- Email: [email protected]
ASTHMA AND SOCIAL CLASS
321
depression and those who had had reactive depression were included, the findings carinot be compared with the previous work. Nevertheless, the direction of change in 5-H.I.A.A. was also the same as in the earlier study. The information to date still suggests a decline in the concentration of 5-hydroxyindoles in the brainstems of endogenously depressed individuals, but obviously further studies are
collected
warranted. The fact that Dr. Pare and his colleagues had one depressive (type not stated) in their series whose brainstem contained high levels of amines following therapy with a monoamine oxidase inhibitor, is of considerable interest. If this finding can be substantiated in a series of predominantly endogenously depressed individuals, it may help to undermine some of the more naive approaches to the role of amines in affective illness. M.R.C. Neuropsychiatric Research Unit, DAVID MURRAY SHAW. Carshalton, Surrey.
ORAL CONTRACEPTIVES AND DEPRESSION SIR,-The letters by Dr. Winston (June 14, p. 1209) and by Dr. Price and Dr. Toseland (July 19, p. 158) prompt me to write. Dr. Price and Dr. Toseland quoted Dr. Winston as suggesting that the depressive illness which may complicate the use of oral contraceptives is the result of a functional deficiency of pyridoxine, with impaired activity of enzymes concerned in the metabolism of tryptophan to nicotinic acid ribonucleotide, brought about by raised levels of tryptophan oxygenase (tryptophan pyrrolase). Dr. Winston’s proposal was, in fact, that contraceptive steroids, and particularly the oestrogen component, loosen the binding between pyridoxal phosphate and the apoenzyme of some vitamin-B 6-dependent enzyme systems. In my original report of abnormal tryptophan metabolism in women using oral contraceptives I suggested that these steroids induce an increase in the activity of one or more of the enzymes concerned in the metabolism of tryptophan to nicotinic acid ribonucleotide.1 Since then, preliminary studies in the rat have shown that the administration of mestranol and norethynodrel in combination (as used in ’ Enovid-E ’) produces a significant increase in liver tryptophan oxygenase.2 It is of interest that pregnant rats also have raised levels of tryptophan-oxygenase activity,34 and that pregnant women show abnormalities of tryptophan metabolism that are similar to those observed in women using oral contraceptives.5 The mechanism by which a combination of mestranol and norethynodrel increases tryptophan-oxygenase activity in rat liver is currently under investigation in this laboratory. Our hypothesis is that the effect is mediated by way of the hypothalamo-pituitary-adrenal axis. The administration of cestrogens produces a raised level of plasma-17-hydroxycorticosteroids.6 Although most of this increase represents protein-bound steroid, which has been considered generally to be physiologically inert, recent work by Keller et al.’ has shown that an oestrogen-produced rise in plasma-17hydroxycorticosteroids will cause a rise in the activity of the cortisol-inducible enzyme alanine aminotransferase in rat liver. These workers propose that the protein-bound steroid is able to pass through the plasma membrane of the hepatic 1. 2. 3.
Rose, D. P. Clin. Sci. 1966, 31, 265. Rose, D. P., Brown, R. R. Unpublished. Auricchio, S., Rigillo, N., Di Toro, R. Minerva pœdiat. 1960, 12, 1463. 4. Greengard, P., Kalinsky, H. J., Manning, T. J. Biochim. Biophys. Acta, 1968, 156, 198. 5. Brown, R. R., Thornton, M. J., Price, J. M. J. clin. Invest. 1961, 40, 617. 6. Sandberg, A. A., Slaunwhite, W. R. ibid. 1959, 38, 1290. 7. Keller, N., Richardson, U. I., Yates, F. E. Endocrinology, 1969, 84, 49.
cell-but not the membranes of other cell-types such as those of the pancreas-by pinocytosis. Once inside the cell the steroid may dissociate from the binding globulin to yield the active corticosteroid. If such a mechanism is responsible for the raised level of hepatic alanine aminotransferase it is to be expected that it will apply also to hepatic tryptophan oxygenase, increased activity of which is also known to be induced by cortisol (hydrocortisone).88 Dr. Price and Dr. Toseland suggest that there may be a place for the routine administration of pyridoxine to women who are taking oral contraceptives. While it is true that large doses of this vitamin reduce the raised urinary excretion of tryptophan metabolites to normal levels, it is not certain that this would ease the situation with respect to the levels of 5-hydroxytryptamine in the brain. When there is already a high level of tryptophan-oxygenase activity the effect of giving pyridoxine may be to promote the metabolism of tryptophan along the pathway leading to nicotinic acid ribonucleotide-by removing a partial block at the level of 3-hydroxyanthranilic acid productionrather than to allow the aminoacid to be metabolised to 5-hydroxytryptamine. This seems particularly likely since kynureninase, the enzyme responsible for 3-hydroxyanthranilic-acid formation, is vitamin-Bs-dependent, and the level of the apoenzyme is raised in the liver of mestranolnorethynodrel-treated rats.9 If, contraceptive steroids inhibit the decarboxylation of tryptophan to yield tryptamine and 5-hydroxytryptamine by competing with pyridoxal phosphate for the apoenzyme, as was postulated by Dr. Winston, then the administration of pyridoxine to women with depression associated with the use of these hormones may prove of value. Alexander Simpson Laboratory for Metabolic Research, St. Mary’s Hospital Medical School, D. P. ROSE. London W.2.
however,
ASTHMA AND SOCIAL CLASS SIR,-Our observations support those of Dr. Dawson and her colleagues,lO who found no significant association between socio-economic group and the prevalence of asthma in Aberdeen schoolchildren. We accumulated our data in the course of a survey on hearing-loss in Vancouver primary-school children." There was no significant relationship between socio-economic group and any of the indications of allergy which we looked for-namely, history of wheezing, symptoms or signs of nasal allergy, nasal secretion eosinophilia, or the family doctor’s diagnosis of asthma, hay fever, or eczema in the child. Graham et al.l2 found that, on the Isle of Wight, asthma was over-represented in the upper and middle social classes and under-represented in the lower social class. His information came chiefly from the school doctors’ records. Since upper and middle-class mothers more frequently attended school medical examinations with their children than did working-class mothers, his finding was possibly due to under-reporting of asthma in the lower class. Freeman and Johnson 13 asked mothers of grade-8 schoolchildren in Denver, Colorado, to complete questionnaires, and obtained a history of allergic disease three times as frequently in the upper as in the lower socio-economic level. This might be expected, however, where the 8. Thomson, J. F., Mikuta, E. T. ibid. 1954, 55, 232. 9. Rose, D. P., Brown, R. R. Biochim. Biophys. Acta, 1969, 184, 412. 10. Dawson, B., Horobin, G., Illsley, R., Mitchell, R. Lancet, 1969, i, 827. 11. Robinson, G. C., Anderson, D. O., Moghadam, H. K., Cambon, K. G., Murray, A. B. Can. med. Ass. J. 1967, 97, 1199. 12. Graham, P. J., Rutter, M. L., Yule, W. E., Less, B. P. Br. J. prev. soc. Med. 1967, 21, 78. 13. Freeman, G. L., Johnson, S. Am. J. Dis. Childh. 1964, 107, 549.
322
availability of medical advice depends on the patient’s ability to pay for it. This is not a major factor in Vancouver, where the great majority of the population was, at the time of our survey, covered by medical-insurance schemes. The commonly held clinical impression that asthma is over-represented in upper and middle classes and underrenresented in the lower classes,14 of Paediatrics and Health Care and Epidemiology, University of British Columbia.
Departments
mav not
be
correct.
A. B. MURRAY D. O. ANDERSON.
SECRETARIES AND SURGEONS SIR,-As the co-author of the article on Cervical Cytology Consent Rate (July 26, p. 207), you should have accorded me the qualification of an incorporated secretary (F.C.C.S.). Instead, you credited me with being a surgeon (F.R.C.S.). I fear I am nothing of the kind. I couldn’t possibly do his job. Nor, I suspect, could he do mine! County Health Department; J. SAUNDERS. Chichester, Sussex.
*** We apologise to Mr. Saunders for this lapse.-ED. L. MEASUREMENT OF CENTRAL VENOUS PRESSURE SIR,-A device for simplifying the measurement of central venous pressure (c.v.p.), designed to take a Baxter ’B.R.5 ’ c.v.p. set, was described in your columns in 1966.15 The apparatus, which employs a horizontal " gunsight " mounted on a movable frame, has proved highly satisfactory in the operating-theatre and intensive-care unit.
PARACERVICAL BLOCK IN OBSTETRICS
SIR,-Dr. Gomez1 questions the validity of reported of fetal intoxication after paracervical block in
cases
obstetrics.2 His letter prompts us to describe a case in which we have recovered mepivacaine from the urine, blood, and cerebrospinal fluid (c.s.F.) of an infant whose death has been attributed to mepivacaine intoxication following paracervical block. The infant, a boy, was born after 42 weeks’ gestation to a 23-year-old primigravida. Birth-weight was 4090 g. The mother had received no medications other than vitamins during the pregnancy. Labour had lasted a total of 14 hours with spontaneous rupture of membranes 4 hours before delivery. The second stage of labour lasted an estimated 2 hours. 7 hours before delivery, with the cervix 5 cm. dilated, a bilateral paracervical block was performed, using 10 ml. of 1% mepivacaine (’ Carbocaine ’, Sterling-Winthrop) on each side. The procedure was repeated 21/2 hours later (41/2 hours before birth). 15 minutes before delivery cyclopropane and oxygen were given by mask. Vertex vaginal delivery was easily accomplished with low forceps. Immediately after birth the infant began to have tonic and clonic seizures. Between seizures he was limp. Investigations yielded no cause. Serum calcium and glucose were normal and lumbar puncture and skull X-rays also revealed no abnormality. The seizures continued unabated for the first 3 hours of life until partial suppression was obtained with phenobarbitone. The infant was tremulous between episodes. At 16 hours an electroencephalogram (E.E.G.) showed " severe, diffuse disturbance of cerebral function ". Cerebral oedema developed, and despite vigorous therapy with mannitol and cortisone, respiratory impairment became progressively worse and the baby died at 25 hours of age. Post-mortem examination showed cerebral oedema, with diffuse neuronal degeneration (ischaemic change) in all areas and layers of the cerebral cortex, but most marked in the superior temporal gyri and hippocampi, where almost every neurone was affected. There was redema of the white matter with astrocytic swelling and occasional mitoses. The Purkinje cells showed central chromatolysis, as did those of the dentate nuclei, without any ischaemic or homogenising changes. The cerebellar white matter showed redema and astrocytic swelling. Death was attributed to perinatal anoxia secondary to intoxication with mepivacaine.
Intoxication of the fetus by a local anaesthetic was originally reported as a complication of puncture of the scalp during maternal caudal anxsthesia .4 The present controversy over paracervical block is centred on the possibility of absorption of toxic amounts of the agent by the fetus. In
3-way tap clipped in place.
Baxter’s have improved their B.R.5 c.v.p. set by replacing the Y connection and two of the three flowcontrol clamps of the previous version with a 3-way tap. We have modified the measuring device by removing the round bobbin against which the U of the Y connection was seated, and have replaced it with two spring clips taken from a disposable " clip-stick " manometer scale, also supplied by Baxters. The clips, which can be fitted in a moment by means of pop-rivets ", hold the 3-way "
tan
securelv (see accomnanvins figure).
R. D. MARSHALL Hospital, R. MILLER. Northampton. Lancet, 1967, i, 1266. Bethune, D. W., Gillett, G. B., Watson, A. C., Crichton, T. A. ibid. 1966, ii, 684.
General 14. 15.
this connection, Shnider et al. have found instances where there is a reversal of the maternal-fetal gradient, with fetalmepivacaine levels higher than maternal levels after paracervical block. They suggest that under such circumstances the injection had been carried out into or near to the placental intervillous space. In the case we report here it is necessary, in considering the question of toxicity, to relate the levels of mepivacaine to the time since administration. The serum level of 2-5 fLg./ml. at 31/2hour of age (8 hours after injection) had fallen to nil by 231/2 hours. It seems likely that at birth the serum level for this infant would have been about 5-0 ug./ml., which is certainly within the toxic
range.s We believe that this case supports the view that paracervical block can cause serious effects in the fetus. That Gomez, D. F. Lancet, 1969, i, 1163. Rosefsky, J. B., Petersiel, M. E. New Engl. J. Med. 1968, 278, 530. Pratt, E. L., Warrington, H. P., Grego, J. Anæsthesiology, 1967, 28, 432. 4. Sinclair, J. C., Fox, H. A., Lentz, J. F., Fuld, G. L., Murphy, J. New Engl. J. Med. 1965, 273, 1173. 5. Shnider, S. M., Asling, J. H., Margolis, A. J., Way, E. L., Wilkinson, G. R. ibid. 1968, 279, 943. 6. Shnider, S. M. Personal communication. 1. 2. 3.
depression and those who had had reactive depression were included, the findings carinot be compared with the previous work. Nevertheless, the direction of change in 5-H.I.A.A. was also the same as in the earlier study. The information to date still suggests a decline in the concentration of 5-hydroxyindoles in the brainstems of endogenously depressed individuals, but obviously further studies are
collected
warranted. The fact that Dr. Pare and his colleagues had one depressive (type not stated) in their series whose brainstem contained high levels of amines following therapy with a monoamine oxidase inhibitor, is of considerable interest. If this finding can be substantiated in a series of predominantly endogenously depressed individuals, it may help to undermine some of the more naive approaches to the role of amines in affective illness. M.R.C. Neuropsychiatric Research Unit, DAVID MURRAY SHAW. Carshalton, Surrey.
ORAL CONTRACEPTIVES AND DEPRESSION SIR,-The letters by Dr. Winston (June 14, p. 1209) and by Dr. Price and Dr. Toseland (July 19, p. 158) prompt me to write. Dr. Price and Dr. Toseland quoted Dr. Winston as suggesting that the depressive illness which may complicate the use of oral contraceptives is the result of a functional deficiency of pyridoxine, with impaired activity of enzymes concerned in the metabolism of tryptophan to nicotinic acid ribonucleotide, brought about by raised levels of tryptophan oxygenase (tryptophan pyrrolase). Dr. Winston’s proposal was, in fact, that contraceptive steroids, and particularly the oestrogen component, loosen the binding between pyridoxal phosphate and the apoenzyme of some vitamin-B 6-dependent enzyme systems. In my original report of abnormal tryptophan metabolism in women using oral contraceptives I suggested that these steroids induce an increase in the activity of one or more of the enzymes concerned in the metabolism of tryptophan to nicotinic acid ribonucleotide.1 Since then, preliminary studies in the rat have shown that the administration of mestranol and norethynodrel in combination (as used in ’ Enovid-E ’) produces a significant increase in liver tryptophan oxygenase.2 It is of interest that pregnant rats also have raised levels of tryptophan-oxygenase activity,34 and that pregnant women show abnormalities of tryptophan metabolism that are similar to those observed in women using oral contraceptives.5 The mechanism by which a combination of mestranol and norethynodrel increases tryptophan-oxygenase activity in rat liver is currently under investigation in this laboratory. Our hypothesis is that the effect is mediated by way of the hypothalamo-pituitary-adrenal axis. The administration of cestrogens produces a raised level of plasma-17-hydroxycorticosteroids.6 Although most of this increase represents protein-bound steroid, which has been considered generally to be physiologically inert, recent work by Keller et al.’ has shown that an oestrogen-produced rise in plasma-17hydroxycorticosteroids will cause a rise in the activity of the cortisol-inducible enzyme alanine aminotransferase in rat liver. These workers propose that the protein-bound steroid is able to pass through the plasma membrane of the hepatic 1. 2. 3.
Rose, D. P. Clin. Sci. 1966, 31, 265. Rose, D. P., Brown, R. R. Unpublished. Auricchio, S., Rigillo, N., Di Toro, R. Minerva pœdiat. 1960, 12, 1463. 4. Greengard, P., Kalinsky, H. J., Manning, T. J. Biochim. Biophys. Acta, 1968, 156, 198. 5. Brown, R. R., Thornton, M. J., Price, J. M. J. clin. Invest. 1961, 40, 617. 6. Sandberg, A. A., Slaunwhite, W. R. ibid. 1959, 38, 1290. 7. Keller, N., Richardson, U. I., Yates, F. E. Endocrinology, 1969, 84, 49.
cell-but not the membranes of other cell-types such as those of the pancreas-by pinocytosis. Once inside the cell the steroid may dissociate from the binding globulin to yield the active corticosteroid. If such a mechanism is responsible for the raised level of hepatic alanine aminotransferase it is to be expected that it will apply also to hepatic tryptophan oxygenase, increased activity of which is also known to be induced by cortisol (hydrocortisone).88 Dr. Price and Dr. Toseland suggest that there may be a place for the routine administration of pyridoxine to women who are taking oral contraceptives. While it is true that large doses of this vitamin reduce the raised urinary excretion of tryptophan metabolites to normal levels, it is not certain that this would ease the situation with respect to the levels of 5-hydroxytryptamine in the brain. When there is already a high level of tryptophan-oxygenase activity the effect of giving pyridoxine may be to promote the metabolism of tryptophan along the pathway leading to nicotinic acid ribonucleotide-by removing a partial block at the level of 3-hydroxyanthranilic acid productionrather than to allow the aminoacid to be metabolised to 5-hydroxytryptamine. This seems particularly likely since kynureninase, the enzyme responsible for 3-hydroxyanthranilic-acid formation, is vitamin-Bs-dependent, and the level of the apoenzyme is raised in the liver of mestranolnorethynodrel-treated rats.9 If, contraceptive steroids inhibit the decarboxylation of tryptophan to yield tryptamine and 5-hydroxytryptamine by competing with pyridoxal phosphate for the apoenzyme, as was postulated by Dr. Winston, then the administration of pyridoxine to women with depression associated with the use of these hormones may prove of value. Alexander Simpson Laboratory for Metabolic Research, St. Mary’s Hospital Medical School, D. P. ROSE. London W.2.
however,
ASTHMA AND SOCIAL CLASS SIR,-Our observations support those of Dr. Dawson and her colleagues,lO who found no significant association between socio-economic group and the prevalence of asthma in Aberdeen schoolchildren. We accumulated our data in the course of a survey on hearing-loss in Vancouver primary-school children." There was no significant relationship between socio-economic group and any of the indications of allergy which we looked for-namely, history of wheezing, symptoms or signs of nasal allergy, nasal secretion eosinophilia, or the family doctor’s diagnosis of asthma, hay fever, or eczema in the child. Graham et al.l2 found that, on the Isle of Wight, asthma was over-represented in the upper and middle social classes and under-represented in the lower social class. His information came chiefly from the school doctors’ records. Since upper and middle-class mothers more frequently attended school medical examinations with their children than did working-class mothers, his finding was possibly due to under-reporting of asthma in the lower class. Freeman and Johnson 13 asked mothers of grade-8 schoolchildren in Denver, Colorado, to complete questionnaires, and obtained a history of allergic disease three times as frequently in the upper as in the lower socio-economic level. This might be expected, however, where the 8. Thomson, J. F., Mikuta, E. T. ibid. 1954, 55, 232. 9. Rose, D. P., Brown, R. R. Biochim. Biophys. Acta, 1969, 184, 412. 10. Dawson, B., Horobin, G., Illsley, R., Mitchell, R. Lancet, 1969, i, 827. 11. Robinson, G. C., Anderson, D. O., Moghadam, H. K., Cambon, K. G., Murray, A. B. Can. med. Ass. J. 1967, 97, 1199. 12. Graham, P. J., Rutter, M. L., Yule, W. E., Less, B. P. Br. J. prev. soc. Med. 1967, 21, 78. 13. Freeman, G. L., Johnson, S. Am. J. Dis. Childh. 1964, 107, 549.
322
availability of medical advice depends on the patient’s ability to pay for it. This is not a major factor in Vancouver, where the great majority of the population was, at the time of our survey, covered by medical-insurance schemes. The commonly held clinical impression that asthma is over-represented in upper and middle classes and underrenresented in the lower classes,14 of Paediatrics and Health Care and Epidemiology, University of British Columbia.
Departments
mav not
be
correct.
A. B. MURRAY D. O. ANDERSON.
SECRETARIES AND SURGEONS SIR,-As the co-author of the article on Cervical Cytology Consent Rate (July 26, p. 207), you should have accorded me the qualification of an incorporated secretary (F.C.C.S.). Instead, you credited me with being a surgeon (F.R.C.S.). I fear I am nothing of the kind. I couldn’t possibly do his job. Nor, I suspect, could he do mine! County Health Department; J. SAUNDERS. Chichester, Sussex.
*** We apologise to Mr. Saunders for this lapse.-ED. L. MEASUREMENT OF CENTRAL VENOUS PRESSURE SIR,-A device for simplifying the measurement of central venous pressure (c.v.p.), designed to take a Baxter ’B.R.5 ’ c.v.p. set, was described in your columns in 1966.15 The apparatus, which employs a horizontal " gunsight " mounted on a movable frame, has proved highly satisfactory in the operating-theatre and intensive-care unit.
PARACERVICAL BLOCK IN OBSTETRICS
SIR,-Dr. Gomez1 questions the validity of reported of fetal intoxication after paracervical block in
cases
obstetrics.2 His letter prompts us to describe a case in which we have recovered mepivacaine from the urine, blood, and cerebrospinal fluid (c.s.F.) of an infant whose death has been attributed to mepivacaine intoxication following paracervical block. The infant, a boy, was born after 42 weeks’ gestation to a 23-year-old primigravida. Birth-weight was 4090 g. The mother had received no medications other than vitamins during the pregnancy. Labour had lasted a total of 14 hours with spontaneous rupture of membranes 4 hours before delivery. The second stage of labour lasted an estimated 2 hours. 7 hours before delivery, with the cervix 5 cm. dilated, a bilateral paracervical block was performed, using 10 ml. of 1% mepivacaine (’ Carbocaine ’, Sterling-Winthrop) on each side. The procedure was repeated 21/2 hours later (41/2 hours before birth). 15 minutes before delivery cyclopropane and oxygen were given by mask. Vertex vaginal delivery was easily accomplished with low forceps. Immediately after birth the infant began to have tonic and clonic seizures. Between seizures he was limp. Investigations yielded no cause. Serum calcium and glucose were normal and lumbar puncture and skull X-rays also revealed no abnormality. The seizures continued unabated for the first 3 hours of life until partial suppression was obtained with phenobarbitone. The infant was tremulous between episodes. At 16 hours an electroencephalogram (E.E.G.) showed " severe, diffuse disturbance of cerebral function ". Cerebral oedema developed, and despite vigorous therapy with mannitol and cortisone, respiratory impairment became progressively worse and the baby died at 25 hours of age. Post-mortem examination showed cerebral oedema, with diffuse neuronal degeneration (ischaemic change) in all areas and layers of the cerebral cortex, but most marked in the superior temporal gyri and hippocampi, where almost every neurone was affected. There was redema of the white matter with astrocytic swelling and occasional mitoses. The Purkinje cells showed central chromatolysis, as did those of the dentate nuclei, without any ischaemic or homogenising changes. The cerebellar white matter showed redema and astrocytic swelling. Death was attributed to perinatal anoxia secondary to intoxication with mepivacaine.
Intoxication of the fetus by a local anaesthetic was originally reported as a complication of puncture of the scalp during maternal caudal anxsthesia .4 The present controversy over paracervical block is centred on the possibility of absorption of toxic amounts of the agent by the fetus. In
3-way tap clipped in place.
Baxter’s have improved their B.R.5 c.v.p. set by replacing the Y connection and two of the three flowcontrol clamps of the previous version with a 3-way tap. We have modified the measuring device by removing the round bobbin against which the U of the Y connection was seated, and have replaced it with two spring clips taken from a disposable " clip-stick " manometer scale, also supplied by Baxters. The clips, which can be fitted in a moment by means of pop-rivets ", hold the 3-way "
tan
securelv (see accomnanvins figure).
R. D. MARSHALL Hospital, R. MILLER. Northampton. Lancet, 1967, i, 1266. Bethune, D. W., Gillett, G. B., Watson, A. C., Crichton, T. A. ibid. 1966, ii, 684.
General 14. 15.
this connection, Shnider et al. have found instances where there is a reversal of the maternal-fetal gradient, with fetalmepivacaine levels higher than maternal levels after paracervical block. They suggest that under such circumstances the injection had been carried out into or near to the placental intervillous space. In the case we report here it is necessary, in considering the question of toxicity, to relate the levels of mepivacaine to the time since administration. The serum level of 2-5 fLg./ml. at 31/2hour of age (8 hours after injection) had fallen to nil by 231/2 hours. It seems likely that at birth the serum level for this infant would have been about 5-0 ug./ml., which is certainly within the toxic
range.s We believe that this case supports the view that paracervical block can cause serious effects in the fetus. That Gomez, D. F. Lancet, 1969, i, 1163. Rosefsky, J. B., Petersiel, M. E. New Engl. J. Med. 1968, 278, 530. Pratt, E. L., Warrington, H. P., Grego, J. Anæsthesiology, 1967, 28, 432. 4. Sinclair, J. C., Fox, H. A., Lentz, J. F., Fuld, G. L., Murphy, J. New Engl. J. Med. 1965, 273, 1173. 5. Shnider, S. M., Asling, J. H., Margolis, A. J., Way, E. L., Wilkinson, G. R. ibid. 1968, 279, 943. 6. Shnider, S. M. Personal communication. 1. 2. 3.