- Email: [email protected]
COMPUTERS IN INTENSIVE CARE
1081
detailed examination of antifibrinolytic agents in this extremely hazardous clinical situation. For the purposes of this trial, E.A.C.A. was replaced by tranexamic acid (A.M.C.A.) (12 g. in 24 hours). Of 182 patients who were treated thus, 22 (12-1%) re-bled in the first 14 days from the original ictus, and of these 14 (7-7%) succumbed to their haemorrhage. In terms of protecting patients during this critical period, these figures are much superior to the natural history of the condition. Diarrhoea was by far the commonest complication, occurring in some degree in almost every patient. A rapidly reversible toxic confusional state was noted in 7 patients. Clinically evident thromboembolic phenoa
mena were not
observed.
Atkinson Morley’s Hospital,
DAVID UTTLEY ALAN E. RICHARDSON.
Wimbledon, London SW20.
FALSE-POSITIVES
SiR,-Dr Kohn and Mr Weaver (Aug. 10, p. 334) present a well-documented argument for alpha-fetoprotein testing in conditions known to be associated with a high risk of hepatocellular carcinoma. They tell us that " the frequency of false-positives was 1-8%. A.F.P. detection and assay correctly performed and interpreted is a valuable, sensitive, and specific serological marker of hepatocellular carcinoma". Their estimate of false-positives is, however, incorrect and misleading. The accepted method for calculating the predictive value of a laboratory test and, therefore, the false-positive rate 1-5 is, using their data, as follows:
Sensitivity 90/107 = 84 %. Specificity 2079/2118 98-2 %. Predictive value of positive test 90/129 False positives 39/129 30 %. =
=
=
=
=
70 %-
=
Sensitivity, specificity, predictive value, and efficiency define a laboratory test’s accuracy. Sensitivity indicates the frequency of positive test results in patients with a particular disease, whereas specificity indicates the frequency of negative test results in patients without that disease. The predictive value of a positive test result indicates the frequency of diseased patients in all patients with positive test results. The predictive value of a negative test result indicates the frequency of non-diseased patients in all patients with negative test results. The efficiency of a test indicates the percentage of patients correctly classified (diseased and non-diseased) by the test. False-positive results are therefore calculated as 100% -predictive value of the positive test. If a test has a predictive value (+) of 90%, then 90% of the positives are true positives and 10% are false-positives. Using Dr Kohn and Mr Weaver’s data the predictive value of a
positive A.F.P. screening test is only 70%. Therefore, 30% of patients with positive results will not have hepatocarcinoma and will therefore be false-positives ". Kohn and Weaver feel " that 1-8% false-positives is a small price to pay for a diagnostic procedure capable of detecting "
1. 2.
3. 4. 5.
Department of Pathology, College of Physicians and Surgeons of Columbia University, New York, N.Y. 10032, U.S.A.
Do they feel the
same
ROBERT S. GALEN.
COMPUTERS IN INTENSIVE CARE appears from the title of your editorial, ComNurses ? (Oct. 12, p. 877) that the problem is wrongly defined. The computer is a machine, a tool, and as such cannot be considered in isolation from the person using it. Professor Alwyn Smith, of the Department of Community Medicine in the University of Manchester, has described the computer as doing for the mind what the microscope has done for the eye, which is a good description of the relationship involved; computers do not replace nurses any more than a microscope replaces the human eye but they do add to their existing power. We have been privileged to see a number of intensivecare units outside the U.K. (N.H.S.) and the question we " always ask is what happens when you switch the system off " ? The units we have visited are usually long established (7-10 years) and the almost invariable answer to this question is that the nursing staff complain and say that they want the system switched back on again. In other words their job is made more difficult without the computer. As well as assisting the nurse in some of her routine tasks, the computer performs calculations (e.g., of cardiac output) which no one would be prepared to tackle without the aid of a machine. These can yield valuable additional information to help her take the most suitable course of action. The point about large machines and small machines raises the question of what is meant by " large "-physically large, or large in terms of computer power ? Manchester Medical School has a physically large computer, some 14 years old, that today with micro-miniaturisation could be reduced to one-eighth of its present size and do the same
SIR,-It
puters
or
job.
&mid ot;
=
approximately 85% of true cases ". about 30% false-positives ?
Vecchio, T. J. New Engl.J. Med. 1966, 274, 1171. Sunderman, F. W., Van Soestbergen, A. A. Am. J. clin. Path. 1971, 55, 105. Werner, M., Brooks, S. H., Wette, R. Hum. Path. 1973, 4, 17. Holland, W. W., Whitehead, T. P. Lancet, 1974, ii, 391. Schwartz, W. B., Gorry, G. A., Kassirer, J. P., Essig, A. Am. J. Med. 1973, 55, 459.
Modern machines cost one-tenth of the price of old machines for the same computer power. Some medical problems can be managed on modern mini-computers which have the power of some of the older machines but are very modest in price and size. In view of this it is envisaged that it will soon be possible to have all of the computer power needed in an intensivecare unit for a few thousand pounds. However, the cost of the software-the programs which " drive " the computer and allow it to perform useful tasks-has not decreased over the years, and it is not surprising that the units which have succeeded in making things work are, to some extent, those with the money. However, once a program has been designed it can be used anywhere in the world provided technical problems of compatibility between The different types of computer can be overcome. Wythenshawe experimentdemonstrated that the same set of programs could be used in the different clinical environments with very little alteration. So there is hope that once sufficient capital has been expended by the larger research units-notably in the United States and Western Europe-to develop the necessary programs, it will no longer be necessary for individual hospitals to spend vast sums of money on getting their own individual systems into
operation. Clinical medicine has continually expanded, absorbing from many branches of science; there is no
techniques reason 1.
to
believe
that
computer
technology-already
Ashcroft, J. M., Berry J. L. Proceedings of I.F.I.P. Medinfo 74 conference, Stockholm, Sweden, Aug. 5-10, 1974.
1082
yielding results the exception.
in many
areas
Medical Computing Unit, Clinical Sciences Building, York Place, Manchester M13 0JJ.
of medical research-will be
D. E. CLARK T. C. SHARPE.
CARE OF THE CRITICALLY ILL SIR,-Dr Skillman’s article (Sept. 14, p. 634) is an important contribution. However, it does not undertake the issue surrounding the physician faced with the patient wishing to withdraw from maintenance haEmodialysis. This issue was discussed at a panel on problems in adaptation to hasmodialysis at the 1972 annual meeting of the American Psychiatric Association.1 Such patients should not be approached in terms of " right to die ", which diverts the question from the psychiatric area where it may belong to a legal or moral question. Haemodialysis patients wishing to withdraw should be carefully examined for depression and suicidal tendency, since suicide is much commoner among these patients than in the general population.2 All patients undergoing haemodialysis should be monitored in an ongoing way for depression, the most common psychological complication iri these patients.33 If picked up relatively early and treated with tricyclic antidepressants and/or psychiatric consultation, suicidal behaviour, including withdrawal from medical care, may be minimised. Discussion of the issue of withdrawal from hsemodialysis before the patient starts on such a programme may be helpful.4 Such discussion may enable the patient to bring up the question of continuing treatment earlier in his care, thus helping to prevent it from festering and emerging later as a fixed decision or being acted out in unannounced suicidal behaviour. Departments of Psychiatry and Medicine, State University of New York, Downstate Medical Center, College of Medicine, Brooklyn, New York 11203, U.S.A.
to
Poisons Unit, New Cross Hospital,
Avonley Road, London SE14 5ER.
F. HARVEY R. GOULDING.
CHONDROITINSULPHATURIA WITH &agr;-L-IDURONIDASE DEFICIENCY SIR,-Dr Babarik and associatesrefer to two sisters with chondroitinsulphaturia whom we reported in 1971.2 Recently, we have re-studied these patients and found a similar deficiency of, oc-L-iduronidase activity in cultured fibroblasts as described by Babarik et. al. in their patient. The activities of other lysosomal hydrolases (p-glucuroni-
P-N-acetylhexosaminidase, a-Nacetylglucosaminidase, K-L-fucosidase, rt.-D-mannosidase, P-D-xylosidase, arylsulphatase A, and acid phosphatase) were dase, P-galactosidase,
NORMAN B. LEVY.
ACTION OF CYSTEAMINE IN PARACETAMOL POISONING SIR,-Cysteamine has been advocated5 as an effective antidote in the treatment of paracetamol poisoning. The underlying rationale was that cysteamine would act within the hepatocyte by combining with an unidentified toxic metabolite of paracetamol formed by microsomal oxidation, though the alternative possibility that it could have inhibited the formation of such metabolites was also mentioned. In the course of a comprehensive study here on drug metabolism by the use of the isolated perfused rat liver, we have investigated the biliary excretion of paracetamol and its metabolites and the effects of various sulphydryl compounds on this system. The proportions of thio-ether-containing metabolites, which comprise those formed by conjugation between the toxic metabolite and glutathione or cysteamine, have been compared with those arising by direct conjugation of paraLevy, N. B., Abram, H. S., Kempf, J. P., McKegney, F. P., Scribner, B. H. in Living or Dying: Adaptation to Hemodialysis (edited by N. B. Levy); p. 3. Springfield, Illinois, 1974. 2. Abram, H. S., Moore, G. I., Westervelt, F. B., Jr. Am. J. Psychiat. 1971, 127, 1199. 3. Levy, N. B., in Clinical Aspects of Uremia and Hemodialysis, (edited by S. G. Massry and A. L. Sellers) (in the press). 4. McKegney, F. P., Lange, P. F. Am. J. Psychiat. 1971, 128, 267. 5. Prescott, L. F., Newton, R. W., Swainson, C. P., Wright, N., Forrest, A. R. W., Matthew, H. Lancet, 1974, i, 588. 1.
yield glucuronides and sulphates. Our prestudies demonstrated that the addition of cysteliminary amine to the system resulted in a 33% reduction in thioether-conjugated excretion coupled with a 70% increase in glucuronide excretion, both compared with controls. This implies either stimulation of glucuronidation, or inhibition of microsomal oxidation. To test this hypothesis, the rates of disappearance of phenazone and acetanilide, two compounds extensively metabolised by microsomal oxidation, have been compared in perfused liver preparations with and without the addition of cysteamine. Cysteamine was shown to bring about a drastic reduction in the rate of disappearance of both compounds. It seems likely, therefore, that the protective action of cysteamine results primarily from its ability to block formation of the toxic metabolite, rather than inactivating that metabolite by conjugation to.thio-ether compounds. In view of this we suggest that i’uture search for nontoxic antidotes for paracetamol poisoning need not concentrate solely on compounds with a possible scavenging action, but also upon those capable of inhibiting paracetamol oxidation. cetamol
within normal limits. There was an increase in accumulaturnover time of 35S-sulphated mucopolysaccharides (mainly dermatan sulphate) in the patient’s fibroblasts. Our studies therefore seem to confirm the observations of Dr Babarik and co-workers of chondroitinsulphaturia in certain patients with (x-L-iduronidase deficiency. Since chondroitin sulphate is known to contain &bgr;-D-glucuronic, but no K-L-iduronic acid residues, the apparent defect in chondroitin sulphate catabolism may be only indirectly related to the deficiency of M-L-iduronidase. Our patients differ clinically from the known phenotypes of K-L-iduronidase deficiency, Hurler disease, and Scheie disease. They might therefore be examples of HurlerScheie compound3 caused by double heterozygosity of the Hurler and Scheie genes. However,an allelic mutation at the iduronidase locus differing from that causing the Hurler and Scheie disease is an equally plausible explanation. Assuming that the enzyme is composed of more than one subunit transcribed from different cistrons, the varying clinical expression of x-L-iduronidase deficiency may also be the result of different non-allelic mutations.
, tion and
Department of Paediatrics, University of Mainz. Department of Pædiatrics, University of Kiel, Fröbelstrasse 15/17, 23 Kiel 1, West Germany. 1. 2. 3.
J. SPRANGER. J. GEHLER J. F. O’BRIEN M. CANTZ.
Babarik, A., Benson, P. F., Dean, M. F., Muir, H. Lancet, Aug. 24, 1974, p. 464. Spranger, J. W., Schuster, W., Freitag, F. Helv. pœdiat. Acta, 1971, 26, 387. McKusick, V. A., Howell, R. R., Hussels, I. E., Neufeld, E. F., Stevenson, R. E. Lancet, 1972, i, 993.
detailed examination of antifibrinolytic agents in this extremely hazardous clinical situation. For the purposes of this trial, E.A.C.A. was replaced by tranexamic acid (A.M.C.A.) (12 g. in 24 hours). Of 182 patients who were treated thus, 22 (12-1%) re-bled in the first 14 days from the original ictus, and of these 14 (7-7%) succumbed to their haemorrhage. In terms of protecting patients during this critical period, these figures are much superior to the natural history of the condition. Diarrhoea was by far the commonest complication, occurring in some degree in almost every patient. A rapidly reversible toxic confusional state was noted in 7 patients. Clinically evident thromboembolic phenoa
mena were not
observed.
Atkinson Morley’s Hospital,
DAVID UTTLEY ALAN E. RICHARDSON.
Wimbledon, London SW20.
FALSE-POSITIVES
SiR,-Dr Kohn and Mr Weaver (Aug. 10, p. 334) present a well-documented argument for alpha-fetoprotein testing in conditions known to be associated with a high risk of hepatocellular carcinoma. They tell us that " the frequency of false-positives was 1-8%. A.F.P. detection and assay correctly performed and interpreted is a valuable, sensitive, and specific serological marker of hepatocellular carcinoma". Their estimate of false-positives is, however, incorrect and misleading. The accepted method for calculating the predictive value of a laboratory test and, therefore, the false-positive rate 1-5 is, using their data, as follows:
Sensitivity 90/107 = 84 %. Specificity 2079/2118 98-2 %. Predictive value of positive test 90/129 False positives 39/129 30 %. =
=
=
=
=
70 %-
=
Sensitivity, specificity, predictive value, and efficiency define a laboratory test’s accuracy. Sensitivity indicates the frequency of positive test results in patients with a particular disease, whereas specificity indicates the frequency of negative test results in patients without that disease. The predictive value of a positive test result indicates the frequency of diseased patients in all patients with positive test results. The predictive value of a negative test result indicates the frequency of non-diseased patients in all patients with negative test results. The efficiency of a test indicates the percentage of patients correctly classified (diseased and non-diseased) by the test. False-positive results are therefore calculated as 100% -predictive value of the positive test. If a test has a predictive value (+) of 90%, then 90% of the positives are true positives and 10% are false-positives. Using Dr Kohn and Mr Weaver’s data the predictive value of a
positive A.F.P. screening test is only 70%. Therefore, 30% of patients with positive results will not have hepatocarcinoma and will therefore be false-positives ". Kohn and Weaver feel " that 1-8% false-positives is a small price to pay for a diagnostic procedure capable of detecting "
1. 2.
3. 4. 5.
Department of Pathology, College of Physicians and Surgeons of Columbia University, New York, N.Y. 10032, U.S.A.
Do they feel the
same
ROBERT S. GALEN.
COMPUTERS IN INTENSIVE CARE appears from the title of your editorial, ComNurses ? (Oct. 12, p. 877) that the problem is wrongly defined. The computer is a machine, a tool, and as such cannot be considered in isolation from the person using it. Professor Alwyn Smith, of the Department of Community Medicine in the University of Manchester, has described the computer as doing for the mind what the microscope has done for the eye, which is a good description of the relationship involved; computers do not replace nurses any more than a microscope replaces the human eye but they do add to their existing power. We have been privileged to see a number of intensivecare units outside the U.K. (N.H.S.) and the question we " always ask is what happens when you switch the system off " ? The units we have visited are usually long established (7-10 years) and the almost invariable answer to this question is that the nursing staff complain and say that they want the system switched back on again. In other words their job is made more difficult without the computer. As well as assisting the nurse in some of her routine tasks, the computer performs calculations (e.g., of cardiac output) which no one would be prepared to tackle without the aid of a machine. These can yield valuable additional information to help her take the most suitable course of action. The point about large machines and small machines raises the question of what is meant by " large "-physically large, or large in terms of computer power ? Manchester Medical School has a physically large computer, some 14 years old, that today with micro-miniaturisation could be reduced to one-eighth of its present size and do the same
SIR,-It
puters
or
job.
&mid ot;
=
approximately 85% of true cases ". about 30% false-positives ?
Vecchio, T. J. New Engl.J. Med. 1966, 274, 1171. Sunderman, F. W., Van Soestbergen, A. A. Am. J. clin. Path. 1971, 55, 105. Werner, M., Brooks, S. H., Wette, R. Hum. Path. 1973, 4, 17. Holland, W. W., Whitehead, T. P. Lancet, 1974, ii, 391. Schwartz, W. B., Gorry, G. A., Kassirer, J. P., Essig, A. Am. J. Med. 1973, 55, 459.
Modern machines cost one-tenth of the price of old machines for the same computer power. Some medical problems can be managed on modern mini-computers which have the power of some of the older machines but are very modest in price and size. In view of this it is envisaged that it will soon be possible to have all of the computer power needed in an intensivecare unit for a few thousand pounds. However, the cost of the software-the programs which " drive " the computer and allow it to perform useful tasks-has not decreased over the years, and it is not surprising that the units which have succeeded in making things work are, to some extent, those with the money. However, once a program has been designed it can be used anywhere in the world provided technical problems of compatibility between The different types of computer can be overcome. Wythenshawe experimentdemonstrated that the same set of programs could be used in the different clinical environments with very little alteration. So there is hope that once sufficient capital has been expended by the larger research units-notably in the United States and Western Europe-to develop the necessary programs, it will no longer be necessary for individual hospitals to spend vast sums of money on getting their own individual systems into
operation. Clinical medicine has continually expanded, absorbing from many branches of science; there is no
techniques reason 1.
to
believe
that
computer
technology-already
Ashcroft, J. M., Berry J. L. Proceedings of I.F.I.P. Medinfo 74 conference, Stockholm, Sweden, Aug. 5-10, 1974.
1082
yielding results the exception.
in many
areas
Medical Computing Unit, Clinical Sciences Building, York Place, Manchester M13 0JJ.
of medical research-will be
D. E. CLARK T. C. SHARPE.
CARE OF THE CRITICALLY ILL SIR,-Dr Skillman’s article (Sept. 14, p. 634) is an important contribution. However, it does not undertake the issue surrounding the physician faced with the patient wishing to withdraw from maintenance haEmodialysis. This issue was discussed at a panel on problems in adaptation to hasmodialysis at the 1972 annual meeting of the American Psychiatric Association.1 Such patients should not be approached in terms of " right to die ", which diverts the question from the psychiatric area where it may belong to a legal or moral question. Haemodialysis patients wishing to withdraw should be carefully examined for depression and suicidal tendency, since suicide is much commoner among these patients than in the general population.2 All patients undergoing haemodialysis should be monitored in an ongoing way for depression, the most common psychological complication iri these patients.33 If picked up relatively early and treated with tricyclic antidepressants and/or psychiatric consultation, suicidal behaviour, including withdrawal from medical care, may be minimised. Discussion of the issue of withdrawal from hsemodialysis before the patient starts on such a programme may be helpful.4 Such discussion may enable the patient to bring up the question of continuing treatment earlier in his care, thus helping to prevent it from festering and emerging later as a fixed decision or being acted out in unannounced suicidal behaviour. Departments of Psychiatry and Medicine, State University of New York, Downstate Medical Center, College of Medicine, Brooklyn, New York 11203, U.S.A.
to
Poisons Unit, New Cross Hospital,
Avonley Road, London SE14 5ER.
F. HARVEY R. GOULDING.
CHONDROITINSULPHATURIA WITH &agr;-L-IDURONIDASE DEFICIENCY SIR,-Dr Babarik and associatesrefer to two sisters with chondroitinsulphaturia whom we reported in 1971.2 Recently, we have re-studied these patients and found a similar deficiency of, oc-L-iduronidase activity in cultured fibroblasts as described by Babarik et. al. in their patient. The activities of other lysosomal hydrolases (p-glucuroni-
P-N-acetylhexosaminidase, a-Nacetylglucosaminidase, K-L-fucosidase, rt.-D-mannosidase, P-D-xylosidase, arylsulphatase A, and acid phosphatase) were dase, P-galactosidase,
NORMAN B. LEVY.
ACTION OF CYSTEAMINE IN PARACETAMOL POISONING SIR,-Cysteamine has been advocated5 as an effective antidote in the treatment of paracetamol poisoning. The underlying rationale was that cysteamine would act within the hepatocyte by combining with an unidentified toxic metabolite of paracetamol formed by microsomal oxidation, though the alternative possibility that it could have inhibited the formation of such metabolites was also mentioned. In the course of a comprehensive study here on drug metabolism by the use of the isolated perfused rat liver, we have investigated the biliary excretion of paracetamol and its metabolites and the effects of various sulphydryl compounds on this system. The proportions of thio-ether-containing metabolites, which comprise those formed by conjugation between the toxic metabolite and glutathione or cysteamine, have been compared with those arising by direct conjugation of paraLevy, N. B., Abram, H. S., Kempf, J. P., McKegney, F. P., Scribner, B. H. in Living or Dying: Adaptation to Hemodialysis (edited by N. B. Levy); p. 3. Springfield, Illinois, 1974. 2. Abram, H. S., Moore, G. I., Westervelt, F. B., Jr. Am. J. Psychiat. 1971, 127, 1199. 3. Levy, N. B., in Clinical Aspects of Uremia and Hemodialysis, (edited by S. G. Massry and A. L. Sellers) (in the press). 4. McKegney, F. P., Lange, P. F. Am. J. Psychiat. 1971, 128, 267. 5. Prescott, L. F., Newton, R. W., Swainson, C. P., Wright, N., Forrest, A. R. W., Matthew, H. Lancet, 1974, i, 588. 1.
yield glucuronides and sulphates. Our prestudies demonstrated that the addition of cysteliminary amine to the system resulted in a 33% reduction in thioether-conjugated excretion coupled with a 70% increase in glucuronide excretion, both compared with controls. This implies either stimulation of glucuronidation, or inhibition of microsomal oxidation. To test this hypothesis, the rates of disappearance of phenazone and acetanilide, two compounds extensively metabolised by microsomal oxidation, have been compared in perfused liver preparations with and without the addition of cysteamine. Cysteamine was shown to bring about a drastic reduction in the rate of disappearance of both compounds. It seems likely, therefore, that the protective action of cysteamine results primarily from its ability to block formation of the toxic metabolite, rather than inactivating that metabolite by conjugation to.thio-ether compounds. In view of this we suggest that i’uture search for nontoxic antidotes for paracetamol poisoning need not concentrate solely on compounds with a possible scavenging action, but also upon those capable of inhibiting paracetamol oxidation. cetamol
within normal limits. There was an increase in accumulaturnover time of 35S-sulphated mucopolysaccharides (mainly dermatan sulphate) in the patient’s fibroblasts. Our studies therefore seem to confirm the observations of Dr Babarik and co-workers of chondroitinsulphaturia in certain patients with (x-L-iduronidase deficiency. Since chondroitin sulphate is known to contain &bgr;-D-glucuronic, but no K-L-iduronic acid residues, the apparent defect in chondroitin sulphate catabolism may be only indirectly related to the deficiency of M-L-iduronidase. Our patients differ clinically from the known phenotypes of K-L-iduronidase deficiency, Hurler disease, and Scheie disease. They might therefore be examples of HurlerScheie compound3 caused by double heterozygosity of the Hurler and Scheie genes. However,an allelic mutation at the iduronidase locus differing from that causing the Hurler and Scheie disease is an equally plausible explanation. Assuming that the enzyme is composed of more than one subunit transcribed from different cistrons, the varying clinical expression of x-L-iduronidase deficiency may also be the result of different non-allelic mutations.
, tion and
Department of Paediatrics, University of Mainz. Department of Pædiatrics, University of Kiel, Fröbelstrasse 15/17, 23 Kiel 1, West Germany. 1. 2. 3.
J. SPRANGER. J. GEHLER J. F. O’BRIEN M. CANTZ.
Babarik, A., Benson, P. F., Dean, M. F., Muir, H. Lancet, Aug. 24, 1974, p. 464. Spranger, J. W., Schuster, W., Freitag, F. Helv. pœdiat. Acta, 1971, 26, 387. McKusick, V. A., Howell, R. R., Hussels, I. E., Neufeld, E. F., Stevenson, R. E. Lancet, 1972, i, 993.