183 GLYCEROL IN CEREBRAL ŒDEMA
SiR,-Professor Gilsanz and his colleaguessuggest that patients with acute cerebral infarction fare better in terms of survival and of residual disability when treated with intravenous infusions of glycerol than with dexamethasone. Several aspects of their report deserve further
comment.
The authors’ conclusions are based largely on a clinical scoring scale, which was administered by the same observer to all patients. Such a scoring system can be quite arbitrary and subject to the observer’s bias, especially when the observer knows which patients are receiving which drugs. Furthermore, both groups of patients included subjects whose initial total scores were 72
maximum of 75 and who had such minimal findings as " slightly impaired comprehension" or " slightly impaired ability to follow commands " as their sole neurological deficit over a
24 hours after the initial insult. The same two groups also included comatose patients with severe neurological deficits. Since the initial mean score for the dexamethasone-treated group was lower than that for the glycerol-treated group, it can be assumed that, among the patients who received dexamethasone, there were more who had severe initial neurological insults. Such gross differences in the extent of neurological deficit could explain the different final results between the two groups, irrespective of the treatment modality employed. This assumption is further supported by the fact that patients with intracerebral haemorrhage, with more severe neurological deficits (maximum score for either group, 27), had a similar outcome whether given
glycerol or dexamethasone. The beneficial effect of glycerol on acute cerebral infarction, if any, is far from clear. The authors state that " the osmotic action of glycerol interferes with the production of brain oedema ..." It may be recalled that the dehydrating effect of any hyperosmolar agent is due largely to a relative impermeability of the blood-brain barrier to the substance, thereby creating an osmotic gradient between brain and blood. No osmotic gradient can be expected when blood-brain-barrier permeability is grossly altered, as may be the case in many patients with cerebral oedema complicating acute cerebral infarction. In this case, any dehydrating effect of glycerol is effected on the normal brain tissue surrounding the oedematous area.2,3 The authors used a 10% solution of glycerol infused intravenously to adult subjects at a rate of 20ml. per hour or 22-6 mmol per hour. Since glycerol half-life in the intact animal is about 180 minutes,4 such a rate of infusion would not be expected to raise plasma osmolality by more than 5-10 mosmol per litre. Since it has been shown that an osmotic gradient of at least 35 mosmol per litre is required to induce a net movement of water from brain to blood,4,6 the small doses of glycerol used in this study could not have induced any significant dehydration of brain tissue.
It has been suggested that the beneficial effect of glycerol cerebral infarction is due to its ability to improve oxidative phosphorylation through its conversion to alpha-glycerophosphate.1 Most of the available evidence, however, is against significant metabolism of glycerol by brain tissue. 7.8 Furthermore, the enzyme alpha-glycerophosphate dehydrogenase, which is needed to convert alpha-glycerophosphate to dihydroxyacetone phosphate, is either absent or present to a negligible extent in brain tissue.’ Even if such were the action of glycerol in brain, it would make far more sense to administer pyruvate, which can be converted to acetate and enter the Krebs cycle on acute
directly. 1.
Gilsanz, V., Rebollar, J. L., Buencuerpo, J., Chantres, M. T. Lancet, 1975, i, 1048. 2. Pappius, H. M., Dayes, L. A. Archs Neurol. 1965, 13, 395. 3. Guisado, R., Arieff, A. I., Tourtellotte, W. W., Massry, S. G. Clin. Res. 1974, 22, 105A. 4. Guisado, R., Arieff, A. I., Massry, S. G. Am. J. Physiol. 1974, 227, 865. 5. 6. 7.
Stern, E. W., Coxon, R. V. ibid. 204, 1. Arieff, A. I., Kleeman, C. R., Keushkerian, A., Bagdoyan, H. J. Lab. clin. Med. 1972, 79, 334. Coxon, R. V., Waterhouse, J. M. Riv. Patol. nerv. ment. 1970, 91,
323. 8. Waterhouse, J. M., Coxon, R. V. J. neurol. Sci. 1970, 10, 305. 9. Balazs, R. in Handbook of Neurochemistry (edited by A. Lajtha); vol. III, p. 8. New York, 1970.
In summary, the evidence to date does not support the of glycerol for the treatment of acute cerebral infarction. If glycerol does have a role in the therapy of cerebral oedema associated with stroke, the action is not an osmotic one, for reasons elucidated. At this time, evidence for another action of glycerol on brain is lacking, and the use of glycerol in acute cerebral infarction must be systematically evaluated with appropriate double-blind studies. It would also be most helpful if plasma-glycerol levels and changes in plasma osmolality during therapy were known, as the extremely variable natural history of acute stroke is in itself a formidable barrier to evaluation of any method of use
treatment.
University of California Nephrology Service, Veterans Administration Hospital 111J, 4150 Clement Street, San Francisco, CA 94121, U.S.A.
RAUL GUISADO ALLEN I. ARIEFF.
ASTHMA MORTALITY ASSOCIATED WITH PNEUMOTHORAX SIR,-In his description (April 12, p. 828) of two asthma deaths associated with pneumothorax and intermittent-positive-pressure breathing, Dr Karetzky does not mention the immediate prescription of high doses of steroids. Case 1 was on 10 mg. prednisolone daily, but the first dose of extra steroid (200 mg. hydrocortisone) was given on day 5. Case 2 received 100 mg. of hydrocortisone 6 hours after admission, but there was no mention of any subsequent steroid therapy. Undergraduates at Edinburgh are taught to give steroids in high dosage to all patients with acute asthma. In a case of average severity 100-500 mg. of hydrocortisone is given intravenously at once, and 60 mg. per day of prednisolone by mouth is then prescribed until clinical improvement occurs. Much higher doses are advised for very severe cases. In the United Kingdom the administration of a bronchodilator aerosol by I.P.P.B. is regarded as a safe and effective form of treatment for severe asthma. If Dr Karetzky wishes to challenge this view, it would be better to base his criticism on more scientifically and statistically acceptable data than those he has reported. Royal Infirmary, Edinburgh.
NIGEL J. COOKE.
** * We showed this letter follows.-ED. L.
to
Dr
Karetzky, whose reply
SIR,-Ishould like to point out that one of the unfortunate positions a consultant occasionally finds himself in is trying to deal with a problem that was not initially handled in the manner he would have preferred and more rarely beyond the point of reversibility. The cases presented are examples of the latter situation. I agree with Dr Cooke’s prescription for corticosteroid therapy in acute asthma and routinely recommend much the same regimen.1 In the United States the administration of a bronchodilator aerosol by i.P.P.B. has been widely used in acute asthma for over 20 years. Despite the lack of data supporting its supposed benefits and the significant number of studies indicating its ineffectiveness if not dangerS,2-4 it is only recently that its therapeutic efficacy is being
seriously questioned. If signs are to be listed
for
diagnosing
a
pneumothorax
asthma I would suggest sudden and dramatic clinical deterioration, much as one might see in patients
in
1. 2. 3. 4.
acute
Mithoefer, J. C., Karetzky, M. S. E.E.N.T. Dig. 1968, 30, 65. Karetzky, M. S., Brandstetter, R. Am. J. med. Sci. 1974, 267, 213. Barach, A. L., Segal, M. S. J. Am. med. Ass. 1975, 231, 1141. Karetzky, M. S. Medicine (in the press).
SiR,-Professor Gilsanz and his colleaguessuggest that patients with acute cerebral infarction fare better in terms of survival and of residual disability when treated with intravenous infusions of glycerol than with dexamethasone. Several aspects of their report deserve further
comment.
The authors’ conclusions are based largely on a clinical scoring scale, which was administered by the same observer to all patients. Such a scoring system can be quite arbitrary and subject to the observer’s bias, especially when the observer knows which patients are receiving which drugs. Furthermore, both groups of patients included subjects whose initial total scores were 72
maximum of 75 and who had such minimal findings as " slightly impaired comprehension" or " slightly impaired ability to follow commands " as their sole neurological deficit over a
24 hours after the initial insult. The same two groups also included comatose patients with severe neurological deficits. Since the initial mean score for the dexamethasone-treated group was lower than that for the glycerol-treated group, it can be assumed that, among the patients who received dexamethasone, there were more who had severe initial neurological insults. Such gross differences in the extent of neurological deficit could explain the different final results between the two groups, irrespective of the treatment modality employed. This assumption is further supported by the fact that patients with intracerebral haemorrhage, with more severe neurological deficits (maximum score for either group, 27), had a similar outcome whether given
glycerol or dexamethasone. The beneficial effect of glycerol on acute cerebral infarction, if any, is far from clear. The authors state that " the osmotic action of glycerol interferes with the production of brain oedema ..." It may be recalled that the dehydrating effect of any hyperosmolar agent is due largely to a relative impermeability of the blood-brain barrier to the substance, thereby creating an osmotic gradient between brain and blood. No osmotic gradient can be expected when blood-brain-barrier permeability is grossly altered, as may be the case in many patients with cerebral oedema complicating acute cerebral infarction. In this case, any dehydrating effect of glycerol is effected on the normal brain tissue surrounding the oedematous area.2,3 The authors used a 10% solution of glycerol infused intravenously to adult subjects at a rate of 20ml. per hour or 22-6 mmol per hour. Since glycerol half-life in the intact animal is about 180 minutes,4 such a rate of infusion would not be expected to raise plasma osmolality by more than 5-10 mosmol per litre. Since it has been shown that an osmotic gradient of at least 35 mosmol per litre is required to induce a net movement of water from brain to blood,4,6 the small doses of glycerol used in this study could not have induced any significant dehydration of brain tissue.
It has been suggested that the beneficial effect of glycerol cerebral infarction is due to its ability to improve oxidative phosphorylation through its conversion to alpha-glycerophosphate.1 Most of the available evidence, however, is against significant metabolism of glycerol by brain tissue. 7.8 Furthermore, the enzyme alpha-glycerophosphate dehydrogenase, which is needed to convert alpha-glycerophosphate to dihydroxyacetone phosphate, is either absent or present to a negligible extent in brain tissue.’ Even if such were the action of glycerol in brain, it would make far more sense to administer pyruvate, which can be converted to acetate and enter the Krebs cycle on acute
directly. 1.
Gilsanz, V., Rebollar, J. L., Buencuerpo, J., Chantres, M. T. Lancet, 1975, i, 1048. 2. Pappius, H. M., Dayes, L. A. Archs Neurol. 1965, 13, 395. 3. Guisado, R., Arieff, A. I., Tourtellotte, W. W., Massry, S. G. Clin. Res. 1974, 22, 105A. 4. Guisado, R., Arieff, A. I., Massry, S. G. Am. J. Physiol. 1974, 227, 865. 5. 6. 7.
Stern, E. W., Coxon, R. V. ibid. 204, 1. Arieff, A. I., Kleeman, C. R., Keushkerian, A., Bagdoyan, H. J. Lab. clin. Med. 1972, 79, 334. Coxon, R. V., Waterhouse, J. M. Riv. Patol. nerv. ment. 1970, 91,
323. 8. Waterhouse, J. M., Coxon, R. V. J. neurol. Sci. 1970, 10, 305. 9. Balazs, R. in Handbook of Neurochemistry (edited by A. Lajtha); vol. III, p. 8. New York, 1970.
In summary, the evidence to date does not support the of glycerol for the treatment of acute cerebral infarction. If glycerol does have a role in the therapy of cerebral oedema associated with stroke, the action is not an osmotic one, for reasons elucidated. At this time, evidence for another action of glycerol on brain is lacking, and the use of glycerol in acute cerebral infarction must be systematically evaluated with appropriate double-blind studies. It would also be most helpful if plasma-glycerol levels and changes in plasma osmolality during therapy were known, as the extremely variable natural history of acute stroke is in itself a formidable barrier to evaluation of any method of use
treatment.
University of California Nephrology Service, Veterans Administration Hospital 111J, 4150 Clement Street, San Francisco, CA 94121, U.S.A.
RAUL GUISADO ALLEN I. ARIEFF.
ASTHMA MORTALITY ASSOCIATED WITH PNEUMOTHORAX SIR,-In his description (April 12, p. 828) of two asthma deaths associated with pneumothorax and intermittent-positive-pressure breathing, Dr Karetzky does not mention the immediate prescription of high doses of steroids. Case 1 was on 10 mg. prednisolone daily, but the first dose of extra steroid (200 mg. hydrocortisone) was given on day 5. Case 2 received 100 mg. of hydrocortisone 6 hours after admission, but there was no mention of any subsequent steroid therapy. Undergraduates at Edinburgh are taught to give steroids in high dosage to all patients with acute asthma. In a case of average severity 100-500 mg. of hydrocortisone is given intravenously at once, and 60 mg. per day of prednisolone by mouth is then prescribed until clinical improvement occurs. Much higher doses are advised for very severe cases. In the United Kingdom the administration of a bronchodilator aerosol by I.P.P.B. is regarded as a safe and effective form of treatment for severe asthma. If Dr Karetzky wishes to challenge this view, it would be better to base his criticism on more scientifically and statistically acceptable data than those he has reported. Royal Infirmary, Edinburgh.
NIGEL J. COOKE.
** * We showed this letter follows.-ED. L.
to
Dr
Karetzky, whose reply
SIR,-Ishould like to point out that one of the unfortunate positions a consultant occasionally finds himself in is trying to deal with a problem that was not initially handled in the manner he would have preferred and more rarely beyond the point of reversibility. The cases presented are examples of the latter situation. I agree with Dr Cooke’s prescription for corticosteroid therapy in acute asthma and routinely recommend much the same regimen.1 In the United States the administration of a bronchodilator aerosol by i.P.P.B. has been widely used in acute asthma for over 20 years. Despite the lack of data supporting its supposed benefits and the significant number of studies indicating its ineffectiveness if not dangerS,2-4 it is only recently that its therapeutic efficacy is being
seriously questioned. If signs are to be listed
for
diagnosing
a
pneumothorax
asthma I would suggest sudden and dramatic clinical deterioration, much as one might see in patients
in
1. 2. 3. 4.
acute
Mithoefer, J. C., Karetzky, M. S. E.E.N.T. Dig. 1968, 30, 65. Karetzky, M. S., Brandstetter, R. Am. J. med. Sci. 1974, 267, 213. Barach, A. L., Segal, M. S. J. Am. med. Ass. 1975, 231, 1141. Karetzky, M. S. Medicine (in the press).
