- Email: [email protected]
Metabolic studies in eclampsia
Metabolic studies in eclampsia I. Nitrogen,
potassium,
FREDERICK
P.
SAMUEL Augusta,
M.
and sodium
ZUSPAN,
GOODRICH,
alterations
M.D. M.D.
Georgia
Methods
METABOLIC STUDIES duringnormal pregnancy have generally indicated positive nitrogen, sodium, and potassium balances antepartum and negative balances during the immediate postpartum period.‘> ‘1 3l 4l 5, 6, 7 Chesley, Valenti, and Uichanco’ studied normal patients post partum and did not find evidence for excessive hydration or excess exchangeable sodium. Other investigators have found water and sodium retention to be most marked in toxemia of pregnancy. 1. 9. 111.11 Subclinical malnutrition, as seen in lower socioeconomic groups, has been implicated as a major factor in the pathogenesis of toxemia.12 Recently, BrewerI has focused attention on the inability of the liver to detoxify normal products absorbed from the gastrointestinal tract in toxemic patients. Our objective has been to study the metabolic changes that occur in normal pregnancy, pre-eclampsia, and eclampsia. This report deals with the results of complete balance ward studies on 4 eclamptic patients.
From the Department Gynecology,
Medical
The eclamptic patients were admitted to the Clinical Investigation Unit (CIU : of the Eugene Talmadge Memorial Hospital and metabolic balances were begun as soon after the initial convulsion as was possible. All balance periods were 3 days except for the first periods of Patients K. B. and Z. K.: which were 4 days. The carefully controlled metabolic balance techniques used weiqhtd and analyzed diets. I4 Enough food for an individual study was purchased in one iarqc uniform lot to minimize variations in rritrogen and electrolyte content. A known high carbohydrate, high protein, low sodium diet was administered to each patient (Table Vj . Caloric values for protein, carbohydrate, and fat were calculated from standard tables by a nutritionist Accurate specimen collections were assured by constant supervision of patients with special personnel trained in balance ward stctdies. Each patient was weighed before breakfast on a Fairbanks Morris and Company balance scale which is sensitive to 10 qrams (0.0 1 kilogram) . Daily urine was collected as a 24 bout specimen and kept refrigerated. Stools wrrr collected and pooled to coincide with the 3 day balance cycle. Carmine dye was used to mark the end of the 3 day balance period. The diet, stools, urine, vomitus, and plate waste were analyzed for sodium and potassium by a flame photometer’” and for nitrogen by the micro-Kjeldahl method.16 All
of Obstetrics and College of Georgia.
Supported in part by Public Health Service Research Grant HD 00531-03 from the National Institutes of Child Health and Human Development, and Grant 03-I 120 from the National Institutes of Health. Presented at the Twenty-seventh Annual Meeting of the South Atlantic Association of Obstetricians and Gynecologists, Hot Springs, Virginia, Feb. 7-10, 1965. 357
358
Zuspan
and
Goodrich
urine samples were analyzed in duplicate. Three samples of diet, stool, vomitus, and plate waste from each period were analyzed in duplicate. The CIU is air-conditioned in the summer and centrally heated in the winter, affording essentially standardized temperature and humidity conditions in order to minimize loss of electrolytes and nitrogen in the sweat. Analysis of lochia and sweat were not performed. Graphic data will be presented in the customary fashion with intake graphed from the base line downward and output graphed from the bottom of the intake upward. Theoretical weight curves were calculated from the formulas of Reifenstein, Albright, and We1ls.l” Case reports Patient R. B., a 20-year-old, gravida iii, para ii Negro female at 36 weeks’ gestation noted the onset of visual disturbances, severe headaches and moderate edema 2 days before she had a grand ma1 seizure. The past history revealed an elevated blood pressure during 2 previous pregnancies. Pertinent physical findings were blood pressure of 160/100, hyperactive deep tendon
RR
9m 0
AVERAOE FOR
DAILY 3-DAY
and 2+ prctibial edema. Medical iuduction was begun on the last day of the iirst balance period and resulted in the delivery (If a 1,610 gram female infant (Apgar score IO). Balance studies were continued for an additional 21 days. The diagnosis was essential vascular hypertension with superimposed eclampsia. Data on nitrogen, potassium, and sodium balances and blood pressure and weight changes are given in Table I and Fig. IA. A positive nitrogen balance was observed for all postpartum study periods except study period II (the first 3 days post partum). Sixtynine gramsof nitrogen (3.3 Gm. per day) and 199 mEq. of potassium (9.5 mEq. per day) wrrr retained during the immediate 21 days post partum. The potassium:nitrogen ratio was 2.9: 1. A positive sodium balance was observed post partum totaling 418 mEq. of sodium (19.9 mEq. per day). A negative sodium balance occurred during the first study period (antepartum period) when the patient lost 175 mEq. of sodium. Fig. IB shows the actual and theoretical weight changes based on changes in nitrogen, sodium, and potassium balances and also changes in blood pressure during the study. A postpartum weight gain was observed in all study periods totaling 2.62 kilograms. A weight loss of 1.29 kilograms was observed in period I (antrpartum) in excess of that accounted for by the reflexes
EXCnLTIoN PERloo
72 60 46 36
150J ‘ta’a’~ ,‘A’ I i213’4’S’6’7’6 SODIUM
(mEq/day)
Fig. 1A. Graphic presentation of nitrogen, potassium, and sodium balances on Patient R. B. Intake is graphed from the base line downward and output from the bottom of the intake upward. Data above the base line indicates a negative balance and space below the base line, a positive balance.
Metabolic
Table I. Nitrogen, potassium, changes on Patient R. B.*
and sodium
studies
balances, blood pressure,
in eclampsia
and weight
-.I_--
_-._-.- _.
Pe7iod I II III IV V VI VII VIII *Each
study
144/106 136/100 140/106 150/106 125/90 120/80 120/90 120/90 was 3 days
+ 3.8 - 2.8 + 8.3 + 6.8 +13.6 t16.2 112.0 +15.3
-42.6 - 3.5 +45.1
-175.2 + 57.9 +135.9 - 768 + 27.9 + 36.0 + 70.8 f 12.9
+ 3.0
+24.0 t60.6 +35.7 131.8
in dwation.
RB 47 46
i
\ \
44 -;
I \ \ 43- ;
\
. ...’ 40 t
-E- iE-
I Study Period
t
AN AN‘?
AK Alheor. AActual
Wt. Wt.
to. 11 -1.17 -0.37 -1.43 -1.29’ ‘Actual
-0.08 to. 39 to.02 to.33 +o. 19 Wt. loss
+o. 24 to.85 +a. 17 +1.26 +o. 22 -4.26
Ip to. M to. 47 -0.10 +o. 57 +o. 56 kg. lPrcducts
P +o.40
“I”
+o. 11 -0.09 +O. 42 to. 27 of Conception
to.47 to. 15 +O. 11 +o. 73 +o. 73
Diir +o. 35 ‘0.41 +o. 02 +o. 78 to.43
I to.46 0.00 -0.07 +o. 39 +o. 22
- 2.97 kg. 1
Fig. 1B. Actual and theoretical weight curves and data based on changes in nitrogen, potassium, and sodium balances on Patient R. B. Blood pressure is graphically illustrated at the top.
359
360
Zuspan
and
Goodrich
products of conception. However, this loss can be accounted for by excretion of sodium and osmatically equivalent water. The theoretical weight curve is in close agreement with the actual weight curve. Patient Z. N., a 13-year-old, gravida i, para 0, Negro female at 40 weeks’ gestation noted the onset of edema and severe headaches 2 days before a grand ma1 seizure. Pertinent physical findings were blood pressure of 144/110, generalized edema, and hyperactive deep tendon reflexes. Labor was spontaneous and was augmented with oxytocin infusion resulting in the delivery of a live-born 2,965 gram male infant (Apgar score 10). Balance ward studies were
Table II. Nitrogen, changes
on Patient
potassium, Z. N.”
I
176,‘112
II III IV
V
116/68 124/70 120/70
blood
+296 - 12 + 18 + 12 + 21 + 60 + 48
pressure,
and
weight
-885.0 -112.5 + 98.4 +105.6 f 795 + 43.5 + 48.6
-5.05 -1.35 +0.24 +0.43 +0.54 to.58 to.37
l68o-8l6-
#ER@E DULY EXCRETION FOR 3-CMY mt(Xl
rl.. ,214’ I
balances,
study is 3 days in duration.
Z.N
om
sodium
+23.85 + 5.40 + 8.70 t 6.00 + 7.50 t15.90 +13.50
126/84 1'20/80 120/70
VI VII *Each
and
begun on the first postpartum day. The diagnosis was eclampsia. Data on nitrogen, potassium, and sodium balances and blood pressure and weight changes are given in Table II and Fig. 2A. Eighty gratns of nitrogen (3.9 Gm. per day) and 443 mEq. of potassium (21 mEq. per day) were retained during the entire postpartum study. The potassium:nitrogen ratio was 5.5 : 1. The major portion of potassium retained (+296 mEq.) was during the first study period. During the first 7 postpartum days (study periods I and II) 998 mEq. of sodium (143 mEq. per day) was excreted. A positive sodium balance of 376 mEq. (27 mEq. per day) was observed during the re-
’ ’ ’ ’ 234367 NITNOOEN (gnlrd)
Fig. 2A. Graphic Data above base balance.
’
’
presentation line indicate
24324045566472SO88SS104112120l28-
“I’W
,
‘11234567 POTASSWM of nitrogen, a negative
,
,
,
(mWvol.1
,
I234567
SODIUM (mEq/vol)
potassium, and sodium balances on Patient Z. N. balance and space below the base line a positive
Volumr Numhvr
Metabolic
95 3
studies in eclampsia
361
I80 I 125 loo 70 60
d 5
47
W
F 2 o 46 i
Study
Period
IrldmlmlnldnI
A.y ANa
AK ATheor. Ahk3i
Wt. Wt.
+0.70 -5.97 +I.61 -3.66 -5.05
to.16 -0.77 -0.18 -0.79 -1.35
to.25 +0.60 -0.03 +0.82 +0.24
to. 18 to.66 -0.03 +0.81 to.43
a.22 CO.48 0.00 +0.70 +0.54
to. 46 +0.2u +o. 11 +0.77 to.58
to.39 +0.25 +0.07 +0.71 to.37
Fig. 2B. Actual and theoretical weight curves and data based on changes in nitrogen, potassium. and sodium balances on Patient Z. N. Blood pressure is graphically illustrated at the top of the illustration. mainder of the study. Fig. ‘2B shows the actual and theoretical weight changes based on changes of nitrogen, sodium, and potassium balance and also changes in blood pressure during the study. The weight loss of 6.40 kilograms during the first 7 days of the puerperium is greater than the theoretical weight loss of 4.45 kilograms. This discrepancy of 1.95 kilograms can be accounted for by excretion of water in excess of electrolytes and is confirmed by an increase in serum sodium levels during this time. The return of blood pressure to normal coincides with major electrolyte and fluid changes. Patient P. K., a 17-year-old white female, gravida i, para 0, at 32 weeks’ gestation was hospitalized by hrr family physician for severe
pre-eclampsia. Shortly after admission she had three grand ma1 seizures and was referred to this hospital for definitive care. Pertinent physical findings were blood pressure 170/l 20, anasarc‘a, jaundice, and hyperactive deep tendon rcflcxcx Her past history revealed “kidney infections” and a one year history of “high blood pressurr.” Her father is known to have hypertension. Surgical and medical induction of labor resulted in delivery of a live-born male infant weighing 1,910 grams (Apgar score, 4). Balance ward studies were started on the serond postpartum day. The diagnosis was essential vasrular hypertension with superimposed eclampsia; abruptio placentae; hrpatocellular jaundice srcortdary to eclampsia. Data on nitrogrn, potassium, and sodiunl bal-
362
Zuspan
and
Goodrich
Table III. changes
Nitrogen, potassium, on Patient P. IL*
/ Blood
pressure
and
I-
sodium
balances,
yg2;Tj
blood
;gg
Pressure,
and weight
-y-Lj;;~-~;;~.,..
Period
I
218/120 164/96
II III IV V VI VII “Each
e!R.
study
-22.2 - 1.3 + 1.0 + 8.8 + 7.3 + 8.3 + 8.8
150/100 172/100 134/80 106/80 124/80 period
AVERAGE FOR
is 3 days
DAILY 3-DAY
in
-22.0 - 6.0 t14.0 +49.0 t38.0 +42.5 149.0
-5.62 -3.24 -2.60 -1.57 -0.99 +0.21 to.22
duration.
EXCRETION PERIOD
-- . . . I
NITROBEN
-535 0 -236.0 -324.0 -2 10.0 -169.0 - 14.0 + 30.5
(gm/vol)
266J5, 2 345 POTASSIUM
67 mEq/rol)
‘I
2
. 1 . ’ ’ 345 67 SODIUM hwd)
’
Fig. 3A. Graphic presentation of nitrogen, potassium, and sodium balances on Patient P. R. Data above base line indicate a negative balance and space below the base line a positive balance. antes and blood pressure and weight changes are given in Table III and Fig. 3A. A negative nitrogen balance was observed in the first two study periods (23.5 Gm. or 3.9 Gm. per day), however, during the remainder of the study a positive nitrogen balance of 34.2 Gm. (2.3 Gm. per day) was observed. A negative potassium balance of 28 mEq. was noted in the first two study periods; however, she was in positive balance through the remainder of the study retaining 193 mEq. of potassium. The potassium:nitrogen ratio was 5.6: 1. A negative sodium balance was observed throughout the
study (1,488 mEq. or 83 mEq. per day) except for the last study period when she retained 30.5 mEq. Fig. 3B shows the actual and theoretical weight changes based on nitrogen, sodium, and potassium balances and also changes in blood pressure during the study. The actual weight loss of 14.02 kilograms during the first 15 days post partum is grcatrr than the theoretical weight loss of 9.27 kilograms. This discrepancy again can be accounted for by excretion of water in excess of electrolytes which was confirmed by an increase in serum sodium levels during this observation period. The patient’s blood pressure
Metabolic
studies
in eclampsia
363
PR
81 80
sludy
Pabd
AN .ANB AK AlRaW. WI. AAdwlwt
-a65
1
-Fir 4.09
-3. a +a26 -3. a -5.62
-1.55 +.a 3.61 -3.24
Fig. 3B. Actual and theoretical sium, and sodium balances on top of the illustration.
weight Patient
+a03 -2.15 +a 07 -2.66 -260
Ip:
P
+a26 -1.43 +a17 -1. all -1.57
+an -1.15 +a 12 -an il.99
4.26
T
-0.13 +a 13 +a26 +aa 1
+a26 +a26 +a. 00 +a56 +a22
curves and data based on changes P. R. Blood pressure is graphically
returned to normal levels during the fifth period which is concomitant with the cessation of the weight loss due to sodium and water excretion. Patient R. F., a 20-year-old Negro female, gravida i, para 0 at 36 weeks’ gestation was refurred to this hospital 4 days following a grand ma1 srizurc. Prrtinent physical findings were
in nitrogen, illustrated
potasat the
blood pressure 170/130, l+ pretibial edema, and hyperactive derp tendon reflexes, Labor began spontaneously 6 days after admission and resulted in the delivery of a live-born male infant weighing 1,995 grams ( Apgar score 10). Balancc ward studies were begun on the tiny of delivery. The diagnosis was eclampsia.
364
Zuspan
and
Goodrich
Table IV. Nitrogen, changes
on Patient
potassium, B. F.”
and sodium
balances,
blood
pressure,
and weight
Balance Period
Blood
I II III IV V VI VII *Each study
pressure
Nitrogen (Cm.)
130/98 127/87 115/75 i27/80 125/87 110/77 ii9/85 period
is
3 days
+1.4 -0.6 -3.9 -0.7 +0.2 +o. 7 +5.8
Fig. 4A. Graphic Data above base balance.
Sodium Cm.%.)
-12.0 +23.0 +12.0 +47.0 +54.0 +12.0 +17.0
Weight
-195.9 + 27.0 + 10.0 + 6.0 + 34.0 + 24.0 + 29.0
changes (QT.)
-1.33 -0.62 -0.12 +0.06 1-0.26 +0.43 +0.13
in duration.
AVERA6E
NITROBEN
Potassium Cm-Q.)
DAILY
EXCRETION
tor3.W
PERlOO
(gm/voO presentation line indicate
SODIUM
of nitrogen, a negative
Data on nitrogen, potassium, and sodium balances and blood pressure and weight change are given in Table IV and Fig. 4A. This patient’s nitrogen balance was essentially in equilibrium during the study with a cumulative positive nitrogen balance of 2.9 Gm. A positive potassium balance of 153 mEq. was noted except in the first study period. A positive sodium balance for each period was observed during the study except for a negative balance of 196 mEq. in the first study period. Fig. 4B shows the actual and theoretical weight changes based on changes
(mEW’W
and sodium balances on Patient B. F. potassium, balance and space below the base line a positive
in nitrogen, sodium and potassium balance and also changes in blood pressure during the study. There is close agreement between the actual and theoretical weight changes during the study. The patient’s blood pressure returned to normal during the second period concomitantly with the cessation of the negative sodium balance.
Comment A positive in
the
first
nitrogen
3 patients
balance
was
and nitrogen
observed
balance
Metabolic
studies
in
eclampsia
365
BF BP 130 110 so
o*---1-0 . n-,-m-,.
Actual A N
x-x
AN&No
. “.,,,,,o.,,,.,,. A N,No,
Wt. Change
K
47 t
-Studb
Period
I
A\ AU AK ATheOr.
i’.t.
aActual
i’.!
i
J
1 -0.04
It
m7G
-0.02
-0.12
-0.02
-1.30 -0.11 -1.37 -1.33
*o. 18 -0.17 +0.33 -0.62
to.08 +o. 15 +o. 12 -0.12
to. 04 to.34 +O. 36 +o. ob
XI
PT
+o. 01 +o. 22 +o. 37 to.60 +O. 26
to. 02 +o. 15 to. 07 +O. 24 to.43
to. 17 +o. 16 t0.00 to. 34 +o. 13
Fig. 4B. Actual and theoretical weight curves and data based on changes in nitrogen, potassium, and sodium balances on Patient B. F. Blood pressure is xraphirally illustrated at the top of the illustration.
Table V.
Laboratory
analysis
and
caloric
content
equilibrium in the last patient (Table VI). Two, Patients IL B., and Z. N., had an anabolic response as great as others have reported for the antepartum period in normal pregnancy.".*- n, ?' Other investigators studying normal pregnant patients have observed
of diet
a negative nitrogen balance for as long as 2 weeks in the postpartum period.“. “. Ii These studies are in agreement with our obser\,ations on normal pregnant patients.” The potassium: nitrogen ratio in normal muscle is 3: l*!’ and was present in one lra-
366
Zuspan
and
Goodrich
K: N RATIO POSTPARTUM
R B.
luortnal
Muscle Fig. total
5. Potassium:nitrogen postpartum period
Table VI. 4 eclamptic
of
each
balance
nitrogen
patient.
on
patients* Nitrogen balance (Cm.)
Metabolic period
B. F.
I II III IV V VI VII Total “All
Summary
ratio on of 21 days.
patients
/
2’. R.
/
Z. N.
+1.4 -0.6 -3.9 -0.7 +0.2 to.7 +6 8
-22.2 - 1.3 + 1.0 + 8.8 + 7.3 + 8.3 + 8.8
+23.9 + 5.4 + 8.7 + 6.0 + 7.5 t15.9 +13.5
+2.9
+10.7
+80.9
had
a net
total
positivr
nitroqen
1 R. B. - 2.8 + a3 + 6.8 +13.6 +16.2 +12 0 +15.3 t69.4 halanw.
tient (R. B., 2.87 : 1) . The remaining patients had higher ratios indicating an excessive retention of potassium in proportion to nitrogen. This probably represents an intracellular deficit of potassium. The exchange of sodium for potassium within the cell could account for vascular hypersensitivity since the blood pressure returned to normal concomitant with a positive electrolyte balance in these patients (Fig. 5). Two of the patients, Z. N., and P. R., had large weight losses post partum due to electrolyte and fluid losses. Their blood pressure returned to normal coincidental with the cessation of these losses. One patient, R. R.,
5.5: I
5.6: I
ZN
F’.R.
Time
period
for
B.lF
calculations
extends
over
lost the least amount of actual weight and sodium post partum. The fact that Patient B. F. did not lose amounts of sodium and water comparable to Patients P. R., and Z. N. may be related to diuretic therapy before admission to this hospital. Summary
1. Complete metabolic studies were done on 4 eclamptic patients for 21 days post partum. 2. All patients had a positive nitrogen balance post partum. 3. Potassium : nitrogen ratios were higher than in muscle indicating an excessive retention of potassium in proportion to nitrogen. This may represent an intracellular deficit of potassium. 4. The blood pressure return-d to normal coincidentally with the cessation of electrolyte and fluid losses. 5. The nitrogen retention observed during the postpartum period reflects the recovery from
the
catabolic
effect
of toxemia.
We would like to express our appreciation to Dr. Charles Bragassa, Director of the Computer Center at the Medical College of Georgia, for assistance in tabulation of these data. We would especially like to thank all the personnel in the Clinical Investigation Unit for making such a study possible.
Metabolic
studies
in eclampsia
267
REFERENCES
W. J,, and Pottinger, R. E.: AM. 1. Difckmann, J. OBST. & GYNEC. 70: 822, 1955. 2. Gray, M. J., and Plentl, A.A.: J. Clin. Invest. 33: 347, 1954. 3 Hunscher. H. A.. Donelson, E., Nims, B., Kenyon. F. and Macy J, G.: J. Biol. Chem. 99: 507, 1933. H. E. and Pommerenke W. T., 4. Thompson Jr.: J. Nutrition 17: 383, 1939. E. H., Dyrenfurth, I., Lowenstein, 5. Venning, I,.. and Beck, J.: J. Clin. Endocrinol. 1% 403. 1959. 6. Wilson, K. M.: Bull. Johns Hopkins Hosp. 27: 121. 1916. 7. Barnes. A. C., and Buckingham, J. C.: ANI. J. OXST. & Gvsec. 76: 955, 1958. L. C., Valenti, C., and Uichanco, 8. Chesley, L.: AIM. 1. OBST. & GYNEC. 77: 1054. 1959. C., Moore, D. B., and 9. Larnbiottz-Escoffier. Taylor. H. C.. Jr.: AM. J. OBST. & GYNEC. 66: 18, 1953. 10. Plentl, A. A.. and Gray, M. J.: AXI. J. Oll:T. & Gus~c. 78: 472, 1959.
Discussion 1)~. \Y.ZI:I.EK B. CHERN'I., Durham, North Carolina. Only those who have attempted to conduct metabolic balance studies in pregnant patirrlts c.an fully apprrciate the difficulties and tril)ulations that thtt authors must have encountc,red in completing this and other related invcstiaations. The techniques ustd must be planned with exacting precision, and carried out with painstaking and calculated efficiency. 34uch of the data thus far published as a rcwlc of halance stud& in toxemic patients has t’oinc prirn:lrily from prt,-eclamptic patients or from patit=nts who have benign hypertensive dis<‘ahe. In comparison, there is a paucity of inforniation available about eclampsia. It may not n~~,.essarily 1,~ true that the erlamptic state is riic~rr~l! an caxagg-cration, a more serious compIi,-ation, of a prcbccding metabolic disturbance. It ma) vc*ry well 1~1 that metabolic changes in cc,iampsia are strikingly different from those of pry.-t~c~lnmpsi;t. LII the antcpartum state, in pre-eclampsia, rsi‘(‘s% loss of nitrogen has been noted. This led to thr, conclusion that thert is maternal protein calaholism despite. the fact that the products of conct>lltion c.ontinut> to assimilate protein in utero to term. It would srcm logical, therefore, that followin.q dclivrry, a rc~v~~rsal of this phrnomcncln should oc(‘ur and positive nitrogen balancrn sh~)uld lIecome apparent. We have just seen in thta foregoing presentation that this is probably tlltc iI1 c~clampuia. Dieckmann” also found this
11. 12.
13. 14. 15.
16. 17.
18. 19.
in
Dnvey, D. A., and O’Sullivan, W. J.: 1’:) th et microbial. 24: 642: 1961. Burke. B. S.. Beal. V. A.. Kirkwood. S. 8. and Stuart: H. C.: A~I. J. 0~s~. B C:\.\-tx:. 46: 38, 1943. Brewer. T. H.: AM. .I. OHST. 8 GYSEC:. 84: 1253, 1962. Rcifenstein, E. C.. Albright, F., and M’~,lls. S. L.: Clin. Endocrinol. 5: 367, 19f-5. Flame Photometer Instruction Manual ( Morlel KY-1 1 Baird-Atomic. Inc.. 33 Univrr?it\Road. Cambridge 38, Massachusetts, Jat1 5, 1962. Millrr, L., and Houghton, J. .\.: J. I:illl. Chem. 159: 373, 1945. Hunscher. H. .4.. Hummell, F. C.: Eric-kion. B. N., and Mary, I. G.: J. Nutritioll 10: 579, 1935. Zuspan. F. P., and Goodrich. S. M.: 1:rtlj!il)lished data. Moore. F. D.: Metabolic care of the surgical patirnt, Philadelphia and London. 1959. M’. B. Saunders Company, p. 34.
a paricnt b-ho had cclampsia. How(‘v(‘t. in i,! prp-rclampsia tht patients rc~port~~d up011 Dicckmann had nqative nitrogen balances pcsst partum in most instancrs. Barnes and Huchinpham1 have shown positivt balances for nitrtlgS.cn and potassium in th(t normal put~rpe~al pa~~vrlt. But at the sam(’ time thertl appcaars to 1~7 ;I negative balance for sodium. In fact, thcl(b is common supposition that any shift in sotliutn balancc~ is mually oppositcx to ihat OF pot,~\~,illl~l and nitrng~n. Undeniably. thtl toxtmic. paticsnt’s ahilic I to move
368
Zuspan
and
Goodrich
state as evidenced by significant pressure and increases of proteinuria.
risrs
of
blood
REFERENCES
Barnes, A. C., and Buckingham, J. C.: Electrolyte balance studies with the anti-hormones, AM. J. OBST. & GYNEC. 76: 955, 1958. Dieckmann, W. J.: Toxemias of pregnancy, A Ciba Foundation Symposium, London, 1950, J. & A. Churchill, Ltd. Dieckmann, W. J., and Pottinger, R. E.: Etiology of pre-eclampsia-eclampsia, AM. J. OBST. & GVNEC. 70: 822, 1955. DR. E. J. DENNIS, Charleston, South Carolina. Such studies as reported here lend credence to the hypothesis that toxemia of pregnancy represents a profound pathophysiologic change involving multiple body systems in a complex series of humoral, enzymatic, and anatomical alterations. It would tend to detract from the concept of a single noxious etiologic agent produced in the placenta or decidua unless such substance was indeed unique in precipitating or producing such profound and widespread changes as those alluded to above The retention of potassium suggesting an intracellular deficit of this ion is intriguing. Venningr has shown that the excretion of aldosterone in pre-eclampsia is lower than that in normal pregnant women. Kumar and others? have shown that this lowered excretion in pre-erlampsia is due to a diminished secretion of the hormone. of aldosterone is that it One of the actions seems to enhance the rate of active sodium extrusion from all cells in the body. Normal pregnant women have been shown to have a low intracellular sodium content and high intracellular sodium content and high aldosterone production. Conversely, patients with toxemia have high intracellular sodium content and low aldosterone production. In the 4 cases here prcsented, blood pressure levels returned to normal coincidental and fluid losses, compartmental pathophysiologic toward normal.
with the cessation of electrolyte stuggesting that once electrolyte homeostasis is achieved, the alterations of toxemia revert
REFERENCES
1. 2.
Venning. E. H., et al,: J. Clin. Endocrinol. 473, 1957. Kumar, D., et al.: Lancet 1: 541. 1959.
17:
DR. R. GORDON DOUGLAS, New York, New York. Balance studies are difficult to interpret, particularly if balance is not achieved (as is the case in the studies reported in the paper by
Zuspan and Goodrich). Balance studies clonic following delivery are also difficult to interpret with respect to the etiology of eclampsia since one does not know if the metabolic changes observed during the recovery period are occurring because of alterations or deficiencies causing the disease, caused by the disease or secondary to the disease. With respect to this paper, any patient whose intake of protein and potassium dccreases (as might happen in patients who drvelop toxemia) actually goes into negative nitrogen balance when the intake of nitrogen and potassium falls below the losses of these elrments. For example, a patient on parenteral fluids is in negative nitrogen balance if she does not receive adequate protein and is in negative potassium balance if she does not receive adequate potassium. Bearing in mind these reservations, these studies are of interest and certainly add to our knowledge of the metabolic effects of cclampjia and add quantitative data on the order of magnitude of nitrogen, potassium, and sodium dcfitits which can develop in eclampsia. Of interest and supporting the data presented are some studies carried out at The New York Lying-In Hospital by Dr. Bonsnes some years ago. In his Annual Report on Eclampsia Research for 1952 he wrote on his Electrolyte Studies as follows: “Last year we reported on the blood serum values for sodium, potassium, chloride, and total bicarbonate in patients with mild and severe pre-eclampsia and on the sodium and potassium excretion of patients with severe pre-eclampsia and eclampsia. These studies have been extended this year. The studies of the excretion of these substances seemed to lead to no usable data unless thr intakes of these substances were also known. “To obtain an accurate record of the intake of patients requires a metabolism ward. Lacking this, we have achieved what may be called a first order estimate. through the active COoperation of Miss Kellerman of the Nutrition Department of The New York Hospital. She calculates, from tables, the approximate amount of sodium and potassium in the food ingested by the patient being studied. We determine the amount excreted in the urine. Using the procedure WC have carried out sodium and potassium balance studies in 4 patients with severe pre-eclampsia and in 3 patients with diabetes who were also pregnant. The incidrncc of toxemia of pregnancy in such patients is high.
Metabolic
“The patients with toxemia were studied from th(a time they were hospitalized, acutely ill, up to the timcl of delivery (which usually occurs a few days after they are admitted to the hospital then through the time of the early pucrperium. usually 7 to 8 days following delivery. Thcsc patients all had negative sodium and potassium balances while maintained only on intmvc>nous fluids while they were acutely ill, 4niply hecause they had no intake of either sodium or potassium. During the early puerpa-ium. i.r., during recovery, they all continued to have, nrgativc sodium balances for about 5 to 6 days. Aftcsr this time they appear to be more or 1~ in balance with respect to sodium. Rut th(,y wcrt~ all retaining potassium up to the time t1tc.y were discharged from the hospital. One p:lGent whom WC were able to follow longer than the other 3 (for some 15 days following drlivery) qPc&rned to be retaining potassium still 15 days post partum when the last observations M’I’I-c mndr, but seemed to have achieved equi1if)rium with respect to sodium at the sixth postp:\rtum d:Ly. ““These observations are consonant with the JXIX’aiJing concept of sodium retention during the toxtmias of pregnancy. They further sug-
studies in eclampsia
369
gest that there might bc an associated pota+ium deficiency. “Sodium and potassium balances w~rr also obtained on 3 diabetic patients. These wrr(‘ ‘8 to 35 weeks pregnant. Sodium and potas:;ium balances were estimated for 49, 44, and 18 dayi; before thes:, patients delivered. Ha1ancc.s K(YY~ obtained on 2 for 5 and 6 days post partum iZll 3 retained potassium and lost sodium ovl,r-all while observed during the antepartum C~OIII’SP. These data suggest again a sodium rrtcntic,n in pregnancy with a possihlc potassium dt+cie,nry. What happens in a normal pregnant ~~om~‘n at these times remains to be determined.” Only in recent years have facilitirs bctn ;.vailable at The New York Hospital which has ~~~ad~~ it possible to determine what happens dalrirtg normal pregnancy. Up to the present tinlr metabolic studies on 3 normal pregnant ~:VI,CYI have been carried out: one having balance, studits for 38, another 88, and the third fat 11’3 days beforca delivery. When the evaluation ( f the data collected on these women is compit,t(d, there will be a basr for comparing data collected from those having toxemia. It is caxpcxctt,d our data will confirm in essence that of %~lsp;m and Goodrich.
potassium,
FREDERICK
P.
SAMUEL Augusta,
M.
and sodium
ZUSPAN,
GOODRICH,
alterations
M.D. M.D.
Georgia
Methods
METABOLIC STUDIES duringnormal pregnancy have generally indicated positive nitrogen, sodium, and potassium balances antepartum and negative balances during the immediate postpartum period.‘> ‘1 3l 4l 5, 6, 7 Chesley, Valenti, and Uichanco’ studied normal patients post partum and did not find evidence for excessive hydration or excess exchangeable sodium. Other investigators have found water and sodium retention to be most marked in toxemia of pregnancy. 1. 9. 111.11 Subclinical malnutrition, as seen in lower socioeconomic groups, has been implicated as a major factor in the pathogenesis of toxemia.12 Recently, BrewerI has focused attention on the inability of the liver to detoxify normal products absorbed from the gastrointestinal tract in toxemic patients. Our objective has been to study the metabolic changes that occur in normal pregnancy, pre-eclampsia, and eclampsia. This report deals with the results of complete balance ward studies on 4 eclamptic patients.
From the Department Gynecology,
Medical
The eclamptic patients were admitted to the Clinical Investigation Unit (CIU : of the Eugene Talmadge Memorial Hospital and metabolic balances were begun as soon after the initial convulsion as was possible. All balance periods were 3 days except for the first periods of Patients K. B. and Z. K.: which were 4 days. The carefully controlled metabolic balance techniques used weiqhtd and analyzed diets. I4 Enough food for an individual study was purchased in one iarqc uniform lot to minimize variations in rritrogen and electrolyte content. A known high carbohydrate, high protein, low sodium diet was administered to each patient (Table Vj . Caloric values for protein, carbohydrate, and fat were calculated from standard tables by a nutritionist Accurate specimen collections were assured by constant supervision of patients with special personnel trained in balance ward stctdies. Each patient was weighed before breakfast on a Fairbanks Morris and Company balance scale which is sensitive to 10 qrams (0.0 1 kilogram) . Daily urine was collected as a 24 bout specimen and kept refrigerated. Stools wrrr collected and pooled to coincide with the 3 day balance cycle. Carmine dye was used to mark the end of the 3 day balance period. The diet, stools, urine, vomitus, and plate waste were analyzed for sodium and potassium by a flame photometer’” and for nitrogen by the micro-Kjeldahl method.16 All
of Obstetrics and College of Georgia.
Supported in part by Public Health Service Research Grant HD 00531-03 from the National Institutes of Child Health and Human Development, and Grant 03-I 120 from the National Institutes of Health. Presented at the Twenty-seventh Annual Meeting of the South Atlantic Association of Obstetricians and Gynecologists, Hot Springs, Virginia, Feb. 7-10, 1965. 357
358
Zuspan
and
Goodrich
urine samples were analyzed in duplicate. Three samples of diet, stool, vomitus, and plate waste from each period were analyzed in duplicate. The CIU is air-conditioned in the summer and centrally heated in the winter, affording essentially standardized temperature and humidity conditions in order to minimize loss of electrolytes and nitrogen in the sweat. Analysis of lochia and sweat were not performed. Graphic data will be presented in the customary fashion with intake graphed from the base line downward and output graphed from the bottom of the intake upward. Theoretical weight curves were calculated from the formulas of Reifenstein, Albright, and We1ls.l” Case reports Patient R. B., a 20-year-old, gravida iii, para ii Negro female at 36 weeks’ gestation noted the onset of visual disturbances, severe headaches and moderate edema 2 days before she had a grand ma1 seizure. The past history revealed an elevated blood pressure during 2 previous pregnancies. Pertinent physical findings were blood pressure of 160/100, hyperactive deep tendon
RR
9m 0
AVERAOE FOR
DAILY 3-DAY
and 2+ prctibial edema. Medical iuduction was begun on the last day of the iirst balance period and resulted in the delivery (If a 1,610 gram female infant (Apgar score IO). Balance studies were continued for an additional 21 days. The diagnosis was essential vascular hypertension with superimposed eclampsia. Data on nitrogen, potassium, and sodium balances and blood pressure and weight changes are given in Table I and Fig. IA. A positive nitrogen balance was observed for all postpartum study periods except study period II (the first 3 days post partum). Sixtynine gramsof nitrogen (3.3 Gm. per day) and 199 mEq. of potassium (9.5 mEq. per day) wrrr retained during the immediate 21 days post partum. The potassium:nitrogen ratio was 2.9: 1. A positive sodium balance was observed post partum totaling 418 mEq. of sodium (19.9 mEq. per day). A negative sodium balance occurred during the first study period (antepartum period) when the patient lost 175 mEq. of sodium. Fig. IB shows the actual and theoretical weight changes based on changes in nitrogen, sodium, and potassium balances and also changes in blood pressure during the study. A postpartum weight gain was observed in all study periods totaling 2.62 kilograms. A weight loss of 1.29 kilograms was observed in period I (antrpartum) in excess of that accounted for by the reflexes
EXCnLTIoN PERloo
72 60 46 36
150J ‘ta’a’~ ,‘A’ I i213’4’S’6’7’6 SODIUM
(mEq/day)
Fig. 1A. Graphic presentation of nitrogen, potassium, and sodium balances on Patient R. B. Intake is graphed from the base line downward and output from the bottom of the intake upward. Data above the base line indicates a negative balance and space below the base line, a positive balance.
Metabolic
Table I. Nitrogen, potassium, changes on Patient R. B.*
and sodium
studies
balances, blood pressure,
in eclampsia
and weight
-.I_--
_-._-.- _.
Pe7iod I II III IV V VI VII VIII *Each
study
144/106 136/100 140/106 150/106 125/90 120/80 120/90 120/90 was 3 days
+ 3.8 - 2.8 + 8.3 + 6.8 +13.6 t16.2 112.0 +15.3
-42.6 - 3.5 +45.1
-175.2 + 57.9 +135.9 - 768 + 27.9 + 36.0 + 70.8 f 12.9
+ 3.0
+24.0 t60.6 +35.7 131.8
in dwation.
RB 47 46
i
\ \
44 -;
I \ \ 43- ;
\
. ...’ 40 t
-E- iE-
I Study Period
t
AN AN‘?
AK Alheor. AActual
Wt. Wt.
to. 11 -1.17 -0.37 -1.43 -1.29’ ‘Actual
-0.08 to. 39 to.02 to.33 +o. 19 Wt. loss
+o. 24 to.85 +a. 17 +1.26 +o. 22 -4.26
Ip to. M to. 47 -0.10 +o. 57 +o. 56 kg. lPrcducts
P +o.40
“I”
+o. 11 -0.09 +O. 42 to. 27 of Conception
to.47 to. 15 +O. 11 +o. 73 +o. 73
Diir +o. 35 ‘0.41 +o. 02 +o. 78 to.43
I to.46 0.00 -0.07 +o. 39 +o. 22
- 2.97 kg. 1
Fig. 1B. Actual and theoretical weight curves and data based on changes in nitrogen, potassium, and sodium balances on Patient R. B. Blood pressure is graphically illustrated at the top.
359
360
Zuspan
and
Goodrich
products of conception. However, this loss can be accounted for by excretion of sodium and osmatically equivalent water. The theoretical weight curve is in close agreement with the actual weight curve. Patient Z. N., a 13-year-old, gravida i, para 0, Negro female at 40 weeks’ gestation noted the onset of edema and severe headaches 2 days before a grand ma1 seizure. Pertinent physical findings were blood pressure of 144/110, generalized edema, and hyperactive deep tendon reflexes. Labor was spontaneous and was augmented with oxytocin infusion resulting in the delivery of a live-born 2,965 gram male infant (Apgar score 10). Balance ward studies were
Table II. Nitrogen, changes
on Patient
potassium, Z. N.”
I
176,‘112
II III IV
V
116/68 124/70 120/70
blood
+296 - 12 + 18 + 12 + 21 + 60 + 48
pressure,
and
weight
-885.0 -112.5 + 98.4 +105.6 f 795 + 43.5 + 48.6
-5.05 -1.35 +0.24 +0.43 +0.54 to.58 to.37
l68o-8l6-
#ER@E DULY EXCRETION FOR 3-CMY mt(Xl
rl.. ,214’ I
balances,
study is 3 days in duration.
Z.N
om
sodium
+23.85 + 5.40 + 8.70 t 6.00 + 7.50 t15.90 +13.50
126/84 1'20/80 120/70
VI VII *Each
and
begun on the first postpartum day. The diagnosis was eclampsia. Data on nitrogen, potassium, and sodium balances and blood pressure and weight changes are given in Table II and Fig. 2A. Eighty gratns of nitrogen (3.9 Gm. per day) and 443 mEq. of potassium (21 mEq. per day) were retained during the entire postpartum study. The potassium:nitrogen ratio was 5.5 : 1. The major portion of potassium retained (+296 mEq.) was during the first study period. During the first 7 postpartum days (study periods I and II) 998 mEq. of sodium (143 mEq. per day) was excreted. A positive sodium balance of 376 mEq. (27 mEq. per day) was observed during the re-
’ ’ ’ ’ 234367 NITNOOEN (gnlrd)
Fig. 2A. Graphic Data above base balance.
’
’
presentation line indicate
24324045566472SO88SS104112120l28-
“I’W
,
‘11234567 POTASSWM of nitrogen, a negative
,
,
,
(mWvol.1
,
I234567
SODIUM (mEq/vol)
potassium, and sodium balances on Patient Z. N. balance and space below the base line a positive
Volumr Numhvr
Metabolic
95 3
studies in eclampsia
361
I80 I 125 loo 70 60
d 5
47
W
F 2 o 46 i
Study
Period
IrldmlmlnldnI
A.y ANa
AK ATheor. Ahk3i
Wt. Wt.
+0.70 -5.97 +I.61 -3.66 -5.05
to.16 -0.77 -0.18 -0.79 -1.35
to.25 +0.60 -0.03 +0.82 +0.24
to. 18 to.66 -0.03 +0.81 to.43
a.22 CO.48 0.00 +0.70 +0.54
to. 46 +0.2u +o. 11 +0.77 to.58
to.39 +0.25 +0.07 +0.71 to.37
Fig. 2B. Actual and theoretical weight curves and data based on changes in nitrogen, potassium. and sodium balances on Patient Z. N. Blood pressure is graphically illustrated at the top of the illustration. mainder of the study. Fig. ‘2B shows the actual and theoretical weight changes based on changes of nitrogen, sodium, and potassium balance and also changes in blood pressure during the study. The weight loss of 6.40 kilograms during the first 7 days of the puerperium is greater than the theoretical weight loss of 4.45 kilograms. This discrepancy of 1.95 kilograms can be accounted for by excretion of water in excess of electrolytes and is confirmed by an increase in serum sodium levels during this time. The return of blood pressure to normal coincides with major electrolyte and fluid changes. Patient P. K., a 17-year-old white female, gravida i, para 0, at 32 weeks’ gestation was hospitalized by hrr family physician for severe
pre-eclampsia. Shortly after admission she had three grand ma1 seizures and was referred to this hospital for definitive care. Pertinent physical findings were blood pressure 170/l 20, anasarc‘a, jaundice, and hyperactive deep tendon rcflcxcx Her past history revealed “kidney infections” and a one year history of “high blood pressurr.” Her father is known to have hypertension. Surgical and medical induction of labor resulted in delivery of a live-born male infant weighing 1,910 grams (Apgar score, 4). Balance ward studies were started on the serond postpartum day. The diagnosis was essential vasrular hypertension with superimposed eclampsia; abruptio placentae; hrpatocellular jaundice srcortdary to eclampsia. Data on nitrogrn, potassium, and sodiunl bal-
362
Zuspan
and
Goodrich
Table III. changes
Nitrogen, potassium, on Patient P. IL*
/ Blood
pressure
and
I-
sodium
balances,
yg2;Tj
blood
;gg
Pressure,
and weight
-y-Lj;;~-~;;~.,..
Period
I
218/120 164/96
II III IV V VI VII “Each
e!R.
study
-22.2 - 1.3 + 1.0 + 8.8 + 7.3 + 8.3 + 8.8
150/100 172/100 134/80 106/80 124/80 period
AVERAGE FOR
is 3 days
DAILY 3-DAY
in
-22.0 - 6.0 t14.0 +49.0 t38.0 +42.5 149.0
-5.62 -3.24 -2.60 -1.57 -0.99 +0.21 to.22
duration.
EXCRETION PERIOD
-- . . . I
NITROBEN
-535 0 -236.0 -324.0 -2 10.0 -169.0 - 14.0 + 30.5
(gm/vol)
266J5, 2 345 POTASSIUM
67 mEq/rol)
‘I
2
. 1 . ’ ’ 345 67 SODIUM hwd)
’
Fig. 3A. Graphic presentation of nitrogen, potassium, and sodium balances on Patient P. R. Data above base line indicate a negative balance and space below the base line a positive balance. antes and blood pressure and weight changes are given in Table III and Fig. 3A. A negative nitrogen balance was observed in the first two study periods (23.5 Gm. or 3.9 Gm. per day), however, during the remainder of the study a positive nitrogen balance of 34.2 Gm. (2.3 Gm. per day) was observed. A negative potassium balance of 28 mEq. was noted in the first two study periods; however, she was in positive balance through the remainder of the study retaining 193 mEq. of potassium. The potassium:nitrogen ratio was 5.6: 1. A negative sodium balance was observed throughout the
study (1,488 mEq. or 83 mEq. per day) except for the last study period when she retained 30.5 mEq. Fig. 3B shows the actual and theoretical weight changes based on nitrogen, sodium, and potassium balances and also changes in blood pressure during the study. The actual weight loss of 14.02 kilograms during the first 15 days post partum is grcatrr than the theoretical weight loss of 9.27 kilograms. This discrepancy again can be accounted for by excretion of water in excess of electrolytes which was confirmed by an increase in serum sodium levels during this observation period. The patient’s blood pressure
Metabolic
studies
in eclampsia
363
PR
81 80
sludy
Pabd
AN .ANB AK AlRaW. WI. AAdwlwt
-a65
1
-Fir 4.09
-3. a +a26 -3. a -5.62
-1.55 +.a 3.61 -3.24
Fig. 3B. Actual and theoretical sium, and sodium balances on top of the illustration.
weight Patient
+a03 -2.15 +a 07 -2.66 -260
Ip:
P
+a26 -1.43 +a17 -1. all -1.57
+an -1.15 +a 12 -an il.99
4.26
T
-0.13 +a 13 +a26 +aa 1
+a26 +a26 +a. 00 +a56 +a22
curves and data based on changes P. R. Blood pressure is graphically
returned to normal levels during the fifth period which is concomitant with the cessation of the weight loss due to sodium and water excretion. Patient R. F., a 20-year-old Negro female, gravida i, para 0 at 36 weeks’ gestation was refurred to this hospital 4 days following a grand ma1 srizurc. Prrtinent physical findings were
in nitrogen, illustrated
potasat the
blood pressure 170/130, l+ pretibial edema, and hyperactive derp tendon reflexes, Labor began spontaneously 6 days after admission and resulted in the delivery of a live-born male infant weighing 1,995 grams ( Apgar score 10). Balancc ward studies were begun on the tiny of delivery. The diagnosis was eclampsia.
364
Zuspan
and
Goodrich
Table IV. Nitrogen, changes
on Patient
potassium, B. F.”
and sodium
balances,
blood
pressure,
and weight
Balance Period
Blood
I II III IV V VI VII *Each study
pressure
Nitrogen (Cm.)
130/98 127/87 115/75 i27/80 125/87 110/77 ii9/85 period
is
3 days
+1.4 -0.6 -3.9 -0.7 +0.2 +o. 7 +5.8
Fig. 4A. Graphic Data above base balance.
Sodium Cm.%.)
-12.0 +23.0 +12.0 +47.0 +54.0 +12.0 +17.0
Weight
-195.9 + 27.0 + 10.0 + 6.0 + 34.0 + 24.0 + 29.0
changes (QT.)
-1.33 -0.62 -0.12 +0.06 1-0.26 +0.43 +0.13
in duration.
AVERA6E
NITROBEN
Potassium Cm-Q.)
DAILY
EXCRETION
tor3.W
PERlOO
(gm/voO presentation line indicate
SODIUM
of nitrogen, a negative
Data on nitrogen, potassium, and sodium balances and blood pressure and weight change are given in Table IV and Fig. 4A. This patient’s nitrogen balance was essentially in equilibrium during the study with a cumulative positive nitrogen balance of 2.9 Gm. A positive potassium balance of 153 mEq. was noted except in the first study period. A positive sodium balance for each period was observed during the study except for a negative balance of 196 mEq. in the first study period. Fig. 4B shows the actual and theoretical weight changes based on changes
(mEW’W
and sodium balances on Patient B. F. potassium, balance and space below the base line a positive
in nitrogen, sodium and potassium balance and also changes in blood pressure during the study. There is close agreement between the actual and theoretical weight changes during the study. The patient’s blood pressure returned to normal during the second period concomitantly with the cessation of the negative sodium balance.
Comment A positive in
the
first
nitrogen
3 patients
balance
was
and nitrogen
observed
balance
Metabolic
studies
in
eclampsia
365
BF BP 130 110 so
o*---1-0 . n-,-m-,.
Actual A N
x-x
AN&No
. “.,,,,,o.,,,.,,. A N,No,
Wt. Change
K
47 t
-Studb
Period
I
A\ AU AK ATheOr.
i’.t.
aActual
i’.!
i
J
1 -0.04
It
m7G
-0.02
-0.12
-0.02
-1.30 -0.11 -1.37 -1.33
*o. 18 -0.17 +0.33 -0.62
to.08 +o. 15 +o. 12 -0.12
to. 04 to.34 +O. 36 +o. ob
XI
PT
+o. 01 +o. 22 +o. 37 to.60 +O. 26
to. 02 +o. 15 to. 07 +O. 24 to.43
to. 17 +o. 16 t0.00 to. 34 +o. 13
Fig. 4B. Actual and theoretical weight curves and data based on changes in nitrogen, potassium, and sodium balances on Patient B. F. Blood pressure is xraphirally illustrated at the top of the illustration.
Table V.
Laboratory
analysis
and
caloric
content
equilibrium in the last patient (Table VI). Two, Patients IL B., and Z. N., had an anabolic response as great as others have reported for the antepartum period in normal pregnancy.".*- n, ?' Other investigators studying normal pregnant patients have observed
of diet
a negative nitrogen balance for as long as 2 weeks in the postpartum period.“. “. Ii These studies are in agreement with our obser\,ations on normal pregnant patients.” The potassium: nitrogen ratio in normal muscle is 3: l*!’ and was present in one lra-
366
Zuspan
and
Goodrich
K: N RATIO POSTPARTUM
R B.
luortnal
Muscle Fig. total
5. Potassium:nitrogen postpartum period
Table VI. 4 eclamptic
of
each
balance
nitrogen
patient.
on
patients* Nitrogen balance (Cm.)
Metabolic period
B. F.
I II III IV V VI VII Total “All
Summary
ratio on of 21 days.
patients
/
2’. R.
/
Z. N.
+1.4 -0.6 -3.9 -0.7 +0.2 to.7 +6 8
-22.2 - 1.3 + 1.0 + 8.8 + 7.3 + 8.3 + 8.8
+23.9 + 5.4 + 8.7 + 6.0 + 7.5 t15.9 +13.5
+2.9
+10.7
+80.9
had
a net
total
positivr
nitroqen
1 R. B. - 2.8 + a3 + 6.8 +13.6 +16.2 +12 0 +15.3 t69.4 halanw.
tient (R. B., 2.87 : 1) . The remaining patients had higher ratios indicating an excessive retention of potassium in proportion to nitrogen. This probably represents an intracellular deficit of potassium. The exchange of sodium for potassium within the cell could account for vascular hypersensitivity since the blood pressure returned to normal concomitant with a positive electrolyte balance in these patients (Fig. 5). Two of the patients, Z. N., and P. R., had large weight losses post partum due to electrolyte and fluid losses. Their blood pressure returned to normal coincidental with the cessation of these losses. One patient, R. R.,
5.5: I
5.6: I
ZN
F’.R.
Time
period
for
B.lF
calculations
extends
over
lost the least amount of actual weight and sodium post partum. The fact that Patient B. F. did not lose amounts of sodium and water comparable to Patients P. R., and Z. N. may be related to diuretic therapy before admission to this hospital. Summary
1. Complete metabolic studies were done on 4 eclamptic patients for 21 days post partum. 2. All patients had a positive nitrogen balance post partum. 3. Potassium : nitrogen ratios were higher than in muscle indicating an excessive retention of potassium in proportion to nitrogen. This may represent an intracellular deficit of potassium. 4. The blood pressure return-d to normal coincidentally with the cessation of electrolyte and fluid losses. 5. The nitrogen retention observed during the postpartum period reflects the recovery from
the
catabolic
effect
of toxemia.
We would like to express our appreciation to Dr. Charles Bragassa, Director of the Computer Center at the Medical College of Georgia, for assistance in tabulation of these data. We would especially like to thank all the personnel in the Clinical Investigation Unit for making such a study possible.
Metabolic
studies
in eclampsia
267
REFERENCES
W. J,, and Pottinger, R. E.: AM. 1. Difckmann, J. OBST. & GYNEC. 70: 822, 1955. 2. Gray, M. J., and Plentl, A.A.: J. Clin. Invest. 33: 347, 1954. 3 Hunscher. H. A.. Donelson, E., Nims, B., Kenyon. F. and Macy J, G.: J. Biol. Chem. 99: 507, 1933. H. E. and Pommerenke W. T., 4. Thompson Jr.: J. Nutrition 17: 383, 1939. E. H., Dyrenfurth, I., Lowenstein, 5. Venning, I,.. and Beck, J.: J. Clin. Endocrinol. 1% 403. 1959. 6. Wilson, K. M.: Bull. Johns Hopkins Hosp. 27: 121. 1916. 7. Barnes. A. C., and Buckingham, J. C.: ANI. J. OXST. & Gvsec. 76: 955, 1958. L. C., Valenti, C., and Uichanco, 8. Chesley, L.: AIM. 1. OBST. & GYNEC. 77: 1054. 1959. C., Moore, D. B., and 9. Larnbiottz-Escoffier. Taylor. H. C.. Jr.: AM. J. OBST. & GYNEC. 66: 18, 1953. 10. Plentl, A. A.. and Gray, M. J.: AXI. J. Oll:T. & Gus~c. 78: 472, 1959.
Discussion 1)~. \Y.ZI:I.EK B. CHERN'I., Durham, North Carolina. Only those who have attempted to conduct metabolic balance studies in pregnant patirrlts c.an fully apprrciate the difficulties and tril)ulations that thtt authors must have encountc,red in completing this and other related invcstiaations. The techniques ustd must be planned with exacting precision, and carried out with painstaking and calculated efficiency. 34uch of the data thus far published as a rcwlc of halance stud& in toxemic patients has t’oinc prirn:lrily from prt,-eclamptic patients or from patit=nts who have benign hypertensive dis<‘ahe. In comparison, there is a paucity of inforniation available about eclampsia. It may not n~~,.essarily 1,~ true that the erlamptic state is riic~rr~l! an caxagg-cration, a more serious compIi,-ation, of a prcbccding metabolic disturbance. It ma) vc*ry well 1~1 that metabolic changes in cc,iampsia are strikingly different from those of pry.-t~c~lnmpsi;t. LII the antcpartum state, in pre-eclampsia, rsi‘(‘s% loss of nitrogen has been noted. This led to thr, conclusion that thert is maternal protein calaholism despite. the fact that the products of conct>lltion c.ontinut> to assimilate protein in utero to term. It would srcm logical, therefore, that followin.q dclivrry, a rc~v~~rsal of this phrnomcncln should oc(‘ur and positive nitrogen balancrn sh~)uld lIecome apparent. We have just seen in thta foregoing presentation that this is probably tlltc iI1 c~clampuia. Dieckmann” also found this
11. 12.
13. 14. 15.
16. 17.
18. 19.
in
Dnvey, D. A., and O’Sullivan, W. J.: 1’:) th et microbial. 24: 642: 1961. Burke. B. S.. Beal. V. A.. Kirkwood. S. 8. and Stuart: H. C.: A~I. J. 0~s~. B C:\.\-tx:. 46: 38, 1943. Brewer. T. H.: AM. .I. OHST. 8 GYSEC:. 84: 1253, 1962. Rcifenstein, E. C.. Albright, F., and M’~,lls. S. L.: Clin. Endocrinol. 5: 367, 19f-5. Flame Photometer Instruction Manual ( Morlel KY-1 1 Baird-Atomic. Inc.. 33 Univrr?it\Road. Cambridge 38, Massachusetts, Jat1 5, 1962. Millrr, L., and Houghton, J. .\.: J. I:illl. Chem. 159: 373, 1945. Hunscher. H. .4.. Hummell, F. C.: Eric-kion. B. N., and Mary, I. G.: J. Nutritioll 10: 579, 1935. Zuspan. F. P., and Goodrich. S. M.: 1:rtlj!il)lished data. Moore. F. D.: Metabolic care of the surgical patirnt, Philadelphia and London. 1959. M’. B. Saunders Company, p. 34.
a paricnt b-ho had cclampsia. How(‘v(‘t. in i,! prp-rclampsia tht patients rc~port~~d up011 Dicckmann had nqative nitrogen balances pcsst partum in most instancrs. Barnes and Huchinpham1 have shown positivt balances for nitrtlgS.cn and potassium in th(t normal put~rpe~al pa~~vrlt. But at the sam(’ time thertl appcaars to 1~7 ;I negative balance for sodium. In fact, thcl(b is common supposition that any shift in sotliutn balancc~ is mually oppositcx to ihat OF pot,~\~,illl~l and nitrng~n. Undeniably. thtl toxtmic. paticsnt’s ahilic I to move
368
Zuspan
and
Goodrich
state as evidenced by significant pressure and increases of proteinuria.
risrs
of
blood
REFERENCES
Barnes, A. C., and Buckingham, J. C.: Electrolyte balance studies with the anti-hormones, AM. J. OBST. & GYNEC. 76: 955, 1958. Dieckmann, W. J.: Toxemias of pregnancy, A Ciba Foundation Symposium, London, 1950, J. & A. Churchill, Ltd. Dieckmann, W. J., and Pottinger, R. E.: Etiology of pre-eclampsia-eclampsia, AM. J. OBST. & GVNEC. 70: 822, 1955. DR. E. J. DENNIS, Charleston, South Carolina. Such studies as reported here lend credence to the hypothesis that toxemia of pregnancy represents a profound pathophysiologic change involving multiple body systems in a complex series of humoral, enzymatic, and anatomical alterations. It would tend to detract from the concept of a single noxious etiologic agent produced in the placenta or decidua unless such substance was indeed unique in precipitating or producing such profound and widespread changes as those alluded to above The retention of potassium suggesting an intracellular deficit of this ion is intriguing. Venningr has shown that the excretion of aldosterone in pre-eclampsia is lower than that in normal pregnant women. Kumar and others? have shown that this lowered excretion in pre-erlampsia is due to a diminished secretion of the hormone. of aldosterone is that it One of the actions seems to enhance the rate of active sodium extrusion from all cells in the body. Normal pregnant women have been shown to have a low intracellular sodium content and high intracellular sodium content and high aldosterone production. Conversely, patients with toxemia have high intracellular sodium content and low aldosterone production. In the 4 cases here prcsented, blood pressure levels returned to normal coincidental and fluid losses, compartmental pathophysiologic toward normal.
with the cessation of electrolyte stuggesting that once electrolyte homeostasis is achieved, the alterations of toxemia revert
REFERENCES
1. 2.
Venning. E. H., et al,: J. Clin. Endocrinol. 473, 1957. Kumar, D., et al.: Lancet 1: 541. 1959.
17:
DR. R. GORDON DOUGLAS, New York, New York. Balance studies are difficult to interpret, particularly if balance is not achieved (as is the case in the studies reported in the paper by
Zuspan and Goodrich). Balance studies clonic following delivery are also difficult to interpret with respect to the etiology of eclampsia since one does not know if the metabolic changes observed during the recovery period are occurring because of alterations or deficiencies causing the disease, caused by the disease or secondary to the disease. With respect to this paper, any patient whose intake of protein and potassium dccreases (as might happen in patients who drvelop toxemia) actually goes into negative nitrogen balance when the intake of nitrogen and potassium falls below the losses of these elrments. For example, a patient on parenteral fluids is in negative nitrogen balance if she does not receive adequate protein and is in negative potassium balance if she does not receive adequate potassium. Bearing in mind these reservations, these studies are of interest and certainly add to our knowledge of the metabolic effects of cclampjia and add quantitative data on the order of magnitude of nitrogen, potassium, and sodium dcfitits which can develop in eclampsia. Of interest and supporting the data presented are some studies carried out at The New York Lying-In Hospital by Dr. Bonsnes some years ago. In his Annual Report on Eclampsia Research for 1952 he wrote on his Electrolyte Studies as follows: “Last year we reported on the blood serum values for sodium, potassium, chloride, and total bicarbonate in patients with mild and severe pre-eclampsia and on the sodium and potassium excretion of patients with severe pre-eclampsia and eclampsia. These studies have been extended this year. The studies of the excretion of these substances seemed to lead to no usable data unless thr intakes of these substances were also known. “To obtain an accurate record of the intake of patients requires a metabolism ward. Lacking this, we have achieved what may be called a first order estimate. through the active COoperation of Miss Kellerman of the Nutrition Department of The New York Hospital. She calculates, from tables, the approximate amount of sodium and potassium in the food ingested by the patient being studied. We determine the amount excreted in the urine. Using the procedure WC have carried out sodium and potassium balance studies in 4 patients with severe pre-eclampsia and in 3 patients with diabetes who were also pregnant. The incidrncc of toxemia of pregnancy in such patients is high.
Metabolic
“The patients with toxemia were studied from th(a time they were hospitalized, acutely ill, up to the timcl of delivery (which usually occurs a few days after they are admitted to the hospital then through the time of the early pucrperium. usually 7 to 8 days following delivery. Thcsc patients all had negative sodium and potassium balances while maintained only on intmvc>nous fluids while they were acutely ill, 4niply hecause they had no intake of either sodium or potassium. During the early puerpa-ium. i.r., during recovery, they all continued to have, nrgativc sodium balances for about 5 to 6 days. Aftcsr this time they appear to be more or 1~ in balance with respect to sodium. Rut th(,y wcrt~ all retaining potassium up to the time t1tc.y were discharged from the hospital. One p:lGent whom WC were able to follow longer than the other 3 (for some 15 days following drlivery) qPc&rned to be retaining potassium still 15 days post partum when the last observations M’I’I-c mndr, but seemed to have achieved equi1if)rium with respect to sodium at the sixth postp:\rtum d:Ly. ““These observations are consonant with the JXIX’aiJing concept of sodium retention during the toxtmias of pregnancy. They further sug-
studies in eclampsia
369
gest that there might bc an associated pota+ium deficiency. “Sodium and potassium balances w~rr also obtained on 3 diabetic patients. These wrr(‘ ‘8 to 35 weeks pregnant. Sodium and potas:;ium balances were estimated for 49, 44, and 18 dayi; before thes:, patients delivered. Ha1ancc.s K(YY~ obtained on 2 for 5 and 6 days post partum iZll 3 retained potassium and lost sodium ovl,r-all while observed during the antepartum C~OIII’SP. These data suggest again a sodium rrtcntic,n in pregnancy with a possihlc potassium dt+cie,nry. What happens in a normal pregnant ~~om~‘n at these times remains to be determined.” Only in recent years have facilitirs bctn ;.vailable at The New York Hospital which has ~~~ad~~ it possible to determine what happens dalrirtg normal pregnancy. Up to the present tinlr metabolic studies on 3 normal pregnant ~:VI,CYI have been carried out: one having balance, studits for 38, another 88, and the third fat 11’3 days beforca delivery. When the evaluation ( f the data collected on these women is compit,t(d, there will be a basr for comparing data collected from those having toxemia. It is caxpcxctt,d our data will confirm in essence that of %~lsp;m and Goodrich.