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PARACETAMOL AND METHÆMOGLOBINÆMIA
1360
Differing local circumstances and availability of trained anaesthetic staff to provide 24-hour supervision of all paralysed cases may explain why our mortality is appreciably less than that in the Durban series where i.p.v. was necessary. We are only too aware that this form of treatment carries risks of its own (and accounted for at least one death in our series), but regular monitoring of blood-gases and pH, which is not mentioned in the South African paper, contributes to its safety. It is costly and time-consuming, but it is the only form of treatment which offers a hope to really severe cases of tetanus. Respiratory Unit, Royal Victoria Hospital, Grosvenor Road, Belfast 12.
ROBERT C. GRAY JOHN W. DUNDEE.
LUXURIOUS NOMENCLATURE SIR,-May I make a plea for caution and discretion in contemporary nomenclature in medicine ? Dr. Lassen, in an admirable hypothesis in your issue of Nov. 19 (p. 1113), has concocted the term luxury-perfusion syndrome ". While this undoubtedly conveys a vivid picture to Dr. Lassen, it certainly fails to bring to my mind a picture of An acute derangement of the cerebral circulation associated with severe brain damage ... characterised by an over-abundant cerebral blood-flow relative to the metabolic needs of the brain tissue ..." I would consider it preferable for Dr. Lassen to call this syndrome after his name rather than apply titles which are calculated to baffle and astound students of the future. "
"
Fibrinolytic Laboratory, St. Laurence’s Hospital, North Brunswick Street, Dublin 7.
EOIN T. O’BRIEN.
PARACETAMOL AND METHÆMOGLOBINÆMIA
SIR,-It is well known that many aromatic amines and amides can induce the formation of methxmoglobin when administered to animals and man. It has been shown that different species of animals show different sensitivities to a particular amide (e.g., acetanilide),1 and it has also been reported that there is a wide difference in the methxmoglobin level obtained when one dose of a compound is given to either cats ’-’ or man.3 We have reported that paracetamol and phenacetin induce the formation of the same amount of methaemoglobin in cats when given orally in a dose of 1 mmole per kg.2 Since phenacetin has been under some suspicion recently and it is claimed that paracetamol is free from the problems associated with phenacetin, it was thought worth while to investigate the methaemoglobin levels attained in man when paracetamol is administered in normal therapeutic doses. An opportunity to do this occurred when a product containing paracetamol along with other ingredients was examined for the incidence of sideeffects. 160 subjects took part in the trial, and these were divided into four equal groups. The average age was 21 years, and there were equal numbers of males and females. The dosage of paracetamol used was: group 1, 500 mg. q.d.s.; group 2, 500 mg. t.d.s.; group 3, 500 mg. nocte; group 4, placebo. Blood was taken from each subject 1 hour after the midday dose of the product had been taken and was diluted immediately in phosphate buffer. This procedure was adopted because it has been shown that the methxmoglobin level in whole blood falls quite rapidly on standing at room temperature.4 Methxmoglobin was estimated spectrophotometrically by the cyanmethaemoglobin method.5 The dosage scheme was such that groups 1 and 2 took paracetamol at midday while groups 3 and 4 did not. Blood-samples were taken from 10 subjects in each of the four groups on the 3rd, 4th, 5th, and 6th days of the trial. No methaemoglobin was detected in any blood-sample. Lester, D. J. Pharmac. exp. Ther. 1943, 77, 154. McLean, S., Murphy, B. P., Starmer, G. A., Thomas, J. J. Pharm. Pharmac. (in the press). 3. Hjelm, M., Holmdahl, M. H. Acta anæsth. scand. 1965, 2, 99. 4. Climie, C. R., McLean, S., Starmer, G. A., Thomas, J. Br. J. Anœsth. (in the press). 5. Evelyn, K. A., Mallory, H. T. J. biol. Chem. 1938, 126, 655. 1. 2.
Methaemoglobinaemia is not therefore a side-effect of paracetamol when it is used in normal therapeutic doses, even when it is taken continuously for up to a week. But the compound has the intrinsic ability to induce the formation of methxmoglobin in both cats2 and man f; in abnormally high doses. Departments of Pharmacy and
Pharmacology, University of Sydney, New South Wales, Australia.
J. THOMAS S. MCLEAN G. A. STARMER P. R. CARROLL.
IRREVERSIBILITY AFTER INIURY
SIR,-Dr. Sevitt (Dec. 3, p. 1203) is to be thanked for his useful contribution to the subject of renal failure. Obstetricians could add to its value, and supplement his findings, in anuria complicating concealed-but not revealed-accidental hrmorrhage. They have observed that blood-loss alone could not cause renal failure, for similar or even on occasion greater revealed haemorrhage associated with a low-lying placenta fails to cause this complication. Certainly in retained bleeding within the uterus there is a further occult adjunct in the a’tiology-a nervous intrusion. The experiments of Franklin et al. 7 showed that renal cortical ischasmia, the precursor of renal failure, that accompanies anoxia, can be prevented by denervation in areas of the kidney deprived of their nerve supply. Further, Franklin and I 8 showed that stimulation of the renal nerves could eventually provoke cortical necrosis, preceded by cortical blood-flow diversion. In renal ischaemia anoxia could be the equivalent of a deficient oxygen supply to the kidney that severe haemorrhage would bring about, while stimulation of the renal nerves could be reasonably equated with nervous impulses reaching the kidney from " traumatised areas ", or from such areas that could give rise if stimulated to a renal reflex (e.g., the utero-renal reflex). The substantial intrusion of nervous effects in the precipitating of anuria can be inferred from the experiments of SheehanH and Balint.’" Whereas total clipping of the renal pedicle (including artery, vein, and nerve) for two hours invariably produces cortical necrosis (" tubular necrosis "), it failed to do so in the experiments of the former if an anaathetic such as ether or hypnotics such as pentobarbitone sodium (’ Nembutal’) or urethane had been administered continuously starting two hours before the application of the clamp; likewise in the experiments of the latter chloralose anaesthesia was equally effective as a protection of the kidney against the clipping. In man, though evidence of the acute renal abnormality in concealed accidental haemorrhage is still meagre, Louw"11 actually felt the renal artery on laparatomy for concealed accidental haemorrhage as a hard cord greatly reduced in size, while Jeffcoate 12 found in similar circumstances, after anuria had developed, a bloodless cortex with a highly vascular medulla in contrast. Both abnormalities could explain the pathological anatomy of cortical necrosis-in which destruction of the cortex dominates the picture, while the medulla survives in keeping with Trueta’s finding when sympathetic stimulation is indirectly applied to the kidney-and also the dramatic therapeutic effect of rupture of the membranes combined with conduction anaesthesia reaching the llth dorsal nerve (supplying the kidney).13 14 There is also a good deal of evidence that sympathetic stimulation accompanies concealed accidental haemorrhage, among many others Combrinkl,’, describes six patients with 6. 7.
Kiese, M., Meizel, H. Arch. exp. Path. Pharmak. 1962, 242, 551. Franklin, K. J., McGee, L. E., Ullman, E., J. Physiol., Lond. 1951, 112,
8.
Franklin,
43. K.
J., Sophian, J. Toxaemias of Pregnancy; p. 184. London,
1953.
9. 10. 11. 12. 13. 14. 15.
Sheehan, H. L., Davis, J. C. J. Path. Bact. 1960, 79, 337. Balint, P. in Acute Renal Failure (edited by S. Shaldon and G. C. Cook), p. 7. Oxford, 1964. Louw, J. Personal communication. Jeffcoate, F. N. A. Cited by Franklin, K. J. Ir. J. med. Sci. 1955, May. p. 220. Barry, A. P., Geoghegan, P. ibid. 1954, January, p. 189. Feeney, K J. J. Ir. med. Ass. 1953, 32, 36. Combrink, P. B. J. Obstet. Gynæc. Br. Commonw. 1964, 71, 461
Differing local circumstances and availability of trained anaesthetic staff to provide 24-hour supervision of all paralysed cases may explain why our mortality is appreciably less than that in the Durban series where i.p.v. was necessary. We are only too aware that this form of treatment carries risks of its own (and accounted for at least one death in our series), but regular monitoring of blood-gases and pH, which is not mentioned in the South African paper, contributes to its safety. It is costly and time-consuming, but it is the only form of treatment which offers a hope to really severe cases of tetanus. Respiratory Unit, Royal Victoria Hospital, Grosvenor Road, Belfast 12.
ROBERT C. GRAY JOHN W. DUNDEE.
LUXURIOUS NOMENCLATURE SIR,-May I make a plea for caution and discretion in contemporary nomenclature in medicine ? Dr. Lassen, in an admirable hypothesis in your issue of Nov. 19 (p. 1113), has concocted the term luxury-perfusion syndrome ". While this undoubtedly conveys a vivid picture to Dr. Lassen, it certainly fails to bring to my mind a picture of An acute derangement of the cerebral circulation associated with severe brain damage ... characterised by an over-abundant cerebral blood-flow relative to the metabolic needs of the brain tissue ..." I would consider it preferable for Dr. Lassen to call this syndrome after his name rather than apply titles which are calculated to baffle and astound students of the future. "
"
Fibrinolytic Laboratory, St. Laurence’s Hospital, North Brunswick Street, Dublin 7.
EOIN T. O’BRIEN.
PARACETAMOL AND METHÆMOGLOBINÆMIA
SIR,-It is well known that many aromatic amines and amides can induce the formation of methxmoglobin when administered to animals and man. It has been shown that different species of animals show different sensitivities to a particular amide (e.g., acetanilide),1 and it has also been reported that there is a wide difference in the methxmoglobin level obtained when one dose of a compound is given to either cats ’-’ or man.3 We have reported that paracetamol and phenacetin induce the formation of the same amount of methaemoglobin in cats when given orally in a dose of 1 mmole per kg.2 Since phenacetin has been under some suspicion recently and it is claimed that paracetamol is free from the problems associated with phenacetin, it was thought worth while to investigate the methaemoglobin levels attained in man when paracetamol is administered in normal therapeutic doses. An opportunity to do this occurred when a product containing paracetamol along with other ingredients was examined for the incidence of sideeffects. 160 subjects took part in the trial, and these were divided into four equal groups. The average age was 21 years, and there were equal numbers of males and females. The dosage of paracetamol used was: group 1, 500 mg. q.d.s.; group 2, 500 mg. t.d.s.; group 3, 500 mg. nocte; group 4, placebo. Blood was taken from each subject 1 hour after the midday dose of the product had been taken and was diluted immediately in phosphate buffer. This procedure was adopted because it has been shown that the methxmoglobin level in whole blood falls quite rapidly on standing at room temperature.4 Methxmoglobin was estimated spectrophotometrically by the cyanmethaemoglobin method.5 The dosage scheme was such that groups 1 and 2 took paracetamol at midday while groups 3 and 4 did not. Blood-samples were taken from 10 subjects in each of the four groups on the 3rd, 4th, 5th, and 6th days of the trial. No methaemoglobin was detected in any blood-sample. Lester, D. J. Pharmac. exp. Ther. 1943, 77, 154. McLean, S., Murphy, B. P., Starmer, G. A., Thomas, J. J. Pharm. Pharmac. (in the press). 3. Hjelm, M., Holmdahl, M. H. Acta anæsth. scand. 1965, 2, 99. 4. Climie, C. R., McLean, S., Starmer, G. A., Thomas, J. Br. J. Anœsth. (in the press). 5. Evelyn, K. A., Mallory, H. T. J. biol. Chem. 1938, 126, 655. 1. 2.
Methaemoglobinaemia is not therefore a side-effect of paracetamol when it is used in normal therapeutic doses, even when it is taken continuously for up to a week. But the compound has the intrinsic ability to induce the formation of methxmoglobin in both cats2 and man f; in abnormally high doses. Departments of Pharmacy and
Pharmacology, University of Sydney, New South Wales, Australia.
J. THOMAS S. MCLEAN G. A. STARMER P. R. CARROLL.
IRREVERSIBILITY AFTER INIURY
SIR,-Dr. Sevitt (Dec. 3, p. 1203) is to be thanked for his useful contribution to the subject of renal failure. Obstetricians could add to its value, and supplement his findings, in anuria complicating concealed-but not revealed-accidental hrmorrhage. They have observed that blood-loss alone could not cause renal failure, for similar or even on occasion greater revealed haemorrhage associated with a low-lying placenta fails to cause this complication. Certainly in retained bleeding within the uterus there is a further occult adjunct in the a’tiology-a nervous intrusion. The experiments of Franklin et al. 7 showed that renal cortical ischasmia, the precursor of renal failure, that accompanies anoxia, can be prevented by denervation in areas of the kidney deprived of their nerve supply. Further, Franklin and I 8 showed that stimulation of the renal nerves could eventually provoke cortical necrosis, preceded by cortical blood-flow diversion. In renal ischaemia anoxia could be the equivalent of a deficient oxygen supply to the kidney that severe haemorrhage would bring about, while stimulation of the renal nerves could be reasonably equated with nervous impulses reaching the kidney from " traumatised areas ", or from such areas that could give rise if stimulated to a renal reflex (e.g., the utero-renal reflex). The substantial intrusion of nervous effects in the precipitating of anuria can be inferred from the experiments of SheehanH and Balint.’" Whereas total clipping of the renal pedicle (including artery, vein, and nerve) for two hours invariably produces cortical necrosis (" tubular necrosis "), it failed to do so in the experiments of the former if an anaathetic such as ether or hypnotics such as pentobarbitone sodium (’ Nembutal’) or urethane had been administered continuously starting two hours before the application of the clamp; likewise in the experiments of the latter chloralose anaesthesia was equally effective as a protection of the kidney against the clipping. In man, though evidence of the acute renal abnormality in concealed accidental haemorrhage is still meagre, Louw"11 actually felt the renal artery on laparatomy for concealed accidental haemorrhage as a hard cord greatly reduced in size, while Jeffcoate 12 found in similar circumstances, after anuria had developed, a bloodless cortex with a highly vascular medulla in contrast. Both abnormalities could explain the pathological anatomy of cortical necrosis-in which destruction of the cortex dominates the picture, while the medulla survives in keeping with Trueta’s finding when sympathetic stimulation is indirectly applied to the kidney-and also the dramatic therapeutic effect of rupture of the membranes combined with conduction anaesthesia reaching the llth dorsal nerve (supplying the kidney).13 14 There is also a good deal of evidence that sympathetic stimulation accompanies concealed accidental haemorrhage, among many others Combrinkl,’, describes six patients with 6. 7.
Kiese, M., Meizel, H. Arch. exp. Path. Pharmak. 1962, 242, 551. Franklin, K. J., McGee, L. E., Ullman, E., J. Physiol., Lond. 1951, 112,
8.
Franklin,
43. K.
J., Sophian, J. Toxaemias of Pregnancy; p. 184. London,
1953.
9. 10. 11. 12. 13. 14. 15.
Sheehan, H. L., Davis, J. C. J. Path. Bact. 1960, 79, 337. Balint, P. in Acute Renal Failure (edited by S. Shaldon and G. C. Cook), p. 7. Oxford, 1964. Louw, J. Personal communication. Jeffcoate, F. N. A. Cited by Franklin, K. J. Ir. J. med. Sci. 1955, May. p. 220. Barry, A. P., Geoghegan, P. ibid. 1954, January, p. 189. Feeney, K J. J. Ir. med. Ass. 1953, 32, 36. Combrink, P. B. J. Obstet. Gynæc. Br. Commonw. 1964, 71, 461