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Massive Bleeding in Diverticular Disease of the Colon
706
In this situation of uncertainty and anxiety, drugs are being put, often in haphazard fashion, to tests for teratogenicity of various degrees of stringency. But now
positive result mean ? With our present it knowledge, would be hard to refute the hypothesis that all drugs of therapeutic value are potentially toxic to the embryo of some animal if the right conditions of timing and dosage can be achieved. Indeed some teratologists would not entirely oppose the view that a drug is either a teratogen or a placebo. There may be a real danger that valuable drugs which are in reality innocuous to the human foetus, but which have come into disrepute as a result of laboratory tests, will be withdrawn from use, while other drugs of less therapeutic value and more danger to the foetus remain available, because they have passed less rigorous tests or because they have yet to be tested. If the fact that a drug is capable of producing malformations in laboratory animals is not to be regarded as an absolute bar to its use, some formula must be devised to express the danger to the embryo in relation to the therapeutic dose. The difficulties in attempting to draw up such a scheme are not hard to illustrate: 6 times the therapeutic dosage of aspirin on a weight-for-weight basis produced malformations in rats, while 75 times the therapeutic dose of thalidomide was required to produce malformations in rabbits 9-observations which, uncritically interpreted, might suggest that aspirin was almost twelve times as toxic to the embryo as thalidomide. SOMERS 10 and ROBSON 11 have lately put forward ingenious proposals for indices to express toxicity to the foetus, and their suggestions will obviously receive further detailed conwhat does
a
sideration. Until more physiology, and
is
known
about of the
the
anatomy, embryo and the
pharmacology placenta, it is important to strike as satisfactory a balance as possible between, on the one hand, letting a dangerous teratogen loose on the market and, on the other, missing a drug of great therapeutic potential. It is for the of a to see that it is tested in labordrug proprietors to the animals for limits atory teratogenic properties of available knowledge, and to ensure that the data are freely available to all potential prescribers. A committee with Lord CoHEN OF BIRKENHEAD as chairman is advising the Health Ministers on the measures needed to secure satisfactory testing of new drugs 12, and its recommendations may show how best to achieve this.
routine barium-enema examinations by DEBRAY et all in 500 unselected subjects, about a quarter of the population aged between 60 and 70, and about half of those over 70, have diverticulosis. Now that people live longer, more of them have diverticular disease; complications are commoner; and among these, undeniably, is profuse bleeding. A survey of published reports over the past fifteen years leads to the conclusion that about a fifth of the patients with diverticular disease have bleeding from the bowel, though only about 4% lose enough to require transfusion. But massive bleeding from the colon is, in fact, almost certainly due to diverticular disease, and not (contrary to what most doctors have been taught) to carcinoma. Clearly, prevalent views need to be overhauled.15-25 The distinction between diverticulitis and diverticulosis is unimportant; indeed, bleeding is seen more often in uncomplicated diverticulosis. The cause is generally ulceration of the mucosa with erosion of a vessel or inversion of a diverticulum. 26 27 From examination of injection preparations, NOER 28 suggested that bleeding was due to the increased concentration of intramural blood-vessels passing from the serosal surface towards the mucosal surface in the region of the diverticula. Many of the patients are hypertensive, and this may have some significance. Even afterremoval of the diseased segment of colon the bleeding-point may be impossible to find. This adds to the difficulty of treatment. A familiar finding at operation is a pale-blue colon, filled with blood from cascum to rectum, with nothing externally to show where the blood is coming from. Grape-like clusters of diverticula extend well beyond the sigmoid colon, and the offending one is often hidden in the fat of the appendices epiploicae or the mesentery. In this dilemma, the surgeon is variously advised to do one of a number of things. He can instil topical coagulants through a caecostomy 29; he can make a proximal colostomy 30 31; he can isolate with nonserial segments of the colon, each crushing clamps " milked " empty of blood, and observe previously which segment fills with blood 23 ; he can make a transverse colostomy and follow this with a hemicolectomy, according to which half of the colon the blood seems to be coming from 32;he can resect blindly the more obviously diseased part of the colon (usually the sigmoid) 33 ; he can combine colotomy with operative endoscopy 33; or he can remove the whole colon.27 34 35 14.
Massive
in Diverticular Disease of the Colon
Bleeding
IN 1954, at
joint meeting of the American College of Surgeons and the Royal College of Surgeons of England,13 a panel was asked: " Can massive bleeding arise from diverticulitis of the colon ?" All on the panel answered that they had no experience of the complication. If we accept as typical the figures derived from a
S. Q. Medical Tribune. 1962, 3, 24. Somers, G. F. Study Group on Toxicity of Drugs, Alderley Park, Sept. 25, 1962. 11. Robson, J. M. Section of Experimental Medicine, Royal Society of Medicine, March 20, 1963. 12. Lancet, 1962, ii, 1048. 13. ibid. 1954. i, 1124. 9. 10.
Cohlan,
15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27.
Debray, C., Hardouin, J. P., Besançon, F., Raimbault, J. Sem. Hôp. Paris, 1961, 37, 1743. Stone, H. B. Ann. Surg. 1944, 120, 582. Rives, J. D., Emmett, R. O. Amer. Surg. 1954, 20, 458. Greene, W. W. Amer. J. Surg. 1957, 94, 282. Quinn, W. C., Ochsner, A. Ann. Surg. 1961, 153, 851. Bell, H. G. Sth. med. J. 1953, 46, 453. Buck, R. L. Dis. Colon Rect. 1958, 1, 205. Quinn, W. C., Ochsner, A. Amer. Surg. 1960, 26, 171. Browne, D. G. Amer. J. dig. Dis. 1961, 6, 791. Myburgh, J. A. S. Afr. med. J. 1961, 35, 668. Hubbard, T. B., Jr. Amer. J. Surg. 1960, 100, 600. Covey, M. C., Moeller, H. G. Amer. J. Gastroent. 1961, 35, 42. Young, J. M., Howorth, M. B. Jr., Ann. Surg. 1954, 140, 128. Mobley, J. E., Dockerty, M. D., Waugh, J. M. Amer. J. Surg. 1957,
94, 44. 28. Noer, R. J. Ann. Surg. 1955, 141, 674. 29. Kunath, C. A. Amer. J. Surg. 1956, 91, 911. 30. Knight, C. D. Surgery, 1957, 42, 853. 31. Foster, R. L., Fisher, R. E. Amer. Surg. 1954, 20, 734. 32. Sandegard, E. Acta. chir. scand. 1959, 117, 465. 33. Jensen, G. L. Amer. J. Surg. 1958, 95, 813. 34. Welch, C. E., Rodkey, G. V. Surgery, 1956, 39, 712. 35. Teicher, I., Abrahame, J. I. Surg. Gynec. Obstet. 1956,
103, 136.
707
None of these measures in itself, except subtotal colectomy, can be claimed to stop the bleeding. What can be said is that the results of operation in these emergency circumstances are not encouraging. The patients are old and very often obese; they have lost a lot of blood; and they do not take kindly to surgical acrobatics. In practice, the choice most often lies between closure of the abdomen and total colectomy. Fortunately, the occasion for the choice should seldom arise. Conservative measures-replacement of blood and the administration of antibiotics-are successful in nearly every case. Out of 317 patients, 18 who had massive bleeding were treated in this way by QUINN 18 ; all recovered. The patients were followed up for four to ten years. 2 bled again, but no patient died from hxmorrhage. 14 patients who needed from 500 ml. to 2500 ml. of blood were reported by STANTON 36 to have recovered successfully. The experience of BARBORKA 31 confirms the value of a conservative regimen. But the danger of missing a malignant growth is inherent in a policy of conservative management. The wise clinician will make every effort to ensure that he is, in fact, dealing with diverticular disease. Many surgeons who recognise the hazards of operating only when grave complications have arisen advocate intervention at an early stage of the disease. 38-40 The dficulty is that diverticulitis does not, save exceptionally, manifest itself in early life, and symptoms are often trivial and easily controlled. Even in these advanced days segmental resection of the colon is not to be embarked upon lightheartedly-particularly for a disease which tends to progress with age. Other serious complications of diverticulitis, such as obstruction and fistula formation, favour early operation. But bleeding is not one.
Living with Insecticide Resistance MODERN synthetic insecticides have revolutionised preventive medicine in the tropics. But the mounting number of reports of resistant strains of important vectors is a matter for concern. Over 70 arthropod species of public-health importance are involved, from one region or another. The World Health Organisation responded to this challenge in 1956, and since then it has coordinated the attack on resistance by establishing standard test methods of detecting resistance, circularising information, and fostering research; and some of the latest moves in this campaign can be seen in a W.H.O. Bulletin.41 Most of the contributions concern resistance in anopheline mosquitoes and means of overcoming it. In the work on genetics of resistance in anopheline mosquitoes (much of it done by G. DAVIDSON) such instances as could be investigated in the laboratory :i.e., in mosquitoes which will breed in captivity) have shown resistance to be a normal mendelian character,
recent
36 Stanton, A. Amer. J. Gastroent. 1955, 24, 77. 37.Barborka, C. J. Gastroenterology, 1958, 34, 278. 38.DeBakey, M. E. The Yearbook of General Surgery.
p. 434,Chicago. 39.Colcock, B. P. Amer. Surg. 1958, 24, 738. 40.McGregor, R. A., Bacon, H. E. Dis. Colon Rect. 1958, 41. Bull. Wld Hlth Org. 1963, 28, no. 1.
1957-58
1,
197.
series;
inherited by a single pair of genes. D.D.T. (dicophane) resistance is recessive (or nearly so), whereas dieldrin/ benzene-hexachloride (B.H.c.) is partially dominant. As a result, the heterozygotes of D.D.T. resistance have no advantage, so that emergence of this type of resistance must await selection from rare homozygotic resistants. In contrast, dieldrin/B.H.c. resistance should respond much earlier to selection, because the heterozygotes already survive preferentially. Use of basic data of this kind, to interpret complex happenings in the field, is made by J. HAMON and C. GARRETT-JoNES in an excellent detailed study of the incidence of resistance in five major malaria vectors of the Old World. Their most cheering conclusion is that, despite the almost worldwide use of residual insecticides, resistant strains have emerged only in relatively restricted areas in the distribution of the major vectors. No-one can say why this is, unless perhaps the genes for resistance are only present in localised
mosquito populations. Resistance to dieldrin and B.H.c. appears rapidly, usually within two years of general house-spraying. The resistance levels are very high (especially towards dieldrin) so that malaria transmission returns; and if the immunity of the human population has waned, an epidemic is likely. Nothing can be done except to change the insecticide (perhaps to D.D.T.); and then the resistance to dieldrin declines only very slowly in the mosquito population. In contrast, D.D.T. resistance appears considerably later and is usually less intense, so that malaria transmission does not always result. The irritant action of D.D.T. on mosquitoes, which drives them out of treated houses (sometimes without killing them), may sometimes allow transmission; but this phenomenon discourages the rapid development of resistance. On the other hand, resistance in malaria vectors in several countries has been stimulated by the wide use of insecticides in agriculture and the consequent contamination of the mosquito breeding grounds. In view of the importance of the world malaria-eradication programme, Government action is called for in malarial countries to prevent this danger. At present, nearly all the big malaria eradication campaigns rely on D.D.T. or dieldrin, both of which have a long residual effect of about six months. Of the five vectors discussed, however, four are resistant to both D.D.T. and dieldrin at one point or another; and where both forms of resistance arise together, a totally different insecticide must be used to kill the mosquitoes. There is thus an urgent need for alternative insecticides to supplement D.D.T. and dieldrin, and though the search for new types has been intensified, nothing entirely satisfactory has yet been found. The most promising are either organophosphorus compounds or carbamates, and several papers in the W.H.C. Bulletin report tests of these substances in Britain and Nigeria. The toxicity of anti-cholinesterase compounds is not their main drawback (some, like malathion, are probably at least as safe as D.D.T.): unfortunately, their physical properties do not allow long residual action and it is hard to see how this can be overcome.
In this situation of uncertainty and anxiety, drugs are being put, often in haphazard fashion, to tests for teratogenicity of various degrees of stringency. But now
positive result mean ? With our present it knowledge, would be hard to refute the hypothesis that all drugs of therapeutic value are potentially toxic to the embryo of some animal if the right conditions of timing and dosage can be achieved. Indeed some teratologists would not entirely oppose the view that a drug is either a teratogen or a placebo. There may be a real danger that valuable drugs which are in reality innocuous to the human foetus, but which have come into disrepute as a result of laboratory tests, will be withdrawn from use, while other drugs of less therapeutic value and more danger to the foetus remain available, because they have passed less rigorous tests or because they have yet to be tested. If the fact that a drug is capable of producing malformations in laboratory animals is not to be regarded as an absolute bar to its use, some formula must be devised to express the danger to the embryo in relation to the therapeutic dose. The difficulties in attempting to draw up such a scheme are not hard to illustrate: 6 times the therapeutic dosage of aspirin on a weight-for-weight basis produced malformations in rats, while 75 times the therapeutic dose of thalidomide was required to produce malformations in rabbits 9-observations which, uncritically interpreted, might suggest that aspirin was almost twelve times as toxic to the embryo as thalidomide. SOMERS 10 and ROBSON 11 have lately put forward ingenious proposals for indices to express toxicity to the foetus, and their suggestions will obviously receive further detailed conwhat does
a
sideration. Until more physiology, and
is
known
about of the
the
anatomy, embryo and the
pharmacology placenta, it is important to strike as satisfactory a balance as possible between, on the one hand, letting a dangerous teratogen loose on the market and, on the other, missing a drug of great therapeutic potential. It is for the of a to see that it is tested in labordrug proprietors to the animals for limits atory teratogenic properties of available knowledge, and to ensure that the data are freely available to all potential prescribers. A committee with Lord CoHEN OF BIRKENHEAD as chairman is advising the Health Ministers on the measures needed to secure satisfactory testing of new drugs 12, and its recommendations may show how best to achieve this.
routine barium-enema examinations by DEBRAY et all in 500 unselected subjects, about a quarter of the population aged between 60 and 70, and about half of those over 70, have diverticulosis. Now that people live longer, more of them have diverticular disease; complications are commoner; and among these, undeniably, is profuse bleeding. A survey of published reports over the past fifteen years leads to the conclusion that about a fifth of the patients with diverticular disease have bleeding from the bowel, though only about 4% lose enough to require transfusion. But massive bleeding from the colon is, in fact, almost certainly due to diverticular disease, and not (contrary to what most doctors have been taught) to carcinoma. Clearly, prevalent views need to be overhauled.15-25 The distinction between diverticulitis and diverticulosis is unimportant; indeed, bleeding is seen more often in uncomplicated diverticulosis. The cause is generally ulceration of the mucosa with erosion of a vessel or inversion of a diverticulum. 26 27 From examination of injection preparations, NOER 28 suggested that bleeding was due to the increased concentration of intramural blood-vessels passing from the serosal surface towards the mucosal surface in the region of the diverticula. Many of the patients are hypertensive, and this may have some significance. Even afterremoval of the diseased segment of colon the bleeding-point may be impossible to find. This adds to the difficulty of treatment. A familiar finding at operation is a pale-blue colon, filled with blood from cascum to rectum, with nothing externally to show where the blood is coming from. Grape-like clusters of diverticula extend well beyond the sigmoid colon, and the offending one is often hidden in the fat of the appendices epiploicae or the mesentery. In this dilemma, the surgeon is variously advised to do one of a number of things. He can instil topical coagulants through a caecostomy 29; he can make a proximal colostomy 30 31; he can isolate with nonserial segments of the colon, each crushing clamps " milked " empty of blood, and observe previously which segment fills with blood 23 ; he can make a transverse colostomy and follow this with a hemicolectomy, according to which half of the colon the blood seems to be coming from 32;he can resect blindly the more obviously diseased part of the colon (usually the sigmoid) 33 ; he can combine colotomy with operative endoscopy 33; or he can remove the whole colon.27 34 35 14.
Massive
in Diverticular Disease of the Colon
Bleeding
IN 1954, at
joint meeting of the American College of Surgeons and the Royal College of Surgeons of England,13 a panel was asked: " Can massive bleeding arise from diverticulitis of the colon ?" All on the panel answered that they had no experience of the complication. If we accept as typical the figures derived from a
S. Q. Medical Tribune. 1962, 3, 24. Somers, G. F. Study Group on Toxicity of Drugs, Alderley Park, Sept. 25, 1962. 11. Robson, J. M. Section of Experimental Medicine, Royal Society of Medicine, March 20, 1963. 12. Lancet, 1962, ii, 1048. 13. ibid. 1954. i, 1124. 9. 10.
Cohlan,
15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27.
Debray, C., Hardouin, J. P., Besançon, F., Raimbault, J. Sem. Hôp. Paris, 1961, 37, 1743. Stone, H. B. Ann. Surg. 1944, 120, 582. Rives, J. D., Emmett, R. O. Amer. Surg. 1954, 20, 458. Greene, W. W. Amer. J. Surg. 1957, 94, 282. Quinn, W. C., Ochsner, A. Ann. Surg. 1961, 153, 851. Bell, H. G. Sth. med. J. 1953, 46, 453. Buck, R. L. Dis. Colon Rect. 1958, 1, 205. Quinn, W. C., Ochsner, A. Amer. Surg. 1960, 26, 171. Browne, D. G. Amer. J. dig. Dis. 1961, 6, 791. Myburgh, J. A. S. Afr. med. J. 1961, 35, 668. Hubbard, T. B., Jr. Amer. J. Surg. 1960, 100, 600. Covey, M. C., Moeller, H. G. Amer. J. Gastroent. 1961, 35, 42. Young, J. M., Howorth, M. B. Jr., Ann. Surg. 1954, 140, 128. Mobley, J. E., Dockerty, M. D., Waugh, J. M. Amer. J. Surg. 1957,
94, 44. 28. Noer, R. J. Ann. Surg. 1955, 141, 674. 29. Kunath, C. A. Amer. J. Surg. 1956, 91, 911. 30. Knight, C. D. Surgery, 1957, 42, 853. 31. Foster, R. L., Fisher, R. E. Amer. Surg. 1954, 20, 734. 32. Sandegard, E. Acta. chir. scand. 1959, 117, 465. 33. Jensen, G. L. Amer. J. Surg. 1958, 95, 813. 34. Welch, C. E., Rodkey, G. V. Surgery, 1956, 39, 712. 35. Teicher, I., Abrahame, J. I. Surg. Gynec. Obstet. 1956,
103, 136.
707
None of these measures in itself, except subtotal colectomy, can be claimed to stop the bleeding. What can be said is that the results of operation in these emergency circumstances are not encouraging. The patients are old and very often obese; they have lost a lot of blood; and they do not take kindly to surgical acrobatics. In practice, the choice most often lies between closure of the abdomen and total colectomy. Fortunately, the occasion for the choice should seldom arise. Conservative measures-replacement of blood and the administration of antibiotics-are successful in nearly every case. Out of 317 patients, 18 who had massive bleeding were treated in this way by QUINN 18 ; all recovered. The patients were followed up for four to ten years. 2 bled again, but no patient died from hxmorrhage. 14 patients who needed from 500 ml. to 2500 ml. of blood were reported by STANTON 36 to have recovered successfully. The experience of BARBORKA 31 confirms the value of a conservative regimen. But the danger of missing a malignant growth is inherent in a policy of conservative management. The wise clinician will make every effort to ensure that he is, in fact, dealing with diverticular disease. Many surgeons who recognise the hazards of operating only when grave complications have arisen advocate intervention at an early stage of the disease. 38-40 The dficulty is that diverticulitis does not, save exceptionally, manifest itself in early life, and symptoms are often trivial and easily controlled. Even in these advanced days segmental resection of the colon is not to be embarked upon lightheartedly-particularly for a disease which tends to progress with age. Other serious complications of diverticulitis, such as obstruction and fistula formation, favour early operation. But bleeding is not one.
Living with Insecticide Resistance MODERN synthetic insecticides have revolutionised preventive medicine in the tropics. But the mounting number of reports of resistant strains of important vectors is a matter for concern. Over 70 arthropod species of public-health importance are involved, from one region or another. The World Health Organisation responded to this challenge in 1956, and since then it has coordinated the attack on resistance by establishing standard test methods of detecting resistance, circularising information, and fostering research; and some of the latest moves in this campaign can be seen in a W.H.O. Bulletin.41 Most of the contributions concern resistance in anopheline mosquitoes and means of overcoming it. In the work on genetics of resistance in anopheline mosquitoes (much of it done by G. DAVIDSON) such instances as could be investigated in the laboratory :i.e., in mosquitoes which will breed in captivity) have shown resistance to be a normal mendelian character,
recent
36 Stanton, A. Amer. J. Gastroent. 1955, 24, 77. 37.Barborka, C. J. Gastroenterology, 1958, 34, 278. 38.DeBakey, M. E. The Yearbook of General Surgery.
p. 434,Chicago. 39.Colcock, B. P. Amer. Surg. 1958, 24, 738. 40.McGregor, R. A., Bacon, H. E. Dis. Colon Rect. 1958, 41. Bull. Wld Hlth Org. 1963, 28, no. 1.
1957-58
1,
197.
series;
inherited by a single pair of genes. D.D.T. (dicophane) resistance is recessive (or nearly so), whereas dieldrin/ benzene-hexachloride (B.H.c.) is partially dominant. As a result, the heterozygotes of D.D.T. resistance have no advantage, so that emergence of this type of resistance must await selection from rare homozygotic resistants. In contrast, dieldrin/B.H.c. resistance should respond much earlier to selection, because the heterozygotes already survive preferentially. Use of basic data of this kind, to interpret complex happenings in the field, is made by J. HAMON and C. GARRETT-JoNES in an excellent detailed study of the incidence of resistance in five major malaria vectors of the Old World. Their most cheering conclusion is that, despite the almost worldwide use of residual insecticides, resistant strains have emerged only in relatively restricted areas in the distribution of the major vectors. No-one can say why this is, unless perhaps the genes for resistance are only present in localised
mosquito populations. Resistance to dieldrin and B.H.c. appears rapidly, usually within two years of general house-spraying. The resistance levels are very high (especially towards dieldrin) so that malaria transmission returns; and if the immunity of the human population has waned, an epidemic is likely. Nothing can be done except to change the insecticide (perhaps to D.D.T.); and then the resistance to dieldrin declines only very slowly in the mosquito population. In contrast, D.D.T. resistance appears considerably later and is usually less intense, so that malaria transmission does not always result. The irritant action of D.D.T. on mosquitoes, which drives them out of treated houses (sometimes without killing them), may sometimes allow transmission; but this phenomenon discourages the rapid development of resistance. On the other hand, resistance in malaria vectors in several countries has been stimulated by the wide use of insecticides in agriculture and the consequent contamination of the mosquito breeding grounds. In view of the importance of the world malaria-eradication programme, Government action is called for in malarial countries to prevent this danger. At present, nearly all the big malaria eradication campaigns rely on D.D.T. or dieldrin, both of which have a long residual effect of about six months. Of the five vectors discussed, however, four are resistant to both D.D.T. and dieldrin at one point or another; and where both forms of resistance arise together, a totally different insecticide must be used to kill the mosquitoes. There is thus an urgent need for alternative insecticides to supplement D.D.T. and dieldrin, and though the search for new types has been intensified, nothing entirely satisfactory has yet been found. The most promising are either organophosphorus compounds or carbamates, and several papers in the W.H.C. Bulletin report tests of these substances in Britain and Nigeria. The toxicity of anti-cholinesterase compounds is not their main drawback (some, like malathion, are probably at least as safe as D.D.T.): unfortunately, their physical properties do not allow long residual action and it is hard to see how this can be overcome.