267
Measurement of serum levels is not a substitute for good clinical assessment. Of equal value to
monitoring
serum
is
levels, and considerably less
good clinical record of the patient’s expensive, fits, preferably plotted as a chart from which the relationship between fit frequency and drug administration can be seen at a glance. If this is done, the ineffectiveness of drug treatment received by many patients becomes immediately obvious. Here is a strong argument for the epilepsy clinic, where a multidisciplinary team skilled in the management of a
this difficult disorder can make the fullest drug measurement and clinical assessment.
use
of
SERUM BILE-ACIDS AS A TEST OF LIVER FUNCTION As long ago as 1948 it was known that the total serum bile-acids were increased in hepatobiliary disease,1 and the observation has often been confirmed.2-5 The many technical problems encountered in measuring serum bile-acids prevented the estimation being introduced widely as a clinical test of liver function. Gas-liquid chromatography 6 and an enzymatic assay using hydroxysteroid dehydrogenaseenabled the bile-acids to be measured in
of laboratories, but the methodology remains complex for routine hospital biochemistry laboratories. The introduction in 1973 of a radioimmunoassay for conjugated cholyl bile-acids was an imaginative marriage of the well-established technology of radioimmunoassay with the rapidly expanding sphere of human bile-acid metabolism.At once there was the potential for rapid simple measurement of serum bileacids in health and disease. The radioimmunoassay system uses an antiserum to cholylglycine which is coupled by an amide linkage to bovine serum albumin. The antibody binds to the trihydroxy bile-salts, glycocholate and taurocholate, but has a low affinity for dihydroxy bile-acids and unconjugated bile-acids. Now the Mayo Clinic group have introduced the radioimmunoassay method as a clinical test of liver function, and the preliminary results are distinctly encouraging.9 In 38 patients with active chronic hepatitis, fasting serum bile-acids (measured as the conjugates of cholic acid) proved to be a more sensitive indication of disease activity than the conventional tests of liver function-serum bilirubin, proteins, alkaline phosphatase, transaminase, prothrombin-time, and bromsulphthalein retention. A rise in serum bile-acid levels preceded changes in transaminase activity in those patients who relapsed.
a number
too
1. 2.
3. 4. 5.
Sherlock, S., Walshe, V. Clin. Sci. 1948, 6, 223. Carey, J. B., Jr., Figen, J., Watson, C. J. J. Lab. clin. Med. 1955, 46, 802. Rudman, D., Kendall, F. E. J. clin. Invest. 1967, 36, 530. Makino, I., Nakagawana, S., Mashimo, K. Gastroenterology, 1969, 56, 1033. Neale, G., Lewis, B., Weaver, V., Panveliwalla, D. Gut, 1971, 12, 145.
Sandberg, D. H., Sjovall, J., Sjovall, K., Turner, D. A. J. Lipid Res. 1965, 6, 182. 7. Murphy, G. M. Ann. clin. Biochem. 1972, 9, 67. 8. Simmonds, W. J., Korman, M. G., Go, V. L. W., Hofmann, A. F. Gastroenterology, 1973, 65, 705. 9. Korman, M. G., Hofmann, A. F., Summerskill, W. H. J. New Engl. J. Med. 1974, 290, 1399.
Of greater significance was the suggestion that the serum bile-acids might be raised before any histological changes were evident. Serum bile-acids discriminate even better between normal and abnormal if the measurement is underThis might be taken as a bile-acid tolerance test. achieved by estimating the bile-acids after a meal, which is equivalent to performing an endogenous tolerance test, 10 or by giving bile-acids intravenously.11 In the latter test an intravenous dose of 5 µmo1/kg cholylglycine was shown to be cleared within 10 minutes by the normal liver, whereas clearance was delayed if the liver was diseased. In such patients the tolerance test was found to be more sensitive than either the conventional liver-function tests or the fasting bile-acid level. 12 Thus the bile-acid tolerance test, too, is of considerable interest to clinicians, though it needs further evaluation before it will be widely accepted. More experience is needed with the radioimmunoassay of bile-acids: the test is rapid, depending upon conventional competitive binding techniques, but how readily and reliably the antibody can be raised remains to be seen. Intravenous injection of a small quantity of bile-acid is apparently safe, but it is not without effect. Careful technique is essential, since the injection can cause local pain, and there is a small amount of haemolysis. The test is, of course, of no value in the icteric patient and, like most biochemical tests of liver function, it gives no reliable indication of the underlying disease process. It is essentially a screening test for liver function. Because of its simplicity and serum bile-acid estimation, either as a sensitivity, or as a value tolerance test, has considerable fasting for the routine method for monitorpotential becoming but it liver is function; ing unlikely to replace liver biopsy as the definitive method for diagnosing the presence and nature of liver disease.
A NEW APPROACH TO COLLES’ FRACTURES
ALTHOUGH Colles’ fractures are probably the most common seen in the accident department of any hospital, the results of treatment are by no means uniformly good. Very often with comminuted fractures the radiographs taken at the end of the period of immobilisation in plaster differ little from the original films showing the unreduced fracture, despite good initial reduction. This is not so surprising when one remembers that the fracture occurs in cancellous bone; if the bone is fragmented at the time of injury it may collapse during the process of healing. Perkins 13 wrote that " a patient should always be warned that a Colles’ fracture however skilfully treated may leave behind a deformed wrist". Golden 14 concluded after careful follow-up of 210 patients that no method has so far been found to overcome the instability of Colles’ fractures. He noted, however, that there was a close 10.
6.
Kaplowitz, N., Kok,
M.
S., Javitt, N. B. J. Am. med. Ass. 1973, 225,
292.
Korman, M. G., La Russo, N. F., Hoffman, N. E., Hofmann, A. F. New Engl. J. Med. 1975, 292, 1205. 12. La Russo, N. F., Hoffman, N. E., Hofmann, A. F., Korman, M. G. ibid. p. 1209. 13. Perkins, G. Fractures and Dislocations. London, 1958. 14. Golden, G. N. Lancet, 1963, i, 511.
11.
268 Forum1 reviews the ways in which doctors learn about drugs. Because progress is so rapid, drug therapy is clearly a particularly important subject for continuing educationbut, according to the report, the attention it receives in journals and at postgraduate centres is disproportionately low.
correlation between the maintenance of satisfactory reduction and a good ultimate result. Another longterm investigation 15 showed that most patients regained painless useful movement in time and that assessments of function under one year could be mis-
leading. A method of preventing the seemingly inevitable collapse at the fracture site in the comminuted Colles’ fracture and many of its sequelse has been described by Sarmiento and his co-workers at the University of Miami School of Medicine. 16 Sarmiento has shown that the pull of the brachioradialis muscle is a major factor in the typical deformity after Colles’ fracture. 17 This muscle is the only one attached to the distal fragment of the radius and acts as a deforming force when the wrist is in a position of pronation, as is the case with the conventional method of immobilisation in plaster. In order effectively to eliminate the pull of brachioradialis a method has been designed to hold the wrist in supination while allowing freedom of palmar flexion and dorsiflexion. The fractures are initially reduced and splinted in an above-elbow plaster cast with the elbow flexed to 90°, the forearm in supination, and the wrist in ulnar deviation and slight palmar flexion. A week later the cast is removed and replaced by a special’Orthoplast ’ splint which limits pronation and supination and does not allow full extension of the elbow. The wrist portion is hinged to allow for dorsiflexion and palmar flexion. The effectiveness of this type of functional treatment has already been proved by Sarmiento et al. in dealing with fractures of the femoral and tibial shafts.18, 19
Not all new drugs represent important advances, but it is not easy for the practising clinician to discriminate between them. He must rely heavily on personal advice and on published reports, which are often scattered among journals that he may not see. It seems incongruous that, for months after a new drug is marketed, almost all the information reaching the doctor should come from the manufacturer and next to nothing from disinterested sources. One of the most important recommendations in the report is that doctors should be provided with early impartial appraisals of new products in relation to the alternatives available. These should be updated at intervals to form a readily accessible and reliable source of reference. Of course it may be two years or more before a final evaluation can be made, but it would surely be better if independent experts were to make a preliminary assessment of what information there is. More difficult to implement in the existing economic climate is the recommendation that district hospitals should appoint physicians with a special interest in clinical pharmacology and therapeutics. An outline job specification has been drawn up,3 but the process could usefully be taken further. The crucial test will be whether the first appointees convincingly demonstrate their value. If they do, a new career structure in clinical pharmacology will be created and the present impasse may be resolved, with great benefit to the development of the discipline.
The results of this new method of treating Colles’ fractures are impressive. Whereas in a carefully documented survey by Gartland and Werley 2081 % of patients with intra-articular fractures had residual dorsal tilt, 61 % of the Miami patients healed in either anatomical position or slight deformity. Gartland and Werley graded 68-3% of their results as satisfactory (i.e., excellent or good) as against the 82% of Sarmiento et al. This new technique seems to be an advance in a previously stationary area of fracture treatment. It is attractive because it produces good function at an early stage. It should avoid the sometimes protracted struggle by patients to overcome the stiffness and swelling of their deformed wrists and so lighten the burden on physiotherapy departments.
HYPOTENSIVE ANÆSTHESIA
Furthermore,
HOW DO DOCTORS LEARN ABOUT DRUGS? AT least two-thirds of doctors now practising in the U.K. were never taught the basic principles of clinical pharmacology, so that many are ill-equipped to use medicinal therapy to full advantage: there is enormous scope for suboptimal prescribing, through inappropriate choice or use of drugs. Efforts to improve the general standard of prescribing might result in great public benefit and possibly a net saving on the national drug bill. A recent report from the Medico-Pharmaceutical ‘
15. 16. 17. 18. 19. 20.
Casselbaum, W. H. J. Am. med. Ass. 1950, 143, 963. Sarmiento, A., Pratt, G. W., Berry, N. C., Sinclair, W. F. J. Bone Jt Surg. 1975, 57A, 311. Sarmiento, A. Clin. Orthop. 1965, 38, 86. Sarmiento, A. J. Bone Jt Surg. 1970, 52A, 295. Sarmiento, A. Clin. Orthop. 1972, 82, 2. Gartland, J. J., Werley, C. W. J. Bone Jt Surg. 1951, 33A, 895.
SUCCESSFUL management of deliberate hypotension during anaesthesia-to produce a relatively bloodless operative field-requires considerable anaesthetic skill and is not without danger to the patient. Though the clinical aspects of hypotensive anaesthesia have been developed over about 25 years, little is generally known about the fundamental physiological and biochemical changes in the patient whose circulation has been reduced to a critical level. The boundaries of existing knowledge of these changes were defined at a symposium just published.4. Cerebral ischaemia is the principal hazard of hypotensive anaesthesia and we are reminded that general underperfusion of the brain will particularly affect certain border-zones between the distribution territories of the major cerebral arteries, with the result that unexpected focal defects may occur in the brain. Reduced oxygen supply to the brain as a whole can cause progressive biochemical changes that include Party on the Continuing Education of Therapeutics. Medico-Pharmaceutical Wimpole Street, London W1M 8AE. 50p plus
1. Report of the Working Doctors in Medicinal
Forum,
1
postage 5p per copy. 2. See Lancet, 1974, i, 1027. 3. Report of the Clinical Pharmacology of Physicians, London, 1975. 4. Br. J. Anœsth. 1975, 47, 743.
Committee, Royal College
Measurement of serum levels is not a substitute for good clinical assessment. Of equal value to
monitoring
serum
is
levels, and considerably less
good clinical record of the patient’s expensive, fits, preferably plotted as a chart from which the relationship between fit frequency and drug administration can be seen at a glance. If this is done, the ineffectiveness of drug treatment received by many patients becomes immediately obvious. Here is a strong argument for the epilepsy clinic, where a multidisciplinary team skilled in the management of a
this difficult disorder can make the fullest drug measurement and clinical assessment.
use
of
SERUM BILE-ACIDS AS A TEST OF LIVER FUNCTION As long ago as 1948 it was known that the total serum bile-acids were increased in hepatobiliary disease,1 and the observation has often been confirmed.2-5 The many technical problems encountered in measuring serum bile-acids prevented the estimation being introduced widely as a clinical test of liver function. Gas-liquid chromatography 6 and an enzymatic assay using hydroxysteroid dehydrogenaseenabled the bile-acids to be measured in
of laboratories, but the methodology remains complex for routine hospital biochemistry laboratories. The introduction in 1973 of a radioimmunoassay for conjugated cholyl bile-acids was an imaginative marriage of the well-established technology of radioimmunoassay with the rapidly expanding sphere of human bile-acid metabolism.At once there was the potential for rapid simple measurement of serum bileacids in health and disease. The radioimmunoassay system uses an antiserum to cholylglycine which is coupled by an amide linkage to bovine serum albumin. The antibody binds to the trihydroxy bile-salts, glycocholate and taurocholate, but has a low affinity for dihydroxy bile-acids and unconjugated bile-acids. Now the Mayo Clinic group have introduced the radioimmunoassay method as a clinical test of liver function, and the preliminary results are distinctly encouraging.9 In 38 patients with active chronic hepatitis, fasting serum bile-acids (measured as the conjugates of cholic acid) proved to be a more sensitive indication of disease activity than the conventional tests of liver function-serum bilirubin, proteins, alkaline phosphatase, transaminase, prothrombin-time, and bromsulphthalein retention. A rise in serum bile-acid levels preceded changes in transaminase activity in those patients who relapsed.
a number
too
1. 2.
3. 4. 5.
Sherlock, S., Walshe, V. Clin. Sci. 1948, 6, 223. Carey, J. B., Jr., Figen, J., Watson, C. J. J. Lab. clin. Med. 1955, 46, 802. Rudman, D., Kendall, F. E. J. clin. Invest. 1967, 36, 530. Makino, I., Nakagawana, S., Mashimo, K. Gastroenterology, 1969, 56, 1033. Neale, G., Lewis, B., Weaver, V., Panveliwalla, D. Gut, 1971, 12, 145.
Sandberg, D. H., Sjovall, J., Sjovall, K., Turner, D. A. J. Lipid Res. 1965, 6, 182. 7. Murphy, G. M. Ann. clin. Biochem. 1972, 9, 67. 8. Simmonds, W. J., Korman, M. G., Go, V. L. W., Hofmann, A. F. Gastroenterology, 1973, 65, 705. 9. Korman, M. G., Hofmann, A. F., Summerskill, W. H. J. New Engl. J. Med. 1974, 290, 1399.
Of greater significance was the suggestion that the serum bile-acids might be raised before any histological changes were evident. Serum bile-acids discriminate even better between normal and abnormal if the measurement is underThis might be taken as a bile-acid tolerance test. achieved by estimating the bile-acids after a meal, which is equivalent to performing an endogenous tolerance test, 10 or by giving bile-acids intravenously.11 In the latter test an intravenous dose of 5 µmo1/kg cholylglycine was shown to be cleared within 10 minutes by the normal liver, whereas clearance was delayed if the liver was diseased. In such patients the tolerance test was found to be more sensitive than either the conventional liver-function tests or the fasting bile-acid level. 12 Thus the bile-acid tolerance test, too, is of considerable interest to clinicians, though it needs further evaluation before it will be widely accepted. More experience is needed with the radioimmunoassay of bile-acids: the test is rapid, depending upon conventional competitive binding techniques, but how readily and reliably the antibody can be raised remains to be seen. Intravenous injection of a small quantity of bile-acid is apparently safe, but it is not without effect. Careful technique is essential, since the injection can cause local pain, and there is a small amount of haemolysis. The test is, of course, of no value in the icteric patient and, like most biochemical tests of liver function, it gives no reliable indication of the underlying disease process. It is essentially a screening test for liver function. Because of its simplicity and serum bile-acid estimation, either as a sensitivity, or as a value tolerance test, has considerable fasting for the routine method for monitorpotential becoming but it liver is function; ing unlikely to replace liver biopsy as the definitive method for diagnosing the presence and nature of liver disease.
A NEW APPROACH TO COLLES’ FRACTURES
ALTHOUGH Colles’ fractures are probably the most common seen in the accident department of any hospital, the results of treatment are by no means uniformly good. Very often with comminuted fractures the radiographs taken at the end of the period of immobilisation in plaster differ little from the original films showing the unreduced fracture, despite good initial reduction. This is not so surprising when one remembers that the fracture occurs in cancellous bone; if the bone is fragmented at the time of injury it may collapse during the process of healing. Perkins 13 wrote that " a patient should always be warned that a Colles’ fracture however skilfully treated may leave behind a deformed wrist". Golden 14 concluded after careful follow-up of 210 patients that no method has so far been found to overcome the instability of Colles’ fractures. He noted, however, that there was a close 10.
6.
Kaplowitz, N., Kok,
M.
S., Javitt, N. B. J. Am. med. Ass. 1973, 225,
292.
Korman, M. G., La Russo, N. F., Hoffman, N. E., Hofmann, A. F. New Engl. J. Med. 1975, 292, 1205. 12. La Russo, N. F., Hoffman, N. E., Hofmann, A. F., Korman, M. G. ibid. p. 1209. 13. Perkins, G. Fractures and Dislocations. London, 1958. 14. Golden, G. N. Lancet, 1963, i, 511.
11.
268 Forum1 reviews the ways in which doctors learn about drugs. Because progress is so rapid, drug therapy is clearly a particularly important subject for continuing educationbut, according to the report, the attention it receives in journals and at postgraduate centres is disproportionately low.
correlation between the maintenance of satisfactory reduction and a good ultimate result. Another longterm investigation 15 showed that most patients regained painless useful movement in time and that assessments of function under one year could be mis-
leading. A method of preventing the seemingly inevitable collapse at the fracture site in the comminuted Colles’ fracture and many of its sequelse has been described by Sarmiento and his co-workers at the University of Miami School of Medicine. 16 Sarmiento has shown that the pull of the brachioradialis muscle is a major factor in the typical deformity after Colles’ fracture. 17 This muscle is the only one attached to the distal fragment of the radius and acts as a deforming force when the wrist is in a position of pronation, as is the case with the conventional method of immobilisation in plaster. In order effectively to eliminate the pull of brachioradialis a method has been designed to hold the wrist in supination while allowing freedom of palmar flexion and dorsiflexion. The fractures are initially reduced and splinted in an above-elbow plaster cast with the elbow flexed to 90°, the forearm in supination, and the wrist in ulnar deviation and slight palmar flexion. A week later the cast is removed and replaced by a special’Orthoplast ’ splint which limits pronation and supination and does not allow full extension of the elbow. The wrist portion is hinged to allow for dorsiflexion and palmar flexion. The effectiveness of this type of functional treatment has already been proved by Sarmiento et al. in dealing with fractures of the femoral and tibial shafts.18, 19
Not all new drugs represent important advances, but it is not easy for the practising clinician to discriminate between them. He must rely heavily on personal advice and on published reports, which are often scattered among journals that he may not see. It seems incongruous that, for months after a new drug is marketed, almost all the information reaching the doctor should come from the manufacturer and next to nothing from disinterested sources. One of the most important recommendations in the report is that doctors should be provided with early impartial appraisals of new products in relation to the alternatives available. These should be updated at intervals to form a readily accessible and reliable source of reference. Of course it may be two years or more before a final evaluation can be made, but it would surely be better if independent experts were to make a preliminary assessment of what information there is. More difficult to implement in the existing economic climate is the recommendation that district hospitals should appoint physicians with a special interest in clinical pharmacology and therapeutics. An outline job specification has been drawn up,3 but the process could usefully be taken further. The crucial test will be whether the first appointees convincingly demonstrate their value. If they do, a new career structure in clinical pharmacology will be created and the present impasse may be resolved, with great benefit to the development of the discipline.
The results of this new method of treating Colles’ fractures are impressive. Whereas in a carefully documented survey by Gartland and Werley 2081 % of patients with intra-articular fractures had residual dorsal tilt, 61 % of the Miami patients healed in either anatomical position or slight deformity. Gartland and Werley graded 68-3% of their results as satisfactory (i.e., excellent or good) as against the 82% of Sarmiento et al. This new technique seems to be an advance in a previously stationary area of fracture treatment. It is attractive because it produces good function at an early stage. It should avoid the sometimes protracted struggle by patients to overcome the stiffness and swelling of their deformed wrists and so lighten the burden on physiotherapy departments.
HYPOTENSIVE ANÆSTHESIA
Furthermore,
HOW DO DOCTORS LEARN ABOUT DRUGS? AT least two-thirds of doctors now practising in the U.K. were never taught the basic principles of clinical pharmacology, so that many are ill-equipped to use medicinal therapy to full advantage: there is enormous scope for suboptimal prescribing, through inappropriate choice or use of drugs. Efforts to improve the general standard of prescribing might result in great public benefit and possibly a net saving on the national drug bill. A recent report from the Medico-Pharmaceutical ‘
15. 16. 17. 18. 19. 20.
Casselbaum, W. H. J. Am. med. Ass. 1950, 143, 963. Sarmiento, A., Pratt, G. W., Berry, N. C., Sinclair, W. F. J. Bone Jt Surg. 1975, 57A, 311. Sarmiento, A. Clin. Orthop. 1965, 38, 86. Sarmiento, A. J. Bone Jt Surg. 1970, 52A, 295. Sarmiento, A. Clin. Orthop. 1972, 82, 2. Gartland, J. J., Werley, C. W. J. Bone Jt Surg. 1951, 33A, 895.
SUCCESSFUL management of deliberate hypotension during anaesthesia-to produce a relatively bloodless operative field-requires considerable anaesthetic skill and is not without danger to the patient. Though the clinical aspects of hypotensive anaesthesia have been developed over about 25 years, little is generally known about the fundamental physiological and biochemical changes in the patient whose circulation has been reduced to a critical level. The boundaries of existing knowledge of these changes were defined at a symposium just published.4. Cerebral ischaemia is the principal hazard of hypotensive anaesthesia and we are reminded that general underperfusion of the brain will particularly affect certain border-zones between the distribution territories of the major cerebral arteries, with the result that unexpected focal defects may occur in the brain. Reduced oxygen supply to the brain as a whole can cause progressive biochemical changes that include Party on the Continuing Education of Therapeutics. Medico-Pharmaceutical Wimpole Street, London W1M 8AE. 50p plus
1. Report of the Working Doctors in Medicinal
Forum,
1
postage 5p per copy. 2. See Lancet, 1974, i, 1027. 3. Report of the Clinical Pharmacology of Physicians, London, 1975. 4. Br. J. Anœsth. 1975, 47, 743.
Committee, Royal College
