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EFFECT OF ORTHOPHOSPHATE ON URINARY PYROPHOSPHATE EXCRETION AND THE PREVENTION OF UROLITHIASIS
1065
EFFECT OF ORTHOPHOSPHATE ON URINARY
PYROPHOSPHATE EXCRETION AND THE PREVENTION OF UROLITHIASIS H. FLEISCH
S. BISAZ
M.D. Lausanne
Ph.D. Zurich
A. D. CARE Leeds, B.V.M.S. Edin.* From the Laboratory for Experimental Surgery, Schweizerisches Forschungsinstitut, Davos, Switzerland M.A. Cantab., Ph.D.
THE mechanism and rationale of treatment of urolithiasis still poorly understood. In earlier years emphasis was laid on the importance of hypothetical urinary inhibitors, the so-called " colloid protectors ", which were supposed to prevent the precipitation of minerals. The supersaturation of most urines with calcium phosphate and calcium oxalate (Fleisch 1962) and the recent discovery that an organic matrix can activate the precipitation of minerals (Boyce et al. 1954, Dulce 1958) by forming crystalline nuclei (Neuman and Neuman 1958, Glimcher 1959, Fleisch and Neuman 1961) support the existence of an inhibitory mechanism. The actual presence in urine of such inhibitors, however, has only recently been demonstrated (Howard and Thomas 1958, Vermeulen et al. 1958, Thomas and Howard 1959, Fleisch and Bisaz 1962a). We have isolated one of these inhibitors, which is noncolloidal, and identified it as inorganic pyrophosphate (Fleisch and Bisaz 1962a, b). Its concentration, varying between 1-7 x10-5M, is high enough to inhibit strongly the precipitation in vitro of calcium phosphate, and offers an explanation of the high supersaturation of normal urine with calcium salts. Latterly, high doses of inorganic orthophosphate by mouth have been recommended for the prevention of urinary calculi (Howard 1962, Howard et al. 1962). However paradoxical this may seem in the case of phosphatic calculi, laboratory results (Vermeulen et al. 1959) and clinical results (Howard 1962, Howard et al. 1962) are surprisingly good. But this favourable effect is still are
*
Present address: Rowett Research Institute, Bucksburn, Aberdeen.
Previous work in our laboratory had shown correlation between orthophosphate and pyrophosphate excretion in urine (Fleisch and Bisaz 1963). It was tempting therefore to speculate that high doses of oral orthophosphate helped to prevent the formation of stones by increasing the excretion of urinary pyrophosphate. In a preliminary study on rats we showed that adding orthophosphate to food, or simply increasing its availability, raised pyrophosphate excretion in urine; by contrast, the suppression of dietary orthophosphate diminished the urinary level (Care et al., unpublished data). Accordingly we set out to determine whether this was so in man.
unexplained. some
Material and Methods
healthy, ambulant persons of both sexes were given orthophosphate in a dosage of 1 g. P daily for four days followed by 2 g. P daily for four days. The orthophosphate was administered in capsules throughout the day as a mixture of 1 Af KH2P04 and 4 M Na2HP04 in order to obtain a pH near 7-4. The 24-hour excretion of orthophosphate, pyrophosphate, and calcium in urine was measured during the time the phosphate was being taken and for four days before and after. To find out whether urinary pyrophosphate could be raised by administering the compound itself, two of the subjects were given increasing doses of Na4P207’ 10 H2O coated in acid-resistant pills. Nine
Calcium was titrated with edetic acid (E.D.T.A.) in an alkaline medium, in the presence of calceine. Orthophosphate was estimated by a colorimetric method, using molybdate in the presence of ascorbic acid as a reducing agent (Chen et al. 1956). Pyrophosphate was determined by the following method (Fleisch and Bisaz 1963): a homogeneous sample of the 24-hour urine was boiled for 2 minutes to destroy the pyrophosphatase; any precipitate was dissolved by acidifying with 4 N hydrochloric acid to a pH of 5.0, and if necessary by dilution in equal proportions with water; 2-4 ml. of urine was passed through a column 8-9 mm. in diameter, containing 10 ml. ’Dowex’ 1 x 10,100-200 mesh, chloride form; the column was then rinsed with 10 ml. water, the reaction of which for orthophosphate had to be negative (if not, the column was overloaded and the determination had to be repeated with a reduced amount of urine). Afterwards, orthophosphate was eluted with 100 ml. N/20 hydrochloric acid or with 100 ml. Af/7’5 potassium chloride; pyrophosphate could then be eluted with 7V/2 hydrochloric acid and was recovered in six fractions of 3 ml. each. These were hydrolysed for
TABLE I-EFFECT OF ORTHOPHOSPHATE INGESTION ON DAILY URINARY EXCRETION OF ORTHOPHOSPHATE,
PYROPHOSPHATE, AND
CALCIUM
1066 a boiling waterbath, care being taken to add 0’125 ml. concentrated hydrochloric acid to the first two fractions which were not acid enough; pyrophosphate was thus transformed into orthophosphate which could then be assessed colorimetrically.
thirty minutes in
TABLE II-URINARY
PYROPHOSPHATE, ORTHOPHOSPHATE, AND CALCn;M SUBJECTS AFTER PYROPHOS-
EXCRETION IN TWO HEALTHY AMBULANT PHATE INGESTION.
Results The influence of oral administration of orthophosphate on the urinary excretion of orthophosphate, pyrophosphate, and calcium is shown in table I. In eight out of the nine test subjects the ingestion of orthophosphate induced an increase of urinary orthophosphate accompanied by an immediate rise in pyrophos-
phate. Only one subject (case 2), who actually also reacted with diarrhoea, showed no such rise.
All subjects also had decreased urinary calcium. A typical
example (case 6) of the influof orthophosphate administration is shown in fig. 1. ence
Consequently, oral administration of
orthophosphate significantly increased the
urinary
excre-
tion of pyro-
phosphate. 1-Effect of increased
Fig. orthophosphate ingestion on daily urinary excretion of orthophosphate (hatched columns), pyrophosphate (shaded), and calcium (dark) in a healthy woman, aged 29.
On the other hand the administration of
pyrophosphate induced
index) and the frequency of stone formation in the various age-groups (fig. 2); thus in the middle years, when the inhibitor index is low, stones are common, whereas in the old and especially in the young the index is high and urolithiasis is uncommon. Another suggestive feature in our preliminary findings is that many people with recurrent stones have a significantly decreased inhibitor index. But pyrophosphate is certainly not the whole answer to the problem, as is shown by the finding that the lower frequency of stones in women is not associated with a higher inhibitor index. The precise mode of action of pyrophosphate is not entirely clear yet; at such low concentrations it cannot be influenced by a decrease in ionic calcium due to binding by pyrophosphate; it is more likely to act by blocking crystal nucleation and growth after adsorption on to the growing surface. This property of polyphosphates has long been known in industry, where it is used to prevent the precipitation of calcium carbonate in water containers tor
(Rudy 1960). If pyrophosphate is the factor preventing stone formation in orthophosphate therapy, its administration seems reasonable. But in none of our subjects were the doses given by mouth excreted in the urine in significant amounts; this accords with the findings in rats fed on radioactive pyrophosphate (Care et al. unpublished data). Thus, until a polyphosphate is found that is excreted in urine, administration of orthophosphate is likely to remain
no
significant increase in urinary excretion (table 11). The daily doses of Na4P207 10 H20were not increased beyond 70 mg. P, as abdominal discomfort and diarrhoea developed. Discussion
Oral administration of orthophosphate to healthy subjects induces a significant increase in urinary pyrophosphate excretion. The effect of orthophosphate therapy in patients is currently also being investigated elsewhere (Russell 1963). Since pyrophosphate is a potent inhibitor of the precipitation of calcium phosphate and calcium oxalate (Fleisch and Bisaz 1962a, 1964), an increase in its urinary excretion could account for the reduced frequency of both phosphate and oxalate stones that follows an increase in dietary orthophosphate. Certainly the favourable results cannot be explained by a fall in urinary calcium, since this decrease is for the most part transient and the drop in calcium excretion is more than counteracted by the increase in orthophosphate excretion. The suggestion that pyrophosphate plays some part in the mechanism of urolithiasis is supported by the inverse relation we found (Fleisch and Bisaz 1964) between the ratio " pyrophosphate-P/calcium x phosphate-P (inhibi"
-’ I t 3 1 . j
Fig. 2-Daily urinary excretion of pyrophosphate, phosphate, and calcium expressed as the ratio " pyrophosphate-P/calcium phosphate-P" (inhibitor index) in males and females of different age-groups. Numbers represent people investigated.
1067
only method of increasing urinary inhibitors of crystal formation. the
Conclusions of Oral administration inorganic orthophosphate induces a significant increase in urinary inorganic pyrophosphate excretion. Since this compound is a potent inhibitor of the precipitation of calcium phosphate and calcium oxalate, its increased excretion in the urine could account for the good clinical results of oral phosphate therapy in the prevention of urolithiasis. This work zur
was supported by the Schweizerischer Nationalfonds Forderung der wissenschaftlichen Forschung; the U.S. Public
Health Service grant AM 07266-01 of the National Institute of Arthritis and Metabolic Diseases; and the Sandoz Stiftung zur Förderung der medizinisch-biologischen Wissenschaften. We should like to thank Prof. H. Pfaendler, interpreter at W.H.O., for translating our
paper.
REFERENCES C. M. (1954) J. Urol. 72, 1019. Care, A. D., Bisaz, S., Fleisch, H. Unpublished data. P. Chen, S., Toribara, T. Y., Warner, H. (1956) Analyt. Chem. 28, 1756. Dulce, H. J. (1958) Urol. int., Basle, 7, 137. Fleisch, H. (1962) Schweiz. med. Wschr. 92, 1197. Bisaz, S. (1962a) Amer. J. Physiol. 203, 671. (1962b) Nature, Lond. 195, 911. (1963) Helv. physiol. acta, 21, 88. (1964) Experientia, Basle (in the press). Neuman, W. F. (1961) Amer. J. Physiol. 200, 1296. M. Glimcher, (1959) Rev. mod. Phys. 31, 359. Howard, J. E. (1962) Canad. med. Ass. J. 86, 1001. Thomas, W. C. (1958) Trans. Amer. clin. climat. Ass. 70, 94. — — Mukai, T., Johnston, R. A., Pascoe, B. J. (1962) Trans. Ass. Amer. Phycns, 75, 301. Neuman, W. F., Neuman, M. W. (1958) The Chemical Dynamics of Bone
Boyce, W. H., Garvey, F. K., Norfleet,
—
— —
— —
— —
—
—
Mineral. Chicago. Rudy, H. (1960) Altes und Neues über kondensierte Phosphate. Ludwigshafen-am-Rhein.
Russell, G. (1963) Personal communication. Thomas, W. C., Howard, J. E. (1959) Trans. Ass. Amer. Phycns, 72, 181. Vermeulen, C. W., Lyon, E. S., Gill, W. B., Chapman, W. H. (1959) J. Urol. 82, 249. Miller, G. H. (1958) ibid. 79, 596. —
—
ORAL ATROPINE IN PREMEDICATION FOR ELECTROCONVULSIVE THERAPY W. LL. PARRY-JONES M.A., M.B. Cantab. PSYCHIATRIC
REGISTRAR,
NORTH WALES
HOSPITAL,
DENBIGH
ATROPINE is used in premedication for modified electroconvulsive therapy (E.c.T.) primarily to prevent the development of any cardiac arrhythmia due to excitation of the vagus nerves following electric stimulation: it does this by producing a vagal blocking (Nowill et al. 1954, Lewis et al. 1955). The anti-sialogogue action of atropine is of secondary importance in E.c.T. The need for adequate atropinisation is confirmed by the findings of Maclay (1953) who, in his analysis of the 62 deaths occurring after E.C.T. in England and Wales between 1947 and 1952, showed that over half (34) were due to disturbance of the cardiovascular system. Intravenous and subcutaneous administration of atropine have recently been evaluated (Clements 1962, Hargreaves 1962, Whitwam et al. 1963, Bhattacharya and West 1963). Although Joseph and Vale (1960) described a trial of atropine given by mouth to children before tonsillectomy, there appears to have been no recent reference to the use of oral atropine before E.e.T. A simple clinical study into the efficiency of a method of premedication by mouth is now described. This investigation originated as an inquiry into the efficiency of the method of premedication for E.C.T. which had been in use in one admission unit of this hospital, without fatality, for many years. It had been the custom to give atropine gr.] /so (12 mg.) to all patients due for E.c.T. approximately 111, hours before the start of the treatment session. (This practice was introduced in order to combine the administration of atropine and a sedative, so avoiding the need for a subsequent subcutaneous injection.) Depending, however, upon such factors
as the number of patients to be treated, unexpected problems in the ward, and emergencies, the actual interval between atropine administration and the shock might vary from 11/4 to approximately 21/2 hours, and it was in view of the possibility of inadequate atropinisation in some cases that this inquiry was undertaken. When the method was seen to be unsatisfactory, the investigation was modified in order to compare the results with those obtainable with the intravenous route. Subcutaneous administration was not considered in view of several inherent disadvantages. Method
Fifty male patients in good physical health were divided two groups (i and 11) of very similar age-distribution, ranging from 17 to 77 years (mean age 46 years and 46-8 years). Atropine was given orally to the patients in group i, and intravenously to those in group 11. All the patients were sedated with amylobarbitone sodium into
(200 mg.) approximately 11/4 hours before the treatment session. Before the shock all received hexobarbitone sodium (3 to 5 ml. of 10% solution) and suxamethonium bromide (’Brevidil’ E, 62-5 to 75 mg. cation) by intravenous injection, and they were ventilated with 100 % oxygen until spontaneous respiration returned after the convulsion. Group i were given atropine sulphate B.P. tablets gr. 1/50 11/4 hours before the start of the E.C.T. session. Group 11 received atropine sulphate B.P. intravenously, in the same syringe as the hexobarbitone, 70 to 75 seconds before the shock: doses of gr. 1/50 and gr. 1/100 (0-6 mg. in 1 ml.) were given alternately to each patient in this group to compare the effectiveness of the two dosages (thus forming groups na and lib). The heart-sounds were checked by precordial auscultation, starting 15 seconds before the shock and continuing until 60 seconds after it.
gr. 3
Results and Comment Observations were made during 254 treatments on fifty patients, comprising 119 in group i and 135 in group 11 (69 in group iia and 66 in group lib). The average number of treatments per patient was 4-8 in group i and 5-4 in group 11. Abnormalities of varying severity were recorded during 93 of the treatments. On many occasions more than one abnormality was noted during the course of a single treatment. The distribution of normal and abnormal responses in the two groups is shown in table i. Table 11 presents the numbers of patients showing abnormality during treatment. The results given in table 11 have been evaluated using the X2 test, and the difference between the two groups is statistically
significant (p < 0-01). In eighteen patients
in group i (oral) complete absence of heart-sounds was recorded 52 times, for periods ranging from 1 to 15 seconds after the beginning of the shock. TABLE I-NUMBERS WITH ABNORMAL HEART-SOUNDS
TABLE II-NUMBERS OF PATIENTS SHOWING ABNORMALITIES
EFFECT OF ORTHOPHOSPHATE ON URINARY
PYROPHOSPHATE EXCRETION AND THE PREVENTION OF UROLITHIASIS H. FLEISCH
S. BISAZ
M.D. Lausanne
Ph.D. Zurich
A. D. CARE Leeds, B.V.M.S. Edin.* From the Laboratory for Experimental Surgery, Schweizerisches Forschungsinstitut, Davos, Switzerland M.A. Cantab., Ph.D.
THE mechanism and rationale of treatment of urolithiasis still poorly understood. In earlier years emphasis was laid on the importance of hypothetical urinary inhibitors, the so-called " colloid protectors ", which were supposed to prevent the precipitation of minerals. The supersaturation of most urines with calcium phosphate and calcium oxalate (Fleisch 1962) and the recent discovery that an organic matrix can activate the precipitation of minerals (Boyce et al. 1954, Dulce 1958) by forming crystalline nuclei (Neuman and Neuman 1958, Glimcher 1959, Fleisch and Neuman 1961) support the existence of an inhibitory mechanism. The actual presence in urine of such inhibitors, however, has only recently been demonstrated (Howard and Thomas 1958, Vermeulen et al. 1958, Thomas and Howard 1959, Fleisch and Bisaz 1962a). We have isolated one of these inhibitors, which is noncolloidal, and identified it as inorganic pyrophosphate (Fleisch and Bisaz 1962a, b). Its concentration, varying between 1-7 x10-5M, is high enough to inhibit strongly the precipitation in vitro of calcium phosphate, and offers an explanation of the high supersaturation of normal urine with calcium salts. Latterly, high doses of inorganic orthophosphate by mouth have been recommended for the prevention of urinary calculi (Howard 1962, Howard et al. 1962). However paradoxical this may seem in the case of phosphatic calculi, laboratory results (Vermeulen et al. 1959) and clinical results (Howard 1962, Howard et al. 1962) are surprisingly good. But this favourable effect is still are
*
Present address: Rowett Research Institute, Bucksburn, Aberdeen.
Previous work in our laboratory had shown correlation between orthophosphate and pyrophosphate excretion in urine (Fleisch and Bisaz 1963). It was tempting therefore to speculate that high doses of oral orthophosphate helped to prevent the formation of stones by increasing the excretion of urinary pyrophosphate. In a preliminary study on rats we showed that adding orthophosphate to food, or simply increasing its availability, raised pyrophosphate excretion in urine; by contrast, the suppression of dietary orthophosphate diminished the urinary level (Care et al., unpublished data). Accordingly we set out to determine whether this was so in man.
unexplained. some
Material and Methods
healthy, ambulant persons of both sexes were given orthophosphate in a dosage of 1 g. P daily for four days followed by 2 g. P daily for four days. The orthophosphate was administered in capsules throughout the day as a mixture of 1 Af KH2P04 and 4 M Na2HP04 in order to obtain a pH near 7-4. The 24-hour excretion of orthophosphate, pyrophosphate, and calcium in urine was measured during the time the phosphate was being taken and for four days before and after. To find out whether urinary pyrophosphate could be raised by administering the compound itself, two of the subjects were given increasing doses of Na4P207’ 10 H2O coated in acid-resistant pills. Nine
Calcium was titrated with edetic acid (E.D.T.A.) in an alkaline medium, in the presence of calceine. Orthophosphate was estimated by a colorimetric method, using molybdate in the presence of ascorbic acid as a reducing agent (Chen et al. 1956). Pyrophosphate was determined by the following method (Fleisch and Bisaz 1963): a homogeneous sample of the 24-hour urine was boiled for 2 minutes to destroy the pyrophosphatase; any precipitate was dissolved by acidifying with 4 N hydrochloric acid to a pH of 5.0, and if necessary by dilution in equal proportions with water; 2-4 ml. of urine was passed through a column 8-9 mm. in diameter, containing 10 ml. ’Dowex’ 1 x 10,100-200 mesh, chloride form; the column was then rinsed with 10 ml. water, the reaction of which for orthophosphate had to be negative (if not, the column was overloaded and the determination had to be repeated with a reduced amount of urine). Afterwards, orthophosphate was eluted with 100 ml. N/20 hydrochloric acid or with 100 ml. Af/7’5 potassium chloride; pyrophosphate could then be eluted with 7V/2 hydrochloric acid and was recovered in six fractions of 3 ml. each. These were hydrolysed for
TABLE I-EFFECT OF ORTHOPHOSPHATE INGESTION ON DAILY URINARY EXCRETION OF ORTHOPHOSPHATE,
PYROPHOSPHATE, AND
CALCIUM
1066 a boiling waterbath, care being taken to add 0’125 ml. concentrated hydrochloric acid to the first two fractions which were not acid enough; pyrophosphate was thus transformed into orthophosphate which could then be assessed colorimetrically.
thirty minutes in
TABLE II-URINARY
PYROPHOSPHATE, ORTHOPHOSPHATE, AND CALCn;M SUBJECTS AFTER PYROPHOS-
EXCRETION IN TWO HEALTHY AMBULANT PHATE INGESTION.
Results The influence of oral administration of orthophosphate on the urinary excretion of orthophosphate, pyrophosphate, and calcium is shown in table I. In eight out of the nine test subjects the ingestion of orthophosphate induced an increase of urinary orthophosphate accompanied by an immediate rise in pyrophos-
phate. Only one subject (case 2), who actually also reacted with diarrhoea, showed no such rise.
All subjects also had decreased urinary calcium. A typical
example (case 6) of the influof orthophosphate administration is shown in fig. 1. ence
Consequently, oral administration of
orthophosphate significantly increased the
urinary
excre-
tion of pyro-
phosphate. 1-Effect of increased
Fig. orthophosphate ingestion on daily urinary excretion of orthophosphate (hatched columns), pyrophosphate (shaded), and calcium (dark) in a healthy woman, aged 29.
On the other hand the administration of
pyrophosphate induced
index) and the frequency of stone formation in the various age-groups (fig. 2); thus in the middle years, when the inhibitor index is low, stones are common, whereas in the old and especially in the young the index is high and urolithiasis is uncommon. Another suggestive feature in our preliminary findings is that many people with recurrent stones have a significantly decreased inhibitor index. But pyrophosphate is certainly not the whole answer to the problem, as is shown by the finding that the lower frequency of stones in women is not associated with a higher inhibitor index. The precise mode of action of pyrophosphate is not entirely clear yet; at such low concentrations it cannot be influenced by a decrease in ionic calcium due to binding by pyrophosphate; it is more likely to act by blocking crystal nucleation and growth after adsorption on to the growing surface. This property of polyphosphates has long been known in industry, where it is used to prevent the precipitation of calcium carbonate in water containers tor
(Rudy 1960). If pyrophosphate is the factor preventing stone formation in orthophosphate therapy, its administration seems reasonable. But in none of our subjects were the doses given by mouth excreted in the urine in significant amounts; this accords with the findings in rats fed on radioactive pyrophosphate (Care et al. unpublished data). Thus, until a polyphosphate is found that is excreted in urine, administration of orthophosphate is likely to remain
no
significant increase in urinary excretion (table 11). The daily doses of Na4P207 10 H20were not increased beyond 70 mg. P, as abdominal discomfort and diarrhoea developed. Discussion
Oral administration of orthophosphate to healthy subjects induces a significant increase in urinary pyrophosphate excretion. The effect of orthophosphate therapy in patients is currently also being investigated elsewhere (Russell 1963). Since pyrophosphate is a potent inhibitor of the precipitation of calcium phosphate and calcium oxalate (Fleisch and Bisaz 1962a, 1964), an increase in its urinary excretion could account for the reduced frequency of both phosphate and oxalate stones that follows an increase in dietary orthophosphate. Certainly the favourable results cannot be explained by a fall in urinary calcium, since this decrease is for the most part transient and the drop in calcium excretion is more than counteracted by the increase in orthophosphate excretion. The suggestion that pyrophosphate plays some part in the mechanism of urolithiasis is supported by the inverse relation we found (Fleisch and Bisaz 1964) between the ratio " pyrophosphate-P/calcium x phosphate-P (inhibi"
-’ I t 3 1 . j
Fig. 2-Daily urinary excretion of pyrophosphate, phosphate, and calcium expressed as the ratio " pyrophosphate-P/calcium phosphate-P" (inhibitor index) in males and females of different age-groups. Numbers represent people investigated.
1067
only method of increasing urinary inhibitors of crystal formation. the
Conclusions of Oral administration inorganic orthophosphate induces a significant increase in urinary inorganic pyrophosphate excretion. Since this compound is a potent inhibitor of the precipitation of calcium phosphate and calcium oxalate, its increased excretion in the urine could account for the good clinical results of oral phosphate therapy in the prevention of urolithiasis. This work zur
was supported by the Schweizerischer Nationalfonds Forderung der wissenschaftlichen Forschung; the U.S. Public
Health Service grant AM 07266-01 of the National Institute of Arthritis and Metabolic Diseases; and the Sandoz Stiftung zur Förderung der medizinisch-biologischen Wissenschaften. We should like to thank Prof. H. Pfaendler, interpreter at W.H.O., for translating our
paper.
REFERENCES C. M. (1954) J. Urol. 72, 1019. Care, A. D., Bisaz, S., Fleisch, H. Unpublished data. P. Chen, S., Toribara, T. Y., Warner, H. (1956) Analyt. Chem. 28, 1756. Dulce, H. J. (1958) Urol. int., Basle, 7, 137. Fleisch, H. (1962) Schweiz. med. Wschr. 92, 1197. Bisaz, S. (1962a) Amer. J. Physiol. 203, 671. (1962b) Nature, Lond. 195, 911. (1963) Helv. physiol. acta, 21, 88. (1964) Experientia, Basle (in the press). Neuman, W. F. (1961) Amer. J. Physiol. 200, 1296. M. Glimcher, (1959) Rev. mod. Phys. 31, 359. Howard, J. E. (1962) Canad. med. Ass. J. 86, 1001. Thomas, W. C. (1958) Trans. Amer. clin. climat. Ass. 70, 94. — — Mukai, T., Johnston, R. A., Pascoe, B. J. (1962) Trans. Ass. Amer. Phycns, 75, 301. Neuman, W. F., Neuman, M. W. (1958) The Chemical Dynamics of Bone
Boyce, W. H., Garvey, F. K., Norfleet,
—
— —
— —
— —
—
—
Mineral. Chicago. Rudy, H. (1960) Altes und Neues über kondensierte Phosphate. Ludwigshafen-am-Rhein.
Russell, G. (1963) Personal communication. Thomas, W. C., Howard, J. E. (1959) Trans. Ass. Amer. Phycns, 72, 181. Vermeulen, C. W., Lyon, E. S., Gill, W. B., Chapman, W. H. (1959) J. Urol. 82, 249. Miller, G. H. (1958) ibid. 79, 596. —
—
ORAL ATROPINE IN PREMEDICATION FOR ELECTROCONVULSIVE THERAPY W. LL. PARRY-JONES M.A., M.B. Cantab. PSYCHIATRIC
REGISTRAR,
NORTH WALES
HOSPITAL,
DENBIGH
ATROPINE is used in premedication for modified electroconvulsive therapy (E.c.T.) primarily to prevent the development of any cardiac arrhythmia due to excitation of the vagus nerves following electric stimulation: it does this by producing a vagal blocking (Nowill et al. 1954, Lewis et al. 1955). The anti-sialogogue action of atropine is of secondary importance in E.c.T. The need for adequate atropinisation is confirmed by the findings of Maclay (1953) who, in his analysis of the 62 deaths occurring after E.C.T. in England and Wales between 1947 and 1952, showed that over half (34) were due to disturbance of the cardiovascular system. Intravenous and subcutaneous administration of atropine have recently been evaluated (Clements 1962, Hargreaves 1962, Whitwam et al. 1963, Bhattacharya and West 1963). Although Joseph and Vale (1960) described a trial of atropine given by mouth to children before tonsillectomy, there appears to have been no recent reference to the use of oral atropine before E.e.T. A simple clinical study into the efficiency of a method of premedication by mouth is now described. This investigation originated as an inquiry into the efficiency of the method of premedication for E.C.T. which had been in use in one admission unit of this hospital, without fatality, for many years. It had been the custom to give atropine gr.] /so (12 mg.) to all patients due for E.c.T. approximately 111, hours before the start of the treatment session. (This practice was introduced in order to combine the administration of atropine and a sedative, so avoiding the need for a subsequent subcutaneous injection.) Depending, however, upon such factors
as the number of patients to be treated, unexpected problems in the ward, and emergencies, the actual interval between atropine administration and the shock might vary from 11/4 to approximately 21/2 hours, and it was in view of the possibility of inadequate atropinisation in some cases that this inquiry was undertaken. When the method was seen to be unsatisfactory, the investigation was modified in order to compare the results with those obtainable with the intravenous route. Subcutaneous administration was not considered in view of several inherent disadvantages. Method
Fifty male patients in good physical health were divided two groups (i and 11) of very similar age-distribution, ranging from 17 to 77 years (mean age 46 years and 46-8 years). Atropine was given orally to the patients in group i, and intravenously to those in group 11. All the patients were sedated with amylobarbitone sodium into
(200 mg.) approximately 11/4 hours before the treatment session. Before the shock all received hexobarbitone sodium (3 to 5 ml. of 10% solution) and suxamethonium bromide (’Brevidil’ E, 62-5 to 75 mg. cation) by intravenous injection, and they were ventilated with 100 % oxygen until spontaneous respiration returned after the convulsion. Group i were given atropine sulphate B.P. tablets gr. 1/50 11/4 hours before the start of the E.C.T. session. Group 11 received atropine sulphate B.P. intravenously, in the same syringe as the hexobarbitone, 70 to 75 seconds before the shock: doses of gr. 1/50 and gr. 1/100 (0-6 mg. in 1 ml.) were given alternately to each patient in this group to compare the effectiveness of the two dosages (thus forming groups na and lib). The heart-sounds were checked by precordial auscultation, starting 15 seconds before the shock and continuing until 60 seconds after it.
gr. 3
Results and Comment Observations were made during 254 treatments on fifty patients, comprising 119 in group i and 135 in group 11 (69 in group iia and 66 in group lib). The average number of treatments per patient was 4-8 in group i and 5-4 in group 11. Abnormalities of varying severity were recorded during 93 of the treatments. On many occasions more than one abnormality was noted during the course of a single treatment. The distribution of normal and abnormal responses in the two groups is shown in table i. Table 11 presents the numbers of patients showing abnormality during treatment. The results given in table 11 have been evaluated using the X2 test, and the difference between the two groups is statistically
significant (p < 0-01). In eighteen patients
in group i (oral) complete absence of heart-sounds was recorded 52 times, for periods ranging from 1 to 15 seconds after the beginning of the shock. TABLE I-NUMBERS WITH ABNORMAL HEART-SOUNDS
TABLE II-NUMBERS OF PATIENTS SHOWING ABNORMALITIES