Thrombolysis of acute or subacute nonembolic arterial thrombosis

JOURNAL

OF SURGICAL

Thrombolysis FREDERICK

RESEARCH

22,202-208 (1977)

of Acute or Subacute

A. REICHLE,

Nonembolic

Arterial

Thrombosis’

M.D., NARASIMHA S. RAO, M.D., KAM H. Y. CHANG, M.D., M.D., AND KENNETH ALGAZY, M.D.

VICTOR MARDER,

Section of Peripheral Vascular Surgery, Department of Surgery, and Specialized Center for Research in Thrombosis, Temple University Health Sciences Center, 3400 North Broad Street, Philadelphia, Pennsylvania 19140

Submitted for publication November 23, 1976

The cause of arterial occlusion in patients with peripheral arterial disease is usually atherosclerosis. However, arterial thrombosis is at times associated with the intrinsic arterial disease. Progressive arterial stenosis by atherosclerosis may cause decreased arterial flow and eventual intra-arterial thrombosis. This is manifested clinically as an acute or subacute exacerbation of chronic arterial insufficiency. The objective of this study was to evaluate the capability of thrombolysis by Streptokinase in acute or subacute exacerbations of chronic arterial occlusive disease by randomized single-blind comparison to standard anticoagulant therapy.

mented by determination of Doppler pedal blood pressures. Pedal blood pressure was determined by Doppler auscultation over dorsalis pedis or posterior tibial arteries distal to a sphygmomanometer cuff in the calf. Pallor and decreased temperature were consistent findings in the acutely ischemic lower extremity. Rubor was not a consistent finding in the acutely ischemic extremity. Extremity temperature, color, and neurological function was carefully assessed to determine whether or not the limb was threatened with imminent tissue loss. A clinical judgment regarding the immediate survival of the extremity was reached in each patient prior to randomization. Patients with hemorrhagic diatheses associated with liver disease, recent history METHODS of peptic ulcer disease, or history of gastrointestinal hemorrhage were excluded Patient Selection from the study. Patients with a history of Seventeen consecutive patients with cerebral vascular accident or carotid artery recent (l- 14 days) onset of nonembolic bruit were also excluded from the study. arterial occlusion, in whom severe ischemia Patients having had any invasive study was not imminently threatening limb sur- within 2 weeks prior to the onset of arterial vival, were randomized into two groups. insufficiency were not randomized into the One group received either fibrinolytic study. Arteriograms were generally not (streptokinase) or routine anticoagulant performed prior to therapy because of the (heparin) therapy. Severe ischemia of the frequency of hemorrhage associated with lower extremity was documented primarily fibrinolytic therapy in patients who have by routine physical examination and supple- had arterial punctures. Eleven patients (seven male, four female) received strepto1 This work was performed during the tenure of kinase and six patients (three male, three an Established Investigatorship of the American female) received heparin. Criteria for exHeart Association. Supported in part by a grant from the Heart Association of Southeastern Pennsyl- clusion from the study included altered sensory function such as parathesias or vania. 202 Copyright All rights

0 1977 by Academic Press, Inc. of reproduction in any form reserved.

ISSN 0022.4804

REICHLE

ETAL.:

NONEMBOLIC

THROMBOSIS

203

RESULTS numbness, unrelenting rest pain, or marked color or temperature changes suggesting Duration and Dose of Drug Administration imminent tissue loss due to severe ischemia. Streptokinase was infused for an average of 66.7 +- 2.9 hr and heparin infusion Drug Administration averaged 55.7 ? 4.9 hr. In each group the Either heparin or streptokinase was given average duration of therapy was less than intravenously over a 72-hr period by the total 72 hr inasmuch as the therapy was infusion pump. Patients who were ran- terminated when deemed clinically necesdomized to receive streptokinase were sary because of concern regarding severity given cortisone prior to therapy to avert of peripheral ischemia. Patients receiving the severity of the febrile reactions regu- streptokinase received a total average dose larly associated with thrombolysis. Heparin, of 6,164,OOO4 745,000 units. Patients re10,000 units, was administered as a loading ceiving heparin received an average total dose followed by 1000units/hr for the 72-hr dose of 63,000 ? 6000 units. The average period. Streptokinase, 100,000 units, was age of patients receiving streptokinase was administered hourly for 72 hr following an 58 + 2 years and the average age of those initial loading dose of 250,000 units. Follow- receiving heparin was 60 ? 2.5 years. ing streptokinase infusion, anticoagulants were administered for several days when Znfiuence of Laboratory Tests on clinically feasible to prevent the theoretical Coagularion Parameters potential of recurrent arterial thrombosis. Thrombin time averaged two to five times Either medication was discontinued if control values in patients treated with deemed necessary in the judgment of the streptokinase. Platelet count was slightly attending surgeons. In less responsive cases decreased 48 hr after streptokinase treatthe infusion was stopped, no anticoagulants ment (average pretreatment, 394,000 were administered, and arteriograms and + 188,000; 48 hr posttreatment, 291,000 appropriate operations were performed. k 138,000). This difference was not statisSimilarly, after heparin therapy arteriotically significant. No significant change grams and consideration to arterial reconstruction were performed promptly as in platelet count occurred after heparin infusion (average pretreatment, 358,500 indicated. ? 85,000; 48 hr postinfusion, 335,000 ? 15,000). Fibrinogen level decreased after Evaluation of Peripheral Ischemia Streptokinase (average pretreatment, 322 -+ 25 g/100 ml; 48 hr post-treatment, Both clinical evaluation and Doppler 118 & 12 g/100 ml, P < 0.01). No significant blood pressure determinations were perchange occurred in fibrinogen level after formed daily in patients in both treatment Heparin infusion (average pretreatment groups. In addition to the routine clinical level, 446 ? 54 g/l00 ml; 48 hr postassessment of revascularization such as treatment, 373 + 8 g/100 ml). The partial pain, color, temperature and palpation of thromboplastin time in patients receiving distal pulses, pedal blood pressure deterheparin was between two and two and oneminations were performed at regular inhalf times control range. tervals before and after therapy using Doppler ascultation distal to a sphygChange in Doppler Pedal Blood Pressure momanometer cuff to provide a specific and Pedal blood pressure increased an avobjective assessment of distal perfusion erage of 52 mm Hg after streptokinase pressure.

204

JOURNAL OF SURGICAL RESEARCH: VOL. 22, NO. 3, MARCH 1977 TABLE 1 SUMMARY

OF PATIENTS Pretreatment pedal pressure

CaSe

Diagnosis

(mm W

RANDOMIZED POst-treatment pedal pressure (mm Hg)

INTO STREPTOKINASE THERAPY

Procedure

Results

D.K.

Rheumatoid vasculitis, pedal thrombosis

0

0

Thrombectomy

Amputation

F.T.

Superficial femoral thrombosis

0

0

No operation

Delayed

R.B.

Ischemia of B/K stump, popliteal artery thrombosis

0

75

No higher

Bifurcation

H.E.

Thrombosis of superficial femoral artery

0

140

No operation

Delayed revascularization 8 months

W.W.

Thrombosis of superticial femoral artery

0

I20

No operation

Limb well vascularized after therapy

6 months

D.M.

Thrombosis of superficial femoral artery

0

II0

No operation

Limb well vascularized after therapy

I8 months

T.W.

Thrombosis

Revision

Limb

artery

of iliac graft

58

70

amputation

of the graft

after 6 weeks

amputation

graft after

I8 months

after

salvage

F.E.

Digital

120

120

Improved

Sympathectomy

after eight months

E.H.

Thrombosis of superlicial femoral artery

0

80

No operation

Femoropopliteal six months

bypass after

F.A.

Thrombosis of superficial femoral artery

0

60

Intracerebral accident (died)

Died

R.G.

Thrombosis of right iliac artery

0

0

Y graft of aortic bifurcation

Doing well

ischemia

therapy; there was a very little change thrombosis of a previous Dacron graft. Total limb salvage was thus achieved in (0.6 mm Hg) after heparin infusion (P < 0.01). All patients receiving strepto- eight of the eleven patients. There was kinase showed objective and clinical one mortality and two patients underwent evidence of improvement (Table 1). Five limb loss. of the eleven streptokinase patients had an excellent objective clinical response. In Results of Heparin Therapy these five patients, urgent arterial operation All six patients receiving heparin required was not necessary but delayed arterial early post-treatment operative revascularireconstruction was recommended. Two of zation (Table 2). Limb salvage occurred in these five patients refused further study and treatment and are currently doing well only two patients. Delayed amputation was necessary in one patient. Early post6 and 18 months post-treatment. Three of treatment and postarterial reconstruction the five patients subsequently underwent limb loss occurred in three of the six arterial reconstruction of atherosclerotic patients. Thus the limb salvage was arterial segments with limb salvage. Thus achieved in only two patients in the all five patients who had excellent thromheparin-treated group and four patients lost bolysis with revascularization after acute major portions of the extremity. arterial thrombosis enjoyed limb salvage. Five other patients receiving streptokinase Complications of Treatment improved significantly but did require arterial operation. Of these five, three had Hyperpyrexia occurred in all patients limb salvage. One patient was treated for receiving streptokinase therapy. Significant

REICHLE ET AL.: NONEMBOLIC

THROMBOSIS

205

TABLE 2 SUMMARY OF PATIENTS RANDOMIZED INTO HEPARIN THERAPY

Diagnosis

Case

Pretreatment pedal pressure (mm W

Post-treatment pedal pressure (mm Hg)

Procedure

Results

R.R.

Thrombosis of superficial femoral artery

0

0

Femoropopliteal bypass

Doing well

M.R.

Femoropopliteal bypass thrombosis

0

0

Revision of graft

Delayed amputation

L.D.

Left iliac thrombosis

0

0

Aortic Y graft

Early amputation

J.R.

Iliac occlusion

0

0

Aortic Y graft

Early amputation

I.C.

Thrombosis of femoropopliteal graft

0

0

Revision of the graft

Early amputation

J.J.

Digital ischemia

80

80

Thrombectomy, auxiliary artery

Doing well

hemorrhage requiring blood transfusion occurred in one patient. Multiple, minute, punctate subserosal .hemorrhages were found in the small bowel of a patient at the time of post treatment aorto-iliac reconstruction. The areas of hemorrhage were very small and were of no clinical significance. Definite evidence of intra-arterial embolization into the distal vessels occurred in the contralateral extremity during the course of thrombolytic therapy. In that patient the thrombolytic therapy was continued and severe contralateral ischemia resolved completely. However, this is illustrative of a definite potential of intravascular embolization of lysing thrombus within the arterial system. In patients receiving heparin, intramuscular hematoma and subcutaneous hematomas occurred. None of these necessitated blood transfusions and all hematomas were self-limiting. Mortality Mortality occurred in one patient in each treatment group. One patient receiving streptokinase therapy developed a cerebral

vascular accident 12 hrs after cessation of thrombolytic therapy. The causal relationship of this mortality to the thrombolytic therapy is unknown. One patient who had received heparin therapy subsequently developed aspiration and asphyxia while eating. This occurred after cessation of the therapy but during the same hospitalization following both the heparin treatment and the subsequent limb amputation. DISCUSSION

Background of Fibrinolytic Treatment of Acute or Subacute Arterial Thrombosis In 1969 Poliwoda et al. [3] reported successful reconstitution of iliac and femoral arterial flow by fibrinolytic therapy in 17 of 27 patients with long standing arterial occlusive disease. Improvement in claudication distance occurred. Successful results were obtained in cases where the history of exacerbation of symptoms were limited to 1 to 3 months before thrombolytic therapy. Martin et al. [4], in 1970, reported successful revascularization of acute ex-

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JOURNAL OF SURGICAL RESEARCH: VOL. 22, NO. 3, MARCH 1977

acerbation of chronic arterial disease by fibrinolytic therapy in 170 patients. Improvement occurred in 75% of patients with aortic occlusive disease and 56% improvement occurred with patient with iliac artery stenosis. 20% success rate occurred in patients with femoral or distal arterial occlusion. Hume et al. [l], in 1970, reported improvement in short segmental chronic arterial occlusions associated with thrombolysis. In 1973 Persson et al. [2] reported 24 patients who were treated with streptokinase with symptoms of arterial occlusive disease. Patients with sudden onset of symptoms were found to respond to fibrinolytic therapy whereas patients with gradual onset of arterial insufficiency had little response. The Clinical Problem of Early Nonembolic Arterial Occlusion Patients undergoing thrombosis of severely atheroclerotic distal arterial tree with severe tissue ischemia represent a particularly difficult clinical problem. It has been our experience that patients with acute or subacute nonembolic arterial occlusions in whom ischemia is severe enough to warrant urgent arterial reconstruction do not have a favorable prognosis for limb salvage following arterial reconstruction. Therefore, efforts directed at least temporarily improving distal extremity ischemia by fibrinolytic therapy may be warranted to avert the need for emergency or urgent arterial reconstruction. All patients receiving thrombolytic therapy in this review showed some evidence of intra-arterial thrombolysis. In some patients there was complete clinical revascularization of moderately ischemic extremities and early operation was thereby averted. In this particular group of patients results were uniformly good without any patients undergoing tissue loss. In the patients in whom some improvement occurred but an early arterial operation was nevertheless necessary, results were also good if the patient

did not have prior arterial bypass. In patients who had previous arterial operations including bypasses (two patients) one patient did undergo limb loss. Within the limitations of the number of patients within the various subgroups of this study, it is possible that patients who had previous arterial operations may respond less favorably to the use of thrombolysis as an adjunct to the surgical management of early arterial occlusive disease. Complications of Thrombolytic Therapy and Their Prevention Hemorrhage and fever are the two major complications associated with streptokinase therapy. In this series fever occurred in every patient treated with streptokinase. Fever usually occurs within the first 12 hr and it rises to 102 to 104°F. The febrile reaction did not necessitate cessation of therapy in any of our patients. Cortisone was given to all of our patients prior to streptokinase therapy to avert the febrile reaction which may be related to an allergic response. Supplemental cortisone was given if the fever rose above 102°Fand was administered as often as every 8 hr if necessary. The cortisone was discontinued promptly at the cessation of therapy or if the fever remained less than 102°F. In addition, Benadryl, 25 or 50 mg, was given orally as often as every 6 hr if patients developed a fever over 102°F in conjunction with the cortisone. Aspirin was not given to any patient. Tylenol was also administered as needed to control the fever. Hemorrhage is an ever present potential threat in patients undergoing fibrinolytic therapy. Therefore patients with potential of increased chance of hemorrhage were excluded from the study as outlined above. Intramuscular injections should not be administered in any patient undergoing fibrinolytic therapy. The intravenous access route must be performed with great care. Only a single 1Pgauge needle should be used in patients undergoing fibrinolytic

REICHLE

ET AL. : NONEMBOLIC

therapy. The same needle is used to administer medication intravenously and to withdraw periodic blood samples for testing of coagulation profile at regular intervals. Almost every patient receiving streptokinase developed a minor to moderate subcutaneous hematoma at the site of the intravenous access route. Local compression and observation only was required to control these hematomas.

THROMBOSIS

207

of therapy. We therefore recommend when possible that embolic complications be treated with a continuation of the ongoing fibrinolytic program. However should the ischemia related to distal intra-arterial embolization be imminently limb threatening, prompt cessation of therapy and consideration to embolectomy may become necessary. Severity of the Ischemia

Dosage of Streptokinase In accordance with a view held by other investigators, we have adhered to a fixed dosage schedule for administration of streptokinase. This includes a loading dose of 250,000 units for the first 45 min and a consistant administration by intravenous infusion pump of 100,000 units/hr thereafter. Thrombin time initially increased and then decreased somewhat after 48 hr of streptokinase infusion, being maintained at about 3 min for the first 48 hr. During a period of time when the thrombin time is prolonged, consideration to diminishing streptokinase infusion could have been given in order to allow plasminogen levels to revert back toward more normal levels. Intravascular Thrombus Embolization Associated with Fibrinolytic Therapy Distal embolization of lysing intraarterial thrombosis is a definite potential complication with fibrinolytic therapy. To our knowledge this occurred only once in this series of patients. After 24 hr of fibrinolytic therapy, one patient developed contralateral extremity embolization, presumably from aorto-iliac segment. Severe ischemia developed suddenly in the contralateral previously asymptomatic extremity. This occurred during the period of time in which improvement was occurring in the symptomatic extremity. Streptokinase was continued and an improvement occurred in both lower extremities. The contralateral extremity improved and reverted to the normal level of perfusion before the beginning

It is recommended that only patients with a moderate degree of severe ischemia should be considered for thrombolytic therapy. Revascularization by arterial thrombolysis requires considerably more time than revascularization by arterial reconstruction. Characteristically improvement may occur within the first 12 to 24 hr, in other patients significant revascularization is not observed clinically until after 48 hr of therapy. Therefore patients with severe ischemia must have relief of arterial insufficiency more promptly and this is best achieved by attempted operation in arterial reconstruction following arteriography. Careful monitoring of the degree of ischemia must be continued throughout the course of fibrinolytic therapy. If ischemia becomes more severe or limb loss is threatened, patients should be discontinued from therapy and operation should be performed. Prognosis of the Patient with Early Nonembolic Arterial Thrombosis No patient treated with heparin showed any evidence of improvement in ischemia either clinically or by Doppler pressure measurements. A high incidence of tissue loss was encountered in this group. These observations are in keeping with our clinical impression which suggest that patients with acute or subacute arterial occlusions and which are nonembolic in origin carry an unfavorable prognosis for revascularization. This poor prognosis may be related to the hemodynamic instability resulting

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from the acute arterial occlusion. This may theoretically be due to possible small arterial thrombosis within the distal arterial tree. This could theoretically impede the outflow tract and increase peripheral arterial resistance which may in turn render arterial reconstruction considered less favorable than in the chronic, more stabilized, situation. If thrombolysis can be achieved, the patient may then be operated subsequently under more elective conditions when hemodynamic stability may have been achieved. CONCLUSION

1. Fibrinolytic therapy is a significantly more effective in contributing to intraarterial thrombolysis than anticoagulant therapy alone. 2. Revascularization of acute or subacute intra-arterial thrombosis may be achieved by thrombolytic therapy. Thrombolytic therapy may therefore be considered as initial modality of treatment in acute or subacute exacerbation in patients with chronic occlusive disease. 3. Fibrinolytic therapy may also play a role in surgically inaccessible acute arterial thrombosis, e.g., small distal arterial throm-

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1977

bosis, stump ischemia following acute or subacute arterial thrombosis. 4. Urgent operations can be deferred by interim revascularization by fibrinolysis. Subsequent elective arterial reconstruction can then be performed under more stable circulatory hemodynamics. 5. Thrombolytic therapy may be an adjunct to the operative management of nonembolic acute or subacute arterial thrombosis. ACKNOWLEDGMENTS The authors acknowledge Dr. Niewiarowski’s cooperation in the laboratory supervision of the patients and the technical assistance of Ms. Maxine Millmen.

REFERENCES I. Hume, M., Garewich, V., and Thomas, D. P. Streptokinase for chronic arterial occlusive disease. Arch. Surg. 101: 653, 1970. 2. Perrson, A. V., Thompson, J. E., and Patman, R. D. Streptokinase as an adjunct to arterial surgery. Arch. Surg. 107: 779, 1973. 3. Poliwoda, H., Alexander, K., and Buhl, V. Treatment of chronic arterial occlusions with Streptokinase. N. Engl. J. Med. 280: 689, 1969. 4. Martin, M., Schoop, W., and Zeitler, E. Streptokinase in chronic arterial occlusive disease. JAMA

211: 1169, 1970.