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Clinical and laboratory observations on eclampsia
Clinical and laboratory observations
on
eclampsia JACK
A.
STUART Dallas,
PRITCHARD, R.
STONE,
M.D M.D.
Texas
Sixty-nine Memorial
consecutive patients with eclampsia have been cared for at Parkland Hospital using magnesium sulfate to control convulsions followed soon by appropriate steps to accomplish delivery. Apresoline was given intravenously if hypertension was quite severe. Morphine, large doses of barbiturates, tranquilizers, alkaloidal vasodepressors, diuretics, and hypertonic solutions of dextrose, mannitol, urea, and sodium chloride were avoided. All the mothers survived. The perinatal salvage rate was 79 per cent for all fetuses and 89 per cent for those weighing 1,000 grams or more. All fetuses alive when eclampsia was diagnosed and weighing 2,000 grams or more survived. None of the commonly performed laboratory tests proved to be uniquely essential to the successful treatment of eclampsia.
S I N c E October, 1955, the basic treatment applied uniformly to all cases of eclampsia at Parkland Memorial Hospital has consisted of ( 1) magnesium sulfate both intravenously and intramuscularly to control convulsions followed by serial intramuscular injections to prevent their recurrence; (2) hydralazine ( Apresoline) intravenously to lower blood pressure when severely elevated; and (3; steps to effect delivery once the patient has regained consciousness. Since then 69 cases of eclampsia have been so managed. Reported now are several clinical and laboratory observations made on these women and their off spring.
past 11~12 years had eclampsia. Convulsions began prior to delivery in 61 and up to 36 hours post partum in 8 more. Most commonly, the patient with eclampsia was undelivered (88 per cent), teen-age ( 71 per cent), nulliparous (84 per cent), and Negro (75 per cent). She had been seen either not at all or very infrequently by a physician Therupy
Magnesium sulfate. Magnesium sulfate* (4 Gm.) in a 20 per cent solution was injected intravenously at the rate of about 1 Cm. per minute. As soon as this was accomplished, IO Gm. of magnesium sulfate in a 50 per cent solution (20 ml.) was injected one-half deeply into each buttock using a No. 20 gauge needle at least 3 inches in length.’ Infrequently, the convulsions were not controlled within 15 minutes after the intravenous and intramuscular injections. Then, the intravenous medication was repeated administering 4 Gm. more of the 20 per cent solution in 4 to 5 minutes unless the patient was unusually small-then only 2 Cm. was given.
Material
Sixty-nine at Parkland
of the 67,000 women delivered Memorial Hospital during the
From the Departments of Obstetrics and Gynecology of The University of Texas Southwestern Medical School and Parkland Memorial Hospital. This study was supported in part by Grant HE-02516-11 from the National Heart Institute, United States Public Health Service. Presented at the Ninetieth Annual Meeting of the. Amerjcan Gynecological f;;ty, Phoentx, Arezona, May 4-6,
“Magnesium
754
wllate
USP
~MgS0~~7HzC)i.
Volume Number
99 6
Every 4 hours thereafter, 5 Gm. of magnesium sulfate as a 50 per cent solution was injected deeply into alternate buttocks using the following safeguards prior to each dose: ( 1) The patellar reflex was demonstrated to be present. (2) The urine output during the previous 4 hours measured 100 ml. or more. (3) Respirations were not depressed. Magnesium sulfate therapy was continued for about 24 hours after delivery. Other anticonvulsants. In those infrequent cases where the convulsions persisted after magnesium sulfate therapy, either sodium phenobarbital, 0.2 to 0.3 Gm., or sodium amobarbital, 0.25 to 0.5 Cm., was injected slowly intravenously to control the convulsions. Antihypertensive agents. If severe hypertension persisted, i.e., if the diastolic blood pressure remained greater than 110 mm. Hg, Apresoline was given intravenously in 5 to 20 mg;. doses every 15 to 30 minutes until the blood pressure was reduced to the range of 140-150,/90-100 mm. Hg. It was repeated as needed. Twenty-seven of the patients received one or more doses of Apresoline. Analgesia. Individual doses of meperidine (Demerol), when given during labor, were limitecl to 50 mg.; if the fetus was premature, narcotics were avoided. After cesarean section, meperidine was administered in doses of 50 to 75 mg. every 3 hours as needed. Anesthesia. General anesthesia was used 35 times ( 57 per cent), pudendal block usually with nitrous oxide-oxygen analgesia 14 times (23 per cent), saddle block 7 times (12 per cent), and none 5 times (8 per cent). General anesthesia for cesarean section most often consisted of a single small dose of Pentothal or Surital followed by nitrous oxide-oxygen and sufficient succinyl choline to produce adequate muscle relaxation, Saddle block anesthesia for vaginal delivery, consisting of 3 to 4 mg. of hyperbaric Pontocaine, was used only during the early years when anesthesiology coverage was grossly inadequate. Unfortunately, careful attempts to produce true saddle- block anesthesia with
Eclampsia
755
the mother in the sitting position sometimes were followed by significant hypotension. Parenteral fluids. An intravenous infusion system was promptly established. The total fluid intake, barring hemorrhage or unusual fluid loss, was limited to 2 liters or less of 5 per cent dextrose in water solution per 24 hours. Hypertonic solutions of dextrose, mannitol, urea, or saline were not used. Other therapy. During and immediately after a convulsion, a padded tongue blade was inserted between the teeth. The patient was continuously observed in a well-lighted room until she was conscious. If secretions or vomitus were evident, she was kept on her side and the pharynx suctioned. Oxygen moistened with water vapor was administered as soon as practicable after a convulsion. While unconscious, an adult-size Guedal oral airway was used to prevent airway obstruction by the tongue. In no instance was tracheostomy necessary. No diuretics were used. Prophylactic digitalization was avoided although digitalization was initiated once because pulmonary congestion was thought to be present and once because of persistent tachycardia. Neither patient subsequently demonstrated evidence of pulmonary edema. Delivery
Vaginal. Forty-eight,
or 79 per cent, of the 61 patients who developed eclampsia prior to delivery were delivered vaginally. Twenty-eight went into labor spontaneously; 19 of these demonstrated some evidence of labor at the time the diagnosis of eclampsia was made and the other 9 were in labor
Table I. Method
of delivery
Vaginal
Spontaneous labor Induced
labor
Cesarean section Fetal distress Breech presentation Failed forceps (elsewhere) Unsuccessful induction Elective Cephalopelvic disproportion
48
(79%)
13
(21%)
28 20 2 2 2 4 1 2
756
Pritchard
and
Stone
sometime thereafter, Induction of labor with the use of an intravenous infusion of dilute oxytocin resulted in vaginal delivery in 20 out of 24 patients. Cesarean section. This operation was performed on 13 for the reasons listed in Table I. The 2 instances of fetal distress were characterized by overt bradycardia. Partial placental abruption was demonstrated in both; the infants survived. Induction of labor with oxytocin was avoided in 2 instances of breech presentation; instead cesarean section was performed. In 2 more patients, attempts at forceps delivery at other hospitals had been unsuccessful: N. H., a 41-year-old woman pregnant for the fifth time, developed eclampsia manifested by convulsions, a blood pressure of 180/120 mm. Hg, 4+ proteinuria, and gross edema while hospitalized some distance from Dallas. Attempts at delivery with forceps were unsuccessful. After transfer, the convulsions were controlled with magnesium sulfate. The cervix was completely dilated but the head was not engaged. At laparotomy, a small rent in the lower uterine segment was identified so a total hysterectomy was done. The fetus which weighed 3,487 grams survived. It is of interest perhaps that this patient had had convulsions earlier in this pregnancy. When the pregnancy was finally recognized, electroshock therapy for schizophrenia was discontinued. E. D., a 17-year-old nullipara, was admitted to another hospital where attempts to effect delivery with forceps were unsuccessful. When transferred to Parkland Memorial Hospital the fetal heart could not be heard, the cervix was incompletely dilated, and lacerations were apparent in the posterior fornix as well as elsewhere in the vagina. The stillborn infant delivered 1)) cesarean section weighed 3,600 grams. The 4 patients in whom attempts at induction of labor were unsuccessful were delivered of premature or immature fetuses, 2 of which survived. Sterilization was also desirable in 3 of the women because of known chronic hypertension, high gravidity, and advanced age. These factors contributed to the decision to deliver by laparotomy with tubal ligation rather than prolong the attempts at inducing labor with oxytocin. The
t’ourtli pat&l was ati 18-vea1~-~1ici piinrigravida with \cry se\ erc bypertcnsion. crliguria, and a.Lotemia. Oxytocin infusiotr t’ol 8 hours produced no demonstrable clrange so a cesarean section was done. ‘l‘his case. I,. M.. is described further under I omplications. Maternal and The 69 mothers
fetul mortality all survived. Perinatal mortality. Sixty-three infants, including 2 sets of twins, were born of the 61 women in whom eclampsia developed prior to delivery. Seventy-nine per cent oi these fetuses survived. Of those weighing 1,000 grams or more, 89 per cent lived. The fate of the fetuses is demonstrated in Table II and Fig. 1. The 6 stillborn fetuses were dead when the diagnosis of eclampsia was
Table II. Perinatal fetuses whose prior to delivery
mortality mothers had
among 63 eclampsia
I
Birth weight (iv-1
/ I
,411 fetuses 1,000 or more
21 11
1,500 or rnore or more
Birth
1. Fate
Stippled
deaths; survived.
0
Wright
of the fetus
bars indicate
cate neonatal infants that
11 5 3
8 3
2,000
Fig.
Fetuses alive when ecEampsia iuas diagnosed (70 I
/ei!Ltes (%)
(Cm.1
according
stillbirths; open
bars
to birth
weight.
solid bars indiindicate
live-born
Volume 99 Number 6
first made; at least the fetal heart was not heard. Seven of the 57 born alive died. The weights of the live-born infants who died were ,510, 620, 720, 880, 1,095, 1,635, and 1,890 grams. Gross immaturity certainly accounted for the death of the 5 weighing 1,095 grams or less. Delivery of the primigravid mother of the infant weighing 1,635 grams was accomplished with low forceps and episiotomy after a vigorous spontaneous labor of only 2yJ hours. The infant died 32 hours later. Subdural and subarachnoid hemorrhages were prominent at autopsy. In the case of the infant weighing 1,890 grams, saddle block anesthesia was followed by maternal hypotension, the first recorded blood pressure being 90/60 mm. Hg. The infant developed severe hyaline membrane disease and died 26 hours later. The 8 infants of the women who developed eclampsia post partum survived.
Related to magnesium sulfate. The combined intravenous and intramuscular magnesium sulfate therapy given as outlined above failed to abolish convulsions in 6 patients. However, the addition of sodium phenobarbital or sodium amobarbital did so using the rather modest doses described. Five women in whom magnesium sulfate therapy had been initiated prophylactically during labor because of severe pre-eclampsia later had convulsions. In all but one this occurred post partum. In 4 of the 5, the intramuscular dosage schedule of 5 Gm. every 4 hours had not been adhered to, the last intramuscular injection having been due anywhere from 5 1.0 13 hours prior to the convulsion. In each instance, 2 to 4 Gm. of magnesium sulfate given intravenously plus 5 to 10 Gm. intramuscularly followed by 5 Gm. intramuscularly every 4 hours prevented further comulsions. The fifth patient with pre-eclampsia who subsequently had convulsions had initially received 10 Gm. of magnesium sulfate intramuscularly followed presumably by 5 Gm. intramuscularly every 4 hours. Eight hours after delivery and within 10 minutes after receiving her
Eclampsia
757
scheduled intramuscular dose of 5 Gm. she had a convulsion. Four grams of magnesium sulfate was administered intravenously and the schedule for intramuscular administration was continued. She too had no more convulsions. Evidence suggesting potentially dangerous magnesium intoxication was limited to one case: L. M., an 18-year-old primigravid Latin American patient, about 25 weeks pregnant and weighing but 99 pounds, was admitted convulsing. Her blood pressure was 190/140 mm. Hg and the urine contained 4+ proteinuria. After failing to initiate labor with oxytocin, cesarean section was done using initially a small dose of Surital followed by nitrous oxide-oxygen and succinyl choline. The 620 gram infant lived 4 hours. Thirty minutes after completing the operation, the next scheduled dose of magnesium sulfate was due. Although the patellar reflex was hypoactive, 5 Gm. of magnesium sulfate was given intramuscularly. Within an hour, overt respiratory depression was evident. Hypoxia was promptly corrected using an endotracheal tube and a mechanical ventilator. The patient promptly made efforts to respire, although she would hypoventilate without assistance. The plasma magnesium was 12.9 mEq. per liter. Renal biopsy subsequently demonstrated glomerular changes typical of both toxemia of pregnancy and chronic glomerulonephritis. Prior to discharge one month post partum, the creatinine clearance was 50 ml. per minute. She was still moderately hypertensive although her blood pressure had decreased markedly. The retinal exudates which were quite prominent soon after delivery had resolved during this time.
Other. Partial
premature separation of the placenta was recognized in 4 of the 61 in whom eclampsia was diagnosed prior to delivery. Marginal placenta previa was identified in one case first by vaginal examination during labor and later when the placenta was manually removed. The one case of rupture of the lower uterine segment after unsuccessful attempts at delivery with forceps has been described. Gross postpartum hemorrhage was diagnosed 8 times following vaginal delivery but
758
Pritchard
and
Stone
it certainly was more common than this. Hemorrhage from delivery is considered further under Laboratory Studies. Hemiparesis which persisted for several days was apparent in 2 patients. It is of interest that in neither of these did thtb initial intravenous plus intramuscular magnesium sulfate therapy control the convul.sions. The neurological abnormalities cleared completely prior to discharge. There was one case of intravascular hcmolysis with gross hemoglobinemia, hemoglobinuria, and thrombocytopenia. All evidence of hemolysis promptly disappeared after delivery and the platelet count rose to normal levels during the next 4 days. The infant survived. Overt psychosis developed in 4 during the early puerperium. Therapy consisted of chlorpromazine and good supportive care. Over a period of several days the psychosis cleared completely.
laboratory
studies
Hematocrit. For the 61 undelivered patients with eclampsia, the hematocrit done soon after the diagnosis was made averaged 38.4 and ranged from 31.0 to 51.0. The final hematocrit done on each several days post partum was only 32.0 even though 21 per cent of the women had received one or more blood transfusions. The hematocrit values of 200 consecutive unselected pregnant women performed the same way when admitted to the labor-delivery suite at Parkland Memorial Hospital averaged 38.5 and ranged from 26.5 to 49.0. Blood and red cell volumes. These were measured in 13 women with antepartum eclampsia, who were not bleeding, by labeling their own red cells with radiochromium. The technique has been described previously.’ As shown in Table III, the hematocrits, total red cell volumes, and blood volumes did not differ significantly from those present several months later when not pregnant. Thus the hypervolemia and increase in red cell volume of normal pregnancy were absent in these women with eclampsia. When 7 of them were studied a third time near the end of a normal
Blood loss. Hemorrhage due to parturitiol~ was evaluatecl in 22 patients, none of whom demonstrated abnormal bleeding prior to delivery. The volume of circulating red cells was rneasured before delivery and again several hours post partum using their Cr”‘labeled red cells.’ The magnitude of the hemorrhage was calculated from the \;olume of red cells lost from the materrlal circulation and the predelivery hematocrit. As much as possible of the blood shed by 4 of these 22 patients during and after delivery, including the maternal blood in the placenta, was collected. As shown in Table IV, the amounts recovered were quite similar to the amounts which disappeared from the maternal circulation. Maternal blood loss averaged 940 ml. in the 16 cases which were delivered vaginally and 916 ml. in the 6 delivered by cesarean section. Five of the 22 were thrombocyto-
Table III.
Blood volumes, red cell volumes, and hematocrits of 13 women when eclamptic, when nonpregnant, and of 7 of them again when normally pregnant __.._._~~_. -..- ~-- -.~ -.--~ --._~ ~~-- ..___-. ..._ 1 /
Ante-
’
/ Normnl
1
Non-
eclampsia j
pregnant
partum
(13) Blood volume 3,043 Red blood cell volume 1,195 Hematocrit __ -. .~_.-.-_-.~__ 39.3
/
~
late
/ Pregnancy
(13)
(
(7)
2,963
4,170
1,185 ~_--I-~~40.0
1,562 37.8 ~~-~..
-
Table IV. Volumes compared maternal
Case
of shed blood collected to the amounts lost from the circulation during parturition / I /
1 2 3 4 Average _.._._.
Shed blood collected (ml.)
i ! /
860 630 975 728 --_~_ 798
Amounts lost by diference (ml.) 970 810 1,020 797
-~__--..-.----
894
~-
Volume Number
Eclampsia
99 6
Blood urea, uric acid, electrolyte, and protein concentrations. These values for
penic, their direct platelet counts ranging from 48,000 to 69,000. However, the thrombocytopenia did not seem to contribute in any major way to the blood loss associated with delivery since the mean blood loss for these 5 averaged 880 ml. The appreciable fall i:n the hematocrits which followed vaginal delivery and. cesarean section is shown in Table V. The clinical estimates of blood loss due to parturition averaged 600 ml. for the 61 with eclampsia diagnosed prior to delivery. While this value is less than the measured losses described above, nonetheless it is higher than the clinical estimates for delivery loss in the general obstetric population.
Table V. Maternal
blood
blood drawn soon after the diagnosis of eclampsia was made are presented in Table VI. The initial BUN was greater than 20 mg. per 100 ml. in 6. The blood pressures in these 6 ranged from 162/120 to 230/150 mm. Hg. All but one ultimately became normotensive after delivery. The exception whose case is summarized under Complications was an 18-year-old now primiparous white woman who had chronic glomerulonephritis determined by renal biopsy. Fetal salvage in this group was only 50 per cent. When the cases of eclampsia with uric acid levels below 6 mg. and above 10 mg. per 100 ml. were compared, no evidence was found to suggest that those with the highest uric acid concentration were more seriously ill than those with the lowest. Observations made on the 5 cases of uric acid levels less than 6 mg. and the 5 of levels above 10 mg. per 100 ml. are compared in Table VII. None of these patients had been taking thiazide diuretics. The plasma CO, content was 12 mM. per liter or less in 5 women with antepartum eclampsia. Almost certainly the low CO, content was due primarily to metabolic acidosis resulting from lactic acidemia caused by the convulsions. No therapy was initiated other than that to control the convulsions, give oxygen by mask, and administer small amounts of glucose intravenously. Alkalizing agents were not given. The 5 infants were live-born but 3 died; those that died weighed 510, 1,095, and 1,890 grams. Delivery was accomplished anywhere from 8f/2 to 38 hours after the last convulsion at which time the mother was no longer severely acidotic.
loss and effect on
hema.tocrit Hematocrit 6 - 7 days postpartum
Predelivery Vaginal (16)”
*Two
39.1
940
Cesan:an section (6) patients
916
Table VI. Initial
29.8
43.4
received
a 1,000
blood
ml.
29.2 blood
transfusion.
chemical
determinations 1 Average Blood urea nitrogen (mg./lOO ml.) Uric .acid (mg./lOO Sodium (mEq./L.) PotaGum (mEq./L.) Chloride (mEq./L.) COz (mM./L.) Serum proteins (Cm./100 ml.)
1 Range
12 a.4 137 3.8 103 17.6
ml.)
5-28 3.1 - 12.9 128 - 148 2.7 - 5.9 94- 112 8.5 - 26.0
6.1
4.8 - 8.0
Table VII.
Observations on eclamptic patients 5 mg. and greater than 10 mg. per 100 ml.
IJric acid ml.) A (my./100 <5 Y-10 *One
unknown.
I
Age 17 18
I
Diastolic blood pressure (mmg. Hd 120 110
759
with
BUN (me./100 14 14
serum
uric
Perinatal ml.)
acid less than
mortality (%) 60 20
Subsequently normotensive 3/4* 3/5
760
Pritchard
and Stone
The serum protein concentrations of tho~c~ with antepartum eclampsia measured using the biuret reaction averaged 6.1 Gm. and ranged from 4.8 Gm. to 8.0 Gm. per 100 ml. The serum levels were measured in 10 of these women again late in a normal pregnancy. Their mean values were the same when normally pregnant as when eclamptic. Electroencephalogram. Seventeen of the 29 patients evaluated were considered to demonstrate some degree of electroencephalographic abnormality during the puerperium. Most commonly these were diffuse changes compatible with a recent convulsive state. Urine culture. An indwelling Foley catheter was used to monitor urine flow throughout the period of active treatment. It was usually removed about 24 hours post partum. In 47 cases urine was collected for culture prior to removing the catheter. Significant bacteriuria was identified 18 times or in 38 per cent. Subsequent
observations
Thirty-nine of the primiparas and 11 of the multiparas have been observed one or more times after discharge. If the diastolic blood pressure readings were more than 85 mm. or the systolic readings were more than 140 mm. the patient has been classified as hypertensive. Some so classified were examined only once about 6 weeks post partum. By these criteria 33 of the 39 primiparas when nonpregnant. were normotensive Twenty of these, all of whom had been identified as normotensive one or more times when nonpregnant, were subsequently delivered one or more times at Parkland Memorial Hospital. Only 2 of the 20 demonstrated hypertension during a subsequent pregnancy. In both instances the hypertension was mild and limited to the intrapartum period. Using the same criteria, 6 of the 11 multiparous women were classified normotensive when nonpregnant. Four of these were subsequently delivered again at Parkland Memorial Hospital. One developed severe hypertension late in pregnancy.
Comment ‘The rnatc~rnai outctrrne using t111\ li~t1~0l.j of treatment has been quite gratifying. Nor onI>- did all of the 69 mottltzrh li\-c. hut tilt.1 appear, to date at. lrast, to ham ~tlffc~r~~cl little in the cvay of serious perman~~nt physical sequelae as the consequence ol’ CCllullpSiil. Fetal salvage> did not r~yual that of tlx mother. Nonetheless, all frtuses alivt~ wht’u rclampsia \vas first diagnosed and weighing 2,000 grams or more survi~~ecl. The long history of the use of magnesium sulfate to control convulsions in c,arious hy1JertensiL.c disorders including toxemia of pregnancy is \vell known. 3 Moreover? Zuspan’ has recently documented that parenterally administered magnesium sulfate currently i, used extensively in the treatment of eclanlpsia at the medical centers of several different universities. Yet, in spitr of its rather widespread LISP, the possibility of adverse effects from magncsi1mi sulfate therap) srerris 10 be a source’ of conct’ln not only to sorn~ obstetricians, but to pediatricians, internists, anesthesiologists, and pharmacologists as well. Our experience with the parentera use of magnesiunl sulfate in women with toxemia of pregnancy has not been limited to thcscn 69 cases. During the same I 14’2 year period, pearly 8.000 cases of pre-eclampsia also rt:ceived this drug at Parkland Memorial Hospital. Those considered to be stt\‘t‘re on thr bases of marked hyperreflexia, intrnse hratlache. visual scotomas. or epigastric pain were treated initially with both intravenously and intramuscularly administertsd magnesium sulfate. The initial intravenous dose was ornitted in the cases considered less sevttr‘e. All things considered, magnesium sulfate when administrred as described in this rcport has berrl demonstrated to be remarkably effective and safe for both arresting and preventing the convulsions of eclampsia. At first it was somewhat disconcerting to discover that in 4 of the 69 cases of eclampsia in this report. magnesium sulfate had hec*n administered prophylactically prior to any convulsions yet the patient went on to develop eclampsia. Now, after considering the total number of cases of prc-eclampsia so
Volume Number
99 6
treatetd, it seems more remarkable that only 4 out of 8,000 patients with pre-eclampsia did! Moreover, in 3 of the 4 cases of apparent failure of magnesium sulfate to prevent convulsions, the recommended treatment schedule had not been followed. Evidence of magnesium intoxication has been most scant. Calcium gluconate, for instance, has been given but once. The only case of respiratory depression in these 8,000 cases has been described in some detail under Complications. Almost certainly, depressed respirations exhibited by Patient L. M. were due to magnesium intoxication. A variety of factors undoubtedly contributed to its development: She weighed less than 100 pounds. Renal function was considerably impaired due to eclampsia plus chronic glomcrulonephritis. She was markedly hypovolemic both from eclampsia and from blood loss at cesarean section. Finally, succinyl choline had been used very recently to produce muscle paralysis. In retrospect, it seems remarkable that the patellar reflex described as hypoactive was at all demonstrable 30 minutes postoperatively. There was little evidence other than cessation of convulsions to suggest that magnesium sulfate produced depression of the central nervous system. The eclamptic patient treated with magnesium sulfate soon awakened enough to respond to vocal commands and usually to the extent that she soon became oriented, at least as to place. The prompt return of consciousness not only was a welcome sign prognosis wise, but it reduced markedly the problem of nursing care. Undoubtedly, the general lack of druginduced central nervous system depression contributed significantly to the excellent materna and relatively good fetal salvage. Magnesium sulfate both in vitro and in viva inhibits myometrial contractility if the c’oncentration of the ion is raised high enough. ‘9 6 If myometrial contractility was impaired in our patients, it did not seem to be of great clinical importance. Its use did not prevent labor spontaneous in onset in 9 women so treated, nor did “secondary” uterine inertia develop in any of those who were
Eclampsia
761
already in active labor prior to treatment. Moreover, labor was successfully induced with oxytocin in 20 out of 24 cases. The possibility that depression of myometrial contractility by magnesium ion following delivery caused excessive hemorrhage has been considered. While blood 10~s with vaginal delivery was greater than in the general obstetric population, blood 10s~ from cesarean section was not.7-” Moreover, magsulfate similarly administered to nesium women without toxemia of pregnancy did not enhance significantly blood loss from parturiti0n.l’ All women studied with eclampsia had severe hypovolemia compared to normal late pregnancy.l’ Consequently, they could be predicted to be much less tolerant of hemorrhage at parturition than normal women. Throughout this study those instances of a dramatic drop in blood pressure very soon after delivery almost certainly resulted from hemorrhage superimposed on pregnancy hypovolemia rather than the abrupt disappearance of some unique pressor substance. Although hyponatremia has been implicated in the etiology of puerperal hypotension in some cases of severe toxemia, it was not identified in any of our cases of eclampsia which became hypotensive.12 During this period of time, however, acute hyponatremia and water intoxication severe enough to cause convulsions were induced in 2 cases of preeclampsia. The serum sodium concentrations dropped from nearly 145 mEq. to less than 120 mEq. per liter. In both, because of somewhat excessive bleeding from the uterus after delivery, a 5 per cent aqueous solution of dextrose was used as a vehicle for administering oxytocin. Unwittingly, they received rather large volumes of water which was not excreted due to the antidiuretic effect of oxytocin. Neither was considered to have eclampsia. One case has been reported previously.l? The hematocrit of patients with eclampsia has long been considered to parallel quite closely the degree of hemoconcentration. During this study it became apparent that considerable hemoconcentration was the rule for practically all cases of eclampsia and, there-
762
Pritchard
and Stone
fore, the hematocrit actually rrllcctcd 111Iwarily the variations in total red ccl1 vr)lu~n~: and only to a much lesser degree variaticms in blood volume. Appreciable decreases in tht hematocrit following delivery most often dicl not signify expansion of the blood voiumc but instead indicated appreciable blood loss. Quite likely, the improvement noted simultaneously with the fall in hematocrit was rclated to the fall only to the extent that d+ livery causes improvement and delivery causes a loss of red cells which: in turn, drops the hematocrit. Actually, none of the commonly performed laboratory tests proved to be
Addendum
Since th
REFERENCES
Pritchard, J. A., Baldwin, R. M., Dickey, J. C., and Wiggins, K. M.: AM. J. OBST. &
1. Pritchard, J. A.: Surg., Gynec. & Obst. 100: 131, 1955. 2. Pritchard, J. A., Wiggins, K. M., and Dickey, J. C.: AM. J. OBST. & GYNEC. 80: 956, 1960. 3. Chesley, L. C., and Tepper, I.: S. Clin. North America 37: 353, 1957. 4. Zuspan. F. P.: Clin. Obst. & Gynec. 9: 954, 1966. 5. Hall, D. G., McGaughey, H. S., Jr., Corey, E. L., and Thornton, W. N.: AM. J. OBST. & GYNEC. 78: 27, 1959. 6. Kumar, D., Zourlas, P. A., and Barnes, A. C.: AM. J. OBST. & GYNEC. 86: 1036, 1963. 7. Newton, M., Mosey, L. M., Egli, G. E., Gifford, W. B., and Hull, C. T.: Obst. & Gynec. 17: 9, 1961.
GYNEC.
84:
1271,
1962.
Wilcox, C. F., III, Hunt, A. B., and Owen, C. A., Jr.: AM. J. OBST. & GYNEC. 77: 772. 1959.
10. Rowland, R. C., and Pritchard, J. A.: AM. J. OBST. & GYNEC. 89: 261, 1964. 11. Pritchard, J. A.: Anesthesiology 26: 393, 1965. 12. Tatum, H. J., and Mulk, J. G.: .4w. J. OBST. & GYNEC. 71: 492, 1956. 13. Whalley, P. J., and Pritchard, J. rl.: J. -4. M. A. 186: 601, 1963.
Discussion
W. NORMAN THORNTON, JR. Charlottrsville,Virginia. In the brief period of three minutes permitted for discussion of this significant presentation, I would like to point out some similarities and differences observed in a series of
168 eclamptic patients managed in our institution over a 25 year period terminating on Dec. 31, 1963. Parenteral magnesium sulfate has been consistently employed to control convulsions, and
DR.
Table
Type
I.
Labor
and delivery
of delivery
Vaginal Spontaneous labor Induced labor Cesarean section Died undelivered
I
1 Antepartum
1
Zntrapartum eclampsia
j
Postpartum eclampsia
1 I
Total
83 (1 -42 days)* 18 (4- 16 days)*
20
34 1
137 (81.5%) 19 (11.3%) _^_.____ 156 (92.8%)
7 (5 - 25 days)*
1
2
10 ( 6.0%)
2 110
*Time interval
eclampsia
0 (65.5%)
between diagnosis of eclampsia and delivery.
21 (12.5%)
0 37 (22.0%)__.-_-
2 (-----.1.2%) 168--- .~~ _.....
Volume Number
99 6
Eclampsia
763
spontaneous in 81.5 per cent of the patients. Forty-seven of the 83 patients in whom eclampsia antedated spontaneous initiation of labor were delivered within 48 hours of the first convulsion. In the remaining .36 patients the time interval between occurrence of convulsions and spon-
taneous onset of labor ranged from 93 hours to 42 days. It was elected to terminate pregnancy in 29 patients. None of these pregnancies were interrupted because of uncontrolled convulsions, but as a result of unsatisfactory medical control of the toxemia. Ten patients in this group of 29 patients were delivered by cesarean section but only 6 of these for eclampsia per se. The maternal mortality was 4.7 per cent (8 patients), However, between Dec. 9, 1944, and the termination of the study period on Dec. 31, 1963, 108 consecutive eclamptic patients have been managed without loss of a mother. The uncorrected perinatal mortality of 21.6 per cent in our series as shown in Table II is essentially the same as obtained by the authors. Loss to follow-up of 20.8 per cent of 158 surviving patients does not permit valid interpretation of the relationship of prolongation of pregnancy complicated by eclampsia to the incidence of residual hypertension in our survey as illustrated in Table III. Finally, I trust that the decreasing incidence of this major obstetric complication, as shown in Table IV, will not permit Dr. Pritchard’s
Table II. Perinatal
Table
since (954 has been administered exclusively by the intravenous route for the reasons advocated by one of our associates.1 Antihypertensive drugs have been employed infrequently, but morphine sulfate and phenobarbital have been used frequently in conjunction with magnesium sulfate. We are in complete agreement with the authors in regard to the safeguards which should be employed prior to the administration of additional magnesium ion after the initial dose. Fluid replacement has been based on measured urinary output and insensible loss without emphasis on fluid restriction or hydration. Constant emphasis has been placed upon meticulous individualization of therapy and dosage in each patient. In our own series, we have not been as concerned: as the authors about prompt termination of the pregnancy after convulsions have been controlled as indicated in Table I. Onset of labor was
mortality
Weight (grams) 999 and less 1,oco - 1,499 1,5co - 1,999 2,000 - 2,499 2,5CO and over Unknown Total
Table Patients
III. with
Incidence adequate
Infants at risk 5 9 16 30 105
4
171
37
)
% 80.0 66.6 43.8 10.0 12.4
21.6
hypertension
among
incidence
normal
blood
pressure
vascular
of eclampsia
Year
Total births
Cases of eclampsia
1939 - 43 1944 - 48 1949 - 53
4,561 6,993 $2l-Id7
56 50 75
n 42
1954 - 58 1959 - 63
9,579 _- ^^^
1UJZY
17 1^ IU
0.17 ^ ^^
U.UY
Total
39,399
168
0.42
“,”
158 surviving
IY
Incidence 1.22 0.71
“.,
“.
A.,
patients
follow-up
Patients with subsequent diagnosis of hypertensive Pre-existing hypertensive vascular disease No previous history Patients with subsequent 6 weeks to 24 years)
Declining
Deaths No. 4 6 7 133
6
of residual
IV.
disease
27
(16.9%)
98
(61.6%)
125
(79.2%)
33
(20.8%)
3 24 (follow-up
Patients with inadequate follow-up P.re-existing hypertensive vascular disease (no follow-up) H’ypertension 6 weeks postpartum (no follow-up) Hypertension on discharge (no follow-up) Normotensive on discharge (no follow-up)
from
3 9 5 16
764
Pritchard
and Stone
REFERENCE
1. Hall,
D. G.: Obst. & Gynrc. 9: 158, 1957.
DR. S. R. M. REYNOLDS, Chicago, Illinois. In this regimen is there any untoward effect from the intramuscular or paravascular use of magnesium sulfate? It would be minor in relation to the results achieved, I quite recognize. Some 35 years ago, there was a vogue for the use of calcium therapy, calcium chloride ot calcium sulfate being the substances employed. These fell into disuse because of the fact that the anions of sulfate or chloride caused tissue dcstruction, but this was very easily avoided by the use of calcium gluconate. I had some magnesium gluconate prepared at one time for use in animals and found that magnesium gluconate could be injected paravascularly with no tissue destruction whatsoever as Gantarowl had found with respect to calcium and magnesium gluconate. Going back one more step, before 1920, Bayliss, the British general physiologist, found that one of the primary effects of the magnesium ion is to antagonize the hyperexcitatory effects of calcium ions in various tissues, including nervous tissue. In my own observations of many years ago, I was able to induce hyperexcitability of the uterus, for example, and modifications of vascular tone as evidenced by changes of blood pressure. I could specifically abolish these by the use of magnesium ions given as magnesium gluconate but magnesium in the absence of Cat, had no effect on uterine contractability. It might be worth considering the use of magnesium gluconate when this is to be used paravascularly. You will have to get a pharmaceutical company to make it up for you, but it is not a patented manufacturing process. REFERENCE
1. Cantarow, A.: Calcium Metabolism cium Therapy, ed. 2, Philadelphia, & Febiger.
and Cal1933, Lea
DR. HOWARD J. TATUM, New York, New York. The only facts that Dr. Pritchard presented that disturbed me were in regard to the 6 patients who required more medication to control additional convulsions after a delay of perhaps 15 minutes following the initial anticonvulsant ther-
.41X?, I \volrld caution against tla! u*1e of phenobarbital
Volume 95' Number6
would like to re-emphasize the point that drugs other than magnesium were sparingly used. This I feel is the most important item in lowering of fetal loss. DR. PRITCHARD (Closing). In regard to Dr. Thornton’s comments, eclampsia is a disappearing disease. I organized this anterospective study when I moved to Dallas in the fall of 1955 and promised that when we had observed 100 cases a report would be issued. The infrequency of eclampsia compared with the frequency of my birthdays led us to clescribe our results now. One of the greatest dangers to a woman with eclampsia in this day is the situation that Dr. Lock mentioned. She may have had nearly as much experience with the disease as the doctor caring for her. Moreover, not infrequently, he is surrounded by help which seems to come out of every nook and cranny when one of these patients arrives-an internist, an anesthesiologist, and maybe even a neurologist-and they each have something different that they must give for convulsions. The first thing you know, the immediate problem becomes one of toxicology rather than the problem of safe but effective treatment of eclampsia. Dr. Thornton and his group use magnesium sulfate intravenously and so did Dr. Zuspan. One objection I have to the intravenous route is that it takes more manpower to monitor it continuously than it does to give magnesium sulfate intramuscularly every 4 hours. In response to Dr. Reynolds’ questions, I should say that the perivascular injection of magnesium sulfate does one thing-it hurts. We try to modify this with the use of local anesthetic agents, but it still can be painful. As for other adverse effects on local tissues, there seem to be none unless, of course, one were to inject a large bolos directly into the sciatic nerve, and then the result is predictable. It is the same as if Imferon or Achromycin or most
Eclampsia
765
any drug was injected directly into the sciatic nerve. I do not see why one should use morphine intravenously because of the fear that maybe more magnesium would overwhelm the patient. Morphine plus magnesium, as far as I am concerned, is a potentially more dangerous combination that more magnesium, as long as the knee jerk is present. There is an excellent paper in the Journal of Pharmacology and Experimental Therapeutics, December, 1966, by a group at Duke University who attempted to duplicate some of the studies that were done a long time ago concerning the anesthetic effect of magnesium ion. Two of the authors were the subjects and intravenous magnesium sulfate was administered at such a rate as to build the blood level up eventually to about 15 mEq. per liter. There was no loss of consciousness; these people were able to relate practically everything that happened. There was respiratory depression and there was a mild degree of apparent neuromuscular block in the form of weakness. It did very little to inhibit central nervous system activity other than cause respiratory depression. Therefore, with an inadvertent overdose of magnesium sulfate, an adequate airway and some means of mechanical ventilation are needed the same way as in the individual recovering from succinylcholine administration. I appreciate Dr. Zuspan’s comments emphasizing something brought out in the manuscript, that is, minimizing the use of other drugs and thereby keeping the regimen simple as well as effective and safe. Anesthesia for the past several years has consisted almost totally of pudendal block plus nitrous oxide and oxygen for vaginal delivery or a trace of Pentothal or Surital followed by nitrous oxide and oxygen plus succinylcholine for cesarean section.
on
eclampsia JACK
A.
STUART Dallas,
PRITCHARD, R.
STONE,
M.D M.D.
Texas
Sixty-nine Memorial
consecutive patients with eclampsia have been cared for at Parkland Hospital using magnesium sulfate to control convulsions followed soon by appropriate steps to accomplish delivery. Apresoline was given intravenously if hypertension was quite severe. Morphine, large doses of barbiturates, tranquilizers, alkaloidal vasodepressors, diuretics, and hypertonic solutions of dextrose, mannitol, urea, and sodium chloride were avoided. All the mothers survived. The perinatal salvage rate was 79 per cent for all fetuses and 89 per cent for those weighing 1,000 grams or more. All fetuses alive when eclampsia was diagnosed and weighing 2,000 grams or more survived. None of the commonly performed laboratory tests proved to be uniquely essential to the successful treatment of eclampsia.
S I N c E October, 1955, the basic treatment applied uniformly to all cases of eclampsia at Parkland Memorial Hospital has consisted of ( 1) magnesium sulfate both intravenously and intramuscularly to control convulsions followed by serial intramuscular injections to prevent their recurrence; (2) hydralazine ( Apresoline) intravenously to lower blood pressure when severely elevated; and (3; steps to effect delivery once the patient has regained consciousness. Since then 69 cases of eclampsia have been so managed. Reported now are several clinical and laboratory observations made on these women and their off spring.
past 11~12 years had eclampsia. Convulsions began prior to delivery in 61 and up to 36 hours post partum in 8 more. Most commonly, the patient with eclampsia was undelivered (88 per cent), teen-age ( 71 per cent), nulliparous (84 per cent), and Negro (75 per cent). She had been seen either not at all or very infrequently by a physician Therupy
Magnesium sulfate. Magnesium sulfate* (4 Gm.) in a 20 per cent solution was injected intravenously at the rate of about 1 Cm. per minute. As soon as this was accomplished, IO Gm. of magnesium sulfate in a 50 per cent solution (20 ml.) was injected one-half deeply into each buttock using a No. 20 gauge needle at least 3 inches in length.’ Infrequently, the convulsions were not controlled within 15 minutes after the intravenous and intramuscular injections. Then, the intravenous medication was repeated administering 4 Gm. more of the 20 per cent solution in 4 to 5 minutes unless the patient was unusually small-then only 2 Cm. was given.
Material
Sixty-nine at Parkland
of the 67,000 women delivered Memorial Hospital during the
From the Departments of Obstetrics and Gynecology of The University of Texas Southwestern Medical School and Parkland Memorial Hospital. This study was supported in part by Grant HE-02516-11 from the National Heart Institute, United States Public Health Service. Presented at the Ninetieth Annual Meeting of the. Amerjcan Gynecological f;;ty, Phoentx, Arezona, May 4-6,
“Magnesium
754
wllate
USP
~MgS0~~7HzC)i.
Volume Number
99 6
Every 4 hours thereafter, 5 Gm. of magnesium sulfate as a 50 per cent solution was injected deeply into alternate buttocks using the following safeguards prior to each dose: ( 1) The patellar reflex was demonstrated to be present. (2) The urine output during the previous 4 hours measured 100 ml. or more. (3) Respirations were not depressed. Magnesium sulfate therapy was continued for about 24 hours after delivery. Other anticonvulsants. In those infrequent cases where the convulsions persisted after magnesium sulfate therapy, either sodium phenobarbital, 0.2 to 0.3 Gm., or sodium amobarbital, 0.25 to 0.5 Cm., was injected slowly intravenously to control the convulsions. Antihypertensive agents. If severe hypertension persisted, i.e., if the diastolic blood pressure remained greater than 110 mm. Hg, Apresoline was given intravenously in 5 to 20 mg;. doses every 15 to 30 minutes until the blood pressure was reduced to the range of 140-150,/90-100 mm. Hg. It was repeated as needed. Twenty-seven of the patients received one or more doses of Apresoline. Analgesia. Individual doses of meperidine (Demerol), when given during labor, were limitecl to 50 mg.; if the fetus was premature, narcotics were avoided. After cesarean section, meperidine was administered in doses of 50 to 75 mg. every 3 hours as needed. Anesthesia. General anesthesia was used 35 times ( 57 per cent), pudendal block usually with nitrous oxide-oxygen analgesia 14 times (23 per cent), saddle block 7 times (12 per cent), and none 5 times (8 per cent). General anesthesia for cesarean section most often consisted of a single small dose of Pentothal or Surital followed by nitrous oxide-oxygen and sufficient succinyl choline to produce adequate muscle relaxation, Saddle block anesthesia for vaginal delivery, consisting of 3 to 4 mg. of hyperbaric Pontocaine, was used only during the early years when anesthesiology coverage was grossly inadequate. Unfortunately, careful attempts to produce true saddle- block anesthesia with
Eclampsia
755
the mother in the sitting position sometimes were followed by significant hypotension. Parenteral fluids. An intravenous infusion system was promptly established. The total fluid intake, barring hemorrhage or unusual fluid loss, was limited to 2 liters or less of 5 per cent dextrose in water solution per 24 hours. Hypertonic solutions of dextrose, mannitol, urea, or saline were not used. Other therapy. During and immediately after a convulsion, a padded tongue blade was inserted between the teeth. The patient was continuously observed in a well-lighted room until she was conscious. If secretions or vomitus were evident, she was kept on her side and the pharynx suctioned. Oxygen moistened with water vapor was administered as soon as practicable after a convulsion. While unconscious, an adult-size Guedal oral airway was used to prevent airway obstruction by the tongue. In no instance was tracheostomy necessary. No diuretics were used. Prophylactic digitalization was avoided although digitalization was initiated once because pulmonary congestion was thought to be present and once because of persistent tachycardia. Neither patient subsequently demonstrated evidence of pulmonary edema. Delivery
Vaginal. Forty-eight,
or 79 per cent, of the 61 patients who developed eclampsia prior to delivery were delivered vaginally. Twenty-eight went into labor spontaneously; 19 of these demonstrated some evidence of labor at the time the diagnosis of eclampsia was made and the other 9 were in labor
Table I. Method
of delivery
Vaginal
Spontaneous labor Induced
labor
Cesarean section Fetal distress Breech presentation Failed forceps (elsewhere) Unsuccessful induction Elective Cephalopelvic disproportion
48
(79%)
13
(21%)
28 20 2 2 2 4 1 2
756
Pritchard
and
Stone
sometime thereafter, Induction of labor with the use of an intravenous infusion of dilute oxytocin resulted in vaginal delivery in 20 out of 24 patients. Cesarean section. This operation was performed on 13 for the reasons listed in Table I. The 2 instances of fetal distress were characterized by overt bradycardia. Partial placental abruption was demonstrated in both; the infants survived. Induction of labor with oxytocin was avoided in 2 instances of breech presentation; instead cesarean section was performed. In 2 more patients, attempts at forceps delivery at other hospitals had been unsuccessful: N. H., a 41-year-old woman pregnant for the fifth time, developed eclampsia manifested by convulsions, a blood pressure of 180/120 mm. Hg, 4+ proteinuria, and gross edema while hospitalized some distance from Dallas. Attempts at delivery with forceps were unsuccessful. After transfer, the convulsions were controlled with magnesium sulfate. The cervix was completely dilated but the head was not engaged. At laparotomy, a small rent in the lower uterine segment was identified so a total hysterectomy was done. The fetus which weighed 3,487 grams survived. It is of interest perhaps that this patient had had convulsions earlier in this pregnancy. When the pregnancy was finally recognized, electroshock therapy for schizophrenia was discontinued. E. D., a 17-year-old nullipara, was admitted to another hospital where attempts to effect delivery with forceps were unsuccessful. When transferred to Parkland Memorial Hospital the fetal heart could not be heard, the cervix was incompletely dilated, and lacerations were apparent in the posterior fornix as well as elsewhere in the vagina. The stillborn infant delivered 1)) cesarean section weighed 3,600 grams. The 4 patients in whom attempts at induction of labor were unsuccessful were delivered of premature or immature fetuses, 2 of which survived. Sterilization was also desirable in 3 of the women because of known chronic hypertension, high gravidity, and advanced age. These factors contributed to the decision to deliver by laparotomy with tubal ligation rather than prolong the attempts at inducing labor with oxytocin. The
t’ourtli pat&l was ati 18-vea1~-~1ici piinrigravida with \cry se\ erc bypertcnsion. crliguria, and a.Lotemia. Oxytocin infusiotr t’ol 8 hours produced no demonstrable clrange so a cesarean section was done. ‘l‘his case. I,. M.. is described further under I omplications. Maternal and The 69 mothers
fetul mortality all survived. Perinatal mortality. Sixty-three infants, including 2 sets of twins, were born of the 61 women in whom eclampsia developed prior to delivery. Seventy-nine per cent oi these fetuses survived. Of those weighing 1,000 grams or more, 89 per cent lived. The fate of the fetuses is demonstrated in Table II and Fig. 1. The 6 stillborn fetuses were dead when the diagnosis of eclampsia was
Table II. Perinatal fetuses whose prior to delivery
mortality mothers had
among 63 eclampsia
I
Birth weight (iv-1
/ I
,411 fetuses 1,000 or more
21 11
1,500 or rnore or more
Birth
1. Fate
Stippled
deaths; survived.
0
Wright
of the fetus
bars indicate
cate neonatal infants that
11 5 3
8 3
2,000
Fig.
Fetuses alive when ecEampsia iuas diagnosed (70 I
/ei!Ltes (%)
(Cm.1
according
stillbirths; open
bars
to birth
weight.
solid bars indiindicate
live-born
Volume 99 Number 6
first made; at least the fetal heart was not heard. Seven of the 57 born alive died. The weights of the live-born infants who died were ,510, 620, 720, 880, 1,095, 1,635, and 1,890 grams. Gross immaturity certainly accounted for the death of the 5 weighing 1,095 grams or less. Delivery of the primigravid mother of the infant weighing 1,635 grams was accomplished with low forceps and episiotomy after a vigorous spontaneous labor of only 2yJ hours. The infant died 32 hours later. Subdural and subarachnoid hemorrhages were prominent at autopsy. In the case of the infant weighing 1,890 grams, saddle block anesthesia was followed by maternal hypotension, the first recorded blood pressure being 90/60 mm. Hg. The infant developed severe hyaline membrane disease and died 26 hours later. The 8 infants of the women who developed eclampsia post partum survived.
Related to magnesium sulfate. The combined intravenous and intramuscular magnesium sulfate therapy given as outlined above failed to abolish convulsions in 6 patients. However, the addition of sodium phenobarbital or sodium amobarbital did so using the rather modest doses described. Five women in whom magnesium sulfate therapy had been initiated prophylactically during labor because of severe pre-eclampsia later had convulsions. In all but one this occurred post partum. In 4 of the 5, the intramuscular dosage schedule of 5 Gm. every 4 hours had not been adhered to, the last intramuscular injection having been due anywhere from 5 1.0 13 hours prior to the convulsion. In each instance, 2 to 4 Gm. of magnesium sulfate given intravenously plus 5 to 10 Gm. intramuscularly followed by 5 Gm. intramuscularly every 4 hours prevented further comulsions. The fifth patient with pre-eclampsia who subsequently had convulsions had initially received 10 Gm. of magnesium sulfate intramuscularly followed presumably by 5 Gm. intramuscularly every 4 hours. Eight hours after delivery and within 10 minutes after receiving her
Eclampsia
757
scheduled intramuscular dose of 5 Gm. she had a convulsion. Four grams of magnesium sulfate was administered intravenously and the schedule for intramuscular administration was continued. She too had no more convulsions. Evidence suggesting potentially dangerous magnesium intoxication was limited to one case: L. M., an 18-year-old primigravid Latin American patient, about 25 weeks pregnant and weighing but 99 pounds, was admitted convulsing. Her blood pressure was 190/140 mm. Hg and the urine contained 4+ proteinuria. After failing to initiate labor with oxytocin, cesarean section was done using initially a small dose of Surital followed by nitrous oxide-oxygen and succinyl choline. The 620 gram infant lived 4 hours. Thirty minutes after completing the operation, the next scheduled dose of magnesium sulfate was due. Although the patellar reflex was hypoactive, 5 Gm. of magnesium sulfate was given intramuscularly. Within an hour, overt respiratory depression was evident. Hypoxia was promptly corrected using an endotracheal tube and a mechanical ventilator. The patient promptly made efforts to respire, although she would hypoventilate without assistance. The plasma magnesium was 12.9 mEq. per liter. Renal biopsy subsequently demonstrated glomerular changes typical of both toxemia of pregnancy and chronic glomerulonephritis. Prior to discharge one month post partum, the creatinine clearance was 50 ml. per minute. She was still moderately hypertensive although her blood pressure had decreased markedly. The retinal exudates which were quite prominent soon after delivery had resolved during this time.
Other. Partial
premature separation of the placenta was recognized in 4 of the 61 in whom eclampsia was diagnosed prior to delivery. Marginal placenta previa was identified in one case first by vaginal examination during labor and later when the placenta was manually removed. The one case of rupture of the lower uterine segment after unsuccessful attempts at delivery with forceps has been described. Gross postpartum hemorrhage was diagnosed 8 times following vaginal delivery but
758
Pritchard
and
Stone
it certainly was more common than this. Hemorrhage from delivery is considered further under Laboratory Studies. Hemiparesis which persisted for several days was apparent in 2 patients. It is of interest that in neither of these did thtb initial intravenous plus intramuscular magnesium sulfate therapy control the convul.sions. The neurological abnormalities cleared completely prior to discharge. There was one case of intravascular hcmolysis with gross hemoglobinemia, hemoglobinuria, and thrombocytopenia. All evidence of hemolysis promptly disappeared after delivery and the platelet count rose to normal levels during the next 4 days. The infant survived. Overt psychosis developed in 4 during the early puerperium. Therapy consisted of chlorpromazine and good supportive care. Over a period of several days the psychosis cleared completely.
laboratory
studies
Hematocrit. For the 61 undelivered patients with eclampsia, the hematocrit done soon after the diagnosis was made averaged 38.4 and ranged from 31.0 to 51.0. The final hematocrit done on each several days post partum was only 32.0 even though 21 per cent of the women had received one or more blood transfusions. The hematocrit values of 200 consecutive unselected pregnant women performed the same way when admitted to the labor-delivery suite at Parkland Memorial Hospital averaged 38.5 and ranged from 26.5 to 49.0. Blood and red cell volumes. These were measured in 13 women with antepartum eclampsia, who were not bleeding, by labeling their own red cells with radiochromium. The technique has been described previously.’ As shown in Table III, the hematocrits, total red cell volumes, and blood volumes did not differ significantly from those present several months later when not pregnant. Thus the hypervolemia and increase in red cell volume of normal pregnancy were absent in these women with eclampsia. When 7 of them were studied a third time near the end of a normal
Blood loss. Hemorrhage due to parturitiol~ was evaluatecl in 22 patients, none of whom demonstrated abnormal bleeding prior to delivery. The volume of circulating red cells was rneasured before delivery and again several hours post partum using their Cr”‘labeled red cells.’ The magnitude of the hemorrhage was calculated from the \;olume of red cells lost from the materrlal circulation and the predelivery hematocrit. As much as possible of the blood shed by 4 of these 22 patients during and after delivery, including the maternal blood in the placenta, was collected. As shown in Table IV, the amounts recovered were quite similar to the amounts which disappeared from the maternal circulation. Maternal blood loss averaged 940 ml. in the 16 cases which were delivered vaginally and 916 ml. in the 6 delivered by cesarean section. Five of the 22 were thrombocyto-
Table III.
Blood volumes, red cell volumes, and hematocrits of 13 women when eclamptic, when nonpregnant, and of 7 of them again when normally pregnant __.._._~~_. -..- ~-- -.~ -.--~ --._~ ~~-- ..___-. ..._ 1 /
Ante-
’
/ Normnl
1
Non-
eclampsia j
pregnant
partum
(13) Blood volume 3,043 Red blood cell volume 1,195 Hematocrit __ -. .~_.-.-_-.~__ 39.3
/
~
late
/ Pregnancy
(13)
(
(7)
2,963
4,170
1,185 ~_--I-~~40.0
1,562 37.8 ~~-~..
-
Table IV. Volumes compared maternal
Case
of shed blood collected to the amounts lost from the circulation during parturition / I /
1 2 3 4 Average _.._._.
Shed blood collected (ml.)
i ! /
860 630 975 728 --_~_ 798
Amounts lost by diference (ml.) 970 810 1,020 797
-~__--..-.----
894
~-
Volume Number
Eclampsia
99 6
Blood urea, uric acid, electrolyte, and protein concentrations. These values for
penic, their direct platelet counts ranging from 48,000 to 69,000. However, the thrombocytopenia did not seem to contribute in any major way to the blood loss associated with delivery since the mean blood loss for these 5 averaged 880 ml. The appreciable fall i:n the hematocrits which followed vaginal delivery and. cesarean section is shown in Table V. The clinical estimates of blood loss due to parturition averaged 600 ml. for the 61 with eclampsia diagnosed prior to delivery. While this value is less than the measured losses described above, nonetheless it is higher than the clinical estimates for delivery loss in the general obstetric population.
Table V. Maternal
blood
blood drawn soon after the diagnosis of eclampsia was made are presented in Table VI. The initial BUN was greater than 20 mg. per 100 ml. in 6. The blood pressures in these 6 ranged from 162/120 to 230/150 mm. Hg. All but one ultimately became normotensive after delivery. The exception whose case is summarized under Complications was an 18-year-old now primiparous white woman who had chronic glomerulonephritis determined by renal biopsy. Fetal salvage in this group was only 50 per cent. When the cases of eclampsia with uric acid levels below 6 mg. and above 10 mg. per 100 ml. were compared, no evidence was found to suggest that those with the highest uric acid concentration were more seriously ill than those with the lowest. Observations made on the 5 cases of uric acid levels less than 6 mg. and the 5 of levels above 10 mg. per 100 ml. are compared in Table VII. None of these patients had been taking thiazide diuretics. The plasma CO, content was 12 mM. per liter or less in 5 women with antepartum eclampsia. Almost certainly the low CO, content was due primarily to metabolic acidosis resulting from lactic acidemia caused by the convulsions. No therapy was initiated other than that to control the convulsions, give oxygen by mask, and administer small amounts of glucose intravenously. Alkalizing agents were not given. The 5 infants were live-born but 3 died; those that died weighed 510, 1,095, and 1,890 grams. Delivery was accomplished anywhere from 8f/2 to 38 hours after the last convulsion at which time the mother was no longer severely acidotic.
loss and effect on
hema.tocrit Hematocrit 6 - 7 days postpartum
Predelivery Vaginal (16)”
*Two
39.1
940
Cesan:an section (6) patients
916
Table VI. Initial
29.8
43.4
received
a 1,000
blood
ml.
29.2 blood
transfusion.
chemical
determinations 1 Average Blood urea nitrogen (mg./lOO ml.) Uric .acid (mg./lOO Sodium (mEq./L.) PotaGum (mEq./L.) Chloride (mEq./L.) COz (mM./L.) Serum proteins (Cm./100 ml.)
1 Range
12 a.4 137 3.8 103 17.6
ml.)
5-28 3.1 - 12.9 128 - 148 2.7 - 5.9 94- 112 8.5 - 26.0
6.1
4.8 - 8.0
Table VII.
Observations on eclamptic patients 5 mg. and greater than 10 mg. per 100 ml.
IJric acid ml.) A (my./100 <5 Y-10 *One
unknown.
I
Age 17 18
I
Diastolic blood pressure (mmg. Hd 120 110
759
with
BUN (me./100 14 14
serum
uric
Perinatal ml.)
acid less than
mortality (%) 60 20
Subsequently normotensive 3/4* 3/5
760
Pritchard
and Stone
The serum protein concentrations of tho~c~ with antepartum eclampsia measured using the biuret reaction averaged 6.1 Gm. and ranged from 4.8 Gm. to 8.0 Gm. per 100 ml. The serum levels were measured in 10 of these women again late in a normal pregnancy. Their mean values were the same when normally pregnant as when eclamptic. Electroencephalogram. Seventeen of the 29 patients evaluated were considered to demonstrate some degree of electroencephalographic abnormality during the puerperium. Most commonly these were diffuse changes compatible with a recent convulsive state. Urine culture. An indwelling Foley catheter was used to monitor urine flow throughout the period of active treatment. It was usually removed about 24 hours post partum. In 47 cases urine was collected for culture prior to removing the catheter. Significant bacteriuria was identified 18 times or in 38 per cent. Subsequent
observations
Thirty-nine of the primiparas and 11 of the multiparas have been observed one or more times after discharge. If the diastolic blood pressure readings were more than 85 mm. or the systolic readings were more than 140 mm. the patient has been classified as hypertensive. Some so classified were examined only once about 6 weeks post partum. By these criteria 33 of the 39 primiparas when nonpregnant. were normotensive Twenty of these, all of whom had been identified as normotensive one or more times when nonpregnant, were subsequently delivered one or more times at Parkland Memorial Hospital. Only 2 of the 20 demonstrated hypertension during a subsequent pregnancy. In both instances the hypertension was mild and limited to the intrapartum period. Using the same criteria, 6 of the 11 multiparous women were classified normotensive when nonpregnant. Four of these were subsequently delivered again at Parkland Memorial Hospital. One developed severe hypertension late in pregnancy.
Comment ‘The rnatc~rnai outctrrne using t111\ li~t1~0l.j of treatment has been quite gratifying. Nor onI>- did all of the 69 mottltzrh li\-c. hut tilt.1 appear, to date at. lrast, to ham ~tlffc~r~~cl little in the cvay of serious perman~~nt physical sequelae as the consequence ol’ CCllullpSiil. Fetal salvage> did not r~yual that of tlx mother. Nonetheless, all frtuses alivt~ wht’u rclampsia \vas first diagnosed and weighing 2,000 grams or more survi~~ecl. The long history of the use of magnesium sulfate to control convulsions in c,arious hy1JertensiL.c disorders including toxemia of pregnancy is \vell known. 3 Moreover? Zuspan’ has recently documented that parenterally administered magnesium sulfate currently i, used extensively in the treatment of eclanlpsia at the medical centers of several different universities. Yet, in spitr of its rather widespread LISP, the possibility of adverse effects from magncsi1mi sulfate therap) srerris 10 be a source’ of conct’ln not only to sorn~ obstetricians, but to pediatricians, internists, anesthesiologists, and pharmacologists as well. Our experience with the parentera use of magnesiunl sulfate in women with toxemia of pregnancy has not been limited to thcscn 69 cases. During the same I 14’2 year period, pearly 8.000 cases of pre-eclampsia also rt:ceived this drug at Parkland Memorial Hospital. Those considered to be stt\‘t‘re on thr bases of marked hyperreflexia, intrnse hratlache. visual scotomas. or epigastric pain were treated initially with both intravenously and intramuscularly administertsd magnesium sulfate. The initial intravenous dose was ornitted in the cases considered less sevttr‘e. All things considered, magnesium sulfate when administrred as described in this rcport has berrl demonstrated to be remarkably effective and safe for both arresting and preventing the convulsions of eclampsia. At first it was somewhat disconcerting to discover that in 4 of the 69 cases of eclampsia in this report. magnesium sulfate had hec*n administered prophylactically prior to any convulsions yet the patient went on to develop eclampsia. Now, after considering the total number of cases of prc-eclampsia so
Volume Number
99 6
treatetd, it seems more remarkable that only 4 out of 8,000 patients with pre-eclampsia did! Moreover, in 3 of the 4 cases of apparent failure of magnesium sulfate to prevent convulsions, the recommended treatment schedule had not been followed. Evidence of magnesium intoxication has been most scant. Calcium gluconate, for instance, has been given but once. The only case of respiratory depression in these 8,000 cases has been described in some detail under Complications. Almost certainly, depressed respirations exhibited by Patient L. M. were due to magnesium intoxication. A variety of factors undoubtedly contributed to its development: She weighed less than 100 pounds. Renal function was considerably impaired due to eclampsia plus chronic glomcrulonephritis. She was markedly hypovolemic both from eclampsia and from blood loss at cesarean section. Finally, succinyl choline had been used very recently to produce muscle paralysis. In retrospect, it seems remarkable that the patellar reflex described as hypoactive was at all demonstrable 30 minutes postoperatively. There was little evidence other than cessation of convulsions to suggest that magnesium sulfate produced depression of the central nervous system. The eclamptic patient treated with magnesium sulfate soon awakened enough to respond to vocal commands and usually to the extent that she soon became oriented, at least as to place. The prompt return of consciousness not only was a welcome sign prognosis wise, but it reduced markedly the problem of nursing care. Undoubtedly, the general lack of druginduced central nervous system depression contributed significantly to the excellent materna and relatively good fetal salvage. Magnesium sulfate both in vitro and in viva inhibits myometrial contractility if the c’oncentration of the ion is raised high enough. ‘9 6 If myometrial contractility was impaired in our patients, it did not seem to be of great clinical importance. Its use did not prevent labor spontaneous in onset in 9 women so treated, nor did “secondary” uterine inertia develop in any of those who were
Eclampsia
761
already in active labor prior to treatment. Moreover, labor was successfully induced with oxytocin in 20 out of 24 cases. The possibility that depression of myometrial contractility by magnesium ion following delivery caused excessive hemorrhage has been considered. While blood 10~s with vaginal delivery was greater than in the general obstetric population, blood 10s~ from cesarean section was not.7-” Moreover, magsulfate similarly administered to nesium women without toxemia of pregnancy did not enhance significantly blood loss from parturiti0n.l’ All women studied with eclampsia had severe hypovolemia compared to normal late pregnancy.l’ Consequently, they could be predicted to be much less tolerant of hemorrhage at parturition than normal women. Throughout this study those instances of a dramatic drop in blood pressure very soon after delivery almost certainly resulted from hemorrhage superimposed on pregnancy hypovolemia rather than the abrupt disappearance of some unique pressor substance. Although hyponatremia has been implicated in the etiology of puerperal hypotension in some cases of severe toxemia, it was not identified in any of our cases of eclampsia which became hypotensive.12 During this period of time, however, acute hyponatremia and water intoxication severe enough to cause convulsions were induced in 2 cases of preeclampsia. The serum sodium concentrations dropped from nearly 145 mEq. to less than 120 mEq. per liter. In both, because of somewhat excessive bleeding from the uterus after delivery, a 5 per cent aqueous solution of dextrose was used as a vehicle for administering oxytocin. Unwittingly, they received rather large volumes of water which was not excreted due to the antidiuretic effect of oxytocin. Neither was considered to have eclampsia. One case has been reported previously.l? The hematocrit of patients with eclampsia has long been considered to parallel quite closely the degree of hemoconcentration. During this study it became apparent that considerable hemoconcentration was the rule for practically all cases of eclampsia and, there-
762
Pritchard
and Stone
fore, the hematocrit actually rrllcctcd 111Iwarily the variations in total red ccl1 vr)lu~n~: and only to a much lesser degree variaticms in blood volume. Appreciable decreases in tht hematocrit following delivery most often dicl not signify expansion of the blood voiumc but instead indicated appreciable blood loss. Quite likely, the improvement noted simultaneously with the fall in hematocrit was rclated to the fall only to the extent that d+ livery causes improvement and delivery causes a loss of red cells which: in turn, drops the hematocrit. Actually, none of the commonly performed laboratory tests proved to be
Addendum
Since th
REFERENCES
Pritchard, J. A., Baldwin, R. M., Dickey, J. C., and Wiggins, K. M.: AM. J. OBST. &
1. Pritchard, J. A.: Surg., Gynec. & Obst. 100: 131, 1955. 2. Pritchard, J. A., Wiggins, K. M., and Dickey, J. C.: AM. J. OBST. & GYNEC. 80: 956, 1960. 3. Chesley, L. C., and Tepper, I.: S. Clin. North America 37: 353, 1957. 4. Zuspan. F. P.: Clin. Obst. & Gynec. 9: 954, 1966. 5. Hall, D. G., McGaughey, H. S., Jr., Corey, E. L., and Thornton, W. N.: AM. J. OBST. & GYNEC. 78: 27, 1959. 6. Kumar, D., Zourlas, P. A., and Barnes, A. C.: AM. J. OBST. & GYNEC. 86: 1036, 1963. 7. Newton, M., Mosey, L. M., Egli, G. E., Gifford, W. B., and Hull, C. T.: Obst. & Gynec. 17: 9, 1961.
GYNEC.
84:
1271,
1962.
Wilcox, C. F., III, Hunt, A. B., and Owen, C. A., Jr.: AM. J. OBST. & GYNEC. 77: 772. 1959.
10. Rowland, R. C., and Pritchard, J. A.: AM. J. OBST. & GYNEC. 89: 261, 1964. 11. Pritchard, J. A.: Anesthesiology 26: 393, 1965. 12. Tatum, H. J., and Mulk, J. G.: .4w. J. OBST. & GYNEC. 71: 492, 1956. 13. Whalley, P. J., and Pritchard, J. rl.: J. -4. M. A. 186: 601, 1963.
Discussion
W. NORMAN THORNTON, JR. Charlottrsville,Virginia. In the brief period of three minutes permitted for discussion of this significant presentation, I would like to point out some similarities and differences observed in a series of
168 eclamptic patients managed in our institution over a 25 year period terminating on Dec. 31, 1963. Parenteral magnesium sulfate has been consistently employed to control convulsions, and
DR.
Table
Type
I.
Labor
and delivery
of delivery
Vaginal Spontaneous labor Induced labor Cesarean section Died undelivered
I
1 Antepartum
1
Zntrapartum eclampsia
j
Postpartum eclampsia
1 I
Total
83 (1 -42 days)* 18 (4- 16 days)*
20
34 1
137 (81.5%) 19 (11.3%) _^_.____ 156 (92.8%)
7 (5 - 25 days)*
1
2
10 ( 6.0%)
2 110
*Time interval
eclampsia
0 (65.5%)
between diagnosis of eclampsia and delivery.
21 (12.5%)
0 37 (22.0%)__.-_-
2 (-----.1.2%) 168--- .~~ _.....
Volume Number
99 6
Eclampsia
763
spontaneous in 81.5 per cent of the patients. Forty-seven of the 83 patients in whom eclampsia antedated spontaneous initiation of labor were delivered within 48 hours of the first convulsion. In the remaining .36 patients the time interval between occurrence of convulsions and spon-
taneous onset of labor ranged from 93 hours to 42 days. It was elected to terminate pregnancy in 29 patients. None of these pregnancies were interrupted because of uncontrolled convulsions, but as a result of unsatisfactory medical control of the toxemia. Ten patients in this group of 29 patients were delivered by cesarean section but only 6 of these for eclampsia per se. The maternal mortality was 4.7 per cent (8 patients), However, between Dec. 9, 1944, and the termination of the study period on Dec. 31, 1963, 108 consecutive eclamptic patients have been managed without loss of a mother. The uncorrected perinatal mortality of 21.6 per cent in our series as shown in Table II is essentially the same as obtained by the authors. Loss to follow-up of 20.8 per cent of 158 surviving patients does not permit valid interpretation of the relationship of prolongation of pregnancy complicated by eclampsia to the incidence of residual hypertension in our survey as illustrated in Table III. Finally, I trust that the decreasing incidence of this major obstetric complication, as shown in Table IV, will not permit Dr. Pritchard’s
Table II. Perinatal
Table
since (954 has been administered exclusively by the intravenous route for the reasons advocated by one of our associates.1 Antihypertensive drugs have been employed infrequently, but morphine sulfate and phenobarbital have been used frequently in conjunction with magnesium sulfate. We are in complete agreement with the authors in regard to the safeguards which should be employed prior to the administration of additional magnesium ion after the initial dose. Fluid replacement has been based on measured urinary output and insensible loss without emphasis on fluid restriction or hydration. Constant emphasis has been placed upon meticulous individualization of therapy and dosage in each patient. In our own series, we have not been as concerned: as the authors about prompt termination of the pregnancy after convulsions have been controlled as indicated in Table I. Onset of labor was
mortality
Weight (grams) 999 and less 1,oco - 1,499 1,5co - 1,999 2,000 - 2,499 2,5CO and over Unknown Total
Table Patients
III. with
Incidence adequate
Infants at risk 5 9 16 30 105
4
171
37
)
% 80.0 66.6 43.8 10.0 12.4
21.6
hypertension
among
incidence
normal
blood
pressure
vascular
of eclampsia
Year
Total births
Cases of eclampsia
1939 - 43 1944 - 48 1949 - 53
4,561 6,993 $2l-Id7
56 50 75
n 42
1954 - 58 1959 - 63
9,579 _- ^^^
1UJZY
17 1^ IU
0.17 ^ ^^
U.UY
Total
39,399
168
0.42
“,”
158 surviving
IY
Incidence 1.22 0.71
“.,
“.
A.,
patients
follow-up
Patients with subsequent diagnosis of hypertensive Pre-existing hypertensive vascular disease No previous history Patients with subsequent 6 weeks to 24 years)
Declining
Deaths No. 4 6 7 133
6
of residual
IV.
disease
27
(16.9%)
98
(61.6%)
125
(79.2%)
33
(20.8%)
3 24 (follow-up
Patients with inadequate follow-up P.re-existing hypertensive vascular disease (no follow-up) H’ypertension 6 weeks postpartum (no follow-up) Hypertension on discharge (no follow-up) Normotensive on discharge (no follow-up)
from
3 9 5 16
764
Pritchard
and Stone
REFERENCE
1. Hall,
D. G.: Obst. & Gynrc. 9: 158, 1957.
DR. S. R. M. REYNOLDS, Chicago, Illinois. In this regimen is there any untoward effect from the intramuscular or paravascular use of magnesium sulfate? It would be minor in relation to the results achieved, I quite recognize. Some 35 years ago, there was a vogue for the use of calcium therapy, calcium chloride ot calcium sulfate being the substances employed. These fell into disuse because of the fact that the anions of sulfate or chloride caused tissue dcstruction, but this was very easily avoided by the use of calcium gluconate. I had some magnesium gluconate prepared at one time for use in animals and found that magnesium gluconate could be injected paravascularly with no tissue destruction whatsoever as Gantarowl had found with respect to calcium and magnesium gluconate. Going back one more step, before 1920, Bayliss, the British general physiologist, found that one of the primary effects of the magnesium ion is to antagonize the hyperexcitatory effects of calcium ions in various tissues, including nervous tissue. In my own observations of many years ago, I was able to induce hyperexcitability of the uterus, for example, and modifications of vascular tone as evidenced by changes of blood pressure. I could specifically abolish these by the use of magnesium ions given as magnesium gluconate but magnesium in the absence of Cat, had no effect on uterine contractability. It might be worth considering the use of magnesium gluconate when this is to be used paravascularly. You will have to get a pharmaceutical company to make it up for you, but it is not a patented manufacturing process. REFERENCE
1. Cantarow, A.: Calcium Metabolism cium Therapy, ed. 2, Philadelphia, & Febiger.
and Cal1933, Lea
DR. HOWARD J. TATUM, New York, New York. The only facts that Dr. Pritchard presented that disturbed me were in regard to the 6 patients who required more medication to control additional convulsions after a delay of perhaps 15 minutes following the initial anticonvulsant ther-
.41X?, I \volrld caution against tla! u*1e of phenobarbital
Volume 95' Number6
would like to re-emphasize the point that drugs other than magnesium were sparingly used. This I feel is the most important item in lowering of fetal loss. DR. PRITCHARD (Closing). In regard to Dr. Thornton’s comments, eclampsia is a disappearing disease. I organized this anterospective study when I moved to Dallas in the fall of 1955 and promised that when we had observed 100 cases a report would be issued. The infrequency of eclampsia compared with the frequency of my birthdays led us to clescribe our results now. One of the greatest dangers to a woman with eclampsia in this day is the situation that Dr. Lock mentioned. She may have had nearly as much experience with the disease as the doctor caring for her. Moreover, not infrequently, he is surrounded by help which seems to come out of every nook and cranny when one of these patients arrives-an internist, an anesthesiologist, and maybe even a neurologist-and they each have something different that they must give for convulsions. The first thing you know, the immediate problem becomes one of toxicology rather than the problem of safe but effective treatment of eclampsia. Dr. Thornton and his group use magnesium sulfate intravenously and so did Dr. Zuspan. One objection I have to the intravenous route is that it takes more manpower to monitor it continuously than it does to give magnesium sulfate intramuscularly every 4 hours. In response to Dr. Reynolds’ questions, I should say that the perivascular injection of magnesium sulfate does one thing-it hurts. We try to modify this with the use of local anesthetic agents, but it still can be painful. As for other adverse effects on local tissues, there seem to be none unless, of course, one were to inject a large bolos directly into the sciatic nerve, and then the result is predictable. It is the same as if Imferon or Achromycin or most
Eclampsia
765
any drug was injected directly into the sciatic nerve. I do not see why one should use morphine intravenously because of the fear that maybe more magnesium would overwhelm the patient. Morphine plus magnesium, as far as I am concerned, is a potentially more dangerous combination that more magnesium, as long as the knee jerk is present. There is an excellent paper in the Journal of Pharmacology and Experimental Therapeutics, December, 1966, by a group at Duke University who attempted to duplicate some of the studies that were done a long time ago concerning the anesthetic effect of magnesium ion. Two of the authors were the subjects and intravenous magnesium sulfate was administered at such a rate as to build the blood level up eventually to about 15 mEq. per liter. There was no loss of consciousness; these people were able to relate practically everything that happened. There was respiratory depression and there was a mild degree of apparent neuromuscular block in the form of weakness. It did very little to inhibit central nervous system activity other than cause respiratory depression. Therefore, with an inadvertent overdose of magnesium sulfate, an adequate airway and some means of mechanical ventilation are needed the same way as in the individual recovering from succinylcholine administration. I appreciate Dr. Zuspan’s comments emphasizing something brought out in the manuscript, that is, minimizing the use of other drugs and thereby keeping the regimen simple as well as effective and safe. Anesthesia for the past several years has consisted almost totally of pudendal block plus nitrous oxide and oxygen for vaginal delivery or a trace of Pentothal or Surital followed by nitrous oxide and oxygen plus succinylcholine for cesarean section.