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Human Serum Albumin in the Treatment of Eclamptogenic Toxemia*†
HUMAN SERUM ALBUMIN IN THE TREATMENT OF ECLAMPTOGENIC TOXEMIA*t CHARLES c. ROBY, PH.D., CRAWFORD H. HINMAK, :M.D., AND DUKCAN
E. REID, M.D.,
BOSTOK, MASS.
(From the Department of Obstetrics, Harvcml Medical School and Boston Ly·ing-in Hospital)
T
HE variation in concentration of plasma protein during pregnancy has presented a problem to investigators for many years. 'l'his has been particularly true to those who ar(~ searching for the possible relationship of plasma protein values to the etiology of eclamptogenic toxemia. Plass and Mathews 1 in 1926 presented observations on the level of the plasma protein fractions in a series of patients throughout gestation. Since that time other reports 2 have appeared which confirm earlier studies. In brief, these ehanges show a progressive decrease in the concentration of total plasma proteins, particularly the albumin fraction, during the course of normal pregnane;'>:. Associated with the changes in albumin conrentration are those in plasma volume, extracellular fluid, and red-cell mass. 3 • ·I During normal gestation, the plasma volume increases until the last six weeks of pregnancy when it begins to decrease from the maximum hwel attained. The extracellular fluid volume on the other hand increases up to the onset of labor. This inerease is most marked during the last ten weeks of pregnancy. In unpublished studies it has been found that the total circulating red-rell mass does not decrease hut there is actually a definite increase during pregnancy. Observations in eelamptogenic toxemia show an aetual decrease in total circulating protein as compared with that in normal pregnancies. The associated changes show an increase in plasma volume equal to or !Pss than that oecurring in normal pregnancy. The extracellular fluid volume shows an increase greater than that occurring· in normal gestation.~ This would indieate that, in eclamptogenic toxemia, there may be an alteration in the normal ratio of the volume of fluid inside and outside the vascular system. The resnlts of studies made of the total red-cell mass in eelamptogenic toxemia have never been reported. Many substances have been used in an attempt to correct the hypoproteinemia of eclamptogenic toxemia. Among these may be mentioned amino acids and protein hydrolysate" and concentrated plasma. 7 The results of these studies *Supported in part by a grant from the Charles H. H(lod Foundation. tThe serum albumin used in this study was processed by the American National :Red Cross from blood which it collected from voluntary donors. This is one of a series of investigations on serum albumin being carried out with material supplied by the American National :Red Cross. As soon as sufficient data become available to justify final conclusions concerning its therapeutic value, a full report on the use of serum albumin In medical practice will be published by the Committee on Blood and Blood Derivatives of the Advisory Board on Health Services of the American National Red Cross.
19()
Volume w Number 1
HUMAN SERUM AtBUMIN AND ECLAMPTO(lENIC TOXEMIA
1~"'1
·'
indicate that protein therapy is a valuable adjunct in the treatment of eclamptogenic toxemia. Definitive treatment, however, is still the object of investigation. During the last two years at the Boston Lying-in Hospital, patients with cclamptogenic toxemia have been treated using large amounts of concentrated human serum albumin. Table I indicates the pertinent clinical and laboratory findings in six of these patients who were given amounts of albumin varying from 75 to 250 Gm. intravenously. HUMAN SERUM ALBUMIN IN ECLAMPTOGENIC TOXEMIA
SERUM PROTEIN
M.Cl.
N.T,
M.P.
r
[6 rn 1 r
6
%
5
4
ALBUMIN C:.M
75
45
50
50
l l l
100
l
F.F.
Al>.
~~~ m~~~ ~m ~ r
50
r
r
so so
r r 1r
50
50
l l l l l
50
l
50
l
r !:>0r !:10r 50r $0r $0r
l
50
l l 1 1 1
40
30
Fig. 1.
Comment One can readily see that there is no continuity in the response of these patients to intravenous albumin. Human serum albumin can he given to the eclamptogenic toxemic patient with minimal danger of pulmonary edema or renal failure. With the administration of 50 Gm. of albumin over periods ranging from seventeen minutes to four hours, there was no persistent rise in systolic blood pressure, evidence of pulmonary rales, nor evidence of suppression of urine output. The most consistent finding following albumin therapy in these patients was the fall in large vein hematocrit (Fig. 1). Although this is not an indication of change in total body hematocrit, transient hemodilution may be assumed to have occurred since only a slight rise in serum protein concentration was generally seen. A further indication of the transient increase in plasma volume was seen in a temporar;.' diuresis during and following albumin therapy. The results obtained using salt-poor human serum albumin were unsatisfactory in several respects. Hypertension was not relieved. It was hoped that by increasing the plasma volume, the vascular tree would become more completely fllled with blood, thus allowing for compensatory vascular dilatation.
PATIENT
1
21
22
160/110
150/100
140/100
136/96 142/100
5:)
51)
50 50
1/li/11:0 178/115 194/120 190/126
155/108 150/120 178/114
--1-140/100
50
50
50
50 50
50 50 100
75
(GM.)
1
134/86
142/90
50
160/118
;)0
50
2. Values after albumin.
38 38
148/10(1
:l6
35 35
3()
37
41
38 40 40
43 41 44
1 41
3ri
34
35
35 33 36
2 35
~
6.li
6.1
5.0
6.3 (j .0
I
I
3550 n1agncsiun1 ;;ul·
units Yertavis, 4+ albuminuria. per os Seconal, 20% mag- Eclamptic convulsion 5 hours after nesium sulfate albumin therapy. Pitocin stim25% glueo~e, i.v. ulation of labor; Voorhees bag; internal version. Delivered 2 pound, 8 ounces stillborn 3+ albuminuJ;ia··-
2 -: OTHEli C\1EDICATION REMARKS 7.1 10% Glucose i.v. mag- Convulsions before therapy, 1400 nesium sulfate, i.m. c.c. urine in 5 hours following albumin. Bag induction; version; delivered stillborn. 5U units Vertavi~, 4.3 Mild headache; minimal eflema;
5.7 5.9
I
5.6
5.~
4.1
1 li.7
%*
SEll.U:\1 PROTEIN
I
.....
•_")~)
v.~
fate, i.m. (}.1 25% magnesium snl- Fetal heartbeat disappeared. (i.S ::\8 fatt>, i.m. Spontaneous delivery. - - - - - - - - - - - - -;),:J ---------------47 pound weight gain; 2+ albu5.1 minuria. 14 pouml weight loss; 4+ albu30 6.4 5.8 minuria. Chill following infusion: induction 30 l1.4 6.0 i12 of labor. Delivered 5 5.4 5.5 2 ounce><, active infant. " ,, 25% magnesium sul- 4+ albuminuria. Chill following 35 6.0 fate, i.m. infusion. 36 Normal saline, i.v. 1+ albuminuia; fetal heartbeat dis· 5.6 5.5 appeared. Spontaneous delivery, nonviable fetus. 5.9 31 40 pound weight gain; il+ albu6.8 minuria. 6.1 35 5.9 Induction of labo1·; delivered :) 4 ounce activP infant.
1
'70 ··
IIEMAT;?CIUT
150/100
144/9G
140/9_0_
120/76 132/96
114/90
145/100
140/90
176/112 178/112 160/100 154/90
134/98 175/120 168/116
130/90
~--2-
_, I BLOOD PRESSURE·
---1----~- 144/llG
I
!
IAl.BUJ.ll~ I GIVEN
*1. Values before albumin.
G~-
M.D.
A.
1
20
F. F.
~
_,
•)
1
I PARITY
22
Mm
1
I
M:-G:--~-23-
.:\f. P.
N. T.
I
TABLE
"-0
......
ctt) ~
o·
~g
[ ?f.:, ~SJ _,
0
:--
§'
b
t'>j H
~
z>t:l
~
"" >
z....,
H
~'<
~
00
Volume 60 ~umber 1
HUMAN SERUM ALBUMIN AND ECLAMPTOGENIC TOXEMIA
199'
Second, the increase in urinary output following albumin therapy was fleeting. No effective diuresis was obtained until either intrauterine death had occurred or delivery had been effected. (It may be of interest that urinary albumin determination in one patient showed a marked increase in the amount of albumin excreted during treatment. This may be a limiting factor in achieving desirable results.) Last, only two of the six eclamptogenic toxemia patients obtained viable infants, and these two were the least severely ill mothers. Of the four mothers >vho lost their infants, two had spontaneous intrauterine death on the fourth and eighth hospital days with subsequent improvement of their illness. The remaining two mothers lost their extremely premature infants as a direct result of the ohstptrical method elected to terminate their pregnancieR.
Summary 1. Observations are presented on six patients with eclamptogenic toxemia receiving salt-poor human serum albumin. 2. Salt-poor human serum albumin was administered intravenously in doses of 50 Gm., with total amounts varying from 75 to 250 Gm. over periods of five hours to eleven days. 3. Transient hemodilution and diuresis wel'e produced. 4. In these six patients, no pulmonary edema or urinary suppression was observed. 5. Hypertension and edema were unchanged. 6. The patients' courses were not appreciably affected by this treatment. 'l'wo viable infants were obtained. Two infants underwent spontaneous intrauterine death and the remaining two infants died following obstetl'ical intervention. References 1. Plass, E. D., and Mathews, E. W.: AM. J. 0BST. & GYNEC. 12: 346, 1926. 2. Dieckman, W. J.: The Toxemias of Pr•"gnancy, St. Louis, 1941, The C. V. Mosby Company. ::. Caton, W. L., Roby, C. C., Reid, D. E., and Gibson, J. G. II: AM. J. OBST. & GYNEc. 57: 471, 1949. 4. Caton, W. L., Roby, C. C., Reid, D. E., and Gibson, J. G., II: Unpublished data. 5. Freis, E. n., and Kenny, J. W.: J. Clin. Investigation 'Z7: 276, 1947. 6. MacArthur, J. W.: AM. J. 0BST. & GYNJW. 55: 382, 1948. i. GoldPn, A., and Fraser, G.: AM . .T. ORST. & GYKJ<:c, 54: 523, 1947.
E. REID, M.D.,
BOSTOK, MASS.
(From the Department of Obstetrics, Harvcml Medical School and Boston Ly·ing-in Hospital)
T
HE variation in concentration of plasma protein during pregnancy has presented a problem to investigators for many years. 'l'his has been particularly true to those who ar(~ searching for the possible relationship of plasma protein values to the etiology of eclamptogenic toxemia. Plass and Mathews 1 in 1926 presented observations on the level of the plasma protein fractions in a series of patients throughout gestation. Since that time other reports 2 have appeared which confirm earlier studies. In brief, these ehanges show a progressive decrease in the concentration of total plasma proteins, particularly the albumin fraction, during the course of normal pregnane;'>:. Associated with the changes in albumin conrentration are those in plasma volume, extracellular fluid, and red-cell mass. 3 • ·I During normal gestation, the plasma volume increases until the last six weeks of pregnancy when it begins to decrease from the maximum hwel attained. The extracellular fluid volume on the other hand increases up to the onset of labor. This inerease is most marked during the last ten weeks of pregnancy. In unpublished studies it has been found that the total circulating red-rell mass does not decrease hut there is actually a definite increase during pregnancy. Observations in eelamptogenic toxemia show an aetual decrease in total circulating protein as compared with that in normal pregnancies. The associated changes show an increase in plasma volume equal to or !Pss than that oecurring in normal pregnancy. The extracellular fluid volume shows an increase greater than that occurring· in normal gestation.~ This would indieate that, in eclamptogenic toxemia, there may be an alteration in the normal ratio of the volume of fluid inside and outside the vascular system. The resnlts of studies made of the total red-cell mass in eelamptogenic toxemia have never been reported. Many substances have been used in an attempt to correct the hypoproteinemia of eclamptogenic toxemia. Among these may be mentioned amino acids and protein hydrolysate" and concentrated plasma. 7 The results of these studies *Supported in part by a grant from the Charles H. H(lod Foundation. tThe serum albumin used in this study was processed by the American National :Red Cross from blood which it collected from voluntary donors. This is one of a series of investigations on serum albumin being carried out with material supplied by the American National :Red Cross. As soon as sufficient data become available to justify final conclusions concerning its therapeutic value, a full report on the use of serum albumin In medical practice will be published by the Committee on Blood and Blood Derivatives of the Advisory Board on Health Services of the American National Red Cross.
19()
Volume w Number 1
HUMAN SERUM AtBUMIN AND ECLAMPTO(lENIC TOXEMIA
1~"'1
·'
indicate that protein therapy is a valuable adjunct in the treatment of eclamptogenic toxemia. Definitive treatment, however, is still the object of investigation. During the last two years at the Boston Lying-in Hospital, patients with cclamptogenic toxemia have been treated using large amounts of concentrated human serum albumin. Table I indicates the pertinent clinical and laboratory findings in six of these patients who were given amounts of albumin varying from 75 to 250 Gm. intravenously. HUMAN SERUM ALBUMIN IN ECLAMPTOGENIC TOXEMIA
SERUM PROTEIN
M.Cl.
N.T,
M.P.
r
[6 rn 1 r
6
%
5
4
ALBUMIN C:.M
75
45
50
50
l l l
100
l
F.F.
Al>.
~~~ m~~~ ~m ~ r
50
r
r
so so
r r 1r
50
50
l l l l l
50
l
50
l
r !:>0r !:10r 50r $0r $0r
l
50
l l 1 1 1
40
30
Fig. 1.
Comment One can readily see that there is no continuity in the response of these patients to intravenous albumin. Human serum albumin can he given to the eclamptogenic toxemic patient with minimal danger of pulmonary edema or renal failure. With the administration of 50 Gm. of albumin over periods ranging from seventeen minutes to four hours, there was no persistent rise in systolic blood pressure, evidence of pulmonary rales, nor evidence of suppression of urine output. The most consistent finding following albumin therapy in these patients was the fall in large vein hematocrit (Fig. 1). Although this is not an indication of change in total body hematocrit, transient hemodilution may be assumed to have occurred since only a slight rise in serum protein concentration was generally seen. A further indication of the transient increase in plasma volume was seen in a temporar;.' diuresis during and following albumin therapy. The results obtained using salt-poor human serum albumin were unsatisfactory in several respects. Hypertension was not relieved. It was hoped that by increasing the plasma volume, the vascular tree would become more completely fllled with blood, thus allowing for compensatory vascular dilatation.
PATIENT
1
21
22
160/110
150/100
140/100
136/96 142/100
5:)
51)
50 50
1/li/11:0 178/115 194/120 190/126
155/108 150/120 178/114
--1-140/100
50
50
50
50 50
50 50 100
75
(GM.)
1
134/86
142/90
50
160/118
;)0
50
2. Values after albumin.
38 38
148/10(1
:l6
35 35
3()
37
41
38 40 40
43 41 44
1 41
3ri
34
35
35 33 36
2 35
~
6.li
6.1
5.0
6.3 (j .0
I
I
3550 n1agncsiun1 ;;ul·
units Yertavis, 4+ albuminuria. per os Seconal, 20% mag- Eclamptic convulsion 5 hours after nesium sulfate albumin therapy. Pitocin stim25% glueo~e, i.v. ulation of labor; Voorhees bag; internal version. Delivered 2 pound, 8 ounces stillborn 3+ albuminuJ;ia··-
2 -: OTHEli C\1EDICATION REMARKS 7.1 10% Glucose i.v. mag- Convulsions before therapy, 1400 nesium sulfate, i.m. c.c. urine in 5 hours following albumin. Bag induction; version; delivered stillborn. 5U units Vertavi~, 4.3 Mild headache; minimal eflema;
5.7 5.9
I
5.6
5.~
4.1
1 li.7
%*
SEll.U:\1 PROTEIN
I
.....
•_")~)
v.~
fate, i.m. (}.1 25% magnesium snl- Fetal heartbeat disappeared. (i.S ::\8 fatt>, i.m. Spontaneous delivery. - - - - - - - - - - - - -;),:J ---------------47 pound weight gain; 2+ albu5.1 minuria. 14 pouml weight loss; 4+ albu30 6.4 5.8 minuria. Chill following infusion: induction 30 l1.4 6.0 i12 of labor. Delivered 5 5.4 5.5 2 ounce><, active infant. " ,, 25% magnesium sul- 4+ albuminuria. Chill following 35 6.0 fate, i.m. infusion. 36 Normal saline, i.v. 1+ albuminuia; fetal heartbeat dis· 5.6 5.5 appeared. Spontaneous delivery, nonviable fetus. 5.9 31 40 pound weight gain; il+ albu6.8 minuria. 6.1 35 5.9 Induction of labo1·; delivered :) 4 ounce activP infant.
1
'70 ··
IIEMAT;?CIUT
150/100
144/9G
140/9_0_
120/76 132/96
114/90
145/100
140/90
176/112 178/112 160/100 154/90
134/98 175/120 168/116
130/90
~--2-
_, I BLOOD PRESSURE·
---1----~- 144/llG
I
!
IAl.BUJ.ll~ I GIVEN
*1. Values before albumin.
G~-
M.D.
A.
1
20
F. F.
~
_,
•)
1
I PARITY
22
Mm
1
I
M:-G:--~-23-
.:\f. P.
N. T.
I
TABLE
"-0
......
ctt) ~
o·
~g
[ ?f.:, ~SJ _,
0
:--
§'
b
t'>j H
~
z>t:l
~
"" >
z....,
H
~'<
~
00
Volume 60 ~umber 1
HUMAN SERUM ALBUMIN AND ECLAMPTOGENIC TOXEMIA
199'
Second, the increase in urinary output following albumin therapy was fleeting. No effective diuresis was obtained until either intrauterine death had occurred or delivery had been effected. (It may be of interest that urinary albumin determination in one patient showed a marked increase in the amount of albumin excreted during treatment. This may be a limiting factor in achieving desirable results.) Last, only two of the six eclamptogenic toxemia patients obtained viable infants, and these two were the least severely ill mothers. Of the four mothers >vho lost their infants, two had spontaneous intrauterine death on the fourth and eighth hospital days with subsequent improvement of their illness. The remaining two mothers lost their extremely premature infants as a direct result of the ohstptrical method elected to terminate their pregnancieR.
Summary 1. Observations are presented on six patients with eclamptogenic toxemia receiving salt-poor human serum albumin. 2. Salt-poor human serum albumin was administered intravenously in doses of 50 Gm., with total amounts varying from 75 to 250 Gm. over periods of five hours to eleven days. 3. Transient hemodilution and diuresis wel'e produced. 4. In these six patients, no pulmonary edema or urinary suppression was observed. 5. Hypertension and edema were unchanged. 6. The patients' courses were not appreciably affected by this treatment. 'l'wo viable infants were obtained. Two infants underwent spontaneous intrauterine death and the remaining two infants died following obstetl'ical intervention. References 1. Plass, E. D., and Mathews, E. W.: AM. J. 0BST. & GYNEC. 12: 346, 1926. 2. Dieckman, W. J.: The Toxemias of Pr•"gnancy, St. Louis, 1941, The C. V. Mosby Company. ::. Caton, W. L., Roby, C. C., Reid, D. E., and Gibson, J. G. II: AM. J. OBST. & GYNEc. 57: 471, 1949. 4. Caton, W. L., Roby, C. C., Reid, D. E., and Gibson, J. G., II: Unpublished data. 5. Freis, E. n., and Kenny, J. W.: J. Clin. Investigation 'Z7: 276, 1947. 6. MacArthur, J. W.: AM. J. 0BST. & GYNJW. 55: 382, 1948. i. GoldPn, A., and Fraser, G.: AM . .T. ORST. & GYKJ<:c, 54: 523, 1947.