EXPERIENCE WITH FIBRINOLYTIC THERAPY OF VASCULAR OCCLUSIVE DISEASE W. L.
WARNER, M.D., F.I.C.A.
Berkeley, California Reviews of experience with fibrinolytic therapy usually include deep vein thrombosis and pulmonary embolism, but studies for other indications should also be reported. These uses are discussed as subtopics below. Streptokinase resistance is also included because it is applicable to all clinical uses of streptokinase. The new data to be presented were results of efforts of many contributing investigators identified in the appropriate sections below. CHRONIC ARTERIAL OCCLUSIONS
From a theoretical standpoint, the use of lytic therapy for occlusions of a chronic nature was initially assumed inadvisable since an organized thrombus could not be amenable to fibrin dissolution. But in recent years attempts have been made to treat chronic arterial occlusions, because these patients constitute an important segment of patients with occlusive disease, and are therapeutic dilemmas. Verstraete’ reviewed the published data in 1971. He concluded from this review and from his own experience that occlusions in the femoral artery were generally not amenable to streptokinase (SK) therapy, although small lesions in the common femoral were perhaps more susceptible than long lesions in the superficial femoral. The experience published by Martin,2 however, is slightly better in all categories, although it still shows a lower success rate in the femoral artery. The overall success rate from this study was approximately 50%. A study by LeVeen3 yielded similar results. Hume et al.~ have also reported experience with 15 patients with relatively poor results. None of these reports included comprehensive information on adverse effects experienced during therapy, and follow-up data are incomplete. Some investigators!’ 5 have attempted to segregate from the clinic population those patients whose lesions may respond better than others. Attempts were made to correlate the appearance of angiograms with some indication of the microscopic structure, with a smooth, rounded lesion suggesting endothelial covering of an old thrombus. An irregular outline of the occlusion, conversely, might indicate more recent occlusion without endothelial &dquo;smoothing.&dquo; Also, the accessibility of the lesion through collateral channels or branching might provide some prognostic indication. However, this attempt at selection has not been pursued extensively. The success rate is sufficiently high to warrant further study. From Cutter Laboratories
Inc., 4th and Parker Streets, Berkeley, California. 364
Downloaded from ves.sagepub.com at BRIGHAM YOUNG UNIV on June 26, 2015
365
While we cannot hope to alter the basic underlying pathology of an atherosclerotic vessel, we may be able to buy time with medical therapy. Surgical therapy is limited to relatively circumscribed lesions in vessels with adequate caliber to permit successful manipulation, and these procedures also carry their own morbidity. In some cases a combination of streptokinase followed by surgery may be most useful; after lytic therapy, a subsequent arteriogram will be more helpful to the surgeon in determining the extent of the lesion and the possibility for outflow. Lytic agents may be the only therapy available for smaller vessel disease. ARTERIOVENOUS CANNULA OCCLUSIONS
Occlusions of AV cannulae were an important clinical application of lytic therapy until the development of the AV fistula, and in some centers there is still interest in this application. The AV cannula presented an interesting challenge for lytic therapists, because the occlusion was available to direct inspection and manipulation, essentially an in plastico model of thrombosis with a minimum contribution of the vessel wall to the pathologic picture. Review of the literature on this subject yielded nine publications,~l4 all involving small groups of patients (from 3 to 22) with immediate success rate&dquo; of 50 to 100%. Protocols and dosage varied rather widely, including extremes of systemic treatment of over 1 million IU of streptokinase, to cannula treatments of 50,000 IU. It may be noted that the one study reported by Arisz,7 who used the lowest dosage (50,000-100,000 U in the cannula) had the lowest success rate. These treatments in the cannula were not accomplished without adverse effects. Some of the relatively minor adverse reactions encountered in systemic therapy, such as back pain, pyrexia, and allergic reactions, were also observed in significant numbers of cannula patients. Based on these studies and some of our own preliminary studies, a cooperative study was carried out between 1971 and 1973, involving 56 patients under a definitive protocol, and 8 investigators.* There were 82 treatments of cannula occlusion performed in these patients. In addition to the 56 protocol patients, 30 additional patients were treated before the definitive protocol was developed. Table 1 indicates the flow data resulting from the protocol steps as listed. The protocol calls for determination of baseline flow, if any, by standardized Doppler flowmeters. The flow had previously been established as inadequate for dialysis. Flushing with heparinized saline was attempted in each case by syringe aspiration, which resulted in a small incremental increase in flow. A cannulogram was then performed to document the appearance and extent of * John D. Bower, M.D., University of Mississippi; Robert E. Cuddihee, M.D., Cochran V.A. Hospital, St. Louis, Missouri; Francisco Gonzalez, M.D., Charity Hospital of Louisiana; Joseph H. Holmes, M.D., University of Colorado Medical Center; Robert G. Muth, M.D., Research Hospital & Medical Center, Kansas City, Missouri; Alfred V. Persson, M.D., Baylor University Medical Center; Arthur J. Seaman, M.D., University of Oregon Medical School; Dana Shires, M.D., V.A. Hospital, Tampa; and John F. Sullivan, M.D., New York Hospital.
Downloaded from ves.sagepub.com at BRIGHAM YOUNG UNIV on June 26, 2015
366 the occlusion. This in itself, being an additional flushing maneuver, also increased the flow slightly. Cumulative increase by these two maneuvers resulted in a statistically significant increase in flow when compared to baseline. The resulting flow, however, was still inadequate for dialysis, and 250,000 IV of streptokinase (Streptase@, Hoechst) was instilled in each occluded limb of the cannula by syringe pump. The SK was dissolved in 2 ml of saline and injected over a 30-minute period. This volume was approximately equivalent to that within a limb of cannula so that systemic infusion would be avoided. The cannula was allowed to remain undisturbed for 2 hours, after which time the cannula was aspirated and blood flow again measured. The incremental increase after SK treatment was much greater than the previous maneuvers. At this point a second cannulogram was done to visualize the patency of the cannula, and the cannula was reconnected. Flow was measured again at the time of the subsequent dialysis. Streptokinase resistance was calculated before treatment and scheduled for redetermination at monthly intervals thereafter. Repeat treatment of the cannula was permitted at any time, without regard for the resistance at that
point. Table 2 shows the results of treatment in all protocol cases, using the three criteria employed to evaluate the clinical status. An arbitrary figure of 100 ml per minute of flow through the cannula was selected as the major criterion for sufficient flow to resume dialysis. Another criterion was the surgical procedure, if any, required after SK treatment. Obviously, if the clotted cannula could not be cleared, the alternative was a surgical revision of the shunt. If no surgical revision was required after treatment, or if the surgical maneuver TABLE 1
Streptaseg
* P
WARNER, M.D., F.I.C.A.
Berkeley, California Reviews of experience with fibrinolytic therapy usually include deep vein thrombosis and pulmonary embolism, but studies for other indications should also be reported. These uses are discussed as subtopics below. Streptokinase resistance is also included because it is applicable to all clinical uses of streptokinase. The new data to be presented were results of efforts of many contributing investigators identified in the appropriate sections below. CHRONIC ARTERIAL OCCLUSIONS
From a theoretical standpoint, the use of lytic therapy for occlusions of a chronic nature was initially assumed inadvisable since an organized thrombus could not be amenable to fibrin dissolution. But in recent years attempts have been made to treat chronic arterial occlusions, because these patients constitute an important segment of patients with occlusive disease, and are therapeutic dilemmas. Verstraete’ reviewed the published data in 1971. He concluded from this review and from his own experience that occlusions in the femoral artery were generally not amenable to streptokinase (SK) therapy, although small lesions in the common femoral were perhaps more susceptible than long lesions in the superficial femoral. The experience published by Martin,2 however, is slightly better in all categories, although it still shows a lower success rate in the femoral artery. The overall success rate from this study was approximately 50%. A study by LeVeen3 yielded similar results. Hume et al.~ have also reported experience with 15 patients with relatively poor results. None of these reports included comprehensive information on adverse effects experienced during therapy, and follow-up data are incomplete. Some investigators!’ 5 have attempted to segregate from the clinic population those patients whose lesions may respond better than others. Attempts were made to correlate the appearance of angiograms with some indication of the microscopic structure, with a smooth, rounded lesion suggesting endothelial covering of an old thrombus. An irregular outline of the occlusion, conversely, might indicate more recent occlusion without endothelial &dquo;smoothing.&dquo; Also, the accessibility of the lesion through collateral channels or branching might provide some prognostic indication. However, this attempt at selection has not been pursued extensively. The success rate is sufficiently high to warrant further study. From Cutter Laboratories
Inc., 4th and Parker Streets, Berkeley, California. 364
Downloaded from ves.sagepub.com at BRIGHAM YOUNG UNIV on June 26, 2015
365
While we cannot hope to alter the basic underlying pathology of an atherosclerotic vessel, we may be able to buy time with medical therapy. Surgical therapy is limited to relatively circumscribed lesions in vessels with adequate caliber to permit successful manipulation, and these procedures also carry their own morbidity. In some cases a combination of streptokinase followed by surgery may be most useful; after lytic therapy, a subsequent arteriogram will be more helpful to the surgeon in determining the extent of the lesion and the possibility for outflow. Lytic agents may be the only therapy available for smaller vessel disease. ARTERIOVENOUS CANNULA OCCLUSIONS
Occlusions of AV cannulae were an important clinical application of lytic therapy until the development of the AV fistula, and in some centers there is still interest in this application. The AV cannula presented an interesting challenge for lytic therapists, because the occlusion was available to direct inspection and manipulation, essentially an in plastico model of thrombosis with a minimum contribution of the vessel wall to the pathologic picture. Review of the literature on this subject yielded nine publications,~l4 all involving small groups of patients (from 3 to 22) with immediate success rate&dquo; of 50 to 100%. Protocols and dosage varied rather widely, including extremes of systemic treatment of over 1 million IU of streptokinase, to cannula treatments of 50,000 IU. It may be noted that the one study reported by Arisz,7 who used the lowest dosage (50,000-100,000 U in the cannula) had the lowest success rate. These treatments in the cannula were not accomplished without adverse effects. Some of the relatively minor adverse reactions encountered in systemic therapy, such as back pain, pyrexia, and allergic reactions, were also observed in significant numbers of cannula patients. Based on these studies and some of our own preliminary studies, a cooperative study was carried out between 1971 and 1973, involving 56 patients under a definitive protocol, and 8 investigators.* There were 82 treatments of cannula occlusion performed in these patients. In addition to the 56 protocol patients, 30 additional patients were treated before the definitive protocol was developed. Table 1 indicates the flow data resulting from the protocol steps as listed. The protocol calls for determination of baseline flow, if any, by standardized Doppler flowmeters. The flow had previously been established as inadequate for dialysis. Flushing with heparinized saline was attempted in each case by syringe aspiration, which resulted in a small incremental increase in flow. A cannulogram was then performed to document the appearance and extent of * John D. Bower, M.D., University of Mississippi; Robert E. Cuddihee, M.D., Cochran V.A. Hospital, St. Louis, Missouri; Francisco Gonzalez, M.D., Charity Hospital of Louisiana; Joseph H. Holmes, M.D., University of Colorado Medical Center; Robert G. Muth, M.D., Research Hospital & Medical Center, Kansas City, Missouri; Alfred V. Persson, M.D., Baylor University Medical Center; Arthur J. Seaman, M.D., University of Oregon Medical School; Dana Shires, M.D., V.A. Hospital, Tampa; and John F. Sullivan, M.D., New York Hospital.
Downloaded from ves.sagepub.com at BRIGHAM YOUNG UNIV on June 26, 2015
366 the occlusion. This in itself, being an additional flushing maneuver, also increased the flow slightly. Cumulative increase by these two maneuvers resulted in a statistically significant increase in flow when compared to baseline. The resulting flow, however, was still inadequate for dialysis, and 250,000 IV of streptokinase (Streptase@, Hoechst) was instilled in each occluded limb of the cannula by syringe pump. The SK was dissolved in 2 ml of saline and injected over a 30-minute period. This volume was approximately equivalent to that within a limb of cannula so that systemic infusion would be avoided. The cannula was allowed to remain undisturbed for 2 hours, after which time the cannula was aspirated and blood flow again measured. The incremental increase after SK treatment was much greater than the previous maneuvers. At this point a second cannulogram was done to visualize the patency of the cannula, and the cannula was reconnected. Flow was measured again at the time of the subsequent dialysis. Streptokinase resistance was calculated before treatment and scheduled for redetermination at monthly intervals thereafter. Repeat treatment of the cannula was permitted at any time, without regard for the resistance at that
point. Table 2 shows the results of treatment in all protocol cases, using the three criteria employed to evaluate the clinical status. An arbitrary figure of 100 ml per minute of flow through the cannula was selected as the major criterion for sufficient flow to resume dialysis. Another criterion was the surgical procedure, if any, required after SK treatment. Obviously, if the clotted cannula could not be cleared, the alternative was a surgical revision of the shunt. If no surgical revision was required after treatment, or if the surgical maneuver TABLE 1
Streptaseg
* P
