Magnesium sulfate in obstetrics

Magnesium sulfate in obstetrics A study

of magnesium

CHARLES

E.

Chapel

Hill,

North

in plasma,

FLOWERS,

urine,

JR.,

This study grant from

muscle

M.D.

Carolina

D E s P I I‘ E the many significant advances that have been made in science and medicine, the toxemias of pregnancy remain an enigma. The incidence of the disease has declined only as the nutritional, educational, and socioeconomic status of the population has risen. Ninety-four per cent of all patients seen at the University of North Carolina with toxemia of pregnancy have been in the two lowest social groups.’ The explanation of this complication of pregnancy must include an understanding of how the stresses associated with the lives of patients in the lower socia1 groups and their nutrition affect the complicated metabolism of the syncytial cell and renal function. The management of the toxemias of pregnancy has gradually evolved with the devclopment and modification of a number of therapeutic adjuncts. Magnesium sulfate is recognized as the most satisfactory agent for the prevention and control of eclampsia. Despite the classic studies and dosage schedules developed by Eastman,” Chesley and Tepper,3 Pritchard,4 Hall,” and Zuspan and Ward,G magnesium is too often administered in unrealistic doses, and its use is not combined with reasonable obstetrical jud,gment.

From the Department Gynecology, University School of Medicine.

and

Our studies with magnesium sulfate were initiated in 1958. They were motivated by eclamptics being referred to the University of North Carolina Medical School after they had had repeated convulsions due to inadequate magnesium sulfate therapy and a maternal death which was probably associated with hypermagnesemia. It was hoped to develop a simple dosage schedule for magnesium sulfate and a practical method of measuring magnesium in plasma and urine in order that the average hospital with the usual clinical chemistry laboratory could safely and properly treat patients with eclamptogenic toxemia. A calorimetric method using titian yellow and a dosage schedule based on body weight was published in 1962.’ Pharmacological magnesium

in part

by a

and Company. Presented at the Seventy-jifth Annual Meeting of the American Association Obstetricians and Gynecologists, Hot Springs, Virginia, Sept. 10-12, 1964.

of

sulfate

Magnesium apparently prevents or controls convulsions by blocking neuromuscular transmission and decreasing the amount of acetylcholine liberated by the motor nerve impulse. Magnesium is administered to control convulsions and not as a hypotensive agent. The initial intravenous dose of magnesium often lowers the blood pressure by perfusing the vasomotor center with a high concentration of magnesium. However, there is rapid compensation; the fall in blood pressure is no greater than in similarly ill patients who do not receive magnesium sulfate. Magnesium is not used as a therapeutic agent to treat or manage the underlying pathology of toxemia of pregnancy. It is used only to prevent or control convulsions

of Obstetrics and of North Carolina

was supported G. D. Searle

action

of

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March 15, lybj AIII. J. Obst. & Gynec.

Flowers

until bed rest has temporarily reversed the process in the pre-eclamptic or induction of labor and delivery are used as curative measures in eclamptic and severe pre-eclamptic patients. The plasma concentration of magnesium that is necessary to prevent or control convulsions varies among individuals. Three to 6 mg. per cent is generally considered a satisfactory plasma level. Plasma levels below 16 mg. per cent are not toxic unless there is altered calcium metabolism. This method of therapy was designed to maintain a plasma concentration of magnesium between 3 and 8 mg. per cent. Magnesium is distributed in extracellular compartments, in tissue and in bone. It is thus felt that the dosage of magnesium sulfate should be a function of the weight of the individual. Parenterally administered magnesium is excreted only in the urine; the rate of excretion is a function of the plasma level of magnesium and the glomerular filtration.” Three factors have made this regimen of magnesium sulfate therapy practical : ( 1) A patient who is severely ill with toxemia of pregnancy excretes magnesium less efficiently than normal patients or patients with mild toxemia since there is generally a direct relationship between the severity of toxemia and the renal excretion of magnesium. These patients maintain a satisfactory therapeutic plasma level of magnesium throughout a 24 hour period when an intramuscular dosage schedule is used. This allows an 8:00 A.M. plasma level of magnesium to represent the plasma level throughout a 24 hour period. A patient who is not severely ill with toxemia of pregnancy excretes magnesium readily making it almost impossible to maintain a theoretical therapeutic level of magnesium (3 to 6 mg. per cent) with intramuscular-y administered magnesium sulfate. However. such a level is unnecessary. (2) The renal excretion of magnesium in a 24 hour collcction of urine varies widely among patients; however, the actual excretion of magnesium is similar in each patient from one 24 hour period to another. Thus the number of grams excreted in one 24 hour period can be used

Table I. Dosage of magnesium

100 to 120 to 140 to 160 to 180to 200 and

chart sulfate

119 139 159 179 199 above

4 -1 4 4 -1 1

for the administration

4 6 7 8 10 11

5 6 7 8 9 10

1.75 L’.oo 2.25 2.50 2.75 3.00

“The intravenous dose is placed in 250 C.C. oi 5 peg cent dextrose and given as rapidly as gravity will drlivrl it through a No. 19 gauge needle.

to calculate the magnesium sulfate dosage for the next 24 hours with inconsequential error.? (3) Spectrometric methods for measuring magnesium in plasma and urine are unnecessary since magnesium can be determined with the Titian yellow method by visually comparing unknowns with standards. This allows the laboratory to augment the physician’s clinical judgment in the treatment of the toxemias of pregnancy. Titian

yellow

magnesium

method in

plasma

of

determining and

urine9

One-half milliliter of plasma is pipetted into a 15 C.C. centrifuge tube and 5.5 ml. of 10 per cent trichloroacetic acid is rapidly added from a burette. Following mixing of the plasma and acid, the tube is centrifuged at 2,500 r.p.m. for 10 minutes. Five milliliters of the clear supernatant liquid is pipetted into a 50 ml. test tube into which is added 5 ml. of 0.1 per cent polyLinyl alcohol, 5 ml. of 7.5 mg. per cent of Titian yellow (this diluted solution of Titian yellow is kept in a dark place and prepared fresh every 2 to 3 weeks) and 10 ml. of 12 per cent sodium hydroxide. A glass top is placed over the test tube and the solution is thoroughly mixed. The color develops in 5 minutes. The magnesium hydroxide Titian yellow lake of the unknown is compared with known standards prepared from a stock solution of 10 Gm. of crystalline MgNH,PO,.GH,O

Magnesium

dissolved in 1 L. of O.lN HCl. The working standards are prepared by diluting 2, 4, 6, 8, and 10 ml. of the stock solution in 100 ml. of distilled water in volumetric flasks. The final standards are made by substitution of 0.5 ml. of each standard for the plasma in the procedure. The standards may be kept in a dark place and used for 3 days. The unknowns are visually compared with the known standards against a white background and are read as milligrams per cent. The urinary excretion of magnesium is similarly determined. The urine is diluted ten to twenty times since the amount of magnesium in urine may be as high as 12 mg. per cent. At this and higher levels a red precipitate of magnesium hydroxide forms rendering the readings inaccurate. Following the dilution of the urine, 0.5 ml. of the diluted urine is used in the method in lieu of the plasma. This regimen of magnesium therapy can best be understood by describing the clinical management of a patient with eclampsia and reviewing the previously published material7 The admission blood pressure of the patient was 190/100; there was 3+ albuminuria. She was in the thirty-seventh week of gestation and weighed 163 pounds. The dosage schedule, Table I, indicates that she should receive an initial dose of 12 Gm. of magnesium sulfate (MgS0,.7H?O). Four grams of magnesium sulfate was placed in 250 cc. of 5 per cent dextrose and given as rapidly as gravity would deliver it through a No. 19 gauge needle. The remaining 8 Gm. were given intramuscularly. Six hours later she received the first sustaining dose of 8 Gm. of magnesium sulfate. Deep tendon reflexes and her general condition were checked prior to each dose of magnesium sulfate. Before the second sustaining dose of magnesium sulfate was administered, the plasma level and the urinary excretion of magnesium were measured. The second sustaining dose

sulfate

in obstetrics

765

of magnesium sulfate was based upon the plasma level and the urinary excretion of magnesium for the first 12 hours of therapy. The subsequent doses of magnesium sulfate were based upon the 8: 00 A.M. plasma level and the 24 hour urinary excretion of magnesium. The plasma level of magnesium after 12 hours of therapy was 4 mg. per cent. Since the desired theoretical therapeutic level of magnesium is 6 mg. per cent, the plasma correction factor (Table I) was used to obtain this level. This was calculated as follows: 2 (the number of milligrams of magnesium the plasma level is to be raised) x 2.50 (the plasma correction for a patient weighing 160 to 179 pounds) = 5 Gm. of MgSOa.7Hz0. The patient excreted 300 ml. of urine containing 0.6 Gm. of magnesium in a 12 hour period. This has been calculated as shown below : MgSO,.7H,O contains only 10 per cent Mg++. Thus the 600 mg. of Mg++ would require 6 Gm. of MgS0,.7H,O to be administered for its replacement in 12 hours or 12 Gm. of magnesium sulfate for 24 hours. Thus the 12 Gm. of magnesium sulfate which represents the expected urinary excretion for 24 hours was added to the 5 Gm. necessary to raise the plasma level to the therapeutic level of 6 mg. per cent. Thus the patient received 17 Gm. of magnesium sulfate during the next 24 hours or 4.2 Gm. of magnesium sulfate every 6 hours. Thereafter the dosage schedule for each succeeding 24 hours was calculated from the 8:00 A.M. plasma level and the 24 hour urinary excretion of magnesium. If any question arises as to the general condition of a patient, an emergency plasma level of magnesium should be obtained. One is usually indicated every 12 hours in severely ill patients for the first 2 days of therapy. The combination of laboratory data and clinical evaluation of the patient increases the safety of magnesium sulfate therapy whether

\

1 Hundreds

of ml.

\

766

Flowers

this or other dosage schedules are used. The eclamptogenic toxemias are as serious medical complications to the obstetrician as diabetic coma and renal failure are to the internist. There is no reason obstetricians should be less demanding in their laboratory reyuiremcnts than other medical specialists. Results

Iluring the last 5 years, 12 eclamptic patients and 154 patients with severe preeclampsia have been studied when this method of magnesium sulfate therapy was used. The longest period of therapy was 7 days; the largest amount of magnesium given an individual was 147 Gm. The mean duration of therapy was 3 days and dosage was 70 Gm.? respectively. This regimen has simplified the management of patients with toxemia of pregnancy. Patients are no longer placed in a dark room and kept heavrily sedated. They are allowed to take fluids and food and are able to cooperate with the medical team during induction of labor and delivery. Labor is generally induced in eclamptic patients after convulsions have been controlled for 12 to 24 hours. Pre-eclamptics are managed as previously described according to the seriousness of disease and the duration of gestati0n.l” Patients with toxemia are generally delivered vaginally under pudendal block and 60 to 40 nitrous oxide oxyygen analgesia. Eclampsia and severe pre-eclampsia are not considered as primary indications for cesarean section; cesarean sections are performed when there are other fetal or obstetrical indications. The favorable effect that eclamptogenic toxemias have upon labor has not been fully appreciated. Patients who are sufficiently ill to require prompt delivery are usually easily induced with the judicious use of oxytccin despite the seemin,g unfavorability of their cervix.1° Plasma levels and urinary excretion of magnesium and electrolyte studies among a representative group of patients with severe toxemia are given in Table II. The first 3 patients did not maintain therapeutic levels of magnesium because of the excretion of

large amounts of magnesium. Despite their sevrerely elevated blood pressure and significant amounts of albuminuria, their blood urea nitrogen level (BUN) and electrolytes were normal. These patients delivered infants in good condition and probably would not have developed eclampsia had magnesium not been given. The last 5 patients among the severely pm-eclamptic cases maintained therapeutic levels of magnesium since they were unable to excrete magnesium as efficiently as the less ill patients. The seriousness of their toxemia is indicated by the elevations in BUN, uric acid, and their acidosis and hyponatremia. These patients might have become eclamptic had magnesium therapy not been used. The data among the eclamptic patients are particularly striking (Table III). All these patients maintained therapeutic levels of magnesium due to their limited ability to excrete this cation, Patients with an elevated BUN usually- had the lowest urinary excretion of magnesium. The elevation of blood pressure and the extent of the albuminuria were similar in the pre-eclamptic and the eclamptic patients. Therefore, these are not necessarily reliable indices as to the seriousness of the disease. The inability to excrete magnesium is a better index of the toxemic process than blood pressure and is a guide in assessing glomerular filtration and renal blood flow. Magnesium was the primary therapy for these patients; rarely was morphine or intravenous prntobarbital used. Five preeclamptic patients received intravenous veratrum viride and hydralazine as prophylactic agents to prevent cerebral vascular accidents. There were no further convulsions among those with eclampsia after the initiation of magnesium therapy; none of those with severe pre-eclampsia developed eclampsia during prophylactic therapy. The therapeutic effectiveness of any agent will vary among individuals. It should not be surprising that an occasional patient will have a convulsion while receiving magnesium sulfate. Cheslev” reported upon a patient who

Magnesium

Table II. Plasma levels and urinary of therapy -

among

excretion patients

pre-eclamptic Blood

Lowest Mg++

Highest Mg++

of magnesium

the initial

in obstetrics

767

2 days

Urine

___ Lowest 24 hours

BUN

Na

Uric acid

D. E.

(mg. %) 1

(mg. %) 3

Co, 4 24

K 139 4.1

E. M.

1

3

4 ____ 26

136 3

M. M.

2

4

N. F.

3

5

M. J.

4

a

44 ____ 19

137 3.7

10.2

L. B.

4

9

42 ____ 18

135 5.8

B. G.

5

7.5

25 ____ 20.3

K. K.

6

6

D. M.

7.8

9

Patient

during

sulfate

(Gm.

Highest 24 hours (Cm. Mg++)

Highest blood

Duration of labor

1+

(hours) 7 )/2

204 110

2+

5

2.0

154 110

lt

4

1.6

150 100

4+

12

0.4

0.6

220 130

3-t

1

-

0.4

2.0

230 130

2+

4

123 4.1

10.2

1.1

2.0

200 130

4+

3 y2

11 ____ 28

138 4.7

-

0.95

1.2

240 __ 140

4+

4

200 14.5

112 5

-

0.1

0.1

200 130

3+

4

had convulsions when the plasma magnesium level was 7.5 mg. per cent3 We observed a patient with severe pre-eclampsia develop convulsions with a plasma magnesium level of 4.5 mg. per cent. This patient had received 10 Gm. of magnesium sulfate intramuscularly but had not received the initial 4 Gm. intravenously. She is therefore not a failure of this regimen of therapy. The management of severely ill patients require vigilance and mature judgment. One must not hesitate to use various therapeutic adjuncts in treating these patients. One hundred fifty to two hundred milligrams of intravenous pentobarbital is most beneficial in reducing postconvulsion irritability. If the reflexes are hyperactive and do not respond to the initial doses of magnesium sulfate, a 2 per cent magnesium drip as described by Hall” can be most helpful during the first 6 hours of therapy. Thereafter, intramuscular magnesium may be used according to this

Mg++)

5.4

1.9

3.5

4.9

1.3

2.4

1.8

pressure 190 100

Highest albumin

regimen of therapy. It is an unusual hospital that can provide constant observation of patients receiving an intravenous drip of magnesium for several days. Ten milligram per cent was the highest plasma level of magnesium that was obtained in this study. This level was present in 5 patients. Such a concentration is not considered toxic since respiratory arrest does not generally appear until the serum levels are above 16 mg. per cent. However, Patient I). M. in Table II developed respiratory difficulty which, responded to calcium gluconate, with a magnesium level of 9 mg. per cent. This patient was severely azotemic and hyponatremic; her BUN was 200. Azotemia is a complicated metabolic condition. It is thus impossible to say why this patient developed respiratory difficulty with a magnesium level of 9 mg. per cent. It was probably related to the deficiency of calcium in her plasma and tissues secondary to her chronic renal

768

Flowers

Table III.

Plasma levels and urinary excretion days of therapy among eclamptic patients

Lou,est

Highest

,t

III

of magnesium

during

the initial

I!

Patient

J. B.

44 19.8

I :i:!

136 3.9 133 4.2

M. C.

5.5

7.5

“0 ‘)‘I --. 7

J. S.

6

8

66 19.5

.4.1

disease. No other patient experienced such difficulty. It is felt, however, that magnesium levels should not be allowed to exceed 5 mg. per cent when the BUN is 75 or over or there is evidence of calcium deficiency. Calcium gluconate should be readily available for patients receiving magnesium therapy.

Magnesium in skeletal and uterine muscle. The clinical evaluation of labor among these patients did not indicate that labor was prolonged or induction was inhibited. The duration of labor for a sample of the severe cases of pre-eclampsia and the eclampsia is given in Tables II and III. The mean duration of labor of all primiparas was 93/4 hours and all multiparas was Sj/, hours. These durations of labor are similar to those found for the entire service, namely. 1 I J/* hours for primiparas and 7 hours for multiparas.l’ The occurrence of apparently normal labor in this series is consistent with Eastman’s’” observations. These patients received intramuscular, ma‘gnesium after the initial intravenous priming dose. They thus correspond to Hall’< patients who received low magnesium dosagc:.

6.2

11 141)

During the past 10 years, we have observed the gradual shortening of labor among all patients. This trend, associated with minimal analgesia, and increased uterine tonus among toxemic patients probably explains the lack of adverse effects upon labor of magnesium in this series. However, the clinical estimation of labor yields crude data and cannot be compared with the values obtained from intraamniotic tracings. The studies of Hall’” and Kumar, Zourlas, and Barnes,‘l’ of the effect of magnesium on myometrial strips and uterine contractility unquestionably indicate the depressant effects of the magnesium ion on the myometrium. Studies of the magnesium content of uterine and skeletal muscles were made to determine if the depressant effect on this ion on the myometrium could possibly be a function of the muscle content of magnesium as well as the concentration of the cation which perfuses the mrwzlr. These data are presented in Table I\‘. Skeletal and uterine muscle were obtained at cesarean section at varying times after the administration of magnesillm. Magnesium

Volume 91

Magnesiumsulfate in obstetrics 769

Number 6

Table IV. Magnesium after the administration

levels in plasma and fat-free of magnesium sulfate Dosage

muscular

E. B. P. M. D. L. E. B.

H. W. A. L. H. M. H. G.

(cm.1

Zntravenous (Cm.)

4 7 8 8 32

and skeletal

* Time of administration of MgSO, (hr.)

Control 6

uterine

of MgSO,

ZntraPatients

dried

6 270 drip 4 7 4 4 4

was administered according to this regimen or the intravenous drip method of Ha1L5 The muscle samples were made fat-free, dried and ashed, and checked for water content to ensure uniformity. Unfortunately, the number of patients who have been available for study is limited. Additional studies must be made in order to obtain additional data that can be statistically evaluated using regression techniques. These data indicate, however, the possibility that there may be an increase in the magnesium content of skeletal and uterine muscles after repeated administration of magnesium sulfate. Additional data are required using a standard dosage schedule and 2 patients for each time interval from 1 to 12 hours.

Magnesium content in the muscles of the rabbit. The ability of magnesium to block neuromuscular transmission is recognized as a physiological fact. There is, however, considerable conjecture as to why some cases of eclampsia are controlled more easily than others. There may be quantitative differences in the stimuli from the central nervous system, differences in the magnesium content of muscle, differences in the penetration of magnesium at the plasma membrane, or differences in the ability of calcium and magnesium to compete at binding sites. Patients having a disease process as complicated as eclampsia may exhibit variation in these and many other factors. It was decided to study the simplest of these possible explanations by measuring the magnesium content of the muscle in an experimental animal.

2Yh 3 y2 3 4% 8 12 20

Plasma

(mg. 70) 2 7.6 4.7 5.4 4.4 10.5 4.7 3.7

Skeletal

muscle

muscle

Uterine

muscle

(FFD)

CFFD)

(mg./lOO

(mg./lOO

grams)

77.2 82.9 61 88.4 73 96.7 74.4

grams) 56.2 65.2 62 70.8 68 54.3 62.5 64.4

Healthy adult New Zealand rabbits were given intramuscular magnesium according to their body weight using the same schedule as described for humans. An equivalent priming dose and sustaining doses were given every 6 hours. Another group of rabbits were anesthetized with Nembutal and received an intravenous drip of magnesium using a Harvard pump. These animals received the same amount of magnesium according to their weight that humans would receive using Hall’s technique.5 Two rabbits were used for each time and all determinations were made in duplicate. Muscle and plasma samples were taken from rabbits after they had been killed by cervical fracture and were clinically dead. Five to 8 Gm. samples of muscle were taken from the thigh which was not the site of the magnesium injection. These samples were made fat free, dried, and ashed. These data are presented in Fig. 1. Intravenous studies were limited to four hours since it was difficult to maintain the rabbits in good homeostasis after 4 hours of anesthesia. It is apparent that rabbits receiving intravenous magnesium had a slightly higher content of magnesium in their muscle. However, the intravenous data are not significant since there were too few samples and variability in the values; no slope could be determined. The intramuscular experiment yielded significant data. We were fortunate in having two determinations in duplicate for each time period for 12 hours. Using regression

770

Flowers

IO 9 8

i

” P

90 0 0

I

x---IV - ---IV x-IM+IV -IM+IV

Drop CFFD musclei Drip blasma 1 (FFD muscle1 lplosma)

2

4

3

5

6

7

8

9

IO If

I2

/3 I4

levels

of magnesium

hOW

Fig. 1. Plasma and n&depleted rabbits.

fat-free

dried

muscle

techniques, the fitted line had a positive slope significantly different from zero indicating that the amount of magnesium per 100 grams of dried fat free muscle increased with time under these conditions. A second group of adult New Zealand rabbits were given a magnesium deficient diet containing 2.8 mg. of magnesium per 100 grams and distilled water for 30 days. They were then given magnesium sulfate as previously described except that one group receiving intramuscular magnesium sulfate received the initial intramuscular and intravenous priming dose intramuscularly. The data of these studies are presented in Fig. 2. It is evident that although the levels of magnesium in the muscles of rabbits receiving intramuscular magnesium were similar to the nondepleted rabbits, plasma levels were more difficult to maintain. Possibly the administered magnesium went more easily into bone and tissues other than muscle. The efficiency of the intravenous technique in maintaining satisfactory plasma levels of magnesium under these conditions is evident. There is an interesting fall in the magnesium content of muscle after thirty minutes. This may possibly be explained by the increased sensitivity of the vasomotor center to magnesium after depletion causing a fall in blood pressure and a reduction of blood supply to muscle. The variability of results and the short duration of the experiment in the magnesium depleted rabbits prevented statis-

in

tically significant data from being obtained. Using regression techniques the slopes of the fitted lines were not sufficiently different from zero. Additional experiments including Mg’” studies are necessary to understand the movement of magnesium into muscle of depleted animals. The study of magnesium in muscle, tissue, and bone and the renal excretion of this cation in severe pre-eclampsia and eclampsia will be more difficult but such studies are fundamental in understanding this complication of pregnancy. Comment Magnesium sulfate is now recognized as the single most important drug in the management of the eclamptogenic toxemias of pregnancy. The dosage schedules and methods of administration which have been developed have proved their validity. The development of a simplified method of monitoring the plasma level and the urinary excretion of magnesium is but a logical step in improving magnesium sulfate therapy. The great majority of toxemic patients do not

require

magnesium

therapy,

and

when

it

administered prophylactically, it is needed for only a short time. These patients can be safely managed with an empiric dosage schedule that does not require laboratory assistance. However, the severely ill toxemic patient generally has oliguria and may have is

various

daily

responses

to the

and the emergency

magnesium

monitoring

ion.

The

of these

Volume Number

91 6

Magnesium

sulfate

in obstetrics

771

x---IV o---IV x-h4

drip (muscle) drip (plosmo) only (muscle) .--IM (plasma) A---IM+IV (muscle) cIM tIV (plasma) I

1

Of2345 hour

Fig. 2. Plasma and depleted rabbits.

fat-free

dried

muscle

levels

of magnesium

patients’ response to Mg++ seems consistent with modern medical management of a severely ill patient. It is recommended that all patients receiving magnesium sulfate have laboratory determinations of this cation in order for the staff and laboratory to work efficiently when a severely ill patient is admitted. It was hoped to include in this report the development of permanent standards for the Titian yellow technique. This would allow magnesium to be measured as simply as one performs a phenolsulfonphthalein determination. The Eastman Kodak Company volunteered their services and prepared satisfactory permanent gelatin standards. A commercial company has, however, not yet been found which will use these standards in preparing a simple calorimetric device. However, the technique which has been described is simple. The laboratory prepared standards may be used for 3 days, when they are kept in a dark place, and determinations of magnesium in plasma and urine generally require only 30 to 40 minutes. The intramuscular route of magnesium sulfate has been criticized because of the difficulty in maintaining plasma levels of 3 to 6 mg. per cent. The study of these patients indicates why this route has proved to be clinically acceptable, Severely ill patients maintain a satisfactory plasma Ievel of magnesium when it is administered intramuscularly. The

in magnesium-

less ill patient who does not maintain a satisfactory plasma level of magnesium probably does not require magnesium sulfate in the management of her toxemia. Previously reported human studies and these animal data attest to the efficiency of the intravenous drip technique. It would seem reasonable to use this method in certain cases for the first 6 hours. Thereafter, the usually available hospital personnel can administer magnesium sulfate intramuscularly. It was hoped to obtain sufficient human data to determine if there was a sufficient movement of magnesium in skeletal and uterine muscles to explain the adverse effect of a high magnesium plasma level upon labor and the success of the magnesium ion in reducing the irritability of skeletal muscle. The human data are only suggestive. Animal data indicated there was movement of magnesium into skeletal muscle after repeated administration. The experiments in magnesium depleted animals were conducted in an effort to explain the difficulty in establishing and maintaining adequate magnesium levels in some patients who have little urinary excretion of magnesium. It was thought that possibly these patients had a deficiency of magnesium in their muscles, tissue, and bone. A deficiency of magnesium in muscle, tissue, and binding sites could explain the variation in

Flowers

772

response of reflexes to magnesium sulfate as well as the occasional convulsion which occurs in the initial hour of therapy. Because of the paucity of data and the difficulties encountered with some of the experiments, a statistically significant answer to this question must await additional studies. Summary

1. The management of 166 patients with eclamptogenic toxemia indicates the efficiency of magnesium sulfate in controling and preventing convulsions. A dosage schedule based on body weight and the estimation of magnesium in plasma and urine has

proved to be safe and efficient. The intramuscular route of therapy has proved to be satisfactory. 2. Animal studies have confirmed the efficiency of the intravenous drip regimen and indicates that this method can be used as an adjunct when necessary to this or other intramuscular regimens of therapy for the first 6 to 8 hours. The intramuscular administration of magnesium sulfate caused a statistical increase in the concentration of this cation in the muscle of normal rabbits. Appreciation is particularly 1,ynda Jensen whose excellent made

this

study

expressed to Mrs. technical

assistance

possible.

REFERENCES I. ‘2.

3. 4.

5. 6. 7.

Flowers,

C.

E.:

Texas

M.

J. 59:

Eastman, N. J., and Hellman,

858,

1963.

liams’ Obstetrics, ed. 12, New York, 1961, Appleton-Century-Crofts, Inc. Chesley. L. C., and Tepper, Ira: S. Clin. North America 37: 353, 1957. Pritchard, J. A.: Surg. Gynec. & Obst. 180: 131, 1955. Hall, D. G.: Obst. & Gynec. 9: 158, 1957. Zuspan, F. P., and Ward, M. C.: South. M. J. 57: 964, 1964. Flowers, C. E., et al.: Obst. & Gynec. 19: 315, 1962.

C. MACK, Detroit, Michigan. I have often wondered how it came about that a vile-tasting, violent purgative like magnesium HAROLD

sulfate came to be used parenterally for the treatment of a perilous condition such as eclampsia. After reading this stimulating paper by Dr. Flowers, I discovered through a search of the literature that it is, indeed, a time-honored drug whose sedative and anesthetic properties were recognized almost a century ago. For more than a half century, magnesium sulfate has been administered intrathecally, intramuscularly, and subcutaneously for convulsive states with apparent success, especially in eclampsia. Its curare-like

action on the neuromuscular effects of overdosage, and

9. IO. Il. 12. 13. l-1.

Chesley, L. C.. and Tepper, Ira: J. Clin. Invest. 37: 1362, 1958. Orange, M., and Rhein, H. C.: J. Biol. Chem. 189: 379, 1951. Flowers, C. E.: Obst. & Gynec. 19: 649, 1962. Flowers, C. E.. Littlejohn, T. W., and Wells, B.: Obst. & Gynec. 16: 210, 1960. Eastman, N. J.: Obst. & Gynec. Surv. 10: 497, 1955. Hall. D. G.: AM. J. OBST. & GYNEC. 78: 27, 1959. Kumar, D.. Zourlas, P. A.. and Barnes, A. C. : .4~. J. OBST. & GYNEC. 86: 1036, 1963.

Despite

Discussion DR.

8.

L. M.: Wil-

synapse, the lethal

the effectiveness of calcium as an antidote for magnesium intoxication were all firmly established long ago.

applications

the many years that have gone by, of magnesium

ment of toxemia

sulfate

of pregnancy

in the manage-

still vary widely,

both with respect to dosage and modes of administration. Consequently, the enthusiasm for this mode of toxemia management is not universal, perhaps principally because, through fear of toxicity, the dosage employed is most often inadequate. Despite the contributions of Eastman. Chesley, Pritchard, and Hall, all of whom have provided effective dosage schedules within recent years, magnesium sulfate therapy by and large has remained half-hearted and inexact. The paper Dr. Flowers has presented today is another effort to place magnesium sulfate therapy on a sound and safe footing by doing away with guess work. The dosage schedule which has been proposed was designed to fit the needs of the individual patient and is derived by

Magnesium

precise calculations based on body weight and monitoring plasma level and urinary output of magnesium. The appeal of the Flowers regimen is that it attempts to provide custom-made precision without complicated and time-consuming laboratory procedures. Any usual hospital laboratory should be able to perform the tests, and the skills necessary to administer the original intravenous priming doses and sustaining intramuscular injections are also within the capabilities of small-hospital personnel. While the regimen Dr. Flowers has presented today is a significant effort to simplify and control the dosage of magnesium sulfate, the essential ingredient of toxemia management is still vigilance and sound clinical judgement. The results achieved in preventing convulsions in 154 severely pre-eclamptic patients and the recurrence of seizures in 12 women presumably admitted with actual eclampsia is evidence of the skill with which this mode of therapy was carried out. The dosages of magnesium sulfate exceeded the amounts usually employed. A most significant accomplishment, it seems to me, is that these patients were managed without heavy sedation and without seclusion in a darkened room, The fact that they were permitted and were able to take food and fluids freely, and, finally, could cooperate effectively during labor and delivery is in striking contrast to the climate of the usual toxemia ward with deep barbiturate and narcotic sedation. A disturbing feature in determining the effectiveness of toxemia management has been our limited ability to determine what is truly mild and what is truly severe pre-eclampsia. I am therefore particularly intrigued by the 154 socalled “severely” pre-eclamptic patients who received “prophylactic” magnesium sulfate therapy or, at least, did not develop convulsions. I am sure that all of us would agree in the clinical classification. Nonetheless, the information in Table II for a “representative” group of these “severely“ pre-eclamptic patients shows that not all were equally severe. Despite superficial resemblances, testing of blood and urine after magnesium sulfate administration showed important differences: the first 3 patients (D. E.; E. M.; M. M.) excreted magnesium sulfate efficiently due to unimpaired renal function; the remainder retained magnesium sulfate and, by this and other laboratory criteria (blood urea nitrogen, uric acid, acidosis, etc.), were indistinguishable essentially from cases of true eclampsia. On this basis and on the basis of their

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clinical outcome, the first 3 cases of “severe” pre-eclampsia were relatively benign and the remainder truly of the preconvulsive variety. At the risk of oversimplification, it would appear that magnesium sulfate can have significant therapeutic value only when impaired renal function is present permitting the retention of magnesium at therapeutic levels (3 to 6 mg. per cent) ; in all others it would appear that magnesium sulfate is probably useless. It would seem, then, that the Flowers regimen provides both a test and a treatment. As a criterion of renal function in toxemia, magnesium clearance or magnesium tolerance may be the test to replace the many others that have been tried and found wanting. If substantiated by a detailed analysis of the remaining 145 cases of severe pre-eclampsia (which I hope Dr. Flowers will include in a future paper) the magnesium sulfate clearance test may well be the most important feature of this paper. To judge the effectiveness of anticonvulsive therapy it would be important to know how many of the 145 cases met the magnesium sulfate criteria for truly severe toxemia. I would welcome also a detailed report concerning the clinical outcomes in patients with less than one per cent magnesium excretion for whom immediate induction was recommended. Of course, as Dr. Flowers freely states, all is not always cIear-cut and simple in so complex a disease as eclampsia. Hence it is not surprising that some cases of eclampsia are more readily controlled than others despite the efficient neuromuscular blocking ability of magnesium. Dr. Flowers speculates about possible reasons for this. For the present, the established depressant action of magnesium on uterine muscle and his own experimental evidence that magnesium concentration in uterine and skeletal muscle is increased after magnesium sulfate therapy are difficult to interpret in the light of his experience that toxemic patients under magnesium sulfate therapy appear to have shorter labors. Twenty years ago, before this Society, Abarbanel presented the 1944 Prize Award Thesis in which he demonstrated by external hysterography that magnesium acts as a powerful “ myometrial sedative” by direct action on the myometrium itself sufficient to overcome tctanic uterine contractions induced by oxytocics. More recently, Hall and his associates demonstrated almost complete inhibition of contractility when muscle strips from gravid uteri were immersed in concentrations of magnesium approximating 8 to 10 mEq. per liter. These findings support Hall’s contention that protracted labor is

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a side effect therapeutic no difficulty ening rather

of magnesium sulfate therapy. Despite doses, Dr. Flowers nonetheless notes in inducing labor and reports shortthan lengthening of labor in tox-

emia. He attributes ease of induction to the increased uterine irritability of toxemia. In addition, Dr. Flowers also notes a general shortening of all labors in his clinic. With the latter observation I can most certainly agree: shortened second stages through outlet forceps; early recognition and management of dysfunctional labor; avoidance of extreme sedation; improvement in the entire spectrum of antenatal and intrapartum well-being including better care and maintenance of the psyche-all these contribute to diminished labors in recent years. That labors are shortened specifically by toxemia has not been my observation, perhaps because I have not had the opportunity to manage large numbers with intensive magnesium sulfate therapy and without additional sedation. I believe, too, that induction in toxemia is usually carried out more energetically because wr know that delivery alone will bring about the final cure. Like vcratrum viride which, after years of empiricism and patient espousal by a faithful few, has recently found its place in ohstctrics, it seems likely that magnesium sulfate, after a halfcentury or more of hit and miss may at last, through efforts such as these, he coming into its own. DR. WILLIAM j. MCGANITY,* Galveston, Texas. The whole body contains about 20 Gm. of magnesium. During pregnancy there is an additional accumulation of approximately 10 Gm. Fifty per cent of the body magnesium is in the skeleton, 25 per cent in soft tissue bound to a protein moiety. It has

It is the fourth most abundant cation. been known as an essential nutrient in human metabolism since 1932. It is required by several enzyme systems and is involved in the cnrrigy transfer of phosphate bonds. The avrragr American diet contains ‘LOO to 400 mg. per day-two thirds of this coming from cereal and vrgetablr sources. In contrast, populations who have evaporatrd sra salt as their sourc(‘ of salt have daily intakes of magnesium many times our l~vcls. In Korea, as an example, with an average daily salt intake of 30 Gm. or more, o\‘cr 2 Gm. is in the form of magnesium salts. While the Koreans’ incidence of toxemia is not well defined, it does not appear to he significantly higher than some segments of our population. “By

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The proposed recommendation pregnancy is 400 mg. per day. The minimal adult dietary

for

intake

requirement

during is in

the neighborhood of 100 to 200 mg. per day. Of this, only 4 to 12 per cent is actually absorbed from the gut. Depletion of body stores occurs rxccedingly slowly. Absorption is accomplished with difficulty via the gastrointestinal tract. It is increased in an acid media and with a low fat diet, as is seen in the Southeast Asian dietary where 15 per cent of the calories come from fat in contrast to almost 45 per cent of the calories as provided in the American diet. Intestinal ahsorption is decreased in the presence of an alkalint media, high fat, or high calcium intake. When a high magnesium intake occurs, there is ;I concomitant drcrease in the urinary calcium excretion. While magnesium parallels calcium in many respects, there is no known relationship to vitamin D metabolism. When taken by mouth. 51) to 80 per cent of the magnesium is excreted in the feces and the remainder in urine. When given intravenously in the presence of normal 90 per cent is excreted by the renal function. kidneys. It is filtered through the glomeruli and reabsorbed at the tubular level. The variations in tissue and fluid levels in the body may be summarized as follows: Magnesium is grrater in the red blood cell than in plasma; it is greater in muscle and intracellular space; rqual concentrations occur in the maternal and fetal sides of the placenta; it is decreased during pregnancy; it is equal in normal and toxemic patients; 70 to 85 per cent of the magnesium ion occurs in the diffusible form; decreased serum calcium levels lead to an increased magnesium serum concentration; increased serum magnesium lcvcls lead to decreased levels of calcium which can drop to tetanic values; increased serum magnesium levels occur with the administration of vitamin B,. Human magnesium deficiency has been induced, initially in 19.56 and again in 1960. It has heen described among alcoholics and with patients having protein calorie malnutrition as induced hy surgical procedures or in its naturally occurring form-Kwashiorkor. The clinical manifrstations are hyperirritability, tremors, chronic ronvulsions, hyperactive reflexes, hypertension, and cardiovascular and renal abnormalities. If WC nrr to understand the role of magnesium in pregnancy and in response to therapy, it appears that future studies are needed with more rigid rontrol of the dietary factors which influrnrc absorption and utilization of this ion; paral-

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lel and concurrent studies of magnesium, calcium and vitamin Be. The impact on the fetus in utero and the newborn immediately post delivery needs to be evaluated in reference to the maternal levels of magnesium. Finally, the requirement and relationships of magnesium, as well as other trace minerals, in enzymatic systems as necessary for metabolic maintenance requires clarification. DR. JACK A. PRITCHARD, Dallas, Texas. Dr. Flowers stated this morning that in a previous publication he reported attempts to develop a simple dosage schedule for the use of magnesium sulfate in the treatment of toxemia of pregnancy and a practical method for measuring magnesium that could be carried out in an average hospital laboratory. I contend that Dr. Flowers’ dosage schedule is not simple. A decade and a half or so ago Drs. Chesley and Hellman and I myself independently arrived at a dosage schedule which was a modification (an intensification, if you will) of a dosage schedule previously suggested by Dr. Eastman. It is somewhat as follows. In the case of the patient actually in convulsions, 4 Gm. of magnesium sulfate is injected intravenously over a period of 4 to 5 minutes, and then 10 Gm. is injected intramuscularly, one-half in each buttock. This is followed by 5 Gm. intramuscularly every 4 hours as long as ( 1) the deep tendon reflex in the form of patellar knee jerk can be demonstrated and (2) the urinary output per 4 hours is 100 cc. or more. A very sensitive indicator of magnesium toxicity-one that is present before any other evidence of physiologic disturbance-is the loss of the patellar reflex. This has been described in the 1930’s by a group of pharmacologists and internists at Yale who were treating patients with uremic convulsions. The reason for monitoring urinary output, of course, is that the sole route of excretion of injected magnesium is by way of the kidney. After utilizing this dosage schedule, in a series of patients approximately six times the number reported upon by Dr. Flowers this morning, our results appear to have been very good. We have had no overt evidence of magnesium intoxication. With this dosage schedule, our experience has been the same as that of Chesley. Convulsions usually are promptly controlled. Equally, or perhaps more, important, in the large group of patients with the severe pre-eclampsia, convulsions are prevented while we go about our business of getting the women delivered and the baby to the nursery alive.

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In regard to the calorimetric comparator block, I do not know if it was apparent to you or not but there was only a slight difference in the degree of color when going from a magnesium level of 2 mg. per cent to 10 mg. per cent. I have had personal experience with just such a visual comparator device and the intensity of change with an increase in concentration of approximately fivefold tends to escape my visual acuity. Furthermore, with the Titian yellow method for measuring magnesium there are many pitfalls. This is a sort of Betty Cracker type of laboratory determination depending upon the development of a colloidal complex of magnesium and Titian yellow. Sometimes it is a little bit more colloidal; sometimes it is a little bit more flocculent. A little polyvinyl alcohol is thrown in to keep it in a fairly uniform state of suspension or so one hopes. This is a tricky method, to say the least, and I would hesitate to trust a general hospital laboratory to obtain routinely precise results. Moreover, the reflex hammer is a more fool proof method for detecting impending toxicity. In regard to the one patient with a magnesium level of 9 mg. per cent in the plasma who showed respiratory depression, I would contend that her magnesium level probably was higher than this. This patient had a blood urea nitrogen of 200 mg. per cent. With a blood urea nitrogen of this level, she must have had a very high serum phosphorus level. An elevation of the phosphate content in the Titian yellow reaction mixture gives a false low level. I doubt if this patient was unique in terms of developing respiratory depression at this level. I would contend that the magnesium level was higher than the test indicated. The knee jerks almost certainly would have been found to be absent. DR. R. A. H. KINCH,* London, Ontario, Canada. Anything that will keep the patient with severe eclampsia or pre-eclampsia conscious and able to cooperate is good treatment. A long time sulfate ago we converted to the magnesium regime, but we have always, for the hypertensive crisis, added a hypotensive drug. I would like to ask Dr. Flowers two questions. First, does he find it ever necessary to use a hypotensive drug as well as magnesium sulfate and, second, has he done any studies on the serum magnesium level of the child? DR. FLOWERS (Closing). We can determine the severity of toxemia of pregnancy by evaluat*By

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ing the rate of excretion of magnesium and the ease of induction of labor. No difficulty was experienced in the induction of labor among the severely ill patients. Moreover, oxytocin did not seem to cause any greater change in the blood pressure than occurred among patients who went into labor spontaneously. It must be made clear, however, that oxytocin was used in sufficient strength to cause real uterine contractions every 5 minutes and lasting 30 seconds. If the cervix did not become sufficiently favorable to allow the rupture of membranes after 6 hours of such osytocic stimulation, consideration was given toward managing the pre-eclamptic patient conservatively and delaying delivery. Patients with tclampsia were given oxytocin each day until labor ensued. In general, the initial attempt to induce labor was successful. Intramuscularly administered magnesium sulfate does not interfere with labor since the concentration of magnesium ions perfusing the uterine muscle is not great. Dr. McGanity’s comments are most interesting and indicate the importance of the magnesium ion in the electrolyte balance of pregnant patients with and without toxemia. Our preliminary studies with animals did not indicate that the administration of magnesium caused any significant change in the muscle content of calcium, sodium, or potassium. The magnesium ion apparently competes at the binding sites with calcium and goes into the mitochondria. In regard to Dr. Kinch’s questions, 5 patients received hypotensive agents and magnesium levels were essentially the same in the mother and infant. It is important to discuss Dr. Pritchard’s remarks. I did not include in this report 106 patients who had mild toxemia and were given

magnesium sulfate for less than 24 hours. These patients recovered quickly from their toxemia following delivery or with bed rest alone. They excreted magnesium in large quantities and were obviously not ill. The Beckman spectrophotometer was used in all the experimental studies. The severely ill patient with a blood urea nitrogen level of 200 had a number of magnesium levels checked with thr Zeiss flame photometer, The permanent standards which were alluded to were the gelatin standards prepared by the Eastman Kodak Company. When visual estimation of magnesium was made, Titian yellow standards were prepared fresh every 3 days and kept in a dark place. Laboratory technicians can determine the magnesium content of an unknown sample with an 80 per cent confidence rate. I can find no criticism of Dr. Pritchard’s dosage schedule. It was tried on our service for 9 months. We found, however, certain confusion when the reflexes remained active, yet less than 100 ml. of urine were excreted in the 4 hour period. It is felt under these conditions it would have been valuable to know what the actual conccntration of magnesium was in the plasma and the rapidity with which the patient was excreting magnesium in the urine. The important point that I want to emphasi~c* is that the ma,gncsium ion will prevent the occurrence of comrulsions and control them in the eclamptic patient. This regimen of therapy is of course not the only way to manage the eclamptic patient. However, I helievc that a reflex hammer and the laboratory estimation of the magnesiunt content in the plasma and the determination of the rate of magnesium excretion in thr urine is preferable to the reflex hammer alone.