170
the somatic component of the sphincter complex. After the abdomen is closed the anal sphincter is incised vertically a little to one side of the mid-line posteriorly and divided until the gut tube is exposed. The portion of gut tube bearing the tumour is then delivered and the resection carried out. The line of the anastomosis is easily accessible and it is then a straight-forward matter to achieve a really low resection with a technically satisfactory anastomosis. Recovery of sphincter function after resuture of the somatic sphincter is excellent. An alternative method of achieving a low anastomosis has been described using the transanal approach.10 The anorectal stump is dilated sufficiently to admit a specially designed retractor. The tumour is resected through the abdomen. The cut end of the left colon is then drawn down into the pelvis and sutured to the anorectal stump from within the lumen using a specially designed needle. Again the functional results of this operation are very satisfactory. In summary, then, it is no longer satisfactory always to treat carcinoma of the rectum by either abdominoperineal excision or a standard anterior resection. A clear understanding of the pathological nature of the disease and the fact that further techniques are available to allow a really low anastomosis means that growths of even 6 cm and upwards should be considered for some sort of restorative procedure, especially if the tumour is of average or below average malignancy. Morgan, C. N., Annals of the Royal College of Surgeons of England, 1965, 36, 73. Bennett, R. C., Medical3Journal of Australia, 1974, 2, 83. 3 Devlin, H. B., Plant, J. A., and Griffin, M., British Medical Journal, 1971, 3, 413. 4 Quer, E. A., Dahlin, D. C., and Mayo, C. W., Surgery, Gynecology and Obstetrics, 1953, 96, 24. 5 Goligher, J. C., et al., British Journal of Surgery, 1965, 52, 323. 6 Goligher, J. C., Graham, N. G., and De Dombal, F. T., British Journal of Surgery, 1970, 57, 109. Mann, C. V., Proceedings of the Royal Society of Medicine, 1972, 65, 976. 8 Kennedy, J. T., et al., British Journal of Surgery, 1970, 57, 589. 9 Mason, A. Y., Proceedings of the Royal Society of Medicine, 1972, 65, 974. 1 Parks. A. G., Proceedings of the Royal Society of Medicine, 1972, 65, 975.
BRITISH MEDICAL JOURNAL
25 JANUARY 1975
DDT and phenobarbitone; so it is a matter of opinion how far the production of these liver tumours in mice given aldrin or dieldrin is a reliable index of a hazard to man. It is not a matter of the credibility of witnesses: the facts are not in dispute, it is their interpretation that is a matter of debate. These observations are not new but were available for discussion at the time the British Government's review of the problem of persistent organochlorine pesticides was in preparation.' Much of the work on the effects of dieldrin on mice had been carried out in the laboratories of the manufacturer, whose research workers discussed the significance of their findings on many occasions with the scientists advising the committee. The decision taken then was that the use of dieldrin and aldrin should be phased out-because they were persistent and not because of any toxic hazard they present to man. There is good evidence that this phasing out is in fact happening. In the absence of any new evidence that aldrin or dieldrin are carcinogenic to animals or man there seems no reason for the authorities in this country to follow the American recommendation. Furthermore, where there is no consensus of opinion on the interpretation of findings in animals studies designed to provide evidence of possible toxic hazards to man, the procedure adopted by the Environmental Protection Agency for reaching a decision is not one we should attempt to imitate.
1
2
Insecticides and Cancer In assessing any risk that people exposed to drugs and chemicals in the environment or at their place of work might develop acute or chronic poisoning, it is frequently and rightly emphasized that judgement is required. Experts who are familiar with the practical situation and those who are competent to judge the available evidence (be it of a statistical, biochemical, or pathological nature) must use their professional judgement when offering an opinion on its interpretation. The Environmental Protection Agency of the U.S.A. has recently recommended a ban on the further production of the insecticides aldrin and dieldrin on the grounds that they present "a significant potential of an unreasonable risk of cancer in the American public." The agency's inquiry was held by a judge on its staff, who rejected the evidence of one expert witness who had served on committees on the safety of insecticides. In fact there is no direct evidence that aldrin and dieldrin cause cancer in man nor, with one exception, in animal experiments. The evidence on which the suggestion of "an unreasonable risk of cancer" is based is the production in mice given diets containing aldrin or dieldrin of tumours in the livers, some of which had metastasized to the lungs. Similar tumours can, however, occur in mice on normal diets and are produced by other compounds including
I
Department of Education and Science, Further Review of Certain Persistent Organochlorine Pesticides. London, H.M.S.O., 1969.
Calcium, Magnesium, and Diuretics Since oral diuretic agents are given to so many patients with hypertension and heart failure for long periods of their lives the toxicology of these drugs is important. Can they cause diabetes mellitus de novo or do they merely exacerbate preexisting disease? Is diuretic-induced hyperuricaemia merely a biochemical epiphenomenon or itself a cause of renal impairment? If diuretics do lower serum potassium concentrations, do they also cause depletion of whole-body potassium stores, and if so, does this matter ? As if these questions were not enough to tax most doctors, another facet of diuretic therapy has recently emerged and deserves attention: the effect of diuretics on calcium and magnesium homoeostasis. Benzothiadiazine (or thiazide) diuretics have two effects on calcium metabolism which are not produced by other diuretic agents. When given for the first time, diuretics such as frusemide,' ethacrynic acid,2 and aldosterone antagonists3 will enhance calcium excretion by the kidney along with sodium elimination. Not so the thiazides, which affect calcium eliminatlon very little in those circumstances4; and indeed long-term thiazide administration results in a persistent reduction in renal calcium elimination5 which may lead to hypercalcaemia. The mechanism of this renal effect of the thiazides is not clear. It has been attributed to the ability of thiazide diuretics to deplete extracellular volume, but this appears unlikely since infusion of a thiazide into one renal artery results in unilateral hypocalciuria.6 Stimulation of parathyroid hormone secretion does not appear to be a likely explanation, since the effect is seen in animals after thyro-parathyroidectomy,7 and, more-
BRITISH MEDICAL JOURNAL
25 JANUARY 1975
over, circulatory levels of parathyroid hormone are not altered by thiazide administration.8 The cause of the hypocalciuria seems to be a direct effect of the drug on renal tubular function.6 Whatever the mechanism, the effect has been put to good therapeutic use. Thiazides will prevent the formation of renal calculi in patients with idiopathic hypercalciuria and will diminish the incidence of renal colic in patients who already have stones. Some convincing evidence has come from Yendt and his colleagues in Kingston, Ontario.9 They gave 100 mg hydrochlorthiazide daily to 67 patients with recurrent renal calculi. Thirty-three of these patients were stone-free when the thiazide administration started, and whereas before treatment they had, between them, had 194 episodes either of renal colic or of passing a stone in 343 patient-years observation, thiazides cut down such episodes to 2 in 72 patient years. In 34 patients known to have renal calculi administration of thiazides led to a similar reduction from 365 episodes in 343 patient years to 34 episodes in 64 patient years. In another study'0 bendrofluazide 7*5 mg/day was shown to increase renal calcium reabsorption and cut down renal calcium excretion by 52% in 20 patients with renal calculi, 10 of whom had hyperparathyroidism. The hypercalciuric effect of frusemide has also been used therapeutically in patients with hypercalcaemia. Given in divided doses to a total ranging from 160 to 3200 mg in 8 patients" it caused a fall in serum calcium ranging from 2-3 to 3.8 mg/100 ml, due to increased urinary calcium elimination. This form of treatment appears to work even in the presence of compromised renal function. What effects have diuretics on magnesium handling ? Surprisingly little attention has been paid to this important cation in therapeutics. Most established diuretics such as thiazides12 and frusemide"3 will increase renal magnesium clearance in the long term, though this is probably not true of spironolactone14 or bumetanide.'5 Moreover many patients with heart failure are already magnesium depleted before the start of drug treatment, since secondary aldosteronism results in increased urine magnesium losses.16 Magnesium may be very important in these conditions, for depletion will predispose to ventricular extrasystoles and may exacerbate digitalis toxicityl7 in the same way as potassium deficiency. Other clinical manifestations of magnesium depletion include muscular cramps, paraesthesiae, nausea, and vomiting. In a series of 10 patients who had been on diuretics for a mean of 3-3 years five had considerable magnesium deficiency as shown by low muscle magnesium levels.'8 Each of these five had clinical features compatible with magnesium deficiency, and these reverted with replacement therapy using oral magnesium hydroxide and intravenous magnesium sulphate. Interestingly, low potassium concentrations in muscle were also corrected by magnesium replacement. How can one diagnose magnesium depletion ? The suspicion should be raised in patients with heart failure on long-term diuretic therapy who have the characteristic symptoms, especially ifthey have a normal serum potassium concentration. Patients on digitalis are particularly at risk. Measurement of serum magnesium concentration is, then, worthwhile, for when low it usually signifies depletion of whole body stores. Perhaps in the not too distant future we shall be giving our patients on diuretics not only potassium supplements but magnesium too. ITambyah, J. A., and Lim, M. K. L., British Medical_Journal, 1969, 1, 751. Demartini, F. E., Briscoe, A. M., and Ragan, C., Proceedings of the Society for Experimental Biology and Medicine, 1967, 124, 320. 3 Ben-Ishay, D., Viskoper, R. J., and Menczel, J., Israel Journal of Medical Sciences, 1972, 8, 495. Kiil, F., Circulation, 1960, 21, 717. 2
171
5 Higgins, B. A., et al., Clinical Science, 1964, 27, 457. of Clinical Investigation, 1974, Costanzo, L. S., and Weiner, I. 54, 628. Jorgensen, F. S., Acta Pharmacologica et Toxicologica, 1971, 30, 296. Stote, R. M., et al., Annals of Internal Medicine, 1972, 77, 587. 9 Yendt, E. R., Guay, G. F., and Garcia, D. A., Canadian Medical Association Journal, 1970, 102, 614. 10 Schonau Jorgensen, F., and Transbol, I., Acta Medica Scandinavica, 1973, 194, 327. 1 Suki, W. N., Yium, J. J., Von Minden, M., et al., New England Journal of Medicine, 1970, 283, 836. 12 Robinson, R. R., Murdaugh, H. V., and Peschel, E., Circulation, 1958, 18, 771. 13 Duarte, C. G., Metabolism, 1968, 17, 867. 14 Leman, J., Piering, W. F., and Lennon, E. J., Clinical Research, 1967, 15, 362. 15 Olesen, K. H., et al., Acta Medica Scandinavica, 1973, 193, 119. 16 Horton, R., and Biglieri, E. G., Journal of Clinical Endocrinology and Metabolism, 1962, 22, 1187. 17 Vitale, J. J., et al., Circulation Research, 1961, 9, 387. 18 Lim, P., and Jacob, E., British Medical,Journal, 1972, 3, 620. 6
M.,J_ournal
Keeping Rabies Out Medical opinion will welcome the stiffer penalties announced last week by the Ministry of Agriculture (see p. 221) for offences associated with the smuggling of animals into Britain. Our enviable record of freedom from rabies will be maintained only by strict attention to the quarantine regulations governing international movement of dogs, cats, and other animals that can carry the disease. Rabies is a growing problem in Europe, where the main reservoir of infection is among foxes.' More than 5000 cases of animal rabies were reported in France in 1973, and the total for 1974 is expected to be higher still. Treatment for human rabies continues to improve-at least one patient has recovered2 after treatment by curarization and prolonged artificial respiration-but better vaccines are still required.3 For the foreseeable future we must continue to rely on our geographical isolation from Europe to keep the disease a textbook curiosity in Britain. 1 2
The Times, 16 January 1975. Hathwick, M. A. W., et al., Annals of Internal Medicine, 1972, 76, 931. 3 British Medical Journal, 1974, 1, 45.
Victims of Rape What should the doctor do when asked to see the victim of a rape ? If he is called by the police he has certain legal duties to perform, though usually this work is done by appointed police surgeons trained in forensic medicine who will have had experience in interpreting the clinical findings and taking the necessary pathological specimens (vaginal swabs, nail cuttings, hair, venous blood, and saliva). In the larger urban areas the police have a team of women doctors who specialize in sexual assault on women and children, but, subject to the consent of the victim, a male police surgeon may carry out the examination if a woman doctor is not available. The victim may, however, not go to the police but instead consult her own general practitioner, or another doctor, or go to a hospital casualty department. What should this doctor do ? Obviously he must see the patient, if only for humanitarian reasons. However, there is also a legal aspect because later he may be called to give evidence in court, at which time his
the somatic component of the sphincter complex. After the abdomen is closed the anal sphincter is incised vertically a little to one side of the mid-line posteriorly and divided until the gut tube is exposed. The portion of gut tube bearing the tumour is then delivered and the resection carried out. The line of the anastomosis is easily accessible and it is then a straight-forward matter to achieve a really low resection with a technically satisfactory anastomosis. Recovery of sphincter function after resuture of the somatic sphincter is excellent. An alternative method of achieving a low anastomosis has been described using the transanal approach.10 The anorectal stump is dilated sufficiently to admit a specially designed retractor. The tumour is resected through the abdomen. The cut end of the left colon is then drawn down into the pelvis and sutured to the anorectal stump from within the lumen using a specially designed needle. Again the functional results of this operation are very satisfactory. In summary, then, it is no longer satisfactory always to treat carcinoma of the rectum by either abdominoperineal excision or a standard anterior resection. A clear understanding of the pathological nature of the disease and the fact that further techniques are available to allow a really low anastomosis means that growths of even 6 cm and upwards should be considered for some sort of restorative procedure, especially if the tumour is of average or below average malignancy. Morgan, C. N., Annals of the Royal College of Surgeons of England, 1965, 36, 73. Bennett, R. C., Medical3Journal of Australia, 1974, 2, 83. 3 Devlin, H. B., Plant, J. A., and Griffin, M., British Medical Journal, 1971, 3, 413. 4 Quer, E. A., Dahlin, D. C., and Mayo, C. W., Surgery, Gynecology and Obstetrics, 1953, 96, 24. 5 Goligher, J. C., et al., British Journal of Surgery, 1965, 52, 323. 6 Goligher, J. C., Graham, N. G., and De Dombal, F. T., British Journal of Surgery, 1970, 57, 109. Mann, C. V., Proceedings of the Royal Society of Medicine, 1972, 65, 976. 8 Kennedy, J. T., et al., British Journal of Surgery, 1970, 57, 589. 9 Mason, A. Y., Proceedings of the Royal Society of Medicine, 1972, 65, 974. 1 Parks. A. G., Proceedings of the Royal Society of Medicine, 1972, 65, 975.
BRITISH MEDICAL JOURNAL
25 JANUARY 1975
DDT and phenobarbitone; so it is a matter of opinion how far the production of these liver tumours in mice given aldrin or dieldrin is a reliable index of a hazard to man. It is not a matter of the credibility of witnesses: the facts are not in dispute, it is their interpretation that is a matter of debate. These observations are not new but were available for discussion at the time the British Government's review of the problem of persistent organochlorine pesticides was in preparation.' Much of the work on the effects of dieldrin on mice had been carried out in the laboratories of the manufacturer, whose research workers discussed the significance of their findings on many occasions with the scientists advising the committee. The decision taken then was that the use of dieldrin and aldrin should be phased out-because they were persistent and not because of any toxic hazard they present to man. There is good evidence that this phasing out is in fact happening. In the absence of any new evidence that aldrin or dieldrin are carcinogenic to animals or man there seems no reason for the authorities in this country to follow the American recommendation. Furthermore, where there is no consensus of opinion on the interpretation of findings in animals studies designed to provide evidence of possible toxic hazards to man, the procedure adopted by the Environmental Protection Agency for reaching a decision is not one we should attempt to imitate.
1
2
Insecticides and Cancer In assessing any risk that people exposed to drugs and chemicals in the environment or at their place of work might develop acute or chronic poisoning, it is frequently and rightly emphasized that judgement is required. Experts who are familiar with the practical situation and those who are competent to judge the available evidence (be it of a statistical, biochemical, or pathological nature) must use their professional judgement when offering an opinion on its interpretation. The Environmental Protection Agency of the U.S.A. has recently recommended a ban on the further production of the insecticides aldrin and dieldrin on the grounds that they present "a significant potential of an unreasonable risk of cancer in the American public." The agency's inquiry was held by a judge on its staff, who rejected the evidence of one expert witness who had served on committees on the safety of insecticides. In fact there is no direct evidence that aldrin and dieldrin cause cancer in man nor, with one exception, in animal experiments. The evidence on which the suggestion of "an unreasonable risk of cancer" is based is the production in mice given diets containing aldrin or dieldrin of tumours in the livers, some of which had metastasized to the lungs. Similar tumours can, however, occur in mice on normal diets and are produced by other compounds including
I
Department of Education and Science, Further Review of Certain Persistent Organochlorine Pesticides. London, H.M.S.O., 1969.
Calcium, Magnesium, and Diuretics Since oral diuretic agents are given to so many patients with hypertension and heart failure for long periods of their lives the toxicology of these drugs is important. Can they cause diabetes mellitus de novo or do they merely exacerbate preexisting disease? Is diuretic-induced hyperuricaemia merely a biochemical epiphenomenon or itself a cause of renal impairment? If diuretics do lower serum potassium concentrations, do they also cause depletion of whole-body potassium stores, and if so, does this matter ? As if these questions were not enough to tax most doctors, another facet of diuretic therapy has recently emerged and deserves attention: the effect of diuretics on calcium and magnesium homoeostasis. Benzothiadiazine (or thiazide) diuretics have two effects on calcium metabolism which are not produced by other diuretic agents. When given for the first time, diuretics such as frusemide,' ethacrynic acid,2 and aldosterone antagonists3 will enhance calcium excretion by the kidney along with sodium elimination. Not so the thiazides, which affect calcium eliminatlon very little in those circumstances4; and indeed long-term thiazide administration results in a persistent reduction in renal calcium elimination5 which may lead to hypercalcaemia. The mechanism of this renal effect of the thiazides is not clear. It has been attributed to the ability of thiazide diuretics to deplete extracellular volume, but this appears unlikely since infusion of a thiazide into one renal artery results in unilateral hypocalciuria.6 Stimulation of parathyroid hormone secretion does not appear to be a likely explanation, since the effect is seen in animals after thyro-parathyroidectomy,7 and, more-
BRITISH MEDICAL JOURNAL
25 JANUARY 1975
over, circulatory levels of parathyroid hormone are not altered by thiazide administration.8 The cause of the hypocalciuria seems to be a direct effect of the drug on renal tubular function.6 Whatever the mechanism, the effect has been put to good therapeutic use. Thiazides will prevent the formation of renal calculi in patients with idiopathic hypercalciuria and will diminish the incidence of renal colic in patients who already have stones. Some convincing evidence has come from Yendt and his colleagues in Kingston, Ontario.9 They gave 100 mg hydrochlorthiazide daily to 67 patients with recurrent renal calculi. Thirty-three of these patients were stone-free when the thiazide administration started, and whereas before treatment they had, between them, had 194 episodes either of renal colic or of passing a stone in 343 patient-years observation, thiazides cut down such episodes to 2 in 72 patient years. In 34 patients known to have renal calculi administration of thiazides led to a similar reduction from 365 episodes in 343 patient years to 34 episodes in 64 patient years. In another study'0 bendrofluazide 7*5 mg/day was shown to increase renal calcium reabsorption and cut down renal calcium excretion by 52% in 20 patients with renal calculi, 10 of whom had hyperparathyroidism. The hypercalciuric effect of frusemide has also been used therapeutically in patients with hypercalcaemia. Given in divided doses to a total ranging from 160 to 3200 mg in 8 patients" it caused a fall in serum calcium ranging from 2-3 to 3.8 mg/100 ml, due to increased urinary calcium elimination. This form of treatment appears to work even in the presence of compromised renal function. What effects have diuretics on magnesium handling ? Surprisingly little attention has been paid to this important cation in therapeutics. Most established diuretics such as thiazides12 and frusemide"3 will increase renal magnesium clearance in the long term, though this is probably not true of spironolactone14 or bumetanide.'5 Moreover many patients with heart failure are already magnesium depleted before the start of drug treatment, since secondary aldosteronism results in increased urine magnesium losses.16 Magnesium may be very important in these conditions, for depletion will predispose to ventricular extrasystoles and may exacerbate digitalis toxicityl7 in the same way as potassium deficiency. Other clinical manifestations of magnesium depletion include muscular cramps, paraesthesiae, nausea, and vomiting. In a series of 10 patients who had been on diuretics for a mean of 3-3 years five had considerable magnesium deficiency as shown by low muscle magnesium levels.'8 Each of these five had clinical features compatible with magnesium deficiency, and these reverted with replacement therapy using oral magnesium hydroxide and intravenous magnesium sulphate. Interestingly, low potassium concentrations in muscle were also corrected by magnesium replacement. How can one diagnose magnesium depletion ? The suspicion should be raised in patients with heart failure on long-term diuretic therapy who have the characteristic symptoms, especially ifthey have a normal serum potassium concentration. Patients on digitalis are particularly at risk. Measurement of serum magnesium concentration is, then, worthwhile, for when low it usually signifies depletion of whole body stores. Perhaps in the not too distant future we shall be giving our patients on diuretics not only potassium supplements but magnesium too. ITambyah, J. A., and Lim, M. K. L., British Medical_Journal, 1969, 1, 751. Demartini, F. E., Briscoe, A. M., and Ragan, C., Proceedings of the Society for Experimental Biology and Medicine, 1967, 124, 320. 3 Ben-Ishay, D., Viskoper, R. J., and Menczel, J., Israel Journal of Medical Sciences, 1972, 8, 495. Kiil, F., Circulation, 1960, 21, 717. 2
171
5 Higgins, B. A., et al., Clinical Science, 1964, 27, 457. of Clinical Investigation, 1974, Costanzo, L. S., and Weiner, I. 54, 628. Jorgensen, F. S., Acta Pharmacologica et Toxicologica, 1971, 30, 296. Stote, R. M., et al., Annals of Internal Medicine, 1972, 77, 587. 9 Yendt, E. R., Guay, G. F., and Garcia, D. A., Canadian Medical Association Journal, 1970, 102, 614. 10 Schonau Jorgensen, F., and Transbol, I., Acta Medica Scandinavica, 1973, 194, 327. 1 Suki, W. N., Yium, J. J., Von Minden, M., et al., New England Journal of Medicine, 1970, 283, 836. 12 Robinson, R. R., Murdaugh, H. V., and Peschel, E., Circulation, 1958, 18, 771. 13 Duarte, C. G., Metabolism, 1968, 17, 867. 14 Leman, J., Piering, W. F., and Lennon, E. J., Clinical Research, 1967, 15, 362. 15 Olesen, K. H., et al., Acta Medica Scandinavica, 1973, 193, 119. 16 Horton, R., and Biglieri, E. G., Journal of Clinical Endocrinology and Metabolism, 1962, 22, 1187. 17 Vitale, J. J., et al., Circulation Research, 1961, 9, 387. 18 Lim, P., and Jacob, E., British Medical,Journal, 1972, 3, 620. 6
M.,J_ournal
Keeping Rabies Out Medical opinion will welcome the stiffer penalties announced last week by the Ministry of Agriculture (see p. 221) for offences associated with the smuggling of animals into Britain. Our enviable record of freedom from rabies will be maintained only by strict attention to the quarantine regulations governing international movement of dogs, cats, and other animals that can carry the disease. Rabies is a growing problem in Europe, where the main reservoir of infection is among foxes.' More than 5000 cases of animal rabies were reported in France in 1973, and the total for 1974 is expected to be higher still. Treatment for human rabies continues to improve-at least one patient has recovered2 after treatment by curarization and prolonged artificial respiration-but better vaccines are still required.3 For the foreseeable future we must continue to rely on our geographical isolation from Europe to keep the disease a textbook curiosity in Britain. 1 2
The Times, 16 January 1975. Hathwick, M. A. W., et al., Annals of Internal Medicine, 1972, 76, 931. 3 British Medical Journal, 1974, 1, 45.
Victims of Rape What should the doctor do when asked to see the victim of a rape ? If he is called by the police he has certain legal duties to perform, though usually this work is done by appointed police surgeons trained in forensic medicine who will have had experience in interpreting the clinical findings and taking the necessary pathological specimens (vaginal swabs, nail cuttings, hair, venous blood, and saliva). In the larger urban areas the police have a team of women doctors who specialize in sexual assault on women and children, but, subject to the consent of the victim, a male police surgeon may carry out the examination if a woman doctor is not available. The victim may, however, not go to the police but instead consult her own general practitioner, or another doctor, or go to a hospital casualty department. What should this doctor do ? Obviously he must see the patient, if only for humanitarian reasons. However, there is also a legal aspect because later he may be called to give evidence in court, at which time his
