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Surgical implications of fibrinolytic therapy
Surgical Implications of Fibrinolytic Therapy
Joseph J. Hurley, MD, St. Louis, Missouri Michael J. Burrell, MD, St. Louis, Missouri Arthur I. Auer, MD, St. Louis, Missouri John J. Woods, Jr., MD, St. Louis, Missouri H. Bradley Blnnington,MD, St. Louis, Missouri Falls B. Hershey, MD, St. Louis, Missouri
Intraarterial fibrinolytic therapy for severe peripheral ischemia is a comparatively new modality frequently requiring operative intervention to obtain bptimal results. Most current reports describe lytic therapy utilized alone or in conjunction with percutaneous angioplasty [I-51. Surgery, although not always necessary, can help ensure continued initial good results or salvage ischemic limbs when prior intraarterial fibrinolytic therapy has been unsuccessful [6-8]. Our purpose is to detail the surgical implications of intraarterial fibrinolytic therapy in 37 cases (34 patients) for management of peripheral arterial ischemia.
Material and Methods This is a retrospective review of patients treated with intraarterial streptokinase or urokinase from July 1982 to March 1984. No patients were excluded from the study. Intraarterial fibrinolytic therapy was used in all 37 cases (34 patients). Patients were treated with streptokinase unless they had already received streptokinase within the previous 12 months, in which case urokinase was admin-
istered (three patients). Femoral angiography was performed before initiation of therapy, and streptokinase or urokinase was given intraarterially, either through the retograde angiograph catheter with the catheter tip in the iliac artery (26 cases, 46 percent successful) or through a catheter placed antegrade with the catheter tip at the site of the occlusion (11 cases, 64 percent successful). A bolus of 5,000 to 20,000 units of streptokinase was given over 20 minutes followed by a continuous infusion ranging from 3,000 to 19,000 units/hour of streptokinase (average 8,700 units/hour). The dose was titrated to achieve a mild systemic effect, with the fibrinogen level decreasing to around 100 mg/dl. Much higher doses of urokinase were needed to achieve the same effect (75,000 and 90,000 units/hour) From St. John’s Mercy Medical Center, Department of Surgery, Section of Vascular Surgery, St. Louis, Missouri. kWests for reprints should be addressed to Joseph J. Hurley, MD, 621 South New BallasRoad, Suite 307, St. Louis, Missouri 63141. Presented at the 36th Annual Weting of the Southwestern Surgical Congress. Honolulu, Hawaii, April 21-28, 1984.
830
in the two patients in whom a systemic lytic state was achieved. The patients were treated for an average of 671/2 hours. Fibrinogen and hematocrit values were obtained at 6 to 8 hour intervals. Portable angiography through the intraarterial catheter was performed on a daily basis in patients without chronic renal disease. The ankle-to-arm index was also used to monitor therapy. Results Successful fibrinolytic therapy (19 cases, 51 percent) included 13 cases in which no surgery was required (Group A) (Figure 1) and 6 cases in which adjuvant vascUlar surgery was performed (Group B) (Figure 2). This latter group (Figure 3) included patients whose surgery was made possible by fibrinolytic therapy opening an occluded graft and demonstrating a correctable anatomic cause for graft failure (three cases), opening the distal circulation which allowed bypass grafting to the newly opened segment (two cases), and correcting a complication of the catheter itself (intimal flap, common iliac artery) after opening the distal circulation (one case). Failures included five cases in which no further surgery was performed (Group C), eight cases that required reconstructive surgery (Group D), and five cases in which amputation was performed (Group E). Group C included one patient who was admitted with severe congestive heart failure and- died and four patients who had relatively recent onset of severe ischemia (average ankle-to-arm index of 0.22 with no open ulceration or rest pain) who were otherwise not reconstructable but did not require amputation. Three of these four patients had occluded vascular grafts. Patients who were successfully treated with fibrinolytic therapy (Groups A and B) differed from those in whom treatment failed (Groups C, D, and E) in the duration of symptoms before initiation of therapy. Groups were comparable with respect to the pretreatment ankle-to-arm index, incidence of dia-
TheAmerican
Journal of Surgery
Surgical Implications of Fibrinolytic Therapy
Figure 1. Anglographk documentatkm of occkmkm of d/stat popllteal, proximal anterior tlblal, and t/b/al peroneal artertes (A), showed partial resolution at 48 hours ( B) and complete clearance afler 5 days ( C) of Intraarterial streptoklnase lnfWon.
whkh
Flgun, 2. proxknel qenlng of occluded In situ veln bypass grafl ls demonstrated after 18 horn of lntraatierlal uroklnase therapy (A). llm upper end of the opened graft reveals clot adherence to the valve cusp, which was not totally dlsmpted ( B). The excelhbntdistal clrwlatlon ls shown after successful lytkz therapy (C).
Vohmo 148, December 1884
831
Hurley et
I
al
STREPTOLYTIC THERAPY SUCCESSRJL 19 (51%)
II
<
STREPTOLYTIC FAILURE 18 (49%)
t Figure
A
NO SURGERY
0
ADJUVANT (RECONSTRUCTIVE) SURGERY
bleeding, 4 hematurias, 3 azotemias, 2 catheter dislodgements, and 1 case of extravascular hemolytic anemia. A temperature higher than lOOoF was also noted in 18 cases. There were no allergic reactions requiring steroids. There were nine major complications in eight cases (22 percent) and one death (2.9 percent). These included three technical complications requiring surgery (two cases of proximal occlusion around an antegrade femoral catheter and one case of an intimal flap in the common iliac artery), three major hematologic complications (two retroperitoneal hematomas, one of which contributed to an acute myocardial infarction, and one case of gastrointestinal bleeding), two cerebrovascular accidents, and one death. Both cerebrovascular accidents occurred 24 to 48 hours after discontinuing streptolytic therapy and neither was associated with coagulation abnormalities. One was a hemorrhagic infarct in the left parietal region with evidence of old infarcts in the right parietal and left internal capsule on computerized tomographic scan; the second was an ischemic infarct in the right parietal region probably secondary to embolism from a left ventricular aneurysm. The death occurred in a 74 year old patient admitted with severe congestive heart failure in whom acute arterial occlusion developed. He was placed on streptolytic therapy for 12 hours, at which time it was discontinued because of progressive cardiac deterioration. There were 23 patients whose lowest fibrinogen level was less than 100 mg/dl(20 of whom had minor bleeding complications) and 8 whose lowest fibrinogen level was greater than 100 mg/dl(4 of whom had minor bleeding complications). Fibrinogen was not measured in six cases. The decrease in hematocrit values in the two groups averaged 8.02 and 6.9 percent; and the amount of blood transfused was 1.3 units and 1 unit, respectively. In the three patients with major hematologic complications, the lowest fibrinogen levels were 12, 82, and 115 mg/dl with transfusion requirement of 8,7, and 6 units, respectively.
13 (35%)
C
NO SURGERY
D
RECONSTRUCTIVE SURGERY
E
AMPUTATION
6 (16%)
5 (13.5%)
8 (22%)
5 (13.5%)
3. F/ow chart of therapeutic groups,
betes, and fibrinogen levels before and after treatment, as well as duration of therapy (Table I). In the former group, embolus was the most prevalent cause of occlusion (58 percent), followed by graft occlusion (21 percent) and atherosclerotic or thrombotic occlusion (21 percent) as opposed to 17 percent, 39 percent, and 44 percent, respectively, in the group in which fibrinolytic therapy failed. Of the cases of embolic origin (11 of 14 cases), 79 percent were treated successfully with fibrinolytic therapy, both without and with adjuvant vascular surgery. Only 36 percent of occluded vascular grafts (4 of 11 cases) and 33 percent of atherosclerotic or thrombotic occlusions (4 of 12 cases) were successfully treated with streptokinase or urokinase (Groups A and B). In 17 cases (46 percent) there was no audible Doppler signal in the involved ankle before initiation of therapy and in 12 of these cases (71 percent), treatment with fibrinolytic therapy was successful with an ankle-to-arm index of 0.71 in Group A and 0.62 in Group B after fibrinolytic therapy but before adjuvant surgical therapy. Of the patients in whom fibrinolytic therapy failed who needed surgery (Groups D and E), eight underwent reconstructive procedures, including four distal bypass grafts, two thrombectomies, and two inflow procedures. Five patients underwent amputations (four above the knee and one below the knee), none of which were believed to be reconstructable. Twenty-three of the 37 cases (62 percent) involved 36 complications, most of which were relatively minor but related to streptolytic therapy and included 8 cases of groin hematoma, 4 cases of catheter site TABLE I
Comments Threatened limb loss resulting from acute thromboembolic disease initiates decision-making processes regarding treatment modalities. Intraar-
Group Summary of Fibrinolytic Parameters Symptom Duration
Treatment Duration
Diabetes
Ankle-to-Arm index BT AS A0
Group
n
Ag8 WI
(days)
(h)
A :
13 5 6
73.3 66.6 55
6113 216 215
2.6 3.3 7.4
64 60 65
0.15 0.22 0.16
0.61 0.32 0.61
D E
6 5
57.6 71.2
418 315
12.1 10
51 64
0.20 0.10
0.14 0
37
65.75
17137
...
67
0.22
0.44
Total
Fibrinogen (mg/dU BT AT
Change in Hematocrit (“/)
d.83
402 357 303
66 160 96
9.1 5.6 5.7
c&s ...
354 442
94 110
5.8 9.4
329
97
7.1
A0 = after operation; AS = after streptokinase; AT = after treatment; BT = before treatment.
832
lhe American Journal ol Surgery
Surgical Implications
terial fibrinolytic therapy is appealing because of its ease of management, suitability for severely ill patients, and effectiveness in areas not treatable surgically. Complications, although frequent, are generally relatively minor. Nevertheless, surgical intervention sometimes becomes necessary to correct conditions exposed by intraarterial fibrinolytic therapy or when clot is refractory with the distal circulation remaining compromised. Indications for pursuing intraarterial fibrinolytic therapy in preference to surgery are sometimes vague. Acceptance of an operative approach when lytic therapy has been correct but ineffective allows optimal limb salvage. Indications for intraarterial fibrinolytic therapy include acute ischemia of either thrombotic or embolic origin [2]. Dardik et al [9] noted the greatest success when embolism or native vessel thrombosis, either peripherally or at the renal artery level, was etiologic. These events bring the patient to medical attention early. Difficulty in interpreting the meaning of “acute” used in the literature revolves around varied temporal definitions from less than 7 days to 2 months [4,6,9]. Dardik’s group [9] likewise noted that only 30 percent of thrombosed bypass grafts were successfully opened when either an intraarterial or an intravenous route was used. Although the Doppler technique has been suggested as helpful in selecting the modality of therapy for severe ischemia, we found it useful only for following patients. Reichle et al [IO] noted 9 of their 11 patients to have no Doppler pedal pressure before initiation of intraarterial fibrinolytic therapy. We had 17 of 37 cases in this category. In neither study did this necessarily portend a negative outcome. In fact, as Blaisdell et al [II] have suggested, this may represent an acute vasospastic response preventing early small vessel thrombosis and may indicate early intervention in the ischemic limb is taking place. Results of nearly all series indicate that intraarterial fibrinolytic therapy is contraindicated in those patients unable to pass the temporal requirement of 24 to 48 hours of additional ischemia. Reference is made to intraarterial fibrinolytic therapy being utilized in patients with limited surgical options. No criteria for making this clinical determination have been offered. Finally, a large percentage of patients (50 percent in our series) with acute &hernia were diabetics in whom peripheral neuropathy confused clinical examination findings. The experience and judgment of the surgeon will continue to be required. Surgically inaccessible thrombus or strong medical contraindications to surgery are the most urgent indicators for utilizing lytic therapy. Although embolectomies may be performed with the patient under local infiltrative anesthesia, more involved thrombosis, or even embolization in atherosclerotic vessels might require more involved surgery and prolonged time. This increases the risk in the mediVolume 148, December 1984
of Fibrinolytic
Therapy
cally compromised patient. Digital artery embolization and thrombosis remain beyond the realm of current operative vascular surgery. Likewise, options are sought when open infected wounds near the operative site exist. Although complications cannot be totally eliminated, we concur with Bell and Meek [12] in pursuing careful management procedures to limit such untoward results. Specifically, careful initial hematologic screening and serial follow-up in an intensive care facility should be adhered to. Minimal patient handling, avoidance of antiplatelet aggregating agents, and careful use of anticoagulants is wise management. Serial fibrinogen and hemoglobin hematocrit determinations provide adequate indicators of a lytic state while also providing clues of overly aggressive therapy. Katzen and Van Breda [I], using intraarterial streptokinase infusion of 5,000 units/hour, noted that clotting parameters and fibrinogen levels remained within normal limits in all patients despite success in 11 of 12 patients. Perhaps their short duration of therapy is factorial. Bell [8] has reported that the only test required to monitor and manage a patient receiving either streptokinase or urokinase is thrombin time. Berni et al [6], utilizing a dosage of 5,000 units/hour of streptokinase, has noted fibrinogen to be the first parameter to decrease, usually within 16 hours. They noted increased hemorrhagic problems when fibrinogen levels decreased below 100 mg/dl. Van Breda et al [7] have suggested that monitoring hematologic parameters cannot predict the safety or efficacy of thrombolytic infusion. They further noted that their two major bleeding complications occurred with decreased serum fibrinogen levels, but gave no specific values. Rush et al [4] reported that in four of six patients with bleeding complications, the plasma fibrinogen levels were decreased below 100 mg/dl. We have attempted to decrease fibrinogen close to this arbitrary level without dropping below it. Intraarterial fibrinolytic therapy is difficult if not contraindicated after recent surgical intervention. Lytic therapy employed preoperatively might reveal etiologic stenosis or might fail to clear the offending blockage. Discontinuation of fibrinolysin, infusion of fresh frozen plasma, or more ideally, cryoprecepitam, can allow surgical intervention within the hour. Operative intervention became necessary in many series despite reasonable success with the fibrinolytic agents [4,6,7,9]. Often, transluminal angioplasty or direct operative intervention was undertaken to correct severe anastomotic stenosis. Dardik et al [9] have reported that attempts to correct graft failure by surgical treatment when lysis failed were often unsuccessful. Our experience with lytic failure in eight patients undergoing reconstructive salvage operations was positive. All eight patients had successful surgical intervention resulting in an increase of the ankle-to-arm index of 0.83 for the group. 033
Hurley
et
al
Ideally, intraarterial fibrinolytic therapy provides total resolution of thromboembolic disease confirmed by noninvasive and angiographic studies. Patients are then converted to intravenous heparin and eventually oral warfarin therapy. Perhaps the group to eliminate from intraarterial fibrinolytic therapy is Group D, in which the Doppler indices deteriorated and surgery was used successfully to salvage the limbs. The relatively long period of ischemia of 11.2 days in this group is also certainly a factor. Hess et al [3], using an aggressive percutaneous approach with streptokinase and transluminal angioplasty, might have been more successful than we were with these patients. We await confirmation of their success by others. At the present time, combining well-controlled intraarterial fibrinolytic therapy with follow-up surgical intervention when indicated offers adequate salvage of severely ischemic limbs. Cost-effectiveness probably makes this a questionable approach in otherwise healthy patients who are seemingly surgically treatable. Likewise, it is doubtful that intraarterial fibrinolytic therapy as a sole treatment modality will ever be employed in the majority of patients who sustain thromboembolic events. Nevertheless, it can be a highly effective alternative to surgery, perhaps limiting the surgical morbidity and mortality in poor-risk patients.
Intraarterial fibrinolytic therapy was used in 37 cases (34 patients) of severe peripheral ischemia. Nineteen patients (56 percent) required surgical intervention (5 amputations and 14 successful reconstructive procedures). Twenty-four patients (71 percent) were significantly improved (average ankle-to-arm index 0.84), whereas only 5 patients (15 percent) lost their limbs. Five patients were angiographically unchanged with no or slight improvement in the ankle-to-arm index (0.22 to 0.32) and were discharged on anticoagulant therapy. One death and two cerebrovascular accidents occurred. The usefulness of intraarterial fibrinolytic therapy needs to be evaluated within the total realm of vascular surgery. It offers options for therapy where previously none existed. Some situations might be treated equally well with either intraarterial fibrinolytic therapy or surgery. Finally, surgery might be required to maintain initial successful results with intraarterial fibrinolytic therapy or to rescue intraarterial fibrinolytic therapy failures in striving to achieve superior results in limb salvage. References 1. Katzen BT, van Breda A. Low dose streptokinase in the treatment of arterial occlusions. Am J Radio1 1981;136:11718. 2. Sharma GVRK, Cella G, Parisi A, Sasahara A. Thrombolytic therapy. N Engl J Med 1982;306: 1268-76. 3. Hess H, lngrisch H, Mietaschk A, Rath H. Local lowdose a34
4.
5. 6.
7.
8.
9.
10.
11.
12.
thrombolytic therapy of peripheral arterial occlusions. N Engl J Med 1982;307:1627-30. Rush DS, Gewerta BL, Lu C-T, et al. Selective infusion of streptokinase for arterial thrombosis. Surgery 1983;93: 828-33. Persson AV, Thompson JE, Patman D. Streptokinase as an adjunct to arterial surgery. Arch Surg;1973;107:779-84. Berni GA, Bandy DF, Zierler RE, Thiele BL, Strandness DE. Streptokinase treatment of acute arterial occlusion. Ann Surg 1983;198:185-93. van Breda A, Robinson JC, Feldman L, et al. Local thrombolysis in the treatment of arterial graft occlusions. J Vast Surg 1984;1:103-12. Bell WR. Thrombolytic therapy: a new realistic approach in treatment of thromboocclusive vascular disease. Surgery 1983;92:913-4. Dardik H, Sussman BC, Kahn M, et al. Lysis of arterial clot by intravenous or intra-arterial administration of streptokinase. Surg, Gynecol Obstet 1984; 158: 137-40. Reichle FA, Rao NS, Chang KHY, Marder V, Algazy K. Thrombolysis of acute or subacute nonembolic arterial thrombosis. J Surg Res 1977;22:202-6. Blaisdell FW, Steele M, Allen RE. Management of acute lower extremity arterial ischemia due to embolism and thrombosis. Surgery 1978;84:822-33. Bell WR, Meek AG. Guideline for ths use of thrombolytic agents. N Engl J Med 1979;301:1266-70.
Discussion Robert W. Barnes (Little Rock AR): The authors made the statement, “Indications for pursuing intraarterial fibrinolytic therapy in preference to surgery are sometimes vague.” Unfortunately, I am still left with that impression, but I hasten to add that even in my own practice, I vascillate depending on what the outcome was in the last patient I referred to the radiologist. I think when one is dealing with fibrinolytic therapy, one has to be fairly clear about the indications and what the surgical limitations are. Ideally, of course, we would like to use it in situations of distal thrombi or emboli that are really surgically incurable, and we have had successes in those areas. The second area that would represent the greatest application in my own practice is the patient with a thrombosed femoropopliteal or femorotibial graft which, if it can be lysed, may permit visualization of an offending lesion that could then subsequently be treated by balloon dilatation. Unfortunately, our radiologists have frequently been unable to cannulate the femorpopliteal graft orifice. As the authors have pointed out, the best results are associated with infusions directed distally with a catheter in the thrombus. This raises the question of whether or not we should make the orifice of our femoral distal bypasses radiopaque in a manner similar to that employed by some cardiac surgeons for coronary bypass grafts to facilitate proper positioning of catheters. Dr. Hurley, what are your current indications for streptokinase therapy versus operative therapy? What do you ask of your radiologist in terms of the catheter position or the direction of the infusion? You have pointed out the need for fibrinogen monitoring because of the increased risk associated with systemic effects, and yet 15 percent of your patients did not have such monitoring studies. What was the reason for that? You implied that postoperative application of this technique is probably not feasible, although some investigators have suggested that distally directed catheters can permit this form of therapy. I would like your further thoughts about that. My only final comment is that if one is going to pursue this technique, one has The American Journal of Surgery
Surgical Implications of Fibrinolytic Therapy
to think about it long before any intervention is started because an ill-advised arteriographic puncture site or an ill-advised operation may negate using this potentially helpful form of therapy. George J. Collins (Fort Sam Houston, TX): The authors have addressed themselves to the difficult task of defining the role of streptokinase in the management of patients with severe limb ischemia by retrospectively reviewing the outcome in such patients who received the drug at their institution. Their results were largely negative and document the high percentage of major complications. Among these were one death, two cerebrovascular accidents, one myocardial infarction, three hemorrhagic complications requiring transfusion of 6 to 8 units of blood, and one technical complication requiring operation. Although few could defend such results in a comparably small operative series, the streptokinase enthusiasts seldom factor such complications into the risk-benefit equation when considering the drug. Most importantly, the data presented demonstrate that only a small percentage (35 percent of the patients) clearly benefit from streptokinase alone, and another small contingent may benefit, but only if adjunctive surgery is also used. The data as presented do not answer the important question of whether or not most of these patients could have been adequately treated by surgery alone. Dr. Hurley, will you comment on that? Finally, the data show that in many instances, the effects of intraarterial streptokinase become systemic at some point. This negates the benefit of and greatly increases the risk of intraarterial infusion. One wonders if equivalent results and fewer complications would accrue if one were to administer streptokinase to clearly defined subgroups of patients only by the intravenous route, delaying arteriography and the risk of puncture site bleeding until streptokinase either clearly failed or clearly succeeded. Dr. Hurley, I hope you will express your views on intravenous streptokinase. Dr. Hurley, would you further define for us the types of patients in whom streptokinase is clearly more effective and no more risky than immediate heparinixation followed by arteriography and corrective surgery?
Volume 148. December 1984
Joseph J. Hurley (closing): I think there are good indications for lytic therapy, particularly distal thromboemboli, that is thrombi at the ankle level or below, which Dr. Barnes mentioned and which we may not have emphasized as much in this paper. In addition, its use in medically compromised patients is beneficial. Dr. Andrew Dale recently published an article on doing exactly what Dr. Collins has suggested: giving heparin, then operating on all patients under local anesthesia. He had a 73 percent limb salvage rate, as opposed to our 85 percent rate, and he had almost a 12 percent mortality rate, opposed to our less than 3 percent rate. We had hoped that lytic therapy would be most successful in cases of bypass graft failure. This has not been the case, perhaps because of catheter positioning. It should be antegrade not retrograde. The technique of Hess, which was later described by Hargrove, that Dr. Barnes mentioned (antegrade catheterization combined with balloon angioplasty) might be more successful in this group and in fact, might take care of the problem of any therapy after the stenosis is uncovered. The five patients who did not have fibrinogen levels determined had thrombin time studies early in our series, but we found that they were too insensitive in comparison to fibrinogen levels. No patients in our group had surgery less than 6 weeks before we administered lytic therapy. I would be very reluctant to administer lytic therapy sooner than that. I think the comment about administering lytic therapy before intended surgery is quite real, Dr. Collins, the death in our series was not really related to lytic therapy. It was of a patient who perhaps should not have even been treated. Clearly, the eight patients in Group D who required surgery did not get any better with lytic therapy. Anatomically, they did not benefit from the lytic therapy. If we could identify this group and avoid lytic therapy; it would be preferable. Neither we nor other investigators, to our knowledge, have been able to identify better indicators than what we have reported. Lytic therapy is fraught with complications. Nevertheless, I think it is something that should be in the armentarium of every vascular surgeon, but I suspect its role is quite small, being useful in probably 10 to 15 percent of patients.
835
Joseph J. Hurley, MD, St. Louis, Missouri Michael J. Burrell, MD, St. Louis, Missouri Arthur I. Auer, MD, St. Louis, Missouri John J. Woods, Jr., MD, St. Louis, Missouri H. Bradley Blnnington,MD, St. Louis, Missouri Falls B. Hershey, MD, St. Louis, Missouri
Intraarterial fibrinolytic therapy for severe peripheral ischemia is a comparatively new modality frequently requiring operative intervention to obtain bptimal results. Most current reports describe lytic therapy utilized alone or in conjunction with percutaneous angioplasty [I-51. Surgery, although not always necessary, can help ensure continued initial good results or salvage ischemic limbs when prior intraarterial fibrinolytic therapy has been unsuccessful [6-8]. Our purpose is to detail the surgical implications of intraarterial fibrinolytic therapy in 37 cases (34 patients) for management of peripheral arterial ischemia.
Material and Methods This is a retrospective review of patients treated with intraarterial streptokinase or urokinase from July 1982 to March 1984. No patients were excluded from the study. Intraarterial fibrinolytic therapy was used in all 37 cases (34 patients). Patients were treated with streptokinase unless they had already received streptokinase within the previous 12 months, in which case urokinase was admin-
istered (three patients). Femoral angiography was performed before initiation of therapy, and streptokinase or urokinase was given intraarterially, either through the retograde angiograph catheter with the catheter tip in the iliac artery (26 cases, 46 percent successful) or through a catheter placed antegrade with the catheter tip at the site of the occlusion (11 cases, 64 percent successful). A bolus of 5,000 to 20,000 units of streptokinase was given over 20 minutes followed by a continuous infusion ranging from 3,000 to 19,000 units/hour of streptokinase (average 8,700 units/hour). The dose was titrated to achieve a mild systemic effect, with the fibrinogen level decreasing to around 100 mg/dl. Much higher doses of urokinase were needed to achieve the same effect (75,000 and 90,000 units/hour) From St. John’s Mercy Medical Center, Department of Surgery, Section of Vascular Surgery, St. Louis, Missouri. kWests for reprints should be addressed to Joseph J. Hurley, MD, 621 South New BallasRoad, Suite 307, St. Louis, Missouri 63141. Presented at the 36th Annual Weting of the Southwestern Surgical Congress. Honolulu, Hawaii, April 21-28, 1984.
830
in the two patients in whom a systemic lytic state was achieved. The patients were treated for an average of 671/2 hours. Fibrinogen and hematocrit values were obtained at 6 to 8 hour intervals. Portable angiography through the intraarterial catheter was performed on a daily basis in patients without chronic renal disease. The ankle-to-arm index was also used to monitor therapy. Results Successful fibrinolytic therapy (19 cases, 51 percent) included 13 cases in which no surgery was required (Group A) (Figure 1) and 6 cases in which adjuvant vascUlar surgery was performed (Group B) (Figure 2). This latter group (Figure 3) included patients whose surgery was made possible by fibrinolytic therapy opening an occluded graft and demonstrating a correctable anatomic cause for graft failure (three cases), opening the distal circulation which allowed bypass grafting to the newly opened segment (two cases), and correcting a complication of the catheter itself (intimal flap, common iliac artery) after opening the distal circulation (one case). Failures included five cases in which no further surgery was performed (Group C), eight cases that required reconstructive surgery (Group D), and five cases in which amputation was performed (Group E). Group C included one patient who was admitted with severe congestive heart failure and- died and four patients who had relatively recent onset of severe ischemia (average ankle-to-arm index of 0.22 with no open ulceration or rest pain) who were otherwise not reconstructable but did not require amputation. Three of these four patients had occluded vascular grafts. Patients who were successfully treated with fibrinolytic therapy (Groups A and B) differed from those in whom treatment failed (Groups C, D, and E) in the duration of symptoms before initiation of therapy. Groups were comparable with respect to the pretreatment ankle-to-arm index, incidence of dia-
TheAmerican
Journal of Surgery
Surgical Implications of Fibrinolytic Therapy
Figure 1. Anglographk documentatkm of occkmkm of d/stat popllteal, proximal anterior tlblal, and t/b/al peroneal artertes (A), showed partial resolution at 48 hours ( B) and complete clearance afler 5 days ( C) of Intraarterial streptoklnase lnfWon.
whkh
Flgun, 2. proxknel qenlng of occluded In situ veln bypass grafl ls demonstrated after 18 horn of lntraatierlal uroklnase therapy (A). llm upper end of the opened graft reveals clot adherence to the valve cusp, which was not totally dlsmpted ( B). The excelhbntdistal clrwlatlon ls shown after successful lytkz therapy (C).
Vohmo 148, December 1884
831
Hurley et
I
al
STREPTOLYTIC THERAPY SUCCESSRJL 19 (51%)
II
<
STREPTOLYTIC FAILURE 18 (49%)
t Figure
A
NO SURGERY
0
ADJUVANT (RECONSTRUCTIVE) SURGERY
bleeding, 4 hematurias, 3 azotemias, 2 catheter dislodgements, and 1 case of extravascular hemolytic anemia. A temperature higher than lOOoF was also noted in 18 cases. There were no allergic reactions requiring steroids. There were nine major complications in eight cases (22 percent) and one death (2.9 percent). These included three technical complications requiring surgery (two cases of proximal occlusion around an antegrade femoral catheter and one case of an intimal flap in the common iliac artery), three major hematologic complications (two retroperitoneal hematomas, one of which contributed to an acute myocardial infarction, and one case of gastrointestinal bleeding), two cerebrovascular accidents, and one death. Both cerebrovascular accidents occurred 24 to 48 hours after discontinuing streptolytic therapy and neither was associated with coagulation abnormalities. One was a hemorrhagic infarct in the left parietal region with evidence of old infarcts in the right parietal and left internal capsule on computerized tomographic scan; the second was an ischemic infarct in the right parietal region probably secondary to embolism from a left ventricular aneurysm. The death occurred in a 74 year old patient admitted with severe congestive heart failure in whom acute arterial occlusion developed. He was placed on streptolytic therapy for 12 hours, at which time it was discontinued because of progressive cardiac deterioration. There were 23 patients whose lowest fibrinogen level was less than 100 mg/dl(20 of whom had minor bleeding complications) and 8 whose lowest fibrinogen level was greater than 100 mg/dl(4 of whom had minor bleeding complications). Fibrinogen was not measured in six cases. The decrease in hematocrit values in the two groups averaged 8.02 and 6.9 percent; and the amount of blood transfused was 1.3 units and 1 unit, respectively. In the three patients with major hematologic complications, the lowest fibrinogen levels were 12, 82, and 115 mg/dl with transfusion requirement of 8,7, and 6 units, respectively.
13 (35%)
C
NO SURGERY
D
RECONSTRUCTIVE SURGERY
E
AMPUTATION
6 (16%)
5 (13.5%)
8 (22%)
5 (13.5%)
3. F/ow chart of therapeutic groups,
betes, and fibrinogen levels before and after treatment, as well as duration of therapy (Table I). In the former group, embolus was the most prevalent cause of occlusion (58 percent), followed by graft occlusion (21 percent) and atherosclerotic or thrombotic occlusion (21 percent) as opposed to 17 percent, 39 percent, and 44 percent, respectively, in the group in which fibrinolytic therapy failed. Of the cases of embolic origin (11 of 14 cases), 79 percent were treated successfully with fibrinolytic therapy, both without and with adjuvant vascular surgery. Only 36 percent of occluded vascular grafts (4 of 11 cases) and 33 percent of atherosclerotic or thrombotic occlusions (4 of 12 cases) were successfully treated with streptokinase or urokinase (Groups A and B). In 17 cases (46 percent) there was no audible Doppler signal in the involved ankle before initiation of therapy and in 12 of these cases (71 percent), treatment with fibrinolytic therapy was successful with an ankle-to-arm index of 0.71 in Group A and 0.62 in Group B after fibrinolytic therapy but before adjuvant surgical therapy. Of the patients in whom fibrinolytic therapy failed who needed surgery (Groups D and E), eight underwent reconstructive procedures, including four distal bypass grafts, two thrombectomies, and two inflow procedures. Five patients underwent amputations (four above the knee and one below the knee), none of which were believed to be reconstructable. Twenty-three of the 37 cases (62 percent) involved 36 complications, most of which were relatively minor but related to streptolytic therapy and included 8 cases of groin hematoma, 4 cases of catheter site TABLE I
Comments Threatened limb loss resulting from acute thromboembolic disease initiates decision-making processes regarding treatment modalities. Intraar-
Group Summary of Fibrinolytic Parameters Symptom Duration
Treatment Duration
Diabetes
Ankle-to-Arm index BT AS A0
Group
n
Ag8 WI
(days)
(h)
A :
13 5 6
73.3 66.6 55
6113 216 215
2.6 3.3 7.4
64 60 65
0.15 0.22 0.16
0.61 0.32 0.61
D E
6 5
57.6 71.2
418 315
12.1 10
51 64
0.20 0.10
0.14 0
37
65.75
17137
...
67
0.22
0.44
Total
Fibrinogen (mg/dU BT AT
Change in Hematocrit (“/)
d.83
402 357 303
66 160 96
9.1 5.6 5.7
c&s ...
354 442
94 110
5.8 9.4
329
97
7.1
A0 = after operation; AS = after streptokinase; AT = after treatment; BT = before treatment.
832
lhe American Journal ol Surgery
Surgical Implications
terial fibrinolytic therapy is appealing because of its ease of management, suitability for severely ill patients, and effectiveness in areas not treatable surgically. Complications, although frequent, are generally relatively minor. Nevertheless, surgical intervention sometimes becomes necessary to correct conditions exposed by intraarterial fibrinolytic therapy or when clot is refractory with the distal circulation remaining compromised. Indications for pursuing intraarterial fibrinolytic therapy in preference to surgery are sometimes vague. Acceptance of an operative approach when lytic therapy has been correct but ineffective allows optimal limb salvage. Indications for intraarterial fibrinolytic therapy include acute ischemia of either thrombotic or embolic origin [2]. Dardik et al [9] noted the greatest success when embolism or native vessel thrombosis, either peripherally or at the renal artery level, was etiologic. These events bring the patient to medical attention early. Difficulty in interpreting the meaning of “acute” used in the literature revolves around varied temporal definitions from less than 7 days to 2 months [4,6,9]. Dardik’s group [9] likewise noted that only 30 percent of thrombosed bypass grafts were successfully opened when either an intraarterial or an intravenous route was used. Although the Doppler technique has been suggested as helpful in selecting the modality of therapy for severe ischemia, we found it useful only for following patients. Reichle et al [IO] noted 9 of their 11 patients to have no Doppler pedal pressure before initiation of intraarterial fibrinolytic therapy. We had 17 of 37 cases in this category. In neither study did this necessarily portend a negative outcome. In fact, as Blaisdell et al [II] have suggested, this may represent an acute vasospastic response preventing early small vessel thrombosis and may indicate early intervention in the ischemic limb is taking place. Results of nearly all series indicate that intraarterial fibrinolytic therapy is contraindicated in those patients unable to pass the temporal requirement of 24 to 48 hours of additional ischemia. Reference is made to intraarterial fibrinolytic therapy being utilized in patients with limited surgical options. No criteria for making this clinical determination have been offered. Finally, a large percentage of patients (50 percent in our series) with acute &hernia were diabetics in whom peripheral neuropathy confused clinical examination findings. The experience and judgment of the surgeon will continue to be required. Surgically inaccessible thrombus or strong medical contraindications to surgery are the most urgent indicators for utilizing lytic therapy. Although embolectomies may be performed with the patient under local infiltrative anesthesia, more involved thrombosis, or even embolization in atherosclerotic vessels might require more involved surgery and prolonged time. This increases the risk in the mediVolume 148, December 1984
of Fibrinolytic
Therapy
cally compromised patient. Digital artery embolization and thrombosis remain beyond the realm of current operative vascular surgery. Likewise, options are sought when open infected wounds near the operative site exist. Although complications cannot be totally eliminated, we concur with Bell and Meek [12] in pursuing careful management procedures to limit such untoward results. Specifically, careful initial hematologic screening and serial follow-up in an intensive care facility should be adhered to. Minimal patient handling, avoidance of antiplatelet aggregating agents, and careful use of anticoagulants is wise management. Serial fibrinogen and hemoglobin hematocrit determinations provide adequate indicators of a lytic state while also providing clues of overly aggressive therapy. Katzen and Van Breda [I], using intraarterial streptokinase infusion of 5,000 units/hour, noted that clotting parameters and fibrinogen levels remained within normal limits in all patients despite success in 11 of 12 patients. Perhaps their short duration of therapy is factorial. Bell [8] has reported that the only test required to monitor and manage a patient receiving either streptokinase or urokinase is thrombin time. Berni et al [6], utilizing a dosage of 5,000 units/hour of streptokinase, has noted fibrinogen to be the first parameter to decrease, usually within 16 hours. They noted increased hemorrhagic problems when fibrinogen levels decreased below 100 mg/dl. Van Breda et al [7] have suggested that monitoring hematologic parameters cannot predict the safety or efficacy of thrombolytic infusion. They further noted that their two major bleeding complications occurred with decreased serum fibrinogen levels, but gave no specific values. Rush et al [4] reported that in four of six patients with bleeding complications, the plasma fibrinogen levels were decreased below 100 mg/dl. We have attempted to decrease fibrinogen close to this arbitrary level without dropping below it. Intraarterial fibrinolytic therapy is difficult if not contraindicated after recent surgical intervention. Lytic therapy employed preoperatively might reveal etiologic stenosis or might fail to clear the offending blockage. Discontinuation of fibrinolysin, infusion of fresh frozen plasma, or more ideally, cryoprecepitam, can allow surgical intervention within the hour. Operative intervention became necessary in many series despite reasonable success with the fibrinolytic agents [4,6,7,9]. Often, transluminal angioplasty or direct operative intervention was undertaken to correct severe anastomotic stenosis. Dardik et al [9] have reported that attempts to correct graft failure by surgical treatment when lysis failed were often unsuccessful. Our experience with lytic failure in eight patients undergoing reconstructive salvage operations was positive. All eight patients had successful surgical intervention resulting in an increase of the ankle-to-arm index of 0.83 for the group. 033
Hurley
et
al
Ideally, intraarterial fibrinolytic therapy provides total resolution of thromboembolic disease confirmed by noninvasive and angiographic studies. Patients are then converted to intravenous heparin and eventually oral warfarin therapy. Perhaps the group to eliminate from intraarterial fibrinolytic therapy is Group D, in which the Doppler indices deteriorated and surgery was used successfully to salvage the limbs. The relatively long period of ischemia of 11.2 days in this group is also certainly a factor. Hess et al [3], using an aggressive percutaneous approach with streptokinase and transluminal angioplasty, might have been more successful than we were with these patients. We await confirmation of their success by others. At the present time, combining well-controlled intraarterial fibrinolytic therapy with follow-up surgical intervention when indicated offers adequate salvage of severely ischemic limbs. Cost-effectiveness probably makes this a questionable approach in otherwise healthy patients who are seemingly surgically treatable. Likewise, it is doubtful that intraarterial fibrinolytic therapy as a sole treatment modality will ever be employed in the majority of patients who sustain thromboembolic events. Nevertheless, it can be a highly effective alternative to surgery, perhaps limiting the surgical morbidity and mortality in poor-risk patients.
Intraarterial fibrinolytic therapy was used in 37 cases (34 patients) of severe peripheral ischemia. Nineteen patients (56 percent) required surgical intervention (5 amputations and 14 successful reconstructive procedures). Twenty-four patients (71 percent) were significantly improved (average ankle-to-arm index 0.84), whereas only 5 patients (15 percent) lost their limbs. Five patients were angiographically unchanged with no or slight improvement in the ankle-to-arm index (0.22 to 0.32) and were discharged on anticoagulant therapy. One death and two cerebrovascular accidents occurred. The usefulness of intraarterial fibrinolytic therapy needs to be evaluated within the total realm of vascular surgery. It offers options for therapy where previously none existed. Some situations might be treated equally well with either intraarterial fibrinolytic therapy or surgery. Finally, surgery might be required to maintain initial successful results with intraarterial fibrinolytic therapy or to rescue intraarterial fibrinolytic therapy failures in striving to achieve superior results in limb salvage. References 1. Katzen BT, van Breda A. Low dose streptokinase in the treatment of arterial occlusions. Am J Radio1 1981;136:11718. 2. Sharma GVRK, Cella G, Parisi A, Sasahara A. Thrombolytic therapy. N Engl J Med 1982;306: 1268-76. 3. Hess H, lngrisch H, Mietaschk A, Rath H. Local lowdose a34
4.
5. 6.
7.
8.
9.
10.
11.
12.
thrombolytic therapy of peripheral arterial occlusions. N Engl J Med 1982;307:1627-30. Rush DS, Gewerta BL, Lu C-T, et al. Selective infusion of streptokinase for arterial thrombosis. Surgery 1983;93: 828-33. Persson AV, Thompson JE, Patman D. Streptokinase as an adjunct to arterial surgery. Arch Surg;1973;107:779-84. Berni GA, Bandy DF, Zierler RE, Thiele BL, Strandness DE. Streptokinase treatment of acute arterial occlusion. Ann Surg 1983;198:185-93. van Breda A, Robinson JC, Feldman L, et al. Local thrombolysis in the treatment of arterial graft occlusions. J Vast Surg 1984;1:103-12. Bell WR. Thrombolytic therapy: a new realistic approach in treatment of thromboocclusive vascular disease. Surgery 1983;92:913-4. Dardik H, Sussman BC, Kahn M, et al. Lysis of arterial clot by intravenous or intra-arterial administration of streptokinase. Surg, Gynecol Obstet 1984; 158: 137-40. Reichle FA, Rao NS, Chang KHY, Marder V, Algazy K. Thrombolysis of acute or subacute nonembolic arterial thrombosis. J Surg Res 1977;22:202-6. Blaisdell FW, Steele M, Allen RE. Management of acute lower extremity arterial ischemia due to embolism and thrombosis. Surgery 1978;84:822-33. Bell WR, Meek AG. Guideline for ths use of thrombolytic agents. N Engl J Med 1979;301:1266-70.
Discussion Robert W. Barnes (Little Rock AR): The authors made the statement, “Indications for pursuing intraarterial fibrinolytic therapy in preference to surgery are sometimes vague.” Unfortunately, I am still left with that impression, but I hasten to add that even in my own practice, I vascillate depending on what the outcome was in the last patient I referred to the radiologist. I think when one is dealing with fibrinolytic therapy, one has to be fairly clear about the indications and what the surgical limitations are. Ideally, of course, we would like to use it in situations of distal thrombi or emboli that are really surgically incurable, and we have had successes in those areas. The second area that would represent the greatest application in my own practice is the patient with a thrombosed femoropopliteal or femorotibial graft which, if it can be lysed, may permit visualization of an offending lesion that could then subsequently be treated by balloon dilatation. Unfortunately, our radiologists have frequently been unable to cannulate the femorpopliteal graft orifice. As the authors have pointed out, the best results are associated with infusions directed distally with a catheter in the thrombus. This raises the question of whether or not we should make the orifice of our femoral distal bypasses radiopaque in a manner similar to that employed by some cardiac surgeons for coronary bypass grafts to facilitate proper positioning of catheters. Dr. Hurley, what are your current indications for streptokinase therapy versus operative therapy? What do you ask of your radiologist in terms of the catheter position or the direction of the infusion? You have pointed out the need for fibrinogen monitoring because of the increased risk associated with systemic effects, and yet 15 percent of your patients did not have such monitoring studies. What was the reason for that? You implied that postoperative application of this technique is probably not feasible, although some investigators have suggested that distally directed catheters can permit this form of therapy. I would like your further thoughts about that. My only final comment is that if one is going to pursue this technique, one has The American Journal of Surgery
Surgical Implications of Fibrinolytic Therapy
to think about it long before any intervention is started because an ill-advised arteriographic puncture site or an ill-advised operation may negate using this potentially helpful form of therapy. George J. Collins (Fort Sam Houston, TX): The authors have addressed themselves to the difficult task of defining the role of streptokinase in the management of patients with severe limb ischemia by retrospectively reviewing the outcome in such patients who received the drug at their institution. Their results were largely negative and document the high percentage of major complications. Among these were one death, two cerebrovascular accidents, one myocardial infarction, three hemorrhagic complications requiring transfusion of 6 to 8 units of blood, and one technical complication requiring operation. Although few could defend such results in a comparably small operative series, the streptokinase enthusiasts seldom factor such complications into the risk-benefit equation when considering the drug. Most importantly, the data presented demonstrate that only a small percentage (35 percent of the patients) clearly benefit from streptokinase alone, and another small contingent may benefit, but only if adjunctive surgery is also used. The data as presented do not answer the important question of whether or not most of these patients could have been adequately treated by surgery alone. Dr. Hurley, will you comment on that? Finally, the data show that in many instances, the effects of intraarterial streptokinase become systemic at some point. This negates the benefit of and greatly increases the risk of intraarterial infusion. One wonders if equivalent results and fewer complications would accrue if one were to administer streptokinase to clearly defined subgroups of patients only by the intravenous route, delaying arteriography and the risk of puncture site bleeding until streptokinase either clearly failed or clearly succeeded. Dr. Hurley, I hope you will express your views on intravenous streptokinase. Dr. Hurley, would you further define for us the types of patients in whom streptokinase is clearly more effective and no more risky than immediate heparinixation followed by arteriography and corrective surgery?
Volume 148. December 1984
Joseph J. Hurley (closing): I think there are good indications for lytic therapy, particularly distal thromboemboli, that is thrombi at the ankle level or below, which Dr. Barnes mentioned and which we may not have emphasized as much in this paper. In addition, its use in medically compromised patients is beneficial. Dr. Andrew Dale recently published an article on doing exactly what Dr. Collins has suggested: giving heparin, then operating on all patients under local anesthesia. He had a 73 percent limb salvage rate, as opposed to our 85 percent rate, and he had almost a 12 percent mortality rate, opposed to our less than 3 percent rate. We had hoped that lytic therapy would be most successful in cases of bypass graft failure. This has not been the case, perhaps because of catheter positioning. It should be antegrade not retrograde. The technique of Hess, which was later described by Hargrove, that Dr. Barnes mentioned (antegrade catheterization combined with balloon angioplasty) might be more successful in this group and in fact, might take care of the problem of any therapy after the stenosis is uncovered. The five patients who did not have fibrinogen levels determined had thrombin time studies early in our series, but we found that they were too insensitive in comparison to fibrinogen levels. No patients in our group had surgery less than 6 weeks before we administered lytic therapy. I would be very reluctant to administer lytic therapy sooner than that. I think the comment about administering lytic therapy before intended surgery is quite real, Dr. Collins, the death in our series was not really related to lytic therapy. It was of a patient who perhaps should not have even been treated. Clearly, the eight patients in Group D who required surgery did not get any better with lytic therapy. Anatomically, they did not benefit from the lytic therapy. If we could identify this group and avoid lytic therapy; it would be preferable. Neither we nor other investigators, to our knowledge, have been able to identify better indicators than what we have reported. Lytic therapy is fraught with complications. Nevertheless, I think it is something that should be in the armentarium of every vascular surgeon, but I suspect its role is quite small, being useful in probably 10 to 15 percent of patients.
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