Pulmonary embolectomy, heparin, and streptokinase: Their place in the treatment of acute massive pulmonary embolism G. A. H. Miller, D.M., F.R.C.P. R. J. C. Hall, M.R.C.P. M. Paneth, F.R.C.S. London, England
The place of pulmonary embolectomy in the treatment of pulmonary embolism has been the subject of much discussion but few definite conclusions since a randomized trial of embolectomy and alternative t r e a t m e n t does not seem feasible.' Our reasons for adding to the already voluminous literature on the subject are as follows. 1. In most series the mortality rate quoted for pulmonary embolectomy is, in our view. considerably higher than can be achieved, thus providing a false basis for comparison with other forms of treatment. 2. It has been suggested that pulmonary embolectomy is seldom both technically feasible and clinically appropriate. In one series of 45 patients with massive pulmonary embolism 2 there were only four in whom embolectomy was judged to be technically feasible. All four had another lethal condition such as metastatic neoplasm or endstage cirrhosis which made embolectomy inappropriate. Th e present series includes 23 patients in shock in whom embolectomy was performed; none had terminal carcinomatosis or similar contraindication to embolectomy. 3. Our own relatively large series of patients (68 with isolated active massive pulmonary embolism reported here} have been treated by embolectomy or medically with anticoagulants or streptokinase, thus permitting some comparison between From the Brompton Hospital, London, England. Received for publication Dec. 9, 1975. Reprint requests: G. A. H. Miller, D.M.. Director. Cardiac Laboratories, Brompton Hospital, Fulham Rd., London SW3 6HP England.
568
the different t r e a t m e n t regimes. As a result of this experience, we have developed an approach to t reat m ent selection which includes a place for pulmonary embolectomy. Case material and definitions 1. Pulmonary embolectomy. Since June, 1964, a total of 53 patients with massive pulmonary embolism have undergone emergency embolectomy with total cardiopulmonary bypass. Of these, 20 had associated cardiorespiratory disease or had embolism of uncertain duration and have been excluded from this study. The remaining 33 patients, in whom the primary* t reat m ent was pulmonary embolectomy, had isolated acute massive p u l m o n a r y embolism, as defined below. These 33 patients together with 35 medically treated patients with isolated acute massive pulmonary embolism form the basis of this report. Isolated: No patient had any other cardiorespiratory disease. Acute: All patients were admitted and specific treatment was begun 2 to 48 hours from the onset of symptoms of massive embolism. Massive p u l m o n a r y embolism: Involved at least 50 per cent of the pulmonary arterial tree as demonstrated by pulmonary arteriography (10 *Primary treatment refers to the specific treatment initially employed by us; final treatment may be different. Thus, of the 18 patients in whom heparin was the primary treatment adopted, five had a subsequent embolectomy. Primary treatment ignores t r e a t m e n t given a~ the referring hospital, although five of the patients treated by embolectomy had been given heparin at the referring hospital for periods ranging from 2 to 48 hours.
May, 1977, Vol. 93, No. 5, pp. 568-574
Pulmonary embolectomy, heparin, and streptokinase patients) a n d / o r findings at e m b o l e c t o m y (23 patients). T h e r e were six m e n and 27 women; their average age was 43 years (21 to 68 years), 2. Medical treatment. Over the same period of time there were 35 patients with angiographically proved isolated acute massive p u l m o n a r y embolism (as defined above) in w h o m the p r i m a r y t r e a t m e n t was with heparin (18 patients) or streptokinase ( 17 patients). Details of administra tion and dosage of heparin or streptokinase have been described elsewhere 3 b u t are s u m m a r i z e d briefly below. Following p u l m o n a r y arteriography a c a t h e t e r was left in position in the main p u l m o n a r y a r t e r y for 72 hours and used for infusion of either (1) streptokinase (Kabikinase), 600,000 units in the first 30 m i n u t e s followed by 100,000 units per hour, (2) heparin, 5,000 units in the first 30 minutes followed by 2,500 units per hour for 72 hours. Following the d e m o n s t r a t i o n by B a r r i t t and J o r d a n 17 of the protective effect of heparin in acute p u l m o n a r y embolism it is probably unethical to withhold heparin unless alternative t h e r a p y (e.g., streptokinase) is employed. It is for this reason t h a t heparin was administered to the " c o n t r o l " group. In some, b u t not all, of these patients t r e a t m e n t was selected on a r a n d o m basis2 T h e results of medical treatm e n t are s u m m a r i z e d here for purposes of comparison with the results of embolectomy. In the h e p a r i n - t r e a t e d group there were seven men and 11 women; their average age was 52 years (38 to 69 years). In the streptokinase-treated group there were five men and 12 women; their average age was 49 years (19 to 71 years). 3. " S h o c k " / " N o n s h o c k . " All 68 patients were divided into two groups according to the presence or absence of "shock," defined as a systolic arterial pressure of 100 mm. Hg or less. (In one "shock" p a t i e n t undergoing e m b o l e c t o m y pressure was above this level b u t could only be maintained by a continuous infusion of large doses of metaraminol.) T h e s e categories were determined in relation to the patients' state at the
time when primary treatment was initiated by us-i.e., referral for e m b o l e c t o m y or the institution of heparin or streptokinase therapy. M a n y patients had a low or u n r e c o r d a b l e blood pressure with the onset of embolism b u t were in a stable state with a blood pressure of over 100 mm. Hg systolic by the time t h e y were transferred to our hospital. Such patients are not categorized as having "shock." Conversely, some patients
American Heart Journal
became hypotensive after arrival and are categorized as having "shock" if this was their state when specific t h e r a p y was instituted at this hospital. 4. Treatment failures. It is our practice that, when a patient deteriorates during medical treatment, alternative measures are employed. (Streptokinase or e m b o l e c t o m y when the p r i m a r y treatm e n t is with heparin; e m b o l e c t o m y when it is with streptokinase.) T h u s the m o r t a l i t y rate for medical t r e a t m e n t m a y appear falsely low due to the potential which alternative t r e a t m e n t m a y have for retrieving a deteriorating situation. For this reason we report b o t h the actual m o r t a l i t y figures and the " t r e a t m e n t failures." T r e a t m e n t failure refers to the situation of h e m o d y n a m i c deterioration (falling arterial pressure or continued intolerably low levels of arterial pressure) which lead to substitution of alternative therapy. Episodes of r e c u r r e n t embolism are included as t r e a t m e n t failures. Results
For the whole group the over-all m o r t a l i t y rate was 16 per cent (11 of 68). "Nonshock," 27 patients (Table I}.
l. Primary treatment-pulmonary embolectomy: 10 patients. One patient in this group died (mortality rate 10 per cent). CAUSE OF DEATH. Circulatory arrest occurred during induction of anesthesia. T h e p a t i e n t died 7 days later without having regained consciousness. This patient is discussed more fully below. 2. Primary treatment-streptokinase: nine patients. No deaths and no t r e a t m e n t failures occurred in this group. 3. Primary treatment-heparin: eight patients. One patient had a gastrointestinal h e m o r r h a g e during heparin therapy, which was therefore abandoned, and e m b o l e c t o m y was performed. Oral anticoagulants were given in the postoperative period and he died 9 days after the original embolus from a f u r t h e r gastrointestinal hemorrhage despite a satisfactory p r o t h r o m b i n ratio. One patient b e c a m e hypotensive after 7 days of heparin due to bleeding from a h y s t e r e c t o m y wound and gastrointestinal hemorrhage. Embolectomy was successfully carried out after blood transfusion. One patient suffered a n o n f a t a l r e c u r r e n t embolism for which he was t h e n treated with streptokinase.
569
Miller, Hall, and Paneth
Table I. " N o n s h o c k " - B . P . > 100 mm. Hg
Primary treatment T o t a l n u m b e r of p a t i e n t s Deaths " T r e a t m e n t failure" Recurrent embolism T o t a l d e a t h s a n d failures
I
Embolectomy
Streptokinase
Hepann
Total
I0 1 0 1 (10%)
9 0 0 0 0
8 1 1 1 3 (37.5%}
27 2 (7.4%)
Streptokinase
Heparin
Total
1
Table II. " S h o c k " - B . P . < 100 mm. Hg
Primary treatment
Embolectomy
T o t a l n u m b e r of p a t i e n t s Deaths " T r e a t m e n t failure" Recurrent embolism T o t a l d e a t h s a n d failures
23 6 0 6 (26%)
8 1 (2") 1" 1" 2 (25%)
10 1 4 it 5 c50%)
41 9 (21.9%) 2
*This patient failed treatment (haemodynamic deterioration) but died 3 months later of a recurrent embolus. He therefore appears in the "failure" and recurrent columns and tin bracketsl in deaths. tThis patient died of recurrent embolism and also appears in the deaths column.
T h e combined d e a t h / t r e a t m e n t failure rate was therefore 37.5 per cent. " S h o c k , " 41 patients (Table II).
1. Primary treatment-pulmonary embolectomy: 23 patients. Six patients in this group died (mortality r a t e 26 per cent). CAUSES OF DEATH. All patients who died had suffered at least one episode of circulatory arrest prior to surgery. (Of the 17 survivors in this group five had suffered an episode of circulatory arrest.) T h r e e deaths were "neurologic," i.e., the patients came off bypass in a satisfactory state but died 2 to 28 days later w i t h o u t having regained consciousness. T w o of these patients were unconscious on arrival from the referring hospital (one was hemiplegic). In the o t h e r blood pressure was unrecordable at the time of referral for e m b o l e c t o m y and c a r d i o p u l m o n a r y bypass was established while cardiac massage was being performed. T w o f u r t h e r patients died in the operating theater; both, with unrecordable blood pressure, were having external massage while cardiopulm o n a r y bypass for e m b o l e c t o m y was being established. T h e last patient who died had severe intraabdominal h e m o r r h a g e as a result of a lacerated liver caused by preoperative resuscitative efforts and had fixed dilated pupils prior to operation. 2. Primary treatment-streptokinase: eight patients. One p a t i e n t in this group died: one p a t i e n t deteriorated ( t r e a t m e n t failure) and e v e n t u a l l y died of a r e c u r r e n t embolus 3 m o n t h s later. T h e 570
combined d e a t h / t r e a t m e n t failure rate was therefore 25 per cent. CAUSES OF DEATH. One p a t i e n t was unconscious on admission, because of a prior circulatory arrest, and died 3 m o n t h s later, never having regained consciousness, despite complete hemodynamic recovery with streptokinase. T h e o t h e r patient remained hypotensive after 12 hours' t r e a t m e n t with streptokinase and was therefore submitted to e m b o l e c t o m y ( = t r e a t m e n t failure}. Convalescence was complicated by bleeding leading to hypotension and renal failure for which hemodialysis was successfully performed at a n o t h e r hospital. During convalescence he suffered a f u r t h e r p u l m o n a r y embolus and inferior vena caval plication was carried out. Two m o n t h s after his first massive embolus and just prior to discharge he suffered a t h i r d - and f a t a l - p u l m o n a r y embolus despite inferior vena caval (IVC) plication. 3. Primary treatment-heparin: 10 patients. One patient in this group died. T h e r e were four t r e a t m e n t failures ( h e m o d y n a m i c deterioration leading to alternative t r e a t m e n t - e m b o l e c t o m y two, streptokinase two). T h e combined d e a t h / t r e a t m e n t failure rate was therefore 50 per cent. CAUSES OF DEATH. One p a t i e n t died of a recurrent embolus at 6 days. E m e r g e n c y embolect o m y was performed while external massage was being carried out b u t was unsuccessful. The effect of previous circulatory arrest (Fig. 1). In the whole group of 68 patients, 20 had suffered at least one episode of circulatory arrest
May, 1977, Vol. 93, No. 5
Pulmonary embolectomy, heparin,, and streptokinase E p i s o d e of Circulatory
28
E
Streptokinase
Heparin
Arrest
I--I No Circulatory I I Arrest
24
5O 40'
~%%%% I I I
20
30-
I 16
20-
p
The place of pulmonary embolectomy in the treatment of pulmonary embolism has been the subject of much discussion but few definite conclusions since a randomized trial of embolectomy and alternative t r e a t m e n t does not seem feasible.' Our reasons for adding to the already voluminous literature on the subject are as follows. 1. In most series the mortality rate quoted for pulmonary embolectomy is, in our view. considerably higher than can be achieved, thus providing a false basis for comparison with other forms of treatment. 2. It has been suggested that pulmonary embolectomy is seldom both technically feasible and clinically appropriate. In one series of 45 patients with massive pulmonary embolism 2 there were only four in whom embolectomy was judged to be technically feasible. All four had another lethal condition such as metastatic neoplasm or endstage cirrhosis which made embolectomy inappropriate. Th e present series includes 23 patients in shock in whom embolectomy was performed; none had terminal carcinomatosis or similar contraindication to embolectomy. 3. Our own relatively large series of patients (68 with isolated active massive pulmonary embolism reported here} have been treated by embolectomy or medically with anticoagulants or streptokinase, thus permitting some comparison between From the Brompton Hospital, London, England. Received for publication Dec. 9, 1975. Reprint requests: G. A. H. Miller, D.M.. Director. Cardiac Laboratories, Brompton Hospital, Fulham Rd., London SW3 6HP England.
568
the different t r e a t m e n t regimes. As a result of this experience, we have developed an approach to t reat m ent selection which includes a place for pulmonary embolectomy. Case material and definitions 1. Pulmonary embolectomy. Since June, 1964, a total of 53 patients with massive pulmonary embolism have undergone emergency embolectomy with total cardiopulmonary bypass. Of these, 20 had associated cardiorespiratory disease or had embolism of uncertain duration and have been excluded from this study. The remaining 33 patients, in whom the primary* t reat m ent was pulmonary embolectomy, had isolated acute massive p u l m o n a r y embolism, as defined below. These 33 patients together with 35 medically treated patients with isolated acute massive pulmonary embolism form the basis of this report. Isolated: No patient had any other cardiorespiratory disease. Acute: All patients were admitted and specific treatment was begun 2 to 48 hours from the onset of symptoms of massive embolism. Massive p u l m o n a r y embolism: Involved at least 50 per cent of the pulmonary arterial tree as demonstrated by pulmonary arteriography (10 *Primary treatment refers to the specific treatment initially employed by us; final treatment may be different. Thus, of the 18 patients in whom heparin was the primary treatment adopted, five had a subsequent embolectomy. Primary treatment ignores t r e a t m e n t given a~ the referring hospital, although five of the patients treated by embolectomy had been given heparin at the referring hospital for periods ranging from 2 to 48 hours.
May, 1977, Vol. 93, No. 5, pp. 568-574
Pulmonary embolectomy, heparin, and streptokinase patients) a n d / o r findings at e m b o l e c t o m y (23 patients). T h e r e were six m e n and 27 women; their average age was 43 years (21 to 68 years), 2. Medical treatment. Over the same period of time there were 35 patients with angiographically proved isolated acute massive p u l m o n a r y embolism (as defined above) in w h o m the p r i m a r y t r e a t m e n t was with heparin (18 patients) or streptokinase ( 17 patients). Details of administra tion and dosage of heparin or streptokinase have been described elsewhere 3 b u t are s u m m a r i z e d briefly below. Following p u l m o n a r y arteriography a c a t h e t e r was left in position in the main p u l m o n a r y a r t e r y for 72 hours and used for infusion of either (1) streptokinase (Kabikinase), 600,000 units in the first 30 m i n u t e s followed by 100,000 units per hour, (2) heparin, 5,000 units in the first 30 minutes followed by 2,500 units per hour for 72 hours. Following the d e m o n s t r a t i o n by B a r r i t t and J o r d a n 17 of the protective effect of heparin in acute p u l m o n a r y embolism it is probably unethical to withhold heparin unless alternative t h e r a p y (e.g., streptokinase) is employed. It is for this reason t h a t heparin was administered to the " c o n t r o l " group. In some, b u t not all, of these patients t r e a t m e n t was selected on a r a n d o m basis2 T h e results of medical treatm e n t are s u m m a r i z e d here for purposes of comparison with the results of embolectomy. In the h e p a r i n - t r e a t e d group there were seven men and 11 women; their average age was 52 years (38 to 69 years). In the streptokinase-treated group there were five men and 12 women; their average age was 49 years (19 to 71 years). 3. " S h o c k " / " N o n s h o c k . " All 68 patients were divided into two groups according to the presence or absence of "shock," defined as a systolic arterial pressure of 100 mm. Hg or less. (In one "shock" p a t i e n t undergoing e m b o l e c t o m y pressure was above this level b u t could only be maintained by a continuous infusion of large doses of metaraminol.) T h e s e categories were determined in relation to the patients' state at the
time when primary treatment was initiated by us-i.e., referral for e m b o l e c t o m y or the institution of heparin or streptokinase therapy. M a n y patients had a low or u n r e c o r d a b l e blood pressure with the onset of embolism b u t were in a stable state with a blood pressure of over 100 mm. Hg systolic by the time t h e y were transferred to our hospital. Such patients are not categorized as having "shock." Conversely, some patients
American Heart Journal
became hypotensive after arrival and are categorized as having "shock" if this was their state when specific t h e r a p y was instituted at this hospital. 4. Treatment failures. It is our practice that, when a patient deteriorates during medical treatment, alternative measures are employed. (Streptokinase or e m b o l e c t o m y when the p r i m a r y treatm e n t is with heparin; e m b o l e c t o m y when it is with streptokinase.) T h u s the m o r t a l i t y rate for medical t r e a t m e n t m a y appear falsely low due to the potential which alternative t r e a t m e n t m a y have for retrieving a deteriorating situation. For this reason we report b o t h the actual m o r t a l i t y figures and the " t r e a t m e n t failures." T r e a t m e n t failure refers to the situation of h e m o d y n a m i c deterioration (falling arterial pressure or continued intolerably low levels of arterial pressure) which lead to substitution of alternative therapy. Episodes of r e c u r r e n t embolism are included as t r e a t m e n t failures. Results
For the whole group the over-all m o r t a l i t y rate was 16 per cent (11 of 68). "Nonshock," 27 patients (Table I}.
l. Primary treatment-pulmonary embolectomy: 10 patients. One patient in this group died (mortality rate 10 per cent). CAUSE OF DEATH. Circulatory arrest occurred during induction of anesthesia. T h e p a t i e n t died 7 days later without having regained consciousness. This patient is discussed more fully below. 2. Primary treatment-streptokinase: nine patients. No deaths and no t r e a t m e n t failures occurred in this group. 3. Primary treatment-heparin: eight patients. One patient had a gastrointestinal h e m o r r h a g e during heparin therapy, which was therefore abandoned, and e m b o l e c t o m y was performed. Oral anticoagulants were given in the postoperative period and he died 9 days after the original embolus from a f u r t h e r gastrointestinal hemorrhage despite a satisfactory p r o t h r o m b i n ratio. One patient b e c a m e hypotensive after 7 days of heparin due to bleeding from a h y s t e r e c t o m y wound and gastrointestinal hemorrhage. Embolectomy was successfully carried out after blood transfusion. One patient suffered a n o n f a t a l r e c u r r e n t embolism for which he was t h e n treated with streptokinase.
569
Miller, Hall, and Paneth
Table I. " N o n s h o c k " - B . P . > 100 mm. Hg
Primary treatment T o t a l n u m b e r of p a t i e n t s Deaths " T r e a t m e n t failure" Recurrent embolism T o t a l d e a t h s a n d failures
I
Embolectomy
Streptokinase
Hepann
Total
I0 1 0 1 (10%)
9 0 0 0 0
8 1 1 1 3 (37.5%}
27 2 (7.4%)
Streptokinase
Heparin
Total
1
Table II. " S h o c k " - B . P . < 100 mm. Hg
Primary treatment
Embolectomy
T o t a l n u m b e r of p a t i e n t s Deaths " T r e a t m e n t failure" Recurrent embolism T o t a l d e a t h s a n d failures
23 6 0 6 (26%)
8 1 (2") 1" 1" 2 (25%)
10 1 4 it 5 c50%)
41 9 (21.9%) 2
*This patient failed treatment (haemodynamic deterioration) but died 3 months later of a recurrent embolus. He therefore appears in the "failure" and recurrent columns and tin bracketsl in deaths. tThis patient died of recurrent embolism and also appears in the deaths column.
T h e combined d e a t h / t r e a t m e n t failure rate was therefore 37.5 per cent. " S h o c k , " 41 patients (Table II).
1. Primary treatment-pulmonary embolectomy: 23 patients. Six patients in this group died (mortality r a t e 26 per cent). CAUSES OF DEATH. All patients who died had suffered at least one episode of circulatory arrest prior to surgery. (Of the 17 survivors in this group five had suffered an episode of circulatory arrest.) T h r e e deaths were "neurologic," i.e., the patients came off bypass in a satisfactory state but died 2 to 28 days later w i t h o u t having regained consciousness. T w o of these patients were unconscious on arrival from the referring hospital (one was hemiplegic). In the o t h e r blood pressure was unrecordable at the time of referral for e m b o l e c t o m y and c a r d i o p u l m o n a r y bypass was established while cardiac massage was being performed. T w o f u r t h e r patients died in the operating theater; both, with unrecordable blood pressure, were having external massage while cardiopulm o n a r y bypass for e m b o l e c t o m y was being established. T h e last patient who died had severe intraabdominal h e m o r r h a g e as a result of a lacerated liver caused by preoperative resuscitative efforts and had fixed dilated pupils prior to operation. 2. Primary treatment-streptokinase: eight patients. One p a t i e n t in this group died: one p a t i e n t deteriorated ( t r e a t m e n t failure) and e v e n t u a l l y died of a r e c u r r e n t embolus 3 m o n t h s later. T h e 570
combined d e a t h / t r e a t m e n t failure rate was therefore 25 per cent. CAUSES OF DEATH. One p a t i e n t was unconscious on admission, because of a prior circulatory arrest, and died 3 m o n t h s later, never having regained consciousness, despite complete hemodynamic recovery with streptokinase. T h e o t h e r patient remained hypotensive after 12 hours' t r e a t m e n t with streptokinase and was therefore submitted to e m b o l e c t o m y ( = t r e a t m e n t failure}. Convalescence was complicated by bleeding leading to hypotension and renal failure for which hemodialysis was successfully performed at a n o t h e r hospital. During convalescence he suffered a f u r t h e r p u l m o n a r y embolus and inferior vena caval plication was carried out. Two m o n t h s after his first massive embolus and just prior to discharge he suffered a t h i r d - and f a t a l - p u l m o n a r y embolus despite inferior vena caval (IVC) plication. 3. Primary treatment-heparin: 10 patients. One patient in this group died. T h e r e were four t r e a t m e n t failures ( h e m o d y n a m i c deterioration leading to alternative t r e a t m e n t - e m b o l e c t o m y two, streptokinase two). T h e combined d e a t h / t r e a t m e n t failure rate was therefore 50 per cent. CAUSES OF DEATH. One p a t i e n t died of a recurrent embolus at 6 days. E m e r g e n c y embolect o m y was performed while external massage was being carried out b u t was unsuccessful. The effect of previous circulatory arrest (Fig. 1). In the whole group of 68 patients, 20 had suffered at least one episode of circulatory arrest
May, 1977, Vol. 93, No. 5
Pulmonary embolectomy, heparin,, and streptokinase E p i s o d e of Circulatory
28
E
Streptokinase
Heparin
Arrest
I--I No Circulatory I I Arrest
24
5O 40'
~%%%% I I I
20
30-
I 16
20-
p
