American Journal of
Obstetrics and Gynecology volume
133
number
1
JANUARY
1, 1979
Parenteral magnesium sulfate and the distribution, plasma levels, and excretion of magnesium LEON
C. CHESLEY,
PH.D.
Brooklyn, New York The calibrated infusion method was used in trying to measure the apparent volumes of distribution of sucrose and magnesium in three nonpregnant, three normal pregnant, and 3 pre-eclamptic women. The data for one normal pregnant woman were vitiated by mechanical difficulties and equilibrium for sucrose was not established in one nonpregnant and two pre-eclamptic subjects. The rapid renal excretion of infused magnesium prevents accurate estimate of the apparent magnesium space. In five satisfactory observations, magnesium moved rapidly beyond the sucrose space, that is, it entered cells, bone, and probably those portions of the fetus and amniotic fluid not included in the estimate of the sucrose space. By w) minutes, about half of the retained magnesium had moved beyond the sucrose space. The concentration in serum and the cumulative renal excretions of magnesium were measured in three eclamptic and seven severely pre-eclamptic patients given 3 Gm. of magnesium sulfate intravenously and 10 Gm. intramuscularly as the initial therapeutic dose. The highest single level in plasma, observed at 60 minutes, was 6.0 mEq per liter (7.2 mg. per 100 ml.) in an oliguric eclamptic woman. The average peak level, also at 60 minutes, was 4.5 mEq. per liter. At the end of four hours the cumulative renal excretions ranged from 33 to 53 per cent of the dose injected. Calculation of the concentration to be expected in serum (plasma) indicates that the initial dose is safe, even in anuric patients; repeated doses might not be safe. (AM. J. OBSTET. GYNECOL.
THE
133:1,
1979.)
of parenteral magnesium sulfate and control of eclamptic convulsions
EFFICACY
the prevention
From the Department of Obstetrics and Gynecology, State University of New York, Downstate Medical Center, and Kings County Hospital. Supported bj a research grant (H-l 83 7) from the National Institutes of Health, United States Public Service. Receivedfor Revised
publication
December
Accepted August
October
Health
11, 1977.
9, 1977. 3, 1978.
Reprint requests: Dr. Leon C. Chesley, Box 24, 450 Clarkson Ave., Brooklyn, New York 11203. 0002-9378/79/010001+07$00.70/0
0 1979 The C. V.
Mosby
Co.
in is
well established’s * and in the United States it probably is the most popular agent used for those purposes. Pritchard2 reported 154 consecutive cases of eclampsia, treated with magnesium sulfate, without a maternal death and with a perinatal mortality rate of only 15.4 per cent in antenatal eclampsia (9.9 per cent, excluding birth weights of less than 1,000 grams). Pritchard* gives an initial dose of magnesium sulfate of 4 Gm. intravenously, followed at once by 10 Gm. intramuscularly; thereafter 5 Gm. are injected intramuscularly every four hours, but any of the later doses are postponed if: (1) the knee jerk is absent, (2) the respiratory rate is depressed, or (3) the urinary output has 1
2 Chesley
Table
January Am. J. Obstet.
I. The apparent
volumes
of distribution
(spaces) of sucrose and magnesium Apparent
DiagTWSiS
Pre-eclampsia* Pre-eclampsia Pre-eclampsia Normal pregnancy Normal pregnancy Nonpregnant Nonpregnant Nonpregnant
SlrcroJr .spm (rd. /Kg.,
230 : 183 196 t 170 185
1. 1979 Gynecol.
magnesium
space (ml. /Kg.)
-/5 min.
60 min.
90 mirr.
120 mm.
150 min.
180 min.
210 min.
204 319 313 222 216 185 205 192
278
262 340 473 272 306 218 273 301
248 386 460 288 382 232 315 308
280 403 442 288 376 250 324 298
290
290
290
278
255
255
247 310 303
253 324
244 334
438 240 272 223 250 213
240
f&c.
*Patient had lost 10 pounds in five days while receiving acetazolamide and chlorothiazide. tEquilibrium not established. not been at least 100 ml. since the preceding dose. Also the antidote to magnesium toxicity (10 ml. of’ 10 pel cent calcium gluconate) must be readily available. Our” use of the drug at the Kings County and University Hospitals of the State University of New York Downstate Medical Center differs only in that we give 3 Gm., rather than 4 Gm., as the initial intravenous dose. Thus, Pritchard injects 39 Gm. in the first 24 hours, and we inject 38 Gm. Many obstetricians in the past, and still, use far smaller amounts because toxicity does occur if too much magnesium is given. The first sign of an adverse effect is a depression of the respiratory rate, but that is preceded by disappearance of the tendon reflexes; those are the reasons for the first and second precautions, above. Magnesium is excreted almost solely by the kidney. which is the reason for the third precaution. Several investigators have related the pharmacologic effects of magnesium to its concentration in plasma. Smith and colleagues,” using dogs, found that respiratory arrest does not occur until the levels of magnesium reach from 17 to 27 mEq. per liter (20 to 32 mg. per 100 ml.). Hoff and co-workers” observed that in man the patellar reflex (knee jerk) is lost with concentrations of magnesium between 7 and 10 mEq. per liter (8.4 to 12 mg. per 100 ml.). Thus, the suppression of the knee jerk occurs before respiratory depression and it serves as a warning clinical sign that the magnesium in plasma may be approaching a toxic level. Moore and Wingo,’ using dogs and cats, found the fatal level of magnesium to be from 17.5 to 45 mEq. per liter (21 to 54 mg. per 100 ml.). Pritchard’ saw respiratory depression in but one patient; she weighed only 99 pounds before delivery and had severe renal impairment, and the anesthesia for hysterotomy had been supplemented with succinylcholine. She developed respiratory depression postoperatively, which was corrected by calcium gluconate. We have used the antidote in three patients but nevel
in any of the hundreds treated as outlined. Each of three house officers injected intravenously the 20 ml. of 50 per cent magnesium sulfate (10 Gm., 82 mEq. of magnesium) that should have been given as the initial intramuscular dose. One patient manifested no adverse effect, but the house officer gave her calcium gluconate as soon as he realized his mistake. One patient had respiratory arrest, which quickly yielded to the antidote, and the third had both respiratory and cardiac arrest; external cardiac massage and 10 ml. of 10 per cent calcium gluconate intravenously were promptly effective. Pritchard’s and our experience attests to the safety of large doses of magnesium sulfate if the precautions are observed. The level of magnesium attained in plasma after parenteral administration of a given dose depends upon the volume of distribution and renal excretion of the magnesium. In the presence of severe oliguria or advanced renal failure, the volume of distribution determines the concentration. The present paper is prompted by a maternal death and its purpose is to indicate that the initial dose of 3 Gm. of magnesium sulfate intravenously plus 10 Gm. intramuscularly (107 mEq. of magnesium) is safe because of the volume in which it is diluted. Needless to say, a second and later dose probably would not be safe in a severely oliguric patient. Case report M. T., an obese, black woman, aged 29, para 7-O-O-4, was admitted to the Kings County Hospital at term, complaining of left-sided thoracic and upper abdominal pain for two hours’ duration. The blood pressure was 160/ 110; she had no edema and no urine could be obtained by catheter. The house officer attributed the high blood pressure to essential hypertension and the pain to the fried chicken that she had eaten six hours earlier. His only consultant, a gastroenterologist, concurred. The patient had the first of seven convulsions at about three hours after admittance. Recause of the
Volume Number
Parenteral magnesium sulfate
133 1
supposed anuria, the house officer did not give her magnesium sulfate but treated her with diphenylhydantoin, phenobarbital, and diazepam. The patient recovered consciousness after each of the first three convulsions but was unresponsive thereafter and died about 13 hours after admittance. At autopsy, she was found to have a massive hemorrhage involving the midbrain, pons, and medulla and a subarachnoid hemorrhage over the right frontal and temporal lobes. The liver had extensive lesions characteristic of eclampsia and a diagnosis of “shock kidney” was made. It is probable that magnesium sulfate would have prevented further convulsions if it had been given after the first one or would have prevented the first one if given earlier. Whether the prevention of repeated convulsions would have averted the cerebral hemorrhages and death is speculative.
Material and methods The hitherto unpublished data were obtained in studies made with Ira H. Tepper, M.D., in 1955 and 1956 and with Peter Kaufmann, M.D., in 1958 and 1959. The calibrated infusion method of Deane and associates’ was used for the estimation of the volumes of distribution (spaces) of sucrose and magnesium in nine women (shown in Table I). One was excluded because of mechanical difficulties in controlling the rate of infusion. The fluid infused was made up of 48 ml. of 50 per cent sucrose, 75 ml. of 10 per cent magnesium sulfate (MgSO, . 7H,O), and 177 ml. of distilled water. Duplicate analyses of each of three or four separate dilutions of the fluid were made for sucrose and magnesium, in conjunction with the duplicate or quadruplicate analyses of serum and urine. The infusion was given by a Bowman pump powered by a Sola constant voltage regulator, at a rate of about.l.12 ml. per minute; the rate of delivery was calibrated before and after each experiment. As soon as the infusion was started, a priming dose of 20 ml. of 10 per cent magnesium sulfate (16.4 mEq.) was given intravenously. In addition to the blank, blood samples were taken at intervals of about 30 minutes, beginning at about 45 minutes after starting the infusion. The blood was centrifuged at once, while clotting, and the analyses were made of serum. Urine was obtained through a multiple-eyed catheter and the bladder was washed out once or twice with 20 to 30 ml. of water, with the injection of about 30 ml. of air. The urinary collections were completed at from five to seven minutes after each sampling of blood. Sucrose clearances were calculated as a check on the completeness of the urinary collections. Sucrose was measured by the method of Roe and colleagues8 in urine suitably diluted (usually 1: 250 or
I
2 HOURS
3
3
4
Fig. 1. Serial estimates of the sucrose and apparent magnesium spaces by the method of calibrated infusion. Sucrose space, l ; apparent magnesium space, X. 1 : 500) and in serum diluted 1 : 10 in the precipitation of proteins by zinc hydroxide. Magnesium was measured by the method of Simonsen and co-workers” in undiluted serum and in urine suitable diluted (usually 1 : 5 or 1: IO). Blood, urine, water, and reagent blanks were run with all measurements. Serum proteins were measured by the biuret method” and plasma volumes were measured with T-1824 (Evans blue). All readings were made with a spectrophotometer.* Ultrafiltrable magnesium was derived from the nomogram of Willis and Sunderman,” which relates it to the concentration: of total magnesium and proteins in serum. The apparent volumes of distribution of sucrose were corrected for the nonaqueous portion of serum.
Results and comment Apparent volume of distribution of magnesium. Fig. 1 exemplifies the serial estimates of the apparent sucrose and magnesium spaces in a patient with moderately severe pre-eclampsia in the thirty-fourth week of pregnancy. She had lost 10 pounds in five days during acetazolamide and chlorothiazidei administration and that undoubtedly reduced the spaces. In the calibrated infusion method for measuring a volume of distribution, one must know accurately the cumulative amount of the substance infused and must measure accurately the cumulative amounts excreted. The difference is the residual amount in the body and dividing that by the concentration in plasma gives the apparent volume of distribution. Serial estimates, at intervals of about half an hour in the present study, show increasing volumes until equilibrium is attained. In the case of sucrose, the apparent volume usually becomes constant within two hours in normal nonpregnant subjects. In pregnant women, however, the apparent vol*Model DU, Beckman Instruments, Inc., Fullerton, California. tThe patient was seen in 1958. We now believe that diuretic drugs ate contraindicated in pre-eclampsia.
4
January 1. 1979 Am. J. Obstet. Gynecol.
Chesley
Table II. Magnesium in and beyond the sucrose space in a nonpregnant woman kilograms; plasma volume, 3,000 ml.; plasma proteins, 6.6 Cm. per 100 ml.)
with leiomyomas
(weight,
66.8
Time in minutes 45
Cumulative infusion of Mg (mEq.) Cumulative excretion of Mg (mEq.) Residual Mg (mEq.) Increment in plasma Mg (mEq./L.) Apparent Mg space (L.) Increment in ultrafiltrable Mg (mEq./L.) Total incremental Mg in extravascular sucrose space (mEq.) Total incremental Mg in plasma
31.8 7.4 24.4
1.78 13.7
1.31
70
92
38.6 11.4 27.2
44.6 15.0 29.6
1.63 16.7
1.19
1.63 18.2
1.19
122 52.8 20.0 32.8
1.56 21.0
1.14
153 61.3 25.5 35.8
1.66 21.6
1.21
18.2 69.2 30.6 38.6
1.87 20.7
1.38
208
226
76.3 35.1 41.2
81.2 38.6 42.6
1.91 21.6
1.40
1.91 22.3
1.40
11.0
10.0
10.0
9.6
10.2
11.6
11.8
11.8
5.3
4.9
4.9
4.7
5.0
5.6
5.7
5.7
16.3
14.9
14.9
14.3
15.2
17.2
17.5
17.5
8.1
12.3
14.7
18.5
20.6
21.4
23.7
25.1
45
49
56
58
56
58
59
(mEq.1
Total incremental Mg in sucrose space (mEq.) Total incremental space WW:
Mg beyond sucrose
Percentage of total
33
umes often are increasing slowly at the end of four hours, presumably because sucrose has not equilibrated in the fetus and amniotic fluid. In three of eight cases in the present study, it was obvious that equilibrium had not been established and it may not have been in the case shown in Fig. 1. Fig. 1 suggests that the apparent magnesium space may have approached constancy between the third and fourth hours, but the appearance probably is spurious because the patient had excreted more than half of the infused magnesium. In the calibrated infusion method calculations become inaccurate when the cumulative excretion of the test substance approaches or exceeds half of the cumulative infusion, which happened in three of eight cases. For that reason, the method probably cannot measure the definitive volume of distribution of magnesium. The renal clearance of magnesium increases linearly and steeply with increases in the plasma level.*2 As an example, one pregnant hypertensive patient had a magnesium clearance of 3.4 ml. per minute when the plasma level was 1.69 mEq. per liter: as the plasma level rose during the infusion of magnesium, the clearance increased progressively and attained 63.5 ml. per minute when the plasma level reached 5.0 mEq. per liter. Table I summarizes the serial estimates of the apparent magnesium spaces, which are not corrected for the protein binding of magnesium in plasma or for the Gibbs-Donnan effect. In several of the cases there are improbable fluctuations from period to period. Each is associated with a measured plasma level of magnesium that diverges from the trend in that particular patient, Although the recovery of magnesium added to serum
was excellent, with a maximal error of about 6 per cent, I suspect that some measurements were erroneous. Aside from the aberrant values, the data do provide estimates that can be used in assessing the safety of our initial dose of magnesium sulfate. The variation from subject to subject is wide. In several periods, there is a twofold difference between the lowest volumes (in a nonpregnant woman) and the highest (in an edematous pre-eclamptic patient). The two extreme cases can be used for the calculation of the concentrations of magnesium expected in the plasma if none of the dose was excreted. The nonpregnant woman weighed 48.8 kilograms and her apparent volume of distribution of magnesium was about 250 ml. per kilogram, or 12.2 L. Our initial dose of magnesium sulfate is 13 Cm. (107 mEq. of magnesium; 24.6 mEq. given intravenously plus 82.4 mEq. intramuscularly). When all of the magnesium is absorbed from the intramuscular depot, with none excreted, there would be 107 mEq. in 12.2 L.. or 8.8 mEq. per liter. If the original level of endogenous magnesium had been 2.0 mEq. per liter, the final concentration would be 10.8, probably high enough to abolish the tendon reflexes but unlikely to depress respiration. The pre-eclamptic patient weighed 64.1 kilograms, with an apparent magnesium space of 460 ml. per kilogram. The increment in the level of magnesium in plasma would be only 3.6 mEq. per liter. It is unlikely that either patient could tolerate the intravenous injection of 13 Gm. of magnesium sulfate if given within a few minutes. Ten of the 13 Gm. is given intramuscularly, and the absorption is rather slow. Pritchard,13 Chesley and Tepper,3 and Flowers
Volume Number
Parenteral magnesium sulfate
133 1
and associates” observed that the concentration of magnesium in plasma rises gradually after such injecv tions, with from 90 to 120 minutes being the usual time required for reaching the maximal level in plasma. In.deed, that was their basis for adding the priming intravenous dose. During the time required for absorption, magnesium is leaving the bloodstream rapidly ant1 its volume of distribution is increasing. Pritchard’” measured the apparent magnesium spaces in five dogs, four with bilateral ligation of the ureters and one with bilateral nephrectomy. The apparent volumes of distribution increased rapidly during the first four to six hours, then more slowly, to attain values ranging from 400 to 490 ml. per kilogram, which were about twice the inulin spaces measured simultaneously in three of the dogs. He also estimated the apparent magnesium spaces in four patients, two with acute renal failure and two with chronic glomerulonephritis and severe renal impairment. The apparent spaces ranged from 370 to 430 ml. per kilogram at the end of 20 to 23 hours; there was no mention of the rates of increase. Distribution of magnesium. Although the apparent volume of distribution is a major determinant of the plasma level after the parenteral administration of a magnesium salt, it does not define the true volume of distribution, As previously mentioned. the apparent spaces were not corrected for protein-bound magnesium in plasma or for the Gibbs-Donnan effect. From 20 to 35 per cent of the magnesium in plasma is bound to proteins and is not ultrafiltrable. The concentration in extravascular extracellular fluid is, therefore, significantly lower than that in the water of plasma. The apparent volume of distribution is calculated by dividing the incremental amount in the body by the concentration in plasma, which underestimates the true distribution. Moreover, magnesium enters bone and cells, where the incremental concentrations are known. Brandt and colleagues’” studied the uptake of radioactive magnesium in dogs and found wide vari.dtions from organ to organ, with the heart, kidney, liver, and pancreas having the highest, but differing radioactivities. Bones, which contain much labile magnesium, differed greatly from one another in the same animal. Pregnancy further complicates the estimation of the volume of distribution of any substance that crosses the placenta, because variable and unknown proportions of fetal and amniotic Huids are included. When parenteral magnesium is administered, it requires from two to three hours for fetal and maternal blood to come into equilibrium.3. I3 The concentration of magnesium in amniotic Huid rises rather slowly and
5
’
:
40
80
120 160 MINUTES
200
240
Fig. 2. The proportions of retained magnesium beyond the sucrose space: nonpregnant women, m----e and o--o; normal pregnant women, X----X and n-n; pre-eclamptic patient, e---o. erratically, perhaps in part by way of fetal urine.3x I3 The measurement of the true magnesium space seems to be impossible, clinically, on the theoretical bases mentioned. However, certain interesting calculations can be made. Table II, representing one of five subjects, summarizes the derivations of incremental extracellular magnesium and the proportions of incremental magnesium that moved beyond the extracellular fluid (estimated by the sucrose space). In the example shown in Table II, about 58 per cent of the incremental magnesium had moved beyond the sucrose space, that is, it had been taken up by bones and cells where its concentrations are variable and unknown. Some may have entered the amniotic Huid and some portions of the fetus more rapidly than sucrqse did. Fig. 2 shows that the proportion of incremental magnesium beyond the sucrose space increases with time for the first two hours and then seems to level off at roughly half. The lowest proportion, 30 per cent, was observed in the previously mentioned pre-eclamptic patient who had been given diuretic drugs for live days. In the other four subjects, two nonpregnant and two normal pregnant women, the proportions of magnesium beyond the sucrose space were 48, 50, 58, and 58 per cent at 145 to 241 minutes. Except in the pre-eclamptic patient, from 47 to 50 per cent of the infused magnesium had moved into bones and cells by 90 minutes after the beginning of the infusions. As previously mentioned, maximal concentrations of magnesium in plasma do not occur until 90 to 120 minutes after intramuscular injection of magnesium sulfate. 3* I33 I4 Thus, the rapid distribution of magnesium in a large pool is a buffering action that prevents accumulation and attainment of toxic concen-
January
6 Chesley
4”a -rJ t-Qa _
0
1, 1979
ilm. J. Obstet. Gynecol.
I
2
3 4 HOURS
5
6
Fig. 3. The highest, average, and lowest levels of magnesium in serum and the highest, average, and lowest renal excretions of magnesium in three eclamptic and seven severely preeclamptic patients given magnesium sulfate, 3 Gm. (24.6 mEq.) intravenously and 10 Cm. (82.4 mEq.) intramuscularly. trations in plasma. The one pre-eclamptic patient had an unusually small volume of distribution of magnesium, at 290 ml. per kilogram. The other two preeclamptic women represented in Table I had much greater apparent volumes and large amounts of magnesium must have moved beyond the sucrose space. Plasma levels and excretion of magnesium. Pritchard,‘” Chesley and Tepper,3 and Flowers and associates”’ have published graphs illustrating the levels of magnesium in plasma attained after the parenteral
administration of magnesium sulfate in various doses and given in several ways. All agree that the large doses used by Pritchard’s I3 and by us” are safe in eclamptic and severely pre-eclamptic women, many of whom are oliguric (remember the precautions in the presence ofoliguria). Fig. 3 depicts the range and average plasma levels observed in three eclamptic and seven severely eclamptic- women, each given 9 Gm. (24.6 ml%].) of maguesium sulfate intravenously plus 10 Gm. (82.4 mEq.) intramuscularly. The highest single concentration in plasma was 6.0 mEq. per liter (7.2 mg. per 100 ml.). seen in an oliguric eclamptic woman. Despite the oliguria, the concentration fell to 3.9 mEq. per liter by the sixth hour after injection. Parenthetically, such observations led Pritchard’” and us3 to give additional magnesium sulfate (5 Gm.) intramuscularly at intervals of four hours, with the precautions described. Fig. S also shows the remarkably similar cumulative excretions of magnesium in the same patients. At the end of four hours, fi-om 38 to .53 (average 44) per cent of the total injected magnesium had been excreted. Thus, somewhat more than half of the magnesium in.jected in the initial dose is still present in the body when the second dose of 5 Gm. is injected intramuscularly. If such residual and cumulative proportions were present at the end ofeach four hours, repeated doses might be expected to build up toxic levels in the plasma. As the published graphs show, :Z ‘L I4 howe\rer, that does not happen. The reason must be the great increases in renal clearance of magnesium as the plasma level rises.‘” If‘ the patient has severe renal impairment, repeated doses of magnesium sulfate could lead to toxicity. but we have a safeguard in that the tendon reflexes disappear before respiratory depression occurs.
REFERENCES
1. Eastman, N. J,: Editorial comment, Obstet. Gynecol. Surv. 10: 497, 1955. 2. Pritchard, J. A.: Standardized treatment of 154 consecutive cases of eclampsia, AM. J, OBSTET. GYNECOL. 123: 543. 1975. 3. Chesley. L. C., and Tepper, I.: Plasma levels of magnesium attained in magnesium sulfate therapy for preeclampsia and eclampsia, Surg. Clin. North Am., April, 1957, p. 353. 4. Smith, P. K., Winkler, A. W., and Hoff, H. E.: Electrocardiographic changes and concentration of magnesium in serum following intravenous injections of magnesium salts, Am. J. Physiol. 126: 720, 1939. 5. Hoff, H. E., Smith, P. Ii., and Winkler, A. W.: Effects of magnesium on nervous system in relation to its concentration in serum, Am. J. Physiol. 130: 292, 1940. 6. Moore, R. M.. and Wingo, W. J.: Blood levels of mag-
7.
8. 9. 10. 11.
nesium ion in relation to lethal, anesthetic, analgesic and antitetanic effects, Am. J. Physiol. 135: 492, 1942. Deane, N.. Schreiner. G. E., and Robertson, J. S.: The velocity of distribution of sucrose between plasma and interstitial fluid, with reference to the use of sucrose for the measurement of extracellular Huid in man, .J. Clin. Invest. 30: 1463. 1951. Roe, J. H., Epstein, J. H., and Goldstein, N. P.: A photometric method for the determination of inulin in plasma and urine, J. Biol. Chem. 178: 839, 1949. Simonsen, D. G.. Westover, L. M., and Wertman, M.: The determination of serum magnesium by the molybdivanadate method for phosphate, J. Biol. Chem. 169: 39, 1947. Fister, H. J.: Manual of Standardized Procedures for Spectrophotometric Chemistry, New York, 1950, Standard Scientific Supply Corporation. Willis. M. J.. and Sunderman, F. W.: Studies in serum
Volllme Number
13.7 1
electrolytes. XIX. Nomograms for calculating magnesium in serum and ultrafiltrates,J. Biol. Chem. 197: 343,195Z. 12. Chesley-, L. C., and Tepper, I.: Some effects of magnesium loading upon renal excretion of magnesium and certain other electrolytes, J. Clin. Invest. 37: 1362, 1958. 13. Pritchard, J. A.: The use of the magnesium ion in the management of eclamptogenic toxemias, Surg. Gynecol Obstet. 100: 131, 1955.
Parenteral magnesium sulfate
7
14. Flowers. C. E., Jr., Easterling, W. E., Jr., White, F. Jung. J. M., and Fox, J. T., Jr.: Magnesium sulfate toxemia of pregnancy. New dosage schedule based body weight, Obstet. Gynecol. 19: 315, 1962. 15. Brandt, J. L., Glaser. W., and Jones, A.: Soft tissue tribution and plasma disappearance of intravenously administered isotopic magnesium with observations uptake in bone, Metabolism 7: 355, 1958.
D., in on
Information for authors Most of the provisions of the Copyright Act of 1976 became effective on January 1, 1978. Therefore, all manuscripts must be accompanied by the following written statement, signed by one author: “The undersigned author transfers all copyright ownership of the manuscript (title of article) to The C. V. Mosby Company in the event the work is published. The undersigned author warrants that the article is original, is not under consideration by another journal, and has not been previously published. I sign for and accept responsibility for releasing this material on behalf of any and all co-authors.” Authors will be consulted, when possible, regarding republication of their material.
dison
Obstetrics and Gynecology volume
133
number
1
JANUARY
1, 1979
Parenteral magnesium sulfate and the distribution, plasma levels, and excretion of magnesium LEON
C. CHESLEY,
PH.D.
Brooklyn, New York The calibrated infusion method was used in trying to measure the apparent volumes of distribution of sucrose and magnesium in three nonpregnant, three normal pregnant, and 3 pre-eclamptic women. The data for one normal pregnant woman were vitiated by mechanical difficulties and equilibrium for sucrose was not established in one nonpregnant and two pre-eclamptic subjects. The rapid renal excretion of infused magnesium prevents accurate estimate of the apparent magnesium space. In five satisfactory observations, magnesium moved rapidly beyond the sucrose space, that is, it entered cells, bone, and probably those portions of the fetus and amniotic fluid not included in the estimate of the sucrose space. By w) minutes, about half of the retained magnesium had moved beyond the sucrose space. The concentration in serum and the cumulative renal excretions of magnesium were measured in three eclamptic and seven severely pre-eclamptic patients given 3 Gm. of magnesium sulfate intravenously and 10 Gm. intramuscularly as the initial therapeutic dose. The highest single level in plasma, observed at 60 minutes, was 6.0 mEq per liter (7.2 mg. per 100 ml.) in an oliguric eclamptic woman. The average peak level, also at 60 minutes, was 4.5 mEq. per liter. At the end of four hours the cumulative renal excretions ranged from 33 to 53 per cent of the dose injected. Calculation of the concentration to be expected in serum (plasma) indicates that the initial dose is safe, even in anuric patients; repeated doses might not be safe. (AM. J. OBSTET. GYNECOL.
THE
133:1,
1979.)
of parenteral magnesium sulfate and control of eclamptic convulsions
EFFICACY
the prevention
From the Department of Obstetrics and Gynecology, State University of New York, Downstate Medical Center, and Kings County Hospital. Supported bj a research grant (H-l 83 7) from the National Institutes of Health, United States Public Service. Receivedfor Revised
publication
December
Accepted August
October
Health
11, 1977.
9, 1977. 3, 1978.
Reprint requests: Dr. Leon C. Chesley, Box 24, 450 Clarkson Ave., Brooklyn, New York 11203. 0002-9378/79/010001+07$00.70/0
0 1979 The C. V.
Mosby
Co.
in is
well established’s * and in the United States it probably is the most popular agent used for those purposes. Pritchard2 reported 154 consecutive cases of eclampsia, treated with magnesium sulfate, without a maternal death and with a perinatal mortality rate of only 15.4 per cent in antenatal eclampsia (9.9 per cent, excluding birth weights of less than 1,000 grams). Pritchard* gives an initial dose of magnesium sulfate of 4 Gm. intravenously, followed at once by 10 Gm. intramuscularly; thereafter 5 Gm. are injected intramuscularly every four hours, but any of the later doses are postponed if: (1) the knee jerk is absent, (2) the respiratory rate is depressed, or (3) the urinary output has 1
2 Chesley
Table
January Am. J. Obstet.
I. The apparent
volumes
of distribution
(spaces) of sucrose and magnesium Apparent
DiagTWSiS
Pre-eclampsia* Pre-eclampsia Pre-eclampsia Normal pregnancy Normal pregnancy Nonpregnant Nonpregnant Nonpregnant
SlrcroJr .spm (rd. /Kg.,
230 : 183 196 t 170 185
1. 1979 Gynecol.
magnesium
space (ml. /Kg.)
-/5 min.
60 min.
90 mirr.
120 mm.
150 min.
180 min.
210 min.
204 319 313 222 216 185 205 192
278
262 340 473 272 306 218 273 301
248 386 460 288 382 232 315 308
280 403 442 288 376 250 324 298
290
290
290
278
255
255
247 310 303
253 324
244 334
438 240 272 223 250 213
240
f&c.
*Patient had lost 10 pounds in five days while receiving acetazolamide and chlorothiazide. tEquilibrium not established. not been at least 100 ml. since the preceding dose. Also the antidote to magnesium toxicity (10 ml. of’ 10 pel cent calcium gluconate) must be readily available. Our” use of the drug at the Kings County and University Hospitals of the State University of New York Downstate Medical Center differs only in that we give 3 Gm., rather than 4 Gm., as the initial intravenous dose. Thus, Pritchard injects 39 Gm. in the first 24 hours, and we inject 38 Gm. Many obstetricians in the past, and still, use far smaller amounts because toxicity does occur if too much magnesium is given. The first sign of an adverse effect is a depression of the respiratory rate, but that is preceded by disappearance of the tendon reflexes; those are the reasons for the first and second precautions, above. Magnesium is excreted almost solely by the kidney. which is the reason for the third precaution. Several investigators have related the pharmacologic effects of magnesium to its concentration in plasma. Smith and colleagues,” using dogs, found that respiratory arrest does not occur until the levels of magnesium reach from 17 to 27 mEq. per liter (20 to 32 mg. per 100 ml.). Hoff and co-workers” observed that in man the patellar reflex (knee jerk) is lost with concentrations of magnesium between 7 and 10 mEq. per liter (8.4 to 12 mg. per 100 ml.). Thus, the suppression of the knee jerk occurs before respiratory depression and it serves as a warning clinical sign that the magnesium in plasma may be approaching a toxic level. Moore and Wingo,’ using dogs and cats, found the fatal level of magnesium to be from 17.5 to 45 mEq. per liter (21 to 54 mg. per 100 ml.). Pritchard’ saw respiratory depression in but one patient; she weighed only 99 pounds before delivery and had severe renal impairment, and the anesthesia for hysterotomy had been supplemented with succinylcholine. She developed respiratory depression postoperatively, which was corrected by calcium gluconate. We have used the antidote in three patients but nevel
in any of the hundreds treated as outlined. Each of three house officers injected intravenously the 20 ml. of 50 per cent magnesium sulfate (10 Gm., 82 mEq. of magnesium) that should have been given as the initial intramuscular dose. One patient manifested no adverse effect, but the house officer gave her calcium gluconate as soon as he realized his mistake. One patient had respiratory arrest, which quickly yielded to the antidote, and the third had both respiratory and cardiac arrest; external cardiac massage and 10 ml. of 10 per cent calcium gluconate intravenously were promptly effective. Pritchard’s and our experience attests to the safety of large doses of magnesium sulfate if the precautions are observed. The level of magnesium attained in plasma after parenteral administration of a given dose depends upon the volume of distribution and renal excretion of the magnesium. In the presence of severe oliguria or advanced renal failure, the volume of distribution determines the concentration. The present paper is prompted by a maternal death and its purpose is to indicate that the initial dose of 3 Gm. of magnesium sulfate intravenously plus 10 Gm. intramuscularly (107 mEq. of magnesium) is safe because of the volume in which it is diluted. Needless to say, a second and later dose probably would not be safe in a severely oliguric patient. Case report M. T., an obese, black woman, aged 29, para 7-O-O-4, was admitted to the Kings County Hospital at term, complaining of left-sided thoracic and upper abdominal pain for two hours’ duration. The blood pressure was 160/ 110; she had no edema and no urine could be obtained by catheter. The house officer attributed the high blood pressure to essential hypertension and the pain to the fried chicken that she had eaten six hours earlier. His only consultant, a gastroenterologist, concurred. The patient had the first of seven convulsions at about three hours after admittance. Recause of the
Volume Number
Parenteral magnesium sulfate
133 1
supposed anuria, the house officer did not give her magnesium sulfate but treated her with diphenylhydantoin, phenobarbital, and diazepam. The patient recovered consciousness after each of the first three convulsions but was unresponsive thereafter and died about 13 hours after admittance. At autopsy, she was found to have a massive hemorrhage involving the midbrain, pons, and medulla and a subarachnoid hemorrhage over the right frontal and temporal lobes. The liver had extensive lesions characteristic of eclampsia and a diagnosis of “shock kidney” was made. It is probable that magnesium sulfate would have prevented further convulsions if it had been given after the first one or would have prevented the first one if given earlier. Whether the prevention of repeated convulsions would have averted the cerebral hemorrhages and death is speculative.
Material and methods The hitherto unpublished data were obtained in studies made with Ira H. Tepper, M.D., in 1955 and 1956 and with Peter Kaufmann, M.D., in 1958 and 1959. The calibrated infusion method of Deane and associates’ was used for the estimation of the volumes of distribution (spaces) of sucrose and magnesium in nine women (shown in Table I). One was excluded because of mechanical difficulties in controlling the rate of infusion. The fluid infused was made up of 48 ml. of 50 per cent sucrose, 75 ml. of 10 per cent magnesium sulfate (MgSO, . 7H,O), and 177 ml. of distilled water. Duplicate analyses of each of three or four separate dilutions of the fluid were made for sucrose and magnesium, in conjunction with the duplicate or quadruplicate analyses of serum and urine. The infusion was given by a Bowman pump powered by a Sola constant voltage regulator, at a rate of about.l.12 ml. per minute; the rate of delivery was calibrated before and after each experiment. As soon as the infusion was started, a priming dose of 20 ml. of 10 per cent magnesium sulfate (16.4 mEq.) was given intravenously. In addition to the blank, blood samples were taken at intervals of about 30 minutes, beginning at about 45 minutes after starting the infusion. The blood was centrifuged at once, while clotting, and the analyses were made of serum. Urine was obtained through a multiple-eyed catheter and the bladder was washed out once or twice with 20 to 30 ml. of water, with the injection of about 30 ml. of air. The urinary collections were completed at from five to seven minutes after each sampling of blood. Sucrose clearances were calculated as a check on the completeness of the urinary collections. Sucrose was measured by the method of Roe and colleagues8 in urine suitably diluted (usually 1: 250 or
I
2 HOURS
3
3
4
Fig. 1. Serial estimates of the sucrose and apparent magnesium spaces by the method of calibrated infusion. Sucrose space, l ; apparent magnesium space, X. 1 : 500) and in serum diluted 1 : 10 in the precipitation of proteins by zinc hydroxide. Magnesium was measured by the method of Simonsen and co-workers” in undiluted serum and in urine suitable diluted (usually 1 : 5 or 1: IO). Blood, urine, water, and reagent blanks were run with all measurements. Serum proteins were measured by the biuret method” and plasma volumes were measured with T-1824 (Evans blue). All readings were made with a spectrophotometer.* Ultrafiltrable magnesium was derived from the nomogram of Willis and Sunderman,” which relates it to the concentration: of total magnesium and proteins in serum. The apparent volumes of distribution of sucrose were corrected for the nonaqueous portion of serum.
Results and comment Apparent volume of distribution of magnesium. Fig. 1 exemplifies the serial estimates of the apparent sucrose and magnesium spaces in a patient with moderately severe pre-eclampsia in the thirty-fourth week of pregnancy. She had lost 10 pounds in five days during acetazolamide and chlorothiazidei administration and that undoubtedly reduced the spaces. In the calibrated infusion method for measuring a volume of distribution, one must know accurately the cumulative amount of the substance infused and must measure accurately the cumulative amounts excreted. The difference is the residual amount in the body and dividing that by the concentration in plasma gives the apparent volume of distribution. Serial estimates, at intervals of about half an hour in the present study, show increasing volumes until equilibrium is attained. In the case of sucrose, the apparent volume usually becomes constant within two hours in normal nonpregnant subjects. In pregnant women, however, the apparent vol*Model DU, Beckman Instruments, Inc., Fullerton, California. tThe patient was seen in 1958. We now believe that diuretic drugs ate contraindicated in pre-eclampsia.
4
January 1. 1979 Am. J. Obstet. Gynecol.
Chesley
Table II. Magnesium in and beyond the sucrose space in a nonpregnant woman kilograms; plasma volume, 3,000 ml.; plasma proteins, 6.6 Cm. per 100 ml.)
with leiomyomas
(weight,
66.8
Time in minutes 45
Cumulative infusion of Mg (mEq.) Cumulative excretion of Mg (mEq.) Residual Mg (mEq.) Increment in plasma Mg (mEq./L.) Apparent Mg space (L.) Increment in ultrafiltrable Mg (mEq./L.) Total incremental Mg in extravascular sucrose space (mEq.) Total incremental Mg in plasma
31.8 7.4 24.4
1.78 13.7
1.31
70
92
38.6 11.4 27.2
44.6 15.0 29.6
1.63 16.7
1.19
1.63 18.2
1.19
122 52.8 20.0 32.8
1.56 21.0
1.14
153 61.3 25.5 35.8
1.66 21.6
1.21
18.2 69.2 30.6 38.6
1.87 20.7
1.38
208
226
76.3 35.1 41.2
81.2 38.6 42.6
1.91 21.6
1.40
1.91 22.3
1.40
11.0
10.0
10.0
9.6
10.2
11.6
11.8
11.8
5.3
4.9
4.9
4.7
5.0
5.6
5.7
5.7
16.3
14.9
14.9
14.3
15.2
17.2
17.5
17.5
8.1
12.3
14.7
18.5
20.6
21.4
23.7
25.1
45
49
56
58
56
58
59
(mEq.1
Total incremental Mg in sucrose space (mEq.) Total incremental space WW:
Mg beyond sucrose
Percentage of total
33
umes often are increasing slowly at the end of four hours, presumably because sucrose has not equilibrated in the fetus and amniotic fluid. In three of eight cases in the present study, it was obvious that equilibrium had not been established and it may not have been in the case shown in Fig. 1. Fig. 1 suggests that the apparent magnesium space may have approached constancy between the third and fourth hours, but the appearance probably is spurious because the patient had excreted more than half of the infused magnesium. In the calibrated infusion method calculations become inaccurate when the cumulative excretion of the test substance approaches or exceeds half of the cumulative infusion, which happened in three of eight cases. For that reason, the method probably cannot measure the definitive volume of distribution of magnesium. The renal clearance of magnesium increases linearly and steeply with increases in the plasma level.*2 As an example, one pregnant hypertensive patient had a magnesium clearance of 3.4 ml. per minute when the plasma level was 1.69 mEq. per liter: as the plasma level rose during the infusion of magnesium, the clearance increased progressively and attained 63.5 ml. per minute when the plasma level reached 5.0 mEq. per liter. Table I summarizes the serial estimates of the apparent magnesium spaces, which are not corrected for the protein binding of magnesium in plasma or for the Gibbs-Donnan effect. In several of the cases there are improbable fluctuations from period to period. Each is associated with a measured plasma level of magnesium that diverges from the trend in that particular patient, Although the recovery of magnesium added to serum
was excellent, with a maximal error of about 6 per cent, I suspect that some measurements were erroneous. Aside from the aberrant values, the data do provide estimates that can be used in assessing the safety of our initial dose of magnesium sulfate. The variation from subject to subject is wide. In several periods, there is a twofold difference between the lowest volumes (in a nonpregnant woman) and the highest (in an edematous pre-eclamptic patient). The two extreme cases can be used for the calculation of the concentrations of magnesium expected in the plasma if none of the dose was excreted. The nonpregnant woman weighed 48.8 kilograms and her apparent volume of distribution of magnesium was about 250 ml. per kilogram, or 12.2 L. Our initial dose of magnesium sulfate is 13 Cm. (107 mEq. of magnesium; 24.6 mEq. given intravenously plus 82.4 mEq. intramuscularly). When all of the magnesium is absorbed from the intramuscular depot, with none excreted, there would be 107 mEq. in 12.2 L.. or 8.8 mEq. per liter. If the original level of endogenous magnesium had been 2.0 mEq. per liter, the final concentration would be 10.8, probably high enough to abolish the tendon reflexes but unlikely to depress respiration. The pre-eclamptic patient weighed 64.1 kilograms, with an apparent magnesium space of 460 ml. per kilogram. The increment in the level of magnesium in plasma would be only 3.6 mEq. per liter. It is unlikely that either patient could tolerate the intravenous injection of 13 Gm. of magnesium sulfate if given within a few minutes. Ten of the 13 Gm. is given intramuscularly, and the absorption is rather slow. Pritchard,13 Chesley and Tepper,3 and Flowers
Volume Number
Parenteral magnesium sulfate
133 1
and associates” observed that the concentration of magnesium in plasma rises gradually after such injecv tions, with from 90 to 120 minutes being the usual time required for reaching the maximal level in plasma. In.deed, that was their basis for adding the priming intravenous dose. During the time required for absorption, magnesium is leaving the bloodstream rapidly ant1 its volume of distribution is increasing. Pritchard’” measured the apparent magnesium spaces in five dogs, four with bilateral ligation of the ureters and one with bilateral nephrectomy. The apparent volumes of distribution increased rapidly during the first four to six hours, then more slowly, to attain values ranging from 400 to 490 ml. per kilogram, which were about twice the inulin spaces measured simultaneously in three of the dogs. He also estimated the apparent magnesium spaces in four patients, two with acute renal failure and two with chronic glomerulonephritis and severe renal impairment. The apparent spaces ranged from 370 to 430 ml. per kilogram at the end of 20 to 23 hours; there was no mention of the rates of increase. Distribution of magnesium. Although the apparent volume of distribution is a major determinant of the plasma level after the parenteral administration of a magnesium salt, it does not define the true volume of distribution, As previously mentioned. the apparent spaces were not corrected for protein-bound magnesium in plasma or for the Gibbs-Donnan effect. From 20 to 35 per cent of the magnesium in plasma is bound to proteins and is not ultrafiltrable. The concentration in extravascular extracellular fluid is, therefore, significantly lower than that in the water of plasma. The apparent volume of distribution is calculated by dividing the incremental amount in the body by the concentration in plasma, which underestimates the true distribution. Moreover, magnesium enters bone and cells, where the incremental concentrations are known. Brandt and colleagues’” studied the uptake of radioactive magnesium in dogs and found wide vari.dtions from organ to organ, with the heart, kidney, liver, and pancreas having the highest, but differing radioactivities. Bones, which contain much labile magnesium, differed greatly from one another in the same animal. Pregnancy further complicates the estimation of the volume of distribution of any substance that crosses the placenta, because variable and unknown proportions of fetal and amniotic Huids are included. When parenteral magnesium is administered, it requires from two to three hours for fetal and maternal blood to come into equilibrium.3. I3 The concentration of magnesium in amniotic Huid rises rather slowly and
5
’
:
40
80
120 160 MINUTES
200
240
Fig. 2. The proportions of retained magnesium beyond the sucrose space: nonpregnant women, m----e and o--o; normal pregnant women, X----X and n-n; pre-eclamptic patient, e---o. erratically, perhaps in part by way of fetal urine.3x I3 The measurement of the true magnesium space seems to be impossible, clinically, on the theoretical bases mentioned. However, certain interesting calculations can be made. Table II, representing one of five subjects, summarizes the derivations of incremental extracellular magnesium and the proportions of incremental magnesium that moved beyond the extracellular fluid (estimated by the sucrose space). In the example shown in Table II, about 58 per cent of the incremental magnesium had moved beyond the sucrose space, that is, it had been taken up by bones and cells where its concentrations are variable and unknown. Some may have entered the amniotic Huid and some portions of the fetus more rapidly than sucrqse did. Fig. 2 shows that the proportion of incremental magnesium beyond the sucrose space increases with time for the first two hours and then seems to level off at roughly half. The lowest proportion, 30 per cent, was observed in the previously mentioned pre-eclamptic patient who had been given diuretic drugs for live days. In the other four subjects, two nonpregnant and two normal pregnant women, the proportions of magnesium beyond the sucrose space were 48, 50, 58, and 58 per cent at 145 to 241 minutes. Except in the pre-eclamptic patient, from 47 to 50 per cent of the infused magnesium had moved into bones and cells by 90 minutes after the beginning of the infusions. As previously mentioned, maximal concentrations of magnesium in plasma do not occur until 90 to 120 minutes after intramuscular injection of magnesium sulfate. 3* I33 I4 Thus, the rapid distribution of magnesium in a large pool is a buffering action that prevents accumulation and attainment of toxic concen-
January
6 Chesley
4”a -rJ t-Qa _
0
1, 1979
ilm. J. Obstet. Gynecol.
I
2
3 4 HOURS
5
6
Fig. 3. The highest, average, and lowest levels of magnesium in serum and the highest, average, and lowest renal excretions of magnesium in three eclamptic and seven severely preeclamptic patients given magnesium sulfate, 3 Gm. (24.6 mEq.) intravenously and 10 Cm. (82.4 mEq.) intramuscularly. trations in plasma. The one pre-eclamptic patient had an unusually small volume of distribution of magnesium, at 290 ml. per kilogram. The other two preeclamptic women represented in Table I had much greater apparent volumes and large amounts of magnesium must have moved beyond the sucrose space. Plasma levels and excretion of magnesium. Pritchard,‘” Chesley and Tepper,3 and Flowers and associates”’ have published graphs illustrating the levels of magnesium in plasma attained after the parenteral
administration of magnesium sulfate in various doses and given in several ways. All agree that the large doses used by Pritchard’s I3 and by us” are safe in eclamptic and severely pre-eclamptic women, many of whom are oliguric (remember the precautions in the presence ofoliguria). Fig. 3 depicts the range and average plasma levels observed in three eclamptic and seven severely eclamptic- women, each given 9 Gm. (24.6 ml%].) of maguesium sulfate intravenously plus 10 Gm. (82.4 mEq.) intramuscularly. The highest single concentration in plasma was 6.0 mEq. per liter (7.2 mg. per 100 ml.). seen in an oliguric eclamptic woman. Despite the oliguria, the concentration fell to 3.9 mEq. per liter by the sixth hour after injection. Parenthetically, such observations led Pritchard’” and us3 to give additional magnesium sulfate (5 Gm.) intramuscularly at intervals of four hours, with the precautions described. Fig. S also shows the remarkably similar cumulative excretions of magnesium in the same patients. At the end of four hours, fi-om 38 to .53 (average 44) per cent of the total injected magnesium had been excreted. Thus, somewhat more than half of the magnesium in.jected in the initial dose is still present in the body when the second dose of 5 Gm. is injected intramuscularly. If such residual and cumulative proportions were present at the end ofeach four hours, repeated doses might be expected to build up toxic levels in the plasma. As the published graphs show, :Z ‘L I4 howe\rer, that does not happen. The reason must be the great increases in renal clearance of magnesium as the plasma level rises.‘” If‘ the patient has severe renal impairment, repeated doses of magnesium sulfate could lead to toxicity. but we have a safeguard in that the tendon reflexes disappear before respiratory depression occurs.
REFERENCES
1. Eastman, N. J,: Editorial comment, Obstet. Gynecol. Surv. 10: 497, 1955. 2. Pritchard, J. A.: Standardized treatment of 154 consecutive cases of eclampsia, AM. J, OBSTET. GYNECOL. 123: 543. 1975. 3. Chesley. L. C., and Tepper, I.: Plasma levels of magnesium attained in magnesium sulfate therapy for preeclampsia and eclampsia, Surg. Clin. North Am., April, 1957, p. 353. 4. Smith, P. K., Winkler, A. W., and Hoff, H. E.: Electrocardiographic changes and concentration of magnesium in serum following intravenous injections of magnesium salts, Am. J. Physiol. 126: 720, 1939. 5. Hoff, H. E., Smith, P. Ii., and Winkler, A. W.: Effects of magnesium on nervous system in relation to its concentration in serum, Am. J. Physiol. 130: 292, 1940. 6. Moore, R. M.. and Wingo, W. J.: Blood levels of mag-
7.
8. 9. 10. 11.
nesium ion in relation to lethal, anesthetic, analgesic and antitetanic effects, Am. J. Physiol. 135: 492, 1942. Deane, N.. Schreiner. G. E., and Robertson, J. S.: The velocity of distribution of sucrose between plasma and interstitial fluid, with reference to the use of sucrose for the measurement of extracellular Huid in man, .J. Clin. Invest. 30: 1463. 1951. Roe, J. H., Epstein, J. H., and Goldstein, N. P.: A photometric method for the determination of inulin in plasma and urine, J. Biol. Chem. 178: 839, 1949. Simonsen, D. G.. Westover, L. M., and Wertman, M.: The determination of serum magnesium by the molybdivanadate method for phosphate, J. Biol. Chem. 169: 39, 1947. Fister, H. J.: Manual of Standardized Procedures for Spectrophotometric Chemistry, New York, 1950, Standard Scientific Supply Corporation. Willis. M. J.. and Sunderman, F. W.: Studies in serum
Volllme Number
13.7 1
electrolytes. XIX. Nomograms for calculating magnesium in serum and ultrafiltrates,J. Biol. Chem. 197: 343,195Z. 12. Chesley-, L. C., and Tepper, I.: Some effects of magnesium loading upon renal excretion of magnesium and certain other electrolytes, J. Clin. Invest. 37: 1362, 1958. 13. Pritchard, J. A.: The use of the magnesium ion in the management of eclamptogenic toxemias, Surg. Gynecol Obstet. 100: 131, 1955.
Parenteral magnesium sulfate
7
14. Flowers. C. E., Jr., Easterling, W. E., Jr., White, F. Jung. J. M., and Fox, J. T., Jr.: Magnesium sulfate toxemia of pregnancy. New dosage schedule based body weight, Obstet. Gynecol. 19: 315, 1962. 15. Brandt, J. L., Glaser. W., and Jones, A.: Soft tissue tribution and plasma disappearance of intravenously administered isotopic magnesium with observations uptake in bone, Metabolism 7: 355, 1958.
D., in on
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dison
