- Email: [email protected]
Streptokinase therapy in acute major pulmonary embolism
574
.ir,rrr~. Heart J. April, 1970
Annota.tions
manual hold, an additional sweep is used at the bottom of the screen; erase is inhibited, and a Lissajous pattern is generated. This causes the beam to move too fast to be stored and permits the ECG to be displayed in a repetitive fashion to resemble the conventional trace. The amount of ECG information to be displayed is a function of the sweep speed as well as the number of stair-steps generated. Examples of rhvthm disturbances are shown in Fie. 1. Thev were simulated (“Polyrhythm” simulator, khysio-Control Corp.) to show the ease by which rhythm disturbances can be detected and identified by using the system. The total cost of the entire display system is little more than that of the ordinary system. It is considerably less expensive than monitor systems using video-scan techniques now becoming available. The
A thought
about
donor
There must come a time when a donor heart in a recipient survives long enough so that every atom and every molecule of the heart are replaced by new ones through kinetic metabolic processes of the recipient and of the donor heart. But, are the exchanges in the donor heart programmed by the genes of the donor cells without influence from the recipient? Or, are the programmings which are governed by the recipient’s genes so different from those of the donor heart that once in the recipient and with the passage of sufficient time the donor heart is an entirely different one, all atoms and all molecules being new and organized differently, more like that of the recipient? If different, ho.Kr different and how “foreipn” with time to that of the recipient? It may be possible for the kinetics of exchange among atoms and molecules to produce eventually a new and “nonforeign” organ for the
equipment can be mounted in standard relay-rack enclosures and may be adapted to any physical configuration desired. Since the storage oscilloscope has its own built in “memory,” a memory unit is no longer essential. Permanent records can be obtained easily and economically by using a camera adapted to the storage oscilloscope by the manufacturer (Model C-3OP, Tektronix, Inc.). It was used to obtain the photographs in Fig. 1. Loyal L. Conrad, M.D. Professor of Medicine University of Oklahoma Medical Center Veterans Administration Hospital Robert L. Trendley Coronary Care Unit Project Engineer Oklahoma Regional Medical Program Oklahoma City, Okla.
hearts
recipient with the donor heart as the “base.” Perhaps with a little help, the new molecules and their spatial interrelationships and interactions can be made to resemble the recipient sufficiently to be accepted forever. One can only recall the response of George Bernard Shaw to a critic who accused him of writing a bad play 20 years earlier. Shaw replied that the man who wrote that play no longer existed. It was a different George Bernard Shaw who had written that play, for his physiologist friends had told him that all atoms and molecules of man are completely turned over every 14 years. George Burch, M.D. T. D. Giles, M.D. H. L. Colcolough, M.D. Tulane University School of Medicine New Orleans, La.
Streptokinase therapy in acute major pulmonary embolism *
The feasibility by enzymatic *This
of producing dissolution of thrombi means has been demonstrated in ex-
study was supported Foundation of Australia
by a grant
from the National
Heart
perimental thrombi’J and pulmonary emboli3J in animals, in experimental thrombi in man,6 and in patients with acute venous and arterial thromboembolic disease.6J7 Of the enzymes investigated, only the two plasminogen activators, streptokinase
Annotations
and urokinase, have proved acceptable as thrombolytic agents for clinical use.18 Streptokinase is now readily available in a highly purified form but has the disadvantage of being antigenic in man. Pyrogenicity, a major difficulty with early preparations,rsJg is no longer a significant problem provided that prophylactic corticosteroids are used.20J1 Urokinase is of human origin, not antigenic to man, and initiai clinical investigations suggest that it produces a predictable dose response effect in most patients.8 The extraction and purification of this enzyme in a form acceptable for human use has proved difficult, and although this has now been achieved, the drug is still very expensive and relatively unavailable. Clinical studies with urokinase are currently in progress in the United State9 but by comparison with streptokinase, experience in the use of urokinase in man is limited.18 The problems of the antigenicity of streptokinase are manifest in two ways. The first is due to the fact that stre’ptococcal antibodies react with streptokinase. These antibodies, the result of previous streptococcal infections, are present in most patients and have to be neutralized before thrombolysis can be induced.24 The neutralizing dose of streptokinase cannot be predicted with any certainty because the concentration of streptokinase antibodies varies over a wide range from patient to patient.20.24 For this reason it is commonly recommended that a resistance test be performed and the dose of streptokinase individualized for each patient. The second problem arising from the antigenicity of streptokinase is that treatment is followed by a marked increase in the levels of streptokinase antibodies, and this precludes further therapy, should this be necessary, over the next one to six months.zl The use of streptokinase has been limited in the past by the need to perform streptokinase resistance tests on patients before commencing treatment. Although these tests are relatively simple, it may not always be convenient to perform them before starting treatment. In recent years attempts have been made to overcome this problem by introducing various standard dosage schedules.i6J0 With this approach it is inevitable that some patients will receive an inducing dose in excess of their resistance and others a dose which fails to neutralize their streptokinase antibodies. High inducing doses in excess of the patient’s resistance have been shown to be safe and effective16J0; they produce rapid activation and depletion of plasminogen and give rise to a hemostatic defect which, however, is transient and asymptomatic provided that the circulating plasminogen is maintained at a low level by an adequate sustaining dose.90 On the other hand, inducing doses which fail to neutralize the circulating antibodies are pharmacologically ineffective. Therefore, to be of practical value, an arbitrary inducing dose should be sufficiently large to overcome the streptokinase resistance in a very large percentage of the population; this dose will be strongly influenced by the range and distribution of streptokinase resistance in the particular community in question. Verstraete and associates20 demonstrated that a standard dosage schedule was both effective and free of hemorrhagic complications. However,
575
the very high inducing dose of 1,250,OOO U. of streptokinase used by these investigators has the disadvantage that treatment in some patients becomes unnecessarily expensive. Other investigators when using a standard dosage regimen have used lower inducing doses, but the fibrinolytic effects of these lower dosage schedules has not been systematically evaluated.16e2’ Recently we investigated the safety and effectiveness of a standard dosage schedule of streptokinase (Streptase, Australian Hoechst Ltd.) in 50 randomly selected patients with thromboembolic disease.25 A streptokinase resistance test was performed on each patient who was then treated with a standard dose of 250,000 U. of streptokinase infused over 30 minutes followed by 100,000 U. per hour. The results of serial tests of fibrinolytic activity were then correlated with the streptokinase resistance in each patient, particular attention being directed to those patients with resistances in excess of the inducing dose. Forty-six of the 50 patients had a resistance of 250,000 U. or lower and all of these patients developed an active thrombolytic state with rapid plasminogen depletion. The 4 patients with a streptokinase resistance in excess of 250,000 U. showed a delayed fibrinolytic response, but, once obtained, the fibrinolytic effects were similar to those found in the other 46 patients. In general, the treatment was well tolerated; bleeding, the major complication, was usually restricted to oozing from sites of venipuncture but was severe in 2 patients. These findings, together with other reports,20 indicate that it is possible to obtain a satisfactory fibrinolytic response with streptokinase in a large percentage of a community using a standard dosage schedule. The routine use of such a schedule would be acceptable only if a thrombolytic state could be achieved in a very high percentage of the community with a reasonably low inducing dose. On the other hand, if the distribution of streptokinase resistance in a community shows a very wide scatter with a significant proportion having a very high resistance, it would be far more economical to individualize treatment than to treat all patients with a very high inducing dose. Theoretically, major pulmonary embolism is a particularly attractive indication for thrombolytic therapy. The embolus is usually composed of recent thrombus and the effects of therapy can be assessed objectively by angiographic, hemodynamic, and lung scanning studies. It has been shown that both streptokinase and urokinase accelerate resolution of pulmonary emboli in animals.304 More recently, angiographic improvement has been documented following thrombolytic therapy with streptokinase and urokinase in patients with severe pulmonary embolism.1+14Jr Despite these encouraging results the question as to whether or not the plasminogen activators accelerate dissolution of pulmonary embolism and improve immediate survival in man remains unanswered. Spontaneous resolution of massive pulmonary embolism has been demonstrated in man by serial angiography,*e-** but the speed with which resolution occurs is unknown. Recent investigations28 suggest that the majority of large
.4rbicv. Heart 1. .4jvi/, 1970
pulmonary emboli in otherwise healthy patients eventually undergo resolution in a matter of weeks, but that resolution is often delayed for many months in patients with underlying cardiac or respiratory disease. In a recent study the clinical, hemodynamic, and angiographic effects of streptokinase were investigated in 18 patients with major pulmonary embolism.‘” The diagnosis of major pulmonary embolism was confirmed by pulmonary angiography and the catheter was then left in the main pulmonary artery and used for the streptokinase infusion, for serial pulmonary artery pressure measurements and for further pulmonary angiograms. The loading dose of streptokinase was calculated from the resistance test, but in 12 patients a standard loading dose of 250,000 U. was infused over 30 minutes before the result of the resistance test was available. Treatment was continued for at least 24 hours with a maintenance dose of 100,000 U. per hour and the fibrinolytic and therapeutic effects were assessed by serial tests of fibrinoiytic activity, serial pulmonary artery pressure measurements, and by a second angiogram. One patient was treated within 48 hours of abdominal surgery with a modified dosage schedule which was carefully monitored to produce only mild systemic fibrinolytic activity.10 Fourteen of the 18 patients improved clinically in the 24 hour period following the commencement of streptokinase therapy. Of the 4 who failed to show initial improvement, 2 subsequently died and 2 required pulmonary embolectomy which was successfully performed in both. The indications for embolectomy were cardiac arrest 3 hours after beginning streptokinase in one and recurrent pulmonary embolism 24 hours after beginning therapy in the other. Autopsy in the other 2 cases showed severe pulmonary arterial obstruction by organized thromboembolism. Sixteen patients had angiograms repeated 24 hours after streptokinase therapy. Eight showed marked improvement, 3 moderate improvement, 2 slight improvement, 1 had a recurrent embolus, and the 2 patients who died showed no significant change. In general, the clinical, angiographic, and hemodynamic improvement was most marked in patients who were treated soon after a single episode of major pulmonary embolism and least marked in those who had evidence of progressive or persistent pulmonary embolic obstruction for more than 1 week. These findings are consistent with the experimental observations both in man5 and in animals* that venous thrombi become more resistant to therapeutic thrombolysis as they age. The findings with streptokinase may be compared with observations made on 7 patients with major pulmonary embolism following 24 hours of treatment with continuous intravenous heparinZ9 Three of these patients had recent acute embolic episodes and the other 4 had recurrent emboli with a recent major episode. Five of the 7 patients (including the 3 with single acute episodes) showed no evidence of resolution, either hemodynamically or angiographically, after 24 hours, and the other 2 showed only minimal resolution. Thus, although spontaneous resolution of major pulmonary em-
bolism eventually takes place,28 it is probable that significant resolution of 24 hours is uncommon. Even if thrombolytic therapy does accelerate early resolution of major pulmonary embolism in man, it is unlikely that this form of treatment will ever have a strong influence on the overall mortality rate from pulmonary embolism. This is because the majority of patients who die from pulmonary embolism do so before any treatment can be instituted.30t31 It is probable that a very significant number of these deaths would be prevented if anticoagulants were used prophylactically in high-risk patient+36 and if clinically recognizable minor thrombcembolic episodes were treated promptly with adequate doses of heparin.36-41 Nevertheless, a significant proportion of patients who die with major pulmonary embolism do survive for 24 to 48 hours, and it is in this time period that thrombolytic therapy may fill an important role. While some of the delayed deaths may be caused by recurrence or propagation of the embolus, it is likely that many are caused by the direct hemodynamic consequences of the initial embolic obstruction. The survival rate in this group should be improved if rapid resolution of the embolus is achieved. Thrombolytic therapy may have an even more important place in patients with underlying cardiac or respiratory disease in whom spontaneous resolution is often delayed.28 Resolution in these patients may not only improve the immediate mortality rate from acute pulmonary embolism but may decrease morbidity from the consequences of persistent embolic obstruction. In spite of the encouraging results obtained thus far, the ultimate assessment of the role of thrombolytic therapy in the treatment of pulmonary embolism must await controlled clinical trials. One such trial with urokinase is currently in progress in the United States23 and its outcome is awaited with interest. Whatever the result, major pulmonary embolism is likely to remain a common cause of death in hospital patients until more attention is directed to prophylaxis in high-risk groups and to early and adequate heparin treatment of patients withfminor thromboembolic episodes. J. Hirsh, M.D., M.R.A.C.P.* I. G. McDonald, M.D., M.R.A.C.P. G. S. Hale, M.D., F.R.A.C.P. i?niuersity of Melbourne Department of Medicine St. Vincent’s Hospital Melbourne, Victoria, Australia *Present
address:
Medicine,
Department of McMaster University.
Pathology. Hamilton,
Faculty of Ontario,
Canada.
REFERENCES 1. Johnson, A. J., and Tillet, W. S.: The lysis in rabbits of intravascular blood clots by the streptococcal fibrinolytic system (streptokinase). 1. Exo. Med. 95:449. 1952. 2. Sherry, S.,’ Titchener, A., Gotterman, L., Wasserman, P., and Troll, W.: The enzymatic dissolution of experimental arterial thrombi
volume
Number
79
Annotations
4
in the dog by trypsin, chymotrypsin, and plasminogen activators, J. Clin. Invest. 33:1303, 1954. 3. Browse, N. L., and James, D. C. D.: Streptokinase and pulmonary embolism, Lancet 2:1039, 1964. 4. Genton, E., and Wolf, P. S.: Experimental pulmonary embolism: Effects of urokinase therapy on organizing thrombi, J. Lab. Clin. Med. 70:311, 1967. 5. Johnson, A. J., and McCarty, W. R.: The lysis of artificially induced intravascular clots in man by intravenous infusions of streptokinase, J. Clin. Invest. 38:1627, 1959. 6. Winckelmann, G., and Hiemeyer, V.: Experience with streptokinase as a thrombolytic agent, Stand. J. Clin. Lab. Invest. 16 (Suppl. 78):7, 1964. 7. McNicol, G. P., and Douglas, A. S.: Treatment of peripheral vascular occlusion by streptokinase perfusion, Stand. J. Clin. Lab. Invest. 16 (SuppI. 78):23, 1964. 8. Verstraete, M., Vermylen, J., de Vreker, R., Amerv. A.. and Vermvlen. C.: Efficacv of thrombolytic therapy with streptokinase using a new administration scheme, Stand. J. Clin. Lab. Invest. 16 (SuppI. 78):15, 1964. 9. Gormsen. 1.. and Larsen. B.: Treatment of acute phlebothrombosis with streptase, Acta Med. Stand. 181:373, 1967. 10. Hirsh, J., Hale, G. S., McDonald, I. G., McCarthv. R. A.. and Cade. 1. F.: Resolution of acute massive pulmonary embolism after pulmonary arterial infusion of streptokinase, Lancet 2:593, 1967. 11. Tow, W. S., Wagner, H. N., and Holmes, R. A.: Urokinase in pulmonary embolism, New Eng. J. Med. 277:1161, 1967. 12. Sasahara, A. A., Cannilla, J. E., Belko, J. S., Morse, R. L., and Criss, A. J.: Urokinase therapy in clinical pulmonary embolism, New Eng. J. Med. 277:1168, 1967. 13. Sautter, R. D., Emanuel, D. A., and Wenzel, F. J.: Treatment of acute massive pulmonary embolism, Ann. Thorac. Surg. 4:95, 1967. 14. Hirsh, J., Hale, G. S., McDonald, I. G., McCarthy, R. A., and Pitt, A.: Streptokinase therapy in acute major pulmonary embolism: effectiveness and problems, Brit. Med. J, 4:729, 1968. 15. Browse, N. L., Thomas, M. L., and Pim, H. P.: Streptokinase and deep vein thrombosis, Brit. Med. J. 3:717, 1968. 16. Robertson, B. R., Nilsson, I. M., and Nylander, G.: Value of streptokinase and heparin in treatment of acute deep venous thrombosis, Acta Chir. Stand. 134:203. 1968. 17. Genton, E., and Wolf, P. S.: Urokinase therapy in pulmonary thromboembolism, AMER. HEART J. 76:628, 1968. 18. Sherry, S.: Fibrinolysis, Ann. Rev. Med. 19:247, 1968. 19. Tillet, W. S., Johnson, A. J., and McCarthy, W. R.: The intravenous infusion of the streptccoccal fibrinolytic principle (streptokinase) into patients, J. Clin. Invest. 84:169, 1955. I
20.
21.
22.
23. 24.
25.
26.
27.
”
28.
29. 30.
31.
32.
33.
34.
35.
36.
37.
577
Verstraete, M., Vermylen, J., Amery, A., and Vermylen, C.: Thrombolytic therapy with streptokinase using a standard dosage scheme, Brit. Med. J. 1:454, 1966. Schmutzler, R., Hechner, F., Kortge, P., van der Loo, J., Pezold, A., Poliwoda, H., Praetorius, F., and Zekorn, D.: Thrombolytic therapy of recent myocardial infarction, German Med. Monthly 11:308, 1966. Fletcher, A. P., Alkjaersig, N., Sherry, S., Genton, E., Hirsh, J., and Bachman, F.: Development of urokinase as a thrombolytic agent. Maintenance of a sustained thrombolytic state by intravenous infusion, J. Lab. Clin. Med. 65:713, 1965. Editorial: Urokinase, New Eng. J. Med. 277: 1203, 1967. Fletcher, A. P., Alkjaersig, N., and Sherry, S.: The maintenance of a sustained thrombolytic state in man. I. Induction and effects, J. Clin. Invest. 88:1096, 1959. Hirsh, J., O’Sullivan, E. F., and Martin, M.: Thrombolytic therapy with streptokinase: the case for a standard dosage schedule, 1969. In press. Fred, H. L., Axelrad, M. A., Lewis, J. M., and Alexander, J. K.: Rapid resolution of pulmonary thromboemboli in man, an angiographic study, J. A. M. A. 1%:1137, 1966. Tow, D. E., and Wagner, H. N.: Recovery of pulmonary arterial blood flow in patients with pulmonary embolism, New Eng. J. Med. 276:1053, 1967. Chait, A., Summers, D., Krasnow, N., and Wechsler, B. M.: Observations on the fate of large pulmonary emboli, J. Roentgenol. 100:364, 1967. Hirsh, J., McDonald, I. G., and Hale, G. S.: Unpublished observations, 1969. Donaldson, G. A., Williams, C., Scannell, J. G., and Shaw, R. S.: A reappraisal of the application of the Trendelenburg operation to massive pulmonary embolism, New Eng. J. Med. 268:171, 1963. Rosenberg, D. M. L., Pearce, C., and McNulty, J.: Surgical treatment of pulmonary embolism, J. Thorac. Cardiov. Surg. 47:1, 1964. Anderson, G. M., and Hull, E.: Effect of dicumarol on mortality and incidence of thromboembolic complications in congestive cardiac failure, AMER. HEART J. 39:697, 1950. Sevitt, S., and Gallagher, N. G.: Prevention of venous thrombosis and pulmonary embolism in injured patients, Lancet 2:981, 1959. Chalmers, D. G., Marks, J., Bottomley, J. E., and Lloyd, D.: Postoperative prophylactic anticoagulants. Five year study in an obstetric and gynaecological unit, Lancet 2:220, 1960. Skinner, D. B., and Salzman, E. W.: Anticoagulant prophylaxis in surgical patients, Surg. Gynec. Obstet. 125:741, 1967. Murray, G.: Anticoagulants in venous thrombosis and the prevention of pulmonary embolism, Surg. Gynec. Obstet. 84:665, 1947. Jorpes, J. E.: The origin and physiology of
378
38.
39.
dnnotations
heparin: the specific therapy in thrombosis, Ann. Intern. Med. 27:361, 1947. Bauer, G.: Nine years experience with heparin in acute venous thrombosis, Angiology 1:161, 1950. Barritt, D. \I’., and Jordan, S. C.: Anticoagulant drugs in the treatment of pulmonary embolism: a controlled trial, Lancet 1:1309, 1960.
40.
41.
Morris, L. E., and Balk, I’.: ‘lhe management and mismanagement of acute venous thrombosis of the extremities, angiology 16:339, 1965. O’Sullivan, E. F., Hirsh, J., McCarthy, R. A., and de Gruchy, G. C.: Heparin in the treatment of venous thrombo-embolic disease: Administration, control and results, Med. J. Aust. 2:1.53, 1968.
.ir,rrr~. Heart J. April, 1970
Annota.tions
manual hold, an additional sweep is used at the bottom of the screen; erase is inhibited, and a Lissajous pattern is generated. This causes the beam to move too fast to be stored and permits the ECG to be displayed in a repetitive fashion to resemble the conventional trace. The amount of ECG information to be displayed is a function of the sweep speed as well as the number of stair-steps generated. Examples of rhvthm disturbances are shown in Fie. 1. Thev were simulated (“Polyrhythm” simulator, khysio-Control Corp.) to show the ease by which rhythm disturbances can be detected and identified by using the system. The total cost of the entire display system is little more than that of the ordinary system. It is considerably less expensive than monitor systems using video-scan techniques now becoming available. The
A thought
about
donor
There must come a time when a donor heart in a recipient survives long enough so that every atom and every molecule of the heart are replaced by new ones through kinetic metabolic processes of the recipient and of the donor heart. But, are the exchanges in the donor heart programmed by the genes of the donor cells without influence from the recipient? Or, are the programmings which are governed by the recipient’s genes so different from those of the donor heart that once in the recipient and with the passage of sufficient time the donor heart is an entirely different one, all atoms and all molecules being new and organized differently, more like that of the recipient? If different, ho.Kr different and how “foreipn” with time to that of the recipient? It may be possible for the kinetics of exchange among atoms and molecules to produce eventually a new and “nonforeign” organ for the
equipment can be mounted in standard relay-rack enclosures and may be adapted to any physical configuration desired. Since the storage oscilloscope has its own built in “memory,” a memory unit is no longer essential. Permanent records can be obtained easily and economically by using a camera adapted to the storage oscilloscope by the manufacturer (Model C-3OP, Tektronix, Inc.). It was used to obtain the photographs in Fig. 1. Loyal L. Conrad, M.D. Professor of Medicine University of Oklahoma Medical Center Veterans Administration Hospital Robert L. Trendley Coronary Care Unit Project Engineer Oklahoma Regional Medical Program Oklahoma City, Okla.
hearts
recipient with the donor heart as the “base.” Perhaps with a little help, the new molecules and their spatial interrelationships and interactions can be made to resemble the recipient sufficiently to be accepted forever. One can only recall the response of George Bernard Shaw to a critic who accused him of writing a bad play 20 years earlier. Shaw replied that the man who wrote that play no longer existed. It was a different George Bernard Shaw who had written that play, for his physiologist friends had told him that all atoms and molecules of man are completely turned over every 14 years. George Burch, M.D. T. D. Giles, M.D. H. L. Colcolough, M.D. Tulane University School of Medicine New Orleans, La.
Streptokinase therapy in acute major pulmonary embolism *
The feasibility by enzymatic *This
of producing dissolution of thrombi means has been demonstrated in ex-
study was supported Foundation of Australia
by a grant
from the National
Heart
perimental thrombi’J and pulmonary emboli3J in animals, in experimental thrombi in man,6 and in patients with acute venous and arterial thromboembolic disease.6J7 Of the enzymes investigated, only the two plasminogen activators, streptokinase
Annotations
and urokinase, have proved acceptable as thrombolytic agents for clinical use.18 Streptokinase is now readily available in a highly purified form but has the disadvantage of being antigenic in man. Pyrogenicity, a major difficulty with early preparations,rsJg is no longer a significant problem provided that prophylactic corticosteroids are used.20J1 Urokinase is of human origin, not antigenic to man, and initiai clinical investigations suggest that it produces a predictable dose response effect in most patients.8 The extraction and purification of this enzyme in a form acceptable for human use has proved difficult, and although this has now been achieved, the drug is still very expensive and relatively unavailable. Clinical studies with urokinase are currently in progress in the United State9 but by comparison with streptokinase, experience in the use of urokinase in man is limited.18 The problems of the antigenicity of streptokinase are manifest in two ways. The first is due to the fact that stre’ptococcal antibodies react with streptokinase. These antibodies, the result of previous streptococcal infections, are present in most patients and have to be neutralized before thrombolysis can be induced.24 The neutralizing dose of streptokinase cannot be predicted with any certainty because the concentration of streptokinase antibodies varies over a wide range from patient to patient.20.24 For this reason it is commonly recommended that a resistance test be performed and the dose of streptokinase individualized for each patient. The second problem arising from the antigenicity of streptokinase is that treatment is followed by a marked increase in the levels of streptokinase antibodies, and this precludes further therapy, should this be necessary, over the next one to six months.zl The use of streptokinase has been limited in the past by the need to perform streptokinase resistance tests on patients before commencing treatment. Although these tests are relatively simple, it may not always be convenient to perform them before starting treatment. In recent years attempts have been made to overcome this problem by introducing various standard dosage schedules.i6J0 With this approach it is inevitable that some patients will receive an inducing dose in excess of their resistance and others a dose which fails to neutralize their streptokinase antibodies. High inducing doses in excess of the patient’s resistance have been shown to be safe and effective16J0; they produce rapid activation and depletion of plasminogen and give rise to a hemostatic defect which, however, is transient and asymptomatic provided that the circulating plasminogen is maintained at a low level by an adequate sustaining dose.90 On the other hand, inducing doses which fail to neutralize the circulating antibodies are pharmacologically ineffective. Therefore, to be of practical value, an arbitrary inducing dose should be sufficiently large to overcome the streptokinase resistance in a very large percentage of the population; this dose will be strongly influenced by the range and distribution of streptokinase resistance in the particular community in question. Verstraete and associates20 demonstrated that a standard dosage schedule was both effective and free of hemorrhagic complications. However,
575
the very high inducing dose of 1,250,OOO U. of streptokinase used by these investigators has the disadvantage that treatment in some patients becomes unnecessarily expensive. Other investigators when using a standard dosage regimen have used lower inducing doses, but the fibrinolytic effects of these lower dosage schedules has not been systematically evaluated.16e2’ Recently we investigated the safety and effectiveness of a standard dosage schedule of streptokinase (Streptase, Australian Hoechst Ltd.) in 50 randomly selected patients with thromboembolic disease.25 A streptokinase resistance test was performed on each patient who was then treated with a standard dose of 250,000 U. of streptokinase infused over 30 minutes followed by 100,000 U. per hour. The results of serial tests of fibrinolytic activity were then correlated with the streptokinase resistance in each patient, particular attention being directed to those patients with resistances in excess of the inducing dose. Forty-six of the 50 patients had a resistance of 250,000 U. or lower and all of these patients developed an active thrombolytic state with rapid plasminogen depletion. The 4 patients with a streptokinase resistance in excess of 250,000 U. showed a delayed fibrinolytic response, but, once obtained, the fibrinolytic effects were similar to those found in the other 46 patients. In general, the treatment was well tolerated; bleeding, the major complication, was usually restricted to oozing from sites of venipuncture but was severe in 2 patients. These findings, together with other reports,20 indicate that it is possible to obtain a satisfactory fibrinolytic response with streptokinase in a large percentage of a community using a standard dosage schedule. The routine use of such a schedule would be acceptable only if a thrombolytic state could be achieved in a very high percentage of the community with a reasonably low inducing dose. On the other hand, if the distribution of streptokinase resistance in a community shows a very wide scatter with a significant proportion having a very high resistance, it would be far more economical to individualize treatment than to treat all patients with a very high inducing dose. Theoretically, major pulmonary embolism is a particularly attractive indication for thrombolytic therapy. The embolus is usually composed of recent thrombus and the effects of therapy can be assessed objectively by angiographic, hemodynamic, and lung scanning studies. It has been shown that both streptokinase and urokinase accelerate resolution of pulmonary emboli in animals.304 More recently, angiographic improvement has been documented following thrombolytic therapy with streptokinase and urokinase in patients with severe pulmonary embolism.1+14Jr Despite these encouraging results the question as to whether or not the plasminogen activators accelerate dissolution of pulmonary embolism and improve immediate survival in man remains unanswered. Spontaneous resolution of massive pulmonary embolism has been demonstrated in man by serial angiography,*e-** but the speed with which resolution occurs is unknown. Recent investigations28 suggest that the majority of large
.4rbicv. Heart 1. .4jvi/, 1970
pulmonary emboli in otherwise healthy patients eventually undergo resolution in a matter of weeks, but that resolution is often delayed for many months in patients with underlying cardiac or respiratory disease. In a recent study the clinical, hemodynamic, and angiographic effects of streptokinase were investigated in 18 patients with major pulmonary embolism.‘” The diagnosis of major pulmonary embolism was confirmed by pulmonary angiography and the catheter was then left in the main pulmonary artery and used for the streptokinase infusion, for serial pulmonary artery pressure measurements and for further pulmonary angiograms. The loading dose of streptokinase was calculated from the resistance test, but in 12 patients a standard loading dose of 250,000 U. was infused over 30 minutes before the result of the resistance test was available. Treatment was continued for at least 24 hours with a maintenance dose of 100,000 U. per hour and the fibrinolytic and therapeutic effects were assessed by serial tests of fibrinoiytic activity, serial pulmonary artery pressure measurements, and by a second angiogram. One patient was treated within 48 hours of abdominal surgery with a modified dosage schedule which was carefully monitored to produce only mild systemic fibrinolytic activity.10 Fourteen of the 18 patients improved clinically in the 24 hour period following the commencement of streptokinase therapy. Of the 4 who failed to show initial improvement, 2 subsequently died and 2 required pulmonary embolectomy which was successfully performed in both. The indications for embolectomy were cardiac arrest 3 hours after beginning streptokinase in one and recurrent pulmonary embolism 24 hours after beginning therapy in the other. Autopsy in the other 2 cases showed severe pulmonary arterial obstruction by organized thromboembolism. Sixteen patients had angiograms repeated 24 hours after streptokinase therapy. Eight showed marked improvement, 3 moderate improvement, 2 slight improvement, 1 had a recurrent embolus, and the 2 patients who died showed no significant change. In general, the clinical, angiographic, and hemodynamic improvement was most marked in patients who were treated soon after a single episode of major pulmonary embolism and least marked in those who had evidence of progressive or persistent pulmonary embolic obstruction for more than 1 week. These findings are consistent with the experimental observations both in man5 and in animals* that venous thrombi become more resistant to therapeutic thrombolysis as they age. The findings with streptokinase may be compared with observations made on 7 patients with major pulmonary embolism following 24 hours of treatment with continuous intravenous heparinZ9 Three of these patients had recent acute embolic episodes and the other 4 had recurrent emboli with a recent major episode. Five of the 7 patients (including the 3 with single acute episodes) showed no evidence of resolution, either hemodynamically or angiographically, after 24 hours, and the other 2 showed only minimal resolution. Thus, although spontaneous resolution of major pulmonary em-
bolism eventually takes place,28 it is probable that significant resolution of 24 hours is uncommon. Even if thrombolytic therapy does accelerate early resolution of major pulmonary embolism in man, it is unlikely that this form of treatment will ever have a strong influence on the overall mortality rate from pulmonary embolism. This is because the majority of patients who die from pulmonary embolism do so before any treatment can be instituted.30t31 It is probable that a very significant number of these deaths would be prevented if anticoagulants were used prophylactically in high-risk patient+36 and if clinically recognizable minor thrombcembolic episodes were treated promptly with adequate doses of heparin.36-41 Nevertheless, a significant proportion of patients who die with major pulmonary embolism do survive for 24 to 48 hours, and it is in this time period that thrombolytic therapy may fill an important role. While some of the delayed deaths may be caused by recurrence or propagation of the embolus, it is likely that many are caused by the direct hemodynamic consequences of the initial embolic obstruction. The survival rate in this group should be improved if rapid resolution of the embolus is achieved. Thrombolytic therapy may have an even more important place in patients with underlying cardiac or respiratory disease in whom spontaneous resolution is often delayed.28 Resolution in these patients may not only improve the immediate mortality rate from acute pulmonary embolism but may decrease morbidity from the consequences of persistent embolic obstruction. In spite of the encouraging results obtained thus far, the ultimate assessment of the role of thrombolytic therapy in the treatment of pulmonary embolism must await controlled clinical trials. One such trial with urokinase is currently in progress in the United States23 and its outcome is awaited with interest. Whatever the result, major pulmonary embolism is likely to remain a common cause of death in hospital patients until more attention is directed to prophylaxis in high-risk groups and to early and adequate heparin treatment of patients withfminor thromboembolic episodes. J. Hirsh, M.D., M.R.A.C.P.* I. G. McDonald, M.D., M.R.A.C.P. G. S. Hale, M.D., F.R.A.C.P. i?niuersity of Melbourne Department of Medicine St. Vincent’s Hospital Melbourne, Victoria, Australia *Present
address:
Medicine,
Department of McMaster University.
Pathology. Hamilton,
Faculty of Ontario,
Canada.
REFERENCES 1. Johnson, A. J., and Tillet, W. S.: The lysis in rabbits of intravascular blood clots by the streptococcal fibrinolytic system (streptokinase). 1. Exo. Med. 95:449. 1952. 2. Sherry, S.,’ Titchener, A., Gotterman, L., Wasserman, P., and Troll, W.: The enzymatic dissolution of experimental arterial thrombi
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in the dog by trypsin, chymotrypsin, and plasminogen activators, J. Clin. Invest. 33:1303, 1954. 3. Browse, N. L., and James, D. C. D.: Streptokinase and pulmonary embolism, Lancet 2:1039, 1964. 4. Genton, E., and Wolf, P. S.: Experimental pulmonary embolism: Effects of urokinase therapy on organizing thrombi, J. Lab. Clin. Med. 70:311, 1967. 5. Johnson, A. J., and McCarty, W. R.: The lysis of artificially induced intravascular clots in man by intravenous infusions of streptokinase, J. Clin. Invest. 38:1627, 1959. 6. Winckelmann, G., and Hiemeyer, V.: Experience with streptokinase as a thrombolytic agent, Stand. J. Clin. Lab. Invest. 16 (Suppl. 78):7, 1964. 7. McNicol, G. P., and Douglas, A. S.: Treatment of peripheral vascular occlusion by streptokinase perfusion, Stand. J. Clin. Lab. Invest. 16 (SuppI. 78):23, 1964. 8. Verstraete, M., Vermylen, J., de Vreker, R., Amerv. A.. and Vermvlen. C.: Efficacv of thrombolytic therapy with streptokinase using a new administration scheme, Stand. J. Clin. Lab. Invest. 16 (SuppI. 78):15, 1964. 9. Gormsen. 1.. and Larsen. B.: Treatment of acute phlebothrombosis with streptase, Acta Med. Stand. 181:373, 1967. 10. Hirsh, J., Hale, G. S., McDonald, I. G., McCarthv. R. A.. and Cade. 1. F.: Resolution of acute massive pulmonary embolism after pulmonary arterial infusion of streptokinase, Lancet 2:593, 1967. 11. Tow, W. S., Wagner, H. N., and Holmes, R. A.: Urokinase in pulmonary embolism, New Eng. J. Med. 277:1161, 1967. 12. Sasahara, A. A., Cannilla, J. E., Belko, J. S., Morse, R. L., and Criss, A. J.: Urokinase therapy in clinical pulmonary embolism, New Eng. J. Med. 277:1168, 1967. 13. Sautter, R. D., Emanuel, D. A., and Wenzel, F. J.: Treatment of acute massive pulmonary embolism, Ann. Thorac. Surg. 4:95, 1967. 14. Hirsh, J., Hale, G. S., McDonald, I. G., McCarthy, R. A., and Pitt, A.: Streptokinase therapy in acute major pulmonary embolism: effectiveness and problems, Brit. Med. J, 4:729, 1968. 15. Browse, N. L., Thomas, M. L., and Pim, H. P.: Streptokinase and deep vein thrombosis, Brit. Med. J. 3:717, 1968. 16. Robertson, B. R., Nilsson, I. M., and Nylander, G.: Value of streptokinase and heparin in treatment of acute deep venous thrombosis, Acta Chir. Stand. 134:203. 1968. 17. Genton, E., and Wolf, P. S.: Urokinase therapy in pulmonary thromboembolism, AMER. HEART J. 76:628, 1968. 18. Sherry, S.: Fibrinolysis, Ann. Rev. Med. 19:247, 1968. 19. Tillet, W. S., Johnson, A. J., and McCarthy, W. R.: The intravenous infusion of the streptccoccal fibrinolytic principle (streptokinase) into patients, J. Clin. Invest. 84:169, 1955. I
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Morris, L. E., and Balk, I’.: ‘lhe management and mismanagement of acute venous thrombosis of the extremities, angiology 16:339, 1965. O’Sullivan, E. F., Hirsh, J., McCarthy, R. A., and de Gruchy, G. C.: Heparin in the treatment of venous thrombo-embolic disease: Administration, control and results, Med. J. Aust. 2:1.53, 1968.