- Email: [email protected]
POSTOPERATIVE PROPHYLACTIC ANTICOAGULANTS IN GYNÆCOLOGY
835
patient may not visit a physician specially because of the persistence of a small skin lesion, but he will probably report it while attending for coincident disease. The number of cancer patients in the present study is too small to permit comparison of the course in any one organ, using patients not having anticoagulants as controls. In the absence of a matched, controlled, and untreated group, statistical comparisons are not meaningful. For the reasons given, the present findings can only be interpreted as suggesting that anticoagulant therapy may alter the natural history of cancer. This must be considered a preliminary survey-highlighting the need for a fully controlled prospective study. This is now being A
TABLE I-TYPE OF OPERATION AND AGE-DISTRIBUTION OF PATIENTS
TABLE
II-EFFECT
OF
THERAPEUTIC
MEASURES
ON
INCIDENCE
OF
THROMBOEMBOLIC DISEASE
undertaken.
Summary The
incidence and
mortality have been studied patients having anticoagulant therapy for thromboembolic disease. The observed incidence and mortality have been compared with those expected on the basis of the known behaviour of cancer in the general population. A total of twenty-two cancers developed in 19 out of 540 patients observed for 1569 patient-years. There was only 1 death from cancer, as opposed to 8 predicted. In all only two organs were invaded by distant metascancer
in
tases, and no deaths were attributable to metastases. The findings suggest the need for a fully controlled prospective study of the effect of anticoagulants on the natural history of cancer in man. REFERENCES
Bjerkelund, C. J. (1957) Acta med. scand. 158, suppl. 330. Cliffton, E. E., Agostino, D. (1962) Cancer (Philad.), 15, 276. Engell, H. C. (1959) Ann. Surg. 149, 457. Hughes, L. E. (1964) Lancet, i, 408. Iwasaki, T. (1915) J. Path. Bact. 20, 85. Lacour, F., Oberling, Ch., Guerin, M. (1957) Bull. Ass. franç. Cancer, 44, 88. Manchester, B. (1963) Prog. cardiovasc. Dis. 6, 272. O’Meara, R. A. Q., Jackson, R. D. (1958) Irish J. med. Sci. 391, 327. O’Halloran, M. J. (1963) Lancet, ii, 613. Thornes, R. D. (1961) Irish J. med. Sci. 423, 106. Schmidt, M. B. (1903) cited by Iwasaki, T. (1915) J. Path. Bact. 20, 85. Suzman, M. M. (1961) in Symposium on Anticoagulant Therapy (edited by Sir George Pickering); p. 153. Birkenhead. Terranova, T., Chiossone, F. (1952) Boll. Soc. ital. Biol. sper. 28, 1224. Westlund, K., Hougen, A. (1956) J. Amer. med. Ass. 162, 1003. Wood, S., Jr. (1958) Arch. Path. 66, 550. Holyoke, E. D., Yardley, J. H. (1956) Proc. Amer. Ass. Cancer Res. —
—
—
2, 157.
(1961) Canadian Cancer Research Conference; vol. p. 167. New York.
—
—
—
IV.
POSTOPERATIVE PROPHYLACTIC ANTICOAGULANTS IN GYNÆCOLOGY A
Ten-year Study
J. E. BOTTOMLEY M.A. Cantab., M.D. Lond., F.R.C.S., F.R.C.O.G.
O. LLOYD M.A. Cantab., M.D. Lond., F.R.C.S., F.R.C.O.G.
CONSULTANT GYNÆCOLOGIST
CONSULTANT GYNÆCOLOGIST
UNITED CAMBRIDGE HOSPITALS
M.A.
D. G. CHALMERS Cantab., M.B. Lond., M.C.Path.
UNIVERSITY HÆMATOLOGIST TO ADDENBROOKE’S HOSPITAL, CAMBRIDGE
IN 1954 a trial of anticoagulant therapy in selected postoperative gynaecological patients was instituted. After five years the results were reported (Chalmers et al. 1960). The benefit conferred by this treatment was so impressive and the dangers so slight that it was instituted as a routine postoperative procedure. The results presented here cover
*
Data
insufficiently accurate.
The anticoagulant used throughout the trial was phenindione. The patients are maintained on a level of between 10% and 20% of the normal. This form of control has two advantages: (a) capillary blood is used and the work of the technician is reduced; and (b) the degree of control is more accurate, and upward or downward trends can be predicted more quickly. Results
In the
June, 1953, to June, 1963, 3777 were treated with prophylactic anticoagulants patients The (table i). patients received phenindione from the third to the tenth postoperative day in doses sufficient to maintain the thrombotest level at between 10% and 20%. As previously reported, the total prevalence of thromboten years,
embolic disease fell from an average of 38 cases per annum for the period 1949-53 to 4-3 cases per annum over the period 1953-63. The fatal pulmonary-embolism rate per annum fell from 1.8 to 0-3 in the corresponding period
(table 11). The frequency of fatal pulmonary embolism in general surgical and medical patients in the same hospital over the relevant periods is given in table ill. Of the 5 cases of fatal embolism recorded in the gynaecological admissions during the period 1954-63, 2 were not included in the trial. Of the 44 patients in whom thromboembolic disorders developed, 20 were not being treated with anticoagulants at the time of the episode. In 6, embolism occurred before the third day, and in 8 after the twelfth day; 6, in error, TABLE III-MORTALITY DUE TO THROMBOEMBOLIC DISEASE
1954-63
the years 1954-63 inclusive. Patients and Methods
The selection of cases, the timing of anticoagulant therapy, and the control were as described in our previous report (Chalmers et al. 1960). Since 1961 anticoagulant therapy has been controlled by means of ’Thrombotest ’ (Evans Medical).
*
These figures include svnxcoloeical Datients
not
included in the trial.
836 received
no
treatment.
HYPERBARIC OXYGEN AND CORNEAL NEOVASCULARISATION
who were considered to be the time of the episode.
Of the 24 17
patients
receiving anticoagulants, inadequately controlled at Hcemorrhage There were 160 episodes of bleeding; 28 required no active treatment, and anticoagulants were not discontinued. In 104, anticoagulants were discontinued, and in a proportion of these, patients in addition received local treatment in the form of vaginal douches and packs in the ward. No steps were taken to reverse the lowered prothrombin level. In 28 patients severe haemorrhage necessitated further intervention. All these patients received vitamin Kl intravenously until the thrombotest was within normal range. 12 were transfused only; 13 were taken to the theatre for vaginal packing, 6 needing transfusion in addition; and 3 patients underwent laparotomy for evacuation of clots or ligature of a vessel. 1 patient subsequently got staphylococcal bronchopneumonia and died. were
PAUL HENKIND M.D., M.Sc. New York SPECIAL FELLOW OF THE DIVISION OF NEUROLOGICAL DISEASES AND BLINDNESS OF THE NATIONAL INSTITUTES OF HEALTH,
BETHESDA,
operative
Summary and Conclusions 3777 patients have been treated with anticoagulants in the postoperative period. The control of treatment can be efficiently and economically carried out by means of the capillary thrombotest technique keeping the thrombotest level at 10 to 20%. Frequent estimations are necessary to The frequency of secondary ensure adequate control. not increased is (4-2%) (the majority greatly hxmorrhage of these required no treatment apart from withdrawal of anticoagulant therapy), and can be adequately controlled. The patients received phenindione from the third to the tenth postoperative day in doses sufficient to maintain the thrombotest level at between 10-20%. The frequency of thrombotic disease was reduced by a factor of 5. After ten years of experience in the use of prophylactic anticoagulants this treatment is now an established part of the postoperative gynaecological regimen. REFERENCES
Chalmers, D. G., Marks, J., Bottomley, J. C., Lloyd, O. (1960) Lancet, ii, 220. Dick, W., Matis, P., Mayer, W. (1959) Thrombos. Diathes. Hœmorrh., Stuttgart, 3 11. Morrell, M. T., Truelove, S. C., Barr, A. (1963) Brit. med. J. ii, 830. Sevitt, S., Gallagher, N. G. (1959) Lancet, ii, 981.
*
THE effects of hyperbaric oxygen are being studied both in vivo and in vitro. Apart from its proven efficacy in conditions characterised by deficient circulation or lowered oxygen tension, there is the possibility that the toxic effects of hyperbaric oxygen might prove useful therapeutically, particularly in discouraging the growth of vessels in some pathological conditions (Winstanley 1963). Heppleston and Simnett (1964) have recently demonstrated the damaging effect of pressurised oxygen on various in-vitro tissues of the mouse; they wondered whether it might similarly affect new-vessel formation in vivo. While much is known about the effect on vessels of ambient hyperoxia (Ashton 1957), few studies have been conducted with hyperbaric oxygen. The present experiment was designed to demonstrate the possible effect of hyperbaric oxygen on actively growing vessels. The cornea was chosen for this study because it is normally avascular, and any response of newly proliferating vessels could easily be recognised both in vivo and in vitro.
Discussion
We have previously discussed the prevalence of postthromboembolism and in particular, pulmonary embolism, and our views have been substantiated not only by our increased experience but by the findings of Morrell et al. (1963). The decision to introduce the study without a control group has in our view been fully justified. We consider the figures presented are impressive on their own, and taken in conjunction with other control trials-e.g., Sevitt and Gallagher (1959), Dick et al. (1959)-leave little room for argument. Criticism will no doubt be directed at the frequency of haemorrhage, and its associated dangers. It is right and proper in dealing with a complication with an overall frequency of roughly 1-2% and a fatality-rate of 3 per 1000 that the treatment should not further increase the risk. In our series, the total incidence of bleeding was 4-2%, and either transfusion or further medical treatment 1 patient died after operative was needed in 0-8%. and her death can be attributed indirectly to interference, We believe that the almost comanticoagulant therapy. elimination of thromboembolic complications, with plete the increased patient turnover that this implies and the almost total elimination of sudden loss of life in an apparently fit woman, more than justifies the possible increase of secondary haemorrhage.
MARYLAND
Material and Methods Sixteen adult guineapigs were anaesthetised with intraperitoneal sodium pentobarbitone; then, using a modification of Langham’s method (Ashton et al. 1951), 0-1 ml. of sterile 0-3 M alloxan was injected into the right anterior chamber of each animal. 5 to 7 days after injection, corneal neovascularisation became evident, and eight of the animals were placed in a pressure chamber supplied continuously with 100% oxygen at 1.5 to 2 atmospheres of pressure. The chamber held two guineapigs at a time, and was provided with a ’Plexiglas’ front window through which the animals were continually observed. Carbon dioxide was absorbed with soda lime placed in a tray beneath the animal platform. The control guineapigs were kept in their usual cages. When severe respiratory difficulty ensued (after 17 to 37 hours of continuous exposure to hyperbaric oxygen) the pressure chamber was slowly decompressed, and the guineapigs were removed to the atmosphere where their eyes were examined with a hand slit-lamp (Krimsky 10 x ) and a binocular dissecting microscope. All the oxygen-treated animals died spontaneously within several hours of being removed from the pressure chamber, and after death their chests were opened and their lungs were examined. Indian ink was then injected through the left ventricle of the heart until the corneal vessels appeared filled with ink. The eyes were enucleated and placed in pots containing 10% formol-saline. Upon the death of an oxygen-treated animal a paired control was killed with intraperitoneal sodium pentobarbitone, and studied as described above. After 24 hours’ fixation the eyes of the treated and control guineapigs were compared, using a binocular dissecting microscope, and flat preparations of the cornea were then made and examined by light microscopy. Results oxygen the adult guineapigs survived from 20 to 40 hours. Approximately 3 to 4 hours before their death severe respiratory distress characterised by gasping irregular respirations developed; but, despite slow decompression and removal to normal atmospheric conditions, they all died within 1-2 hours of leaving the pressure chamber. The lungs of the
In
*
hyperbaric
On leave from the Department of Ophthalmology, New York University College of Medicine. Present address: Department of Pathology, Institute of Ophthalmology, University of London, Judd Street, London, W.C.1.
patient may not visit a physician specially because of the persistence of a small skin lesion, but he will probably report it while attending for coincident disease. The number of cancer patients in the present study is too small to permit comparison of the course in any one organ, using patients not having anticoagulants as controls. In the absence of a matched, controlled, and untreated group, statistical comparisons are not meaningful. For the reasons given, the present findings can only be interpreted as suggesting that anticoagulant therapy may alter the natural history of cancer. This must be considered a preliminary survey-highlighting the need for a fully controlled prospective study. This is now being A
TABLE I-TYPE OF OPERATION AND AGE-DISTRIBUTION OF PATIENTS
TABLE
II-EFFECT
OF
THERAPEUTIC
MEASURES
ON
INCIDENCE
OF
THROMBOEMBOLIC DISEASE
undertaken.
Summary The
incidence and
mortality have been studied patients having anticoagulant therapy for thromboembolic disease. The observed incidence and mortality have been compared with those expected on the basis of the known behaviour of cancer in the general population. A total of twenty-two cancers developed in 19 out of 540 patients observed for 1569 patient-years. There was only 1 death from cancer, as opposed to 8 predicted. In all only two organs were invaded by distant metascancer
in
tases, and no deaths were attributable to metastases. The findings suggest the need for a fully controlled prospective study of the effect of anticoagulants on the natural history of cancer in man. REFERENCES
Bjerkelund, C. J. (1957) Acta med. scand. 158, suppl. 330. Cliffton, E. E., Agostino, D. (1962) Cancer (Philad.), 15, 276. Engell, H. C. (1959) Ann. Surg. 149, 457. Hughes, L. E. (1964) Lancet, i, 408. Iwasaki, T. (1915) J. Path. Bact. 20, 85. Lacour, F., Oberling, Ch., Guerin, M. (1957) Bull. Ass. franç. Cancer, 44, 88. Manchester, B. (1963) Prog. cardiovasc. Dis. 6, 272. O’Meara, R. A. Q., Jackson, R. D. (1958) Irish J. med. Sci. 391, 327. O’Halloran, M. J. (1963) Lancet, ii, 613. Thornes, R. D. (1961) Irish J. med. Sci. 423, 106. Schmidt, M. B. (1903) cited by Iwasaki, T. (1915) J. Path. Bact. 20, 85. Suzman, M. M. (1961) in Symposium on Anticoagulant Therapy (edited by Sir George Pickering); p. 153. Birkenhead. Terranova, T., Chiossone, F. (1952) Boll. Soc. ital. Biol. sper. 28, 1224. Westlund, K., Hougen, A. (1956) J. Amer. med. Ass. 162, 1003. Wood, S., Jr. (1958) Arch. Path. 66, 550. Holyoke, E. D., Yardley, J. H. (1956) Proc. Amer. Ass. Cancer Res. —
—
—
2, 157.
(1961) Canadian Cancer Research Conference; vol. p. 167. New York.
—
—
—
IV.
POSTOPERATIVE PROPHYLACTIC ANTICOAGULANTS IN GYNÆCOLOGY A
Ten-year Study
J. E. BOTTOMLEY M.A. Cantab., M.D. Lond., F.R.C.S., F.R.C.O.G.
O. LLOYD M.A. Cantab., M.D. Lond., F.R.C.S., F.R.C.O.G.
CONSULTANT GYNÆCOLOGIST
CONSULTANT GYNÆCOLOGIST
UNITED CAMBRIDGE HOSPITALS
M.A.
D. G. CHALMERS Cantab., M.B. Lond., M.C.Path.
UNIVERSITY HÆMATOLOGIST TO ADDENBROOKE’S HOSPITAL, CAMBRIDGE
IN 1954 a trial of anticoagulant therapy in selected postoperative gynaecological patients was instituted. After five years the results were reported (Chalmers et al. 1960). The benefit conferred by this treatment was so impressive and the dangers so slight that it was instituted as a routine postoperative procedure. The results presented here cover
*
Data
insufficiently accurate.
The anticoagulant used throughout the trial was phenindione. The patients are maintained on a level of between 10% and 20% of the normal. This form of control has two advantages: (a) capillary blood is used and the work of the technician is reduced; and (b) the degree of control is more accurate, and upward or downward trends can be predicted more quickly. Results
In the
June, 1953, to June, 1963, 3777 were treated with prophylactic anticoagulants patients The (table i). patients received phenindione from the third to the tenth postoperative day in doses sufficient to maintain the thrombotest level at between 10% and 20%. As previously reported, the total prevalence of thromboten years,
embolic disease fell from an average of 38 cases per annum for the period 1949-53 to 4-3 cases per annum over the period 1953-63. The fatal pulmonary-embolism rate per annum fell from 1.8 to 0-3 in the corresponding period
(table 11). The frequency of fatal pulmonary embolism in general surgical and medical patients in the same hospital over the relevant periods is given in table ill. Of the 5 cases of fatal embolism recorded in the gynaecological admissions during the period 1954-63, 2 were not included in the trial. Of the 44 patients in whom thromboembolic disorders developed, 20 were not being treated with anticoagulants at the time of the episode. In 6, embolism occurred before the third day, and in 8 after the twelfth day; 6, in error, TABLE III-MORTALITY DUE TO THROMBOEMBOLIC DISEASE
1954-63
the years 1954-63 inclusive. Patients and Methods
The selection of cases, the timing of anticoagulant therapy, and the control were as described in our previous report (Chalmers et al. 1960). Since 1961 anticoagulant therapy has been controlled by means of ’Thrombotest ’ (Evans Medical).
*
These figures include svnxcoloeical Datients
not
included in the trial.
836 received
no
treatment.
HYPERBARIC OXYGEN AND CORNEAL NEOVASCULARISATION
who were considered to be the time of the episode.
Of the 24 17
patients
receiving anticoagulants, inadequately controlled at Hcemorrhage There were 160 episodes of bleeding; 28 required no active treatment, and anticoagulants were not discontinued. In 104, anticoagulants were discontinued, and in a proportion of these, patients in addition received local treatment in the form of vaginal douches and packs in the ward. No steps were taken to reverse the lowered prothrombin level. In 28 patients severe haemorrhage necessitated further intervention. All these patients received vitamin Kl intravenously until the thrombotest was within normal range. 12 were transfused only; 13 were taken to the theatre for vaginal packing, 6 needing transfusion in addition; and 3 patients underwent laparotomy for evacuation of clots or ligature of a vessel. 1 patient subsequently got staphylococcal bronchopneumonia and died. were
PAUL HENKIND M.D., M.Sc. New York SPECIAL FELLOW OF THE DIVISION OF NEUROLOGICAL DISEASES AND BLINDNESS OF THE NATIONAL INSTITUTES OF HEALTH,
BETHESDA,
operative
Summary and Conclusions 3777 patients have been treated with anticoagulants in the postoperative period. The control of treatment can be efficiently and economically carried out by means of the capillary thrombotest technique keeping the thrombotest level at 10 to 20%. Frequent estimations are necessary to The frequency of secondary ensure adequate control. not increased is (4-2%) (the majority greatly hxmorrhage of these required no treatment apart from withdrawal of anticoagulant therapy), and can be adequately controlled. The patients received phenindione from the third to the tenth postoperative day in doses sufficient to maintain the thrombotest level at between 10-20%. The frequency of thrombotic disease was reduced by a factor of 5. After ten years of experience in the use of prophylactic anticoagulants this treatment is now an established part of the postoperative gynaecological regimen. REFERENCES
Chalmers, D. G., Marks, J., Bottomley, J. C., Lloyd, O. (1960) Lancet, ii, 220. Dick, W., Matis, P., Mayer, W. (1959) Thrombos. Diathes. Hœmorrh., Stuttgart, 3 11. Morrell, M. T., Truelove, S. C., Barr, A. (1963) Brit. med. J. ii, 830. Sevitt, S., Gallagher, N. G. (1959) Lancet, ii, 981.
*
THE effects of hyperbaric oxygen are being studied both in vivo and in vitro. Apart from its proven efficacy in conditions characterised by deficient circulation or lowered oxygen tension, there is the possibility that the toxic effects of hyperbaric oxygen might prove useful therapeutically, particularly in discouraging the growth of vessels in some pathological conditions (Winstanley 1963). Heppleston and Simnett (1964) have recently demonstrated the damaging effect of pressurised oxygen on various in-vitro tissues of the mouse; they wondered whether it might similarly affect new-vessel formation in vivo. While much is known about the effect on vessels of ambient hyperoxia (Ashton 1957), few studies have been conducted with hyperbaric oxygen. The present experiment was designed to demonstrate the possible effect of hyperbaric oxygen on actively growing vessels. The cornea was chosen for this study because it is normally avascular, and any response of newly proliferating vessels could easily be recognised both in vivo and in vitro.
Discussion
We have previously discussed the prevalence of postthromboembolism and in particular, pulmonary embolism, and our views have been substantiated not only by our increased experience but by the findings of Morrell et al. (1963). The decision to introduce the study without a control group has in our view been fully justified. We consider the figures presented are impressive on their own, and taken in conjunction with other control trials-e.g., Sevitt and Gallagher (1959), Dick et al. (1959)-leave little room for argument. Criticism will no doubt be directed at the frequency of haemorrhage, and its associated dangers. It is right and proper in dealing with a complication with an overall frequency of roughly 1-2% and a fatality-rate of 3 per 1000 that the treatment should not further increase the risk. In our series, the total incidence of bleeding was 4-2%, and either transfusion or further medical treatment 1 patient died after operative was needed in 0-8%. and her death can be attributed indirectly to interference, We believe that the almost comanticoagulant therapy. elimination of thromboembolic complications, with plete the increased patient turnover that this implies and the almost total elimination of sudden loss of life in an apparently fit woman, more than justifies the possible increase of secondary haemorrhage.
MARYLAND
Material and Methods Sixteen adult guineapigs were anaesthetised with intraperitoneal sodium pentobarbitone; then, using a modification of Langham’s method (Ashton et al. 1951), 0-1 ml. of sterile 0-3 M alloxan was injected into the right anterior chamber of each animal. 5 to 7 days after injection, corneal neovascularisation became evident, and eight of the animals were placed in a pressure chamber supplied continuously with 100% oxygen at 1.5 to 2 atmospheres of pressure. The chamber held two guineapigs at a time, and was provided with a ’Plexiglas’ front window through which the animals were continually observed. Carbon dioxide was absorbed with soda lime placed in a tray beneath the animal platform. The control guineapigs were kept in their usual cages. When severe respiratory difficulty ensued (after 17 to 37 hours of continuous exposure to hyperbaric oxygen) the pressure chamber was slowly decompressed, and the guineapigs were removed to the atmosphere where their eyes were examined with a hand slit-lamp (Krimsky 10 x ) and a binocular dissecting microscope. All the oxygen-treated animals died spontaneously within several hours of being removed from the pressure chamber, and after death their chests were opened and their lungs were examined. Indian ink was then injected through the left ventricle of the heart until the corneal vessels appeared filled with ink. The eyes were enucleated and placed in pots containing 10% formol-saline. Upon the death of an oxygen-treated animal a paired control was killed with intraperitoneal sodium pentobarbitone, and studied as described above. After 24 hours’ fixation the eyes of the treated and control guineapigs were compared, using a binocular dissecting microscope, and flat preparations of the cornea were then made and examined by light microscopy. Results oxygen the adult guineapigs survived from 20 to 40 hours. Approximately 3 to 4 hours before their death severe respiratory distress characterised by gasping irregular respirations developed; but, despite slow decompression and removal to normal atmospheric conditions, they all died within 1-2 hours of leaving the pressure chamber. The lungs of the
In
*
hyperbaric
On leave from the Department of Ophthalmology, New York University College of Medicine. Present address: Department of Pathology, Institute of Ophthalmology, University of London, Judd Street, London, W.C.1.