348 Two other workers repeated this sequence of events before Starr undertook the first serious investigation in 1936. He was searching for the cardiological lodestone-a non-invasive method of measuring cardiac output. Whatever its merits in this respect, he recognised from the first that the B.C.G. closely reflects the vigour of myocardial contraction. More recently the animal experiments of Guz and his co-workers" have clearly demonstrated how sensitive it can be to even minor changes in contractility. However, B.c.G. has never really caught on as a diagnostic or investigational tool because it demands cumbersome and elaborate equipment and because the records obtained are very difficult to calibrate or express in numerical terms. Other methods of measuring myocardial contractility12 13 have captured the imagination and the research funds. Now, renewed interest in non-invasive investigative techniques has prompted re-evaluation of the B.C.G. In 1947 Starr 14 observed that, no matter what the difficulties in calibration, a simple qualitative classification of the resting B.C.G. could be used as a predictor of the development of ischsemic myocardial disease with considerable confidence even when all other predictors, including the electrocardiogram, were normal. This observation was confirmed by Baker et al.15 in a group of 400 controls and 300 patients with heart-disease. Lynn and Wolf’6 studied the B.c.G. in 73 subjects with ischaemic heart-disease and 50 matched normal controls over a seven-year period. Using only qualitative interpretation they found that the tracings could be used to predict "coronary events" with high accuracy. Kiessling17 studied the predictive value of the B.c.G. in 6000 people and again found a good correlation between an abnormal record and mortality from ischaemic heartdisease over a seventeen-year period. From these results a good case can be made for inclusion of the B.C.G. in cardiovascular screening and epidemiological studies. Equipment presents a major obstacle, but this may now be surmounted by a portable accelerometer device18 which writes out on an ordinary E.C.G. machine. This instrument is a simple capsule which can be strapped to the shoulder or the head of any patient or subject. Quantification is not attempted, tracings being interpreted on the simple qualitative lines suggested by Starr-big regular complexes indicate vigorous myocardial contractility and small irregular complexes indicate poor contractility. It can be used in many situations, including the coronary-care and intensive-therapy unit, and could give as much information on changes in left-ventricular contractility as the E.c.G. gives on changes in rhythm. The elaborate computer-aided methods which have been devised to express left-ventricular function numerically do not seem to have made much impact on clinical practice. It may be that we are attempting to be too precise in our measuring techniques and that qualitative analysis of the B.C.G. would be equally useful. At least it would be much cheaper. Winter, P. J., Deuchar, D. C., Noble, M. I. M., Trenchard, D., Guz, A. Cardiovasc. Res. 1967, 1, 194. 12. Swanton, R. H., Coltart, D. J., Jenkins, B. S., Webb-Peploe, M. M. Br. Heart J. 1975, 37, 216. 13. Gibson, D. G., Brown, D. J. ibid. p. 677. 11.
14. Starr, I. Am. J. med. Sci. 1947, 214, 233. 15. Baker, B. M., Scarborough, W. M., Davis, F. W., L. S. Proc. R. Soc. Med. 1967, 60, 1290. 16. Lynn, T. N., Wolf, S. Am. Heart J. 1974, 88, 277. 17. Kiessling, C. E. Bibl. Cardiol. 1970, 26, 292. 18. Wright, B. M. ibid. 1970, 33, 72.
Mason,
P.
E., Martin,
EDUCATION ON THE PERIPHERY part of England until lately without a medical the Wessex region, an enlightened regional board school, for many years made generous allocations for postgraduate education. It reaped its reward: junior posts attracted good candidates, and standards of care were high. Now the new medical school at Southampton is tapping the same rich source of clinical material and teaching ability: undergraduates get some of their instruction in hospitals far from the university centre. The programme was described at a meeting in Southampton last month, and similar schemes were reported from elsewhere. Though many peripheral consultants are keen to participate in such schemes, there are problems. Sometimes there is not enough space in the hospital for undergraduate teaching. Tutorials may be less frequent than they would be in a traditional teaching hospital, because registrars have little time to spare. Consultants, too, may find that service needs conflict with teaching. There may be difficulties in coordinating teaching in hospitals remote from the professorial seat. Further, if more than the occasional student is to be accepted, there are the administrative tasks of finding them somewhere to live and allocating them to units where they will learn. Students enjoy these attachments because of the close contact with patients. And, whereas in a teaching hospital the diseases tend to reflect the research interests of the staff, in a peripheral hospital the student will see a more typical tange. Rarities will be a rarity. But the trainee on the periphery also pays a price. He will probably have to maintain a base near the university as well as paying for accommodation in the hospital. He may find himself unable to take part in organised games, Finally, if he is sent out prematurely, without a good grounding in methods of clinical examination, his stint in the peripheral hospital may turn out to be quite useless. IN
one
HOW DOUBLE BLIND?
UNCONSCIOUS bias by doctor or patient, and the placebo effect, are some of the pitfalls when the clinical investigator tries to evaluate a treatment. In drug trials these difficulties can be avoided by allocating the test treatments and apparently identical control treatments (or dummies) in such a way that neither doctor nor patient knows who is taking what: this is the double-blind controlled trial. To some the very idea is still absurd-not to know whether your patient is on lactose or levamisole or is being injected with morphine or saline solution seems ridiculous-but the benefits have won over all but a few doubters. In some drug trials and in many other controllable studies (such as surgical v. conservative management, surgery v. surgery, and different forms of health-care) double blindedness and even single-blinded ness may be impossible. Characteristic side-effects cannot be disguised, for example. On p. 352 Hill and colleagues make the sensible point that if perfect matching of trial preparations is known to be impossible then allowance for this fact should be made at the design stage of the trial. But in most instances, albeit after repeated attempts, some sort of match for properties such as colour, taste, and viscosity can be achieved. Car-
349 sules are a useful device, and those giving the treatment can be kept apart from those who evaluate it. How far should we go? Hill et al. have found that, if you set your mind to it, it is really quite easy to tell apart two preparations that are supposed to be the same. Of 22 pairs tested only 5 were thought to be identical by all four observers. However, the panel were inspecting pairs side by side, which is a bit unrealistic, and being able to say that two things are different is not the same as saying which is which. If tablets, capsules, or ampoules have to be made and coded so that doctors cannot deliberately cheat (say, by cutting open the capsule), then investigators may have chosen the wrong people rather than the wrong design; it is possible to be fussily precise on these matters. If double-blindedness is paramount in clinical investigations then a lot of useful work that is done on non-drug treatments will be invalid. If investigators who have done their best to match are still worried, they can always ask trial personnel and patients to say what they thought they had been giving or taking.
DIALYSIS DEMENTIA: ALUMINIUM AGAIN? A FEW years ago the use of aluminium hydroxide in renal failure enjoyed a brief burst of notoriety in these excitement so columns.’-3 Interest and excitement soon flagged; nephwith their voted rologists prescription pads and aluminium hydroxide continued to be recommended for the control of hyperphosphataemia without even a mention of the postulated danger.4Nevertheless, not all doubts about the safety of aluminium were stilled. Patients with chronic renal failure who are maintained on dialysis may receive large amounts of aluminium hydroxide, over the years, to prevent phosphate retention. With the further factor of reduced renal excretion, there is clearly a risk of chronic accumulation. Tissue analysis suggests that renal failure does, in fact, lead to retention of aluminium.1-3 Some aluminium probably enters bone,67 although the quantity is debatable (neutron-activation analysis probably resulted in an over estimate). The stage was therefore set for a syndrome of toxicity to be described, but no convincing denouement ensued. Clearly phosphate depletion could cause clinical problems, and such have indeed been described:8 however, the consequences of therapeutic overenthusiasm were not the point of issue. Berlyne’s group2 produced acute toxicity and mortality in rats, but in these experiments large doses of soluble aluminium salts were given, or injection was used. In other experiments where more conventional forms of aluminium were presented and where
avoided, no toxicity was seen.33 These were of course acute experiments and they do not provide a very close analogy with the position of patients
hypophosphatsemia
1
was
G. M., Ben An, J., Pest, D., Weinberger, J., Stern, M., Gilmore, G. R., Levine, R. Lancet, 1970, ii, 494. 2. Berlyne, G. M., Yagil, R., Ben Ari, J., Weinberger, G., Knopf, E., Danovitch, G. M. ibid. 1972, i, 564. 3 Thurston, H., Gilmore, G. R., Swales, J. D. ibid. p. 881. 4. Goldsnuth, R. S., Arnaud, C. D., Johnson, W. J. Kidney int. 1975, 7, suppl.
Berlyne,
chronic dialysis hydroxide. The unanimity
on
maintained for years
on
aluminium
with which groups observed aluminium retention created some unease, but this did not greatly limit clinical practice: nephrologists felt that the abundance of aluminium in man’s natural environment made toxicity unlikely. Now this complacency has been challenged. Over the past four years there have been reports of a relentlessly progressive form of dementia in chronic-dialysis patients. This disorder is characterised
by speech disturbance, dyspraxia, tremor, psychosis, personality changes, and psychosis, and it results in death within 6-7 months.9 In certain units it has attained a terrifying frequency. Amongst one group of patients at Denver, it was the most common cause of mortality, accounting for the death of 7 out of 28 patients maintained for more than three years on dialysis.’" At first, retention of tin by brain tissue was suspected, but now the accusing finger has been pointed firmly at aluminium.10 A study from Denver reports a substantial increase in the aluminium content of the grey matter of patients who died of this disorder compared with those dying of other causes. All dialysis patients had received aluminium hydroxide containing 2 g of elemental aluminium for the period of dialysis treatment and the aluminium content of the grey matter was correlated with the duration of dialysis. Again, it was possible to demonstrate retention of aluminium by other tissues. It seems possible, therefore, that aluminium is a potential toxin that has now found a toxic syndrome. At the moment the evidence is only suggestive. Many centres use aluminium hydroxide and progressive dementia is not the widespread problem that might be expected. In the Denver study, the duration of dialysis (which was substantially greater in the demented patients) may have been correlated independently with tissue aluminium and with the development of dementia, giving rise to a spurious correlation between the two. Alternatively, aluminium may have a predilection for damaged brain tissue. Raised brain-aluminium concentrations have also, for instance, been detected in Alzheimer’s disease."Nevertheless, the work requires urgent attention. It should not be difficult for dialysis units with different policies for controlling hyperphosphataemia to pool their experience, and perhaps their necropsy material, for analysis. Meanwhile, it would be premature for units without experience of this form of dementia to abandon aluminium hydroxide. This is another warning sign that, as experience with long-term dialysis grows, so the full range of pathological sequelae of this highly artificial means of maintaining life becomes apparent. The outlook for patients who are currently well is not quite as rosy as earlier experience suggested. Besides the well-aired problems of metabolic bone disease5 it is increasingly clear that the dialysis patient stands a much greater risk of death from cardiovascular accidents than the normal subject of the same age.12 Life is undoubtedly prolonged; but as experience grows we can expect a new range of medical problems of which dialysis dementia is only one.
1, p S-118.
5 Slatopolsky, E. ibid. p. S-253. 6
Parsons, V., Davies, C. G., Goode, C., Ogg, C., Siddiqui, J. Br. med. J. 1971, iv, 273. 7 Clarkson, E. M., Luck, V. A., Hynson, W. V., Bailey, R. R., Eastwood, J. B., Woodhead, J. S., Clements, V. R., O’Riordan, J. L. H., de Wardener, H E. Clin.Sci. 1972, 43, 519. 8 Dent, C. E., Harper, C.M., Philpot, G. R. Q. Jl Med., 1969, 280, 240.
A. C., Mishell, J. M., Burke, J. Trans. Am. Soc. artif. int. Organs, 1972, 18, 257. 10. Alfrey, A. C., LeGendre, G. R., Kaehny, W. D. New Engl. J. Med. 1976, 294, 184. 11. Crapper, D. R., Krishnan, S. S., Dalton, A. J. Science, 1973, 180, 511. 12. Lazarus, J. M., Lowrie, E. G., Hampers, C. L., Merril, J. P. Kidney int. 1975, 7, suppl. 1., p. S-167. 9.
Alfrey,
14. Starr, I. Am. J. med. Sci. 1947, 214, 233. 15. Baker, B. M., Scarborough, W. M., Davis, F. W., L. S. Proc. R. Soc. Med. 1967, 60, 1290. 16. Lynn, T. N., Wolf, S. Am. Heart J. 1974, 88, 277. 17. Kiessling, C. E. Bibl. Cardiol. 1970, 26, 292. 18. Wright, B. M. ibid. 1970, 33, 72.
Mason,
P.
E., Martin,
EDUCATION ON THE PERIPHERY part of England until lately without a medical the Wessex region, an enlightened regional board school, for many years made generous allocations for postgraduate education. It reaped its reward: junior posts attracted good candidates, and standards of care were high. Now the new medical school at Southampton is tapping the same rich source of clinical material and teaching ability: undergraduates get some of their instruction in hospitals far from the university centre. The programme was described at a meeting in Southampton last month, and similar schemes were reported from elsewhere. Though many peripheral consultants are keen to participate in such schemes, there are problems. Sometimes there is not enough space in the hospital for undergraduate teaching. Tutorials may be less frequent than they would be in a traditional teaching hospital, because registrars have little time to spare. Consultants, too, may find that service needs conflict with teaching. There may be difficulties in coordinating teaching in hospitals remote from the professorial seat. Further, if more than the occasional student is to be accepted, there are the administrative tasks of finding them somewhere to live and allocating them to units where they will learn. Students enjoy these attachments because of the close contact with patients. And, whereas in a teaching hospital the diseases tend to reflect the research interests of the staff, in a peripheral hospital the student will see a more typical tange. Rarities will be a rarity. But the trainee on the periphery also pays a price. He will probably have to maintain a base near the university as well as paying for accommodation in the hospital. He may find himself unable to take part in organised games, Finally, if he is sent out prematurely, without a good grounding in methods of clinical examination, his stint in the peripheral hospital may turn out to be quite useless. IN
one
HOW DOUBLE BLIND?
UNCONSCIOUS bias by doctor or patient, and the placebo effect, are some of the pitfalls when the clinical investigator tries to evaluate a treatment. In drug trials these difficulties can be avoided by allocating the test treatments and apparently identical control treatments (or dummies) in such a way that neither doctor nor patient knows who is taking what: this is the double-blind controlled trial. To some the very idea is still absurd-not to know whether your patient is on lactose or levamisole or is being injected with morphine or saline solution seems ridiculous-but the benefits have won over all but a few doubters. In some drug trials and in many other controllable studies (such as surgical v. conservative management, surgery v. surgery, and different forms of health-care) double blindedness and even single-blinded ness may be impossible. Characteristic side-effects cannot be disguised, for example. On p. 352 Hill and colleagues make the sensible point that if perfect matching of trial preparations is known to be impossible then allowance for this fact should be made at the design stage of the trial. But in most instances, albeit after repeated attempts, some sort of match for properties such as colour, taste, and viscosity can be achieved. Car-
349 sules are a useful device, and those giving the treatment can be kept apart from those who evaluate it. How far should we go? Hill et al. have found that, if you set your mind to it, it is really quite easy to tell apart two preparations that are supposed to be the same. Of 22 pairs tested only 5 were thought to be identical by all four observers. However, the panel were inspecting pairs side by side, which is a bit unrealistic, and being able to say that two things are different is not the same as saying which is which. If tablets, capsules, or ampoules have to be made and coded so that doctors cannot deliberately cheat (say, by cutting open the capsule), then investigators may have chosen the wrong people rather than the wrong design; it is possible to be fussily precise on these matters. If double-blindedness is paramount in clinical investigations then a lot of useful work that is done on non-drug treatments will be invalid. If investigators who have done their best to match are still worried, they can always ask trial personnel and patients to say what they thought they had been giving or taking.
DIALYSIS DEMENTIA: ALUMINIUM AGAIN? A FEW years ago the use of aluminium hydroxide in renal failure enjoyed a brief burst of notoriety in these excitement so columns.’-3 Interest and excitement soon flagged; nephwith their voted rologists prescription pads and aluminium hydroxide continued to be recommended for the control of hyperphosphataemia without even a mention of the postulated danger.4Nevertheless, not all doubts about the safety of aluminium were stilled. Patients with chronic renal failure who are maintained on dialysis may receive large amounts of aluminium hydroxide, over the years, to prevent phosphate retention. With the further factor of reduced renal excretion, there is clearly a risk of chronic accumulation. Tissue analysis suggests that renal failure does, in fact, lead to retention of aluminium.1-3 Some aluminium probably enters bone,67 although the quantity is debatable (neutron-activation analysis probably resulted in an over estimate). The stage was therefore set for a syndrome of toxicity to be described, but no convincing denouement ensued. Clearly phosphate depletion could cause clinical problems, and such have indeed been described:8 however, the consequences of therapeutic overenthusiasm were not the point of issue. Berlyne’s group2 produced acute toxicity and mortality in rats, but in these experiments large doses of soluble aluminium salts were given, or injection was used. In other experiments where more conventional forms of aluminium were presented and where
avoided, no toxicity was seen.33 These were of course acute experiments and they do not provide a very close analogy with the position of patients
hypophosphatsemia
1
was
G. M., Ben An, J., Pest, D., Weinberger, J., Stern, M., Gilmore, G. R., Levine, R. Lancet, 1970, ii, 494. 2. Berlyne, G. M., Yagil, R., Ben Ari, J., Weinberger, G., Knopf, E., Danovitch, G. M. ibid. 1972, i, 564. 3 Thurston, H., Gilmore, G. R., Swales, J. D. ibid. p. 881. 4. Goldsnuth, R. S., Arnaud, C. D., Johnson, W. J. Kidney int. 1975, 7, suppl.
Berlyne,
chronic dialysis hydroxide. The unanimity
on
maintained for years
on
aluminium
with which groups observed aluminium retention created some unease, but this did not greatly limit clinical practice: nephrologists felt that the abundance of aluminium in man’s natural environment made toxicity unlikely. Now this complacency has been challenged. Over the past four years there have been reports of a relentlessly progressive form of dementia in chronic-dialysis patients. This disorder is characterised
by speech disturbance, dyspraxia, tremor, psychosis, personality changes, and psychosis, and it results in death within 6-7 months.9 In certain units it has attained a terrifying frequency. Amongst one group of patients at Denver, it was the most common cause of mortality, accounting for the death of 7 out of 28 patients maintained for more than three years on dialysis.’" At first, retention of tin by brain tissue was suspected, but now the accusing finger has been pointed firmly at aluminium.10 A study from Denver reports a substantial increase in the aluminium content of the grey matter of patients who died of this disorder compared with those dying of other causes. All dialysis patients had received aluminium hydroxide containing 2 g of elemental aluminium for the period of dialysis treatment and the aluminium content of the grey matter was correlated with the duration of dialysis. Again, it was possible to demonstrate retention of aluminium by other tissues. It seems possible, therefore, that aluminium is a potential toxin that has now found a toxic syndrome. At the moment the evidence is only suggestive. Many centres use aluminium hydroxide and progressive dementia is not the widespread problem that might be expected. In the Denver study, the duration of dialysis (which was substantially greater in the demented patients) may have been correlated independently with tissue aluminium and with the development of dementia, giving rise to a spurious correlation between the two. Alternatively, aluminium may have a predilection for damaged brain tissue. Raised brain-aluminium concentrations have also, for instance, been detected in Alzheimer’s disease."Nevertheless, the work requires urgent attention. It should not be difficult for dialysis units with different policies for controlling hyperphosphataemia to pool their experience, and perhaps their necropsy material, for analysis. Meanwhile, it would be premature for units without experience of this form of dementia to abandon aluminium hydroxide. This is another warning sign that, as experience with long-term dialysis grows, so the full range of pathological sequelae of this highly artificial means of maintaining life becomes apparent. The outlook for patients who are currently well is not quite as rosy as earlier experience suggested. Besides the well-aired problems of metabolic bone disease5 it is increasingly clear that the dialysis patient stands a much greater risk of death from cardiovascular accidents than the normal subject of the same age.12 Life is undoubtedly prolonged; but as experience grows we can expect a new range of medical problems of which dialysis dementia is only one.
1, p S-118.
5 Slatopolsky, E. ibid. p. S-253. 6
Parsons, V., Davies, C. G., Goode, C., Ogg, C., Siddiqui, J. Br. med. J. 1971, iv, 273. 7 Clarkson, E. M., Luck, V. A., Hynson, W. V., Bailey, R. R., Eastwood, J. B., Woodhead, J. S., Clements, V. R., O’Riordan, J. L. H., de Wardener, H E. Clin.Sci. 1972, 43, 519. 8 Dent, C. E., Harper, C.M., Philpot, G. R. Q. Jl Med., 1969, 280, 240.
A. C., Mishell, J. M., Burke, J. Trans. Am. Soc. artif. int. Organs, 1972, 18, 257. 10. Alfrey, A. C., LeGendre, G. R., Kaehny, W. D. New Engl. J. Med. 1976, 294, 184. 11. Crapper, D. R., Krishnan, S. S., Dalton, A. J. Science, 1973, 180, 511. 12. Lazarus, J. M., Lowrie, E. G., Hampers, C. L., Merril, J. P. Kidney int. 1975, 7, suppl. 1., p. S-167. 9.
Alfrey,
