HAZARDS OF MANNITOL INFUSIONS

421

Summary

Hyoscine butylbromide (’Buscopan ’) is an atropinelike drug with a very brief action. Infusion experiments suggest that it is rapidly inactivated or excreted. There is no evidence that its ganglion-blocking actions are important in man. After parenteral doses, paralysis of accommodation is particularly prominent. By mouth, joses of up to 600 mg. are inactive in man. Observations on human urine and on isolated rat intestine suggest that very little is absorbed. We thank Dr. C. Friedmann, Dr. A. D’Mello and Mr. A. D. Cohen for allowing us to include their results; Dr. R. M. Greenwood for help with the class experiments; Dr. J. F. Dunne and Miss B. Bunn for help with the infusion experiments; Mr. P. B. Broadbery for the photographs; and all the volunteers. Dr. D. A. Middleton, of Boehringer Ingelheim Ltd., provided ample supplies of the drug and kmdly arranged for Mrs. J. Percy to carry out the analyses of

covariance.

Requests for reprints should be addressed to A. H. REFERENCES

Brownlee, G., Wilson, A. B., Birmingham, A. T. (1965) Clin. Pharmac. Ther. 6, 177. Drug and Therapeutics Bulletin (1963) 1, 39. Fisher, R. B., Parsons, D. S. (1949)7. Physiol. 110, 36. Hetxhcuner, A. (1958) Br. J. Pharmac. Chemother. 13, 184. Holtz, P., Schumann, H. J. (1956) Arch. exp. Path. Pharmak. 229, 101. Kadatz, R. (1950) ibid. 210, 159. ltechelke, K, Nusser, E. (1955) ibid. 224, 338. Sntdecor, G. W. (1956) Statistical Methods-5th ed. Ames, Iowa. Wada, M. (1950) Science, 3, 376. Wick, H. (1951) Arch. exp. Path. Pharmak. 213, 485. (1955) Unpublished observations cited by Boehringer Ingelheim -

Ltd.

HAZARDS OF MANNITOL INFUSIONS B. E. ROBERTS Leeds, M.C.Path.

M.B.

LECTURER IN DEPARTMENT OF

(1 PART) (4 PARTS)

TABLE 11-RESULTS OF MIXING FRESH BLOOD

PATHOLOGY, UNIVERSITY OF

LEEDS

P. H. SMITH Leeds, F.R.C.S.

HYPERTONIC SOLUTIONS

IN A.C.D. WITH

upon the red blood-cells and the hazards which may ensue.

Methods Various proportions of mannitol and fresh blood with acidcitrate/dextrose (A.C.D.) in a ratio of four parts of blood to one of A.C.D. were mixed and incubated at room temperature for 15 minutes. For comparison similar experiments were performed with blood 7 and 14 days old, which had been collected into sterile A.C.D. and stored at 4°C. As initial experiments showed that 25 g. per 100 ml. mannitol, which is a supersaturated solution, was liable to undergo spontaneous crystallisation when mixed with blood under these conditions, 10 g. per 100 ml. solutions were used throughout. Results were observed with the unaided eye and microscopically (table i). Samples were examined for haemolysis after a further 3 hours incubation under similar conditions. Mixtures of 1 part blood in A.C.D. to 4 parts of other hypertonic solutions available for clinical use were made for com-

parison (table II). To assess the reversibility of the changes, a further 5 ml. of A.C.D. blood was similarly mixed 1 to 4 with 10 g. per 100 ml. mannitol for 15 minutes after which the red blood-cells were washed in isotonic saline solution and resuspended in 5 ml. of serum for 30 minutes. They were then examined microscopically and saline-osmotic and mechanical-fragility tests (Dacie and Lewis 1963) performed as a further estimation of cellular integrity. Results No haemolysis was detected in any of the mixtures. Crenation of red blood-cells was seen in the range

MANNITOL, a hexahydric alcohol, has been widely used in the prevention and treatment of acute renal failure (Powers et al. 1964, Dawson 1965, Luck and Irvine 1965, Luke et al. 1965). It is given intravenously and suggested concentrations have varied from 5 g. per 100 ml. (Powers etd. 1964) to 25 g. per 100 ml. (Barry and Malloy 1962). Reported side-effects have included sodium depletion Boba et al. 1962), and a tendency to precipitate cardiac failure in patients with a limited cardiac reserve (Powers et al.1964). If mannitol is infused into a peripheral vein, or if it is allowed to mix with blood in a drip chamber, the red blood-cells are bathed for a time in a very hypertonic

shown in table i and was proportional to the concentration of mannitol. The crenation was partially reversed by resuspending the cells in serum but they never regained their normal shape and there was no sign of biconcavity. Despite this, however, saline-osmotic-fragility curves and mechanical-fragility tests showed no significant deviation from normal. A hitherto unexpected finding was red-blood-cell aggregation or clumping. Microscopically there was no difference between this effect and true agglutination. The agglutination ranged from the naked-eye appearances of two or three large clumps in tube 1 (table I) to a suspension of small microscopic agglutinates composed of 4-6 cells in tube 3 (table i). Stored blood showed slightly more crenation than fresh blood but there was no difference in the pattern of

medium. We report here the effects of this treatment

agglutination.

M.B. SENIOR SURGICAL

REGISTRAR,

THE GENERAL INFIRMARY AT LEEDS

TABLE I-RESULTS OF MIXING FRESH AND STORED BLOOD IN A.C.D. WITH MANNITOL

Crenation

or

(10

g. per 100

agglutination in tube no. (with ratio, v/v, of mannitol solution to

A.C.D.

blood)

ml.)

422 As the results in table 11 show, there was gross crenation of red blood-cells with all the other solutions tested but only 10 g. per 100 ml. dextrose produced agglutination and this was only microscopic in degree. Discussion Red-blood-cell agglutination was the most striking and significant finding. It could happen easily in a drip set, if mixing of blood and mannitol was allowed, or in veins into which mannitol was infused rapidly. The danger of such agglutinates lodging in branches of the pulmonary artery is obvious and has been recorded as a complication of cardioangiography with hypertonic agents (Read 1959). It follows therefore that hypertonic solutions of mannitol should never be mixed with blood in a transfusion set and that intravenous infusions should always be administered at a carefully controlled slow rate. Red-blood-cell crenation, by means of an associated fall in hxmatocrit, has been considered beneficial to the action of mannitol (Lilien et al. 1963) but this has been refuted by Lucas and Read 1966. Although we found that mannitol did not affect the mechanical and saline-osmoticfragility tests there seems little doubt that it permanently damages red blood-cells, for normal morphology could not be restored despite washing in saline and suspension in serum.

Preliminary Communications THE BIOLOGICAL PURPOSE OF THE BLOOD-CYCLE OF THE MALARIA PARASITE

PLASMODIUM CYNOMOLGI MALARIA parasites in the blood have a clearly defined cycle of development which is a multiple of 24 hours; and all parasites come to schizogony at approximately the same time every 24, 48, or 72 hours according to the species. Clinically, the synchronous division of the parasites produces the well-known tertian or quartan paroxysms of fever which begin about midday. The

Our results were obtained with 10 g. per 100 mi. mannitol and the precautions suggested are even more important if 25 g. per 100 ml. solutions are used.

Summary Mannitol can cause agglutination and irreversible crena. tion of red blood-cells. The dangers of mixing mannîtû: and blood in a transfusion set are emphasised. We thank Dr. F. M. Parsons, consultant in clinical renal physiology the General Infirmary at Leeds, for suggesting this work and for h constructive criticism, and -Miss Marion Burnley for her technical assistance. Requests for reprints should be addressed to Dr. B. E. Rober; Department of Pathology, the General Infirmary, Great Geor;: Street, Leeds 1. REFERENCES

Barry, K. G., Malloy, J. P. (1962) J. Am. Med. Ass. 179, 510. Boba, A., Gainor, J., Powers, S. R. Jr. (1962) Surgery, St. Louis, 52, 188 Dacie, J. V., Lewis, S. M. (1963) Practical Hæmatology. London. Dawson, J. L. (1965) Br. med. J. i, 82. Lilien, O. M., Jones, S. G., Mueller, C. B. (1963) Surgery Gynec Obstet 117, 221. Lucas, C. E., Read, R. C. (1966) Surgery, St. Louis, 59, 408. Luck, R. J., Irvine, W. T. (1965) Lancet, ii, 409. Luke, R. G., Linton, A. L., Briggs, J. D., Kennedy, A. C. (1965) ibid. 980.

Powers, S. R., Jr., Boba, A., Hostnik, W., Stein, A. (1964) Surgery, St. Louis. 55, 15. Read, R. C. (1959) J. thorac. cardiovasc. Surg. 38, 685. reason for this cycle has hitherto been obscure, The purpose of the present article is to show that the cycle is designed to facilitate insect-vector transmission by timing the formation of new gametocytes so that they reached the short-lived peak of infectivity just at the time of night when mosquitoes are most likely to suck blood,

biological

METHODS

The malaria parasite used was the Langur M69 strain of Plasmodium cynomolgi isolated by Prof. A. S. Dissanaike and provided by Prof. P. C. C. Gamham. This produces an infection of moderate intensity (maximum parasitaemia approximately 10% of red blood-cells infected) in rhesus monkeys. The asexual cycle is 48 hours, and in our laboratory schizogon.v happens at about 11 A.M. and 3 P.M., Greenwich Mean Time, The mosquitoes were a strain of Anopheles stephensi, established from eggs kindly provided by Mr. P. G. Shute and Mr, R, Killick-Kendrick. The experiments consisted of feeding a new batch of mosquitoes on an infected monkey every 4 hours Mosquitoes which had fed were separated from the others: they were dissected 6-7 days later, and the number of oocvsc on the wall of the stomach were counted. The number e’

700

Fig. 1—The 48-hour variation in mosquito infectivity of the blood of monkey 334, infected with P. cynomolgi. The figures for oocysts represent the mean for all mosquitoes in each batch. The arrows below the base-line indicate the approximate time of schizogony.

I

I HOURS

Fig. 2-Mosquito infectivity of the blood of monkey 33b.