860 PRESERVATIVES IN HEPARIN
SERUM-PHENYTOIN, SEIZURES, AND
SIR,—Dr Ainley and his colleagues (March 26, p. 705) describe an allergic reaction to chlorocresol, the preservative in
ELECTROENCEPHALOGRAPHY
certain brands of heparin. Leo Laboratories are manufacturers of pure porcine mucous heparin, and the preservative we use is chlorbutol, which is not a phenol derivative. Adverse reactions to Leo heparin were monitored over a three year period between 1973 and 1976, during which time over 30 000 million units of heparin with chlorbutol were used worldwide, in addition to the bulk supplies made available to other companies. No allergic reactions to chlorbutol were reported during this period or since. Replacement of the multidose rubbercapped vial by single-dose preservative-free ampoules would create problems with certain concentrations of heparin, and single-dose ampoules are more expensive. We do make a preservative-free single-dose ampoule of 5000 units of heparin in 5 ml. Medical Department, Leo Laboratories Ltd, Hayes, Middlesex
B. T. MARSH
HEART-RATE VARIABILITY IN BRAIN-DAMAGED ADULTS
SIR,—Dr Lowensohn and his colleagues (March 19, p. 626) describe a diminished variation in heart-rate in patients with acute brain damage. By contrast, others have reported an increase in heart-rate variability associated with raised intracranial pressure (I.C.P.).12 It is not clear whether the reduction of "normal cyclic changes" refers to the variations over periods of tto 1 h which Lowensohn et al. describe or to variability on a much shorter time scale, which they show in the published example. From this example, it would appear that their observations could be related, at least in part, to alterations in sinus arrhythmia-the fluctuation of heart-rate with the respiratory cycle which is normal in all age-groups.34 This fluctuation is greater when breathing is slower; any comparison between patterns at different times and in different conditions must, therefore, take account of any change in breathing pattern. Sinus arrhythmia decreases in amplitude as the mean heart-rate rises and is not usually definable at rates above about 100 beats/min;-’ any comparison between heart-rate patterns must, therefore, take account also of the mean heartrate,’ since a decrease in variation would be unusual only it it accompanied a steady or decreasing heart-rate. The example of increased variability attributed by Lowensohn et al. to postoperative decrease in i.c.P. could, thus, be related to the decrease in mean heart-rate (130 to 100 beats/ min) and possibly also to a slower breathing pattern: the lower published trace seems to reveal, despite random variations, a background sinus arrhythmia with a breathing frequency of around 12/min; breathing might have been more rapid during the period of raised I.C.P. Although acute brain damage and raised :.c.p. may sometimes be associated with slow or periodic breathing, there is no consistency in this association, and there may often be rapid regular breathing;6 indeed we have found in neurosurgical patients that rapid breathing may be trig-
gered by rising I.C.P.7 For all these reasons, it would seem unwise to assign signifialteration in heart-rate pattern, particularly in the absence of information on the breathing pattern, in the evaluation of brain damage or dysfunction. cance to
Institute of Physiology, University of Glasgow, Glasgow G12 8QQ
in 3 of their 16 patients (19%); in 10 patients (62%) major seizures were abolished or reduced. The increase in serumphenytoin also caused an increase (mean 42%) in serumphenobarbitone. Could the reduction of seizures not be achieved merely by increasing the dosage of phenobarbitone or primidone, a much less dangerous procedure? Phenytoin can activate seizures in man, and, experimentally, at high dose levels all animals became irritable and had ataxia and convulsions.2 In Lambie’s series, 4 epileptics had serum-phenytoins over 80 µmol/l. E.E.G. recordings were not monitored. In a retrospective study we examined 131 mentally subnormal epileptics on long-term phenytoin. 70 (53%) had clinical evidence of toxicity which remitted, at least partly, after a reduction of phenytoin dosage, and serum-phenytoins of 2S µg/ml or more. The duration of phenytoin intoxication averaged 47 months. 18 patients permanently lost their ability to walk. In 122 (93%) pneumoencephalographic findings were abnormal. The statistical correlation between the degree of the cerebellar atrophy and the severity of epilepsy was less striking than the correlation between the cerebellar atrophy and the serum-phenytoin.3 The phenytoin-treated epileptics, especially those with phenytoin intoxication, had significantly more E.E.G. abnormalities than the 68 epileptics without phenytoin treatment. Because phenytoin intoxication can provoke both seizures and E.E.G. abnormalities,4 the conclusion that more severe epilepsy was being treated more effectively does not follow. In epileptics on long-term phenytoin,’ E.E.G.S were normal in 20%, and serum-phenytoin levels averaged 10 µg/ml. In the epileptics with abnormal E.E.G.S, the average serum-phenytoins were within the range 15-21 µg/ml. Approximately a third of the patients had seizures months or years apart and a mean serum-phenytoin of 12.0 µg/ml. In another third seizure intervals were measured in days, and the average serum-phenytoin was 18-0 g/ml. Thus there seems to be a relation between seizure frequency, serum-phenytoin, and E.E.G. abnormalities in epileptics under long-term phenytoin treatment. One can expect that there are at least some epileptics with phenytoinactivated seizures among drug-resistant patients with high serum-phenytoin. High serum levels of phenytoin may be hazardous to patients6 and of little benefit. The E.E.G. is of value in detecting the silent toxicity of phenytoin or other anti epileptic drugs. Roseman4 stated in 1961 that: "The minimal early slowing of the alpha activity seems to act as a titrating end point [for phenytoin]. Once this point is reached, not only has the therapeutic dose been exceeded but toxic symptoms and signs may be expected. Therefore, it is useless to push the dosage higher, particularly if control of seizures has not been effected." One cannot rely on serum concentrations alone. Some patients are very sensitive to phenytoin toxicity,’ and severe intoxication has been recorded at a phenytoin concentration of only 1 tg/Ml.7 In toxic combinations of anticonvulsants the individual drugs may have their concentrations within therapeutic range yet a toxic encephalopathy will be revealed by the E.E.G. Monitoring drug levels and E.E.G.S seems to be the method of choice for ensuring safe and effective medication in epileptics on multiple drug therapy. An example is sodium valproate which seems clinically to increase the effects of other anticon-
SHEILA JENNETT
Fitch, W., McDowall, D. G. in Brain Hypoxia (edited by J. B. Brierley and B. S. Meldrum); p. 113. London, 1971. 2. Heck, A. F. in Cerebral Blood Flow and Intracranial Pressure (edited by C. Fieschi); p. 486. Basle, 1972. 3. Jennett, S., McKillop, J. H.J. Physiol., Lond. 1970, 213, 58P. 4. Davies, C. T. M., Neilson, J. M. M.J. appl. Physiol. 1967, 22, 947. 5. Davies, C. T. M., Neilson, J. M. M. ibid. p. 943. 6. North, J. B., Jennett, S. Archs Neurol. 1974, 31, 338. 7 North, J. B., Jennett, S. Unpublished. 1.
SIR,—Lambie et al.’ favour raising serum-phenytoin concentrations, yet when this was done major seizures increased
1.
Lambie, D. G., Johnson, R. H., Nanda, R. N., Shakir, R. A. Lancet, 1976, ii, 386. 2. Levy, L. L, Fenichel, G. M. Neurology, 1965,15, 716. 3. Iivanainen, M., Viukari, M., Helle, E.-P. Unpublished. 4. Roseman, E. Neurology, 1961, 11, 912. 5. Stensrud, P. A., Palmer, H. Epilepsia, 1964, 5, 364. 6. Ghatak, N. R., Santoso, R. A., McKinney, W. M. Neurology, 1976, 26, 818 7. Ahmad, S., Laidlaw, J., Houghton, G. W., Richens, A. J. Neurol. Neurosurg. Psychiat. 1975, 38, 225.
SERUM-PHENYTOIN, SEIZURES, AND
SIR,—Dr Ainley and his colleagues (March 26, p. 705) describe an allergic reaction to chlorocresol, the preservative in
ELECTROENCEPHALOGRAPHY
certain brands of heparin. Leo Laboratories are manufacturers of pure porcine mucous heparin, and the preservative we use is chlorbutol, which is not a phenol derivative. Adverse reactions to Leo heparin were monitored over a three year period between 1973 and 1976, during which time over 30 000 million units of heparin with chlorbutol were used worldwide, in addition to the bulk supplies made available to other companies. No allergic reactions to chlorbutol were reported during this period or since. Replacement of the multidose rubbercapped vial by single-dose preservative-free ampoules would create problems with certain concentrations of heparin, and single-dose ampoules are more expensive. We do make a preservative-free single-dose ampoule of 5000 units of heparin in 5 ml. Medical Department, Leo Laboratories Ltd, Hayes, Middlesex
B. T. MARSH
HEART-RATE VARIABILITY IN BRAIN-DAMAGED ADULTS
SIR,—Dr Lowensohn and his colleagues (March 19, p. 626) describe a diminished variation in heart-rate in patients with acute brain damage. By contrast, others have reported an increase in heart-rate variability associated with raised intracranial pressure (I.C.P.).12 It is not clear whether the reduction of "normal cyclic changes" refers to the variations over periods of tto 1 h which Lowensohn et al. describe or to variability on a much shorter time scale, which they show in the published example. From this example, it would appear that their observations could be related, at least in part, to alterations in sinus arrhythmia-the fluctuation of heart-rate with the respiratory cycle which is normal in all age-groups.34 This fluctuation is greater when breathing is slower; any comparison between patterns at different times and in different conditions must, therefore, take account of any change in breathing pattern. Sinus arrhythmia decreases in amplitude as the mean heart-rate rises and is not usually definable at rates above about 100 beats/min;-’ any comparison between heart-rate patterns must, therefore, take account also of the mean heartrate,’ since a decrease in variation would be unusual only it it accompanied a steady or decreasing heart-rate. The example of increased variability attributed by Lowensohn et al. to postoperative decrease in i.c.P. could, thus, be related to the decrease in mean heart-rate (130 to 100 beats/ min) and possibly also to a slower breathing pattern: the lower published trace seems to reveal, despite random variations, a background sinus arrhythmia with a breathing frequency of around 12/min; breathing might have been more rapid during the period of raised I.C.P. Although acute brain damage and raised :.c.p. may sometimes be associated with slow or periodic breathing, there is no consistency in this association, and there may often be rapid regular breathing;6 indeed we have found in neurosurgical patients that rapid breathing may be trig-
gered by rising I.C.P.7 For all these reasons, it would seem unwise to assign signifialteration in heart-rate pattern, particularly in the absence of information on the breathing pattern, in the evaluation of brain damage or dysfunction. cance to
Institute of Physiology, University of Glasgow, Glasgow G12 8QQ
in 3 of their 16 patients (19%); in 10 patients (62%) major seizures were abolished or reduced. The increase in serumphenytoin also caused an increase (mean 42%) in serumphenobarbitone. Could the reduction of seizures not be achieved merely by increasing the dosage of phenobarbitone or primidone, a much less dangerous procedure? Phenytoin can activate seizures in man, and, experimentally, at high dose levels all animals became irritable and had ataxia and convulsions.2 In Lambie’s series, 4 epileptics had serum-phenytoins over 80 µmol/l. E.E.G. recordings were not monitored. In a retrospective study we examined 131 mentally subnormal epileptics on long-term phenytoin. 70 (53%) had clinical evidence of toxicity which remitted, at least partly, after a reduction of phenytoin dosage, and serum-phenytoins of 2S µg/ml or more. The duration of phenytoin intoxication averaged 47 months. 18 patients permanently lost their ability to walk. In 122 (93%) pneumoencephalographic findings were abnormal. The statistical correlation between the degree of the cerebellar atrophy and the severity of epilepsy was less striking than the correlation between the cerebellar atrophy and the serum-phenytoin.3 The phenytoin-treated epileptics, especially those with phenytoin intoxication, had significantly more E.E.G. abnormalities than the 68 epileptics without phenytoin treatment. Because phenytoin intoxication can provoke both seizures and E.E.G. abnormalities,4 the conclusion that more severe epilepsy was being treated more effectively does not follow. In epileptics on long-term phenytoin,’ E.E.G.S were normal in 20%, and serum-phenytoin levels averaged 10 µg/ml. In the epileptics with abnormal E.E.G.S, the average serum-phenytoins were within the range 15-21 µg/ml. Approximately a third of the patients had seizures months or years apart and a mean serum-phenytoin of 12.0 µg/ml. In another third seizure intervals were measured in days, and the average serum-phenytoin was 18-0 g/ml. Thus there seems to be a relation between seizure frequency, serum-phenytoin, and E.E.G. abnormalities in epileptics under long-term phenytoin treatment. One can expect that there are at least some epileptics with phenytoinactivated seizures among drug-resistant patients with high serum-phenytoin. High serum levels of phenytoin may be hazardous to patients6 and of little benefit. The E.E.G. is of value in detecting the silent toxicity of phenytoin or other anti epileptic drugs. Roseman4 stated in 1961 that: "The minimal early slowing of the alpha activity seems to act as a titrating end point [for phenytoin]. Once this point is reached, not only has the therapeutic dose been exceeded but toxic symptoms and signs may be expected. Therefore, it is useless to push the dosage higher, particularly if control of seizures has not been effected." One cannot rely on serum concentrations alone. Some patients are very sensitive to phenytoin toxicity,’ and severe intoxication has been recorded at a phenytoin concentration of only 1 tg/Ml.7 In toxic combinations of anticonvulsants the individual drugs may have their concentrations within therapeutic range yet a toxic encephalopathy will be revealed by the E.E.G. Monitoring drug levels and E.E.G.S seems to be the method of choice for ensuring safe and effective medication in epileptics on multiple drug therapy. An example is sodium valproate which seems clinically to increase the effects of other anticon-
SHEILA JENNETT
Fitch, W., McDowall, D. G. in Brain Hypoxia (edited by J. B. Brierley and B. S. Meldrum); p. 113. London, 1971. 2. Heck, A. F. in Cerebral Blood Flow and Intracranial Pressure (edited by C. Fieschi); p. 486. Basle, 1972. 3. Jennett, S., McKillop, J. H.J. Physiol., Lond. 1970, 213, 58P. 4. Davies, C. T. M., Neilson, J. M. M.J. appl. Physiol. 1967, 22, 947. 5. Davies, C. T. M., Neilson, J. M. M. ibid. p. 943. 6. North, J. B., Jennett, S. Archs Neurol. 1974, 31, 338. 7 North, J. B., Jennett, S. Unpublished. 1.
SIR,—Lambie et al.’ favour raising serum-phenytoin concentrations, yet when this was done major seizures increased
1.
Lambie, D. G., Johnson, R. H., Nanda, R. N., Shakir, R. A. Lancet, 1976, ii, 386. 2. Levy, L. L, Fenichel, G. M. Neurology, 1965,15, 716. 3. Iivanainen, M., Viukari, M., Helle, E.-P. Unpublished. 4. Roseman, E. Neurology, 1961, 11, 912. 5. Stensrud, P. A., Palmer, H. Epilepsia, 1964, 5, 364. 6. Ghatak, N. R., Santoso, R. A., McKinney, W. M. Neurology, 1976, 26, 818 7. Ahmad, S., Laidlaw, J., Houghton, G. W., Richens, A. J. Neurol. Neurosurg. Psychiat. 1975, 38, 225.
