63
injections, the only cause for concern is the risk of bleeding and haematoma formation. Blood-loss during surgery was considered excessive in a rather greater number of heparin-treated than control patients, and there was a statistically significant increase in wound haematoma formation in the
Prevention of Postoperative Thromboembolism death in a surgical ward is be the result of massive pulmonary likely embolism. Repeated experience of such disasters has stimulated many surgeons to try to improve methods of diagnosing and preventing postoperative venous thrombosis. In 1970 SHARNOFF and DEBLASIO1 claimed that small doses of heparin injected subcutaneously would effectively reduce the incidence of fatal pulmonary embolism. J. G. SHARNOFF’s work may have lacked the rigorous control required of therapeutic trials, but he is now no longer on his own. Subcutaneous heparin has been shown to prevent the formation of peripheral venous thrombosis detected by 125I-fibrinogen uptake. 2,3 Such isotopically detected thrombi are usually small and of little SUDDEN
most
unexpected to
clinical significance-that is, they generate emboli of sufficient size to and they do not damage the veins
are
unlikely
cause
to
symptoms
the extent of producing post-thrombotic swelling or ulceration.44 It is therefore important to establish that a method capable of preventing isotopically detected " mini " thrombi also effectively prevents propagation to form clinically significant or " maxi " thrombi. V. V. KAKKAR and his colleagues, whose report appears at the start of this issue, have provided many of the answers to this question in a clinical trial involving twenty-eight centres and 4471 patients -an exercise requiring considerable organisational and persuasive ability. Their results indicate the effectiveness of low-dose heparin, which reduced the incidence of fatal pulmonary embolism from 16 in the control group to 2 in the treatment group. Deep-vein thromboses were detected isotopically in 24-6% of the controls and in 7-7% of those on heparin, and the numbers of phlebographically detected thrombi were 32 and 11, respectively. Apart from the minor discomfort and additional nursing workload imposed by repeated subcutaneous 1. 2.
to
Sharnoff, J. G., DeBlasio, G. Lancet, 1970, ii, 1006. Kakkar, V. V., Field, E. S., Nicolaides, A. N., Flute, P.
T. ibid.
1971, ii, 669. 3. Gordon-Smith, I. C., Grundy, D. J., Le Quesne, L. P., Newcombe, J. F., Bramble, F. J. ibid. 1972, i, 1133. 4. Hedlund, P. O. Scand. J. Urol. Nephrol. 1975, suppl. 27.
heparin-treated group. Bleeding problems, though apparently never severe, required heparin to be discontinued in 54 of the 2045 treated patients. Perhaps this is a reflection of the dose used; 5000 units 8-hourly in the postoperative period is a rather larger dose than the original 2500 units 6-hourly used by SHARNOFF and DEBLASIO. More probably the earlier workers avoided hxmorrhagic complications because they monitored coagulation-times and were thus able to forestall possible haemorrhage by administration of protamine. Such monitoring is timeconsuming, and the small incidence of haemorrhagic complications is doubtless the reason that KAKKAR and his colleagues considered it unnecessary. Calcium heparin was used in the multicentre trial, but we do not yet know if this has any advantages over the sodium form. What of other methods ? Dextran 70 reduces the incidence of isotopically detected mini thrombi,5.6 though less effectively than low-dose heparin,7 and in the double-blind Cardiff trial involving 831 patients significant pulmonary embolism developed in 13 (7 fatal) in the control group compared with 3 (1 fatal) in the treated patients.7 Minor bleeding required the code to be broken in 4 patients, but the dextran prophylaxis never had to be stopped. The intravenous route avoided repeated subcutaneous injections in patients who anyway needed intravenous fluids during and immediately after major surgery. In the area of mechanised treatment, both calfmuscle stimulation8 and intermittent calf compression effectively reduce the incidence of isotopically detected mini thrombi,9,IO but no large-scale trial of these methods has yet been undertaken. The importance of such large-scale trials is illustrated by the work on stockiiigs in thrombosis prevention. 125I-fibrinogen studies have shown these to be ineffectual in preventing small calf thrombi,11,12 but a study based on clinical and post-mortem findings 13 showed that significant pulmonary embolism occurred in 12 cases (4 fatal) among 2395 control patients compared with 2 (no deaths) in 2395 patients wearing stockings. The explanation may be that, while thrombus Lambie, J. M., Barker, D. C., Dhall, D. P., Matheson, H. A. Br. med. J. 1970, ii, 144. 6. Bonnar, J., Walsh, J. Lancet, 1972, i, 614 7. Kline, A., Hughes, L. E., Campbell, H., Williams, A., Zlosnick, J., Leach, K. G. Br. med. J. 1975, ii, 109. 8. Browse, N. L., Negus, D. ibid. 1970, iii, 615. 9. Hills, N. H., Pflug, J. J., Jeyasingh, K., Boardman, L., Calnan, J. S. ibid. 1972, i, 131. 10. Sabri, S., Roberts, V. C., Cotton, L. T. ibid. 1971, iii, 82. 11. Rosengarten, D. S., Laird, J. Br. J. Surg. 1971, 58, 182. 12. Browse, N. L., Jackson, B. T., Mayo, M. E., Negus, D. ibid. 1974, 61, 219. 13. Wilkins, R. W., Mixter, G., Jr., Stanton, J. R., Litter, J. New Engl. J. Med. 1952, 246, 360. 5.
64
formation is unaffected
by stockings, subsequent inhibited, and this effect may apply in other methods of prophylaxis.
propagation
is
choose between heparin and dextran in terms of the prevention of fatal pulmonary embolism. Heparin is the more effective in preventing peripheral thrombus formation, but has the minor disadvantages of repeated injections and, in a few patients, haematoma formation and bleeding. The choice will be dictated by the preferences of individual surgeons and nurses. Mechanical methods may be as effective in preventing massive embolism, but the answers will only be provided by large-scale trials similar to those of KAKKAR et al. and the Cardiff group. Such trials require considerable effort from the organisers, but those who have tried unsuccessfully to resuscitate a patient dying from pulmonary embolism will surely feel that this is worth while.
There
seems at
present little
to
Non-A, Non-B? BLOOD-TRANSFUSION is dangerous
at
the
best
1
of times.
It takes place over hours, or even days, during which time the patient’s circulation is invaded by an indwelling needle or cannula. The patient is infused with a biological fluid of variable and uncertain composition from a group of potentially infective living donors and, perhaps most hazardous of all, the volume of fluid transferred is, by micro-
biological standards, enormous. The transmission of syphilis and malaria is well recognised. Bacterial infections are fortunately rare nowadays. However, it is the viruses which have come to the fore in recent years. Of these, the best known, and conceptually the most simple, is the agent of hepatitis B. This can be transmitted by a blood-transfusion because the virus concerned may be present in the blood of symptom-free blood-donors.22 Potentially infective donors can be identified by testing their blood for HB antigen (HBAg). In fact, HBAg 3 has supplied the marker which had been needed ever since blood-transfusion came into general use; and testing donations for HBAg has, at least in the United Kingdom, undoubtedly reduced the incidence of post-transfusion hepatitis, although the extent of this reduction is difficult to gauge exactly. Even when a case of hepatitis is recognised as being " transfusion-associated ", it is a long, and sometimes hard, road to trace the source with certainty and identify the virus with precision. The crux of the matter is to determine how much " transfusion-associated hepatitis is definitely due to virus and hence, in theory at least, hepatitis-B the earliest studies on the preventable. One of "
1. 2. 3.
Titmuss, R. M. The Gift Relationship. London, 1970. Gocke, D. J. J. Am. med. Ass. 1972, 219, 1165. Almeida, J. D. Postgrad. med. J. 1971, 47, 484.
subject,
from
very few screened
cases
Scotland,4suggested that there were of hepatitis in patients receiving blood by even the relatively insensitive immunoelectrophoresis test, and MAYCOCK5 has claimed that, for the United Kingdom as a whole, some 575 cases a year could have been prevented in 1970. In addition, it is well known that commercially acquired blood is, at the same time, both much more icterogenic and more likely to be2 HBAg-positive than blood from volunteer donors. Besides this, surveillance for HBAg has gone most of the way in clearing British hsemodialysis units of hepatitis. All this seems to point strongly to hepatitis-B virus being the major hazard of blood-transfusion so far as hepatitis viruses are concerned, although posttransfusion hepatitis is certainly not the exclusive preserve of hepatitis-B virus.6 But this -is not the view of a Los Angeles group1 who state that most post-transfusion hepatitis is HBAg-negative 1; and PRINCE and his co-workers,8 in New York, record that " although most cases of hepatitis with a severe clinical course appear to be predominantly type B, careful prospective follow-up of transfused patients reveals that the major proportion of all hepatitis cases are of unknown aetiology ". PRINCE et al. give as reasons for supposing that these HBAg-negative cases are not hepatitis A, that the incubation period was relatively long and that there were no cases among the household contacts. Neither of these criteria could be described as virologically precise. Another report from the U.S.A. attempts to clear up some of the confusion, even though the findings FEINSTONE and his are tantalisingly negative. colleagues9 studied 22 cardiac-surgery patients who had HBAg-negative hepatitis deemed to be transfusion-associated. These patients were examined for serum-antibody rises to various viral antigens. None showed rises to HBAg, cytomegalovirus, or Epstein-Barr virus, all of which are known causes of hepatitis. In the past, these cases might well have been attributed to hepatitis-A virus, for which, until very lately, no serological marker was available. These workers tested for hepatitis A using as antigen extracts of stools containing a 27 nm. particle believed to be the virus of hepatitis A. The sera were tested by immune electron microscopy.10 The particle concerned is probably the particle of MS1 hepatitis,’ 1, 12which has been equated with hepatitis 4. 5. 6. 7. 8.
9. 10. 11.
Wallace, J., Milne, G. R., Barr, A. Br. med. J. 1972, i, 663. Maycock, W. d’A. Br. med. Bull. 1972, 28, 163. Purcell, R. H., Walsh, J. H., Holland, P. V., Morrow, A. G., Wood, S., Chanock, R. M. J. infect. Dis. 1971, 123, 406. Koretz, R. L., Klahs, D. R., Ritman, S., Damus, K. H., Gitnick, G. L. Lancet, 1973, ii, 694. Prince, A. M., Brotman, B., Grady, G. F., Kuhns, W. J., Hezzi, C., Levine, R. W., Million, S. J. ibid. 1974, ii, 241. Feinstone, S. M., Kapikian, A. Z., Purcell, R. H., Alter, H. J., Holland, P. V. New Engl. J. Med. 1975, 292, 767. Almeida, J. D., Waterson, A. P. Adv. Vir. Res. 1969, 15, 307. Feinstone, S. M., Kapikian, A. Z., Purcell, R. H. Science, 1973, 182, 1026.
12.
Krugman, S., Giles, J. P., Hammond, J. J. Am. med. Ass. 1967, 200, 365.
injections, the only cause for concern is the risk of bleeding and haematoma formation. Blood-loss during surgery was considered excessive in a rather greater number of heparin-treated than control patients, and there was a statistically significant increase in wound haematoma formation in the
Prevention of Postoperative Thromboembolism death in a surgical ward is be the result of massive pulmonary likely embolism. Repeated experience of such disasters has stimulated many surgeons to try to improve methods of diagnosing and preventing postoperative venous thrombosis. In 1970 SHARNOFF and DEBLASIO1 claimed that small doses of heparin injected subcutaneously would effectively reduce the incidence of fatal pulmonary embolism. J. G. SHARNOFF’s work may have lacked the rigorous control required of therapeutic trials, but he is now no longer on his own. Subcutaneous heparin has been shown to prevent the formation of peripheral venous thrombosis detected by 125I-fibrinogen uptake. 2,3 Such isotopically detected thrombi are usually small and of little SUDDEN
most
unexpected to
clinical significance-that is, they generate emboli of sufficient size to and they do not damage the veins
are
unlikely
cause
to
symptoms
the extent of producing post-thrombotic swelling or ulceration.44 It is therefore important to establish that a method capable of preventing isotopically detected " mini " thrombi also effectively prevents propagation to form clinically significant or " maxi " thrombi. V. V. KAKKAR and his colleagues, whose report appears at the start of this issue, have provided many of the answers to this question in a clinical trial involving twenty-eight centres and 4471 patients -an exercise requiring considerable organisational and persuasive ability. Their results indicate the effectiveness of low-dose heparin, which reduced the incidence of fatal pulmonary embolism from 16 in the control group to 2 in the treatment group. Deep-vein thromboses were detected isotopically in 24-6% of the controls and in 7-7% of those on heparin, and the numbers of phlebographically detected thrombi were 32 and 11, respectively. Apart from the minor discomfort and additional nursing workload imposed by repeated subcutaneous 1. 2.
to
Sharnoff, J. G., DeBlasio, G. Lancet, 1970, ii, 1006. Kakkar, V. V., Field, E. S., Nicolaides, A. N., Flute, P.
T. ibid.
1971, ii, 669. 3. Gordon-Smith, I. C., Grundy, D. J., Le Quesne, L. P., Newcombe, J. F., Bramble, F. J. ibid. 1972, i, 1133. 4. Hedlund, P. O. Scand. J. Urol. Nephrol. 1975, suppl. 27.
heparin-treated group. Bleeding problems, though apparently never severe, required heparin to be discontinued in 54 of the 2045 treated patients. Perhaps this is a reflection of the dose used; 5000 units 8-hourly in the postoperative period is a rather larger dose than the original 2500 units 6-hourly used by SHARNOFF and DEBLASIO. More probably the earlier workers avoided hxmorrhagic complications because they monitored coagulation-times and were thus able to forestall possible haemorrhage by administration of protamine. Such monitoring is timeconsuming, and the small incidence of haemorrhagic complications is doubtless the reason that KAKKAR and his colleagues considered it unnecessary. Calcium heparin was used in the multicentre trial, but we do not yet know if this has any advantages over the sodium form. What of other methods ? Dextran 70 reduces the incidence of isotopically detected mini thrombi,5.6 though less effectively than low-dose heparin,7 and in the double-blind Cardiff trial involving 831 patients significant pulmonary embolism developed in 13 (7 fatal) in the control group compared with 3 (1 fatal) in the treated patients.7 Minor bleeding required the code to be broken in 4 patients, but the dextran prophylaxis never had to be stopped. The intravenous route avoided repeated subcutaneous injections in patients who anyway needed intravenous fluids during and immediately after major surgery. In the area of mechanised treatment, both calfmuscle stimulation8 and intermittent calf compression effectively reduce the incidence of isotopically detected mini thrombi,9,IO but no large-scale trial of these methods has yet been undertaken. The importance of such large-scale trials is illustrated by the work on stockiiigs in thrombosis prevention. 125I-fibrinogen studies have shown these to be ineffectual in preventing small calf thrombi,11,12 but a study based on clinical and post-mortem findings 13 showed that significant pulmonary embolism occurred in 12 cases (4 fatal) among 2395 control patients compared with 2 (no deaths) in 2395 patients wearing stockings. The explanation may be that, while thrombus Lambie, J. M., Barker, D. C., Dhall, D. P., Matheson, H. A. Br. med. J. 1970, ii, 144. 6. Bonnar, J., Walsh, J. Lancet, 1972, i, 614 7. Kline, A., Hughes, L. E., Campbell, H., Williams, A., Zlosnick, J., Leach, K. G. Br. med. J. 1975, ii, 109. 8. Browse, N. L., Negus, D. ibid. 1970, iii, 615. 9. Hills, N. H., Pflug, J. J., Jeyasingh, K., Boardman, L., Calnan, J. S. ibid. 1972, i, 131. 10. Sabri, S., Roberts, V. C., Cotton, L. T. ibid. 1971, iii, 82. 11. Rosengarten, D. S., Laird, J. Br. J. Surg. 1971, 58, 182. 12. Browse, N. L., Jackson, B. T., Mayo, M. E., Negus, D. ibid. 1974, 61, 219. 13. Wilkins, R. W., Mixter, G., Jr., Stanton, J. R., Litter, J. New Engl. J. Med. 1952, 246, 360. 5.
64
formation is unaffected
by stockings, subsequent inhibited, and this effect may apply in other methods of prophylaxis.
propagation
is
choose between heparin and dextran in terms of the prevention of fatal pulmonary embolism. Heparin is the more effective in preventing peripheral thrombus formation, but has the minor disadvantages of repeated injections and, in a few patients, haematoma formation and bleeding. The choice will be dictated by the preferences of individual surgeons and nurses. Mechanical methods may be as effective in preventing massive embolism, but the answers will only be provided by large-scale trials similar to those of KAKKAR et al. and the Cardiff group. Such trials require considerable effort from the organisers, but those who have tried unsuccessfully to resuscitate a patient dying from pulmonary embolism will surely feel that this is worth while.
There
seems at
present little
to
Non-A, Non-B? BLOOD-TRANSFUSION is dangerous
at
the
best
1
of times.
It takes place over hours, or even days, during which time the patient’s circulation is invaded by an indwelling needle or cannula. The patient is infused with a biological fluid of variable and uncertain composition from a group of potentially infective living donors and, perhaps most hazardous of all, the volume of fluid transferred is, by micro-
biological standards, enormous. The transmission of syphilis and malaria is well recognised. Bacterial infections are fortunately rare nowadays. However, it is the viruses which have come to the fore in recent years. Of these, the best known, and conceptually the most simple, is the agent of hepatitis B. This can be transmitted by a blood-transfusion because the virus concerned may be present in the blood of symptom-free blood-donors.22 Potentially infective donors can be identified by testing their blood for HB antigen (HBAg). In fact, HBAg 3 has supplied the marker which had been needed ever since blood-transfusion came into general use; and testing donations for HBAg has, at least in the United Kingdom, undoubtedly reduced the incidence of post-transfusion hepatitis, although the extent of this reduction is difficult to gauge exactly. Even when a case of hepatitis is recognised as being " transfusion-associated ", it is a long, and sometimes hard, road to trace the source with certainty and identify the virus with precision. The crux of the matter is to determine how much " transfusion-associated hepatitis is definitely due to virus and hence, in theory at least, hepatitis-B the earliest studies on the preventable. One of "
1. 2. 3.
Titmuss, R. M. The Gift Relationship. London, 1970. Gocke, D. J. J. Am. med. Ass. 1972, 219, 1165. Almeida, J. D. Postgrad. med. J. 1971, 47, 484.
subject,
from
very few screened
cases
Scotland,4suggested that there were of hepatitis in patients receiving blood by even the relatively insensitive immunoelectrophoresis test, and MAYCOCK5 has claimed that, for the United Kingdom as a whole, some 575 cases a year could have been prevented in 1970. In addition, it is well known that commercially acquired blood is, at the same time, both much more icterogenic and more likely to be2 HBAg-positive than blood from volunteer donors. Besides this, surveillance for HBAg has gone most of the way in clearing British hsemodialysis units of hepatitis. All this seems to point strongly to hepatitis-B virus being the major hazard of blood-transfusion so far as hepatitis viruses are concerned, although posttransfusion hepatitis is certainly not the exclusive preserve of hepatitis-B virus.6 But this -is not the view of a Los Angeles group1 who state that most post-transfusion hepatitis is HBAg-negative 1; and PRINCE and his co-workers,8 in New York, record that " although most cases of hepatitis with a severe clinical course appear to be predominantly type B, careful prospective follow-up of transfused patients reveals that the major proportion of all hepatitis cases are of unknown aetiology ". PRINCE et al. give as reasons for supposing that these HBAg-negative cases are not hepatitis A, that the incubation period was relatively long and that there were no cases among the household contacts. Neither of these criteria could be described as virologically precise. Another report from the U.S.A. attempts to clear up some of the confusion, even though the findings FEINSTONE and his are tantalisingly negative. colleagues9 studied 22 cardiac-surgery patients who had HBAg-negative hepatitis deemed to be transfusion-associated. These patients were examined for serum-antibody rises to various viral antigens. None showed rises to HBAg, cytomegalovirus, or Epstein-Barr virus, all of which are known causes of hepatitis. In the past, these cases might well have been attributed to hepatitis-A virus, for which, until very lately, no serological marker was available. These workers tested for hepatitis A using as antigen extracts of stools containing a 27 nm. particle believed to be the virus of hepatitis A. The sera were tested by immune electron microscopy.10 The particle concerned is probably the particle of MS1 hepatitis,’ 1, 12which has been equated with hepatitis 4. 5. 6. 7. 8.
9. 10. 11.
Wallace, J., Milne, G. R., Barr, A. Br. med. J. 1972, i, 663. Maycock, W. d’A. Br. med. Bull. 1972, 28, 163. Purcell, R. H., Walsh, J. H., Holland, P. V., Morrow, A. G., Wood, S., Chanock, R. M. J. infect. Dis. 1971, 123, 406. Koretz, R. L., Klahs, D. R., Ritman, S., Damus, K. H., Gitnick, G. L. Lancet, 1973, ii, 694. Prince, A. M., Brotman, B., Grady, G. F., Kuhns, W. J., Hezzi, C., Levine, R. W., Million, S. J. ibid. 1974, ii, 241. Feinstone, S. M., Kapikian, A. Z., Purcell, R. H., Alter, H. J., Holland, P. V. New Engl. J. Med. 1975, 292, 767. Almeida, J. D., Waterson, A. P. Adv. Vir. Res. 1969, 15, 307. Feinstone, S. M., Kapikian, A. Z., Purcell, R. H. Science, 1973, 182, 1026.
12.
Krugman, S., Giles, J. P., Hammond, J. J. Am. med. Ass. 1967, 200, 365.
