534
The serum-iron level may fall sharply since in infections and inflammatory conditions iron is no longer released from the reticuloendothelial system. Transferrin synthesis in the liver may be depressed, causing the serum total iron-binding capacity to fall slowly over a period of weeks, and this should be diagnostically helpful as it contrasts with the raised transferrin level of uncomplicated iron deficiency, but there is often difficulty in its interpretation. Serum-ferritin is more reliable: a subnormal concentration correlates well with lack of iron in the bone-marrow .10 However, the serum-ferritin may be raised in acute or chronic liver disease," and occasionally in infections and malignant conditions.6 It is also increased if there is haemolysis leading to increased red-blood-cell turnover.2 Where doubt remains, the most reliable test of iron deficiency is still to stain a bone-marrow aspirate with prussian blue.
stantially different from the other or that, if it is, the possible side-effects might cancel out any benefits. But he may be sincerely mistaken, so that if he refuses to do a trial on these grounds his ethical behaviour-ethical, as he sees it-may not be in the best interests of the patient. The unreliability of doctors’ impressions is a powerful argument for the value of controlled trials. Secondly, a placebo should be used only if there is a good chance of a placebo response or a spontaneous remission, or if the active drug has important sideeffects. Thirdly, mutual trust between doctor and patient is maintained by a trial being double-blind. Both are in the same boat of ignorance and this, like informed consent, brings otherwise inherently unequal parties into a joint adventure or partner-
ship.3
of avoiding deception lies in the exact of the wording explanation given to the patient. This is well illustrated by a "placebo controlled double blind cross-over investigation of the side effects attributed to oral contraceptives" reported Controlled Trials: Planned in 1971.4 The women who had come expressly for Deception? contraception were advised that since the pill had not been proven to be completely reliable they IN the old days, placebos were a normal part of should use vaginal cream as well. Six pregnancies treatment for many self-limiting diseases. There in the group receiving dummy pills. This occurred were too few reliable drugs to satisfy the patients’ seems a clear case of inadequate explanation, if not demand for medicine. (A placebo has been defined deception; but most situations are not so clearcut. as "any therapy or component of therapy that is Undoubtedly consent should be sought for any deliberately or knowingly used for its non-specific drug trial, and where two active drugs are to be psychologic or psycho-physiologic effect".’) Then compared, the details should be explained. With the pharmaceutical industry burst into activity, placebo, the patient may be told that one drug is and it became accepted that the plethora of new active and the other a dummy or inactive, but, as drugs should be tested against placebos or wellwe have seen, this is not strictly true if a placebo tried remedies. So double-blind, randomised contrial is justified at all. Alternatively the investigator trolled trials have become the hallmark of theramay say that one tablet has a specific effect on the peutic respectability. But not everyone is happy illness and the other a general effect, or that two about them. tablets are being compared one of which contains The first main objection to controlled trials, and a new drug. Whatever formula is used, working out placebo trials in particular, is that the patient is the exact wording highlights the ethical issues and being deceived. SIMMONS2 weighs the benefits of this wording should be available to the institution’s placebo trials against "all the ethical costs of decepethical review committee. Particular problems tion and dishonesty" if the patient is not aware occur in psychiatry where full explanation may be that a placebo is being used. "Deception", she difficult; these are well discussed by PRYCE.5 writes, "is ethically degrading to both parties not The second main accusation against controlled only being a breach of trust, but denying the moral trials is that one group of patients will receive inautonomy of the patient or subject to make his own ferior treatment. A recent article from Germany6 choice". In drug trials the patient knows that the treatments are "experimental", but some investigaquotes FINCKE’s discussion of a hypothetical trial of a new anti-cancer drug. FINCKE concludes that, tors believe that to tell the patient that one of the if uncontrolled studies suggested that the drug was tablets is a dummy will either annul the placebo effect or put him off taking part in the trial. How highly effective, and more patients died in the control group, the doctors would be guilty of mancan a controlled trial be conducted without deceivthe the doctor must be conpatient? Firstly, ing vinced in his own mind that one drug is not sub3. Ramsay, P. The Patient As a Person; p.1 New Haven, 1970. 11. Prieto, J., Barry, M., Sherlock, S. Gastroenterology, 1975, 68, 525. 1. Shapiro, A. K. quoted by Bok, S. Scient. Am. 1974, 231, no. 5, p. 2. Simmons,B.J. med. Ethics, 1978, 4, 172.
17.
The
crux
4. Goldzieher, J. W., et al. Fert. Steril 1971, 22, 609. 5. Pryce, I. G. Br. JPsychiat. 1978, 132, 366 6. Burkhardt, R., Kienle, G. Lancet, 1978, ii, 1356. 7. Fincke, M. Arzneimittelprüfung: Strafbare Versuchsmethoden. Heidelberg Karlsruhe, 1977.
535
Even though the investigators may have idea at the beginning which drug is best, it may become obvious during the course of the trial. Should they stop before statistical significance has been reached? This dilemma faced those involved in the trial of clofibrate in the prevention of ischxmic heart-disease.8It became clear from "an early phase" that the mortality was higher in those taking the active drug and they seriously considered stopping the trial. The conflict is between medical judgment and statistical significance. Refined statistical methods can help to solve the problem. Sample size is important ; it is unethical to use too few or too many patients. Sequential analyses or their modification-skew plans9-allow any superiority to be detected as soon as possible. Another device is data-
slaughter.
no
dependent allocation or "play the winner".10 Rather than allocate patients equally to two treatment groups and then suddenly, at the end, transfer them all to the better group, this technique gradually increases the proportion during the trial that are recruited to the better treatment. Probably strictly randomised designs should be used sparingly, particularly in cancel," and in conditions with a high early mortality historical controls may be entirely acceptable.I2 It is obviously important that the clinicians assessing symptoms are ignorant of the results, but the monitoring, both statistical and ethical, can be done by a surveillance committee." This does not solve the ethical dilemma but transfers it from the individual to a more detached group. The Federal Republic of Germany introduced a new drug law in 1978 stating that controlled trials are no longer demanded for the acceptance and registration of new drugs.6There is no doubt that the concept of controlled trials has been given undue deference and it would be unwise to wait for the results of these before some therapeutic measures are introduced. For example, advice to cut down cigarette smoking or eat a high-residue diet has rightly been given on strong circumstantial evidence : any controlled trial, even if possible, would take twenty years. This does not mean that controlled trials should be abandoned, especially for powerful drugs with possible side-effects; but investigators should be looking more carefully at their design, statistics and ethics. There is no justification for many of the placebo trials, apart from the speed with which the statisticians can be satisfied; and there is all the difference between statistical significance and biological significance. The phys-
ician treating a patient with a painful duodenal ulcer does not really want to know that a new treatment is better than placebo. He wants to know if it is better than the best alternative treatment he can give. The surgeon treating severe postoperative pain is not concerned with placebos ; he wants to know if the new analgesic is better and safer than
morphine. INTESTINAL PSEUDO-OBSTRUCTION INTESTINAL pseudo-obstruction means symptoms and signs of intestinal obstruction without any evidence of actual lesion obstructing the bowel. Three distinct syndromes have been described2—an acute and usually transient form affecting the colon; a chronic form associated with other disease; and an idiopathic form which is also chronic and recurrent. Most surgeons sooner or later encounter a case of colonic obstruction in which operation reveals no cause. Acute pseudo-obstruction of the colon is of unknown aetiology but arises most commonly in the presence of chronic renal, respiratory, or cardiovascular disease; doubtless several different factors can be responsible.3 In those cases with chronic renal failure, metabolic disturbance probably leads to an altered milieu intérieur for the intestinal neuromuscular system. In chronic respiratory disease, laboured respiration leads to an excessive amount of air being sucked into the esophagus with subsequent intestinal distension. In addition to this, the sympathomimetic drugs given to relieve bronchospasm tend to inhibit colon The combination pf these two factors may well result in large-bowel obstruction. It is fortunate that colonic pseudo-obstruction is usually transient, for no effective treatment has yet been sug-
motility.
gested. Chronic pseudo-obstruction, affecting many parts of the intestinal tract, is often associated with other conditions. Well-recognised associations are primary muscle disorders such as scleroderma, muscular dystrophy, and amyloidosis; neurological diseases such as Hirschsprung’s disease, Chagas’ disease, and Parkinson’s disease; and the use of phenothiazines, tricyclic antidepressants, and some antiparkinsonian drugs. Many cases, however, show no such association and are properly described as idiopathic. A paper by Faulk et al.4 throws fascinating new light on the subject. They give a detailed account of two sisters with chronic pseudo-obstruction. The main symptoms were epigastric cramping pains and episodic diarrhoea. X-rays revealed megaduodenum in both cases and manometric studies showed abnormal oesophageal and duodenal motility. Specimens of duodenum showed normal ganglion cells but thinning and collagen replacement of the longitudinal muscle. Even more interesting was the sisters’ mother who, though symptomless, agreed to undergo Dudley, H. A. F., Sinclair, I. S., McLaren, I. F., McNair, T. J., Newsham, J. E. Jl. R. Coll. Surg. Edinb. 1958, 3, 206. 2. Faulk, D. L., Anuras, S., Christensen, J. Gastroenterology, 1978, 74, 922. 3. LeQuesne, L. P., Wilson, J. P. Scientific Foundations of Surgery; p. 538. 1.
8 9
10 11 12 13
Oliver, M. F., Heady, J A., Morris, J. N., et al. Br. Heart J. 1978, 40, Armitage, P.Sequential Medical Trials; p. 70. London, 1975. Armitage,P.ibid p. 91. Weinstein.M.C.New Engl.J.Med 1974, 291, 1278. McCartney, J. J Hastings Center Report, 1978, 8, no. 6, p. 5. Chalmers, T.C., Block, J. B., Lee, S. Clin.Cancer Res. 1972, 287, 75.
1069.
4.
London, 1974. Faulk, D. L., Anuras, S., Gardner, G. D., Mitros, F. A., Summers, Christensen, J. Ann. intern. Med. 1978, 89, 600.
R.
W.,
The serum-iron level may fall sharply since in infections and inflammatory conditions iron is no longer released from the reticuloendothelial system. Transferrin synthesis in the liver may be depressed, causing the serum total iron-binding capacity to fall slowly over a period of weeks, and this should be diagnostically helpful as it contrasts with the raised transferrin level of uncomplicated iron deficiency, but there is often difficulty in its interpretation. Serum-ferritin is more reliable: a subnormal concentration correlates well with lack of iron in the bone-marrow .10 However, the serum-ferritin may be raised in acute or chronic liver disease," and occasionally in infections and malignant conditions.6 It is also increased if there is haemolysis leading to increased red-blood-cell turnover.2 Where doubt remains, the most reliable test of iron deficiency is still to stain a bone-marrow aspirate with prussian blue.
stantially different from the other or that, if it is, the possible side-effects might cancel out any benefits. But he may be sincerely mistaken, so that if he refuses to do a trial on these grounds his ethical behaviour-ethical, as he sees it-may not be in the best interests of the patient. The unreliability of doctors’ impressions is a powerful argument for the value of controlled trials. Secondly, a placebo should be used only if there is a good chance of a placebo response or a spontaneous remission, or if the active drug has important sideeffects. Thirdly, mutual trust between doctor and patient is maintained by a trial being double-blind. Both are in the same boat of ignorance and this, like informed consent, brings otherwise inherently unequal parties into a joint adventure or partner-
ship.3
of avoiding deception lies in the exact of the wording explanation given to the patient. This is well illustrated by a "placebo controlled double blind cross-over investigation of the side effects attributed to oral contraceptives" reported Controlled Trials: Planned in 1971.4 The women who had come expressly for Deception? contraception were advised that since the pill had not been proven to be completely reliable they IN the old days, placebos were a normal part of should use vaginal cream as well. Six pregnancies treatment for many self-limiting diseases. There in the group receiving dummy pills. This occurred were too few reliable drugs to satisfy the patients’ seems a clear case of inadequate explanation, if not demand for medicine. (A placebo has been defined deception; but most situations are not so clearcut. as "any therapy or component of therapy that is Undoubtedly consent should be sought for any deliberately or knowingly used for its non-specific drug trial, and where two active drugs are to be psychologic or psycho-physiologic effect".’) Then compared, the details should be explained. With the pharmaceutical industry burst into activity, placebo, the patient may be told that one drug is and it became accepted that the plethora of new active and the other a dummy or inactive, but, as drugs should be tested against placebos or wellwe have seen, this is not strictly true if a placebo tried remedies. So double-blind, randomised contrial is justified at all. Alternatively the investigator trolled trials have become the hallmark of theramay say that one tablet has a specific effect on the peutic respectability. But not everyone is happy illness and the other a general effect, or that two about them. tablets are being compared one of which contains The first main objection to controlled trials, and a new drug. Whatever formula is used, working out placebo trials in particular, is that the patient is the exact wording highlights the ethical issues and being deceived. SIMMONS2 weighs the benefits of this wording should be available to the institution’s placebo trials against "all the ethical costs of decepethical review committee. Particular problems tion and dishonesty" if the patient is not aware occur in psychiatry where full explanation may be that a placebo is being used. "Deception", she difficult; these are well discussed by PRYCE.5 writes, "is ethically degrading to both parties not The second main accusation against controlled only being a breach of trust, but denying the moral trials is that one group of patients will receive inautonomy of the patient or subject to make his own ferior treatment. A recent article from Germany6 choice". In drug trials the patient knows that the treatments are "experimental", but some investigaquotes FINCKE’s discussion of a hypothetical trial of a new anti-cancer drug. FINCKE concludes that, tors believe that to tell the patient that one of the if uncontrolled studies suggested that the drug was tablets is a dummy will either annul the placebo effect or put him off taking part in the trial. How highly effective, and more patients died in the control group, the doctors would be guilty of mancan a controlled trial be conducted without deceivthe the doctor must be conpatient? Firstly, ing vinced in his own mind that one drug is not sub3. Ramsay, P. The Patient As a Person; p.1 New Haven, 1970. 11. Prieto, J., Barry, M., Sherlock, S. Gastroenterology, 1975, 68, 525. 1. Shapiro, A. K. quoted by Bok, S. Scient. Am. 1974, 231, no. 5, p. 2. Simmons,B.J. med. Ethics, 1978, 4, 172.
17.
The
crux
4. Goldzieher, J. W., et al. Fert. Steril 1971, 22, 609. 5. Pryce, I. G. Br. JPsychiat. 1978, 132, 366 6. Burkhardt, R., Kienle, G. Lancet, 1978, ii, 1356. 7. Fincke, M. Arzneimittelprüfung: Strafbare Versuchsmethoden. Heidelberg Karlsruhe, 1977.
535
Even though the investigators may have idea at the beginning which drug is best, it may become obvious during the course of the trial. Should they stop before statistical significance has been reached? This dilemma faced those involved in the trial of clofibrate in the prevention of ischxmic heart-disease.8It became clear from "an early phase" that the mortality was higher in those taking the active drug and they seriously considered stopping the trial. The conflict is between medical judgment and statistical significance. Refined statistical methods can help to solve the problem. Sample size is important ; it is unethical to use too few or too many patients. Sequential analyses or their modification-skew plans9-allow any superiority to be detected as soon as possible. Another device is data-
slaughter.
no
dependent allocation or "play the winner".10 Rather than allocate patients equally to two treatment groups and then suddenly, at the end, transfer them all to the better group, this technique gradually increases the proportion during the trial that are recruited to the better treatment. Probably strictly randomised designs should be used sparingly, particularly in cancel," and in conditions with a high early mortality historical controls may be entirely acceptable.I2 It is obviously important that the clinicians assessing symptoms are ignorant of the results, but the monitoring, both statistical and ethical, can be done by a surveillance committee." This does not solve the ethical dilemma but transfers it from the individual to a more detached group. The Federal Republic of Germany introduced a new drug law in 1978 stating that controlled trials are no longer demanded for the acceptance and registration of new drugs.6There is no doubt that the concept of controlled trials has been given undue deference and it would be unwise to wait for the results of these before some therapeutic measures are introduced. For example, advice to cut down cigarette smoking or eat a high-residue diet has rightly been given on strong circumstantial evidence : any controlled trial, even if possible, would take twenty years. This does not mean that controlled trials should be abandoned, especially for powerful drugs with possible side-effects; but investigators should be looking more carefully at their design, statistics and ethics. There is no justification for many of the placebo trials, apart from the speed with which the statisticians can be satisfied; and there is all the difference between statistical significance and biological significance. The phys-
ician treating a patient with a painful duodenal ulcer does not really want to know that a new treatment is better than placebo. He wants to know if it is better than the best alternative treatment he can give. The surgeon treating severe postoperative pain is not concerned with placebos ; he wants to know if the new analgesic is better and safer than
morphine. INTESTINAL PSEUDO-OBSTRUCTION INTESTINAL pseudo-obstruction means symptoms and signs of intestinal obstruction without any evidence of actual lesion obstructing the bowel. Three distinct syndromes have been described2—an acute and usually transient form affecting the colon; a chronic form associated with other disease; and an idiopathic form which is also chronic and recurrent. Most surgeons sooner or later encounter a case of colonic obstruction in which operation reveals no cause. Acute pseudo-obstruction of the colon is of unknown aetiology but arises most commonly in the presence of chronic renal, respiratory, or cardiovascular disease; doubtless several different factors can be responsible.3 In those cases with chronic renal failure, metabolic disturbance probably leads to an altered milieu intérieur for the intestinal neuromuscular system. In chronic respiratory disease, laboured respiration leads to an excessive amount of air being sucked into the esophagus with subsequent intestinal distension. In addition to this, the sympathomimetic drugs given to relieve bronchospasm tend to inhibit colon The combination pf these two factors may well result in large-bowel obstruction. It is fortunate that colonic pseudo-obstruction is usually transient, for no effective treatment has yet been sug-
motility.
gested. Chronic pseudo-obstruction, affecting many parts of the intestinal tract, is often associated with other conditions. Well-recognised associations are primary muscle disorders such as scleroderma, muscular dystrophy, and amyloidosis; neurological diseases such as Hirschsprung’s disease, Chagas’ disease, and Parkinson’s disease; and the use of phenothiazines, tricyclic antidepressants, and some antiparkinsonian drugs. Many cases, however, show no such association and are properly described as idiopathic. A paper by Faulk et al.4 throws fascinating new light on the subject. They give a detailed account of two sisters with chronic pseudo-obstruction. The main symptoms were epigastric cramping pains and episodic diarrhoea. X-rays revealed megaduodenum in both cases and manometric studies showed abnormal oesophageal and duodenal motility. Specimens of duodenum showed normal ganglion cells but thinning and collagen replacement of the longitudinal muscle. Even more interesting was the sisters’ mother who, though symptomless, agreed to undergo Dudley, H. A. F., Sinclair, I. S., McLaren, I. F., McNair, T. J., Newsham, J. E. Jl. R. Coll. Surg. Edinb. 1958, 3, 206. 2. Faulk, D. L., Anuras, S., Christensen, J. Gastroenterology, 1978, 74, 922. 3. LeQuesne, L. P., Wilson, J. P. Scientific Foundations of Surgery; p. 538. 1.
8 9
10 11 12 13
Oliver, M. F., Heady, J A., Morris, J. N., et al. Br. Heart J. 1978, 40, Armitage, P.Sequential Medical Trials; p. 70. London, 1975. Armitage,P.ibid p. 91. Weinstein.M.C.New Engl.J.Med 1974, 291, 1278. McCartney, J. J Hastings Center Report, 1978, 8, no. 6, p. 5. Chalmers, T.C., Block, J. B., Lee, S. Clin.Cancer Res. 1972, 287, 75.
1069.
4.
London, 1974. Faulk, D. L., Anuras, S., Gardner, G. D., Mitros, F. A., Summers, Christensen, J. Ann. intern. Med. 1978, 89, 600.
R.
W.,
