349 tined to develop the disease. Perhaps by this means we may also obtain a clearer understanding of the progress of pre-eclampsia itself.
tients with unequivocal pre-eclampsia. Furthermore, Pritchard et al. 15 have described a series of patients in some of whom eclampsia occurred without evidence of
coagulopathy. In normal pregnancy,
serum-urate
Requests for reprints should be addressed to W.
concentration 12 In the pres-
be lower the earlier the gestation. study, patients with severe pre-eclampsia, although they had an earlier mean gestation, showed a significantly higher serum-urate concentration than normotensive controls. The group with mild pre-eclampsia also had significantly higher serum-urate levels than the normotensive group. Differences in urate clearance became apparent between each pre-eclamptic group and each control group, confirming the observations of Hayashi. 16 These differences were predominantly due to altered renal handling of urate, resulting in increased net tubular reabsorption.3 Changes in these aspects of renal function correlated significantly with the degree of proteinuria in the group with severe pre-eclampsia. Thus, assessment of renal function is more likely than measurement of coagulation changes to be of practical value in managing patients with severe pre-eclampsia. Conclusions about the predictive value of such tests must await adequate serial investigation of patients des-
tends
to
REFERENCES
ent
1. 2. 3. 4.
5. 6.
7.
Department of Medicine and School of Pharmacy, Faculty of Medicine, University of Tasmania
Summary
high-density polyethylene tubing. INTRODUCTION
ii, 323. Redman, C. i, 1370. Redman, C.
W.
G., Beilin, L. J., Bonnar, J., Wilkinson, R. H. ibid. 1976,
W.
G., Beilin, L. J., Bonnar, J. J. clin. Path. 1976, 29, suppl.
C. W. G., Beilin, L. J., Bonnar, J. Br. J. Obstet. Gynæc. 1977, 84, 395. 8. Hill, L. M., Furness, C., Dunlop, W. Br. med. J. 1977, ii, 1520. 9. Breckenridge, R. T., Ratnoff, O. D. Blood, 1962, 20, 137. 10. Kageyama, N. Clinica chim. Acta, 1971, 31, 421. 11. Bierans De Haan, J. in Reaction Rate Analyser Instruction Manual. L. K. B. Limited, Bromma, Sweden, 1972. 12. Dunlop, W., Davison, J. M. Br. J. Obstet. Gynœc. 1977, 84, 13. 13. Chesley, L. C. in Hypertensive Disorders in Pregnancy; p. 157. New York, 1978. 14. Kendall, M. G. in Rank Correlation Methods. London, 1970. 15. Pritchard, J. A., Cunningham, F. G., Mason, R. A. in Hypertension in Pregnancy (edited by M. D. Lindheimer, A. I. Katz, and F. P. Zuspan); p. 95. New York, 1976. 16. Hayashi, T. Am. J. Obstet. Gynec. 1956, 71, 859.
A. J. GALBRAITH GRAHAM W. BOYD
During initial studies with nitroglycerin infusion in patients with acute myocardial infarction, higher doses than previously reported were required to achieve the desired hæmodynamic effect. A flow-rate-dependent loss of drug from the plastic infusion set was demonstrated during simulated infusion. This loss was considerably reduced when nitroglycerin was infused from glass syringes through
Bonnar, J., McNicol, G. P., Douglas, A. S. Br. med. J. 1971, ii, 12. Slemons, J. M., Bogert, L. J.J. biol. Chem. 1917, 22, 63. Chesley, L. C., Williams, L. O. Am. J. Obstet. Gynec. 1945, 50, 367. Howie, P. W., Purdie, D. W., Begg, C. B., Prentice, C. R. M. Lancet, 1976,
10, 91.
LOSS OF NITROGLYCERIN FROM INTRAVENOUS INFUSION SETS P. A. COSSUM M. S. ROBERTS
D.
_
Redman,
flow-rate. The volume of solution in the burette chamber was kept at between 40 and 50 ml. Flow-rates were checked by collection of efflux from the tubing of the giving-set in a glass measuring cylinder. Flow-rates used were 0.07, 0.17, 0.30, 0.91 ml/min (equivalent to 7, 17, 30, 91 µg/min, respectively). Samples were placed in glass bottles with metal screw tops. In a second experiment, nitroglycerin in 5% dextrose solution was pumped from a 50 ml glass syringe via a high-density polyethylene cannula (80 x 0 15 cm). The glass syringe was driven by a Braun pump to give a constant flow-rate of 0.05 ml/min (equivalent to 5 µg/min). Efflux was collected from the end of the tubing and samples were stored in glass bottles with metal screw tops. Samples were assayed for nitroglycerin by means of the kinetic assay of Yap et awl. In this assay an alkaline methanolic solution degrades nitroglycerin in stages with the formation of a chromophoric intermediate which has a wavelength of maximum absorbance at 328 nm. In all experiments, a sample volume of nitroglycerin solution was stored in glass bottles for the duration of the experiment. All work was done at room temperature.
NITROGLYCERIN has been used in an attempt to reduce the size of myocardial infarcts.l In preliminary experiments we infused several patients with this drug from a plastic infusion bag through a standard intravenous giving-set with a burette. The rate of infusion was controlled with a Houlter pump. We found that doses as high as 300 µg/min were needed to produce the desired hsmodynamic effect. This is a much higher dose than others2 found necessary and suggested to us that loss of nitroglycerin might have been caused by interaction with the plastic of the infusion set. METHODS AND MATERIALS
A stock solution of 5% nitroglycerin in ethanol was diluted in 5% dextrose solution to give a 001% nitroglycerin solution. 500 ml of the 001% nitroglycerin solution was placed in glass infusion bottles to which standard plastic giving-sets with burettes (Buretrol) were connected. Nitroglycerin solution flowed through the giving-sets under gravity and careful monitoring ensured a constant desired
Fig. 1—Effect of flow-rate on percentage of nitroglycerin remaining after passage through plastic infusion sets.
350 with a Harvard pump and although they do not say so in their reports, they may well have used glass syringes attached to relatively short lengths of plastic tubing. Such a technique would certainly have reduced any
absorption. drugs are often infused by of plastic infusion sets with burettes, and our investigation indicates that nitroglycerin interacts with certain plastics and that care must be taken in the choice of materials for the infusion set. We found that nitroglycerin loss was much reduced when glass syringes attached to high-density polyethylene tubing were used instead. Similar problems may arise with other drugs given routinely by infusion. In Australia and-the U.K.
means
Fig. 2-Percentage of initial nitroglycerin concentration remaining after passage through 80cm polyethylene tubing attached to glass syringe. -
RESULTS
Fig. 1 shows the loss of nitroglycerin from plastic giving-sets over 9 h. The loss was in part flow-rate-dependent, the fraction of the original nitroglycerin concentration which remained in the eluting solution being greater at faster rates. Nitroglycerin content decreased rapidly within the first hour at all the flow-rates used, but with faster flow-rates, a subsequent small increase occurred before a steady-state fraction was reached. For the fastest flow-rate, this level was 70% of the original nitroglycerin concentration. Very little nitroglycerin was lost when a 0.01% solution was delivered from a glass syringe through a short length of high-density polyethylene tubing (fig. 2). At a comparable flow-rate to that used in this second experiment 80% of nitroglycerin would have been lost from the plastic giving-set. Less than 1% of nitroglycerin was lost on storage in all the glass containers for 24 h.
We thank the Pharmacy Department of the Royal Hobart Hospital for valuable assistance. Requests for reprints should be addressed to G.W.B., Department of Medicine, University of Tasmania, 43 Collins Street, Hobart, Tasmania 7000. REFERENCES 1. 2.
Figueras, J., Forrester, J. S. Chest, 1978, 73, 1. Flaherty, J. T., Come, P. C., Baird, M. G., Rouleau, J., Taylor, D. R., Weistedt, M. L., Greene, H. L., Becker, L. C., Pitt,
B. Br.
Heart J. 1976, 38,
612. 3. Yap, S. K.,
Rhodes, C. T., Fung, Ho-Leung. Am. J. hosp. Pharmac. 1975, 32, 1039. 4. Edelman, B. A., Contractor, A. V., Shangraw, R. F. J. Am. Pharm. Ass. 1971, N.S.II 30. 5. Servant, R. M. Cited by Edelman, B. A., Contractor, A. E., Sharngraw, R. F. ibid. p. 30. 6. Weisenfeld, S., Podolsky, S., Goldsmith, L., Ziff, L. Diabetes, 1968, 17, 766. 7. Roberts, M. S., Cossum, P. A., Galbraith, A. J., Boyd, G. W. Unpublished.
Methods and Devices A RAPID SIMPLIFIED METHOD FOR ROUTINE MEASUREMENT OF GLYCOSYLATED HÆMOGLOBIN
D.
R. E. DAVIS
J. NICOL
Department of Hœmatology, Royal Perth Hospital, Western Australia
DISCUSSION
Our experiments showed that loss of nitroglycerin from our infusion set was considerable, and we believe that this caused us to use higher doses in our clinical investigations. Nitroglycerin was probably lost by diffusion into and through the plastic of the set. There was a similar considerable loss of potency when nitroglycerin tablets were stored in plastic containers.4 Plastics associated with loss included polystyrene, polypropylene, polyvinyl chloride, and polyethylene.5 Glass and high-density polyethylene reduced the extent of loss from tablets. Loss of insulin from parenteral infusion solutions due to drug/plastic interaction can be reduced by the addition of albumin,6 but this did not prevent nitroglycerin loss in our investigations.7 We demonstrated that the loss of nitroglycerin was dependent on flow-rate, with the greatest percentage loss occurring at the slowest flow-rates. The relation between flow-rate and nitroglycerin concentration in the effluent was not simple, partly as a result of the slightly variable volume in the burette. American workers who infused patients with nitroglycerin achieved hsemodynamic effects with much lower doses than we used.2 These workers infused the drug
THE concentration of
glycosylated haemoglobin
is
higher in
patients with diabetes mellitus than in non-diabetics1-3 and is useful index of control in diabetic patients.4-6. Unlike single of blood-glucose, the glycosylated hmmoglobin concentration reflects integrated blood-glucose concentration over the previous 8-10 weeks. a
measurements
Glycosylated haemoglobin comprises three fast-moving com(Hb A1a + Alb and A Ie) which may be separated from haemoglobin A and A2 either together or separately by column chromatography with an ion-exchange resin. These minor components are usually measured together as glycosylated haemoglobin. Chromatographic procedures requiring many hours to complete the separation2 have restricted the use of the ponents
test.
and Lehmann’ have described a rapid method for of glycosylated haemoglobin which could be completed in 2yh. This was an important advance but ideally a method is required which can be completed in a few minutes and which will enable a patient to be assessed during a single consultation. We describe such a method.
Kynoch
the
measurement
REAGENTS AND APPARATUS
Buffer 1 pH 6-7 5.18 g sodium dihydrogen orthophosphate dihydrate 1.18 g disodium hydrogen orthophosphate anhydrous 0.65gpotassium cyanide Dissolve in distilled water to make 1 litre
tients with unequivocal pre-eclampsia. Furthermore, Pritchard et al. 15 have described a series of patients in some of whom eclampsia occurred without evidence of
coagulopathy. In normal pregnancy,
serum-urate
Requests for reprints should be addressed to W.
concentration 12 In the pres-
be lower the earlier the gestation. study, patients with severe pre-eclampsia, although they had an earlier mean gestation, showed a significantly higher serum-urate concentration than normotensive controls. The group with mild pre-eclampsia also had significantly higher serum-urate levels than the normotensive group. Differences in urate clearance became apparent between each pre-eclamptic group and each control group, confirming the observations of Hayashi. 16 These differences were predominantly due to altered renal handling of urate, resulting in increased net tubular reabsorption.3 Changes in these aspects of renal function correlated significantly with the degree of proteinuria in the group with severe pre-eclampsia. Thus, assessment of renal function is more likely than measurement of coagulation changes to be of practical value in managing patients with severe pre-eclampsia. Conclusions about the predictive value of such tests must await adequate serial investigation of patients des-
tends
to
REFERENCES
ent
1. 2. 3. 4.
5. 6.
7.
Department of Medicine and School of Pharmacy, Faculty of Medicine, University of Tasmania
Summary
high-density polyethylene tubing. INTRODUCTION
ii, 323. Redman, C. i, 1370. Redman, C.
W.
G., Beilin, L. J., Bonnar, J., Wilkinson, R. H. ibid. 1976,
W.
G., Beilin, L. J., Bonnar, J. J. clin. Path. 1976, 29, suppl.
C. W. G., Beilin, L. J., Bonnar, J. Br. J. Obstet. Gynæc. 1977, 84, 395. 8. Hill, L. M., Furness, C., Dunlop, W. Br. med. J. 1977, ii, 1520. 9. Breckenridge, R. T., Ratnoff, O. D. Blood, 1962, 20, 137. 10. Kageyama, N. Clinica chim. Acta, 1971, 31, 421. 11. Bierans De Haan, J. in Reaction Rate Analyser Instruction Manual. L. K. B. Limited, Bromma, Sweden, 1972. 12. Dunlop, W., Davison, J. M. Br. J. Obstet. Gynœc. 1977, 84, 13. 13. Chesley, L. C. in Hypertensive Disorders in Pregnancy; p. 157. New York, 1978. 14. Kendall, M. G. in Rank Correlation Methods. London, 1970. 15. Pritchard, J. A., Cunningham, F. G., Mason, R. A. in Hypertension in Pregnancy (edited by M. D. Lindheimer, A. I. Katz, and F. P. Zuspan); p. 95. New York, 1976. 16. Hayashi, T. Am. J. Obstet. Gynec. 1956, 71, 859.
A. J. GALBRAITH GRAHAM W. BOYD
During initial studies with nitroglycerin infusion in patients with acute myocardial infarction, higher doses than previously reported were required to achieve the desired hæmodynamic effect. A flow-rate-dependent loss of drug from the plastic infusion set was demonstrated during simulated infusion. This loss was considerably reduced when nitroglycerin was infused from glass syringes through
Bonnar, J., McNicol, G. P., Douglas, A. S. Br. med. J. 1971, ii, 12. Slemons, J. M., Bogert, L. J.J. biol. Chem. 1917, 22, 63. Chesley, L. C., Williams, L. O. Am. J. Obstet. Gynec. 1945, 50, 367. Howie, P. W., Purdie, D. W., Begg, C. B., Prentice, C. R. M. Lancet, 1976,
10, 91.
LOSS OF NITROGLYCERIN FROM INTRAVENOUS INFUSION SETS P. A. COSSUM M. S. ROBERTS
D.
_
Redman,
flow-rate. The volume of solution in the burette chamber was kept at between 40 and 50 ml. Flow-rates were checked by collection of efflux from the tubing of the giving-set in a glass measuring cylinder. Flow-rates used were 0.07, 0.17, 0.30, 0.91 ml/min (equivalent to 7, 17, 30, 91 µg/min, respectively). Samples were placed in glass bottles with metal screw tops. In a second experiment, nitroglycerin in 5% dextrose solution was pumped from a 50 ml glass syringe via a high-density polyethylene cannula (80 x 0 15 cm). The glass syringe was driven by a Braun pump to give a constant flow-rate of 0.05 ml/min (equivalent to 5 µg/min). Efflux was collected from the end of the tubing and samples were stored in glass bottles with metal screw tops. Samples were assayed for nitroglycerin by means of the kinetic assay of Yap et awl. In this assay an alkaline methanolic solution degrades nitroglycerin in stages with the formation of a chromophoric intermediate which has a wavelength of maximum absorbance at 328 nm. In all experiments, a sample volume of nitroglycerin solution was stored in glass bottles for the duration of the experiment. All work was done at room temperature.
NITROGLYCERIN has been used in an attempt to reduce the size of myocardial infarcts.l In preliminary experiments we infused several patients with this drug from a plastic infusion bag through a standard intravenous giving-set with a burette. The rate of infusion was controlled with a Houlter pump. We found that doses as high as 300 µg/min were needed to produce the desired hsmodynamic effect. This is a much higher dose than others2 found necessary and suggested to us that loss of nitroglycerin might have been caused by interaction with the plastic of the infusion set. METHODS AND MATERIALS
A stock solution of 5% nitroglycerin in ethanol was diluted in 5% dextrose solution to give a 001% nitroglycerin solution. 500 ml of the 001% nitroglycerin solution was placed in glass infusion bottles to which standard plastic giving-sets with burettes (Buretrol) were connected. Nitroglycerin solution flowed through the giving-sets under gravity and careful monitoring ensured a constant desired
Fig. 1—Effect of flow-rate on percentage of nitroglycerin remaining after passage through plastic infusion sets.
350 with a Harvard pump and although they do not say so in their reports, they may well have used glass syringes attached to relatively short lengths of plastic tubing. Such a technique would certainly have reduced any
absorption. drugs are often infused by of plastic infusion sets with burettes, and our investigation indicates that nitroglycerin interacts with certain plastics and that care must be taken in the choice of materials for the infusion set. We found that nitroglycerin loss was much reduced when glass syringes attached to high-density polyethylene tubing were used instead. Similar problems may arise with other drugs given routinely by infusion. In Australia and-the U.K.
means
Fig. 2-Percentage of initial nitroglycerin concentration remaining after passage through 80cm polyethylene tubing attached to glass syringe. -
RESULTS
Fig. 1 shows the loss of nitroglycerin from plastic giving-sets over 9 h. The loss was in part flow-rate-dependent, the fraction of the original nitroglycerin concentration which remained in the eluting solution being greater at faster rates. Nitroglycerin content decreased rapidly within the first hour at all the flow-rates used, but with faster flow-rates, a subsequent small increase occurred before a steady-state fraction was reached. For the fastest flow-rate, this level was 70% of the original nitroglycerin concentration. Very little nitroglycerin was lost when a 0.01% solution was delivered from a glass syringe through a short length of high-density polyethylene tubing (fig. 2). At a comparable flow-rate to that used in this second experiment 80% of nitroglycerin would have been lost from the plastic giving-set. Less than 1% of nitroglycerin was lost on storage in all the glass containers for 24 h.
We thank the Pharmacy Department of the Royal Hobart Hospital for valuable assistance. Requests for reprints should be addressed to G.W.B., Department of Medicine, University of Tasmania, 43 Collins Street, Hobart, Tasmania 7000. REFERENCES 1. 2.
Figueras, J., Forrester, J. S. Chest, 1978, 73, 1. Flaherty, J. T., Come, P. C., Baird, M. G., Rouleau, J., Taylor, D. R., Weistedt, M. L., Greene, H. L., Becker, L. C., Pitt,
B. Br.
Heart J. 1976, 38,
612. 3. Yap, S. K.,
Rhodes, C. T., Fung, Ho-Leung. Am. J. hosp. Pharmac. 1975, 32, 1039. 4. Edelman, B. A., Contractor, A. V., Shangraw, R. F. J. Am. Pharm. Ass. 1971, N.S.II 30. 5. Servant, R. M. Cited by Edelman, B. A., Contractor, A. E., Sharngraw, R. F. ibid. p. 30. 6. Weisenfeld, S., Podolsky, S., Goldsmith, L., Ziff, L. Diabetes, 1968, 17, 766. 7. Roberts, M. S., Cossum, P. A., Galbraith, A. J., Boyd, G. W. Unpublished.
Methods and Devices A RAPID SIMPLIFIED METHOD FOR ROUTINE MEASUREMENT OF GLYCOSYLATED HÆMOGLOBIN
D.
R. E. DAVIS
J. NICOL
Department of Hœmatology, Royal Perth Hospital, Western Australia
DISCUSSION
Our experiments showed that loss of nitroglycerin from our infusion set was considerable, and we believe that this caused us to use higher doses in our clinical investigations. Nitroglycerin was probably lost by diffusion into and through the plastic of the set. There was a similar considerable loss of potency when nitroglycerin tablets were stored in plastic containers.4 Plastics associated with loss included polystyrene, polypropylene, polyvinyl chloride, and polyethylene.5 Glass and high-density polyethylene reduced the extent of loss from tablets. Loss of insulin from parenteral infusion solutions due to drug/plastic interaction can be reduced by the addition of albumin,6 but this did not prevent nitroglycerin loss in our investigations.7 We demonstrated that the loss of nitroglycerin was dependent on flow-rate, with the greatest percentage loss occurring at the slowest flow-rates. The relation between flow-rate and nitroglycerin concentration in the effluent was not simple, partly as a result of the slightly variable volume in the burette. American workers who infused patients with nitroglycerin achieved hsemodynamic effects with much lower doses than we used.2 These workers infused the drug
THE concentration of
glycosylated haemoglobin
is
higher in
patients with diabetes mellitus than in non-diabetics1-3 and is useful index of control in diabetic patients.4-6. Unlike single of blood-glucose, the glycosylated hmmoglobin concentration reflects integrated blood-glucose concentration over the previous 8-10 weeks. a
measurements
Glycosylated haemoglobin comprises three fast-moving com(Hb A1a + Alb and A Ie) which may be separated from haemoglobin A and A2 either together or separately by column chromatography with an ion-exchange resin. These minor components are usually measured together as glycosylated haemoglobin. Chromatographic procedures requiring many hours to complete the separation2 have restricted the use of the ponents
test.
and Lehmann’ have described a rapid method for of glycosylated haemoglobin which could be completed in 2yh. This was an important advance but ideally a method is required which can be completed in a few minutes and which will enable a patient to be assessed during a single consultation. We describe such a method.
Kynoch
the
measurement
REAGENTS AND APPARATUS
Buffer 1 pH 6-7 5.18 g sodium dihydrogen orthophosphate dihydrate 1.18 g disodium hydrogen orthophosphate anhydrous 0.65gpotassium cyanide Dissolve in distilled water to make 1 litre
