NUMBER 4 • AUGUST 1992
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LAWRENCE & GOODMAN
plasminogen via formation of streptokinase-plasminogen cofactor. This cofactor converts plasminogen to plasmin, which cleaves fibrin and fibrinogen. Plasminogen is depleted in this two-stage process more than with other thrombolytic agents. Streptokinase causes breakdown of both circulating fibrinogen and clot-bound fibrin: it is not clot specific. In addition, streptokinase is antigenic and causes fever and minor allergic reactions, as well as severe anaphylactic reactions in 0.1 % of patients treated. Many patients have been exposed to streptococcal infections, and they may carry high antibody titers, which leads to drug inactivation. Therefore, a loading dose of streptokinase should be given to bind antibody, preventing this reaction. Recent streptococcal infections or streptokinase infusions may stimulate higher antibody titers, decreasing the effectiveness of the drug. Streptokinase is inexpensive and is still used clinically in spite of its adverse systemic effects. Urokinase
Urokinase is an enzyme with a molecular weight of 54,000 that was identified in normal urine in 1952. Because it is not a foreign protein, it has many advantages over streptokinase. It does not stimulate antibody formation and can therefore be used repeatedly in the same patient without inactivation; it also does not require a loading dose. Commercial urokinase in the United States is obtained from kidney cell culture and is a lower molecular-weight (32,000) product that has been broken down enzymatically. Urokinase has a high affinity for the activation site on plasminogen, acting directly on it to yield plasmin. Clinically, this enzyme has a lower incidence of bleeding complications than streptokinase, in spite of the fact that both agents have effects on circulating as well as clot fibrin and fibrinogen. This agent is considerably more expensive than streptokinase.
tPA
Tissue plasminogen activator is an enzyme that is made by the vascular endothelium of many tissues. It is clot specific (unlike streptokinase and urokinase) and therefore should be associated with a lower risk of systemic bleeding. It binds tightly to fibrin and therefore is immediately adjacent to plasminogen, which it converts into plasmin. Although tPA is "clot specific," there are a limited number of binding sites on the clot surface, leading to a spill of tPA into the systemic circulation and some fibrinogenolysis. In addition, the fibrin degradation products from the lysing thrombus activate tPA in the peripheral circulation, leading to systemic effects. The product is considerably more expensive than either streptokinase or urokinase.
Other Agents
Several other thrombolytic agents are either in the development phase or in clinical trials. Each new agent attempts to improve the efficacy of clot fibrinolysis while minimizing the systemic activation of the fibrinolytic system and the resultant risks of bleeding. None of these agents is currently available for routine clinical use.
r
THROMBOLYTIC THERAPY
901
PERCUTANEOUS THERAPY FOR ARTERIAL OCCLUSION
In 1959, Fletcher and associates13 reported the initial use of streptokinase in patients with peripheral artery occlusions. Since that time, the use of thrombolysis for arterial occlusion has evolved with respect to indications, agents, delivery techniques, doses, and adjunctive therapy. Initially, intravenous thrombolysis was used, with a low success rate and a high incidence of complications. McNicol and associates,>! in 1963, advocated an intra-arterial approach to improve efficacy and reduce bleeding complications. This low-dose intra-arterial approach, which was then tried at many other centers, was still associated with a relatively low success rate with long infusion times (35-40 hours), and high complication rates continued. The availability of new thrombolytic agents such as urokinase and tPA, as well as changes in doses, with high concentrations infused over shorter periods of time, has led to a faster, more effective lysis of thrombus with a lower complication rate. In addition, this technique has been extended to patients with both acute and chronic arterial occlusions caused by embolus, thrombosis, aneurysms, and graft failure. Indications and Contraindications
Patients with an acute arterial occlusion are considered to be optimal candidates for percutaneous thrombolysis, which is often used as an adjunct to diagnostic angiography. Any patient who has acute arterial insufficiency of the upper or lower extremity with collateral perfusion adequate to maintain limb viability for 10 to 12 hours is a potential candidate for percutaneous thrombolysis. Conversely, patients with severe limb-threatening ischemia who cannot tolerate 10 to 12 more hours of ischemia should be taken to the operating room immediately for surgical thromboembolectomy, bypass, or intraoperative thrombolysis. Although judgment is necessary to determine the degree of ischemia, any patient with loss of motor function, anesthesia, or muscle rigor is a poor candidate for percutaneous thrombolysis. In addition, patients need to have an adequate arterial access site for sheath and catheter placement in the ipsilateral limb, contralateral limb, or brachial artery. Occasionally, obesity, extensive scarring, or calcific arterial disease precludes percutaneous thrombolytic therapy for technical reasons. Other contraindications to percutaneous thrombolysis are relative and include a history of gastrointestinal bleeding, intracardiac thrombus, recent major surgery or trauma (within 10 days), recent stroke, severe hypertension or proliferative diabetic retinopathy, and an acquired or hereditary coagulation disorder. With these diseases, an assessment of the relative risks of complications of bleeding must be weighed against the risk of limb ischemia. In general, patients with contraindications to percutaneous thrombolysis should be managed operatively if the ischemia is severe enough to warrant therapy. Technique
Although many variables contribute to the successful lysis of thrombus, none is more critical than the technique of infusion of the thrombolytic agent. Technical considerations include the vessel used for access, catheter delivery system, rate and concentration of infusion, and concomitant use of other
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anticoagulants. Many authors have reported the technical details of their approach, but that of McNamara and Fischero is the most commonly used. Their system is based on a large clinical experience and attempts to determine rapidly whether lytic therapy is likely to succeed, to complete lysis rapidly to achieve a high success rate, and to minimize complications. This approach has increased the success rate from 45% to 75%, reduced the incidence of bleeding from 13% to 4%, and shortened the infusion duration (as brief as 18 hours) compared with the low-dose infusions (5000 U/hour) previously reported. Once the decision is made to institute percutaneous thrombolysis, the access vessel must be selected. For iliac or common femoral artery thromboemboli, the contralateral femoral artery is the preferable vessel for access; superficial femoral, popliteal, or infrapopliteal occlusions are approached from either the ipsilateral or the contralateral femoral artery. Ipsilateral vessel access reduces the chance of a catheter-related complication making both limbs ischemic; it also allows access to trifurcation vessels, which may be inaccessible from the arm or contralateral leg. In patients who have known atherosclerotic disease of the access vessel and a diminished pulse, the contralateral artery or an upperextremity vessel is the preferred access site. OccaSionally, the lack of an acceptable access vessel precludes a percutaneous approach, and operative embolectomy or thrombolysis must be performed. A coaxial infusion system allows infusion of lytic agents at several levels within the clot (Fig. 1). A 5-Fr catheter is placed within 2 to 3 cm of the occlusion after a guidewire has been passed through the entire extent of the clot. Successful passage of the guidewire predicts a high likelihood (>95%) of successful lysis, while inability to pass a guidewire through the thrombus reduces the likelihood of success. An infusion guidewire (0.035-inch outer diameter) is then positioned in the middle of the thrombus. During the passage of the infusion guidewire, urokinase can be "laced" through the thrombus, establishing a channel, which increases the speed of recanalization. New catheters that spray the lytic agents into the thrombus to distribute it throughout the clot are being tested clinically. Once the catheter is positioned in the thrombus, an infusion rate of 4000 U/minute for 2 to 4 hours is used to determine the susceptibility of the thrombus to lytic therapy. If angiography demonstrates that the clot is being lysed, the rate of infusion is reduced to 100,000 U/hour. ThrombolysiS with repositioning of the distal catheter into the clot is continued for up to 48 hours, as long as lysis is progressing. To prevent pericatheter thrombosis, patients are systemically heparinized to maintain their partial thromboplastin time (PIT) at greater than 100 seconds. Results
Table 1 summarizes the results of several of the larger recent series of percutaneous thrombolysis procedures for native artery and graft occlusions. 7, 17,23, 30, 31, 38 Because there have been no randomized studies, and because there are many variations in the indications, techniques, doses, and agents used, only generalizations can be made about the results and complications. However, many authors have come to similar conclusions. First, occlusions at all levels of the peripheral arterial tree can be opened with lytic therapy, including those in the iliac, femoral, popliteal, or infra popliteal vessels. Second, all causes of arterial occlusions, including emboli and thrombi proximal to atherosclerotic plaque, aneurysms, or grafts to suprapopliteal and infrapopliteal arteries, and
? THROMBOLYTIC THERAPY
903
CONTRALATERIAL PUNCTURE SITE
r-"'.J (
TIP OF INFUSION CATHETER IN THE PROXIMAL FEW CM OF CLOT
\
\
, ,, ,,
\
TIP OF INFUSION GUIOEWIRE IN THE MID OR DISTAL PORTION OF CLOT
: :f
': ,~:
i II: ! 1J, I
:" : I J: :
/>Ih\ \" / )
t, I
'1"'~"
'· •• It'·. "
:
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Figure 1. The percutaneous thrombolytic technique using a coaxial delivery system to infuse the lytic agent in the proximal and mid portion of the clot.
occlusions in the upper extremity may be lysed. 32 Third, streptokinase, urokinase, and tPA are capable of opening thrombosed vessels with nearly equal success rates;!9 however, streptokinase has a much higher incidence of significant bleeding complications when used in the higher, effective doses.! Consequently, most centers preferentially use urokinase or tPA rather than streptokinase. Fourth, both prosthetic and autogenous grafts can be reopened with thrombolysis. Their long-term patency is determined by the presence or absence of a correctable stenosis in the graft inflow or outflow vessel. If a stenosis is present and corrected, the long-term patency rate is considerably higher. Fifth, the length of time between vessel occlusion and thrombolysis contributes to the likelihood of successful lysis-old occlusions fare worse than recent ones, although thrombolysis may still be effective months after an occlusion. Sixth, native artery occlusions have a lower initial recanalization rate, but a higher long-term patency rate, than autogenous or prosthetic grafts. Seventh, the initial success rate with thrombolysis is high for arterial occlusions. However, few studies report 1- and 5-year patencies: when they do, the patency rate rapidly falls over time, particularly when a correctable lesion is not found. 2 Consequently, one of the chief functions of percutaneous thrombolytic therapy is to identify and correct the lesion in the artery that is responsible for the
I.C
~
Table 1. OUTCOMES OF PERCUTANEOUS THROMBOSIS FOR ARTERIAL OCCLUSIONS IN RECENT SERIES Success (%) Series
No. of Patients
Graor et ai, 1990 17
465
Sicard et ai, 198530
40
Camerata et ai, 19877
34
Sullivan et ai, 1991"
43
Whittemore, 199238 O'Donnell et ai, 199023
Level of Occlusion"
Occluded Vessel Bypass graft Native artery
342 123
35
Bypass graft Native artery Bypass graft Native artery or vein Prasth. graft Autogen. graft Native artery Autogen. vein graft
12 28 10 24 29 11 0 35
33
PTFE graft
33
AI Fem-pop AI Fem-pop Fem-pop Fem-distal
tSK = streptokinase, UK = urokinase.
6 30 0 13 35 8
Fem-pop 12 Fem-tib 10 Infrainguinal 33
*NA = not available, AI = aortoiliac, Fem = femoral, pop = popliteal, tib = tibial.
Initial
1 Yr
SK 200 UK 200 tPA 65 SK 36 UK 7 SK 32 UK 2 UK 43
5000 U/hr 4000 U/min 0.1 mg/kg/h 5000 U/hr 440 U/kg/hr 5-10 K U/hr NA 4000 U/min
72 89 94 21 45 41
NA NA NA NA NA NA
21
88
56
23
UK
35
4000 U/min
60
37
NA
UK SK
17 16
4000 U/min 10-15 K U/hr
82 44
NA
0 19
Agentt
NA
Initial Dose
Major Complications (%) 28 69 12 44
THROMBOLYTIC THERAPY
90S
occlusion. Without such correction, the long-term patency rate can be expected to be low «30%). Replacement of a prosthetic graft with autogenous vein should be considered if no correctable lesion is identified, as rethrombosis is frequent. A series of angiograms (Fig. 2) demonstrates the effective use of percutaneous thrombolysis. A patient who had undergone an axillofemoral bypass graft for aortoiliac occlusive disease presented with a cool, ischemic, but viable leg. Angiography demonstrated the occluded graft, which was successfully cleared in 4 hours with urokinase using the McNamara and Fischer protocol. After thrombolysis had opened the entire graft, angiography demonstrated a stenosis at the femoral anastomosis, which was revised under local anesthesia. Complications The complications of percutaneous thrombolysis are dependent on many variables involved in the technique. Most important, however, is the agent used. Virtually every retrospective study has come to the same conclusion: streptokinase is associated with the highest incidence of bleeding complications (15%-40%) because of its activation of the systemic thrombolytic system. Systemic fibrinogenolysis can be monitored by serum fibrinogen concentrations-when they fall to less than 100 mgldL, the risk of pericatheter or systemic hemorrhage increases. In addition, agents such as streptokinase that require long infusion times to complete clot lysis are associated with a greater incidence of significant bleeding complications. Agent-specific complications such as fever, anaphylaxis, and urticaria generally are either rare or are selflimited when the agent is discontinued. Catheter-related complications such as thrombosis, emboli, and pericatheter bleeding can be limited by strict adherence to the technical details described by McNamara and Fischer. INTRAOPERATIVE THERAPY
There are clinical situations in which percutaneous thrombolysis of acute or chronic arterial occlusions is not appropriate or is contraindicated. In some patients, for example, the degree of ischemia is so severe that the time necessary to re-establish flow by thrombolysis (12-48 hours) would result in limb loss. In addition, many patients have contraindications to percutaneous thrombolytic therapy, such as recent major surgery or a high risk of hemorrhage. Lastly, technical factors, such as obesity, extensively scarred groins, or aneurysmal access vessels may contraindicate a percutaneous technique. In these patients, surgical exploration of the vessels of an ischemic limb may be the only acceptable option. Since the Fogarty catheter was introduced in 1963,'4 it has remained the most commonly employed surgical device for removing emboli and thrombi in the treatment of acute peripheral artery occlusion. Although the catheter has greatly improved the management of thromboembolic disease, this approach is not uniformly successful and is not without complications. Failure to restore adequate perfusion to the ischemic extremity may be related to residual thrombus in the artery after thrombectomy, occurring as often as 36% to 85% of the time,25. 28 or to distal thrombus inaccessible to this catheter. 11 Furthermore, the catheter preferentially travels into the peroneal artery during thrombectomy because of the vascular anatomy,29 making it difficult to gain access to either
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LAWRENCE & GOODMAN
Figure 2. Angiograms show the preinfusion (A) and postinfusion (8) appearance of an acutely thrombosed axillofemoral graft. C. Note the residual stenosis at the level of the anastomosis.
lHROMBOLYTIC THERAPY
907
the anterior or the posterior tibial vessels. Finally, the catheter induces endothelial damage' with late arterial stenosis and has been associated with perforation of the vessel during repeated passes. '5 In 1962, the use of streptokinase following unsuccessful surgical thromboembolectomy was described by Cotton et aLB In 196433 and again in 1974,'2 thrombolytic agents were used in patients with residual thrombus as an aid in establishing reperfusion of an occluded vessel. None of these patients sustained hemorrhagic complications related to the use of thrombolytic agents in association with surgery. Subsequently, intraoperative thrombolysis as an adjunct to balloon catheter thromboembolectomy has become an increasingly accepted technique for clearing the arteries of residual clot. Indications
Recent reports of operative thrombolysis have rarely indicated the reasons percutaneous thrombolysis was contraindicated. However, the authors have noted that most patients receiving intraoperative thrombolysis have undergone balloon catheter embolectomy, with incomplete removal of distal clot seen on completion angiogram. In addition, some patients have known operative lesions such as an aneurysm, anastomotic stricture, arterial occlusive disease, or a graft failure that requires surgical therapy. Technique
Recent reports of intraoperative thrombolysis have continued to advocate thrombolytic therapy as an adjunct to balloon catheter thromboembolectomy. 2', 27 The technique involves removal of as much of the proximal thrombus as possible with a balloon catheter. With the inflow vessel still occluded, an irrigation catheter is introduced into the artery and the thrombolytic agent administered either by infusion (usually over 30 minutes in a small volume) or by slow bolus (Fig. 3). Commonly, doses of 50,000 to 100,000 U of urokinase are used, with the total dose depending on the location of the thrombus and the size of the limb. Angiography or angioscopy is used to determine the completeness of clot lysis; the infusion is repeated if there is no improvement. Maximum total doses of 200,000 to 375,000 U of urokinase have been used without severe hemorrhagic complications. Performing catheter thromboembolectomy prior to infusion of lytic agents has several theoretical advantages over percutaneous thrombolysis alone. It reduces the total amount of thrombus that must be lysed, thus decreasing the amount of thrombolytic agent used and the overall infusion time. Additionally, occlusion of the inflow helps to concentrate the agent at the site of the thrombus and reduce washout. This helps to minimize the activation of systemic fibrinolysis, theoretically reducing the incidence of hemorrhagic complications. 16, 26 Furthermore, use of the Fogarty catheter after thrombolytic therapy removes additional thrombus that was either missed on earlier passes or had been freed by thrombolysis. 22 The principal disadvantage of intraoperative thrombolysis is the need for a surgical incision, which becomes a potential site of hemorrhage when combined with anticoagulation and thrombolytic therapy. Results
Since 1985, seven clinical reports have been published that describe the use of thrombolytic agents in the operating room as an adjunct to thrombec-
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Figure 3. Intraoperative lytic therapy is delivered by catheter through the arteriotomy with proximal inflow occluded.
tomy. In these studies, a total of 142 patients underwent thrombolytic therapy for limb salvage after balloon catheter thromboembolectomy had failed (Table 2). All studies included patients with thromboembolic disease of native vessels or autogenous grafts (saphenous vein), and three of the studies included patients with synthetic grafts. Streptokinase was used in 65 patients and urokinase in 77 patients. The total doses ranged from 20,000 to 250,000 U of streptokinase and 35,000 to 375,000 U of urokinase, most often in multiple doses of 20,000 to 50,000 U. The method of administration was bolus injection in five studies and infusion over a 30-minute period in two studies. All but one of the studies used postoperative anticoagulation with heparin in at least some of the patients. Many factors, including the agent used, the method of administration, the optimum dosage needed for rapid, complete lysis, and postoperative anticoagulation, make comparisons between the studies difficult. In the group of patients represented in these studies, streptokinase appears to be slightly more effective (87.5%) than urokinase (82%), although differences in patient selection
Table 2. RESULTS OF INTRAOPERATIVE THROMBOLYSIS Agent* Source
SK
Ouinones-Baldrich et ai, 198526 Cohen et ai, 19865
5 13
100 85
Norem et ai, 198822
19
100
Comerota et ai, 19896 Parent et ai, 19892•
14 7
24 21
64 83
73 90
7
16
100
75
65
16 77
87.5
87 82
Ouinones-Baldrich et ai, 198927 Garcia et ai, 1990'6 Total
'SK = streptokinase; UK = urokinase.
~
ID
UK
Success (%) SK
UK
Administration Infusion
Bolus
Yes
Complications Anticoagulation
Yes
Heparin postop Heparin after Fib > 150
Yes
Heparin in 12 postop
Yes Yes
Heparin in selected patients None
Yes
Heparin/Coumadin in selected patients Heparin postop
Yes
SK 0 2 major 2 minor (38%) 2 minor (10.5%) 0 2 major (28.6%) 1 minor (14.3%) 15.4%
UK
0 1 minor (4.8%) 0 0 1.3%
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LAWRENCE & GOODMAN
may account for this. When used as an infusion, therapy was successful in 85%, compared with an 83% success rate for bolus therapy. Bleeding complications occurred in 0 to 38% of patients and included minor bleeding such as wound hematomas in seven patients (5%) and hemorrhage necessitating surgery in four (2.8%), resulting in the death of one patient (0.7%). Bleeding
was more common when streptokinase was used and included all four major hemorrhagic complications (6.2%), three of which required surgical intervention. There were no significant bleeding episodes associated with the use of urokinase. Although no specific laboratory values have been shown to correlate completely with hemorrhagic complications, low fibrinogen concentrations systemically are associated with bleeding. In these studies, all four patients who developed significant post-therapy hemorrhage had low fibrinogen concentrations systemically. 5, 2. Anticoagulation is used after catheter thromboembolectomy in many patients because the vessels are thought to be relatively hypercoagulable from thrombus remaining in the vessels or from intimal damage by the catheter. Anticoagulation after thrombolytic therapy is thought to reduce the incidence of rethrombosis but is also thought by many to contribute significantly to hemorrhagic complications. Of the four major bleeding complications, however, all occurred in association with low fibrinogen concentrations and without heparinization.
ISOLATED EXTREMITY THERAPY
Although balloon catheter embolectomy combined with intraoperative thrombolysis treats acute peripheral artery occlusion effectively, there frequently develops a systemic lytic state with associated hemorrhage, especially when thrombolysis is combined with major surgery. In addition, some patients require such high doses of lytic agents to remove the clot that bleeding complications are virtually assured. In an effort to decrease the incidence of hemorrhage and to improve efficacy, we have developed a technique for isolating the extremity prior to the infusion of the thrombolytic agents, preventing the agent from activating systemic fibrinolysis. This method is based on the tourniquet-isolated limb technique first described in 1950 for the treatment of melanoma of an extremity. 9 This technique cart be adapted for thromboembolic disease of an extremity to protect the systemic circulation from fibrinolysis and its associated potential for hemorrhage during infusion of high doses of lytic agents. Isolated limb perfusion with thrombolytic agents takes intraoperative therapy one step further by allowing delivery of extremely high doses of the agent and maximum concentration with little or no washout into the systemic circulation. Because the extremity is completely isolated and the lytic agent never enters the systemic circulation, even patients with absolute contraindications to conventional thrombolytic therapy may become candidates. This would be particularly applicable to patients who have recently undergone major surgery, which places them at risk for major hemorrhagic complications with thrombolytic therapy. Because high doses of these agents lyse thrombus more rapidly than lower doses, 3 infusion of ultra-high doses not only reduces the time necessary for infusion (reducing operative time as well), but also further improves success rates.
THROMBOLYTIC THERAPY
911
Clinical Studies
Seven patients have undergone high-dose, isolated-limb thrombolytic therapy at our institution (Table 3). The patients ranged from 39 to 72 years old, and the duration of their preoperative symptoms ranged from several hours to 3 months. All patients had a traditional balloon catheter thrombectomy, which was unsuccessful in restoring adequate blood flow to the affected extremity prior to infusion of the thrombolytic agent. The agent was administered as a slow bolus. Streptokinase (27,000 and 200,000 U) was used in two patients and urokinase (150,000-500,000 U) in five patients. Technique
The site of exposure of the artery is at the usual site of thrombectomyfemoral, popliteal, or tibial (at the ankle)-and is determined by the preoperative clinical examination or angiogram. Once the vessel has been fully mobilized, the patient is systemically heparinized if this was not performed preoperatively, the vessel is clamped proximally, and an arteriotomy is created. All accessible thrombus is extracted with forceps and a balloon catheter. Once several passes are made with no residual clot removed, a completion angiogram or angioscopy should be performed to identify residual clot. If none is seen, flow should be re-established to the limb with an assessment of foot color and pulses. If no persistent ischemia is identified, thrombolysis is not indicated. If persistent clot or ischemia is identified by angiography, angioscopy, or clinical examination, the patient is a candidate for intraoperative thrombolysis. The technique involves placement of a sterile tourniquet, the Banana Cuff disposable pneumatic tourniquet (Zimmer-Jackson, Warsaw, Indiana), proximal to the arteriotomy used for thrombectomy of the involved limb (Fig. 4). If a tourniquet must be placed below a femoral incision, then long cannulas are passed down the vessels to infuse and aspirate below the tourniquet. The tourniquet is inflated to a pressure at least 50 mm Hg greater than the patient's systemic arterial pressure. While flow is controlled with a proximal arterial clamp, an irrigation catheter is placed through the arteriotomy using a Silastic loop around the distal vessel to control backflow. The thrombolytic agent in a volume of approximately 100 ml is gradually infused into the distal vessel over a 1- to 5minute period. The vessel should remain occluded for 30 minutes to allow lysis of the thrombus. The success of lysis should then be re-evaluated by angiography, angioscopy, or Doppler scanning. Repeat doses can be used in patients who fail the initial attempt. Total doses as great as 250,000 U of urokinase have been reported without hemorrhagic complications. Once the thrombus has been lysed, standard techniques are used to close the wound. Prior to reperfusion, as much of the agent as possible is removed by one of two methods. One involves aspiration of blood from the arterial catheter and a large vein (either superficial or deep) while exsanguinating the isolated portion of the limb. The second method involves flushing the agent from the limb by infusing heparinized saline into the arterial catheter until the effluent retrieved from a venous cannula is clear. Results
Using the isolated-limb perfusion technique, all patients had flow reestablished to the affected limb. Two patients underwent amputation of the
ID
I-'
N
Table 3. SUMMARY OF USE OF ISOLATED-LIMB THROMBOLYSIS
Patient
Age 72
2
71
3
59
4
39
5
66
6
66
7
56
Duration of Symptom
Units of Thrombolytic Agent Etiology
Thrombosis distal to Acute fern-pop PTFE graft ischemia 3 months Embolus to tibperoneal trunk Thrombosis of fern-pop 3 days & pop-tib PTFE graft 3 weeks Traumatic thrombosis
Ax-fern PTFE graft Acute ischemia thrombosis embolus to arm Iliac dissection & pop 8 days embolus Subclavian stenosis & 2 hours embolus to arm
Extremity
SK
Left foot Left foot
UK
Before
After
300,000
255
245
27,000
Left leg Right foot
Fibrinogen (mg/dL) Immediate Outcome Limb salvage Limb salvage
500,000
405
405
Limb salvage
400
Initial limb salvage, rethrombosis at 10 days Limb salvage
200,000
Right arm
150,000
Left foot
250,000
412
412
Limb salvage
Left arm
250,000
460
460
Limb salvage
*BKA = below-knee amputation, DP = dorsalis pedis, PT = posterior tibial.
Follow-up* Rethrombosed at 1 mo.-BKA Palpable DP pulse at 24 mo. Palpable PT pulse at 6 mo. Amputation at 10 days
Palpable radial pulse at 2 mo. Palpable DP pulse at 6 mo. Hand viable at 6 mo.
T
THROMBOLYTIC THERAPY
913
I
I
Figure 4. The isolated limb technique provides a high concentration of a lytic agent in the clot without systemic infusion. Aspiration of the artery and vein should be performed prior to re-establishing flow.
affected extremity after they developed recurrent thrombosis refractory to further thrombolytic therapy. There were no bleeding complications, even in the four patients who were fully anticoagulated or in the two patients who underwent therapy within 1 week of major surgery. No patients developed a systemic lytic state as determined by fibrinogen levels and coagulation parameters measured postoperatively. Since our first description of this technique in 1986, two other patients have been reported who underwent isolation of the limb by tourniquet for administration of thrombolytic therapy. 6, 24 In one patient, the isolated-limb method was used because the patient had undergone major surgery within the previous 24 hours. One million units of urokinase was infused into her popliteal artery after isolation with a tourniquet, and blood flow to the extremity was re-established without bleeding complications. The second patient, despite initial reperfusion, ultimately required amputation. It is important to realize that the patient population involved in operative thrombolytic procedures often has severe chronic atherosclerotic disease. Despite initial reperfusion, many will experience rethrombosis unless the underlying lesion in the diseased vessels can be repaired or bypassed. Anticoagulation postoperatively may help decrease the incidence of rethrombosis, and when the isolated-limb technique is used, the risk of associated hemorrhage is reduced because the two drugs have been effectively isolated from each other. Furthermore, use of the newer thrombolytic agents in association with the isolatedlimb technique may increase the success of intraoperative thrombolysis because of their more specific mechanisms of action on fibrin-bound thrombus. THERAPEUTIC STRATEGY IN ARTERIAL OCCLUSION
In a patient who presents with acute arterial occlusion or exacerbation of chronic arterial disease, the algorithm in Figure 5 helps guide the strategy. If there is an immediate threat to limb viability, the patient should immediately undergo surgical embolectomy, with thrombolysis reserved for residual intravascular clot. If chronic occlusive disease is found during exploration, bypass
-
0039-6109/92 $0.00 + .20
THROMBOLYTIC THERAPY Peter F. Lawrence, MO, and Greg R. Goodman, MO
Thrombolytic agents have been known to exist for longer than 100 years, although clinical applications have been reported only since 1949. The first large prospective clinical trials of thrombolysis for venous thrombosis and pulmonary embolism 36, 37 resulted in approval of both streptokinase and urokinase for pulmonary embolism in 1978. Since that time, both of these agents, as well as the recently approved tissue plasminogen activator (tPA), have been used to treat patients with acute myocardial infarction, thrombosed venous catheters, acute thrombosis of the deep veins of the legs and arms, and acute and chronic peripheral arterial occlusions, These agents are particularly indicated for peripheral vascular applications either when the clot is surgically inaccessible or in patients with a high operative risk. In addition, these agents provide a minimally invasive alternative to surgical extraction of the clot, even when the two approaches, surgery and clot lysis, might be equally effective. Most surgeons, however, have found that thrombolytic therapy is a useful adjunct to surgical therapy of peripheral arterial and venous occlusions, often with results superior to those achieved by thrombolytic therapy or surgery alone. THROMBOLYTIC AGENTS
Streptokinase Streptokinase is a single-chain polypeptide with a molecular weight of 47,000 that is produced by hemolytiC streptococci. It was the first thrombolytic agent used clinically: in 1949, Tillett and Sherry injected cultures of hemolytic streptococcus in the pleural space to lyse fibrin. Since that time, streptokinase has been, and continues to be, used clinically for deep vein thrombosis, pulmonary emboli, arterial thrombosis, and acute myocardial infarction. The mechanism of action of streptokinase is through indirect activation of From the Department of Surgery, University of Utah School of Medicine, Salt Lake City, Utah
SURGICAL CLINICS OF NORTH AMERICA VOLUME 72 • NUMBER 4 • AUGUST 1992
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LAWRENCE & GOODMAN
plasminogen via formation of streptokinase-plasminogen cofactor. This cofactor converts plasminogen to plasmin, which cleaves fibrin and fibrinogen. Plasminogen is depleted in this two-stage process more than with other thrombolytic agents. Streptokinase causes breakdown of both circulating fibrinogen and clot-bound fibrin: it is not clot specific. In addition, streptokinase is antigenic and causes fever and minor allergic reactions, as well as severe anaphylactic reactions in 0.1 % of patients treated. Many patients have been exposed to streptococcal infections, and they may carry high antibody titers, which leads to drug inactivation. Therefore, a loading dose of streptokinase should be given to bind antibody, preventing this reaction. Recent streptococcal infections or streptokinase infusions may stimulate higher antibody titers, decreasing the effectiveness of the drug. Streptokinase is inexpensive and is still used clinically in spite of its adverse systemic effects. Urokinase
Urokinase is an enzyme with a molecular weight of 54,000 that was identified in normal urine in 1952. Because it is not a foreign protein, it has many advantages over streptokinase. It does not stimulate antibody formation and can therefore be used repeatedly in the same patient without inactivation; it also does not require a loading dose. Commercial urokinase in the United States is obtained from kidney cell culture and is a lower molecular-weight (32,000) product that has been broken down enzymatically. Urokinase has a high affinity for the activation site on plasminogen, acting directly on it to yield plasmin. Clinically, this enzyme has a lower incidence of bleeding complications than streptokinase, in spite of the fact that both agents have effects on circulating as well as clot fibrin and fibrinogen. This agent is considerably more expensive than streptokinase.
tPA
Tissue plasminogen activator is an enzyme that is made by the vascular endothelium of many tissues. It is clot specific (unlike streptokinase and urokinase) and therefore should be associated with a lower risk of systemic bleeding. It binds tightly to fibrin and therefore is immediately adjacent to plasminogen, which it converts into plasmin. Although tPA is "clot specific," there are a limited number of binding sites on the clot surface, leading to a spill of tPA into the systemic circulation and some fibrinogenolysis. In addition, the fibrin degradation products from the lysing thrombus activate tPA in the peripheral circulation, leading to systemic effects. The product is considerably more expensive than either streptokinase or urokinase.
Other Agents
Several other thrombolytic agents are either in the development phase or in clinical trials. Each new agent attempts to improve the efficacy of clot fibrinolysis while minimizing the systemic activation of the fibrinolytic system and the resultant risks of bleeding. None of these agents is currently available for routine clinical use.
r
THROMBOLYTIC THERAPY
901
PERCUTANEOUS THERAPY FOR ARTERIAL OCCLUSION
In 1959, Fletcher and associates13 reported the initial use of streptokinase in patients with peripheral artery occlusions. Since that time, the use of thrombolysis for arterial occlusion has evolved with respect to indications, agents, delivery techniques, doses, and adjunctive therapy. Initially, intravenous thrombolysis was used, with a low success rate and a high incidence of complications. McNicol and associates,>! in 1963, advocated an intra-arterial approach to improve efficacy and reduce bleeding complications. This low-dose intra-arterial approach, which was then tried at many other centers, was still associated with a relatively low success rate with long infusion times (35-40 hours), and high complication rates continued. The availability of new thrombolytic agents such as urokinase and tPA, as well as changes in doses, with high concentrations infused over shorter periods of time, has led to a faster, more effective lysis of thrombus with a lower complication rate. In addition, this technique has been extended to patients with both acute and chronic arterial occlusions caused by embolus, thrombosis, aneurysms, and graft failure. Indications and Contraindications
Patients with an acute arterial occlusion are considered to be optimal candidates for percutaneous thrombolysis, which is often used as an adjunct to diagnostic angiography. Any patient who has acute arterial insufficiency of the upper or lower extremity with collateral perfusion adequate to maintain limb viability for 10 to 12 hours is a potential candidate for percutaneous thrombolysis. Conversely, patients with severe limb-threatening ischemia who cannot tolerate 10 to 12 more hours of ischemia should be taken to the operating room immediately for surgical thromboembolectomy, bypass, or intraoperative thrombolysis. Although judgment is necessary to determine the degree of ischemia, any patient with loss of motor function, anesthesia, or muscle rigor is a poor candidate for percutaneous thrombolysis. In addition, patients need to have an adequate arterial access site for sheath and catheter placement in the ipsilateral limb, contralateral limb, or brachial artery. Occasionally, obesity, extensive scarring, or calcific arterial disease precludes percutaneous thrombolytic therapy for technical reasons. Other contraindications to percutaneous thrombolysis are relative and include a history of gastrointestinal bleeding, intracardiac thrombus, recent major surgery or trauma (within 10 days), recent stroke, severe hypertension or proliferative diabetic retinopathy, and an acquired or hereditary coagulation disorder. With these diseases, an assessment of the relative risks of complications of bleeding must be weighed against the risk of limb ischemia. In general, patients with contraindications to percutaneous thrombolysis should be managed operatively if the ischemia is severe enough to warrant therapy. Technique
Although many variables contribute to the successful lysis of thrombus, none is more critical than the technique of infusion of the thrombolytic agent. Technical considerations include the vessel used for access, catheter delivery system, rate and concentration of infusion, and concomitant use of other
902
LAWRENCE & GOODMAN
anticoagulants. Many authors have reported the technical details of their approach, but that of McNamara and Fischero is the most commonly used. Their system is based on a large clinical experience and attempts to determine rapidly whether lytic therapy is likely to succeed, to complete lysis rapidly to achieve a high success rate, and to minimize complications. This approach has increased the success rate from 45% to 75%, reduced the incidence of bleeding from 13% to 4%, and shortened the infusion duration (as brief as 18 hours) compared with the low-dose infusions (5000 U/hour) previously reported. Once the decision is made to institute percutaneous thrombolysis, the access vessel must be selected. For iliac or common femoral artery thromboemboli, the contralateral femoral artery is the preferable vessel for access; superficial femoral, popliteal, or infrapopliteal occlusions are approached from either the ipsilateral or the contralateral femoral artery. Ipsilateral vessel access reduces the chance of a catheter-related complication making both limbs ischemic; it also allows access to trifurcation vessels, which may be inaccessible from the arm or contralateral leg. In patients who have known atherosclerotic disease of the access vessel and a diminished pulse, the contralateral artery or an upperextremity vessel is the preferred access site. OccaSionally, the lack of an acceptable access vessel precludes a percutaneous approach, and operative embolectomy or thrombolysis must be performed. A coaxial infusion system allows infusion of lytic agents at several levels within the clot (Fig. 1). A 5-Fr catheter is placed within 2 to 3 cm of the occlusion after a guidewire has been passed through the entire extent of the clot. Successful passage of the guidewire predicts a high likelihood (>95%) of successful lysis, while inability to pass a guidewire through the thrombus reduces the likelihood of success. An infusion guidewire (0.035-inch outer diameter) is then positioned in the middle of the thrombus. During the passage of the infusion guidewire, urokinase can be "laced" through the thrombus, establishing a channel, which increases the speed of recanalization. New catheters that spray the lytic agents into the thrombus to distribute it throughout the clot are being tested clinically. Once the catheter is positioned in the thrombus, an infusion rate of 4000 U/minute for 2 to 4 hours is used to determine the susceptibility of the thrombus to lytic therapy. If angiography demonstrates that the clot is being lysed, the rate of infusion is reduced to 100,000 U/hour. ThrombolysiS with repositioning of the distal catheter into the clot is continued for up to 48 hours, as long as lysis is progressing. To prevent pericatheter thrombosis, patients are systemically heparinized to maintain their partial thromboplastin time (PIT) at greater than 100 seconds. Results
Table 1 summarizes the results of several of the larger recent series of percutaneous thrombolysis procedures for native artery and graft occlusions. 7, 17,23, 30, 31, 38 Because there have been no randomized studies, and because there are many variations in the indications, techniques, doses, and agents used, only generalizations can be made about the results and complications. However, many authors have come to similar conclusions. First, occlusions at all levels of the peripheral arterial tree can be opened with lytic therapy, including those in the iliac, femoral, popliteal, or infra popliteal vessels. Second, all causes of arterial occlusions, including emboli and thrombi proximal to atherosclerotic plaque, aneurysms, or grafts to suprapopliteal and infrapopliteal arteries, and
? THROMBOLYTIC THERAPY
903
CONTRALATERIAL PUNCTURE SITE
r-"'.J (
TIP OF INFUSION CATHETER IN THE PROXIMAL FEW CM OF CLOT
\
\
, ,, ,,
\
TIP OF INFUSION GUIOEWIRE IN THE MID OR DISTAL PORTION OF CLOT
: :f
': ,~:
i II: ! 1J, I
:" : I J: :
/>Ih\ \" / )
t, I
'1"'~"
'· •• It'·. "
:
" .-
Figure 1. The percutaneous thrombolytic technique using a coaxial delivery system to infuse the lytic agent in the proximal and mid portion of the clot.
occlusions in the upper extremity may be lysed. 32 Third, streptokinase, urokinase, and tPA are capable of opening thrombosed vessels with nearly equal success rates;!9 however, streptokinase has a much higher incidence of significant bleeding complications when used in the higher, effective doses.! Consequently, most centers preferentially use urokinase or tPA rather than streptokinase. Fourth, both prosthetic and autogenous grafts can be reopened with thrombolysis. Their long-term patency is determined by the presence or absence of a correctable stenosis in the graft inflow or outflow vessel. If a stenosis is present and corrected, the long-term patency rate is considerably higher. Fifth, the length of time between vessel occlusion and thrombolysis contributes to the likelihood of successful lysis-old occlusions fare worse than recent ones, although thrombolysis may still be effective months after an occlusion. Sixth, native artery occlusions have a lower initial recanalization rate, but a higher long-term patency rate, than autogenous or prosthetic grafts. Seventh, the initial success rate with thrombolysis is high for arterial occlusions. However, few studies report 1- and 5-year patencies: when they do, the patency rate rapidly falls over time, particularly when a correctable lesion is not found. 2 Consequently, one of the chief functions of percutaneous thrombolytic therapy is to identify and correct the lesion in the artery that is responsible for the
I.C
~
Table 1. OUTCOMES OF PERCUTANEOUS THROMBOSIS FOR ARTERIAL OCCLUSIONS IN RECENT SERIES Success (%) Series
No. of Patients
Graor et ai, 1990 17
465
Sicard et ai, 198530
40
Camerata et ai, 19877
34
Sullivan et ai, 1991"
43
Whittemore, 199238 O'Donnell et ai, 199023
Level of Occlusion"
Occluded Vessel Bypass graft Native artery
342 123
35
Bypass graft Native artery Bypass graft Native artery or vein Prasth. graft Autogen. graft Native artery Autogen. vein graft
12 28 10 24 29 11 0 35
33
PTFE graft
33
AI Fem-pop AI Fem-pop Fem-pop Fem-distal
tSK = streptokinase, UK = urokinase.
6 30 0 13 35 8
Fem-pop 12 Fem-tib 10 Infrainguinal 33
*NA = not available, AI = aortoiliac, Fem = femoral, pop = popliteal, tib = tibial.
Initial
1 Yr
SK 200 UK 200 tPA 65 SK 36 UK 7 SK 32 UK 2 UK 43
5000 U/hr 4000 U/min 0.1 mg/kg/h 5000 U/hr 440 U/kg/hr 5-10 K U/hr NA 4000 U/min
72 89 94 21 45 41
NA NA NA NA NA NA
21
88
56
23
UK
35
4000 U/min
60
37
NA
UK SK
17 16
4000 U/min 10-15 K U/hr
82 44
NA
0 19
Agentt
NA
Initial Dose
Major Complications (%) 28 69 12 44
THROMBOLYTIC THERAPY
90S
occlusion. Without such correction, the long-term patency rate can be expected to be low «30%). Replacement of a prosthetic graft with autogenous vein should be considered if no correctable lesion is identified, as rethrombosis is frequent. A series of angiograms (Fig. 2) demonstrates the effective use of percutaneous thrombolysis. A patient who had undergone an axillofemoral bypass graft for aortoiliac occlusive disease presented with a cool, ischemic, but viable leg. Angiography demonstrated the occluded graft, which was successfully cleared in 4 hours with urokinase using the McNamara and Fischer protocol. After thrombolysis had opened the entire graft, angiography demonstrated a stenosis at the femoral anastomosis, which was revised under local anesthesia. Complications The complications of percutaneous thrombolysis are dependent on many variables involved in the technique. Most important, however, is the agent used. Virtually every retrospective study has come to the same conclusion: streptokinase is associated with the highest incidence of bleeding complications (15%-40%) because of its activation of the systemic thrombolytic system. Systemic fibrinogenolysis can be monitored by serum fibrinogen concentrations-when they fall to less than 100 mgldL, the risk of pericatheter or systemic hemorrhage increases. In addition, agents such as streptokinase that require long infusion times to complete clot lysis are associated with a greater incidence of significant bleeding complications. Agent-specific complications such as fever, anaphylaxis, and urticaria generally are either rare or are selflimited when the agent is discontinued. Catheter-related complications such as thrombosis, emboli, and pericatheter bleeding can be limited by strict adherence to the technical details described by McNamara and Fischer. INTRAOPERATIVE THERAPY
There are clinical situations in which percutaneous thrombolysis of acute or chronic arterial occlusions is not appropriate or is contraindicated. In some patients, for example, the degree of ischemia is so severe that the time necessary to re-establish flow by thrombolysis (12-48 hours) would result in limb loss. In addition, many patients have contraindications to percutaneous thrombolytic therapy, such as recent major surgery or a high risk of hemorrhage. Lastly, technical factors, such as obesity, extensively scarred groins, or aneurysmal access vessels may contraindicate a percutaneous technique. In these patients, surgical exploration of the vessels of an ischemic limb may be the only acceptable option. Since the Fogarty catheter was introduced in 1963,'4 it has remained the most commonly employed surgical device for removing emboli and thrombi in the treatment of acute peripheral artery occlusion. Although the catheter has greatly improved the management of thromboembolic disease, this approach is not uniformly successful and is not without complications. Failure to restore adequate perfusion to the ischemic extremity may be related to residual thrombus in the artery after thrombectomy, occurring as often as 36% to 85% of the time,25. 28 or to distal thrombus inaccessible to this catheter. 11 Furthermore, the catheter preferentially travels into the peroneal artery during thrombectomy because of the vascular anatomy,29 making it difficult to gain access to either
906
LAWRENCE & GOODMAN
Figure 2. Angiograms show the preinfusion (A) and postinfusion (8) appearance of an acutely thrombosed axillofemoral graft. C. Note the residual stenosis at the level of the anastomosis.
lHROMBOLYTIC THERAPY
907
the anterior or the posterior tibial vessels. Finally, the catheter induces endothelial damage' with late arterial stenosis and has been associated with perforation of the vessel during repeated passes. '5 In 1962, the use of streptokinase following unsuccessful surgical thromboembolectomy was described by Cotton et aLB In 196433 and again in 1974,'2 thrombolytic agents were used in patients with residual thrombus as an aid in establishing reperfusion of an occluded vessel. None of these patients sustained hemorrhagic complications related to the use of thrombolytic agents in association with surgery. Subsequently, intraoperative thrombolysis as an adjunct to balloon catheter thromboembolectomy has become an increasingly accepted technique for clearing the arteries of residual clot. Indications
Recent reports of operative thrombolysis have rarely indicated the reasons percutaneous thrombolysis was contraindicated. However, the authors have noted that most patients receiving intraoperative thrombolysis have undergone balloon catheter embolectomy, with incomplete removal of distal clot seen on completion angiogram. In addition, some patients have known operative lesions such as an aneurysm, anastomotic stricture, arterial occlusive disease, or a graft failure that requires surgical therapy. Technique
Recent reports of intraoperative thrombolysis have continued to advocate thrombolytic therapy as an adjunct to balloon catheter thromboembolectomy. 2', 27 The technique involves removal of as much of the proximal thrombus as possible with a balloon catheter. With the inflow vessel still occluded, an irrigation catheter is introduced into the artery and the thrombolytic agent administered either by infusion (usually over 30 minutes in a small volume) or by slow bolus (Fig. 3). Commonly, doses of 50,000 to 100,000 U of urokinase are used, with the total dose depending on the location of the thrombus and the size of the limb. Angiography or angioscopy is used to determine the completeness of clot lysis; the infusion is repeated if there is no improvement. Maximum total doses of 200,000 to 375,000 U of urokinase have been used without severe hemorrhagic complications. Performing catheter thromboembolectomy prior to infusion of lytic agents has several theoretical advantages over percutaneous thrombolysis alone. It reduces the total amount of thrombus that must be lysed, thus decreasing the amount of thrombolytic agent used and the overall infusion time. Additionally, occlusion of the inflow helps to concentrate the agent at the site of the thrombus and reduce washout. This helps to minimize the activation of systemic fibrinolysis, theoretically reducing the incidence of hemorrhagic complications. 16, 26 Furthermore, use of the Fogarty catheter after thrombolytic therapy removes additional thrombus that was either missed on earlier passes or had been freed by thrombolysis. 22 The principal disadvantage of intraoperative thrombolysis is the need for a surgical incision, which becomes a potential site of hemorrhage when combined with anticoagulation and thrombolytic therapy. Results
Since 1985, seven clinical reports have been published that describe the use of thrombolytic agents in the operating room as an adjunct to thrombec-
908
LAWRENCE & GOODMAN
Figure 3. Intraoperative lytic therapy is delivered by catheter through the arteriotomy with proximal inflow occluded.
tomy. In these studies, a total of 142 patients underwent thrombolytic therapy for limb salvage after balloon catheter thromboembolectomy had failed (Table 2). All studies included patients with thromboembolic disease of native vessels or autogenous grafts (saphenous vein), and three of the studies included patients with synthetic grafts. Streptokinase was used in 65 patients and urokinase in 77 patients. The total doses ranged from 20,000 to 250,000 U of streptokinase and 35,000 to 375,000 U of urokinase, most often in multiple doses of 20,000 to 50,000 U. The method of administration was bolus injection in five studies and infusion over a 30-minute period in two studies. All but one of the studies used postoperative anticoagulation with heparin in at least some of the patients. Many factors, including the agent used, the method of administration, the optimum dosage needed for rapid, complete lysis, and postoperative anticoagulation, make comparisons between the studies difficult. In the group of patients represented in these studies, streptokinase appears to be slightly more effective (87.5%) than urokinase (82%), although differences in patient selection
Table 2. RESULTS OF INTRAOPERATIVE THROMBOLYSIS Agent* Source
SK
Ouinones-Baldrich et ai, 198526 Cohen et ai, 19865
5 13
100 85
Norem et ai, 198822
19
100
Comerota et ai, 19896 Parent et ai, 19892•
14 7
24 21
64 83
73 90
7
16
100
75
65
16 77
87.5
87 82
Ouinones-Baldrich et ai, 198927 Garcia et ai, 1990'6 Total
'SK = streptokinase; UK = urokinase.
~
ID
UK
Success (%) SK
UK
Administration Infusion
Bolus
Yes
Complications Anticoagulation
Yes
Heparin postop Heparin after Fib > 150
Yes
Heparin in 12 postop
Yes Yes
Heparin in selected patients None
Yes
Heparin/Coumadin in selected patients Heparin postop
Yes
SK 0 2 major 2 minor (38%) 2 minor (10.5%) 0 2 major (28.6%) 1 minor (14.3%) 15.4%
UK
0 1 minor (4.8%) 0 0 1.3%
910
LAWRENCE & GOODMAN
may account for this. When used as an infusion, therapy was successful in 85%, compared with an 83% success rate for bolus therapy. Bleeding complications occurred in 0 to 38% of patients and included minor bleeding such as wound hematomas in seven patients (5%) and hemorrhage necessitating surgery in four (2.8%), resulting in the death of one patient (0.7%). Bleeding
was more common when streptokinase was used and included all four major hemorrhagic complications (6.2%), three of which required surgical intervention. There were no significant bleeding episodes associated with the use of urokinase. Although no specific laboratory values have been shown to correlate completely with hemorrhagic complications, low fibrinogen concentrations systemically are associated with bleeding. In these studies, all four patients who developed significant post-therapy hemorrhage had low fibrinogen concentrations systemically. 5, 2. Anticoagulation is used after catheter thromboembolectomy in many patients because the vessels are thought to be relatively hypercoagulable from thrombus remaining in the vessels or from intimal damage by the catheter. Anticoagulation after thrombolytic therapy is thought to reduce the incidence of rethrombosis but is also thought by many to contribute significantly to hemorrhagic complications. Of the four major bleeding complications, however, all occurred in association with low fibrinogen concentrations and without heparinization.
ISOLATED EXTREMITY THERAPY
Although balloon catheter embolectomy combined with intraoperative thrombolysis treats acute peripheral artery occlusion effectively, there frequently develops a systemic lytic state with associated hemorrhage, especially when thrombolysis is combined with major surgery. In addition, some patients require such high doses of lytic agents to remove the clot that bleeding complications are virtually assured. In an effort to decrease the incidence of hemorrhage and to improve efficacy, we have developed a technique for isolating the extremity prior to the infusion of the thrombolytic agents, preventing the agent from activating systemic fibrinolysis. This method is based on the tourniquet-isolated limb technique first described in 1950 for the treatment of melanoma of an extremity. 9 This technique cart be adapted for thromboembolic disease of an extremity to protect the systemic circulation from fibrinolysis and its associated potential for hemorrhage during infusion of high doses of lytic agents. Isolated limb perfusion with thrombolytic agents takes intraoperative therapy one step further by allowing delivery of extremely high doses of the agent and maximum concentration with little or no washout into the systemic circulation. Because the extremity is completely isolated and the lytic agent never enters the systemic circulation, even patients with absolute contraindications to conventional thrombolytic therapy may become candidates. This would be particularly applicable to patients who have recently undergone major surgery, which places them at risk for major hemorrhagic complications with thrombolytic therapy. Because high doses of these agents lyse thrombus more rapidly than lower doses, 3 infusion of ultra-high doses not only reduces the time necessary for infusion (reducing operative time as well), but also further improves success rates.
THROMBOLYTIC THERAPY
911
Clinical Studies
Seven patients have undergone high-dose, isolated-limb thrombolytic therapy at our institution (Table 3). The patients ranged from 39 to 72 years old, and the duration of their preoperative symptoms ranged from several hours to 3 months. All patients had a traditional balloon catheter thrombectomy, which was unsuccessful in restoring adequate blood flow to the affected extremity prior to infusion of the thrombolytic agent. The agent was administered as a slow bolus. Streptokinase (27,000 and 200,000 U) was used in two patients and urokinase (150,000-500,000 U) in five patients. Technique
The site of exposure of the artery is at the usual site of thrombectomyfemoral, popliteal, or tibial (at the ankle)-and is determined by the preoperative clinical examination or angiogram. Once the vessel has been fully mobilized, the patient is systemically heparinized if this was not performed preoperatively, the vessel is clamped proximally, and an arteriotomy is created. All accessible thrombus is extracted with forceps and a balloon catheter. Once several passes are made with no residual clot removed, a completion angiogram or angioscopy should be performed to identify residual clot. If none is seen, flow should be re-established to the limb with an assessment of foot color and pulses. If no persistent ischemia is identified, thrombolysis is not indicated. If persistent clot or ischemia is identified by angiography, angioscopy, or clinical examination, the patient is a candidate for intraoperative thrombolysis. The technique involves placement of a sterile tourniquet, the Banana Cuff disposable pneumatic tourniquet (Zimmer-Jackson, Warsaw, Indiana), proximal to the arteriotomy used for thrombectomy of the involved limb (Fig. 4). If a tourniquet must be placed below a femoral incision, then long cannulas are passed down the vessels to infuse and aspirate below the tourniquet. The tourniquet is inflated to a pressure at least 50 mm Hg greater than the patient's systemic arterial pressure. While flow is controlled with a proximal arterial clamp, an irrigation catheter is placed through the arteriotomy using a Silastic loop around the distal vessel to control backflow. The thrombolytic agent in a volume of approximately 100 ml is gradually infused into the distal vessel over a 1- to 5minute period. The vessel should remain occluded for 30 minutes to allow lysis of the thrombus. The success of lysis should then be re-evaluated by angiography, angioscopy, or Doppler scanning. Repeat doses can be used in patients who fail the initial attempt. Total doses as great as 250,000 U of urokinase have been reported without hemorrhagic complications. Once the thrombus has been lysed, standard techniques are used to close the wound. Prior to reperfusion, as much of the agent as possible is removed by one of two methods. One involves aspiration of blood from the arterial catheter and a large vein (either superficial or deep) while exsanguinating the isolated portion of the limb. The second method involves flushing the agent from the limb by infusing heparinized saline into the arterial catheter until the effluent retrieved from a venous cannula is clear. Results
Using the isolated-limb perfusion technique, all patients had flow reestablished to the affected limb. Two patients underwent amputation of the
ID
I-'
N
Table 3. SUMMARY OF USE OF ISOLATED-LIMB THROMBOLYSIS
Patient
Age 72
2
71
3
59
4
39
5
66
6
66
7
56
Duration of Symptom
Units of Thrombolytic Agent Etiology
Thrombosis distal to Acute fern-pop PTFE graft ischemia 3 months Embolus to tibperoneal trunk Thrombosis of fern-pop 3 days & pop-tib PTFE graft 3 weeks Traumatic thrombosis
Ax-fern PTFE graft Acute ischemia thrombosis embolus to arm Iliac dissection & pop 8 days embolus Subclavian stenosis & 2 hours embolus to arm
Extremity
SK
Left foot Left foot
UK
Before
After
300,000
255
245
27,000
Left leg Right foot
Fibrinogen (mg/dL) Immediate Outcome Limb salvage Limb salvage
500,000
405
405
Limb salvage
400
Initial limb salvage, rethrombosis at 10 days Limb salvage
200,000
Right arm
150,000
Left foot
250,000
412
412
Limb salvage
Left arm
250,000
460
460
Limb salvage
*BKA = below-knee amputation, DP = dorsalis pedis, PT = posterior tibial.
Follow-up* Rethrombosed at 1 mo.-BKA Palpable DP pulse at 24 mo. Palpable PT pulse at 6 mo. Amputation at 10 days
Palpable radial pulse at 2 mo. Palpable DP pulse at 6 mo. Hand viable at 6 mo.
T
THROMBOLYTIC THERAPY
913
I
I
Figure 4. The isolated limb technique provides a high concentration of a lytic agent in the clot without systemic infusion. Aspiration of the artery and vein should be performed prior to re-establishing flow.
affected extremity after they developed recurrent thrombosis refractory to further thrombolytic therapy. There were no bleeding complications, even in the four patients who were fully anticoagulated or in the two patients who underwent therapy within 1 week of major surgery. No patients developed a systemic lytic state as determined by fibrinogen levels and coagulation parameters measured postoperatively. Since our first description of this technique in 1986, two other patients have been reported who underwent isolation of the limb by tourniquet for administration of thrombolytic therapy. 6, 24 In one patient, the isolated-limb method was used because the patient had undergone major surgery within the previous 24 hours. One million units of urokinase was infused into her popliteal artery after isolation with a tourniquet, and blood flow to the extremity was re-established without bleeding complications. The second patient, despite initial reperfusion, ultimately required amputation. It is important to realize that the patient population involved in operative thrombolytic procedures often has severe chronic atherosclerotic disease. Despite initial reperfusion, many will experience rethrombosis unless the underlying lesion in the diseased vessels can be repaired or bypassed. Anticoagulation postoperatively may help decrease the incidence of rethrombosis, and when the isolated-limb technique is used, the risk of associated hemorrhage is reduced because the two drugs have been effectively isolated from each other. Furthermore, use of the newer thrombolytic agents in association with the isolatedlimb technique may increase the success of intraoperative thrombolysis because of their more specific mechanisms of action on fibrin-bound thrombus. THERAPEUTIC STRATEGY IN ARTERIAL OCCLUSION
In a patient who presents with acute arterial occlusion or exacerbation of chronic arterial disease, the algorithm in Figure 5 helps guide the strategy. If there is an immediate threat to limb viability, the patient should immediately undergo surgical embolectomy, with thrombolysis reserved for residual intravascular clot. If chronic occlusive disease is found during exploration, bypass
-
