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).
184 with other forms of underlying chronic pulmonary disease. This would be a major indication for an immediate chest X-ray. Subcutaneous emphysema would be another indication for a chest X-ray, since this may occur in asthma in the absence of a pneumothorax. Routine auscultation and palpation signs of pneumothorax are undependable in asthma, but in a crisis the results of needle aspiration can be convincing. Rutgers Medical School, Piscataway, New Jersey 08854, U.S.A.
MONROE S. KARETZKY.
EFFECT OF OPERATING-THEATRE TEMPERATURES ON THE SETTING-TIMES OF ACRYLIC CEMENTS FOR USE IN ORTHOPAEDIC SURGERY SiR,—The use of acrylic cements is well established in orthopaedic surgery, but few data appear to have been published on the acceleration of the setting-time as a function of increasing the theatre ambient temperature. Measurements have been carried out using unsterilised CMW bone cement to establish the relationship between the setting-time (corresponding approximately to the maximum temperature reached during setting) and the temperature at which the polymerisation was being carried out. Under carefully controlled conditions it was found that the time to set varied with temperature of polymerisation as follows: 77 59 68 (°F) 15 20 25 (°C) 7-5 4-9 12-6 Setting-time (min.) Thus between 68 °F and 77 °F there is
86 30 3-3
Ambient temp. Ambient temp.
95 35 2-5
reduction in setting-time of approximately 34%, and this may be vital during the manipulation and insertion of the cement into the prepared bone cavity. We recommend that, in order to achieve a desirable extension of setting-time, the unmixed components of the cement should not be stored in the operating-theatre, but be refrigerated to approximately 0°C for a period of 10 minutes before mixing in order to prolong the handlingtime if so desired. G. P. PEARSON School of Polymer Science, D. F. JONES. University of Bradford. Rheumatism Research Unit, University of Leeds.
a
V. WRIGHT.
ENDEMIC GOITRE AND CRETINISM to
SiR,—Your important editorial (March 15, p. 619) fails mention endemic cretinism as a major indicator for
urgency in
embarking on a programme for correction of iodine deficiency. The presence of this condition, now demonstrated to be due to severe iodine deficiency and preventable by its correction, makes an iodisation programme mandatory.l,2In the absence of cretinism there is less urgency, even though the benefits of an iodisation programme are substantial in prevention of morbidity. Endemic cretinism occurs only with severe iodine deficiency associated with more remote regions in endemic areasiodised oil has been shown to be a practicable and effective method where distribution of iodised salt is not possible. 3,44 Department of Social and Preventive
Medicine, Monash Medical School, Alfred Hospital, Prahran, Victoria 3181, Australia. 1. 2. 3.
BASIL S. HETZEL.
Lancet, 1972, ii, 365. Hetzel, B. S. N.Z. med. J. 1974, 80, 482. Stanbury, J. B., Ermans, A. M., Hetzel, B. S., Pretell, E. A., Querido, A. Wld Hlth Org. Chron. 1974, 28, 220. 4. Thilly, C. H., Delange, F., Goldstein-Golaire, J., Ermans, A. M. J. clin. Endocr. Metab. 1973, 36, 1196.
ALPHA-FETOPROTEIN AS AN INDICATOR OF FETAL CONDITION SiR,—Brock and Sutcliffe,! as well as others, have demonstrated the specific fetal antigen, alpha-fetoprotein (A.F.P.), to be a useful in-utero predictor of fetal neural-tube defects. Several investigators, using radioimmunoassay, have also suggested a correlation between elevated A.F.P. concentrations and fetal death or fetal compromise in pregnancies complicated by Rh disease and maternal diabetes. 2-5 For the past 3 years we have used a radial immunodiffusion technique to determine amniotic-fluid A.F.P. levels in secondtrimester patients whose fetuses were genetically at risk for neural-tube defects. In this preliminary study the immunodiffusion assay, sensitive to 165 ng. per ml., was utilised to determine A.F.P. concentrations in 80 amnioticfluid samples from second and third trimester patients whose pregnancies were either completely normal or complicated by toxasmia, diabetes, Rh immunisation, fetal anencephaly, or fetal death. In this study, the mean A.F.P. concentration in 26 samples from normal pregnancies between 15 and 18 weeks’ gestation was 8-6 g. per ml. (range 2-6-17-5 g. per ml.). In 11 samples from normal 19 to 22 weeks’ gestation, the A.F.P. levels varied between 2-4 and 9-1 g. per ml. (mean 4-2 jjg. per ml.). These findings agree with those of other investigators using radioimmunoassay. 6-8 It is of note that the only other second-trimester fluid sample, obtained from a 19-week pregnancy complicated by trisomy 18, severe Rh sensitisation, and fetal death, revealed an A.F.P. concentration of 16.2 g. per ml., which was elevated but not outside the 95% confidence limit. The results obtained from 40 patients in the third trimester are summarised in the figure. With the exception of 2 samples from anencephalic pregnancies, where A.F.P. concentrations were well above 20 g. per ml., all other A.F.P. levels obtained after the 32nd week of gestation were less than 0-8 tg. per ml. A.F.P. concentrations in all 10 normal pregnancies between the 36th and 40th week of gestation were undetectable (< 165 ng. per ml.), also correlating with published radioimmunoassay data.9 The mean A.F.P. levels in 15 samples from diabetic patients between 36 and 40 weeks of gestation were significantly higher than in the normal controls (p < 0-0005). Concentrations in toxeemic pregnancies were raised, but the number of samples precluded statistical evaluation. A.F.P. levels from our 6 Rh-sensitised pregnancies were not raised in comparison with other published data from normal pregnancies at the same stage of gestation.88 These preliminary data from a small but representative normal and high-risk sampling agree with the results of other investigators using the more sensitive but more ’
complex radioimmunoassay. Our results further confirm a tenfold increase in A.F.P. levels in anencephalic pregnancies noted by other investigators.1, 2,10,11 Furthermore, this study suggests a correlation between elevated A.F.P. levels and certain abnormal condiBrock, D. J. H., Sutcliffe, R. G. Lancet, 1972, ii, 197. Higa, Y., Sasazuki, T., Nakajima, H., Takayama, M., Tada, M., Soma, H. Am. J. Obstet. Gynec. 1974, 119, 932. 3. Norgaard-Pederson, B., Klebe, J. G. Acta endocr., Copenh. suppl., 1974, 182, 81. 4. Seppälä, M., Ruoslahti, E. Obstet. Gynec., N.Y. 1973, 42, 701. 5. Seppälä, M., Ruoslahti, E. Lancet, 1973, i, 155. 6. Allen, L. D., Ferguson-Smith, M. A., Donald, I., Sweet, E. M., Gibson, A. A. M. ibid. 1973, ii, 522. 7. Hull, E. W., Carbones, P. P., Moertel, C. G., O’Conor, G. T. ibid. 1970, i, 779. 8. Seppälä, M., Ruoslahti, E. Am. J. Obstet. Gynec. 1972, 114, 595. 9. Seller, M. J., Coltart, T. M., Campbell, S., Singer, J. D. Lancet, 1973, i, 73. 10. Harris, R., Jennison, R. F., Barson, A. J., Laurence, K. M., Ruoslahti, E., Seppälä, M. ibid. 1974, i, 429. 11. Purves, L. R., Branch, W. R., Boes, E. G. M. ibid. 1967, i, 1007. 1. 2.
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).
184 with other forms of underlying chronic pulmonary disease. This would be a major indication for an immediate chest X-ray. Subcutaneous emphysema would be another indication for a chest X-ray, since this may occur in asthma in the absence of a pneumothorax. Routine auscultation and palpation signs of pneumothorax are undependable in asthma, but in a crisis the results of needle aspiration can be convincing. Rutgers Medical School, Piscataway, New Jersey 08854, U.S.A.
MONROE S. KARETZKY.
EFFECT OF OPERATING-THEATRE TEMPERATURES ON THE SETTING-TIMES OF ACRYLIC CEMENTS FOR USE IN ORTHOPAEDIC SURGERY SiR,—The use of acrylic cements is well established in orthopaedic surgery, but few data appear to have been published on the acceleration of the setting-time as a function of increasing the theatre ambient temperature. Measurements have been carried out using unsterilised CMW bone cement to establish the relationship between the setting-time (corresponding approximately to the maximum temperature reached during setting) and the temperature at which the polymerisation was being carried out. Under carefully controlled conditions it was found that the time to set varied with temperature of polymerisation as follows: 77 59 68 (°F) 15 20 25 (°C) 7-5 4-9 12-6 Setting-time (min.) Thus between 68 °F and 77 °F there is
86 30 3-3
Ambient temp. Ambient temp.
95 35 2-5
reduction in setting-time of approximately 34%, and this may be vital during the manipulation and insertion of the cement into the prepared bone cavity. We recommend that, in order to achieve a desirable extension of setting-time, the unmixed components of the cement should not be stored in the operating-theatre, but be refrigerated to approximately 0°C for a period of 10 minutes before mixing in order to prolong the handlingtime if so desired. G. P. PEARSON School of Polymer Science, D. F. JONES. University of Bradford. Rheumatism Research Unit, University of Leeds.
a
V. WRIGHT.
ENDEMIC GOITRE AND CRETINISM to
SiR,—Your important editorial (March 15, p. 619) fails mention endemic cretinism as a major indicator for
urgency in
embarking on a programme for correction of iodine deficiency. The presence of this condition, now demonstrated to be due to severe iodine deficiency and preventable by its correction, makes an iodisation programme mandatory.l,2In the absence of cretinism there is less urgency, even though the benefits of an iodisation programme are substantial in prevention of morbidity. Endemic cretinism occurs only with severe iodine deficiency associated with more remote regions in endemic areasiodised oil has been shown to be a practicable and effective method where distribution of iodised salt is not possible. 3,44 Department of Social and Preventive
Medicine, Monash Medical School, Alfred Hospital, Prahran, Victoria 3181, Australia. 1. 2. 3.
BASIL S. HETZEL.
Lancet, 1972, ii, 365. Hetzel, B. S. N.Z. med. J. 1974, 80, 482. Stanbury, J. B., Ermans, A. M., Hetzel, B. S., Pretell, E. A., Querido, A. Wld Hlth Org. Chron. 1974, 28, 220. 4. Thilly, C. H., Delange, F., Goldstein-Golaire, J., Ermans, A. M. J. clin. Endocr. Metab. 1973, 36, 1196.
ALPHA-FETOPROTEIN AS AN INDICATOR OF FETAL CONDITION SiR,—Brock and Sutcliffe,! as well as others, have demonstrated the specific fetal antigen, alpha-fetoprotein (A.F.P.), to be a useful in-utero predictor of fetal neural-tube defects. Several investigators, using radioimmunoassay, have also suggested a correlation between elevated A.F.P. concentrations and fetal death or fetal compromise in pregnancies complicated by Rh disease and maternal diabetes. 2-5 For the past 3 years we have used a radial immunodiffusion technique to determine amniotic-fluid A.F.P. levels in secondtrimester patients whose fetuses were genetically at risk for neural-tube defects. In this preliminary study the immunodiffusion assay, sensitive to 165 ng. per ml., was utilised to determine A.F.P. concentrations in 80 amnioticfluid samples from second and third trimester patients whose pregnancies were either completely normal or complicated by toxasmia, diabetes, Rh immunisation, fetal anencephaly, or fetal death. In this study, the mean A.F.P. concentration in 26 samples from normal pregnancies between 15 and 18 weeks’ gestation was 8-6 g. per ml. (range 2-6-17-5 g. per ml.). In 11 samples from normal 19 to 22 weeks’ gestation, the A.F.P. levels varied between 2-4 and 9-1 g. per ml. (mean 4-2 jjg. per ml.). These findings agree with those of other investigators using radioimmunoassay. 6-8 It is of note that the only other second-trimester fluid sample, obtained from a 19-week pregnancy complicated by trisomy 18, severe Rh sensitisation, and fetal death, revealed an A.F.P. concentration of 16.2 g. per ml., which was elevated but not outside the 95% confidence limit. The results obtained from 40 patients in the third trimester are summarised in the figure. With the exception of 2 samples from anencephalic pregnancies, where A.F.P. concentrations were well above 20 g. per ml., all other A.F.P. levels obtained after the 32nd week of gestation were less than 0-8 tg. per ml. A.F.P. concentrations in all 10 normal pregnancies between the 36th and 40th week of gestation were undetectable (< 165 ng. per ml.), also correlating with published radioimmunoassay data.9 The mean A.F.P. levels in 15 samples from diabetic patients between 36 and 40 weeks of gestation were significantly higher than in the normal controls (p < 0-0005). Concentrations in toxeemic pregnancies were raised, but the number of samples precluded statistical evaluation. A.F.P. levels from our 6 Rh-sensitised pregnancies were not raised in comparison with other published data from normal pregnancies at the same stage of gestation.88 These preliminary data from a small but representative normal and high-risk sampling agree with the results of other investigators using the more sensitive but more ’
complex radioimmunoassay. Our results further confirm a tenfold increase in A.F.P. levels in anencephalic pregnancies noted by other investigators.1, 2,10,11 Furthermore, this study suggests a correlation between elevated A.F.P. levels and certain abnormal condiBrock, D. J. H., Sutcliffe, R. G. Lancet, 1972, ii, 197. Higa, Y., Sasazuki, T., Nakajima, H., Takayama, M., Tada, M., Soma, H. Am. J. Obstet. Gynec. 1974, 119, 932. 3. Norgaard-Pederson, B., Klebe, J. G. Acta endocr., Copenh. suppl., 1974, 182, 81. 4. Seppälä, M., Ruoslahti, E. Obstet. Gynec., N.Y. 1973, 42, 701. 5. Seppälä, M., Ruoslahti, E. Lancet, 1973, i, 155. 6. Allen, L. D., Ferguson-Smith, M. A., Donald, I., Sweet, E. M., Gibson, A. A. M. ibid. 1973, ii, 522. 7. Hull, E. W., Carbones, P. P., Moertel, C. G., O’Conor, G. T. ibid. 1970, i, 779. 8. Seppälä, M., Ruoslahti, E. Am. J. Obstet. Gynec. 1972, 114, 595. 9. Seller, M. J., Coltart, T. M., Campbell, S., Singer, J. D. Lancet, 1973, i, 73. 10. Harris, R., Jennison, R. F., Barson, A. J., Laurence, K. M., Ruoslahti, E., Seppälä, M. ibid. 1974, i, 429. 11. Purves, L. R., Branch, W. R., Boes, E. G. M. ibid. 1967, i, 1007. 1. 2.
